Oxaliplatin (eloxatin): Fortschritte In Der Tumortherapie 2004 (Onkologie)

Dokumentation und Evaluation der Weiterbildung Originalarbeit · Original Article

Supplement 1 zu Band 27, August 2004

Oxaliplatin (Eloxatin®) Fortschritte in der Tumortherapie 2004

Herausgeber H.-J. Schmoll, Halle/Saale

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Contents · InhaltDokarbeit · Original Article Vol. 27, Supplement 1, August 2004

1

Vorwort Schmoll, H.-J. (Halle/Saale)

2

Einleitung Oxaliplatin beim Kolorektalkarzinom: Von der Palliation zur Kuration

12

ASCO-Abstracts

12 13

16 16 17 33 37 40 44 44 46 50 51 52 55 56 57 58

Breast Cancer Developmental Therapeutics – Cytotoxic Chemotherapy Developmental Therapeutics – Molecular Therapeutics Gastrointestinal Cancer – Colorectal/Liver A. Adjuvant Colorectal Cancer B. Previously Untreated Advanced Colorectal Cancer C. Previously Treated Advanced Colorectal Cancer D. Hepatic Metastases of Colorectal Cancer E. Rectal Cancer Gastrointestinal Cancer – Non-Colorectal/Liver A. Pancreas Cancer B. Gastric and Esophageal Cancer C. Hepatocellular and Biliary Cancer Genitourinary Cancer Gynecologic Cancer Adult Leukemia, Lymphoma and Transplantation Lung Cancer Patient Care Tumor Biology / Immunobiology / Human Genetics

59

Autorenverzeichnis

II

Impressum

14

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VorwortDokumentation und Evaluation der Weit Onkologie 2004;27(suppl 1):1

Vorwort Auch der kritische und eher skeptische Beobachter wird feststellen, dass sich die klinische Tumorforschung – basierend auf den mit großer Dynamik voranschreitenden Erkenntnissen der molekularen Tumorbiologie – in einem seit vielen Jahren nicht mehr gekannten Aufschwung befindet: Davon zeugt die Vielfalt der neuen, auf spezifische molekulare Mechanismen der Tumorzellen zielenden Substanzen, die «small molecules», die Antikörper oder Kombinationsprodukte sowie die damit verbundene große Zahl klinischer Explorations- und randomisierter Studien, die in kurzer Zeit neue Erkenntnisse zur Wirksamkeit und zum klinischen Nutzen bringen. Wir erleben jetzt den Beginn der Ernte von intensiver Forschung in der Vergangenheit; zugleich ist auf Grund der technologischen Entwicklungen in Zukunft mit einer noch schnelleren Entwicklung zu rechnen. Wer jedoch geglaubt hatte, neue molekulare Therapeutika würden die klassischen Zytostatika überflüssig machen, hat sich getäuscht. Vielmehr verhelfen die Substanzen, die auf neue Targets zielen, nicht nur dem «targeted treatment» zu neuer Blüte (schon Methotrexat und 5-FU sind klassische «targeted drugs» mit Dihydrofolatreduktase bzw. Thymidilatsynthase als Target), da sie vielfach mit den Zytostatika synergistisch wirken und Resistenzen vermindern. Glücklicherweise ist das Nebenwirkungsspektrum dieser neuen Substanzen ein anderes als das der klassischen Zytostatika, so dass sich der Kombination dieser beiden «Substanzgruppen» große Möglichkeiten eröffnen. Für die Entwicklung dieser neuen Therapieoptionen und -kombinationen bei den verschiedenen Tumoren ist der Einschluss vieler Patienten in klinische Studien nötig und damit ganz besonders die Aktivität von kooperativen Studiengruppen gefragt. Nur eine Gruppe, die in kurzer Zeit viele Patienten einbinden kann, wird an den neuen Entwicklungen in vollem Maß teilhaben und sie voranbringen. Dies zeigt sich auch in den in diesem Heft zusammengestellten Abstracts: Während ein großer Teil von Studien solche Kombinationen, die vor 1–2 Jahren noch neu waren, erneut oder in abgewandelter Form präsentiert, ohne dass hieraus eine wichtige, Therapiestandard-verändernde Erkenntnis zu gewinnen ist oder für den Patienten ein wesentlicher Nutzen entspringt, untersucht ein Drittel aller präsentierten Studien die Integration von Substanzen mit neuen Targets. Hierzu gehören die Inhibitoren des epidermalen Wachstumsfaktor-Rezeptor-Pathways, des Neo-

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angiogenese-Pathways, des Insulin like growth factor-Mechanismus, sowie den Inhibitoren weiterer Signaltransduktionswege wie z.B. raf-Kinase. Die Daten sind viel versprechend und lassen auf mögliche therapeutische Fortschritte bei einer ganzen Reihe zentraler Tumorarten hoffen. Dies gilt insbesondere für die kolorektalen und HNO-Tumoren, das Ösophaguskarzinom, eventuell das Magenkarzinom, aber auch für das Mamma- und Ovarialkarzinom. Oxaliplatin hat sich mittlerweile durchgesetzt als wichtiger Kombinationspartner für diverse First-line- und Salvage-Protokolle bei einer Vielzahl von Tumoren, vom kolorektalem Karzinom über das Magenkarzinom, Pankreaskarzinom, Gallenblasen-/Gallengangskarzinom, Mamma- und Ovarialkarzinom und vielen weiteren Tumoren bis hin zum hochmalignen B-Zell-Lymphom und der Hämoblastose. Wegen seiner verbesserten Verträglichkeit und leichteren Applizierbarkeit gegenüber Cisplatin ist Oxaliplatin immer häufiger Partner in Kombinationstherapien. Noch wichtiger hierfür ist bei einer Vielzahl von Tumorentitäten allerdings die ausgeprägte Synergie zwischen Oxaliplatin und Fluoropyrimidinen und anderen Substanzen, insbesondere den EGF-Inhibitoren. So verwundert es nicht, dass die auf neue molekulare Targets zielenden Substanzen, insbesondere die Kombinationen mit Oxaliplatin-haltigen Protokollen, geprüft werden. Das Beispiel des kolorektalen Karzinoms mit einer Remissionsrate von 81% bei der Kombination von FU/FA, Oxaliplatin plus Cetuximab oder Iressa zeigt, dass der Synergismus zwischen FU und Oxaliplatin durch EGF-Inhibitoren weiter verstärkt werden kann und damit ein großes Entwicklungspotenzial für Kombinationstherapien vorhanden ist. In einer weiteren, sehr wichtigen Arbeit konnte D. J. Sargent von der Mayo Clinic Rochester zeigen, dass DFS ein valider Endpunkt für die Durchführung adjuvanter Studien beim Kolonkarzinom ist (mittlerweile auch von der U.S. Food and Drug Administration anerkannt). Dadurch können nun neue und effektive Therapiekonzepte den Patienten schneller zur Verfügung gestellt werden. Die in diesem Heft zusammengestellte Auswahl an Arbeiten gibt einen aktuellen Überblick und ermöglicht eine schnelle Orientierung in diesem sich dynamisch entwickelnden Feld. H.-J. Schmoll, Halle

Einleitung Onkologie 2004;27(suppl 1):2–11

Oxaliplatin beim Kolorektalkarzinom: Von der Palliation zur Kuration

Mit jährlich fast 60 000 Neuerkrankungen in Deutschland ist das kolorektale Karzinom eine der häufigsten Neoplasien. Zwar kann bei etwa 70% der betroffenen Patienten eine potenziell kurative Tumorresektion durchgeführt werden. Bei etwa der Hälfte der Patienten rezidiviert die Erkrankung jedoch und führt letztlich zum Tod. Doch kann eine adjuvante Chemotherapie auf Basis von 5-Fluorouracil (5-FU) die Prognose dieser Patienten deutlich verbessern: Im Vergleich zur alleinigen Resektion wird eine Mortalitätsreduktion um rund ein Drittel erreicht. Seit 1990 gilt daher die 6-monatige Therapie mit 5-FU/Folinsäure (5-FU/FS) im Stadium UICC III als Standard [20]. Bislang noch kontrovers diskutiert wird die adjuvante Chemotherapie für Patienten im Stadium II, da der Überlebensvorteil hier nur moderat ist. Daher beschränkt man die adjuvante Therapie in diesem Stadium meist auf Patienten mit erhöhtem Rezidivrisiko.

FOLFOX4 auf dem Weg in die adjuvante Therapie Erst 2003 wurde auf der Jahrestagung der American Society of Clinical Oncology (ASCO) mit MOSAIC (Multicenter International Study of Oxaliplatin/5-FU/LV in the Adjuvant Treatment of Colon Cancer) eine adjuvante Therapiestudie vorgestellt, die die klinische Routine verändern wird: Die gerade im New England Journal of Medicine publizierte Studie [1] untersuchte die zusätzliche Gabe von Oxaliplatin (Eloxatin) zu einem 5-FU/FS-Infusionsregime (FOLFOX4) – ein Protokoll, das sich bereits in der First-line-Therapie beim metastasierten Kolorektalkarzinom aufgrund der Steigerung von Ansprechraten und Überleben bewährt hat. In der multizentrischen MOSAIC-Studie wurden 2246 Patienten mit Kolonkarzinomen der Stadien II (T3 oder T4, N0, M0) und III (jedes T, N1 oder N2, M0) nach R0-Resektion randomisiert entweder dem Protokoll nach de Gramont (200 mg FS über 2 Std. i.v., 400 mg/m2 5-FU als Bolus, 600 mg/m2 5-FU i.v. über

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22 Std., Tag 1 und 2) oder dem gleichen Schema plus Oxaliplatin (85 mg/m2 an Tag 1) zugeteilt [1]. Die Therapie wurde 14-tägig über insgesamt 12 Zyklen verabreicht. Im FOLFOX4-Arm erhielten 74,7%, im Kontrollarm 86,5% der Patienten alle geplanten Therapiezyklen. In beiden Gruppen konnten über 80% der geplanten Dosis appliziert werden. Die Patientencharakteristika beider Studienarme waren ausgewogen: Jeweils 60% der Teilnehmer hatten ein Kolonkarzinom im Stadium III, je 40% einen Tumor im Stadium II.

Zusätzliche Oxaliplatin-Gabe verhindert ein Viertel aller Rezidive Nach einem medianen Follow-up von knapp 38 Monaten waren im Kontrollarm 293 Rezidive und Todesfälle (26,1%) aufgetreten, im FOLFOX4-Arm dagegen nur 237 Ereignisse (21,1%). Daraus berechnet sich eine Hazard Ratio für Rezidive von 0,77 für den Oxaliplatin-haltigen Arm im Vergleich zur Kontrolle (p = 0,002). Anders ausgedrückt: In der MOSAICStudie konnte das Rezidivrisiko durch die zusätzliche Gabe von Oxaliplatin zur Standardtherapie mit 5-FU/FS um 23% verringert werden (Abb. 1). Die Rate des krankheitsfreien Überlebens als primärem Endpunkt wurde von 72,9% im Kontrollarm um absolut 5,3% auf 78,2% im FOLFOX4-Arm erhöht. Da die meisten Rezidive innerhalb der ersten 3 Jahre nach kurativer Therapie auftreten, gehen die Autoren jedoch davon aus, dass die Verbesserung des krankheitsfreien Überlebens auch in einer signifikanten Überlebensverlängerung resultieren wird.

Effektivitätssteigerung nicht auf Kosten der Sicherheit Die zusätzliche Gabe von Oxaliplatin zum 5-FU/FS-Regime wurde generell gut toleriert. Häufigste Nebenwirkungen vom

3 Jahre krankheitsfreies Überleben 1

FOLFOX 4 (n = 1123) 78,2 % LV5FU2 (n = 1123)

0,9 Wahrscheinlichkeit

Tab. 1. MOSAIC-Studie: Verbesserung des krankheitsfreien Überlebens nach 3 Jahren um absolut 5% bei Hochrisikopatienten im Stadium II [16]

72,9 %

0,8 0,7 0,6 Hazard Ratio: 0,77 (0,65–0,92)

p < 0,002

0 0

10

20

30

40

50

Parameter

FOLFOX4

FU/FS

Patientenzahl Zahl der Ereignisse Wahrscheinlichkeit des ereignisfreien Überlebens nach 3 Jahren Hazard Ratio Relative Risikoreduktion

286 40 (14,0%)

290 54 (18,6%)

84,9%

79,8%

DFS (Monate)

Abb. 1. MOSAIC-Studie: Signifikante Reduktion der Ereignisrate um 23% nach 3 Jahren durch zusätzliche Gabe von Oxaliplatin zur 5-FU/FSTherapie [1]. DFS = Krankheitsfreies Überleben. FOLFOX4-Arm: 23% Risikoreduktion gegenüber LV5FU2.

