Cancer Management in Man: Chemotherapy, Biological Therapy, Hyperthermia and Supporting Measures (Cancer Growth and Progression, Volume 13)

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Cancer Management in Man: Chemotherapy, Biological Therapy, Hyperthermia and Supporting Measures

Cancer Growth and Progression Volume 13 Founding Editor Hans E. Kaiser† , D. Sc. Series Editors Aejaz Nasir, M.D., M.Phil., FCAP Department of Interdisciplinary Oncology-Pathology, Moffit Cancer Center & Research Institute, Tampa, FL, U.S.A. Timothy J. Yeatman, M.D. Professor of Surgery, Executive Vice President Translational Research, President & Chief Scientific Officer M2Gen, Moffit Cancer Center & Research Institute, Tampa, FL, USA

For further volumes: http://www.springer.com/series/5721

Cancer Management in Man: Chemotherapy, Biological Therapy, Hyperthermia and Supporting Measures

Edited by Boris R. Minev Moores UCSD Cancer Center and UCSD Division of Neurosurgery, University of California San Diego (UCSD), La Jolla, CA, USA Genelux Corporation, San Diego Science Center, San Diego, CA 92109, USA

13

Editor Boris R. Minev Moores UCSD Cancer Center and UCSD Division of Neurosurgery University of California San Diego (UCSD) 3855 Health Sciences Drive 0820 92093-0820 La Jolla CA, USA and Genelux Corporation San Diego Science Center San Diego, CA 92109 USA [email protected]

ISBN 978-90-481-9703-3 e-ISBN 978-90-481-9704-0 DOI 10.1007/978-90-481-9704-0 Springer Dordrecht Heidelberg London New York © Springer Science+Business Media B.V. 2011 No part of this work may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording or otherwise, without written permission from the Publisher, with the exception of any material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Cover illustration: Tumor therapy with vaccinia virus. Mice were i.v. injected with a single dose (1 × 107 pfu per mice) of the light-emitting oncolytic vaccinia virus GLV-1h68 (row 2–4) or PBS control (row 1) 30 d after breast tumor cell implantation. Bright field photographs (left column), GFP fluorescence images (middle column), and immunohistochemical analyses of expression of GLV-1h68-encoded β-galactosidase (right column) in tumors were done 14 (row 2), 28 (row 1 and 3), and 56 d (row 4) after virus or PBS injection. Two weeks after virus injection, strong fluorescence of GFP was seen in tumors with a volume of ∼1400 mm3 . An additional 2 wk later, a much reduced GFP fluorescence was observed at tumor size of ∼480 mm3 in the same mouse. After 56 d, no GFP fluorescence was seen in the tumor which was ∼180 mm3 in size. β-galactosidase activity was detected concomitant with light emission and was completely eliminated as light emission was extinguished. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

Dedicated to Professor Hans E. Kaiser, an unforgettable mentor, colleague and friend. Boris R. Minev

Contents

Part I

Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1

1 Plant-Derived Natural Products as Anticancer Agents . . . . . . . . David G.I. Kingston

3

2 The Vinca Alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . Nicole Coufal and Lauge Farnaes

25

3 Taxanes and Epothilones in Cancer Treatment . . . . . . . . . . . . Edward F. McClay

39

4 Alkylating Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . Laurent Gate and Kenneth D. Tew

61

5 Anthracyclines and Anthracenediones . . . . . . . . . . . . . . . . Nicole Coufal and Lauge Farnaes

87

6 Topoisomerase I Inhibitors – The Camptothecins . . . . . . . . . . Michael Newton, Gene Wetzstein, and Daniel Sullivan

103

7 Folate Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . Alex Ko

125

8 Platinum Complexes for the Treatment of Cancer . . . . . . . . . . David Roberts, Peter J. O’Dwyer, and Steven W. Johnson

145

9 Hormonal Therapy in Cancer . . . . . . . . . . . . . . . . . . . . . Soe T. Maunglay, Julia A. Cogburn, and Pamela N. Munster

165

10

Effects of Cancer Chemotherapy on Gonadal Function . . . . . . . Angela R. Bradbury and Richard L. Schilsky

11

Targeting the Tumor Microenvironment for Enhancing Chemotherapy in Hematologic Malignancies . . . . . . . . . . . . . Luis A. Crespo, Xinwei Zhang, and Jianguo Tao

Part II 12

191

215

Biological Therapy . . . . . . . . . . . . . . . . . . . . . . . . .

235

Cytokines in the Treatment of Cancer . . . . . . . . . . . . . . . . . Adrian Bot

237

vii

viii

Contents

13 Antibody-Based Therapies for Solid Tumors . . . . . . . . . . . . . Satish Shanbhag and Barbara Burtness

245

14 Cancer Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Stephanie Schroter, Melanie Hayden, Wenxue Ma, Nellia Fleurov, Neha Rahan, and Boris R. Minev

257

15 Adoptive Immunotherapy of Cancer Using Autologous Lymphocytes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Yoshiyuki Yamaguchi, Riki Okita, Akiko Emi, Katsuji Hironaka, Makoto Okawaki, Takuhiro Ikeda, Masahiro Ohara, Ichiro Nagamine, and Jun Hihara

285

16 Oncolytic Virotherapy of Cancer . . . . . . . . . . . . . . . . . . . Nanhai G. Chen and Aladar A. Szalay

295

Part III Other . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

317

17 Protein Kinase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . Daanish Hoda and Adil Daud

319

18 Inhibitors of Tumor Angiogenesis . . . . . . . . . . . . . . . . . . . Anaadriana Zakarija and William J. Gradishar

331

19 Transcatheter Management of Neoplasms . . . . . . . . . . . . . . Christos S. Georgiades and Jean-Francois Geschwind

341

20 Tumor Stem Cells: Therapeutic Implications of a Paradigm Shift in Multiple Myeloma . . . . . . . . . . . . . . . . . . . . . . . Neil H. Riordan, Thomas E. Ichim, Famela Ramos, Samantha Halligan, Rosalia De Necochea-Campion, Grzegorz W. Basak, Steven F. Josephs, Boris R. Minev, and Ewa Carrier

349

Part IV Hyperthermia . . . . . . . . . . . . . . . . . . . . . . . . . . . .

363

21 Induced Hyperthermia in the Treatment of Cancer . . . . . . . . . Bert Hildebrandt, Johanna Gellermann, Hanno Riess, and Peter Wust

365

Part V

Supporting Measures . . . . . . . . . . . . . . . . . . . . . . . .

379

22 Hematologic Support of the Patient with Malignancy . . . . . . . . Thomas A. Lane

381

23 Current Status of Bone Marrow Transplantation for Treatment of Cancer . . . . . . . . . . . . . . . . . . . . . . . . Edward D. Ball, Asad Bashey, Ewa Carrier, Januario E. Castro, Peter Holman, and Thomas A. Lane 24 Pain Management in Cancer Patients . . . . . . . . . . . . . . . . . Hrachya Nersesyan, Jeffrey J. Mucksavage, Eljim Tesoro, and Konstantin V. Slavin

407

437

Contents

ix

25

Management of Nausea and Vomiting in Cancer Patients . . . . . . Rudolph M. Navari, Paula P. Province, and Steven D. Passik

453

26

Nutrition in the Management of the Cancer Patient . . . . . . . . . Cheryl L. Rock

473

27

Predictive Value of IFN-γ γ-Induced Indoleamine 2,3-Dioxygenase (IDO) Expression in Cancer Patients . . . . . . . . G. Brandacher, A. Amberger, K. Schroecksnadel, R. Margreiter, and Dietmar Fuchs

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

495

509

Contributors

A. Amberger Department of General and Transplant Surgery, Tyrolean Cancer Research Institute, Innsbruck Medical University, Innsbruck, Austria, [email protected] Edward D. Ball Department of Medicine and Moores UCSD Cancer Center, La Jolla, CA 92093-0960, USA, [email protected] Grzegorz W. Basak Department of Hematology, Oncology and Internal Diseases, Medical University of Warsaw, Warszawa, Poland, [email protected] Asad Bashey Department of Medicine and Moores UCSD Cancer Center, La Jolla, CA 92093-0960, USA, [email protected] Adrian Bot Scientific Management, MannKind Corporation, Valencia, CA 91354, USA, [email protected] Angela R. Bradbury Department of Medicine, Fox Chase Cancer Center, Philadelphia, PA 19111, USA, [email protected] G. Brandacher Department of General and Transplant Surgery, Tyrolean Cancer Research Institute, Innsbruck Medical University, Innsbruck, Austria, [email protected] Barbara Burtness Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA, [email protected] Ewa Carrier Moores UCSD Cancer Centre, San Diego, CA, USA, [email protected] Januario E. Castro Department of Medicine and Moores UCSD Cancer Center, La Jolla, CA 92093-0960, USA, [email protected] Nanhai G. Chen Genelux Corporation, San Diego Science Center, San Diego, CA, USA, [email protected] Julia A. Cogburn Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center, Experimental Therapeutics and Breast Medical Oncology, 12902 Magnolia Dr, Tampa, FL 33612, USA Nicole Coufal UCSD Department of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA, [email protected]

xi

xii

Luis A. Crespo Hematopathology and Laboratory Medicine, University of South Florida College of Medicine, H. Lee Moffitt Cancer Center and Research Institute, 12901 Magnolia Drive, Tampa, FL 33612, USA Adil Daud Department of Medicine, Division of Hematology Oncology, University of California, 1600 Divisadero Street, San Francisco, CA 94010, USA, [email protected], [email protected] Rosalia DeNecochea-Campion Moores UCSD Cancer Centre, San Diego, CA, USA, [email protected] Akiko Emi Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi 1-2-3, Minami-Ku, Hiroshima 734-8553, Japan Lauge Farnaes UCSD Department of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA, [email protected] Nellia Fleurov Moores UCSD Cancer Center, La Jolla, CA 92093-0820, USA, [email protected] Dietmar Fuchs Department of Biological Chemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria, [email protected] Laurent Gate INRS, 54000 Nancy, France Johanna Gellermann Klinik für Strahlenheilkunde, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Humboldt-Universität, D-13344 Berlin, Germany, [email protected] Christos S. Georgiades Division of Vascular and Interventional Radiology, Department of Vascular and Interventional Radiology, The Johns Hopkins Hospital, Baltimore, MD 21287, USA, [email protected] Jean-Francois Geschwind Division of Vascular and Interventional Radiology, Department of Vascular and Interventional Radiology, The Johns Hopkins Hospital, MD, Baltimore 21287, USA William J. Gradishar Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, 676 N. St. Clair, Suite 850, Chicago, IL 60611, USA, [email protected] Samantha Halligan Moores UCSD Cancer Centre, San Diego, CA, USA, [email protected] Melanie Hayden Moores UCSD Cancer Center, La Jolla, CA 92093-0820, USA, [email protected] Jun Hihara Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi 1-2-3, Minami-Ku, Hiroshima 734-8553, Japan Bert Hildebrandt Medizinische Klinik für Hämatologie und Onkologie, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Humboldt-Universität, D-13344 Berlin, Germany, [email protected]

Contributors

Contributors

xiii

Katsuji Hironaka Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi 1-2-3, Minami-Ku, Hiroshima 734-8553, Japan Daanish Hoda Division of Hematology Oncology, Department of Medicine, University of California, 1600 Divisadero Street, San Francisco, CA 94010, USA Peter Holman Department of Medicine and Moores UCSD Cancer Center, La Jolla, CA 92093-0960, USA, [email protected] Thomas E. Ichim Medistem Inc, San Diego, CA, USA, [email protected] Takuhiro Ikeda Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi 1-2-3, Minami-Ku, Hiroshima 734-8553, Japan Steven W. Johnson Department of Hematology/Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA, [email protected] Steven F. Josephs Therinject LLC, San Diego, CA, USA, [email protected] David G.I. Kingston Department of Chemistry, M/C 0212, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA, [email protected] Alex Ko UCSD Department of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA, [email protected], [email protected] Thomas A. Lane UCSD Transfusion Services and Stem Cell Processing Lab, Moores UCSD Cancer Center, La Jolla, CA 92093-0960, USA, [email protected] Wenxue Ma Moores UCSD Cancer Center, La Jolla, CA 92093-0820, USA, [email protected] R. Margreiter Department of General and Transplant Surgery, Tyrolean Cancer Research Institute, Innsbruck Medical University, Innsbruck, Austria Soe T. Maunglay Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center, Experimental Therapeutics and Breast Medical Oncology, 12902 Magnolia Dr, Tampa, FL 33612, USA Edward F. McClay Melanoma Research Center, Pacific Oncology and Hematology Associates, San Diego, CA, USA, [email protected], [email protected] Boris R. Minev Moores UCSD Cancer Center and UCSD Division of Neurosurgery, La Jolla, CA 92093-0820, USA; Genelux Corporation, San Diego Science Center, San Diego, CA 92109, USA, [email protected] Jeffrey J. Mucksavage Department of Pharmacy Practice, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA Pamela N. Munster Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center, Experimental Therapeutics and Breast Medical Oncology, 12902 Magnolia Dr, Tampa, FL 33612, USA, [email protected]

xiv

Ichiro Nagamine Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi 1-2-3, Minami-Ku, Hiroshima 734-8553, Japan Rudolph M. Navari Department of Medicine, Indiana University School of medicine South Bend, South Bend, IN 46617, USA, [email protected] Hrachya Nersesyan Illinois Neurological Institute, OSF Saint Francis Medical Center, 530 N.E. Glen Oak Avenue, Peoria, IL 61637, USA, [email protected] Michael Newton Department of Clinical Pharmacy, West Virginia University School of Pharmacy and Mary Babb Randolph Cancer Center, Morgantown, WV 26506, USA Peter J. O’Dwyer Department of Hematology/Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA Masahiro Ohara Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi 1-2-3, Minami-Ku, Hiroshima 734-8553, Japan Makoto Okawaki Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi 1-2-3, Minami-Ku, Hiroshima 734-8553, Japan Riki Okita Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi 1-2-3, Minami-Ku, Hiroshima 734-8553, Japan Steven D. Passik Sloan Kettering Cancer Center, Cornell University School of Medicine, New York, NY, USA Paula P. Province Walther Cancer Research Center, University of Notre Dame, South Bend, IN 46617, USA Famela Ramos Medistem Inc, San Diego, CA, USA, [email protected] Neha Rahan Moores UCSD Cancer Center, La Jolla, CA 92093-0820, USA, [email protected] Hanno Riess Medizinische Klinik für Hämatologie und Onkologie, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Humboldt-Universität, D-13344 Berlin, Germany Neil H. Riordan Medistem Inc, San Diego, CA, USA, [email protected] David Roberts Department of Hematology/Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA Cheryl L. Rock Department of Family and Preventive Medicine, and Cancer Prevention and Control Program, School of Medicine, University of California, San Diego, CA, USA, [email protected] Richard L. Schilsky Department of Medicine, University of Chicago Medical Center, Chicago, IL 60637, USA, [email protected]

Contributors

Contributors

xv

K. Schroecksnadel Department of Biological Chemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria Stephanie Schroter Moores UCSD Cancer Center, La Jolla, CA 92093-0820, USA, [email protected] Satish Shanbhag Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA, [email protected] Konstantin V. Slavin Section of Functional and Stereotactic Neurosurgery, Department of Neurosurgery, University of Illinois at Chicago, 912 South Wood Street, Chicago, IL 60612, USA, [email protected] Daniel Sullivan Experimental Therapeutics Program and Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA, [email protected] Aladar A. Szalay Genelux Corporation, San Diego Science Center, San Diego, CA 92109, USA; Rudolf Virchow Center for Experimental Biomedicine, Institute for Biochemistry and Institute for Molecular Infection Biology, University of Würzburg, Würzburg, Germany; Department of Radiation Oncology, Rebecca and John Moores Comprehensive Cancer Center, University of California, San Diego, CA, USA, [email protected] Jianguo Tao Hematopathology and Laboratory Medicine, University of South Florida College of Medicine, H. Lee Moffitt Cancer Center and Research Institute, 12901 Magnolia Drive, Tampa, FL 33612, USA, [email protected] Eljim Tesoro Department of Pharmacy Practice, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA Kenneth D. Tew Department of Pharmacology, Medical University South Carolina, 173 Ashley Ave, Charleston, SC 29466, USA, [email protected] Gene Wetzstein Malignant Hematology Program and Department of Pharmacy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA Peter Wust Klinik für Strahlenheilkunde, Campus Virchow Klinikum, Charité Universitätsmedizin Berlin, Humboldt-Universität, D-13344 Berlin, Germany Yoshiyuki Yamaguchi Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Kasumi 1-2-3, Minami-Ku, Hiroshima 734-8553, Japan, [email protected] Anaadriana Zakarija Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, 676 N. St. Clair, Suite 850, Chicago, IL 60611, USA, [email protected] Xinwei Zhang Hematopathology and Laboratory Medicine, University of South Florida College of Medicine, H. Lee Moffitt Cancer Center and Research Institute, 12901 Magnolia Drive, Tampa, FL 33612, USA

Part I

Chemotherapy

Chapter 1

Plant-Derived Natural Products as Anticancer Agents David G.I. Kingston

1.1 Introduction and Scope Natural products have proved to be an excellent source of lead compounds for anticancer drug discovery, and a recent survey by Newman et al. indicates that 40% of all the anticancer drugs developed before 2002 are natural products, while another 20% are synthetic compounds based on a natural product pharmacophore [1]. In addition to the three plant-derived natural products discussed in this chapter, several other natural products or modified natural products are in current clinical use as cancer chemotherapeutic agents. Many of these are microbial products, and are often referred to as antibiotics. The anthracycline antibiotics include daunorubicin, doxorubicin, and the newer epirubicin and idarubicin [2, 3]. The phenoxazinone chromopeptide antibiotic antinomycin D is clinically used for the treatment of Wilms’ Tumor in children and of rhabdomyosarcoma, Ewing’s Tumor, and Hodgkin’s disease [4]. The bleomycin group of glycosylated oligopeptide antibiotics is used in combination with other drugs for the treatment of testicular cancers, germ cell ovarian cancers, Hodgkin’s lymphomas, and some non-Hodgkin’s lymphomas [5]. The pyrroloindole antibiotic mitomycin C is used primarily in combination with other drugs, most commonly for the treatment of gastric and pancreatic carcinomas [6]. Several natural products with excellent anticancer activity have been isolated from marine organisms, and

one, ecteinascidin or YondelisTM , is in clinical use. In addition to their coverage in this volume, microbial and marine-derived anticancer agents in clinical use or in clinical trials are discussed in a recent book [7]. The plant kingdom has provided four current clinical agents or groups of related agents: the podophyllotoxin derivatives etoposide (VP16–213) and teniposide (VM26), the taxanes paclitaxel (TaxolTM ) and docetaxel (TaxotereTM ), the camptothecin analogs topotecan (HycamptinTM ) and irinotecan (CamptosarTM ), and the Vinca alkaloids vinblastine, vincristine, and the semisynthetic analog vinorelbine. The Vinca alkaloids are discussed in another chapter in this volume, and so this chapter covers the podophyllotoxin derivatives, the taxanes, and the camptothecin derivatives.

1.2 Podophyllotoxin Derivatives 1.2.1 Introduction The podophyllotoxin derivatives etoposide and teniposide are important anticancer drugs in their own right, but they are also important as examples of the development of a toxic natural product into clinically effective drugs with a different mechanism of action than the parent compound. The newer podophyllotoxin derivative etopophos is also included in this discussion.

1.2.2 History D.G.I. Kingston () Department of Chemistry, M/C 0212, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA e-mail: [email protected]

The dried roots and rhizomes of the North American plant Podophyllum peltatum L. (the American

B.R. Minev (ed.), Cancer Management in Man: Chemotherapy, Biological Therapy, Hyperthermia and Supporting Measures, Cancer Growth and Progression 13, DOI 10.1007/978-90-481-9704-0_1, © Springer Science+Business Media B.V. 2011

3

4

D.G.I. Kingston

mandrake or May apple) and of the related Indian species Podophyllum emodi Wallich have long been known to possess medicinal properties [8]. The major active substance in podophyllin, which is the resin product obtained by extraction of the dried roots and rhizomes with ethanol, was shown to be the lignan lactone podophyllotoxin (2.1), although a variety of other lignans and lignan glycosides have also been isolated from podophyllin. OH O O O O

OCH3

CH3O OCH3

2.1 Podophyllotoxin

Podophyllin was shown by Kaplan in 1942 to have curative effects on the benign tumor Condylomata acuminate [9], and this discovery served to increase interest in this substance. Podophyllin and its constituents were then studied by several investigators, including Jonathan Hartwell at the National Cancer Institute (NCI). These studies led indirectly to the establishment of the very successful NCI program in natural products drug discovery, and so in a real sense podophyllotoxin can be considered to be the “scientific grandfather” of later compounds such as paclitaxel, camptothecin, and a whole group of other compounds in advanced clinical and preclinical development. A review of the chemistry and pharmacology of podophyllin and its constituents summarizes developments to about 1957 [10]. Podophyllotoxin itself is a potent antimitotic agent, but it proved to be too toxic to be useful in the treatment of human neoplasms. A variety of podophyllotoxin derivatives have been isolated from natural sources or prepared by partial synthesis, however, and the two cyclic acetals of 4 -demethylepipodophyllotoxin β-D-glucopyranoside known as etoposide (VP16–213) and teniposide (VM26) gave promising results in both in vitro and in vivo screening trials and were selected for clinical trials. These trials have proved the efficacy of these compounds in treating certain tumors. The remainder of this section will thus be concerned with these two compounds and the newer derivative etopophos.

Information on various aspects of the podophyllotoxin class of compounds, including their use as anticancer agents, is contained in various reviews [11–15].

1.2.3 Chemistry The chemical structures of etoposide (2.2) (VP16–213) and teniposide (2.3) (VM26) are shown below. They differ from podophyllotoxin in having a 4 -hydroxyl group instead of a 4 -methoxyl group, in having the epi configuration at the 4-position, and in having a substituted glucose residue at the 4-position. They differ from each other only in the nature of the substituent on the glucose ring: etoposide is the cyclic acetal prepared from 4 -demethylepipodophyllotoxin β-Dglucopyranoside and acetaldehyde (as its dimethyl acetal), while teniposide is the cyclic acetal prepared when 2-thiophenecarboxaldehyde replaces acetaldehyde [16]. The two compounds are essentially insoluble in water, but are readily soluble in organic solvents such as chloroform.

R

O O HO

O OH

O

O O O O

CH3O

OCH3 OH

2.2 Etoposide R = CH3 2.3 Teniposide R = S

The chemistry and structure-activity relationships of etoposide have been reviewed [17, 18], and it is concluded that there is a great deal of room for additional chemical work on the molecule. The lack of a practical synthetic route to the parent basic aglycone may be a barrier to this work, however. The poor water solubility of etoposide and teniposide make them difficult to administer, and this

1

Plant-Derived Natural Products as Anticancer Agents

led to the development of the water-soluble etoposide phosphate etopophos (2.4) [19]. H3C

O O HO

5

is only weakly active in mouse lung carcinoma assays. This difference of response between species has also been observed with other antineoplastic agents.

O OH

1.2.5 Structure-Activity Studies and Mechanism of Action

O

O O O O

CH3O

OCH3 OPO3H2

2.4 Etopohos

1.2.4 Activity in In Vitro and In Vivo Assay Systems In vitro activity of etoposide and teniposide has been shown against a number of cell lines [8, 16, 20]. Etoposide was active in P-815 murine mastocytoma with an ED50 of 0.031 μg/ml, while teniposide had an ED50 of 0.0048 μg/ml in this system [16]. Human lymphoid cells exposed to etoposide at 1.0 μg/ml for 24 h have the major part of the population arrested with their DNA in the S part of the cell cycle [21]. Other results suggest that etoposide arrests cells in the late S or G2 phases of the cell cycle [20]. In animal studies etoposide is generally more active than teniposide; thus it give an increase in survival time in the L1210 mouse leukemia system of 167%, while teniposide gives a 121% increase in the same system [16]. In a comparative study of various dosage schedules in mice with L1210 leukemia, Dombernowsky and Wissen [22] concluded that etoposide was one of the most active drugs yet tested in the L1210 system. In a discussion of the results of in vitro and in vivo assays, Rose and Bradner [23] point out that etoposide shows a broad-spectrum activity, but there is no correlation in activity for specific histologic types of neoplasms between species. Thus although etoposide shows excellent activity in the L1210 and P-388 leukemia assays, it is not particularly active in human leukemias. On the other hand, etoposide shows good activity in certain types of human lung carcinomas, but

In the initial search for podophyllotoxin derivatives with useful anticancer activity, a large number of modified podophyllotoxins were prepared. Initial findings indicated that some podophyllotoxin derivatives such as podophyllinic acid ethylhydrazide (SP-1) did have some therapeutic activity, but the most active derivatives prepared were those of the type exemplified by etoposide and teniposide. Interestingly, the corresponding compounds in which the 4 -hydroxyl group is methylated (i.e., the epipodophyllotoxin derivatives) are much less active than the corresponding 4 -demethyl-epipodophyllotoxin derivatives. Of the many 4 -demethyl-epipdophyllotoxin β-Dglucopyranoside acetals prepared, etoposide showed the best activity in the L1210 in vivo system, while teniposide was one of the most active derivatives in the P-815 mouse mastocytoma cell assay. Changing the sugar moiety to galactose rather than glucose gave derivatives with lower activity [16]. Various analogs of etoposide modified in the lactone ring have also been prepared, but they were uniformly less active than the parent compound [24]. Interestingly, the modes of action of etoposide and teniposide differ markedly from that of the parent compound podophyllotoxin. Podophyllotoxin is a potent inhibitor of microtubule assembly in vitro, and competitively inhibits the binding of colchicines to microtubules [25, 38]. Because of this property, it arrests cells at mitosis by disrupting the equilibrium between tubulin polymer and tubulin dimer, thereby destroying the cytoskeletal framework from chromosome separation and arresting cell division at the mitotic stage of the cell cycle. Etoposide, teniposide, and etopophos, on the other hand, have a quite different mechanism of action. These compounds arrest cells in the late S and G2 phase of the cell cycle, and have no effect on tubulin assembly. Instead, they induce single strand breaks in DNA (etoposide) or in the DNA in L1210 cells (teniposide) [26–28]. In the case of teniposide, these breaks are predominantly double-stranded. These effects are

6

due to the ability of these compounds to inhibit DNA topoisomerase II (topo II) [29]. DNA topoisomerases are enzymes that allow DNA to coil and uncoil (i.e. change its topology), which is a necessary prelude to mitosis. DNA topoisomerase II mediates double-strand breaks by forming a complex with DNA, the so-called cleavable complex. Etoposide stabilizes this complex and inhibits the enzyme, thus leading to double-strand breaks and ultimately to cell death [30].

1.2.6 Pharmacology Etoposide and teniposide are only sparingly soluble in water, and are supplied for clinical use in nonaqueous formulations. Etoposide is supplied in 5 mL ampules at a concentration of 20 mg/mL, while the teniposide ampules contain 10 mg/mL in a total of 5 mL. Etoposide is also available for oral administration in 10 and 50 mg gelatin capsule formulations [36]. It is stable for at least 3 h in various aqueous solutions, and is stable for up to 72 h in aqueous dextrose or normal saline when its concentration does not exceed 0.25 mg/ml [33]. Dose schedules for etoposide are normally 300– 600 mg/m2 i.v. divided over 3 or 5 days and repeated every 3–4 weeks. For teniposide the schedule for adults is similar, but at a lower dose of 300 mg/m2 . The limiting toxicity in treatment with these drugs is myelosuppression, and hence a lower dose range is indicated for those patients whose bone marrow function has been compromised by prior radiation therapy or chemotherapy. For children, teniposide monotherapy is commonly used at a dose of 150–200 mg/m2 weekly or 100 mg/m2 twice weekly [36]. Studies on the clinical pharmacology of the drugs indicate that absorption from the lipophilic capsules is erratic, but that absorption from oral solution and hydrophilic gelatin capsules is much better. Plasma levels of unchanged drug have been monitored both by thin layer chromatography and high performance liquid chromatography (HPLC), and these studies have shown that etoposide has a shorter terminal half-life than teniposide Both drugs are reported to have activity against intracranial neoplasms, with most work having been done on teniposide. Only low levels of this drug have been found in the cerebrospinal fluid, however; typically these levels were 0.2–14.3% of the plasma levels found in the same patient [35].

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Excretion of both drugs is primarily in the urine, with approximately 50% of the administered radioactivity being recovered in the urine within 72 h of administration. Fecal excretion is variable, with amounts varying from 0 to 16% of the administered radioactivity being recovered in the feces of patients administered intravenous [3 H]etoposide. In the case of [3 H]teniposide, only 21% of the radioactivity recovered in the urine corresponded to unchanged drug, with the major metabolite being the ring-opened lactone 4 -demethyl-epipodophyllic acid-9-(4,6-O-ethylideneβ-D-glucopyranoside). In the case of [3 H]etoposide, 67% of the urinary radioactivity was in the form of unchanged drug, and the major metabolite has been shown to be the acid corresponding to the major metabolite of teniposide [31, 32]. The chemotherapy and pharmacology of the podophyllotoxin derivatives etoposide and teniposide have been discussed extensively in various reviews [33–39], and these reviews provide convenient sources of additional information on the subject. Reviews of the clinical pharmacology of etoposide in adults [40] and in children [41] have also appeared.

1.2.7 Clinical Single Agent Activity The composite response rates for etoposide and teniposide have been compiled by Issell [36], and a more recent review by Hande gives the single agent response rates for etoposide [42]. Etoposide is one of the most active single agents in small lung cancer with a composite single agent response rate of 44% in previously untreated patients, and a 13% response rate in previously treated patients [43]. Teniposide has been less thoroughly evaluated in this cancer, but preliminary results show a 28% response rate with 8% complete responses in one trial. For testicular cancer, response rates of up to 33% are reported with etoposide, and activity is retained even in patients refractory to front-line combination therapy [44]. Teniposide has not been adequately tested in this situation. Both etoposide and teniposide show activity against Hodgkin’s disease and other malignant lymphomas, with especially encouraging results in treatment of diffuse histocytic lymphoma with etoposide in patients who had become refractory to front-line combination chemotherapy.

1


Etoposide shows some activity against adult acute myelogenous leukemia, with a good response rate for patients with myelomonocytic and monocytic leukemia. Teniposide and etoposide are both useful in pediatric leukemia, with teniposide showing activity against refractory acute lymphoblastic leukemia and etoposide against acute monocytic leukemia. Etoposide and teniposide both have meaningful activity in pediatric refractory neuroblastoma, with responses in up to 50% of the patients evaluated. Teniposide appears to have some activity in brain tumors, with responses in up to 35% of the patients evaluated; responses were seen in patients who were progressing on nitrosoureas. Etoposide has some effect on breast cancer, with useful partial responses reported for 17% of heavily pretreated patients. Finally, etoposide has activity against Kaposi’s sarcoma associated with acquired immunodeficiency syndrome (AIDS); it is the most active single agent tested to date, with a response rate of 34% [45, 46]. Etopophos is essentially a prodrug form of etoposide, since it is converted to this compound by endogenous phosphatases; it thus has a similar pharmacological profile to etoposide [42]. It has improved water-solubility as compared with etoposide, and it also has a higher bioavailability than etoposide. It is has thus been preferred for clinical use since its approval by the FDA in 1996, although its higher cost may be a factor in some cases [42].

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of multi-drug treatment protocols for non-Hodgkins lymphomas, refractory childhood leukemia, various lymphomas, and other types of cancer [13, 36, 47].

1.2.9 Toxicity The two dose-limiting toxic effects of etoposide and teniposide are myelosuppression and gastrointestinal disturbances, with the former being the more important since the latter effect is usually easily controlled. Other toxicities include alopecia, and less commonly peripheral neuropathy and acute toxicities such as fever, chills, hypertension, and brochospasm [36].

1.2.10 New Analogs in Development Several new analogs of podophyllotoxin are in development, and three have reached clinical trials. The derivative NK-611 (2.5) differs from etoposide only in having an dimethylamino group in place of the 2-OH group of glucose [49]. Clinical tests of NK-611 suggest that it has better bioavailability than etoposide, but evidence for cross-resistance between etoposide and NK-611 was found [15]. H3C

O O HO

O NMe2 O

1.2.8 Clinical Combination Therapy O

O

The drugs etoposide and teniposide are suitable candidates for combination therapy, since their toxicity is relatively low and they have unique modes of action. At this point, a number of combinations have been tested in experimental animals, but only a few are at the point where they are clinically useful. The most interesting situation to date is that of the combination of teniposide with cytarabine (ara C) in the treatment of refractory pediatric acute lymphoblastic leukemia. The drugs are reported to show a synergistic effect, and in one study 9 of 14 patients achieve complete remission after they had failed remission induction with standard therapy [13, 47, 48]. Etoposide is effective in combination with cisplatin for treatment of small cell lung cancer, non-small cell lung cancer, and refractory testicular cancer. It is also used as part

O O

CH3O

OCH3 OH

2.5 NK - 611

The derivative GL-331 (2.6) is a 4β-arylamino analog of etoposide in which the sugar moiety is replaced by a p-nitro anilino group. GL-331 is more active than etoposide in causing DNA double-strand breakage and G2-phase arrest [50], and it is also more potent against tumor cells both in vitro and in vivo. Initial results from Phase I clinical trials in non-small and small cell lung, colon, and head/neck cancers were encouraging, with

8

D.G.I. Kingston

minimal side effects. Phase II clinical evaluation in gastric cancer patients, however, showed no objective response [51]. NO2

HN O O O

is a standard agent in the treatment of small cell lung cancer, testicular cancer, and lymphomas, and it also has activity against monocytic or myelomonocytic leukemia, non-Hodgkin’s lymphomas, and hepatocellular carcinoma. Teniposide has a role in the treatment of Hodgkin’s disease, non-Hodgkin’s lymphomas, neuroblastoma, and childhood acute lymphoblastic leukemia. New analogs of etoposide have been developed and are at various stages of clinical trial [15], and prospects are good that improved analogs will contribute significantly to cancer chemotherapy.

O

CH3O

1.3 Paclitaxel

OCH3 OH

1.3.1 Introduction

2.6 GL - 331

The derivative TOP-53 (2.7) is an aminopodophyllotoxin derivative [52]. It was a more potent inhibitor of topoisomerase II than etoposide, and showed excellent activity against a mutant yeast type II enzyme highly resistant to etoposide. TOP-53 exhibited especially high activity against non-small cell lung cancer in both tumor cells and animal tumor models [53]. This compound is currently in phase I clinical trials. NMe2

N

O O O O

CH3O

OCH3

When the first edition of this book was published in 1989, paclitaxel (TaxolTM ) merited only three paragraphs of text, as an interesting compound in development. What a difference 15 years makes! Paclitaxel is now a widely used chemotherapeutic agent and it has been joined by its semisynthetic derivative docetaxel (TaxotereTM ). Several additional analogs are in development, with six currently in clinical trials. The diterpenoid paclitaxel (3.1) was first reported by Wani and Wall in 1971 [54], and emerged from being a laboratory curiosity in the 1970s and 1980s to a drug of major clinical importance in the 1990s. It is currently approved for the treatment of breast and ovarian cancers and for AIDS-related Kaposi’s sarcoma, and it is also used or under investigation for the treatment of a number of other cancers [55]. The combined annual sales of it and its semisynthetic analog docR [56]) (3.2) are well over $1 billion. etaxel (Taxotere

OH 2.7 TOP - 53

R2O

O

OH

O R1

1.2.11 Conclusion

NH

O

Ph OH

The modified podophyllotoxin derivatives etoposide and teniposide have demonstrated significant clinical activity in treatment of several tumors. Etoposide

O

O OH PhCOO

3.1 R1 = C6H5, R2 = Ac 3.2 R1 = Me3CO, R2 = H

OAc

1


1.3.2 History Taxol was discovered as a fruit of a systemic search by the National Cancer Institute (NCI) for naturally occurring anticancer agents. A sample of the bark of the western yew, Taxus brevifolia, was collected in 1962, and an extract of the bark was found to be cytotoxic to KB cells. The extract was assigned to Dr. Monroe Wall and his team at the Research Triangle Institute (RTI), and taxol (as it was then known) was isolated in 1967. The structure was not published until 1971, however, in part because of its complexity. Paclitaxel (3.1) is a complex diterpenoid with a phenylisoserine side chain, and its structure was finally solved by a combination of chemical degradations and x-ray crystallography [57]. The selection of T. brevifolia by the original collectors turns out in retrospect to have been providential. Had a different yew species been investigated, it is likely that fractionation would have led to the isolation of toxic taxine alkaloids as the cytotoxic constituents, and the smaller amounts of taxol present might have gone undetected [58]. The initial reaction to the discovery of paclitaxel was underwhelming. It has a very complex structure, and it was thus essentially inaccessible by synthesis, and it was only available in low yield from T. brevifolia. The supply of enough compound for clinical use was thus a major problem. In addition, it is very insoluble in water, so formulation was also clearly going to be a major problem. Small wonder then that the compound languished for several years before it was brought to clinical trial! Fortunately for clinicians and cancer patients, a few dedicated scientists, and especially Monroe Wall at RTI and Matthew Suffness at the NCI, believed in paclitaxel and continued to investigate it. Three key discoveries in the mid to late 1970s helped to move paclitaxel into clinical trials. The first was that it showed excellent activity against various human tumor xenografts in nude mice. This finding led to a decision by the NCI to move paclitaxel into preclinical development, and this led to the second important advance, which was the discovery of an effective formulation in a mixture of ethanol and Cremophor EL. The final discovery was made in 1979 by Susan Horwitz, who found that paclitaxel had a totally different mechanism of action from any previously known anticancer agent. Instead of preventing the assembly

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of tubulin into microtubules, as was known for such compounds as the Vinca alkaloids and podophyllotoxin, paclitaxel promotes the assembly of tubulin into microtubules [59]. Taken together, these discoveries maintained interest in paclitaxel when toxicity was encountered in its clinical trials, and ultimately led to its successful development as a clinical agent. The history of paclitaxel’s early development has been documented in an interesting book [60].

1.3.3 Mechanism of Action As noted earlier, paclitaxel’s primary mechanism is as a tubulin-polymerization agent. This mechanism has been shown to result from promotion of the polymerization of tubulin heterodimers to microtubules. Paclitaxel binds to microtubules with a stoichiometry of approximately 1 mole of drug to 1 mole of tubulin dimer [59]. Although the drug stabilizes microtubules and also increases the total polymer mass at high concentrations [61], these concentrations are higher than those needed to inhibit microtubule functions [62]. The key feature of paclitaxel’s action from a clinical perspective is that it suppresses dynamic changes in microtubules at clinically relevant concentrations, leading to mitotic arrest [63]. It does this by interfering with the formation of the mitotic spindle, thus preventing the chromosomes from separating [64]. Further details of the tubulin-binding action of paclitaxel can be found in various reviews [65, 66]. The binding of paclitaxel to tubulin polymers and the associated interruption of the cell cycle is not the only biological effect produced by paclitaxel. Other effects at the cellular level include phosphorylation of and binding to Bcl-2, direct activation of signal transduction pathways, induction of the production and release of cytokines [67], and activation of transcription factors AP-1 or NF-κB. Probably the most important of these is paclitaxel’s ability to inactivate the antiapoptotic protein Bcl-2, which it does by inducing phosphorylation, which then leads to inactivation [68]. The phosphorylation of Bcl-2 may occur through activation of Raf-1 kinase, and it has been proposed that Raf-1 is activated following drug-induced disruptions of microtubules [69], but paclitaxel also binds directly to Bcl-2 [70]. These events have been

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critically reviewed by Blagosklonny and Fojo [71], who conclude that all of paclitaxel’s effects occurring in vitro at clinically relevant concentrations are related to microtubule binding and cell-cycle arrest at G2/M. Although the clinical effects of paclitaxel may thus be traced to its microtubule binding activity, the actual cellular events resulting from this binding are rather complex. The situation has been aptly summarized as follows: “Depending on the phase of the cell cycle, taxanes can affect spindle formations, chromosome segregation, or completion of mitosis, thus activating the mitotic or the DNA-damage checkpoints and blocking cell-cycle progression. This complex scenario, with different cell cycle responses related to the specific microtubule function affected in each phase, is reflected in the variety of pathways described to result in apoptosis upon taxane treatment. . .” [72]. Although it is not relevant to paclitaxel’s use as a cancer chemotherapeutic agent, it should be noted that various analogs of the drug have been shown to have activity against other diseases, at least in vitro. Thus modified paclitaxels have shown activity against in vitro models of malaria [73, 74] and Alzheimers’ disease [75].

1.3.4 The Paclitaxel-Tubulin Interaction Since the most important biological effects of taxol can be attributed to its microtubule stabilization, the nature of its binding to microtubules becomes of great importance; this subject thus merits a separate discussion. Ideally the binding site of taxol on tubulin would be elucidated by x-ray crystallography, but because tubulin forms microtubules on attempted crystallization it has not proved possible to obtain an x-ray crystal structure of the protein. It has however proved possible to prepare stabilized crystalline sheets of “microtubules” in the presence of paclitaxel and zinc, and the structure of these sheets has been determined by electron crystallography at a resolution of 3.7 Å [76–78]. The location of the paclitaxel binding site on the tubulin molecule was shown to be on β-tubulin by photoaffinity labeling studies with azidobenzoyl paclitaxel derivatives, which photolabeled the N-terminal proton of β-tubulin [79] or amino acids 217–231 of β-tubulin [80], depending on the location of the azidobenzoyl group on paclitaxel. Some

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paclitaxel analogs do however label α-tubulin as well as (or instead of) β-tubulin [81, 82], leading to the suggestion that the drug most probably occupies a binding site located between α- and β-tubulin, but largely on β-tubulin. In the electron diffraction structure of the αβtubulin-taxol complex described above, taxol occupies a hydrophobic cleft on β-tubulin, and this binding converts it into a hydrophilic surface [83, 84]. This binding location is consistent with the photoaffinity results reported above showing labeling of β-tubulin by taxol; the labeling of α-tubulin is difficult to explain. Although these results show the general location of paclitaxel on tubulin, its actual binding conformation(s) cannot be discerned at the resolution obtained. Studies of the NMR spectra of paclitaxel in solution indicated the presence of three conformers; a nonpolar conformer [85–87] a polar form [88–90], and a third minor conformer, designated T-taxol, in which the C-2 benzoyl group bisects the angle between the C-3 phenyl and C-3 benzamido side chains [91]. Initial support for the T-taxol conformation as the binding conformation on tubulin was obtained by two studies using solid state NMR to probe the conformation of tubulin-bound drug [92, 93]; these results were also consistent with the unexpected activity of 2-mazidobaccatin III [94]. Final support for the T-taxol conformation came from synthesis of the constrained analog (3.3) [95]. This compound, which has a similar conformation to T-taxol, is about twentyfold more cytotoxic than paclitaxel to A2780 cells and has a critical concentration for tubulin polymerization over threefold lower than that of paclitaxel. It also fits the paclitaxel-binding pocket on β-tubulin, and it thus represents the best available model of the tubulin-bound conformation of paclitaxel.

AcO

O

OH

O HO

O

H

O

O

HO BzO N H

O O

3.3

1


11

Although the above discussion has focused on paclitaxel, much of the discussion applies to its sister drug docetaxel (3.2), although there are differences in the details of their effects. Nevertheless, both are potent anticancer drugs which promote the assembly of microtubules as their primary action relevant to cancer chemotherapy. It is worth noting that several other natural products with this mechanism have been identified over the last 10 years; these include the epothilones, discodermolide, eleutherobin, and laulimalide, among others, and the epothilione analog ixabepilone has been approved for clinical use. The importance of this class of microtubule-stabilizing agents has been recognized by several recent reviews [96–99].

1.3.5 Paclitaxel Analogs In the chemistry area virtually every position on the ring and on the side chain has been subjected to O

AcO O NH

Ph

O O

O

NH

Ph

O

Ph

H AcO HO OCOPh

O OH

O

AcO

OH

O

O

H AcO HO OCOPh

OH

O

AcO

OR

O

Ph

structural modifications. Space does not permit even a brief review of the synthetic and structure-activity relationship (SAR) work that has been carried out on paclitaxel, and reference is thus made to some reviews which discuss the work that has been done [100–106]. Suffice it to say that all the functional groups in the compound have been modified, in some cases in a combinatorial fashion, and that several improved analogs have been developed. A complete list of paclitaxel analogs in preclinical and clinical development as of late 2003 is provided in a review by Cragg and Newman of the NCI [107]. The six analogs DHA-paclitaxel (Taxoprexin, (3.4)) [108], 7hexanoylpaclitaxel (3.5) [108], the C-7 thioether (3.6) (BMS-184476) [109], the cyclopropyl derivative (3.7) (RPR-109881A) [110], the C-4 carbonate (3.8) (BMS188797) [111], and the 7,10-dimethyl ether (3.9) (TXD258) [112] are currently in Phase II clinical trial, while the four additional paclitaxel analogs ortataxel (3.10) [113], TL-00139 (3.13) [114], DJ-927 (3.14) [115], and BMS-275183 (3.15) are in Phase I clinical trial.

O

NH

O

HO

OH

3.7

3.4 R = COCH2(CH2CH=CH)6CH2CH3 3.5 R = CO(CH2)5CH3

O

H

O

Ph

OCOOCH3 OCOPh

3.8

3.6 R = OCH2SCH3 O CH3O

O O

NH

O

O

Ph

O NH

O O

OH

H AcO OH OCOPh

O

AcO

OCH3

O O

OH

O

3.9

H AcO O OCOPh O

O

O

AcO

O

NH

O

O

N

O OH F

H AcO OH OCOPh

3.13

O

NH

H

O OH

OH

OH

O

OCOOCH3 OCOPh

3.14

OH

H OH

OAc OCOPh 3.12

O

Ph

O O

O

3.10

O

O

NH

O

N

O

O

O

O

O

O

HO

OH

O

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A further 23 paclitaxel analogs are in preclinical development; their structures are given in the review cited above. It thus seems clear that paclitaxel and docetaxel are simply the first examples of a whole new class of anticancer agents, and that more efficacious analogs will be available to the clinician within a few years’ time.

1.3.6 Mechanisms of Resistance There are two major mechanisms of acquired resistance to the taxane drugs. The first general mechanism involves tumors that contain mutated α- and β-tubulins. In some cases these tubulins have an impaired ability to assemble to microtubules, and in these cases the taxanes act to make the cells more normal [116]. In other cases the tubulins have mutated so that they are less susceptible to the taxanes; as one example, β-tubulin mutations were shown to be strong determinants of paclitaxel resistance in patients with non-small cell lung cancer [117]. The second general mechanism of resistance involves the well-known multi-drug resistant phenotype of tumor cells, which confers varying degrees of cross-resistance to structurally bulky natural products. Reversal of resistance to paclitaxel and docetaxel can be achieved with several classes of drugs, including the principal component of the vehicles used to formulate paclitaxel (Cremophor EL) and docetaxel (polysorbate 80) [118].

1.3.7 Formulation of Paclitaxel and Docetaxel Paclitaxel is very sparingly soluble in water, and it has a low oral bioavailability. It thus requires administration in a solubilizing formulation, and the current formulation consists of 30 mg of the drug in a 50/50 mixture of Cremophor EL (a polyethoxylated castor oil) and ethanol. As noted above this formulation has some benefits in assisting in the reversal of resistance by the MDR phenotype, but it also creates problems since it almost certainly is the cause of the hypersensitivity reactions associated with paclitaxel administration [119].

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Docetaxel is slightly more water-soluble than paclitaxel, and is administered with polysorbate 80 as its emulsifier. Many new formulations for the taxanes have been developed, and are summarized in a review [120]. Not included in this review is the announcement of the successful phase III trial of the albumin nanoparticlebased formulation of taxol ABI-007 [121]. This result shows that improved formulations can have a dramatic effect; the overall response rate for ABI-007 in patients with metastatic breast cancer was 33%, compared with 19% for taxol.

1.3.8 Paclitaxel Metabolism The human metabolism of paclitaxel has been studied by several researchers. Renal clearance contributes little to systemic clearance, and metabolism, biliary excretion, and tissue binding account for the bulk of the disposition of the administered doses of paclitaxel. Studies of the biliary metabolites of paclitaxel have shown that the major human metabolite is 6αhydroxypaclitaxel (3.15) [122]. This metabolite is significantly less active than paclitaxel, and so one fruitful goal of research has been the development of paclitaxel analogs which are resistant to this pathway of metabolic inactivation. Two other minor metabolites have also been identified, one hydroxylated on the para-position of the 3 -phenyl group (3.16) and the other hydroxylated on both the para-position of the 3 phenyl and on C-6 (3.17). The metabolism of paclitaxel in the rat has also been studied; in this case (3.16) is the major metabolite, and several metabolites that are not found in humans have also been identified. This subject has been reviewed [123, 124].

AcO

O

OH

O Ph

R2 NH

O O

O R1

OH

OH

AcO OCOPh

3.15 R1 = H, R2 = OH 3.16 R1 = OH, R2 = H 3.17 R1 = R2 = OH

1


1.3.9 Cancer Therapy with Paclitaxel and Docetaxel The use of taxol in cancer therapy has recently been reviewed [125], and several reviews have covered the use of taxol or docetaxel for the treatment of specific cancers [126–130]. This section will summarize the major results from these studies by cancer type.

1.3.9.1 Ovarian Cancer The initial report of the clinical activity of paclitaxel was made for ovarian cancer [131], and this continues to be an important indication for this drug. Paclitaxel is effective as a single agent [131, 132], but the preferred treatment is by combination therapy. The standard treatment for ovarian cancer prior to the advent of paclitaxel was cyclophosphamide-cisplatin, but paclitaxel-cisplatin has been shown to be more effective [133], and this now the standard of care for women with advanced ovarian cancer. The risks and benefits of taxanes in breast and ovarian cancer have been reviewed [134].

1.3.9.2 Breast Cancer Paclitaxel was first shown to have activity against breast cancer in 1991, and this finding immediately transformed it from “orphan drug” to “blockbuster” status. Both paclitaxel and docetaxel have shown excellent activity in treating advanced metastatic breast cancer [135], and their value in treating early stage breast cancer has also been demonstrated. One reviewer states “The evidence is now clear that taxanes added to standard adjuvant regimens . . . can improve outcomes for patients with breast cancer” [136]. A second systematic review of taxane versus non-taxane regimens for treatment of early breast cancer concludes “The results of this systematic review support the use of taxanes as adjuvant chemotherapy for women with early breast cancer and involved lymph nodes” [137]. In the studies summarized in this review, the 5-year relapse-free survival rate was 74% for the control (non-taxane) group versus 79% for the taxane-treated group [137].

13

1.3.9.3 Lung Cancer Docetaxel is the drug of choice for the treatment of advanced non-small cell lung cancer that is refractory to primary chemotherapy [138]. A study to compare the efficacy of three different treatment regimens (cisplatin and gemcitabine, cisplatin and docetaxel, or carboplatin and paclitaxel) found that the response rates and survival did not differ significantly between the regimens [135]. The combination of paclitaxel and carboplatin is also a standard treatment for patients with advanced non-small cell lung cancer [139].

1.3.9.4 AIDS-Related Kaposi’s Sarcoma Paclitaxel induces apoptosis in AIDS-related Kaposi’s sarcoma cells [140], and it has been approved for treatment of this disease.

1.3.10 Summary Paclitaxel and docetaxel may not be the wonder drugs they were thought to be in 1991, but they have nevertheless brought significant benefits to many cancer patients. The new analogs in clinical trials promise real improvements in efficacy over taxol and docetaxel, and improvements in drug delivery will also play a major role in improving treatment. Paclitaxel and its analogs can thus be expected to play an important role in cancer chemotherapy well into the 21st century.

1.4 Camptothecin and Analogs 1.4.1 Introduction The 1960s was a significant decade at the Research Triangle Institute, since both paclitaxel (TaxolTM ) and the alkaloid camptothecin (4.1) [141] were isolated there by Wani and Wall during this period. Ironically, the work on camptothecin had a higher priority at the time than work on paclitaxel, and this was a factor which contributed to delays in the structure elucidation of the latter. Camptothecin was obtained from

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D.G.I. Kingston

extracts of Camptotheca acuminata Decne., 1873, and it showed good activity against L1210 leukemia. Since it had very low solubility in water, clinical studies were carried out on the water-soluble sodium salt (4.2). Unfortunately these trials revealed numerous problems and were suspended [142]. Interest in camptothecin revived when it was discovered that it had a previously unknown mechanism of action, namely the ability to inhibit topoisomerase I (topo I) [143]. This discovery led to the synthesis and evaluation of a large number of camptothecin analogs, and the two water-soluble analogs topotecan (Hycamtin) (4.3) and irinotecan (Camptosar) (4.4) have been approved for clinical use.

1.4.2 Mechanism of Action 1.4.2.1 Inhibition of Topoisomerase I As noted above, camptothecin acts by inhibiting the enzyme topoisomerase I, which it does by binding to the DNA-topoisomerase I covalent binary complex [3]. The topoisomerases I and II are enzymes that allow chromosomal DNA to undergo changes in topology (i.e. relaxation) prior to replication; any interference with this process would have obvious negative consequences for cell viability. This mechanism is thus consistent with the fact that camptothecin is capable of inhibiting DNA synthesis, leading to cell death dur-

ing the S-phase of the cell cycle [144]. Support for the inhibition of topo I as the target of camptothecin comes from studies showing that many camptothecinresistant cell lines have mutated variants of topo I [145], and that Saccharomyces cerevisiae cells in which the gene for topo I has been deleted (and which then overexpress topo II in compensation) are resistant to camptothecin [146]. It is noteworthy that camptothecin shows remarkable specificity in binding only to the cleavable complex formed between topo I and DNA; it does not bind to DNA alone or to topo I alone. Although topoisomerase I is an enzyme found in all cell types, its levels are elevated in tumors of the colon, ovary and the prostrate, and this is presumably a significant part of the reason for the effectiveness of the camptothecin analogs against the first two of these tumors [147]. Some cancer cells may be more susceptible to the camptothecins because of deficiencies in DNA repair capabilities, and dividing cell populations are also likely to be more susceptible to inhibition by topoisomerase poisons. 1.4.2.2 Other Biochemical Effects of Camptothecin Various other activities have been observed for the camptothecins. These include activation of the transcription factor NFκB [148], regulation of transcription [149], base mismatch nicking activity [150], and phosphorylation of SR proteins [151].

O

N

N

N

O

N OH O–Na+

O OH O

4.1

4.2

OH O

N

CH2NMe2 HO N

CH2CH3 N

O

O N

O

N

N

O

4.3

OH O

O

O

4.4

OH O

1


1.4.3 Mechanisms of Resistance Resistance to camptothecin analogs can take several forms in vitro. Topotecan is known to be susceptible to the classic multidrug resistance (MDR) phenotype, although several related compounds are apparently not susceptible [152]. The effect of this susceptibility is however less than for several other classes of anticancer drug such as the taxanes and the Vinca alkaloids, so the clinical significance of this finding is not clear [152]. Resistance may also result from decreased expression of topoisomerase I [153, 154], although clinical studies have not yet confirmed the significance of this finding [155]. Reduced or altered catalytic activity of topoisomerase I resulting from mutations has also been shown to cause resistance [156], while topoisomerase II is upregulated in human tumor cells after exposure to topotecan in vitro [157]. Further details on these and other possible mechanisms of resistance are given in an excellent recent review [158]. Although resistance to camptothecin and its analogs can take different forms, it is not yet clear which if any of these pathways contributes significantly to drug resistance in a clinical setting.

1.4.4 Camptothecin Supply As noted above, camptothecin was initially isolated from Camptotheca acuminata, but it has also been isolated from several other species; a full survey of the distribution of camptothecin and its metabolites is provided in a review [159]. In spite of the importance of camptothecin and its analogs as anticancer agents, the compounds are still obtained from the bark and seeds of C. acuminata and Nothapodytes foetida. Recent studies with hairy root cultures of C. acuminata and Ophiorrhiza pumila, however, offer the hope that plant tissue culture methods of production will prove feasible in the future, as is the case with paclitaxel [159].

15

syntheses have been reported by Ejima et al. [163], Comins et al. [164], Tagami et al. [165], Bennasar et al. [166], Ciufolini and Roschangar [167], Imura et al. [168], Fang et al. [169], Jew et al. [170], Blagg and Boger [171], and Curran et al. [172, 173]. The clinical drugs topotecan and irinotecan were both prepared initially by partial synthesis from naturally occurring precursors. Irinotecan (4) was prepared by Sawada et al. from 20(S)-camptothecin [174], with a photochemical rearrangement of an N-oxide derivative as the key step. Topotecan was synthesized by Kingsbury et al. in two steps from 20(S)-camptothecin [175], with a Mannich reaction on 10-hydroxycamptothecin furnishing the final product.

1.4.6 Medicinal Chemistry As has been the case with podophyllotoxin and paclitaxel described earlier, many analogs of camptothecin have been prepared and much is known about its SAR profile. This subject has recently been reviewed [176], and this discussion can thus be abbreviated. Studies of compounds modified on the quinoline ring system have shown that substitutions at C-11and C-12 normally result in a reduction of activity, while substitutions at C-7, C-9, and C-10 can lead to enhanced activity [176]. The E-ring lactone is important for activity, and almost all modifications to this ring have led to less active compounds; the homocamptothecins represent an important exception. Although the camptothecins are the only topo 1 inhibitors currently in clinical use, several compound classes are under investigation as sources of alternative inhibitors. These include the indolocarbazoles, indenoisoquinolines, benzacridines, and the benzimidazoles [177].

1.4.7 Camptothecin Analogs in Clinical Use

1.4.5 Synthetic Studies 1.4.7.1 Topotecan The synthesis of camptothecin has been achieved by several workers, following the first total synthesis in 1971 [160]; this work has been reviewed [161, 162], and thus will not be discussed in detail. Asymmetric

Topotecan (4.3) (Hycamtin) has a N,N-dimethylaminomethyl substituent at C-9; this basic functional group confers improved water solubility. Topotecan is

16

D.G.I. Kingston

presently utilized as second-line therapy for advanced ovarian cancer in patients who have failed to respond to treatment regimens that include platinum or paclitaxel. Recent results from a Phase III study, however, have shown that long-term survival of patients with advanced epithelial ovarian cancer was comparable for those on topotecan and those on paclitaxel [178]. Recurrent small-cell lung cancer is also an approved indication; it has been shown to increase the time to disease progression for patients previously treated with etoposide plus cisplatin [158]. It is usually administered as an intravenous infusion. Because topotecan binds relatively poorly to human plasma proteins, its half-life is much shorter than that of other camptothecin derivatives and thus drug accumulation is not apparent. The most common dose-limiting toxicity is neutropenia, although topotecan treatment can also be associated with some thrombocytopenia. Topotecan also has activity against hematological malignancies in addition to its action on ovarian and small-cell lung cancers. As is common for antitumor agents, combination regimens with many other agents including paclitaxel and cisplatin are under development [186]. 1.4.7.2 Irinotecan Irinotecan (4.4) (Camptosar) is a water-soluble prodrug of the 7-ethyl-10-hydroxycamptothecin ana-

log SN-38 (4.5). Carboxylesterase cleavage of the bispiperidine group at the 10-position affords the biologically active compound SN-38, which is three orders of magnitude more potent than irinotecan as an inhibitor of topoisomerase I in vitro. Irinotecan has been approved for the treatment of advanced colorectal cancer. It is approved both as first-line therapy (in combination with 5-fluorouracil) and as salvage treatment for 5-fluorouracil-resistent tumors. It is most commonly administered as an intravenous infusion [158]. One advantage of irinotecan over topotecan is that the biological half-life of the lactone form of SN-38 (4.5) exceeds that of topotecan. Since the lactone form binds preferentially to serum albumin, this results in the persistence in the plasma after drug administration of a relatively large percentage of the intact lactone form of both irinotecan and SN-38. The major mechanisms of elimination of SN-38 are glucuronidation and biliary excretion. Its principal dose-limiting toxicity is delayed diarrhea, with or without neutropenia, and it has been suggested that the risk of diarrhea is inversely related to the extent of glucuronidation [179]. Promising antitumor activity has also been observed against small-cell and nonsmall lung cancer, ovarian cancer, cervical cancer, and in recent clinical trials involving patients with malignant gliomas. Studies to evaluate additional irinotecan drug combinations with taxanes, anthracyclines, Vinca alkaloids, or alkylating agents are in progress.

N R HO

O

O

O

N

OH O OBut

OH O

4.8

NMe2

O

OH O

N

N O

4.11

OH O

O

N

N O

4.9

F

O

N

N

O

OH O

O

N

N

SiMe3

N

4.10

F O

O 4.6 R = NH2 4.7 R = NO2

N

N

O

N O

O

O N

N

N

4.5

NH2

N

OH O

F

N O

O 4.12

OH O

4.13 OH

O

1


1.4.8 Camptothecin Analogs in Clinical Trial or Preclinical Development The work summarized briefly above in Section 1.4.5 has led to the development of several camptothecin derivatives addition to topotecan and irinotecan.as clinical candidates. These are described briefly below. 9-Aminocamptothecin (IDEC-132) (4.6) was discovered by Monroe Wall and his group, and is being developed by the National Cancer Institute. Initial clinical trials using intravenous infusion gave disappointing results, but a solid oral dosage form was developed by incorporating the drug into poly(ethylene)glycol1000. Testing of the conjugate in cancer patients yielded bioavailabilities of 49% [180], and phase II studies using this formulation have been initiated. 9-Nitrocamptothecin (Rubitecan) (4.7) was developed for oral administration; it is metabolically converted 9-aminocamptothecin into in vivo, and is thus likely to share many of the characteristics of this compound. It is in phase II clinical trials [181]. Lurotecan (4.8) is more cytotoxic than topotecan [182], but initial clinical studies failed to show any clear advantage over topotecan. A liposomal formulation of the drug known as OSI-211 did however give encouraging results, and responses were observed in a phase I trial in patients with solid malignancies [183]. Exactecan (4.9) is a potent water soluble analog that is active in vitro against tumors resistant to topotecan and irinotecan [184]; it is currently in phase II clinical trials. Gimatecan (4.10) has shown excellent cytotoxicity, and it is currently in phase I clinical trials [185]. CKD-602 (4.11) has better water solubility and lower toxicity than camptothecin, and is more potent against several cell lines [181]. It is in phase II clinical trials, where responses have been seen in patients with stomach and ovarian cancer [181]. Karenitecin (BNP-1350) (4.12) is a lipophilic compound that is more cytotoxic than camptothecin both in vitro and in vivo. It has enhanced oral bioavailability. Its lactone ring is also more stable than those of most other analogs, which could be clinically advantageous. Having completed phase I clinical trials for pancreatic and colorectal cancer, it is currently in phase II clinical trials [181]. Diflomotecan (BN-80915) (4.13) is the only homocamptothecin analog in clinical trials; the extra

17

carbon in the lactone ring gives it enhanced stability. Diflomotecan showed strong antiproliferative activity towards a panel of tumor cell lines, including MDR cell lines, and was also active at low doses in several human tumor xenografts. It is currently undergoing phase I clinical trials in Europe [181, 186–188].

1.4.9 Conclusions The major importance of camptothecin and its analogs is that they represent a new class of antineoplastic agents with a previously unknown mechanism of action. They are thus of considerable interest, and studies continue to offer meaningful insights into the drug nearly 40 years after Wani and Wall first reported its structure. The most promising of the current analogs is irinotecan, which is the only new cytotoxic drug to be approved for colorectal cancer in decades, and it is presently the drug of choice for this disease in combination with fluoropyrimidines. The biochemical basis of camptothecin activity is now well understood, and recent advances in the synthesis of camptothecin and its analogs allow construction of new analogs on a scale not possible previously. Novel analogs are now being reported that optimize and exploit important structural features and further expand the therapeutic potential of camptothecin. Another exciting aspect of the camptothecin analogs is that they have the potential of synergistic interactions with cell cycle inhibitors such as UCN-01 (7-hydroxystaurosporine). Thus UCN-01 selectively enhances the antiproliferative activity of camptothecin in p53-deficient cells [189], and it has been suggested that inhibitors of the enzyme checkpoint kinase 2 could be used in association with the camptothecins to increase the effectiveness of the latter drugs [190]. In addition to their intrinsic value, the camptothecin analogs have opened up the whole area of inhibitors of topoisomerase I as drug targets, and the next generation of topoisomerase I inhibitors is now beginning to enter clinical trials. These compounds lack the unstable lactone ring of camptothecin, and it will be interesting to see if any of them prove to be more clinically efficacious than topotecan or irinotecan. Whatever the outcome of these investigations, camptothecin retains its importance as the progenitor of a new class of anticancer agents.

18 Acknowledgements The author’s work on paclitaxel mentioned in Section 1.3 was supported by the National Cancer Institute (grants CA-55131 and CA-69571), and this support is gratefully acknowledged. The author is also grateful to Dr. S. M. Hecht (University of Virginia) for advice and assistance in the preparation of Section 1.4.

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154. Eng WK, McCabe FL, Tan KB, Mattern MR, Hofmann GA, Woessner RD et al (1990) Development of stable camptothecin-resistant subline of P388 leukemia with reduced topoisomerase I content. Mol Pharmacol 38:471–480 155. Kaufmann SH, Gore SD, Letendre L, Svingen PA, Kottke T, Buckwalter CA et al (1996) Factors affecting topotecan sensitivity in human leukemia samples. Ann NY Acad Sci 803:128–142 156. Rubin E, Pantazis P, Bharti A, Toppmeyer D, Giovanella B, Kufe D (1994) Identification of amutant human topoisomerase I with intact catalytic activity and resistance to 9-nitrocanmptothecin. J Biol Chem 269:2433–2439 157. Woessner RD, Eng WK, Hofmann GA, Rieman DJ, McCabe FL, Hertzberg RP et al (1992) Camptothecin hyper-resistant P388 cells: drug-dependent reduction in topoisomerase I content. Oncol Res 4:481–488 158. Garcia-Carbonero R, Supko JG (2002) Current perspectives on the clinical experience, pharmacology, and continued development of the camptothecins. Clin Cancer Res 8:641–661 159. Lorence A, Nessler CL (2004) Camptothecin, over four decades of surprising findings. Phytochemistry 65: 2735–2749 160. Stork G, Schultz AG (1971) The total synthesis of dlcamptothecin. J Am Chem Soc 93:4074–4075 161. Jew S-S, Kim G, Kim H-J, Roh E-Y, Park H (1996) Synthesis and antitumor activity of camptothotecin analogues. Korean J Med Chem 6:263–282 162. Thomas CJ, Rahier NJ, Hecht SM (2004) Camptothecin: current perspectives. Bioorg Med Chem 12:1585–1604 163. Ejima A, Teresawa H, Sugimori M, Tagawa H (1990) Antitumour agents. Part 2. Asymmetric synthesis of (S)camptothecin. J Chem Soc Perkin Trans 1:27–31 164. Comins DL, Nolan JM (2001) A practical six-step synthesis of (S)-camptothecin. Org Lett 3:4255–4257 165. Tagami K, Nakazawa N, Sano S, Nagao Y (2000) Asymmetric synthesis of (+)-camptothecin and (+)-7-ethyl-10-methoxycamptothecin. Heterocycles 53:771–776 166. Bennasar M.-L Zulaica E, Juan C, Alonso Y, Bosch J (2002) Addition of ester enolates to N-alkyl-2fluoropyridinium salts: total synthesis of (±)-20deoxycamptothecin and (+)-camptothecin. J Org Chem 67:7465–7474 167. Ciufolini MA, Roschangar F. (2000) Practical synthesis of (20 S)-(+)-camptothecin: the progenitor of a promising group of anticancer agents. Targets Heterocyclic Systems 4:25–55 168. Imura A, Itoh M, Miyadera A (1998) Enantioselective synthesis of 20(S)-camptothecin using an enzymecatalyzed resolution. Tetrahedron: Asymmetry 9: 2285–2291 169. Fang FG, Xie S, Lowery MW (1994) Catalytic enantioselective synthesis of 20(S)-camptothecin: a practical application of the sharpless asymmetric dihydroxylation reaction. J Org Chem 59:6142–6143 170. Jew S-S, Ok K, Kim H, Kim MG, Kim JM, Hah JM et al (1995) Enantioselective synthesis of 20(S)-camptothecin using sharpless catalytic asymmetric dihydroxylation. Tetrahedron: Asymmetry 6:1245–1248

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171. Blagg BSJ, Boger DL (2002) Total synthesis of (+)camptothecin. Tetrahedron 58:6343–6349 172. Curran DP, Josien H, Bom D, Gabarda AE, Du W (2000) The cascade radical annulation approach to new analogues of camptothecins. Combinatorial synthesis of silatecans and homosilatecans. Ann NY Acad Sci 922:112–121 173. Yabu K, Masumoto S, Kanai M, Curran DP, Shibasaki M (2002) Studies toward practical synthesis of (20S)camptothecin family through catalytic enantioselective cyanosilylation of ketones: improved catalyst efficiency by ligand-tuning. Tetrahedron Lett 43:2923–2926 174. Sawada, S, Okajima S, Aiyama R, Nokata K, Furuta T, Yokokura T et al (1991) Synthesis and antitumor activity of 20(S)-camptothecin derivatives: carbamate-linked, water-soluble derivatives of 7-ethyl-10hydroxycamptothecin. Chem Pharm Bull 39:1446–1454 175. Kingsbury WD, Boehm JC, Jakas DR, Holden KG, Hecht SM, Gallagher G et al (1991) Synthesis of water-soluble (aminoalkyl)camptothecin analogs: inhibition of topoisomerase I and antitumor activity. J Med Chem 34:98–107 176. Thomas CJ, Rahier NJ, Hecht SM (2004) Camptothecin: current perspectives. Bioorg Med Chem 12:1585–1604 177. Meng L, Liao Z, Pommier Y (2003) Non-camptothecin DNA topoisomerase I inhibitors in cancer therapy. Curr Top Med Chem 3:305–320 178. Ten Bokkel Huinink W, Lane SR, Ross GA (2004) Longterm survival in a phase III, randomized study of topotecan versus paclitaxel in advanced epithelial ovarian carcinoma. Ann Oncol 15:100–103 179. Abigerges D, Chabot GG, Armand JP, Herait P, Gouyette A, Gandia G (1995) Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients. J Clin Oncol 13:210–221 180. Sparreboom A, de Jonge MJ, Punt CJ, Nooter K, Loos WJ, Porro MG et al (1998) Pharmacokinetics and bioavailability of oral 9-aminocamptothecin capsules in adult patients with solid tumors. Clin Cancer Res 4:1915–1919 181. Kim D-K, Lee N (2002) Recent advances in topoisomerase I-targeting agents, camptothecin analogues. Mini Rev Med Chem 2:611–619

23 182. Luzzio MJ, Besterman JM, Emerson DL, Evans MG, Lackey K, Leitner PL et al (1995) Synthesis and antitumor activity of novel water soluble derivatives of camptothecin as specific inhibitors of topoisomerase I. J Med Chem 38:395–401 183. MacKenzie MJ, Hirte HW, Siu LL, Gelmon K, Ptaszynski M, Fisher B, Eisenhauer E (2004) A phase I study of OSI211 and cisplatin as intravenous infusions given on days 1:2 and 3 every 3 weeks in patients with solid cancers. Ann Oncol 15:665–670 184. van Hattum AH, Pinedo HM, Schluper HMM, Erkelens CAM, Tohgo A, Boven E (2002) The activity profile of the hexacyclic camptothecin derivative DX-8951f in experimental human colon cancer and ovarian cancer. Biochem Pharm 64:1267–1277 185. Dallavalle S, Ferrari A, Biasotti B, Merlini L, Penco S, Gallo G et al (2002) Novel 7-oxyiminomethyl derivatives of camptothecin with potent in vitro and in vivo antitumor activity. J Med Chem 44:3264–3274 186. Ulukan H, Swaan PW (2002) Camptothecins. A review of their chemotherapeutic potential. Drugs 62: 2039–2057 187. Dallavalle S, Merfini, L, Penco S, Zunino F (2002) Perspectives in camptothecin development. Exp Opin Ther Patents 12:837–844 188. Bailly C (2003) Homocamptothecins: potent topoisomerase I inhibitors and promising anticancer drugs, Critical Rev Oncol/Hematol 45:91–108 189. Shao R-G, Cao C-X, Shimizu T, O’Connor P, Kohn KW, Pommier Y (1997) Abrogation of an S-phase checkpoint and potentiation of camptothecin cytotoxicity by 7-hydroxystaurosporine (UCN-O1) in human cancer cell lines, possibly influenced by p53 function. Cancer Res 57:4029–4035 190. Pommier Y. (2004) Camptothecins and topoisomerase I: a foot in the door. Targeting the genome beyond topoisomerase I with camptothecins and novel anticancer drugs: importance of DNA replication, repair, and cell cycle checkpoints. Curr Med Chem Anticancer Agents 4:429–434

Chapter 2

The Vinca Alkaloids Nicole Coufal and Lauge Farnaes

2.1 Introduction The periwinkle plant, Cantharanthus roseus G. Don (Vinca rosea Linn.) is endemic to the island of Madagascar, and has long been ascribed a wide assortment of medicinal properties ranging from the treatment of diabetes to wound healing. Of the over fifty alkaloids present in minute quantities within the plant, only two (vincristine and vinblastine) have been isolated, synthesized, and are widely used as chemotherapeutic agents [1, 2]. The antitumor activity of the vinca alkaloids was identified by two independent groups both investigating extracts of Vinca rosea for hypoglycemic activity in the late 1950s [2, 3]. Numerous other natural alkaloids were also investigated but not pursued due to severe toxicity [4]. Now the vinca alkaloids have become part of the standard of care for more than 30 years. A number of semisynthetic derivates have since been identified and tested. Two of these, vindesine and vinorelbine, are currently used in clinical practice. A third, vinflunine, is presently in phase III clinical trials [5, 6]. These compounds are commonly administered as sulfate salts to enhance solubility and increase stability. All members of this family of molecules enact their cytotoxic activity primarily by binding to tubulin and inhibiting polymerization or extension of microtubules. Microtubules are crucial for a wide range of cellular activities, including mitotic spindles formation necessary for cell division. The naturally occurring

vinca alkaloids have been used in the treatment of a wide range of malignancies, most prominently hematological cancers such as leukemia and lymphoma, but also testicular cancer. The semi-synthetics have exhibited clinical activity against lung, ovarian, and breast malignancies.

2.2 Chemistry The vinca alkaloids are bulky molecules with closely related structures (Fig. 2.1), containing both an indole nucleus (catharanthine portion) and a dihydroindole nucleus (vindoline portion) connected by a carbon– carbon ring with variable substituents attachment to the rings. Vincristine differs from vinblastine, vindesine, and vinorelbine as it has an acetaldehyde group at the nitrogen atom at position one (see vincristine in Fig. 2.1 for numbering) in the vindoline nucleus instead of a methyl group. Vincristine, vinblastine, and vinorelbine all have a methyl ester moiety attached to carbon 3 in the vindoline nucleus while vindesine has an amide attached at this same site. Vincristine, vinblastine, and vinorelbine are all acetylated at carbon 4 while vindesine has a hydroxyl group. Vinorelbine also has a different structure in the catharanthine portion of the molecule with the 11-membered ring being replaced with a 10-membered ring by the elimination of carbon 7 .

2.3 Mechanism of Action N. Coufal () UCSD Department of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA e-mail: [email protected]

The vinca alkaloids interact with tubulin thereby disrupting the mitotic spindle apparatus [7–9]. Tubulin is usually present as a heterodimer of α-tubulin and


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26

N. Coufal and L. Farnaes 7'

N

N

N

N N H O

H 1

O O

3

N

O

O

H O

O

O

Vinblastine N

N

N

N H O O

O

OH O

O

O

Vincristine

N H O

O

N O

OH O

O

O

4

N H O

N O

OH OH NH2

Vindesine

N H O

H O O

N O

O

OH O

Vinorelbine

Fig. 2.1 The structure of the vinca alkaloids

β-tubulin each with a molecular weight of 55 kDa. The heterodimers polymerize to form microtubules which are involved in mitosis and meiosis through the formation of the spindle apparatus which separates the chromosomes. In addition microtubules are involved in cell shape, axonal transport, and secretion [10]. The biological function of microtubules is determined largely by their polymerization dynamics [11]. The two main types of dynamic behavior are “dynamic instability” and “treadmilling.” The assembly and disassembly of the microtubule polymers are regulated by the binding of tubulin and guanosine 5-triphoshpate (GTP) [12]. All microtubules have a plus end of the microtubule that polymerizes faster and thereby grows faster than the opposing minus end. Dynamic instability is characterized by changes in the length of the microtubule structure, primarily at the plus end whereas treadmilling is characterized by the movement of cellular components along a tubule that is maintained at constant length, with equal addition at the minus end and subtraction at the plus end. It has been suggested that treadmilling might be particularly important in mitosis [13]. In mitosis the microtubules form the spindle apparatus which aligns the chromosomes along the metaphase plate and then pulls the chromosomes apart during the mitotic process.

All the vinca alkaloids bind to tubulin with high affinity and inhibit further polymerization. Since microtubules are in a constant dynamic state of polymerization and depolymerization the inhibition of polymerization by the vinca alkaloids functions to create a state of net depolymerization. The interaction of the vinca alkaloids with the microtubules of the spindle apparatus disrupts the spindle apparatus and leads to metaphase arrest. Vinorelbine, vincristine, and vinblastine have all been shown to possess roughly equal tubulin binding constants [8] and cause metaphase block at roughly the same concentrations. It has been suggested that the differences in the relative potencies of the vinca alkaloids may not be due to their binding efficiencies but rather to differences in their intracellular retention times or the stability of the drug-tubulin complexes [14]. In addition, vincristine is a much more potent inhibitor of axonal microtubule formation [15]. While the disruption of the mitotic process is the key feature of the vinca alkaloids the final effect of this metaphase arrest is the death of the cell through activation of apoptotic pathways [16, 17]. In vitro experiments with these agents have shown that exposure can lead to apoptosis through both p53-dependent and p53-independent pathways [18–20]. Tumor cells that have been exposed to the agents show characteristic morphological and molecular changes that are

2

The Vinca Alkaloids

associated with the induction of apoptosis in a dose and time dependent fashion. Since the drugs attempt to induce apoptosis by halting the cell in mitosis, cytotoxicity is strongly dependent on the duration of exposure. A number of other cellular effects beyond microtubule inhibition have also been reported for the vinca alkaloids. These include inhibition of amino acid metabolism [21], calmodulin-dependent Ca2+ ATPase activity [22], nucleic acid synthesis [4]. In order to achieve these other effects though the concentrations of the drugs had to be at much higher levels than are achieved in vivo.

2.4 Clinical Use The vinca alkaloids are broad acting mitotic inhibitors used in the treatment of numerous malignancies [23]. They have been used for both curative and palliative aims in the treatment of a variety of tumors, most often Hodgkin’s disease, acute lymphocytic leukaemia, testicular cancer, breast carcinoma, ovarian cancer, and non-small-cell lung cancer (NSCLC). Other malignancies treated with vinca alkaloids include Wilms’ tumor, Ewing’s sarcoma, neuroblastomas, hepatoblastoma, and rhabdomyosarcoma. Vincristine is part of a front-line therapy for the treatment of acute lymphocytic leukaemia. It is also commonly used in pediatric oncology owing to the higher level of sensitivity of pediatric malignancies and the better tolerance of therapeutic doses in children. Vincristine is also a standard treatment for non Hodgkin’s lymphoma as part of the chemotherapy regimen CHOP (Cytoxan, Hydroxyrubicin (Adriamycin), Oncovin (Vincristine), Prednisone) [24] and as a treatment of Hodgkin’s lymphoma as part of MOPP or COPP. Vincristine is also generally used in the treatment of multiple myeloma as a bolus or daily infusion in combination with doxorubicin and dexamethasone [25]. Vinblastine is used in combination with other agents as a front-line therapy for the treatment of Hodgkin’s disease and testicular cancer. It is also approved for use as a single agent or in combination with cisplatin for the treatment of NSCLC and advanced breast cancer [26, 27]. Vindesine is used in combination with other agents, such as mytomycin C and/or platinating agents in the treatment of

27

NSCLC [28]. Vinorelbine is the only vinca which can be administered orally, and resistance to vinorelbine develops more slowly and is less cross-resistant with resistance to vincristine and vinblastine. Vinflunine is currently being investigated for use in the treatment of metastatic breast cancer and NSCLC trials [5, 6]. The vinca alkaloids are routinely administered by direct intravenous injection. They are extreme vesicants (see Section 2.8) so are often administered as a rapid bolus. Vinorelbine can be administered orally. The single dose cap for vincristine is 2.0 (mg/m2 ) due to substantial neurotoxicity reported at higher doses. However, significant interpatient variability exist, and some patients can tolerate much higher doses with limited toxicity [29, 30]. For vinblastine, initial dose recommendations are 2.5 and 3.7 mg/m2 for children and adults, respectively, with gradual dose escalation based on hematologic tolerance. Vinesine has been evaluated for weekly and biweekly administrations, and is most commonly administered at 2–4 mg/m2 every 7–14 days [27]. Additionally, prolonged infusion schedules have been evaluated to increase the critical threshold concentration of vincristine, vinblastine, and vindesine, and all indicate an increased dose can be administered safely without major toxicity for 1–2 days (vindesine) or up to 5 days (vincristine) [27]. However, there is little evidence that prolonged infusions are more effective than bolus schedules. Vinorelbine is most commonly administered at a dose of 30 mg/m2 weekly or biweekly. It can be administered as a slow infusion or bolus, although evidence indicates decreased local venous toxicity with a bolus [31].

2.5 Mechanisms of Resistance Resistance to the vinca alkaloids develops rapidly and can occur through alterations in numerous cell pathways. For chemotherapeutic agents, resistance is commonly due to decreased drug accumulation and retention within target tumor cells. The most widely documented mechanism of vinca alkaloid efflux is by members of the ATP-binding cassette (ABC) transporter family, a huge gene family of transmembrane transporters which efflux large endobiotic and xenobiotic compounds from cells in an ATP dependent fashion. Resistance via multidrug resistance channels

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(MDR) can be innate or acquired. These transporters not only confer resistance to the vinca alkaloids, but also to a variety of other well known pharmacologic agents such as taxanes, anthracyclines, epipodophyllotoxins, dactinomycin and colchicine [32]. The two most investigated members of this family in regards to vinca alkaloid resistance are the permeability glycoprotein (P-gp)/MDR1 endcoded gene product (ABC subfamily B1;ABCB1) and the multidrug resistance protein MRP (ABC subfamily C2; ABCB1) [33–37]. Although these two transport systems have the same end result, they appear to utilize slightly different mechanisms. For instance, P-gp vesicles have been shown to directly transport vinca alkaloids, whereas MRP vesicles transport in a glutathione dependent fashion [34]. MDR1 is a 170-kD P-gp transmembrane pump that regulates efflux of large amphipathic hyrdophic substances in an energy dependent fashion. Drug resistance is proportional to the amount of channel present in the cell membrane [36]. Innate resistance is offered by tissues which constitutively express a high amount of the channel, such as endothelium and epithelial tissue, especially renal epithelium and colonic endothelium [38]. This channel is highly expressed in tumors arising from constitutively expressing tissues (kidney and colon cancer). Secondarily tumors can overexpress MDR1 or related ABC transporters as a result of treatment with vinca alkaloids, a phenomenon which has been observed in post-treatment leukemia, lymphoma, and multiple myeloma. MRP is a 190-kD transmembrane protein with a 15% homology to MDR1 which has been shown to mediate vinca alkaloid resistance as well as resistance to other chemotherapeutic agents such as methotrexate [32, 39–41]. Although many other ABC transporters have been characterized and implicated in vinca alkaloid resistance, their role is even less apparent than that of MDR1 and MRP. One important feature of MDR1 and MRP resistance is that is reversible in specific conditions, such as after treatment with calcium channel blockers, detergents, progesterone or estrogenic antagonists, antibiotics, antihypertensives, antimalarials, antiarrhythmics, and immunosuppressives [32]. All of these agents bind directly to the channel and inhibit efflux, thereby increasing intracellular concentrations of chemotherapeutic agents. To date the usefulness of this observation has been limited as these agents also act to enhance drug uptake into normal cells,

N. Coufal and L. Farnaes

thereby decreasing biliary elimination and decreasing drug clearance, ultimately lead to enhanced toxicity [42–44]. In addition, MDR1 has been shown to respond to environmental stress by producing multiple alternative proteins, which could explain the unsatisfactory outcomes from pharmacologic modulations efforts thus far [32]. Other mechanisms of resistance to the vinca alkaloids have also been identified, although primarily in preclinical models. Each of these represents a different modification in the mechanism of vinca alkaloid action or of downstream signaling to allow the tumor cell to escape programmed cell death. For instance, changes in tubulin expression or tubulin binding [45] can lead to resistance. Resistant tumors have been found to contain mutations which lead to amino acid substitutions or posttranslational modifications such as acetylation or phosphorylation and thereby change the structure of tubulin [46, 47]. Although the mechanism of resistance in these cases is not entirely clear, it is thought to be as a result of hyper-stabilization of tubulin rather than a change in the drug binding affinity of the vinca alkaloids [48]. In addition, changes in heat shock response [49] or alterations in apoptotic signaling allowing cells to escape apoptosis [50, 51]. Typically apoptosis in response to the vinca alkaloids is initiated through a lengthy set of signaling pathways comprising c-jun and stress-activated protein kinase activation [19]. Therefore, overexpression of anti-apoptotic genes such as Bcl-2 and Bcl-XL has been shown to afford resistance to a wide assortment of chemotherapeutic agents including vincristine and vinblastine [52, 53].

2.6 Pharmacokinetics Pharmacokinetic data on the vinca alkaloids has been hampered by a lack of sensitive, specific, and reliable detection methods in the past. Since the vinca alkaloids are given in such minute amounts it had been necessary to trace them with radioactively labeled drugs. This was a difficult process as the vinca alkaloids can be somewhat unstable and rapidly form degradation products which can be separated by highpressure liquid chromatography (HPLC) [54]. In an effort to further understand the distribution of the vinca alkaloid, radioimmuno assay and enzyme-linked immunosorbent assay (ELISA) have been developed that can observe the vinca alkaloids in the picomolar

2

The Vinca Alkaloids

29

concentraton range [27]. These assays were originally performed with polyclonal antisera which were hampered by reactions with possible metabolites but in the interim monoclonal antibodies were raised which have allowed for more precise tracking of the vinca alkaloids in vivo. The vinca alkaloids are most commonly given intravenously by bolus injection or brief infusion and their pharmacokinetic profile most closely fits a three compartment model [27]. Characteristics of the vinca alkaloids include large volumes of distribution, high clearance rates, long terminal half lives (T1/2 ), significant hepatic metabolism, and biliary/fecal metabolism. With a normal adult dose peak plasma concentrations of 100–500 nmol are maintained for only a few minutes with concentrations of 1–2 nmol persisting for longer durations [55, 56]. There can be a significant variation in the pharmacokinetics of these drugs in different patients. This may be due to variations in protein or tissue binding, hepatic metabolism and/or biliary clearance [57]. Although prolonged infusion schedules may help to avoid excessively toxic peak concentration levels and increase the duration of drug exposure, there is no evidence that prolonged infusion schedules are more effective than bolus schedules [58]. Vincristine, vinblastine, and vindesine are only given by an intravenous route but vinorelbine can be given both by intravenous and oral routes. Oral absorption of vinorelbine is rapid with maximal drug concentrations achieved in 1–2 h with an absolute Table 2.1 Properties of the vinca alkaloids Vincristine

bioavailability of approximately 27% with a range of 10–60% [58] when given in soft gelatin capsules. The oral clearance of vinorelbine approaches hepatic flow (0.8 L/H/Kg) suggesting a significant first-pass effect. Due to the large first pass effect, oral doses may need to be up to three times larger than intravenous doses to achieve the same effect. In addition the bioavailability of oral vinorelbine may be lowered slightly by food [59] (Table 2.2). The vinca alkaloids all bind strongly to plasma proteins including albumin, lipoproteins, and α1-acid glycoprotein [61]. The primary binding protein for the vinca alkaloids is α1-acid glycoprotein with an approximately 10 fold higher affinity for these compounds than for albumin [62, 63]. At drug concentrations similar to those achieved in vivo protein binding of vincristine and vinblastine is 99% suggesting that the total binding sights for the vinca alkaloids are saturatable [64]. In addition to the binding of vinca alkaloids to serum proteins the vinca alkaloids also rapidly bind to platelets and lymphocytes after intravenous infusion [61, 65]. Platelet bound drug accounts for approximately 80% of the blood bound drug. The distribution of the drug into platelets and lymphocytes is 1/2 h for vinorelbine, 1 h for vinblastine, and 3 h for vincristine [61, 65]. Since the binding of the drug to platelets is a reversible process and the release of vincristine is much slower than it is vinblastine or vinorelbine this may explain the differences in their respective T1/2 (see Table 2.1).

