Evolving Approaches to Improve Outcomes and Minimize Toxicities in Radiation Therapy (Oncology)

Evolving Approaches to Improve Outcomes and Minimize Toxicities in Radiation Therapy San Francisco, Calif., USA, November 4, 2001

Guest Editor

Gillian M. Thomas, Toronto, Canada

24 figures and 17 tables, 1999

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Vol. 63, Suppl. 2, 2002

Contents

1

Foreword Thomas, G.M. (Toronto)

2

Radioprotectants: Current Status and New Directions Grdina, D.J.; Murley, J.S.; Kataoka, Y. (Chicago, Ill.)

11

Prevalence of Anemia in Cancer Patients Undergoing Radiotherapy: Prognostic Significance and Treatment Harrison, L.B.; Shasha, D.; Homel, P. (New York, N.Y.)

19

Raising Hemoglobin: An Opportunity for Increasing Survival? Thomas, G.M. (Toronto)

29

New Chemotherapeutic Agents: Update of Major Chemoradiation Trials in Solid Tumors Curran, W.J. (Philadelphia, Pa.)

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Oncology 2002;63(suppl 2):1 DOI: 10.1159/00067144

Foreword

A variety of techniques are now available to radiation oncologists to optimize treatment of cancers, including altered fractionation schedules, enhanced image guidance, intensity modulation allowing radiation dose escalation and improved brachytherapy techniques. In recent years, there has been increasing interest in the concurrent or sequential use of chemotherapeutic agents with radiosensitizing ability to enhance the effectiveness of radiotherapy. These agents include cisplatin, 5-fluorouracil, taxanes, topotecan, gemcitabine, vinorelbine, and tirapazamine. In certain malignancies (e.g., non-small-cell lung cancer, head and neck cancers, esophageal cancer and cervical cancer), concurrent chemotherapy and radiotherapy protocols have resulted in better tumor control and/or patient survival than with radiotherapy alone. The review by Dr. Curran in this supplement provides an update of recent clinical trials in this area, and emphasizes that while much has been achieved in the quest for new combined modality regimens capable of improving the outcomes for patients with cancer, important questions concerning the selection of patients, and the optimal dosages and timing of sequential therapies remain to be answered in future studies. Other evolving approaches to optimizing radiotherapy include the use of radioprotectants to reduce radiotherapy-induced toxicity without affecting its antitumor efficacy, cytotoxic agents such as mitomycin C to specifically target hypoxic tumor cells, and strategies to counter anemia such as treatment with epoetin alfa (recombinant human erythropoietin). It is postulated that anemia in cancer patients may result in a poor treatment outcome because of an increased resistance to radiation or chemotherapy. Radioprotectants currently under investigation include amifostine (WR-1065), which has been shown in experimental studies to prevent both radiation-induced cell death and radiation-induced mutagenesis. Moreover, this agent reduced the incidence of early and late radiotherapy-induced xerostomia in a multicenter clinical

ABC

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study of patients with head and neck cancers. Other potential applications of amifostine are reviewed in the article by Dr. Grdina and colleagues, along with recent advances in the development of newer cytoprotectants to reduce the acute and chronic toxicities associated with high-dose treatment strategies and aggressive combined modality protocols. The occurrence of anemia in cancer patients is an often overlooked complicating factor that is associated with poorer outcome possibly by decreasing the response to radiotherapy, presumably via lowering the oxygen-carrying capacity of the blood and thus exacerbating intratumoral hypoxia. In addition, anemia has an adverse effect on the quality of life of cancer patients, as evidenced by the increased fatigue that has been associated with low hemoglobin levels. Studies in various types of cancers have indicated that a high proportion of patients are anemic prior to or during radiotherapy, and that low hemoglobin levels are associated with poor clinical outcomes with radiotherapy. As emphasized in other articles in this supplement, these findings underline the importance of early detection and treatment of anemia in cancer patients. Administration of epoetin alfa to correct anemia has been reported to enhance locoregional response rates to chemoradiation therapy in patients with certain types of cancers (e.g., oropharyngeal squamous cell carcinomas) and to improve quality of life. Whether epoetin alfa therapy will also increase long-term survival is currently being investigated. Other ongoing studies are investigating whether epoetin alfa may also be effective in protecting against radiotherapy-induced neurotoxicity. The challenge for the future is to utilize our present knowledge to optimize the management of cancer patients undergoing radiotherapy or combined modality protocols with the objective of improving both the outcome of treatment and quality of life. Gillian M. Thomas

Gillian M. Thomas Radiation Oncology, Obstetrics & Gynecology University of Toronto Toronto-Sunnybrook Regional Cancer Centre Toronto, Onta. (Canada)

Oncology 2002;63(suppl 2):2–10 DOI: 10.1159/000067146

Radioprotectants: Current Status and New Directions David J. Grdina Jeffrey S. Murley Yasushi Kataoka Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, Ill., USA

Key Words Cytoprotection W Radiotherapy W Radiation-induced toxicity W Mutagenesis W Amifostine W Thiol compounds

Abstract The ability to prevent radiotherapy-induced toxicity without affecting antitumor efficacy has the potential to enhance the therapeutic benefit for cancer patients without increasing their risk of serious adverse effects. Among the currently available cytoprotective agents capable of protecting normal tissue against damage caused by either chemo- or radiotherapy, only amifostine has been shown in clinical trials to reduce radiationinduced toxicity. Most notably, it reduces the incidence of xerostomia, which is a clinically significant long-term toxicity arising in patients undergoing irradiation of head and neck cancers. In vitro studies with the active metabolite of amifostine (WR-1065) have shown it to prevent both radiation-induced cell death and radiation-induced mutagenesis. The potential of this agent to prevent secondary tumors, as well as other radiation-induced toxicities is now the focus of ongoing research. Among other novel approaches to radioprotection being explored are methods to increase levels of the antioxidant mitochondrial enzyme manganese superoxide dismutase

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(MnSOD). In addition, the use of epoetin alfa, alone or in combination with cytoprotectants (e.g., amifostine), to treat radiation-induced anemia is also being investigated. The objective of developing newer cytoprotective therapies is to improve the therapeutic ratio by reducing the acute and chronic toxicities associated with more intensive and more effective anticancer therapies. Copyright © 2002 S. Karger AG, Basel

Introduction

Radiotherapy is toxic not only toward cancer cells but also to healthy cells, particularly those with a high rate of proliferation, which may result in serious adverse effects for patients. The risk of cell toxicity is increased with the application of more intensive radiotherapy techniques intended to increase tumor cell kill. Radiation-induced adverse effects commonly include mucositis and/or dermatitis, and are usually managed symptomatically as they manifest. However, preventing these complications is clearly more desirable, and various approaches to reducing radiation-induced toxicities while maintaining antitumor efficacy have been investigated. These include altered radiation dose fractionation, the use of physical shielding or intensity modulated radiation therapy to

David J. Grdina Department of Radiation and Cellular Oncology University of Chicago Medical Center, MC 1105 5841 S. Maryland Avenue, Chicago, IL 60637 (USA) Tel. +1 773 702 5250, Fax +1 773 702 5940, E-Mail [email protected]

Pharmacologic Strategies for Cytoprotection of Normal Cells

In recent years, a number of cytoprotective agents capable of protecting normal tissue against damage caused by either chemo- or radiotherapy have been developed. As a result of studies implicating toxic metabolites of chemotherapeutic agents and/or the generation of highly reactive species or free radicals in the etiology of DNA damage [3–5], a number of different strategies have been proposed for cytoprotection of normal cells, including: E preventing the generation of toxic metabolites of chemotherapeutic agents; E enhancing the elimination of toxic metabolites of chemotherapeutic agents; E neutralizing DNA adduct-forming metabolites; E detoxifying free radicals. A number of compounds have been investigated with the objective of providing site-specific protection for normal tissues without compromising the antitumor efficacy of chemotherapeutic agents and/or radiotherapy, including amifostine (WR-2721), dexrazoxane, mesna, glutathione, and N-acetylcysteine. Among these, amifostine, dexrazoxane and mesna have FDA approval for use in cytoprotection. Amifostine Amifostine (WR-2721) is a nucleophilic sulfur prodrug that is dephosphorylated in vivo by membrane-bound alkaline phosphatase to the active, free thiol metabolite

Prevention of Radiation-Induced Toxicity

100

Probability of tumor control or normal tissue damage (%)

reduce the volume of exposure, and pharmacologic approaches. The latter can be divided into radiosensitizers which ideally differentially enhance the sensitivity of tumors rather than normal tissue, and radioprotectants to reduce the detrimental effects of radiation on normal tissue while maintaining tumor sensitivity [1, 2]. This article reviews the current status of radioprotectants in cancer therapy and provides an insight into some of the new directions that research in this area is taking. Typical response curves illustrating the probability of tumor control and normal tissue damage at varying radiation doses are shown in figure 1. The objective of radioprotection is to shift the response curve for normal tissue as far as possible to the right to achieve the highest probability of tumor control with the least amount of damage to normal tissue. The ideal radioprotectant is one that protects normal tissue while preserving antitumor effectiveness, and is itself without moderate or severe toxicity.