Tab. 2. MOSAIC-Studie: Schwere Sicherheitsereignisse waren bei Patienten im Stadium II seltener als bei Patienten im Stadium III [16] Stadium

Patienten, %

100 90

Grad 0: keine Veränderung, keine Symptome

80

Grad 1: leichte

70

Parästhesie, Verlust der tiefen Sehnenreflexe

60

Grad 2: leichter oder

50

mittelschwerer objektiver sensorischer Verlust, mittelschwere Parästhesie

40 30

objektiver sensorischer Verlust oder Parästhesie mit Funktionsbeeinträchtigung

10 0

Patientenzahl Patienten mit SAE Therapieabbruch wegen Toxizität

Tod unter Therapie

Grad 3: schwerer

20

Während 1 Monat der Therapie

0,72 28%

Schwere Sicherheitsereignisse

6 Monate 12 Monate 18 Monate

Follow-up

II

III

FOLFOX4 5-FU/FS

891 18,8% 13,5%

1328 25,4% 15,3%

FOLFOX4 5-FU/FS

12,1% 5,8%

16,0% 5,3%

FOLFOX4 5-FU/FS

0,2% 0,7%

0,8% 0,5%

FOLFOX4 5-FU/FS

24,2% 15,3%

33,7% 17,6%

SAE = Serious adverse events. Abb. 2. MOSAIC: Periphere sensorische Neuropathie.

Grad 3/4 waren im FOLFOX4-Arm Neutropenie, Erbrechen und Diarrhoe. Eine Neutropenie vom Grad 3/4 war bei zusätzlicher Oxaliplatin-Gabe zwar häufiger als im Kontrollarm (41,1 vs. 4,7%), die Rate daraus resultierender Komplikationen (Fieber, Infektionen) war jedoch mit beiden Regimen vergleichbar (1,8 vs. 0,2%). Häufigste Nebenwirkung unter FOLFOX4 war erwartungsgemäß die durch Oxaliplatin bedingte periphere Neuropathie 12,4% (Grad 3). Sie war jedoch in der Regel rasch reversibel (Abb. 2). Die therapiebedingte Mortalität in der MOSAIC-Studie war mit je 0,5% in beiden Gruppen niedrig.

Ein weiteres wichtiges Ergebnis der MOSAIC-Studie ist die Tatsache, dass die Teilnehmer unabhängig vom Tumorstadium von der adjuvanten Therapie mit FOLFOX4 profitierten. Das belegt eine auf der diesjährigen ASCO-Tagung vorgestellte Subgruppenanalyse der 899 Patienten im Stadium II [16]: Während sich die Reduktion des Rezidivrisikos bei Patienten im Stadium III auf 24% belief, fiel sie

bei Patienten im Stadium II mit 20% etwas geringer aus. Die Autoren weisen jedoch darauf hin, dass Kolonkarzinome im Stadium II eine heterogene Gruppe darstellen und daher neben dem Nodalstatus weitere Faktoren für die Risikostratifizierung herangezogen werden sollten. Identifizierte man Patienten im Stadium II mit mindestens einem weiteren Risikofaktor (z.B. T4, Obstruktion oder geringer Differenzierungsgrad), so konnte die Wahrscheinlichkeit für das krankheitsfreie Überleben nach 3 Jahren durch FOLFOX4 um absolut 5% im Vergleich zum Kontrollarm gesteigert werden (Tab. 1). Das entspricht einer relativen Risikoreduktion durch die zusätzliche Oxaliplatin-Gabe um 28%, die die für Patienten im Stadium III noch übertrifft. Auch im Stadium II sollte daher anhand des individuellen Rezidivrisikos durchaus eine adjuvante Therapie mit dem FOLFOX4-Regime in Erwägung gezogen werden, resümieren Hickish und Mitarbeiter [16]. Diese Empfehlung ist auch deswegen gerechtfertigt, weil schwere Beeinträchtigungen der Sicherheit im Studienverlauf (Inzidenz schwerwiegender Nebenwirkungen, Abbruch und/oder Tod) im Stadium II noch seltener registriert wurden als im Stadium III (19,8 vs. 25,6%; Tab. 2).

Einleitung

Onkologie 2004;27(suppl 1):2–11

Vorteil von FOLFOX4 auch im Stadium II

3

Das FOLFOX4-Regime ist damit auf dem besten Weg, sich als neuer Standard in der adjuvanten Chemotherapie des Kolonkarzinoms zu etablieren. Auch der Einwand, dass bislang keine langfristigen Gesamt-Überlebensdaten vorliegen, ist wenig stichhaltig, wie eine von D.J. Sargent, Mayo Clinic Rochester, vorgestellte Analyse großer Phase-III-Studien zur adjuvanten Therapie des Kolonkarzinoms belegt [23]. Zwar war die 5-Jahres-Überlebensrate bislang traditioneller Endpunkt in den großen adjuvanten Therapiestudien. Würde dieser Parameter jedoch zukünftig durch die Rate für das krankheitsfreie Überleben nach 3 Jahren ersetzt, so ließen sich therapeutische Fortschritte zum Wohle betroffener Patienten rascher in die klinische Praxis einführen. Voraussetzung ist allerdings, dass beide Parameter korrelieren, dass also die Rezidivfreiheit 3 Jahre nach der Operation prädiktiv für das weitere Überleben ist, erläuterte Sargent. Um diese Hypothese zu überprüfen, analysierte seine Arbeitsgruppe die individuellen Daten von mehr als 17 000 Patienten mit Kolorektalkarzinomen aus 17 adjuvanten Therapiestudien. Sie waren in insgesamt 39 Armen mit auf 5-FU basierenden Regimen behandelt worden oder gehörten dem Kontrollarm ohne Therapie an.

Verlässlicher Parameter: Krankheitsfreies Überleben Die ungeheure Informationsbasis macht deutlich, dass drei Viertel aller Rezidive beim Kolorektalkarzinom innerhalb der ersten 3 Jahre nach Tumorresektion auftreten. «Das Maximum der Rezidivrate ist bereits nach 1,5 Jahren erreicht. Danach sinkt die Wahrscheinlichkeit für eine Rezidivierung sehr rasch ab», berichtete Sargent. Und wenn Rezidive verhindert werden, verbessert sich auch die Heilungschance: Entsprechend konnte eine sehr enge Korrelation zwischen der Rate für das krankheitsfreie Überleben nach 3 Jahren und der 5-Jahres-Gesamt-Überlebensrate nachgewiesen werden, sodass Sargent den ersten Parameter als «exzellenten Prädiktor» für das Gesamt-Überleben qualifizierte. In 22 vergleichenden Analysen von krankheitsfreiem und Gesamt-Überleben ergab sich in 19 Fällen für beide Parameter eine identische Aussage. Lediglich bei 3 Analysen zeigte sich ein signifikanter Vorteil nur für das krankheitsfreie Überleben. Gerade in diesen nicht übereinstimmenden Fällen war der Benefit der adjuvanten Therapie jedoch nur von marginaler Signifikanz. «Ein gering ausgeprägter Nutzen beim krankheitsfreien Überleben resultiert demnach nicht zwangsläufig in einem verbesserten Gesamt-Überleben», kommentierte Sargent. Insgesamt erlaubt das von seiner Arbeitsgruppe entwickelte Modell anhand der Therapieeffekte auf das krankheitsfreie Überleben eine gute Vorhersage des Gesamt-Überlebens. Seiner Meinung nach ist diese Variable daher als geeigneter Endpunkt anzusehen, der bevorzugt eingesetzt werden sollte, um die Erkenntnisse klinischer Studien rascher in die tägliche Praxis zu implementieren. Auf Basis dieser stringenten Analyse hat das Oncology

4

Onkologie 2004;27(suppl 1):2–11

Drug Advisory Committee (ODAC), ein Beratungsgremium der amerikanischen Zulassungsbehörde FDA (Federal Drug Administration), kürzlich die einstimmige Empfehlung ausgesprochen, das krankheitsfreie Überleben als validen Parameter bei der Bewertung neuer Zulassungsanträge anzusehen.

Irinotecan-Regime: Kein Benefit in der Adjuvanz Im Gegensatz zur zusätzlichen Gabe von Oxaliplatin zu 5-FU/FS haben Kombinationsregime mit Irinotecan bislang keinen Vorteil in der adjuvanten Therapie gezeigt. So fiel die von Leonard Saltz, Memorial Sloan-Kettering Cancer Center, vorgestellte Studie CALBG C89803 der Cancer and Leukemia Group B, in der das 5-FU/FS-Bolusregime nach Roswell Park über 4 Zyklen mit dem IFL- oder Saltz-Regime über 6 Zyklen verglichen wurde, in doppelter Hinsicht negativ aus [21]. In die Studie waren zwischen April 1999 und April 2001 insgesamt 1264 Patienten im Stadium III aufgenommen worden. Die Rekrutierung war dann aber wegen der erhöhten Toxizität im experimentellen IFL-Arm vorzeitig gestoppt worden: Therapiebedingte Todesfälle (2,8 vs. 1,0%; p = 0,008) und febrile Neutropenien (4 vs. 1%; p = 0,0005) wurden mit dem Saltz-Regime signifikant häufiger registriert als im Kontrollarm. Auch hinsichtlich der Effektivität konnte die IrinotecanKombination nicht überzeugen: Nach 2,6-jährigem Follow-up zeigte sich beim ereignisfreien Überleben kein Vorteil im Vergleich zum Kontrollarm. «Die jetzt vorgestellten Ergebnisse sind endgültig, und C89803 kann daher nicht als positive Studie betrachtet werden», resümierte Saltz die Ergebnisse. Eric van Cutsem, University Hospital Gasthuisberg, Leuven, kam deshalb in seinem Diskussionsbeitrag zu dem eindeutigen Schluss: «Das IFL-Bolusregime sollte in der adjuvanten Therapie des Kolorektalkarzinoms nicht eingesetzt werden. Derzeit hat von den Kombinationsregimen nur FOLFOX4 seine Effektivität in der adjuvanten Situation belegt». Um die Rolle von Irinotecan zu klären, muss laut van Cutsem die Studie PETACC 3 (Pan European Trials in Adjuvant Colorectal Cancer) mit einem Irinotecan-haltigen 5-FU/FS-Infusionsregime abgewartet werden.

Die Zukunft der adjuvanten Therapie Nach der Präsentation von X-ACT (Xeloda Adjuvant Colon Cancer Trial) werden 5-FU/FS-Regime zukünftig wohl ohnehin ihren Platz zugunsten der oralen Fluoropyrimidine räumen müssen. Für die Studie wurden 1987 Patienten mit einem Kolonkarzinom im Stadium III nach Resektion zum 5-FU/FSBolusregime der Mayo-Klinik oder zu Capecitabin randomisiert [5]. Nach median 3-jähriger Beobachtungszeit zeigte sich hinsichtlich des krankheitsfreien Überlebens als primärem Endpunkt zumindest eine Äquieffektivität beider Regime, tendenziell sogar ein Vorteil zugunsten des oralen Fluoropyri-

Einleitung

midins gegenüber dem Kontrollarm (64,2 vs. 60,6%), berichtete J. Cassidy, Universität Glasgow. Darüber hinaus überzeugte die Substanz aufgrund der besseren Verträglichkeit. Aufgrund dieser Ergebnisse sollte Capecitabine zukünftig 5-FU/FS in der adjuvanten Therapie des Kolonkarzinoms ersetzen, resümierte van Cutsem. Er sieht die Zukunft der adjuvanten Therapie in der Kombination oraler Fluoropyrimidine mit Zytostatika wie Oxaliplatin und mit neuen «targeted therapies» wie Bevacizumab, Cetuximab und Tyrosinkinase(TK)-Inhibitoren des EGFR (epidermal growth factor receptor).