Vinblastine

Vindesine

Vinorelbine

Mechanism of action

Low concentrations inhibit changes in microtubule length (treadmilling and dynamic instability) whereas high concentrations inhibit polymerization of tubulin Standard Dose (mg/m2 ) 1–1.4 every 3 weeks 6–8 every week 3–4 every 1–2 weeks 15–30 every 1–2 weeks Route of administration Intravenous Intravenous Intravenous Intravenous, oral Metabolism Predominantly P450 Predominantly P450 Predominantly P450 Predominantly P450 IIIA IIIA IIIA IIIA Elimination Biliary/Fecal Biliary/Fecal Biliary/Fecal Biliary/Fecal Terminal half-life (h) (T1/2 ) 95 (range 19–155) 25 (range 7–47) 24 (range 12–42) 33 (range 14–44) Principal toxicity Peripheral Neuropathy Neutropenia Neutropenia Neutropenia Table 2.2 Disposition of vinca alkaloids by bolus injection in patients with normal organ function [60] Volume of Elimination Fecal Clearance distribution (l/kg) half-life (h) Clearance (l/h/kg) (%)

Renal Clearance (%)

Vincristine Vinblastine Vindesine Vinorelbine

4–13.5 5.5–34 4–19 3.3–24.6

7.2 (3.1–11.0) 24.7 (17.3–35.1) 8.6 (6.8–10.5) 54.3 (44.7–75.6)

45.1 (8.2–144) 25.6 (19.6–29.2) 23.6 (19.0–34.8) 41.2 (31.2–62.4)

0.16 (0.1–0.3) 0.79 (0.7–0.9) 0.22 (0.1–0.3) 0.95 (0.8–1.3)

69 25–41 ND 40–58

30

Animal studies using radiolabeled drugs show that, following intravenous administration the vinca alkaloids are rapidly and widely distributed throughout the body [66–70]. After treatment with radiolabeled vincristine, vinblastine, or vindesine radioactivity is concentrated in the spleen, liver, kidney, lymph nodes, and thymus. Moderate levels are found in lungs, heart, and skeletal muscle. Brain and fat contain low levels. Not all of these studies were able to clearly distinguish between drug and degradation products. Vinorelbine also accumulates in the spleen, liver, kidney, and to very high levels in the lungs. Tracing the distribution of radioactively labeled vinorelbine in patients shows that the concentration of drug in the lungs may be up to 300 times greater than that in the serum and 3.4–13.8 fold higher than the lung concentration that is achieved by vincristine or vindesine [71]. This higher concentration of vinorelbine in the lungs is a primary reason for its preferential use in the treatment of non-small cell lung cancer. In addition, vinblastine is more actively sequestered in tissue than is vincristine as demonstrated by a retention of 73% of radioactivity in the body six days post-treatment [72]. The vinca alkaloids have poor penetration into the central nervous system (CNS). Although these drugs have a high lipophilicity their extensive lymphocyte, platelet and protein binding prevents them from penetrating the blood brain barrier (BBB). Additionally, since the vinca alkaloids are substrates for permeability glycoprotein (P-gp) and this protein is an active part of the blood brain barrier, any vinca alkaloid that does pentrate the BBB is actively removed. It has been found that mice that lack P-gp have a 22 fold higher accumulation of the vinca alkaloids when compared to mice that express wild-type P-gp [73]. Accumulation and uptake of the vinca alkaloids shows a direct correlation to their respective lipophilicities. Since vinorelbine is the most lipophilic of the vinca alkaloids it also exhibits the most liver uptake of the vinca alkaloids [74]. In vitro experiments using freshly isolated hepatocytes have shown that vincristine, vinblastine, vindesine, and vinorelbine are almost totally converted to water soluble metabolites which are then excreted into the extracellular fluid [56, 70, 75]. The nature of the metabolites that have been identified so far suggest that the vinca alkaloids are metabolized by the hepatic cytochrome P-450 mixed function oxidase CYP3A [26, 54, 56, 76–78]. The importance of CYP3A


in the metabolism of the drug is the observation of increased clearance of the drug when used in conjunction with drugs that induce CYP3A, such as phenytoin and carbamazepine and the incidence of increased toxicity with CYP3A inhibitors such as itraconazole [77, 79]. It also appears that the individual vinca alkaloids inhibit the biotransformation of one another indicating a common metabolic pathway that is saturable. Although few of the metabolites of the vinca alkaloids have been actively studied, low levels of deacetylated vinblastine and vinorelbine have been detected in the feces, urine and tissues of animals [80, 81]. In human patients only deacetylated vinorelbine has been observed in a very small amount in the urine. It appears though that the deacetylated metabolite of vinorelbine is equipotent to the parent compound [81]. The vinca alkaloids are primarily eliminated by the hepatobiliary system. There is some variation in the percentages of metabolites that are excreted in the feces or the urine between the various vinca alkaloids but roughly between 33 and 80% excreted in the feces with up to 40% consisting of metabolites and 12 and 30% excreted in the urine most of which is unmetabolized [26, 56, 67, 69, 72, 76, 81–84]. Vincristine is rapidly excreted into the bile with an initial bile to plasma concentration ratio of 100:1 which declines to 20:1 by 72 h post treatment [67]. As a result of compounds being eliminated through the hepatobiliary system extra care must be exercised in patients with compromised liver function such as liver metastases or cirrhosis of the liver.

2.7 Doses and Schedules The vinca alkaloids are most commonly administered by direct intravenous injection. Only experienced oncology personnel should administer these agents as extravasation causes severe soft tissue injury.

2.7.1 Vincristine Vincristine may be given to pediatric patients weighing less than 10 kg (body surface area 3.0 mg/ml. There is no dosage reduction indicated for renal dysfunction [88, 89].

2.7.2 Vinblastine Vinblastine may be given to pediatric patients on a weekly schedule starting at 2.5 mg/m2 followed by dose escalation of 1.25 mg/m2 each week based on hematological tolerance of the drug. It is not recommended to administer a dose higher than 12.5 mg in pediatric patients although most patients have myelosuppression before this dose level is reached. Adults may be given a weekly schedule starting at 3.7 mg/m2 followed by dose escalation of 1.8 mg/m2 each week based on hematological tolerance of the drug. It is not recommended to use a dose higher than 18.5 mg in adult patients although most patients have myelosuppression at submaximal doses regardless. Vinblastine is also commonly used as a bolus

31

injection of 6 mg/m2 in cyclic combination chemotherapy regimens. Because leukopenia occurring with the administration of vinblastine can vary widely with identical doses, vinblastine should not be administered more than once per week. Although there are no specific guidelines for dose reduction in patients with compromised liver function it would most likely be necessary to significantly reduce the dosage of the drugs due to the hepatic role in the clearing of these drugs.

2.7.3 Vindesine Vindesine is most commonly given as an intravenous bolus of 2–4 mg/m2 weekly to biweekly which is associated with antitumor activity and a tolerable toxicity prolfile [27]. Intermittent or continuous schedules usually infuse 1–2 mg/m2 per day for 1–2 days or 1.2 mg/m2 for 5 days every 3–4 weeks [27, 56]. As with the other vinca alkaloids a dose reduction is warranted if the patient has hepatic dysfunction.

2.7.4 Vinorelbine Vinorelbine is commonly given intravenously at dose of 30 mg/m2 as an injection using the sidearm port of a running infusion. Alternatively vinorelbine may be given as a slow bolus injection followed by flushing with 0.9% sodium chloride or a short infusion over 20 min. It appears that the shorter infusions are associated with a decrease in local venous toxicity [31]. Patients with hepatic dysfunction should be given a lower dose [90]. Dosage reductions for hepatic dysfunction include a 50% reduction in patients with serum total bilirubin between 1.5 and 3.0 mg/dl and a 75% reduction in patients with serum total bilirubin >3.0 mg/dl. As with the other vinca alkaoids dosage reductions are not indicated in patients with renal insufficiency.

2.8 Toxicity Despite the structural and pharmacologic resemblance between vinca alkaloid family members, a broad range of adverse reactions have been noted, and

32

there are striking differences in the severity and incidence of adverse reactions for each. There is no precise explanation for these side-effects, however the affinity for tubulin and the cellular uptake rate is likely the culprit. The predominant toxicity for vincristine is neurotoxicity, whereas myelosuppresion is most frequent with vinblastine, vinesine, and vinorelbine. However, peripheral neurotoxicity and myelosuppresion can be associated with any vinca alkaloid as a result of prolonged treatment, unintentional high-dose treatment, or in highly susceptible patients (e.g., individuals with hepatic dysfunction or the elderly). The ability of the vinca alkaloids to bind tightly to microtubules present in peripheral nerves, which are essential for axonal transport and secretory functions makes neurotoxicity unavoidable. Axonal degeneration and decreased axonal transport result, and can be measured as diminished amplitude of sensory and motor nerve action potentials and prolonged distal latencies [26, 91]. Despite being highly lipophilic, the large size and significant platelet and protein binding activity of these agents prevents them from crossing the blood-brain barrier. Additionally, MDR1 is highly expressed in brain capillary endothelium, resulting in drug efflux [92]. As a result, neural toxicity is primarily as a result of peripheral nerve damage, and central nervous system toxicity is rare [2]. There are numerous reports of seizures after administration, but due to low CNS penetration, are unlikely to be directly due to vinca alkaloid administration. They are more likely a result of intracranial metastasis, infection, or as a result of hyponatremia secondary to inappropriate antidiuretic hormone secretion which can be caused by vincristine [93]. Neurotoxicity as a result of vinca alkaloid treatment is characterized by peripheral, symmetric mixed sensory, motor, and autonomic polyneuropathy [26, 94, 95]. Neurotoxicity occurs as a welldocumented progression in most patients, usually beginning with asymptomatic Achilles tendon reflex loss [93], followed by paresthesias in the hands and feet. This is followed by neuritic pain, and can progress to foot drop, wrist drop, muscle pain, weakness, ataxia, and paralysis. Deficits are symmetrical and may persist for weeks or months after therapy is discontinued [93]. Rarely the cranial nerves are affected, resulting in dipolopia, hoarseness, and facial palsies. Severe jaw pain has been reported shortly


after administration, but does not usually persist [93]. Autonomic neuropathies are common, ranging from constipation, bloating, and abdominal pain to paralytic ileus in the more severe cases. Paralytic ileus, intestinal necrosis, and perforation have lead to several deaths as a consequence of vinca alkaloid treatment [93, 96]. Gastrointestinal effects are generally most severe with vincristine [2, 58]. Autonomic neurotoxicity secondary to vincristine may produce bladder atony and resulting polyuria, dysuria, and urinary retention [97]. Cardiovascular autonomic neurotoxicities have also been reported, most frequently hypertension and hypotension, but also rarely cardiac ischemia and massive myocardial infarctions when vinca alkaloids are combined with cisplatin and bleomycin [98, 99]. Frequently mild autonomic neuropathies precede more severe peripheral neuropathies. Attempts to reverse or prevent neurotoxicity have been largely unsuccessful, as a result supportive care and dose adjustments are the primary treatments [94, 100]. There has been limited success with folinic acid (not folic acid) which has been shown to protect against an otherwise lethal dose of vincristine in animal models, and used in several overdose patients [88, 89]. Also shown to have some efficacy is gluatmic acid and a mixture of gangliosides to reduce neurotoxicity [101, 102]. Patients should be routinely treated with dietary bulk, stool softeners, and laxatives to prevent severe constipation. All the vinca alkaloids have been shown to act directly on the hypothalamus, posterior pituitary, or neurohypophyseal tract (where the blood-brain barrier is the least robust) and can cause syndrome of inappropriate antidiuretic hormone secretion (SIADH). Patients who are already receiving extensive hydration are particularly susceptible to hyponatremia as a result of SIADH and can result in generalized seizures [2, 27]. Usually elevated plasma ADH levels return to normal within two to three days. Hyponatremia should be treated with fluid restriction, as SIADH would be treated from other causes. Bone marrow suppression is a common side effect of the vinca alkaloids. Leukopenia is common, peaking 5–10 days after drug administration. Extent and duration of leucopenia is dose dependent. White cell count returns to normal within 1–2 weeks, and myelosuppression is not typically cumulative. Thrombocytopenia and anemia are less common and severe, unless used in combination with radiation or

2

The Vinca Alkaloids

other agents. Leukopenia is least pronounced with vincristine, and is therefore the agent of choice if bone marrow suppression is dose-limiting. Vincristine, vinblastine, and vindesine are strong vesicants, and extreme caution should be taken in their administration to avert leakage into surrounding tissues. They should never be administered intramuscularly, subcutaneously, or intraperitoneally. Inadvertent intrathecal injection, which has occurred in clinical accidents, induces severe myeloencephalopathy including ascending motor and sensory neuropathies and rapid death [103]. It is recommended that these agents be administered as a bolus whenever possible to minimize risk of extravasation. Injection site reactions include erythema, pain, and venous discoloration. There is a risk of phlebitis if veins are not flushed after administration. If extravasation is suspected, treatment should cease, and aspiration of any residual drug attempted [104]. Extravasation has been successfully treated with corticosteroids to limit tissue damage [104]. Immediate surgical consultation to consider early debridement should be considered. Dosage modifications should be based on toxicity, although mild toxicity is acceptable in a curative setting. Severe toxicities, such as ileus and sensory, motor, and cranial nerve deficits indicate a need for dose modification. In palliative situations, modifying doses or increasing dosing intervals may be justified even with moderate neurotoxicity. Due to their hepatic clearance, vinca alkaloid dose modifications should be considered for patients with low hepatic function [100]. A 75% dose reduction is recommended for patients with serum total bilirubin levels < 3.0 mg/dL, and a 50% dose reduction for patients with plasma total bilirubin of 1.5–3.0 mg/dL [88, 89]. Dose reductions is not indicated for patients with renal dysfunction [88, 89]. Lastly, dose reductions should be considered with elderly patients, who often exhibit reduced hepatic function.

2.9 Drug Interactions Pharmacokinetic interactions have not been extensively studied. Those pharmaceuticals which are known to interact with the vinca alkaloids are primarily those which utilize the same elimination pathway, liver cytochrome P450 3A (CYP3A) metabolism. This includes drugs such as quinine, cyclosporine, and

33

nifedipine which are also substrates for CYP3A, and have been shown to inhibit vinca alkaloid metabolism in vitro [75]. Nifedipine has been shown to decrease patient’s plasma clearance of vincristine by 69% [105]. Administration of vinca alkaloids in combination with drugs which actively inhibit CYP3A, such as erythromycin and itraconazole, can lead to severe toxicity. There are several medications where administration concomitantly with vinca alkaloids can lead to excessive toxicity. For instance, the use of mitomycin C in combination with vinca alkaloids is associated with pulmonary toxicity [106, 107]. These reactions are usually either acute bronchospasm or subacute reversible cough and dyspnea 1 h after treatment. Furthermore, treatment with vinblastine in combination with either erythromycin or cyclopsorin leads to greater than predicted vincristine toxicity [108, 109]. Similarly, vincristine associated toxicity is much higher with concomitant etoposide treatment (another substrate for CYP3A) [110]. Lastly, the large degree of variability within and between individuals in vincristine pharamcokinetics has been ascribed to unpredictable CYP3A induction secondary to corticosteroid therapy [111]. Pharmaceuticals which upregulate liver enzymes may increase vinca alkaloid metabolism (e.g., phenytoin and phenobarbitol) and decrease their efficacy [112, 113]. Conversely, treatment with vinca alkaloids has precipitated seizures associated with subtherapeutic plasma phenytoin concentrations, likely as a result of CYP3A induction [86, 114]. Reduced phenytoin levels have been documented 24 h–10 days post treatment with vinblastine and vincristine.

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105. Fedeli L, Colozza M, Boschetti E, Sabalich I, Aristei C, Guerciolini R et al (1989) Pharmacokinetics of vincristine in cancer patients treated with nifedipine. Cancer 64(9):1805–1811 106. Ballen KK, Weiss ST (1988) Fatal acute respiratory failure following vinblastine and mitomycin administration for breast cancer. Am J Med Sci 295(6):558–560 107. Hohneker JA (1994) A summary of vinorelbine (Navelbine) safety data from North American clinical trials. Semin Oncol 21(5 Suppl 10):42–46; discussion 46–47 108. Samuels BL, Mick R, Vogelzang NJ, Williams SF, Schilsky RL, Safa AR et al (1993) Modulation of vinblastine resistance with cyclosporine: a phase I study. Clin Pharmacol Ther 54(4):421–429 109. Tobe SW, Siu LL, Jamal SA, Skorecki KL, Murphy GF, Warner E. (1995) Vinblastine and erythromycin: an unrecognized serious drug interaction. Cancer Chemother Pharmacol 35(3):188–190

37 110. Thant M, Hawley RJ, Smith MT, Cohen MH, Minna JD, Bunn PA et al (1982) Possible enhancement of vincristine neuropathy by VP-16. Cancer 49(5):859–864 111. Sathiapalan RK, El-Solh H (2001) Enhanced vincristine neurotoxicity from drug interactions: case report and review of literature. Pediatr Hematol Oncol 18(8):543–546 112. Crom WR, de Graaf SS, Synold T, Uges DR, Bloemhof H, Rivera G et al (1994) Pharmacokinetics of vincristine in children and adolescents with acute lymphocytic leukemia. J Pediatr 125(4):642–649 113. Chan JD (1998) Pharmacokinetic drug interactions of vinca alkaloids: summary of case reports. Pharmacotherapy 18(6):1304–1307 114. Jarosinski PF, Moscow JA, Alexander MS, Lesko LJ, Balis FM, Poplack DG (1988) Altered phenytoin clearance during intensive chemotherapy for acute lymphoblastic leukemia. J Pediatr 112(6): 996–999

Chapter 3

Taxanes and Epothilones in Cancer Treatment Edward F. McClay

There is no subject so old that something new cannot be said about it. Dostoyevsky, A Diary of a Writer (1876), 3, July–August

3.1 Introduction The discovery of compounds that bind and inhibit the function of microtubules dates back many centuries. The first compound to be used medicinally in humans, ultimately identified to have anti-microtubule properties, was colchicine. Colchicine, extracted from the plant Colchicum autumnale, was first administered to humans with gout in the sixth century A.D. [1]. After it was identified that colchicine blocked cells in metaphase, the compound became an important tool in the study of the cell cycle and mitosis [2]. The vinca alkaloids represent the first class of antimicrotubule agents to enter the field of chemotherapy [3]. They act to depolymerize the microtubule and block the cell cycle at the metaphase/anaphase junction in mitosis. Since the identification of the vinca alkaloids, there have been other anti-microtubule compounds added to the list of active chemotherapeutic agents including estramustine and the taxanes. Similar to the vinca alkaloids, the taxanes arrest cells in metaphase, however, their mechanism of action was to stabilize the microtubule and therefore they represented a new class of anticancer agents. The taxanes have been identified as amongst the most active

E.F. McClay () Melanoma Research Center, Pacific Oncology and Hematology Associates, San Diego, CA, USA e-mail: [email protected]

chemotherapeutic agents with a broad spectrum of activity against a variety of different tumors. More recently, the discovery of the epothilones has extended our armamentarium of potentially useful agents.

3.2 Microtubules Microtubules are ubiquitous in eukaryotic cells and are vital to the performance of many important cellular functions, including the maintenance of cell shape, intracellular transport, secretion, neurotransmission. Additionally, they participate in the development of the mitotic spindle, a function critically important in cell division [4, 5]. Microtubules are composed of molecules of the protein, tubulin and exist in dynamic equilibrium due to their ability to polymerize and de-polymerize as required by cellular needs. Tubulin exists as a dimmer composed of α and ß proteins, each having a molecular mass close to 50 kd, forming a tightly packed globular subunit [5, 6]. Several isoforms of both α and β tubulin exist in human cells [7, 8]. As tubulin molecules are assembled into microtubules, one α-tubulin subunit combines stoichiometrically with a β-tubulin molecule forming a protofilament. Microtubules consist of 13 protofilaments aligned in a side by side structure around a central core [9]. Each of the protofilaments is aligned with the same polarity where there is one end of the molecule


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exhibiting rapid growth while the other end is growing more slowly. Both the α- and β-tubulin molecules may undergo posttranslational modification including acetylation and detyrosylation [10]. These modifications only occur on microtubule polymers and not on individual tubulin proteins which likely account for the different functions of microtubules. In some cases the microtubule is modified in a specific region, providing a binding site for microtubuleassociated proteins. The binding of such proteins can stabilize the microtubule against disassembly and can also mediate or modulate interactions with other cellular components [11]. Microtubules are incredibly dynamic polymers, constantly undergoing modification of their structure, exhibiting a plus and a minus end. While both ends alternately grow or shorten, net growth occurs at the plus end and net shortening occurs at the minus end. Soluble tubulin binds GTP in a reversible fashion at a site on the β subunit. GTP is subsequently hydrolyzed very quickly to GDP and Pi [12]. The irreversible hydrolysis of GTP provides energy for two distinct microtubule behaviors, treadmilling and dynamic instability [13]. Treadmilling is characterized by net growth at the plus end and net shortening at the minus end occurring simultaneously. This process allows the plus end of the microtubule to probe the cytoplasm during prometaphase, forming a link with the kinetochore of the chromosome [14]. The ends of the microtubule switching stochastically between episodes of slow steady growth and rapid shortening characterize dynamic instability. Both of these functions play an important role in many microtubule-dependent cell functions. These activities appear to be critically important during mitosis and are essential for proper spindle assembly and function [13]. By modifying the activity of each of these functions, the cell can control a variety of specific activities. Modification of microtubules by proteins can also suppress these functions and likely plays a role in stabilizing the microtubule against de-polymerization, thus allowing the cell to organize its cytoplasm. Given their importance to the normal homeostasis of the cell, microtubules represent an important target for anticancer compounds.

E.F. McClay

3.3 Taxanes 3.3.1 Background The development of the taxane family of chemotherapeutic agents has had a profound effect on the treatment of patients with a variety of malignancies. Interest in the first of these compounds, paclitaxel (Taxol), began in the 1960s when a crude extract of the bark from the Pacific yew tree, Taxus brevifolia, demonstrated significant anti-tumor activity in the screening program of the National Cancer Institute. In 1971, Wani and co-workers identified Taxol as the active agent in the bark extract [15]. Initially, there was not much enthusiasm for further development of this compound because the Pacific yew was a relatively scarce, slow-growing tree found in the old growth forests of the Pacific Northwest. Additionally, the compound did not appear to be significantly more active than other compounds being tested at the same time [16]. It wasn’t until 1979 that Schiff et al. identified the unique activity of this compound [17]. Unlike the vinca alkaloids that act to inhibit tubulin assembly into microtubules, the taxanes stabilize the structure of the microtubule, preventing disassembly [18]. This discovery heralded a new class of anticancer agents, the taxoids, and resulted in significant interest in the further development of these agents. In 1986, docetaxel was semi synthetically produced at the Institut de Chimie des Substances Naturalles (Gif sur Yvette, France) through a collaborative effort between the Centre National de la Recherche Scientifique and Rhône-Poulenc Rorer [19]. Whereas Taxol was derived form the bark of the Taxus brevifolia, docetaxel was synthesizes from a noncytotoxic precursor from the needles of the Taxus baccata, a European yew [19]. In this process, 10-deacetyl baccatin III was esterified with a chemically synthesized side chain. As a result of the unique chemical structure of the taxanes, significant problems were encountered in their production and development. Developing a formulation, that would allow the delivery of these compounds intravenously, required the use of surfactant solvents. Paclitaxel required a formulation that was a

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Taxanes and Epothilones in Cancer Treatment

combination of 50% ethanol and 50% polyoxylethyR while lated castor oil surfactant (Cremophor-EL) docetaxel was formulated in a mixture of ethanol and polysorbate 80 initially and later changed to polysorbate 80 alone. In the case of paclitaxel, the addition of these agents results in an increase in measurable side effects, primarily in the form of hypersensitivity reactions (HSR), that in come cases can be life threatening. AbraxaneTM (nanoparticle albumin-bound paclitaxel, nab-paclitaxel), the most recently approved form of the taxane compounds, is an albumin-coated formulation of paclitaxel. In order to eliminate the need for the solvents required to increase the solubility of the parent paclitaxel molecule, investigators at Abraxis Bioscience Inc. coated the molecule with nanoparticles of albumin. While the molecular activity of the nabpaclitaxel molecule is the same as that for paclitaxel, the resultant 130 nm nab-molecule is better tolerated, can be administered at higher doses and can be given to a higher cumulative dose with less toxicity.

3.3.2 Mechanism of Action As a class of compounds, the taxanes exert their anti-tumor activity primarily through binding to the β subunit of tubulin causing the stabilization of the polymerized microtubule [20]. Paclitaxel binds to the N-terminal 31 amino acids of the β tubulin subunit in the microtubule but does not bind to tubulin dimers [21]. The actual site appears to be on the inside of the microtubule surface and it is likely that paclitaxel gains access to this area through small pores in the surface lattice of the microtubule [22]. This binding of paclitaxel to the microtubule results in the bundling of microtubules and the formation of a large number of mitotic spindle asters [23]. Additionally, paclitaxel alters the structure of microtubules. Microtubules formed in the presence of paclitaxel frequently have only 12 protofilaments instead of the 13 found in normal microtubules [24]. Microtubules formed in the presence of paclitaxel are extremely stable and therefore dysfunctional. Of all of the microtubule structures, paclitaxel exerts its greatest influence on the mitotic spindle. The

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stabilization of the mitotic spindle results in cell cycle arrest at the G2 /M phase. This produces a sustained mitotic block at the metaphase-anaphase boundary, resulting in inhibition of mitosis. Paclitaxel can cause this disruption of the cell cycle at concentrations much less than those required to increase microtubule mass. A small ratio of bound paclitaxel molecules to total tubulin in a microtubule is sufficient to produce a high degree of stability [25]. Paclitaxel has activities in addition to effects on microtubules. Paclitaxel as been shown to inhibit the transition from G0 to S in human fibroblasts, delay the passage of sensitive leukemia cells through nonmitotic phases of the cell cycle, inhibit many functions of human neutrophils and decrease the production of tumor necrosis factor-α receptors and release [26–29]. Exposure of human tumor cells to paclitaxel results in the phosphorylation of bcl-2 resulting in the induction of apoptosis [30]. Finally paclitaxel has demonstrated anti-angiogenesis properties. At concentrations lower than those required for tumor cell cytotoxicity, paclitaxel inhibits the proliferation of vascular endothelial cells [31]. In contrast to paclitaxel, docetaxel exerts its greatest influence on the microtubules of the centrosome. Interfering with the organization of centrosomes results in inhibition of the cell cycle in the S/G2 /M phases [3]. While paclitaxel has essentially no activity against cells in S phase, docetaxel has been shown to be extremely cytotoxic to S-phase cells [32]. Docetaxel has a higher binding affinity for β-tubulin (1.9 vs. 1.0) than paclitaxel and inhibits microtubule depolymerization at a drug concentration that is half (0.2 vs. 0.4 μM) of that required for paclitaxel [20]. Unlike paclitaxel, docetaxel does not alter the number of protofilaments incorporated into microtubules [24]. Finally, docetaxel has been shown to induce Bcl-2 phosphorylation and apoptotic cell death at concentrations that are 100-fold less than those required by paclitaxel [30]. Other studies have demonstrated that docetaxel is taken up by tumor cells in higher concentrations and is effluxed from the cell at a slower rate leading to higher retention times for docetaxel [33]. The latter has been proposed as at least part of the reason for incomplete cross-resistance between the compounds. Since the early work of McGuire et al and Mastrangelo et al. demonstrating that pre-treatment

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with certain chemotherapeutic agents enhances immunologic response to vaccinations, other compounds have been tested to determine if they have similar properties [34–36]. More recently, several investigators have begun to evaluate the effect of taxanes on immunologic response. In an animal model using HER-2/neu tolerized mice, Machiels et al. demonstrated that pre-treatment of the animals with paclitaxel actually enhanced rather than depleted T-cell precursors [37]. Pre-treatment with paclitaxel 1 day prior to vaccination resulted in a delay in tumor growth related at least in part to an increase in antigen-specific T cells. More recently, Arlen et al. demonstrated that pretreatment of patients with metastatic prostate cancer with docetaxel enhanced immunologic response to a prostate cancer specific vaccine [38]. In this study, patients with androgen-independent prostate cancer were prospectively randomized to receive either vaccine alone or vaccine following pre-treatment with docetaxel. The vaccine consisted of a vaccinia virus expressing a prostate specific antigen gene admixed with the B7.1 costimulatory gene. Of interest, patients were treated with dexamethasone along with docetaxel raising the concern that this might inhibit the ability of the patient to mount an appropriate immunologic response. Despite the inclusion of dexamethasone, the median progression free survival for patients treated with docetaxel plus vaccine was 6.1 months vs. 3.7 months for the vaccine alone arm. The molecular targets for nab-paclitaxel are the same as paclitaxel. Entry into the cell appears to be enhanced for this molecule.

3.3.2.1 Mechanism of Resistance Several mechanisms of resistance to taxanes have been proposed and demonstrated to be important over time. One of the earliest proposed mechanisms is related to the presence in some tumors, of α and β-tubulin isoforms with impaired ability to polymerize into microtubules [39]. Giannakakou et al reported that a paclitaxel resistant human ovarian cancer cell line contained mutant β-tubulin that exhibited impaired paclitaxel driven polymerization [40]. In contrast, Ranganathan et al. demonstrated that estramustine induced resistance resulted in the over-expression of Class III

E.F. McClay

β-tubulin [41]. The expression of the isoform was associated with resistance to taxanes. In general, one of the most commonly cited mechanisms of resistance to the anti-microtubule agents is the expression of the MDR phenotype, which is mediated by the presence of the 170-kd Pgp efflux pump, encoded by the msr1 gene [3, 42, 43]. Horowitz et al. was amongst the first to demonstrate paclitaxel susceptibility to this very common mechanism of resistance [44], Antimicrotubule agents are substrates for this energy dependent pump. Other mechanisms of resistance have also been proposed. Masuda el al reported a link between impairment of the mitotic spindle checkpoint and resistance to anti-microtubule agents [45]. The mitotic spindle checkpoint is activated by the presence of unattached kinetochores resulting in arrest of the cell cycle at prometaphase [46]. Activation of this checkpoint prevents abnormal chromosome segregation because of the lack of bipolar attachment of kinetochores to the mitotic spindle. Several human cancer cell lines with abnormal mitotic spindle checkpoint activity, demonstrated impaired sensitivity to anti-microtubule agents including the taxanes. As mentioned earlier, several different proteins, termed microtubule-binding proteins (MAP), have been associated with normal or abnormal microtubule function. Recently, the MAP-Tau protein has been shown to be an important predictor of paclitaxel sensitivity in patients with breast cancer [47, 48]. This observation, first made by Rouzier et al., was further investigated by Wagner et al. Gene expression profiling using Affymetrix chips, was examined in 82 patients who underwent pre-operative treatment with paclitaxel, 5-FU, doxorubicin and cyclophosphamide [48]. Tau mRNA expression was statistically significantly lower in patients who experience a pathologic complete response when compared to patients who only achieved a partial or no response. Resistance in cells with higher levels of MAP-Tau appears to be related to the fact that MAP-Tau binds to both the inner an outer surface of microtubules and binds to the same pocket on the inner surface that also binds paclitaxel [49]. Ramanathan et al have shown that nitric oxide (NO) is also an important mediator of paclitaxel cytotoxicity [50]. Agents with antioxidant activity interfered with paclitaxel cytotoxicity while inhibitors of antioxidants increased paclitaxel cytotoxicity. These authors also introduced an important concept related to cellular

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antioxidant capacity. This study demonstrated that resistance to paclitaxel is related to the total antioxidant properties of the cell rather than the level of any one antioxidant moiety. Thus, combining paclitaxel with agents that inhibit antioxidants may prove to be an important component of increasing the activity of paclitaxel. Mutation of the p53 tumor suppressor gene has been identified as one of the most ubiquitous genetic mutations found in cancer cells and has been linked to drug resistance. Van Poznak et al. retrospectively evaluated breast cancer tumor tissue from 144 patients treated with single agent paclitaxel to determine if there was any relationship between the expression of a variety of biomarkers, including p53, and response [51]. This study found no correlation between the expression of p53 and response to paclitaxel. In contrast, Schmidt et al prospectively examined tumor tissue from thirtythree patients scheduled to be treated with paclitaxel [52]. No patient with p53 mutation responded while 10 of 22 patients without mutation exhibited clinical response. The role of Her-2/neu expression and response to taxanes has also been investigated. Her-2/neu is a receptor tyrosine kinase that triggers a cascade of events that ultimately results in an increase in cell proliferation [53]. Her-2/neu is over expressed in 20–30% of breast cancers and is associated with aggressive disease and poorer survival [53, 54] Gandour-Edwards et al. found that Her-2/neu was over expressed in 71% of patients with advanced urothelial malignancies [55]. In this small study of 39 patients, elevated Her2/neu expression was associated with a non-significant increase in the response over those patients low expression. Conversely, several studies have associated elevated Her-2/neu expression with resistance to paclitaxel. Yu et al transfected Her-2/neu into MDA-MB435 human breast cancer cells and increased resistance to paclitaxel [56]. Similarly, Perez-Soler transplanted human non-small cell lung cancer cells into nude mice and tested for response to paclitaxel [57]. None of the responding animals expressed Her-2/neu while 48% of the non-responders expressed the protein, Witters et al, transfected Her-2/neu into the human breast cancer cell line MCF-7 and tested for a differential response to paclitaxel vs. docetaxel [58]. Expression of Her-2/neu significantly reduced the effectiveness of paclitaxel, while there was essentially no effect of expression on the cytotoxicity of docetaxel.

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Glutathione (GST) and its related enzymes, the glutathione S transferases are part of a major detoxification route employed by cells to metabolize xenobiotics and endogenous products of reactive oxygen species (ROS) [59]. These compounds have been shown to be an important component in metabolizing anticancer agents. Over-expression of GST’s has been associated with drug resistance in many different cancers and is a major obstacle to successful chemotherapeutic intervention in patients. Over-expression of GST is typically isozyme specific and GSTP1–1 is amongst the most frequently reported form associated with resistance in malignant tumors and cell lines resistant to anthracyclines [60]. To determine the role of this protein in the clinical response of patient with metastatic breast cancer, Arai et al. examined GSTP1 expression in clinical specimens [61]. The study included 62 patients who underwent treatment with either paclitaxel or docetaxel, correlating their clinical response with GSTP1 expression. The authors demonstrated a statistically significant difference in response in this group of patients. Those patients with absent GSTP1 exhibited a significantly higher reduction in tumor than those with GSTP1 expression. Recently, there has been increased interest in ROS and their effect on cancer initiation, progression and resistance to anti-cancer modalities [62]. Reactive oxygen species include the super anion radical (O2 − ), singlet oxygen (1 O2 ), hydrogen peroxide (H2 O2 ) and the highly reactive hydroxyl radical (OH). These species exist in all aerobic cells and are usually in balance with biochemical antioxidants. Oxidative stress occurs, when this critical balance is disrupted because of excess reactive oxygen species, depletion of antioxidants or both. Cancer cells are usually in a state of oxidative stress and therefore typically have elevated levels of ROS. Several chemotherapeutic agents have been associated with the generation of increased levels of ROS in treated cancer cells, including the taxanes [63–65]. Alexandre has recently shown that treatment of human breast cancer cells with the anti-microtubule agents paclitaxel, docetaxel and vincristine results in an increase in extracellular O2 − and H2 O 2 [65]. This increase in ROS resulted in lethal damage to non-paclitaxel treated bystander breast cancer cells. The generation of the ROS was mediated by membrane bound NADPH oxidase. Furthermore, the same author demonstrated that co-treatment of BALB/c mice implanted with CT26 human cancer cells with

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paclitaxel and mangafodipir, a superoxide dismutase mimic, resulted in an enhanced growth inhibitory effect on the malignant tumors [64]. Modulation of ROS through the use of taxanes and other like-acting compounds may prove to be an important pathway to take advantage of in the fight against cancer.

3.3.3 Pharmacology There are substantial differences in the pharmacokinetic and the pharmacodynamic profiles of the three taxanes currently used clinically. These differences are responsible for the varied delivery schedules employed for the three agents. All of the taxanes are administered intravenously, however their infusion times are different. Early in the development of paclitaxel, prolonged infusion times (6–24 h) were employed because of hypersensitivity reactions [66]. However, when patients were premedicated for these reactions, it was demonstrated that there was no difference in the occurrence of hypersensitivity reactions between the 3 and 24 h infusion times, thus allowing a shorter infusion times to be explored [67]. The taxanes are extensively metabolized in the liver by the cytochrome P-450 system. This leads to biliary excretion as the main route of elimination. It is also the reason that the dose of taxanes must be lowered in patients with elevated liver enzymes. The major fraction of metabolized taxanes is excreted in the feces as either parent drug or as hydorxylated metabolites [20]. The known metabolites of taxanes are either inactive of less active than the parent compound. Renal excretion of the taxanes is 0.05 μM. Docetaxel, in contrast, exhibits linear pharmacokinetics, and is typically administered over 1 h. Adjustments in the dose either up or down results in a proportional change in the AUC as well as the Cmax . Population pharmacokinetic studies demonstrated that the clearance of docetaxel is significantly lower with increasing age, less body surface area and decreased liver function [71]. While the action of nab-paclitaxel on microtubules is essentially the same as paclitaxel, the compound is quite a bit different from a pharmacologic perspective. Nab-paclitaxel is formulated by high-pressure homogenization of paclitaxel in the presence of human serum albumin [72]. Nab-paclitaxel is much more solR paclitaxel. uble in normal saline than Cremophor-El The solubility of nab-paclitaxel is 2–10 mg/ml compared to 0.3–1.2 mg/ml for paclitaxel. This allows a significant reduction in volume of administration and therefore also allows the nab-paclitaxel to be administered faster. Like docetaxel, nab-paclitaxel exhibits linear pharmacokinetics [73]. The properties of albumin have contributed to several other differences between paclitaxel and nabpaclitaxel that give the latter further advantage. Albumin is the natural transporter of endogenous hydrophobic molecules such as water insoluble vitamins and hormones [74]. In this context, it binds to the gp60 receptor initiating caveolar- mediated endothelial transport of protein bound and unbound plasma constituents [75]. Another unexpected benefit of nabpaclitaxel is the fact that osteonectin, also known as SPARC (secreted protein acid rich in cystine) which shares sequence homology with gp60, also binds albumin [76, 77]. A number of human tumors express SPARC, thus providing a target for nab-paclitaxel binding [42, 78–81]. Additionally, recent studies have as have shown that albumin accumulates in some tumors, likely the result of binding to SPARC, potentially facilitating the intracellular accumulation of drug [82]. This has been shown convincingly by Desai et al. [83]. The authors used a nude mouse/human R tumor xenograft model to explore Cremophor-El paclitaxel and nab-paclitaxel transport. Lung, breast, ovarian, prostate and colon tumors were implanted in nude mice and the intra-tumor concentrations and endothelial cell transport of the compounds was calculated. Using the same dose of each compound, the

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intra-tumor accumulation of nab-paclitaxel as measured by the absorption constant, was 3.3-fold greater R paclitaxel; the difference was for Cremophor-El apparent as early as 5 min after injection. Similarly, the endothelial cell binding for nab-paclitaxel was 9.9-fold greater and the endothelial transport was R 4.3-fold greater compared with Cremophor-El paclitaxel. The volume of distribution for the taxanes is significantly higher than the volume of total body water, indicating that the taxanes are extensive bound to plasma proteins and other tissue constituents. The drugs are metabolized via the cytochrome P450 system with the CYP3A, CYP2B and CYP1A isoforms playing a major role in this regard [19, 84, 85]. Early studies of this class of drugs suggested that they do not penetrate into the brain as evidenced by the fact, that detection of the compounds in the cerebral spinal fluid (CSF) was negligible [86]. However, two recent studies measuring both bound and unbound paclitaxel and docetaxel in CSF, have demonstrated cytotoxic levels of both compounds [87, 88].

3.3.4 Dose and Schedule Paclitaxel – As mentioned above, the presence of R in the formulation of paclitaxel was Cremophor-El responsible for an unusually high incidence of hypersensitivity reactions (HSR). In an attempt to lessen the frequency of this clinically problematic side effect, paclitaxel was initially administered over 24 h. In fact, this was the schedule initially approved for clinical use inpatient with ovarian cancer. Paclitaxel was administered together with steroids, diphenhydramine and a H2 blocker in an attempt to further decrease the incidence of HSR’s. Further study of schedules demonstrated that a 3-h infusion was tolerated well and demonstrated that it was equally effective as the 24h schedule [67]. Since these early studies there have been a multitude of studies using paclitaxel as a single agent as well as in combination with other compounds, Currently the most commonly employed dosing schedules for paclitaxel range from135 to 175 mg/m2 when administered as a 3 h infusion every 3 weeks. Doses up to 250 mg/m2 given as a 24 h infusion have been reported in bladder and head and neck maligR nancies [89, 90]. The presence of Cremophor-El

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also proved problematic during administration of the R can cause leaching compound. As the Cremophor-El of the polyvinylchloride out of containers or tubing, it must be administered in glass or polyolefin containers using a 0.22 μM filter and polyethylene-administration sets. One approach to decrease toxicity of various chemotherapeutic agents is to administer lower doses on a more frequent schedule [91]. In this fashion, toxicity is decreased while anti-tumor activity is maintained through the effect of dose intensity. Paclitaxel has been administered weekly both as a single agent as well as in combination regimens [92]. In single agent regimens, the dose of weekly paclitaxel ranged from 80 mg/m2 every week for 15 weeks with a 1 week rest to 175 mg/m2 weekly for 6 weeks followed by a 2 week rest [93, 94]. Overall response rates using the weekly schedule range from 22 to 78% [94, 95]. In general, the most common toxicities observed with weekly schedule include neutropenia, anemia, neuropathy, mucositis and diarrhea. Various other chemotherapeutic agents have been combined with weekly paclitaxel including anthracyclines, platinum agents, vinorelbine, and trastuzumab [96–100]. Overall response rates in patients with metastatic breast cancer have ranged from 48 to 88% with a toxicity spectrum similar to that observed with single agent weekly paclitaxel [96, 101]. Docetaxel – The every 3-week schedule of docetaxel is typically administered within a dose range between 60 and 100 mg/m2 as a 1-h infusion. As the polysorbate-80 formulation of docetaxel is less allerR used with paclitaxel, genic than the Cremophor-El it can be administered faster and without pretreatment using H1 and H2 blockers. Fluid retention, usually a minor problem, can be minimized through the use of dexamethasone. Weekly single agent docetaxel has also been the subject of intense study [92]. The dose range is quite a bit narrower for docetaxel in comparison to paclitaxel. Studies have tested docetaxel at a dose of 35–40 mg/m2 weekly for 6 weeks with 2 weeks off [102, 103]. The response rates range from 29 to 42% in patients with metastatic breast cancer with a spectrum of toxicity similar to that observed in patients treated with weekly paclitaxel [92]. Non-hematologic toxicity including alopecia, nail and skin changes, increased lacrimation resulting from cananicular stenosis and asthenia were also commonly observed [92, 104].

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Combination regimens of weekly docetaxel include anthracyclines, gemcitabine, vinorelbine and trastuzumab [105–110]. Overall response rates for weekly docetaxel combinations in breast cancer patients range from 21 to 90% with complete response rates in the 0–33% range [106, 111, 112]. Toxicity has included neutropenia, leukopenia, thrombocytopenia, alopecia, anemia, neuropathy, nausea, vomiting and diarrhea [92]. Nab-paclitaxel – As mentioned above, this novel formulation delivers paclitaxel as a suspension of albumin bound particles in saline that range in size from 130 to 150 nm. This formulation allows for the delivR obviating ery of paclitaxel without Cremophor-El, the need for pre-medication with anti-histamines and steroids, provides for a much shorter infusion time and allows the use of standard infusion sets. Nab-paclitaxel is typically administered at a dose of 260 mg/m2 as a 30 min IV infusion one a q 3-week schedule. Nyman et al. investigated the pharmacokinetics of weekly nab-paclitaxel in a phase I trial [113]. The schedule for this trial was administration weekly for 3 weeks with 1 week off. The maximum tolerated dose (MTD) for patients with minimal previous treatment was 150 mg/m2 , while heavily pretreated patients had an MTD of 100 mg/m2 . Combination regimens with nab-paclitaxel are just beginning to be reported. Moreno-Aspitia and Perez reported the experience of the North Central Cancer Treatment Group Study NO531 which was a phase I study testing the combination of weekly nab-paclitaxel and gemcitabine, while Stinchcombe et al combined carboplatin with nab-paclitaxel three different doses and schedules [114, 115].

3.3.5 Toxicity Paclitaxel – As mentioned previously, the R component is responsible for Cremophor-El the HSR’s experienced with this compound with a reported incidence of 25–30% [14]. This potentially fatal toxicity typically occurs within 10 min of starting the infusion and is manifested by dyspnea with bronchospasm, urticaria and when severe hypotension. Pre-medication with H1 and H2 blockers along with steroids has decreased the incidence of major HSR’s to less than 3% [21]. Hematologic

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toxicity, primarily in the form of neutropenia, is also a major problem with paclitaxel. The onset is typically around days 8–10 with recovery between days 15–20. Peripheral neuropathy represents the most common form of neurotoxicity. The distribution is in the usual glove-stocking pattern and is usually bilateral and symmetrical. Not uncommonly, there is loss of both large fibers important for proprioception and vibration as well as thin fibers important to temperature and pinprick. Several cardiac arrhythmias including sinus bradycardia, Mobitz type I and II, as well as third degree heart block have been observed. Myocardial ischemia, atrial arrhythmias, ventricular tachycardia and myocardial infarction have also been reported [116]. Like many other chemotherapeutic agents, paclitaxel has been associated with alopecia, nausea, vomiting, and mucositis. Paclitaxel is a vascular irritant and has been associated with radiation recall reactions [21, 117] Docetaxel – docetaxel has many side effects similar to paclitaxel, however, HSR’s are uncommon. Fluid retention characterized by edema, weight gain, pleural effusions and ascites is common and can be cumulative [19, 118]. Additionally, docetaxel is associated with a incidence of dermatologic complications including a macular papular rash on the forearms and hands as well as nail changes such as onchodystrophy, onycholysis and brittle nails [119–121]. Finally, asthenia is a complaint of 58–67% of patients and is occasionally severe enough to require a dose reduction [14, 19]. Nab-paclitaxel – Unlike the HSR’s for paclitaxel and the fluid retention for docetaxel, there does not appear to be a toxicity that is more or less unique to nab-paclitaxel. Anemia, neutropenia, alopecia and sensory neuropathy are the most commonly encountered toxicities using the q 3 week schedule [122]. A similar toxicity profile is observed with the weekly schedule [113].

3.3.6 Spectrum of Antitumor Activity As a class of chemotherapeutic agents, the taxanes have had a significant impact in several cancers. They have had their greatest effect in the treatment of breast, non-small cell lung, ovarian and prostate cancers. However, the spectrum of activity extends well beyond these cancers to include most major malignancies.

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3.3.6.1 Breast Cancer Metastatic Breast Cancer – Two prospective randomized trials have compared single agent paclitaxel to doxorubicin in patients with metastatic disease [123, 124]. Paridaens et al. randomized 331 patients between treatment with single agent paclitaxel (200 mg/m2 3h infusion q 3 weeks) and doxorubicin (75 mg/m2 IV bolus q 3 weeks) [123]. The overall response rate (ORR) for paclitaxel (25%) was inferior to the doxorubicin (41% p = 0.003) although there was no statistically significant difference in the overall survival (OS) (15.6 vs. 18.3 months). Sledge et al. randomized 739 patients between doxorubicin (d) (60 mg/m2 ), paclitaxel (P) (175 mg/m2 over 24 h) and the combination (D = 50 mg/m2 , P = 150 mg/m2 / 24 h) [124]. The ORR was 36%, 34% and 47% respectively. The comparison for the combination vs. each of the single agents was statistically significant. The medial time to treatment failure (TTF) was 5.8, 6.0 and 8.0 months respectively. Again the comparison of the combination vs. each of the single agents was statistically significant. Docetaxel has also been tested as a single agent and compared with doxorubicin in a prospective randomized fashion [125]. In this study 326 patients were randomly assigned to either docetaxel (100 mg/m2 ) or doxorubicin (75 mg/m2 ) administered every 3 weeks. Docetaxel produced a statistically significantly higher ORR (48% vs. 33%; p = 0.008) however, time to progression (TTP) and OS were similar. Single agent nab-Paclitaxel has also demonstrated significant activity in patients with metastatic breast cancer. Ibrahim et al. reported a study evaluating nabpaclitaxel in both untreated and previously treated patients [126]. In this study sixty-three patients (39 untreated for metastatic disease; 48 chemotherapy naive) received nab-paclitaxel at a dose of 400 mg/m2 as a 30-min infusion with no pre-medication. The ORR was 48% (95% CI, 35.3–60.0%) with an ORR of 64% (95% CI, 49.0–79.2%) for previously untreated patients and 21% (95% CI, 7.1–42.1%) for previously treated patients. The median time to progression was 26.6 weeks and median survival was 63.3 weeks. There were no episodes of severe hypersensitivity reactions. Toxicity was mild with neutropenia (24%) and peripheral neuropathy (11%) the most common problems encountered. Gradishar et al compared single agent nab-paclitaxel to paclitaxel in 454 previously untreated

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patients with metastatic breast cancer [127]. In this phase III study both agents were administered on an every 3-week schedule. Nab-paclitaxel has a significantly higher response rate than paclitaxel (33% vs. 19%; P = 0.001) and a significantly longer TTP (23.0 b 16.9 weeks; P = 0.006). The incidence of grade 4 neutropenia was significantly lower for nab-paclitaxel compared with paclitaxel (9% vs. 22%; P < 0.001) despite the fact that the dose of nab-paclitaxel resulted in a 49% increase in the absolute of paclitaxel. Grade 3 sensory neuropathy was higher in the nab-paclitaxel arm (10% vs. 2%; P < 0.001) but was easily managed and resolved quickly. Paclitaxel/anthracycline containing combinations have been tested in several studies with modest benefit [124, 128–130]. Only the study of Jassem et al comparing doxorubicin/paclitaxel to fluorouracil, doxorubicin and cyclophosphamide demonstrated a benefit in TTP for the paclitaxel containing regimen (8.3 vs. 6.2 months; p < 0.05) [129]. In contrast, docetaxel/anthracycline containing regimens consistently demonstrated superior response in four distinct randomized studies [131]. Three of the four studies also demonstrated a significant improvement in TTP and two studies demonstrated superior OS [132–135]. Both paclitaxel and docetaxel have been extensively studied as single agents and in combination with a variety of other compounds using a weekly schedule in patients with metastatic breast cancer [92]. In general, the weekly schedule is active for both compounds, even in heavily pre-treated patients with refractory disease. It has been shown to be safe in elderly patients and those with poor performance status and is associated with a very low incidence of severe hematologic toxicities. Blum et al investigated nab-paclitaxel using the weekly schedule in heavily taxane treated patients with metastatic breast cancer [136]. Two doses 100 and 125 mg/m2 administered on days 1, 8 and 15 of a 28-day schedule were shown to have similar response rates (14 and 16% respectively), progression free (3.0 vs. 3.5 months respectively) and overall survival (9.2 vs. 9.1 months respectively) survival. Two groups have reported studies using nabpaclitaxel in combination with other agents treating patients with metastatic breast cancer. Roy et al. combined nab-paclitaxel with gemcitabine in previously untreated patients [137]. Nab-paclitaxel (125 mg/m2 ) and gemcitabine (1000 mg/m2 ) were administered

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on days 1 and 8 of a 21-day cycle. Treatment was continued until disease progression. Fifty patients were treated with neutropenia the most frequently observed toxicity (42% grade 3 and 12% grades 4). Progression free survival and overall survival were 95 and 92% respectively. In a somewhat different approach link et al reported a retrospective review of 40 patients treated with the combination of bevacizumab and nab-paclitaxel [138]. In a group of heavily pre-treated group of women they observed an overall response rate of 48.5%. Median time to progression was 128 days in responding women with relatively modest toxicity (fatigue, neuropathy, pain and hypertension). Early Breast Cancer; Neo-adjuvant Treatment – Two prospective randomized studies have investigated paclitaxel in the neoadjuvant setting. In the Arbeitsgemeinschaft Gastorenterologische Onkologie (AGO) study, 631 patients were randomized to receive concurrent vs. sequential dose dense paclitaxel and epirubicin [139]. A benefit for sequential therapy was found. Green et al randomized 258 patients to receive paclitaxel either on a weekly schedule for 12 weeks or every 3 weeks followed by 4 cycles of fluorouracil, doxorubicin and cyclophosphamide (FAC)[140]. The weekly schedule was associated with a higher rate of pathologic complete remissions (pCR) (28% vs. 16%; p = .02) and a higher rate of breast conserving surgery (p=0.05). Several studies have investigated the benefit of docetaxel in the neo-adjuvant setting. The NSABP B-27 study compared 4 cycles of doxorubicin/cyclophosphamide (AC) vs. the same regimen followed by 4 cycles of docetaxel [141]. There was a statistically significant improvement in the pCR rate observed in the docetaxel treated group (26% vs. 14%). Achieving a pCR was associated with a significant improvement in both disease free survival (DFS) (HR, 0.45; p < 0.0001) and OS (HR, 0.33; p < 0.0001). The Aberdeen trial compared 8 cycles of cyclophosphamide, vincristine, doxorubicin and prednisone (CVAP) vs. 4 cycles of CVAP and 4 cycles of docetaxel [142]. The docetaxel-containing regimen was associated with a higher pCR rate (31% vs. 15%), 5-year DFS rate (90% vs. 72%; p = 0. 04) and 5-year OS rate (97% vs. 78%; p = 0.04). Similar findings of an improved pCR rate for docetaxel containing regimens was observed in both the German Pre-operative Adriamycin and Docetaxel Study III

E.F. McClay

and the Anglo-Celtic Cooperative Oncology Group Studies [143, 144]. Adjuvant Treatment – Henderson et al reported the results of CALGB 9344, a phase III study that compared four cycles of adjuvant adriamycin/cyclophosphamide (AC) vs. AC followed by 4 cycles of paclitaxel (175 mg/m2 q 3 weeks) in 3,121 patients with node positive breast cancer [145]. The study demonstrated a statistically significant improvement in both DFS (70% vs. 65%) and OS (80% vs. 77%) in favor of the patients receiving the paclitaxel. The addition of 4 cycles of paclitaxel resulted in a modest increase in toxicity. Similarly, NSABP B-28 randomized 3,060 patients with node-positive breast cancer to AC +/– paclitaxel (225 mg/m2 ) [146]. A statistically significant improvement in DFS but not OS was found. Martin et al., reporting for the Breast Cancer International Research Group 001, compared docetaxel, adriamycin, cyclophosphamide (TAC) to fluorouracil, adriamycin cyclophosphamide (FAC) in a prospective randomized trial in 1,491 patients with node-positive breast cancer [147]. Treatment with docetaxel resulted in a 28% reduction in the risk of relapse (p = 0.001) and a 30% reduction in the risk of death (p = 0.008). The estimated rates of overall survival at five years were 87 percent for patients treated with TAC and 81 percent for patients treated with FAC. There was a statistically significant increase in the incidence of grade 3/4 neutropenia, febrile neutropenia and infection for the TAC group, however, there were no deaths associated with this difference.

3.3.6.2 Prostate Cancer Hormone-refractory prostate cancer has proved to be a particularly difficult malignancy to treat. Until the introduction of docetaxel, there was little to be enthusiastic about in the chemotherapy world. Beginning in the 1990s, several phase I and II studies including docetaxel reported interesting response rates [148–150]. However, it wasn’t until 2004 that two phase III clinical trails were published demonstrating for the first time, a statistically significant improvement in survival of patients with metastatic prostate cancer [151, 152]. Tannock et al. reported the results of a phase III trial comparing docetaxel plus prednisone to mitoxantrone plus prednisone [151]. This study tested two

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doses and schedules of docetaxel in combination with a fixed dose of prednisone. No benefit was observed for patients treated with docetaxel administered every 3-weeks as compared with weekly schedule, however, both schedules were superior to the mitoxantrone arm. The median OS for the three arms is 19.2 vs. 17,8 vs. 16,3 months respectively [153]. Petrylak et al. and the South West Oncology Group (SWOG) conducted a phase III trial comparing the combination of docetaxel/estramustine vs. mitoxantrone/prednisone [152]. Treatment with the docetaxel-containing regimen resulted in a 20% reduction in the risk of death (hazard ratio [HR], 0.80; 95% CI 0.67–0.97). Median OS was improved for the docetaxel arm (17.5 vs. 15.6 months; logrank P = 0.020). A decline in PSA was observed in 50% of the patients treated with docetaxel vs. 27% on the mitoxantrone arm (P < 0.0001). A trend toward an improved ORR was also observed (17% vs. 11%). Together, these two studies have changed the standard treatment of patients with metastatic prostate cancer.

3.3.6.3 Lung Cancer Both paclitaxel and docetaxel have been an important part of the treatment of patients with lung cancer. For the most part, these compounds have been tested in combination with cisplatin or carboplatin and found to be effective in the previously untreated patient groups [154]. The best taxane, the best combination and the best schedule is yet to be determined and is the subject of intense investigation [155]. One-year survival rates in the range of 31–48% provided oncologists reason for optimism in an area where therapeutic nihilism was the rule. In a recent phase III study conducted by the Eastern Cooperative Oncology group (ECOG), the addition of bevacizumab to the combination of paclitaxel and carboplatin resulted in a statistically significant improvement in OS and has become the standard of care in many offices [156]. Docetaxel was the first agent approved for treatment of patients with metastatic lung cancer in the secondline setting [157]. While overall response rates were low (7–10%) the 1-year survival rates ranged from 19 to 37% [158–160]. More recently, Rizvi et al have reported their phase I/II experience with nab-paclitaxel administered on days 1, 8, and 15 of a 28-day schedule [161].

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Nab-paclitaxel administered as a dose of 125 mg/m2 was found to be active and well tolerated. The overall response rate was encouraging at 30% with a median time to progression of 5 months and medial overall survival at 11 months.

3.3.6.4 Other Cancers The combination of a platinum compound plus a taxane has been the preferred first line chemotherapy regimen for patients with ovarian cancer. In 1996, the Gynecology Oncology Group (GOG) demonstrated that the combination of paclitaxel/cisplatin was superior to cyclophosphamide/cisplatin on the basis of the following results of that trial: an overall improved response rate (73% vs. 60%; P = 0.01); an increased clinical complete response rate (54% vs. 32%); an increase in progression-free survival (PFS; 18.1 vs. 13.6 months; P < 0.001); and, most importantly, an increased overall median survival (38 vs. 24 months; P < 0.001) [162]. A subsequent GOG study demonstrated that carboplatin could be substituted for cisplatin with equivalent efficacy and less toxicity [163]. More recently the benefit of administration of chemotherapeutic agents via the intraperitoneal (IP) route has been confirmed. Armstrong et al. reported the results of another GOG study testing the benefit of IP cisplatin and IV paclitaxel vs. IV administration of both agents [164]. This study once again demonstrated the benefit of the IP route. Patients treated with IP cisplatin and paclitaxel enjoyed a statistically significant improvement of both PFS (23.8 vs. 18.3 months; logrank P = 0.05) and OS (65.6 vs. 45.7 months; logrank P = 0.03). Teneriello et al. reported the results of a phase II trial testing nab-paclitaxel in patients with recurrent peritoneal, ovarian or fallopian tube carcinomas [165]. The patients were platinum sensitive and received a dose of 260 mg/m2 on an every 3 weeks schedule. The overall response rate was 64% with 7 patients achieving a complete remission. The estimated median progression-free survival was 8.5 months. The most frequent grade 3/4 treatment-related toxicities were neutropenia (24%) and neuropathy (9%). In addition to the above, the taxanes are an important part of the chemotherapy armamentarium and are currently used to treat patients with squamous cell

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carcinoma of the head and neck, renal cell carcinoma, gastric cancer, esophageal cancer and bladder carcinoma to name a few [166–170]. To further underscore the importance of this class of anti-tumor compounds, there are at least 11 different formulations of taxanes in various stages of development ensuring that they will be important for the foreseeable future [171].

3.4 Epothilones The epothilones are a new class of anti-microtubule agents that were isolated as cytotoxic metabolites of the myxobacterium sorangium cellulosum [172]. They were originally described as antifungal macrolides; however, subsequent studies demonstrated that they stabilized microtubules at sub-micromolar concentrations [172, 173]. Similar to taxanes they induce microtubule bundling, formation of multipolar spindles and mitotic arrest [173]. Epothilones are similar to paclitaxel in that they compete with paclitaxel for binding to the microtubule and suppress the activity of these structures [174, 175]. Cell lines that are resistant to epothilones have a mutation in the β-tubulin-binding site that maps near the binding site for taxanes. This has lead to the suggestion that there is a common pharmacophore for microtubule binding. Nettles et al. using nuclear magnetic resonance spectroscopy, electron crystallography and molecular modeling derived the conformation of epothilone A in complex with β-tubulin subunits in zinc-stabilized tubulin sheets [176]. This study demonstrated that while epothilones and paclitaxel overlap in their occupation of a large common binding site, the ligands exploit the pocket in a unique and qualitatively different manner. A recent study demonstrated differences in binding between these two classes of compounds. Bode et al. found that epothilones stabilize the microtubules in Saccharomyces cervisiae whereas paclitaxel did not, demonstrating that there are differences in the binding interactions between the two compounds [177]. Taken together, these studies support the concept that the two classes of compounds have similar but unique binding sites. A variety of epothilone analogues have been synthesized and many are currently in clinical trials including patupilone (epothilone B, EPO906), ixabepilone (azaepothilone B; BMS-247550), BMS-310705 (a water

E.F. McClay

soluble semisynthetic analog of epothilone B), KOS862 (epothilone D) and ZK-EPO [178]. The natural epothilones (A and B) have significant anti-tumor activity even against taxane-resistant cell lines, however, because of their toxicity, they have met with limited success in the clinic. This has lead to the development of more then 350 semi-synthetic analogs. Modifications of the compounds near C12–13 seem to have the greatest effect on microtubule stabilizing activity [179]. The addition of a methyl group at this location yields epothilone B which is twice as potent as epothilone A in inducing microtubule polymerization [180]. To date, the epothilones have demonstrated broad spectrum activity against a variety of human malignances in cell culture and xenograft models [178]. Additionally, the epothilones are generally more cytotoxic than paclitaxel in cell culture studies with the typical IC50 values in the nano- or sub-nanomolar concentration range [181–183]. These same preclinical studies have demonstrated that there are important differences with regard to the mechanism of drug resistance between paclitaxel and the epothilones. Over-expression of p-glycoprotein has minimal effect on the cytotoxicity of epothilone B, aza-epothilone B and desoxyepothilone in cell culture models [173, 179, 181–183]. Additionally, the difference between the IC50 values for epothilones in the sensitive and p-glycoprotein expressing resistant cells are very small in comparison to the differences observed in paclitaxel-resistant cells. This suggests that the epothilones may be more active in p-glycoprotein expressing cancers. Aza-epothilone B is highly active in ovarian, colon and breast cancer xenograft models and has induced cures in the ovarian xenograft model Par-7 that is resistant to paclitaxel. Additionally, aza-epothilone B is active when administered orally. This likely relates to the fact that p-glycoprotein is expressed in the GI mucosa and therefore the absorption of paclitaxel is inhibited [184]. Point mutations in β-tubulin that confer resistance to paclitaxel do not affect epothilones. The alanine to threonine substitution at residue 364 in β-tubulin that confers resistance to paclitaxel has no effect on the sensitivity to epothilones [40, 174]. In contrast, a mutation of threonine to isolucine at residue 274 and arginine to glutamine at residue 282 in β-tubulin was found in ovarian cancer cells resistant to epothilones. Interestingly these cells are

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cross resistant to paclitaxel [185]. Similarly, desoxyepothilone resistant cells were found to have an alanine to threonine mutation in β-tubulin at residue 231 and are also cross-resistant to paclitaxel [186].

3.5 Clinical Activity of Epothiones Currently, there are five epothilones in clinical trials. The majority are either in phase I or II trials, as dose and schedule remains to be more clearly defined. Similarly, combinations regimens including epothilones are just beginning to be reported [187].

3.5.1 Ixabepilone (Ixempra) Ixabepilone is the furthest along in clinical development with regards to the number of clinical trials evaluating this compound. Due to solubility issues similar to paclitaxel, this compound is formulated R [188]. A single hypersensitivin Cremophor-EL ity reaction observed during a phase I trial at the 30 mg/m2 dose, has resulted in prophylaxis with oral H1 and H2 blockers [188]. The compound exhibits linear pharmacokinetics with an overall mean half-life of 36 h [189]. The mean steady state values for volume of distribution suggest extensive extravascular distribution. Additionally, the total body clearance did not correlate with body weight or surface area suggesting that non-BSA based dosing regimens should be explored [190]. The extent of microtubule bundling correlated well with AUC and negatively with clearance [191]. Microtubule bundling was also observed in tumor removed from a patient with a chest wall mass. The bundling was observed at 1 and 24 h after the infusion [191]. A variety if intravenous infusion schedules have been investigated to determine that best approach to the future development of this compound (Table 3.1). Phase I studies testing a single dose every 3 weeks, daily dose for 3 days every 3 weeks, a weekly schedule and a daily dose for 5 days every 3 weeks have been completed. The recommended phase II dose for the single dose every 3 weeks is 40–50 mg/m2 [178, 188, 189, 192, 193]. Dose limiting toxicity at this dose and schedule included neutropenia, peripheral

51

neuropathy, fatigue, nausea, and vomiting. For the daily × 3 and daily × 5 schedule every 3 weeks, neutropenia proved to be the dose limiting toxicity, while patients treated weekly schedules experienced neutropenia, fatigue and sensory neuropathy [190, 194–197]. In some patients, early signs of sensory neuropathic changes with increased vibration sensation were evident after only 2 cycles [189]. Two phase I studies evaluating ixabepilone in combination with other chemotherapeutic agents have been reported. Plummer et al. included ixabepilone with carboplatin while Smaletz et al. combined ixabepilone with estramustine [198, 199]. The combination arm was associated with an increased incidence of sensory neuropathy. An phase II trial that updates the estramustine combination trial included 92 chemotherapy naive patients randomized between ixabepilone alone (35 mg/m2 ) vs. the combination of ixabepilone and estramustine (280 mg PO TID × 5 days) administered every 3 weeks [200]. A PSA decline of > 50% was observed in 21 of 44 patients (48%; 95% CI, 33–64%) on the ixabepilone arm and 31 of 45 patients (69%; 95% CI, 55–82%) on the combination arm. In patients with measurable disease a PR was observed in 8 of 25 patients (32%; 95% CI, 14–50%) of patients on the ixabepilone arm and 11 of 23 patients (48%; 95% CI, 27–68%). In this previously untreated group of patients, the incidence of neuropathy was 13% on the ixabepilone arm and 7% on the combination arm. This supports the position of Gianni who has suggested that ixabepilone induced sensory neuropathy is observed much less frequently when ixabepilone is used in untreated patients [201]. To date, response has been observed in patients with melanoma, non-small cell lung cancer, (post docetaxel), ovarian cancer (post-paclitaxel) and breast cancer (both taxane naïve and refractory) [178]. Recent studies in patients with metastatic breast cancer have reported relatively low response rates for patients previously treated and resistant to taxanes (12%), and anthracyclines, taxanes and capecitabine (11.5%) [202, 203]. However, patients treated with an anthracycline based regimen (only 17% of patients had prior taxane exposure) in the adjuvant setting enjoyed a response rate of 41.5% [204]. While patients with no previous taxane exposure had an ORR of 57%. Vansteenkiste et al. randomized patients with previous platinum based treatment to receive ixabepilone either as a single dose every 3 weeks (Arm A) or as

52

E.F. McClay

Table 3.1 Representative phase I and II studies with ixabepilone Number of Phase patients Schedule Dose MTD (mg) Response (%)

Toxicity

References

6

Neutropenia, peripheral neuropathy, fatigue Neutropenia

[189, 192, 193] [190]

6–18

8–10

Neutropenia

[194]

1–30 6

25

Neutropenia, fatigue Neutorpenia, fatigue, diarrhea, nausea,vomiting Myalgia, arthralgia, neuropathy, neutropenia Neuropathy, fatigue, mucositis Neutropenia, mucositis, myalgia, arthralgia

[195–197] [207]

I

Q 21 days

7.4–64

40, 50

I

Daily × 5 q 3 weeks Daily × 3 q 3 weeks Weekly Daily × 5 q 3 weeks

1.5–8

I I II

37

II

49

Q 21 days

40

6(12)

II

126

Q 21 days

40

14(11.5)

II

164

Q 21 days

40

31(19)

a 5-day program every 3 weeks (Arm B) [205]. More than 90% of patients on both arms had previous exposure to taxanes. There was essentially no difference in the ORR of either arm (14.3% Arm A; 11.6% Arm B). While the ORR is low, it is encouraging that refractory patients respond to this compound. Additionally, based upon the experience observed in patients with breast cancer, we would expect this ORR to increase in untreated patients. In 2007, Thomas et al reported the results of a randomized prospective open-label phase III trial comparing the combination of ixabepilone and capecitabine vs. capecitabine alone in patients with metastatic breast cancer who progressed after treatment with an anthracycline and taxane [206]. Ixabepilone was administered at a dose of 40 mg/m2 every 3 weeks in combination with capecitabine (1000 mg/m2 bid × 2 weeks). The authors demonstrated an improvement in progression free survival from 4.1 months to 5.7 months (p < 0.001) in comparison to capecitabine monotherapy. As a result of this study, ixabepilone became the first epothilone to be approved for clinical use in the United States.

3.5.2 Patupilone (EPO906) Patupilone, formulated using polyethylene glycol 300, has been tested at several doses and schedules in phase I study (Table 3.2) and has entered phase II

8(22)

[208]

[202] [209]

testing. Elimination is consistent with first order kinetics and the volume of distribution suggests extensive tissue binding [210]. Consistent with this observation, investigators found tissue levels of patupilone 10-fold higher in tumor removed from a patient with a soft tissue sarcoma when compared to plasma levels [211]. Elimination is prolonged in humans with a mean terminal half-life of 4 days with essentially no renal clearance. Diarrhea has been the most commonly encountered dose limiting toxicity although nausea, vomiting and fatigue have also been encountered. In contrast to ixabepilone, significant neuropathy is uncommon and there was essentially no grade 3/4 myelosuppression [211, 212]. Early phase I combination regimens have included carboplatin, capecitabine, gemcitabine and estramustine [178]. Response has been observed in patients with breast, colon, and unknown primary and ovarian cancers. Ten Bokkel Huinink have reported their phase I experience with patupilone in women with advanced ovarian, fallopian tube and peritoneal cancers [213]. Previous experience with this compound identified diarrhea as the dose limiting toxicity therefore a standardized aggressive anti-diarrhea program was employed. The dose was escalated from 6.5 to 11 mg/m2 administered as a 20 min infusion. While the overall response rate was low (19.5%) the median duration of disease stabilization was prolonged at 15.8 months,

3


53

Table 3.2 Phase I studies of selected epothilones Drug name Schedule Dose (mg/m2 )

MTD (mg)

Toxicity

References

Patupilone

0.3–8

6

Diarrhea

[212]

0.3–3.6

2.5

Diarrhea

[222]

0.6–70

40

[216]

Weekly × 3 Q 28 days Day 1,8,15 Q 21 days Day 1 and 8 Q 21 days Q 21 days

5–30

15

Neutropenia, hyponatremia Diarrhea

[223]

5–30

15

Diarrhea, paresthesia

[224]

5–30

20

Diarrhea

[224]

9–185

120

[217]

Daily × 3 Q 21 days Weekly × 3 Q 28 days 24 or 72 h infusion Q 2 weeks Q 21 days

20–50

40

16–100

100

Gait, cognitive dysfunction Chest pain, sensory neuropathy Not observed

[218]

1–6 mg/h

Not reported

Sensory neuropathy

[225]

0.6–29

Not reached

Peripheral neuropathy, ataxia

[220]

Patupilone

BMS-310705 BMS-310705 BMS-310705 BMS-310705 KOS-862 KOS-862 KOS-862 KOS-862

ZK-EPO

5–10 min bolus Q 21 days Weekly × 6 every 9 weeks Q 21 days

Patupilone has been combined with both carboplatin and gemcitabine in phase I studies [214, 215]. These studies represent early attempts using new combinations that will require additional study.

[217]

non-small cell lung cancer experiencing a complete remission [188]

3.5.4 KOS-862 (Epothilone D) 3.5.3 BMS-310705 BMS-310705, a semi-synthetic analog of epothilone B, is water-soluble and therefore does not require R Preliminary pharmaformulation in Cremophor-EL. cokinetic studies suggest linearity across the range of doses studied with an elimination half–life of 42 h [212, 216]. No pre-medications have been used and only one hypersensitivity reaction has been encountered. This occurred in a patient receiving the compound weekly for 3 consecutive weeks and occurred despite the incorporation of steroid prophylaxis after the first episode. The dose limiting toxicities have included neutropenia and hyponatremia. Sensory neuropathy was observed at higher doses. Responses have been observed in patients with ovarian, bladder, gastric and breast cancer with one patient with

KOS-862 demonstrates linear pharmacokinetics regardless of the dose or schedule that is used [217, 218]. The mean half-life is approximately 10 h, considerably shorter than ixabepilone, patupilone or BMS310705. In phase I studies (Table 3.2), dose limiting toxicities have been primarily neurologic in nature. The symptoms most commonly appear within 1–2 days of the infusion, reverse within 1 week and do not appear to be cumulative. Response to the single agent has been observed in patients with breast, testicular, ovarian and pancreatic cancers, Phase Ib and II studies combining KOS-862 with gemcitabine, carboplatin and trastuzumab have been reported [178, 188, 219]. The trastuzumab was administered in a loading dose of 4 mg/kg followed by 2 mg/kg weekly while KOS-862 was administered as a 90 min infusion every 3 weeks

54

[219]. The KOS0862 was escalated up to 100 mg/m2 without encountering dose limiting toxicity although cumulative neurotoxicity was observed.

3.5.5 Sagopilone (ZK-EPO) ZK-EPO is a fully synthetic epothilone designed to overcome multi-drug resistance [220]. Development of this compound is in the early stages. In the reported phase I trial neuropathy was encountered and proved to be dose limiting. Response has been observed in patients with breast cancer with prolonged stable disease observed in patients with non-small cell lung cancer, cholangiocarcinoma, head and neck cancer uveal melanoma and adrenal carcinoma. More recently, Arnold et al have reported a phase I trial employing a weekly schedule [221]. Twentyseven pre-treated patients were entered onto this trial that escalated the dose from 6 to 7 mg/m2 . The dose of 5.3 mg/m2 was identified as the MTD with stable disease as the best-observed response.

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58 132. Bonneterre J et al (2004) Phase II multicentre randomised study of docetaxel plus epirubicin vs 5-fluorouracil plus epirubicin and cyclophosphamide in metastatic breast cancer. Br J Cancer 91(8):1466–1471 133. Mackey JR, Paterson A, Drix LY et al (2002) Final results of the phase III randomized trial comparing docetaxel (T), doxorubicin (A) and cyclophosphamide (C) to FAC as first line chemotherapy (CT) for patients (pts) with metastatic breast cancer (MBC). in Proc ASCO 21:35a 134. Nabholtz JM et al (2003) Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as firstline chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol 21(6):968–975 135. Bontenbal M et al (2005) Phase II to III study comparing doxorubicin and docetaxel with fluorouracil, doxorubicin, and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer: results of a Dutch community setting trial for the clinical trial group of the comprehensive cancer centre. J Clin Oncol 23(28): 7081–7088 136. Blum JL et al (2007) Phase II study of weekly albuminbound paclitaxel for patients with metastatic breast cancer heavily pretreated with taxanes. Clin Breast Cancer 7(11):850–856 137. Roy V et al (2009) Phase II trial of weekly nab (nanoparticle albumin-bound)-paclitaxel (nab-paclitaxel) (Abraxane) in combination with gemcitabine in patients with metastatic breast cancer (N0531). Ann Oncol 20(3):449–453 138. Link JS et al (2007) Bevacizumab and albumin-bound paclitaxel treatment in metastatic breast cancer. Clin Breast Cancer 7(10):779–783 139. Untch M, Konecny G, Ditsch N et al (2002) Dose-dense sequential epirubicin-paclitaxel as preoperative treatment of breast cancer: results of a randomized AGO study. Proc ASCO 21:133a 140. Green MC et al (2005) Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. J Clin Oncol 23(25):5983–5992 141. Bear HD et al (2006) Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: national surgical adjuvant breast and bowel project protocol B-27. J Clin Oncol 24(13):2019–2027 142. Hutcheon AW, Heys SD, Sarkar TK (2003) Neoadjuvant docetaxel in locally advanced breast cancer. Breast Cancer Res Treat 79(Suppl 1):S19–S24 143. von Minckwitz G et al (2005) Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: the GEPARDUO study of the German breast group. J Clin Oncol 23(12):2676–2685 144. Evans TR et al (2005) Phase III randomized trial of doxorubicin and docetaxel versus doxorubicin and cyclophosphamide as primary medical therapy in women with breast cancer: an anglo-celtic cooperative oncology group study. J Clin Oncol 23(13):2988–2995

E.F. McClay 145. Henderson IC et al (2003) Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21(6):976–983 146. Mamounas EP et al (2005) Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol 23(16):3686–3696 147. Martin M et al (2005) Adjuvant docetaxel for nodepositive breast cancer. N Engl J Med 352(22): 2302–2313 148. Pienta KJ (2001) Preclinical mechanisms of action of docetaxel and docetaxel combinations in prostate cancer. Semin Oncol 28(4 Suppl 15):3–7 149. Raghavan D (2004) Chemotherapy for prostate cancer: small steps or leaps and bounds? No huzzahs just yet! Br J Cancer 91(6):1003–1004 150. Canil CM, Tannock IF (2004) Is there a role for chemotherapy in prostate cancer? Br J Cancer 91(6):1005–1011 151. Tannock IF et al (2004) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 351(15):1502–1512 152. Petrylak DP et al (2004) Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 351(15):1513– 1520 153. Berthold DR, Pond G, de Wit R et al (2007) Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival of the TAX 327 study. Proc ASCO Abstract #147 Prostate Cancer Symposium 154. Ramalingam S, Belani C (2008) Systemic chemotherapy for advanced non-small cell lung cancer: recent advances and future directions. Oncologist 13(Suppl 1): 5–13 155. Ramalingam S, Sandler AB (2006) Salvage therapy for advanced non-small cell lung cancer: factors influencing treatment selection. Oncologist 11(6):655–665 156. Sandler A et al (2006) Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355(24):2542–2550 157. Stinchcombe TE, Socinski MA (2008) Considerations for second-line therapy of non-small cell lung cancer. Oncologist 13(Suppl 1):28–36 158. Hanna N et al (2004) Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22(9):1589–1597 159. Shepherd FA et al (2000) Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18(10): 2095–2103 160. Fossella FV et al (2000) Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 non-small cell lung cancer study group. J Clin Oncol 18(12):2354–2362

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59 179. Wartmann M, Altmann KH (2002) The biology and medicinal chemistry of epothilones. Curr Med Chem Anticancer Agents 2(1):123–148 180. Nicolaou KC et al (1997) Synthesis of epothilones A and B in solid and solution phase. Nature 387(6630):268–272 181. Lee FY et al (2001) BMS-247550: a novel epothilone analog with a mode of action similar to paclitaxel but possessing superior antitumor efficacy. Clin Cancer Res 7(5):1429–1437 182. Chou TC et al (1998) Desoxyepothilone B: an efficacious microtubule-targeted antitumor agent with a promising in vivo profile relative to epothilone B. Proc Natl Acad Sci USA 95(16):9642–9647 183. Newman RA et al (2001) Antitumor efficacy of 26-fluoroepothilone B against human prostate cancer xenografts. Cancer Chemother Pharmacol 48(4):319–326 184. Schinkel AH (1997) The physiological function of drug-transporting P-glycoproteins. Semin Cancer Biol 8(3):161–170 185. Giannakakou P et al (2000) A common pharmacophore for epothilone and taxanes: molecular basis for drug resistance conferred by tubulin mutations in human cancer cells. Proc Natl Acad Sci USA 97(6):2904–2909 186. Verrills NM et al (2003) Microtubule alterations and mutations induced by desoxyepothilone B: implications for drug-target interactions. Chem Biol 10(7):597–607 187. Forster M et al (2007) A phase Ib and pharmacokinetic trial of patupilone combined with carboplatin in patients with advanced cancer. Clin Cancer Res 13(14):4178–4184 188. Goodin S, Kane MP, Rubin EH (2004) Epothilones: mechanism of action and biologic activity. J Clin Oncol 22(10):2015–2025 189. Mani S et al (2004) Phase I clinical and pharmacokinetic study of BMS-247550, a novel derivative of epothilone B, in solid tumors. Clin Cancer Res 10(4):1289–1298 190. Abraham J et al (2003) Phase I trial and pharmacokinetic study of BMS-247550, an epothilone B analog, administered intravenously on a daily schedule for five days. J Clin Oncol 21(9):1866–1873 191. McDaid HM et al (2002) Validation of the pharmacodynamics of BMS-247550, an analogue of epothilone B, during a phase I clinical study. Clin Cancer Res 8(7):2035–2043 192. Spriggs D, Soignet SA, Bienvenu B et al (2001) Phase I first in man study of epothilone B analog BMS-247550 in patients with advanced cancer. Proc ASCO 20:108a, Abstract #428 193. Gadgeel SM et al (2005) Phase I clinical trial of BMS-247550, a derivative of epothilone B, using accelerated titration 2B design. Clin Cancer Res 11(17): 6233–6239 194. Zhuang SH et al (2005) A Phase I clinical trial of ixabepilone (BMS-247550), an epothilone B analog, administered intravenously on a daily schedule for 3 days. Cancer 103(9):1932–1938 195. Awada A, Bleiberg H, de Valeriola D et al (2001) Phase I clinical and pharmacology study of the epothilone analog BMS-247550 given weekly in patients with advanced solid tumors. Proc ASCO 20:103a, Abstract #421 196. Hao D, Hammond LA, deBono JS et al (2002) Continuous weekly administration of the epothilone-B derivative,

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211. Rubin, EH, Siu, LL, Beers S et al (2001) A phase I and pharmacokindtic trial of weekly epothiline B in patients with advanced malignancies. Proc ASCO 20:68a, Abstract #270 212. Calvert AH, O’Neill V, Twelves C et al (2001) A phase I and pharmacokinetic study of EPO906 (epothilone B), given every three weeks, in patients with advanced solid malignancies. Proc ASCO 20:108a, Abstract #429 213. Ten Bokkel Huinink WW et al (2009) Safety and efficacy of patupilone in patients with advanced ovarian, primary fallopian, or primary peritoneal cancer: a phase I, open-label, dose-escalation study. J Clin Oncol 27(19): 3097–3103 214. Forster M, Kaye S, Oza A, Sklenar I, Johri A, Cheung W, Zaknoen S, Gore M (2007) A phase Ib and pharmacokinetic trial of patupilone combined with carboplatin in patients with advanced cancer. Clin Cancer Res 13(14):4178–4184 215. Schelman W et al (2008) A phase I trial of gemcitabine in combination with patupilone in patients with advanced solid tumors. Cancer Chemother Pharmacol 62(4): 727–733 216. Mekhail T et al (2003) Phase I trial of novel epothilone B analog BMS-310705 IV q 21 days. Proc ASCO 22:130, Abstract #515 217. Piro LD, Rosen LS, Parson M et al (2003) KOS862 (Epothilone D) a comparison of two schedules in patients with advanced malignancies. Proc ASCO 22:135, Abstract #539 218. Spriggs D, Pezzulli S et al (2003) KOS-862 (epothilone D): phase I dose escalating and pharmacokinetic study in patients with advanced malignancies. Proc ASCO 22:223, Abstract #894 219. Cortes J, Gomez P et al (2006) A phase I trial of weekly combination KOS-862 (epothilone D) and trastuzumab in HER-2 overexpressing melignancies. Proc ASCO 25:2028a 220. Schmid P, Kuehnhardt D et al (2005) A phase I study of the novel, third generation epothilone ZK-EPO in patients with advanced solid tumors. Proc ASCO 24:2051a 221. Arnold D et al (2009) Weekly administration of sagopilone (ZK-EPO), a fully synthetic epothilone, in patients with refractory solid tumours: results of a phase I trial. Br J Cancer 101(8):1241–1247 222. Rubin EH et al (2005) Phase I dose-finding study of weekly single-agent patupilone in patients with advanced solid tumors. J Clin Oncol 23(36):9120–9129 223. Sessa C, Malossi A et al (2003) Phase I and pharmacokinetic study of the novel epothilone BMS-31–705 in patients with advanced solid cancer. Proc ASCO 22:519a 224. Sessa C et al (2007) Phase I clinical study of the novel epothilone B analogue BMS-310705 given on a weekly schedule. Ann Oncol 18(9):1548–1553 225. Holen KZD, Hannah AL et al (2004) Phase I study using continuous intravenous KOS-862 (Epothilone D) in patients with solid tumors. Proc ASCO 23:2024a

Chapter 4

Alkylating Agents Laurent Gate and Kenneth D. Tew

4.1 Introduction Anticancer chemotherapy along with surgery and radiotherapy represent the primary treatment modalities in cancer patients. Chemotherapy emerged during the 1940s from the work of Gilman and Phillips [71] who demonstrated the clinical utility of nitrogen mustards. These agents were derived from the deadly sulphur mustard gas developed and used as a military weapon during World War I which had been shown to be effective against squamous cell carcinoma [2]. These drugs were the first generation of anticancer agents used to treat cancer patients. Since the identification of nitrogen mustards as clinically useful anticancer agents, tremendous efforts have been made by academic scientists and pharmaceutical companies to develop new generations of alkylating agents with less toxicity and more therapeutic efficacy.