75

Tumor Normal tissue

50

25

0

A B Radiation dose

C

Fig. 1. Tumor and normal tissue response curves to radiotherapy, illustrating the probability of tumor control and normal tissue damage at varying radiation doses (reproduced with permission from Hall [12]).

WR-1065. This metabolite is then oxidized to the disulfide form WR-33278 [4–6]. Numerous preclinical studies have shown that amifostine protects normal cells against the adverse effects of both radiation and chemotherapeutic agents (e.g., alkylating agents, platinum compounds, anthracyclines and taxanes) without attenuating their cytotoxic effects on large solid tumors. This selective protection is due, in part, to the more efficient conversion and uptake of the active metabolite WR-1065 in normal tissue in comparison with neoplastic tissue, as a result of the higher alkaline phosphatase activity, greater vascularization, and higher pH of normal tissue [4–6]. Following intravenous administration, amifostine is rapidly and extensively taken up by normal tissue. Animal studies have indicated that maximal concentrations of the active metabolite WR-1065 occur 5–15 min after administration [7]. Uptake of WR-1065 in normal tissue is not uniform, and appears to be greatest in the kidney, salivary glands, intestinal mucosa, liver and lung [6]. Once inside the cell, WR-1065 protects against chemotherapy- and radiotherapy-induced DNA damage by (1) binding to and neutralizing the reactive species of organoplatinum and alkylating agents, thus preventing formation of adducts with DNA, and (2) scavenging free radicals [5–7].

Oncology 2002;63(suppl 2):2–10

3

Table 1. Net charges of thiol compounds with putative cytoprotec-

tive activity Compound

Net charge

WR-33278 (disulfide metabolite of amifostine) WR-1065 (free thiol metabolite of amifostine) Cystamine Cysteamine Captopril Dithiothreitol (DTT) 2-Mercaptoethanol (2-ME) N-Acetyl-L-cysteine (L-NAC) N-Acetyl-D-cysteine (D-NAC) Mesna Glutathione, reduced (GSH) Glutathione, oxidized (GSSG)

+4 +2 +2 +1 0 0 0 –1 –1 –1 –1 –2

The efficacy of amifostine in protecting cancer patients against radiotherapy-induced toxicity is discussed below. Currently, amifostine has FDA approval to reduce the incidence of xerostomia in patients undergoing radiation treatment for head and neck cancers. It is also approved to reduce cumulative renal toxicity associated with cisplatin treatment in patients with ovarian cancer or non-smallcell lung cancer. Dexrazoxane Dexrazoxane (ICRF-187) is a cyclic derivative of the metal-chelating agent ethylenediamine-tetraacetic acid (EDTA) that provides protection against the cardiotoxicity of anthracycline-based chemotherapeutic agents, such as doxorubicin. Although the risk of cardiotoxicity appears to be reduced with newer formulations, such as peglyated liposomal doxorubicin [8], cardiotoxicity is a well-recognized, serious, treatment-limiting adverse effect of these compounds. It occurs via the generation of reactive oxygen species, which are highly toxic to cardiac tissues, by the stable complexes formed between anthracycline drugs and iron [9]. The cardioprotective effect of dexrazoxane is believed to result from its intracellular metabolism to a ring-opened hydrolysis product (ICRF198), which is a strong chelator of free and bound intracellular iron in the myocardium. As a consequence, the amount of iron available to form complexes with anthracyclines is reduced and formation of the reactive oxygen species is blocked. Importantly, the protective effect of dexrazoxane against the cardiotoxicity of anthracycline drugs occurs without affecting their antitumor activity. This may be due, in part, to differences in the intracellular

4

Oncology 2002;63(suppl 2):2–10

metabolism of dexrazoxane and/or differences in its uptake between normal cardiac cells and tumor cells [5, 9–11]. Currently, dexrazoxane has FDA approval to reduce the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received cumulative doses 1300 mg/m2. Mesna Mesna (sodium 2-mercaptoethane sulfonate) was developed as a specific chemoprotectant against the toxicity of acrolein, a urotoxic metabolite of oxazaphosphorinebased alkylating agents (e.g., ifosfamide and cyclophosphamide), which produces hemorrhagic cystitis following its excretion into the urinary bladder. Following intravenous administration, mesna is converted into an inactive disulfide form in the blood and is then metabolized back to mesna in the urinary tract where its free sulfhydryl groups bind to and inactivate acrolein, forming a stable, non-toxic thioether that is rapidly excreted in the urine. Mesna also inhibits the further formation of acrolein in the bladder. Because its activity is restricted to the urinary tract, the systemic activity and non-urologic toxicity of oxazaphosphorine drugs are not affected [4, 5]. Currently, mesna has FDA approval for the prophylaxis of ifosfamide-induced hemorrhagic cystitis.

Relationship Between the Net Charge of Thiol Compounds and Their Ability to Protect Against Radiation-Induced DNA Damage

The mechanism by which radiation induces DNA damage is slightly different to that of chemotherapeutic agents. Radiation-induced damage is introduced into a genome by either a direct action, where the energy is deposited directly on the genome, or indirectly via the formation of free radicals which are responsible for the resultant cell killing, mutagenesis, transformation, and carcinogenesis. The latter mechanism, which accounts for about 75% of radiation-induced DNA damage by photons, can be abrogated with free radical scavengers present in the local microenvironment at the time the free radicals are formed. However, in the case of direct damage, there are no known radioprotectants as this process occurs too rapidly to be prevented by a pharmacologic agent [12]. Studies performed several years ago by Fahey et al. have shown that the net charge of thiol compounds with putative cytoprotective activity (table 1) markedly in-

Grdina/Murley/Kataoka

1.0

a

a Surviving fraction of cells

Surviving fraction of cells

1.0

0.1

60

0.1

60

Co g-radiation

Co γ - radiation

WR - 1065 after

WR-1065 before Co γ-radiation

60

Co γ - radiation

60

0.01 100 HPRT mutants per 106 survivors

HPRT mutants per 106 survivors

0.01 100

b

80 60 40 20

0

b

80

60

40

20

0

0

2

4 60

6

8

10

12

0

2

Co g dose (Gy)

4 60

6 8 Co γ dose (Gy)

10

12

Fig. 2. Response to varying doses of 60Co Á-radiation of V79 Chinese

Fig. 3. Response to varying doses of 60Co Á-radiation of V79 Chinese

hamster lung fibroblast cells in the absence or presence of WR-1065 4 mmol/l added to cell cultures 30 min before irradiation and allowed to remain until 3 h after irradiation. a Surviving fraction of cells. b Mutation induction at the HPRT (hypoxanthine-guanine phosphoribosyl transferase) locus among surviving cells that were grown in a non-selective medium for 6 days and then exposed to 6-thioguanine 5 Ìg/ml in ·-MEM-10 medium (containing hypoxanthine, aminopterin and thymidine) for 7 days and stained with 0.5% methylene blue. Bars indicate the standard errors of the mean of two or more replicate experiments (reproduced with permission from Grdina et al. [15]).

hamster lung fibroblast cells exposed immediately after irradiation to WR-1065 4 mmol/l added to cell cultures and allowed to remain for 3 h. a Surviving fraction of cells. b Mutation induction at the HPRT (hypoxanthine-guanine phosphoribosyl transferase) locus among surviving cells (assessed as described in fig. 2). The broken lines represent the radiation-only curves and are presented for comparison. Bars represent the standard errors of the mean of two or more replicate experiments (reproduced with permission from Grdina et al. [15]).

fluences the degree of protection that they provide against the DNA-damaging effects of radiation [13, 14]. Because WR-1065 has a net charge of +2, it will be attracted to DNA (which is negatively charged) and is therefore more likely to exert a protective effect against radiationinduced damage than a compound with a net charge of 0 or a negative net charge. Evidence in support of this hypothesis has come from studies with WR-1065, captopril, and N-acetylcysteine in Chinese hamster lung fibroblast and ovary cells.

Protective Effect of WR-1065 (Amifostine Metabolite) Studies in our institution using V79 Chinese hamster lung fibroblast cells have shown that WR-1065 in a concentration of 4 mmol/l protects against radiation-induced cell death when added to cell cultures 30 min before various doses of 60Co Á-radiation, but not when it is added immediately after irradiation (fig. 2a, 3a). This treatmentschedule dependence in the protective effect of WR-1065 is to be expected if it is acting as a free radical scavenger, since protection could only be expected to occur when the compound is present during irradiation [15].

Prevention of Radiation-Induced Toxicity

Oncology 2002;63(suppl 2):2–10

5

10 0

10 0

Co γ-radiation

60

Surviving fraction of cells

Surviving fraction of cells

60

10 -1

10 -1

Radiation only 10

Radiation + 4 mmol/l N-acetylcysteine Radiation + 0.04 mmol/l N-acetylcysteine

-2

Without captopril With 1 mmol/l captopril

10 -2

Co -radiation

10 - 3

0

200

400

600

800

1,000

60

Co γ dose (cGy)

0

200

400 600 Co γ dose (cGy)

800

1,000

60

Fig. 4. Surviving fractions of Chinese hamster ovary (CHO)-AA8 cells exposed to varying doses of 60Co Á-radiation in the absence or presence of captopril 1 mmol/l added to the cell cultures 30 min prior to irradiation (Grdina DJ, unpubl. data).