Tab. 3. Intergroup-Studie N9741: Über 70% der Patienten beider Studienarme erhielten eine Second-line-Therapie, davon über die Hälfte mit der jeweils anderen Substanz [13]

Zahlreiche neue Kombinationsstudien mit molekularen Therapien

hinsichtlich Gesamt-Überlebenszeit (19,5 vs. 14,8 Monate) als auch hinsichtlich Ansprechraten (45 vs. 31%) und Zeit bis zur Progression (8,7 vs. 6,9) schnitt das Oxaliplatin-Regime bei gleichzeitig besserer Verträglichkeit günstiger ab und avancierte damit zum neuen Standard in der First-line-Therapie des metastasierten Kolorektalkarzinoms. Auf der diesjährigen ASCO-Tagung wurden die Endresultate von 355 Patienten der NCI-Studie vorgestellt, die zu FOLFOX4 oder dem modifizierten R-IFL-Regime randomisiert wurden. Sie sprechen ebenfalls für die Oxaliplatin-Kombination [13]. So konnte die mediane Überlebenszeit nach 22,5monatigem Follow-up mit dem FOLFOX4-Regime bis auf 18,8 Monate verlängert werden – gegenüber nur 16,3 Monaten mit R-IFL. Dieser Unterschied ist umso bemerkenswerter, kommentieren Goldberg et al., als dass jetzt in der Secondline-Therapie die Mehrzahl aller Patienten das zuvor in der First-line-Therapie nicht eingesetzte Zytostatikum (d.h. auch Oxaliplatin im R-IFL-Arm) erhielt (Tab. 3), während der Zugang zu Oxaliplatin in früheren Studienphasen noch limitiert und eine effektive Second-line-Therapie daher nur eingeschränkt möglich war. Auch bei Zeit bis zur Progression (10,0 vs. 6,9 Monate; p75 Jahre), die oft aus klinischen Studien ausgeschlossen werden, sind die Oxaliplatin-haltigen Kombinationen geeignet, wie eine exploratorische Analyse im Rahmen von OPTIMOX 1 belegt. Von den 37 über 75-jährigen Patienten in OPTIMOX1 erhielten 20 das FOLFOX4Standardregime, 17 FOLFOX7 [7]. Die Gesamtansprechraten waren mit 65% für FOLFOX4 und 53% für FOLFOX7 vergleichbar. Ähnliches gilt für das progressionsfreie Überleben mit 7,6 bzw. 9,4 Monaten (p = 0,96) und das Gesamt-Überleben mit 14,9 bzw. 25,1 Monaten (p = 0,15). Die Verträglichkeit des FOLFOX4-Regimes bei über 75-jährigen Patienten ist ähnlich günstig wie bei den jüngeren Studienteilnehmern; lediglich Neutropenien treten deutlich häufiger auf. FOLFOX4 und FOLFOX7 unterscheiden sich hinsichtlich ihres Toxizitätsprofils bei den über 75-Jährigen kaum, wobei die Rate an Neutropenien vom Grad 3/4 mit FOLFOX7 niedriger ist. Insgesamt bleibt das günstige Nutzen-Risiko-Profil der Oxaliplatin-haltigen Regime damit auch bei älteren Patienten erhalten, sodass die Autoren diese in ausgewählten Kollektiven mit gutem Performance-Status als sicher erachten. Ebenfalls effektiv sind FOLFOX-Regime bei Patienten mit ungünstiger Prognose, definiert anhand eines stark erhöhten Spiegels an alkalischer Phosphatase – so eine weitere exploratorische Analyse von OPTIMOX1 mit insgesamt 67 Teilnehmern [26]. Die Gesamtresponseraten waren mit 48,5% im FOLFOX4-Arm und 63,4% im FOLFOX7-Arm hoch und unterschieden sich nicht von denen im Gesamtkollektiv. Gesamt-Überlebenszeit und progressionsfreie Zeit waren mit 14 versus 11 Monaten bzw. 6,7 versus 6,5 Monaten in beiden Armen vergleichbar. Demnach kann Oxaliplatin das Überleben im Vergleich zu einer reinen 5-FU/FS-Therapie auch in diesem Kollektiv verlängern. Es ist jedoch mit rund 12 Monaten deutlich kürzer als der sonst mögliche Medianwert von rund 21 Monaten.

Mehr Lebensqualität durch therapiefreies Intervall? In OPTIMOX2 soll der Stellenwert der zwischen den FOLFOX7-Zyklen verabreichten LV5FU2-Erhaltungstherapie geklärt werden. Zu diesem Zweck erfolgt eine Randomisierung zu dem gleichen Regime wie in Arm B von OPTIMOX 1 oder zu einem «Stop-and-go»-Verfahren mit 6 Zyklen FOLFOX7, anschließender Therapiepause und erneuter Gabe von 6 Zyklen FOLFOX7 (Abb. 3). Davon verspricht man sich eine mit bessere Lebensqualität und eine Minimierung von Resistenzrisiko und Kosten. Im Rahmen einer Phase-II-Studie untersuchten T. André, Hôpital Tenon, Paris, und Mitarbeiter gleichzeitig als neue Strategie den Einsatz des antineoplastisch wirkenden, selektiven Cyclooxygenase-2-Hemmers Celecoxib im chemotherapiefreien Intervall des experimentellen Arms [2]. Bei bislang 42 evaluierbaren

Einleitung

Patienten überzeugte dieses Konzept durch ein gutes Sicherheitsprofil. Die Responserate liegt mit 47% – davon 2 Komplettremissionen (CR) – im üblichen Bereich. Das progressionsfreie Überleben in dieser Phase-II-Studie ist mit 6 Monaten jedoch enttäuschend kurz, kommentieren die Autoren. Zum Vergleich: In OPTIMOX1 betrug dieses Intervall im FOLFOX7-Arm 9 Monate. Ob die intermittierende Therapie mit chemotherapiefreien Intervallen eine Zukunft hat, muss die Phase III der OPTIMOX2-Studie zeigen. Grundsätzlich bietet es sich nach Ansicht der Autoren an, die Therapiepausen zur Applikation neuer molekularer Substanzen zu nutzen. Dagegen bezeichnete Hoff ein chronomoduliertes Regime mit Oxaliplatin und 5-FU/FS (FFL4–10), das in der Studie 05963 der European Organization for Research and Treatment of Cancer zur Verbesserung von Effektivität und Verträglichkeit erprobt wurde, als für den Routineeinsatz wenig geeignet [10]. Das chronomodulierte Regime, das höhere Dosen bei weniger Toxizität ermöglichen soll, war bei 554 Patienten mit metastasiertem Kolorektalkarzinom mit dem FOLFOX2-Regime verglichen worden. Die Autoren hatten eine 10%-ige Steigerung der 2-Jahres-Überlebensrate als primären Endpunkt durch die Chronomodulation erhofft. Mit Gesamt-Überlebenszeiten von 19,6 Monaten für FOLFOX2 und 18,7 Monaten für das chronomodulierte Regime hatten sich jedoch beide Therapien als vergleichbar effektiv herausgestellt. Progressionsfreies Überleben und Ansprechraten waren mit 8,4 Monaten bzw. gut 40% in beiden Armen praktisch identisch. Einziger Vorteil der Chronomodulation war die deutliche Reduktion der Neutropenierate von 25,3% mit FOLFOX2 auf 7,3%; ansonsten war die Toxizität in beiden Armen akzeptabel. Für das FOLFOX-Regime spricht jedoch die sehr viel einfachere Applikation, bei der die Infusionszyklen nicht an den zirkadianen Rhythmus angepasst werden müssen.

Tab. 4. Phase-III-Studie der AIO: Nebenwirkungsraten unter FUFOXversus CAPOX-Regime [3] Patienten, %  Capox (n = 164) FUFOX (n = 145)   Grad 1/2 Grad 3/4 Grad 1/2 Grad 3/4 Durchfall Übelkeit Erbrechen Neuropathie Stomatitis HFS Schmerz Fieber Infektion

33 49 27 52 12 29 30 17 12

12 7 5 16 1 1 5 0 3

35 62 31 45 16 27 33 18 14

14 9 7 25 3 0 4 1 4

In der adjuvanten Therapie des Kolorektalkarzinoms ist die Prüfung oraler 5-FU-Prodrugs in Kombination mit Oxaliplatin gerade angelaufen. Anders beim metastasierten Tumor, für den bereits vielversprechende Ergebnisse zu derartigen Kombinationen vorliegen. So zeigt eine deutsche randomisierte Phase-II-Studie, dass Kombinationen von Capecitabin (2 × 1000 mg/m2/Tag, Tage 1–14) mit Oxaliplatin (70 mg/m2 i.v. Tage 1 und 8; CAPOX) oder mit Irinotecan (100 mg/m2 i.v. Tage 1 und 8; CAPIRI) machbar sind und sich durch gute Verträglichkeit und hohe Aktivität auszeichnen. Wie auf der letztjährigen ASCO-Tagung berichtet, werden in der First-lineTherapie Gesamtresponseraten von 51,3%, davon 6,6% CR, mit CAPOX und von 42,6% (CR: 2,9%) mit CAPIRI erreicht [14]. Auch in der Second-line-Therapie nach dem protokollarisch vorgesehenen Cross-over bei Progress waren beide Regime weiterhin effektiv und gut verträglich [15]. Die Re-

sponserate betrug mit CAPIRI 21%, mit CAPOX 13%; bei jeweils etwa der Hälfte der Patienten wurde eine Stabilisierung erreicht. Schwere Nebenwirkungen (Grad 3/4) waren insgesamt selten. Diese Studie war die Basis für eine deutsche Phase-III-Studie der Arbeitsgemeinschaft internistischer Onkologen (AIO), in der die CAPOX-Kombination mit dem 5-FU/FS-Infusionsregime der AIO plus Oxaliplatin (FUFOX) bei 399 Patienten mit metastasiertem Kolorektalkarzinom als First-line-Therapie verglichen wird. Der auf der ASCO-Tagung 2004 vorgestellten Sicherheitsanalyse zufolge ist das Toxizitätsprofil der Zweierkombination mindestens ebenso günstig wie das des gut verträglichen FUFOX-Regimes [Arkenau et al.]. Häufigkeit und Schweregrad gastrointestinaler Nebenwirkungen und des Hand-Fuß-Syndroms sind in beiden Gruppen vergleichbar. Eine schwere sensorische Neuropathie vom Grad 3/4 tritt unter CAPOX sogar deutlich seltener auf als mit dem FUFOX-Regime (Tab. 4). Eine Hämatotoxizität vom Grad 3/4 war insgesamt selten; häufiger wurden lediglich Neutropenien im FUFOX-Arm dokumentiert. Drei verschiedene Oxaliplatin-Kombinationen werden in der Studie TREE 1 bei 150 Patienten mit metastasiertem Kolorektalkarzinom untersucht. Hier wird das klassische FOLFOX4-Regime mit CapeOx (130 mg/m2 Oxaliplatin i.v. Tag 1 plus 1000 mg/m2 Capecitabin 2x/Tag, 14 Tage alle 3 Wochen) und dem bFOL-Regime mit Oxaliplatin (85 mg/m2, Tag 1, 15) plus 5-FU-Bolusregime (500 mg/m2 Tag 1, 8, 15 alle 4 Wochen) verglichen [27]. Die Gesamtansprechraten liegen zwischen 38% (bFOL) und 52% (FOLFOX) ohne signifikante Unterschiede zwischen den drei Armen. Hinsichtlich Verträglichkeit erwies sich das bFOL-Regime als am günstigsten; im CapeOx-Arm mussten 38% der Patienten die Therapie toxizitätsbedingt in den ersten 12 Wochen unterbrechen. Entsprechend wurde die Capecitabin-Dosis für die Studie TREE 2 auf 850 mg zweimal täglich abgesenkt. Diese Studie, für die 223 Patienten rekrutiert wurden, gehört bereits einer neuen Generation an, da die 3 Therapieregime aus TREE 1

Einleitung

Onkologie 2004;27(suppl 1):2–11

Orale Prodrugs ersetzen 5-FU

7

Tab. 5. Hohe Responseraten in der Phase-II-Studie mit der Kombination aus FOLFOX4 plus Cetuximab [24]. Bei 7 Patienten erfolgte eine Resektion von Lebermetastasen. Gesamtansprechraten

N/%

95% CI

Komplettes Ansprechen Partielles Ansprechen Stabilisierung Progression

2 / 5% 32 / 76% 7 / 17% 1 / 2%

1–16 61–88 7–32 1–13

mit Bevacizumab kombiniert werden. Die jetzt präsentierten Sicherheitsdaten aus TREE 2 sind sehr beruhigend und sprechen für das akzeptable Toxizitätsprofil aller drei Arme – einschließlich CapeOx. Mit Spannung werden jetzt die Effektivitätsdaten dieser Studie erwartet, da eine weitere Überlebensverlängerung auf bis zu 24 Monate angenommen wird. Damit hätte man die Lebenserwartung von Patienten mit fortgeschrittenem Kolorektalkarzinom in den vergangenen Jahren etwa vervierfacht, betrug doch das mittlere Überleben noch in den achtziger Jahren bei alleiniger Supportivtherapie nur rund 6 Monate.

Vielversprechende Ergebnisse mit molekularen Therapieansätzen Welche beeindruckenden Ergebnisse mit Kombinationen der klassischen Chemotherapie plus Biologicals zu erreichen sind, zeigt eine internationale Phase-II-Studie, in der das FOLFOX4-Regime zusammen mit dem monoklonalen, gegen EGFR gerichteten Antikörper Cetuximab als Firstline-Therapie verabreicht wurde [24]. In die Studie wurden bislang 43 Patienten mit fortgeschrittenem Kolorektalkarzinom und Nachweis einer EGFR-Expression in Tumorgewebe oder Metastasen aufgenommen. Sie erhielten als First-line-Therapie zusätzlich zum FOLFOX4-Regime Cetuximab in einer Dosis von 400 mg/m2 i.v. an Tag 1; anschließend wurde Cetuximab wöchentlich in einer Dosis von 250 mg/m2 verabreicht. Die Effektivität der innovativen Kombination bei den 42 evaluierbaren Patienten ist ausgesprochen hoch: Insgesamt sprachen 34 Patienten (81%) an, zwei davon komplett. Werden auch Stabilisierungen berücksichtigt, so steigt die Tumorkontrollrate auf 98% an (Tab. 5). Das Sicherheitsprofil der Kombination beschreiben die Autoren als akzeptabel: Als häufigste Nebenwirkungen vom Grad 3/4 wurden Diarrhöen (26%), akneformer Ausschlag (21%) und Neutropenien (14%) registriert. In seiner Diskussion der Studienergebnisse bezeichnete Saltz die erreichten Responseraten als sehr ermutigend und als gute Basis für eine Phase-III-Studie. Der routinemäßige Einsatz der FOLFOX4-Cetuximab-Kombination außerhalb klinischer Studien sei jedoch bislang noch nicht gerechtfertigt. Hier seien die Ergebnisse einer CALBG-Studie an 1100 Pa-

8

Onkologie 2004;27(suppl 1):2–11

tienten abzuwarten, in der die Kombination von mFOLFOX6 mit oder ohne Cetuximab mit dem FOLFIRI-Regime, ebenfalls mit oder ohne Antikörper, in der First-line-Therapie des fortgeschrittenen Kolorektalkarzinoms verglichen werde.