4.2 Mechanism of Action Due to their chemical properties, alkylating agents can, either directly or after biological activation react and form covalent bonds with nucleophilic centers found in DNA, RNA and proteins. Traditionally, alkylating reactions have been divided into two groups termed SN 1 (nucleophilic substitution, first order) and SN 2 (nucleophilic substitution, second order), respectively (Fig. 4.1). In the SN 1 reaction, a highly reactive

K.D. Tew () Department of Pharmacology, 173 Ashley Ave, Charleston, SC 29466, USA e-mail: [email protected]

Fig. 4.1 SN1 and SN2 reactions of alkylating agents

intermediate is initially formed and this reacts with a nucleophilic molecule to produce a covalently alkylated product. In this reaction, the rate-limiting step is the initial formation of the reactive intermediate. Therefore, the reaction exhibits first-order kinetics with regard to the concentration of the original alkylating agent, and the rate is essentially independent of the concentration of the substrate. The SN 2 alkylation reaction represents a bimolecular nucleophilic displacement. The rate of this reaction is dependent of the concentration of both alkylating agent and the nucleophilic target. Thus, this reaction follows second-order kinetics. In consequence, the drugs that alkylate via a highly reactive intermediate such as the aliphatic nitrogen mustard mechlorethamine, would be expected to be less selective in their targets than the less reactive SN 2 reagents, like the alkyl alkane sulfonate busulfan. However, there is no direct relationship between the cytoxicity of the alkylating agents and their chemical reactivity. Anticancer drugs used in chemotherapy include agents that alkylate through both SN 1 and SN 2 mechanisms. The antitumor effect of these agents is primarily based on their high reactivity with DNA. When bifunctional alkylating agents are used, this can lead


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to the formation of monoadducts and subsequently interstrand or intrastrand DNA crosslinks. In contrast, monofunctional drugs that also form covalent bonds with DNA cannot induce DNA crosslinks. Although, it has been suggested that virtually all the oxygen and nitrogen atoms of the purine and pyrimidine bases can be alkylated, usually, alkylating drugs show nucleophilic selectivity towards the N7 position of the guanine. These covalent bonds occur preferentially at G-G-C sequences, which are potential sites for various bifunctional alkylations involving guanine N7 [21]. DNA alteration will cause either cell cycle arrest to allow DNA repair or cell death if the DNA is too damaged. Based on their chemical reactivity, alkylating agents will tend to target tumor cells that proliferate quickly and are characterized by uncontrolled proliferation. However, these drugs are also toxic in normal cells (e.g. hematopoietic or gastrointestinal cells) which, due to their physiological function, divide often. This is responsible for the main side-effects of alkylating agents, including myelosuppression.

4.3 Types of Agent 4.3.1 Nitrogen Mustards Although, many nitrogen mustards have been developed and tested in preclinical models, only 5 are currently used in chemotherapy. These are mechlorethamine, cyclophosphamide, ifosfamide, melphalan and chlorambucil (Fig. 4.2). They are characterized by a bis-chloroethyl group and react with nucleophilic sites through an aziridinium intermediate (Fig. 4.3). They commonly alkylate the N7 of guanine and alternatively can react with the O6 of guanine and the N3 and N7 of adenine [45]. Mechlorethamine was the first used, with the other four derived from it by substituting the methyl group with a variety of side groups. Despite their lower intrinsic alkylating activity, these analogs have a higher therapeutic index and a broader range of clinical activity and can be administrated either orally or intravenously. In contrast to mechlorethamine that reacts spontaneously with cellular nucleophiles at physiological pH, cyclophosphamide and ifosfamide possess no alkylating activity until they are metabolically

L. Gate and K.D. Tew

activated (Fig. 4.4). Cyclophos-phamide which is the most commonly prescribed member of this family, is first activated in the liver by cytochrome P450’s which mediate its microsomal oxidation to 4-hydroxycyclophosphamide which is in spontaneous equilibrium with its tautomer aldophosphamide. This metabolite will then distribute throughout the body and because of its non-polar properties will penetrate the cell membrane. This intermediate will be further degraded into acrolein and phosphoramide mustard. The latter is a potent cytotoxic alkylating agent that will induce cell death [155, 195]. The 4-hydroxycyclophosphamide and aldophosphamide are also susceptible to oxidation by soluble enzymes to generate 4-ketocyclophosphamide and carboxyphosphamide respectively. These non-toxic metabolites which are excreted in the urine, represent about 80% of the administered cyclophosphamide [164]. In principle, phosphoramide mustard could also be spontaneously generated in the plasma. However due to its polar nature, it is not likely that it will cross the cell membrane and might not be a therapeutically meaningful reservoir for the active component of the drug. In addition, it has been shown that the other product of degradation of 4-hydroxycyclophosphamide, acrolein does not exhibit potent antitumor activity, however it is considered to be the cause of a variety of dose-limiting side effects including haemorrhagic cystitis [6, 47]. Ifosfamide was first introduced in clinical treatment in the early seventies and is an isomeric analog of cyclophosphamide. Like cyclophosphamide, it is a prodrug which undergoes the same metabolic activation, but because of the different location of the chloroethyl groups, its quantitative metabolism and subsequently its pharmacological properties differ from that of cyclophosphamide [43]. Ifosfamide is first metabolized and activated in the liver by cytochrome P-450’s to produce its active intermediates that are found in urine and plasma. Similar to cyclophosphamide, it undergoes hepatic activation into aldoifosfamide which will be degraded into acrolein and an alkylating agent [88]. The rate of hepatic activation of ifosfamide is lower than that of cyclophosphamide. Because of this, about 4 times as much drug is required to give the same cytotoxic effect as cyclophosphamide. However, this also results in a higher level of acrolein which is a dose-limiting factor. Aldophosphamide and aldoifosfamide can be further metabolized and inactivated

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Fig. 4.2 Structures of nitrogen mustards

Cl CH2CH2

Cl CH2CH2 S

N

Cl CH2CH2

Cl CH2CH2

CH2CHCOOH NH2

Sulfur mustard (bischloroethylsulfide) Cl CH2CH2 Cl CH2CH2

Melphalan

Cl CH2CH2

N-CH3

CH2CH2COOH

N

Cl CH2CH2

Mechlorethamine

Chlorambucil CH2CH2

Cl CH2CH2

O HN N

Cl CH2CH2

N

O H Cl CH2CH2 N

P

P

O

O

Cyclophosphamide

Fig. 4.3 Mechanism of alkylation by nitrogen mustards

Ifosfamide

RN

CH2CH2Cl CH2CH2

CH2CH2Cl

RN

RN

CH2CH2Cl

H2C

Nitrogen mustard

O

H 2N

N

CH2CH2Cl

O

N

CH2

N

Aziridium intermediate

H2CH2C

HN

+

Cl

NH N

NH2

DNA

(N7 - guanyl)-DNA monoadduct

H N CH2CH2

N

N

N

N

DNA

DNA

O NH N

NH2

Bis(N7 - guanyl)-DNA interstrand cross-link

by aldehyde dehydrogenase. This enzyme is highly expressed in both hematopoietic and gastrointestinal tissues and does contribute to the protection of these tissues from both cyclophosphamide and ifosfamide toxicity [44]. Melphalan is an amino acid analog that can cross cell membranes and the blood-brain barrier through an active transport system. It has been suggested that this drug uses a specific amino acid transporter to access membrane barriers [23, 182, 183]. Chlorambucil has been also used extensively in the treatment of various tumors [7, 16, 77] and since it is well tolerated it is a valuable alternative to melphalan or cyclophosphamide in patients who have drug related nausea and vomiting triggered by these drugs.

4.3.2 Aziridines Aziridine alkylating agents are characterized by an aziridine ring that is structurally similar to the iminium ring in nitrogen mustards. Because this group is uncharged in aziridines, they are less reactive than nitrogen mustards. However, the reactivity of the aziridine group is increased by protonation and thus is enhanced at low pH. The opening of the aziridine ring is believed to be responsible for the alkylating activity of the molecule. However, by comparison with the nitrogen mustards, the mechanism of action of these drugs has not been as extensively studied. Three of these drugs, thiotepa (triethylenethiophosphoramide), mitomycin C and diaziquone (AZQ) are currently used

64


Fig. 4.4 Metabolism of cyclophosphamide

NH O P

O

CH2CH2Cl

N

H

O

H

Monochloroethylcyclophosphamide

Chloroacetaldehyde

OOH

NH O N

P

NH O

CH2CH2Cl

P

CH2CH2Cl

O

O

NH O N

NH O

CH2CH2Cl

P

4-Ketocyclophosphamide

H2N N

CH2CH2Cl

Aldehyde

CH2CH2Cl dehydrogenase

CH2CH2 C O

Aldophosphamide

O

H2 N

O P

-

O

N

OH CHCH2C O O

O P

N

CH2CH2Cl CH2CH2Cl

Carboxyphosphamide

O

CH2 CH2 Cl +

CH2 CHC

CH2 CH2 Cl

Phosphoramide mustard

in chemotherapy (Fig. 4.5). Thiotepa has been frequently prescribed for the treatments of breast and ovarian carcinomas [52, 99, 168]. Thiotepa is oxidatively desulfurated by hepatic cytochrome P450’s to produce TEPA, a less cytotoxic form of the molecule [111, 122]. Both compounds are found in the patient plasma. The aziridines can be activated by enzymatic oxidation or spontaneously produce an active species that can alkylate the N1 of thymidine, O2 of cytosine, N1, N6 and N7 of adenine, and N1, N7 and O6 of guanine [106]. As previously mentioned, the N7 of guanine is the preferential site of alkylation leading to the formation of guanine-guanine and adenineguanine interstrand cross-links [11]. The formation of DNA adducts by Thiotepa can follow two pathways, the first involves a sequential reaction that leads to DNA cross-link formation (Fig. 4.6). In the second

CH2CH2Cl

O

4-Hydroxycyclophosphamide

O

CH2CH2Cl

N

P

CH2CH2Cl

O

H

CH2CH2Cl

4-Hydroperoxycyclophosphamide

OH

H2N

CH2CH2Cl

N

O

Cyclophosphamide

P

C

ClH2C

+

H

Acrolein

pathway, a hydrolytic cleavage liberates the aziridine group which induces monofunctional adducts [106] (Fig. 4.7). Mitomycin C is a natural product that has been used in the treatment of breast cancer and tumors of the gastrointestinal tract [9, 29, 80, 95]. Like the other members of the aziridine family, this drug induces DNA-crosslinks that have been suggested to be sequence specific [27, 28]. Mitomycin C undergoes reduction by cytochrome P450’s increasing its affinity for nucleophilic sites in DNA [184]. AZQ is a synthetic and lipophilic aziridine designed to cross cell membranes and the blood brain barrier. This drug has been used in cancer of the CNS and has demonstrated therapeutic activities toward those tumors [49]. AZQ has also been used in the treatment of other solid tumors and leukemia [32, 167].

4

Alkylating Agents

Fig. 4.5 Structures of aziridine alkylating agents

65 O S

H2C N

H2C

CH2

P N

CH2

N H2C

O

H3CH2COCN H H 2C N H2C

CH2

Thiotepa

CH2

N

CH2 O NCOCH2CH3 H

O

Diaziquone (AZQ) O O CH2O C NH2 OCH3

H3C H3C

N

O

NH

Mitomycin C

Fig. 4.6 Mechanisms of cross-linking by thiotepa. Alkylation and cross-linking by sequential reaction of a single aziridine group

N

S P N

S P N

+

H

N

N

HN+

N

S P N NH

+

CH2 N

N H2O

S P N

N

P N +

H2 C

+ CH2

N

N

NH2 CH2

+

N

O

N HN

N HN N

R-N

N

O NH

+

N

N

H2C CH2 N+

O NH

N-R

S P N NH CH2

+

N

N-R

N-R O

R-N

N HN

S P N +

NH2

H2C+

O + NH3

OH

S N

N-R

N-R

N

O HN

N

O HN

66 Fig. 4.7 Mechanisms of cross-linking by thiotepa. Cross-linking produced by sequencial alkylating reactions of two aziridine groups from the same parent drug

L. Gate and K.D. Tew S N

P

S

H+

N

N

+

P

HN

N

N-R

N

N

N

O HN

S N+ P NH H N

+

H +

N-R

O

S P NH N +

N-R

N

O N

N

N

N

O

N

HN

HN

N HN

S HN

P NH N

R-N

N+

N

+

O

O

NH

4.3.3 Epoxides

N-R

N

N HN

H2C

CH2Br O

The epoxides are also called hexitol derivatives (Fig. 4.8). Their reactive groups are chemically related to those of the aziridines and are believed to alkylate nucleophilic macromolecules in a similar manner. Phase I and II clinical trials have shown that dianhydrogalacticol demonstrates therapeutic activities against cancers of the CNS but was shown to be less effective against other solid tumors [38, 83, 87]. Another epoxide, dibromodulcitol has also shown some antitumor activity and is a prodrug that can be hydrolyzed to dianhydrogalacticol [83, 131].

H2 C

CHOH

CHOH

CHOH

CHOH

CHOH

CH

CHOH O

H2C

Dianhydrogalactitol

CH2Br

Dibromodulcitol

Fig. 4.8 Structures of epoxide alkylating agents

N-R

4

Alkylating Agents

67

4.3.4 Alkyl Sulfonate

O

O H3C

Busulfan (Fig. 4.9) is the major representative of this family and has been extensively used in the treatment of chronic myeloid leukemias [142]. This molecule has a higher reactivity towards thiol groups of amino acids and proteins than the other nitrogen mustards. Indeed, it has been suggested that this function could be responsible for the cytotoxic properties of busulfan [53, 132]. However, it has also been shown that this alkyl sulfonate can react with the N7 of guanine and induce DNA cross-links and that this correlates with its cytotoxicity (Fig. 4.10) [22]. Another alkyl sulfonate, hepsulfam has a higher cytotoxic activity toward L1210 in vitro and in vivo, and this correlates with an increase in DNA interstrand cross-linking [132]. Because of their strong myelosuppressive properties, due to their toxicity toward hematopoietic stem cells [65], high dose protocols with alkyl sulfonates are frequently employed in bone marrow transplant procedures [177].

4.3.5 Nitrosoureas Clinically useful nitrosoureas are derived from methylnitrosoguanidine and methylnitrosourea agents initially screened by the National Cancer Institute (NCI) and shown to exhibit antitumor activities

S

O CH2CH2CH2CH2

S

O

Busulfan

O

O O

S

H3C

CH2CH2CH2CH2CH2CH2CH2

O

O

S

CH3

O

Hepsulfam Fig. 4.9 Structure of alkyl sulfonates

against experimental mouse cancer models [157]. Structure:function studies have demonstrated that chloroethyl derivatives such as chloroethylnitrosourea (CENU), BCNU (carmustine), CCNU (lomustine) and Methyl-CCNU (semustine) had more potent anticancer activities than the parent compounds (Fig. 4.11) [86, 152]. Under physiological conditions, proton abstraction by a hydroxyl ion initiates spontaneous decomposition and activation of the molecule into a number of metabolites including an isocyanate and a highly unstable 2-chloroethyldiazene hydroxide molecule that becomes an alkylating 2-chloroethyl carbonium ion (Fig. 4.12) [102]. This reactive ion will akylate predominantly at the N7 position of guanine in a sequence dependent manner [100]. The alkylation of nitrogen in DNA yields chloroethylamino groups on the nucleotide, and these are capable through a R

O O

CH3

S

O

O H3C

O

CH2CH2CH2CH2

O

S

CH3 + H

N

H

O

O

R H

O H3C

S

O

H

CH2CH2CH2CH2

O

S CH3

H

O H3 C

S

O

CH2CH2CH2CH2 +

O

O O

Fig. 4.10 Mechanism of alkylation by busulfan

N

O O

H+ + O

S CH3

O

N

R

68


Fig. 4.11 Structures of nitrosoureas

O

ClH2CH2C

O

N

O

H

N

C

N

CH2CH2Cl

ClH2CH2C

BCNU (Carmustine)

N

O

H

N

C

N

CCNU (Lomustine)

O

ClH2CH2C

N

O

H

N

C

N

CH3

Methyl-CCNU (Semustine) O

ClH2CH2C

NH2

N

O

H

H

N

C

N

C

ACNU

O

ClH2CH2C

O

H

N

C

N

N

O

H 3C

OH O CH OH 2

Chlorozotocin OH

CH3

H

OH

N

dehalogenation step of a second alkylation to produce a DNA-DNA or DNA-protein cross-link [102]. Alkylating 2-chloroethyl carbonium ions can also alkylate at the O6 position of guanine (Fig. 4.12); this mono-functional O6 DNA adduct can be removed from DNA by O6-alkylguanine-DNA alkyltransferase, also referred to as the Mer phenotype [30, 58]. Overexpression of this enzyme increases resistance to nitrosoureas [8, 18]. In large part, the promise of nitrosoureas in early preclinical mouse studies did not translate into humans. As research on the Mer phenotype progressed an explanation for this species-specific effect became apparent. Despite the effective response (frequent cures) of mouse tumors to nitrosourea therapy, human tumors were always more resistant to the drugs. The high expression of O6-alkylguanine-DNA alkyltransferase in human tumors provided the explanation for this disparity. The relative low expression of this enzyme in mice made them more sensitive to either methyl or chloroethyl nitrosourea treatment [70]. The other product of nitrosourea decomposition is an isocyanate species. This product has been shown

N

OH

N

O

H

N

C

N

OH O CH OH 2

Streptozotocin OH

to carbamoylate a broad range of proteins with sensitive lysine residues as the primary target (Fig. 4.12). The consequence of carbamoylation is the inhibition of the activity of a variety of enzymes, including DNA polymerase [17], DNA ligase, RNA related enzymes [89, 90] and glutathione reductase [134, 135]. Despite their pharmacological activities, there is no direct link between the carbamoylation function of the isocyanate compound and the cytotoxicity of the parent drug. For example chlorozotocin and streptozotocin, have low carbamoylation activities but have a strong cytotoxic activity [4]. BCNU is currently used for the treatment of primary brain tumors [63, 129] and occasionally in the treatment of lymphomas, lung and colon cancers [42, 55, 56, 91]. CCNU and methyl-CCNU which present a greater activity against solid tumors in preclinical studies [151], are used in the treatment of brain tumors [146], lymphomas [165], gastrointestinal cancers [35]. ACNU, a more water-soluble nitrosourea has been used in the treatment of brain tumors and other solid tumors [150, 191, 193].

4

Alkylating Agents

69

Fig. 4.12 Mechanism of BCNU activation and alkylation of guanine

O C

N H

N

CH2CH2Cl

NO

ClH2CH2C

NO O

H

N

N

C

O CH2CH2Cl

HOH2 CH2C

N

C

N H

CH2 CH2 Cl

NO NOH

NOH ClH2CH2C N Chloroethyldiazene hydroxide

O

HOH2CH2C N Hydroxyethyldiazene hydroxide

N CH2CH2Cl Isocyanate

C

Protein

O N2 + OH− + +CH2CH2Cl

Protein

Cl-carbonium ion

O

N CH2CH2Cl H Carbamoylation

CH2CH2Cl

O

N

HN

H2N

C

N

DNA N7 -(chloroethyl)guanyl DNA monoadduct HN

H2N

O-CH2CH2Cl N

N

N

DNA O6 -(chloroethyl)guanyl DNA monoadduct

Streptozotocin, a natural nitrosourea isolated from Streptomyces species, is a potent antileukemic agent that, in contrast to the other nitrosoureas, presents limited myelotoxicity [153]. However, this drug has been shown to be a strong diabetogenic; because of this specific toxicity, streptozotocin has been used against islet cell carcinoma and showed significant clinical activity [116]. In order to increase the antitumor activity of the drug while keeping its bone marrow-sparing properties, a derivative of streptozotocin, chlorozotocin in which 1-methyl group was replaced by a chloroethyl group, was synthesized and tested [10]. Despite its clinical antitumor property, it induced myelosuppression in patients [34, 74, 75].

H 2N

OH-carbonium ion

CH2CH2OH N

HN N

N2 + OH– + +CH2CH2OH

N

N

DNA N7-(hydroxyethyl)guanyl DNA monoadduct HN

H2N

O-CH2CH2OH N

N

N

DNA O6 -(Hydroxyethyl)guanyl DNA monoadduct

4.3.6 Triazene Compounds Procarbazine, dacarbazine and temozolomide are three of the most commonly used members of this family of agents (Fig. 4.13). Procarbazine and dacarbazine spontaneously decompose or can be metabolized to produce methyl diazonium intermediates that can alkylate biological molecules [120]. Both drugs have been used in the treatment of Hodgkin’s disease [169]. Procarbazine is also given to patients with brain tumors [180] while dacarbazine is used in the treatment of melanomas [175]. Temozolomide (TMZ) is a relatively novel anticancer drug which undergoes spontaneous hydrolysis

70


H3C

H

H

H

O

H

CH3

N

N

C

C

N

CH CH3

H

Procarbazine O

O N

N

C

H2N NH2

N CH3

N

N

C

N

N

N

N

N

CH3 CH3

Dacarbazine

O

Temozolomide

Fig. 4.13 Structures of triazenes

to form the same active metabolite as produced from dacarbazine [162]. Because of its high bioavailability, its small size and its lipophilic properties, high amounts of TMZ are able to cross the blood-brain barrier. These pharmacologic properties have made it an agent of choice for the treatment of central nervous system malignancies [1]. This alkylating agent has demonstrated promising activity in brain tumors [1, 51, 66] and melanomas [85], but was less effective in the treatment of mesotheliomas and prostate cancers [179, 181].

4.3.7 Prodrugs of Alkylating Agents 4.3.7.1 Glutathione S-Transferase-Activated Prodrug The development of new antitumor drugs able to target preferentially, and even specifically, tumor tissues represents an emerging alternative to the standard anticancer agents currently used in chemotherapy. These new molecules are frequently inactive precursors that are preferentially activated in tumors as a consequence of the overexpression of an enzyme responsible for the metabolism of the prodrug and subsequent release of the pharmacological active form of the agent. Potential advantages of these new molecules include (1) decrease in the amount of the active chemotherapeutic agent which reaches normal

dose-limiting tissues; (2) increase in the intracellular localization and bioavailability of the active drug and (3) preferential tumor targeting. Although cyclophosphamide is an inactive prodrug, the cytochrome P450’s activation step is not localized to the targeted tumor. Other detoxification enzymes do have a less random distribution. For example, within the phase II glutathione S-transferase family, the GSTπ isoform is overexpressed with a high frequency in many tumors particularly those that are resistant to a range of alkylating drugs [170, 173]. For this reason, a prodrug, TLK286 (Telcyta) [(γ-glutamyl-α-amino-β-(2-ethyl-N,N,N,Ntetrakis(2-chloroethyl)-phosphorodiamidate)-sulfonylpropio-nyl-(R)-phenylglycine] (Fig. 4.14) was designed to be preferentially activated by GSTP1–1. In this compound, the sulfhydryl group of a glutathione conjugate has been oxidized to a sulfone, the tyrosine-7 located in the active site of GSTπ promotes a β-elimination reaction that cleaves the compound. The cleavage products are a glutathione analogue (vinyl sulfone derivative) and a phosphorodiaminidate, which in turn, spontaneously forms an aziridinium species, the actual alkylating moiety that reacts with cellular nucleophiles [103] (Fig. 4.14). The efficacy of this new compound was tested in cancer cell lines and in animal tumor models. TLK286 exhibited cytotoxic activity against a broad range of cell lines and tumors [119]. An M7609 human colon carcinoma cell line resistant to doxorubicin and an MCF-7 breast carcinoma cell line resistant to cyclophosphamide, which both expressed high levels of GSTπ, were more sensitive to TLK286 than their respective wild type counterparts. Antitumor activity was also shown in murine xenografts of M7609 expressing different levels of GSTπ, and in xenografted MX1 human breast carcinomas. The extent of the responses to this prodrug was positively correlated with the expression levels of GSTπ. In rodents, the myelosuppressive effect of this compound was found to be relatively mild, causing a marginal depletion of bone marrow stem cells, with a similarly modest depletion of peripheral white blood cells [119]. Using transfected NIH3T3 cell lines, resistance to TLK286 was associated with overexpression of the de novo glutathione synthetic enzyme, γ-glutamylcysteinylglycine synthetase (γ-GCS) and the ABC transporter with specificity for transport of glutathione conjugates, MRP. Resistance to the drug could be

4

Alkylating Agents

71

Fig. 4.14 Structure and mechanism of activation of GSTP1–1 activated prodrug TLK286

Cl

GST

Cl

Active site tyrosine residue

N

O O

TLK286

P

–

H

N

O

Cl

O S

Cl

O

O H N

H2N

COOH

N H COOH

Cl

O S

O

Cl

O H N

H 2N

O

+

COOH

N P

N H

O-

N

Cl

COOH Cl

Vinyl Sulfone Derivative

+ N

O

+

P O

Active Alkylating Agent

partially abrogated by the forced over-expression of GSTπ [125]. Interestingly, while high levels of catalase were evident in an HL60 human promyelocytic cell line made resistant to TLK286, increases in γ-GCS and MRP protein and mRNA levels were not observed [147]. However, a two-fold decreased expression of GSTP1–1 was found in the resistant cell line and this would serve to decrease the activation of the drug. Down-regulation of GSTP1–1 is the obverse of the situation most frequently described in acquired drug resistant phenotypes [166]. This result reflects the unusual principles involved in the structure:activity design of the drug. In addition, it has been shown that TLK286 inhibits the activity of DNAPK (a holoenzyme complex involved in DNA repair). Mechanistically, this inhibition was achieved through drug-induced destabilization of the interaction of the

N

Cl Cl

catalytic subunit of DNA-PK with Ku70 and Ku80, two accessory proteins required for DNA-PK function [176]. This prodrug has undergone preclinical testing, toxicology and phase I clinical analysis [148] and has shown promising antitumor activities against refractory ovarian, colorectal and small cell lung cancers in phase II trials.

4.3.7.2 Antibody- and Gene-Directed Enzyme Prodrug Therapy Antibody-directed enzyme prodrug therapy (ADEPT) is a further approach recently developed to diminish the non-specific toxicity observed with common chemotherapeutic agents by increasing the specific activation of the drug at the tumor site. Most ADEPT

72

systems incorporate a prodrug that is activated by a bacterial enzyme fused to an antibody designed to recognize specific epitopes on a cancer cell. One of the best examples of this strategy is the phenyl mustard glutamate prodrug ZD2767P (4-[N,N-bis(2-iodoethyl) amino] phenol) which is converted at the tumor site to an active bifunctional alkylating drug ZD2767D by the bacterial enzyme carboxypeptidase G2 conjugated to the F(ab’)2 fragment of the anti-CEA antibody A5B7 [160]. Upon activation, this drug induces DNA damage and DNA interstrand crosslinks and subsequently induces apoptosis in tumor cells [117, 188]. This ADEPT system has been shown to induce a regression of colorectal tumor xenografts in nude mice [26] and has undergone phase I clinical trial [188]. Building on this technology, Wentworth et al. used a catalytic antibody instead of a bacterial enzyme, naming this approach antibody-directed “abzyme” prodrug therapy (ADAPT). This was shown to be efficient in tissue culture systems and was suggested to compensate for possible toxicities that may have resulted from a host mediated immunologic response to the bacterial enzyme [192]. Another approach called gene-directed enzyme prodrug (GDEPT) requires the transfection of an enzyme that will specifically activate a prodrug in cancer cells. For example, CB1954 (5-(aziridine-1-yl)-2, 4-dinitrobenzamide) is a weak monofunctional alkylating agent which can be reduced by the nitroreductase from E-coli to a potent cytotoxic species that generates interstrand crosslinks in DNA. Various in vitro studies have shown that the transfection of this enzyme into tumor cells increased their sensitivity to CB1954 [189]. A primary limitation of this strategy is the problem of overexpressing this enzyme specifically in tumor cells. To achieve this goal Bilsland et al. took advantage of the highly specific activation of the telomerase promoter in cancer cells to target them using an adenovirus system containing the bacterial nitroreductase under the control of the telomerase promoter [24]. CB1954 can also be activated by the human NADPH quinone oxidoreductase 2 (NQO2), an enzyme commonly found in cancer cells. However, the enzyme is usually inactive and requires a co-substrate such as nicotinamide riboside to be functional. A lipophilic synthetic analogue of this was synthesized and was co-administered with CB1954; the drug combination increased the cytotoxicity of the prodrug in different in vitro models [92].


Other enzymes such as the cytochrome P450’s and DT-diaphorase (NQO1) have been shown to play an important role in the activation of cyclophosphamide and mitomycin C respectively. As would be expected, high expression of these enzymes in targeted tumor cells does provide a promising therapeutic index and in this regard, promising in vitro results have been obtained [15, 114].

4.3.8 Alkylating Agent-Steroid Conjugates Using the rationale that steroid receptors could serve to focus and concentrate hormones, a number of synthetic conjugates of nitrogen mustards and steroids have been developed. Among those, prednimustine, an ester-linked conjugate of chlorambucil and prednisolone and estramustine, a carbamate ester-linked conjugate of nor-nitrogen mustard and estradiol have been synthesized and are currently used to varying degrees in the clinic. Serum esterases readily cleave the ester bond of prednimustine leading to the release of the steroid and the active alkylating agent. The therapeutic advantage that has been seen to accrue with prednimustine has been attributed primarily to the altered pharmacokinetics with respect to prolonging the half life of chlorambucil, a consequence of the slow hydrolysis of the ester link [121]. In addition, the elimination phase of chlorambucil in patient plasma was significantly longer after administration of prednimustine than after chlorambucil [19]. Although estramustine was designed as an alkylating agent, the marked stability of the carbamate linkage to the steroid carrier molecule prevents the formation of any alkylating intermediates [172]. Detailed studies of the mechanism of action have indicated that the drug has anticancer activity through inhibition of mitotis. Unusually, the drug binds to tubulin and microtubule associated proteins causing depolymerization of the cytoskeleton. Spindle microtubules are particularly sensitive to the drug [98, 161]. At this time, estramustine is used in combination regimens as a front line treatment for hormone refractory prostate cancer [84]. It remains a pharmacological irony that the design and synthetic rationale for estramustine produced an active agent with none of the properties that were initially proposed [174].

4

Alkylating Agents

4.3.9 Alkylating Agent Resistance and Modulation Resistance to anticancer drugs represents one of the main reasons for chemotherapy failure. This process has been extensively studied and various cellular mechanisms of resistance have been discovered and described. Some of these are presented below. Decreased cellular content of alkylating agents in cancer cells could result from a decrease of cell uptake or an increase of efflux. Active cellular uptake of some alkylating agents has been shown. For melphalan, this is because of the structural similarity of the drug with the physiological amino acid substrate of the membrane transporter. Two amino acid transport carriers, the sodium-dependent carrier with substrate preference for alanine, serine and cysteine, and a sodium-independent carrier with preference for leucine have been implicated. In L5178Y cells resistant to melphalan, it was shown that a specific mutation in the low-affinity, high-velocity leucine transport system resulted in a decreased affinity of the carrier protein for leucine and melphalan and subsequently to a decrease in cellular accumulation of the drug [72, 76]. It was also shown that the uptake of melphalan was inversely proportional to the cytosolic concentration of calcium [113]. In contrast to melphalan, mechlorethamine uses the cholinergic membrane transporter expressed on the surface of various cell lines [101]. Enhanced cellular efflux has been also reported as a mechanism of resistance to alkylating agents. Cellular export of these anticancer drugs is mainly mediated by the multidrug resistance-associated protein 1 (MRP1) which is a member of the ATP binding cassette family expressed on the cell membrane. MRP1 is overexpressed in various cell lines resistant to such agents as nitrosoureas, chlorambucil and melphalan [73, 137]. Chlorambucil and melphalan are not direct substrates of MRP1, but their glutathione conjugated forms may be actively transported by this transporter. The conjugation of alkylating agents to glutathione can be spontaneous or mediated by the glutathione S-transferases (GST). For example, the conjugation of chlorambucil to glutathione has been shown to be both spontaneous and mediated by GSTs, both reactions occurring in cells but with different kinetics [39]. Similarly, the formation of GSH-conjugate of melphalan was suggested

73

not to require enzymatic catalysis in melanoma cells [78]. Spontaneous conjugation can occur because of the high degree of nucleophilic selectivity of the thiol group of cysteine in the glutathione molecule with the electrophilic alkylating carbonium ions produced by the majority of alkylating agents. Because of the important role of glutathione in resistance to alkylating agents, an inhibitor of the γ-glutamylcysteinyl synthetase (GGS), a key enzyme of GSH synthesis, L-S, R-buthionine sulfoximine (BSO) was investigated as a potential modulator of resistance. However, contradictory results were obtained; for example BSO was able to potentiate cytotoxic activities of melphalan, BCNU and 4-hydroperoxycyclophosphamide in human breast cancer cells [36], whereas this agent failed to increase sensitivity to busulfan in a busulfan resistant xenograft [79] or to drug combinations including melphalan and cyclophosphamide in vivo [159]. Although BSO increased tumor sensitivity to melphalan in mouse models, it also increased the toxicity of this drug against normal tissues [156]. Because of the limited clinical benefits of BSO, the use of this compound in clinical trials [67, 127], at least for now, has been curtailed. GSTs have been shown to catalyze the formation of glutathione conjugates of alkylating agents and high expression of certain GST isozymes has been linked with resistance to these anticancer drugs. In many cell lines exposed to incremental selective concentrations of alkylating agents, an increased expression of GSTs has been observed [186]. For example, GSTμ was overexpressed in an ovarian carcinoma cell line resistant to chlorambucil [82]. GSTα expression was also stimulated in mammary carcinoma cells following chlorambucil exposure [41]. Alkylating agents can be direct substrates of GSTs. However, specific isoenzymes have been shown to express preferential substrate specificity. For example, Dirven et al. observed that GST A1–1 and P1–1 catalyzed the formation of monoglutathionylthioTepa while A2–2 and M1a1a isozymes poorly catalyzed this reaction. Such a result would suggest that some isoforms have a higher affinity for the aziridine moieties of thiotepa than others [50]. In addition others have observed that GSTμ has activity toward BCNU [158], while GSTα participates in chorambucil and melphalan metabolism [40]. In contrast, GSTπ has a weaker affinity for the majority of the anticancer agents [40] even though increased

74


expression of this isoform is frequently associated with the development of multidrug resistance phenotype. Because of the importance of GSTs in resistance to alkylating agents, inhibitors of these enzymes were developed in an effort to potentiate the effects of these drugs. Ethacrynic acid is a phenolic acid extracted from plant sources (Fig. 4.15). It is a substrate based inhibitor of GST that yields an ethacrynic acid-GSH conjugate. This conjugate is formed both enzymatically and non-enzymatically and is itself a potent inhibitor of GST with the concomitant potential to deplete GSH [13]. Ethacrynic acid has been shown to enhance the cytotoxicity of chlorambucil and melphalan in tissue culture [166, 171]. Ethacrynic acid

underwent a phase I clinical trial in combination with thiotepa. The results obtained showed that the area under the curve (AUC) of thiotepa was approximately twice, and the clearance about one-half, of the values obtained in a previous study of single agent thiotepa. The AUC of TEPA, the main metabolite of thiotepa, was lower than that previously observed with the alkylating agent alone. The data suggest that ethacrynic acid inhibits enzymes involved in the metabolic disposition of thiotepa, including its oxidative desulfuration to TEPA [128]. However, ethacrynic acid is a potent diuretic and because of this side effect the clinical use of this agent was limited by fluid and electrolyte imbalance. The comparative lack of efficacy of

OCH2COOH SH Cl

O H N

H2N N H

Cl COOH

COCCH2CH3

O

Glutathione

CH2

Ethacrynic Acid

S O H N

H2N

COOCH2CH3

N H

TLK199

O

COOCH2CH3

Cellular esterases

S O H N

H2N N H

TLK117 COOH

Fig. 4.15 Structures of glutathione, TLK117, TLK199 and ethacrynic acid

O

COOH

COOH

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Alkylating Agents

modulators of glutathione synthesis or GST activity in some cellular models has been explained by the requirement of a specific intracellular environment. It has been suggested that glutathione synthesis, glutathione conjugation and GSH-conjugate efflux are processes tightly linked together and the combination of such coordinated mechanisms is required for optimal drug detoxification. O’Brien et al. showed that the co-transfection of MRP1, GSTP1–1 and γ-GCS in NIH 3T3 cells conferred a resistance titer to alkylating agents that was more significant than transfection of any combination of two of these proteins or each of them separately [125]. Thus, the overall conclusion from this approach is that these proteins act synergistically and in a coordinated fashion in the detoxification of the alkylating agents. Since ethacrynic acid and other inhibitors of GSTs had significant dose limiting toxicities and were not highly specific of GST isoforms, new inhibitors with pronounced inhibition constants for each isoform were developed. Using combinatorial chemistry with glutathione as a general backbone and substituting sulfydryl and carboxyl groups with a series of substituents, TLK117 (γ-glutamyl-S-(benzyl)cysteinyl-Rphenyl- glycine) (Fig. 4.15) was developed as a specific inhibitor of GSTP1–1. The drug is a peptidomimetic of GSH designed to bind to the “G-site” of GSTP1–1. An esterified form of TLK117, TLK199 was synthesized to enhance cellular uptake and became the lead drug candidate. The inhibition constant (Ki) for GSTP1–1 catalytic activity (chlorodinitrobenzene as substrate) was calculated to be 400 nM. This demonstrates significant specificity for the π-family, since the Ki for the GSTα and μ families range from approximately 20 to 75 μM [104]. This drug enhanced significantly the cytotoxic effect of melphalan in cancer cells resistant to alkylating agents, both in vitro and in animal models [114]. TLK199 also presented an unexpected preclinical result in rodents. The drug administration resulted in myelostimulation. This property has been mechanistically linked with its capacity to interfere with the interaction between GSTπ and cJun N-terminal kinase [3, 68, 149]. As a result of this beneficial therapeutic effect, this inhibitor is now undergoing a phase I/II clinical trial in patients with myelodysplatic syndrome. Others mechanisms involved in alkylating agent detoxification have been reported. Weber et al. observed that microsomal GSTs and cytochrome P450

75

were involved in the inactivation of BCNU by denitrosation [187]. Ranganathan et al. demonstrated that the transfection of glyoxalase I, an enzyme involved in the detoxification of methyglyoxal (a byproduct of the glycolytic pathway) increased the cellular resistance to mitomycin C but not to chlorambucil [143]. As previously described, alkylating agents have the capacity to produce DNA adducts on many of the nucleophilic oxygen and nitrogen atoms of purines and pyimidines. O6-alkylguanines formed by many of these drugs can lead to mutations and apoptosis unless repaired. As discussed previously, the enzyme O6-alkylguanine-DNA alkyltransferase can transfer the alkyl group from the DNA base to a cysteine acceptor site in the enzyme. The DNA integrity is restored completely by the action of this single protein, but the cysteine acceptor site is not regenerated and the number of O6-alkylguanines that can be repaired is equal to the number of active alkyltransferase molecules [138]. Expression of O6-alkylguanine-DNA alkyl-transferase which can be induced by alkylating agents has been linked with resistance, particularly to nitrosoureas [109, 185]. In order to circumvent resistance associated with this enzyme, inhibitors such as O6-benzylguanine were developed [139]. Despite its antitumor efficacy, O6-benzylguanine was found to potentiate the hematopoietic toxicity induced by alkylating agents [37, 60]. In addition, mutant forms of O6-alkylguanine-DNA alkyltransferase insensitive to O6-benzylguanine have now been described [48]. Alkylating agents mediate the death of the cancer cells mainly by altering the integrity of DNA. P53 is a key protein in the recognition of DNA damage. Drug induced damage to DNA causes p53 cellular levels to increase mainly as a consequence of the stabilization of the protein. The result of this is a blockade of cell-cycle progression. Then, the cell initiates attempts to repair DNA and if it fails, will ultimately activate apoptotic pathways. The absence of p53 expression has been associated with an increased sensitivity to alkylating agents [81, 97] probably because of the reduced capacity to repair DNA in a timely fashion resulting in the accumulation of DNA damage. Generally, induction of apoptosis in response to anticancer drugs is tightly regulated at the level of the mitochondria by proteins of the Bcl-2 family. These molecules are divided into two sub-families, one antiapoptotic (including Bcl-2, Bcl-XL ), the other pro-apoptotic (comprising Bax, BclXS , Bad). The balance between pro- and anti-apoptotic

76

members of this family is responsible for the fate of the cell, primarily survival or death [107]. Therefore, any deregulation of the expression of these proteins could contribute to drug resistance. In a human glioma cell line resistant to temozolomide, it was observed that the expression of pro-apoptotic molecules Bad, Bax and Bcl-XS was decreased, whereas no change in the expression of anti-apoptotic members of Bcl-2 family was found [105]. Kojima and colleagues showed that the release of mitochondrial cytochrome c and the activation of caspase-3 was abolished in an alkylating agent resistant cell line, possibly because of the overexpression of Bcl-XL [93]. Because of the protective role of Bcl-2 against the cytotoxic effect of the alkylating agent, Fairbairn et al. transduced hematopoietic progenitors with Bcl-2 and successfully protected these cells against the toxicity of nitrosoureas [59].

4.4 Toxicity


of the enzyme aldehyde dehydrogenase in early hematopoietic progenitors [44]. In contrast, busulfan seems to be especially damaging to hematopoietic stem cells [65] and prolonged hypoplasia of bone marrow is often observed after busulfan administration. Because of its myeloablative properties, busulfan is used extensively in clinical bone marrow transplantation [194]. The hematopoietic depression induced by the nitrosoureas is characteristically delayed. The onset of leukocyte and platelet depression occurs 3–4 weeks after drug administration and may last an additional 2–3 weeks [33]. Myelosupression induced by cyclophosphamide can be partially prevented by the aminothiol WR-2721 (Amifostine) without interfering with the chemotherapeutic effect of the alkylating agent [12]. Amifostine offers the prospect of increasing the therapeutic index of current cancer treatment by allowing the administration of higher thresholds of maximal tolerated doses.

4.4.1 Hematopoietic Suppression 4.4.2 Gastrointestinal Toxicity The usual dose-limiting tissue for alkylating agents is bone marrow. The hematopoietic suppression seems to affect all the hematopoietic lineages leading to a decrease in circulating leukocytes, platelets and erythrocytes. However the degree, time course and cellular pattern of the hematopoietic suppression generally differ dependent upon the type of alkylating agent used. For example, Nissen-Meyer et al. observed that administration of cyclophosphamide (60 mg/kg/day for 4 days) induces a decrease of circulating white blood cells but has no significant effect on platelet counts. In contrast, the authors showed that mechlorethamine (0.1 mg/kg/day for 4 days) leads to a strong fall in both leukocyte and platelet counts [124]. In addition, in vivo studies have suggested that cyclophosphamide has hematopoietic stem cell sparing activities. High doses of cyclophosphamide (4 g/m2 ) followed by G-CSF have even been used for the mobilization of peripheral blood stem cells in patients undergoing autologous blood stem cell transplantation in the treatment of Hodgkin’s lymphomas [145]. The biochemical basis for the stem cell-sparing effect of cyclophosphamide is not entirely understood, but has been associated with the high expression

Damage to the gastrointestinal tract is frequently observed with high-dose regimens. Mucositis, stomatitis, oesophagitis, and diarrhea occur preferentially with high doses of melphalan and thiotepa [175]. In contrast, cyclophosphamide and isofosfamide have low gastrointestinal toxicity because of the high levels of aldehyde dehydrogenase activity in the epithelial cells of the gastrointestinal tract [44]. Nausea and vomiting are also frequent side effects that are mediated through the central nervous system and are apparently not a direct consequence of gastrointestinal cytotoxicity [62]. Although these side effects are not life threatening, they represent major discomforts to the patients and this can sometimes result in delay or discontinuation of therapy. The frequency and degree of these effects are variable among patients, where some can tolerate high doses of alkylating agents without nausea, while others are incapacitated at even low concentrations. However, the frequency of nausea and vomiting increases as the dose of alkylating agent is increased. Antiemetic drugs are usually given to the patients along with the chemotherapeutic agents.

4

Alkylating Agents

4.4.3 Pulmonary Toxicity In general, the initial clinical appearance of pulmonary toxicity includes both constitutional signs of malaise and fever as well as pulmonary complaints. Pulmonary fibrosis has been described as a complication for longterm busulfan therapy which is presumably due to a cytotoxic effect of alkylating agents to pulmonary epithelial cells. The clinical features of this adverse effect are a nonproductive cough and dyspnea which may progress to severe pulmonary insufficiency and death [20]. Similar pulmonary toxicity has been occasionally observed with cyclophosphamide, nitrogen mustards and mitomycin C [14, 130, 136].

4.4.4 Renal Toxicity Urotoxicity is observed with cyclophosphamide and ifosfamide. This effect has been shown to be the consequence of the urinary excretion of the metabolite acrolein, which has been shown to irritate bladder mucosa. The subsequent hemorrhagic cystitis may range from a mild cystitis to severe bladder damage with massive hemorrhage [163]. This side effect can be minimized by adequate hydration, frequent bladder emptying and administration of N-acetylcysteine. Thus, this adverse effect of the oxazaphosphorines can be alleviated by thiol loading of the local environment [133]. The most active agent for prevention of cyclophoshamide- or ifosfamide-induced urotoxicity is 3-mercaptoethane sulfonate (MESNA). This agent dimerizes to an inactive metabolite in plasma, but hydrolyzes in urine to yield the active compound that conjugates acrolein and prevents cystitis. MESNA is usually administrated continuously to patients treated with oxazaphosphorines. Subcutaneous administration of the compound is preferred because it is not associated with inadequate urinary MESNA accumulation and clinical experience suggests that it represents a safe and practical method of drug delivery [108].

4.4.5 Alopecia Alopecia has been mainly observed with cyclophosphamide-based therapy [5]. The degree of alopecia may be severe especially when the drug

77

is used in combination with vincristine sulfate or doxorubicin. Hair regrowth occurs after cessation of the therapy but may be associated with a change in texture [69].

4.4.6 Reproductive Toxicity Alkylating agents have profound effects on reproductive tissue. Aspermia has been observed in patients undergoing therapy with mechlorethamine, chlorambucil and cyclophosphamide [112]. Testicular biopsies have demonstrated that this effect was in most cases associated with germinal aplasia and preservation of Sertoli cells [61]. High frequency of aspermia and oligospermia have been observed in patients for up to 3 years after cessation of therapy. However, in some cases, patients off therapy demonstrated complete spermatogenesis restoration and even fathered children [154]. Amenorrhea and ovarian atrophy have been observed in female patients treated with busulfan and cyclophosphamide [46, 112]. Biopsies of ovaries after cyclophosphamide administration reveal the absence of mature or primordial follicles. This has been associated with a decrease in estrogen and progesterone levels and an elevation of follicle-stimulating hormone and luteinizing hormone plasma concentrations often characteristic of menopause [130].

4.4.7 Teratogenecity Teratogenic activities have been linked with all alkylating agents [25, 57]. This seems to be caused by a direct cytotoxicity to developing embryos by the same DNA damage mechanisms that occur in tumor cells [31]. Because of the teratogenicity of these agents, limits are placed on the use of alkylating agents during pregnancy. It has been shown that if these drugs are given during the first trimester of pregnancy, a high incidence of birth defects is observed. However, if the alkylating agents are administered during the second or third trimester of pregnancy, fetuses do not suffer malformations. Such results suggest that though it is unsafe to administer these chemotherapeutic agents to pregnant women, the risk of birth defects are more restricted during the two last trimesters of pregnancy [123].

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4.4.8 Carcinogenesis In a large number of studies, it was observed that alkylating agent therapy was associated with the appearance of secondary leukemias [54, 144] suggesting that the oncogenic effect of these drugs represents a significant complication of alkylating agent therapy. Because of their structure and mechanism of action, alkylating agents can induce DNA adducts similar to those observed with the carcinogenic polycyclic aromatic hydrocarbons [110, 196].

4.4.9 Immunosuppression Cyclophosphamide is among the most immunossupressive alkylating agents [64] and because of this property it has been utilized in the treatment of auto-immune diseases [178, 190]. However, low doses of cyclophosphamide or melphalan can enhance immune response. Because of this effect, these drugs have been used in combination with cytokines such as IL-2 [96, 115]. One of the main consequences and concerns of immunosuppression is the increased risk and susceptibility to infectious diseases in patients treated with cyclophosphamide [126].

4.4.10 Hypersensitivity Reactions Because alkylating agents covalently bind to biologic macromolecules, these compounds are suspected to act as haptens and can induce allergic reactions. Skin eruption, urticaria and anaphylatic reactions have been reported following the administration of alkylating agents [94, 141]. Although allergic reactions do not represent a frequent side effect observed during chemotherapy, they may be fatal if they lead to anaphylactic shock.

4.5 Conclusion Over the past three decades, the scientific community has gained a better understanding of the biology of cancer cells and identified enzymes and signaling pathways that are specifically dysregulated in tumors.


The design of new alkylating agents could take advantage of this knowledge by synthesizing new drugs that could be activated preferentially by tumor cells and consequently could lack the side effects that limits the use of current alkylating drugs. At this time, one of the best examples of this is TLK286, a prodrug preferentially activated by GSTπ. Any clinically proven activity of this drug should lead the way to a new generation of anticancer drugs that will make chemotherapy more efficient and tolerable for patients.

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85 A comprehensive kinetic analysis of the interconversion of cis- and trans-4-hydroxycyclophosphamide with aldophosphamide and the concomitant partitioning of aldophosphamide between irreversible fragmentation and reversible conjugation pathways. J Med Chem 27(4):466–485 196. Zytkovicz TH, Moses HL, Spelsberg TC (1977) The binding of benzo(alpha)pyrene and N-methyl-N -nitro-Nnitrosoguanidine to subnuclear fractions of AKR mouse embryo cells in culture. Int J Cancer 20(3):408–417

Chapter 5

Anthracyclines and Anthracenediones Nicole Coufal and Lauge Farnaes

5.1 Introduction Daunorubicin was the first anthracycline isolated, a natural product isolated from the actinobacteria Streptomyces peucetius. It was identified in 1963 by both Italian and French groups [7, 38]. The Italian group focused on natural product analogues, and isolated doxorubicin from the S. peucetius caesius variant, and the French group produced semi-synthetic derivates [6]. Although a vast number of analogues were synthesized after these initial discoveries, only two other anthracyclines ever made it to market in most western countries and Japan, idarubicin and epirubicin. Several liposomal formulations have also been marketed. Doxorubicin is the most widely used anthracycline, and therefore the standard by which all new derivatives are evaluated. After years of debate, it is generally accepted that the mechanism of action of the anthracyclines is by targeting the nuclear enzyme DNA topoisomerase II (topo II) and through formation of free radials, although they also exhibit a wide array of other cellular effects. These off-target effects may contribute to their efficacy, however they doubtlessly also play a role in their toxicity. In the pursuit for new anthracycline analogs with chemotherapeutic activity, a variety of multi-ringed structures with the potential to intercalate between the bases of DNA have been identified. Through

N. Coufal () UCSD Department of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA e-mail: [email protected]

this process the anthracenediones were identified as a class of compounds related to anthracyclines which exhibited promising leukemic properties [101]. Mitoxantrone is the only compound in this class currently marketed, with efficacy against a narrower range of tumors than the anthracyclines, but with the benefit of greatly reduced risk of cardiotoxicity.

5.2 Chemistry Anthracyclines are composed of an anthraquinone (a planar polyaromatic ring system with a quinone moiety) linked to an amino sugar. The central anthraquinone is an intense chromophore that absorbs light in both the UV (at 254 nm) and the visible spectrum (at 480 nm). This chromophore gives the compounds their characteristic orange-red color and intense fluorescence. The compounds lose their fluorescence when intercalated in DNA. Although many structural variations have been made to the basic anthracycline structure only four are currently in clinical use. These vary in only three places in the molecule. Idarubicin differs from the other three anthracyclines by not having a methyl ester at carbon 4 of the central chromophore (Fig. 5.1). Another structural difference between the four anthracyclines is that doxorubicin and epirubicin have a hydroxyl moiety at carbon 14 while daunorubicin and idarubicin are missing this hydroxyl group. The final structural variation is found at carbon 4 on the amino sugar where epirubicin has the opposite stereochemical configuration at this carbon from doxorubicin and idarubicin. The anthraquinone head is quite lipophilic and aids anthracyclines binding to targets molecules through


87

88 Fig. 5.1 The structures of anthracyclines in current clinical use and the anthracenedione mitoxatrone. The anthracyclines vary in structure at the carbons marked 4, 14, and 4 on doxorubicin


1

4 O

O

OH

O

O

OH

13 14 OH O

OH OH

OH O

O

O

OH O

O

O

HO NH2

HO NH2

Daunorubicin

Doxorubicin

4'

O

OH

O

O

O

OH

O

OH OH O

O HO

OH

OH O

O

OH O

O

O

NH2

HO NH2

Epirubicin

Idarurubicin

OH O HN

OH O HN

H N

N H

OH

OH

Mitoxantrone

hydrophobic interactions. The amino sugar helps to make the molecules soluble in water. All the anthracyclines are currently marketed as hydrochloric acid salt since this formulation is soluble in both water and polar organic solvents. The anthracyclines have different lipophilicities with idarubicin being the most lipophilic, followed by daunorubicin, epirubicin, and doxorubicin. Metabolic transformations can include reduction of the ketone on carbon 13 (Fig. 5.1) to yield the respective 13-dihydro derivatives, which are usually named by adding the –ol suffix to the parent compound (i.e. doxorubicinol). Another structural variation that is observed in metabolites is compounds where the sugar has been eliminated to yield either 7-deoxy or 7-hydroxy aglycones. In order to reduce the anthracycline to the 7-deoxyaglycone a stepwise reaction with flavin containing enzymes must occur. This has been used as evidence to support the existence of an anthracycline redox cycle. The 7-hydroxyaglycones result from the hydrolysis of the sugar-anthraquinone bond. Therefore the 7-hydroxyaglycones can arise

as artifacts in the handling or processing of the drug. American Cyanamid Laboratories synthesized a class of compounds similar to the anthracyclines in the late 1970s [101]. This resulted in the anthracenediones class of molecules, of which the most active is mitoxantrone. Mitoxantrone has a dihydroxyanthraquinone central chromophore with two symmetrical aminoalkyl side chains. These side chains may undergo oxidation to yield the mono- and dicarboxylic acids of the anthracenedione.

5.3 Mechanism of Action It was rapidly realized that the anthracyclines have a profound inhibitory effect on nucleic acid synthesis [6]. There has been some controversy over the exact mechanism of the anthracyclines. It is possible that the anthracyclines have a few potential mechanisms of action and which of these is most important may

5

Anthracyclines and Anthracenediones

depend on the cellular and extracellular environment in which they are acting. It seems most likely that the anthracyclines act by interaction with topoisomerase II and/or by the creation of oxygen free radicals, which can subsequently lead to the creation of the hydroxyl radical, a very destructive chemical entity. It has also been noted that the anthracyclines may have effects on signal transduction and effects at the cellular membrane [26]. Anthracyclines intercalate into DNA but it is unclear if this process is important in the cytotoxic effects of these drugs when used in the same concentrations as seen in vivo. Topoisomerase II (Topo II) is a nuclear enzyme that is responsible for the tertiary structure of DNA. One of the main roles for topo II is to control the amount of positive and negative supercoiling of DNA. In order to create alterations in the tertiary structure of the DNA, topo II binds to specific recognition sites and cleaves one phosphodiester bond on each strand of DNA. The broken strands are stabilized by topo II in a “cleavable complex.” While both strands of the DNA chain are broken another DNA chain can pass through the break before the two broken chains are relegated. This allows DNA to be knotted and unknotted. Investigations have shown that anthracyclines may work to stabilize this cleavable complex. If the cleavable complex is stabilized for too long then topo II may not be able to adequately religate the phosphodiester bonds. This leads to topo II associated DNA cleavage, which can be demonstrated at concentrations (10−8 ) that are well below the dissociation constant for the intercalation of anthracyclines in DNA [113]. It is also possible that the anthracyclines may work to not only stabilize the cleavable complex but also inactivate the catalytic activity of the enzyme. When the anthracyclines interact with topo II they act as chemically inert compounds, however the anthracyclines are chemically reactive compounds with complex redox chemistry [1]. One-electron reduction of the anthracyclines was initially described in in vitro systems [10] and was later shown to play a role in the cardiotoxicity that is seen with anthracyclines administration [44, 102]. It has also been suggested that the reduction of the anthracyclines may be responsible for some of the anti-neoplastic effects of the anthracyclines [43, 129]. Anthracyclines are able to undergo one and two electron reduction to create reactive compounds that can cause widespread damage to cellular components [25, 64, 114]. In the presence of

89

NADH or NADPH, flavoproteins can induce a oneelectron reduction of the anthracyclines, generating a reduced semi-quinone radical form. Oxygen allows this semiquinone to generate a superoxide anion [74]. This superoxide anion can then form hydrogen peroxide with another oxygen radical, leading to the creation of the hydroxyl radical in the presence of metal ions such as the iron found in myoglobin (Fig. 5.2). The hydroxyl radical is one of the most destructive chemical entities known. Doxorubicin has been shown to oxidize bases in chromatin which may provide a cytotoxic action for the drugs when they interact directly with DNA [2, 100]. Hydrogen peroxide and hence the hydroxyl free radical may also be created in normal tissue so there are cellular defenses against these species. The cardiotoxicity of the anthracyclines may partially be due to the lower levels of catalase in the heart as compared with other tissue. Anthracycline exposure causes changes in cardiac biochemistry which eventually leads to cumulative cardiotoxicity. These changes include alterations in calcium handling characterized by inhibition of calcium sequestration by the sarcoplasmic reticulum. Damage to the sarcoplasmic reticulum is postulated to be secondary to drug-induced free radical damage. Free radical damage is increased by inhibition of the cardiac tissues’ ability to detoxify free radicals by

Fig. 5.2 The reduction of doxorubicin to the semi-quinone and the subsequent oxidation back to doxorubicin creates the superoxide anion which can in turn react with hydrogen peroxide to create the oxygen free radical which can have broad destructive cellular effects

90

glutathione peroxidase, which is inhibited by anthracyclines [104]. It has been found that doxorubicin resistance in neoplastic cells is associated with increased glutathione (a sulfur containing short peptide that acts to inactivate free radicals) concentrations [120] which could potentially be reversed by decreasing the ability of the cells to neutralized free radicals. It has also been noted that transfection of cells with glutathione peroxidase induces doxorubicin resistance while antisense expression sensitizes the cells to doxorubicin [42, 143]. In addition to one-electron reductions two-electron reductions of the anthracyclines also exist. In these two electron reductions the sugar is lost and the deoxyaglycone, a non-cytotoxicly active metabolite is formed [1].

5.4 Pharmacokinetics Isolation and characterization of anthracyclines and their metabolites is greatly aided by their fluorescence and UV/visible absorption of the compounds allowing detection levels as low as 1 ng/ml. High Performance Liquid Chromatography (HPLC) can usually achieve separation using reversed phase columns and a solvent made with acetonitrile or methanol and an aqueous buffer at pH2–4 [71]. Anthracycline accumulation in cells can be measured using fluorescent microscopy or flow cytometry [90]. Since the fluorescence of the anthracyclines is quenched when the molecules intercalate in DNA it is possible to directly measure uptake in a cell suspension, as the fluorescence decreases in direct proportion to the amount of compound that is taken up [142]. The anthracyclines are usually administered intravenously, although intraperitoneal or intra-arterial routes may also be utilized for doxorubicin. The only anthracycline that is given orally is idarubicin. After oral administration of idarubicin, the amount of intact drug is higher under non-fasting conditions. The pharmacokinetics of idarubicinol (the 13-dihydro derivative of idarubicin) is not affected by food intake [49]. The extensive binding of these drugs to DNA and proteins, therefore the free drug pool, represents a fraction of the drug measured in both plasma and cells. Therefore, 75% of the drug in plasma is protein bound [61]. Although there is a high amount of


protein binding, tissue plasma ratios of 10:1–500:1 are regularly observed due to the higher DNA content in tissue [137]. Doxorubicin and daunorubicin appear to cross the plasma membrane of cells through free diffusion of the non-ionized drug [110]. This becomes an issue because anthracyclines have pKa’s in the physiological range. Acidosis can therefore trap drug either in the intracellular or extracellular space depending on where the acidosis is concomitantly present. It has been noted that the pH can have a significant effect on the activity of the anthracyclines [54, 109]. Many solid tumors may create an internal acidic environment with a pH as low as 6 [150]. This would function to withhold anthracyclines from the cells, thereby maintain a more alkaline internal environment than the acidic extracellular fluid in the tumors [115]. In addition, the acidification of internal organelles may work to sequester the anthracyclines away from their targets within the cells [5]. The cytotoxic effect of the anthracyclines has been found to correlate with the area under the curve (AUC), not the peak drug levels. The myelosuppression that is often seen with the administration of the anthracyclines is also correlated with the area under the curve, but cardiotoxicity is correlated with peak drug levels. Since cytotoxic effect of the drug is determined by AUC there has been an interest in prolonging the infusion to reduce the incidence of cardiotoxicity. One study was able to limit the cardiotoxicity of doxorubicin by administering a prolonged 96 h infusion [81]. Nausea and vomiting were also greatly reduced through the use of this prolonged infusion. Doxorubicin disappears from the plasma in triexponential decay after bolus administration. The decay is characterized by three successive half lives of 3–5 min, 1–2 h, and 24–36 h [72, 97, 119, 146]. Idarubicin’s decay after an intravenous injection is best described by a biexponential model with two successive half lives of 20 min and 15–20 h [21, 139]. The pharmacokinetics of these drugs is dominated by its tissue binding. In the early distributive phase the drug levels fall rapidly as the drug gains access to all tissues except the brain. Generally, anthracyclines do not cross the blood brain barrier, however it has been reported that idarubicinol may be able to cross the blood brain barrier [118] but the CSF concentrations are very low (0.5 ng/ml). The majority of the drug bind to DNA throughout the body and therefore has a tissue

5


distribution profile that is consistent with tissue DNA content [144]. There is substantial interpatient variability and also significant intergender variability in drug metabolism. Studies have shown that men with normal hepatic function have approximately twice the clearance of doxorubicin (when given as a bolus) as women. This increased clearance was associated with a greater conversion of drug into its alcohol derivatives [40, 41]. The total plasma clearance of doxorubicin is approximately 30 l/h/m2 and its total volume of distribution at steady state is 800 l/m2 [119]. The total plasma clearance and volume of distribution for doxorubicin are the lowest for any of the anthracyclines, such that epirubicin has a total plasma clearance of 43.1 l/h/m2 and a volume of distribution of 1272 l/m2 , daunorubicin has a value of 95.0 l/h/m2 and 1334 l/m2 respectively, and idarubicin has respective values of 56 l/h/m2 and 1138 l/m2 [22, 116, 139]. Mitoxantrone, an anthracenedione, has a pharmacokinetic profile that is also characterized a triexponential decay with three successive half lives of 10 min, 1.6 h, and 23–42 h. This drug also distributes in high concentrations into tissue with the highest concentrations being found in the liver and bone marrow [3]. One of the most prevalent biotransformations of anthracyclines is reduction of the ketone at C-13 to yield 13-dihydro derivatives. The enzyme responsible for this reduction is a ubiquitous aldoketoreductase located in the cytoplasm of all cells and tissues with an especially high concentration in the liver, kidney, and RBC’s [52]. In vitro, the 13-dihydro derivatives are much less cytotoxic than their parent compounds with the exception of idarubicinol which is as active metabolite [125]. The majority of daunorubicin that is found in the plasma a few hours after a bolus injection is the alcohol metabolite daunorubinicol. Daunorubinicol has a longer half life than it’s parent drug and therefore may be responsible for the majority of the effect of this drug [57, 68]. It is possible that the 13-dihydro derivatives may be responsible for the largest part of the cardiotoxicity as well [57]. The aglycones (anthracyclines which have lost their sugar residue) are a cytotoxicly inactive metabolite that has been shown to be produced under anaerobic conditions in vitro using microsomal enzymes [8]. The deoxyglycones and their 13-dihydroderivatives are sometimes observed in the urine and plasma of patients, however their appearance is usually transient and unpredictable. Epirubicin can also form a β-O-glucuronide conjugate

91

in a metabolic pathway unique to humans [154]. The side chains of mitoxantrone undergo oxidation to yield the mono- and dicarboxylic acid form of the compound. Neither of these two forms have any cytotoxic activity [29]. Elimination of the anthracyclines occurs mainly through the biliary tract with urinary excretion barely exceeding 10% of the injected dose [141]. All of the blood metabolites that are commonly detected are also found in feces and in urine. Urine discoloration is possible due to the anthracycline chromophore. It has been noted that altered liver function can have profound effects on the elimination of both doxorubicin and epirubicin [23, 111]. Dose adjustments are suggested for both doxorubicin and epirubicin according to total bilirubin plasma levels with a reduction of 50% when bilirubinemia reaches 25 μM, and 100% when bilirubinemia reaches 50 μM [147]. Renal elimination is more important for idarubicin than for other anthracyclines and therefore a dose reduction is also recommended for patients with renal dysfunction [21]. Less than 10% of mitoxantrone is found in the urine of patients and only 20% can be accounted for in the stool. It is likely that the hepato-biliary system plays a role in the metabolism of this drug as several people have noted an extended half life in patients with compromised liver function [122, 131].

5.5 Clinical Uses Doxorubicin is widely used in the treatment of adult solid tumors of many types. It is the most broadly useful of the anthracyclines, having exhibited efficacy against carcincomas of the breast, ovary, bladder, stomach, and thyroid, as well as small-cell lung cancer, soft-tissue and osteogenous sarcoma, and numerous pediatric solid tumors. It also has proven useful in the treatment of hematopoietic malignancies such as leukemias, lymphomas (Hodgekin’s and nonHodgekin’s), and multiple myeloma [26]. Epirubicin has similar properties to doxorubicin, but its use is limited primarily to the treatment of solid tumors. Epirubicin has significantly less cardiotoxicity, but is also relatively less potent. Thus epirubicin is of limited utility, as there are currently other methods of lessening anthracycline induced cardiotoxicity without sacrificing efficacy. Daunorubicin and idarubicin

92


are used primarily for the treatment of adult and childhood leukemias, although also useful for the treatment of lymphoma and breast cancer. Daunorubicin is routinely used for treatment of acute myelogenous leukemia (AML) and acute lymphocytic leukemia (ALL). Liposomal formulation of doxo- and daunorubicin have been utilized for treatment of Kaposi’s sarcoma. Key features of the anthracyclines are summarized in Table 5.1. Doxorubicin and daunorubicin are active over a wide range of doses and administration regimes, varying from monthly boli to weekly injections, to prolonged infusions [80, 81]. Additionally, the anthracyclines do not have any apparent negative interactions with other chemotherapeutic agents. While the clinically significant toxicities include myelosuppression, alopecia, and mucositis, by far the most significant and potentially dangerous toxicity of the anthracyclines is a cumulative cardiotoxicity. Once the mechanism of cardiotoxicity was revealed, an ironchelating agent with moderate antineoplastic activity was identified, dexrazoxane (ICRF-187), which has been shown to block this drug-induced cardiotoxicity in clinical trials. Myelosuppression has also

been ameliorated by co-administration of colonystimulating factors combined with peripheral blood progenitors. Altogether this has allowed for lesser dosing intervals, and greater dose intensity and duration [20, 95, 133]. The anthracyclines are generally administered intravenously, and are mostly sold as lyophilized powders or ready formulations of 2 mg/ml. Formulations vary from 10 to 200 mg for doxorubicin and epirubicin, and are marketed as 20 mg daunorubicin and 5 or 10 mg idarubicin product. Idarubicin can be administered orally as well, as 1, 5, 10, or 20 mg of drug. Generally in all situations these medications are further diluted in 5% glucose before administration to patients [26]. Although administration dosing regimes do not affect antitumor efficacy, it does alter normal tissue toxicity. Several alternative routes of administration have been investigated. Intraperitoneal administration of anthracyclines can also be valuable for the treatment of peritoneal ovarian metastases, as it targets the malignancy directly without extensive systemic effects [106]. Fluid exchange between the peritoneal fluid and plasma is low, on the order of 2–25 ml/min, such that doxorubicin has a half life in the peritoneal fluid of

Table 5.1 Key features of the anthracyclines Doxorubicin Epirubicin

Daunorubicin

Family Mechanism of action Standard Dose (mg/m2 )

Route of administration

Metabolism to 13-dihydro derivatives Elimination Terminal half-life (h) Principal Toxicity

Idarubicin

Mitoxantrone

Anthracycline Anthracycline Anthracycline Anthracycline Anthracenedione (1) Inhibit the nuclear enzyme DNA topoisomerase II by intercalating between the DNA bases and stabilizing the DNA-TopoII cleavage complex. (2) generate reactive oxygen intermediates (3) stimulate apoptosis 35–70 every Up to 120 every 30–45 per day, 8–15 per day, 12–14 every 3 weeks 3 weeks 3–5 days 3–5 days IV or 3 weeks or 12 30–50 per week ever 3 days for orally AML Intravenous mainly, Intravenous only Intravenous only Intravenous or oral Intravenous, also intraperitoneal intraperitoneal and intra-arterial Low Low High High N/A

Hepatic and 10% renal 20–30



Cardiomyopathy, Neutropenia, mucositis, alopecia

Cardiomyopathy, Neutropenia, mucositis, alopecia

Neutropenia, mucositis, alopecia, cardiomyopathy

80% in urine 12–16 Neutropenia, mucositis, alopecia, cardiomyopathy (less than doxorubicin)

Partially hepatic, partially renal 9 Less toxic than anthracyclines, especially less cardiotoxicity

5


approximately 2 h [36]. For the treatment of bladder cancer, intravesical anthracycline treatments have been well tolerated, with little systemic leakage [28, 98]. In addition, loco-regional administration of anthracyclines has been investigated, in order to increase intra-tumoral concentrations, and theoretically reduce the amount of systemic toxicity, especially cardiotoxicity. This route of administration is most effective for drugs which have high uptake in the target organ, and high total body clearance, so is best suited for doxorubicin. Intra-arterial administration has been utilized for head and neck cancer, limb sarcoma, bladder cancer, and breast carcinoma. However, these have not shown significant improvement over systemic administration [37]. In addition to novel routes of administration, numerous carriers for anthracyclines have been tested, endeavoring to increase the positive targeting of the drug to the tumor, or decrease inadvertent targeting of other organs, such as the heart. Liposomal formulations of the less lipophilic anthracyclines are currently marketed. These liposomes of duano- and doxorubicin are formulated as administration-ready formulations of 50 mg dauno- or 10 mg doxorubicin at 2 mg/mL. Research has shown decreased cardiotoxicity with liposomal administration of doxorubicin [149]. The current main use for liposomal formulations is in the treatment of AIDS related Kaposi’s sarcoma, although other uses are being investigated. In order to increase the dose of drug specifically to the tumor, lipiodol suspensions have also been employed. Lipiodol undergoes embolization in the tumor vasculature and reduces the arteriolar flow rate, such that drug accumulation is enhanced within the tumor [117]. A number of other conjugates are currently in early clinical trials. This notably includes doxorubicin-N-(2hydroxypropyl) methacrylamide copolymers of high molecular weight where the drug is bound to a polymer via an aminosugar. In preclinical testing this formulation cannot diffuse through cellular membranes until it is activated by proteolytic extracellular degradation on the tumor, thereby showing a high degree of tumor specificity, and reduced cardiotoxicity [47, 126]. Anthracycline dose modifications should be considered for some patients. Alterations in renal function do not appear to modify the pharmacokinetics of most anthracyclines, other than idarubicin. Patients with renal dysfunction (creatinine clearance 100 mg/m2 develop decreases in LV ejection fraction [55, 59]. Patients with prior chest irradiation, prior cardiac disease, or prior anthracycline exposure are at increased risk [65, 127]. A minor side effect of mitoxantrone is a blue discoloration of the sclera, fingernails, and urine [136].

5.8 Drug Interactions Only a few medications are known to interact with the anthracyclines. The anthracyclines interact with some chemotherapeutic agents, for instance coadministration of doxorubicin and etoposide has been shown to decrease doxorubicin clearance at least twofold [33]. Additionally, concomitant administration of paclitaxel and doxorubicin leads to non-linear disposition of both drugs, likely as a result of competition for biliary secretion [56]. Doxorubicin, daunorubicin, and the anthracenediones mitoxantrone can cause radiosensitization of normal tissues. This is significant in cases of mediastinal or chest wall radiation therapy for breast cancer or Hodgekin’s lymphoma. A dose of 2,000 cGy given in 200 cGy/day fractions results in a two fold increase in cardiotoxicity. In such situations only half the dose of doxorubicin should be administered. Daunorubicin binds to heparin leading to aggregate formation, such that co-administration can lead to an increase in the rate of daunorubicin clearance [26]. There is evidence that mitoxantrone acts synergistically with arabinosylcytosine, and is therefore frequently used in combination to treat acute nonlymphocytic leukemia [65]. Combining doxorubicin or epirubicin with the cardioprotectant dexrazoxane (ICRF-187) does not seem to alter their pharmacokinetics [67]. Numerous pharmaceuticals have been shown to reverse MDR associated resistance, such as

5


cyclosporine A, verapamil, and quinine [53, 92]. Clinical trials investigating the efficacy and feasibility of these medications in reversal of MDR resistance have had mixed results [11, 87, 93, 155]. These studies have shown that MDR reversal strategies are most effective for leukemias and lymphomas, but are generally hampered by associated toxicity of the reversal agent at therapeutic doses. The pharmacokinetics of the reversal agent can alter clearance of the anthracyclines, such that concomitant administration of cyclosporine with either doxorubicin or daunorubicin decreases clearance of either. Despite these caveats, a large randomized study of AML patients established that cyclosporine A combined with daunorubicin as part of a standard daunorubicin and cytosine arabinoside regimen significantly improved overall survival and relapse rates in patients [86]. The changes in anthracycline clearance which occur with MDR reversal agents indicates a different administration strategy should be considered. Sikic et al. [128] has proposed that instead of administering standard anthracycline doses combined with an increasing dose of reversal agent, instead it would be wise to administer the maximally tolerated reversal agent dose, and then gradually increase anthracycline doses to predetermined tolerance levels (e.g., myelosuppression tolerance limits).

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N. Coufal and L. Farnaes with myeloma treated with ninety-six-hour continuous infusion. Clin Pharmacol Ther 41(6):661–665 Speyer JL, Green MD, Kramer E, Rey M, Sanger J, Ward C et al (1988) Protective effect of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer. N Engl J Med 319(12):745–752 Stewart DJ, Grewaal D, Green RM, Verma S, Maroun JA, Redmond D et al (1991) Bioavailability and pharmacology of oral idarubicin. Cancer Chemother Pharmacol 27(4):308–314 Swain SM, Whaley FS, Gerber MC, Weisberg S, York M, Spicer D et al (1997) Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 15(4):1318–1332 Takanashi S, Bachur NR (1976) Adriamycin metabolism in man. Evidence from urinary metabolites. Drug Metab Dispos 4(1):79–87 Tarasiuk J, Garnier-Suillerot A (1992) Kinetic parameters for the uptake of anthracycline by drug-resistant and drugsensitive K562 cells. Eur J Biochem 204(2):693–698 Taylor SD, Davenport LD, Speranza MJ, Mullenbach GT, Lynch RE (1993) Glutathione peroxidase protects cultured mammalian cells from the toxicity of adriamycin and paraquat. Arch Biochem Biophys 305(2):600–605 Terasaki T, Iga T, Sugiyama Y, Hanano M (1982) Experimental evidence of characteristic tissue distribution of adriamycin. Tissue DNA concentration as a determinant. J Pharm Pharmacol 34(9):597–600 Torti FM, Bristow MR, Howes AE, Aston D, Stockdale FE, Carter SK et al (1983) Reduced cardiotoxicity of doxorubicin delivered on a weekly schedule. Assessment by endomyocardial biopsy. Ann Intern Med 99(6): 745–749 Twelves CJ, Dobbs NA, Aldhous M, Harper PG, Rubens RD, Richards MA (1991) Comparative pharmacokinetics of doxorubicin given by three different schedules with equal dose intensity in patients with breast cancer. Cancer Chemother Pharmacol 28(4):302–307 Twelves CJ, Dobbs NA, Michael Y, Summers LA, Gregory W, Harper PG et al (1992) Clinical pharmacokinetics of epirubicin: the importance of liver biochemistry tests. Br J Cancer 66(4):765–769

148. Unverferth DV, Unverferth BJ, Balcerzak SP, Bashore TA, Neidhart JA (1983) Cardiac evaluation of mitoxantrone. Cancer Treat Rep 67(4):343–350 149. van Dalen EC, Michiels EM, Caron HN, Kremer LC (2006) Different anthracycline derivates for reducing cardiotoxicity in cancer patients. Cochrane Database Syst Rev(4):CD005006 150. Vaupel PW, Frinak S, Bicher HI (1981) Heterogeneous oxygen partial pressure and pH distribution in C3H mouse mammary adenocarcinoma. Cancer Res 41(5):2008–2013 151. Venturini M, Michelotti A, Del Mastro L, Gallo L, Carnino F, Garrone O et al (1996) Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer. J Clin Oncol 14(12):3112–3120 152. Von Hoff DD, Layard MW, Basa P, Davis HL Jr, Von Hoff AL, Rozencweig M et al (1979) Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91(5):710–717 153. Von Hoff DD, Rozencweig M, Layard M, Slavik M, Muggia FM (1977) Daunomycin-induced cardiotoxicity in children and adults. A review of 110 cases. Am J Med 62(2):200–208 154. Weenen H, van Maanen JM, de Planque MM, McVie JG, Pinedo HM (1984) Metabolism of 4 -modified analogs of doxorubicin. unique glucuronidation pathway for 4 epidoxorubicin. Eur J Cancer Clin Oncol 20(7):919–926 155. Wishart GC, Bissett D, Paul J, Jodrell D, Harnett A, Habeshaw T et al (1994) Quinidine as a resistance modulator of epirubicin in advanced breast cancer: mature results of a placebo-controlled randomized trial. J Clin Oncol 12(9):1771–1777 156. Withoff S, Keith WN, Knol AJ, Coutts JC, Hoare SF, Mulder NH et al (1996) Selection of a subpopulation with fewer DNA topoisomerase II alpha gene copies in a doxorubicin-resistant cell line panel. Br J Cancer 74(4):502–507 157. Yamamoto M, Maehara Y, Oda S, Ichiyoshi Y, Kusumoto T, Sugimachi K (1999) The p53 tumor suppressor gene in anticancer agent-induced apoptosis and chemosensitivity of human gastrointestinal cancer cell lines. Cancer Chemother Pharmacol 43(1):43–49

Chapter 6

Topoisomerase I Inhibitors – The Camptothecins Michael Newton, Gene Wetzstein, and Daniel Sullivan

6.1 Introduction

6.2 Chemistry

The camptothecins are a class of antineoplastic agents that inhibit the enzyme DNA topoisomerase I and have established activity in the treatment of various human malignancies. Camptothecin (CPT) was originally isolated in 1966 from the bark and stem of the native Chinese tree, Campotheca acuminate [155]. Although camptothecin demonstrated promising antitumor effects in animal systems , its utility was compromised in the clinical setting because of erratic absorption, insolubility, and severe toxicities. However, interest was renewed in the mid-1980s when the topoisomerase enzyme was identified as the cellular target of camptothecin. This led to the development of more soluble and less toxic camptothecin analogs with even greater preclinical anticancer activity, including the two FDA approved agents, irinotecan and topotecan. There are several other campothecin analogs in various stages of clinical investigation including SN-38, 9-aminocamptothecin (9-AC), 9-Nitrocamptothecin (9-NC), lurtotecan (GI-47211), rubitecan, OSI-211, exatecan mesylate (DX8951f), diflomotecan (BN80915), gimatecan (ST1481), CKD602, DB-67, and karenitecin (BNP1350). The advancement of these agents and further development within the class may further signify the importance of topoisomerase I inhibition as a major target for cancer chemotherapy [105].

The characteristic structural features of the camptothecins include a five-ring backbone in which a quinolone moiety on one end is attached to an α-hydroxy-δ-lactone ring at position C-20 (Fig. 6.1). The naturally occurring 20S-isomer of camptothecin inhibits purified topoisomerase I 10–100 times more potently than the 20R-isomer [157]. The electrophilic center and chemical reactivity of the lactone ring is essential for the camptothecins biological activity. Substitution at positions C-7, C-9, C-10 and C-11 of the aromatic A ring of the quinolone moiety can have positive effects on CPT potency and physical properties (Fig. 6.2) [75, 163]. At the same time, the lactone ring is also vulnerable to reversible hydrolysis to a less active carboxylate species at neutral and alkaline pH [36]. This reaction is reversible, pH dependent, and influenced by solution composition (Fig. 6.3).

D. Sullivan () Experimental Therapeutics Program and Department of Blood and Marrow Transplantation, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA e-mail: [email protected]

Fig. 6.1 Camptothecin backbone structure


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Fig. 6.2 Modification of camptothecin structure

Analogue

R1

R2

Topotecan

-H

CH2N(CH3)2 -OH

H

Irinotecan

CH2CH3

H

H

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BNP 1350

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OH

H

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F

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NH2

Exatecan

Lurtotecan

H

ST 1481

CH NOC(CH3)3

CKD 602

CH2CH2NHCH(CH3)2

H

H

H

H

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Fig. 6.3 Camptothecin lactone and carboxylate equilibrium

6.3 Mechanisms of Action Topoisomerase enzymes are found in all organisms. Their primary function is to alter DNA topology, which plays a critical role in facilitating replication, transcription, recombination and repair. DNA is packaged in cells in a highly compact, supercoiled state. DNA metabolism requires that the strands of the double helix be separated into their individual strands so that they can serve as templates for transcription and replication complexes. The separation of the individual strands results in torsional stress, both upstream and downstream on the double helix. Type I topoisomerases introduce a single stranded break in DNA, and then form a covalent intermediate with the 3’ end of the strand, resulting in the “cleavable complex” [156]. The cleaved strand is then able to swivel around the intact strand, resulting in DNA relaxation [19]. This releases the topographic constraints of supercoiled DNA and relieves torsional stress. Religation of the strand then occurs and topoisomerase I releases itself from the complex. The camptothecins form a complex with topoisomerase I, which stabilizes the normally transient bond between topoisomerase I and DNA. This reversible stabilization of the cleavable complex prevents the religation step. Irreversible double strand breaks occur when a replication fork collides with the cleavable complex, which is still bound. This leads to cell cycle arrest and cell death [64]. Topoisomerase I inhibitors exert these effects primarily during DNA or RNA synthesis, and are thus considered to be S-phase specific. The camptothecins also seem to inhibit angiogenesis [21]. Inhibition of hypoxia inducible factor 1 (HIF-1) accumulation is achieved by topotecan through a mechanism that is independent of replication mediated DNA damage [111]. HIF-1 is a major regulator of vascular endothelial growth factor (VEGF). In an in vitro study of neuroblastoma cell lines, topotecan

blocked insulin-like growth factor-1 induced HIF-1α, which resulted in a decrease in VEGF expression [4]. The precise mechanism through which topotecan inhibits HIF-1α remains to be determined; however it appears to be through a novel pathway involving topoisomerase I and independent of PI3k-Akt-mTOR pathway or HIF-1 degradation. Unlike the cytotoxic mechanism of the topoisomerase I inhibitors, this effect is cell cycle independent, and may guide future investigation in solid tumors with HIF-1 dependent responses.

6.4 Clinical Use 6.4.1 Irinotecan Irinotecan has exhibited activity in a number of solid tumors. It gained initial approval in the United States in 1996 for the treatment of metastatic carcinoma of the colon or rectum that has progressed during or after first-line chemotherapy with 5-fluorouracil. It was the first novel, effective treatment for colon cancer in decades. In 2000, irinotecan gained FDA indication as a component of first line therapy in combination with 5-FU and leucovorin for patients with metastatic carcinoma of the colon or rectum. Irinotecan has also been studied in several other tumor types, including other gastrointestinal malignancies, gliomas, sarcoma [7], breast cancer [103], lymphomas [133], and MDS [114]. Several phase II trials examining irinotecan’s activity as a second line agent in metastatic colon cancer revealed response rates ranging from 9 to 23%. Median response duration was 6–8 months and median overall survival was 8–13 months [2, 39, 147, 120, 121, 124]. Most of these studies utilized the dosing strategy of either 350 mg/m2 every 3 weeks or 125 mg/m2

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weekly for 4 weeks followed by two weeks of rest. In one of the studies an alternate dose of 100 mg/m2 substituted for the 125 mg/m2 dose resulted in suboptimal response rates without a reduction in toxicity [120]. Irinotecan’s clinical utility in second line treatment of metastatic colon cancer was confirmed by two subsequent phase III trials. The first trial randomized patients who had progressed on standard 5-FU therapy within 6 months to either receive best supportive care (BSC) or irinotecan 350 mg/m2 (300 mg/m2 in patients age 70 or older or with performance status of 2) every 3 weeks. Median survival was 9.2 months for the irinotecan group and 6.5 months for the BSC group (p = 0.0001). One year overall survival was 36.2% in the irinotecan group vs. 13.8% in the BSC group. Quality of life analysis favored the irinotecan group in all scores except diarrhea [27]. The second trial compared irinotecan to regimens that utilized a continuous infusion of 5-FU. The three 5-FU control regimens utilized in this trial were widely considered equivalent to one another at the time in Europe, and the regimen selected was left to the discretion of the individual physician. Median survival was 10.8 months for the group treated with an irinotecan containing regimen and 8.5 months for the 5-FU group (p = 0.035). There was not a statistically significant difference in survival between the different 5-FU groups. Progression free (4.2 months vs. 2.9 months) and one year survival (45% vs. 32%) also favored irinotecan. Quality of life scores were similar for both regimens [125]. Two international phase III trials led to the approval of irinotecan in first line therapy of metastatic colorectal cancer. The first trial compared irinotecan 125 mg/m2 combined with a bolus regimen of 5-FU + leucovorin weekly for 4 of 6 weeks with the “Mayo Clinic” 5-FU + leucovorin regimen, which consisted of 5-FU 425 mg/m2 per day combined with leucovorin 20 mg/m2 daily for 5 consecutive days every 4 weeks. A third arm received irinotecan alone. Overall median survival was found to be significantly longer in the irinotecan combination arm vs. 5-FU/leucovorin arm (14.8 vs. 12.6 months, p = 0.04). Response rates and progression free survival were also longer in the irinotecan combination arm. The single agent irinotecan arm had similar response and survival rates as the 5-FU + leucovorin arm [129]. The second trial utilized irinotecan in combination with 2 different infusional combinations of 5-FU/leucovorin. Comparator groups consisted of

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infusional 5-FU/leucovorin alone. Doses of irinotecan were based on the 5-FU infusional regimen selected. Once again, overall median survival was higher in the irinotecan arm (median 17.4 vs. 14.1 months, p = 0.031). Overall response was 41% vs. 23% in favor of the irinotecan group, and time to progression was also significantly in favor of the irinotecan group [33]. Neither of the first line trials showed that use of irinotecan contributed to a negative impact on quality of life. Irinotecan is widely used in combination with two recently introduced biologic agents for metastatic colon cancer. Cetuximab, a monoclonal antibody that inhibits the epidermal growth factor receptor (EGFR), exhibited a 23% partial response rate with 4.1 month time to progression when combined with irinotecan in those patients that had failed a previous irinotecanbased therapy [26]. Another monoclonal antibody, bevacizumab, which targets the vascular endothelial growth factor receptor ligand, has resulted in increased median survival for metastatic colon cancer patients to over 20 months when it is combined with an irinotecan and 5-FU containing regimen [65]. Unfortunately, irinotecan’s benefit in the metastatic setting has not translated to the adjuvant setting when added to 5-FU/leucovorin in high risk stage II and stage III colon cancer patients [130]. Irinotecan has demonstrated activity in solid tumor types other than colorectal cancer. A Japanese phase II trial found irinotecan to have high response rates in small cell lung cancer [78]. This led to a phase III trial in Japan that investigated irinotecan combined with cisplatin in comparison to etoposide and cisplatin in metastatic small cell lung cancer patients. Enrollment was terminated early as an interim analysis found a statistically significant increase in median survival in the irinotecan containing arm (12.8 vs. 9.4 months, p = 0.002) [98]. Notably, only 80.4% of planned dose intensity of irinotecan was delivered in this study due to toxicity. A confirmatory study was initiated in the United States, Canada and Australia utilizing the same combinations as the Japanese study with some dose modification intended to improve delivery and reduce toxicity; however, this study failed to demonstrate a statistically significant difference in response, time to progression or survival [55]. The failure of this study could be attributed to either the dosing differences between the studies or pharmacogenomic differences between North American and

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Japanese patient populations. In advanced non-small cell lung cancer (NSCLC), irinotecan has been shown to be a viable agent when used in combination with cisplatin, and is considered noninferior to other commonly used platinum based doublets in this patient population [101]. Irinotecan has also shown activity in pancreatic cancer in phase II trials, and a phase III trial utilizing irinotecan combined with gemcitabine showed increased response rates but no improvement in survival [117]. In Phase I/II trials, irinotecan has shown modest response rates between 6 and 15% in recurrent malignant glioma [3, 18, 22, 37, 107]. Many of these studies utilized dose-escalation strategies for patients receiving enzyme-inducing anti-epileptic drugs (EIAEDs) or corticosteroids as these agents alter the metabolism and elimination of irinotecan [51] (see Section 6.6). A phase II trial combining irinotecan with bevacizumab in recurrent glioblastoma showed compelling results, including an overall response rate of 57% and 6 month progression free survival (PFS) rate of 46% [153]. This resulted in wide adoption of the combination of bevacizumab and irinotecan as the regimen of choice for recurrent glioblastoma. The activity of this combination was confirmed recently in a phase II non-comparative trial that examined bevacizumab combined with irinotecan vs. bevacizumab alone [38]. In this study, the combination resulted in a response rate of 38% and a 6 month progression free survival of 50%. It should be noted that in the bevacizumab alone arm, response rate and 6 month PFS were 43 and 29% respectively. Since the study was not comparative, it is not possible to draw a conclusion as to whether irinotecan truly adds a significant benefit when combined with bevacizumab in recurrent gliomas.