Fig. 5. Surviving fractions of Chinese hamster ovary (CHO)-AA8 cells exposed to varying doses of 60Co Á-radiation in the absence or presence of N-acetylcysteine 0.04 mmol/l and 4 mmol/l added to the cell cultures 30 min prior to irradiation (Grdina DJ, unpubl. data).

As well as increasing the surviving fraction of cells when administered before irradiation, WR-1065 has also been shown to reduce the degree of radiation-induced mutagenesis in V79 Chinese hamster lung fibroblast cells (expressed as the HPRT mutant frequency per 106 survivors exposed to 6-thioguanine 5 Ìg/ml) (fig. 2b). In contrast to the treatment-schedule dependence for the protective effect against cell killing, the antimutagenic effect of WR-1065 is also observed when it is administered after irradiation (fig. 3b), indicating that its post-irradiation action can effectively alter mutation induction in surviving cells [16].

of a protective effect against radiation-induced cell killing with either drug (fig. 4, 5) [Grdina DJ, unpubl. data]. Thus, key factors governing the radioprotective efficacy of a drug acting as free radical scavenger are: (1) an ability to concentrate within the nucleus or microenvironment of DNA (dependent on its net charge), and (2) the presence of the protectant at the radiation target at the time it is irradiated (important for prevention of cell death). No clinical advantage is achieved if the protector does not differentially protect normal tissues compared to tumor.

Lack of Protective Effect of Captopril and N-Acetylcysteine Because the net charges of captopril and N-acetylcysteine are 0 and –1, respectively, these thiol compounds would not be expected to concentrate within the negatively charged nucleus or the microenvironment of DNA to the same extent as those with positive net charges. Studies using Chinese hamster ovary (CHO)-AA8 cells exposed to various doses of 60Co Á-radiation in the absence or presence of captopril 1 mmol/l and N-acetylcysteine 0.04 mmol/l or 4 mmol/l have shown no evidence

6

Oncology 2002;63(suppl 2):2–10

Dose-Response Considerations with Amifostine: Prevention of Cell Death vs Prevention of Mutagenesis

The protection factor achievable with a radioprotectant is defined as the ratio of surviving cell fraction for treated cells as compared with untreated cells following radiation exposure. The clinical potential of a putative radioprotectant depends on the tolerability of the drug at a dosage required to achieve a particular protection factor. In studies conducted at our institution using CHO-

Grdina/Murley/Kataoka

8

Protection factor (cell survival)

AA8 cells, the protection factor for cell survival with the amifostine metabolite WR-1065 (i.e., the ratio of cell surviving fractions for WR-1065-treated versus untreated cells) was determined at various concentrations of WR1065 added to the incubation medium 30 minutes prior to exposure to a radiation dose of 750 cGy from a 60Co Á-ray source. As shown in figure 6, the protection factor fell sharply from 16 to around 3 as the concentration of WR-1065 was decreased from 4 to 1 mmol/l, and then declined further to essentially no protection at lower concentrations of 0.01–0.1 mmol/l. In contrast, the protection against mutagenesis (expressed as the HPRT mutant frequency per 106 survivors exposed to 6-thioguanine 5 Ìg/ml) remained largely constant over the same WR-1065 concentration range (0.01–4 mmol/l). This suggests that the mechanism by which WR-1065 provides protection against mutagenesis differs from that for protection against cell killing, and that the antimutagenic effect can be achieved at lower concentrations (as low as 0.01 mmol/l) [16]. Viewed in relation to therapeutic use of amifostine, the concentrations of WR-1065 achieved with dosages of amifostine used clinically are in the range 1.5–3.85 mmol/l [17], which suggests that the degree of cytoprotection provided at antimutagenic dosages are insufficient to increase survival of either normal or neoplastic cells. However, its effect in reducing the risk of radiation-induced mutagenesis, carcinogenesis, and secondary tumors is of considerable interest and this area is now an important focus for ongoing research into the protective effects of amifostine, particularly in view of increasing evidence that the risk of secondary tumors is increased as cancer therapies become more effective and, coincidentally, more damaging to normal tissues.

6

4

2

0 1 0.01 0.1 WR-1065 concentration (mmol/l)

4

Fig. 6. Protection factor for survival of Chinese hamster ovary (CHO)-AA8 cells (i.e., the ratio of cell surviving fractions for WR1065-treated to untreated cells) at varying concentrations of WR1065 added to the incubation medium 30 min prior to exposure to a radiation dose of 750 cGy from a 60Co Á-ray source. All plot points are the average of three separate experiments and the bars represent the standard errors of the mean (reproduced with permission from Grdina et al. [16]).

Clinical trials of the radioprotective effect of amifostine have been undertaken in patients receiving radiotherapy for head and neck, pelvic, and thoracic cancers [6]. Thus far, most studies have involved relatively small numbers of patients but have generally demonstrated significant reductions in the incidence of radiation-induced local toxicities. In the largest trial conducted to date, the efficacy of amifostine in ameliorating the adverse effects of radiotherapy and its influence on the clinical effectiveness of radiotherapy were evaluated in patients with previously untreated head and neck squamous cell carcino-

mas [18]. Patients in this multicenter study (n = 303) received radiotherapy in a dose of 1.8 to 2.0 Gy/day for 30 to 35 fractions (total dose 50–70 Gy), approximately half of whom (n = 153) were randomized to receive amifostine (200 mg/m2 intravenously over 3 min) 15 to 30 min before irradiation and half to receive radiotherapy alone (n = 150). As shown in table 2, amifostine significantly reduced the incidence of both early xerostomia within the first 90 days (as well as the cumulative radiotherapy dose required to cause this adverse effect) and late xerostomia at 1 year after initiation of radiotherapy, although it did not significantly reduce the incidence of acute mucositis. Patients who received amifostine were also found to produce more saliva than those treated with radiotherapy alone (median saliva production 0.26 vs 0.10 g; p = 0.04). When overall survival data for the two groups of patients were compared, there was a slight advantage for those receiving amifostine (fig. 7), but the difference was not statistically significant. Nor was there any significant dif-

Prevention of Radiation-Induced Toxicity

Oncology 2002;63(suppl 2):2–10

Clinical Studies of Amifostine as a Radioprotectant

7

100 (124) 90

(104)

80

(119)

Percent survival

70

Fig. 7. Percentages of survivors over a peri-

od of 27 months among patients with previously untreated head and neck squamous cell carcinomas who were randomized to receive either amifostine (200 mg/m2 i.v. over 3 min) 15–30 min before radiotherapy doses of 1.8–2 Gy/day for 30 to 35 fractions (total 54–70 Gy) or similar doses of radiotherapy alone. The numbers of patients at risk at 12 and 18 months are indicated in parentheses (reproduced with permission from Brizel et al. [18]).

Table 2. Incidence of acute and late

xerostomia 6grade 2 (RTOG acute/late morbidity scoring criteria) in patients with head and neck squamous cell carcinomas who received radiotherapy with or without amifostine (200 mg/m2 i.v. 15–30 min prior to irradiation) [18]

(98)

60 50 40

Amifostine + radiotherapy

30

Radiotherapy alone

Total No. Events of patients 34 153 45

180

Log-rank: p = 0.184 Hazard ratio: 1.351 (95% Cl 0.865 - 2.109)

20 10 0 0

6

3

Complication

Acute xerostomiaa Incidence (% of patients) Cumulative radiotherapy dose to onset

9

12

15 Months

18

21

24

27

Amifostine plus radiotherapy (n = 153)

Radiotherapy alone (n = 150)

p value

51%

78%

! 0.0001

60 Gy

42 Gy

! 0.0001

34%

57%

! 0.002

xerostomiab

Late Incidence (% of patients)

a b

RTOG = Radiation Therapy Oncology Group. Within 90 days of initiation of radiotherapy. At 1 year after initiation of radiotherapy.

ference between the two groups in locoregional tumor control rates. Thus, amifostine significantly reduced acute and chronic xerostomia in these patients without compromising the antitumor effectiveness of radiotherapy [18].

Potential Future Applications of Amifostine

Other potential roles for amifostine that are being explored include reducing renal toxicity associated with cisplatin treatment in ovarian cancer and non-small-cell

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Oncology 2002;63(suppl 2):2–10

lung cancer and reduction of toxicities associated with doxorubicin- and paclitaxel-containing regimens, highdose chemotherapies, and multimodality chemotherapy and radiotherapy for a variety of solid tumors. Possible prevention of secondary tumors (see above), is also being explored. In addition, the observation that amifostine may stimulate bone marrow progenitor cells has led to studies of its use as a potential treatment for patients with myelodysplastic syndrome. As yet, however, clinical data are limited and its value in this setting remains to be clarified [6].