Geprüft werden Antikörper und «small molecules» Ebenfalls durch sehr hohe Ansprechraten fällt eine weitere Phase-II-Studie auf, in der das FOLFOX4-Regime mit dem EGFR-TK-Inhibitor Gefitinib (IFOX) kombiniert wurde [8]. Hier erfolgte eine Stratifizierung der insgesamt 63 Patienten: 31 Teilnehmer waren nicht vortherapiert (Gruppe A), weitere 27 hatten bereits eine Irinotecan-haltige First-line-Therapie erhalten (Gruppe B). In Gruppe A sprachen 23 Patienten (77%) partiell auf die Therapie an, bei weiteren 20% gelang eine Tumorstabilisierung. In Gruppe B lag die Responserate bei 29%, die Stabilisierungsrate bei 58%. Die Zeit bis zur Progression beträgt 9,5 bzw. 5,2 Monate. Das IFOX-Regine ist allerdings durch eine höhere Rate gastrointestinaler Nebenwirkungen (Diarrhöe, Übelkeit, Erbrechen) im Vergleich zu FOLFOX4 charakterisiert. Die hohe Diarrhörate von 54% sollte laut Saltz auf jeden Fall zur Vorsicht bei der weiteren Erprobung von IFOX mahnen. Bislang ist noch unklar, ob die bei Patienten mit Bronchialkarzinom nachgewiesenen aktivierenden Mutationen im EGFR, die zu einer sehr starken Tumorschrumpfung und lang anhaltenden Remissionen führen, auch beim Kolorektalkarzinom auftreten. Die Hypothese, dass eine EGFR-Expression im Tumor Voraussetzung für das Ansprechen auf EGFR-Antagonisten ist, kann heute laut Saltz als widerlegt gelten. Er bezeichnete es als falsch und zynisch, Patienten eine gegen EGFR gerichtete Therapie nur aufgrund einer fehlenden EGFR-Expression vorzuenthalten.

Oxaliplatin ermöglicht Resektion von Lebermetastasen Bei mehr als der Hälfte aller Patienten mit kolorekatalem Karzinom treten im Erkrankungsverlauf Lebermetastasen auf. Lediglich die chirurgische Resektion, die allerdings primär nur in maximal einem Viertel der Fälle möglich ist, bietet den Betroffenen eine Heilungschance. Als effektiv hat sich jedoch die neoadjuvante Chemotherapie erwiesen, die zu Downstaging und verbesserter Resektabilität führt. So gelang in der Sequenzstudie von Tournigand et al. mit dem FOLFOX-Regime als First-line-Therapie bei 21 der 59 Responder eine chirurgische Entfernung zuvor inoperabler Lebermetastasen; 13 von ihnen konnten R0-reseziert werden [25]. Nach einer First-line-Therapie mit dem FOLFIRI-Regime war dagegen nur bei 8 von 61 Respondern eine Resektion möglich. Laut einer retrospektiven Analyse entspricht das Überleben R0-resezierter Patienten mit rund 70 Monaten dem von Patienten, deren Lebermetastasen primär chirurgisch entfernt werden konnten [9].

Einleitung

Problematisch ist allerdings das Vorgehen bei metastasierten Patienten nach Progression unter einer First-line-Therapie, da die Chancen für ein Ansprechen auf Oxaliplatin in der Second line geringer sind. In solchen Fällen könnte eine lokoregionäre Infusionstherapie über die Arteria hepatica (HAI) erfolgreicher sein, da das Tumorgewebe so einer höheren Zytostatikakonzentration ausgesetzt wird [17]. Die Autoren erprobten dieses Vorgehen bei 44 Patienten mit alleinigen, aber inoperablen Lebermetastasen, die auf eine First-line-Chemotherapie, meist mit Irinotecan-Kombinationen, nicht mehr angesprochen hatten. Die HAI wurde mit einer systemischen Chemotherapie kombiniert, um so eine effektive Kontrolle von Lebermetastasen und extrahepatischer Erkrankung zu erreichen. 21 Patienten erhielten neben der HAI mit Floxuridin und Dexamethason eine systemische Chemotherapie mit Oxaliplatin und 5-FU/FS, 23 weitere Patienten zusätzlich zur HAI die Kombination aus Oxaliplatin/Irinotecan. Im Gesamtkollektiv war die Ansprechrate mit 82% hoch, obwohl fast drei Viertel der Teilnehmer unter der vorherigen Therapie progredient geworden waren. In 7% der Fälle gelang eine pathologische Komplettremission. Bei 9 Patienten (20%) konnten die Lebermetastasen bereits erfolgreich reseziert werden; bei weiteren 7 Patienten ist eine Operation möglich. Nach einem medianen Follow-up von jetzt 21 Monaten beträgt die progressionsfreie Zeit bei den systemisch mit Oxaliplatin/5-FU behandelten Patienten 19 Monate, in der Oxaliplatin/IrinotecanGruppe 15 Monate. Die Gesamt-Überlebenszeiten erstrecken sich über mittlerweile 23 bzw. 36 Monate und sind damit als exzellent für dieses Patientenkollektiv zu werten. Die Autoren empfehlen jetzt eine randomisierte Vergleichsstudie, in der ihr Ansatz mit einer alleinigen neoadjuvanten systemischen Chemotherapie verglichen wird.

Pankreaskarzinom: GemOx verbessert Therapieergebnisse

Tab. 6. Therapieergebnisse der Phase-III-Studie von GERCOR/GISCAID mit der Gemcitabin-Monotherapie versus GEMOX-Kombination [19]

Patienten Ansprechrate* Überleben Progressionsfreies Überleben 1-Jahres-Überlebensrate 8-Monats-Überlebensrate

GO

G

157 26,8% 9,0 Monate 5,8 Monate 34,7% 56,5%

156 17,3% 7,1 Monate 3,7 Monate 27,8% 45,3%

P-Wert

0,04 0,13 0,038 0,048

*Remissionen wurden nicht zentral begutachtet, schließen geschätzte partielle Remissionen ein.

Überlebenszeit von immerhin 9,2 Monaten erreicht. Die 1-Jahres-Überlebensraten von 47% bei Patienten mit lokal fortgeschrittenem und von 26% beim metastasierten Pankreaskarzinom lagen in dieser Studie deutlich über denen der Gemcitabin-Monotherapie. Diese ermutigenden Daten rechtfertigten die Initiierung einer Phase-III-Studie, in der die neue Kombination mit Gemcitabin als Monotherapie verglichen wurde. Für die von der französischen GERCOR- und der italienischen GISCAD-Gruppe durchgeführte Studie wurden zwischen März 2001 und Februar 2003 313 Patienten mit histologisch gesichertem Pankreasadenokarzinom rekrutiert [19]. 156 Patienten wurden randomisiert dem Kontrollarm mit Gemcitabin (1 g/m2 wöchentlich als 30-minütige Infusion), 157 Patienten dem experimentellen Arm mit der GEMOX-Kombination zugeteilt. Rund 30% der Patienten in beiden Armen wiesen einen lokal fortgeschrittenen, 70% einen metastasierten Tumor auf. Primäres Ziel der Studie war eine 20%-ige Zunahme der Überlebensrate von 30 auf 50% nach 8 Monaten. Sekundäre Wirkparameter waren progressionsfreies Überleben, Ansprechrate, klinischer Benefit, Verträglichkeit und Lebensqualität.

Überlebensverlängerung um 2 Monate

Zur Sitzung «Gastrointestinal (Noncolorectal) Cancer» unter Leitung von Emily K. Bergsland, University of California, San Francisco Cancer Center, und Charles D. Blanke, Oregon Health and Science University, und zur Postersitzung «Gastrointestinal (Noncolorectal) Cancer» Seit Einführung von Gemcitabin – derzeit immer noch Standard in der Behandlung des Pankreaskarzinoms – versucht man eine Steigerung der unbefriedigenden Ansprech- und Überlebensraten durch Kombination mit weiteren Zytostatika zu erreichen. Am erfolgversprechendsten stellte sich in einer Phase-II-Studie die als GEMOX bezeichnete Kombination mit Gemcitabin (1000 mg/m2 i.v. als 100-min-Infusion, Tag 1) und Oxaliplatin (100 mg/m2 i.v., Tag 2) alle 2 Wochen heraus [18]: Bei guter Verträglichkeit wurden eine hohe Ansprechrate von 30%, eine klinische Benefitrate von fast 40%, ein medianes progressionsfreies Intervall von 5,3 und eine Gesamt-

Die bereits in der Phase-II-Studie beobachtete eindrucksvolle Aktivität der GEMOX-Kombination bestätigte sich auch in dieser randomisierten Vergleichsstudie anhand der signifikant höheren Responserate im Vergleich zur Gemcitabin-Monotherapie (26,8 vs. 17,3%; p = 0,04; Tab. 6). Auch bei der klinischen Benefit-Rate zeigte sich ein signifikanter Vorteil zugunsten des Kombinationsregimes (38,2 vs. 26,9%; p = 0,03), wobei Patienten mit lokal fortgeschrittenem Tumor besonders stark profitierten (45,1 vs. 34,0%). Darüber hinaus gelang eine erhebliche Verlängerung des progressionsfreien Überlebens von nur 3,7 Monaten unter Gemcitabin auf 5,8 Monate mit der Oxaliplatin-Kombination (p = 0,038). Auch die Gesamt-Überlebenszeit konnte durch die Kombinationstherapie um rund 2 Monate verlängert werden (9,0 vs.

Einleitung

Onkologie 2004;27(suppl 1):2–11

9

791 Patienten

R A N D O M I S I E R T

Arm A: Gemcitabin 1000 mg/m2/30 min qw x 3 alle 4 Wochen

Arm B: Gemcitabin 1500 mg/m2/150 min qw x 3 alle 4 Wochen

Arm C: Gemcitabin 1000 mg/m2/100 min Oxaliplatin 100 mg/m2/120 min q 14 Tage

Abb. 4. Design der dreiarmigen ECOG-Studie.

7,1 Monate), was einer 27%-igen Zunahme des medianen Überlebens entspricht. Dieser Unterschied zwischen beiden Studienarmen ist allerdings nicht signifikant, was sich laut Christophe Louvet, Hôpital Saint Antoine, Paris, durch die überraschend positiven Studienresultate, insbesondere auch des Kontrollarms erklären lässt: Erwartet worden waren Überlebenszeiten von 8 bzw. 6 Monaten. Das angestrebte Ziel – die 20%-ige Steigerung der 8-Monats-Überlebensrate – wurde zwar verfehlt (56,5 vs. 45,3%); der Unterschied zwischen beiden Regimen zu diesem Zeitpunkt ist jedoch signifikant, betonte Louvet. Über die Hälfte der Patienten erhielt nach Progression eine Second-line-Therapie. Louvet wies darauf hin, dass diese im Gemcitabin-Arm – entgegen dem Studienprotokoll – in fast drei Viertel der Fälle Platinderivate (einschließlich Oxaliplatin) beinhaltete. Dieser Faktor ist seiner Ansicht nach ein entscheidender Grund für den nur tendenziell ausgeprägten Überlebensvorteil der GEMOX-Kombination. Inwieweit die zusätzliche Gabe von Oxaliplatin oder die Applikation von Gemcitabin mit fixierter Dosierungsgeschwindigkeit zu der Überlebensverlängerung beiträgt, ist laut Louvet schwer auszumachen. Hedy Lee Kindeler, University of Chicago, kritisierte in ihrem Diskussionsbeitrag, dass die Gemcitabin-Regime in den beiden Studienarmen nicht vergleichbar waren. Diese Frage wird jedoch zur Zeit in einer ECOG-Studie der Phase III mit fast 800 Patienten geklärt: In 3 Armen werden Gemcitabin/ Oxaliplatin, die Monotherapie mit Gemcitabin als 30-minütiger Bolus und die Gemcitabin-Infusion verglichen (Abb. 4). Laut Kindler ist es jetzt an der Zeit, auch beim fortgeschrittenen Pankreaskarzinom neue molekulare Substanzen in die Behandlung zu integrieren, da die alleinige konventionelle Chemotherapie den ungünstigen Verlauf bei diesem Tumor voraussichtlich nicht ändern wird. «Solche Ansätze werden die Therapie vermutlich mehr bereichern als die Erprobung weiterer Zytostatika-Doubletten», betonte sie. «Die moleku-

10

Onkologie 2004;27(suppl 1):2–11

laren Therapieansätze sollten zuammen mit der derzeit besten Chemotherapie geprüft werden, und das ist sicherlich die GEMOX-Kombination», so die Meinung von Louvet. Neben der höheren Effektivität zeichnet sich GEMOX auch durch eine gute Verträglichkeit aus; die Toxizität ist im Vergleich zur Gemcitabin-Monotherapie kaum erhöht.