6.4.2 Topotecan Topotecan has received regulatory approval in the United States for second line treatment of ovarian cancer, relapsed small cell lung cancer, and most recently, late stage or recurrent cervical cancer in combination with cisplatin. Topotecan has shown varying degrees of response in several other tumor types, including non-small cell lung cancer [69, 110], pediatric medulloblastoma [140], myelodysplastic syndrome [5] and multiple myeloma [76].

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In a phase II trial, topotecan was administered to patients diagnosed with stage III or IV ovarian cancer that failed to respond to first line therapy with a platinum-containing regimen. Patients who received topotecan 1.5 mg/m2 daily × 5 days per 3 week cycle had an overall response rate of 16.3%. In subgroups of cisplatin refractory, resistant and sensitive patients, the response rates were 5.9, 17.8, and 26.7% respectively [23]. A separate study found that topotecan 1.5 mg/m2 daily × 5 days every 3 weeks resulted in a 33% overall response rate when used upon relapse in platinum sensitive ovarian cancer patients [88]. A phase III trial compared the same topotecan regimen to paclitaxel 175 mg/m2 every 3 weeks in stage III or IV ovarian cancer patients who had progressed on a platinum containing regimen. The overall response rates for the intent to treat populations were 20.5% for the topotecan group and 13.2% for the paclitaxel group (p = 0.138). Time to progression was 23.1 weeks for topotecan and 14 weeks for paclitaxel (p = 0.002). There were no differences in overall survival [145]. Analysis of subsequent crossover between the two study groups upon progression demonstrated a degree of non-cross resistance between topotecan and paclitaxel [46]. A phase III study compared topotecan 1.5 mg/m2 daily × 5 to CAV (cyclophosphamide 1000 mg/m2 , doxorubicin 45 mg/m2 and vincristine 2 mg) every 21 days in small cell lung cancer (SCLC) patients who relapsed at least 60 days after standard first line therapy. Response rates, time to progression and median survival were not statistically different between the groups. Patients in the topotecan arm experienced greater symptom improvement and less grade 4 neutropenia [152]. Topotecan has also been shown to be a well tolerated and reasonable treatment choice in poorer performance status (ECOG PS 2) SCLC patients [146]. Topotecan has traditionally been available exclusively in an intravenous formulation. However, an oral formulation has been investigated, and recently received regulatory approval in the United States. A phase II trial compared an oral formulation of topotecan to intravenous topotecan in relapsed SCLC. This study found similar efficacy, less neutropenia, and greater convenience of administration for the oral formulation [151]. A subsequent phase III trial compared oral topotecan combined with cisplatin vs. etoposide and cisplatin in previously untreated

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extensive-disease SCLC patients. This study showed similar response rates, survival and tolerability for both regimens. There was a slight statistical advantage to the etoposide/cisplatin arm in time to progression and symptom improvement scores but these differences may not be clinically significant [34]. Oral topotecan has also shown activity similar to docetaxel in second line treatment of advanced non-small cell lung cancer [110]. Topotecan’s activity in advanced cervical cancer was identified in a phase II study that showed an objective response rate of 18.6% [94]. The dose of topotecan in this trial was 1.5 mg/m2 daily × 5 days every 4 weeks. A phase III study compared topotecan 0.75 mg/m2 /day × 3 days combined with cisplatin 50 mg/m2 against the standard single agent cisplatin 50 mg/m2 in this patient population. Doses were repeated in each arm every 3 weeks. A third arm utilizing the MVAC regimen (a combination of methotrexate, vinblastine, doxorucibin, and cisplatin) was closed due to deaths secondary to neutropenic sepsis in this group. The combination of topotecan and cisplatin had statistically superior outcomes, including overall survival (9.4 vs. 6.5 months, p = 0.017), and response rates (27% vs. 13%, p = 0.04) [81]. This trial led to FDA approval of topotecan in combination with cisplatin for the treatment of advanced or recurrent cervical cancer in the United States. Although its place in therapy remains an area requiring further research, topotecan has shown promise in hematologic malignancies. In relapsed or resistant multiple myeloma, topotecan exhibited an overall response rate of 16%, with a median survival of 28 months [76]. As a single agent, topotecan has shown a CR rate of 37% in myelodysplastic syndrome (MDS), often resulting in the disappearance of abnormal karyotypes [6]. When utilized in combination with cytarabine as an induction regimen in high risk MDS, topotecan resulted in complete response rates of 50–60%, including in those with poor-prognosis karyotypes and secondary MDS [5]. A retrospective analysis conducted at the MD Anderson Cancer Center showed similar CR and long term survival rates for induction therapy in MDS patients receiving topotecan combined with cytarabine compared with those receiving idarubicin and cytarabine. This analysis associated lower induction mortality rates with the topotecan regimen and suggests this combination may be an appropriate alternative for patients with contraindications to

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anthracyclines [70]. Topotecan has also been shown to be an active agent when combined with fludarabine and cytarabine in refractory AML [45].

6.5 Mechanisms of Resistance Mechanisms of resistance to camptothecins are not well understood and have been characterized mostly in preclinical studies. However, there appear to be several mechanisms by which resistance to camptothecins occur. Inadequate accumulation of drug in the tumor cells, alteration in the structure of topoisomerase I, or alterations in the cellular response to the topoisomerase 1-camptothecin complex are the primary general mechanisms by which clinically significant resistance occur [112]. Inadequate accumulation of active drug in the tumor cells can result from reduced uptake, increased efflux, or altered cellular metabolism. Cellular uptake of camptothecins occurs through both active and passive transport [48]. Active transport appears to be required for the influx of topotecan into ovarian cells [83]. It is unclear if alterations in cellular uptake contribute significantly to clinically relevant resistance to camptothecins. Cellular efflux however is likely to play a large role. As with many chemotherapy agents, membrane proteins belonging to the ATP-binding cassette superfamily (ABC) participate in active efflux of camptothecin derivatives. These transporters are widely studied due to their impact on a wide variety of agents. Over expression of P-glycoprotein is associated with resistance to many classes of cytotoxic compounds, including camptothecins [20]. Several members of the multi-drug resistance protein (MRP) family are also implicated in camptothecin resistance. The over expression of MRP4 appears to confer resistance to both topotecan and irinotecan [143, 144]. Breast Cancer Resistance Protein (BCRP) over expression may also play a role in resistance to some camptothecins [71, 109]. Alterations in the structure and expression of the topoisomerase I enzyme may also have an impact on camptothecin resistance. Cellular topoisomerase I levels exhibit a direct correlation with sensitivity to camptothecins [89]. Topoisomerase I levels vary widely between and within tumor types, and decreased topoisomerase I content is associated with low level

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resistance [137]. Mutations in the structure of topoisomerase I may play a more significant role in resistance to agents that target the enzyme. Structural mutations may or may not affect the enzyme’s activity, but can impact the targeting agent’s ability to bind and stabilize the Top1-DNA complex. Cellular processes that alter response or occur downstream of the camptothecin-TopI-DNA complex may also be important in resistance. DNA replication, damage checkpoint, and damage repair proteins appear to play a role. For example, the topoisomerase I/drug/DNA complexes can be removed and repaired by tyrosyl DNA phosphodiesterase (Tdp1) and polynucleotide kinase phosphatase (PNKP) [106]. Modifications in pro- and anti-apoptotic pathways occur that also may influence resistance to topoisomerase I targeting agents. Up-regulation of inhibitors of apoptosis bcl-2 and p21Waf1/Cip1 has been associated with resistance to camptothecins [162]. Treatment with camptothecins is followed by the downstream activation of the anti-apoptotic factor nuclear factor kappa B (NF-kB). Inhibition of this pathway could augment irinotecan-induced apoptosis [13].

6.6 Pharmacokinetics 6.6.1 Irinotecan The pharmacokinetic profile of irinotecan is complex, involving several metabolic pathways and genetic variability. Peak plasma concentrations of irinotecan occur immediately after short intravenous infusions of 30–90 min. Peak concentration is dose proportional, as is area under the curve (AUC), indicating linear pharmacokinetics (reviewed in [85]). Cleavage of its dipiperidino side chain via carboxylesterases forms the active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38). Peak concentrations of SN-38 occur approximately 1–2 h after infusion of irinotecan. SN-38 levels are approximately 100-fold lower than corresponding irinotecan concentrations, however SN-38 is between 100 and 1000 times more potent in topoisomerase I inhibition than the parent compound [17, 72]. SN-38 also has a longer terminal half life ranging from 6 to 47 h, vs. irinotecan’s 5 to 27 h. Most pharmacokinetic analyses of these compounds assume a two or three compartment model (Table 6.1).

109 Table 6.1 Pharmacokinetic parameters of Irinotecan and SN-38 Parameter Irinotecan (plasma) SN-38 (plasma) Tmax (hrs) 1.5 (90 min infusion) 1534 ± 143 Cmax (ng/ml) AUC (ng · h/ml) 8808 ± 2215 Vd (l/m2 ) 297 ± 119 14.6 (5–27)a t1/2 (h) CL (l/h/m2 ) 12.4 a Denotes range variation published in other studies Adapted from Slatter et al. [135]

2.32 27.1 ± 11.6 400 ± 242 28.5 (6–47)a pharmacokinetic

Irinotecan and SN-38 undergo pH dependent hydrolysis of the lactone ring, resulting in an open carboxylate form (Fig. 6.4). The carboxylate form is not able to passively diffuse across cell membranes, thus only the lactone form is able to function as an inhibitor of topoisomerase I. In comparison to irinotecan, the equilibrium for SN-38 is shifted more towards the active lactone form in the presence of human albumin. The lactone form of SN-38 accounts for a mean of approximately 64% of its total AUC, while irinotecan lactone accounts for 34–44% of total irinotecan AUC [85]. Protein binding of irinotecan is approximately 65% and does not differ significantly between the lactone and carboxylate forms [17]. SN-38 is 95% bound to plasma proteins, with the lactone form binding more potently than the carboxylate. Irinotecan’s volume of distribution at steady state is large, with reported values ranging from 76 to 297 l/m2 . The large volume of distribution is suggestive of extensive tissue penetration, but the specificity of penetration has not been published extensively. In a nonhuman primate model, cerebrospinal fluid concentrations of irinotecan were found to have an AUC(CSF):AUC(plasma) ratio of approximately 14%, while SN-38 carboxylate and lactone were not detectable [11]. A clinical trial conducted in Japan examining the combination of cisplatin and irinotecan in pleural mesothelioma patients found high concentrations of irinotecan and SN-38 in pleural fluid. The maximum concentrations of irinotecan and SN-38 in the pleural fluid were 36.5 and 75.8%, respectively, of the corresponding plasma values [96]. No clear evidence exists of excess accumulation or toxicity in patients with ascites or pleural effusion. Irinotecan is extensively metabolized into both active and inactive forms by various classes of

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Fig. 6.4 Conversion between lactone and carboxylate forms of irinotecan and SN-38 (modified from Tallman et al. [142])

enzymes, including carboxylesterases (CE), UDP glucuronosyl transferases (UGTs), Cytochrome P-450 3A isozymes (CYP3A), and ß-glucuronidases (Fig. 6.5). As mentioned previously, carboxylesterases are responsible for the conversion of irinotecan to the highly active metabolite SN-38. Carboxylesterases are present in the liver and intestine of humans, with human isotype CE-2 being predominantly responsible for conversion of irinotecan to SN-38 [132]. Intratumoral concentrations of CE-2 have large interindividual variation, but it remains unclear if this contributes to variation in therapeutic outcomes or toxicities [131]. Conversion velocity of irinotecan to SN-38 was found to be twofold higher for irinotecan lactone than carboxylate. This may be partially responsible for the predominance of SN-38 in its lactone form in plasma [53]. The cytochrome P-450 enzyme system has also been identified as a pathway of irinotecan metabolism. CYP3A4 mediated oxidation of the distal piperidine group at C10 of irinotecan forms the metabolite APC [52]. APC has little cytotoxic activity, and is a poor substrate for conversion to SN-38 by carboxylesterases. It also does not appear to contribute significantly to clinical toxicities [115]. NPC, another clinically important metabolite, is formed via CYP3A4 mediated cleavage of the distal piperidine ring of irinotecan [51]. Although this metabolite has very little inherent anti-tumor activity, it is a substrate of CE-2, which results in conversion to SN-38, and thus NPC may contribute the activity and toxicity of irinotecan [32]. Although other metabolites generated through CYP3A microsomes have been partially identified,

their exact chemical structure and clinical importance are not yet known. As a substrate for CYP3A4, irinotecan has the potential for serious drug interactions (see Section 6.10). Significant inhibition of the formation of NPC and APC has been observed with known CYP3A4 inhibitors such as ketoconazole [51]. Increased clearance of irinotecan was observed in malignant glioma patients receiving enzyme-inducing anti-epileptic drugs (EIAEDs) and steroids [37]. Concurrent use of EIAEDs with irinotecan increases the role of CYP3A4/5, shifting metabolism more toward APC and NPC rather than the highly active SN-38. This finding is clinically significant and resulted in a number of studies utilizing larger doses of irinotecan in those receiving EIAEDs. SN-38 undergoes glucuronidation in the liver to the inactive SN-38 glucuronide (SN-38G) [116]. The uridine-diphosphate glucuronosyltransferase isozyme 1A1 (UGT1A1) is thought to be the primary mediator of this inactivation [68], but UGT1A9 and extrahepatic UGT 1A7 [40] also play an important role. Patients with impaired ability to conjugate bilirubin (Gilbert syndrome, Crigler-Najjar syndrome) may not effectively conjugate SN-38 and are at increased risk of toxicities such as severe diarrhea [47]. Variation of UGT1A1 activity in patients receiving irinotecan has also been found to be responsible for excessive myelosuppression [66]. One genetic variant occurs in the TATA promoter region consisting of variable repeats of thymine-adenine (TA). The UGT1A1∗ 28 gene polymorphism, involving two alleles with seven TA repeats, has been identified as possibly having

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Fig. 6.5 Metabolic pathways of irinotecan (CPT-11) [85]

predictive value for lower SN-38 glucuronidation and greater susceptibility to irinotecan toxicity [67]. Approximately 10% of North Americans are homozygous (7 TA repeats on each allele, also abbreviated “7/7”) for this genotype [90]. These findings compelled the FDA in 2005 to include a warning on irinotecan’s package insert indicating that patients with the UGT1A1∗ 28 genotype were at increased risk for neutropenia and that a reduced initial irinotecan dosage should be considered. The FDA also approved a molecular assay that tests for the presence of the UGT1A1∗ 28 variant, but predictive power of the test is uncertain and specific dosage reduction recommendations are not available. Inconsistencies also exist in published data examining toxicity in patients with UGT1A1 mutations. For example, pediatric patients homozygous for the UGT1A1∗ 28

genotype who received low-dose irinotecan (15– 75 mg/m2 daily for 5 days for 2 consecutive weeks) did not experience increased toxicity despite higher SN-38 AUC values [141]. After glucuronidation of SN-38, SN-38G is secreted into the intestinal lumen via biliary excretion. Betaglucuronidase enzymes produced by intestinal flora result in intralumenal reactivation of SN-38. This mechanism likely contributes to mucosal damage and the severe late diarrhea associated with irinotecan treatment. In a small case-series, reduction in ß-glucuronidase activity via administration of neomycin resulted in reduced fecal concentrations of SN-38 and diarrhea, without affecting plasma exposure of irinotecan or its metabolites [74]. However, follow-up clinical trials have not produced evidence compelling enough to employ this strategy in clinical practice [29].

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Elimination of irinotecan also occurs via urinary and fecal excretion. The mean 24-h urinary excretion of irinotecan represents 17–25% of the dose, while SN-38 and SN-38 glucuronide account for 1–3% of the dose [17]. Cumulative biliary excretion of irinotecan and its metabolites ranges from 25 to 50% of the dose in 48 h [80]. Fecal excretion accounted for 24.4 ± 13.3% of the total dose [139]. Cyclosporin A has been shown to modulate the biliary excretion of irinotecan [49]. One small clinical trial in humans showed a reduction in irinotecan associated diarrhea when modulated with cyclosporine [31] but the potential impact on efficacy is not known.

6.6.1.1 Topotecan Topotecan undergoes rapid pH dependent, reversible hydrolysis of its lactone ring to an open ring carboxylate form. At physiological pH, the inactive carboxylate form predominates [58]. The ratio of topotecan lactone to total topotecan AUC is approximately 35%. Peak topotecan concentrations occur at the end of a 30 min infusion, with its major N-desmethyl metabolite peaking approximately 2 h later [86]. Topotecan exhibits linear two compartment kinetics at most common dosages [58]. The half life of topotecan is about 3 h, and its metabolite is 8.8 h. Protein binding is 1.5 to 1500 cells/mm3 and platelets > 100,000 cells/mm3 (Prod Info Hycamtin 2007) (Table 6.5).

6.8.2 Irinotecan No dosage adjustments for patients with renal insufficiency or failure are recommended. No specific dosage adjustments exist in patients with hepatic insufficiency. Dosing for patients with bilirubin > 2 mg/dL, or transaminase > 3 times upper limit of normal (ULN) with no liver metastasis, or transaminase > 5 times ULN with liver metastasis, cannot be recommended as there is insufficient information in this patient population. Patients with deficient glucuronidation of bilirubin, such as those with Gilbert’s syndrome, may be at greater risk of myelosuppression (Prod Info Camptosar 2007). Extreme caution should be taken when administering irinotecan to patients with impaired hepatic function and increased bilirubin, and a 43% reduction in dose has been recommended in individuals whose bilirubin is 1.5–3 times ULN [113, 150]. When administered in combination with other agents, or as a single agent, initial dose reductions should be considered in patients with any of the following conditions: age > 65 years, prior pelvic/abdominal radiotherapy, performance status of 2, increased bilirubin levels, or in patients known to be homozygous for the UGT1A1∗ 28 allele [123] (Prod Info Camptosar 2007). Subsequent dosing modifications should be based on worst preceding toxicities. Patients must be closely monitored for toxicity and assessed prior to each treatment. Subsequent dosing should be modified based upon individual tolerance to treatment regimen (see Tables 6.6 and 6.7). A new cycle of therapy should not be initiated until the toxicity has recovered to NCI grade I or less. Treatment may be delayed 1–2 weeks

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Table 6.6 Dose adjustment of irinotecan based on hematologic and nonhematologic toxicities when used in combination with fluorouracil and leucovorin CAMPTOSAR/5-Fluorouracil (5-FU)/Leucovorin (LV) Combination Schedules Patients should return to pre-treatment bowel function without requiring antidiarrhea medications for at least 24 h before the next chemotherapy administration. A new cycle of therapy should not begin until the granulocyte count has recovered to ≥l500 mm3, and the platelet count has recovered to ≥100,000 mm3 , and treatment-related diarrhea is fully resolved. Treatment should be delayed 1–2 weeks to allow for recovery from treatment-related toxicities. If the pa dent has not recovered after a 2-week delay, consideration should be given to discontinuing therapy

Toxicity NCI CTC gradea (value)

During a cycle of therapy

At the start of subsequent cycles of Therapy of therapyb

No toxicity

Maintain dose level

Maintain dose level

Neutropenia 1 (1500–1999 mm3 ) 2 (1000–1499 mm3 ) 3 (500–999 mm3 ) 4 ( pretxc ) 2 (4–6 stools/day> pretx) 3 (7–9 stools/day> pretx) 4 (≥10 stools/day> pretx)

Delay dove until resolved to baseline, then give same dose Omit dose until resolved to baseline, then ↓ 1 dose level Omit dose until resolved to baseline, then ↓ 1 dose level Omit dose until resolved to baseline, then ↓ 2 dose levels

Maintain dose level Maintain dose level ↓ dose level ↓ 2 dose levels

Other nonhematologic toxicitiesd 1 2 3 4

Maintain dose level Omit dose until resolved to ≤ grade 1, then ↓ 1 dose level Omit dose until resolved to ≤ grade 2, then ↓ 1 dose level Omit dose until resolved to ≤ grade 2, then ↓ 2 dose levels

Maintain dose level Maintain dose level ↓ 1 dose level ↓ 2 dose levels

For mucositis/stomatitis decrease only 5-FU, not CAMPTOSAR

For mucositis/stomatitis decrease only 5-FU, not CAMPTOSAR

a National

Cancer Institute Common Toxicity Criteria (version 1.0) to the starting dose used in the previous cycle c Pretreatment d Excludes alopecia, anorexia, asthenia b Relative

for recovery from treatment-related toxicity (Prod Info Camptosar 2007).

6.9 Toxicity 6.9.1 Topotecan Myelosuppression, primarily neutropenia, is the dose limiting toxicity (DLT) for all administration schedules of topotecan in solid tumor patients [15, 24, 25, 60,

79, 104, 126, 149]. It is dose related, reversible, and non-cumulative over time. The incidence of Grade IV neutropenia for the approved dosing regimen was 60% during the first course of treatment (Prod Info Hycamtin 2007). The nadir neutrophil count occurred at a median of 12 days with median duration being one week. Febrile neutropenia occurred in 23% of patients. Severe grade IV thrombocytopenia occurred in nearly 30% with a median duration of 5 days reaching its nadir at day 15. The degree of myelotoxicity appears to be related to administration schedule.

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Table 6.7 Dose modification of irinotecan when given as a single agent A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500 mm3 , and the platelet count has recovered to ≥100,000 mm3 , and treatment-related diarrhea is fully revolved. Treatment should be delayed 1–2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing CAMPTOSAR. Werst toxicity NCI gradeb (value)

During a cycle of therapy

At the start of the next cycles of therapy (after adequate recovery). compared with the starring dose in the previous cyclea

Weekly

Weekly

Once every 3 weeks

Maintain dose level

up to a ↑ 25 maximum dose of 150 mg/m2

Maintain dose level

mg/m2

No toxicity Neutropenia 1 (1500–1999 mm3 ) 2 (1000–1499 mm3 ) 3 (500–999 mm3 )

4 ( pretxc ) 2 (4–6 stools/day > pretx) 3 (7–9 stools/day > pretx)

4 (≥10 stools/day > pretx)

Maintain dose level Maintain dose level Maintain dose level ↓ 25 mg/m2 Maintain dose level Maintain dose level Omit dose until revolved to ↓ 25 mg/m2 ↓ 50 mg/m2 ≤ grade 2, then ↓ 25 mg/m2 Omit dose until revolved to ↓ 50 mg/m2 ↓ 50 mg/m2 ≤ grade 2, then ↓ 50 mg/m2 Omit dose until revolved, ↓ 50 mg/m2 ↓ 50 mg/m2 then v 50 nig in” when resolved Dose modifications for leucopenia, thrombocytopenia, and anemia during a cycle of therapy and at the start of subsequent cycles of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above. Maintain dose level ↓ 25 mg/m2 Omit dose until revolved to ≤ grade 2, then ↓ 25 mg/m2 Omit dose until revolved to ≤ grade 2, then ↓ 50 mg/m2

Other nonhematologicd toxicities 1 2 3

Maintain dose level Maintain dose level ↓ 25 mg/m2

Maintain dose level Maintain dose level ↓ 50 mg/m2

↓ 50 mg/m2

↓ 50 mg/m2

Maintain dose level Maintain dose level ↓ 25 mg/m2 ↓ 25 mg/m2 Omit dose until revolved to ↓ 25 mg/m2 ≤ grade 2, then ↓ 25 mg/m2 4 Omit dose until revolved to ↓ 50 mg/m2 ≤ grade 2, then ↓ 50 mg/m2 a All dose modifications should be based on the worst preceding toxicity b National Cancel Institute Common Toxicity Criteria (version 1.0) c Pretreatment d Excludes alopecia, anorexia, asthenia

In comparison to the standard dosing regimen, continuous infusion regimens have been associated with dose-limiting thrombocytopenia and anemia in addition to severe neutropenia [8, 24, 60, 108, 148].

Maintain dose level ↓ 50 mg/m2 ↓ 50 mg/m2 ↓ 50 mg/m2

At increased dosages of up to 4.5 mg/m2 in the acute leukemia setting, severe mucositis emerged as a complicating feature as well [127]. In addition, the dose-limiting toxicities were an unexpected

6


constellation of adverse events, consisting of high fevers, chills and rigors, sudden decreases in hematocrit, and hyperbilirubinemia. The precise etiology of these effects is unknown; however, high doses of topotecan may induce acute hemolytic reactions in this patient population. Myelosuppression with topotecan has tended to be more severe in patients that have received extensive prior therapy [14, 24] and those receiving concurrent cisplatin chemotherapy [91]. Non-hematologic toxicities are usually mild and self-limiting including nausea and vomiting, fatigue, stomatitis, headache, alopecia, fever, pain, and rash.

6.9.2 Irinotecan The DLT’s for all dosing regimens are severe lateonset diarrhea and neutropenia [85, 97, 122] (Prod Info R ). The incidence of grade III or IV Camptosar 2007 diarrhea was reported in up to 37% of patients in phase I clinical trials. The onset is typically between days 5 and 12 dependent upon dosing regimen and schedule with severe diarrhea lasting 5–7 days. It can be potentially life-threatening so patients should be carefully monitored for dehydration and supported with fluid and electrolyte replacement as needed. Management of diarrhea should include prompt treatment with high dose loperamide [1]. Neutropenia is dose-related, generally brief, and non-cumulative in nature. The frequency of severe neutropenia has been reported in 14– 47% of patients receiving the every 3 week schedule and to a lesser extent, 12–19%, with weekly administration [28, 120, 124, 125]. Patients who have had prior pelvic or abdominal irradiation or those with elevated bilirubin levels have significantly greater likelihood of severe neutropenia (Prod Info Camptosar 2007). Given Table 6.8 Topotecan interactions Agent Effect Phenytoin (Zamboni et al. [159]

Docetaxel (Zamboni et al. [158]

Neupogen (Slichenmyer et al. [136])

Increased topotecan Clearance

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the brief duration of severe neutropenia, the incidence of febrile neutropenia is low with an incidence of 3%. Early-onset diarrhea can occur during or within 24 h of administration. It is usually transient and is felt to be secondary to a cholinergic syndrome resulting from inhibition of acetyl cholinesterase activity. Symptoms may include: rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that can cause abdominal cramping and early-onset diarrhea. These effects are usually short-lasting and respond to atropine 0.5–1 mg IV or subcutaneous as needed. Prophylactic atropine may be considered for subsequent treatments [16]. Other non-hematologic adverse events that have been reported include: nausea and vomiting, abdominal pain, fatigue, alopecia, stomatitis, asthenia, fever, liver transaminase elevation, rash, flushing, and bradycardia. All are highly manageable and self-limiting.

6.10 Drug Interactions 6.10.1 Topotecan Pharmacokinetic studies of the interaction of topotecan with concomitantly administered medications have not been formally investigated. In vitro inhibition studies utilizing marker substrates known to be metabolized by human cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E, CYP3A, CYP4A), or dihydropyridine dehydrogenase indicated no alteration in enzyme activity by topotecan (Prod Info Hycamtin 2007). However, there have been reports of altered clearance in patients receiving concurrent treatment with agents that affect P-450 enzymes (see Table 6.8). These findings are consistent with a potential interaction at the CYP3A level, however, additional study is warranted to better define.

Proposed mechanism Induction of hepatic metabolism

Clinical management

Avoid concurrent therapy if possible; consider increasing dose of topotecan Docetaxel clearance decreased CYP3A4 inhibition altering Change administration by 50% when given on day 4 docetaxel metabolism schedule-administer of topotecan therapy docetaxel on day 1 Increased myelosuppression Increased precursors entering Initiated at least 24 h post S-phase topotecan administration

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Table 6.9 Irinotecan interactions Agent Effect Ketoconazole [73]

St John’s Wort [87]

Enzyme-inducing anti-epileptic May decrease antineoplastic drugs i.e. phenytoin, activity carbamazepine, phenobarbital, valproic acid [41, 50, 54, 95, 107] Dexamethasone chronic May decrease antineoplastic dosing [37] activity

Bevacizumab (Bevacizumab Presribing Info 2006, Genentech) Atazanavir [102]

Proposed mechanism

SN-38 AUC increased by CYP3A4 inhibition 109% while APC was reduced by 87% SN-38 AUC decreased by 42% CYP3A4 induction

Concurrent utilization is contraindicated Induction of hepatic May need to increase irinotecan metabolization via CYP3A4 dose for therapeutic effect or or glucuronidation utilization of a non-enzyme inducing anti-epileptic Induction of hepatic metabolism and increased clearance

SN-38 increased by 33%

Unknown

May increase risk of toxicity

UGT1A1 inhibition

6.10.2 Irinotecan As previously described (see Section 6.6), the metabolism of irinotecan is complex (Fig. 6.5) involving several enzyme systems, including carboxyl esterase isoenzymes, glucuronidation, and CYP3A4mediated oxidation. As a result, the potential for multiple drug interactions exist. The extent and clinical impact of the interaction is dependent upon the enzyme system affected (Table 6.9). Concurrent administration of ketoconazole and St Johns Wort with irinotecan is contraindicated (Product Info Camptosar 2007). And although limited data exists with drug-drug interactions, clinicians must be conscientious of the potential effects when prescribing agents that may interfere with the metabolism of irinotecan as the consequences may be significant.

3.

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58. Herben VM, ten Bokkel Huinink WW, Beijnen JH (1996) Clinical pharmacokinetics of topotecan. Clin Pharmacokinet 31:85–102 59. Herben VMM, Schoemaker NE, Rosing H et al (2002) Urinary and fecal excretion of topotecan in patients with malignant solid tumours. Cancer Chemother Pharmacol 50:59–64 60. Hochster H, Liebes L, Speyer J et al (1994) Phase I trial of low-dose continous topotecan infusion in patients with cancer: an active and well-tolerated regimen. J Clin Oncol 12: 553–559 61. Hochster HS, Plimack ER, Mandeli J et al (2006) Prolonged topotecan infusion with cisplatin in the firstline treatment of ovarian cancer: an nygog and ecog study. Gynecol Oncol 100:324–329 62. Hofstra LS, Bos AM, de Vries EG et al (2001) A phase I and pharmacokinetic study of intraperitoneal topotecan. Br J Cancer 85:1627–1633 63. Homesley HD, Hall DJ, Martin DA et al (2001) A dose-escalating study of weekly bolus topotecan in previously treated ovarian cancer patients. Gynecol Oncol 83: 394–399 64. Hsiang YH, Lihou MG, Liu LF (1989) Arrest of replication forks by drug-stabilized topoisomerase I dna cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res 49:5077–5082 65. Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350: 2335–2342 66. Innocenti F, Undevia SD, Iyer L et al (2004) Genetic variants in the udp-glucuronosyltransferase 1a1 gene predict the risk of severe neutropenia of irinotecan J Clin Oncol 22:1382–1388 67. Iyer L, Das S, Janisch L et al (2002) Ugt1a1∗ 28 polymorphism as a determinant of irinotecan disposition and toxicity. Pharmacogenomics J 2:43–47 68. Iyer L, King CD, Whitington PF et al (1998) Genetic predisposition to the metabolism of irinotecan (cpt-11). role of uridine diphosphate glucuronosyltransferase isoform 1a1 in the glucuronidation of its active metabolite (sn-38) in human liver microsomes. J Clin Invest 101: 847–854 69. Joppert MG, Garfield DH, Gregurich MA et al (2003) A phase II multicenter study of combined topotecan and gemcitabine as first line chemotherapy for advanced nonsmall cell lung cancer. Lung Cancer 39:215–219 70. Kantarjian H, Beran M, Cortes J et al (2006) Long-term follow-up results of the combination of topotecan and cytarabine and other intensive chemotherapy regimens in myelodysplastic syndrome. Cancer 106:1099–1109 71. Kawabata S, Oka M, Shiozawa K et al (2001) Breast cancer resistance protein directly confers SN-38 resistance of lung cancer cells. Biochem Biophys Res Commun 280:1216–1223 72. Kawato Y, Aonuma M, Hirota Y et al (1991) Intracellular roles of sn-38, a metabolite of the camptothecin derivative cpt-11, in the antitumor effect of cpt-11. Cancer Res 51:4187–4191 73. Kehrer DFS, Mathijssen RHJ, Verweij, J et al (2002) Modulation of irinotecan metabolism by ketoconazole. J Clin Oncol 20:3122–3129

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Topoisomerase I Inhibitors – The Camptothecins 74. Kehrer DF, Sparreboom A, Verweij J et al (2001) Modulation of irinotecan-induced diarrhea by cotreatment with neomycin in cancer patients. Clin Cancer Res 7:1136–1141 75. Kingsbury WD, Boehm JC, Jakas DR et al (1991) Synthesis of water-soluble (aminoalkyl) camptothecin analogues: inhibition of topoisomerase I and antimtumor activity. J Med Chem 34:98–107 76. Kraut EH, Crowley JJ, Wade JL et al (1998) Evaluation of topotecan in resistant and relapsing multiple myeloma: a southwest oncology group study. J Clin Oncol 16: 589–592 77. Kruijtzer CMF, Beijnen JH, Rosing H et al (2002) Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and p-glycoprotein inhibitor gf120918. J Clin Oncol 20: 2943–2950 78. Kudoh S, Fujiwara Y, Takada Y et al (1998) Phase ii study of irinotecan combined with cisplatin in patients with previously untreated small-cell lung cancer. west japan lung cancer group. J Clin Oncol 16:1068–1074 79. Law TM, Iison DH, Motzer RJ (1994) Phase II trial of topotecan in patients with advanced renal cell carcinoma. Invest New Drugs 12:143–145 80. Lokiec F, Canal P, Gay C et al (1995) Pharmacokinetics of irinotecan and its metabolites in human blood, bile, and urine. Cancer Chemother Pharmacol 36:79–82 81. Long HJ, Bundy BN, Grendys ECJ et al (2005) Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a gynecologic oncology group study. J Clin Oncol 23: 4626–4633 82. Lotz J, Pautier P, Selle F et al (2006) Phase I study of high-dose topotecan with haematopoietic stem cell support in the treatment of ovarian carcinomas: the ITOV 01 protocol. Bone Marrow Transplant 37:669–675 83. Ma J, Maliepaard M, Nooter K et al (1998) Reduced cellular accumulation of topotecan: a novel mechanism of resistance in human ovarian cancer cell line. Br J Cancer 77:1645–1652 84. Maliepaard M, van Gastelen MA, de Jong LA et al (1999) Overexpression of the bcrp/mxr/abcp gene in a topotecan-selected ovarian tumor cell line. Cancer Res 59:4559–4563 85. Mathijssen RH, van Alphen RJ, Verweij J et al (2001) Clinical pharmacokinetics and metabolism of irinotecan (cpt-11). Clin Cancer Res 7:2182–2194 86. Mathijssen RHJ, Loos WJ, Verweij J et al (2002) Pharmacology of topoisomerase I inhibitors irinotecan (cpt-11) and topotecan. Curr Cancer Drug Targets 2: 103–123 87. Mathijssen RHJ, Verweij, J, de Bruijn P et al (2002) Effects of St John’s wort on irinotecan metabolism. J Natl Cancer Inst 94: 1247–1249 88. McGuire WP, Blessing JA, Bookman MA et al (2000) Topotecan has substantial antitumor activity as first-line salvage therapy in platinum-sensitive epithelial ovarian carcinoma: a gynecologic oncology group study. J Clin Oncol 18:1062–1067 89. McLeod HL, Keith WN (1996) Variation in topoisomerase I gene copy number as a mechanism for intrinsic drug sensitivity. Br J Cancer 74:508–512

121 90. McLeod HL, Watters JW (2004) Irinotecan pharmacogenetics: is it time to intervene? J Clin Oncol 22:1356–1359 91. Miller AA, Lilenbaum RC, Lynch TJ et al (1996) Treatment-related fatal sepsis from topotecan/cisplatin and topotecan/paclitaxel. J Clin Oncol 14:1964–1965 92. Morris RT (2003) Weekly topotecan in the management of ovarian cancer. Gynecol Oncol 90:S34–S38 93. Mould DR, Holford NHG, Schellens JHM et al (2002) Population pharmacokinetic and adverse event analysis of topotecan in patients with solid tumors. Clin Pharmacol Ther 71:334–348 94. Muderspach LI, Blessing JA, Levenback C et al (2001) A phase ii study of topotecan in patients with squamous cell carcinoma of the cervix: a gynecologic oncology group study. Gynecol Oncol 81:213–215 95. Murry DJ, Cherrick I, Salama V et al (2002) Influence of phenytoin on the disposition of irinotecan: a case report. J Pediatr Hematol Oncol 24:130–133 96. Nakano T, Chahinian AP, Shinjo M et al (1999) Cisplatin in combination with irinotecan in the treatment of patients with malignant pleural mesothelioma: a pilot phase ii clinical trial and pharmacokinetic profile. Cancer 85: 2375–2384 97. Negoro S, Fukuoka M, Masuda N et al (1991) Phase I study of weekly intravenous infusions of CPT-11, a new derivative of camptothecin, in the treatment of advanced non-small-cell lung cancer. J Natl Cancer Inst 83: 1164–1168 98. Noda K, Nishiwaki Y, Kawahara M et al (2002) Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer N Engl J Med 346: 85–91 99. O’Reilly S, Rowinsky E, Slichenmyer W et al (1996) Phase I and pharmacologic studies of topotecan in patients with impaired hepatic function. J Natl Cancer Inst 88: 817–824 100. O’Reilly S, Rowinsky EK, Slichenmyer W et al (1996) Phase I and pharmacologic study of topotecan in patients with impaired renal function. J Clin Oncol 14:3062–3073 101. Ohe Y, Ohashi Y, Kubota K et al (2007) Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan. Ann Oncol 18:317–323 102. Orrick JJ, Steinhart CR (2004) Atazanavir. Ann Pharmacother 38:1664–1674 103. Perez EA, Hillman DW, Mailliard JA et al (2004) Randomized phase II study of two irinotecan schedules for patients with metastatic breast cancer refractory to an anthracycline, a taxane, or both. J Clin Oncol 22: 2849–2855 104. Perez-Soler R, Glisson BS, Lee JS et al (1996) Treatment of patients with small-cell lung cancer refractory to teniposide and cisplatin with the topoisomerase I poison topotecan. J Clin Oncol 14:2785–2790 105. Pizzolato JF, Saltz LB (2003) The camptothecins. Lancet 361:2235–2242 106. Plo I, Liao ZY, Barcelo JM et al (2003) Association of XRCC1 and tyrosyl DNA phosphodiesterase (Tdp1) for the repair of topoisomerase I-mediated DNA lesions. DNA Repair 2:1087–1100

122 107. Prados MD, Lamborn K, Yung WKA et al (2006) A phase 2 trial of irinotecan (cpt-11) in patients with recurrent malignant glioma: a North American brain tumor consortium study Neuro Oncol 8:189–193 108. Pratt CB, Steward C, Santana VM et al (1994) Phase I study of topotecan for pediatric patients with malignant solid tumors. J Clin Oncol 12:539–543 109. Rajendra R, Gounder MK, Saleem A et al (2003) Differential effects of the breast cancer resistance protein on the cellular accumulation and cytotoxicity of 9-aminocamptothecin and 9-nitrocamptothecin. Cancer Res 63:3228–3233 110. Ramlau R, Gervais R, Krzakowski M et al (2006) Phase III study comparing oral topotecan to intravenous docetaxel in patients with pretreated advanced non-small-cell lung cancer. J Clin Oncol 24:2800–2807 111. Rapisarda A, Uranchimeg B, Sordet O, Pommier Y, Shoemaker RH, Melillo G (2004) Topoisomerase I mediated inhibition of hypoxia inducible factor 1: mechanism and therapeutic inplications. Cancer Res 64: 1475–1482 112. Rasheed ZA, Rubin EH (2003) Mechanisms of resistance to topoisomerase I-targeting drugs. Oncogene 22: 7296–7304 113. Raymond E, Boige V, Faivre S et al (2002) Dosage adjustment and pharmacokinetic profile of irinotecan in cancer patients with hepatic dysfunction. J Clin Oncol 20:4303–4312 114. Ribrag V, Suzan F, Ravoet C et al (2003) Phase II trial of cpt-11 in myelodysplastic syndromes with excess of marrow blasts. Leukemia 17:319–322 115. Rivory LP, Riou JF, Haaz MC et al (1996) Identification and properties of a major plasma metabolite of irinotecan (cpt-11) isolated from the plasma of patients. Cancer Res 56:3689–3694 116. Rivory LP, Robert J (1995) Identification and kinetics of a beta-glucuronide metabolite of sn-38 in human plasma after administration of the camptothecin derivative irinotecan. Cancer Chemother Pharmacol 36:176–179 117. Rocha Lima CM, Green MR, Rotche R et al (2004) Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol 22:3776–3783 118. Rosing H, Herben VM, van Gortel-van Zomeren DM et al (1997) Isolation and structural confirmation of n-desmethyl topotecan, a metabolite of topotecan. Cancer Chemother Pharmacol 39:498–504 119. Rosing H, van Zomeren DM, Doyle E et al (1998) O-glucuronidation, a newly identified metabolic pathway for topotecan and n-desmethyl topotecan. Anticancer Drugs 9:587–592 120. Rothenberg ML, Cox JV, DeVore RF et al (1999) A multicenter, phase II trial of weekly irinotecan (cpt-11) in patients with previously treated colorectal carcinoma. Cancer 85:786–795 121. Rothenberg ML, Eckardt JR, Kuhn JG et al (1996) Phase II trial of irinotecan in patients with progressive or rapidly recurrent colorectal cancer. J Clin Oncol 14: 1128–1135

M. Newton et al. 122. Rothenberg M, Kuhn J, Burris H et al (1993) Phase I and pharmacokinetic trial of weekly CPT-11. J Clin Oncol 11:2194–2204 123. Rougier P, Bugat R (1996) CPT-11 in the treatment of colorectal cancer: clinical efficacy and safety profile. Semin Oncol 23: 34–41 124. Rougier P, Bugat R, Douillard JY et al (1997) Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy. J Clin Oncol 15:251–260 125. Rougier P, Van Cutsem E, Bajetta E et al (1998) Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer. Lancet 352:1407–1412 126. Rowinski EK, Grochow LB, Hendricks CB et al (1992) Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor. J Clin Oncol 10:647–656 127. Rowinski EK, Kaufmann SH, Baker SD et al (1996) A Phase I and pharmacological study of topotecan infused over 30 minutes for five days in patients with refractory acute leukemia. Clin Cancer Res 2:1921–1930 128. Safra T, Menczer J, Bernstein R et al (2007) Efficacy and toxicity of weekly topotecan in recurrent epithelial ovarian and primary peritoneal cancer. Gynecol Oncol 105: 205–210 129. Saltz LB, Cox JV, Blanke C et al (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan study group. N Engl J Med 343:905–914 130. Saltz LB, Niedzwiecki D, Hollis D et al (2007) Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage iii colon cancer: results of calgb 89803. J Clin Oncol 25:3456–3461 131. Sanghani SP, Quinney SK, Fredenburg TB et al (2003) Carboxylesterases expressed in human colon tumor tissue and their role in cpt-11 hydrolysis. Clin Cancer Res 9:4983–4991 132. Sanghani SP, Quinney SK, Fredenburg TB et al (2004) Hydrolysis of irinotecan and its oxidative metabolites, 7-ethyl-10-[4-n-(5-aminopentanoic acid)-1piperidino] carbonyloxycamptothecin and 7-ethyl-10[4-(1-piperidino)-1-amino]-carbonyloxycamptothecin, by human carboxylesterases ces1a1, ces2, and a newly expressed carboxylesterase isoenzyme, ces3. Drug Metab Dispos 32:505–511 133. Sarris AH, Phan A, Goy A et al (2002) Irinotecan in relapsed or refractory non-hodgkin’s lymphomas. indications of activity in a phase ii trial. Oncology (Williston Park) 16:27–31 134. Schellens JH, Creemers GJ, Beijnen JH et al (1996) Bioavailability and pharmacokinetics of oral topotecan: a new topoisomerase i inhibitor. Br J Cancer 73:1268–1271 135. Slatter JG, Schaaf LJ, Sams JP et al (2000) Pharmacokinetics, metabolism, and excretion of irinotecan (cpt-11) following i.v. infusion of [(14)c]cpt-11 in cancer patients. Drug Metab Dispos 28:423–433 136. Slichenmyer WJ, Rowinsky EK, Donehower RC, Kaufmann SH (1993) The current status of camptothecin analogues as antitumor agents. J Natl Cancer Inst 85:271–291

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137. Sorensen M, Sehested M, Jensen PB (1995) Characterisation of a human small-cell lung cancer cell line resistant to the DNA topoisomerase I-directed drug topotecan. Br J Cancer 72:399–404 138. Spannuth WA, Leath CA3, Huh WK et al (2007) A phase II trial of weekly topotecan for patients with secondary platinum-resistant recurrent epithelial ovarian carcinoma following the failure of second-line therapy. Gynecol Oncol 104:591–595 139. Sparreboom A, de Jonge MJ, de Bruijn P et al (1998) Irinotecan (cpt-11) metabolism and disposition in cancer patients. Clin Cancer Res 4:2747–2754 140. Stewart CF, Iacono LC, Chintagumpala M et al (2004) Results of a phase II upfront window of pharmacokinetically guided topotecan in high-risk medulloblastoma and supratentorial primitive neuroectodermal tumor. J Clin Oncol 22:3357–3365 141. Stewart CF, Panetta JC, O’Shaughnessy MA et al (2007) UGT1A1 promoter genotype correlates with sn-38 pharmacokinetics, but not severe toxicity in patients receiving low-dose irinotecan J Clin Oncol 25:2594–2600 142. Tallman MN, Ritter JK, Smith PC (2005) Differential rates of glucuronidation for 7-ethyl-10-hydroxycamptothecin (sn-38) lactone and carboxylate in human and rat microsomes and recombinant udpglucuronosyltransferase isoforms. Drug Metab Dispos 33: 977–983 143. Tian Q, Zhang J, Chan Sy et al (2006) Topotecan is a substrate for multidrug resistance associated protein 4. Curr Drug Metab 7:105–118 144. Tian Q, Zhang J, Tan TM et al (2005) Human multidrug resistance associated protein 4 confers resistance to camptothecins. Pharm Res 22:1837–1853 145. ten Bokkel Huinink W, Gore M, Carmichael J et al (1997) Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol 15:2183–2193 146. Treat J, Huang CH, Lane SR et al (2004) Topotecan in the treatment of relapsed small cell lung cancer patients with poor performance status. Oncologist 9:173–181 147. Tsavaris N, Polyzos A (1998) Irinotecan (cpt11) in patients with advanced colon carcinoma (acc) relapsing after 5-fluorouracil (5-fu)-leucovorin (lv) combination (meeting abstract). Proc Am Soc Clin Oncol (Abstract 1171) 17:304a 148. Van Warmerdam LJC, Ten Bokkel Huinink WW, Rodenhuis S et al (1995) Phase I clinical and pharmacokinetic study of topotecan administered by a 24-hour continuous infusion. J Clin Oncol 13:1768–1776 149. Van Warmerdam LJC, Verweij J, Schellens JHM et al (1995) Pharmacokinetics and pharmacodynamics of topotecan administered daily for 5 days every 3 weeks. Cancer Chemother Pharmacol 35:237–245 150. Venook AP, Enders Klein C, Fleming G et al (2003) A phase I and pharmacokinetic study of irinotecan in patients with hepatic or renal dysfunction or with prior pelvic radiation: CALGB 9863. Ann Oncol 14:1783–1790

123 151. von Pawel J, Gatzemeier U, Pujol JL et al (2001) Phase II comparator study of oral versus intravenous topotecan in patients with chemosensitive small-cell lung cancer. J Clin Oncol 19:1743–1749 152. von Pawel J, Schiller JH, Shepherd FA et al (1999) Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 17:658–667 153. Vredenburgh JJ, Desjardins A, Herndon JE et al (2007) Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 25:4722–4729 154. Vredenburgh JJ, Desjardins A, Herndon JE et al (2007) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma Clin Cancer Res 13: 1253–1259 155. Wall ME, Wani MC, Cook CE et al (1966) Plant antitumor agents, I: the isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibition from Campotheca acuminata. J Am Chem Soc 88: 3888–3890 156. Wang JC (1996) DNA topoisomerases. Annu Rev Biochem 65:635–692 157. Wani MC, Nicholas AW, Wall ME (1987) Plant antitumor agents. 28. Resolution of a key tricyclic synthon, 5’ (RS)-1,5-dioxo-5’-ethyl’-hydroxy-2’H, 5’H, 6’H-6’oxopyranol [3’,4’-fJdelta 6,8-tetrahydro-indolizine: total R synthesis and antitumor activity of 20(S)- and 20 camptochecin. J Med Chem 30:2317–2319 158. Zamboni WC, Egorin MJ, Van Echo DA et al (2000) Pharmacokinetic and pharmacodynamic study of the combination of docetaxel and topotecan in patients with solid tumors. J Clin Oncol 18(18): 3288–3294 159. Zamboni WC, Gajjar AJ, Heideman RL et al (1998) Phenytoin alters the disposition of topotecan and N-desmethyl topotecan in a patient with medulloblastoma. Clin Cancer Res 4(3):783–789 160. Zamboni WC, Gajjar AJ, Mandrell TD et al (1998) A four-hour topotecan infusion achieves cytotoxic exposure throughout the neuraxis in the nonhuman primate model: implications for treatment of children with metastatic medulloblastoma. Clin Cancer Res 4: 2537–2544 161. Zamboni WC, Lüftner DI, Egorin MJ et al (2001) The effect of increasing topotecan infusion from 30 minutes to 4 hours on the duration of exposure in cerebrospinal fluid. Ann Oncol 12:119–122 162. Zhang Y, Fujita N, Tsuruo T (1999) p21Waf/Cip1 acts in synergy with bcl-2 to confer multidrug resistance in a camptothecins-selected human lung-cancer cell line. Int J Cancer 83:790–797 163. Zunino F, Dallavalle S, Laccabue S, Beretta G, Merlini L, Pratesi G (2002) Current status and perspectives in the development of camptothecins. Curr Pharm Design 8:2505–2520

Chapter 7

Folate Antagonists Alex Ko

7.1 Introduction Folate antagonists, or antifolates, are cytotoxic drugs that have been extensively used for a wide range of diseases. They are part of chemotherapy regimens against many solid and hematologic malignancies, including acute lymphoblastic lymphoma (ALL), choriocarcinoma, osteosarcoma, lymphoma, and cancers of the breast, bladder, and head and neck. Lower doses are given to treat several nonmalignant diseases, including rheumatoid arthritis, systemic lupus erythematosus (SLE), psoriasis, inflammatory bowel disease, graftversus-host disease, and various bacterial, fungal, and protozoal infections. Methotrexate (4-amino-4-deoxy10-N-methyl-pteroylglutamic acid, MTX), introduced over 50 years ago, continues to be the most widely used of the antifolates and its use in cancer treatments will be the focus of this review.

7.2 Historical Background Folate antagonists were originally developed as antileukemic agents. In the early 1940s, the combined observation that many patients with acute leukemia suffered from folate deficiency and that bone marrow megaloblasts of folate-deficient patients morphologically resemble leukemic blasts led to the theory

A. Ko () UCSD Department of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA e-mail: [email protected]; [email protected]

that folate deficiency was the prime culprit in the development of leukemia. However, administration of folic acid, first isolated from spinach in 1941 and synthesized in 1945 [1], to patients with leukemia not only failed to be curative, but also often accelerated the course of disease in patients with acute leukemia and chronic myelocytic leukemia [2]. This finding led to experiments studying the effect of treatment with antagonistic folate analogues to mimic folate deficiency in leukemia patients. In a landmark study, Farber and colleagues showed that aminopterin (AMT), one of the first folate analogues, was able to produce temporary remissions in 5 of 16 children with acute leukemia [3], proving for the first time that an antimetabolite could be antineoplastic. Methotrexate (MTX) soon replaced AMT in the 1950s because of its greater safety profile [4], and its antifolate action was soon shown to be the result of its inhibition of the enzyme dihydrofolate reductase (DHFR). Newer analogues of folates or MTX have since been developed in response to increased cellular resistance to MTX or to target other folate-dependent processes. They are now used to treat a wide variety of malignant and non-malignant diseases.

7.3 Folate Metabolism Folate is a B-vitamin that functions as a single-carbon donor essential for nucleotide, methionine, and consequently, DNA synthesis required for normal cell growth and replication. The folate enters the cell via the reduced folate carrier (RFC), which has a high affinity for reduced folates, such as monoglutammate 5-methyltetrahydrofolate (5-Me-THF), the commonly


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circulating and active form of folate. Once the folate is inside the cell, folylpolyglutamyl synthase (FPGS) adds glutamyl groups to the y-glutamyl group of the folate molecule, trapping it within the cell. Conversely, y-glutamyl hydrolase (GGH) is able to cleave glutamyl groups off the polyglutamated folate. This balance between FPGS and GGH is one important mechanism used to regulate intracellular folate levels, as well as folate antagonist and TS inhibitor levels. 5-Me-THF then serves as a methyl-group donor for the conversion of homocysteine to methionine synthase (MS). THF is converted to 5,10-methylene-THF by either serine hydroxylmethyltransferase (SHMT) or the trifunctional methylenetetrahydrofolate dehydrogenase (MTHFD) enzyme complex. 5,10-methylene-THF is an important substrate in folate metabolism that can be directed towards thymidine, purine, or methionine synthesis depending on its intracellular concentration. Thymidylate synthase (TS) is the limiting irreversible step in de novo DNA synthesis, catalyzing the transfer of a methyl group from 5,10-methylene-THF to deoxyuridine monophosphate (dUMP), creating deoxythymidine monophosphate (dTMP) and dihydrofolate (DHF). The DHF is then recycled back to THF by the enzyme dihydrofolate reductase (DHFR). Both THF and 5,10-methylene-THF can enter the purine synthesis pathway by the addition of a formyl group. The enzyme methylenetetrahydrofolate reductase (MTHFR) can reduce 5,10-methylene-THF and is a key regulatory enzyme that can direct available folate towards the methylation of homocysteine.

7.4 Mechanism of Action of Folate Antagonists Folate antagonists are cytotoxic drugs that inhibit folate production by competing with folates for uptake into cells, by inhibiting folate coenzyme formation, or by inhibiting any of the reactions mediated by folate coenzymes. Today, the most effective and extensively used drugs work by inhibiting dihydrofolate reductase (DHFR) or thymidylate synthase (TS). Structurally similar to folate, folate antagonists are pterin compounds that have their 4-hydroxyl group substituted by an amino group, resulting in a folate analogue with a several thousand-fold increase in affinity for

A. Ko

these folate coenzymes. In MTX’s case, that enzyme is primarily DHFR. Binding to and inhibiting DHFR blocks the production of reduced folates needed for de novo thymidine synthesis [5]. The insufficient conversion of dUMP to dTMP results in uracil misincorporation into DNA strands during replication, leading to increased double-strand DNA breaks during uracil excision repair. There is also evidence that high dose MTX inhibits THF formation, leading to inhibition of purine synthesis and rapid cell death in lymphoblasts [6]. There are two additional mechanisms by which MTX exerts its antineoplastic action. The first includes the inhibition of folate-dependent remethylation of homocysteine to methionine, causing increased intracellular levels of homocysteine and a secondary elevation in S-adenosyl-homocysteine (SAH), a potent inhibitor of many folate-dependent methylation reactions, including the membrane localization of ras [7], a critical signal transduction protein that is constitutively activated in many human cancers. It has also been shown that MTX can inhibit endothelial cell proliferation [8], which may contribute to both its antineoplastic and anti-inflammatory properties when given in sub-cytotoxic amounts. These findings are consistent with several studies that have shown that intracellular reduced folates are depleted by only 50–70% after malignant cells are exposed to inhibitory concentrations of MTX, which insufficiently accounts for the observed inhibition in DNA synthesis [9]. Another group of widely used folate-related drugs include the activated metabolites of fluoropyrimidine, such as 5-fluorouracil (5-FU). This drug is structurally similar to pyrimidine nucleotides and inhibits TS by forming a covalently bound ternary complex with the enzyme. Newer drugs aim at targeting multiple folatemetabolizing enzymes including TS, DHFR, and two of the rate limiting steps of de novo purine synthesis, glycinamide ribonucleotide transformylase (GARFT) and aminoimidazole carboxamide ribonucleotide transformylase (AICARFT) [10]. Since folate is needed for DNA synthesis and repair, rapidly dividing cells such as hematopoietic cells and those found in the gastrointestinal tract are most affected. Hence, folate antagonists are frequently used against gastrointestinal and hematopoietic cancers. For the same reasons, toxicities are also most apparent at these sites. MTX’s action, and consequently, its toxic effects, can

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Folate Antagonists

be prevented or reversed by coadministration of leucovorin (LV), a THF derivative readily converted to reduced folic acid derivatives in a DHFR-independent process. This is often referred to as “LV rescue.”

7.4.1 Pharmacokinetics 7.4.1.1 Absorption Plasma concentrations peak 1–5 h after an oral dose of 15–30 mg/m2 . Since food, antibiotics, and bile salts can decrease the absorption rate, it is recommended that MTX be taken with clear liquids on an empty stomach. While there is some evidence in the unpredictability of oral MTX absorption, a recent study in which four doses of MTX at 25 mg/m2 was given orally every 6 h resulted in a plasma concentration greater than 0.5 uM in more than 85% of pediatric patients with ALL [11]. Even so, MTX is usually administered intravenously.

7.4.2 Distribution After intravenous administration of MTX, the initial volume of distribution (Vd) is approximately 0.18 L/kg, with a steady-state Vd between 0.4 and 0.8 L/kg [12]. The initial distribution phase has a half-life of 30–45 min. Serum concentrations between 0.0001 and 0.001 M are achieved after administration of high doses of MTX (>6 g/m2 ) [13]. MTX enters cells by the same normal folate transport mechanisms, including the classic reduced folate carrier (RFC), which has a relatively low affinity for MTX, and a second, highaffinity folate receptor protein (FR) that is expressed on the surface of various normal tissues, including the choroid plexus, renal tubules, fallopian tubes, and human placenta, and several epithelial tumors, including ovarian cancer. High extracellular concentrations of MTX saturate transmembrane transport and inhibit the uptake of reduced folates, which explains the need for larger doses of exogenously administered leucovorin (LV) to reverse MTX action. Approximately 50% of MTX is bound to plasma proteins, especially albumin [14]. The highest tissueto-plasma concentrations in humans are found in the liver, kidney, and gastrointestinal tract. Prolonged

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plasma levels after high-dose MTX infusions have resulted from decreased transit rate in patients with gastrointestinal obstruction. The blood-brain barrier and several active efflux mechanisms prevent MTX from reaching cerebrospinal fluid concentrations greater than 1% of the serum concentration, with concentrations roughly equal in the lumbar and ventricular CSF. Irradiation followed by MTX treatment may increase the likelihood of adverse neurotoxic effects as a result of damage to the blood-brain barrier. It has also been shown that cytocidal concentrations in the CSF can be reached with higher doses (greater than 500 mg/m2 ) [15]. However, a recent meta-analysis of CNS-directed therapy for pediatric patients with ALL showed that administration of high-dose MTX failed to lower the rate of CNS relapse [16]. While MTX is poorly accumulated in the CSF, small doses of oral LV significantly increase CSF folate concentration, which effectively rescues cells in the CSF compartment [17]. Following intrathecal injection, MTX slowly diffuses into the systemic circulation with a half-life of 8–10 h [18]. Systemic toxicity can result after multiple doses of intrathecal MTX without LV rescue. Increased toxicity to high-dose MTX has been seen secondary to “third-spacing” and the slow release of MTX into the serum in patients with pleural or peritoneal effusions. It is recommended to evacuate these fluid collections before treatment and monitor plasma drug concentrations closely. More prolonged and higher doses of LV may be used until MTX serum level decreases to less than 5 × 10−8 M.

7.4.3 Metabolism MTX is converted into three main metabolites: 1) 7-OH MTX: hepatic aldehyde oxidase converts MTX to its major metabolite, 7-OH MTX, which is only 1% as potent an inhibitor of DHFR as MTX [19]. It is also less water-soluble and may lead to the increased nephrotoxicity seen after high doses of MTX [20]. 2) dAMPA: In the intestine, MTX is hydrolyzed by bacteria to pteroate (4-deoxy-4-amino-N10-methyl pteroic acid, dAMPA) and glutamic acid [21]. dAMPA is also a relatively inactive metabolite with approximately 0.5% the affinity of MTX for DHFR.

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3) MTX polygutamate: Intracellularly, FPGS adds glutamate residues in y-carbyl linkage to both folate coenzymes and classic folate antagonists. Polyglutamation is a time-and concentrationdependent process that occurs predominately in tumor cells. Polyglutamation prevents efflux of the drug from the cell, prolonging its half-life and activity. MTX polyglutamates are more potent inhibitors of DHFR because they dissociate less rapidly than their parent compound [22]. Like MTX, 7-OH MTX is also polyglutamylated intracellularly, contributing to MTX cytotoxicity [23]. As much as 80% of MTX present in malignant tissues is in the polyglutamated forms [24]. Only polyglutamated MTX can act on GARFT and AICARFT. They are hydrolyzed in lysosomes by GGH.

7.4.4 Excretion The elimination half-life of MTX is about 3 h. Most of the administered MTX and its metabolites are renally excreted unchanged in the urine [25], so dosing based on renal function is critical. Active secretion of MTX occurs in the proximal tubules and results in renal clearance of MTX that can exceed creatinine clearance. Excretion through organic acid transporters can be inhibited by probenecid or competitively blocked by other weak organic acids, including aspirin and penicillins. Elimination is increased by drugs that block distal tubular reabsorption, such as folic acid, sulfamethoxazole, and some cephalosporins. Hepatic metabolism is minimal, accounting for approximately 10% of overall MTX clearance when renal function is normal. After IV doses of 30–80 mg/m2 , 0.4–20% of the administered dose is excreted through the canalicular multiorganic acid transporter (cMOAT) into bile, mostly as intact drug. Overexpression of this transporter confers resistance to MTX in vitro [26]. Less than 10% of MTX is excreted in the feces [27].

7.4.5 Drug Interactions Several harmful and even fatal reactions have been reported between MTX and nonsteroidal antiinflammatory drugs (NSAIDs), especially naproxen

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and ketoprofen [28], possibly as the result of competitive inhibition of renal secretion [29]. Phenylbutazone, salicylates, probenecid, and trimethoprim have also been shown to increase MTX toxicity [30, 31]. Trimethoprim, an antifolate antibacterial agent with weak binding affinity to DHFR, lowers folate stores and makes marrow cells more susceptible to the effects of MTX. Concurrent alcohol use increases risk of hepatic fibrosis and cirrhosis, and patients are instructed to abstain from alcohol while on MTX.

7.4.6 Neoplastic Treatments 7.4.6.1 Acute Leukemia MTX is used as part of all postremission chemotherapeutic regimens for acute lymphoblastic leukemia (ALL). The optimum dose and schedule of MTX may vary depending on each disease. Studies have shown that twice-weekly doses of 20 mg/m2 were more effective treatment than daily oral administration during remission [32]. A 5-day course administered every 3–4 weeks and high-dose MTX regimens with LV rescue have also been shown to be beneficial [33, 34]. It is administered intrathecally for the prophylaxis, treatment, and remission induction of meningeal leukemia. In contrast to its effectiveness in treating ALL, MTX has limited efficacy against acute nonlymphocytic leukemias. High dose regimens with LV rescue have rapid, transient effects on peripheral blood count, but have failed to produce marrow remissions in most of these patients [35].

7.4.6.2 Lymphoma MTX with LV rescue is included in chemotherapy regimens for intermediate-grade and high-grade lymphomas. Phase II studies have shown that moderate to high doses of MTX (200–3000 mg/m2 ) with LV rescue promotes transient regression of large-cell lymphomas [36]. MTX and cytarabine, an antimetabolite that leads to termination of DNA synthesis, are used in combination to treat some lymphomas because of their additive and possibly synergistic effects [37]. MTX with LV rescue has also been added to cyclophosphamide, vincristine, doxorubicin (Adriamycin), and

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dexamethasone (CVAD), cytarabine, and intrathecal therapy for patients with Burkitt’s lymphoma [38]. Rituximab can be added to the hyper-CVAD regimen, which involves alternating high-dose MTX with cytarabine, to improve results in patients with B-ALL and Burkitt’s lymphoma, especially in the elderly [39]. Two other currently used regimens for Burkitt’s include CODOX-M (cyclophosphamide, vincristine, doxorubicin, high-dose MTX) and IVAC (ifosfamide, etoposide, high-dose cytarabine, intrathecal MTX), both of which increase survival. A recent study showed that hyper-CVAD treatment induced complete remission in 91% and a 3-year estimated progression-free survival of 66% in 33 patients with ALL [40]. High-dose MTX is effective against primary central nervous system (CNS) lymphomas, with even better results when used with radiotherapy and other agents like cytarabine [41, 42]. A retrospective review of 226 patients with primary CNS lymphoma showed that patients treated with high-dose MTX followed by radiotherapy had improved survival compared with radiation alone without a higher risk of neurotoxicity [43]. Retreatment with high dose MTX is effective for relapsed disease if there had been a prior complete remission with this agent. CNS prophylaxis is critical, since the CNS is a major site for recurrence.

7.4.6.3 Breast Cancer In one study, MTX alone caused regression of breast cancer in 30% of patients. When followed by 5-FU administration, the response rate improved to 50% and improved disease-free survival when used as adjuvant therapy [44]. The combination of cyclophosphamide, MTX, and 5-FU (CMF) significantly reduces the risk of relapse [45]. The regimen of MTX, 5-FU, and vinorelbine (VMF) instead of cyclophosphamide is effective against advanced breast cancer [46]. Low dose oral MTX (2.5 mg twice a day, two times a week) with daily oral cylcophosphamide has shown to be beneficial against heavily pretreated patients with advanced metastatic breast cancer [47]. Adjuvant chemotherapy with standard CMF has been shown effective in older women with early stage breast cancer, with a relapse-free survival of 85% [48]. Many trials have shown anthracycline-based chemotherapies, such

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as FAC (fluorouracil, doxorubicin, cyclophosphamide) to be superior to traditional agents. Combination of standard CMF therapy with the anthracycline epirubicin is superior than CMF alone [49]. High dose chemotherapy results in higher event-free and overall survival compared with a dose-dense conventional regimen [50]. CMF has also been studied as primary chemotherapy prior to breast conservative surgery [51]. 7.4.6.4 Choriocarcinoma Choriocarcinoma is the only cancer known to respond to single-drug treatment with either MTX or actinomycin D [52]. The human choriocarcinoma cell line (JAR) was shown to have active-receptor coupled uptake of folates and antifolates, which may lead to increased accumulation and retention of the drug [53]. MTX is currently used in combination with other drugs in the treatment of choriocarcinoma, including etoposide, actinomycin D, cyclophosphamide, and vincristine, with greater than 90% survival [54]. 7.4.6.5 Osteogenic Sarcoma The survival of patients with malignant bone sarcomas has improved dramatically over the past 30 years as a result of advances in chemotherapy. Before routine use of chemotherapy, approximately 80% of patients developed metastases despite achieving local tumor control, indicating the presence of subclinical metastases. Randomized trials have shown the efficacy of high-dose MTX with LV rescue in treatment of osteogenic sarcoma [55], with some evidence that response rates are correlated with MTX dose density [56]. Another recent study showed that higher MTX doses did not improve outcomes in patients with localized osteosarcoma [57]. When MTX in osteogenic sarcoma biopsy specimens were analyzed, 200-fold increased doses of MTX produced only a 2.5-fold increase in intracellular MTX polyglutamates [58], which may explain the lack of clinical efficacy of these high doses, particularly in older adults. Cisplatin and doxorubicin are the agents most often used to treat osteogenic sarcomas in adults, with high-dose MTX reserved for poor responders [59] or patients under the age of 35.

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7.4.6.6 Neoplastic Meningitis Intrathecal MTX is frequently used in treating solidtumor neoplastic meningitis. High-dose MTX with LV rescue is also used. A recent study showed longer duration of cytotoxic MTX concentrations in the CSF and prolonged survival in patients treated with IV MTX compared with patients administered intrathecal MTX [60]. Another study comparing intrathecal MTX with depot cytosine arabinoside liposomal injection (DepoCyt) showed increased survival, but with more toxicity, with DepoCyt [61].

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of patients with previously treated advanced gastric cancer [68] as well as those with malignant ascites [69].

7.4.6.10 Lung Cancer MTX has limited activity against small-cell lung cancer, while conferring almost no benefit in non-small cell lung cancer [70].

7.4.7 MTX Toxicities

7.4.6.7 Head and Neck Cancer

7.4.7.1 Hematologic

MTX and cisplatin are the two most widely used single agents in the treatment of advanced carcinomas of the head and neck. High-dose MTX with LV rescue improve response rates from 30 to 50%, but do not improve remission duration or survival [62]. The combination of MTX and 5-FU has resulted in response rates of up to 60% [63].

Rapidly dividing cells, which have the highest percentage undergoing DNA synthesis (S-phase), are most affected by the folate antagonists. While differentiation of all bone marrow progenitor cells are inhibited, neutrophils are the most affected, leading to neutropenia. These effects are both dose- and patientdependent. Young age, impaired renal function, previous radiation-induced marrow damage, chemotherapy, infection, or treatment/prophylaxis of Pneumocystic carinii with trimethoprim-sulfamethoxazole (TMPSMX) all increase the risk of MTX toxicity. The nadir is reached 10 days after administration of the drug, and recovery begins approximately 14–21 days later. Giving LV within 42 h of MTX administration can reduce toxicity and allow larger doses to be administered [71].

7.4.6.8 Genitourinary Cancer Studies have shown that MTX alone or in high doses with LV rescue is effective against advanced bladder cancer, with a response rate (approximately 30%) similar to that of cisplatin therapy. The combination of MTX with cisplatin, vinblastine, and doxorubicin (M-VAC) has been shown effective in inducing longterm clinical remissions [64]. MTX in neoadjuvant treatments has conferred a clear survival advantage in patients with bladder cancer [65, 66].

7.4.6.9 Gastrointestinal Cancer Because of its relative ineffectiveness against gastrointestinal cancers, MTX’s main role is to modulate and improve the efficacy of 5-FU. MTX pretreatment 7–24 h before 5-FU administration inhibits purine synthesis and increases phosphoribosyl pyrophosphate (PPRP), a precursor for 5-FU nucleotide formation [67]. Phase II studies from Japan to evaluate the efficacy and toxicity of sequential treatment with MTX and 5-FU have shown efficacy in small percentages

7.4.7.2 Renal Toxicity It is thought that MTX damages the kidneys in two ways, by (1) direct action on the renal tubules, and (2) the precipitation of MTX and its less soluble metabolite, 7-OH MTX, in the renal tubules. Even conventional doses of MTX have been known to cause renal toxicity. In almost all cases, the acute renal failure is nonoliguric and reversible, but high-dose MTX can lead to severe renal damage, which reduces MTX clearance and leads to severe and sometimes fatal bone marrow and GI toxicity. It is essential to maintain creatinine clearance above 50 mL/min before each treatment dose. Vigorous hydration, osmotic diuresis, and alkalinization of urine

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to increase solubility of MTX and its metabolites can minimize toxicity. Methylxanthines like caffeine or aminophylline can also accelerate MTX clearance by acting as a competitive inhibitor of adenosine, which is increased by MTX and decreases the glomerular filtration rate (GFR) [72]. Hemo- and peritoneal dialysis are ineffective in significantly lowering MTX plasma levels. Oral charcoal and acholestyramine can bind to MTX and lower drug absorption [73]. There has been mild success with charcoal hemoperfusion columns [74]. The combination of thymidine, LV, and carboxypeptidase G2 (glucarpidase), a recombinant form of carboxypeptidase G1 that cleaves the peptide bond in MTX to form the inactive metabolites glutamate and dAMPA, has been shown to ameliorate severe MTX toxicity [75]. While not yet commercially available, it can be used uner an open-label Treatment protocol approved by the FDA.

7.4.7.3 CNS Toxicity The most common and immediate side effect of intrathecal MTX is an acute chemical arachnoiditis, a syndrome that includes severe headache, fever, vomiting, meningismus, and CSF pleocytosis. High doses can lead to motor paralysis of extremities, cranial nerve palsies, aphasia, and seizures, which occur within 6 days of treatment and are usually transient (2–3 days), but can lead to coma and death [76]. Subacute neurotoxicity beginning 7–14 days after intrathecal or intravenous high-dose MTX occurs in up to 20% of patients. Delayed MTX-induced development of chronic demyelinating encephalopathy, occurring months to years after receiving intrathecal MTX, is seen in up to 80% of children with ALL [77]. The exact underlying mechanism of CNS toxicity from MTX remains unknown, but it is theorized that increased levels of homocysteine in the CSF from the inhibition of remethylation to methionine by MTX may contribute to the observed CNS symptoms. Studies show that higher CSF homocysteine levels are found in patients with MTX-induced neurotoxicity than in asymptomatic patients receiving similar drug therapies [78]. CT scans show ventricular enlargement, cortical thinning, and diffuse intracerebral calcifications [79]. Methylxanthines, which blocks adenosine’s autocoid effects in the CNS, can be given to lessen toxicity.

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Doses may have to be lowered or treatment changed to cytarabine if CNS symptoms persist. Intrathecal MTX overdoses (>100 mg) are treated by immediate ventricolumbar perfusion [80]. Another studied antidote is intrathecal carboxypeptidase G2, which markedly decreased mortality after lethal intrathecal doses of MTX in animals [81]. There is no evidence that therapeutic use of LV helps patients who develop neurotoxic symptoms.

7.4.7.4 Hepatotoxicity Portal fibrosis and cirrhosis can result from chronic low-dose MTX treatment, such as in patients being treated for psoriasis and rheumatoid arthritis. Liver enzymes, including bilirubin, often become elevated several days after high-dose MTX, but quickly return to baseline within 10 days and is not an accurate predictor of chronic liver toxicity [82]. From studies that show the reversal of MTX hepatotoxicity in rats by choline administration, it is postulated that the liver damage is caused by the inhibition of folate homeostasis [83]. Other hepatotoxic medications and alcohol should be avoided during MTX therapy. 7.4.7.5 Gastrointestinal Mucositis, an early and common side effect of MTX, usually presents in 3–5 days and is a good indicator that the drug should be discontinued. Other presentations of gastrointestinal toxicity include mild to moderate nausea and vomiting. Diarrhea may also occur, even occasionally progressing to bloody diarrhea, usually in the setting of high-dose MTX combined with renal damage. Patients receiving greater than 250 mg/m2 of MTX should be pretreated with a serotonin receptor antagonist and dexamethasone, with or without aprepitant [84]. 7.4.7.6 Pulmonary Pulmonary toxicity has been noted in patients receiving low-dose oral MTX for rheumatoid arthritis [85]. The majority develop toxicity within the first year of therapy, with cases reported between 12 days and 18 years after drug initiation. Subacute presentations are most common, including cough, dyspnea,

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fever, and hypoxemia. Chest X-rays usually show a hypersensitivity pnemonitis involving nonspecific patchy interstitial infiltrates, similar to findings in Pneumocystis carinii infection, which must be ruled out in immunocompromised patients or those taking steroids. Histologic findings include diffuse interstitial lymphocytic infiltrates, noncaseating granulomas, and giant cells. Peripheral eosinophilia, suggesting an allergic pneumonitis, is occasionally observed, although rechallenge with MTX does not uniformly result in the return of symptoms. Failure to discontinue MTX may lead to irreversible pulmonary fibrosis. In contrast to bone marrow and gastrointestinal toxicity, the repletion of folate stores does not reduce the risk of MTX pulmonary toxicity.

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7.4.8 Antifolate Resistance The development of cellular resistance to MTX continues to be a major obstacle to its clinical efficacy. MTX resistance is the result of one or more of the following five mechanisms: 1) 2) 3) 4) 5)

Decreased intracellular transport Decreased metabolism into polyglutamate forms Increased breakdown of polyglutamates Altered interaction with DHFR Increased efflux from cells

7.5 Intrinsic Resistance 7.4.7.7 Skin Approximately 5–10% of patients taking MTX suffer skin toxicity. The main clinical finding is an erythematous, sometimes pruritic rash on the neck and upper trunk that lasts for several days. More severe toxicity can result in bullae formation, desquamation [86], or cutaneous vasculitis [87]. Alopecia is occasionally seen.

7.4.7.8 Teratogenic and Mutagenic MTX is a known potent abortifacient, especially during the first trimester of pregnancy, and is currently used for the early voluntary termination of pregnancies. However, there is no direct evidence of mutagenic or carcinogenic effects from MTX use, and women successfully treated with MTX for choriocarcinoma do not have increased risk of secondary malignancies or fetal defects [88]. Current recommendations are that a woman being treated with MTX avoids pregnancy for at least one ovulatory cycle following treatment. Men on MTX should avoid pregnancy for at least 3 months following treatment.

7.4.7.9 Bone There is some evidence that chronic low-dose MTX can cause osteoporosis, possibly from MTX inhibition of osteoblastic differentiation [89].

Studies show a decreased ability to form long-chain MTX polyglutamates in AML patients versus ALL patients, which may explain the relative clinical resistance of AML to MTX. Sarcoma tumor cells resistant to MTX also do not form MTX polyglutamates as readily [90]. Impaired ability to transport MTX into cells by the reduced folate carrier (RFC) also contributes to intrinsic resistance. RT-PCR of osteosarcoma biopsies have shown decreased expression of RFC mRNA [91]. Mutations in the RFC gene leading to decreased transport function is seen in resistant cell lines [92]. Single nucleotide polymorphisms in the RFC gene result in a decreased affinity for antifolates without significantly affecting the transporter’s affinity for folate. The retinoblastoma protein is often deleted or mutated in many tumors, leading to increased levels of transcription factor E2F and increased production of DHFR [93].

7.6 Acquired Resistance Acquired resistance to MTX occurs through several different mechanisms: 1) DHFR gene amplification: Studies have shown the development of resistance as a result of DHFR gene amplification in patients treated with MTX [94]. The amplified gene can stably integrate into chromosomal DNA in the form of a homogeneously

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staining region or exist in extrachromosomal pieces of DNA called double-minute chromosomes [95]. Approximately 30% of relapsed ALL patients compared with 10% of newly diagnosed patients had some DHF amplification. 2) DHFR mutation: Several point mutations, mostly involving amino acids that bind the folate antagonist by hydrophobic interactions, have been found that decrease DHFR’s binding affinity for MTX [96]. 3) Decreased long-chain polyglutamate formation: Defects in polyglutamation that lead to decreased MTX uptake have been described in several MTXresistant cell lines [97]. Increased breakdown from increased levels of y-glutamylhydrolase (GGH), which removes the glutamate residues, also contributes to acquired resistance. Increased expressionof GGH has been shown to be associated with resistance to MTX in human sarcoma cell lines and a rat hepatoma cell line, although another study showed that forced overexpression of GGH did not result in MTX resistance [98]. 4) RFC mutation: Decreased RFC transport of MTX is a common mechanism of acquired MTX resistance in leukemic blasts from patients with relapsed ALL [99].

7.6.1 Description of Other Folate-Related Agents 7.6.1.1 5-Fluorouracil (5-FU, Efudex) First synthesized in 1957 after the observation that rat hepatoma cells used uracil more efficiently than normal rat intestinal mucosa, this fluoropyrimidine antimetabolite indirectly inhibits the enzyme thymidylate synthase (TS), which leads to depletion of dTMP and dTTP, resulting in decreased DNA synthesis and “thymine-less death.” TS inhibition also leads to an accumulation of dUMP, which is misincorporated into DNA and then excised, causing DNA strand breaks. Unlike folate antagonists, fluoropyrimidine TS inhibitors enter cells via a separate nucleoside transport system and do not require polyglutamation for activity. 5-FU is normally given intravenously because of its erratic bioavailability when given orally due to its rapid

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breakdown by the gut mucosa enzyme dihydropyrimidine dehydrogenase (DPD). A cream incorporating 5-FU is also used topically for treating basal cell carcinomas. It is FDA approved for colon, rectum, gastric, pancreas, and breast carcinomas, and is also used in a wide range of combination regimens. It can be given with LV, which increases intracellular pools of reduced folates, enhancing the stability of the 5-FU-TS complex and prolonging TS inhibition [100]. Various agents, especially LV, have been used as biochemical modulators to enhance 5-FU’s antitumor activity. However, randomized trials have shown increased toxicities and not shown a meaningful survival benefit to adding LV. Another approach has been to alter the schedule of 5-FU administration to prolong the tumor cells’ exposure to the drug. Continuous infusional schedules have shown superior clinical efficacy compared to boluses of FU, and a hybrid schedule of bolus and infusional 5-FU with LV administration has become a main backbone for combination therapy for advanced colorectal cancer [101]. 5-FU also significantly enhances the cytotoxicity of ionizing radiation [102]. Another strategy to increase the effectiveness of 5-FU-based treatment has been to develop oral analogues to increase convenience and avoid complications associated with intravenous infusional therapies.

7.6.1.2 Capecitabine (Xeloda) In contrast to 5-FU, this oral fluoropyrimidine carbamate is rapidly and extensively absorbed by the gut mucosa, with about 80% oral bioavailability and peak blood levels occurring within 2 h. It is converted to its only active metabolite, 5-FU, by thymidine phosphorylase. Higher levels of this enzyme are found in several tumors and the liver, compared with normal healthy tissue. Dose-limiting toxicities include nausea, vomiting, diarrhea, and hand-foot syndrome. The drug is FDA-approved for use as (1) a first-line treatment of metastatic colorectal cancer when fluoropyrimidine therapy alone is preferred, (2) a single agent in metastatic breast cancer patients who are resistant to both anthracycline- and paclitaxel-based regimens or in whom further anthracycline treatment is contraindicated, and (3) in combination with docetaxel after failure of prior anthracycline-based chemotherapy. Single-agent and combination regimens have also

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shown efficacy against prostate, pancreatic, renal cell, and ovarian cancers. Improved tolerability and similar efficacy compared with intravenous FU/LV in addition to oral administration make capecitabine an attractive treatment option as well as the focus of ongoing trials [103]. Capecitabine plus oxaliplatin has shown promise in patients with unresectable rectal cancer [104], advanced pancreatic cancer [105], and advanced esophagogastric cancer [106]. It was shown to be inferior to standard chemotherapy in older patients with breast cancer [107].

7.6.1.3 Aminopterin (4-Aminopteroic Acid, AMT) Discovered prior to MTX, this DHFR inhibitor was soon replaced by MTX, which has similar efficacy with decreased toxicity. However, recent studies have suggested that AMT may have better uptake and polyglutamation than MTX. One study showed that in-vivo activity of MTX and AMT were equivalent in preclinical models [108]. Now in a more pure preparation, aminopterin is back in clinical trials for patients with leukemia [109].

7.6.1.4 Leucovorin Leukovorin (LV) is a folate derivative and an enzyme cofactor for TS and other purine and pyrimidine synthesis steps. It bypasses the DHFR step and therefore can be used to prevent or reverse the toxic side effects of antifolates, allowing higher doses to be used. It can also modulate antitumor activity in some cases, particularly colorectal cancers [110]. As LV can only rescue normal cells that have not already had lethal DNA damage from MTX, it must be initiated within 24–36 h of starting MTX. Given the competitive nature of MTX and LV, the dose of LV must be increased in proportion to the plasma concentration of MTX. LV selectively rescues normal but not malignant cells from the effects of MTX for unclear reasons, and there is no clinical evidence of any LV dose that is high enough to interfere with antitumor efficacy. Plasma MTX levels are followed daily, and LV doses are adjusted based upon MTX drug levels. A typical dosage is 10 mg/m2 IV or 15 mg/m2 orally every 6 h until plasma MTX levels are less than 0.1 microM.

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7.6.2 New Folate Antagonists 7.6.2.1 Edatrexate (10-Ethyldeazaaminopterin) Hydrophobic N-10 substitutions to aminopterin result in improved uptake and retention by tumor cells compared with normal cells [111]. This drug has shown benefit in non-small cell lung cancer, breast cancer, head and neck cancers, and malignant fibrous histiocytoma [112–114]. However, because it uses the same transport and polyglutamylation mechanisms as MTX, it has limited activity against MTX-resistant cells. A newer analogue, 10-propargyl-deazaaminopterin (PDX), has been developed that is more potent than edatrexate because of increased RFC uptake and intracellular polyglutamylation. Phase II trials of PDX given to patients with previously treated non-small cell lung cancer have shown promise [115].

7.6.2.2 Trimetrexate (TMTX) Like MTX, this lipophilic analog is a potent inhibitor of DHFR. Unlike MTX, it lacks a glutamate moiety (making it a nonclassical antifolate) and crosses the cell membrane by passive or facilitative diffusion rather than through the RFC [116]. As a result, TMTX and other nonclassical antifolates are cytotoxic against even MTX-resistant cells. When TMTX is used in combination with LV to specifically target tumor cells that have decreased levels of functional RFC and cannot transport reduced folates; these cells will uptake only the TMTX, while normal cells will also uptake the LV rescue agent [117]. Preclinical data shows that TMTX followed by 5-FU and high-dose LV synergistically kills cells in advanced GI cancers, while the same regimen with TMTX replaced with MTX did not [118]. In another study, treatment with TMTX, 5-FU, and LV (NFL) was well-tolerated in patients with advanced pancreatic cancer, with median survivals and 1-year survivals that compared favorably with other treatment options [119].