Grdina/Murley/Kataoka

New Advances in Cytoprotection

A number of newer potential radioprotectants are currently undergoing preclinical research, including: (1) The amifostine analog S-[2-(3-methylaminopropyl) aminoethyl] phosphorothioate acid, which is orally bioavailable and less toxic than amifostine; (2) thiolamine compounds with thioglycoside-protecting groups; (3) covalent conjugates of thioamines and antioxidant vitamins, and (4) selenazolidine prodrugs. In addition, other approaches to radioprotection are also being explored. These include altering endogenous levels of antioxidant enzymes (specifically the mitochondrial enzyme manganese superoxide dismutase [MnSOD] which protects against oxidative stress induced by various agents including irradiation), and enhancement of erythropoiesis to treat the anemia that commonly occurs during irradiation (see review by Harrison in this supplement). Novel approaches that are currently being investigated include: E The use of MnSOD plasmid/liposome complex gene therapy to protect against radiation-induced esophagitis. Improved tolerance of the esophageal epithelium to fractionated radiation has recently been demonstrated with this approach in a mouse model [19, 20]. E The use of nonprotein thiol-containing compounds to activate MnSOD gene expression, e.g., the amifostine

metabolites WR-1065 and WR-33278, N-acetylcysteine, mesna, captopril, oltipraz, and dithiothreitol [21–23]. In human microvascular endothelial cells, exposure to WR-1065 0.04 mmol/l for 30 min has been shown to cause an increase in MnSOD gene expression that begins about 12 h after exposure to WR-1065, peaks at 16 to 18 h, and ends after about 22 h [21]. E The use of epoetin alfa (recombinant human erythropoietin; r-HuEPO) alone or in combination with cytoprotectants (e.g., amifostine) to treat radiation-induced anemia. The interaction of amifostine with epoetin alfa may produce a synergy in gene activation/expression (e.g., of the c-myb gene thereby leading to an increase in hematopoietic progenitor cells), as well as an increase in myeloproliferation and a reduction of genomic instability [24–26]. The objective of developing newer cytoprotective therapies is to be able to reduce the acute and cumulative toxicities associated with more intensive and more effective therapeutic anticancer regimens now being introduced into clinical practice, whether delivered as radiotherapy, chemotherapy, or combined modality regimens. The merging of these technologies will, it is hoped, enhance the therapeutic benefit for cancer patients without increasing their risk of serious adverse effects, and thus improving both their quality and duration of life.

References 1 Curran WJ: Radiation-induced toxicities: the role of radioprotectants. Semin Radiat Oncol 1998;8(4 suppl 1):2–4. 2 Brizel DM: Future directions in toxicity prevention. Semin Radiat Oncol 1998;8(4 suppl 1):17–20. 3 Schuchter LM: Current role of protective agents in cancer treatment. Oncology (Huntingt) 1997;11:505–512, 515–518. 4 Hoekman K, van der Vijgh WJF, Vermorken JB: Clinical and preclinical modulation of chemotherapy-induced toxicity in patients with cancer. Drugs 1999;57:133–155. 5 Links M, Lewis C: Chemoprotectants: A review of their clinical pharmacology and therapeutic efficacy. Drugs 1999;57:293–308. 6 Culy CR, Spencer CM: Amifostine: an update on its clinical status as a cytoprotectant in patients with cancer receiving chemotherapy or radiotherapy and its potential therapeutic application in myelodysplastic syndrome. Drugs 2001;61:641–684. 7 Schuchter LM: Guidelines for the administration of amifostine. Semin Oncol 1996;23(4 suppl 8):40–43.

Prevention of Radiation-Induced Toxicity

8 Safra T, Muggia F, Jeffers S, Tsao-Wei DD, Groshen S, Lyass O, Henderson R, Berry G, Gabizon A: Pegylated liposomal doxorubicin (doxil): reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m2. Ann Oncol 2000;11:1029– 1033. 9 Wiseman LR, Spencer CM: Dexrazoxane: a review of its use as a cardioprotective agent in patients receiving anthracycline-based chemotherapy. Drugs 1998;56:385–403. 10 Hasinoff BB: The iron(III) and copper(II) complexes of adriamycin promote the hydrolysis of the cardioprotective agent ICRF-187 ((+)-1,2bis(3,5-dioxopiperazinyl-1-yl)propane). Agents Actions 1990;29:374–381. 11 Koning J, Palmer P, Franks CR, Mulder DE, Speyer JL, Green MD, Hellmann K: Cardioxane – ICRF-187 towards anticancer drug specificity through selective toxicity reduction. Cancer Treat Rev 1991;18:1–19.

12 Hall EJ: Radiobiology for the radiologist, ed 5. Philadelphia, Lippincott Williams & Wilkins, 2000. 13 Zheng S, Newton GL, Gonick G, Fahey RC, Ward JF: Radioprotection of DNA by thiols: relationship between the net charge on a thiol and its ability to protect DNA. Radiat Res 1988;114:11–27. 14 Zheng S, Newton GL, Ward JF, Fahey RC: Aerobic radioprotection of pBR322 by thiols: effect of thiol net charge upon scavenging of hydroxyl radicals and repair of DNA radicals. Radiat Res 1992;130:183–193. 15 Grdina DJ, Nagy B, Hill CK, Wells RL, Peraino C: The radioprotector WR1065 reduces radiation-induced mutations at the hypoxanthine-guanine phosphoribosyl transferase locus in V79 cells. Carcinogenesis 1985;6:929–931. 16 Grdina DJ, Shigematsu N, Dale P, Newton GL, Aguilera JA, Fahey RC: Thiol and disulfide metabolites of the radiation protector and potential chemopreventive agent WR-2721 are linked to both its anti-cytotoxic and anti-mutagenic mechanisms of action. Carcinogenesis 1995;16:767–774.

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17 Shaw LM, Bonner HS, Schuchter L, Schiller J, Lieberman R: Pharmacokinetics of amifostine: effects of dose and method of administration. Semin Oncol 1999;26(2 suppl 7):34–36. 18 Brizel DM, Wasserman TH, Henke M, Strnad V, Rudat V, Monnier A, Eschwege F, Zhang J, Russell L, Oster W, Sauer R: Phase III randomized trial of amifostine as a radioprotector in head and neck cancer. J Clin Oncol 2000;18: 3339–3345. 19 Epperly MW, Gretton JA, DeFilippi SJ, Greenberger JS, Sikora CA, Liggitt D, Koe G: Modulation of radiation-induced cytokine elevation associated with esophagitis and esophageal stricture by manganese superoxide dismutaseplasmid/liposome (SOD2-PL) gene therapy. Radiat Res 2001;155:2–14.

10

20 Epperly MW, Kagan VE, Sikora CA, Gretton JE, Defilippi SJ, Bar-Sagi D, Greenberger JS: Manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) administration protects mice from esophagitis associated with fractionated radiation. Int J Cancer 2001;96:221–231. 21 Murley JS, Kataoka Y, Hallahan DE, Roberts JC, Grdina DJ: Activation of NFkappaB and MnSOD gene expression by free radical scavengers in human microvascular endothelial cells. Free Radic Biol Med 2001;30:1426– 1439. 22 Das KC, Lewis-Molock Y, White CW: Activation of NF-kappa B and elevation of MnSOD gene expression by thiol-reducing agents in lung adenocarcinoma (A549) cells. Am J Physiol 1995;269(5 Pt 1):L588–L602. 23 Antras-Ferry J, Maheo K, Chevanne M, Dubos MP, Morel F, Guillouzo A, Cillard P, Cillard J: Oltipraz stimulates the transcription of the manganese superoxide dismutase gene in rat hepatocytes. Carcinogenesis 1997;18:2113– 2117.

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24 List AF: Use of amifostine in hematologic malignancies, myelodysplastic syndrome, and acute leukemia. Semin Oncol 1999;26(2 suppl 7):61–65. 25 Jongen-Lavrencic M, Peeters HR, Vreugdenhil G, Swaak AJ: Interaction of inflammatory cytokines and erythropoietin in iron metabolism and erythropoiesis in anaemia of chronic disease. Clin Rheumatol 1995;14:519–525. 26 Zhu J, Heyworth CM, Glasow A, Huang QH, Petrie K, Lanotte M, Benoit G, Gallagher R, Waxman S, Enver T, Zelent A: Lineage restriction of the RARalpha gene expression in myeloid differentiation. Blood 2001;98:2563– 2567.