Oxaliplatin-Regime bei Magen- und Ösophaguskarzinom Schlecht ist die Prognose auch beim Magenkarzinom: Höchstens ein Drittel der betroffenen Patienten kann R0-reseziert werden; die langfristige Heilungsrate ist niedrig. Der palliativen Chemotherapie kommt daher große Bedeutung zu, weil sie die Lebensqualität im Vergleich zu alleinigen Supportivtherapie verbessert und eine Lebensverlängerung ermöglicht. Referenztherapie ist derzeit das ECF-Regime mit Epirubicin/Cisplatin/5-FU, mit dem Responseraten zwischen 40 und 45% und ein medianes Überleben von rund 9 Monaten erreicht werden. Aber: Das Regime gilt wegen der dauerhaften Versorgung der Patienten mit einer Pumpe als wenig patientenfreundlich, sodass nach therapeutischen Alternativen gesucht wird. L. Cavanna und Mitarbeiter erprobten bei 35 Patienten mit fortgeschrittenem oder metastasierten Magenkrebs die Kombination von Oxaliplatin (85 mg/m2 i.v., Tag 1) mit einem 5-FU/FS-Infusionsregime [4]. Auf die Therapie sprachen 17 Patienten (48,6%) an, einer von ihnen mit einer Komplettremission. Bei 10 weiteren Teilnehmern (28,6%) wurde eine Tumorstabilisierung erreicht. Die hohe Aktivität ging mit einer nur leicht ausgeprägten Toxizität einher: Schwere Nebenwirkungen vom Grad 3/4 waren insgesamt selten. Am häufigsten wurden Neutropenien (21,3%) und Thrombozytopenien registriert. Beim inoperablen Ösophaguskarzinom wird derzeit eine Radiochemotherapie mit 4 Zyklen 5-FU/Cisplatin und einer Bestrahlung mit 50 Gy (RTOG-Regime) als Referenztherapie betrachtet, mit der eine Langzeit-Überlebensrate von 25% erreicht wird. Giovani et al. erprobten in einer Phase-I-Studie ein Radiochemotherapie-Regime mit Ersatz von Cisplatin durch Oxaliplatin [11]. Die Dosisfindungsstudie an 33 Patienten zeigt, dass die Chemotherapie in einer dem FOLFOX4Regime entsprechenden Dosis sicher zusammen mit einer Bestrahlung von 50 Gy verabreicht werden kann. Bei den 28 evaluierbaren Patienten wurde eine Responserate von 61% erzielt: 3 Patienten sprachen komplett, 14 weitere partiell an. Die mediane Zeit bis zur Progression beträgt 5, die GesamtÜberlebenszeit 9 Monate. Jetzt ist geplant, die neue Kombination in einer kontrollierten Studie der Phase II/III mit dem RTOG-Referenzregime zu vergleichen. Bericht: Dr. Katharina Arnheim, Berlin

Einleitung

Literatur 1 André T, Boni C, Mounedji-Boudiaf L et al.: Oxaliplatin, Fluorouracil, and Leucovorin as Adjuvant Treatment for Colon Cancer. N Engl J Med 2004; 350:2343–2351. 2 André T, Maindrault-Goebel F, Mineur L et al.: Phase II study of an optimized 5FU/oxaliplatin strategy (OPTIMOX2) with celecoxib in metastatic colorectal cancer: A GERCOR study. Proc ASCO 2004;23:abstr 3554 (poster presentation). 3 Arkenau HT, Schmoll HJ, Kubicka S et al.: Phase III trial of capecitabine plus oxaliplatin (CAPOX) versus infusional 5-FU/LV plus oxaliplatin (FUFOX) in first-line metastatic colorectal cancer (MCRC): Interim safety analysis. Proc ASCO 2004; 23:abstr 3546 (poster presentation). 4 Cavanna L, Zaniboni A, Artioli F et al.: Oxaliplatin (OXA), 5-fluorouracil (5-FU) and leucovorin (LV) in patients with advanced or metastatic gastric cancer (A/MGC). Proc ASCO 2004;23:abstr 4068 (poster presentation). 5 Cassidy J, Scheithauer W, McKendrick W et al.: Capecitabine (X) vs bolus 5-FU/leucovorine (LV) as adjuvant therapy for colon cancer (the X-ACT study): Positive efficacy results of a phase III trial. Proc ASCO 2004;23:abstr 3509 (oral presentation). 6 De Gramont A, Cervantes A, André T et al.: OPTIMOX study: FOLFOX7/LV5FU2 compared to FOLFOX4 in patients with metastatic colorectal cancer. Proc ASCO 2004;23:abstr 3525 (poster presentation). 7 Figer A, Perez N, Carola E et al.: 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) in very old patients with metastatic colorectal cancer. Proc ASCO 2004;23:abstr 3571 (poster presentation). 8 Fisher GA, Kuo T, Cho CD et al.: A phase II study of IFOX (gefitinib with FOLFOX-4) in patients with metastastic colorectal cancer. Proc ASCO 2004;23:abstr 3514 (poster presentation). 9 Giacchetti S, Itzhaki M, Gruia G et al.: Long-term survival of patients with unresectable colorectal liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin and surgery Ann Oncol 1999;10:663–669. 10 Giacchetti S, Bjarnason G, Garufi C et al.: First line infusion of 5-fluorouracil, leucovorin and oxaliplatin for metastatic colorectal cancer: 4-day chronomodulated (FFL4–19) versus 2-day FOLFOX2. A multicenter randomized phase III trial of the chronotherapy group of the European Organization for Research and Treatment of Cancer (EORTC 05963). Proc ASCO 2004;23:abstr 3526 (poster presentation).

Einleitung

11 Giovani M, Conroy T, Francois E et al.: Phase I study of first line radiochemotherapy with oxaliplatin (Ox), 5-fluoruracil (5-FU) and folinic acid in inoperable locally advanced or metastatic esophageal cancer. Proc ASCO 2004;23:abstr 4044 (poster presentation). 12 Goldberg RM, Morton RF, Sargent DJ et al.: N9741: Oxaliplatin (oxal) or CPT-11 + 5-fluorouracil (5-FU)/leucovorin (LV) or oxal + CPT-11 in advanced colorectal cancer (CRC): Updated efficacy and quality of life (QOL) data from an intergroup study. Proc ASCO 2003;22:abstr 1009 (oral presentation). 13 Goldberg RM, Sargent DJ, Morton RF et al.: N9741: FOLFOX (oxaliplatin (Oxal)/5-Fluoruracil (5-FU)/leucovorin (LV)) or reduced dosis R-IFL (CPT-11 + 5-FU/LV) in advanced colorectal cancer (CRC): Final efficacy data from an intergroup study. Proc ASCO 2004;23:abstr 3621 (poster presentation). 14 Grothey A, Jordan K, Kellner O et al.: Randomized phase II trial of capecitabine plus irinotecan (CapIri) vs capecitabine plus oxaliplatin (CapOx) as first-line-therapy of advanced colorectal cancer. Proc ASCO 2003;22:abstr 1011 (poster presentation). 15 Grothey A, Jordan K, Kellner O et al.: Capecitabine (Xeloda) plus either weekly irinotecan (CAPIRI) or weekly oxaliplatin (CAPOX) are active second-line protocols in patients with metastatic colorectal cancer (MCRC) after failure of firsttime combination therapy: Results of a randomized phase II study. Proc ASCO 2004;23:abstr 3534 (poster presentation). 16 Hickish T, Boni C, Navarro M et al.: FOLFOX 4 as adjuvant treatment for stage II colon cancer: Subpopulation data from the MOSAIC trial. Proc ASCO 2004;23:abstr 3619 (poster presentation). 17 Leonard GD, Fong Y, Jarnagin W et al.: Liver resection after hepatic arterial infusion (HAI) plus systemic oxaliplatin (Oxal) combination in pretreated patients with extensive unresectable colorectal liver metastases. Proc ASCO 2004;23:abstr 3542 (poster presentation). 18 Louvet C, André T, Lledo G et al.: Gemcitabine combined with oxaliplatin in advanced pancreatic adenocarcinoma: Final results of a GERCOR multicenter phase II study. J Clin Oncol 2002;20:1512– 1518.

19 Louvet C, Labianca R, Hammel P et al.: GemOx (gemcitabine + oxaliplatin) versus gem (gemecitabine) in non resectable pancreatic adenocarcinoma: Final results of the GERCOR/GISCAID Intergroup Phase III. Proc ASCO 2004;23:abstr 4008 (oral presentation). 20 NIH consensus conference: Adjuvant therapy for patients with colon and rectal cancer. JAMA 1990; 264:1444–1450. 21 Saltz LR, Niedzwiecki D, Hollis D et al.: Irinotecan plus fluorouracil/leucovorin (IFL) versus fluorouracil/leucovorin alone (FL) in stage III colon cancer (intergroup trial CALBG C89803). Proc ASCO 2004;23:abstr 3500 (oral presentation). 22 Sargent DJ, Niedzwiecki D, O’Connell MJ et al.: Recommendation for caution with irinotecan, fluoruracil, and leucovorin for colorectal cancer. N Engl J Med 2001;345:144–146. 23 Sargent DJ, Wieand S, Benedetti R et al.: Diseasefree survival (DFS) vs. overall survival (OS) as a primary endpoint for adjuvant colon cancer studies: Individual patient data from 12,195 patients on 15 randomized trials. Proc ASCO 2004;23:abstr 3502 (oral presentation). 24 Tabernero JM, van Cutsem E, Sastre J et al.: An international phase II study of cetuximab in combination with oxaliplatin/5-fluorouracil (5-FU)/folinic acid (FA) (FOLFOX-4) in the first-line treatment oft patients with metastatic colorectal cancer (CRC) expressing epidermal growth factor receptor (EGFR). Preliminary results. Proc ASCO 2004;23:abstr 3512 (poster presentation). 25 Tournigand C, Louvet C, Quinaux E et al. FOLFIRI followed by FOLFOX versus FOLFOX followed by FOLFIRI in metastatic colorectal cancer (MRC): Final results of a phase III study. Proc ASCO 2002;22:abstr 494 (oral presentation). 26 Tournigand C, André T, Chirivella I et al.: 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) in poor prognosis. Proc ASCO 2004;23:abstr 3565 (poster presentation). 27 Welles L, Hochster H, Ramanathan R et al.: Preliminary results of a randomized study of the safety and tolerability of three oxaliplatin-based regimens as first-line treatment for advanced colorectal cancer (CRC) (‘Tree’ Study). Proc ASCO 2004;23: abstr 3537 (poster presentation).

Onkologie 2004;27(suppl 1):2–11

11

Dokumentation und Evaluation der Weiterbildung ASCO-Abstracts Onkologie 2004;27(suppl 1):12–58

Breast Cancer 660

A multistep randomized phase II/III trial comparing oxaliplatin (OXA)+5 fluorouracil (FU) to vinorelbine (VIN)+FU (FUN) after taxane (T)/anthracycline (A) failure in advanced/metastatic breast cancer (MBC) patients (pts): Final results. S. Delaloge, M. Tubiana-Hulin, A. Wardley, L. Del Mastro, A. Santoro, A. Zambelli, A. Bonetti, C. Boni, F. Habib, S. Brienza Institut Gustave Roussy, Villejuif, France; Centre René Huguenin, St Cloud, France; Christie Hospital, Manchester, United Kingdom; Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy; Istituto Clinico Humanitas, Rozzano (MI), Italy; Fondazione Salvatore Maugeri, Pavia, Italy; Azienda Ospedaliera di Legnago, Legnago, Italy; Arcispedale Santa Maria Nuova, Reggio Emilia, Italy; Centre d’oncologie Al Azhar, Rabat, Morocco; Debioclinic S.A., Charenton le Pont, France

Background: OXA is a new DACH platinum (Pt) with preclinical evidence of activity in vivo and in mammary cell lines. Previous clinical study has shown promising activity both for OXA alone (Ann Oncol 2001 Feb 12(2):179–82) and with FU (JCO 2002 15;20:2551–8) in pretreated MBC. Methods: In order to compare tolerance and activity of OXA/FU to reference regimen FUN in pts pretreated with both T and A, we conduct a randomized phase II–III trial. Pts are assigned either to OXA 130 mg/m2 2 hours IV on day (D) 1 plus FU 750 mg/m2 daily by continuous IV infusion D1 to D5 q 3 wks or VIN 25 mg/m2 IV bolus plus the same FU. Eligibility criteria included relapsing progressive MBC, at least one previous chemotherapy (CT) for MBC, no more than 3 prior CT, previous A, previous T therapy given for MBC in an appropriate dose and schedule, at least one measurable target lesion (RECIST criteria), WHO PS 0–2, adequate baseline organs functions. Stratification factors: institution, best response

Median age (range) ≥2 previous CT PD as best response to previous T PS 1–2 Nb of cy Neutropenia Mucositis Neurosensory Toxic death RR PFS (wks) OS (wks)

OXA ARM N=68

VIN ARM N=69

p-value

53 (30–78) 21 (31%) 24 (35%)

52 (35–73) 18 (26%) 24 (35%)

0.7809 0.5340 0.9500

28 (42%) 6 (1–21) 9 (13%) 8 (12%) 5 (7.5%) 0 16 (23.5%) 19.1 (16.7–23) 61.7 (44.7–91)

27 (39%) 6 (1–28) 53 (78%) 22 (32%) 0 1 (1.5%) 19 (27.5%) 22.9 (18.6–30.1) 71 (49.3–85)