7.6.2.3 Raltitrexed (Tomudex) This quinazoline folate analogue primarily inhibits thymidylate synthetase, but also inhibits DHFR and GARFT. Like MTX, raltitrexed is actively transported

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into the cell via the RFC and undergoes polyglutamation, which increases cytotoxicity 100-fold (more so than MTX). It is eliminated renally, with a halflife of 10–22 h. Several mechanisms of resistance to Raltitrexed have been identified, including decreased polyglutamation, reduced transport, and overexpression of the target enzyme, TS [120–121]. A phase I trial in children with refractory leukemia showed minimal toxicity and responses in 3 of 18 patients [122]. It has shown clinical efficacy against many solid tumors, including advanced colorectal, breast, hepatocellular, non-small cell lung, and pancreatic cancers. It is licensed in Canada and Europe as a first-line therapy for advanced colon cancer, but it remains an investigational drug in the United States. Novel combination regimens incorporating raltitrexed are in development, and the combination of raltitrexed with oxaliplatin appears especially promising for the treatment of advanced colorectal cancer and malignant mesothelioma [123, 124]. 7.6.2.4 ZD9331 Like raltitrexed, this third-generation specific anitfolate inhibitor of TS does not require polyglutamation for its activity. This quality prevents resistance from reduced expression of folylpolyglutamate synthetase (FPGS), while reducing toxicities from the increased retention of polyglutamated drugs in normal tissues. Preclinical studies have shown it to be transported by the ubiquitously expressed reduced folate carrier as well as the alpha-folate receptor which is overexpressed in some cancers, especially ovarian [125]. A large number of monotherapy and combination studies have been undertaken, and overall activity has been most promising, particularly in platinumrefractory relapsed ovarian [126], pancreatic [127] and gastric cancers [128]. Its role in the treatment of these diseases may be important, especially if patients were to be selected on the basis of their folate transport and FPGS status. 7.6.2.5 Lometrexol (5–10-Dideazatetrahydrofolate, DDTHF, LMTX) An extremely potent inhibitor of purine synthesis, it selectively inhibits glycinamide ribonucleotide

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formyltransferase (GARFT), an enzyme that catalyzes the formation of purines. As an excellent substrate for FPGS, LMTX is very susceptible to polyglutamation, and once formed, these long-chain polyglutamates turn over so slowly intracellularly that they are almost impossible to eliminate. Low doses have led to prolonged bone marrow suppression and thrombocytopenia, possibly due to rapid accumulation in folate receptor-positive cells [129]. Consequently, production of this drug has since stopped in favor of more benign analogues, such as pemetrexed.

7.6.2.6 Pemetrexed (LY231514) In clinical trials since 1995, this pyrrolopyrimidine multi-targeted antifolate analogue primarily inhibits TS, but has activity against several other target enzymes involved in biosynthetic pathway of folate, including GARFT, AICAR transformylase, and DHFR. Its advantages over other antifolates include: (1) its very rapid conversion to active polyglutamate derivatives in cells that build to high and prolonged levels in cells, (2) its high affinity for three different folate transporters, and (3) its marked sensitivity to the level of physiologic folates in cells [130]. The optimal dose schedule is 500–600 mg/m2 intravenously administered every 3 weeks. Toxicities are similar to those of other antifolates, with neutropenia being the major dose-limiting toxicity. Other common adverse events include nausea, vomiting, anorexia, rash, and fatigue. These toxicities are markedly decreased by folic acid supplementation (350 ug daily) and vitamin B12 (1000 ug IM every 3 weeks), with no decrease in pemetrexed’s clinical efficacy [131]. Recent phase III studies showed comparable efficacy of pemetrexed compared with docetaxel in previously treated patients with non-small cell lung cancer, with far less toxicity in patients treated with pemetrexed [132]. As a result, pemetrexed in combination with cisplatin was FDA- approved as a first-line treatment of non-small cell lung cancer. Its use in combination with cisplatin results in increased response rate and overall survival compared to cisplatin alone in the treatment of malignant pleural mesothelioma, and this combination regimen has also been FDA approved [133]. Pemetrexed in combination with other chemotherapeutic agents has shown activity against many other

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solid tumors, including breast, colorectal, gastric, cervical, bladder, and small cell lung cancer [134]. There has been special interest in its co-administration with gemcitabine, which is synergistic in vitro [135]. It is known that pemetrexed increases expression of the hENT1 nucleoside transporter that mediates gemcitabine influx [136], suggesting that pre-treatment with pemetrexed would increase gemcitabine’s efficacy. In a phase II trial in non–small cell lung cancer comparing a variety of pemetrexed-gemcitabine schedules, the response rate to pemetrexed administered 90 min before gemcitabine was far superior to the response rate with the reverse sequence of administration [137].

7.6.2.7 Nolatrexed (Thymitaq, AG337) This drug is a noncompetitive, high-affinity inhibitor of TS synthesis, leading to dTMP depletion and dUMP accumulation and thymine-less death. It is not dependent on the cell cycle and high concentrations fail to induce S-phase arrest while still causing apoptosis. Because of its lipophilic properties, the drug can enter cells via passive diffusion. Since it cannot be polyglutamated, and as a result has no requirements for membrane transport or intracellular activation, it is not susceptible to most mechanisms of drug resistance. Point mutations and TS gene amplification contribute to some acquired resistance. Randomized trials have been done to compare the efficacy of nolatrexed with other currently used agents. One study showed similar efficacies between nolatrexed and methotrexate in the treatment of head and neck cancer [138]. Due to some evidence of activity against hepatocellular cancer, recent efforts have been made to study its possible role in the treatment of HCC. A recent phase III study of nolatrexed in advanced unresectable HCC patients, however, demonstrated minimal activity and significant toxicities, including

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stomatitis, diarrhea, vomiting, and thrombocytopenia [139].

7.7 Conclusions and Future Directions Old and current folate antagonists primarily inhibit thymidylate synthase, DHF reductase, and the enzymes involved in de novo purine synthesis, GARFT and AICARFT. Classical folate antagonists act in the polyglutamated form, leading to the development of resistance through alterations in cellular transport or intracellular polyglutamation mechanisms. Research has thus moved towards the creation and study of lipophilic, nonclassical folate antagonists like trimetrexate and Thymitaq that do not require a transport mechanism or polyglutamation. Since much clinical resistance is the result of amplification or mutation of single target enzymes, there are efforts to find newer drugs, like pemetrexed, that target multiple steps or biosynthetic pathways, which would theoretically minimize the development of significant resistance [140]. Pharmacogenetics is also being utilized as a tool to predict drug response in patients with the hope of reducing toxicities and treatment costs. Initial studies have shown promising relationships between genotype and treatment-related toxicity and outcomes, indicating that certain genetic polymorphisms in folate metabolism can be important predictors of drug response. For example, there is evidence that patient with lower expression of TS have increased drug response as well as toxicities [141]. Most studies have yet to evaluate multiple polymorphisms in the folate pathway simultaneously, and this is an area of future research. Finding ways of relieving cytotoxicity while maintaining a high degree of antitumor efficacy and exploring new synergistic drug combinations are other important goals for the future.

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7.8 Graphics 7.8.1 Folate Metabolism Adapted from cdc.gov

137

138

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7.8.2 Folate-Related Agents Name (brand name)

Target enzyme(s)

Oncologic uses

Methotrexate Trimetrexate (Neutrexin) Edatrexate

DHFR (primary), TS, MTHFR, GARFT, AICARFT DHFR DHFR

Lometrexol (T64) Fluorouracil (5-FU) Capecitabine (Xeloda) Pemetrexed (Alimta) Ralitrexed (Tomudex) Nolatrexed (Thymitaq) ZD9331

GARFT (primary), AICARFT TS TS TS (primary), DHFR, GARFT TS TS TS

Leukemia, lymphomas (Burkitt’s and non-Hodgkin’s), breast cancer, head and neck cancer, osteosarcoma Non-small cell lung, prostate, colorectal Non-small cell lung, advanced breast, head and neck, soft tissue sarcoma, NHL Non-small cell lung Colorectal, pancreatic, stomach, breast, basal cell (skin) Colorectal, breast Malignant pleural mesothelioma, non-small cell lung Colon cancer Hepatocellular Ovarian, pancreatic, gastric

7.8.3 Chemical Structure Comparison of Folate and MTX

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139

7.8.4 Chemical Structures of Folate Antagonists

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colorectal cancer: a phase II multicenter trial. Am J Clin Oncol 27(4):337–342 Laohavinij S, Wedge SR, Lind MJ et al (1996) A phase I clinical study of the antipurine antifolate lometrexol (DDATHF) given with oral folic acid. Invest New Drugs 14(3):325–335 Chattopadhyay S, Moran RG, Goldman ID (2007) Pemetrexed: biochemical and cellular pharmacology, mechanisms, and clinical applications. Mol Cancer Ther 6(2):404–417 Scagliotti GV, Shin DM, Kindler HL et al (2003) Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma. J Clin Oncol 21:1556 Hanna N, Shepherd FA, Fossella FV et al (2004) Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 22: 1589–1597 Vogelzang N, Rusthoven J, Symanowski J et al (2003) Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 21:2636 Adjei AA (2004) Pemetrexed (ALIMTA), a novel multitargeted antineoplastic agent. Clin Cancer Res 10: 4276S–4280S Tonkinson JL, Worzalla JF, Teng CH, Mendelsohn LG (1999) Cell cycle modulation by a multitargeted antifolate, LY231514, increases the cytotoxicity and antitumor activity of gemcitabine in HT29 colon carcinoma. Cancer Res 59:3671–3676 Giovannetti E, Mey V, Nannizzi S et al (2005) Cellular and pharmacogenetics foundation of synergistic interaction of pemetrexed and gemcitabine in human non-small-cell lung cancer cells. Mol Pharmacol 68: 110–118 Ma CX, Nair S, Thomas S et al (2005) Randomized phase II trial of three schedules of pemetrexed and gemcitabine as front-line therapy for advanced non-small-cell lung cancer. J Clin Oncol 23:5929–5937 Pivot X, Wadler S et al (2001) Result of two randomized trials comparing nolatrexed vs methotrexate in patients with recurrent head and neck cancer. Ann Oncol 12(11):1595–1599 Gish RG, Porta C, Lazar L et al (2007) Phase III randomized controlled trial comparing the survival of patients with unresectable hepatocellular carcinoma treated with nolatrexed or doxorubicin. J Clin Oncol 25(21): 3069–3075 Cole PD, Kamen BA, Bertino JR (2006) Folate antagonists. Cancer medicine, 7th edn. BC Decker, Hamilton, ON, pp 648–660 Robien K, Boynton A, Ulrich CM (2005) Pharmacogenetics of folate-related drug targets in cancer treatment. Pharmacogenomics 6(7):673–689

Chapter 8

Platinum Complexes for the Treatment of Cancer David Roberts, Peter J. O’Dwyer, and Steven W. Johnson

8.1 Introduction

8.2 Cisplatin – Discovery

Though its antitumor activity was discovered four decades ago, cis-diamminedichloroplatinum (II) (cisplatin) continues to be widely used for the treatment of many solid tumor types. When combined with other cytotoxic drugs or some of the newer “targeted” agents, significant improvements in response and survival rates have been observed in cancers of the ovary, lung, bladder and head and neck. Its most remarkable contribution, however, has been in the treatment of testicular cancer. Prior to the introduction of cisplatin to the clinic, testicular tumors were treated with a combination of vinblastine, adriamycin and bleomycin resulting in response rates of approximately 50%. Treatment with cisplatin-based therapy now cures the majority of testicular cancer patients presenting with advanced stage disease. The extraordinary antitumor activity observed with cisplatin in early clinical trials prompted further investigations into understanding its mechanism of action and developing less toxic analogs with different cytotoxicity profiles. These efforts have resulted in the development of two more platinum complexes, carboplatin and oxaliplatin, which are approved for clinical use. In this chapter, we will provide a review of the attributes of the platinum drugs including their chemistry, clinical pharmacology, mechanism of action, and mechanisms of resistance.

Though cis-diamminedichloroplatinum II was originally synthesized in 1890, the idea that this inorganic compound had biological activity remained unknown until 1961 when Dr. Barnett Rosenberg initiated a series of experiments at the University of Michigan designed to study the effects of an electromagnetic field on the growth of E. coli bacteria [1]. Using an apparatus consisting of platinum electrodes and bacteria in an ammonium chloride containing medium, Dr. Rosenberg observed that exposure of the bacteria to the electric current caused filamentous growth without cell division. He subsequently discovered this effect was not caused directly by the electric field, but by electrolysis products, of which a major component was ammonium chloroplatinate [NH4 ]2 [PtCl6 ]. This compound was inactive at reproducing the filamentous growth of E. coli, however, Rosenberg discovered that the conversion of this complex to a neutral species by ultraviolet light was required to obtain an active complex. Attempts to synthesize the active neutral platinum complex failed. It was soon realized, however, that the neutral compound could exist in two isomeric forms, cis or trans, and the latter species is the one that they had synthesized. Subsequently, the cis isomer was synthesized and shown to be the active compound. Rosenberg tested the antitumor activity of cis and trans isomers of diamminedichloroplatinum II and diamminetetrachloroplatinum IV in mice bearing Sarcoma-180 solid tumors and L1210 leukemia cells [2]. Though all four compounds exhibited significant antitumor activity, cis-diamminedichloroplatinum II (cisplatin) was the most effective. Studies in other tumor models confirmed these results and indicated

S.W. Johnson () Department of Hematology/Oncology, University of Pennsylvania, Philadelphia, PA 19104, USA e-mail: [email protected]


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that cisplatin exhibited a broad spectrum of activity. Early clinical trials demonstrated cisplatin’s activity against several tumor types, with testicular cancers being particularly sensitive. However, a major problem with cisplatin administration was severe renal and gastrointestinal toxicity. This nearly ended its clinical use until Cvitkovic et al. [3, 4] showed that these toxic side effects could be circumvented by aggressive prehydration. Overcoming this obstacle enabled the large-scale testing of cisplatin alone and in combination with other drugs for the treatment of various malignancies [5].

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8.3 Cisplatin Analogs Platinum complexes primarily exist in either a 2+ or 4+ oxidation state, which determines the overall stereochemistry of the ligands associated with the platinum atom (Fig. 8.1). The structure of these ligands influences the stability of the complex and the rate of substitution. Most platinum complexes exhibiting antitumor activity consist of leaving groups and carrier ligands. In aqueous solution, the leaving groups are labile and are prone to mono- and di-aqua substitution. This process is termed aquation and is a prerequisite step for drug activation. The carrier ligands represent stable moieties that remain bound to the platinum atom during drug uptake, distribution and binding to its cytotoxic target. Progress in understanding the chemistry and pharmacokinetics of cisplatin has guided the development of new analogs. In general, modification of the chloride leaving groups of cisplatin results in compounds with altered pharmacokinetics, whereas modification of the diammine carrier ligands affects the activity of the complex. The systematic design and testing of platinum compounds with various leaving groups and carrier ligands has been a goal of both academic and industrial laboratories in an effort to create drugs with unique activity and reduced toxicity.

8.3.1 Carboplatin The effect of altering the chloride leaving groups of cisplatin on pharmacokinetics and toxicity is exemplified by cis-diamminecyclobutanedicarboxylato platinum II (carboplatin). Carboplatin contains the same

Carrier Ligands

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Fig. 8.1 Structures of the carrier ligands and leaving groups of cis-diamminedichloroplatinum II (cisplatin) and cisdiamminecyclobutanedicarboxylato platinum II (carboplatin)

ammine carrier ligands as cisplatin, however, a more stable cyclobutanedicarboxylate moiety serves as the leaving group [6, 7]. This results in a drug with a considerably longer plasma half-life and reduced renal toxicity. In fact, carboplatin was isolated using a murine screen for nephrotoxicity in an effort to find cisplatin analogs with more favorable toxicity profiles. Carboplatin may be administered at doses approximately ten times that of cisplatin and results in comparatively less nausea, vomiting, nephrotoxicity and neurotoxicity. Calvert and colleagues [8] showed that carboplatin concentration in patient plasma ultrafiltrates is correlated with renal clearance. From this observation, a dosing formula was developed that enables efficacy and toxicity in patients to be more predictable [9]. With respect to preclinical and clinical activity, carboplatin is essentially indistinguishable from cisplatin. Thus, its overall reduced renal and gastrointestinal toxicity and ease of administration has resulted in its substitution for cisplatin in the treatment of most tumor types.

8.3.2 Oxaliplatin and DACH Complexes Just as carboplatin represents a leaving group modification that affects pharmacokinetics, the

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Fig. 8.2 Structures of platinum drugs diaminocyclohexane (DACH) carrier ligand

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diaminocyclohexane (DACH) platinum complexes represent the effects of altering the diammine carrier ligands of cisplatin (Fig. 8.2). Following the discovery of cisplatin’s antitumor activity by Rosenberg, Dr. Tom Connors synthesized and evaluated a series of compounds with varying carrier ligands [10]. He found that platinum analogs containing the DACH moiety were active in preclinical cancer models. These results were confirmed and extended by Burchenal who provided in vivo data showing that DACH compounds were indeed active in tumors in which cisplatin had little or no activity [11]. Subsequent in vitro studies supported the concept that cisplatin-resistant cells are collaterally sensitivity to DACH platinum complexes [12, 13]. In support of these studies, Rixe et al. [14] showed that DACH derivatives exhibit a unique cytotoxicity profile as compared to cisplatin and carboplatin using the NCI 60 cell line screen. The first DACH compound to be tested in the clinic was tetrachloro(d,l-trans)-1,2-diaminocyclohexaneplatinum IV (ormaplatin, tetraplatin), a stable platinum (IV) analog which exhibits activity against cisplatin-resistant cells. Phase I studies conducted in the early 1990s indicated that severe and cumulative neurotoxicity was dose-limiting and prevented further development [15]. Chaney and colleagues have conducted several studies to determine the underlying basis for neurotoxicity associated with ormaplatin therapy [16, 17]. Following injection, ormaplatin undergoes a biotransformation yielding Pt(DACH)Cl2 as the primary metabolite. The plasma levels of this metabolite were associated with neurotoxicity in one study [17]. A second DACH analog, oxalato (transl-1,2-diaminocyclohexane) platinum II (oxaliplatin), has had considerably more clinical success. Originally synthesized by Kidani and colleagues in the early 1970s, oxaliplatin is substantially less lipophilic

than ormaplatin, but retains the DACH spectrum of activity in cisplatin-resistant tumor models. Shord et al. [18] found that oxaliplatin remains relatively intact in patient plasma ultrafiltrates and the concentrations of metabolites such as Pt(DACH)Cl2 are low, which may contribute to lower and reversible neurotoxicity. Oxaliplatin was first studied in two phase I trials in which suitable doses and schedules were evaluated, and an early hint of colorectal cancer activity identified [19, 20]. Oxaliplatin has since demonstrated significant activity in combination with 5-fluorouracil/leucovorin in colon cancer, a disease that was previously considered to be unresponsive to platinum drugs [21]. A series of consistent phase II and III clinical trials which followed confirmed activity of oxaliplatin in colorectal cancer. Oxaliplatin is now approved for the first-line treatment of advanced colorectal cancer, and preliminary data indicate that it improves the survival of patients with Stage II and III disease when used in the adjuvant setting. The antitumor activity of oxaliplatin in other malignancies is currently under investigation.

8.3.3 Other Platinum Complexes Cisplatin, carboplatin and oxaliplatin have been approved by the FDA for the treatment of cancers in the United States. Over the last several decades, however, a variety of other platinum complexes have been synthesized and evaluated preclinically and in clinical trials. Many of these compounds have been discarded while others are maturing and may soon be approved for use against certain tumor types. A summary of selected agents is provided in this section and the chemical structures are shown in Fig. 8.3.

8.3.3.1 Satraplatin (JM216) Platinum IV compounds have been designed in an effort to create platinum molecules with unique cytotoxic activity. Ormaplatin (tetraplatin, tetrachloro(d,ltrans)-1,2-diaminocyclohexaneplatinum) represents the first of this class to undergo clinical testing and the results, as discussed above, were quite negative with marked neurotoxicity preventing its further use. Though considerably less toxic, a second

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Fig. 8.3 Structures of novel platinum drugs that have been clinically tested as anticancer drugs

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complex, iproplatin (cis-dichloro-trans-dihydroxybis-isopropylamine platinum IV, CHIP, JM9), proved to be relatively inactive in phase II trials [22, 23]. Despite these disappointing results, satraplatin [bis(acetato)amminedichloro(cyclohexylamine) platinum (IV)] has yielded promising results. In preclinical studies, satraplatin (JM216) exhibited a lack of cross-resistance in cells that were selected for cisplatin resistance [24]. Another unique feature of this drug is its oral bioavailability, thus facilitating administration. To date, there has only been limited clinical testing of satraplatin, though the results have been encouraging. Activity has been observed in small cell and non-small cell lung cancer [25, 26]. In a phase II trial evaluating 39 patients with hormone-refractory prostate cancer, satraplatin exhibited activity in 2 of 20 (10%) evaluable patients with measurable disease [27]. Further testing of this compound in prostate cancer was done in a phase III trial in combination with prednisone [28]. The addition of satraplatin to a prednisone regimen resulted in an increase in both median survival and progression-free survival. Definitive results await the completion of a large phase III trial currently underway in this disease.

8.3.3.2 AMD473 Substitution of one of the amine groups of cisplatin for a 2-methylpyridine moiety resulted in a “sterically hindered” platinum molecule

know as AMD473 (ZD0473, cis-amminedichloro (2-methylpyridine)platinum II). This drug was rationally designed to react preferentially with nucleic acids over sulphur ligands such as glutathione, thus preventing inactivation from occurring and increasing the relative level of DNA damage [29, 30]. In support of this, AMD473 shows a non-cross-resistant cytotoxicity profile when compared to that of cisplatin and oxaliplatin. Clinical trials have been conducted to assess the toxicity and efficacy of this platinum drug. In a phase I study, single agent AMD473 was found to be well tolerated at a dose of 120 mg/m2 every 21 days [31]. Neutropenia and thrombocytopenia were dose limiting. AMD473 has also been tested in combination with taxanes and gemcitabine [32–34]. In the phase II setting, activity was observed in ovarian cancer (8.3 and 32.4% objective response in platinumresistant and -sensitive patients, respectively), but a low response rate (3.8%) in metastatic breast cancer is likely to preclude further development in this tumor type [35, 36].

8.3.3.3 BBR3464 In yet another approach to augment the cytotoxicity profile of cisplatin and its analogs, Farrell and colleagues [37] have synthesized a series of di- and tri-nuclear platinum molecules representing individual cis- and trans-platin molecules linked together. These molecules form adducts that span greater distances

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across the minor groove of DNA, and exhibit a potent and significantly different cytotoxicity profile from that of other platinum complexes. This may be due in part to the formation of a different platinum-DNA adduct profile, comprised of a larger proportion of interstrand crosslinks. BBR3464 has been tested in phase I and II clinical trials. In a Phase I study involving 14 patients with advanced cancer, BBR3464 was administered beginning at 0.03 mg/ m2 /day and escalated to a dose of 0.17 mg/m2 /day [38]. The maximum tolerated dose in this study was defined as 0.13 mg/m2 /day. Observed toxicity included diarrhea and neutropenia. There was no significant nephrotoxicity, neurotoxicity or pulmonary toxicity. In a phase II study of patients with gastric and gastro-espohageal adenocarcinoma, only 1 of 17 (6%) patients responded [39].

8.3.4 Identification of New Platinum Analogs A number of lessons have been learned from the development of platinum analogs over the last few decades. Most importantly, that careful selection of preclinical models is an important aspect of drug development. This is clearly evident in the use of an antiemetic model for the development of carboplatin. Also, thorough testing of new analogs in both platinumsensitive and –resistant cell lines proved important to the development of DACH platinum complexes such as oxaliplatin. The continued development of platinumresistance models and incorporation of statistically significant numbers of cell lines into the analysis will be an important step to identify unique platinum cytotoxicity profiles. The importance of studying larger models was demonstrated in an analysis of the NCI anticancer drug screen consisting of growth inhibitory data for 60 unrelated cell lines [40]. The relationships between 107 platinum analogs was evaluated using a clustering algorithm and the results clearly showed a distinct pattern of sensitivity based on the structure of the platinum drug tested. Four well-defined groups emerged from this analysis consisting of a cisplatin, DACH, silane and pyridine group. As the latter two groups have not received significant attention, they could certainly represent compounds with unique antitumor activity. Efforts such as this aimed at identifying platinum analogs with unique profiles may

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have a future impact on the treatment of notoriously platinum-insensitive tumors. A major challenge will be to correctly identify the most effective compounds to bring forward into the clinic.

8.4 Pharmacology Early in the clinical development of platinum analogs a dogma emerged regarding the control of drug efficacy and toxicity. It was realized that altering the carrier ligands of cisplatin attenuated the cytotoxicity profile of the drug, whereas changing the leaving groups influenced the pharmacokinetics. This phenomenon is readily apparent for the three FDA approved drugs cisplatin, carboplatin and oxaliplatin. The diaminocyclohexame moiety of oxaliplatin imparts a somewhat noncross-resistant cytotoxicity profile when compared to that of cisplatin and carboplatin. The relative activity of the latter two are nearly identical in preclinical models and are considered nearly equivalent clinically when tumor response and patient survival are considered as endpoints. However, the presence of a cyclobutanedicarboxylate group provides a more favorable pharmacokinetic profile for carboplatin and facilitates its administration.

8.4.1 Pharmacokinetics Of the three drugs, cisplatin has the shortest half-life. Ultrafilterable cisplatin disappears rapidly and in a biphasic fashion [41–43]. Half-lives of 10–30 min have been reported for the first phase and 40–50 min for the second. The disappearance of platinum from plasma following short infusions carboplatin occur in a biphasic or triphasic manner [44, 45]. The half-lives for total platinum during the first phase (t1/2 α) range from 12 to 98 min and from 1.3 to 1.7 h during the second phase (t1/2 β). Half-lives reported for the terminal phase range from 8.2 to 40 h. For oxaliplatin, plasma elimination of ultrafilterable platinum is also biphasic [46, 47]. The half-lives for the first and second phases are 0.3 and 24.2 h, respectively. Significant differences are also observed in protein binding. Following infusion, cisplatin rapidly diffuses into tissues and approximately 90% of platinum is bound to plasma protein after four hours [48].

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Elimination occurs predominantly by the kidneys as approximately 23 and 40% appears in the urine at 24 hours post-infusion [49, 50]. Carboplatin is quite stable in plasma. At 4 hours post-infusion, only 24% of platinum is bound to protein. Carboplatin is excreted predominantly by the kidneys, and cumulative urinary excretion of platinum is 54–82%, most as unmodified carboplatin. The renal clearance of carboplatin is closely correlated with the glomerular filtration rate (GFR) [51]. Based on this observation, Calvert et al. [8] designed a dosing formula which is now widely used and provides a reliable method for controlling the pharmacokinetics and toxicity of carboplatin in individual patients. Similar to cisplatin, the majority (85%) of platinum following an infusion of oxaliplatin is bound to plasma protein. Prolonged retention of oxaliplatin is observed in red blood cells. Unlike cisplatin, however, oxaliplatin does not significantly accumulate following multiple courses of treatment [52]. This may explain why neurotoxicity associated with oxaliplatin is reversible whereas it is cumulative for cisplatin therapy. Oxaliplatin is eliminated predominantly by the kidneys with more than 50% of the platinum being excreted in the urine at 48 h.

8.4.2 Toxicity Initial clinical studies with cisplatin indicated its doselimiting toxicity was nephrotoxicity. This nearly ended its clinical evaluation, however, Cvitkovic and colleagues found that aggressive hydration of patients prior to infusion could prevent the development of acute renal failure [3, 4]. Other side effects include nausea and vomiting, nephrotoxicity, ototoxicity, neuropathy, and myelosuppression. Despite improvements in cisplatin administration and control of its side effects, a search for less toxic analogs was a priority for academia and industry. This led to the discovery of carboplatin. Myelosuppression, which is not usually severe with cisplatin, is the dose-limiting toxicity of carboplatin [53]. The drug is most toxic to the platelet precursors, but neutropenia and anemia are also observed. Other toxicities associated with carboplatin include nausea and vomiting which is easily controlled with standard antiemetics. Renal impairment is infrequent. Neurotoxicity is also less common when compared to cisplatin, although it is observed more frequently with the increasing use of high dose

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regimens. The dose-limiting toxicity of oxaliplatin is sensory neuropathy, a characteristic of all DACHcontaining platinum derivatives. The persistence of neurotoxicity has led to approaches to circumvent it, including the use of protective agents (intravenous calcium and magnesium salts before and after each infusion) [52], or a modified administration schedule [54]. As with other platinum drugs, nausea and vomiting occurs which generally responds to 5-HT3 antagonists. Myelosuppression is uncommon and is not severe and oxaliplatin therapy is not associated with nephrotoxicity.

8.5 Platinum-Induced Cell Death 8.5.1 DNA Adducts DNA has been implicated as the cytotoxic target for the platinum drugs. This has been deduced from a wide variety of experiments [55–57]. Rosenberg’s initial studies showed that cisplatin inhibited DNA synthesis without affecting protein synthesis [1]. It has also been observed that cells deficient in the activity of specific DNA enzymes are hypersensitive to platinum drugs and other DNA damaging agents [58, 59]. Finally, the isolation and identification of individual platinumDNA adducts has been achieved. Platinum drugs bind covalently with DNA to form both monofunctional and bifunctional adducts. Reaction occurs preferentially at the N7 position of guanine and adenine residues [60–62]. The first step of the reaction involves the formation of monoadducts which then react further to form intrastrand or interstrand crosslinks. The relative amount of each adduct depends, in part, on the time of exposure and the manner in which the DNA is processed and analyzed. The predominate bifunctional lesions that are formed include the d(GpG)Pt, d(ApG)Pt and d(GpNpG)Pt intrastrand crosslinks, however, platinum drugs also form interstrand crosslinks between guanine residues located on opposite DNA strands. These lesions represent a minor portion of the total DNA bound platinum, but they may contribute to the drug’s cytotoxicity as they impair process that require the separation of DNA strands. Monoadducts are also formed at relatively high frequency, though they may be converted to bifunctional lesions or subject to quenching by other molecules.

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Reports on the frequency of monoadducts in cultured cells range vary considerably, but these variations are likely due to different experimental conditions, in particular, time of exposure.

8.5.2 Damage Recognition The adducts formed between most platinum analogs are similar in type and frequency, thus the differences observed in cytotoxicity between the diammine (e.g. cisplatin, carboplatin), DACH, and other platinum compounds is more likely due to how the cell interprets and reacts to the presence of the damage. Once bound to DNA, platinum drugs may disrupt a variety of cellular processes while others may be activated. Research done in the last decade has begun to elucidate the pathways that contribute to the cytotoxicity of the platinum drugs. Adduct recognition or lack thereof is likely a key step in determining cell sensitivity or resistance to platinum drugs. A number of proteins have been identified that recognize platinum lesions, but their role in influencing drug sensitivity directly or indirectly remains unknown. One of the first groups of proteins shown to bind to DNA damaged by cisplatin are the HMG proteins. These proteins are capable of bending DNA and recognizing bent DNA structures, such as those produced by cisplatin [63–65]. The affinity for cisplatin-damaged DNA is considerably higher than that for the relatively inactive isomer, transplatin. It has been postulated that HMGB1 influences cisplatin sensitivity through a variety of mechanisms. This may occur directly, through the transmission of a damage signal to the cell’s apoptotic machinery or indirectly involving interactions with other proteins that initiate signal transduction. Evidence for the latter is supported by a study demonstrating an interaction between HMGB1 and p53. Yet another possible role for HMG domain-containing proteins is to shield adducts from recognition by DNA repair proteins. Further studies are still needed in this area to define a functional role for these proteins in platinum sensitivity/resistance and to show that these processes are important in clinical material. In addition to the HMG family members (HMGA, HMGB and HMGN), several other proteins have been shown to recognize platinum-DNA adducts including histone H1, RNA polymerase I transcription upstream binding factor (hUBF), the TATA binding protein

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(TBP) and proteins of the mismatch repair complex. The MSH2 and MLH1 mismatch repair proteins can recognize DNA adducts formed by cisplatin [66]. The presence of a platinum lesion may result in the continuous futile cycle of repair synthesis on the DNA strand opposite the lesion. This could result in the accumulation of DNA strand breaks ultimately leading to cell death. Interestingly, oxaliplatin adducts are not well recognized by the mismatch repair protein complex, which may contribute to the differences in cytotoxicity observed between these two platinum molecules. It is also important to note that loss of mismatch repair activity has been associated with cisplatin resistance [67, 68], though it is not clear whether this is a direct effect on sensitivity or whether defective mismatch repair results in genomic instability, thus providing an environment leading to mutations in other drug sensitivity genes.

8.5.3 Damage Recognition, Signaling and Apoptosis Following platinum-DNA adduct formation, a cascade of signals occurs that leads to apoptosis in drugsensitive cells. At the present time, these events are not completely understood but remain an active area of investigation for platinum drugs and other anticancer agents. Sorting out the drug-specific signaling network(s) associated with cell death has been challenging as a number of factors must be considered including (1) the type of anticancer drug used, (2) drug concentration and exposure conditions, and (3) cell model under study. These factors have led to controversy regarding the role of some signaling molecules in promoting cell survival or cell death. Despite these discrepancies, significant progress has been made in several areas of the drug-induced signaling process including the initiation, commitment and terminal phases. In this section, we will provide a summary of the events that have been the subject of significant study. As discussed above, a number of proteins have been identified that recognize and bind to cisplatin adducts with high affinity. However, it remains unclear whether any of these proteins directly or indirectly initiate a DNA damage signaling event. This will be important to elucidate as resistance to platinum drugs could

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involve the disruption of this process. Downstream of platinum-DNA adduct recognition, a number of signaling events have been shown to occur [69]. The ATM and ATR proteins appear to be important in this process. These kinases are phosphorylated and activated following cisplatin-induced DNA damage. ATM and ATR mediate the activation of serveral signal transduction pathways as a result of DNA damage. ATM interacts and stabilizes several known DNA damageresponse proteins such as p53, E2F1 and BLM. Luo et al. [70] provided evidence that ATM is involved in stabilizing the mismatch repair complex and, in conjunction with hMLH1, localizes this complex to the nucleus. This evidence provides a potentially important connection between platinum-DNA adduct recognition by mismatch repair proteins and the transduction of a repair/apoptotic signal mediated by TP53. The impact of disrupting one or members of this pathway should theoretically result in cells with a cisplatin-resistant phenotype. In the case of ATM, ATR and individual mismatch repair proteins, inhibition or down-regulation has been shown to decrease cisplatin sensitivity by a modest amount (2- to 3-fold). In addition, studies with p53 have been somewhat controversial with some reports of p53 disruption leading to cisplatin sensitivity and others the opposite effect [71, 72]. This raises the question as to the importance of these signaling pathways to drug resistance as it is well documented that cells can achieve quite high levels of cisplatin resistance (up to 1000-fold). It is possible that sufficient redundancy exists in the DNA damage signaling process that other pathways circumvent or complement the pathways described above. This has implications when choosing new targets for the design of therapies to augment cisplatin therapy.

8.5.4 Decision/Commitment Phase Platinum-induced drug sensitivity is intimately tied to the cell cycle. For example, proliferating cells are relatively sensitive to cisplatin, whereas quiescent cells or cells in G0 /G1 are relatively insensitive [73]. Thus, the interplay between DNA damage-induced signaling and cell cycle arrest and how this influences a cell’s decision to repair adducts or undergo apoptosis is important to understand. Shortly after the observation that apoptosis results from exposing cells to

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chemotherapeutic drugs, Eastman and colleagues developed and analyzed the role of cell cycle in cisplatin-induced apoptosis using DNA repairdeficient CHO cells [74, 75]. In these studies, cisplatintreated CHO/AA8 cells experienced slow progression through S phase and accumulated in G2 . At low drug concentrations, the cells recovered and continued to cycle. At high drug concentrations, the cells died following a protracted G2 arrest. An aberrant mitosis was observed prior to apoptosis. Further studies with G2 -synchronized cells revealed that passage through S phase is necessary for G2 arrest and cell death suggesting that DNA replication on a damaged template may result in the accumulation of further damage causing the cells to ultimately die. Abrogating the G2 checkpoint with pharmacologic agents such as caffeine or 7-hydroxystaurosporine was shown to enhance the cytotoxicity of cisplatin [76]. Based on these studies, a connection may be made between signaling events mediated by proteins such as ATM and ATR and the cell cycle. In addition to these events, a number of other proteins/pathways have been shown to be activated by platinum drugs or have been shown to influence cell sensitivity to platinum drugs. Some of these include signaling mediated by AKT, MAP kinases (ERK, JNK, and p38 kinase), c-Abl, ras, p53, p73 and NF-κB [69, 77]. The complexity of the response increases as each of these signaling molecules influences the activity and expression of transcription factors and other proteins. As a result, it is not surprising that a lack of consistency exists in conclusions drawn by investigators as to the role of these pathways in cell survival and apoptosis. This is also due to the various experimental conditions employed including cell type, treatment, selection of endpoints and duration of the effect. As the field of signal transduction has grown, so has the number of candidate effectors and pathways that influence platinum drug sensitivity. The list is large and includes cytokines, growth factors, kinases, phosphatases, second messengers, transcription factors, redox proteins and extracellular matrix proteins. Some of these molecules may attenuate sensitivity to only platinum drugs and DNA damaging agents, whereas others influence cellular sensitivity to a variety of unrelated chemotherapeutic drugs. The collective activity of the signaling events described above may determine whether a cell can survive platinum-induced damage or undergo apoptosis. Thus every tumor cell may have

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a threshold or rheostat that senses the balance of proand anti- apoptotic signals that are invoked following DNA damage.

8.5.5 Apoptosis/Terminal Phase Apoptosis consists of a cascade of events leading to the ordered dismantling of critical cell survival components and pathways. At least two apoptotic pathways exist in cells, each of which is modulated through proteins called caspases. The extrinsic pathway of apoptosis is activated when death domain containing Tumor Necrosis Factor Receptor (TNFR) family members become activated by TNFR ligands (TNFα, Fas-L, TRAIL and Tweak). Activation leads to the formation of a death inducing signaling complex (DISC) consisting of at least three proteins, namely the adaptor molecule Fas-associated death domain and caspases-8 and -10. Caspase 8, once activated by DISC, can activate caspases-3, -6, and -7, which in turn activate various caspase-dependent deoxynucleases (CAD/ICAD) leading to nucleosomal fragmentation. Cells treated with platinum compounds have been shown to induce the expression and/or activity of many members of this pathway. For example, cisplatin exposure has been shown to induce the expression of the DR4 and DR5 pro-apoptotic cell death receptors in esophageal squamous cell carcinoma cell lines [78]. Cisplatin exposure has also been demonstrated to induce the expression of Fas and FasL proteins [79, 80]. Similarly, HT29 human colon carcinoma cell lines treated with cisplatin exhibit enhanced DISC complex formation, while numerous cell model systems have documented cisplatin’s role in inducing caspase-3, -8, and -9 activities and mRNA expression [81–83]. Incidentally, MCF-7 cells deficient in caspase-3 are unable to undergo apoptosis following cisplatin treatment, thus stressing the importance of these proteins in platinum-induced cytotoxicity [84]. In addition to the extrinsic pathway, apoptosis may also be initiated by the release of a number of mitochondrial proteins (cytochrome c, endonuclease G, SMAC, AIF), all of which are frequently observed following platinum treatment [85]. During this process, cytochrome c and ATP are released from the mitochondria and together activate apoptotic protease-activating factor-1 (ApaF1). ApaF1 sequentially triggers caspase9, which is then free to stimulate caspase 3 [86, 87].

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Both extrinsic and intrinsic apoptotic pathways are not mutually exclusive. Signaling through the death receptor pathway may modulate cytochrome c release through caspase-8/caspase-10 dependent Bid cleavage, leading to disruptions in mitochondrial membrane permeability. A number of cellular proteins have the ability to modulate these caspase dependent pathways. Two of the most well documented protein families capable of modulating apoptosis are the Bcl-2 and inhibitor of apoptosis (IAPs) families. The Bcl-2 family includes (but is nor limited to) pro-apoptotic (Bax and Bak) and anti-apoptotic (Bcl-2 and Bcl-XL ) proteins, which regulate mitochondrial permeability via the adenine nucleotide translocator and voltage dependent anion channel [88, 89]. In addition, Bcl-2 and Bcl-XL sequester BH3-only containing Bcl-2 family members (Bid and Bim), thus inhibiting Bax and Bak translocation to the mitochondria where they are thought to instigate the release of mitochondrial factors (cytochrome c). It is therefore not surprising to observe reductions in mRNA transcript and protein levels for Bcl-2 in the cisplatin-sensitive human ovarian cancer cell line 2008 following cisplatin treatment [90]. In contrast to Bcl-2 mRNA and protein reductions following cisplatin treatment, the mRNA expression and translocation of the pro-apoptotic protein Bax has been documented in a number of model systems subsequent to cisplatin exposure [91]. In contrast to the Bcl-2 family, the IAP family of proteins includes approximately eight family members (NAIP, cIAP1, cIAP2, XIAP, Livin-α, Livin-β, ILP-2, and Survivin), each of which has the capability to bind to and inhibit caspase activity [92]. In cisplatin-sensitive human ovarian cancer cell lines, XIAP is down-regulated following cisplatin treatment [93], a process which is antagonized by AKT phosphorylation [94]. Undoubtedly, future insight into cisplatin’s role in affecting this family of proteins, and thus apoptosis, will likely be presented in the future.

8.6 Mechanisms of Resistance Drug resistance is a problem for all types of anticancer drug and this phenomenon limits the effectiveness of the platinum drugs. Platinum resistance may be intrinsic or acquired and is quite pleiotropic. One can divide platinum resistance mechanisms into two

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major groups: those that prevent DNA adduct formation and those that enable cells to survive following DNA damage (Fig. 8.2). The first group of mechanisms includes decreased drug accumulation and increased drug inactivation by cellular protein and non-protein thiols. The second group of mechanisms includes increased platinum-DNA adduct repair and increased platinum-DNA damage tolerance. The identification and measurement of these mechanisms has been possible through the development of resistant cell models and the establishment of cell lines from chemotherapyrefractory tumors. Though progress has been made in identifying putative resistance mechanisms, validating the quantitative and qualitative existence of these in patient tissues in association with response or outcome has been difficult. This will be an important step since identifying reliable markers of resistance will lead to the development of reversal strategies.

8.6.1 Reduced Accumulation Acquired resistance to cisplatin and its analogs frequently results in the emergence of a decrease platinum accumulation phenotype. Unlike that observed in cells that are resistant to natural product drugs, overexpression of P-glycoprotein is not involved platinum drug resistance. Cisplatin and its analogs may accumulate within cells by passive diffusion or facilitated transport [95]. Cisplatin uptake has been shown to be nonsaturable, even up to its solubility limit, and not inhibited by structural analogs. The passive uptake of these drugs may depend, in part, on their relative hydrophobicity. Recently, a significant amount of work in the area of facilitated uptake/efflux has been done by Howell and colleagues [96]. This grew out of early observations that cells resistant to cisplatin are cross-resistant to other metal-containing complexes [97]. A more recent study indicated that cross-resistance to copper also occurred in platinumresistant cells [98]. Insight into the molecular basis for this phenomenon resulted in the identification of several copper transporters previously associated with copper homeostasis. With respect to platinum uptake and efflux, these proteins include CTR1 and ATP7A/ATP7B, respectively. In a study by Lin et al. [99] using a yeast model, the copper transporter, CTR1, was shown to regulate the influx of cisplatin,

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carboplatin, oxaliplatin and AMD473. Comparison of the wild-type and ctr-1 knockout strains revealed an 8-fold reduction in cisplatin uptake after one hour. These ctr-1 deficient yeast cells were also 2-fold more resistant to cisplatin. Analysis of the human CTR1 protein in platinum-sensitive and -resistant small cell lung cancer cells revealed a reduction of CTR1 in one of five resistant sublines [100]. Evidence has also presented to demonstrate a role for the coppertransporting P-type ATPases 7A and 7B in platinum drug efflux. Transfection of epidermoid carcinoma cells with ATP7B led to a 9-fold decrease in cisplatin sensitivity [101]. Howell and colleagues have confirmed this and demonstrated that acquired cisplatin resistance is accompanied by increased expression of these export pumps [102, 103]. This group also found that increased expression of ATP7A is associated with poor survival in ovarian cancer patients treated with platinum-based regimens [104]. The prospect of another active efflux mechanism for platinum drugs has emerged following the discovery of a group of MRP-related transport proteins, which function in the efflux of glutathione-coupled and unmodified anticancer drugs from cells [105]. Overexpression of MRP1 (ABCC1) confers resistance to a variety of drugs, but not to cisplatin. For platinum complexes, the formation of a glutathione-platinum drug conjugate may be the rate-limiting step for producing an MRP substrate. A related homologue, cMOAT (cannalicular multispecific organic anion transporter, ABCC2), has also been shown to have a similar substrate specificity with that of MRP. Overexpression of cMOAT (MRP2) has been found in some cisplatin-resistant human cancer cell lines exhibiting the decreased platinum accumulation phenotype [106]. Transfection of an antisense cMOAT cDNA into HepG2 cells resulted in reduced cMOAT protein levels and a 5-fold increased in cisplatin sensitivity [107]. Further evidence indicating a role for ABC transporters in platinum drug resistance was provided by Kool et al. [108], who examined the expression of MRP, cMOAT, MRP3, MRP4, and MRP5 in a set of cell lines selected for cisplatin resistance in vitro. MRP1 and MRP4 mRNA levels were not increased in any of the cisplatin-resistant sublines. MRP3 and MRP5 were overexpressed in a few cell lines, but the mRNA levels were not associated with cisplatin resistance. With respect to clinical relevance, an immunohistochemical analysis of the expression of P-glycoprotein, MRP1 and MRP2 revealed that none

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of these transporters was associated with response to platinum-based chemotherapy in ovarian cancer [109]. However, Yoh et al. [110] reported increased BCRP levels in association with shorter progressionfree survival and overall survival in non-small cell lung cancer patients treated with platinum-based therapy. Additional translational studies will be required to fully understand the contribution of these transport proteins to platinum drug resistance.

8.6.2 Inactivation Aquated platinum compounds are highly reactive and may bind intracellularly to proteins and nucleic acids. Cells that are resistant to platinum drugs often develop that ability to inactivate these complexes by upregulating the expression of detoxication genes. Both the metallothioneins and glutathione have been implicated in this drug inactivation process. Glutathione (GSH) represents the most abundant non-protein thiol and in fact, the formation of a glutathione-platinum (GSPt) complex has been demonstrated in cultured cells. GSH has also been shown to quench platinum-DNA monoadducts in vitro, thus preventing their conversion to potentially cytotoxic crosslinks [111–113]. Over the years, attempts have been made to correlate platinum drug sensitivity with either GSH levels or the expression/activity of the enzymes involved in GSH metabolism. There have been many reports showing a strong association between platinum drug sensitivity and GSH levels [114–117], however, reducing intracellular GSH levels with modulators such as buthionine sulfoximine (BSO) has resulted in only low to modest potentiation of cisplatin sensitivity [118, 119]. One of the products generated during glutathione catabolism is cysteinylglycine. This reaction is catalyzed by gamma-glutamyltransferase (gamma-GT). The affinity of cysteinylglycine for cisplatin is significantly higher than that of glutathione and transfection studies have demonstrated that overexpression of gamma-GT confers resistance to cisplatin [120]. Direct protein-mediated Inactivation of platinum drugs may occur through binding to one or more of the metallothionein (MT) isoforms. The MT’s are a family of sulfhydryl-rich, small molecular weight proteins that participate in heavy metal binding and detoxication. In vitro, cisplatin binds stochiometrically to

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metallothionein and up to 10 molecules of cisplatin can be bound to one molecule of metallothionein [121]. Kelley et al. [122] demonstrated that overexpression of the full-length MT-IIA in mouse C127 cells conferred a four-fold resistance to cisplatin. Furthermore, this group showed that embryonic fibroblasts isolated from MT-null mice were hypersensitive to cisplatin [123]. These studies clearly show that modulating MT levels can alter cisplatin sensitivity, however, the contribution of MT to clinical platinum drug resistance is unclear. In some cell lines, elevated MT levels have been shown to be associated with cisplatin resistance, while in others, they have not [116, 124]. Studies with human tumors have shown that, in some instances, metallothionein expression level is associated with response to chemotherapy. For example, a significant correlation between MT overexpression and response/survival was reported in urothelial transitional cell carcinoma patients [125]. Overexpression of MT has also been observed in bladder tumors from patients that failed cisplatin chemotherapy [126]. In contrast, a study in ovarian tumor biopsies revealed some increases in metallothionein expression, but this did not reach statistical significance [127].

8.6.3 Increased DNA Repair The failure of drug accumulation and inactivation mechanisms to limit the formation of platinum-DNA adducts mandates that cells must either repair or tolerate this damage in order to survive. As DNA is presumed to be the cytotoxic target of platinum complexes, then ability of cells to rapidly repair platinum lesions is a critical process. Studies done with cell lines established from patients with DNA repair deficiencies such as Xeroderma Pigmentosum clearly show a significant level of platinum drug hypersensitivity in a DNA repair-deficient environment. In addition, there evidence indicating that cell lines derived from tumors that are unusually sensitive to cisplatin, such as testicular non-seminomatous germ cell tumors, are deficient in their ability to repair platinum-DNA adducts [128]. However, resistance to DNA damaging agents would represent the opposite: an induction of the capacity to repair lesions. Therefore, one or more components of the repair machinery must be induced/activated to elevated the cell’s overall DNA repair capacity. Evidence

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of increased repair of platinum-DNA lesions in cisplatin resistant cell lines has been provided for various types of human cancers [129–132] as well as murine leukemia cells [133]. The repair of all types of DNA lesions has been documented including monoadducts, intrastrand- and interstrand-crosslinks. These studies have been done using a variety of repair assays including unscheduled DNA synthesis, host cell reactivation of cisplatin-damaged plasmid DNA, atomic absorption spectrometry, quantitative PCR and renaturing agarose gel electrophoresis. The repair of platinum-DNA adducts occurs predominantly by nucleotide excision repair (NER) and clues to the molecular basis for increased repair activity have emerged. Since the rate-limiting step in this process is platinum-adduct recognition/incision, increased expression of the proteins that control this step are likely to enhance nucleotide excision repair activity. Using an in vitro assay, Ferry et al. [134] demonstrated that the addition of the ERCC1/XPF protein complex increased the platinum-DNA adduct excision activity of an ovarian cancer cell extract. There is also circumstantial evidence that implicates ERCC1 expression with increased NER and cisplatin resistance. For example, expression levels of the ERCC1 and XPA genes have been shown to be higher in malignant tissue from ovarian cancer patients resistant to platinum-based therapy compared with those responsive to treatment [135]. ERCC1 expression has also been shown to correlate with NER activity and cisplatin resistance in human ovarian cancer cells [134]. Increased levels of XPE, a putative DNA repair protein that recognizes many DNA lesions including platinumDNA adducts, has been observed in tumor cell lines resistant to cisplatin [136]. It should be noted, however, that XPE is not a necessary component for the in vitro reconstitution of NER [135, 137]. Inhibiting DNA repair activity in order to enhance platinum drug sensitivity has been an active area of investigation. Selvakumaran et al. [138] showed that down-regulation of ERCC-1 using an antisense approach sensitized a platinum-resistant cell line to cisplatin both in vitro and in vivo. This has also been achieved using siRNA [139]. Unfortunately, there are currently no repair inhibitors that target the recognition/incision step of the NER pathway. Despite this, efforts have been made to inhibit repair at the fill-in step. These include nucleoside analogs such as gemcitabine, fludarabine and cytarabine, the ribonucleotide

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reductase inhibitor, hydroxyurea and the inhibitor of DNA polymerases α and γ, aphidicolin. Since these agents interfere with repair synthesis, they are also likely to effect DNA replication and may not be strictly characterized as repair inhibitors. The potentiation of cisplatin cytotoxicity by treatment with aphidicolin has been studied investigated in human ovarian cancer cell lines. While some studies have demonstrated synergy with this drug combination ([140–141], others have not [142]). In an in vivo mouse model of human ovarian cancer, the combined treatment of cisplatin and aphidicolin glycinate, a water soluble form of the drug, was found to be significantly more effective than cisplatin alone [143].

8.6.4 Increased DNA Damage Tolerance If the repair pathways described above do not sufficiently correct the DNA damage resulting from platinum drug exposure, cells must tolerate this damage in order to survive. Tolerance is a broad term and may involve (1) impaired adduct recognition, (2) attenuated activity of survival and stress signaling pathways, and (3) defects or changes in apoptotic proteins. Thus, influencing the signaling processes from adducts to apoptosis enables cells to ignore the cytotoxic effects of DNA lesions. Platinum-DNA damage tolerance has been observed in both cisplatin-resistant cells derived from chemotherapy-refractory patients and cells selected for primary cisplatin resistance in vitro. The contribution of this mechanism to resistance is significant and it has been shown to correlate strongly with cisplatin resistance as well as resistance to other drugs in two ovarian cancer model systems [130, 144]. It is likely that understanding the basis for the tolerance phenotype will provide new targets for therapy and identify biomarkers to predict response. Sensing the presence of cisplatin-DNA adducts has been proposed to be a function of the DNA mismatch repair (MMR) system. This could provide either a direct cytotoxicity signal or create an environment in which single strand breaks accumulate as a result of futile MMR cycling. Either way, it has been proposed that loss or reduction of the components of this pathway imparts a cisplatin resistance phenotype. There have been studies showing that loss of MMR is associated with low-level cisplatin resistance, and that

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the selection of cells in culture for resistance to this drug often yields cell lines with defective MMR [145]. MSH2 alone, and in combination with MSH6, has been shown to bind to cisplatin 1,2-d(GpG)Pt intrastrand adducts with high efficiency [66, 146]. Additionally, MSH2 and MLH1-containing protein-DNA complexes have been observed when nuclear extracts of MMRproficient cell lines were incubated with DNA preincubated with cisplatin, but not with oxaliplatin. It contrast to these reports, however, Branch et al. [147] found that selecting cells for decreased MLH1 expression, did not result in a predictable degree of cisplatin resistance in a panel of human tumor cell lines. Further studies will be needed to determine whether mismatch repair has a direct effect on drug sensitivity or represents a phenotype that is linked to the emergence of resistance. Another way to ignore or tolerate platinum-DNA damage is to simply replicate DNA past the lesion. Known as replicative bypass, this process has been shown to occur in cisplatin-resistant human ovarian cancer cells [148]. This may also be considered post-replication repair, thus enabling cells to complete S phase and arrest at the G2 checkpoint in order to repair the DNA damage. Chaney and colleagues [149] have carefully studied the ability of individual DNA polymerases to bypass both cisplatin and oxaliplatin adducts. They have shown that oxaliplatin adducts are bypassed with greater efficiency that cisplatin adducts. Analysis of the insertion and extension reactions revealed that both DNA polymerase β and η catalyze this step. The activity of this DNA polymerase β was found to be significantly increased in cells derived from a human malignant glioma resistant to cisplatin compared to its drug sensitive counterpart [132]. Analysis of these markers in tumor biopsies will be necessary to find an association with resistance in vivo. Downstream of platinum-adduct recognition lies a number of signaling events that determine the fate of a tumor cell. These pathways are likely shared by other DNA damaging agents and cytotoxic drugs with other intracellular targets. Thus, tolerance mechanisms in this category may confer a multidrug resistance phenotype. As discussed previously in this chapter, a number of pro- and anti-apoptotic signaling pathways have been implicated in cisplatin sensitivity. One particular signaling pathway that has received significant attention is the JNK/SAPK signaling pathway. The weight of the evidence favors a pro-apoptotic

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role for both JNK and p38 kinase in tumor cells, while their role in normal cells is more equivocal [150–153]. Paradoxically, c-Jun, a target of JNK, may contribute to cisplatin resistance [154, 155], which indicates the importance of characterizing dimers in the MAP kinase pathway, the composition of which may determine the balance of pro- and anti-apoptotic signaling. Signaling for apoptosis in oxaliplatin-treated cells appears qualitatively different from cisplatin. Variation in the activity of the JNK/p38 pathways is not a determinant of cell death signaling in colon cancer cells, while resistance to oxaliplatin is influenced very markedly by the activity of the NF-κB pathway [156]. In other cells the activity of ATF-2, a substrate for JNK and p38 is also a determinant of resistance [157]. The activity of these signaling pathways on mediators of apoptosis cannot easily be separated form effects on transcription of many of the mediators of detoxication, DNA repair and DNA damage tolerance discussed above, and active research is in progress to test their role in the clinic. With respect to the terminal phase of programmed cell death, the overexpression/activation of antiapoptotic genes or down-regulation/inhibition of proapoptotic genes may influence platinum drug sensitivity and confer a DNA damage tolerance phenotype. Members of the Bcl-2 family of proteins are known to regulate mitochondrial function and serve as a cell survival/cell death rheostat by forming homo- and heterodimers with one another. The anti-apoptotic bcl-2 and bcl-XL proteins are localized in the outer mitochondrial membrane and may be involved in the formation of transmembrane channels. Overexpression of bcl-2 or bcl-XL has been shown to prevent disruption of the mitochondrial transmembrane potential and to prolong cell survival in some cells following exposure to cisplatin and other anticancer drugs [158, 159]. The activity of these proteins is negated, however, in the presence of high levels of the pro-apoptotic protein BAX, another bcl-2 family member. Therefore, the relative intracellular levels or ratio of these proteins may confer resistance to platinum drugs. As discussed earlier in this chapter, disruption of caspase function also has the potential to confer a drug resistant phenotype. Caspase 8 and 9 may be candidates for these effects, however, inhibiting late stage caspases such as caspase-3 or -7 may block the phenotypic features of apoptosis, but not the ultimate death of the cell. Efforts have been made to associate the expression of

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pro- and anti-apoptotic genes to clinical parameters in patients treated with platinum-based chemotherapy. In a study of 28 ovarian cancer patients, Williams et al. [160] found that Bcl-xL expression in primary tumors was associated with a significantly shorter diseasefree interval as compared to patients whose tumors did not express Bcl-xL (1.6 months as compared to 7.7 months). A number of other studies have also demonstrated an association of Bcl-2 family members and patient response/outcome following platinum treatment [161–165].

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Chapter 9

Hormonal Therapy in Cancer Soe T. Maunglay, Julia A. Cogburn, and Pamela N. Munster

9.1 Introduction

9.2 Hormonal Therapy in Breast Cancer

Endocrine manipulation as systemic therapy for two of the most common human cancers, breast cancer in women and prostate cancer in men, continues to evolve. In the treatment of breast cancer in postmenopausal women, the development of third generation aromatase inhibitors has had a large impact in the adjuvant setting, building on the success of these agents in the treatment of metastatic disease. Hormone-sensitive disease, in general, portends a better prognosis and higher likelihood of response to treatment in both breast and prostate cancer patients. Cancers of the female reproductive tract organs (ovaries, endometrium and uterus) respond to endocrine manipulation to varying degrees, and hormonal treatment may be valuable in second-line or palliative settings. Malignancies associated with the overproduction of hormones (ectopic ACTH syndrome, neuroendocrine tumors and pituitary adenomas) may often be countered by hormonal antagonists and analogs. The role of hormonal therapy and their potential risks and benefits for each of the prescribed settings will be discussed in further detail for each tumor type.

Selective estrogen receptor modulators (SERMs) and selective estrogen receptor down-regulators (SERDs) bind to the estrogen receptor, and thereby inhibit estrogen-mediated signaling [2]. Compounds in the SERM family include tamoxifen, raloxifene, toremifene, GW5638, GW7604 (the active metabolite of GW5638), idoxifene, bazedoxifene, EM-800, lasofoxifene, arzoxifene, and acolbifene (the active metabolite of EM-800). The SERDs include the recently approved fulvestrant, as well as ZK-703, ZK253, and RU 58668 [3]. TAS-108, a tissue-selective antiestrogen, is currently under development [4]. An alternative strategy to inhibit estrogen mediated signaling is to decrease estrogen levels in the target tissues by blocking the conversion of precursor molecules to estrogen using an aromatase inhibitor (AI). Oophorectomy remains a surgical alternative to blocking estrogen receptor signaling by eliminating the major source of estrogen in premenopausal women. Several studies are currently underway to compare ovarian function suppression in combination SERMs or AIs vs. the standard treatment with a SERM alone as adjuvant therapy for premenopausal women (Table 9.1).

P.N. Munster () Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center, Experimental Therapeutics and Breast Medical Oncology, 12902 Magnolia Dr, Tampa, FL 33612, USA e-mail: [email protected] B.R. Minev (ed.), Cancer Management in Man: Chemotherapy, Biological Therapy, Hyperthermia and Supporting Measures, Cancer Growth and Progression 13, DOI 10.1007/978-90-481-9704-0_9, © Springer Science+Business Media B.V. 2011

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166 Table 9.1 Select hormonal agents used in breast cancer

S.T. Maunglay et al. Anti-estrogens

SERMs Tamoxifen, raloxifene, toremifene SERD Fulvestrant Aromatase inhibitors (AI) Steroidal AIs Exemestane (aromatase inactivator) Formestane Nonsteroidal inhibitors Aminoglutethimide∗ , letrozole, anastrozole, fadrozole, and vorozole Androgen substrate Androstenedione Progestational agents Megestrol acetate and intramuscular medroxyprogesterone acetate Progesterone receptor Antagonists Onapristone and mifepristone Androgens Danazol, testosterone, fluoxymesterone, testolactone and fluoxymesterone SERMs Selective estrogen receptor modulators, SERD Selective Estrogen receptor down regulator, AIs Aromatase Inhibitors. [∗ ]; Nonselective AI

9.2.1 Selective Estrogen Receptor Modulators (SERMs) 9.2.1.1 Tamoxifen The majority of human breast cancers are hormone receptor positive (express estrogen receptors and/or progesterone receptors), and tumor cell growth and proliferation may at least in part be stimulated by endogenous or exogenous estrogen and progesterone. The hormone-mediated effects involve signaling through the estrogen receptors (ERs) and progesterone receptors (PgRs) located in the nucleus of the cell. For many years, tamoxifen has been the mainstay of treatment in early stage and metastatic hormonereceptor positive breast cancers and has an additional role in prevention of hormone-receptor positive breast cancer in high-risk patients. Several meta-analyses showed an unequivocal benefit in patients with hormone-receptor positive cancers early stage breast cancer receiving adjuvant tamoxifen therapy for 5 years, regardless of menopausal status [5]. The use of adjuvant tamoxifen reduced the annual breast cancer death rate by 31%, and the benefits of 5 years of therapy were maintained over 15 years of study follow-up [6]. Tamoxifen was also shown to reduce the risk of developing contralateral breast recurrance [7]. Tamoxifen was associated with a 32% reduction in osteoporotic fractures, but it imparts

a higher risk for thromboembolic events, including strokes, as well as endometrial cancer [8, 9]. Whereas tamoxifen may be replaced by aromatase inhibitors in postmenopausal women, it remains the treatment of choice outside the participation in a clinical trial in premenopausal women as well as in men. Tamoxifen has not shown a benefit in patients with hormone receptor negative tumors.

9.2.1.2 Raloxifene Raloxifene, a nonsteroidal benzothiophene, is a newer SERM that has been studied mainly in the prevention and treatment of osteoporosis. It has been shown to lower serum low-density lipoprotein (LDL) cholesterol levels and, unlike tamoxifen, is not associated with endometrial stimulation in postmenopausal women [10–13]. In long-term follow-up however, thromboembolic events were more frequently seen with raloxifene when compared to placebo but no increased risk in endometrial cancer was observed [12, 13]. In addition to its use in osteoporosis, the potential role of raloxifene in the prevention of breast cancer was evaluated in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial. In this multi-center, randomized, double-blinded study, breast cancer was diagnosed in 13 out of 5129 women assigned to the raloxifene group compared to 27 out of 2576 women

9

Hormonal Therapy in Cancer

who received placebo during 40 months of follow-up. The overall risk of developing invasive breast cancer was decreased by 76% during 3 years of treatment with raloxifene [12]. The Continuing Outcomes Relevant to R (CORE) trial was conducted as a continuaEvista tion of the MORE trial for an additional 4 years [14]. This trial confirmed the findings of the MORE trial, reporting a 66% reduction in the incidence of invasive breast cancer in the treatment group with a 76% reduction in ER-positive invasive breast cancer. Data from the RUTH (Raloxifene Use for the Heart) trial, a randomized study of 10,101 postmenopausal women at increased risk of coronary events suggested that raloxifene reduced the relative risk of developing invasive breast cancer by 44% (40 vs. 70 events; hazard ratio, 0.56; 95% confidence interval, 0.38–0.83), with an absolute risk reduction of 1.2 invasive breast cancers per 1000 women treated for 1 year [15]. These promising early data prompted the initiation of a prospective study to compare the benefits of raloxifene in preventing breast cancer to those seen with tamoxifen in the Study of Tamoxifen and Raloxifene (STAR). Treatment with raloxifene resulted in a similar reduction of developing invasive breast cancer compared to tamoxifen, however there was a numerically but not statistically higher number of noninvasive breast cancers in the raloxifene group. Raloxifene was further associated with a lower incidence of thromboembolic events, cataracts and uterine cancer [16]. Data from several thousands of postmenopausal women suggest that raloxifene is a feasible alternative to tamoxifen for the prevention of invasive breast cancer, and this compound is now approved by the U.S. Food and Drug Administration (FDA) not only for osteoporosis but also for the prevention of breast cancer in high-risk postmenopausal women.

9.2.1.3 Toremifene The efficacy of toremifene, a newer SERM, in comparison to tamoxifen in tamoxifen-naïve patients was evaluated in several studies. Toremifene appeared comparable to tamoxifen in both efficacy and toxicity profile in postmenopausal women with hormone receptor positive or hormone receptor unknown breast cancer [17, 18], however toremifene was not effective as a secondline therapy after tamoxifen failure, possibly due to cross resistance [19].

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9.2.2 Estrogen Receptor Down-Regulators The selective estrogen receptor down-regulators, such fulvestrant, not only inhibit the estrogen receptor but induce its down-regulation [20]. Unlike the SERMs, the SERDs, e.g. fulvestrant are pure anti-estrogens without evidence of estrogen agonist activity [21]. Fulvestrant was compared to tamoxifen as first-line therapy but was not found to be superior to tamoxifen [22]. In smaller studies, fulvestrant has shown activity as second-line therapy in hormone-sensitive advanced breast cancer, after progression on tamoxifen or toremifene [23, 24]. As second-line therapy, fulvestrant was as effective as anastrozole in postmenopausal women with advanced breast carcinoma, showing similar overall survival [25] (see Table 9.2). Fulvestrant has activity in breast cancer patients who progressed after treatment with aromatase inhibitors (AIs) with a 35 and 37% clinical benefits rate (objective response and stable disease >24 weeks) [26, 27]. The convenience of monthly intramuscular injections may render this agent an attractive alternative to the daily oral dosing of most other hormonal therapies.

9.2.3 Aromatase Inhibitors 9.2.3.1 Aromatase Inhibitors for Advanced Breast Cancer Aromatase inhibitors (AIs) effectively suppress plasma estrogen levels by inhibiting or inactivating the aromatase enzyme thereby preventing the conversion of androstenedione to estrone and testosterone to estradiol [28]. Aromatase inhibitors are only approved for postmenopausal women. The third-generation AIs have been shown to be more effective than tamoxifen in postmenopausal women with advanced breast in the first-line setting (Table 9.2), and remain effective as second-line therapy in tamoxifen-resistant disease. The AIs have also proven useful following 5 years of adjuvant tamoxifen [29]. Furthermore, the selective AIs are superior to tamoxifen for adjuvant therapy either as initial therapy or after 2–3 years of tamoxifen in postmenopausal women (see Table 9.3). As discussed previously, tamoxifen for 5 years remains the standard adjuvant hormonal treatment in premenopausal

56% vs. 56% (p = 0.787) 59% vs. 46% (p = 0.098) 83% vs. 56% (p < 0.001) 50% vs. 38% (p = 0.004) 57% vs. 42%

Phase III

Phase III

Phase III

Phase III optional cross-over Phase II open label efficacy study

41% vs. 17%

30% vs. 20% (p =0.0002)

43% vs. 31% (p = 0.172)

21% vs. 17% (p = 0.005)

33% vs. 33%

Studies with AIs as second line after tamoxifen Vorozole 2.5 mg (n = 225) vs. Phase III 24% vs. 27% 9.7% vs.6.8% MA 40 mg (n = 227) (p = 0.24) (p = 0.24) Fulvestrant 250 mg Combined data of 43.5% vs.40.9% 19.2% vs. 16.5% monthly;(n =428) vs. two similarly (95% CI, – 4.42 to (95.14% CI, Anastrozole 1 mg daily, designed Phase III 9.36; p = 0.51) −2.27 to 9.05; (n =423) trials p = 0.31)

Studies with AIs as first line Anastrozole 1 mg (n = 340) vs. Tamoxifen 20 mg (n = 328) Anastrozole 1 mg (n = 511) vs. Tamoxifen 20 mg (n = 510) Anastrozole 1 mg (n = 121) vs. Tamoxifen 40 mg (n = 117) Letrozole 2.5 mg (n = 453) vs. Tamoxifen 20 mg (n = 454) Exemestane 25 mg (n =61) vs. Tamoxifen 20 mg (n = 59)

5.5 vs. 4.1 (HR, 0.95; 95.14% CI, 0.82–1.10; P = 0.48)

Goss et al. [35]

Paridaens et al. [34]

Mouridsen et al. [33]

Milla-Santos et al. [32]

Nabholtz et al. [31]

Bonneterre et al. [30]

27.4 vs. 27.7 (p = 0.809) Howell et al. [25]

2.6 vs.3.3 (p = 0.56) NS 26 vs. 29 (p = 0.94) NS

Median response duration were 16 (95% CI 11–38 months) vs. 22 (95% CI 12–36 months)

9.4 vs. 6.0 (p29.5∗ vs. 28.7 months) 5.6 vs. 5.1 (p = 0.02) 25.3 vs. 21.5 (p = 0.03) Dombernowsky and 5.5 (p = 0.05) NS and 21.5 (p = 0.4) et al. [38] Median 45 months follow up

Overall response rate Median time to tumor (%) progression in months

AI aromatase inhibitors; CR complete response; PR partial response; NC no change; CB clinical benefit (CB =CR+PR+ NC >6 months; NS Not significant; PD progressive disease; CI Confidence Interval ; HR hazard ratio

24.3% (95% CI, 19.0–30.2%) and 1.7% (95% CI, 0.0–9.2%).

Clinical benefit

Phase II or III

AIs as second line after initial first line AI failure Phase II efficacy trial. Exemestane 25 mg Patients with (n = 241) and dose progressive disease escalation of (PD) after treatment exemestane 100 mg with a nonsteroidal (n = 58) upon PD aromatase inhibitor.

Letrozole 2.5 mg. (n = 174) vs. Letrozole 0.5 mg (n = 188) vs. MA 160 mg (n = 189) Letrozole 2.5 mg (n = 199) vs. Letrozole 0.5 mg (n = 202) vs. MA 40 mg (n = 201)

Anastrozole 1 mg (n = 263) vs. Anastrozole 10 mg (n = 248) vs. MA 40 mg (n = 253) Exemestane 25 mg (n = 366) vs. MA 40 mg (n = 403)

Table 9.2 (continued) Design, daily dosage and number of patients

9 Hormonal Therapy in Cancer 169

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S.T. Maunglay et al.

Table 9.3 Phase III randomized trials of aromatase inhibitors as single- agent upfront, sequential, or extended adjuvant hormonal therapy in postmenopausal women Trial DFS OS Contralateral breast cancer ATAC (Arimidex, Tamoxifen Alone or in Combination) [53] (n = 9366) Anastrozole Tamoxifen Tamoxifen + anastrozole∗ BIG 1–98 or BIG FEMTA (Breast International Group 1–98) [54] (Letrozole first n = 4003; tamoxifen first n = 4007) Letrozole ---------------> Tamoxifen -------------> Letrozole -> Tamoxifen Tamoxifen -> Letrozole

Significantly favors anastrozole Trend favors anastrozole (HR (HR 0.87 [95% CI 0.97 [95% CI 0.85–1.12, 0.78–0.97, p = 0.01]) p = 0.7])

Significantly favors anastrozole (35 vs. 59 cases [42% relative reduction, p = 0.01])

Trend favors letrozole (166 Trend favors letrozole (16 5-year DFS estimates = deaths in letrozole group [0.4%] vs. 27 [0.7%] cases) Overall = [4.1%] vs. 192 deaths in Significantly favors letrozole tamoxifen group [4.8%]) (84%) over tamoxifen (81.4%) (HR 0.81 [95% CI 0.70–0.93, p = 0.003]) Subgroups = Node-positive = 77.9% (letrozole) vs. 71.4% (tamoxifen) Node-negative = 88.7% in both groups Significantly favors exemestane Trend favors exemestane (222 Significantly favors exemestane IES (Intergroup Exemestane (56% relative reduction) (OR deaths in exemestane group (unadjusted HR 0.76 [95% Study) [55] 0.44 [95% CI 0.20–0.98, vs. 261 deaths in tamoxifen CI 0.66–0.88, p = 0.0001]) Tamoxifen -> Exemestane p = 0.04]) group) (HR 0.85 [95% CI with an absolute benefit of (n = 2352) 0.71–1.02, p = 0.08]) 3.3% by the end of treatment Tamoxifen ----------------> Subgroup analysis excluding (n = 2372) 122 patients with estrogen receptor-negative disease significantly favors exemestane (HR 0.83 [95% CI 0.69–1.00, p = 0.05) 4-year DFS estimates = MA-17 (National Cancer Trend favors letrozole (17 vs. 4-year OS estimates = Significantly favors letrozole Institute of Canada Clinical 28 cases) (HR 0.63 [95% CI Trend favors letrozole (94.4%) over placebo Trials Group MA-17 Study) 0.18–2.21, p = 0.12]) (95.4%) over placebo (95%) (89.8%) (HR 0.58 [95% CI [29] (HR 0.82 [95% CI 0.45–0.76, p = < 0.001]) Tamoxifen -> Letrozole 0.57–1.19, p = 0.3]) (n = 2593) Subgroup = Tamoxifen -> Placebo Significantly favors letrozole (n = 2594) among lymph node-positive patients (HR 0.61 [95% CI 0.38–0.98, p = 0.04) Meta-analysis of three clinical Significantly favors anastrozole Significantly favors anastrozole Anastrozole = 14 cases vs. (HR 0.59 [95% CI (HR 0.71 [95% CI tamoxifen = 22 cases (1% trials[56] (ABCSG 8, ARNO 0.48–0.74, p < 0.0001]) 0.52–0.98, p = 0.04]) incidence rate in both 95 and ITA) [56] groups) Tamoxifen -> anastrozole (n = 2009) Tamoxifen ---------------> (n = 1997) NSABP B-33 (National Trend favors exemestane (91%) No difference between groups Exemestane = 2 cases vs. Surgical Adjuvant Breast over placebo (89%) (RR (exemestane = 16 deaths and placebo = 8 cases and Bowel Project) [57] 0.68, p = 0.07) placebo = 13 deaths) (n = 1598)∗∗ (RR = 1.2, p = 0.63) Tamoxifen -> Exemestane Tamoxifen -> Placebo DFS disease-free survival; OS Overall survival; HR hazard ratio; OR odds ratio; CI confidence interval; ABCSG Austrian Breast and Colorectal Cancer Study Group; ARNO Arimidex-Nolvadex study; ITA Italian Tamoxifen Anastrozole study; ∗ indicates that this arm was closed and unblinded after the first interim analysis showed its equivalence to tamoxifen; ∗∗ indicates that this trial was electively closed early for accrual, after the results from MA-17 were reported

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women. The role of AIs in premenopausal women in any setting is still unknown and is currently being evaluated in randomized trials in combination with ovarian suppression. Aminoglutethimide (AG) is a nonselective, nonsteroidal anti-adrenal first-generation aromatase inhibitor. In contrast to its use in ectopic ACTH syndrome and against adrenal steroidogenesis, a lower dose was effective for breast cancer treatment [41, 42]. While initial studies showed that AG was not superior to tamoxifen, AG was shown to be beneficial in patients after progressing on tamoxifen. The combination of tamoxifen and AG did not convey additional benefits to either agent given alone. Due to its undesirable toxicity profile, AG is now rarely used. Formestane and fadrozole are members of the second generation steroidal and nonsteroidal AIs. These agents are selective inhibitors of the aromatase enzyme and do not block other adrenal gland steroidogenesis. Fadrozole showed similar efficacy when compared to tamoxifen as first-line treatment in postmenopausal patients with advanced breast cancer [43]. It was found to be a significantly better tolerated alternative to tamoxifen. Another trial found fadrozole to be useful as first-line treatment, although complete response rate and duration of objective response were significantly better in the patients treated with tamoxifen [44]. It was found to be comparable to tamoxifen for both efficacy and tolerability as first-line therapy [45]. However, neither drug is currently commercially available in the United States. The third generation selective aromatase inhibitors include anastrozole, letrozole, exemestane and vorozole, with the first three being approved agents. Anastrozole was found to have a longer time to progression when compared to tamoxifen in an randomized Phase III trial performed in North America [31], however this was not seen in a similar trial performed outside the United States [30]. Neither trial suggested an overall survival benefit when compared to tamoxifen in the treatment of metastatic breast cancer in postmenopausal women, but anastrozole was associated with a lower incidence of thromboembolic events and vaginal bleeding [30–32, 46]. Letrozole was initially shown to be effective when studied as third-line hormonal therapy in women with metastatic breast cancer [47]. Letrozole was compared to tamoxifen as first-line therapy in postmenopausal

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women with locally advanced or metastatic breast cancer and in this study cross-over was allowed. Although the difference in median survival was not statistically significant between the groups, those patients who started in the letrozole arm had both a longer time to progression (median, 16 months and 9.4 months respectively) and a longer time before chemotherapy was initiated when compared to those patients who started in the tamoxifen arm (median, 9 months and 6 months respectively) [48]. Vorozole was found to be as effective as megestrol acetate as secondline hormonal therapy in postmenopausal women with advanced breast cancer who had disease progression following tamoxifen treatment [35]. In contrast to the non-steroidal AIs, letrozole and anastrozole, exemestane is a steroidal selective aromatase inhibitor [49] with irreversible inactivation of the aromatase enzyme. When compared to megestrol acetate in tamoxifen failure, exemestane showed prolonged overall survival, time to tumor progression, and time to treatment failure [37]. Exemestane has shown activity in the setting of primary tamoxifen resistance, as well as in patients who progressed on a non-steroidal aromatase inhibitor, e.g. anastrozole or letrozole [40, 50, 51]. A meta-analysis of 25 clinical trials enrolling a total of 8504 patients found third-generation AIs to have a statistically significant survival benefit over both tamoxifen and secondgeneration AIs in women with metastatic breast cancer. Their efficacy, in addition to their favorable toxicity profile, has rendered the third generation AIs the firstline choice of hormonal therapy in postmenopausal women with hormone receptor positive or unknown advanced breast cancer [52].

9.2.3.2 Aromatase Inhibitors for Early Stage Breast Cancer The AIs have been compared to tamoxifen as upfront adjuvant, sequential and extended adjuvant hormonal treatment in postmenopausal women in large randomized trials (Table 9.3, Fig. 9.1). The ATAC trial (Arimidex, Tamoxifen Alone or in Combination) evaluated 9366 postmenopausal women randomized into three arms of adjuvant hormonal therapy for 5 years (anastrozole, tamoxifen or the combination). Due to inferior efficacy, the combination arm was later closed to accrual. The results significantly favored anastrozole

172 Fig. 9.1 Aromatase inhibitors for early stage breast cancer. Abbreviations: ATAC = Arimidex, Tamoxifen Alone or in Combination study; IES = Intergroup Exemestane Study; MA-17 = National Cancer Institute of Canada Clinical Trials Group MA-17 Study; BIG 1–98 or BIG FEMTA = Breast International Group 1–98 study; ABCSG = Austrian Breast and Colorectal Cancer Study Group; ARNO = ArimidexNolvadex study; ITA = Italian Tamoxifen Anastrozole study; NSABP B-33 = National Surgical Adjuvant Breast and Bowel Project B-33 study. PLAC = Placebo; LET = Letrozole; R = Randomization

S.T. Maunglay et al. 5 years

tamoxifen

ATAC

R

anastrozole tamoxifen + anastrozole

tamoxifen

tamoxifen

3-2 years

R

2-3 years

IES

exemestane

tamoxifen

letrozole MA-17

letrozole

R

tamoxifen 5 years

(PLAC) Placebo (PLAC)

R (PLAC-LET)

5 years

BIG 1.98 (BIG FEMTA)

R

tamoxifen letrozole letrozole tamoxifen tamoxifen letrozole 2 years

ARNO, ITA ABCSG

R

tamoxifen

tamoxifen

tamoxifen

anastrozole

exemestane NSABP B33

tamoxifen 5 years

R placebo 2 years

in terms of disease-free survival and the development of a contralateral breast cancer. The overall survival trend favored anastrozole, but was not statistically significant [53]. The BIG 1–98 (Breast International Group 1–98) or BIG FEMTA trial evaluated 8010 postmenopausal women randomized into four arms of adjuvant hormonal therapy; letrozole or tamoxifen for 5 years, letrozole for 2 years followed by tamoxifen for 3 years or tamoxifen for 2 years followed by letrozole for 3 years. The data was analyzed based on 2 groups of patients – those who initially received tamoxifen (n = 4007) and those who initially received letrozole (n = 4003). The data revealed a statistically significant improvement in disease-free survival in the women treated with letrozole first, with a striking benefit seen in the node-positive subgroup. The overall survival trend, as well as the incidence of developing a

contralateral breast cancer, favored letrozole but neither endpoint reached statistical significance [54]. The Intergroup Exemestane Study (IES) evaluated 4724 postmenopausal women who received adjuvant tamoxifen for 2–3 years and were then randomly assigned to either switch to exemestane or to continue on tamoxifen for the remainder of the 5 years of adjuvant hormonal therapy. The results significantly favored the switch to exemestane in terms of diseasefree survival, with an absolute benefit of 3.3% by the end of treatment. The overall survival trend favored the switch to exemestane, and reached statistical significance in the subgroup analysis excluding patients with ER-negative tumors. The development of contralateral breast cancer was significantly reduced in the exemestane group (relative reduction of 56%) [55]. The MA-17 trial (National Cancer Institute of Canada Clinical Trials Group) evaluated 5187

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postmenopausal women who received tamoxifen for 5 years and were then randomized to extended adjuvant therapy with letrozole for 5 years vs. placebo. The results of this study significantly favored the letrozole group in terms of disease-free survival, with an absolute benefit of 4.6% at 4 years. The overall survival and incidence of contralateral breast cancer trends favored letrozole, and the subgroup of lymph-node positive patients receiving letrozole did show a statistically significant overall survival benefit. A further benefit was seen in the patients who were originally treated with placebo group, but then opted to received letrozole after the trial was unblinded [29]. The meta-analysis of three clinical trials (ABCSG 8, ARNO 95 and ITA) evaluated a total of 4006 postmenopausal women who received adjuvant tamoxifen for 2–3 years and were then randomized to anastrozole or to continue tamoxifen to complete 5 years of adjuvant hormonal therapy. The disease-free survival and overall survival significantly favored the switch to anastrozole, while the incidence rate of contralateral breast cancer was similar between the groups (1%) [56]. The NSABP B-33 trial (National Surgical Adjuvant Breast and Bowel Project) evaluated 1598 postmenopausal women who received adjuvant tamoxifen for 5 years and were then randomized to extended adjuvant therapy with exemestane vs. placebo, initially for 2 years (the protocol was amended in 2002 to extend exemestane or placebo for 5 years). When the substantial benefit of extended adjuvant therapy with letrozole following 5 years of tamoxifen was reported from the MA-17 trial in 2003, the NSABP B-33 trial was electively closed short of its patient accrual goal of 3000 women. The study was unblinded, and exemestane was offered to those patients who had been randomized to the placebo group, with 344 of 779 women opting to cross over to the exemestane group. The early results from the NSABP B-33 trial with a median follow-up of 30 months indicated that there was a trend toward a benefit in diseasefree survival in the exemestane group, translating into an absolute 2% difference between the groups. There was no difference noted in overall survival between the two groups. There were fewer contralateral breast cancers diagnosed in the exemestane group when compared to placebo (2 cases vs. 8 cases respectively) [57].

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9.2.4 Ovarian Function Suppression (OFS) With or Without SERMs in Premenopausal Women Ovarian suppression by oophorectomy in premenopausal women was one of the first therapeutic interventions in the treatment of breast cancer dating back to more than 100 years ago [1]. Ovarian suppression may alternatively be induced by radiation to the ovaries or by chemical means with the use of LHRH agonists [58, 59]. It has not been clearly established whether the addition of ovarian ablation to chemotherapy and/or hormonal therapy is necessary and whether it provides an additional benefit. Premenopausal women with ER-positive early stage breast cancer who were treated with adjuvant chemotherapy and developed chemotherapy-induced amenorrhea were found to have a significant improvement in outcomes [9]. Ovarian suppression combined with tamoxifen has clearly been shown to be superior to ovarian ablation alone [60]. In contrast, the benefits of ovarian ablation in addition to tamoxifen compared to tamoxifen alone in premenopausal women with ERpositive and/or PgR-positive tumors have been shown in some studies [61–63] but were not observed in others [64] and most studies were limited in numbers or in follow up times. A trial of chemotherapy (CMF = cyclophosphamide, methotrexatee and 5-fluorouracil) vs. chemical ovarian ablation as adjuvant therapy in premenopausal women with ER-positive and nodepositive early stage breast cancer suggested that ovarian suppression may as effective but associated with better quality of life (QOL) measures [65]. However, the chemotherapy used in this trial is now rarely used and the patients in neither group received tamoxifen, rendering the value of these findings difficult to assess. In particular as it is felt that ovarian suppression alone may not be the best treatment option for hormonesensitive early stage breast cancer in premenopausal women [66]. The benefits of optimal hormonal therapy in premenopausal women are currently being addressed in several large, randomized studies, including the International Breast Cancer Study Group (IBCSG) trials [67] ,the Suppression of Ovarian Function Trial (SOFT), the Tamoxifen and Exemestane Trial (TEXT)

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and the recently closed Premenopausal Endocrine Responsive Chemotherapy Trial (PERCHE). The details of these trials are summarized in Table 9.4 and Fig. 9.2.

9.2.5 Progestational Agents Megestrol acetate (MA) and intramuscular medroxyprogesterone acetate while active in second-line treatment, these drugs have been replaced upon the introduction of AIs [72]. AIs showed superior activity when compared to MA in multiple settings, and progestational agents are more commonly used in later stages of the disease (Table 9.2).

9.2.6 Progesterone Receptor Antagonists Onapristone and mifepristone are progesterone antagonists that have been evaluated in small studies for the treatment of breast cancer. Onapristone was studied as first-line therapy in 18 patients, benefits were seen in 67% patients with a median duration of benefits of 70 weeks. However, the development of onapristone was stopped due to unacceptable liver toxicity [73, 74]. Mifepristone was studied in 28 patients with PgRpositive recurrent breast cancer who had received no prior therapy, but it showed only minimal activity with a 11% overall response rate.