Grdina/Murley/Kataoka

Oncology 2002;63(suppl 2):11–18 DOI: 10.1159/000067147

Prevalence of Anemia in Cancer Patients Undergoing Radiotherapy: Prognostic Significance and Treatment Louis B. Harrison a Daniel Shasha a Peter Homel b a Department b Department

of Radiation Oncology, Beth Israel Medical Center/St Luke’s-Roosevelt Hospital Center; of Grants and Research, Beth Israel Medical Center, New York, N.Y., USA

Key Words Radiotherapy W Anemia W Hypoxia W Radiation-induced toxicity W Epoetin alfa W Quality of life Abstract As the antitumor activity of radiation is mediated via its interaction with oxygen to form labile free radicals, the intratumoral oxygen level has an important influence on the ability of radiation therapy to kill malignant cells. By decreasing the oxygen-carrying capacity of the blood, anemia may result in tumor hypoxia and may have a negative influence on the outcome of radiotherapy for various malignancies, even for small tumors not normally assumed to be hypoxic. In addition, anemia also has a negative effect on the quality of life of cancer patients, as evidenced by worsening fatigue. As a high proportion (about 50%) of cancer patients undergoing radiotherapy are anemic prior to or during treatment, strategies to correct anemia and/or the resultant tumor hypoxia are increasingly being considered an important component of treatment. In particular, epoetin alfa (recombinant human erythropoietin), which has proved an effective and well-tolerated means of raising hemoglobin levels in anemic patients receiving radiotherapy, potentially could reverse the negative prognostic influence of a low

ABC

© 2002 S. Karger AG, Basel 0030–2414/02/0636–0011$18.50/0

Fax + 41 61 306 12 34 E-Mail [email protected] www.karger.com

Accessible online at: www.karger.com/ocl

hemoglobin in patients with certain malignancies. Radiation oncologists need to be aware of the possibility of anemia in cancer patients undergoing radiotherapy so that timely intervention can be instituted whenever anemia is diagnosed. Copyright © 2002 S. Karger AG, Basel

Introduction

The objective of radiotherapy in cancer treatment is to maximize locoregional tumor control and patient survival. As the antitumor activity of radiation is known to be mediated via its interaction with oxygen to form labile free radicals, the intratumoral oxygen level has an important influence on the number of free radicals produced within a tumor and thus on the ability of radiation therapy to induce DNA damage in malignant cells. Consequently, the presence of acute or chronic anemia, which may decrease the oxygen-carrying capacity of the blood and results in tumor hypoxia, lowers the propensity of radiotherapy to produce DNA damage and is an obstacle to achieving maximal locoregional tumor control [1–3]. It has been estimated that the dose of radiation required to kill tumor cells under hypoxic conditions is 2 to 3 times

Louis B. Harrison, MD Department of Radiation Oncology, Beth Israel Medical Center 10 Union Square East, New York, NY 10003 (USA) Tel. +1 212 844-8087, Fax +1 212 844-8086 E-Mail [email protected]

Fraction of survivng cells

1

Hypoxic Normoxic

0.1

0.01

OER = 1,750 ⴜ 700 = 2.5

0.001 0 200

400

600

800 1,000 1,200 1,400 1,600 1,800 2,000

Radiation dose (cGy)

Fig. 1. Enhancement of radiation resistance by hypoxia. The oxygen enhancement ratio (OER) is the ratio of the radiation dose required to kill a given fraction of malignant cells in a hypoxic environment in relation to that in a normoxic environment.

the dose required in a normoxic environment (fig. 1). Hypoxia has also been found to produce mutations of the p53 suppressor gene, which results in an increase in angiogenesis and an increased tendency for the development of distant metastases. Thus, overcoming hypoxia may have positive effects on not only locoregional tumor control but also on decreasing the risk of developing metastatic disease [1, 3]. Hypoxia is a common characteristic of solid tumors. Athough the number and size of their hypoxic regions varies substantially [1], hypoxia may be present in even small tumors at an early stage of development. In the past, the prevalence of anemia and tumor hypoxia in cancer patients receiving radiotherapy has been an underappreciated problem that has frequently led to undertreatment. This article reviews the prevalence of anemia in patients undergoing radiotherapy, and emphasizes that effective reversal of anemia can be achieved. Until recently, little attention has been paid to hemoglobin levels in cancer patients.

Prognostic Significance of Anemia in Cancer Patients

Relationships between low hemoglobin levels and intratumoral hypoxia, and between intratumoral hypoxia and a less favorable prognosis in various cancers have been identified in studies in which oxygen partial pressures (pO2) were measured in tumor tissue [4–7]. In

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Oncology 2002;63(suppl 2):11–18

patients with head and neck cancers, a pretreatment hemoglobin level !11.0 g/dl was found to be a stronger predictor of poor tumor oxygenation than other factors such as tumor stage, tumor volume and smoking status [4]. Even prostate tumors, which are generally not considered to be hypoxic, have been reported to be associated with significantly lower pO2 levels in comparison with pathologically normal prostate tissue and muscles, particularly in patients with more advanced (T2/T3) prostatic tumors and in older individuals (662 years of age) [5]. Effect on Locoregional Tumor Control and Survival Recent studies have demonstrated an important relationship between anemia on locoregional tumor control and patient survival, principally in head and neck cancers. In patients with early stage glottic cancers, which are amongst the smallest tumors treated by oncologists, a clear relationship has been demonstrated between the pretreatment hemoglobin level and the hazard ratio for local relapse following radiotherapy (50 Gy in 20 fractions over 4 weeks) during a median follow-up period of 6.8 years [8]. Similarly, studies in patients with squamous cell carcinomas of the glottic larynx and head/neck who were treated with radiotherapy have noted significantly better 2-year locoregional tumor control rates and 2-year survival rates in those who presented with normal hemoglobin levels in comparison with those who presented with below-normal hemoglobin levels (!13 g/dl) (table 1) [9, 10]. In the patients with head/neck cancers, 5-year locoregional control and survival rates were also significantly better in those with normal hemoglobin levels (p ! 0.001 and p ! 0.01, respectively; table 1) [10]. Other studies have shown a relationship between the post-radiotherapy hemoglobin level and the outcome of treatment. Among patients with squamous cell carcinomas of either the glottic or supraglottic regions who received primary radiotherapy in doses ranging from 60 to 70 Gy over 6 to 7 weeks, disease-free survival rates were significantly better in those who had normal hemoglobin levels (defined as 12–16 g/dl in women, 13.7– 18 g/dl in men) at day 35 of treatment in comparison with those who had below-normal hemoglobin levels at this time (p = 0.0012 for glottic carcinoma; p = 0.05 for supraglottic carcinoma) (fig. 2) [11]. Effect on Fatigue In addition to locoregional tumor control and survival, other outcomes in patients undergoing radiotherapy may also be influenced by the presence of anemia. Fatigue is

Harrison/Shasha/Homel

Percentage of patients with a fatigue rating >5

40

Not anemic

37%

Anemic 28%]

29%

30

20 14% 10 4% 0

Pre-radiotherapy During radiotherapy Post-radiotherapy Time relative to radiotherapy

Fig. 2. Disease-free survival among patients with squamous cell carcinoma of the glottic and supraglottic regions treated with primary radiotherapy (60–70 Gy in 30–35 fractions over 6–7 weeks) in relation to their hemoglobin (Hb) levels at day 35 of treatment. p Values indicate differences between disease-free survival in each group for patients with normal vs below normal Hb levels. Normal Hb values were defined as 13.7–18 g/dl (8.5–11.0 mmol/l) for men and 12– 16 g/dl (7.5–10.0 mmol/l) for women (reproduced with permission from van Acht et al. [11]).

Fig. 3. Percentages of prostate cancer patients with fatigue ratings

greater than 5 (on a scale of 0–10) before, during and after radiotherapy in relation to whether they were anemic (Hb level ! 12 g/dl) or not anemic at the time (Harrison LB, unpublished data). * Statistically significant versus non-anemic patients (p = 0.015).

Table 1. Influence of anemia on locoregional tumor control rates and survival rates in two studies in patients with squamous cell carcinomas of the glottic larynx (n = 109) or head/neck region (n = 504) [9, 10]

Patient group

Locoregional control rates, %

Survival rates, %

2-year

5-year

2-year

5-year

Glottic squamous cell carcinomas [9] Normal hemoglobin levels Anemiaa

95* 66

NR NR

88** 46

NR NR

Head/neck squamous cell carcinomas [10] Normal hemoglobin levels Anemiab

52** 34

48** 32

51* 37

36* 22

a b

Hemoglobin ! 13 g/dl. Hemoglobin ! 13 g/dl (women) or ! 14.5 g/dl (men). * p ! 0.01 vs anemic patients; ** p ! 0.001 vs anemic patients; NR = not reported.

one such outcome that has been strongly associated with anemia [12–14]. In a group of patients with prostate cancer treated with radiotherapy at our institution, the percentage with a fatigue rating 15 (on a scale of 0–10) following radiotherapy was found to be significantly higher

in those who were anemic (hemoglobin !12 g/dl) than in those who were not anemic (fig. 3). This finding is of interest because fatigue is generally not considered a problem in prostate cancer patients receiving radiotherapy alone.

Prevalence and Treatment of Radiotherapy-Associated Anemia

Oncology 2002;63(suppl 2):11–18

13

100

Baseline

Fig. 4. The prevalence of anemia (Hb ! 12

g/dl) before and during radiotherapy in patients with different types of cancer treated at the Department of Radiation Oncology, Beth Israel Medical Center/St Luke’s-Roosevelt Hospital Center, New York between December 1996 and June 1999. Baseline was defined as within 4 weeks prior to the first radiation dose. During therapy was defined as within 3 to 5 weeks of the first radiation dose.