0.7519 0.5371 Normal £ Normal

1068 231 226 226 198 187 484 471 109 440 480

1.2 1.3 1.3 1.1 1.1 1.0 0.9 1.2 1.3 1.0 1.3

8.3 6.5 7.1 8.7 10.0 9.8 11.8 7.2 3.1 11.2 6.1

PS

LDH

3512

An international phase II study of cetuximab in combination with oxaliplatin/5-fluorouracil (5-FU)/folinic acid (FA) (FOLFOX-4) in the first-line treatment of patients with metastatic colorectal cancer (CRC) expressing Epidermal Growth Factor Receptor (EGFR). Preliminary results J. M. Tabernero, E. Van Cutsem, J. Sastre, A. Cervantes, J.-L. Van Laethem, Y. Humblet, P. Soulié, S. Corretgé, M. Mueser, A. De Gramont Vall d’Hebron University Hospital, Barcelona, Spain; University Hospital Gasthuisberg, Leuven, Belgium; Hospital Clínico San Carlos, Madrid, Spain; Hospital Clínico Universitario, Valencia, Spain; Erasme Hospital, Brussels, Belgium; Cliniques Universitaires St. Luc, Brussels, Belgium; Centre Paul Papin, Angers, France; Merck Farma y Química, SA, Barcelona, Spain; Merck KGaA, Darmstadt, Germany; Hôpital Saint-Antoine, Paris, France

Background: Cetuximab (Erbitux) is an IgG1 monoclonal antibody targeting the EGFR, shown to be effective in patients (pts) with EGFR-expressing metastatic CRC refractory to prior irinotecanbased chemotherapy (Cunningham ASCO 2003). Cetuximab has demonstrated high efficacy with an acceptable safety profile in combination with different regimens of irinotecan/FA/5-FU as 1st-line treatment (Rosenberg ASCO 2002; Van Laethem and Folprecht ASCO 2003). This trial was designed to evaluate the efficacy and safety of cetuximab with the FOLFOX-4 regimen as 1st-line treatment. Methods: Pts received cetuximab (400 mg/m2 week 1 and 250 mg/m2 weekly thereafter) plus FOLFOX-4 (every 2 weeks: oxaliplatin 85 mg/m2, day 1; FA 200 mg/m2 IV 2h and 5-FU 400 mg/m2 IV bolus followed by 600 mg/m2 IV for 22h, days 1 and 2) until PD or unacceptable toxicity. Main inclusion criteria included pts with non-resectable metastatic CRC, EGFR expression on tumor, no previous chemotherapy for metastatic CRC, and ECOG PS = 2. Results: Of the 61 pts screened 50 (82%) showed EGFR expression on the tumor. 43 pts have finally been enrolled. Currently, baseline data from 25 enrolled pts are available: M/F 16/9, median age 65 years (range 43–75), colon/rectum 17/8, ECOG PS=0/1 16/9, number of organs affected=1/2/3: 13/9/3. The observed best overall response was based on 20 evaluable pts: 14 (70%) partial response (of these, 7 responses have been confirmed so far), 5 (25%) stable disease, 1 not evaluable who withdrew his consent after 1st infusion. Two pts underwent curative resection of their hepatic metastasis after confirmed response. So far, 8 serious adverse events were observed (4 5-FU related diarrhea, 1 pulmonary embolism, 1 pneumonia, 1 PD with obstructive jaundice, 1 gout) none of them related to cetuximab. Conclusion: These preliminary data suggest that cetuximab may be safe and effective when combined with FOLFOX-4 in first-line treatment of patients with metastatic CRC.

3514

In a Cox regression analysis, longer OS was better explained by longer (≥6 mo) TTP (p3 years; sch A/B %pts: women, 40.1/40.4; Colon primary, 59.9/58.5; PS 0/1/2, 49.3/40.4/9.2 vs 47.5/40.4/11.7; single M site, 50.7/50; synchronous M, 73/74.1; adjuvant chemo, 16.7/19.1. N of courses: sch A/B: 2916/2783. Toxic deaths: 1/2. OS (Hazard Ratio = 0.94, 95% CI:0.73–1.21) and Progression Free Survival (PFS) (HR=1.01, 95% CI: 0.81–1.26) did not differ significantly. Conclusions: This is the first trial that has compared the two most active treatment schedules as 1st line chemotherapy of MCC. No difference in OS and PFS were observed with a median survival >18 months in both regimens and a different but low toxicity profile (normal / unknown) 51%/27%/22%, metastatic site (1/ >1) 73/27%, alk phosp (nl/elevated/unknown) 59%/35%/6%. Results: 37 pts are evaluable for safety and 35 pts for response. Grade 3-4 toxicities (% of pts, arm A / arm B) were: neutrophils 55/24, platelets 5/0, hemoglobin 5/0, nausea-vomiting 0/12, diarrhea 5/6, neurotoxicity 20/24. Maximal toxicity per patient was grade 3-4 in 80% of arm A pts, and 59% of arm B pts. Response rate (intent-to-treat) was 59.4% (arm A 65%; arm B 53%). Median PFS was 37 weeks (arm A 33 w; arm B 41 w) and median OS was 79 weeks (arm A 65w and arm B 90w). Moreover, in OPTIMOX study, age does not appear as a prognosis factor in a multivariate analysis. Conclusion: These results indicate that efficacy is maintained with Folfox regimens in patients >75years.

3579

Phase 1/2a study of EKB-569, an irreversible inhibitor of epidermal growth factor receptor, in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX-4) in patients with advanced colorectal cancer (CRC) S. Tejpar, E. Van Cutsem, E. Gamelin, D. Machover, P. Soulie, A. Ulusakarya, S. Laurent, J. M. Vauthier, S. Quinn, C. Zacharchuk University Hospital Gasthuisberg, Leuven, Belgium; Centre Paul Pipin, Angers, France; Hopital Paul Brousse, Villejuif, France; Wyeth Research, Paris, France; Wyeth Research, Cambridge, MA

Background: EKB-569 is an orally active, low molecular weight, selective, irreversible inhibitor of the epidermal growth factor receptor tyrosine kinase. In animal models, EKB-569 in combination with different chemotherapy agents shows at least additive effects on growth inhibition of colorectal and other tumors. Methods: This open-label, dose-escalation study evaluates the maximum tolerated dose (MTD), safety, pharmacokinetics, and anti-tumor activity of EKB-569 in combination with the FOLFOX-4 regimen in patients (pts) with previously untreated advanced CRC. Pts (3–6 per cohort) were to receive EKB-569 (25, 35, 50, or 75 mg/day orally) starting on day 3 in combination with the FOLFOX-4 regimen (day 1: oxaliplatin 85 mg/m2 and leucovorin [LV] 200 mg/m2, 120 min, simultaneously, followed by 5fluorouracil [FU] 400 mg/m2, bolus, and FU 600 mg/m2, 22-h continuous infusion; day 2: LV and FU as on day 1). Dose escalation was based on safety evaluations after 2 treatment cycles (14 days/cycle).

Onkologie 2004;27(suppl 1):12–58

25

Treatment continues until evidence of disease progression or unacceptable toxicity. Results: Twenty nine pts were enrolled; enrollment is complete. Median age was 61 yrs (range, 46–70); ECOG performance status was 0: 71% and 1: 29%. Dose-limiting toxicities within the first 2 treatment cycles were grade 3 diarrhea (1 pt) and grade 3 febrile neutropenia (1 pt) in the 35-mg cohort. Thus, the MTD was 25 mg EKB-569, FOLFOX-4. For 25 pts, treatment-emergent adverse events (TEAEs), all grades, with frequency ≥30% were diarrhea (76%), paresthesia (60%), nausea (48%), and neutropenia (40%). Grade 3 or 4 TEAEs with frequency ≥5% were neutropenia (32%) and diarrhea (8%). Of 11 pts who completed ≥4 treatment cycles, 4 had partial response (PR), 6 had stable disease (2 pts for ≥6 mos, 1 pt with unconfirmed PR), and 1 had progressive disease (RECIST guidelines). Conclusions: EKB-569 at an oral dose of 25 mg in combination with the FOLFOX-4 regimen is generally well tolerated and shows promising antitumor activity in pts with previously untreated advanced CRC.

Cohort 2

12 (8:4) 57 (46–71) 10 3 2:8:2 G1–2 G3–4 12 0 11 0 9 0 11 0 11 0 5 0

11 (10:1) 59 (47–71) 11 4 3:6:2 G1–2 G3–4 4 7 5 5 4 2 6 2 7 0 3 0

3599

3585

A phase 1b dose-escalation trial of erlotinib, capecitabine and oxaliplatin in metastatic colorectal cancer (MCRC) patients J. P. Delord, P. Beale, E. Van Cutsem, S. Clarke, C. Verslype, R. Bugat, A. Rakhit, S. Fettner, U. Brennscheidt, A. Feyereislova Institut Claudius Regaud, Toulouse, France; Sydney Cancer Centre, Sydney, Australia; University Hospital Gasthuisberg, Leuven, Belgium; F. Hoffmann-La Roche, Nutley, NJ; F. Hoffmann-La Roche, Inc, Basel, Switzerland; Roche Products Ltd, Welwyn Garden City, United Kingdom

Background: Epidermal growth factor receptor (HER1/EGFR) overexpression occurs in 45–80% of CRC patients (pts). Erlotinib (Tarceva™) is a potent HER1/EGFR inhibitor. Capecitabine and oxaliplatin have proven activity in MCRC pts. This trial determined the safety, the maximum tolerated dose (MTD) and pharmacokinetics (PK) of erlotinib in combination with capecitabine and oxaliplatin. Methods: MCRC pts were previously untreated or had received firstline treatment with 5-FU ± irinotecan. Patients were to receive escalating doses of daily oral erlotinib, capecitabine (days 1–14) (100 mg + 1,650 mg/m2 [Cohort 1]; 100 mg + 2,000 mg/m2 [Cohort 2]; 150 mg + 2,000 mg/m2 [Cohort 3]) and i.v. oxaliplatin 130 mg/m2, every 21 days. Dose-limiting toxicity (DLT) was defined according to NCI-CTC criteria (2.0) in cycle 1 or 2. The MTD was the dose below which >1/3 pts had a DLT. Results: The first 6 pts in Cohort 1 had no DLTs. In Cohort 2, 2/6 pts had DLTs: one with G3 diarrhea and G3 intolerable rash; one with G3 diarrhea. Cohort 2 was expanded to 11 pts and two more pts experienced DLTs: one pt had G4 diarrhea and one pt had G3 pruritic rash. As 4/11 pts had DLTs, this cohort exceeded the definition of MTD. Thus, Cohort 1 was expanded to 12 pts and there were no DLTs in the additional pts. The most common adverse events (AEs) were diarrhea and rash. Preliminary evidence of antitumor activity was seen in both cohorts. Overall, 5 pts had a partial response (PR) and 14 had stable disease (SD). There was no evidence of PK interaction between erlotinib, capecitabine and oxaliplatin. Conclusions: These data indicate that capecitabine 1,650 mg/m2 and oxaliplatin 130 mg/m2 in combination with erlotinib 100 mg/d is the recommended dose for phase II trials in MCRC pts.

26

Number of pts (M:F) Median age (range) Prior surgery Prior chemotherapy Best response PR:SD:PD AEs No. pts with AEs GI disorders Skin General disorder Nervous system Musculoskeletal

Cohort 1

Onkologie 2004;27(suppl 1):12–58

TOMOX compared to FOLFOX4 as first-line treatment in patients (pts) with advanced colorectal cancer (ACRC): Preliminary results of a multicenter randomized phase II trial C. Grávalos, C. García-Girón, A. I. León, A. Salud, B. Esteban, I. Sevilla, J. Maurel, A. Murias, E. García-Rico, H. G. Cortés-Funes Hospital Universitario 12 de Octubre, Madrid, Spain; Hospital General Yagüe, Burgos, Spain; Fundación Jiménez Díaz, Madrid, Spain; H. Arnau de Vilanova, Lleida, Spain; Hospital General de Segovia, Segovia, Spain; Hospital Virgen de la Victoria, Málaga, Spain; Hospital Clinic i Provincial, Barcelona, Spain; Hospital Insular de las Palmas, Las Palmas, Spain; Hospital de Montepríncipe, Madrid, Spain

Background: FOLFOX-4 has shown to be safe and active (response rate (RR): 50.7%) in chemotherapy-naive treated pts (De Gramont, JCO 2000). TOMOX is a promising new combination with RR 61.9% (Douillard J, ASCO 2000). We designed a randomized phase II trial to compare the activity (RR), tolerance, time to progression (TTP), overall survival (OS), quality of life and day-hospital frequentation between the two arms. Methods: From Jan/2002 to Nov/2003, 166 pts without previous treatment for ACRC have been randomized to arm A: FOLFOX-4 or arm B: TOMOX (raltitrexed 3 mg/m2 + OXA 130 mg/m2 d1, q3w). Results: Ninety-five pts are evaluable for efficacy and toxicity. 43/95 pts are still receiving treatment. Baseline data: 56% men; median age 64; ECOG 0/1: 50/45; 38% rectal cancer; 87.4% pts had previous primary tumor resection. Median number cycles were: 6.5 (1–16) in A; 5 (1–13) in B. Efficacy: The RR were: TOMOX 39.1% (95%CI 25–54.6%) and FOLFOX-4: 49% (95%CI 34.4–64.6%). The TTP and OS were similar. Tolerance: G3–4 neutropenia was more frequent in FOLFOX-4 (39.1% vs 2%, p 4 metastases