Table 9.4 Select large trials on ovarian function suppression Trial Patient population Design Studies without tamoxifen ZEBRA Kaufmann et al. [68]

IBCSG VIII IBCSG [66]

Studies with tamoxifen ABCSG Jakesz et al. [69] ZIPP Rutqvist et al. [70]

N+; ER+/−

CMF × 6 months (n = 823). G × 2 years (n = 817)

N−; ER+/−

CMF × 6 (n = 360) G × 24 months (n = 346) CMF × 6 G × 18 months (n = 357)

Node+/−, ER+ (N = 1034)

CMF × 6 G × 3 years + tamoxifen for 5 years G × 2 years tamoxifen for 2 years. G × 2 years+ tamoxifen for 2 years. No adjuvant treatment CAF CAF + G × 5 years CAF + G + Tamoxifen × 5 years

Node+/−, ER+/− (N = 2631)

Node+, ER+ (N = 1504)

Results ER-positive = [DFS = HR = 1.05; 95% CI, 0.88 to 1.24; P = .6] ER negative = CMF > G ER+ = CMF = G [DFS = HR = 0.97; 95% CI, 0.66–1.42; P = 0.86] CMF G = G [DFS = HR = 0.84; 95% CI, 0.56–1.26; P = 0.40] CMF G = CMF [DFS = HR = 0.80; 95% CI, 0.54–1.19; P = 0.26] CMF < G + Tamoxifen for = [DFS = HR = 1.40; 95% CI, 1.06 to 1.87; P = .017] G > no G = [DFS = HR = 0.77; 95% CI, 0.66 to 0.89; P < .001]

CAF + G = CAF = [DFS = HR = 0.93; 95% CI, 0.76 to 1.14; P = .25] CAF + G + Tamoxifen > CAF + G = [DFS = HR = 0.73; 95% CI, 0.59 to 0.90; P < .01] , better than; =, equal to. HR hazard ratio; ZEBRA Zoladex Early Breast Cancer Research Association; CMF cyclophosphamide, methotrexate, fluorouracil; N− node negative; G goserelin; ER estrogen receptor; DFS disease-free survival; IBCSG International Breast Cancer Study Group; N+ node positive; OA ovarian ablation; OS overall survival. ABCSG Austrian Breast and Colorectal Cancer Study Group; ZIPP Zoladex in Premenopausal Patients; INT North American Breast Cancer Intergroup Trial; CAF cyclophosphamide, doxorubicin, fluorouracil; IBCSG International Breast Cancer Study Group; BIG Breast International Group

INT-0101 Davidson et al. [71]

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175 SOFT [IBCSG 24-02, BIG 2-02] Strata

ER ≥ 10% and/or PgR ≥ 10%

Any CT

Patients with estradiol (E2) in the premenopausal range either after CT or without CT

No CT

R A N D O M I Z E

T x 5y OFS + T x 5y OFS + E x 5y

TEXT [IBCSG 25-02, BIG 3-02]

ER ≥ 10% and/or PgR ≥ 10% Candidates to begin GnRH analogue (triptorelin) from the start of adjuvant therapy

Strata** Any CT

No CT

R A N D O M I Z E

GnRH+ Tamoxifen* x 5y +/-CT** GnRH+ Exemestane* x 5y +/-CT**

* to begin at least 6 weeks after start of triptorelin or after CT, whichever is later. ** choice of +/-CT may be made by previous randomization in the PERCHE trial.

PERCHE [IBCSG 26-02, BIG 4-02] Strata

ER ≥ 10% and/or PgR ≥ 10% Patients for whom CT is considered to be a randomized option (lower risk)

Type of chemotherapy Type of OFS TEXT or T or E

R A N D O M I Z E

OFS + TEXT x 5y or T or E x 5y

OFS + any CT+TEXT x5y or T or E x 5y

Fig. 9.2 Hormonal therapy in premenopausal women. Abbreviations: CT=chemotherapy; OFS=ovarian function suppression using triptorelin × 5 years or surgical oophorectomy or radiation; T=tamoxifen; E=exemestane; GnRH

analogue=triptorelin × 5 years (but oophorectomy or radiation is allowed after 6 months; TEXT=randomized trial comparing tamoxifen vs. exemestane (recommended strata)

9.2.7 Androgens

9.2.8 Estrogens

Androgens including danazol, testosterone, fluoxymesterone, testolactone and fluoxymesterone have been studied in breast cancer, but these agents are now rarely used due to their low efficacy and poor side effect profile. Danazol was studied in 41 patients with responses seen in seven patients (17%), but the high dose was associated with significant adverse side effects [75]. Fluoxymesterone was studied in combination with tamoxifen vs. tamoxifen alone in 541 ER-positive postmenopausal women with resected early breast cancer. The combination failed to show an improvement over tamoxifen alone [76].

Diethylstilbestrol (DES) was studied in postmenopausal women with advanced breast cancer after developing resistance to estrogen deprivation [77]. In this study of 32 patients, eight patients discontinued due to side effects in the absence of progression. Five patients had an objective response, and one patient maintained stable disease lasting for 1 year. DES however is no longer commercially available in the United States due to its teratogenic effects. In postmenopausal women, AIs are most commonly recommended as first line for both, adjuvant

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or metastatic disease whereas tamoxifen remains the treatment of choice in premenopausal woman. The SERDs, progestin analogues or estrogens are offered only after multiple hormonal therapy failures.

9.3 Hormonal Therapy in Ovarian Cancer Ovarian cancer is often diagnosed in its advanced stages, due to a lack of specific symptoms or a paucity of clinical findings in early stage disease. Platinum-based chemotherapy is considered front-line treatment, and hormonal therapies have been evaluated for their role in this illness. Tamoxifen has been studied as second-line therapy in platinum-refractory ovarian cancer and yielded an objective response rate of 13% [78] Mifepristone was studied in cisplatinand paclitaxel-resistant ovarian cancer, yielding a 27% response rate, including a 9% complete response rate [79]. The potential benefit of SERMs in the prevention of ovarian cancer was suggested in a small retrospective single institution study of 152 tamoxifentreated breast cancer patients undergoing oophorectomies. Ovarian cancer was found in none of the 53 tamoxifen treated patients where 10 of 99 (17.8%) patients in the untreated group were found to have ovarian cancer [80]. It has been well-established that oral contraceptives may play a preventive role in the development of ovarian cancer. The Cancer and Steroid Hormone Study concluded that the use of oral contraceptives decreases the risk of epithelial ovarian cancer [81, 82]. A report on a quantitative assessment of 20 studies of oral contraceptive (OC) use revealed a 36% reduction in ovarian cancer risk, with a 10% decrease in risk after 1 year of OC use and an approximately 50% decrease after 5 years of OC use [83]. However, given the still not completely resolved debate on whether OCs increase the risk for breast cancer and other adverse events, the use of these agents should be considered on an individual patient basis.

9.4 Hormonal Therapy in Endometrial Cancer The staging and initial management of endometrial cancer generally involves surgical intervention.


Total extrafascial hysterectomy with bilateral salpingooophorectomy is routinely offered except when the tumor is limited to the endometrium and fertilitypreservation is a concern. This group of patient may benefit from hormonal manipulation with progestin until child-bearing is completed, followed by surgery. High-risk organ-confined disease will benefit from radiation therapy, but extra-uterine disease will typically require systemic therapy. At 5 years, 92% of women with early stage disease were disease free compared to only 41% of women with aortic node metastases or gross laparotomy findings [84]. While cytoreductive surgery appears beneficial for most local recurrences [85], central pelvic recurrence may require pelvic exenteration. This procedure carries a high operative morbidity, limiting the surgery to good surgical candidates, and only 20% to 45% of women were reported to survive beyond 5 years [86, 87]. Hormonal therapy is an acceptable first-line systemic treatment in women with inoperable tumors. The various progestational agents have been shown to have similar efficacy. When megestrol acetate was compared with hydroxyprogesterone caproate, an objective response was seen in 15% of the patients and 7% of patients achieved a complete response [88]. In this study, tumors that recurred more than 3 years from initial diagnosis had a superior response rate when compared to tumors that recurred within 3 years of initial diagnosis (33% vs. 8% respectively). A Gynecologic Oncology Group (GOG) study showed that in contrast to its use in breast cancer, high-dose megestrol acetate was not superior to low-dose megestrol acetate [89]. This study showed a 24% response rate with 6% complete responses, and an additional 22% of women in the trial maintained stable disease. Low-grade lesions had a superior response rate of 37%, compared to only 8% in the poorly-differentiated tumors. It has been shown that progesterone receptor (PR) status correlates with response to progestational agents [90]. In a GOG study, 37% of PR-positive tumors responded to progestational agents, compared to only 8% in the PR-negative group [89]. Selective estrogen receptor modulators (SERMs) play a lesser role in the treatment of endometrial cancer as compared to progestational agents. Tamoxifen as a single-agent or in combination with a progestin, in the setting of progestin failure, may have some utility in women who may not tolerate more intensive systemic chemotherapy. A

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GOG study showed a 10% response rate with tamoxifen with 4% complete responses [91]. An Eastern Cooperative Oncology Group (ECOG) study failed to demonstrate superiority of the combination of tamoxifen and progestin over progestin alone when used as initial hormonal therapy (19% vs. 20% response rate respectively), and more toxicity was noted in the combination group [92]. A comparison between oral tamoxifen and intramuscular medroxyprogesterone in advanced endometrial carcinoma of stage III and IV disease showed similar response rates of 53% vs. 56% respectively were seen [93] What was more encouraging in this study was initial non responders of medroxyprogesterone were given combination of the two therapies and 48% responded A comparison between oral tamoxifen and intramuscular medroxyprogesterone in advanced endometrial carcinoma of stage III and IV disease showed similar response rates of 53% vs. 56% respectively were seen [93]. What was more encouraging in this study was initial non responders of medroxyprogesterone were given combination of the two therapies and 48% responded. Additional SERMs are emerging as possible treatment options in advanced endometrial cancer. In a phase II study, arzoxifene showed a 31% overall response rate [94]. The responders included hormone receptor-positive women previously treated with progestins. Thus, as in breast cancer, there is a high likelihood that hormone receptor-positive tumors may also respond to newer generation SERMs. The AIs have shown only minimal activity in the treatment of endometrial cancer. Studies of letrozole and anastrozole as single-agents in patients previously treated with progestin achieved 10% and 9% response rates respectively [95, 96]. A preliminary report on exemestane use in women heavily pretreated with chemotherapy and radiation therapy showed a poor response to treatment [97]. A case report of two women who wished to preserve their fertility described the reversion of well-differentiated endometrialconfined tumors to normal endometrium after treatment with the combination of anastrozole and progestin [98]. GnRH agonists have been evaluated as a means of hormonal blockade but generally yielded poor results. In a phase II study, triptorelin achieved a 9% response rate, but no responses were seen in the previously irradiated or progestin-treated women [99]. Goserelin acetate was studied in a separate

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GOG study, achieving a 12% response rate [100]. Leuprolide was studied in a primarily pre-treated population and also failed to show any response [101]. The current hormonal therapies used in the treatment of endometrial cancer include progestational agents, employed primarily in the setting of metastatic disease. Additional considerations for the use of progestins include women with disease limited to the endometrium who wish to delay surgery for possible child-bearing and women with PR-positive, lowgrade, well-differentiated tumors with a late recurrence beyond 3 years. High-dose progestins failed to provide a superior response when compared to lower doses, thus megestrol acetate 200 mg once a day is most commonly prescribed [102]. The addition of tamoxifen to progestins may be considered but has been associated with a worse toxicity profile. The addition of tamoxifen to progestins may be considered but has been associated with a worse toxicity profile [92, 94].

9.5 Hormonal Therapy in Uterine Sarcomas Uterine sarcomas are categorized as endometrial stromal sarcoma (ESS), undifferentiated sarcoma (highgrade endometrial stromal sarcoma) or pure heterologous sarcoma and leiomyosarcoma. Similar to breast and endometrial cancers, uterine sarcomas express hormone receptors. A study of 43 cases revealed that 56% of tumors expressed estrogen receptor (ER) and 56% of tumors expressed progesterone receptor (PR) [103]. In a separate study of 60 cases, 48% were found to be ER-positive, and 30% were PR-positive [104] of all the varieties of uterine sarcomas, the ESS subtype appears to have the most benefit from hormonal therapy. Hormone therapy may be indicated in medically inoperable endometrial stromal sarcomas in the settings of either limited to uterus or recurrent advanced disease. A retrospective study of a small group of women showed that those who received progestins as adjuvant therapy had fewer recurrences than those who did not receive progestins (31% vs. 67%). The majority of patients who do recur seem to benefit from subsequent progestin therapy, which resulted in stable disease (38%) or complete response (50%) [105]. Megestrol acetate is the most commonly utilized progestin in the clinical setting. AIs may also play a role

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in second-line therapy following the use of progestins [106, 107]. However data on AIs as either first-line [106, 108, 109] or second-line hormonal therapy is sparse [110].

9.6 Hormonal Therapy in Meningioma The management of meningiomas is based on the size and location of the tumor and associated clinical symptoms. The majority of cases are followed over time with serial imaging studies, as these tumors tend to have an indolent course. Surgery or stereotactic radiosurgery (SRS) may be employed, particularly in the event of a symptomatic tumor. Malignant meningiomas may require radiation therapy following surgical resection, and approximately 19% of resected meningiomas will recur following surgery [111]. The recurrence rate varies based on the tumor location and ease of resectability, but multiple attempts at surgical resection may be possible [112]. Radiation therapy may also play a role in the setting of recurrent disease. Systemic treatment options for unresectable meningiomas or malignant meningiomas are limited. Meningiomas tend to be progesterone receptorpositive rather than estrogen receptor-positive [113]. Mifepristone is a progesterone receptor antagonist with antiglucocorticoid receptor activity. Mifepristone was shown to have a 25% objective response rate in an earlier study [114]. A more recent study of 28 patients with a median duration of treatment of 35 months showed improvement in automated visual field examination or improved CT or MRI scans in 8 patients (28%), 7 of whom were either male patients or premenopausal female patients [115]. However, more data is necessary to determine the optimal hormonal manipulations in this disease.

9.7 Hormonal Therapy for Ectopic ACTH Syndrome The most common causes of ectopic corticotropin (ACTH) syndrome are small-cell carcinomas, bronchial carcinoids, and islet cell tumors. Surgical excision of the tumor generally offers the best chance


of cure [116–118], but in many cases the tumor is unresectable or there is evidence of metastatic disease. When the liver is the only site of metastatic disease in neuroendocrine tumors, resection of hepatic metastases, cryoablation and liver transplantation are all practical options in selected patients [119, 120]. Adrenal enzyme inhibitors such as aminoglutethimide and ketoconazole, alone or combination with metyrapone, may be used to control symptoms of hypercortisolism. To prevent acute adrenal insufficiency, exogenous glucocorticoids should be coadministered as needed [121]. Etomidate has also been used with success when intravenous administration is necessary [122, 123]. Somatostatin analogues such as octreotide reduce ectopic ACTH secretion [124, 125] and are especially effective when somatostatin receptor scintigraphy is positive [126]. Mifepristone is a progesterone and glucocorticoid receptor antagonist that may be used for Cushing’s syndrome secondary to ectopic ACTH secretion [127]. Adrenelectomy, followed by life-long glucocorticoid and mineralocorticoid replacement, may sometimes be required when the adrenal enzyme inhibitors fail to control hypercortisolism [128].

9.8 Hormonal Therapy in Neuroendocrine Tumors Metastatic carcinoid tumors are capable of causing carcinoid syndrome through the secretion of serotonin and other vasoactive substances. Cytoreductive surgical resection or hepatic artery embolization should be considered as therapeutic options. Octreotide and lanreotide are somatostatin analogs that have yielded good biochemical and symptomatic responses by acting on somatostatin receptors in the neuroendocrine tumors. A small number of patients has been reported to have tumor regression in addition to biochemical response [129]. In a study of 25 patients with advanced neuroendocrine tumors treated with lanreotide, objective partial responses were seen in 2 patients (8%), both with midgut carcinoids, and an additional 10 patients (40%) had tumor stabilization [130]. Somatostatin analogs have been combined with interferon alfa (IFNa), but a recent randomized trial failed to prove superiority of the combination over octreotide alone [131]. On

9


the basis of previous studies, it may be reasonable to add IFNa to octerotide when octreotide alone fails to control the disease [132, 133].

9.9 Hormonal Therapy in Pituitary Adenoma Pituitary adenomas tend to be asymptomatic until they exceed 10 millimeters in size, at which point they are classified as macroadenomas. Gonadotroph adenomas, the most common type of macroadenoma, are typically non-functioning and may be managed with surgery, or rarely with radiation. In select asymptomatic cases, they may be followed without any intervention. Hormonal manipulation with dopamine agonists may result in a decline in follicular stimulating hormones but has not been shown to reduce tumor size [134, 135]. Thyrotroph adenomas may be clinically non-functioning when only thyroid stimulating hormone subunits are secreted, but increased thyroid stimulating hormone secretion may result in hyperthyroidism. Corticotroph adenomas often cause Cushing’s disease by ACTH production, and primary therapy includes surgery and radiation. In relapsed or inoperable cases, medical adrenalectomy with mitotane may be used in conjunction with pituitary irradiation followed by hormone replacement therapy for each hormone deficient condition. Lactotroph adenomas secrete prolactin (PRL), which leads to hyperprolactinemia and the development of hypogonadism in both men and women. Dopamine agonists are considered the first line of treatment in this condition. Bromocriptine is an ergot derivative with the longest track record, but it requires twice daily administration. Bromocriptine exists in a long-acting formulation with good efficacy data, but this agent is not currently available in the United States [136]. Cabergoline is a long-acting dopamine agonist, specific for the D2 receptor, that can be given once or twice weekly and is associated with less gastrointestinal side effects than bromocriptine [137]. Cabergoline has shown good activity in tumors that previously failed bromocriptine [138, 139]. Pergolide is another drug used for the treatment of hyperprolactinemia, but it was recently withdrawn from the market in the United States due to its association with valvular heart disease [140, 141]. Cabergoline also seemed to carry

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the same risk in these studies. The long-acting nonergot dopamine agonist quinoglide (CV 205–502) has good efficacy data but is not currently available for clinical use [135, 142]. Estrogen and progestin may have a role in woman with hypogonadism secondary to hyperprolactinemia. Somatotroph adenomas are typically growth hormone (GH) releasing tumors. GH excess occurring before the fusion of the epiphyseal growth plates results in gigantism, whereas GH excess occurring after complete epiphyseal fusion results in acromegaly. Transphenoidal surgery is the treatment of choice with the intention to cure. Cranial irradiation could be considered, but it is associated with panhypopituitarism, especially in a developing child. For this reason, in relapsed and unresectable cases, hormonal manipulation plays a significant role. Bromocriptine was found to be effective at lowering GH levels and controlling disease, particularly when concomitant prolactin over secretion is present [143, 144]. Cabergoline, the long acting dopamine agonist, is traditionally more effective and better tolerated than bromocriptine, and is also especially advantageous when the tumor over secretes both GH and PRL [145]. The somatostatin analogs, octerotide and lanreotide, are commonly used with good success, seldomly in combination with a dopamine agonist. In some cases, infusional octerotide may be required if subcutaneous depot formulations are not effective [146]. It may be possible to switch over to long-acting lanreotide once the disease becomes controlled [147]. Pegvisomant, a GH receptor antagonist has shown good activity in both adults and children, and it may be used when the tumor is not responding to other treatments. Elevated liver enzymes were reported in some patients and thus need to be monitored closely during treatment [148–150].

9.10 Hormonal Therapy in Cancer Anorexia, Cachexia and for Hematopoietic Recovery An Eastern Cooperative Oncology Group (ECOG) study revealed that weight loss may correlate with a significantly shorter median survival, a lower response rate to chemotherapy and may influence the performance status in most cancers [151]. In this study,

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weight loss also correlated with more advanced disease. Corticosteroids and progestins are commonly used for the treatment of cancer anorexia and cachexia. Oral methylprednisolone (MP) was evaluated in a randomized, double-blind crossover trial, in which one group of patients received MP for 14 days and the other group of patients received placebo the both groups were given MP for 20 days. There was less pain, lower analgesic use and less depressive symptoms observed in the majority of patients who were on MP [152]. Intravenous MP for 8 weeks was evaluated in a study of terminally-ill women. The MP group reported significant quality of life improvement, but there was no effect on overall mortality rates or time to death [153]. Steroid use for symptom improvement may be best utilized in the setting of palliative treatment of terminally-ill patients with short life expectancy due to its side effects. Megestrol acetate (MA) is the most studied hormonal drug for anorexia and cachexia. It has been approved for this indication in the setting of AIDS since 1993. A recent review of fifty-five studies also concluded that both progestins and corticosteroids are beneficial in anorexia [154]. MA is superior to fluoxymesterone, an anabolic corticosteroid, and it seems to have a better toxicity profile [155]. It has been noted that MA does have a higher rate of deep venous thrombosis than dexamethasone (5% vs. 1%). In addition to fluoxymesterone, oxandrolone is another anabolic steroid that has been studied with final efficacy data not yet reported. Recombinant human growth hormone (rHGH) has been studied in prolonged critical illnesses, but high doses of growth hormone have been associated with an increase in mortality. The group treated with rHGH had a higher relative risk of death of 1.9 and 2.4 in two separate studies [156]. The use of physiological doses of human growth hormone was studied in a recent randomized trial of patients with hematologic malignancies who were receiving intensive chemotherapy. The patients who received rHGH showed significantly faster recovery of platelets when compared to the arm that received placebo, and time to relapse did not differ significantly between the arms [157]. The benefits of physiologic or high normal doses of rHGH for cancer anorexia and cachexia remain to be determined.


9.11 Hormonal Therapy in Prostate Cancer The dependence of prostate cancer on androgens, the male sex steroids, is well-described in the literature. The androgen receptor is a nuclear transcription factor which plays a key regulatory role in the development and progression of prostate cancer. Androgens are produced mainly in the testes, and to a lesser extent in the adrenal glands. In prostate tissue, testosterone and adrenal androgens are converted by 5-alpha reductase to dihydrotestosterone, which acts as the primary ligand for the androgen receptor [158].

9.11.1 Androgen-Deprivation Therapy Androgen-deprivation therapy (ADT) has played a fundamental role in the treatment of advanced prostate cancer since its palliative use was first described in the 1940s by Huggins and Hodges [159]. The goal of ADT in prostate cancer is to reduce levels of circulating androgens, which are felt to drive the malignant transformation and growth of the tumor. Bilateral orchiectomy results in a rapid decline in serum testosterone within hours of surgery, but it is irreversible and may have a considerable negative psychological impact on the patient. The first alternative to orchiectomy was diethylstilbestrol, an estrogen agonist [160]. Luteinizing hormone-releasing hormone (LHRH) or gonadotropin-releasing hormone (GnRH) agonists have also been used to induce medical castration. All three methods of ADT were shown to have similar survival rates in a meta-analysis of men with locally advanced or metastatic prostate cancer [161]. Androgen-deprivation therapy is associated with a number of distinct side effects, including decreased libido and erectile dysfunction, loss of bone mineral density, weight gain and loss of muscle mass, cognitive dysfunction, hot flashes, fatigue, depression and anemia. Additionally, a recent observational study of men treated with a LHRH agonist showed an increased risk of developing diabetes and cardiovascular disease in this group of patients. Men who underwent orchiectomies were observed to be at greater risk for

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developing diabetes, but not cardiovascular disease [162].

9.11.2 The Estrogen Agonists The estrogen agonists, including diethylstilbestrol, suppress the secretion of LHRH by the hypothalamus, resulting in decreased LH levels and testosterone synthesis by the testes. It may take 3 weeks or longer to achieve castrate levels of testosterone with diethylstilbestrol [163]. A meta-analysis of the Veteran’s Affairs Cooperative Urologic Research Group (VACURG) study in 1988 showed prolonged survival in patients with advanced prostate cancer who received treatment with diethylstilbestrol 1 mg daily compared with lower or higher doses or placebo [164]. A major drawback of the estrogen agonists is the associated risk of cardiovascular disease, including thromboembolic events, myocardial infarction and stroke. Diethylstilbestrol is no longer commercially available in the United States [165]. Currently, estrogen therapy is rarely used to treat prostate cancer.

9.11.3 The LHRH Agonists The LHRH agonists include leuprolide, goserelin and triptorelin. These drugs bind continuously to LHRH receptors on pituitary gonadotrope-producing cells. This leads to an initial stimulation of LH release, resulting in a testosterone surge and possible tumor flare. After about one week, the LHRH receptors are downregulated, leading to reduced production of LH and therefore, decreased synthesis of testosterone by the testes. Significant reductions in serum LH and castrate testosterone levels are not seen for up to three to four weeks after initiating therapy with a LHRH agonist [166–168]. Therapy with a LHRH agonist is considered the first-line pharmacologic approach to treating advanced or metastatic prostate cancer. Treatment is considered palliative, not curative, but the Medical Research Council Prostate Cancer Working Party Investigators Group did show a modest prolongation in survival and decreased risk of major complications (pathologic fracture, spinal cord compression, urinary tract obstruction and extraskeletal metastasis)

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when treatment is started early and not delayed until the onset of symptoms [169]. Due to the initial testosterone surge and potential tumor flare associated with the LHRH agonists, the temporary use of an antiandrogen in combination with the LHRH agonist is recommended in certain at-risk patients (i.e. men with severe ureteral obstruction or severe, painful vertebral metastases) [167, 168, 170]. In patients with node-positive disease who have undergone radical prostatectomy and lymph node dissection, immediate treatment with ADT is associated with a significant overall and prostate-cancer-specific survival benefit and progression-free survival benefit, when compared to delayed treatment at the time of disease progression [171]. Biochemical relapse (rising PSA level alone) is a common situation, occurring in up to 20–40% of men within 10 years of definitive treatment with radiation therapy or radical prostatectomy [172]. A large retrospective review examining this group of patients found that in the subgroup of men with high-risk disease (Gleason > 8, PSA doubling time < 12 months), early ADT provided a clinical disease-free survival benefit [173]. Intermittent androgen-deprivation therapy refers to cyclic administration of LHRH agonists and antiandrogens, with the goal of attenuating some of the treatment-associated adverse effects. Usually there is either a fixed interval defined for induction treatment with ADT (i.e. 9–12 months), or treatment is given until maximal PSA response. This is followed by a period of observation of the PSA level off ADT, and once a predefined rise in PSA level is noted, reinitiation of ADT is begun. Apart from the benefits of minimizing adverse side effects and lowering cost, intermittent ADT may also potentially delay the emergence of androgen-independent tumor growth [163, 174–177]. Currently there is insufficient evidence to support the routine use of intermittent ADT, but a number of clinical trials are ongoing to address this issue [178]. A number of randomized trials of radiation therapy alone vs. radiation therapy and ADT showed a significant clinical benefit for the combination treatment in patients with high-risk (i.e. Gleason score 8 to 10, PSA >20 ng/mL), locally advanced prostate cancers. Androgen-deprivation therapy should begin at least two months prior to starting radiation therapy, and continue at least through the course of radiation [179].

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9.11.4 The LHRH Antagonists The LHRH antagonists include abarelix, cetrorelix, ganirelix, antarelix and detirelix. These drugs directly block the LHRH receptors on pituitary gonadotropeproducing cells, inhibiting LH release and resulting in rapid suppression of testosterone production without the tumor flare associated with the LHRH agonists [160, 180]. Unlike LHRH agonists, significant reductions in serum testosterone levels may be seen as early as a few days after starting therapy with a LHRH antagonist [181]. Abarelix was approved in the United States in 2003 for initial treatment of advanced prostate cancer, but the drug was withdrawn from the market in May 2005 due to poor sales and a higher than expected rate of severe allergic reactions [170].

9.11.5 Anti-Androgens Anti-androgens include both non-steroidal (flutamide, bicalutamide, and nilutamide) and steroidal (cyproterone acetate and megestrol acetate) formulations. These drugs compete with dihydrotestosterone by binding to the androgen receptor and blocking its action [172]. In addition, the steroidal anti-androgens inhibit LHRH secretion, resulting in suppression of LH and testosterone. Single-agent use of the non-steroidal anti-androgens is not considered androgen-deprivation therapy, because these drugs raise rather than lower serum testosterone levels. Bicalutamide monotherapy is well-tolerated and has a more favorable toxicity profile (better sexual function and improved bone density) when compared to LHRH agonists or bilateral orchiectomy alone [182]. A common side effect of the anti-androgens is gynecomastia, and the diarrhea associated with flutamide may impact its compliance rate and clinical use. The Early Prostate Cancer trial program comprises a pooled analysis of three studies of high dose bicalutamide (150 mg daily) vs. placebo after standard treatment (watchful waiting, prostatectomy or radiation) in patients with localized or locally advanced nonmetastatic prostate cancer. A significant progressionfree survival benefit was noted in the subgroup of patients with locally advanced, but not early stage, disease who received bicalutamide [183]. Two studies of patients with locally advanced or metastatic disease


comparing high dose bicalutamide (150 mg daily) to castration showed overall similar survival outcomes between the groups and better tolerability with bicalutamide [164, 184]. At the present time, anti-androgens are not approved as monotherapy to treat prostate cancer in the United States, Canada or Europe. Combined androgen blockade (CAB) involves either surgical or medical castration (traditionally with a LHRH agonist) combined with an anti-androgen, with the goal of blocking both testicular and adrenal androgens. A number of meta-analyses of the randomized controlled trials comparing CAB with orchiectomy or LHRH agonist alone in men with advanced prostate cancer suggest a small 5-year survival advantage (0–5%). This survival benefit may be offset by concerns regarding increased adverse side effects and cost [110, 185–187]. The largest meta-analysis, conducted by the Prostate Cancer Trialists’ Collaborative Group, showed no overall survival benefit between CAB and castration alone at 2 or 5 years. However, subgroup analysis did show a 3% absolute survival benefit at 5 years for CAB with the use of a nonsteroidal anti-androgen. The use of the steroidal antiandrogen, cyproterone, in CAB was associated with a 3% absolute increased risk of death at 5 years [185] (Table 9.5). At the present time, CAB may be considered in select patients, but should be recommended under careful consideration of the patient’s underlying medical and social circumstances as well as the tumors molecular make-up and biology [178]. An exception may be the previously mentioned temporary use of CAB when starting treatment in certain at-risk patients to minimize tumor flare and clinical symptoms.

9.11.6 Secondary Hormonal Manipulations Men who develop an increase in PSA or clinical disease progression while receiving ADT, in the presence of castrate levels of testosterone (less than 20 ng/dL), are noted to have androgen-independent prostate cancer. The treatment options for these patients include secondary hormonal manipulations and systemic chemotherapy. Secondary hormonal manipulations typically start with the addition of an antiandrogen to LHRH agonist monotherapy or, if the patient is already receiving CAB, the discontinuation

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Table 9.5 Largest meta-analysis data from 27 randomized clinical trials involving 8275 patients; comparison between monotherapy (medical or surgical castration) vs. combined Treatment 5-year survival

Monotherapy Combined Androgen blockade Survival difference

23.6% 25.4%

androgen blockade (castration plus anti-androgen) in patients with locally advanced or metastatic prostate cancer [185] 5-yr survival = Subgroup receiving steroidal anti-androgen (cyproterone acetate) 18.1% 15.4%

5-yr survival = Subgroup receiving non-steroidal anti-androgen (nilutamide and flutamide) 24.7% 27.6%

1.8% − 2.8% 2.9% [SE 1.3]; logrank 2p = 0.11 [SE 2.4]; logrank 2p = 0.04 [SE 1.3]; logrank 2p = 0.005 adverse

of the anti-androgen agent [188, 189]. Additional strategies include the use of a different anti-androgen agent, estrogens, cytochrome P450 enzyme inhibitors (i.e. ketoconazole), and corticosteroids. The phenomenon of a decline in PSA and occasional symptomatic improvement seen with the withdrawal of an anti-androgen was first described in 1993 [190]. Approximately 20% of patients failing CAB have a PSA response (>50% decline in PSA) when the anti-androgen is discontinued, although the response duration is typically short, in the range of four to six months. Another option is utilizing a different anti-androgen agent, which is based on the premise that specific anti-androgens interact differently with the androgen receptor [191]. For all men with androgen-independent prostate cancer, continuation of the primary testicular androgen deprivation (i.e. LHRH agonist) to maintain castrate levels of testosterone is recommended, as data suggest that there may be a persistent population of tumor cells that remain hormone sensitive despite tumor progression [192]. Ketoconazole is an anti-fungal agent which, at high doses, inhibits the cytochrome P450 enzyme and blocks 17,20-lyase, a crucial enzyme in the testicular and adrenal steroid synthesis pathways [193]. It also exerts a direct cytotoxic effect on prostate cancer cells in vitro and is capable of lowering testosterone levels into castrate range within 24 h [193, 194]. Common side effects associated with ketoconazole include nausea and vomiting, skin rash, fatigue and gynecomastia. Due to the lack of specificity of ketoconazole, concurrent administration of hydrocortisone is necessary to treat the resulting adrenal insufficiency. Several small trials of patients receiving ketoconazole and hydrocortisone as a secondary hormonal manipulation report

PSA responses (>50% decline in PSA) in the 20– 60% range, with duration of response from 3–8 months [195–197].

9.12 Summary Despite the improvements in systemic chemotherapy and the development of targeted agents such as trastuzumab, hormonal therapy remains a central part of therapy in breast cancer. The aromatase inhibitors have moved tamoxifen to the second line setting in the postmenopausal women with advanced as well as those with early stage disease. The potential role of AI’s in combination with ovarian ablation is currently being studied for premenopausal women. The introduction of newer SERMs and SERDs has increased the arsenal of effective hormonal agents for breast cancer. The recent approval of raloxifene as preventive therapy in high-risk postmenopausal women is a positive step toward reducing the development of invasive breast cancer. The ovarian function suppression trials will shed light on our management of premenopausal women with hormone receptor-positive breast cancer. Although prostate cancer is the most common cancer and one of the leading causes of cancer mortality in men, hormonal therapies remain limited mainly to ADT, utilizing medical or surgical castration with or without anti-androgens. Th use of combined hormonal ablation is guided by careful risk assessment of the disease and the individual tolerability and acceptability of treatment-induced short- and longterm sequealae. Hormonal manipulations may play a role in many other diseases but may be of lesser importance than in breast and prostate cancer and may offer predominantly palliative benefits. Further studies are

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needed to optimize the integration of hormonal strategies for the treatment and prevention.

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injection on serum phosphatases in metastatic carcinoma of the prostate. CA Cancer J Clin (reprint from 1941) 22(4):232–240 Debruyne F (2002) Hormonal therapy of prostate cancer. Semin Urol Oncol 20(3 Suppl 1):4–9 Seidenfeld J et al (2000) Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis. Ann Intern Med 132(7):566–577 Keating NL, O’Malley AJ, Smith MR (2006) Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 24(27):4448–4456 Lin BJ et al (1994) The time for serum testosterone to reach castrate level after bilateral orchiectomy or oral estrogen in the management of metastatic prostatic cancer. Urology 43(6):834–837 Byar DP, Corle DK (1988) Hormone therapy for prostate cancer: results of the veterans administration cooperative urological research group studies. NCI Monogr 7: 165–170 Higano C (2006) Androgen deprivation therapy: monitoring and managing the complications. Hematol Oncol Clin North Am 20(4):909–923 Chrisp P, Sorkin EM (1991) Leuprorelin. A review of its pharmacology and therapeutic use in prostatic disorders. Drugs Aging 1(6):487–509 Labrie F et al (1984) Simultaneous administration of pure antiandrogens, a combination necessary for the use of luteinizing hormone-releasing hormone agonists in the treatment of prostate cancer. Proc Natl Acad Sci USA 81(12):3861–3863 Thorpe SC et al (1996) A prospective, randomised study to compare goserelin acetate (Zoladex) versus cyproterone acetate (Cyprostat) versus a combination of the two in the treatment of metastatic prostatic carcinoma. Eur Urol 29(1):47–54 (1997) Immediate versus deferred treatment for advanced prostatic cancer: initial results of the medical research council trial. The medical research council prostate cancer working party investigators group. Br J Urol 79(2): 235–246 Brawer MK (2006) Hormonal therapy for prostate cancer. Rev Urol 8(Suppl 2):S35–S47 Messing EM et al (2006) Immediate versus deferred androgen deprivation treatment in patients with nodepositive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol 7(6):472–479 Moul JW, Ward JF (2006) Management of the patient with a rising PSA alone. Hematol Oncol Clin North Am 20(4):897–908 Moul JW et al (2004) Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy. J Urol 171(3):1141–1147 Grossfeld GD et al (2001) Intermittent androgen deprivation: update of cycling characteristics in patients without clinically apparent metastatic prostate cancer. Urology 58(2):240–245 de Leval J et al (2002) Intermittent versus continuous total androgen blockade in the treatment of patients with advanced hormone-naive prostate cancer: results of a

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prospective randomized multicenter trial. Clin Prostate Cancer 1(3):163–171 Hurtado-Coll A et al (2002) Intermittent androgen suppression in prostate cancer: the Canadian experience. Urology 60(3 Suppl 1):52–56; discussion 56 Higano CS et al (1996) Intermittent androgen suppression with leuprolide and flutamide for prostate cancer: a pilot study. Urology 48(5):800–804 Loblaw DA et al (2007) Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American society of clinical oncology practice guideline. J Clin Oncol 25(12):1596–1605 Lee AK, Frank SJ (2006) Update on radiation therapy in prostate cancer. Hematol Oncol Clin North Am 20(4):857–878 Msaouel P et al (2007) Luteinising hormone-releasing hormone antagonists in prostate cancer therapy. Expert Opin Emerg Drugs 12(2):285–299 Trachtenberg J (2001) Emerging pharmacologic therapies for prostate cancer. Rev Urol 3(Suppl 3):S23–S28 Wellington K, Keam SJ (2007) Spotlight on bicalutamide 150 mg in the treatment of locally advanced prostate cancer. Drugs Aging 24(2):169–171 McLeod DG et al (2006) Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer. BJU Int 97(2):247–254 Tyrrell CJ et al (1998) A randomised comparison of ‘Casodex’ (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer. Eur Urol 33(5):447–456 (2000) Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Prostate cancer trialists’ collaborative group. Lancet 355(9214): 1491–1498 Schmitt BBC, Seidenfeld J, Samson D, Wilt T (1999) Maximal androgen blockade for advanced prostate cancer. Cochrane Database Syst Rev 2(CD001526). doi:10.1002/14651858.CD001526 Klotz L, Schellhammer P, Carroll K (2004) A reassessment of the role of combined androgen blockade for advanced prostate cancer. BJU Int 93(9):1177–1182 Labrie F et al (1988) Benefits of combination therapy with flutamide in patients relapsing after castration. Br J Urol 61(4):341–346 Kucuk O et al (2001) Phase II trial of bicalutamide in patients with advanced prostate cancer in whom conventional hormonal therapy failed: a southwest oncology group study (SWOG 9235). Urology 58(1): 53–58 Kelly WK, Scher HI (1993) Prostate specific antigen decline after antiandrogen withdrawal: the flutamide withdrawal syndrome. J Urol 149(3):607–609 Joyce R et al (1998) High dose bicalutamide for androgen independent prostate cancer: effect of prior hormonal therapy. J Urol 159(1):149–153 Taylor CD, Elson P, Trump DL (1993) Importance of continued testicular suppression in hormone-refractory prostate cancer. J Clin Oncol 11(11):2167–2172 De Coster R et al (1986) Effects of high dose ketoconazole therapy on the main plasma testicular and adrenal

190 steroids in previously untreated prostatic cancer patients. Clin Endocrinol (Oxf) 24(6):657–664 194. Eichenberger T et al (1989) Ketoconazole: a possible direct cytotoxic effect on prostate carcinoma cells. J Urol 141(1):190–191 195. Harris KA et al (2002) Low dose ketoconazole with replacement doses of hydrocortisone in patients with progressive androgen independent prostate cancer. J Urol 168(2):542–545

S.T. Maunglay et al. 196. Small EJ et al (2004) Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583). J Clin Oncol 22(6):1025–1033 197. Small EJ et al (1997) Ketoconazole retains activity in advanced prostate cancer patients with progression despite flutamide withdrawal. J Urol 157(4):1204–1207

Chapter 10

Effects of Cancer Chemotherapy on Gonadal Function Angela R. Bradbury and Richard L. Schilsky

10.1 Introdution During the past 20 years, major strides have been made in the treatment of neoplastic disease with cytotoxic chemotherapy. Progress in understanding tumor cell biology and mechanisms of drug resistance, the introduction of new, effective antineoplastic drugs and technological advances that allow for more detailed and complete pharmacogenetic studies have all contributed to the successful application of cancer chemotherapy. Many patients with Hodgkin’s disease, acute leukemia, non-Hodgkin’s lymphoma, testicular cancer and other tumors now regularly achieve sustained clinical remissions and cures. Moreover, adjuvant chemotherapy is now commonly employed for treatment of micrometastatic disease in clinically well patients with breast cancer, colorectal cancer, lung cancer and soft tissue sarcoma and decreases the relapse rate and prolongs survival for many individuals. Thus many more patients currently receive chemotherapy than ever before and, of greater significance, many more individuals are cured of their tumors and survive to experience the potential late adverse effects of such treatment. Among these, infertility and mutagenesis are often of particular concern to cancer survivors who have new hopes and expectations for a return to normal life style. This chapter will review the effects of cancer chemotherapy on the gonadal function, sexuality and progeny of patients treated for malignant disease.

A.R. Bradbury () Department of Medicine, Fox Chase Cancer Center, Philadelphia, PA 19111, USA e-mail: [email protected]

10.2 Effects of Cancer Chemotherapy on Gonadal Function Neoplastic disease and its treatment can potentially interfere with any of the cellular, anatomic, physiologic or behavioral processes that comprise normal sexual function. The nature of the patient’s illness, the extent of necessary surgery or radiation therapy, and the patient’s relationship with spouse and family may all play an important role in reestablishing normal sexual interest and function following treatment for cancer. Further, many drugs used in the treatment of malignant disease have profound and often lasting effects on the testis and ovary. Germ cell production and endocrine function may both be altered, with the magnitude of the effect related to the age, pubertal status and menstrual status of the patient as well as to the particular drug, dosage or combination administered.

10.2.1 Chemotherapy Effects in Men The normal adult testis is an organ composed of diverse and highly specialized cell types, which may vary in their sensitivity to cytotoxic drugs. The exocrine function of the gland, spermatogenesis, proceeds in the seminiferous tubules, while the interstitial cells of Leydig carry out the primary endocrine function of the testis, testosterone production [1]. The seminiferous tubules, which constitute 75% of the testicular mass, are lined by stratified epithelium composed of two cell types: spermatogenic cells and Sertoli cells. The spermatogenic cells are arranged in an orderly fashion; spermatogonia lie


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directly on the tubular basement membrane, while primary and secondary spermatocytes, spermatids, and maturing spermatozoa progress centrally toward the tubular lumen. Sertoli cells also lie on the basement membrane and serve to regulate the release of mature spermatozoa from the germinal epithelium as well as to maintain the integrity of the blood-testis barrier. Spermatogenesis is a dynamic and complex process which may be divided into three phases: (1) proliferation of spermatogonia to produce spermatocytes and to renew the germ cell pool; (2) meiotic division of spermatocytes to reduce the chromosome number in the germ cells by half; and (3) maturation of the spermatids to become spermatozoa [2]. Cytotoxic drugs could potentially effect this process in a number of ways: (1) a specific cell type within the germinal epithelium might be selectively damaged or destroyed; (2) the proliferative and meiotic phases of spermatogenesis might proceed normally, but sperm maturation might be abnormal, leading to functionally incompetent mature spermatozoa; or (3) chemotherapy might damage Sertoli cells, Leydig cells or other supportive or nutritive constituents of the testis in such a way as to alter the particular microenvironment necessary for normal germ cell production.

A.R. Bradbury and R.L. Schilsky

after doxorubicin administration revealed an absence of pachytene primary spermatocytes, indicating that type A2 (primitive) spermatogonia are most sensitive to injury by that drug [3]. Similar analysis after cisplatin administration demonstrated that intermediate spermatogonia are most sensitive to cisplatin and that at high doses (10 mg/kg), even late-stage spermatids may be affected, suggesting the occurrence of Sertoli cell damage at this dose level [4]. Following administration of 5-fluorouricil (5-FU), spermatogonial damage is not seen; rather arrest of spermatid development is noted [5]. Failure of sperm release from the germinal epithelium has been observed after the administration of 5-FU, cisplatin, doxorubicin, or methotrexate (MTX), suggesting Sertoli cell damage by all these agents [5]. Serial mating studies, whereby animals are mated at varying intervals after drug administration and the onset of infertility is noted, can provide similar, though less precise information. In the rat, an infertile mating occurring six to seven weeks after drug treatment implies that spermatocytes were primarily affected by the drug in question, whereas infertility occurring ten weeks after drug treatment reflects spermatogonial destruction [6, 7].

10.2.3 Clinical Assessment 10.2.2 Animal Models With knowledge of the normal histology of the germinal epithelium and of the kinetics of spermatogenesis, it is possible to estimate the specific site of a drug’s effect, either by examining the testis microscopically or by performing sperm counts or mating studies at some interval after administration of the drug. The morphology of the spermatids can be used to define the stage of the germinal epithelial cycle at the time of biopsy, and the presence or absence of cells expected to occur in association with those spermatids can be noted. Flow cytometry can also be used to examine the DNA content and cell-cycle progression of spermatogenic cells obtained from animals injected with bromodeoxyurdine. Known kinetic parameters can then be used to determine precisely which spermatogenic cell was destroyed by drug administration. For example, examination of mouse testes 11 days

Testicular function in patients receiving cancer chemotherapy can be adequately evaluated with a careful physical examination, semen analysis and determination of serum gonadotropin and testosterone levels (Table 10.1). Occasionally, testicular biopsy is necessary to complete the evaluation. Since the seminiferous tubules comprise such a large portion of the testicular mass, damage to the germinal epithelium frequently results in testicular atrophy, which is readily detected on physical exam. Impaired spermatogenesis is also manifest as a decrease in the number and/or motility of sperm present in the ejaculate and, since pituitary gonadotropin secretion is under feedback control by the testis, an increase in serum follicle stimulating hormone (FSH) level [8, 9]. Leydig cell dysfunction may also occur and is detected by an increase in serum luteinizing hormone (LH) level, and if uncompensated, a fall in serum testosterone level. Subclinical

10 Effects of Cancer Chemotherapy on Gonadal Function Table 10.1 Evaluation of the patient with germinal aplasia Normal Germinal aplasia Testicular Size Length × width (cm) Volume (cc) Sperm count (106/ml) FSH (mIU/ml) LH (mIU/ml) LH response to LH-RH Testosterone (ng/dl)

5.0 × 3.0 16–30 20–100 4–25 4–20 Normal 250–1200

3.7 × 2.3 8–15 0 25–90 8–25 Exaggerated 200–700

abnormalities of Leydig cell function may occasionally be demonstrated by administration of LH releasing hormone. An excessive rise in serum LH levels in this provocative test suggests the presence of abnormal Leydig cell function [10–13].

10.2.4 Drug Effects on Spermatogenesis Following cytotoxic chemotherapy, there appear to be common histopathologic changes that occur in the testis, independent of the type of drug employed but related to the total dose administered. The primary testicular lesion caused by all antitumor agents studied thus far is depletion of the germinal epithelium lining the seminiferous tubules [14–18]. Testicular biopsy in most patients reveals complete germinal aplasia with only Sertoli cells left lining the tubular lumens. Occasionally, scattered spermatogonia, spermatocytes or spermatids may be seen or there may be evidence for maturation arrest occurring at the spermatocyte stage. This latter finding appears most often in patients receiving short courses of chemotherapy with antimetabolites [19]. 10.2.4.1 Drugs Highly Toxic to the Germinal Epithelium Among the anticancer drugs, alkylating agents most consistently caused male infertility. In particular, chlorambucil and cyclophosphamide deplete the testicular germinal epithelium in a dose-related fashion. Progressive oligospermia occurs in men with lymphoma who are treated with up to 400 mg of chlorambucil [18], and those patients receiving cumulative doses in excess of 400 mg are uniformly azoospermic.

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Similarly, decreased sperm counts may occur in men treated with 50–100 mg of cyclophosphamide daily for courses as brief as 2 months, although azoospermia and germinal aplasia are infrequent until higher doses have been administered. Rivkees and Crawford found that 80% of men treated with more than 300 mg/kg of single-agent cyclophosphamide developed gonadal dysfunction [20]. Despite a high incidence of damage to the germinal epithelium, partial or full recovery of gonadal function may be possible for some individuals [21, 22]. One study reported that 40% of men treated with cyclophosphamide-based regimens for sarcoma had recovery of spermatogenesis at 5 years, but only 10% had recovery when cumulative doses exceeded 7.5 g/m2 [23]. Several studies have suggested that procarbazine is particularly damaging to the germinal epithelium [24, 25]. Animal studies have shown that procarbazine is severely toxic to the germinal epithelium in adult male monkeys and rats [26, 27]. Human studies evaluating germinal damage after combination chemotherapy also suggest that procarbazine plays an important role in the development of chemotherapy-related infertility [24, 25]. Several other newer chemotherapy drugs have been recently evaluated with conflicting results. While one group suggested that ifosfamide may be less toxic to the germinal epithelium than cyclophosphamide [28], Longhi et al. evaluated the effect of ifosfamidebased regimens in men with osteosarcoma and found a higher rate of azoospermia with ifosfamide-based regimens when compared to combinations that did not include ifosfamide [29]. In addition, the incidence of azoospermia was related to the total ifosfamide dose. These studies suggest that ifosfamide, like other alkylating agents, has a dose-dependent effect on gonadal function. The effects of cisplatin alone on testicular function are difficult to discern, as the majority of men with testicular cancer have impaired spermatogenesis prior to therapy. While early studies suggested that patients with testicular cancer treated with cisplatin-based combination chemotherapy uniformly become severely oligospermic or azoospermic soon after chemotherapy is initiated [30–35], subsequent studies have suggested that higher doses of cisplatin, or more cycles of chemotherapy, are associated with more profound and persistent decreases in sperm counts [36, 37]. In a review of 5 published studies, DeSantis et al. determined that cumulative cisplatin doses less

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than 400 mg/m2 were unlikely to cause azoospermia, while patients who received higher doses, or more than 4 cycles of chemotherapy, had a higher risk of impaired spermatogenesis when compared to controls [28]. Several groups have recently evaluated the gonadal toxicity of carboplatin. While animal studies suggested a dose-related effect on spermatogenesis similar to cisplatin [38], recent human studies suggest less effect on spermatogenesis with carboplatin-based regimens [39, 40]. Although single agent vincristine was thought to cause only temporary and reversible damage to the germinal epithelium and to have an additive effect when combined with other highly gonadotoxic agents, a recent multivariate analysis suggests that vincristine itself may have a significant effect on fertility [41]. Vincristine is rarely administered as a single-agent, and is often administered with other highly gonadotoxic agents, such as procarbazine. For this reason, it is difficult to assess the germinal toxicity of vincristine in humans.

10.2.4.2 Drugs with Low Toxicity to Male Germ Cells

A.R. Bradbury and R.L. Schilsky Table 10.2 Toxicity of single agents to male germ cells References Drugs highly toxic to male germ cells Chlorambucil Cyclophosphamide Ifosfamide Procarbazine Cisplatin Vincristine

[18, 21] [20, 22, 23] [28, 29] [24–27] [28, 30–40, 264, 265] [41]

Drugs with low toxicity to male germ cells Methotrexate Doxorubicin Interferon alpha-2β

[43, 46] [3, 42, 44, 45, 47–49] [266]

severe or irreversible testicular injury occurs. As newer agents are incorporated into standard cancer treatment programs, additional studies need to be completed to assess their effects on fertility.

10.2.5 Combination Chemotherapy and Disease-Specific Considerations 10.2.5.1 Lymphoma

Antimetabolites in conventional doses seem to have relatively few effects on spermatogenesis, although one study suggested that high-dose methotrexate (MTX 250 mg/kg) may produce transient oligospermia in some patients [42]. This modest effect of MTX on spermatogenesis may be due to the presence of a significant barrier to MTX passage from blood to seminiferous tubule [43]. While doxorubicin produces severe germinal epithelial injury in both the mouse [3] and the rat [44, 45], several reports have suggested that doxorubicin may be less toxic to the human testis than expected based on animal studies, with reversible testicular injury noted in the majority of patients under age 40 [46–49]. In considering individual agents, these data suggest that chemotherapeutic agents vary in toxicity to the germinal epithelium (Table 10.2). In addition, there appears to be a threshold dose for the development of testicular germinal aplasia for each particular drug. However, prospective studies of testicular function in large numbers of men receiving a variety of antitumor agents are needed to provide more reliable information concerning the threshold drug dose above which

As might be expected, combination chemotherapy regimens that include alkylating agents produce germinal aplasia and infertility in the majority of patients. This is clear in Hodgkin’s disease, where the effects of MOPP (nitrogen mustard, vincristine, procarbazine and prednisone) and a related regimen, MVPP (in which vinblastine replaces vincristine) have been extensively investigated. Sherins and DeVita first reported azoospermia or severe oligospermia in 3 of 16 men with lymphoma in complete remission 2 months to 7 years after MOPP, CVP (cyclophosphamide, vincristine and prednisone), or cyclophosphamide alone [50]. Subsequent studies have confirmed that at least 80% of men receiving MOPP combination chemotherapy develop azoospermia, germinal aplasia, testicular atrophy and elevated FSH levels [13, 51–54]. Patients who receive COPP (cyclophosphamide, vinblastine, procarbazine and prednisone) or ChlVPP (chlorambucil, vincristine, procarbazine and prednisolone) have significant gonadal dysfunction as well [55, 56]. Likewise, Chapman et al. found that all 74 men who received cyclic combination chemotherapy for

10 Effects of Cancer Chemotherapy on Gonadal Function

Hodgkin’s disease were azoospermic after treatment, and only four of 74 recovered spermatogenesis after a median follow-up of 27 months. A decline in libido and decreased sexual activity also occurred during therapy and only partially recovered after treatment [52]. Interpretation of this data is complicated by pretreatment azoospermia that occurs in at least 50% of men with advanced Hodgkin’s disease [52, 57]. While reversibility of gonadal dysfunction has been known to occur with single agent therapy, patients who receive combination chemotherapy are likely to develop long-lasting and frequently permanent infertility. Sherins and DeVita [50] noted azoospermia and testicular germinal aplasia in patients as long as 4 years after completion of MOPP chemotherapy. Others have confirmed these findings, and it seems reasonable to conclude that only about 10% of patients receiving MOPP or MVPP will ultimately have a return of spermatogenesis [58, 59]. A number of alternative combination chemotherapy regimens to MOPP have now been developed for the treatment of advanced Hodgkin’s disease. Among these ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) has been shown to be more efficacious and less toxic than the MOPP regimen. A comparison of these regimens revealed that azoospermia occurs in 100% of patients treated with MOPP, but in only 35% of patients receiving ABVD. In addition, recovery of spermatogenesis occurs rarely in MOPP-treated patients but nearly always in those treated with ABVD [60–62]. Hybrid regimens of MOPP or COPP and ABVD also produce persistent testicular dysfunction, with 60–80% of patients experiencing prolonged germinal damage [57, 61]. Unlike patients with Hodgkin’s disease, those with non-Hodgkin’s lymphoma often have normal pretreatment sperm counts and motility [63]. Regimens containing modest doses of cyclophosphamide such as MACOP-B (MTX-leucovorin, Adriamycin, cyclophosphamide, vincristine, prednisone and bleomycin) or VACOP-B (including vinblastine rather than MTX) have produced only transient azoospermia, with recovery of spermatogenesis in 100% of patients at a mean of 28 months after completion of chemotherapy [63]. However, with the standard cyclophosphamide-based regimens, sperm counts recovered in only two-thirds of patients at 7 years. [64]. A small study evaluating 14 patients who received VAPEC-B (vincristine,

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doxorubicin, prednisolone, etoposide, cyclophosphamide and bleomycin) for either Hodgkin’s disease or non-Hodgkin’s lymphoma reported only 1 case of azoospermia in a patient who also received pelvic radiation therapy [65]. As new regimens are developed, they will need to be compared to standard regimens for efficacy. In addition, larger studies are necessary to confirm and compare the effects on spermatogenesis. This information may play an important role in treatment planning for young men with Hodgkin’s disease and non-Hodgkin’s lymphoma who are concerned about preservation of fertility during and after treatment.

10.2.5.2 Testicular Cancer Like patients with Hodgkin’s disease, patients with testicular cancer have a high rate of oligospermia prior to treatment. Studies have shown that up to 50% of men with testicular cancer have oligospermia at diagnosis [40, 66, 67]. Patients with testicular cancer treated with cisplatin-based combination chemotherapy uniformly become severely oligospermic or azoospermic soon after chemotherapy is initiated [30–35, 68]. Despite this immediate gonadal injury, there appears to be a high degree of reversibility of testicular dysfunction, with as many as 50% of patients demonstrating resumption of spermatogensis within 2 years of completing chemotherapy. Among 98 patients with testicular germ cell tumors, 28 were treated with cisplatinbased chemotherapy and had profound decreases in sperm counts 1 year later, but a return to pretreatment levels 3 years after completion of chemotherapy [69], paralleled by a normalization of FSH values. In a study with a median follow-up of 5 years, 27% of men who received PVB (cisplatin, vincristine and bleomycin) were azoospermic. While many studies suggest that recovery of spermatogenesis is rare after 2 years [33, 70], there have been reports of recovery of spermatogenesis and fertility long after completion of treatment [71, 72]. Higher doses of chemotherapy generally induce longer-lasting oligospermia [36]. As described above, patients who receive carboplatinbased therapy are more likely to recover spermatogenesis when compared to those who receive cisplatinbased therapy. Other predictors of recovery include normospermia prior to therapy and less than 5 cycles of chemotherapy [40].

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10.2.5.3 High-Dose Chemotherapy and Bone Marrow Transplantation More information is now available regarding the impact of bone marrow transplantation conditioning regimens on fertility. In general, conditioning regimens involving total body irradiation appear to severely affect fertility, while gonadal recovery occurs in a portion of patients receiving chemotherapy-only conditioning regimens. In men receiving a preparative regimen of high-dose cyclophosphamide alone, potential for recovery of spermatogenesis is reasonably high. In 72 men who received this treatment in Seattle, 65% had a normal FSH and normal sperm counts, and 94% had normal serum LH and testosterone levels [73]. Recovery of spermatogenesis was not agerelated in this population. Recent studies evaluating different conditioning regimens found that 61–90% of men regain spermatogenesis within 3 years after single agent cyclophosphamide [74, 75]. Recovery of spermatogenesis was significantly lower in two studies that employed a busulfan-cyclophosphamide (Bu-Cy) conditioning regimen. While early studies using 200 mg/kg of cyclophosphamide reported a recovery rate of only 17% [74], more recent studies using a lower dose of cyclophosphamide (120 mg/kg + 16 mg/kg busulfan) have reported higher rates of recovery, ranging from 50–84% [75, 76]. Conditioning regimens combining cyclophosphamide with total body irradiation appear to severely affect gonadal function with only 17% of patients recovering spermatogenesis and never earlier than 4 years pos-treatment [75].

10.2.5.4 Leukemia There have been relatively few studies evaluating the gonadal effects of combination chemotherapy for acute lymphoblastic leukemia (ALL). An early study of 44 boys with ALL reported impaired spermatogenesis in 40% of patients and found that combinations including cyclophosphamide and cytosine arabinoside were associated with a higher likelihood of gonadal damage [77]. Quigley et al. also found severe germinal damage in 13 of 25 boys with ALL who received the modified LSA2 L2 protocol, a regimen including both cyclophosphamide and cytosine arabinoside [78]. Despite these discouraging results, other ALL


regimens have been associated with lower rates of gonadal damage. An aggressive eight-drug regimen, that did not contain procarbazine was used in the treatment of adult ALL and was associated with preservation of fertility in the majority of patients [79]. More recently, Wallace et al. evaluated 37 men who received combination chemotherapy for ALL in childhood. Only 6 men had evidence of severe germinal damage at a median follow-up of 10 years. In addition, all six had received either cyclophosphamide or cyclophosphamide and cytosine arabinoside [80], supporting the hypothesis that ALL regimens that exclude cyclophosphamide and cytosine arabinoside are less likely to cause permanent germinal aplasia.

10.3 Chemotherapy Effects in Women Oogenesis is the process of maturation of the primitive female germ cell to the mature ovum. This process occurs primarily during intrauterine life and involves multiple mitotic divisions to increase the number of germ cells, followed by the beginning of the first meiotic division, which will eventually reduce the diploid chromosome number to half before fertilization. At the time of birth, the oocytes are in the long prophase of their first meiotic division, and they remain in that state until the formation of a mature follicle before ovulation [81]. In the postnatal ovary, most of the ongoing cellular growth and replication is related to the growth and development of follicles. Primordial follicles develop during gestation and consist of a primary oocyte covered by a layer of mesenchymal cells called granulosa cells. At the time of birth, the ovary may contain 150,000–500,000 primordial follicles, many of which subsequently become atretic. From childhood to menopause, follicular growth occurs as a continuous process, with ovulation occurring in a cyclic fashion [82]. The granulosa cells surrounding the primary oocyte proliferate, follicular fluid accumulates, and the ovum completes its first meiotic division to become a secondary oocyte. At this time, the follicle is known as a secondary or graafian follicle. The follicle continues to enlarge until the time of ovulation. Those follicles not undergoing ovulation become atretic and regress. During the reproductive life of a woman, only


300–400 oocytes mature and are extruded in the process of ovulation; the remainder undergo some form of atresia.

10.3.1 Assessment of Ovarian Function The evaluation of chemotherapy effects on ovarian function is hampered by the relative inaccessibility of the ovary to biopsy. There is no readily available direct measurement of the female germ cell population analogous to sperm counts in men. Animal models have only recently been developed to assess the effects of cytotoxic drugs on ovarian function. Thus, one must rely primarily on menstrual and reproductive history and on determinations of serum hormone levels to assess the functional status of the ovary. Follicular growth and maturation and estradiol production are under regulatory control of the pituitary and hypothalamus. Pituitary FSH stimulates granulosa cells to replicate and produce estradiol. The midcycle LH surge promotes ovulation and the ruptured follicle becomes the corpus luteum, which produces progesterone thereby suppressing further LH secretion [83]. Drug-induced ovarian failure interrupts this delicate hormonal balance and results in abnormally low serum levels of estradiol and progesterone, markedly elevated levels of FSH and LH, amenorrhea and symptoms of estrogen deficiency. The primary histologic lesion noted in the ovaries of women receiving antineoplastic chemotherapy is ovarian fibrosis and follicle destruction [84, 85]. Clinically, amenorrhea ensues and is accompanied by elevation of serum FSH and LH levels and a fall in serum estradiol. Vaginal epithelial atrophy and endometrial hypoplasia occur, and patients may complain of menopausal symptoms such as vaginal dryness and dyspareunia.

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follicle diameter, and a fall in serum estradiol and progesterone levels in rats receiving the drug [86]. Incubation of mouse oocytes with doxorubicin results in a series of morphologic and biochemical events resembling apoptosis. Indeed, functional bax protein appears to be necessary for doxorubicin-induced cell death to occur [87]. An in vitro model of cisplatin effects on primordial follicles found swelling of the pregranulosa cells and nuclei followed by disappearance of the lumen and oocyte. In addition, there was evidence of apoptosis in chemotherapy treated primordial follicles, but not in controls [88]. Evaluation of human ovaries after chemotherapy treatment reveals a decreased number of oocytes and diffuse fibrosis [85, 89]. These findings are similar to the changes observed in post-menopausal ovaries. Therefore, chemotherapy may reduce the population of oocytes available for follicular recruitment, resulting in progressive, irreversible ovarian failure, as ovarian germ cells can not be regenerated [90]. Others have suggested that there may be impairment of follicular maturation, depletion of primordial follicles, inhibition of pregranulosa cell proliferation or reduced granulosa cell steroid production in primordial follicles that could contribute to ovarian failure [84, 91, 92]. Improved understanding of the molecular events surrounding chemotherapyinduced ovarian failure might permit the development of strategies to prevent this complication of treatment.

10.3.3 Drug Effects on Ovarian Function The onset and duration of amenorrhea seem to be both dose and age-related. Generally, younger patients are able to tolerate larger cumulative drug doses before amenorrhea occurs and have a greater likelihood of resumption of menses when therapy is discontinued.

10.3.2 Animal Studies

10.3.4 Drugs Highly Toxic to Germ Cells

Although the exact mechanism of chemotherapy induced ovarian failure is unclear, it is likely to be the process of follicular growth and maturation that is most affected by cytotoxic chemotherapy. Cyclophosphamide has been noted to cause a doserelated depletion of antral follicles, a decrease in

Among the anticancer drugs, alkylating agents are the most frequent cause of ovarian dysfunction (Table 10.3). During the early clinical trials of busulfan, amenorrhea was a common side effect. Several investigators noted the onset of permanent amenorrhea among patients receiving busulfan in doses varying

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Table 10.3 Toxicity of single agents to female germ cells. References Drugs highly toxic to female germ cells Busulfan Cyclophosphamide Melphalan

[93, 94] [95–97, 101] [267]

Drugs with moderate to low toxicity to female germ cells Methotrexate 5-FU Etoposide/vinca alkaloids Doxorubicin Cisplatin

[42] [101, 267] [106, 109] [107] [108–111]

form 0.5 to 14.0 mg/day for at least 3 months [93, 94]. The effects of cyclophosphamide on ovarian function in humans were first noted in the rheumatology literature, as early cessation of menses and menopausal symptoms developed in six of 33 patients treated for rheumatoid arthritis with daily cyclophosphamide for 6–40 months [95]. Subsequently, several investigators documented the occurrence of amenorrhea in at least 50% of premenopausal women receiving 40–120 mg of cyclophosphamide daily for an average of 18 months [96, 97]. Ovarian biopsy in some patients demonstrated arrest of follicular maturation and absence of ova. Studies of the use of adjuvant chemotherapy for the prevention of recurrence of breast cancer suggest that the onset of amenorrhea and the resumption of menses after cyclophosphamide are related to the age of the patient during chemotherapy and to the total dose administered [98–100]. Amenorrhea developed in 17 of 18 women treated with adjuvant cyclophosphamide for 13–14 months postoperatively [101]. Permanent cessation of menses occurred after a mean total dose of 5.2 g in all patients 40 years of age and older. Amenorrhea also developed in four of five women younger than age 40, but only after a mean cyclophosphamide dose of 9.3 g had been administered. Menses subsequently returned in two of these patients within 6 months of discontinuing therapy. Time to the development of amenorrhea also appears to be age-related after adjuvant treatment with alkylating agents [91, 102–105]. In women younger than 35 who received cyclophosphamide, methotrexate and 5-FU (CMF), mean time to the onset of amenorrhea is 5.54 months; for women aged 35–45 years, the mean time is 2.31 months, and in women older than age 45, amenorrhea

develops very quickly, with a mean onset of 1.01 months [102]. It seems, then, that alkylating agent chemotherapy accelerates the onset of menopause, particularly in older patients, whereas younger patients may tolerate higher total doses before amenorrhea becomes irreversible.

10.3.5 Drugs with Moderate to Low Toxicity to Germ Cells While many other chemotherapeutic agents have been evaluated for long-term ovarian toxicity, the majority of evidence comes from studying the effects of combination chemotherapy regimens. Therefore, it is often difficult to determine the contribution of individual agents. In general, chemotherapeutic agents that are cell cycle specific appear to have low gonadotoxicity in women. While many of these agents are toxic to reproductive germ cells in men, they do not have the same toxicity in women. This is likely because there is constant cell division during spermatogenesis, while in women, there is intermittent cell division involving only a small number of primary oocytes with each menstrual cycle. Among the antimetabolites, high-dose methotrexate and 5-fluorouracil (5-FU) have been evaluated and appear to have no immediate ovarian toxicity [42]. A study of single-agent 5-FU in nine breast cancer patients found no evidence of ovarian failure [101]. The effects of oral etoposide on ovarian function were evaluated in one study of 22 patients receiving this agent. Age-related oligo- or amenorrhea occurred in 41% of patients after a mean cumulative etoposide dose of 5 g [106]. Doxorubicin administration does not appear to have profound ovarian ablative effects [107]. Although platinum chemotherapeutic agents have notable gonadal toxicity in men, the data in women are limited and contradictory. Many studies suggest that the majority of women who receive platinum based chemotherapy have temporary amenorrhea, but resume normal menstrual function [108, 109], while other groups have reported persistent menstrual dysfunction after the administration of cisplatin-based therapies [110, 111]. The inconsistencies in the literature may be explained by differences in defining treatment related ovarian failure, the duration of follow-up, dose received and age at administration. It is clear that further studies are needed to determine the true impact


of platinum-based therapy on fertility. Although taxanes have become widely used in the treatment of breast cancer, there is little data regarding the ovarian toxicity of this class of chemotherapeutics. Early results of the BCIRG 001 trial reported that 51% of patients receiving TAC (docetaxel, Adriamycin, cyclophosphamide) developed amenorrhea∗ . These results are preliminary, follow-up is short and the definition of amenorrhea used in the study is unclear. Therefore, further studies are needed to draw definitive conclusions regarding the incidence of treatment related ovarian failure following taxane therapy.

10.3.6 Combination Chemotherapy and Disease-Specific Considerations 10.3.6.1 Breast Cancer Studies of adjuvant chemotherapy for breast cancer have yielded important information regarding the effects of dose and treatment duration on menstrual cycles. Evaluation of 95 premenopausal women who received cyclophosphamide, MTX, 5-FU, vincristine, and prednisone documented permanent amenorrhea in 70.5% of patients [112]. Women receiving chemotherapy for 12 weeks had a 55% incidence of amenorrhea, whereas 83% of women receiving a 36-week regimen were rendered amenorrheic. Breast cancer recurrence and mortality rates in women who experienced amenorrhea were lower than in those who continued to menstruate, even within each treatment group, suggesting a potential therapeutic benefit of ovarian ablation. However, the contribution of treatment-induced amenorrhea to the beneficial effects of adjuvant chemotherapy remains uncertain and controversial. In counseling women with newly diagnosed breast cancer regarding the risk of chemotherapy-related amenorrhea or ovarian failure, age and risk of recurrence must be considered. Age at treatment is the primary factor in predicting chemotherapy-induced amenorrhea and is the most relevant consideration when counseling women with premenopausal breast cancer. Several studies have shown that younger women have a higher likelihood of resuming their menses and maintaining future fertility. For example, CMF has been associated with persistent amenorrhea in 21–71% of women less than 40 years old, compared to 49–100% in those over age 40 [91].

199

Other groups have found low rates of persistent amenorrhea (0–4%) in women under the age of 30 who received CMF or doxorubicin-based therapy, rates of 50% in women between 30 and 40 years old, and rates of 86% and higher in women over 40 years old [113, 114]. Although the choice of adjuvant therapy is primarily dependent on disease characteristics, in the situation where subsequent fertility is of great importance to the patient, considering the likelihood of amenorrhea with different adjuvant regimens may be helpful. In general, studies suggest that the combination of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) is the regimen with the highest likelihood of causing premature ovarian failure as up to 2/3 of premenopausal women who receive CMF will experience persistent amenorrhea [91]. An early study of doxorubicin-based adjuvant therapy reported persistent amenorrhea in 59% of women [113], but more recent studies have found lower rates of persistent amenorrhea, ranging from 34 to 51% of premenopausal women treated with doxorubicin or epirubicin-based regimens [91, 115]. Although rarely used today, low rates of persistent amenorrhea have been reported with melphalan-based regimens (9%) [91]. These rates ignore the wide variability likely secondary to age at the onset of treatment, so the probability based on the age of the patient must also be considered (Table 10.4).

10.3.6.2 Lymphoma The risk of ovarian failure after other combination chemotherapy for hematologic malignancies is also

Table 10.4 Rates of amenorrhea after adjuvant regimens for breast cancer = 40 yo References CMF = 40 yo

References

33%

96%

[113]

All ages

References

32.8–51% 34% 9%

[91, 115] [91] [91]

200

clearly related to the age of the patient at the time of treatment. Overall, at least 50% of women treated with MOPP or related regimens become amenorrheic [116–123]. The cessation of menses is accompanied by elevations of serum FSH and LH consistent with primary ovarian failure. Apart from age, no clear differences have been noted between those women who become amenorrheic during therapy and those who do not. Moreover, the time of onset of amenorrhea seemed to be age-related; ovarian failure occurred within 1 year of discontinuing therapy in all patients 39 years of age or older, whereas in younger patients there was a gradual decrease in frequency of menses occurring more than several years after therapy. Another group found similar results, as 76% of women who received MOPP or a related hybrid combination of chlorambucil, vinblastine, prednisolone, procarbazine, doxorubicin, vincristine and etoposide developed amenorrhea during or immediately after treatment. Despite this, ten women later regained normal menstrual periods while 16 had permanent amenorrhea. The mean age at treatment among the ten with recovery was 25 years, while the mean age in the latter group was 36 years old, illustrating the importance of age at the time of therapy [123]. At present, it seems unlikely that those patients treated when younger than age 25 will experience any significant therapy-related ovarian dysfunction during the initial 5–10 years after the completion of therapy [124]. As in men, ABVD chemotherapy may be less likely to produce premature ovarian failure, although longer follow-up is required to be certain. In a study comparing MOPP to ABVD, 50% of the patients who received MOPP and were older than 30 years old developed prolonged amenorrhea. All the women who received MOPP under the age of thirty and all the women who received ABVD, regardless of age, had resumption of normal menstrual cycles [60]. Combination chemotherapy regimens for aggressive non-Hodgkin’s lymphoma do not consistently cause premature ovarian failure, perhaps because procarbazine is rarely included in such regimens [25]. Of ten women who received various combined modality regimens for non-Hodgkin’s lymphoma, only one developed gonadal dysfunction. Similarly, among seven women aged 35–43 treated with MACOP-B or VACOP-B for aggressive non-Hodgkin’s lymphoma, only one developed amenorrhea [63].


10.3.6.3 Ovarian Germ Cell Tumors Although malignant germ cell tumors of the ovary are rare, they principally occur during adolescence and early adulthood. Many patients receive combination chemotherapy, and the regimens used appear to cause relatively little ovarian toxicity. In one study, 70% of women maintained regular menses after treatment with a variety of regimens containing drugs such as actinomycin D, vincristine, and cyclophosphamide [125]. Low et al. evaluated 44 women, between the ages of 10 and 35 years old, who received conservative surgery followed by cisplatin based regimens. Although two-thirds experienced amenorrhea during therapy, 43 of 47 (91%) resumed normal menstrual periods after completion of therapy [108]. Other groups have reported similar results, and it appears that the majority of women who receive chemotherapy for germ cell tumors of the ovary will resume menstrual function [126–128]. 10.3.6.4 High-Dose Chemotherapy and Bone Marrow Transplantation The risk of treatment related ovarian failure after high-dose chemotherapy and bone marrow transplant appears to be largely related to age at the time of treatment. From the Seattle experience, cyclophosphamidecontaining preparative regimens for allogeneic bone marrow transplantation induced reversible amenorrhea in women younger than 26 years of age, but permanent amenorrhea in 67% of women older than age 26 [129]. Likewise, Schimmer et al. evaluated 17 premenopausal patients treated with a variety of conditioning regimens followed by autologous bone marrow transplant for predictors of ovarian failure. Of the 17, only 5 (29%) had a return of normal menstrual cycles. The mean age of those with recovery of ovarian function was 19 years, while mean age of those with persistent amenorrhea was 30 years. In their analysis, younger age at treatment was a statistically significant predictor of future ovarian function. The number of prior chemotherapy salvage regimens or number of regimens containing alkylating agents did not predict for permanent amenorrhea [130]. The majority of studies suggest that younger women, who receive chemotherapy-containing conditioning regimens will regain menstrual function, while the majority over age


26 will have treatment related infertility [63, 109, 131, 132]. On the other hand, studies have suggested that regimens using total-body irradiation (TBI) cause premature menopause in nearly all patients [129, 130, 133]. Although most studies have found that the specific chemotherapy conditioning regimen did not appear to affect future fertility, Singhal et al. reported a higher pregnancy rate among women who were conditioned with melphalan alone when compared to those who received other conditioning regimens. These authors suggested that this regimen is adequate for engraftment and may be less likely to cause treatment related ovarian failure [134]. Further studies are needed to confirm these results, as variations in permanent ovarian failure among chemotherapy conditioning regimens could be important to young women undergoing high-dose chemotherapy and bone marrow transplantation.

10.4 Counseling Patients 10.4.1 Assisted Reproductive Techniques (ART) for Men 10.4.1.1 Semen Cryopreservation Pretreatment sperm banking is presently the only proven means of preserving fertility for men who are to receive combination chemotherapy for cancer. While pretreatment sperm banking does not guarantee a successful pregnancy in future years, advances in management of male factor infertility have made pregnancy possible for many men who are not azoospermic [135]. One of the significant challenges for preserving fertility in male patients with cancer has been poor quality semen, even prior to treatment, as close to 50% of male cancer patients have reduced sperm quality prior to chemotherapy [52, 57, 136–140]. Men with testicular cancer and Hodgkin’s disease have significantly lower sperm motility and a higher incidence of azoospermia than men with other malignancies [140, 141]. A review of patients from a single cryopreservation center found that 9.6% of men with testicular cancer and 18% of men with Hodgkin’s disease were azoospermic prior

201

to chemotherapy [140]. The cause of impaired spermatogenesis in male cancer patients prior to therapy is unknown. Despite a high rate of abnormal sperm quality, the majority of male cancer patients have adequate parameters for sperm storage [142]. Recent studies have found that only 12–17% of referred male cancer patients are unable to donate sperm for cryopreservation due to severe azoospermia prior to therapy [140, 143]. In the past, minimal standards of sperm quality for crypreservation were used to maximize the chances of successful insemination, denying cryopreservation to many male cancer patients. More recent data suggest that despite poor semen quality at the time of cryopreservation, many cancer patients are able to have successful pregnancies using advanced reproductive techniques [144–148]. Therefore, many groups suggest that cryopreservation be offered to all male cancer patients as long as the sperm sample contains some motile spermatozoa, even if the quality is below the required minimum standard for IVF (2 × 106 ml) [142, 144, 149, 150]. Although the technology of freezing, preserving, and thawing human semen has advanced considerably, ultimate conception rates using preserved semen have been limited by artificial insemination techniques. In the past, classic artificial insemination by husband (AIH) of the female partner using thawed spermatozoa was the only insemination technique available. AIH requires high numbers of spermatozoa and high quality semen. Most early studies suggest that it is not very effective in subfertility secondary to sperm abnormalities [151, 152]. More recent studies have reported better cumulative pregnancy rates with this technique in male cancer patients, ranging from 20 to 45% [144]. Despite success for some patients, the majority of male cancer patients have inadequate sperm quantity or quality for this procedure. With advances in technology, in vitro fertilization became the standard procedure for men with male factor infertility. In vitro fertilization (IVF) can be used with low spermatozoa quantity or when female factors prevent successful AIH. The fertilization rate with IVF for male factor infertility, and specifically male cancer patients, has been reported at 57–60% [146, 153–155]. The newest advance is intracytoplasmic sperm injection (ICSI), a type of gamete micromanipulation. This procedure has revolutionized the treatment of male factor infertility and holds particular promise for azoospermic and

202

oligospermic cancer survivors. ICSI involves the direct injection of a single spermatozoa into the cytoplasm of an oocyte in the context of in vitro fertilization. In the setting of male factor infertility, pregnancy rates of 52% have been reported with ICSI. The take-homebaby rate has been estimated at 22–37% per cycle, comparable to the 30% rate of successful pregnancy per cycle with natural conception [156–158]. Lass et al. described their experience at a tertiary assisted conception center and reported successful pregnancies in all six cancer patients that returned for use of their cryopreserved sperm. Two were accomplished with AIH cycles, two with in vitro fertilization cycles and two with ICSI [140]. Despite the increased success of semen cryopreservation with ICSI, the utility of sperm banking has been questioned by several authors due to the low percentage of later use to achieve pregnancy [142, 159, 160]. A survey of male cancer survivors found that only 24% of men completed sperm banking prior to cancer treatment [161]. In addition, of those who complete sperm collection 400 cells/mm3 CR complete response; PR partial response

a Data

b Highest

Metastatic RCC, Metastatic melanoma Cutaneous T cell lymphoma (persistent or recurrent) Ph+ CML (previously treated) Hairy cell leukemia AIDS related Kaposi’s sarcoma Condyloma acuminata (refractory or recurrent)

CR 7%, PR 8%a CR 10%, PR 6%a CR 11%, PR 25%b CR 10%, PR 12%c PR+CR 61% CR 3%, PR 3%d CR 24%, PR 21%e CR 54%, PR 26%

12 Cytokines in the Treatment of Cancer

involved with the mechanism of action, on-target toxicity is not unexpected and in fact, numerous times treatment is withheld because of this reason. Compared to the native recombinant IL-2 product (Hoffman La R (Chiron) has a more attenuated Roche), Proleukin safety profile, with fewer events of fever, nausea, hepatic toxicity and vomiting [4]. In addition, irrespective of the version of rIL-2 used, there were instances of exacerbation of inflammatory or autoimmune diseases and/or very serious CNS toxicities [5]. Naturally, the unpredictability of clinical response combined with the toxicity of IL-2 caused by its intrinsic pleiotropism, hamper its clinical applicability. Based on its documented safety and efficacy profile, various investigators evaluated IL-2 as an adjuvant to antigen-based immunization in cancers, more notoriously malignant melanoma. With the progress in understanding the key role of IL-2 in expansion and maintenance of Treg cells, however, there are questions on whether clinical use of IL-2 as adjuvant for immunotherapy does have a dual, somewhat contradictory effect on immunity. An interesting ‘flavor’ of the IL-2 based approach is represented by the use of IL-2-toxin fusion molecules R , encompassing the diphtheria (exemplified by Ontak toxin ADP-ribosylation subunit) [6]. The mechanism of action is direct and consists in binding of the fusion molecule to cells that express IL-2R followed by the internalization of the fusion protein and cellular apoptosis. Certain T cell malignancies (such as cutaneous T cell lymphoma – CTL and acute T cell leukemia/lymphoma – ATL) encompass T cell clonotypes that express CD4 and CD25, the low affinity isoform of the IL-2 receptor. Efficacy clinical trials with the IL-2 – Dyphteria toxin fusion molecule in CTL showed a significant response rate: 11% of patients underwent complete remission and 25% partial remission. On this basis, the drug has been approved for the treatment of CTL (stage Ib to IV), in patients that show CD25 expression on their malignant cells (at least 20% of cancer cells must express the target molecule). This is definitely an example of a targeted approach fitting the “theranostic” concept (use of biomarkers to identify the patients to be treated). Nevertheless, one important limiting factor is the safety profile [7] especially due to instances of vascular leak syndrome (hypotension, hypoalbuminemia, edema) sometimes resulting in life-threatening conditions, acute hypersensitivity in roughly two thirds of the patients, hence the drug can be administered only in the hospitals in

241

units equipped with cardiovascular resuscitation capaR bilities. Since CD25, the desired target of Ontak is the lower affinity IL-2R, it is conceivable that the safety profile of this drug results from off-target toxicity (binding to and killing cells that express other isoforms of IL-2) combined with exaggerated in vivo cytokine production. In addition, Diphteria toxin component is a foreign antigen and since the treatment encompasses multiple intravenous infusions, an antibody response to the drug often develops. Finally, 48% of the patients develop infections, with a quarter of them advancing to serious illness, due to significant depletion of normal T cells. Overall, even if CD25 is used as a biomarker to identify the patient subpopulation to be treated, two thirds of the treated patients do not show a response and many of them, instead, develop toxicities. Conversely, toxicity may become dose limiting in numerous patients that respond to the drug.

12.3 Interferon-Alpha IFN-α is a key cytokine regulating the innate and adaptive immune response at multiple levels. In addition, it may have direct effect on tumor cells of select phenotype. Since its discovery as a crucial mediator and effector molecule in virus infections, it became apparent that IFN-α was a component of the first phase response responsible for both keeping in check replication of extraneous genetic material as well as transmitting “danger signals” to APCs and lymphoid cells. The pleiotropic nature of IFN-α is dramatically reflected by the widespread expression of its receptor on both bone marrow as well as somatic cells, the conserved nature of this defense pathway through evolution, including STAT-1-mediated signaling that in man, results in induction of T1 immunity. In fact, its viral inhibition, capability to restore ALT serum levels and hepatic histology were tested and led to approval of rIFN-α in chronic hepatitis with HCV, a milestone in the therapy of this disorder [8]. In patients that show persisting titers of HCV, rIFN-α is able to keep those in check or trigger their decline, possibly by acting directly on virus infected hepatocytes. Several versions of rIFN-α were tested in cancer indications (Table 12.1) and interestingly, showed beneficial clinical effect and resulted in approval for

242

treatment in CML, hairy cell leukemia, nonHodgkin lymphoma and Kaposi sarcoma [9–12]. In Philadelphia chromosome positive, chronic myelR ) showed ogenous leukemia (CML), rIFN-α (Roferon a 10% complete response and 12% partial response rate when cytogenetic response criteria were used. An exciting overall response rate of 61% was reported in case of hairy cell leukemia. There were responses seen in patients with non-Hodgkin lymphoma as well. Excitingly, AIDS or HIV infected patients with Kaposi sarcoma showed significant response to IFN-α: in patients that are relatively immune competent (CD4+ T cells in blood > 400 mm3 ), the complete response rate was 24% and the partial response rate was 21% (a staggering 45% overall response rate); whereas in immune compromised patients (CD4+ T cells in blood < 200 mm3 ), the response rate was dismal (3% complete and 3% partial response, respectively). This has dual implications: first, it sheds some light on the mechanism of action, likely to be dependent on T helper cells; secondly, it outlines a key biomarker for patient stratification, with clear predictive value, prior to initiating therapy – namely the frequency of CD4+ T cells. A different synthetic IFN-α (interferon-a R ) was tested and approved in a benign n3, Alferon tumor, relapsing or recurring condyloma acuminata resulting from chronic infection with select human paillomavirus (HPV) subtypes [13]. Interestingly and in line with the concept shown in Fig. 12.2, IFN-α was most effective and is being administered by direct tumor injection in this particular case, likely associated with minimal antigen exposure to the immune system. Toxicity, as expected, has been a problem with rIFN-α since its native counterpart mediates a significant portion of flu symptoms such as fever and chills [14]. In addition, there are significant central nervous reactions, psychiatric side-effects in a subset of patients culminating with clinical depression and suicide. Finally, other serious toxicities such as gastrointestinal hemorrhage and bone marrow suppression may occur. To ameliorate these side effects and optimize the administration regimen otherwise requiring frequent injections, second-generation rIFN-α with longer half-life were developed (such as R ) and were initially approved for the most Pegasys common application, HCV positive hepatic disease. Another aspect hampering the chronic use of rIFN-α is represented by induction of antibodies that may

A. Bot

become neutralizing. It has been shown that a potential solution to this problem is the alternate use of natR , the ural IFN-α, hence the approval of Multiferon native human molecules (multiple IFN-α isoforms) purified from stimulated cell cultures and administered to patients with malignant melanoma.

12.4 Challenges Associated with Cytokine Therapy in Cancer Cytokine treatment in cancer represented a significant advent in cancer therapy, with IL-2 and IFN-α leading the path. We are however at a cross road that may result in a significant modification of the therapeutic landscape in oncology practice, fueled by new generations of molecular targeted therapies, both biomolecules and small molecules. This revolution witnessing the coming to age of monoclonal antibodies and emergence of multi-tyrosine kinase inhibitors, may phase out the use of cytokines per se, in the therapy of cancers. This is due to the overall reduced efficacy of cytokines and the associated toxicities. A closer look however offers some hope: a subset of patients treated with IL-2 or IFN-α does respond by complete or partial regression that lasts for a few weeks, months or sometime even years depending on the tumor type. In light of this and the grave side effects experienced by many patients, it is clear that the limitations associated with cytokine therapy (more specifically IL-2 and IFN-α) in cancer are two fold: unpredictability of clinical response and the modest therapeutic index. A stratified medicine concept is in principle able to address both these problems. It is already evident that a biomarker-guided treatment makes a positive albeit relatively modest difference in context of cytokine R (recombitherapy in cancer. For example, Ontak nant IL-2 – Dyphteria toxin fusion protein) is administered to cutaneous T cell lymphoma patients that express CD25 on their malignant cells. Despite the fact that there are little data in patients with CD25 negative malignant cells, a thorough understanding of the mechanism of action including the pharmacelogically relevant target, enables development of ‘upstream’ biomarkers that can be used to stratify the patient population. In this particular case, the stratification leads to two groups: patients that may respond

12 Cytokines in the Treatment of Cancer

243

and patients that do not respond. Thus, since a clinical response requires a number of parameters to be simultaneously met, while clinical failure is easier to achieve (a single pre-requisite not met would suffice), it is thus more straightforward to develop biomarkers predicting lack of response just based on thorough understanding of the mechanism of action and pharmacology. Mathematically, this still makes a significant difference resulting in focusing the therapy to a subset of patients with a higher likelihood of success. Unfortunately, use of IL-2 and IFN-α as immune modulating agents in cancer therapy, is faced with an inherent difficulty to develop predictive biomarkers due to the complexity of the mechanism of action and their pleiotropic activity. Interestingly, in case of Kaposi sarcoma the frequency of CD4+ T cells and thus the degree of immune suppression is a good biomarker: immune suppressed patients have a likelihood of complete response of 400

CD4+ T cells (cells/mm^3)

Differential expression profile (tissue harvested prior to treatment)

Fig. 12.3 Predictive biomarkers in support of cytokine therapies

Develop and refine predictive markers

Biomarkers (focus the treatment to responders and limit exposure of non-responders)

244

predictive tests for cytokine treatment, truly enabling an effective application of such therapies in clinic.