Patients with anemia (%)

During radiotherapy 77%

80

Mean decrease in hemoglobin during radiotherapy (g/dl)

1.6

16% 26%

20

9%

0

Breast cancer (n = 81)

]

]

1.0 0.8 0.6 0.4 0.2 0

Breast Colorectal Lung Prostate Cervical cancer cancer cancer cancer cancer (n = 71) (n = 48) (n = 101) (n = 78) (n = 48)

Head/ neck cancer (n = 86)

Fig. 5. Mean decreases in hemoglobin (Hb) levels during radiotherapy versus preradiotherapy in patients treated at the Department of Radiation Oncology, Beth Israel Medical Center/St Luke’s-Roosevelt Hospital Center, New York between December 1996 and June 1999. Data shown are for patients whose Hb levels decreased during treatment. * Statistically significant difference versus baseline (p ! 0.001).

Prevalence of Anemia in Patients Undergoing Radiotherapy for Various Cancers

Studies of patients presenting for radiotherapy at our institution between December 1996 and June 1999 (n = 574) have revealed a high prevalence of anemia (hemoglobin !12 g/dl) both before and during irradiation. Overall,

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Oncology 2002;63(suppl 2):11–18

44%

40

1.4 1.2

32%

55% 44% 45%

]

]

79%

63% 60

2.0 1.8

75%

Colorectal cancer (n = 64)

Lung/ bronchus cancer (n = 64)

Prostate cancer (n = 90)

Uterine/ cervical cancer (n = 53)

Head/ neck cancer (n = 68)

41% of patients were found to be anemic at baseline (within 4 weeks prior to radiotherapy) and 54% were anemic within 3 to 5 weeks after receiving the first dose of radiation [15]. The prevalence of anemia was higher in women than in men (54 vs 28% at baseline; 63 vs 43% during radiotherapy), and was higher in patients with certain types of cancer than others (fig. 4). In particular, high prevalences of anemia were noted in patients with colorectal, lung/bronchus and uterine/cervical cancers, and increases in prevalence from baseline to end of therapy were most notable for those with colorectal and lung/ bronchus cancers (fig. 4). Among patients who experienced a drop in their hemoglobin level during radiotherapy, the mean decreases ranged from 0.75 g/dl for those with breast cancer to 1.8 g/dl for those with head or neck cancers, and the decreases were statistically significant (p ! 0.001) in all groups except those with breast and cervical cancer (fig. 5). When the prevalence of anemia for each cancer type was stratified by the hemoglobin level measured at baseline and the lowest level recorded during radiotherapy, most patients in each group were found to have mild anemia (hemoglobin levels 610 g/dl), which should be easily correctable. These data, and the findings of studies reviewed previously in this article indicating that the presence of anemia is associated with poorer treatment outcomes, provide compelling evidence for employing strategies to correct anemia and/or the resultant tumor hypoxia in cancer patients undergoing radiotherapy.

Harrison/Shasha/Homel

HBO4 Air

Carbogen patients at 18 months (n = 36) Carbogen patients at 3 years (n = 36) [estimated probabilities]

80

Noncarbogen patients at 18 months (n = 36) 100

60 40

91% 91%

80

75% 75% 69%

20 0 0

1

2

3

4

5

Patients (%)

Local relapse-free rate (%)

100

62% 62% 60

55% 50%

40

Years 20

Fig. 6. Local relapse-free survival over 5 years in patients with locally

advanced squamous cell carcinomas of the head or neck who were randomized to treatment with either radiotherapy under hyperbaric oxygen at 4 atmospheres (HBO4) delivered in two fractions of 11.5 Gy over 21 days (n = 23), or radiotherapy delivered in air in two fractions of 12.65 Gy over 21 days (n = 25) (reproduced with permission from Haffty et al. [17]).

Strategies to Correct Anemia and/or Tumor Hypoxia

0

Local control

Cause-specific survival Overall survival

Fig. 7. Influence of carbogen breathing on local control, cause-specific survival and overall survival in patients with advanced head or neck cancers treated with a hyperfractionated chemoradiotherapy regimen. Patients received either carboplatin 5 mg/m2 administered 45 min before radiotherapy (115 cGy) with carbogen breathed 4 min prior to and during irradiation twice per day on 5 days a week for 7 weeks (n = 36), or the same chemoradiotherapy regimen without carbogen breathing (comparison group; n = 36). Data at 3 years for the carbogen breathing group are estimated probabilities [18].

Strategies that have been proposed to correct anemia and/or the resultant tumor hypoxia include the use of: E Hypoxic cell sensitizers (e.g., cytotoxic agents) E Fluosol infusion E Carbogen breathing E Hyperbaric oxygen E Blood transfusions E Epoetin alfa (recombinant human erythropoietin; r-HuEPO).

rate in comparison with the accelerated regimen alone (48 vs 34% and 39 vs 28%, respectively), indicating that hypoxia can, in part, be overcome by mitomycin C administration. Mitomycin C did not influence the local toxicity of radiotherapy as neither the intensity nor the duration of radiotherapy-induced mucositis was altered by its administration [16].

Hypoxic Cell Sensitizers In a study designed to evaluate the efficacy of the cytotoxic agent mitomycin C in sensitizing hypoxic tumor cells to the effects of radiotherapy, patients with squamous cell carcinomas of the head or neck were treated with either conventional fractionated radiotherapy (70 Gy/35 fractions/7 weeks) or continuous hyperfractionated accelerated radiotherapy (55.3 Gy/17 consecutive days/33 fractions) with or without mitomycin C (20 mg/m2) given on day 5 of treatment [16]. Local tumor control and survival rates over a median follow-up period of 148 months were similar with the two radiotherapy regimens given alone; however, the addition of mitomycin C to the accelerated regimen significantly reduced both the local tumor control rate and the overall survival

Hyperbaric Oxygen and Carbogen Breathing The use of hyperbaric oxygen to overcome tumor hypoxia has been reported to produce an improved response to hypofractionated radiotherapy in a randomized trial in patients with advanced squamous cell carcinoma of the head or neck. Patients who received radiotherapy under hyperbaric oxygen at 4 atmospheres showed a higher 5year local relapse-free rate than those who received a similar radiotherapy regimen delivered in air (29 vs 16%; fig. 6). However, there were no significant differences between the two groups in 5-year survival, distant metastasis, or second primary tumors [17]. Similarly, carbogen breathing has also been shown to improve the results of chemoradiotherapy (carboplatin 5 mg/m2 given before radiation doses of 115 cGy twice

Prevalence and Treatment of Radiotherapy-Associated Anemia

Oncology 2002;63(suppl 2):11–18

15

Table 2. Influence of the pretreatment hemoglobin level and epoetin alfa on the outcome of therapy in patients

undergoing chemoradiation plus surgical treatment for squamous cell carcinomas of the oral cavity or oropharynx [24] Patient group

Group 1: patients with Hb 614.5 g/dl not treated with epoetin alfa (n = 43) Group 2: patients with Hb ! 14.5 g/dl not treated with epoetin alfa (n = 87) Group 3: patients with Hb ! 14.5 g/dl treated with epoetin alfab (n = 57)

Overall complete response, %a

2-year locoregional tumor control, %

2-year survival, %

65*

88**

81**

17

72

60

61*

95*

88*

* p (0.001 compared with group 2; ** p ! 0.05 compared with group 2; Hb = hemoglobin; SC = subcutaneously. Complete responses were determined by histopathologic analysis of the en bloc resection of the primary tumor and regional cervical lymphatics performed 5 to 6 weeks after the completion of chemoradiotherapy. b Dosage: 10,000 IU/kg SC 3 to 6 times per week until week of surgery. a

daily on 5 days per week for 7 weeks) in patients with locally advanced head or neck cancer. Anemic patients also received either blood transfusions or epoetin alfa to correct the anemia. Patients who breathed carbogen 4 min before and during irradiation exhibited improved local control, cause-specific survival, and overall survival at 18 months in comparison with a similar number of patients who received the same chemoradiotherapy regimen without carbogen breathing (fig. 7). The high response rates achieved in this study appeared to persist as the estimated probabilities of local control, cause-specific survival, and overall survival at 3 years in the carbogen breathing group were similar to the rates observed at 18 months [18]. Epoetin Alfa (Recombinant Human Erythropoietin; r-HuEPO) The ability of epoetin alfa to correct anemia prior to and during radiotherapy has been evaluated in cancer patients to determine whether it produces clinically meaningful benefit. Studies in patients receiving radiotherapy for various malignancies have shown that the administration of epoetin alfa, with or without oral iron, is effective in increasing hemoglobin levels and is well tolerated [19–21]. A study in our institution in cancer patients receiving a variety of different chemotherapy regimens with concomitant or sequential radiotherapy has shown that weekly epoetin alfa administration improved the mean hemoglobin level by 1.8–3.4 g/dl [22] (fig. 5). Improvements of this magnitude are similar to or greater than the reductions in hemoglobin noted during radio-

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Oncology 2002;63(suppl 2):11–18

therapy in our earlier study of the prevalence of anemia in patients with various malignancies (fig. 5). The effects of epoetin alfa on the outcomes of therapy have been studied in anemic patients (Hb !14.5 g/dl) with squamous cell carcinomas of the oral cavity or oropharynx [23, 24]. All patients in this study received a regimen consisting of mitomycin C (15 mg/m2 on day 1), 5fluorouracil (750 mg/m2 on days 1–5) and radiotherapy (50 Gy in 25 fractions during weeks 1–5), followed by dissection of the primary tumor bed and a neck dissection. Epoetin alfa (10,000 IU/kg subcutaneously 3 to 6 times per week until the week of surgery) was administered to a group of patients (n = 57) who had a pretreatment hemoglobin level !14.5 g/dl. The outcome in this group of patients was compared with the outcomes in two other groups who did not receive epoetin alfa. One of these nonepoetin alfa groups had a pretreatment hemoglobin level !14.5 g/dl (n = 87) and the other had a pretreatment hemoglobin level 614.5 g/dl (n = 43). The results are summarized in table 2. In the two groups of patients who did not receive epoetin alfa, those with a low pretreatment hemoglobin level (!14.5 g/dl) (group 2) exhibited significantly lower complete response rates, 2-year locoregional control rates, and 2-year survival rates than those who had normal hemoglobin levels (614.5 g/dl) (group 1). However, in the patients with a low pretreatment hemoglobin level who received epoetin alfa (group 3), the rates of complete response, 2-year locoregional control and 2year survival were equivalent to or higher than those in patients with normal pretreatment hemoglobin levels (group 1) [24].