Bilateral disease

Liver involvement with tumor >25%

CEA >10 ng/dl

Synchronous disease

Giacchetti et al* (n=151) Current study (n=44)

58 59

34% 41%

30% 86%

NA 91%

48% 91%

68% 84%

60% 75%

CEA=carcinoembryonic antigen *=Ann Oncol 1999; 10:663–669

34

Onkologie 2004;27(suppl 1):12–58

Abstracts

3551

Chronomodulated irinotecan (I), fluorouracil (F), leucovorin (L), and oxaliplatin (O) (chrono IFLO) as salvage therapy in oxaliplatin- and irinotecan-resistant advanced colorectal cancer (ACRC): Treatment results and toxicity profile D. Gholam, S. Giacchetti, C. Brezault Bonnet, M. Bouchahda, R. Sverdlin, R. Adam, C. Jasmin, F. Levi Hopital Paul Brousse-Hepato-Biliary Center, Dept of Oncology & Chronotherapy Center, Villejuif, France

Background: Combination of FLO or IFL showed superiority over FL in phase III studies in ACRC (Giacchetti, JCO, 2000 - Douillard, JCO, 2000). Chronotherapy showed an impact on tolerability and activity of oxaliplatin, fluorouracil, and irinotecan (Lévi, Lancet, 2001). Methods: 71 patients (pts) received 608 courses (c) of a 5-day chrono IFLO delivered with a multichannel pump (Melodie, Aguettant, F) q 3 weeks (starting dose: I:160, F:2800, L:1200, O:75 mg/m2/c). Thirtyseven pts were men and 34 women. Median age: 58 years (33–82); WHO performance status (PS) 0/I/II: 38/21/12 pts; number of organs involved 1/2/3: 22/36/13 pts; liver: 83% pts; lung: 28%; peritoneum: 28%; prior chemotherapy lines: 2/3/4+: 25%/45%/30% pts; prior FLO and IFL: all pts. Toxicity was assessed every 3 weeks. Response was evaluated every 3c with CT scan and abdominal ultrasound. Results: A median of 7 c (2–20) was administered. Main grade 3–4 toxicities were diarrhea (44% pts, 8% c), neutropenia (31% pts, 6%c), nausea or vomiting (28% pts, 4% c), thrombocytopenia (6% pts, 0,8% c), mucositis (3% pts, 0,5% c). Grade 3 sensory neuropathy occurred in 15% pts only despite extensive prior oxaliplatin. PS remained ≤ 1 in 77% of the pts. 53 pts had stable disease. 3 pts, all with initial PS= 0, had a partial response >50%. Median time to progression is 6 months. At 15 months, overall survival rate is 51% [95% CI, 39 to 63]. Conclusions: After failure of both FLO and IFL, Chrono IFLO offered survival benefit, with good tolerability and quality of life in heavily pre-treated ACRC patients. Chrono IFLO deserves randomized evaluation as a third-line treatment of ACRC.

3562

Phase II study of short-time infusion of oxaliplatin in combination with capecitabine (XELOX30) in patients with progressive colorectal cancer after irinotecan and 5-fluorouracil (FU) treatment P. Pfeiffer, B. Glimelius, H. Sørbye, J. P. Mortensen, L. Baltesgard, K. M. Tveit, D. Ogreid, H. Starkhammar Odense University Hospital, Odense C, Denmark; Karolinska sjukhuset, Stockholm, Sweden; Haukeland University Hospital, Bergen, Norway; Vejle Hospital, Vejle, Denmark; Tromso University Hospital, Tromso, Norway; Ullevaal University Hospital, Oslo, Norway; Rogaland Central Hospital, Stavanger, Norway; Linkoping University Hospital, Linkoping, Sweden

Background: Oxaliplatin (Ox) in combination with FU or Capecitabine (Xel) prolong median survival as first and second line therapy in patients with advanced colorectal cancer (ACRC). Ox induces acute, cold-induced neuropathy in most patients. The incidence is claimed to be infusion rate-dependent and therefore a 2 hour infusion is recommended, but in a prior pilot study (Pfeiffer et al, Acta Oncol 2003; 42: 832) a 30 minutes infusion could be given without additional neuropathy. Methods: For practical and economic reasons, but also for patient´s convenience, we performed this phase II study to examine XELOX30 (Xel 1000 mg/m2 orally twice daily days 1–14 and Ox 130 mg/m2 as 30 minutes infusion day 1) in patients with pro-

Abstracts

gressive colorectal cancer after therapy with irinotecan and FU. Neuropathy was graded 0–3 using the Ox-specific scale. Other adverse events were graded using NCI-CTC. Results: From Nov 2002 to Sept 2003, 69 patients with ACRC were included and treated with XELOX30. Median age was 62 years (33–73), median WHO PS 1 (0–2). Median number of courses was 6 (range 1–10), median cumulative dose of Ox was 830 mg/m2. Response rate was 16%. Median TTP was 5.6 (4.6–7.5) months and median survival was 9.2 (8.6–12.6) months. Neurotoxicity: Grade 0: 9%, grade 1: 68%, grade 2: 17% and grade 3: 5%. Other grade 3 toxicities were nausea/vomiting: 7%, diarrhea: 8% and PPE 8%. Fourty patients have stopped therapy due to PD (n=20), GI-toxicity (n=7), neurotoxicity (n=2), patients wish (n=5) and other (n=6). Conclusions: XELOX30 is an active, and very convenient 2. line regimen with an excellent safety profile similar to other Ox schedules.

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Phase II study of capecitabine, oxaliplatin and erlotinib in previously treated patients with metastatic colorectal cancer (MCRC) J. A. Meyerhardt, A. Xhu, P. C. Enzinger, D. P. Ryan, J. W. Clark, M. H. Kulke, A. Michelini, M. Vincitore, A. Thomas, C. S. Fuchs Dana-Farber Cancer Institute, Boston, MA; Massachusetts General Hospital, Boston, MA; Harvard Medical School, Boston, MA

Background: Erlotinib (Tarceva) is an orally active, selective inhibitor of the HER1/EGFR tyrosine kinase with clinical activity in various solid tumors. The combination of capecitabine (C) and oxaliplatin (O) is becoming an increasingly attractive option to use in the treatment of MCRC. We conducted a phase II study to evaluate the objective response rate (ORR) of O+C+erlotinib in previously treated patients (pts) with MCRC. Methods: Eligible pts had measurable MCRC, either 1 prior systemic regimen for MCRC or progression of disease within 12 months of adjuvant therapy, performance status 0–2. The treatment regimen consisted of 21-day cycles of C at 1000 mg/m2 BID x 14 days (reduced to 750 mg/m2 after first 13 patients experienced excess of grade (gr) 3/4 toxicities), O at 130 mg/m2 on day 1, and erlotinib 150 mg qd. Responses were based on RECIST criteria Results: To date, 22 pts have been enrolled with the following characteristics: male/female, 16/6; PS ECOG 0/1, 11/11; median age 59, range 32–73; 73% prior CPT-11 for metastatic disease. 20 patients are evaluable for response and 22 patients are evaluable for toxicity. The ORR was 20% (0 CR, 4 PR [2 confirmed, 2 unconfirmed]). 64% of patients had stable disease (8 pts >4 months). Prior to the dose reduction of C, 11 of 13 pts had grade 3/4 toxicities (primarily GI toxicities). Since the dose reduction of C (9 pts), there have only been 4 pts with gr 3/4 toxicities and no pts off study due to toxicity. Based on the current enrollment rate, we expect full accrual of 32 pts and updated results (including ORR and time-to-progression) by June 2004. Conclusions: In a population of previously treated patients with MCRC, capecitabine, oxaliplatin and erlotinib appears to be an active regimen. Initial toxicities of the regimen have been markedly improved upon with a modest dose reduction. Supported by: SanofiSynthelabo, Roche Laboratories, Genentech.

Onkologie 2004;27(suppl 1):12–58

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Evaluation of oxaliplatin, 5-FU and leucovorin maintenance treatment in refractory metastatic colon cancer C. Headlee, S. Beasley, D. Jackson, C. Teel, B. C. Mirtsching Center for Oncology Research & Treatment, Dallas, TX

Background: The response rate in ≥2nd-line therapy for Oxaliplatin as salvage therapy after failure of irinotecan (I)- or continuous dosing 5FU-containing regimens is low (8–11% PR) and median time-toprogression is short (3.5–4.5 months). Methods: 40 patients were treated with oxaliplatin, 5FU and leucovorin (OFL), or single-agent oxaliplatin (O). All patients who did not progress were treated continuosly until disease progression. Our observations of a fraction of patients who have protracted disease remission and/or stability are herein reported. Results: Prior treatment was 5FU-containing adjuvant therapy (21), or an I-containing regimen (40), capecitabine (15) or 5FU (bolus or infusion) +/- L (12) for metastatic disease. Baseline characteristics: 31 male (78%), 9 female (22%), 30 white (75%), 5 black (12.5%) and 5 Hispanic (12.5%). Treatment was 1st-line in 4 (10%), second-line in 11 (28%), third-line in 20 (50%) or ≥ to fourthline in 5 (12%). Responses: CR 0 (0%), PR 13 (33%), SD 11 (27%) and PD 16 (40%). The mean number of doses of oxaliplatin was 8 (range: 1–46). Response duration ranged from 109–861d (mean 277 d). SD duration ranged from 17 to 465d (mean 196d). 4 patients (10%) with SD and 6 patients (15%) with response that had non-progression for > than 240 d (8 months). CEA was elevated at baseline in 33 (83%), range 15–2283, mean 504. The mean time to maximum CEA reduction was 143d. 50% of SD patients had a stable or reduced CEA. All other stable patients had minor elevations of CEA ≤5 units changed. The patients with protracted non-progression had the following characteristics: 3 females, 7 males, 2 hispanics, 8 caucasians and the mean age of 56. 1st-line: 2, 2nd-line: 2, 3rd-line: 4, 4th-line: 2. Conclusions: Oxaliplatin-containing salvage therapy for colorectal cancer benefits patients with response or with stable disease similarly, with delayed progression, which may be substantial (greater than 8 months) in 25% of all patients treated, even though many were heavily pre-treated. Maintaining treatment until progression is important in achieving these results.

3690

Second line chemotherapy after first line irinotecan, oxaliplatin and 5-FU/LV (FOLFOXIRI) in metastatic colorectal cancer (MCRC) patients (pts) G. Masi, G. Allegrini, L. Marcucci, S. Cupini, I. Brunetti, E. Fontana, S. Ricci, E. Cerri, C. Barbara, A. Falcone Civil Hospital, Livorno, Italy; S. Chiara Hospital, Pisa, Italy

Background: We conducted a phase I–II study with first line FOLFOXIRI (irinotecan 125–175 mg/sqm on day (d) 1, oxaliplatin 100 mg/sqm d1, LV 200 mg/sqm d1, 5-FU 3800 mg/sqm 48-h IV chronomodulated continuous infusion starting on d1, repeated every 2 weeks) and a phase II study with first line simplified FOLFOXIRI (irinotecan 165 mg/sqm d1, oxaliplatin 85 mg/sqm d1, LV 200 mg/sqm d1, 5-FU 3200 mg/sqm 48-h flat continuous infusion starting on d1, repeated every 2 weeks) respectively in 42 and 32 MCRC pts. Overall response rate, median progression free (PFS) and overall survival (OS) were 71% and 72%, 10.4 months (mos) and 10.8 mos, 26.5 mos and 28.4 mos respectively. A possible concern about the use of all three main active agents up-front is the possibility that this might limit, after progression, disease control with second line treatments. Methods: Among the 70 pts so far progressed 53 (76%) have received second line chemotherapy (22: FOLFIRI, 16: FOLFOXIRI, 5: 5-FU protracted infusion, 3: FOLFOX, 3: 5-FU+MMC, 2: CPT-11, 1: CPT-

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11+LOHP, 1: raltitrexed). Seventeen pts (24%) did not receive second line treatments: 10 because of deterioration of performance status (PS), 4 because of patient refusal and 3 because of death. Patients characteristics at the time of second-line treatment were: M/F 35/18 pts, median age 64 yrs (range 44–75), ECOG PS ≥ 1 21 (40%) pts, multiple sites of disease 33 (47%) pts. Results: A median of 4.2 mos of second-line chemotherapy per patient were administered (range 1–8). Overall response rate (51 out of 53 evaluable pts) was 31% (2CR+14PR, 95%CI=19–46%), stable disease were 19 (38%) and 16 pts (31%) progressed. Median duration of response was 7.7 mos. At a median follow up of 13.5 mos from the start of salvage chemotherapy median PFS and overall survival were respectively 6.7 and 15.2 mos. Conclusions: These results suggest that first line FOLFOXIRI does not impair the possibility to obtain objective responses and delay tumor progression with second line treatments containing the same agents used in first-line.