12.5 Conclusions Implementation of cytokines in therapy of oncologic disorders represented a milestone; nevertheless, there are significant challenges associated with use of such biological response modifiers: a modest response rate and significant side effects. Nevertheless, the quite durable objective response displayed by a subset of patients, such as RCC or melanoma patients treated with rIL-2, provides a strong rationale for the intrinsic capability of immune system to affect cancer progression if harnessed appropriately. However, to continue to compete in a rapidly changing therapeutic landscape, cytokines must raise to the challenge of stratified medicine or biomarker-guided therapy. This will allow improvement of their therapeutic index by focusing the treatment to patient subpopulations that have the highest likelihood of response. In addition, the advent of second generation cytokines – such as IL-15, devoid of some undesirable bystander effects of IL-2 – along with pleiotropic biological response modifiers that elicit a ‘storm’ of synergistic cytokines (such as Toll-like receptor agonists), or block negative regulatory mechanisms (such as α-CTLA4 mAb), carry the promise of furthering this therapeutic area.

References 1. Matzinger P (1994) Tolerance, danger, and the extended family. Annu Rev Immunol 12:991–1045 2. Riker AI, Radfar S, Liu S, Wang Y, Khong HT (2007) Immunotherapy of melanoma: a critical review of current concepts and future strategies. Expert Opin Biol Ther 7(3):345–358 3. Hutson TE, Quinn DI (2005) Cytokine therapy: a standard of care for metastatic renal cell carcinoma? Clin Genitourin Cancer 4(3):181–186

A. Bot 4. Hank JA, Surfus J., Gan J., Albertini M, Lindstrom M, Schiller JH, Hotton KM, Khorsand M, Sondel PM (1999) Distinct clinical and laboratory activity of two recombinant interleukin-2 preparations. Clin Cancer Res 5(2): 281–289 5. Lentsch AB, Miller FN, Edwards MJ (1999) Mechanisms of leukocyte-mediated tissue injury induced by interleukin-2. Cancer Immunol Immunother 47(5): 243–248 6. Turturro F (2007) Denileukin diftitox: a biotherapeutic paradigm shift in the treatment of lymphoid-derived disorders. Expert Rev Anticancer Ther 7(1):11–17. Review 7. Kuzel TM (2000) DAB(389)IL-2 (denileukin diftitox, ONTAK): review of clinical trials to date. Clin Lymphoma 1(Suppl 1):S33–S36. Review 8. Boyer N, Marcellin P (2003) Pathogenesis, diagnosis and management of hepatitis C. J Hepatol 32(1 Suppl):98–112 9. Gidron A, Tallman MS (2006) Hairy cell leukemia: towards a curative strategy. Hematol Oncol Clin North Am 20(5):1153–1162 10. Armitage AE, Armitage JD, Armitage JO (2006) Alphainterferon for relapsed non-Hodgkin’s lymphoma. Bone Marrow Transplant 38(10):701–702 11. Quintas-Cardama A, Cortes JE (2006) Chronic myeloid leukemia: diagnosis and treatment. Mayo Clin Proc 81(7):973–988 12. Vanni T, Sprinz E, Machado MW, Santana Rde C, Fonseca BA, Schwartsmann G (2006) Systemic treatment of AIDSrelated Kaposi sarcoma: current status and perspectives. Cancer Treat Rev 32(6):445–455 13. Kodner CM, Nasraty S (2004) Management of genital warts. Am Fam Physician 70(12):2335–2342 14. Sleijfer S, Bannink M, Van Gool AR, Kruit WH, Stoter G (2005) Side effects of interferon-alpha therapy. Pharm World Sci 27(6):423–431 15. Sabatino M, Kim-Schulze S, Panelli MC, Stroncek D, Wang E, Taback B, Kim DW, Deraffele G, Pos Z, Marincola FM, Kaufman HL (2009) Serum vascular endothelial growth factor and fibronectin predict clinical response to high-dose interleukin-2 therapy. J Clin Oncol 27(16): 2645–2652 16. Panelli MC, Wang E, Phan G, Puhlmann M, Miller L, Ohnmacht GA, Klein HG, Marincola FM (2002) Geneexpression profiling of the response of peripheral blood mononuclear cells and melanoma metastases to systemic IL-2 administration. Genome Biol 3(7):RESEARCH0035. Epub 2002 Jun 25 17. Critchley-Thorne RJ, Yan N, Nacu S, Weber J, Holmes SP, Lee PP (2007) Down-regulation of the interferon signaling pathway in T lymphocytes from patients with metastatic melanoma. PLoS Med 4(5):e176

Chapter 13

Antibody-Based Therapies for Solid Tumors Satish Shanbhag and Barbara Burtness

13.1 Introduction The introduction of monoclonal antibodies into clinical oncology began a new era in cancer therapy. These therapies add new mechanisms of action and possess relatively favorable toxicity profiles compared to standard chemotherapy drugs. Monoclonal antibodies are used widely in clinical medicine. Rituximab, a chimeric antibody directed against the CD20 antigen on B lymphocytes, was the first monoclonal antibody to gain regulatory approval for the treatment of lymphomas, which was granted in 1997 [1]. The current decade has seen the introduction of four therapeutic antibodies for treatment of solid tumors, and these are in wide clinical use. Trastuzumab for breast cancer, bevacizumab for breast, lung and colorectal cancer, cetuximab for colorectal and squamous cell cancers of the head and neck and panitumumab for colorectal cancer are currently approved in the United States; many other novel agents are under investigation. Reference [2], doi:10.1038/35101072

13.2 History Initial monoclonal antibodies in experimental trials were of murine origin. The development of neutralizing human anti-mouse antibodies (HAMA) with

S. Shanbhag () Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111-2497, USA e-mail: [email protected]

repeated use was a significant barrier to the activity and development of these as drugs. To enhance efficacy and minimize immunogenicity, chimeric and humanized antibodies were studied. Chimeric antibodies are obtained by joining the antigen-binding variable domains of a mouse monoclonal antibody to human constant domains and are about 65% human [2]. Humanized antibodies are created by grafting the antigen-binding loops, known as complementarity-determining regions (CDRs), from a mouse antibody into a human IgG. Human


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S. Shanbhag and B. Burtness

Table 13.1 Antibodies in solid malignancies Antibody

Target

Indications

Significant side effects

Bevacizumab

VEGF

Trastuzumab Cetuximab

HER2 EGFR

Colorectal carcinoma, Breast cancer NSCLC HER2 overexpressing breast cancer Colorectal carcinoma

Panitumumab

EGFR

Colorectal carcinoma

Hypertension, Proteinuria, Thrombosis, Bleeding Cardiac dysfunction Skin rash, Hypomagnesemia, Infusion reactions Skin rash, Hypomagnesemia

antibodies are produced from very large, single-chain variable fragments or Fab phage display libraries (Table 13.1) [2].

13.3 Antibodies Targeting VEGF The formation of vascular networks in the developing embryo by endothelial cells is termed vasculogenesis. Angiogenesis is completed when vascular smooth muscle elements associate with the endothelial cell network. VEGF, which is expressed in the tumor microenvironment, mediates angiogenesis which plays a critical role in tumor growth and metastasis [3]. Vascular Endothelial Growth Factor (VEGF) belongs to a sub-family of platelet-derived growth factors (PDGF). The entire VEGF family, consisting of isoforms VEGF-A, VEGF-B, VEGF-C, VEGF-D and VEGF-E (orf virus VEGF), act as important regulators of endothelial cell function controlling vasculogenesis, vascular permeability and endothelial cell survival. VEGF-A is important in pathologic angiogenesis while VEGF-C plays a crucial role in lymphangiogenesis. The exact role of the other VEGF forms in angiogenesis is a subject of investigation. VEGF signal transduction occurs through endothelial cell receptors VEGFR-1, VEGFR-2 and VEGFR-3. Their structures include an extracellular immunoglobulin-like domain and an intracellular tyrosine kinase-like domain. Approaches to angiogenesis inhibition have involved either targeting the extracellular domain with antibodies or the intracellular domain with small molecule tyrosine kinase inhibitors. VEGF stimulates endothelial cells lining nearby microvessels to proliferate and migrate. Proteolysis of extracellular matrix is carried out by the prourokinaseurokinase-plasmin system [4]. This permits leakage of plasma proteins into the extravascular space; the

Antibody type Humanized Humanized Chimeric Fully Human

resultant fibrin gel acts as a matrix for ingrowth of new vasculature and tumor cells [5]. VEGF expression is regulated by the amount of oxygen available in the developing tumor stroma; hypoxia-induced transcription factors play a primary role in up-regulating VEGF in response to hypoxia. VEGF expression is increased in a large variety of cancer types. In normal tissues VEGF is produced by endothelial cells alone, but tumor cells can produce VEGF and may bear VEGFR. VEGF expression is predictive of poor disease-free survival, specifically linked to distant metastasis in patients with locally advanced rectal cancer [6]. A Japanese study found vascular endothelial growth factor-C expression was an independent risk factor for the local recurrence of rectal carcinoma [7]. Similar results have been found in colon cancer, correlating VEGF expression with development of liver metastasis and poor prognosis [8]. Expression of VEGF inversely correlated with overall survival in gastric cancer patients [9]. VEGF upregulation by intra-tumoral hypoxia and aberrant signaling promotes new blood vessel growth connected to the neighbouring vasculature. This “angiogenic switch” provides a novel target for anticancer therapy [10]. Angiogenesis may be inhibited through targeting of the angiogenic growth factors (such as VEGF and HIF1-alpha) or their receptors. The VEGF-directed antibody bevacizumab is the first such agent to impact survival in human cancer.

13.4 Bevacizumab Bevacizumab is a humanized monoclonal antibody that blocks binding of VEGF to the ligand-binding domain in the extracellular portion of VEGF-receptor on vascular endothelium, and likely also when it is expressed by malignant cells.

13 Antibody-Based Therapies for Solid Tumors

13.4.1 Colorectal Carcinoma Bevacizumab was first approved for the treatment of colorectal carcinoma. In a randomised placebocontrolled trial studying addition of bevacizumab to the IFL regimen (irinotecan, 5-fluorouracil and leucovorin), the addition of bevacizumab improved outcome significantly. Median overall survival improved from 15.6 to 20.3 months, and median progression-free survival from 6.2 to 10.6 months [11]. This benefit was maintained when FOLFIRI was used as the chemotherapeutic backbone [12]. The ECOG 3200 trial addressed the question of utility of bevacizumab in second-line therapy of metastatic colon cancer. Eight hundred twenty-nine patients previously treated with a fluoropyrimidine and irinotecan were randomised to three groups: oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) with bevacizumab; FOLFOX4 without bevacizumab; or bevacizumab alone. The median overall survival for the group treated with FOLFOX4 and bevacizumab was 12.9 months compared with 10.8 months for the group treated with FOLFOX4 alone (p = 0.0011) [13]. This study also demonstrated that bevacizumab has relatively little activity in colon cancer when given without chemotherapy. The addition of bevacizumab to modified FOLFOX6 as a part of adjuvant therapy for resected stage II or III carcinoma of the colon did not result in an overall statistically significant prolongation in disease free survival (DFS) [14]. Although there was a transient benefit in DFS during the one-year interval that bevacizumab was utilized, this benefit diminished over time.

13.4.2 Breast Cancer The addition of bevacizumab to cytotoxic chemotherapy in patients with metastatic breast cancer was the subject of ECOG 2100; this randomised 722 patients to paclitaxel with or without bevacizumab. Bevacizumab significantly prolonged progression-free survival when added to paclitaxel (median, 11.8 vs. 5.9 months; P 41.5◦ C and practical guidelines for the treatment of adults. The German “interdisciplinary working group on hyperthermia”. Int J Hyperthermia 21(2):169–183 3. Stewart JHT, Shen P, Levine EA (2005) Intraperitoneal hyperthermic chemotherapy for peritoneal surface

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21 Induced Hyperthermia in the Treatment of Cancer

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376 45. Hildebrandt B, Wust P, Rau B, Schlag PM, Riess H (2000) Regional hyperthermia in rectal cancer. Lancet 356(9231):771–772 46. Prosnitz L (2002) A new phase III trial for treatment of carcinoma of the cervix. Int J Hyperthermia 18(1):31–32 47. Prosnitz L, Jones E (2002) Counterpoint: test the value of hyperthermia in patients with carcinoma of the cervix being treated with concurrent chemotherapy and radiation. Int J Hyperthermia 18(1):13–18 48. van der Zee J, Gonzalez GD (2002) The Dutch Deep Hyperthermia Trial: results in cervical cancer. Int J Hyperthermia 18(1):1–12 49. van der Zee J, Koper PC, Lutgens LC, Burger CW (2002) Point-counterpoint: what is the optimal trial design to test hyperthermia for carcinoma of the cervix? Point: addition of hyperthermia or cisplatin to radiotherapy for patients with cervical cancer; two promising combinations – no definite conclusions. Int J Hyperthermia 18(1):19–24 50. Westermann AM, Jones EL, Schem BC, van der SteenBanasik EM, Koper P, Mella O et al (2005) First results of triple-modality treatment combining radiotherapy, chemotherapy, and hyperthermia for the treatment of patients with stage IIB, III, and IVA cervical carcinoma. Cancer 104(4):763–770 51. Rau B, Wust P, Hohenberger P, Loffel J, Hunerbein M, Below C et al (1998) Preoperative hyperthermia combined with radiochemotherapy in locally advanced rectal cancer: a phase II clinical trial. Ann Surg 227(3):380–389 52. Riess H, Loffel J, Wust P, Rau B, Gremmler M, Speidel A et al (1995) A pilot study of a new therapeutic approach in the treatment of locally advanced stages of rectal cancer: neoadjuvant radiation, chemotherapy and regional hyperthermia. Eur J Cancer 31A:1356–1360 53. Wendtner CM, Abdel-Rahman S, Krych M, Baumert J, Lindner LH, Baur A et al (2002) Response to neoadjuvant chemotherapy combined with regional hyperthermia predicts long-term survival for adult patients with retroperitoneal and visceral high-risk soft tissue sarcomas. J Clin Oncol 20(14):3156–3164 54. Berdov BA, Menteshashvili GZ (1990) Thermoradiotherapy of patients with locally advanced carcinoma of the rectum. Int J Hyperthermia 6(5):881–890 55. Datta NR, Bose AK, Kapoor HK (1987) Thermoradiotherapy in the management of carcinoma of the cervix (stage IIIb): a controlled clinical study. Indian Med Gazette 121:68–71 56. Datta NR, Bose AK, Kapoor HK, Gupta S (1990) Head and neck cancers: results of thermoradiotherapy versus radiotherapy. Int J Hyperthermia 6(3):479–486 57. Harima Y, Nagata K, Harinma K, Ostapenko VV, Tanaka Y, Sawada S (2001) A randomized clinical trial of radiation therapy versus thermoradiotherapy in stage III cervical carcinoma. Int J Hyperthermia 17(2): 97–105 58. Kitamura K, Kuwano H, Watanabe M, Nozoe T, Yasuda M, Sumiyoshi K et al (1995) Prospective randomized study of hyperthermia combines with chemoradiotherapy for esophageal carcinoma. J Surg Oncol 60:55–58 59. Sharma S, Patel FD, Sandhu APS, Gupta BD, Yadav NS (1989) A prospective ramdomised study of local hyperthermia as a supplement to and radiosensitiser in the

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21 Induced Hyperthermia in the Treatment of Cancer 75. Rosen HR, Jatzko G, Repse S, Potrc S, Neudorfer H, Sandbichler P et al (1998) Adjuvant intraperitoneal chemotherapy with carbon-adsorbed mitomycin in patients with gastric cancer: results of a randomized multicenter trial of the Austrian working group for surgical oncology. J Clin Oncol 16(8):2733–2738 76. Sautner T, Hofbauer F, Depisch D, Schiessel R, Jakesz R (1994) Adjuvant intraperitoneal cisplatin chemotherapy does not improve long-term survival after surgery for advanced gastric cancer. J Clin Oncol 12(5):970–974 77. Hildebrandt B, Rau B, Gellermann J, Wust P, Riess H (2004) Hyperthermic intraperitoneal chemotherapy in patients with peritoneal carcinosis. J Clin Oncol 22(8):1527–1529 78. Nadobny J, Wlodarczyk W, Westhoff L, Gellermann J, Felix R, Wust P (2005) A clinical water-coated antenna applicator for MR-controlled deep-body hyperthermia: a comparison of calculated and measured 3-D temperature data sets. IEEE Trans Biomed Eng 52(3):505–519 79. Nadobny J, Wlodarczyk W, Westhoff L, Gellermann J, Rau B, Monich G et al (2003) Development and evaluation of a three-dimensional hyperthermia applicator with WaterCoated Antennas (WACOA). Med Phys 30(8):2052–2064 80. Gellermann J, Wlodarczyk W, Feussner A, Fahling H, Nadobny J, Hildebrandt B et al (2005) Methods and potentials of magnetic resonance imaging for monitoring radiofrequency hyperthermia in a hybrid system. Int J Hyperthermia 21(6):497–513 81. Gellermann J, Wlodarczyk W, Hildebrandt B, Ganter H, Nicolau A, Rau B et al (2005) Noninvasive magnetic resonance thermography of recurrent rectal carcinoma in a 1.5 Tesla hybrid system. Cancer Res 65(13):5872–5880 82. Wust P, Gellermann J, Seebass M, Fahling H, Turner P, Wlodarczyk W et al (2004) Part-body hyperthermia with a radiofrequency multiantenna applicator under online control in a 1.5 T MR-tomograph. Rofo Fortschr Geb Rontgenstr Neuen Bildgeb Verfahr 176(3):363–374 83. Jordan A, Wust P, Fahling H, John W, Hinz A, Felix R (1993) Inductive heating of ferromagnetic particles and magnetic fluids: physical evaluation of their potential for hyperthermia. Int J Hyperthermia 1993(9):51–68 84. Moroz P, Jones SK, Gray BN (2002) Magnetically mediated hyperthermia: current status and future directions. Int J Hyperthermia 18(4):267–284

377 85. Johannsen M, Gneveckow U, Eckelt L, Feussner A, Waldofner N, Scholz R et al (2005) Clinical hyperthermia of prostate cancer using magnetic nanoparticles: presentation of a new interstitial technique. Int J Hyperthermia 21(7):637–647 86. Johannsen M, Thiesen B, Gneveckow U, Taymoorian K, Waldofner N, Scholz R et al (2006) Thermotherapy using magnetic nanoparticles combined with external radiation in an orthotopic rat model of prostate cancer. Prostate 66(1):97–104 87. Kong G, Dewhirst MW (1999) Hyperthermia and liposomes. Int J Hyperthermia 15(5):345–370 88. Lindner LH, Issels R (2003) Thermosensitive liposomes for regional hyperthermia. German. Dt Med Wschr 128:2020–2022 89. Hettinga JV, Konings AW, Kampinga HH (1997) Reduction of cellular cisplatin resistance by hyperthermia – a review. Int J Hyperthermia 13(5):439–457 90. Vanakoski J, Seppälä T (1998) Heat exposure and drugs. Clin Pharmacokinet 34(4):311–322 91. Harris M (2004) Monoclonal antibodies as therapeutic agents for cancer. Lancet Oncol 5(5):292–302 92. Hauck ML, Zalutsky MR (2005) Enhanced tumour uptake of radiolabelled antibodies by hyperthermia. Part II: application of the thermal equivalency equation. Int J Hyperthermia 21(1):13–27 93. Hauck ML, Zalutsky MR (2005) Enhanced tumour uptake of radiolabelled antibodies by hyperthermia: part I: timing of injection relative to hyperthermia. Int J Hyperthermia 21(1):1–11 94. Kinuya S, Yokoyama K, Michigishi T, Tonami N (2004) Optimization of radioimmunotherapy interactions with hyperthermia. Int J Hyperthermia 20(2): 190–200 95. Brade AM, Szmitko P, Ngo D, Liu FF, Klamut HJ (2003) Heat-directed suicide gene therapy for breast cancer. Cancer Gene Ther 10(4):294–301 96. Li CY, Dewhirst MW (2002) Hyperthermia-regulated immunogene therapy. Int J Hyperthermia 18(6):586–596 97. Huang Q, Hu JK, Lohr F, Zhang L, Braun R, Lanzen J et al (2000) Heat-induced gene expression as a novel targeted cancer gene therapy strategy. Cancer Res 60(13):3435–3439

Part V

Supporting Measures

Chapter 22

Hematologic Support of the Patient with Malignancy Thomas A. Lane

22.1 Introduction Patients with malignancy frequently have significant anemia, thrombocytopenia, neutropenia, and coagulation disorders, and therefore frequently require blood component transfusion. As a result, patients with malignancy collectively represent one of the major classes of patients who use blood resources and transfusion services. This chapter will review the transfusion support of patients with malignancy and will not address the role of hematopoietic growth factors in the hematologic support of patients with malignancy, which has recently been reviewed elsewhere [13, 50, 27, 58, 85, 86, 138, 184, 205, 210, 240]. Hematologic disorders in cancer patients may be due either to the disease itself, blood loss, marrow replacement, or cancer treatment [32, 60, 145, 207]. A meta-analysis of the scientific literature regarding anemia in patients with malignancy reported that the prevalence of anemia in cancer patients varies greatly and is a function of the definition of anemia, the type of malignancy, the stage of disease, and the effects of treatment [118]. Focusing on studies that reported anemia not due to therapy (i.e., prior to cancer therapy or in the absence of treatment-related anemia), the authors reported that patients with hematologic malignancy and lymphoma had the highest rates of anemia, exceeding 90%, followed in general order of prevalence and severity by patients with a variety

T.A. Lane () UCSD Transfusion Services and Stem Cell Processing Lab, Moores UCSD Cancer Center, La Jolla, CA 92093-0960, USA e-mail: [email protected]

of solid tumors including gynecologic malignancy (26–85%), breast (41–82%), bone (78%), gastrointestinal (30–67%), head and neck (16–65%), brain (59%), kidney (39%), and lastly prostate cancer (5–32%) [118]. Thus, while patients with malignancy, and especially hematologic malignancy are prone to varying degrees of marrow failure, cancer treatment imparts an added stress on the marrow and represents the principal cause of anemia, thrombocytopenia and leukopenia in cancer patients and increases the likelihood of transfusion [32, 49, 93, 175, 207]. Dramatic evidence of the critical support role for transfusion in patients with hematologic malignancy is provided by the reports of generally poor outcome of treatment of patients with AML who refuse transfusion [54, 122, 137]. Anemia is common in pediatric as well as adult patients with malignancy. It has been reported that anemia occurs in approximately 12% of pediatric patients after standard dose chemotherapy, and the prevalence of anemia increases to approximately 60% after administration of intensive chemotherapy [186]. Considerable resources are required to provide hematologic support for patients with malignancy. Recent reports indicate that from 15 to 48% of all transfusions are administered to patients with malignancy [45, 129, 139, 223, 241, 254] and it has been reported that patients with acute myelogenous leukemia (AML) used more blood resources (8% of total hospital transfusions) than patients with any other individual diagnosis [129]. The intense use of blood by leukemia patients is also reflected by the fact that, in comparison with other disease-related groups (DRG), acute leukemia is reported to be associated with the highest individual mean cost for blood as a percent of total hospital costs (12.7%), followed by bone marrow transplant (8.7%) [112]. Blood resource utilization


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by patients with malignancy has been reported to vary by component. Studies report that 28–42% of all red blood cell units (rbc) transfused, 13–32% of fresh frozen plasma units (FFP) and 53–76% of platelet units (plt) were administered to patients with neoplasms [129, 139]. Furthermore, in the latter study AML patients alone accounted for 17.5% of all plt use. The total cost of blood and component transfusion for the cancer patient includes the direct cost of the unit, which represents approximately 35% of the total cost of blood administration and also the costs involved in storing, handling, testing and infusing the blood and dealing with transfusion reactions and adverse effects. It has been reported that the overall cost of administration of a single unit of rbc to a cancer patient in 1998 varied from $274 to $512 per unit [39, 53]. An accurate understanding of the local cost of blood transfusion is required in order to evaluate the comparative costs, risks and benefits of treating anemia in cancer patients with blood vs. Erythropoietin [200]. In addition, cancer patients frequently have unique requirements that further increase the cost of blood transfusion. These may include the requirement for blood irradiation to prevent graft vs. host disease, leukocyte reduction to prevent alloimmunization to leukocyte antigens, provision of blood from CMV seronegative donors to prevent CMV infection, provision of selective phenotype-matched rbc or plt to patiens who are alloimmunized to foreign rbc or plt-associated antigens, or provision of granulocytes to treat infection in some severely neutropenic patients. Frequently transfused cancer patients who become alloimmunized to leukocyte, red cell, or platelet antigens may also require the expensive services of reference labs to identify the antibody specificity, then to identify adequate donors and finally to provide antigen matched red cells or HLA matched platelets. In view of the above, the national economic impact of the hematologic support of patients with malignancy is considerable. In the USA, approximately 12 million units of blood are collected yearly and 11.5 million units of rbc, 9 million units of plt and 3.3 million units of FFP are transfused yearly [88, 89, 214]. Extrapolating mean reported data from two studies regarding the average use of blood by cancer patients, approximately 4 million units of rbc, 5.8 million units of platelets and 0.8 million units of FFP are expected to be used by cancer patients yearly in the USA [129, 139]. The direct costs of blood vary by location,

T.A. Lane

but assuming conservatively that a unit of rbc costs $250/U, a unit of apheresis plt costs $650 and a unit of FFP costs $45, then the aggregate yearly direct cost of blood for cancer patients in the USA would be approximately 4.8 billion. As previously noted, the direct unit costs of blood represent less than half of the total cost of blood transfusion.

22.2 Blood Component Therapy in Patients with Cancer 22.2.1 Red Cell Transfusion in Patients with Cancer Introduction: As noted above, both anemia and red cell transfusion are common in patients with malignancy and increase due to the effects of intensive chemo-radiotherapy. Transfusion requirements in patients treated for malignancy have been reported to vary by the type of disease, and within disease categories, by the type of chemotherapy administered [93]. Transfusion prevalence and requirements are highest in patients with myeloid malignancy [136], especially in marrow transplant patients [143], followed by patients with lymphoma, lung cancer, ovarian cancer and genitourinary malignancy [93]. In one report of cancer patients treated by a large group practice, 31% of all cancer patients required rbc transfusion, with an average of 5.1 units per patient [74]. In another report on transfusion requirements of solid tumor patients who were treated prior to availability of Erythropoietin, 3.7 units of rbc were used per patient [148]. The approach to an anemic patient with cancer is similar to that for non-cancer patients in that treatable sources and causes of blood loss, hemolysis, and marrow dysfunction should be considered, identified, and treated accordingly. Guidelines for Treatment of Anemia: Guidelines for treatment of anemia have been published [88, 89, 119]. In general, rbc transfusion are reserved for patients who have symptomatic anemia that is not due to B12, folate, or iron deficiency and for emergencies. The need for transfusion in an individual patient is typically based on the presence of symptoms, e.g. fatigue (the commonest symptom reported by cancer patients), weakness, dizziness, the hemoglobin value itself, and the context, ie anticipation of a chronic requirement vs.

22 Hematologic Support of the Patient with Malignancy

acute, self-limited anemia. Patients are typically transfused at hemoglobin levels of 7–8 gm/dl, but this may vary depending on the presence of significant cardiovascular or cerebrovascular disease, other significant organ dysfunction, and on predictions regarding the course of the disease and the effect of its treatment on symptomatic anemia., Hemoglobin levels lower than 12 gm/dl in cancer patients have been reported to play a role in cancer-related symptoms such as fatigue [43, 86, 208, 210, 240]. Likewise, improvements in quality of life have been reported in patients treated to a hemoglobin level higher than 9–10 gm/dl [42, 51, 59, 84, 130–132, 174] and recent ASCO guidelines support the use of Erythropoietin or rbc transfusion in carefully selected patients to achieve this goal [183]. The risk/benefit ratio of maintaining a hemoglobin > 10 gm/dl, < 12 gm/dl by the use of Erythropoietin and/or rbc transfusion should be evaluated in each individual patient. In contrast, more restrictive transfusion thresholds have also been proposed in surgical patients and in those who are unlikely to respond to Erythropoietin as a means of diminishing treatment risk and excess cost [62, 111]. Evaluation of the hemoglobin level at which to treat cancer patients by transfusion or Erythropoietin has been the focus of recent investigation, in part because, in addition to fatigue, anemia in cancer patients has been linked to other possible important adverse outcomes. A host of retrospective reports suggested an association between anemia in cancer patients and both poor tumor response and decreased survival after radiation therapy [92, 123, 221, 237]. Studies in animal models provided the scientific basis for an association between tumor oxygenation and radiation effectiveness at tumor sites [203, 220]. Limited retrospective studies in humans suggested that maintaining a higher hemoglobin by transfusion or EPO improved outcome after radiation therapy [83, 92], but not all studies supported an association between hemoglobin and response to treatment [46, 64]. Moreover, recent reports of prospective randomized trials suggest that cancer patients treated with EPO fared less well than placebo-treated patients [101, 127]. A randomized multicenter, double-blind trial including 351 anemic patients with oral-laryngeal cancer who received either placebo or Erythropoietin prior to and during curative radiation therapy, investigated the effect of EPO therapy on the primary endpoint of time to local-regional progression [101]. In this trial patients in the group

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that received EPO unexpectedly had a statistically significant decrease in the time to progression, despite an increase in hemoglobin, compared with the control patients who did not receive EPO [101]. More recently, a multinational prospective randomized trial in which patients with breast cancer and normal hemoglobin who were receiving first line therapy and who were randomized to receive either placebo or EPO to maintain hemoglobin > 12 gm/dl was terminated early due to an apparent increase in early disease progression and thrombotic events in the group that received EPO [127]. In retrospect, there were unexplained anomalies in randomization and disease course of the control group in this study despite the randomization, and follow-up of the patients was incomplete. However, the study group concluded that the use of EPO in the above manner should be undertaken only in the context of a clinical trial with appropriate safeguards. In addition, a retrospective case-controlled study suggested an increased incidence of thrombotic events in cervical cancer patients who were treated with EPO to correct anemia in the setting of chemo-radiotherapy [247]. In summary, it appears that in persons with a wide range of malignancies, as reviewed above [118], either rbc transfusion or administration of EPO may significantly diminish symptoms of anemia and improve quality of life by increasing the hemoglobin to at least 10 gm/dl. In addition, EPO therapy spares rbc transfusions in those who respond, although perhaps at increased cost. However, currently available information is insufficient to support a policy to maintain hemoglobin above 10 gm/dl as a rationale to improve upon response to radiotherapy or to increase overall survival in patients with oral-laryngeal or breast cancer. Whether these findings can be extended to patients with other types of malignancy and with other treatment remains an open question, however a recent meta-analysis of clinical trials of EPO in cancer patients reported both an increase in the incidence of venous thrombo-embolism (VTE) and mortality in a wide variety of cancer patients [13]. In any event, as a result of these and other studies, on November 8, 2007 the FDA issued a warning regarding the use of EPO in patients with Hb values > 10 gm/dl and CMS has indicated that it would not cover the cost of EPO that is administered outside of the FDA guidelines. These events have resulted in considerable controversy within the medical community, and ultimately in significant changes in patient management. In addition, relevant to this review, it has been

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predicted that the FDA & CMS decisions will result in a significant increase in the rate of blood transfusion in patients who would otherwise have been treated with EPO to a higher level of Hb [231].

22.2.1.1 Transfusion of Red Cell Components Whole blood: A variety of red blood cell (rbc) containing components are available for transfusion to patients in whom this therapy is indicated. The sole indication for administration of whole blood (500 mL volume; Hct approximately 45%) is replacement of combined deficits of oxygen carrying capacity and blood volume such as occurs in acute hemorrhage. In practice, whole blood is rarely available, primarily because of (a) the difficulty in maintaining a ready supply of this component for all blood types, (b) the compelling need for blood suppliers to generate other components (plasma, platelets, cryoprecipitate) from whole blood, and (c) because there are alternatives that are acceptable or in some cases superior to whole blood. In this author’s institution, which includes active services in trauma, cardiac surgery, liver transplant and burns, whole blood is not used except in neonatal transfusion. Packed red blood cells: Packed rbc consist of a volume of approximately 250 ml of blood with a Hematocrit of 65–75% depending on the preservative solution used. Different preservative solutions maintain acceptable rbc viability for 35 (CPDA1) or 42 days (AS1, AS3, AS5). In adult transfusion, there is little or no clinical difference between rbc preserved in one anticoagulant/preservative solution vs. another since the storage life of rbc in all solutions is dictated by a requirement to maintain the 24-h post transfusion recovery of rbc at the date of unit expiration to greater than 75%. Because of a lower content of donor plasma (10 ml vs. 70) units preserved in AS may have a reduced probability of causing plasma-associated adverse effects compared with units preserved with CPD (see Section 22.3). Administration of a single unit of rbc to a 70 kg person with a normal blood volume is expected to increase the Hemoglobin by approximately 1 gm/dl or the Hematocrit by approximately 3%. A patient whose marrow is making no rbc is expected to require approximately 1 unit of rbc per week to maintain a steady Hemoglobin level. Leukocyte-reduced blood: Patients who are transfused with standard (non-leukocyte-reduced) rbc and

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platelets and multiparous women may develop antibodies to leukocyte-specific, platelet specific, and HLA antigens. Blood recipients who have developed alloimmune antibodies to foreign leukocyte antigens, and principally alloimmune antibodies to human leukocyte antigens (HLA) may suffer febrile nonhemolytic transfusion reactions when non-leukocyte reduced rbc or platelets are administered. In addition, alloimmune antibodies to foreign HLA antigens are also responsible for immune-mediated refractoriness to platelet transfusion (discussed below). Between 15 and 50% of leukemia patients develop anti-HLA antibodies during induction therapy [5, 206]. When transfusion is indicated, administration of leukocytereduced rbc are indicated in patients who will require multiple transfusions of cellular blood components in order to: (1) diminish or prevent febrile-non-hemolytic transfusion reactions due to anti-leukocyte antibodies and (2) to diminish the probability of alloimmune reactions (sensitization) to leukocyte antigens [5, 206, 219]. While the early studies that demonstrated the effectiveness of leukocyte-reduced blood in preventing alloimmunization were principally focused on patients with leukemia, more recent retrospective studies indicate that patients with a variety of hematologic and non-hematologic malignancy may also benefit from use of leukocyte-reduced blood [96, 117, 161, 198]. (3) Leukocyte-reduced blood is also effective in preventing cytomegalovirus transmission (discussed below) from rbc transfusion. Leukocyte-reduced rbc are produced by processing of red blood cells through special “3rd generation” filters that remove greater than 99.9% of leukocytes, leaving the rbc with less than 5 × 106 leukocytes per unit. Filter efficiency has improved to the point that the mean level of residual leukocytes per unit is almost always considerably below this level [6, 249]. Leukocyte-reduction is performed most reliably by the blood-collecting facility or in the laboratory prior to blood administration [6], and is referred to as “pre-storage leukocyte-reduction” however there are filters available that permit leukocyte-reduction of blood at the time of blood administration, albeit somewhat less reliably. Transfusion is clearly associated with immune modulation, but it is unclear whether transfusion associated immune modulation is ameliorated or prevented by administration of leukocyte-reduced blood. It has long been appreciated that blood transfusion has immunomodulatory effects, as evidenced by prolonged

22 Hematologic Support of the Patient with Malignancy

renal allograft survival [159]. These findings led to the hypothesis that transfusion-associated diminished immune responsiveness might impair host response to malignancy [21]. More specifically, investigators focused on the possibility that passive transmission of “passenger” blood leukocytes in cellular blood components during surgery in cancer patients might be responsible for diminished anti-cancer immunity and hence an increased rate of tumor recurrence [21, 25]. This topic has generated considerable controversy over the past decade, however at this time there is insufficient evidence to conclude that passenger leukocytes in blood impair the response to cancer treatment or cause increased tumor recurrence. A host of retrospective studies suggested a link between cancer recurrence and transfusion, presumably due to the immunosuppressive effect of passenger leukocytes, however, a meta-analysis of the retrospective studies failed to identify an independent association between cancer recurrence and transfusion or the use of leukocytereduced blood. Instead, the meta-analysis suggested that the association of transfusion with cancer recurrence was due to the fact that patients who have extensive disease require extensive resection and therefore increased transfusion and such patients would also be expected to have a higher rate of cancer recurrence [24, 25, 217, 225, 226]. During the previous decade, considerable attention has been specifically directed toward investigating a potential deleterious effect of blood transfusion on the survival and freedom from recurrence of patients undergoing curative surgical treatment for colorectal cancer. Both retrospective and prospective studies failed to identify a relationship between blood transfusion and colorectal cancer metastasis, but confirmed that patients who required transfusion had poorer survival, presumably as a result of more extensive disease [35, 36, 97]. In one randomized study of similar stage colorectal surgery patients who were scheduled for curative surgery, patients who did not require transfusion had improved disease-free survival compared with patients who were transfused, but the incidence of cancer recurrence was equal in patients who received allogeneic transfusions compared with those who received autologous transfusion or a mix of the two [35]. Another study compared tumor free survival and metastases in similar stage colorectal cancer patients who were scheduled for curative surgery and were randomized to receive either allogeneic or autologous blood [99]. This study found

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no significant difference in disease-free survival or metastasis in the two groups. Patients transfused with allogeneic blood had a higher rate of tumor recurrence than untransfused patients, but this difference disappeared after adjustment for disease stage [99]. A recent prospective investigation reported the outcomes of 697 patients with similar stage colorectal cancer who were scheduled for curative resection and were randomized to receive leukocyte-reduced or standard (buffy coat poor) blood [229]. The study failed to detect a difference in cancer recurrence between patients who were transfused vs. those who were not transfused or between patients who were administered leukocytereduced blood compared with non-leukocyte-reduced blood. Compared with non-transfused patients, those who received any transfusion had lower overall survival and increased local tumor recurrence, but these associations were not independent of tumor stage. In addition to colorectal cancer, observational studies in patients who underwent surgery for non-small cell lung cancer reported a difference in survival between transfused and non-transfused patients and either identified or failed to identify an association between transfusion and disease recurrence [155, 188]. A recent report of an observational study in patients receiving curative resection for gastric cancer concluded that, while transfused patients had poorer overall survival, this finding was associated with the presence of more extensive disease in the transfused patients [26]. Thus, in the types of malignancies studied to date, the weight of evidence does not support an indication for the use of autologous or leukocyte-reduced blood for the purpose of diminishing the probability of tumor recurrence or metastasis after curative surgery. Washed blood: Washed rbc are indicated for patients who have had significant allergic reactions during blood transfusion (anaphylaxis or moderate to severe bronchospasm) or repeated moderate allergic reactions that are unresponsive to pretransfusion administration of antihistamine. Such patients have antibodies to foreign plasma proteins (for example, anti-IgA) and washing rbc eliminates allergic reactions by reducing the amount of plasma protein to $1000 (in 1999 dollars) [69]. These authors subsequently reported on the clinical implications of thrombocytopenia in 609 lymphoma and solid tumor (sarcoma, breast, GU, melanoma, lung, et al.) patients during 1262 treatment cycles. Bleeding occurred in 9% of cycles and the occurrence of major bleeding and was associated with febrile neutropenia and failure to respond to platelet transfusion (which occurred in a surprisingly high 19% of all patients). The clinical implications of major bleeding were significant since such episodes frequently required hospitalization, led to delays in chemotherapy administration, and patients who suffered a major bleeding episode had significantly shorter survival [71]. Goldberg et al reported on the implications of thrombocytopenia in 501 patients with GYN malignancy who were being treated with dose-intensive chemotherapy [87]. They found that 808 of 1546 (36%) of chemotherapy cycles in 186 patients were associated with thrombocytopenia and that 76% of thrombocytopenic patients had no bleeding, while major bleeding occurred in 5%. There were no life-threatening bleeding episodes. These investigators,

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like Elting, found that 27% of platelet transfusions failed to result in the expected post transfusion platelet count increment and that neither single donor nor HLA matched platelets improved transfusion responses in refractory patients. Calhoun, et al reported that the additional direct cost associated with the occurrence of thrombocytopenia during the chemotherapy of patients for ovarian cancer patients was $3268 per episode [38]. Models have been developed to predict both the risk of thrombocytopenia and the need for platelet transfusion in solid tumor patients [23, 70]. These investigators found that a combination prior bleeding history, low platelet count, performance status, type of chemotherapy administered, administration of drugs that interfere with platelet function, the disease, and a number of other parameters prior to chemotherapy enabled prediction of thrombocytopenia and the need for platelet transfusion. Guidelines for platelet transfusion: Platelet Transfusion guidelines for oncology patients have been published and, in general differ little from platelet transfusion guidelines for patients without malignancy [94, 195]. Platelet transfusion is indicated to treat bleeding due to thrombocytopenia or platelet dysfunction. Platelet transfusion is indicated to maintain the platelet count greater than 40,000–50,000 × 106 /L in order to prevent bleeding during an invasive procedure, although simple bone marrow aspiration may be undertaken with a lower count. A post transfusion platelet count should be measured to ensure a satisfactory response to the transfusion. Platelet transfusion is also indicated to prevent bleeding in severely thrombocytopenic patients who are not scheduled for an invasive procedure. The transfusion trigger for prophylactic platelet transfusion support in patients who are not scheduled for an invasive procedure has been the subject of considerable investigation and recent controversy. Early studies indicated an increased bleeding risk in leukemia patients who had platelet counts less than 20,000 per microliter [80] and this finding resulted in the use of a transfusion trigger of 20,000 × 106 /L to prevent bleeding. However the excess bleeding risk in leukemia patients in the past may have been due in part to a lack of appreciation of the relationship between aspirin use and platelet dysfunction [7]. Recent randomized studies in stable patients with acute leukemia indicate that the frequency of bleeding is similar if a 10,000 or a 20,000 trigger is employed [177, 235, 236]. Patients

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with febrile neutropenia appear to be at higher risk of bleeding. Recent ASCO guidelines suggest that prophylactic platelet transfusion support for leukemia patients should be individualized, that a threshold of 10,000 per microliter is equivalent to 20,000 per microliter in most patients, but that platelet transfusion at higher platelet levels may be necessary in patients with a high risk of bleeding or if platelets are not readily available in emergencies. High-risk leukemia patients include newborns, patients with signs of hemorrhage, high fever, hyperleukocytosis, rapid fall of platelet count, or coagulation abnormalities (e.g. acute promyelocytic leukemia) [195]. These guidelines also apply to marrow transplant patients. The ASCO guidelines suggest that cancer patients who are undergoing high dose chemotherapy receive prophylactic platelet transfusion when the platelet count falls to a level of 10,000 per microliter, except for patients with bladder cancer, for whom a platelet count of 20,000 per microliter is suggested. The ASCO guidelines do not support prophylactic platelet transfusion for other non-bleeding patients who have chronic stable thrombocytopenia, e.g. those with myelodysplasia or aplastic anemia. Recent clinical trials comparing the use of standard vs. low doses of platelets disagree on whether the low dose regimen is equally effective in preventing bleeding, but do indicate that low dose platelets is associated with more frequent platelet administration [97, 204]. Thus, while the introduction of low-dose platelets may be beneficial for the blood center, their use may be more cumbersome for patients, especially outpatients, who will require more frequent transfusions, and the overall effect on costs is unclear. Platelet components: Platelet concentrates for transfusion may be obtained by centrifugation of individual units of fresh whole blood. Four to six of these platelet concentrates (PC), each of which should contain at least 5.5 × 1010 platelets suspended in approximately 50 ml of citrated plasma are typically transfused as a single dose for an adult. Alternatively an equivalent number of platelets (at least 3 × 1011 , typically suspended in 200–300 ml citrated plasma) may be obtained from a single blood donor at one time by apheresis (apheresis platelets). These two platelet sources are equally effective in transfusion support of thrombocytopenic patients. By reducing the number of donor exposures per transfusion, apheresis platelets may diminish the likelihood of alloimmunization to

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plasma proteins and leukocyte antigens, and may carry a lower risk of disease transmission, but in some areas apheresis platelets are more expensive and may not be as readily available as PC. Platelets are stored at room temperature, with gentle agitation for up to 5 days. Partially as a result of room temperature storage, platelets have been associated with a relatively high rate of bacterial growth, ie bacteria can be grown from as many as 1 in 2000 units of platelets. In an effort to decrease transfusion-associated sepsis, accrediting agencies (AABB, CAP) now require blood centers and transfusion services to test platelets for bacterial contamination prior to transfusion. This has reduced the rate of platelet-associated sepsis to less than 1 in 75,000 transfusions. It is optimal to administer ABO/Rh-type specific platelets, but given the short shelf-life of platelets, this is not always possible or consistent with optimal inventory management. Donor-recipient ABO incompatibility may reduce the response to platelet transfusion and administration of ABO-incompatible plasma may rarely cause hemolysis of recipient rbc. Apheresis platelets and PC contain a small amount of rbc (generally less than 0.1 ml for the former) consequently, if it is necessary to transfuse platelets from Rh-positive donors to Rh-negative patients (especially children and females with childbearing potential) Rh-immunization to Rh can be prevented by administration of Rh-immune globulin (RhIg), preferably using an IV preparation to avoid intramuscular injection in a thrombocytopenic patient. However, as noted above, the frequency of alloimmunization to Rh is extremely low in cancer patients and reports suggest that RhIg prophylaxis is unnecessary in Rh-negative cancer patients who receive Rh-positive platelets. Leukocyte-reduced platelets: Apheresis platelets may be rendered leukocyte-reduced ( 10 CD34+ cells/microL in pre-apheresis peripheral blood. HPC are collected by a variety of hemapheresis instruments that separate a mononuclear cell rich fraction of WBC from whole blood by centrifugation, taking advantage of the different sedimentation properties of red cells, platelets and leukocytes. Modern instruments employ a two-needle technique in which blood is continuously drawn from the donor, anti-coagulated with citrate, processed in a sterile disposable fluid path; the remainder returned to the donor. Excellent venous access is required, and may necessitate surgical placement of a large bore IV line. Donors may experience citrate-induced hypocalcemia, treated or prevented by infusion of calcium salts. Typically 2 donor blood volumes are processed during a 2–3 h procedure, however, “large-volume” apheresis (4 or more volumes) are increasingly collected, subject to donor tolerance. Product volumes range from 50 to 350 mL. After repeated aphereses, the development of anemia and thrombocytopenia may require transfusion. The CD34+ cell collection efficiency ranges from 30 to 40%, not changing appreciably during collection presumably due to ongoing recruitment of CD34+ cells from the marrow. Consequently, the preapheresis blood level of CD34+ cells may be a general guide to the volume blood required to be processed [46]. Most normal donors require one or two apheresis

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procedures to obtain an adequate collection. To increase the efficiency of stem cell collection, the CD34+ content of the HPC product may be directly measured on a mid-collection sample [109]. In patients with malignant disease, 10–25% do not mobilize sufficiently well to yield a transplant dose (2 × 106 CD34+ cells/kg) [24]. Mobilization capacity is a continuous function of age with no discrete threshold; there is weak correlation with sex and obesity. Factors associated with poor mobilization include receipt of >12 months of myelotoxic therapy, recent myelotoxic therapy, age > 70, and platelet count < 200,000 microL. The SDF-1 inhibitor has recently been associated with good mobilization [50]. Approximately 50% of poor mobilizers produce sufficient cells for transplant after a brief period of rest (10–14 days), along with the administration of a more dose-intensive or combined growth factor regimen [14, 24, 114]. Approximately 2/3 of MM or NHL patients who fail to mibilize well after a first attempt will do so after a second regimen using G-CSF and Plerixafor. Alternatively, BM may be harvested from such patients, with or without HGF administration, and used to successfully support BMT, although engraftment rates are slower [113]. Also, failure to administer 2 × 106 CD34/kg does not necessarily preclude a favorable BMT outcome in individual patients [174].

23.3.5 Future Directions Long acting G-CSF preparations may enable CD34+ collection after a single dose. Novel pharmacologic agents that interfere with stem cell adhesion via the CXCR4 receptor have recently been developed. The SDF-1 inhibitor, plerixifor, has been approved for use in stem cell mobilization in patients with non-Hodgkin lymphoma and multiple myeloma and is in routine clinical use [173].

23.4 Myeloablative and Non-myeloablative Allogeneic Stem Cell Transplantation (NST) Over the past 50 years, the role of BMT has changed from an experimental treatment with a high mortality rate to a curative treatment modality for

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thousands of patients with hematologic diseases. Presently, cure rates with matched sibling donors exceed 85% for some otherwise lethal diseases, such as chronic myelogenous leukemic (CML), aplastic anemic (AA), or βthalassemia. The recent development of non-myeloablative conditioning followed by stem cell transplantation allows this therapy for an older patient population who otherwise suffer unacceptable treatment-related toxicity. This section discusses different aspects of myeloablative and NST with an emphasis on clinical outcomes, complications, and future perspectives.

23.4.1 Clinical Experience with Ablative Allogeneic Transplant (allo-HSCT) is now an established curative treatment for numerous hematologic diseases, such as acute and chronic leukemias. This therapy eliminates malignant cells and generates graft-vs.-leukemia or graft-vs.-tumor (GVL/GVT) effects mediated by donor-derived T-lymphocytes. The IBMTR assessed 2,254 patients with early leukemia who underwent HSCT from an HLA-identical sibling, demonstrating the favorable impact of GVHD on relapse rates [89]. More direct evidence for the existence of potent GVL/GVT effects is seen in studies of donor leukocyte infusions (DLI) [43, 70, 104, 105, 142]. Of these patients, 70–90% enter CR after DLI without further CT [43, 70, 105]. Complete and less durable responses are less frequent in patients with transformed phase CML, AML, and ALL. Despite its curative potential, allo-HSCT has been feasible in only a proportion of patients with malignant hematologic and lymphoid disorders. The limitations are treatment related mortality and the availability of a donor. In the pediatric population, umbilical cord blood has enabled transplants for children without sibling donors. Cord blood stem cells require less stringent matching, and have as much as a 3/6 antigen mismatch, and still yield similar results in terms of engraftment and the incidence of GVHD. Elderly patients and heavily pretreated patients cannot tolerate a fully myeloablative regimen; so the use of standard allogeneic transplant is limited [23, 103, 151]. The development of NST allows older patients to benefit from this modality.

23 Current Status of Bone Marrow Transplantation

23.4.2 Allogeneic Transplantation Using Unrelated Donors Only about 25% of patients in need of HST have an HLA-matched related sibling donor. Therefore, this treatment is not an option for the majority of patients. Advances in molecular tissue typing techniques have made it possible to identify suitable unrelated donors. There are now more than 5 million HLAtyped potential volunteer donors in national registries. The clinical results of unrelated donor transplants are similar in younger patients to sibling related transplants [80].

23.4.3 Graft-Vs.-Host Disease (GVHD) As predicted by dog models of transplantation, even with HLA-matched donors, approximately 50% of patients developed GVHD despite use of post-grafting immunosuppression [32, 190]. The severity of GVHD in humans was not fully appreciated until longterm engraftment of donor marrow was achieved. Better control of GVHD was achieved by combining methotrexate with cyclosporine (CSA) or tacrolimus (FK506) [132, 176–178].

23.4.4 Non-Myeloablative Stem Cell Transplants (NST) The NST is a recently developed procedure that applies the principle of immunotherapy in a variety of malignant disorders. Studies in murine and canine models demonstrated that a state of stable-mixed chimerism can be successfully established using reduced intensity CT or radiation. Storb and colleagues established that the pre-transplant use of cyclosporine (CSA), mycophenylate mofetil (MMF) and reduced dosing of total body radiation [TBI] (2 Gy) allows stable mixed chimerism [179–181]. Studies in humans were primarily initiated for older patients who could not tolerate ablative allo-HSCT, and heavily pre-treated patients who would suffer excessive mortality and morbidity. Storb et al developed human clinical protocols based on their experience in the canine model [175, 200].

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Transplants following 2 Gy TBI, CSA and MMF were performed using PB mononuclear cells from matched sibling donors. Patients experienced no alopecia and minimal nausea and diarrhea. All 28 patients in the first cohort showed donor cell engraftment with mixed donor chimerism. Over the past 6 years, NST has been widely used in patients and the kinetics of engraftment and mechanisms of GVHD are now better understood. NST does not initially eliminate all host hematopoiesis and commonly leads to a state of mixed donor chimerism. Mixed chimerism defines persistence of donor cells with either benign host hematopoietic cells and /or cells of the underlying malignancy. The initial nonmyeloablative treatment is expected to produce only transient suppression of the underlying malignancy, but it allows time for the graft-vs.-tumor (GVT) effect to develop. Patients with mixed donor chimerism after NST may respond to additional immunotherapeutic approaches, such as withdrawal of immunosuppressive therapy, DLI, or a second NST. These immune manipulations can potentially eliminate residual disease and host-hematopoiesis, and produce full-donor chimerism.

23.4.5 Comparison of NST with Fully Myeloablative HSCT A. Infections: Several studies compared NST to historical control populations of patients who received full myeloablative transplant. Factors such as transfusion requirement, incidence of infections and GVHD were analyzed. The incidence of bacterial infections during the first 100 days in these two groups was compared [94]. The 30 and 100 day incidence of bacteremia were 9% and 27% in the NST group vs. 27% and 41% in the control group (p = 0.07) respectively. Invasive aspergillosis occurred in 15% of NST group vs. 9% in control group (not statistically significant). The CMV infection incidence rate was reported in 56 NST recipients and compared to controls. Each NST recipient was matched to 2 controls who received full myeloablative transplants at the same time, and matching criteria included CMV risk group, HSC source, donor type, age, and underlying disease. The 100-day incidence of CMV

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infection was 9% vs. 19% in the control group (p = 0.08). The onset of CMV disease was significantly delayed compared to the control group (130 days vs. 52 days, p = 0.02). These studies suggest that CMV surveillance should be carried out beyond day 100, and pre-emptive gancyclovir given when CMV is detected. B. Transfusion requirement: Another study reviewed transfusion requirements (platelets and red blood cells) in 40 NST patients compared to 67 patients who received myeloablative transplant during the same time period [199]. The incidence of transfusion requirement were 23% and 63% in the NST group vs. 96% in the conventional group respectively, (p 30 years, non-T cell phenotype, and time to achieve CR [87]. Burkitts type leukemia (identified as L3) is recognized as a poor prognostic indicator, yet the prognosis of this subgroup has improved with the advent of combination CT treatments including high-dose methotrexate (MTX) and fractionated higher doses of cyclophosphamide (CY) or ifosfamide [88].

23.5.1.2 HSCT in ALL Allo-HSCT can induce long-term remission and cure in ALL patients. Initial attempts to use this approach were undertaken in the late 1950s [191], and evolved rapidly over the last 40 years. The important role of allo-HSCT for the treatment of ALL patients has evolved from its early applications as a salvage regimen for end-stage patients to its current use in highrisk patients in first CR [145, 189]. Large clinical trials have reported DFS of 30–60%, long term survivors of more than 10 years and overall relapse rates of 15–20%, most in the first 5 years after transplant [97, 192]. It is now recognized that remission status is a major determinant of the transplant outcome since patients in remission at the time of transplant had improved survival, a lower incidence of recurrent

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leukemia, and lower death rates from non-leukemic causes [189]. The use of HSCT in cases of refractory or relapsed ALL still provides better outcomes than CT alone with DFS of 20–40%. Therefore, allo-HSCT should be considered as the best therapeutic option for these patients [111, 145]. If a matched related donor is not available, then efforts should be undertaken to look for an unrelated donor. Recent improvements in post-transplant patient support and high resolution typing provides a better outcome for patients transplanted with unrelated donor cells. Several recent studies have shown that the gap between matched related and unrelated donor HSCT is decreasing, with patients having similar outcomes including 5-year overall DFS of 30–45% [45]. Allo-HSCT produces better outcomes in ALL patients when compared with auto-HSCT or CT. Large randomized trials have been performed comparing Allo-HSCT, auto-HSCT and CT alone. The French Group on Therapy for Adult ALL analyzed the data from 572 ALL patients who achieved remission and were treated with either allo-HSCT, auto-HSCT or CT [8]. Patients were randomized to the allo-HSCT arm if a sibling donor was available. Remaining patients were randomized to receive treatment with auto-HSCT or CT. The 5-year overall DFS was significantly higher for the allogeneic transplant group compared to the other two groups (46% vs. 31%; p = 0.04). There was no significant difference between CT and autoHSCT. The greatest benefit was seen in those with high-risk features, in which the 10-year survival was 44% following allo-HSCT vs. 11% for CT or autoHSCT (p = 0.009). The international MRC–ECOG trial reported similar results; this study has registered over 1,400 patients, and was recently reported [74]. The investigators found that the overall EFS for the subset of patients with standard risk disease who underwent allo-HSCT was 53% vs. 45% for the patients who did not have an HLA-matched sibling donor.

23.5.1.3 Significance of Graft Vs. Leukemia Effect in ALL Clinical trials have shown a correlation between GVHD and relapse rates in ALL [51, 137]. Allo-HSCT promotes a potent and clinically relevant graft vs. leukemia (GVL) effect, reflected by the fact that ALL

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patients have higher relapse risks after auto-HSCT or syngeneic HSCT compared to allo-HSCT, lower incidence of relapse in those who develop GVHD, and increased relapse rates in recipients of T-cell-depleted marrow grafts. In one study [51], the probability of relapse was higher in patients without GVHD compared to patients with GVHD grade II or more (80% vs. 40%). Similar results were found in a larger study involving more that 1,000 patients. In this clinical trial, patients with either acute or chronic GVHD had a decreased relapse risk; this protective effect was observed in both T and B cell lineage ALL [137]. Despite this strong association between GVHD and low risk of relapse, it is still uncertain why ALL patients respond poorly to DLI compared to patients with CML or AML [85, 140, 158]. This limited beneficial effect of DLIs in ALL patients could be due to deficiencies in antigen presentation by the leukemia cells as well as defects in leukemia-reactive T cells, either to be generated or to promote active immune responses. Studies aimed at enhancing cellular responses against leukemia cells in ALL constitute a very active and promising area of research [5].

23.5.1.4 Different Sources of Hematopoietic Cells for Transplants in ALL Recently, mobilized PBSC have become the preferred source of hematopoietic cells in transplantation. Separate studies have previously reported that G-CSF mobilized PBSC leads to rapid engraftment without an apparent increase in GVHD [17, 107]. A large randomized trial confirmed that the use of growth factor mobilized PBSC led to improved survival, a similar incidence of acute GVHD and faster engraftment compared to BM [16]. Another study in patients with different hematological malignancies showed that PBSC transplants had better outcomes. This effect was most obvious in patients with high risk of relapse and complications [17]. There is less available data concerning the use of mobilized PBSC vs. BM in the unrelated donor setting. The use of cryopreserved unrelated cord blood has become a real alternative source of stem cells for patients lacking either a related or unrelated donor [108, 160]. Cord blood hematopoietic cells offer several advantages, particularly a reduced incidence of GVHD even in the setting of HLA mismatch. While

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clinical results are encouraging, long-term follow-up is required to analyze results concerning DFS and OS. Donors with one fully mismatched HLA haplotype (haploidentical donors) are another potential source of hematopoietic cells for transplants. This approach relies upon the use of manipulated grafts in which T cell depletion and a larger number of hematopoietic cells per kilogram are essential to ensure engraftment and control of severe GVHD [11, 86].

23.5.1.5 Conclusions Significant improvements in the treatment of adult ALL have been made during the last 40 years. Significant progress has been made is the development of HCT. Current data supports the use of this matched related donor HCT in CR1 in patients with standard risk features. Patients with high risk features based on age, elevated white blood cell upon presentation, cytogenetic abnormalities, and the subtype of leukemia cells may be offered matched unrelated donor stem cell transplantation. In addition, allo-HSCT should be considered early during the course of treatment for those patients who do not achieve a CR with conventional CT, and in those with refractory disease or in later remissions. Rapid identification of those patient and referral to specialized centers contributes to expedited typing and the search for potential donors.

23.5.2 Acute Myeloid Leukemia Despite recent advances and the use of induction and consolidation CT, the prognosis of adult patients with acute myeloid leukemia (AML) remains poor. Most studies using induction-consolidation therapy report long term DFS 1 year following diagnosis have poorer outcomes than those transplanted earlier – even if patients in more advanced phases are excluded [56]. Patients undergoing alloHSCT from a MUD have traditionally had somewhat inferior outcomes to those from matched-sibling donors. However, recent data, improved HLA-typing and better supportive care, suggest that outcomes for MUD transplants may approximate those for sibling transplants in some centers [124]. Eradication of CML through allo-HSCT appears to result from a potent

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GVL effect as suggested by the major increase in relapse rates following the use of T-cell depleted grafts, and the ability of DLI to effect long-term remissions when performed for cytogenetic and early hematologic relapses. Clinical trials of allo-HSCT have revealed areas of consensus. A randomized trial performed in Seattle demonstrated that the combination of busulfan and cyclophosphamide (BuCy) was better tolerated than Cy +TBI as a preparative regimen; long term OS also appears superior in the BuCy arm [41]. Individualized busulfan (targeted dosing) based upon first-dose pharmacokinetics appears to compensate for individual differences in absorption and metabolism of oral busulfan, and seems to improve outcomes, although no randomized comparisons have been performed [148]. Using IV busulfan may overcome the variability seen with non-targeted oral busulfan; it is not clear whether IV busulfan completely overcomes the need for pharmacokinetic monitoring. Splenectomy or splenic irradiation do not appear to benefit patients prior to allo-HSCT [75]. The role of BM vs. PB as a stem cell source remains controversial in CML. Randomized trials show more rapid engraftment following PB transplants and equivalent GVHD. However, chronic GVHD appears more prevalent in a number of trials. No statistically significant survival advantage has been demonstrated with PB in CML-CP patients. T-cell depletion leads to a severely increased risk of relapse following allo-HSCT for CML [73], and is no longer widely practiced. Patients with advanced phase CML have inferior outcomes to those transplanted in CP with long-term survival in approximately 45% and 15% of patients transplanted in AP and BP respectively using sibling donors. Evidence suggests that patients transplanted in AP defined by cytogenetic evolution only may have superior outcomes to those with AP defined by hematologic parameters [39]. Patients with BP-CML may benefit from attempts to re-instate chronic phase (2nd CP) prior to allo-HSCT [197]. Patients who have undergone allo-HSCT for CML should be monitored using BM karyotyping and/or PB fluorescent–in–situ-hybridization (FISH) since cytogenetic relapse is more successfully treated with DLI than frank hematologic relapse. Molecular monitoring using RT-PCR on PB and/or BM cells becomes predictive of relapse starting 6 months post-transplant [147]. These patients should be monitored by RT-PCR

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starting at this stage. Persistently positive PCR findings beyond 6 months should be treated with immunologic manipulation or imatinib mesylate (Gleevac). Serial monitoring of quantitative RT-PCR can detect rising malignant transcript levels to more readily identify impending cytogenetic or hematologic relapse. Non-transplant management of CML has been transformed by the advent of therapy with tyrosine kinase inhibitors such as imatinib (Gleevec). This orally bio-available tyrosine kinase inhibitor achieves complete hematologic remission in most patients with CP-CML, and in a significant proportion of patients with advanced phase disease. Furthermore, imatinib achieves complete cytogenetic remission in nearly 80% of CP patients within 18 months when used as first-line therapy [136]. There is now significant evidence that patients achieving cytogenetic remissions obtain a prolongation of the duration of chronic phase and survival. Long-term success of imatinib in suppressing, perhaps eradicating, CP-CML has not been demonstrated (in contrast to the clear demonstration of long term cure potential following allo-HSCT). Its potency in inducing complete cytogenetic remissions with its low toxicity and risk of early death make it an attractive initial alternative to allo-HSCT in many patients with CP-CML. In fact, current practice is to treat all new patients with CML with one of the current tyrosine kinase inhibitors such as imatinib. The majority of patients with CML are not likely to need a stem cell transplant. However, there are potential risks to the strategy of initial imatinib therapy in candidates for allo-HSCT. These include the delay in allo-HSCT in light of the known detrimental effects of delay beyond 1 year from diagnosis to transplant, advanced patient age resulting in a possibly higher-risk transplant later in the course of the disease, and the unknown effects of imatinib on transplant efficacy with known effects. However, the use of imatinib as first-line therapy with allo-HSCT only in patients with an unsatisfactory cytogenetic response to the drug is currently the preferred approach. Patients with AP and BP CML have much poorer outcomes with imatinib than patients treated in CP [162, 187]. Eventual development of molecular resistance to single-agent imatinib and disease recurrence is more likely in this setting. Gleevac is best considered a temporary measure to control/debulk the patient’s disease while a donor is identified for allo-HSCT.


23.5.8 Multiple Myeloma Multiple Myeloma (MM) is generally a chemosensitive disease. However, although conventionaldose chemotherapy (CDT) such as the combination of low-dose melphalan and prednisone produced objective responses in > 50% of patients with previously untreated MM, complete responses were rarely achieved and prolongation of survival was relatively small. Two studies assessed very high doses of chemotherapy (HDT) (e.g. melphalan >100 mg/m2 ) in order to improve the response rates and survival seen with CDT [122, 168]. Studies using melphalan 140 mg/m2 without auto-PBSC demonstrated high overall response (OR) rates and CR rates of 25–30% in newly diagnosed patients. However, morbidity and mortality from severe myelosuppression was high. Attempts to ameliorate the myelosuppression caused by HDT with hematopoietic growth factors achieved limited success, most effectively in patients with adequate BM reserve [13, 131]. HDT was better tolerated when accompanied by auto-BM or PB stem cell support (ASCT). When used in primary refractory patients, response rates of 65–88% were reported with an OS up to 42 months [2, 149]. When used in patients who respond to initial CT, non-randomized studies have shown that HDT with autologous PBSC support is safe ( 50,000 IU/L, LDH 10 × upper limit of normal. Patients in this category have an approximately 50% probability of cure with standard therapy. Several phase II studies of HDT-ASCT (including studies in patients with brain metastases and primary mediastinal GCT) suggest a superior outcome to that expected with CT [26, 49, 106]. A matched pair analysis in 292 patients with poor prognosis GCT compared 3 cycles of sequential highdose etoposide, ifosfamide and cisplatin with CDT. Statistically significant absolute improvements (16%


and 11% in DFS and OS respectively) were reported in the HDT treated patients [25]. To date, the only reported phase III randomized trial has been presented solely in abstract form. Patients were randomized to an unusual 4 drug standard dose regimen of cisplatin, etoposide, vinblastine and bleomycin administered for 4 cycles vs. 3 cycles of the same regimen, followed by a single cycle of high-dose cisplatin, etoposide and cyclophosphamide with ASCT. No significant advantage was found for the HDT arm. However, only 114 patients were randomized; approximately 30% of patients randomized to HDT did not receive it [35]. Thus, this trial cannot be considered a definitive answer to the question of early HDT for poor prognosis disease. Three newer randomized phase III trials are being conducted by the US Intergroup, EORTC and NCI Milan. All these trials utilize multiple cycles of HDT. In summary, whereas phase II studies and matchedpair analyses suggest superiority of HDT-ASCT over CDT in both salvage therapy of relapsed GCT and early treatment of poor prognosis GCT by IGCCCG criteria, confirmation of this benefit through well-designed phase III randomized trials is awaited.

23.5.12 Renal Cell Cancer Metastatic renal cell cancer (RCC) that has failed therapy with cytokines has a very poor prognosis, with a median life expectancy of less than 12 months. The ability of cytokine therapy to induce responses in RCC that are sometimes durable implies a susceptibility to immunological activity against the cancer cells in some situations. Childs et al. first demonstrated that adoptive immunotherapy as facilitated by a NST was capable of producing objective disease regressions in some patients with cytokine therapy-refractory RCC [37]. In the initial 19 patients treated, 10 objective regressions occurred including 3 CRs and 7 PRs. The responses occurred relatively late after the allo-HSCT (median 4 months), often after initial tumor progression following the transplant. The responses typically occurred after withdrawal of immunosuppression or DLI. There was a strong correlation between tumor response and the occurrence of GVHD. These data suggest that the responses occurred as a result of adoptive

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immunotherapy rather than the preparative cytotoxic CT used for the allo-HSCT. Since the original publication by Childs, other groups have demonstrated similar responses following NST in metastatic RCC [27, 152]. The delayed and relatively slow nature of the observed responses seen in the reported series, suggest that patients with relatively non-bulky and slowly progressive disease are the most suited to this therapeutic approach. Patients with widespread malignancy that is rapidly growing are unlikely to survive sufficiently long for a clinically significant graft- vs.-tumor effect to develop.

23.5.13 Breast Cancer The role of HDT-ASCT in breast cancer remains undefined, despite the completion of several randomized trials of HDT-ASCT vs. CDT in both metastatic breast cancer (MBC) and HRPBC. A detailed analysis of the randomized trials is beyond the scope of this chapter; the reader is referred to reviews for further information [135, 188]. At least seven randomized trials have been performed for MBC. Most of the reported studies, with the notable exception of the Philadelphia trial [171], demonstrated a statistically significant improvement in disease-free or progression-free survival in the HDT arm. No studies have demonstrated a significantly superior OS in the HDT arm. Potential reasons for the discrepancy between observed results in DFS and OS are discussed in detail in the published reviews. They include cross-over designs, pursuit of HDT offprotocol by relapsed patients in the SDT arm, higher than expected TRM in the HDT arm in some studies, and small size and inadequate length of follow-up in some of the trials. At least 13 randomized trials of adjuvant HDT vs. SDT in HRPBC have been performed worldwide. Of two trials, the Netherlands NWAST trial (the largest trial with 885 accrued patients) [154], and the PEGASE 01 trial [153] demonstrated a superior DFS in the HDT arm. OS was also superior in the Netherlands trial in the first 284 patients analyzed; yet no statistically significant benefit in OS survival was seen in the remaining trials reported. However, the failure to observe an OS benefit may be related to problems with study design. The reported data suggest that although DFS may be improved in patients undergoing HDT for MBC and

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perhaps also for HRPBC, OS is not clearly improved. It is possible that, with continued follow-up and results of trials that have recently completed accrual, a benefit to HDT will emerge in some categories of breast cancer. HDT-ASCT may be an important platform on which to evaluate novel therapies for breast cancer such as mAb and vaccine strategies. That said, at the time of this review, autologous transplants for breast cancer have been essentially abandoned for now.

23.6 Summary and Conclusion This is an exciting time in the basic science and clinical application of HSCT. Advances in the understanding of the conditions necessary for engraftment of allogeneic stem cells has allowed the application of this curative therapy to older patients. Since most hematologic malignancies occur more commonly with advancing age, many more patients are now able to benefit from the hope for cure or prolonged survival that a stem cell transplant provides. Alternative donor sources also are allowing more patients to receive stem cell transplants. As the toxicity of stem cell transplants is reduced through better supportive care, prophylaxis and treatment of GVHD, and donor selection, one can envision the use of HSCT continuing to grow robustly in the upcoming years.

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23 Current Status of Bone Marrow Transplantation 75. Gratwohl A, Hermans J, van Biezen A et al (1996) Splenic irradiation before bone marrow transplantation for chronic myeloid leukaemia. Chronic leukaemia working party of the European group for blood and marrow transplantation (EBMT). Br J Haematol 95:494–500 76. Grimwade D, Walker H, Oliver F et al (1998) The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The medical research council adult and children’s leukaemia working parties. Blood 92:2322–2333 77. Gutierrez-Delgado F, Bensinger W (2001) Safety of granulocyte colony-stimulating factor in normal donors. Curr Opin Hematol 8:155–160 78. Haioun C, Lepage E, Gisselbrecht C et al (2000) Survival benefit of high-dose therapy in poor-risk aggressive nonHodgkin’s lymphoma: final analysis of the prospective LNH87–2 protocol – a groupe d’Etude des lymphomes de l’Adulte study. J Clin Oncol 18:3025–3030 79. Hammert LC, Ball ED (1997) Purging marrow or peripheral blood stem cells for autografting. Curr Opin Hematol 4:423–428 80. Hansen JA, Gooley TA, Martin PJ et al (1998) Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med 338:962–968 81. Harris NL, Jaffe ES, Diebold J et al (1999) World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the clinical advisory committee meeting-Airlie house, Virginia, November 1997. J Clin Oncol 17:3835–3849 82. Harris NL, Jaffe ES, Stein H et al (1994) A revised European-American classification of lymphoid neoplasms: a proposal from the international lymphoma study group. Blood 84:1361–1392 83. Harstrick A, Schmoll HJ, Wilke H et al (1991) Cisplatin, etoposide, and ifosfamide salvage therapy for refractory or relapsing germ cell carcinoma. J Clin Oncol 9:1549–1555 84. Hasenclever D, Diehl V (1998) A prognostic score for advanced Hodgkin’s disease: international prognostic factors project on advanced Hodgkin’s disease. N Engl J Med 339:1506–1514 85. Helg C, Starobinski M, Jeannet M et al (1998) Donor lymphocyte infusion for the treatment of relapse after allogeneic hematopoietic stem cell transplantation. Leuk Lymphoma 29:301–313 86. Henslee-Downey PJ, Parrish RS, MacDonald JS et al (1996) Combined in vitro and in vivo T lymphocyte depletion for the control of graft-versus-host disease following haploidentical marrow transplant. Transplantation 61:738–745 87. Hoelzer D (1992) Prognostic factors in acute lymphoblastic leukemia. Leukemia 6(Suppl 4):49–51 88. Hoelzer D, Ludwig WD, Thiel E et al (1996) Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood 87:495–508 89. Horowitz MM, Gale RP, Sondel PM et al (1990) Graftversus-leukemia reactions after bone marrow transplantation. Blood 75:555–562 90. International Germ Cell Cancer Collaborative Group (1997) International germ cell consensus classification: a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 15:594–603

431 91. Johnson TA, Rassenti LZ, Kipps TJ (1997) Ig VH1 genes expressed in B cell chronic lymphocytic leukemia exhibit distinctive molecular features. J Immunol 158:235–246 92. Jones RJ, Ambinder RF, Piantadosi S et al (1991) Evidence of a graft-versus-lymphoma effect associated with allogeneic bone marrow transplantation. Blood 77:649–653 93. Jung AS, Holman PR, Castro JE et al (2009) Autologous hematopoietic stem cell transplantation as an intensive consolidation therapy for adult patients in remission from acute myelogenous leukemia. Biol Blood Marrow Transplant 15:1306–1313 94. Junghanss C, Boeckh M, Carter RA et al (2002) Incidence and outcome of cytomegalovirus infections following nonmyeloablative compared with myeloablative allogeneic stem cell transplantation, a matched control study. Blood 99:1978–1985 95. Keating MJ, Chiorazzi N, Messmer B et al (2003) Biology and treatment of chronic lymphocytic leukemia. Hematology Am Soc Hematol Educ Program 153–175 96. Keating MJ, Smith TL, Kantarjian H et al (1988) Cytogenetic pattern in acute myelogenous leukemia: a major reproducible determinant of outcome. Leukemia 2:403–412 97. Kebriaei P, Larson RA (2003) Progress and challenges in the therapy of adult acute lymphoblastic leukemia. Curr Opin Hematol 10:284–289 98. Khouri IF, Champlin RE (2004) Nonmyeloablative stem cell transplantation for lymphoma. Semin Oncol 31:22–26 99. Khouri IF, Keating MJ, Saliba RM et al (2002) Long-term follow-up of patients with CLL treated with allogeneic hematopoietic transplantation. Cytotherapy 4:217–221 100. Khouri IF, Keating MJ, Vriesendorp HM et al (1994) Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia: preliminary results. J Clin Oncol 12:748–758 101. Khouri IF, McLaughlin P, Saliba RM et al (2008) Eightyear experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab. Blood 111:5530–5536 102. Khouri IF, Saliba RM, Giralt SA et al (2001) Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatmentrelated mortality. Blood 98:3595–3599 103. Klingemann HG, Storb R, Fefer A et al (1986) Bone marrow transplantation in patients aged 45 years and older. Blood 67:770–776 104. Kolb HJ, Mittermuller J, Clemm C et al (1990) Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 76:2462–2465 105. Kolb HJ, Schattenberg A, Goldman JM et al (1995) Graftversus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 86:2041–2050 106. Kollmannsberger C, Nichols C, Meisner C et al (2000) Identification of prognostic subgroups among patients with metastatic ‘IGCCCG poor-prognosis’ germ-cell cancer: an explorative analysis using cart modeling. Ann Oncol 11:1115–1120

432 107. Korbling M, Przepiorka D, Huh YO et al (1995) Allogeneic blood stem cell transplantation for refractory leukemia and lymphoma: potential advantage of blood over marrow allografts. Blood 85:1659–1665 108. Kurtzberg J, Martin P, Chao N et al (2000) Unrelated placental blood in marrow transplantation. Stem Cells 18:153–154 109. Lane TA, Bashey A, Carrier E et al (2004) Improving the efficiency of PBPC collection by pre-apheresis peripheral blood and mid-apheresis product measurements of CD34 cells. Cytotherapy 6:318–327 110. Lane TA, Law P, Maruyama M et al (1995) Harvesting and enrichment of hematopoietic progenitor cells mobilized into the peripheral blood of normal donors by granulocyte-macrophage colony-stimulating factor (GMCSF) or G-CSF: potential role in allogeneic marrow transplantation. Blood 85:275–282 111. Laport GF, Larson RA (1997) Treatment of adult acute lymphoblastic leukemia. Semin Oncol 24:70–82 112. Laughlin MJ, Barker J, Bambach B et al (2001) Hematopoietic engraftment and survival in adult recipients of umbilical-cord blood from unrelated donors. N Engl J Med 344:1815–1822 113. Lemoli RM, de Vivo A, Damiani D et al (2003) Autologous transplantation of granulocyte colonystimulating factor-primed bone marrow is effective in supporting myeloablative chemotherapy in patients with hematologic malignancies and poor peripheral blood stem cell mobilization. Blood 102:1595–1600 114. Lie AK, Hui CH, Rawling T et al (1998) Granulocyte colony-stimulating factor (G-CSF) dose-dependent efficacy in peripheral blood stem cell mobilization in patients who had failed initial mobilization with chemotherapy and G-CSF. Bone Marrow Transplant 22:853–857 115. Linch DC, Goldstone AH (1999) High-dose therapy for Hodgkin’s disease. Br J Haematol 107:685–690 116. Loehrer PJ Sr, Lauer R, Roth BJ et al (1988) Salvage therapy in recurrent germ cell cancer: ifosfamide and cisplatin plus either vinblastine or etoposide. Ann Int Med 109:540–546 117. Lokhorst HM, Wu K, Verdonck LF et al (2004) The occurrence of graft-versus-host disease is the major predictive factor for response to donor lymphocyte infusions in multiple myeloma. Blood 103:4362–4364 118. Makita K, Ohta K, Mugitani A et al (2004) Acute myelogenous leukemia in a donor after granulocyte colonystimulating factor-primed peripheral blood stem cell harvest. Bone Marrow Transplant 33:661–665 119. Maloney DG, Molina AJ, Sahebi F et al (2003) Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 102:3447–3454 120. Marafioti T, Hummel M, Foss HD et al (2000) Hodgkin and reed-sternberg cells represent an expansion of a single clone originating from a germinal center B-cell with functional immunoglobulin gene rearrangements but defective immunoglobulin transcription. Blood 95:1443–1450 121. Mayer RJ, Davis RB, Schiffer CA et al (1994) Intensive postremission chemotherapy in adults with acute myeloid leukemia: cancer and leukemia Group B. N Engl J Med 331:896–903

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23 Current Status of Bone Marrow Transplantation 135. Nieto Y (2003) The verdict is not in yet: analysis of the randomized trials of high-dose chemotherapy for breast cancer. Haematologica 88:201–211 136. O’Brien SG, Guilhot F, Larson RA et al (2003) Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 348:994–1004 137. Passweg JR, Tiberghien P, Cahn JY et al (1998) Graftversus-leukemia effects in T lineage and B lineage acute lymphoblastic leukemia. Bone Marrow Transplant 21:153–158 138. Pavletic ZS, Arrowsmith ER, Bierman PJ et al (2000) Outcome of allogeneic stem cell transplantation for B cell chronic lymphocytic leukemia. Bone Marrow Transplant 25:717–722 139. Pavletic ZS, Bierman PJ, Vose JM et al (1998) High incidence of relapse after autologous stem-cell transplantation for B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma. Ann Oncol 9:1023–1026 140. Peggs KS, Mackinnon S (2001) Cellular therapy: donor lymphocyte infusion. Curr Opin Hematol 8:349–354 141. Philip T, Guglielmi C, Hagenbeek A et al (1995) Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapysensitive non-Hodgkin’s lymphoma. N Engl J Med 333: 1540–1545 142. Porter DL, Roth MS, McGarigle C et al (1994) Induction of graft-versus-host disease as immunotherapy for relapsed chronic myeloid leukemia. N Engl J Med 330:100–106 143. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project (1993) A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 329:987–994 144. Provan D, Bartlett-Pandite L, Zwicky C et al (1996) Eradication of polymerase chain reaction-detectable chronic lymphocytic leukemia cells is associated with improved outcome after bone marrow transplantation. Blood 88:2228–2235 145. Pui CH, Relling MV, Downing JR (2004) Acute lymphoblastic leukemia. N Engl J Med 350:1535–1548 146. Rabinowe SN, Soiffer RJ, Gribben JG et al (1993) Autologous and allogeneic bone marrow transplantation for poor prognosis patients with B-cell chronic lymphocytic leukemia. Blood 82:1366–1376 147. Radich JP, Gehly G, Gooley T et al (1995) Polymerase chain reaction detection of the BCR-ABL fusion transcript after allogeneic marrow transplantation for chronic myeloid leukemia: results and implications in 346 patients. Blood 85:2632–2638 148. Radich JP, Gooley T, Bensinger W et al (2003) HLAmatched related hematopoietic cell transplantation for chronic-phase CML using a targeted busulfan and cyclophosphamide preparative regimen. Blood 102:31–35 149. Rajkumar SV, Fonseca R, Lacy MQ et al (1999) Autologous stem cell transplantation for relapsed and primary refractory myeloma. Bone Marrow Transplant 23: 1267–1272 150. Ratanatharathorn V, Uberti J, Karanes C et al (1994) Prospective comparative trial of autologous versus allogeneic bone marrow transplantation in patients with nonHodgkin’s lymphoma. Blood 84:1050–1055

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Chapter 24

Pain Management in Cancer Patients Hrachya Nersesyan, Jeffrey J. Mucksavage, Eljim Tesoro, and Konstantin V. Slavin

Cancer is one of the most debilitating and deadly diseases that, broadly speaking, shows no preference for demographic, sex, age, or culture. It is the second leading cause of mortality of all Americans as a single disease [1], and the sheer potential for mortality from cancer can be a horrifying experience for anyone bearing this diagnosis. Pain is probably one of the most common of all cancer symptoms and can be very frightening for patients and their families. According to statistics published by the American Cancer Society in 2002 [2], 50–70% of patients with cancer experience pain, which usually only intensifies as the disease progresses. It was estimated that less than half of cancer patients get adequate relief of their pain, and 25% actually die in pain [3]. This is particularly disappointing because the pain endured by 90% of these patients could have been well managed with relatively simple interventions [4]. This chapter will discuss different options for treating cancer pain focusing on the pharmacological agents and surgical modalities currently available for pain management. Pain associated with cancer is not only at times unbearable for patients, but also can be tormenting to their family members and caretakers [5, 6]. Patients and their families tend to be under great distress after the diagnosis of cancer, and although many of these patients carry a very poor prognosis, prompt and effective pain control can prevent needless suffering and may significantly improve the quality of their lives. Not only may proper management alleviate the pain,

H. Nersesyan () Illinois Neurological Institute, OSF Saint Francis Medical Center, 530 N.E. Glen Oak Avenue, Peoria, IL 61637, USA e-mail: [email protected]

it also could potentially spare families the feeling of helplessness and despair. “Of the increasing grades of pain – from mild through to moderate, severe, very severe, incapacitating to overwhelming – Jane had reached the last stage: the point where consciousness is pain” – this is how one family describes suffering of her daughter diagnosed with skin cancer in Britain in late 70s [7]. Because of the negative consequences on both patients and their families, and wide variety of pain management techniques available nowadays, patients with cancer should be comforted with maximally achievable pain control and not live in fear of inadequately treated pain. Suboptimal pain control can be very debilitating and may impede the healing process. Severe pain can interfere with physical rehabilitation, mobility, and proper nutrition and a significant number of cancer patients are subsequently diagnosed with depression. Therefore, the goals of pain control in any patient with cancer should be to optimize the patient’s comfort and function while avoiding unnecessary adverse effects from medications [8]. Although cancer can be a terminal disease, there should be no reason to deny a patient the opportunity to live productively and free of pain. However, there are many challenges encountered in the treatment of cancer pain. Generally, pain is a subjective feeling that has not to date been easily and universally quantified [9]. Patients with similar cancer types may experience different intensities of pain and may respond to the same analgesic in different ways. Patients may also exhibit varying sensitivities to the adverse effects from many of the drugs used. Because pain is multifaceted, a single analgesic may not be sufficient enough to alleviate all the aspects of pain that the patient is experiencing, thus complicating the pharmacological regimen. Depending on the


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type and extent of the cancer, the administration routes may be limited for some patients and more innovative methods of drug delivery may need to be utilized. For example, as cancer progresses, oral administration may not deliver the appropriate level of analgesia desired due to waning level of consciousness or failure of gastro-intestinal absorption. In addition, persistent nausea and vomiting some patients may experience during the course of chemotherapy will also interfere with oral administration of analgesics. Society has also placed limitations on pain control because of unfounded concerns of addiction or opioid abuse. Patients and their families must realize that in order to attain optimal pain control they must be educated about the pain process, the medications used, and the side effects they can realistically expect. They also need to know that there are many options available to the pain specialist, both pharmacological and surgical, and that pain management can be seen as a multidisciplinary activity, requiring the expertise of physicians, nurses, pharmacists, dietitians, etc. Another challenge to the treatment of cancer pain is the paucity of good clinical trials providing objective data that can be extrapolated to individual patients. Some of the limitations with the clinical trials found in the literature today include the heterogeneity of cancer pain types, the limited number of patients enrolled, the spectrum of available analgesics and doses used for optimal pain control, the lack of a single objective pain scale, and the variable duration of treatment provided in different textbooks or guidelines. Current approach to pain control should be individualized for every patient and will require knowledge of the cancer type, the drugs available on the market, the patients’ metabolism, drug tolerances, and even their genetic morphology. Periodical re-evaluation of patient’s medication regimen is essential to finely tune their analgesia and to minimize the exposure to potentially dangerous adverse effects.