Harrison/Shasha/Homel

These findings suggest that epoetin alfa is an effective and well-tolerated means of achieving normal hemoglobin levels in patients undergoing radiotherapy, and may reverse the negative prognostic influence of a low pretreatment hemoglobin level. Improvements in quality-oflife parameters (linear analog scale assessment) have also been noted with epoetin alfa therapy in groups of patients receiving a variety of different chemotherapy regimens with concomitant or sequential radiotherapy [22].

Potential Benefit of Epoetin Alfa in Reducing Radiotherapy-Induced Neurotoxicity

In addition to studies of the efficacy of epoetin alfa in improving the clinical outcome of radiotherapy in patients with low hemoglobin levels, its potential to reduce radiation-induced neurotoxicity is also being investigated. Studies in experimental animals have revealed that endogenous erythropoietin (EPO) possesses other biological activities in addition to erythropoietic effects, and that many cells besides erythroid progenitors express the erythropoietin receptor, including brain cells. As in the periphery, erythropoietin production is known to be induced by hypoxia in the central nervous system (CNS), and it has been shown in animals to protect CNS neuronal cells from ischemic injury [25]. A recent study found that erythropoietin receptors are abundantly expressed in capillaries of the brain-periphery interface, suggesting that this may provide a route for circulating erythropoietin to enter the brain [26]. In support of this hypothesis, a study in mice showed that systemic administration of epoetin alfa (5,000 IU/kg intraperitoneally) 24 h before or up to 6 h after controlled blunt trauma to the frontal cortex and then continued once daily for 4 additional days (5 doses total) attenuated the resultant brain injury. Quantitative analysis of the cavitary injury volume showed that the concussive injury in mice treated with epoetin alfa was significantly less than in those treated with saline. In addition, epoetin alfa also ameliorated the damage caused by experimentally-induced focal ischemic stroke in rat brains, reduced the severity of experimental autoimmune encephalitis in Lewis rats, and delayed and lessened seizures induced in mice by the glutamate analog kainic acid. These findings in different models of neurologic injury suggest that epoetin alfa is able to cross the bloodbrain barrier and may provide protection against CNS neurologic damage [26]. Further evidence in support of a protective effect of erythropoietin against neurologic damage is provided by

Prevalence and Treatment of Radiotherapy-Associated Anemia

the results of studies in our institution in which visual evoked potentials (VEPs) were measured in animals receiving radiotherapy in the presence and absence of rHuEPO. Pretreatment of animals with epoetin alfa significantly prolonged VEPs as compared with those not receiving epoetin alfa, suggesting that it may protect visual pathways against radiation-induced damage (A. Evans, unpublished data). If confirmed clinically, this finding may have substantial implications for the use of radiotherapy in patients with malignancies of the head, paranasal sinuses and ocular regions because it suggests that epoetin alfa may provide biologic protection of the optic nerve against radiation-induced damage.

Conclusions

Anemia may result in tumor hypoxia by decreasing the oxygen-carrying capacity of the blood, resulting in radiation and, in some instances, chemotherapy resistance. Anemia is associated with a poorer prognosis in a variety of malignancies. It may be an important obstacle to achieving maximal locoregional tumor control and survival with radiotherapy, even for small tumors not normally assumed to be hypoxic. In addition, anemia negatively affects the quality of life of cancer patients, as evidenced by worsening fatigue. In view of the high prevalence of anemia recorded in cancer patients receiving radiotherapy (about 50% at our institution), it is evident that measures to reverse anemia and tumor hypoxia should be considered an important component of treatment for such patients. Indeed, a number of strategies, notably the administration of epoetin alfa, have been found to attenuate the negative prognostic influence of a low hemoglobin level in patients receiving radiotherapy with or without chemotherapy. These findings indicate the need for radiation oncologists to be aware of the possibility of anemia in cancer patients undergoing radiotherapy so that timely intervention with strategies to improve the outcome of treatment can be instituted whenever anemia is diagnosed. In view of the potential benefits of treating anemia, it is hoped that this aspect of cancer management will receive more attention in the future.

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References 1 Shasha D: The negative impact of anemia on radiotherapy and chemoradiation outcomes. Semin Hematol 2001;38(3 suppl 7):8–15. 2 Kumar P: Tumor hypoxia and anemia: impact on the efficacy of radiation therapy. Semin Hematol 2000;37(4 suppl 6):4–8. 3 Dunst J: Hemoglobin level and anemia in radiation oncology: prognostic impact and therapeutic implications. Semin Oncol 2000;27(2 suppl 4):4–8, 16–17. 4 Becker A, Stadler P, Lavey RS, Hansgen G, Kuhnt T, Lautenschlager C, Feldmann HJ, Molls M, Dunst J: Severe anemia is associated with poor tumor oxygenation in head and neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys 2000;46:459–466. 5 Movsas B, Chapman JD, Greenberg RE, Horwitz EM, Pinover WH, Hanlon AL, Stobbe C, Hanks GE: Increasing levels of hypoxia in human prostate carcinoma correlate significantly with increasing clinical stage and age: an Eppendorf pO2 study. Int J Radiat Oncol Biol Phys 1999;45(3 suppl):202. 6 Brizel DM, Dodge RK, Clough RW, Dewhirst MW: Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome. Radiother Oncol 1999;53: 113–117. 7 Höckel M, Vorndran B, Schlenger K, Baussmann E, Knapstein PG: Tumor oxygenation: a new predictive parameter in locally advanced cancer of the uterine cervix. Gynecol Oncol 1993;51:141–149. 8 Warde P, O’Sullivan B, Bristow RG, Panzarella T, Keane TJ, Gullane PJ, Witterick IP, Payne D, Liu FF, McLean M, Waldron J, Cummings BJ: T1/T2 glottic cancer managed by external beam radiotherapy: the influence of pretreatment hemoglobin on local control. Int J Radiat Oncol Biol Phys 1998;41:347–353. 9 Fein DA, Lee WR, Hanlon AL, Ridge JA, Langer CJ, Curran WJ Jr, Coia LR: Pretreatment hemoglobin level influences local control and survival of T1–T2 squamous cell carcinomas of the glottic larynx. J Clin Oncol 1995;13:2077– 2083.

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10 Lee WR, Berkey B, Marcial V, Fu KK, Cooper JS, Vikram B, Coia LR, Rotman M, Ortiz H: Anemia is associated with decreased survival and increased locoregional failure in patients with locally advanced head and neck carcinoma: a secondary analysis of RTOG 85-27. Int J Radiat Oncol Biol Phys 1998;42:1069–1075. 11 van Acht MJ, Hermans J, Boks DE, Leer JW: The prognostic value of hemoglobin and a decrease in hemoglobin during radiotherapy in laryngeal carcinoma. Radiother Oncol 1992; 23:229–235. 12 Groopman JE: Fatigue in cancer and HIV/ AIDS. Oncology (Huntingt) 1998;12:335–344. 13 Sabbatini P: Contribution of anemia to fatigue in the cancer patient. Oncology (Huntingt) 2000;14(11A):69–71. 14 Sobrero A, Puglisi F, Guglielmi A, Belvedere O, Aprile G, Ramello M, Grossi F: Fatigue: a main component of anemia symptomatology. Semin Oncol 2001;28(2 suppl 8):15–18. 15 Harrison LB, Shasha D, Shiaova L, et al: Prevalence of anemia in cancer patients undergoing radiotherapy (abstract). Proc Am Soc Clin Oncol 2000;19:471a. 16 Dobrowsky WH, Naudé J, Widder J, Dobrowsky E: Continuous hyperfractionated accelerated radiotherapy and mitomycin C in head and neck cancer. Int J Radiat Oncol Biol Phys 1999;45(3 suppl):148. 17 Haffty BG, Hurley R, Peters LJ: Radiation therapy with hyperbaric oxygen at 4 atmospheres pressure in the management of squamous cell carcinoma of the head and neck: results of a randomized clinical trial. Cancer J Sci Am 1999;5:341–347. 18 Martinez A, Cabezon M, Fuentes C, Espiñeira M, Perez M, Serdio J, Artazkoz J, Gil J, Borque C, Villar A: Hyperfractionated chemoradiotherapy with carbogen breathing for advanced cancer of the head and neck. Int J Radiat Oncol Biol Phys 1999;45(3 suppl):377. 19 Lavey RS, Dempsey WH: Erythropoietin increases hemoglobin in cancer patients during radiation therapy. Int J Radiat Oncol Biol Phys 1993;27:1147–1152.