24.1 Cancer Pain Types To adequately manage the pain, a basic understanding of its type and pathophysiology are warranted and addressed in details elsewhere. Determining the source of a patient’s pain is a useful first step in attempting to alleviate it. Also, understanding the stimulus for the

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pain can guide clinicians in designing the most appropriate pharmacological, surgical, chemotherapeutic, or non-traditional intervention. Physiologically, there are two distinguished types of pain – nociceptive pain and neuropathic pain. Nociceptive pain stimulus is transmitted by peripheral nerves from specialized pain receptors, called nociceptors, whose function is to report any injury, which in cancer patients is usually secondary to invasion of tumor into bone, joints, or connective tissue. Other types of nociceptive pain are those associated with different procedures (i.e., lumbar puncture, biopsy). Nociceptive pain tends to respond well to opioids and non-opioid analgesics. Neuropathic pain, on the other hand, results from mechanical or metabolic injury to the nervous system itself, either centrally or peripherally, and is generally associated with mishandling of incoming somatosensory stimuli. In patients with advanced cancer this can be a result of tumor infiltration of nerves or nerve roots. Neuropathic pain may respond to traditional analgesics, but more commonly is better alleviated by antiepileptic drugs or tricyclic antidepressant agents, which modulate action potential propagation and the availability of chemical neurotransmitters such as norepinephrine and serotonin. It is important to keep in mind that patients will generally experience a combination of pain types, and the treatment of the disease, i.e. surgery, radiation, chemotherapy, may be a source of the painful stimuli along with progression of the disease itself. The assessment of cancer pain is confounded by its subjective nature placing the onus of judgment on the clinician. This should be avoided and all reports of pain should be appropriately responded to and addressed in a timely manner. It is recommended that pain should be evaluated at every clinical visit and incorporated as the “fifth vital sign” [10]. Ideally, the assessment should target the severity, duration, quality and location of the pain [11]. In addition, it is important for the clinician to inquire about how the pain has affected patient’s daily activities and relationship with others. To help introduce objectivity in the evaluation, a number of pain scales have been utilized to quantify pain intensity. Currently, it is recommended that pain should be measured using a numerical rating scales [10]. These scales generally range from 0 to 10 with 0 indicating no pain and a 10 indicating the worst imaginable pain. Children, the elderly, and patients with language differences, may have difficulty interpreting

24 Pain Management in Cancer Patients

the above scales. In these cases, scales with illustrations depicting levels of pain as facial expressions such as the Wong-Baker scale, should be considered [12]. This enables clinicians to make a continuous objective assessment of pain intensity throughout the course of the treatment. To assess for the quality of the painful stimulus, it is best to allow the patients to describe the pain themselves, which very often helps healthcare practitioners get a better understanding of the source and the type of pain. Clinicians should attempt to obtain more information about the pain by conducting pain histories to determine a cause and the best treatment modality [10]. It has also been suggested that clinicians pay more attention to psychological factors because fear and anxiety may have significant effects on the perception and experience of pain [11].

24.2 Pharmacological Management of Cancer Pain More than 20 years ago, the World Health Organization (WHO) recognized chronic cancer pain as a major public health problem, with the following development of the so-called three-level “analgesic ladder,” a therapeutic strategy designed to facilitate and standardize cancer pain management and advise physicians worldwide how to better provide pain management to their patients [13] (Fig. 24.1). In this guideline, the WHO recommends starting with non-opioid analgesics and then progresses to the addition of opioids in combination and then ends with pure opioid management. Although experience suggests that cancer pain can be relieved in more than 70% of patients using a simple opioid-based regimen [14], a number of specific characteristics may lead to a relatively lesser degree of opioid responsiveness in some patients. Some non-analgesic medications are found to be very helpful in amplifying the effect of many analgesic drugs, particularly in patients with neuropathic pain. The term “adjuvant analgesic” describes any drug with a primary indication other than pain, but with analgesic properties in some painful conditions. They can be added to the regimen at any time depending on the quality of the pain [15]. The non-opioid analgesics include acetaminophen, aspirin, non-steroidal anti-inflammatory drugs

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(NSAIDs), such as ibuprofen or ketorolac, and the most recent addition, the COX-2 inhibitors celecoxib and valdecoxib. Most non-opioid analgesics used for cancer pain treatment are summarized in Table 24.1. Acetaminophen is recommended as a first step analgesic for mild to moderate pain. Although its mechanism of action is not fully understood, it is thought to inhibit central prostaglandin synthesis in the central nervous system, which explains its analgesic and antipyretic activity without any effects on inflammation. Acetaminophen is not generally used alone for cancer pain, but rather in combination with opioids (i.e., hydrocodone, codeine, etc.) Although acetaminophen is effective and well tolerated by most of the patients, its use is limited by a maximum daily dose of 4000 mg (2000 mg/day in patients with hepatic dysfunction) due to potential hepatic toxicity. On the other hand, the gastro-intestinal toxicities seen with chronic NSAIDs use are not seen with acetaminophen. Acetaminophen is excreted by kidneys and dosing must be adjusted in patients with significant renal insufficiency. Aspirin is another drug from this group that can be used for mild to moderate pain control. Unlike acetaminophen, aspirin serves not only as an analgesic and antipyretic but also as an anti-inflammatory agent, which may be an important addition to the therapeutic effect in patients who have severe inflammatory pain. It is a safe over-the-counter drug widely used for non-cancerous acute pain control and for management and prophylaxis of myocardial infarction due to its well-established anti-platelet action. However, it has to be used very cautiously in cancer patients, as in high doses required for adequate pain control (650–1000 mg orally every 4–6 h) aspirin can cause a number of unwanted side effects, such as tinnitus, vertigo, hyperventilation, as well as increased risk of peptic ulcer disease and gastro-intestinal (GI) bleedings. If overdosed, aspirin can cause cardiovascular instability, exacerbate underlying renal insufficiency, and even lead to coma with renal failure, metabolic acidosis and respiratory arrest. NSAIDs are potent analgesics, antipyretics and antiinflammatory agents, which makes them useful for cancer related pain of musculoskeletal origin. They work through non-specific inhibition of cyclooxygenase (COX), an enzyme that mediates prostaglandin synthesis from arachidonic acid. Because of this non-specific activity, all nonselective NSAIDs have

440 Fig. 24.1 The World Health Organization (WHO) cancer pain treatment step ladder

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FREEDOM FROM PAIN

3

Opioids for moderate to severe pain ± Non-opioid ± Adjuvant

2

Opioids for mild to moderate pain ± Non-opioid ± Adjuvant

1

Non-opioids ± Adjuvant

Titrate until adequate pain control is achieved

Proceed to next step if pain persists or increases


PAIN

significant adverse effects on gastric mucosa and renal parenchyma, and some inhibit platelet function. With chronic use, they can cause serious gastric ulcerations and bleeding, which is a result of the inhibition of COX-1 isoenzyme. Therefore, NSAIDs may not be an optimal choice in patients who are experiencing nausea and vomiting associated with receiving chemotherapy. In addition, care must be taken in patients that may already have renal insufficiency related to advanced age or disease progression because of the potential to exacerbate these conditions due to modulation of prostaglandin activity on renal blood flow [16]. The NSAIDs have maximum daily doses that limit their utility in moderate to severe cancer pain management. All of the NSAIDs are available orally, but only ketorolac is available in parenteral form for pain control. Indomethacin, like aspirin, is available in suppository forms for rectal administration. COX-2 inhibitors have less potential for GI and hematological side effects seen with the traditional NSAIDs, a factor that makes them more attractive for cancer pain management. These drugs specifically inhibit the COX-2 isoenzyme, which is considered the inducible isoenzyme during painful stimuli. This selectivity spares the inhibition of COX-1, which is thought to be constitutive in the gastrointestinal tract and required for normal gastrointestinal function. In addition, there are emerging studies that show an antitumoral effect with these agents due to inhibition of cytokine production seen in many solid tumors [17]. This class of drugs is an attractive option in those patients with cancer involving inflammation (i.e., bone metastases) and those who are at high risk for

gastrointestinal bleeding or platelet dysfunction. These agents may also allow smaller doses of opioids to be used thereby minimizing potential risk for narcotic side effects. Because of their relatively short half-lives, they are also capable of treating breakthrough pain. However, like NSAIDs, COX-2 inhibitors should be used with caution with those at risk for renal failure, and case reports have emerged documenting this severe adverse effect [18]. Moreover, the overall safety of COX-2 inhibitors has come into question R ) was linked to increased since rofecoxib (Vioxx risk of acute myocardial infarction (MI) and sudden cardiac death among high-dose chronic users of this drug. The cardiovascular safety of rofecoxib has been questioned since 2000 when Merck submitted a study called VIGOR (Vioxx gastrointestinal outcomes research) to the US Food and Drug Administration (FDA) [19]. The analysis of the VIGOR study showed that patients taking rofecoxib had a higher relative risk of developing adverse cardiovascular events than patients taking naproxen [20]. This led to warnings of this risk imposed by the FDA on the drug’s label in April 2002. In October 2004 rofecoxib has been voluntarily withdrawn from the market by manufacturer (Merck Pharmaceutical) after a 3-year study, which R could prevent the was aimed at showing that Vioxx recurrence of colonic and rectal polyps (APPROVe), discovered that participants had twice the risk of acute MI compared to those taking a placebo [21, 22]. Mechanistically speaking, there are reasons why selectively inhibiting COX-2 isoenzyme might increase cardiovascular risk [23]. Because COX-1 helps promote thrombosis and COX-2 helps inhibit it,

Capsules – 50, 100 mg

Capsules – 250 mg

Tablets – 7.5, 15 mg Suspension – 7.5 mg/5 mL Tablets – 500, 750 mg Tablets – 250, 375, 500 mg

Tablets – 600 mg

Capsules – 10, 20 mg

Tablets – 150, 200 mg Capsules – 400 mg Tablets – 200, 600 mg Capsules – 100, 200 mg Tablets – 12.5, 25, 50 mg Suspension – 12.5 mg/5 ml, 25 mg/5 ml Tablets – 10, 20 mg

Meclofenamate

Mefenamic acid

Meloxicam

Nabumetone Naproxen

Oxaprozin

Piroxicam

Sulindac Tolmetin

∗ Rofecoxib

600 mg–1200 mg PO once a day 10–20 mg PO once a day 150–200 mg PO BID 200–600 mg PO BID-TID 200 mg PO BID 50 mg PO daily for 5 days, then 25 mg PO daily 10–20 mg PO BID

10 mg PO q4–6 h PRN or 30 mg IV/IM q6h 50–100 mg PO q4–6 h PRN 250 mg PO q4–6 PRN 7.5–15 mg PO once a day 500 mg–1000 mg QD to BID 250–500 mg PO BID

25–50 mg PO q6h-q8h

400 mg PO q4–6 h PRN 25–50 mg PO TID

50 mg PO BID-TID 200–400 mg PO q6–8 h

400 mg/day 50 mg/day

400 mg/day 1800 mg/day

20 mg/day

2 g/day 1500 mg/day for 3–5 days 1800 mg/day

15 mg/day

40 mg/day PO OR 120 mg/day IV/IM 400 mg/day

300 mg/day

200 mg/day

3200 mg/day

1200 mg/day

150 mg/day

4000 mg/day

4000 mg/day

Maximum

COX-2 inhibitor

COX-2 inhibitor COX-2 inhibitor

for therapy less than 1 week in duration COX-2 preferential NSAID

IV therapy should not exceed 5 days

Use with caution in patients with history of peptic ulcer Use with caution in patients with history of peptic ulcer

Bleeding risk is the most significant concern.

No anti-inflammatory effect. Hepatotoxic if overdosed.

Comments

(Vioxx) and Valdecoxib (Bextra) were removed from the market at the time of writing this chapter due to increased cardiovascular and dermatological risks

Valdecoxib∗

Celecoxib Rofecoxib∗

Ketorolac

Ketoprofen

Indomethacin

Ibuprofen

Etodolac

Diclofenac

325–650 mg PO q4h PRN

325–650 mg PO q4h PRN

Tablets – 325, 500, 650 mg Suspension – 160 mg/5 ml Suppository – 80, 120, 125, 200, 300, 325, 600, 650 mg Tablets – 81, 162, 325, 500, 650, 975 mg Suppository – 60, 120, 325, 650 mg Tablets – 50 mg Delayed-release – 25, 50, 75, 100 mg Tablets – 400, 500 mg Extended-release – 400, 500, 600 mg Capsules – 200, 300 mg Tablets – 200, 400, 600, 800 mg Suspension – 40 mg/ml, 100 mg/5 ml Capsules – 25, 50 mg Extended-release – 75 mg Suspension – 25 mg/5 ml Suppository – 50 mg Tablets – 12.5 mg Capsules – 25, 50, 75 mg Extended-release – 100, 150, 200 mg Tablets – 10 mg Parenteral – 15 mg/ml, 30 mg/ml

Acetaminophen

Aspirin

Dose

Table 24.1 Most commonly used non-opioid analgesics in U.S. Drug Preparation

24 Pain Management in Cancer Patients 441

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blocking COX-2 but not COX-1 could theoretically increase the risk of myocardial infarction and other thrombotic events. On the other hand, inflammation has also been implicated in cardiovascular events, so controlling inflammation via COX-2 inhibition could conceivably be protective. Although two other COX-2 inhibitors from Pfizer (celecoxib and valdecoxib) available on the market today may be also implicated in increasing cardiovascular risk with chronic use, the Celecoxib Long Term Arthritis Safety Study (CLASS) trial conducted in 2000 did not show a significantly increased rate of myocardial infarction with celecoxib compared with the nonspecific NSAIDs ibuprofen or diclofenac [24]. Therefore, COX-2 inhibitors continue to serve as a good option for long term relief of musculoskeletal pain in patients with terminal cancer. No parenteral forms of COX-2 inhibitors are commercially available at present in the Unites States. Tramadol is a centrally acting non-opiate agonist at the mu receptors, and is effective in the treatment of moderate to severe pain. Unlike the NSAIDs, it has no anti-inflammatory activity. It can be beneficial in patients who fail non-opioid therapy and wish to delay opioid therapy and avoid the common side effects of constipation, somnolence, and fatigue. It has been studied mostly for post-operative pain control after tumor resections, but some studies in chronic cancer pain show marginal to moderate success [25]. It is only available in tablet form. As pain progresses, non-opioid regimens may not be sufficient to provide necessary analgesia or may be approaching maximum recommended daily doses. At this point, a trial of opioid and non-opioid analgesic combination should be instituted. A variety of fixed combinations are available that usually include codeine, hydrocodone, oxycodone, or propoxyphene. This phase requires frequent and constant evaluation of the patient to titrate each drug to a successful dose. The doses of these agents are generally limited by the nonopioid component. Once the limit is reached for these agents (e.g., >4 g/day of acetaminophen), the next step is to advance to pure opioid therapy. The opioids are typically the most common drug class used in the treatment of cancer pain. They work by binding to opioid receptors within the central nervous system. The receptor responsible for the most significant opioid actions is the mu receptor, which mediates analgesia, respiratory depression, sedation, physiological dependence, and tolerance

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[26]. Analgesic effect of opioids is largely dependent on mu receptor saturation and is thus influenced by the type and severity of the pain, prior exposure to opioids, and individual distribution of receptors [4]. There is no maximum dose for these agents; they are only limited by the development of side effects that are patient specific in their onset and severity. Common opioid side effects include nausea, constipation, sedation, and confusion, and they can be often managed without compromising pain control by adjusting the daily dose of the drug or in persistent cases by instituting additional medications, such as metoclopramide for nausea, laxatives for constipation, or methylphenidate for sedation. Wide variety of opioids are currently available in the market (Table 24.2), and are roughly categorized R , into controlled release (CR), such as MS Contin R R R R Avinza , Kadian , Oxycontin , Duragesic , and immediate release (IR) formulations, such as MSIR, R , etc. Oxycodone, Hydromorphone, Actiq It was suggested that for patients with mild to moderate cancer pain opioid analgesic therapy may start with the trial of codeine or hydrocodone [27]. Codeine is a weak opium alkaloid with a potency 1/10 of morphine. Hydrocodone is the more potent hydrogenated ketone derivative of codeine, which is typically available only as a combination product with acetaminophen (Vicodin, Norco) or aspirin. Although both these drugs are very well suited for the treatment of different mild to moderate pain syndromes, they have almost no role in the treatment of severe cancer pain. Morphine is considered the standard opiate and the drug of first choice in the treatment of moderate to severe cancer pain. It should be titrated to maximum tolerability before moving on to another opiate such as fentanyl, hydromorphone, or oxycodone. Morphine, first identified nearly 200 years ago, is available in a variety of formulations (i.e., parenteral, oral, rectal) and the oral form is available in a range of preparations, from immediate release to sustained release, allowing it to be precisely titrated to the patient’s response (Table 24.2). The oral formulation is recommended initially due to its ease of administration and convenience of use. A typical regimen consists of a sustained-release (SR) preparation given every 8–12 h with breakthrough doses in immediate-release (IR) form given every 3–4 h in between if needed. As a guide, the cumulative as-needed doses should not


443

Table 24.2 Most commonly used opioid analgesics in U.S. Drug name Morphine sulfatea MSIR (immediate release) R MS Contin R Oramorph SR R Kadian R Avinza Codeine

Hydromorphonea R Dilaudid (immediate release) R Palladone Oxycodone R Roxycodone (immediate release) R OxyContin Propoxyphene R Darvon Pulvule

Methadone Meperidine (Demerol)

Duration of action (h)

Formulation Tablets: 15 and 30 mg and Suppositories: 5, 10, 20, 30 mg Controlled-release tablets: 15, 30, 60, 100, 200 mg Sustained-release tablets: 15, 30, 60, 100 mg Sustained-release capsules: 20, 30, 50, 60, 100 mg Extended-release capsules: 30, 60, 90, 120 mg Tablets: 15, 30, 60 mg Oral solution: 15 mg/5 ml, 30 mg/5 ml

2–4

Tablets: 2, 4, 8 mg; Oral solution: 5 mg/5 mL; Parenteral solution: 1 mg/ml, 2 mg/ml, 4 mg/ml; and Suppositories: 3 mg Extended-release capsules: 12, 16, 24, 32 mg

2–4

Tablets: 5, 15, 30 mg; Capsules: 5 mg; and Oral solution: 5 mg/5 ml, 20 mg/ml Controlled-release tablets: 10, 20, 40, 80, 160 mg

2–4

Capsules: 65 mg

2–4

Oral solution: 5 mg/5 ml, 10 mg/5 ml, 10 mg/ml Tablets: 5, 10, 40 mg Oral solution: 50 mg/5 ml Tablets: 50, 100 mg

4–8

8–12 8–12 24 24 2–4

24

12

2–4

Fentanyl Actiq

Oral transmucosal lozenge: 200, 400, 600, 800, 2–4 1200, 600 mcg R Duragesic Transdermal patch: 25, 50, 75, 100 mcg/h 72 a Morphine and hydromorphone are the only drugs from this list which are currently approved for intrathecal administration

exceed the total dose given as a sustained preparation for that interval. Thus, a patient requiring morphine 120 mg SR every 12 h should receive morphine 30 mg IR every 3 h for breakthrough pain. Regimens will require frequent adjustments allowing 3–4 days for the patient to respond before initiating a change unless toxicity is apparent. One double-blind, multi-centered crossover study compared the efficacy, safety, and pharmacokinetics of a novel once-daily morphine formulation and a 12-h SR morphine formulation in the treatment of chronic cancer pain [28]. The investigators found that there was no significant difference betweens treatments for evaluations of overall pain intensity, analgesic efficacy, or adverse events. However, the

once-daily formulation showed less fluctuation in plasma morphine concentration to compare with SR form, and most patients chose once-daily morphine dosing for continuing pain management, as it was providing more stable pain control over the day. The most common adverse effects of morphine include sedation and some degree of cognitive impairment which patients may develop a tolerance to given time. Nausea and vomiting are frequently seen upon initiation of therapy and after large dose increases, but usually subside with time. Constipation is seen with chronic therapy; patients do not develop tolerance to it and typically require preemptive treatment with laxatives. The effects of active morphine metabolites can be induced or inhibited by a variety of medications.

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Anti-epileptic drugs carbamazepine, phenobarbital, and phenytoin, as well as antibiotic rifampin can accelerate clearance of morphine. Phenothiazines, tricyclic antidepressants, and cimetidine will interfere with morphine metabolism and may potentate its effect if administered simultaneously. Co-administration of morphine and benzodiazepines may produce strong synergic action resulting in sedation, hypotension, and sometimes delirium [29]. Should a patient fail morphine therapy, another opiate should be instituted and dosed according to its morphine equivalency. Initial dosing of the new opioid should be 25–50% less than the expected equivalent dose of morphine since the patient may not be crosstolerant to the new agent. Cross-tolerance can be seen when changing from a more potent to a less potent agent and is a result of variable effects of each opioid on the pain receptors. R ) is a water-soluble Hydromorphone (Dilaudid opioid that is several times more potent than morphine allowing for smaller doses to be used. It is available in parenteral, rectal, subcutaneous and oral formulations. However, hydromorphone can be also administered via epidural and intrathecal routes [27]. Hydromorphone should be considered particularly for patients on morphine who are having side effects of increased confusion or myoclonus [4]. When using injectable hydromorphone, clinicians must be aware of its potency. Although IV hydromorphone is six to seven times more potent than IV morphine [30], it could be 20 times more potent than oral morphine. Hydromorphone relieves continuous dull pain more effectively than sharp intermittent pain, and when mixed with epinephrine it provides superior pain relief [27]. Fentanyl is a quick acting lipophilic opiate available in parenteral, transmucosal, and transdermal formulations. Intravenous fentanyl is 70 to 100 times more potent than IV morphine [31] and has very rapid onset of action – 5 min to peak analgesia, versus at least 15 min for IV morphine [26]. Fentanyl is most widely used in palliative medicine in the form of a transderR ), which is especially useful mal patch (Duragesic in those patients who do not have enteral access for analgesia or for whom nausea and vomiting limit the ingestion of the required dose of opioid. It is not recommended for breakthrough pain though, since it may take 12–24 h for the onset of action to occur [32], and it is better suited for those patients whose analgesic

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requirements are already stable. Another drawback of transdermal fentanyl is that its elimination half-life is 18 h after patch removal, thus patients who experience side effects will need to be monitored and supported for a full day following discontinuation. A R – the better choice for breakthrough pain is Actiq oral transmucosal fentanyl citrate (OTFC) lozenge that patients can dissolve in the buccal space for immediate relief, usually within 5–10 min. One study compared its use with oral immediate-release morphine and found OTFC to be superior for fast pain control [33]. Other study demonstrated that OTFC may be an effective alternative to intravenous opioids in rapidly titrating analgesia in selected opioid-tolerant cancer patients who are in pain crisis [34]. Another centrally acting synthetic opioid, transdermal buprenorphine, is now being widely prescribed in Europe and Australia for cancer pain management [35, 36]. Transdermal buprenorphine is contained in a matrix patch as opposed to traditional reservoir patch technology used for transdermal fentanyl, which makes it more robust in handling. In a matrix system, the substance is an integral part of the polymer structure of the patch. Thus, while damaging a reservoir patch might result in “dose dumping” and potentially overdosing the patient, damaging a matrix patch will not interfere with the controlled release of the medication [37]. Morphine has also been compared to oral oxycodone, a synthetic opioid that is metabolized hepatically to the active oxymorphone [38]. This study compared controlled-release oxycodone and morphine tablets in 45 cancer patients, and although the authors found that both drugs have provided similar analgesic effects, there were differences in pain relief in those patients who had underlying renal or hepatic dysfunction with pain control in patients receiving oxycodone. This may be due to the accumulation of active metabolites or differences in the phenotype for CYP2D6 that metabolizes oxycodone. This study stresses the importance of pharmacogenomics in guiding and individualizing pain therapy in the future. In most markets, oxycodone is significantly more expensive than morphine and is thus less attractive as a first-line analgesic R ) based on special [4]. CR oxycodone (Oxycontin drug delivery system, known as AcroContin system, and uses a dual-control matrix with two hydrophobic polymers, which are not influenced by pH and R is therefore are independent of acidity. Oxycontin


effective in moderate to severe cancer pain and allows for convenience of every 12 h administration [27]. Methadone is an inexpensive synthetic opioid agonist that has a very long half-life, no active metabolites, and little tendency to induce tolerance in patients. It has unique properties that make it useful in treating pain which is poorly controlled by other opioids. In addition to binding to the opioid mu receptor, methadone produces analgesic effects through its antagonism at the N-methyl-D-aspartate (NMDA) receptor site and by increasing the availability of neurotransmitters serotonin and norepinephrine within the central nervous system [39]. NMDA antagonism also reduces morphine tolerance at the opioid receptor site. Methadone may be an effective alternative for cancer patients, although its equianalgesic dosing to morphine has not been firmly established and can vary widely depending on the cumulative dose of morphine [40–42]. It occurs more frequently in patients previously exposed to high doses of opioids than in patients receiving low dose [27]. Methadone is available for oral, sublingual, rectal, intravenous and subcutaneous administration. Ketamine also has effects in blocking the NMDA receptors and has found some success in treating neuropathic pain [43]. Although it has not been shown to be effective in acute pain, ketamine does have some opioid-sparing benefits, allowing smaller doses of morphine to be given [44]. Limiting its use are the side effects that include sedation and hallucinations at higher doses. There are many other opioids available on the market today. However, they are not usually recommended for routine use in cancer pain management. These include meperidine, propoxyphene, partial agonists (i.e., buprenorphine), and mixed agonist-antagonist agents (i.e., butorphanol, pentazocine, nalbuphine). Meperidine is metabolized to a neurotoxic metabolite normeperidine which can induce seizures if accumulated. The effect of propoxyphene can be considered more euphoric than analgesic. The mixed agents have a ceiling effect as well as the potential in reversing analgesic effects of any pre-existing opioid the patient is already taking and, therefore, they are not considered efficacious. Patients may have varying responses to an individual opioid based on various pharmacodynamic and pharmacokinetic interactions. For example, morphine is hepatically glucuronidated to two

445

metabolites: morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). M3G has no analgesic properties but may be involved in certain side effects such as myoclonus. M6G is a more potent analgesic than the parent compound and passes much more readily into the central nervous system. Morphine and its metabolites are excreted by the kidneys and toxicity can be seen in patients with underlying renal insufficiency or failure. In cirrhosis, the bioavailability of morphine is increased due to the lack of first pass metabolism; however, the production of the more potent M6G metabolite may decrease resulting in a less than optimal analgesic effect. In addition, it should be noted that older individuals, who make the vast majority of terminal cancer patients, may have an increased sensitivity to opioids, due to decreased hepatic metabolism and decreased renal excretion, as well as a reduced number of opioid receptors due to brain atrophy [45]. Therefore, it is vital to incorporate interpatient differences into the dosing scheme in order to arrive at a tolerable but effective regimen. Patients who experience little or no pain relief despite substantial analgesic doses of opiates or who develop intolerable adverse effects are said to exhibit opioid poorly-responsive pain. The terms opioidtolerant or opioid-resistant previously used to label these patients do not reflect the multidimensional aspect of the phenomenon, as unsatisfactory analgesic response may be due to a variety of factors: differences in patient metabolism, multiple pain mechanisms, disease progression, and sensitivity to side effects. In such cases, a variety of strategies can be implemented to improve the pain control and balance between analgesia and side effects [14]. Among these strategies is the use of adjuvant analgesics, although very few of these drugs have been actually studied in cancer populations. There are several major groups of adjuvant analgesics (i.e. antidepressants, antiepileptic drugs, muscle relaxants, corticosteroids, etc.) that are used nowadays to intensify the effect of opioids and NSAIDs on longterm pain control. In some cases, the type of pain suggests the value of one category of adjuvant analgesic over another; in others, the existence of another symptom concurrent with pain favors the use of a specific drug [15]. For example, pain that is neuropathic in nature is typically not amenable to standard opiate therapy, and the addition of tricyclic antidepressants (TCA) or/and antiepileptic drugs (AED) can offer a very effective treatment strategy in such patients [46].

446

TCA such as amitriptyline are attractive adjuvant agents in cancer patients due to their positive effects on mood and sleep. The analgesic properties of TCA have been extensively studied in a variety of chronic nonmalignant pain conditions [47, 48]. Although few clinical trials have specifically evaluated these drugs for cancer pain [49, 50], our experience supports their analgesic effects. Early use of antidepressants is also justified when pain is accompanied by depression, which is fairly common in patients with advanced cancer. However, the use of TCA, especially in medically ill or elderly patients may be limited due to frequent side effects similar to those seen with opiates, which include drowsiness, constipation, urinary retention, and dry mouth, as well as such serious adverse effects as orthostatic hypotension and cardiotoxicity [51]. TCA are contraindicated in patients with a known history of glaucoma and should be avoided in patients who are suicidal. It should be noted that the secondary amine TCA, desipramine and nortriptyline, are less anticholinergic and usually better tolerated than the tertiary amines [15]. In addition, the non-tricyclic compounds, such as selective serotonin reuptake inhibitors (SSRI), are generally safer, have much less side effects than TCA and, therefore, may be considered for patients who have relative contraindications to tricyclics or have experienced severe adverse effects during the treatment [52]. However, there are very limited data supporting the analgesic efficacy of few SSRI, i.e. paroxetine [53], citalopram [54] and venlafaxine [55], in non-malignant pain management, and no studies have been reported on cancer pain. There is good evidence that AED are particularly useful as adjuvant therapy in the long-term management of neuropathic pain [56–60]. These agents can be instituted at any stage of the WHO ladder (Fig. 24.1). Of the all AED, gabapentin (Neurontin) is probably the most widely prescribed medication for the treatment of cancer-related neuropathic pain [61, 62], although its specific mechanism of action has not been fully elucidated at this time. Nonetheless, due to its proven analgesic effects, good tolerability, and a rarity of drugdrug interactions, gabapentin is now recommended as a first-line agent for the treatment of neuropathic pain of diverse etiologies, especially in the medically ill population [63, 64]. It should be initiated at a daily dose of 100–300 mg and can be increased every 3 days. The usual maximum dose is 3,600 mg daily, but can be higher if needed, and an adequate trial should include 1–2 weeks at the maximum-tolerable

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dose [15]. Gabapentin is usually well tolerated, and the most common side effects are somnolence, dizziness, and unsteadiness, which are typically not severe if carefully titrated. There are several other AED, such as carbamazepine [56], phenytoin [65], lamotrigine [66, 67], pregabalin [68], and levetiracetam [69], that have been reported to be efficacious in alleviating different neuropathic pain syndromes, including cancer related pain [65]. In general, the last three drugs are well-tolerated and lack a significant drug-drug interaction, which makes them superior to carbamazepine or phenytoin for the long-term management of neuropathic pain. Corticosteroids belong to another major group of medications widely used as an adjuvant therapy for cancer-related pain syndromes, which include bone pain, neuropathic pain from infiltration or metastatic compression of neural structures, headache due to increased intracranial pressure, arthralgias, and pain due to obstruction of hollow viscus or distention of an organ capsule [15, 70–72]. They can also improve appetite, nausea, malaise, and overall quality of life [73, 74]. The use of adjuvant medications to treat opiate side effects can allow an increase in the analgesic dose. The second-generation (atypical) agent olanzapine (Zyprexa) was reported to decrease pain intensity and opioid consumption, and improve cognitive function and anxiety, in a recent case series of cancer patients [75]. Stimulants such as methylphenidate or caffeine can increase alertness in patients who are experiencing somnolence on a dose of morphine that provides sufficient pain control [76]. In addition, it has been shown that in cancer patients, methylphenidate not only can reduce opioid-induced somnolence, but can also significantly improve cognition, treat depression, and alleviate fatigue [77]. Liberal use of laxatives to treat constipation can also allow an opioid dose to be escalated. Patients who have pain associated with bone metastases may especially benefit from the use of bisphosphonate compounds, such as pamidronate or zolendronate [78, 79]. These agents decrease the effect of bone osteoclast resorption and are typically given intravenously every 4 weeks. Calcitonin has also shown beneficial effects in alleviating the pain associated with bone metastases [80, 81]. Other adjunctive strategies may include topical agents (local anesthetics, capsaicin) useful for mucositis or peripheral neuropathies [82]; clonidine, an alpha-2 adrenergic agonist usually given


intraspinally (to avoid systemic side effects) for the management of severe intractable cancer pain partly responding to opioids [83]; amantadine, a noncompetitive NMDA antagonist, which has been shown to reduce surgical neuropathic cancer pain [84]; or any other unusual adjuvant analgesics, that may be beneficial for the treatment of severe refractory pain not responsive to traditionally used drug combinations.

24.3 Surgical Management of Cancer Pain Surgery is rarely used for the treatment of cancer pain, particularly since longer-acting opioids, such as slow-release oxycodone or morphine, and transcutaneous fentanyl patches became available. In addition to that, prior to considering surgical intervention, one should try a variety of less-invasive techniques, such as nerve blocks, radiofrequency ablations or neurolytic destructions, as well as many other procedures available nowadays from the wide pain management arsenal. When it comes to the choice of pain-relieving surgical procedures, these are usually divided into two broad categories: neurodestruction and neuromodulation. Neurodestructive procedures involve interruption of pain pathways, which can be performed anywhere starting at the level of the nerve, nerve root, ganglion, spinal cord, thalamus or the brain stem depending on the nature and extent of the pain. One of the most commonly used procedures is spinal cordotomy that targets the spinothalamic tract on the cervical or upper thoracic level and results in eliminating pain sensation from the opposite side of the body [85]. Although safe and effective if done on one side only, it may be associated with a very high rate of complications if performed bilaterally. Midline myelotomy is reserved for patients with severe bilateral or visceral pain [86]; it interrupts a non-specific pain-transmitting pathway located in the vicinity of the central canal of the spinal cord. Thalamotomy is usually aimed at either nuclei involved in somatosensory perception or more anteriorly located centers that relay affective aspects of pain [87]. Cingulotomy targets the part of the limbic system that appears to modulate painful sensations and certain psychological aspects of pain experience; it is usually reserved for patients with intractable cancer pain after

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failure of antineoplastic and palliative pharmacological treatments and when more conservative analgesic procedures are not applicable [88]. Among positive sides of neurodestructive procedures are: the relative ease of performance, lower cost due to absence of expensive implantable equipment, lack of hardware related complications, and most of all, immediate pain relief, making these procedures quite attractive to many suffering patients. However, the problems associated with destruction of the nervous tissue include: the irreversibility of action, particularly of the side effects (numbness and weakness that come directly as a result or as a complication of destructive operation may take very long time to recover), inability to test or reliably predict the effect of procedure due to individual anatomical and physiological variability, relatively short duration of the effect (most neurodestructive procedures result in 3 months to 1 year pain relief, mainly due to the plasticity of the central nervous system), and higher risk of complications with bilateral procedures. Also, neurodestructive procedures cannot be performed in patients with coagulopathies, which are developed due to their disease itself or as an unwanted side effect of the treatment. Despite all these, carefully selected and performed neurodestructive procedures may be ideal for certain cancer patient populations [89]. For example, a patient with gynecological malignancy who suffers from unilateral pelvic and leg pain due to radiation effect or direct tumor invasion of the lumbar plexus and has life expectancy of 2–3 months, may be an excellent candidate for a cervical cordotomy, which has a unique chance of rendering patient painless and free of narcotic medication side effects for the rest of her life. As to the neuromodulation, electrical stimulation of neural structures (peripheral nerve, spinal cord or brain stimulation) is rarely used for treatment of cancer pain [90]. It may help significantly for those with primary neuropathic nature of pain, such as patients with arachnoiditis, but is unlikely to eliminate the significant nociceptive component of cancer pain. Chemical neuromodulation, on the other hand, has become widely accepted in the treatment of cancer pain. Intrathecal opioids (such as morphine and hydromorphone) given alone or in combination with adjuvant medications (alpha-adrenergic agonists, e.g., clonidine, or local anesthetics, e.g., bupivacaine) are now commonly used for medically intractable cancer pain [91, 92]. Although these agents may be delivered via variety of catheters and ports, most accepted

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practice consists of the implantation of a self-contained pump that delivers medication at a specific rate into the subarachnoid space via a dedicated intrathecal catheter [93]. Intrathecal administration of opioids is an option for those patients whose effective systemic dose cannot be tolerated due to presence of unacceptable side effects or whose pain is refractory to conventional therapy. Intrathecal infusion bypasses the blood-brain barrier and results in much higher cerebrospinal fluid concentrations with less medication. Compared with the epidural route, intrathecal infusion is associated with higher rates of satisfactory pain relief and lower rates of treatment failure and technical complications [92, 94]. Morphine has been extensively studied intrathecally for patients with cancer and found to be more effective in relieving nociceptive pain versus neuropathic pain [95]. An intrathecal pump can be implanted into the subcutaneous fat of the abdomen to provide a continuous infusion of morphine or other opioid. Some older pumps have pre-set infusion rate (continuous flow pumps); therefore each dose adjustment must be done by changing the concentration of the drug inside the pump. More commonly used nowadays programmable pumps contain an electronic module that can adjust the rate of drug infusion using telemetry programming. All pumps have to be refilled at regular time intervals, but patients usually tolerate these refills quite well as they are done every one to three months in the office or clinic settings by simple insertion of the needle into the center of the reservoir through the skin over the side of the abdomen where the pump is usually placed. The most common side effects of intrathecal opioid therapy noted are nausea and vomiting and the complications include infection or hematoma at the surgical site. Other drugs that can be administered intrathecally include bupivacaine and clonidine. About 10 years ago Elan Pharmaceuticals has introduced a new analgesic drug, ziconotide, which has been now approved by FDA for intrathecal treatment of acute persistent neuropathic pain in the United States. Ziconotide binds to specific N-type voltage-sensitive calcium channels found in neural tissue and acts by blocking neurotransmitter release from primary nociceptive afferents terminating in the superficial layers of the dorsal horn of the spinal cord [96, 97]. This mechanism of action distinguishes ziconotide from all other analgesics, including opioids. In fact, ziconotide is potently anti-nociceptive in animal models of pain in

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which morphine exhibits poor anti-nociceptive activity [98]. The results from few multicenter randomized, double-blind, placebo-controlled trials showed that intrathecal ziconotide provided clinically and statistically significant analgesia in patients with severe pain from cancer or AIDS [99, 100]. However, although the safety of ziconotide administered as a continuous intrathecal infusion has been evaluated in over 1000 patients participating in acute and chronic pain clinical trials, lack of long-term prospective studies and high incidence of dose-dependent adverse effects during the initial titration stage of continuous intrathecal infusion of ziconotide [101–103] currently limit its use as a drug of first choice even in patients with advanced cancer who fail the traditional methods of pain control. Benefits of intrathecal pumps are quite obvious: due to drug delivery route, equianalgesic effect may be reached at doses about 100 times lower than with systemic administration, which significantly decreases dose-related side effects of opioid medications; the patient does not have to think about constant need to have the oral medication available (with associated reduction of risks related to abuse and mishandling of opioids); continuous drug delivery eliminates fluctuations in the drug level that are inevitable with bolus oral or parenteral dosing [104]. In addition to this, chemical neuromodulation is both adjustable and reversible, so the side effects of the treatment may be minimized by either changing the rate of infusion or drug composition, or by stopping the therapy altogether without any lasting side effects. The treatment is also testable; the patient and the caregiver may estimate the degree of pain relief from the results of a pre-surgical medication trial. At the same time, implantable devices are associated with higher upfront costs related to the procedure and the device itself, potential risk for infection and hardware malfunction, need for general anesthesia for system implantation, and similar procedural contraindications (coagulopathy, active systemic infection, etc.) as with any other surgical intervention. Overall, however, hard-to-control cancer related pain in patients with more than 3 months survival is a well-founded indication for intrathecal drug delivery pump implantation. A recent randomized study showed statistically significant superiority of implantable drug delivery systems compared with comprehensive medical management of patients with refractory pain due to cancer not only in degree of pain


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control and reduced drug-related toxicities, but also in improvement of patient survival [92]. As the survival of patients with cancer becomes longer, reliable pain relief is now a high-priority issue that warrants both scientific research and industrial development of new devices and pharmaceutical agents that would make this pain relief complete, safe and lasting. With ongoing progress in the pain management field, a number of palliative care specialists argue that the WHO program, although updated in 1990, had not kept pace with the rapidly changing developments in oncology and pain research [105]. It was reported that the ladder method consistently failed to provide sufficient relief to 10–20% of advanced cancer patients with pain [106].

Pain intensity

Non-opioid analgesics Psychological counseling ± Adjuvant therapy

Thus, it may be reasonable to adjust the WHO pain management ladder from its current three-step approach to a more sophisticated 5-step algorithm that would include physical and psychological modalities along the entire continuum of care and add two more steps related to neuromodulative and neurodestructive procedures once opioids and other drugs fail (Fig. 24.2). The most important part of the entire approach, however, must be its interdisciplinary nature [107]. A surgeon, oncologist, pain anesthesiologist, pharmacist, psychologist, and physical therapist cannot treat the cancer pain alone; only by working together can these specialists give the cancer patient relief from the most fearsome symptom of their disease – their persistent pain.


Weak opioids Psychological counseling ± Non-opioid analgesics ± Adjuvant therapy


Immediate or sustained release strong opioids Psychological counseling ± Non-opioid analgesics ± Adjuvant therapy

Titrate until adequate pain control is achieved; proceed to next step if patient is still in pain or develops severe side effects from therapy

Intrathecal opioids (tunneled catheters, implantable pumps) Peripheral neurodestruction (alcohol/phenol blocks, radiofrequency procedures, etc.) Spinal cord or peripheral nerve stimulation Psychological counseling ± Non-opioid analgesics ± Adjuvant therapy

Central neurodestructive procedures (rhizotomy, ganglionectomy, cordotomy, myelotomy, tractotomy, thalamotomy, etc.) Operations on limbic system (cingulotomy) Psychological counseling ± Intrathecal opioids ± Adjuvant therapy

Fig. 24.2 Modified analgesic ladder for the treatment of cancer pain

Considered in patients who failed all nonsurgical treatment options or developed severe side effects from conventional opioid therapy and have life expectancy more than 3 months

Rarely used nowadays but may be still considered if all other treatment modalities fail particularly in patients with life expectancy less then 3 months

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Chapter 25

Management of Nausea and Vomiting in Cancer Patients Rudolph M. Navari, Paula P. Province, and Steven D. Passik

25.1 Introduction Nausea and vomiting in patients with cancer may be due to the patient’s specific disease state or may be due to cancer treatment interventions such as chemotherapy, radiation therapy, opioids, or other medications. The main approach to the treatment of nausea and vomiting has been the use of antiemetic agents developed primarily for the prevention of chemotherapyinduced nausea and vomiting (CINV). Agents that were considered useful in the prevention of CINV have then been used for the treatment of established nausea and vomiting in cancer patients. Although there have been many clinical trials in the development of agents for the prevention of CINV [62, 64, 70], there have been very few clinical trials evaluating the efficacy of antiemetics in cancer patients with established nausea and vomiting [49, 82].

(CNS). Figure 25.1 shows that chemotherapy agents, or their metabolites in the blood or cerebrospinal fluid, may directly affect areas in the medulla oblongata or stimulate the GI tract via the vagus nerve to send impulses to the medulla. A vomiting center (VC) appears to be located in the lateral reticular formation of the medulla, which coordinates the mechanism of nausea and vomiting. An additional important area, also located in the medulla, is the chemoreceptor trigger zone (CTZ) in the area postrema near the 4th ventricle [7]. It is strongly suspected that the nucleus tractus solitarius (NTS) neurons lying ventrally to the area postrema initiate emesis [108]. This medullary area is a convergence point for projections arising from the area postrema and the vestibular and vagal afferents [108]. The NTS is a good candidate for the site of action of centrally acting antiemetics.

25.2.2 Neurotransmitters and Receptors 25.2 Mechanisms of Emesis 25.2.1 Anatomy The mechanisms of emesis are not well defined, but investigations suggest that emesis may be primarily mediated through neurotransmitters in the gastrointestinal (GI) tract and the central nervous system

The main approach to the control of emesis has been to identify the active neurotransmitters and their receptors in the CNS and the GI tract that mediate the afferent inputs to the VC (Fig. 25.2). Agents that may block these neurotransmitter receptors in the CTZ, the VC, or the GI tract may be useful in preventing or controlling emesis (Table 25.1).

25.2.3 Dopamine Receptor Antagonists R.M. Navari () Department of Medicine, Indiana University School of Medicine, South Bend, IN 46617, USA e-mail: [email protected]

Dopamine receptors are known to exist in the CTZ, and this is the main area of activity of the dopamine


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Higher CNS centers

Chemoreceptor trigger zone Medulla oblongata Vomiting center

Small intestine

Chemotherapy

Increased afferent input to the chemoreceptor trigger zone and vomiting center Cell damage Activation of vagus and splanchnic nerves

Release of neuroactive agents

Fig. 25.1 Proposed pathways of chemotherapy-induced emesis

Fig. 25.2 Neurotransmitters involved in emesis

Histamine

Dopamine

Serotonin

Endorphins

Emetic center Substance P

Acetylcholine

GABA

Table 25.1 Antiemetic receptor antagonists Dopamine Receptor 5-HT3 Receptor Antagonists Antagonists Phenothiazines Butyrophenones

Azasetron Dolasetron Granisetron Ondansetron Palonosetron Ramosetron Tropisetron

antagonists, such as the phenothiazines and the butyrophenones (droperidol, haloperidol). A high level of blockade of the dopamine receptors however, results

Dopa-5-HT3 Receptor Antagonists

NK-1 Receptor Antagonists

Metoclopramide

Vofopitant CP-122,721 CJ-11,794 Fosaprepitant (L758,298) Aprepitant (MK-869) Casopitant

in extrapyramidal reactions, as well as disorientation and sedation, limiting the clinical use of these agents.

25 Management of Nausea and Vomiting in Cancer Patients

25.2.4 Serotonin (5-HT3 ) Receptor Antagonists Serotonin receptors, specifically the 5-HT3 receptors, exist in the CNS and in the GI tract. The 5-HT3 receptor antagonists, such as dolasetron, granisetron, ondansetron, and tropisetron, appear to act through both the CNS and the GI tract via the vagus and splanchnic nerves. The main toxicities of these 5-HT3 receptor antagonists consist only of a mild headache and occasional diarrhea. The effectiveness of the 5-HT3 receptor antagonists in cisplatin-induced acute emesis [42, 73, 74, 85] is believed to be due to a predominately peripheral site of action, the prevention of the stimulation of abdominal vagal afferent fibers by serotonin released from the enterochromaffin cells of the gut by cytotoxic agents. This has been well documented in animal ferret models [92]. 5-HT3 receptor antagonists have been less effective in delayed cisplatin-induced emesis both in humans [4, 55, 76, 100, 101] and in ferret animal models [90]. This may be due to the lack of central effect by the 5-HT3 receptor antagonists, as demonstrated by the ineffectiveness of the 5-HT3 receptor antagonists against the emesis induced by the centrally acting opioids (apomorphine, morphine) in experimental animals [3].

25.2.5 Dopamine-Serotonin Receptor Antagonists Metoclopramide has antiemetic properties both in low doses as a dopamine antagonist and in high doses as a serotonin antagonist. However, high doses may precipitate undesirable extrapyramidal reactions and akathisia.

25.2.6 Substance P Receptor Antagonists Substance P is a mammalian tachykinin that is found in vagal afferent neurons innervating the brainstem NTS, which sends impulses to the VC [19]. Substance P induces vomiting and binds to neurokinin-1 (NK-1) receptors in the abdominal vagus, the NTS, and the area postrema [19]. Compounds that block NK-1

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receptors lessen emesis after cisplatin, ipecac, apomorphine, and radiation therapy [19]. These observations have recently led to the development of NK-1 receptor antagonists and the study of the role they may play in controlling CINV. Studies in rhesus monkeys using PET scans have demonstrated that the NK-1 receptor antagonist vofopitant, when administered peripherally, has a distribution into brain regions consistent with specific binding to NK-1 receptors [25]. Injection of the NK-1 receptor antagonists CP-99,994 or MK-0869 (aprepitant) directly into the vicinity of the NTS neurons inhibited cisplatin-induced emesis in the ferret [99]. These results suggest that NK-1 receptor antagonists may exert their main antiemetic action by depressing the neural activity of the NTS neurons, with possibly some antiemetic effects from peripheral sites through a blockade of the NK-1 receptors located on the vagal terminals in the gut [59, 60]. Tattersall et al. [98] have recently reported that aprepitant (L-754,030, MK-0869) and its watersoluble phosphoryl prodrug, L-758,298, inhibited acute and delayed cisplatin-induced emesis in a ferret animal model. A single dose of aprepitant prior to cisplatin decreased emesis during a 72 h period, and daily dosing eliminated emesis during the entire 72 h observation period. The antiemetic activity of aprepitant also appeared to be enhanced by combination with either dexamethasone or the 5-HT3 receptor antagonist ondansetron. These animal studies have recently led to phase II –III studies of NK-1 receptor antagonists in humans [11, 13, 14, 16, 17, 32, 35, 38, 39, 51, 63–65, 68, 77, 88, 93, 105, 107]. The six investigational NK-1 receptor antagonists studied to date in humans have been GR205171 (vofopitant), CP-122,721, CJ-11,974, MK-0869 (L-754,030; aprepitant), aprepitant’s prodrug fosaprepitant, and casopitant.

25.3 Chemotherapy-Induced Nausea and Vomiting Chemotherapy-induced nausea and vomiting can be a significant problem for patients. They consistently report that vomiting and nausea are among the most unpleasant and distressing aspects of chemotherapy [15, 30]. Even one or two emetic episodes is associated

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with a significant deterioration in the quality of life, as well as physical and cognitive functioning, and may cause patients to delay or refuse potentially curative therapy [80]. There are five distinct but related CINV syndromes [6]: (1) acute CINV; (2) delayed CINV; (3) anticipatory CINV; (4) breakthrough CINV; and (5) refractory CINV. Acute CINV has been traditionally defined as nausea and vomiting occurring within the first 24 h after chemotherapy administration. Delayed CINV has been defined as nausea and vomiting occurring 24 h after chemotherapy and lasting up to 5 days, with recent evidence suggesting that it may begin as early as 16 h after chemotherapy administration. Anticipatory CINV is a conditioned response which occurs prior to a planned course of chemotherapy following significant nausea and vomiting due to previous chemotherapy. Breakthrough CINV occurs despite patients being treated with preventive therapy, and refractory CINV occurs during subsequent cycles of chemotherapy when antiemetic prophylaxis or rescue therapy has failed in earlier cycles. The potential for CINV is influenced by the emetogenicity of the chemotherapeutic agents [29, 41, 79] and patient characteristics [84]. Table 25.2 lists the emetic risk groups with representative agents, and although the emetogenicity of a chemotherapeutic agent is the primary risk factor, coadministration of chemotherapeutic agents [29, 84], as well as repeated cycles of chemotherapy [18], increases the potential for nausea and vomiting. Additional factors contributing to an increased risk for CINV are female gender, younger age, a history of

Table 25.2 Emetic risk groups with representative agents Emetogenic potential Typical agents Definition High

Moderate

Low Minimal

Cisplatin Dacarbazine Nitrogen mustard Carboplatin Anthracyclines Cyclophosphamide Irinotecan Mitoxantrone Taxanes Hormones Vinca alkaloids Bleomycin

Emesis in nearly all patients Emesis in >70% of patients

Emesis in 10%–70% of patients Emesis in < 10% of patients

Table 25.3 Patient-related risk factors for emesis following chemotherapy Major factors Female Age < 50 years History of low prior chronic alcohol intake History of previous chemotherapy-induced emesis Minor factors History of motion sickness Emesis during past pregnancy

motion sickness, and consumption of minimal amounts of alcohol (less than 11/2 ounces of alcohol per day) [29, 79, 84]. The presence or absence of these risk factors, as well as the emetogenicity of the chemotherapeutic agents being administered, determines each patient’s risk of CINV (Table 25.3).

25.4 Agents in Clinical Use for the Treatment of Chemotherapy-Induced Nausea and Vomiting 25.4.1 Serotonin (5-HT3 ) Receptor Antagonists The introduction of 5-hydroxytryptamine3 (5-HT3 ) receptor antagonists for the prevention of CINV, as well as post-operative and radiotherapy-induced nausea and vomiting, has resulted in a major improvement in supportive care [37, 42, 56, 61, 73–75, 85]. Treatment guidelines for the prevention of CINV recommended by a number of international groups [50, 67, 78, 89] suggest the use of a 5-HT3 receptor antagonist and dexamethasone pre-chemotherapy for the prevention of acute CINV and the use of dexamethasone with or without a 5-HT3 receptor antagonist following chemotherapy for the prevention of delayed nausea and vomiting. Table 25.4 shows the 5-HT3 receptor antagonists currently in use. The first generation serotonin (5-HT3 ) receptor antagonists dolasetron, granisetron, and ondansetron, tropisetron [94], azasetron [47] and ramosetron [97] are equivalent in efficacy and toxicities when used in the recommended doses and compete only on an economic basis [36]. They have not been

25 Management of Nausea and Vomiting in Cancer Patients Table 25.4 Serotonin antagonists and chemotherapya Antiemetic Route Dosage

dosage

before

Azasetron Dolasetron

IV 10 mg IV 100 mg or 1.8 mg/kg PO 100 mg Granisetron IV 10 μg/kg or 1 mg PO 2 mg (or 1 mg twice daily) Ondansetron IV 8 mg or 0.15 mg/kg PO 24 mg Palonosetron IV 0.25 mg PO 0.50 mg Ramosetron IV 0.30 mg Tropisetron IV or PO 5 mg a The same doses are used for highly and moderately emetic chemotherapy

associated with major toxicities, with the most commonly reported adverse events being mild headache and mild diarrhea [42, 56, 73, 75, 86]. A prolongation of cardiac conduction intervals has been reported for this class of compounds with dolasetron being more extensively studied than granisetron and ondansetron, but there have been no reported clinical cardiovascular adverse events [75]. The first generation 5-HT3 receptor antagonists have not been as effective against delayed emesis as they are against acute CINV [4, 55, 76, 101]. The available studies show that with corticosteroids alone, or combined with either metoclopramide or a 5-HT3 receptor antagonist in patients receiving cisplatin, the incidence of delayed emesis has been reduced, but remains a significant problem [44, 62]. The first generation 5-HT3 receptor antagonists do not add significant efficacy to that obtained by dexamethasone alone in the control of delayed emesis [101]. Hickok et al. [43] reported that the first generation 5-HT3 receptor antagonists used in the delayed period were no more effective than perchlorperazine in controlling nausea. A recent meta analysis [26] showed that there was neither clinical evidence nor considerations of cost effectiveness to justify using the first generation 5-HT3 receptor antagonists beyond 24 h after chemotherapy for the prevention of delayed emesis. The second generation 5-HT3 receptor antagonist palonosetron has recently been approved for clinical use. Recent studies suggest that it may have efficacy in controlling delayed CINV compared to the first generation 5-HT3 receptor antagonists.

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25.4.2 Palonosetron Palonosetron is a new 5-HT3 receptor antagonist which has antiemetic activity at both central and GI sites. In comparison to the older 5-HT3 receptor antagonists, it has a higher binding affinity to the 5-HT3 receptors, a higher potency, a significantly longer halflife (approximately 40 h, 4–5 times longer than that of dolasetron, granisetron, or ondansetron), and an excellent safety profile [22, 62]. A dose-finding study demonstrated that the effective dose was ≥0.25 mg [22]. In two large studies in patients receiving moderately emetogenic chemotherapy (MEC), complete response (no emesis, no rescue) was significantly improved in the acute and the delayed period for the patients who received 0.25 mg of palonosetron alone compared to either ondansetron or dolasetron alone [21, 28]. Dexamethasone was given with the 5-HT3 receptor antagonists in only a small number of patients (5%) in only one of these studies [21], and it remains to be determined if the differences in complete response would persist if dexamethasone was used. In another study, 650 patients receiving highly emetogenic chemotherapy (HEC) (cisplatin, 60 mg/m2 ) received dexamethasone and one of two doses of palonosetron (0.25 mg or 0.75 mg) or dexamethasone and ondansetron (32 mg) pre-chemotherapy. Patients pre-treated with palonosetron (0.25 mg) plus dexamethasone had significantly higher complete response rates than those receiving ondansetron plus dexamethasone during the delayed and overall periods [1]. In an analysis of the patients in these studies who received repeated cycles of chemotherapy, Cartmell et al. [12] reported that the complete response rates for both acute and delayed CINV were maintained with the single intravenous doses of palonosetron without concomitant corticosteroids. Based on the above studies, palonosetron was approved by the FDA in July, 2003 for the prevention of acute nausea and vomiting associated with initial and repeat courses of moderately and highly emetogenic cancer chemotherapy. It was also approved for the prevention of delayed nausea and vomiting associated with initial and repeat course of moderately emetogenic cancer chemotherapy. Saito et al. [91] conducted a double-blind, doubledummy, randomized, comparative phase III trial in 1143 patients receiving HEC (cisplatin or the

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combination of an anthracycline and cyclophosphamide). Patients were recruited from 75 institutions in Japan and were randomly assigned to either singledose palonosetron (0.75 mg) or granisetron (40 ug/kg) 30 min before chemotherapy on day 1. Both groups also received dexamethasone, (16 mg IV) on day 1 followed by additional doses (8 mg IV for patients receiving cisplatin and 4 mg orally for patients receiving an anthracycline and cyclophosphamide) on days 2 and 3. Four hundred eighteen of 555 patients (75.3%) in the palonosetron group had a complete response during the first 24 h (acute period) compared with 410 of 559 patients (73.3%) in the granisetron group. During the delayed period, 315 of 555 patients (56.8%) had a complete response in the palonosetron group compared with 249 of 559 patients (44.5%) in the granisetron group (p10% of pre-diagnosis body weight. Also, these investigators found that when grouped by cancer type, tumor extent, and activity level, median survival time was shorter in those who had experienced weight loss compared with those who had not experienced weight loss [32]. Historically, providing nutritional care to the patient with cancer has not always been believed to be therapeutically advantageous, due to fear of promoting cancer progression. In laboratory animal and cell culture studies, starvation has been observed to slow tumor growth and proliferation of cancer cells [9, 124], and concern that nutritional repletion would stimulate tumor growth, based on the early studies with animal models, was the basis for concern [27]. However, the health status of the host is concurrently adversely affected by nutritional depletion, and historically, malnutrition was a major cause of cancer-related mortality [127]. More recent studies have shown that providing adequate energy and essential nutrients may improve the efficacy and reduce the toxicity of chemotherapy and other cancer treatments [8, 94]. Another concern has been that the weight loss and malnutrition observed in some cancer patients may not be modifiable. The syndrome of weight loss and malnutrition that occurs in some cancer patients has been termed cancer cachexia, characterized by muscle wasting and increased resting metabolic rate [9]. Cancer cachexia differs from simple starvationrelated protein-energy malnutrition primarily because the compensatory mechanisms that would promote the preservation of muscle mass and adaptation to alternate fuels are not functioning. Specific metabolic characteristics associated with this syndrome include increased protein turnover, decreased muscle protein synthesis, increased glycolysis, increased lipolysis, decreased fat synthesis, decreased glucose tolerance and increased glucose uptake [70, 115]. The fundamental metabolic

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problem is cytokine-induced gluconeogenesis and increased utilization of protein stores for fuel, similar to the acute metabolic stress response, which is promoted by the release of cytokines due to the presence of the tumor and associated circulating factors. However, cancer cachexia and weight loss in those patients who are affected with this syndrome also typically involve loss of appetite (anorexia) and inadequate dietary intake. Low levels of energy intake can occur as a result of altered taste perceptions, due either to systemic effects of the cancer itself or treatment modalities, and psychological factors, such as anxiety, depression, fatigue, and the emotional stress of diagnosis and treatment [15]. Several strategies can be useful to overcome barriers to inadequate intakes of energy and nutrients, and good response to chemotherapy and other treatments of the cancer is associated with normalization of the metabolic effects that increase risk for adverse nutritional consequences [58].

26.3 Nutrition Strategies During Treatment and Recovery The overall goals of nutritional care for the patient undergoing initial treatments for cancer are to maintain a healthy weight, meet requirements for essential nutrients, and minimize adverse effects of treatment that might be modulated by dietary strategies. Table 26.1 lists the current definitions, which are based on body mass index (BMI), for identifying underweight, overweight and obesity. For patients who are underweight and exhibiting weight loss, the goal is to maintain or gain weight. In contrast, evidence suggests that being overweight or obese may increase risk for recurrence

Table 26.1 Underweight, overweight and obesity as defined by body mass index (BMI) BMI (weight [kg]/height Classification [m2 ]) Underweight 40 obesity Expert panel on the identification, evaluation, and treatment of overweight in adults (1998)

26 Nutrition in the Management of the Cancer Patient

for some cancers, such as breast cancer, so for the latter group, modest weight loss (e.g., 1–2 pounds/week) promoted by a moderate reduction in energy intake and increased physical activity can be encouraged during treatment [34, 101]. Cancer treatments (surgery, radiation and chemotherapy) can influence nutrient requirements and eating patterns, which in turn affects nutritional status [77]. Recovery from surgery requires adequate energy, protein and nutrient intakes to enable wound healing and adequate immune system function. Surgeries for cancers of the gastrointestinal tract, in particular, may affect the patient’s ability to swallow, digest and absorb food, so post-surgery diet modifications are typically indicated in order to maintain adequate energy and nutrient intakes. Patients usually benefit from a progressive approach to diet (from clear liquid to low-fiber to regular diet), with the goal being a return to a normal diet based on regular foods. However, there are some patients in whom long-term dietary modifications are necessary, for example, in the management of dumping syndrome following surgical resection of the stomach [1]. Modern approaches to radiation therapy aim to affect only the specific target site, although fatigue is a common systemic side effect that can adversely influence appetite and intake. When the site of radiation therapy is the head and neck, side effects such as xerostomia, sore mouth, mucositis, and dysphagia will reduce voluntary food intake. Gastrointestinal symptoms that affect intake and nutrient absorption, such as diarrhea, can occur as a result of radiation of the abdomen and pelvis. Chemotherapy can cause nutritional problems due to a variety of common side effects, including loss of appetite, fatigue, nausea, vomiting, mucositis, taste alterations, xerostomia, dysphagia and changes in bowel function [77]. The use of anti-emetic medications can help to minimize some of the adverse effects of chemotherapy on dietary intake, and several specific diet modification strategies also can be useful. Immunosuppression often occurs in response to chemotherapy, so strategies to ensure food safety and the avoidance of exposure to pathogenic microorganisms via food and beverages are necessary in those cases to reduce risk for infection and illness. General food safety guidelines, such as washing hands before eating, using food preparation techniques that minimize contamination, washing vegetables and fruit

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thoroughly, cooking foods to proper temperatures, and storing food at temperatures that minimize bacterial growth, are among the general recommendations. Foods at high risk of containing pathogenic microorganisms, such as unpasteurized dairy foods or juice and raw or undercooked meat, fish or eggs should be avoided [89]. Table 26.2 lists examples of nutrition management and counseling strategies for cancer patients experiencing side effects related to treatment modalities that can adversely affect intakes. Several feeding routes may be considered for use in the management of the cancer patient, ranging from strategies that focus on diet modification, enteral nutrition involving feeding tubes, and parenteral nutrition. Overall, oral intake is generally the preferred route, although there are some patients in whom that approach is not optimal or feasible. The usefulness of nutritional counseling and diet modification for cancer patients during initial treatments and recovery has been examined in a few studies. A telephone-based follow-up study of nutrition counseling was reported by Schiller et al. [113] in 400 patients who had been referred for nutrition counseling, of whom 4% of the sample were patients with cancer. Overall, the counseling interaction was found to be well-received by the patients, with 85% reporting at follow-up that they knew what to eat after talking with the dietitian, and 62% reported that they had changed their diets following the counseling while 44% reported health-related changes. In a study of diet modification specifically relevant to patients with cancer, Menashian et al. [79] tested the effect of a modified diet to help control nausea and vomiting in 19 patients receiving cisplatin chemotherapy. Patients in the study group who were advised to consume the modified diet, which consisted of foods observed clinically to be better tolerated during chemotherapy, experienced fewer episodes of emesis when compared to the control subjects and 57% less volume of emesis on the first day of treatment. Liquid dietary supplements are often prescribed to help patients meet energy and nutrient needs in spite of eating problems. These products are theoretically nutritionally complete, with a key determining factor being the amount that is consumed, and proper use is more likely to occur when accompanied by counseling, encouragement and strategies to improve palatability. In a randomized trial [94], effects of individualized dietary counseling focused on regular foods

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Table 26.2 Dietary counseling strategies for treatment-related side effects Nutrition-related side effect Counseling strategies Nausea and vomiting

Diarrhea and bloating

Dysphagia

Pain or dryness (xerostomia)

Taste and odor changes

Fatigue

Eat small, frequent meals and snacks Choose bland-tasting foods and beverages Avoid strong cooking odors Choose foods that are cold or room temperature (rather than hot) Eat salty foods Choose dry foods such as toast or crackers and avoid liquids at mealtimes Drink clear cold beverages Avoid high-fat or greasy foods Avoid high-fiber foods Drink nutrient-dense juices Choose cooked (rather than raw) vegetables and fruit Avoid foods that can cause gas, such as beans, broccoli, cauliflower and cabbage Drink only a small amount of liquid with meals Avoid high-lactose foods (e.g., milk, ice cream, cottage cheese and other cheeses that are not aged) Avoid high-fat or greasy foods Avoid rough-textured foods Choose foods that are cold or room temperature (rather than hot) Eat semisolid or soft foods Drink plenty of fluids and nutrient-dense beverages such as juice Add moisture to foods (e.g., sauces, condiments) Choose soft foods Blenderize foods and have liquid (rather than solid) meals with a straw or from a cup Avoid acid or very salty foods Avoid dry or rough-textured foods cHOOSE foods that are cold or room temperature (rather than hot) Rinse your mouth often Choose foods that are cold or room temperature (rather than hot) Use glass or plastic utensils (rather than metal) utensils and cookware Experiment with new flavors and seasonings Eat small, frequent meals and snacks Keep easy-to-prepare and easy-to-eat foods available Eat energy-dense, high-protein foods and snacks throughout the day Drink nutrient-dense juices and other beverages Ask friends and family members for help with buying and preparing foods to be set aside for meals and snacks

were compared with the effects of prescribing nutrientdense, high-protein liquid dietary supplements or ad libitum intake in 111 colorectal cancer patients treated with radiation therapy. Individualized dietary counseling was found to promote the maintenance of adequate dietary intakes and body weight, resulting in a marked reduction in the incidence and severity of anorexia and diarrhea, and improved quality of life. Notably, the beneficial effects observed in association with dietary counseling were generally maintained three months after the completion of radiation therapy. Although the liquid supplement did facilitate a small increase in energy intake, the other beneficial effects were substantially less than those observed in response to dietary counseling. Enteral nutrition (tube feeding) is indicated when adequate intake cannot be achieved through regular

foods and liquid supplements [80]. Nasogastric tube feeding is typically used when the problem interfering with food intake is likely to be resolved in the shortterm, while more permanent feedings are more acceptable to patients when gastrostomy or jejunostomy is the feeding route utilized. In contrast with the oral diet and enteral approaches, parenteral nutrition, in which energy-producing substrates and nutrients are administered via intravenous access, presents risks for several serious complications and increased risk for adverse effects. This approach, when applied without specific inclusion criteria, has not been shown to improve nutritional measures in the average patient with cancer and is actually associated with increased risk of complications, such as infections. Other complications include fluid overload, hyperglycemia, electrolyte imbalance, and increased serum triglyceride concentrations, and


intensive monitoring of metabolic factors is necessary with this type of nutrition intervention. In 1989, the American College of Physicians [3] published a position paper concluding that parenteral nutrition support was associated with net harm in patients with cancer. In spite of the risk for complications, parenteral nutrition support may be appropriate for some patients with cancer for whom oral intake or enteral nutrition is not an option. The main concern is with the indiscriminate use in patients who are undergoing routine cytotoxic treatments and who do not have pre-existing malnutrition. For example, in the Veterans Affairs Total Parenteral Nutrition Cooperative Study [122], 395 patients who required laparotomy or noncardiac thoracotomy, with the majority having a diagnosis of cancer, were randomly assigned to receive either total parenteral nutrition for 7–15 days prior to surgery and 3 days afterward or no perioperative parenteral nutrition support. Overall, there were more infectious complications in the parenteral nutrition group than in the control group. However, among those who were severely malnourished based on global assessment score, patients who received total parenteral nutrition had fewer noninfectious complications than controls (relative risk [RR] 0.12, 95% confidence interval [CI] 0.02–0.91) with no increase in infectious complications [122]. Another situation in which total parenteral nutrition is currently believed to be beneficial in the management of patients with cancer is in bone marrow transplantation [95]. As summarized by Mercadante [80], the use of parenteral nutrition support should be considered adjuvant treatment and support during therapy for malnourished patients or in those with severely impaired gastrointestinal function who are otherwise expected to survive. Current evidence does not support the concept that specific benefits may be achieved by using high-dose vitamin and mineral supplements during initial treatment and recovery. In fact, some evidence suggests potential harm. High doses of folic acid could interfere with the effectiveness of methotrexate, a chemotherapy drug that targets rapidly proliferating cancer cells by interfering with folate metabolism. Theoretically, high doses of antioxidant vitamins (e.g., vitamin C, vitamin E) also could interfere with the desired effect of cytotoxic cancer treatments such as radiation therapy, in which oxidative damage to cancer cells is among the therapeutic mechanisms [69]. Others have argued that

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antioxidant nutrients at high doses may improve the efficacy of cancer therapies [93]. Evidence from clinical studies that would help to resolve this controversy has not been reported. Currently, the general consensus is that high doses of vitamins, minerals and other dietary constituents should be avoided during initial treatments because this strategy may increase risk of adverse consequences or interference with treatments [34]. In contrast, possible benefit may be achieved by recommending the use of a multiple vitamin supplement that provides 100% of the recommended dietary intakes. The latter strategy presents negligible risk and will prevent micronutrient deficiencies in patients who are at risk of inadequate intakes from the diet.

26.4 Nutritional Factors and Risk for Recurrence and Survival The majority of patients who are diagnosed with cancer will survive at least five years post-diagnosis, due in part to increased screening efforts, which have resulted in most patients being diagnosed at an earlier stage, and improved initial treatments [23, 59]. In these patients, risk for recurrence or a second primary cancer is an important issue in their long-term management [49]. These patients also are at increased risk for other comorbidities, such as cardiovascular disease, type 2 diabetes, and osteoporosis [6, 10, 11]. For many of these comorbid disorders, the benefit of dietary intervention or weight management has a demonstrated role in prevention and management. The relationships between nutritional factors, recurrence and survival have been examined in several observational studies of breast cancer survivors. In contrast, only a few epidemiological studies have examined the relationship between nutritional factors and survival in patients with a history of other cancers, such as cancer of the prostate, colon or ovary. The subjects examined and followed in these studies were cases who originally participated in case-control studies focused on primary breast cancer risk, were identified in clinical series, or were diagnosed with cancer while being followed within ongoing population-based observational studies or other established cohorts. Several clinical trials have tested the effect of dietary

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supplements (or diet modification) on progression or recurrence of selected precancerous lesions, and the results of those studies may be relevant to cancer progression in the patient who has had a clinical cancer diagnosis.

26.4.1 Nutritional Factors and Survival in Breast Cancer As described in several reviews [21, 101], epidemiological studies of the association between nutritional factors and survival following the diagnosis of breast cancer have mainly focused on two nutritional factors: relative body weight or other indicators of adiposity or body fat distribution (e.g., BMI, waist-to-hip circumference) and diet composition. The majority of these studies have focused on obesity or relative body weight, with a smaller number of studies in which data on diet composition were collected and examined. Notably, these characteristics are often interrelated. For example, diets that are energy-dense are more likely to promote excess adiposity, although most observational epidemiological studies attempt to separate the effects of these factors. Since 1990, 28 published studies have examined associations between relative body weight and breast cancer recurrence and survival. In 19 of these studies, increased BMI or body weight was found to be a significant risk factor for recurrent disease, decreased survival, or both; in seven studies, no association was evident; and in two studies, a significant inverse association between weight status and survival was identified (reviewed in [101]). The effect of higher (versus lower) relative body weight was fairly substantial in the studies in which an inverse association was observed, with a 30–540% increased risk of death observed in the heavier women across these studies. The relationship between upper body or android obesity and survival following the diagnosis of breast cancer was examined in two of these studies. In a study of both premenopausal and postmenopausal women by Kumar et al. [67], android body fat distribution, as indicated by a higher suprailiac:thigh ratio, was found to be a significant negative prognostic indicator, even though higher BMI status was protective in that study. In contrast, Zhang et al. [132], found no association between android obesity, as indicated by

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a greater waist-to-hip ratio, and survival, but did detect a significantly greater risk of death among women in the top tertile of BMI. Weight gain often occurs in women after diagnosis of breast cancer, being more prevalent among women who were premenopausal at diagnosis, receive adjuvant chemotherapy, are African-American, and who report higher energy intake [28, 98]. Prediagnosis BMI, age at diagnosis, level of education, and usual exercise level also have been found to be inversely associated with weight gain [98]. There is some evidence, although not consistent, to suggest that weight gain after diagnosis adversely affects disease-free survival. Camoriano et al. [14] followed 646 patients with breast cancer for a median of 6.6 years and found that women who were premenopausal at diagnosis and who gained more than the median amount of weight (5.9 kg) were 1.5 times more likely to relapse and 1.6 times more likely to die of their breast cancer. Results from a study by Chlebowski et al. [20] are similar to these findings. In contrast, other studies have failed to identify an association between post-diagnosis weight gain and prognosis [13, 42, 51]. Increased body fatness, regardless of weight gain, has been noted in five studies that have measured body composition changes in women undergoing adjuvant chemotherapy [101]. A loss of lean body mass that is observed occurs in association with a marked reduction in physical activity [30]. Lean body mass is the major determinant of resting energy expenditure, so these changes in body composition have important implications for long-term weight control. Several mechanisms have been proposed to explain the adverse effect of excess adiposity on prognosis following the diagnosis of breast cancer. One relates to the effect of excess adipose tissue on circulating gonadal hormones, because adipose tissue is an important extragonadal source of estrogens from precursor adrenal androgens [25, 126]. Obesity is associated with increased circulating concentrations of estrone and estradiol in postmenopausal women, and it also is associated with decreased concentrations of sexhormone binding globulin (SHBG), which increases the bioavailable estrogen fraction [124]. Increased circulating estrogen concentrations have been linked to risk for primary breast cancer in postmenopausal women [25, 35, 109] as well as increased risk for recurrence and/or survival recurrence and/or survival among women who have been diagnosed with breast


cancer [102]. Minimizing estrogen stimulation following the diagnosis of breast cancer is a standard management strategy, and antiestrogen therapy has emerged as one of the most effective treatments in the management of endocrine-responsive breast cancers [25]. Another possible mechanism relates to insulin and insulin-like growth factor (IGF) -I, and the interactions of these factors with adiposity and weight gain [60, 90, 107]. Insulin increases the bioactivity of IGF-I by enhancing its synthesis and by altering key binding proteins. In addition to their cellular proliferative effects, insulin and IGF-I both stimulate anabolic processes and can promote tumor development by inhibiting apoptosis [60, 107]. Insulin and IGF-I also stimulate the synthesis of sex steroids and inhibit the synthesis of SHBG, so the effects of these various hormonal factors are biologically related. Fasting insulin concentration has been shown to exhibit an independent effect on survival in a cohort of 512 women without known diabetes who had been diagnosed with early stage breast cancer [44]. Although highly correlated with BMI (r = 0.59, P < 0.001), serum insulin was associated with risk for distant recurrence and death (hazard ratio [HR] 2.1, 95% CI 1.2–3.6, for upper versus lower insulin quartile), adjusted for tumor characteristics and treatment-related variables, in that study. Several studies have examined the link between IGFs and IGF binding proteins and risk for primary breast cancer, and results are not entirely in agreement [60, 90]. The most consistent finding links IGF-I and IGFBP-3 inversely with risk for premenopausal breast cancer [64]. Few studies have examined associations between IGFBP-1 and risk for breast cancer, although this binding protein is inversely related to insulin resistance and hyperinsulinemia [50, 82]. Relationships between IGFs and their binding proteins and prognosis following the diagnosis of breast cancer have been examined in very few studies, with mixed results. Vadgama et al. [125] found IGF-I to be directly associated with risk for recurrence and inversely associated with survival in 130 African-American and Hispanic women diagnosed with breast cancer, but Goodwin et al. [44] did not find an independent association between IGF-I, IGF-II or IGFBP-3 and survival in their cohort. Leptin also may contribute to the link between obesity and breast cancer [55, 104]. Leptin is highly correlated with degree of obesity, increasing in response to insulin secretion and decreasing in response to energy restriction.

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A few small studies have tested whether diet counseling or prescribing increased physical activity can prevent weight gain in women during the immediate post-diagnosis period, with mixed results. Women provided intensive diet counseling to achieve energyrestricted diets did not exhibit differences in weight gain compared to control subjects in a randomized trial of 104 women with early stage breast cancer [71]. In another small randomized controlled study involving early stage breast cancer patients receiving adjuvant chemotherapy (n = 24), prescribing aerobic exercise did not have a significant effect on weight gain, although significant differences were observed in the change in percent body fat (averaging –0.51% in the treatment group versus +2.19% in the control group) [128]. Both diet and physical activity were the behavioral targets in two small studies that found a significant reduction in body weight (or weight maintenance in those not overweight) in women recently diagnosed with breast cancer [43, 78], and the strongest predictor of the program’s success was increased physical activity [43]. Results from one small study aimed toward promoting weight loss in obese breast cancer survivors (n = 48) after the completion of initial treatments, have been reported. Djuric et al. [33] examined the effect of individualized weight-loss counseling with or without participation in the Weight Watcher’s commercial group-based program versus participation in Weight Watcher’s alone. Subjects were within four years of diagnosis and had a BMI of 30–44 kg/m2 . At 12 months, the average weight change was 0.85 (6.0) kg (mean [SD]) for the control group, –2.6 (5.9) kg for the Weight Watcher’s only group, –8.0 (5.5) kg for the individualized counseling only group, and –9.4 (8.6) kg for the combined treatment group. Compared with the control group, the combined group exhibited statistically significant differences at three, six and 12 months, while the individualized counseling group was significantly different only at 12 months. Other studies examining approaches aimed to promote weight loss and maintenance in overweight or obese breast cancer survivors are currently underway. In an earlier review, results were summarized from 13 studies published between 1985 and 2002 that examined the association between diet composition and recurrence or overall survival following the diagnosis of breast cancer [101]. A variety of approaches to diet assessment were used, all involving self-reported

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dietary intakes before, during or after the diagnosis of breast cancer, and variable dietary factors were quantified and examined across these studies. Notably, these studies did not consistently or uniformly adjust for important non-dietary factors known to influence survival, such as stage at diagnosis, which likely contributes to the variable findings and interpretation of the results. The relationship between risk for recurrence or survival and intake of fat or high-fat foods was examined in the majority of these studies. In six of the 13 studies that quantified fat intake and examined associations with recurrence or survival, total fat intake was significantly inversely associated with survival or positively related to treatment failure (defined as recurrence or new cancer of the contralateral breast) [48, 53, 85, 111, 132]. When adjusted for energy intake, however, the relationship with total fat intake and recurrence or death was no longer significant in two of these studies [111, 132], and the energy-adjusted relationship was not examined in two others [48, 85]. In the one study that found energy-adjusted total fat intake to be directly associated with risk for treatment failure [53], this relationship was observed only in women who had tumors that were estrogen receptor (ER) positive (but not in those who had ER-negative tumors). As an example of magnitude of effect, the risk for treatment failure in that study was increased by 13% for each percent energy intake from fat in that study. An additional study found a nonsignificant trend for this relationship [105], and another study found energy-adjusted saturated fat (but not total fat) intake associated with reduced likelihood of survival [57]. In one study in which selected foods (but not quantified fat intake) were the focus of the analysis [52], energy-adjusted butter, margarine and lard intake was directly associated with risk for recurrence but not with risk of death. Nine of the 14 follow-up studies of diet composition and breast cancer recurrence or survival examined the associations between intakes of vegetables, fruit or associated micronutrients (e.g., beta-carotene, vitamin C). Three of these studies found a significant positive relationship with survival [56, 57], one found a marginally significant relationship [105], one described a trend for this relationship [36], and one found a protective effect among women with nodenegative disease (who comprised 62% of the total sample) [54]. The magnitude of the effect was a 20–90%

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reduction in risk for death in those with higher versus lower intakes in the studies that found a beneficial effect for vegetables, fruit and associated micronutrients. Eight of the 14 follow-up studies of diet composition and recurrence or survival reported between 1985 and 2002 specifically examined associations with fiber intake. None of these studies found a significant effect of quantified fiber intake on risk for recurrence or survival, although the point estimates in one study suggest a protective effect [53]. Results from studies that examined relationships between intakes of high-fiber foods (e.g., vegetables, fruit, cereal-grain products) and risk for recurrence or survival are somewhat more supportive. Three (out of a total of four) of these studies found a protective effect of vegetable intake at least at a level of marginal significance in the major subgroups examined [36, 54, 56], and one found bread and cereal intake to be significantly associated with reduced risk for recurrence but not with risk of death [111]. Notably, findings from these observational studies of dietary factors and survival suggest that alcohol intake has no effect on survival. Of the eight of 13 studies that examined this relationship, none found a significant relationship, and a nonsignificant inverse association was observed in only one of them [36]. Several studies have examined selected aspects of dietary intakes and risk for recurrence and survival in women following the diagnosis of breast cancer. Sellers et al. [114] examined the association between folate intake and survival in 177 breast cancer cases treated with chemotherapy, testing the hypothesis that high folate intake could reduce the effectiveness of chemotherapy. Those investigators found no adverse effects of high folate intake on survival through 14 years of follow-up after chemotherapy for breast cancer. Using dietary data collected from 477 women at diagnosis of breast cancer, Goodwin et al. [45] explored whether nonlinear, rather than linear, relationships explained associations between intakes of macronutrients and survival. Indeed, their results suggest an association that may be U-shaped, with midrange intakes of energy-adjusted fat, protein, and carbohydrate intake associated with the most favorable outcomes. Results from studies that have examined the effects of combined dietary and other lifestyle factors indicate potential effects on breast cancer recurrence and/or survival in that context. Kroenke et al. [65] found that


a prudent dietary pattern (high in fruits, vegetables, whole grains, legumes, poultry, and fish) was associated with a 15% reduction in relative risk of overall mortality, and death from causes other than breast cancer (but not breast cancer mortality), when compared with a Western dietary pattern (characterized by refined grains, processed and red meats, desserts, high-fat dairy products, and French fries). In another cohort, the combination of consuming at least five servings/day of fruits and vegetables plus a level of physical activity equivalent to walking 30 minutes six days/week was associated with a 50% reduction in mortality in breast cancer survivors over 7-year follow-up [87], although both of these factors were not significantly protective alone. Women who are breast cancer survivors report a high frequency of use of dietary supplements, with estimates suggesting that the majority (approximately 81%) use dietary supplements regularly [84]. The relationship between use of antioxidant supplements and risk of breast cancer recurrence or survival was examined using data on dietary intakes and supplement use in 385 postmenopausal women who had been diagnosed with breast cancer [39]. Premorbid dietary intakes of vitamin C or vitamin E from diet, supplements or both showed no relationship with risks. During the follow-up period, antioxidant supplement use was reassessed, and use of these supplements was not significantly related to outcome when adjusted for other influencing factors. However, vitamin E supplements had a modest but nonsignificant protective effect when used for more than three years (odds ratio 0.33, 95% CI 0.10–1.07). Given the limitations of diet assessment methodologies and self-reported dietary data [121], follow-up studies based on biomarkers of diet from blood samples collected prior to disease onset and treatment, or following the completion of initial treatments, would be very informative. Only one such study has been reported to date, and the study involved examination of only two biomarkers in plasma samples collected after diagnosis but prior to surgery or adjuvant therapy. In that study [110], 317 cases were followed for a median of eight years post-diagnosis. An increased risk of recurrence was observed in patients with plasma lipoperoxide concentrations, which may be a biomarker for polyunsaturated fat intake, in the highest versus lowest tertile (RR 2.1, 95% CI 1.1–4.0), adjusted for age at diagnosis, menopausal status, and

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ER and progesterone receptor (PR) status. Adjusted for cholesterol concentration, as an indicator of the size of the plasma pool, plasma alpha-tocopherol concentration >22 umol/L (versus those with lower plasma concentrations) was found to be directly associated with an increased risk for death (adjusted RR 1.7, 95% CI 1.0–3.0) in that study. Thus, findings from observational epidemiological studies provide some evidence, although not entirely consistent, that there may be a relationship between dietary factors and survival following the diagnosis of breast cancer. Several mechanisms have been suggested to explain a possible effect of dietary factors, such as fat, fiber and vegetable intake, on breast cancer progression. Results from several feeding studies and short-term diet interventions involving healthy preand postmenopausal women have suggested that a lowfat diet may reduce serum estrogen concentrations, as summarized in a meta-analysis conducted by Wu et al. [130]. However, weight loss occurred in response to reduced fat intake in those studies in which a reduction in serum estrogen concentrations was observed, so dietary fat intake per se cannot be assumed to be the primary influencing factor. Other proposed mechanisms for an effect on fat intake on breast cancer progression include changes in phospholipid composition and fluidity of tumor cell and/or host immune cell membranes, changes in circulating gonadal hormone bioavailability, altered prostaglandin and leukotriene production, altered dynamics of fatty acid/growth factor interactions, and altered regulatory gene expression [19, 131]. In animals, high-fiber diets have been shown to reduce circulating estrogen concentrations via increased fecal excretion of these hormones [4], and high-fiber foods are good sources of other dietary constituents that may influence mammary carcinogeneis (e.g., indoles, isoflavones) [26]. Vegetables are among the primary dietary sources of carotenoids, and in cell culture studies, both retinoids (a product of carotenoids) and carotenoids have been shown to enhance cellular differentiation and to have marked inhibitory effects on mammary cell growth [95]. Both ER-positive and ER-negative mammary cancer cell lines are highly responsive to the beneficial cell growth regulatory effects of both vitamin A precursor and nonvitamin A precursor carotenoids [92, 119]. Another possible effect of dietary intakes on breast cancer progression relates to oxidative stress, because a diet

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with large amounts of antioxidants could theoretically reduce the risk for breast cancer by protecting against DNA damage and other free-radical-induced cellular changes that would promote mammary carcinogenesis. Vegetables and fruit provide numerous antioxidants, including flavonoids, vitamin C, and carotenoids. Two large randomized controlled trials have tested whether diet modification following the diagnosis of early stage breast cancer affects cancer outcomes. The Women’s Intervention Nutrition Study (WINS) tested a low-fat diet (35,000 men enrolled at >400 sites in the U.S. In 2008, the active treatment (supplementation) in this trial was halted because the supplements, taken alone or together for an average of five years, did not prevent prostate cancer. The study was designed to detect a 25% reduction in prostate cancer, and it was evident that effect was unlikely to be achieved even with continuation of treatment, based on the data examined at the five-year time point. Further, there were two findings that caused some concern, although these findings were not statistically significant. Slightly more cases of prostate cancer in men taking only vitamin E and slightly more cases of diabetes in men taking only selenium were observed. Most of the men enrolled in SELECT are to be followed for about three more years, so that their health status can be monitored. In a few small studies, the short-term effects of selected dietary constituents on various metabolic factors have been examined in men who had been diagnosed with prostate cancer. In response to three weeks of daily tomato sauce feeding (which provided 30 mg lycopene/day), a reduction in prostate tissue oxidative DNA damage and serum prostatespecific antigen (PSA) concentration was observed in 32 men with localized prostate adenocarcinoma preceding their scheduled radical prostatectomy [17]. In a small randomized clinical trial involving 26 men with clinically localized prostate cancer, the effect of administering 15 mg lycopene/day for three weeks prior to radical prostatectomy on biomarkers of cellular differentiation and apoptosis was examined [66]. Changes in the various biomarkers were not significantly different in the intervention versus control groups in that study. The effects of dietary fat restriction (

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