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20 Dusenbery KE, McGuire WA, Holt PJ, Carson LF, Fowler JM, Twiggs LB, Potish RA: Erythropoietin increases hemoglobin during radiation therapy for cervical cancer. Int J Radiat Oncol Biol Phys 1994;29:1079–1084. 21 Sweeney PJ, Nicolae D, Ignacio L, Chen L, Roach M 3rd, Wara W, Marcus KC, Vijayakumar S: Effect of subcutaneous recombinant human erythropoietin in cancer patients receiving radiotherapy: final report of a randomised, open-labelled, phase II trial. Br J Cancer 1998; 77:1996–2002. 22 Shasha D, George M, Harrison LB: Onceweekly dosing of epoetin alfa increases hemoglobin and improves quality of life in anemic cancer patients receiving radiation therapy either concurrently or sequentially with chemotherapy. Presented at the 42nd Annual Meeting of the American Society of Hematology, San Francisco, CA, Dec 2000. 23 Glaser CM, Millesi W, Kornek GV, Lang S, Schüll B, Klug K, F, Wanschitz F, Lavey RS: Impact of hemoglobin (Hgb) level and use of recombinant human erythropoietin (r-HuEPO) on response to neoadjuvant chemoradiation therapy, tumor control, and survival in patients with oral or oropharyngeal squamous cell carcinoma (SCCA). Int J Radiat Oncol Biol Phys 1999;45(3 suppl):149. 24 Glaser CM, Millesi W, Kornek GV, Lang S, Schüll B, Watzinger F, Selzer E, Lavey RS: Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx. Int J Radiat Oncol Biol Phys 2001;50:705– 715. 25 Sakanaka M, Wen TC, Matsuda S, Masuda S, Morishita E, Nagao M, Sasaki R: In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci USA 1998;95:4635–4640. 26 Brines ML, Ghezzi P, Keenan S, Agnello D, de Lanerolle NC, Cerami C, Itri LM, Cerami A: Erythropoietin crosses the blood-brain barrier to protect against experimental brain injury. Proc Natl Acad Sci USA 2000;97:10526– 10531.

Harrison/Shasha/Homel

Oncology 2002;63(suppl 2):19–28 DOI: 10.1159/000067148

Raising Hemoglobin: An Opportunity for Increasing Survival? Gillian M. Thomas Department of Radiation Oncology, Obstetrics & Gynecology, University of Toronto, Toronto-Sunnybrook Regional Cancer Centre, Toronto, Canada

Key Words Anemia W Hemoglobin W Hypoxia W Angiogenesis W Cancer W Radiotherapy W Chemotherapy W Surgery W Prognostic factor W Epoetin alfa

creased oxygen carrying capacity may lead to increased tumor hypoxia, radiation resistance and increased tumor angiogenesis. The interrelationship of low hemoglobin levels, hypoxia, tumor angiogenesis and survival is explored in this article. Copyright © 2002 S. Karger AG, Basel

Abstract Although the association between low hemoglobin levels and poorer outcomes in radiation oncology has long been recognized, anemia is often overlooked and untreated. However, a growing body of clinical evidence now indicates that low hemoglobin levels during radiation treatment are associated with decreased response and survival following radiotherapy. For example, a large Canadian retrospective study in patients receiving radical radiotherapy for cervical cancer showed that the 5-year survival rate was 19% higher in those whose hemoglobin during radiation treatment was =12 g/dl compared to those with levels ! 12 g/dl. The data suggest that clinical trials need to be performed to determine whether increasing hemoglobin levels leads to improved local control and survival. The mechanism by which low hemoglobin levels could cause poorer outcomes is not well understood and needs further elucidation. It is postulated that lower hemoglobin levels resulting in de-

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Accessible online at: www.karger.com/ocl

Introduction

In radiation oncology, it is widely accepted that tumor hypoxia causes radiation resistance. Anemia is also associated with poorer outcomes to radiation. It has been inferred that there is a causal relationship between low hemoglobin levels, the resulting hypoxia and a poor outcome of radiotherapy in patients with cancer. Even though hemoglobin levels are monitored at most radiation oncology centers, anemia is often overlooked by radiation oncologists and is frequently only treated if severe. It has been suggested that oncologists do not routinely treat mild-to-moderate anemia as it is perceived to be clinically unimportant [1] and that patients are often not transfused unless hemoglobin levels fell below 10 g/dl or even 8 g/dl [1, 2]. For example, a US study in 1987 showed approximately two-thirds of academic radiation

Gillian M. Thomas, BSc, MD, FRCPC GlaxoSmithKline, 7333 Mississauge Road North Mississauge, Ont. L5N 8L4 (Canada) Tel. +1 905 814 2256, Fax +1 905 814 2100 E-Mail [email protected]

Table 1. Summary of studies which examined the relationship between anemia and outcome (local control B survival) of radiotherapy B chemotherapy in patients with cancer

Tumor site

Number of studies

Effect of anemia on outcome, number of studies Adverse

Bladder Bronchus Cervix Glioma Head and neck Prostate Total

6 5 22 1 17 1 52 (100%)

None

6 0 4 1 19 3 0 1 11 6 0 1 40 (76.9%) 12 (23.1%)

oncology departments transfusedpatients only if their hemoglobin levels were = 10 g/dl [3]. This reluctance to correct anemia was further increased in Canada in the late 1980s when the risk of contracting HIV or hepatitis from contaminated blood was first recognized. Although views are changing, there is still much uncertainty among radiation oncologists about the clinical importance of radiotherapy-associated anemia and the exact benefits of increasing hemoglobin levels. However, a growing body of clinical data is gathering in the medical literature which examines the relationship between hemoglobin levels and response to radiotherapy in patients with cancer. The present article reviews these data and also seeks to explore some of the downstream mechanisms, namely tumor hypoxia and angiogenesis, that may link low hemoglobin levels with clinical outcome in patients with cancer. It also poses questions for future study that may help to clarify treatment options for this patient group.

was no consistency in how it was defined (i.e., cut-off hemoglobin levels ranged from 10 to 12.5 g/dl). Nevertheless, 40 of the 52 (76.9%) studies showed that low hemoglobin levels were adversely related to local control and/or survival after radical adverse radiotherapy (table 1). There are two possible explanations, not mutually exclusive, for the observed relationship between low hemoglobin levels and impaired outcomes with radiotherapy. First, low hemoglobin levels may be a tumor-related marker for an aggressive cancer. In this scenario, it is unlikely that raising hemoglobin levels will improve the outcome of radiotherapy. The second, and more traditional, explanation is that there is a causal relationship between low hemoglobin levels and poor outcome of therapy. With a causal relationship, raising hemoglobin levels might therefore improve outcome following radiotherapy [4]. Until recently, clinical evidence to support a causal relationship between low hemoglobin levels and poor outcome was relatively limited. A single prospective, randomized trial, conducted over 30 years ago, was interpreted as demonstrating some benefit after correcting anemia during radiotherapy in patients with cervical cancer [5]. Pelvic recurrence occurred in 11 of 67 patients (16.4%) who received transfusions and maintained hemoglobin levels 112 g/dl compared with 21 of 68 patients (30.9%) who were given transfusions only if their hemoglobin levels dropped to !10 g/dl. No differences in survival were noted between the two treatment groups [5]. Although this study is widely quoted in the medical literature as proof that correcting hemoglobin levels improves outcomes following radiotherapy, the study was underpowered and had an inconclusive univariate analysis which did not assess the possible effect of other prognostic factors on patient outcome.

Studies in Patients with Cervical Cancer Effect of Hemoglobin Levels on Treatment Outcome

Historic Data More than 50 studies have investigated the effect of low hemoglobin levels at the start of radiotherapy B chemotherapy on outcomes in patients with various cancers [mostly of the cervix (42%) or head and neck (33%)] mainly using univariate analysis. A summary of these studies is provided in table 1. It should be noted that, although the term ‘anemia’ was used in all studies, there

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Oncology 2002;63(suppl 2):19–28

Radiotherapy Alone To examine the relationship between anemia and treatment outcome more rigorously, a large retrospective study using data from seven Canadian radiation oncology centers between 1989 and 1992 was performed [4]. The aim of the study was to examine the prevalence of anemia, its time course, and the effect of anemia and blood transfusions on the treatment outcome in 605 patients who had radical radiotherapy for cervical cancer. At presentation, approximately one-third of patients had hemoglobin levels of =12 g/dl (i.e., below the lower

Thomas

Table 2. Significance of prognostic factors on outcome of radiotherapy in 605 patients with cervical cancer: results of a multivariate analysis (with permission from Grogan et al. [4])

1.0 —– Hb =12.0 g/dl (n = 337) - - - Hb