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Hepatic artery infusion (HAI) of oxaliplatin (Ox) as third and fourth-line therapy for patients with hepatic metastases (M) from colorectal cancer (CRC) pretreated with systemic Ox H. Gollasch, B. Gebauer, I. Sturm, P. Thuss-Patience, D. Pink, C. Stroszczynski, A. Kretzschmar Charité Campus Buch Helios-Klinikum, Medicine & Radiology of Robert Rössle Klinik, Berlin, Germany; Charité Campus Virchow Klinikum, Berlin, Germany

Background: The liver is the predominant site of M from CRC. HAI of cytotoxic agents has a long tradition but due to technical complications and lack of a survival benefit compared to systemic treatment it did not become widely accepted as 1st-line treatment of patients (pts) with M from CRC confined to the liver. HAI might serve as a salvage option for pts in whom all available systemic therapies failed and in whom liver M are still dominant. Methods: We retrospectively analysed the outcome of all pts who were treated with HAI of Ox after systemic pretreatment with Ox in our institution. Results: All 10 pts (age 35–68) had received fluoropyrimidines, irinotecan and Ox in two (5 pts) or three previous palliative lines and were pretreated with liver resection (1) and local thermoablation (3). In 8 cases disease progressed while systemic Ox was given. 2 pts had small lung M beside advanced liver M; CEA median 67 (3–2511). HAI was introduced in median 14 months (8–31) from start of first line palliative therapy. Ox 100 mg/m2 (9 pts) and 130 (1) was infused over 2 h via interventionally placed inguinal port (2) or via repeated single-use catheters (8) (tip in the proper hepatic artery) and accompanied by i.v. 5-FU (FA-modulation/bolus/infusion; mg/m2: 400–400–2400/48 h)in 8 pts or oral capecitabine (2.5 g/m2 d1–14)in 2. In median 6 cycles (2–9), q 2–3 weeks, were applied in an outpatient setting. Toxicity was mild beside one port-infection, one case of prolonged but uncomplicated neutropenia IV° and repeated severe but reversible abdominal pain during HAI in 2 cases. No neurosensory toxicity was seen. Beside 3 PR we observed one MR accompanied by CEA and CA 19-9 drop of 94% and 98% resp. 4 pts had SD while in 2 pts disease in the liver progressed. Extrahepatic progression occured in 5 pts while they received HAI. Median TTP, TTP in the liver and survival from start of HAI were 4 (1–8), 6 (1–8) and 13 (2–15+) months. Conclusions: HAI of Ox via interventionally placed catheters in combination with systemic fluoropyrimidines is a feasible and effective outpatient option for heavily pretreated pts with hepatic M from CRC.

Abstracts

3727

Use of the combination of raltitrexed (R) and oxaliplatin (O) as a salvage treatment for patients with advanced colorectal cancer (ACRC) refractory to 5-fluorouracil (5-FU) based chemotherapy and with hyperexpression of thymidylate synthase (TS): Final report M. Murad, R. Guimaraes, A. O. Scalabrini-Neto, N. Ourives Hospital das Clinicas Federal University of Minas Gerais, Belo Horizonte, MG, Brazil

Background: TS is an important target for fluoropyrimidine based TS inhibitors and its hiperexpression has been correlated with resistance to 5-FU, but not necessarily to R, a folate-based TS inhibitor, which appears to be more correlated to FPGS activity (van Triest et al, 1999; Cheradame et al, 1999). O is a novel diaminocyclohexane platinum agent also active in ACRC and obviously not related to TS status. Methods: 21 patients with ACRC not responsive to a first line 5-FU based chemotherapy: 14(67%) to IFL(Saltz) regimen, 4(19%) to 5FU/LV- (Mayo Clinic) regimen and 3(14%) to capecitabine) and high expression of TS (determined by IHC technique-grades 2+ and 3+) and age less than 70 Y/O, measurable disease, WHO PS 0–2, life expectancy ≥ 2 months, adequate renal and liver functions and informed consent were accrued to receive: T–3.0 mg/m2 and 0–120 mg/m2 every 21 days until progression. Results: Thirteen were male and 8 female; median age: 58(39–67); median PS: 1 (1–2). Number of cycles administered: 98 (median per patient: 4). There were 7 PR (33%), 3 SD(14%) and 11(53%) PD. Clinical benefit based upon weight gain, PSand analgesic consumption was observed in all 7 responders (33%). The median PFS was 6.5 months (1–12) and the median overall SV was 8 months (2–12+). The 1 year SV was 17%. The regimen was well tolerated. WHO grade 4 diarrhea occurred in one patient, grade 3 in 12(12%) cycles; grade 2 vomiting in 10(10%) cycles; grades 3 and 4 neutropenia in 16(16%) cycles; reversible febrile neutropenia in 2 patients: (onedied due to sepsis); grade 3 thrombocitopenia in 6(6%) cycles; anemia grades 2 and 3 in 21(21%) cycles and grade 2 oral mucositis in 3 (3%) of the cycles. Grades 1 and 2 neuropathy was observed in 61% of the cycles. Conclusions: These favorable results suggest that this combination might be effective in the treatment of patients with ACRC with high expression of TS and should be also explored as a first line regimen for this subset of patients with predictable resistance to fluoropyrimidine based chemotherapy.

3729

FOLFOX4 in metastatic colorectal cancer (MCRC) patients who progressed after infusional 5-FU/irinotecan based combination regimens F. Dane, P. F. Yumuk, N. S. Turhal, M. Ekenel, G. Basaran, M. S. Iyikesici, C. Tecimer Marmara University, Istanbul, Turkey; Kadir Has University, Istanbul, Turkey

Background: Irinotecan based regimens are the standard 1st line treatment for MCRC because the other promising agent oxaliplatin is commercially unavailable in Turkey. Oxaliplatin, 5-FU and calcium leucovorine (FOLFOX4) has been reported to be one of the promising treatment options for irinotecan resistant tumors. We want to report our experience of the patients who received FOLFOX4 after progression on irinotecan based combination chemotherapy. Methods: All patients (n=17) with MCRC who received FOLFOX4 were collected retrospectively. Results: Nine (52.9%) patients were male and median age was 59 years (range 50–73). Two (11.8%) had stage II, 8 (47.1%) had stage III disease before relapse and 7 (41.2%) had stage IV disease at presentation. Median time to progression (TTP)

Abstracts

on 1st line chemotherapy for metastatic disease was 6 months. Twelve patients (70.6%) received FOLFOX4 as 2nd line and 5 patients (29.4%) as 3rd line treatment. The TTP was 3 months and median overall survival (OS) was 22 months. There was no statistically significant difference in TTP or OS in between the patients who got FOLFOX4 as 2nd versus 3rd line treatment. TTP was 3 months (95% CI: 2–4) and 4±1 months (95% CI: 3–5) respectively, p=0.48. OS was 32±5 months (95% CI: 23–41) and 19±3 months (95% CI: 14–24) respectively, p=0.146. Conclusion: The benefit of FOLFOX4 in metastatic colorectal cancer patients who progresses after infusional 5-FU and irinotecan containing combination regimens is limited.

Gastrointestinal Cancer – Colorectal/Liver D. Hepatic Metastases of Colorectal Cancer 3550

Resection of non resectable liver metastases after chemotherapy: Prognostic factors and long term results R. Adam, V. Delvart, G. Pascal, D. Castaing, D. Azoulay, S. Giachetti, B. Paule, F. Levi, F. Kunstlinger, H. Bismuth HepatoBiliary Center, Paul Brousse Hospital, Villejuif, France

Background: Chemotherapy allows an increased number of patients with primarily non resectable colorectal liver metastases (CRLM) to be further resected after tumor downstaging. However the benefit of this ”rescue surgery” is still debated and prognostic factors of outcome are lacking Methods: From February 1988 to December 2000, 1400 consecutive patients with CLRM were managed at a single institution. From these, 295 (21%) were primarily resected and 1105 (79%) initially non resectable were treated by systemic chemotherapy using either oxaliplatin or irinotecan regimens. Non resectable patients were routinely reexplored every 3–4 courses. Surgery was reconsidered when potentially curative after response to chemotherapy. Fifteen factors assumed to be predictive of survival were evaluated by uni- and multivariate analysis in patients secondarily resected Results: In the non resectable group, 139 ”good responders” (13%) could be secondarily submitted to hepatic resection after an average of 10 courses of chemotherapy. CRLM were initially non resectable because too large (7%), ill-located (15%), multinodular (55%) or associated to extrahepatic tumor (22%). Operative mortality within 2 months was 0.7% (1/139). Tumor recurrence was treated by repeat hepatectomy in 50 patients (36%) and pulmonary resection in 27 (19%). After a mean follow up of 5.3±3.2 years, overall 5-year survival was 36% (disease-free: 22%) compared to 47% for primarily resected patients (p= 0.02). At multivariate analysis, 4 preoperative factors were independently associated to decreased survival: rectal primary, number of metastases ≥3, CA 19-9 level >100 UI/L and concomitence of peritoneal or lymph nodes metastases. 5-year survival according to the presence of 0,1, 2, 3 or 4 of these factors was respectively 60%, 30–40%, 10–18% and 0–3%. Conclusions: Effective chemotherapy allows 13% of patients with irresectable CRLM to be rescued by liver surgery with a hope of long term remission. Although lower than that of initially resectable patients, the overall 5-year survival is 36% for a similar risk of mortality. 4 preoperative factors are able to predict long-term survival.

Onkologie 2004;27(suppl 1):12–58

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3553

Surgical resection of metastases (mts) after biweekly chemotherapy with irinotecan, oxaliplatin and 5-fluorouracil/leucovorin (FOLFOXIRI) in initially unresectable metastatic colorectal cancer (MCRC) A. Falcone, G. Masi, S. Cupini, L. Marcucci, S. Ricci, I. Brunetti, E. Cerri, E. Fontana, M. Andreuccetti, G. Allegrini Civil Hospital, Livorno, Italy; S. Chiara Hospital, Pisa, Italy

Background: We conducted a phase I–II study with the triple drug combination FOLFOXIRI (irinotecan 125–175 mg/sqm day (d) 1, oxaliplatin 100 mg/sqm d1, l-LV 200 mg/sqm d1, 5-FU 3800 mg/sqm 48-h IV chronomodulated continuous infusion starting on d1, repeated every 2 weeks) and a subsequent phase II study with a simplified FOLFOXIRI regimen (irinotecan 165 mg/sqm d1, oxaliplatin 85 mg/sqm d1, l-LV 200 mg/sqm d1, 5-FU 3200 mg/sqm 48-h flat continuous infusion starting on d1, repeated every 2 weeks) respectively in 42 and 32 unselected MCRC pts with initially unresectable mts. Overall response rate, median progression free (PFS) and overall survival (OS) were 71% and 72%, 10.4 months (mos) and 10.8 mos, 26.5 mos and 28.4 mos respectively. Methods: In consideration of the high activity of these regimens 30 out of 74 pts (40%) could be revaluated for surgical resection of mts after chemotherapy. Among these 30 pts revaluated for surgery a R0 surgical resection could be performed in 19 pts (26% of the initial 74 pts). Characteristics of the 19 radically resected pts were: median age 66 years (45–73), ECOG PS ≥ 1 6 pts (32%), median CEA 10 ng/ml (1–288), median number of mts 3 (1–10), liver involvement ≥ 25% 12 pts (63%). Sites of disease were: liver only 14 pts, liver + lymphnodes 3 pts, liver + peritoneum 1 pt, liver + lung 1 pt. Mts were synchronous in 12 pts (63%) and metachronous in 7 pts with a median disease free interval of 12 mos. Results: After a median follow up of 28.8 mos median PFS is 18.6 mos and median OS is 39.6 mos. In 2 pts progressed after surgery a surgical re-resection and/or radiofrequency ablation was performed. Conclusions: First line FOLFOXIRI enables R0 surgical resection in about a quarter of pts with clearly initially unresectable MCRC. Median OS of resected pts is very promising. Prospective evaluation of FOLFOXIRI as neo-adjuvant treatment in initially unresectable colorectal cancer pts with liver and/or lung metastases is planned.

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The MIROX Regimen: Intensive systemic chemotherapy combined with surgical treatment of colorectal cancer metastases. Results of a phase II study J. Taïeb, P. Artru, F. Paye, M. Hebbar, F. Maindrault Goebel, T. André, C. Tournigand, C. Louvet, R. Parc, A. De Gramont Hopital ST Antoine, Paris, France; Clinique St Jean, Lyon, France; CHRU, Lille, France; Hopital Tenon, Paris, France

Background: This work was designed to evaluate the efficacy and tolerance of adjuvant FOLFOX-7 followed by FOLFIRI (the MIROX strategy) in patients with resectable metastatic colorectal cancer. Methods: Forty seven patients with resectable colorectal cancer metastases were prospectively enrolled in this study between September 1999 and October 2001. The treatment consisted in six cycles of FOLFOX-7 (leucovorin 400 mg/m2, Oxaliplatin 130 mg/m2 and 5-FU 2400 mg/m2 as a 46-hour infusion, every two weeks), followed by six cycles of FOLFIRI (leucovorin 400 mg/m2, CPT11 180 mg/m2 in 90 min infusion, 5-FU 400 mg/m2 and 5-FU 2400 mg/m2 as a 46-hour infusion, every two weeks). Surgery was performed before chemotherapy (26 patients) or after the 6 cycles of FOLFOX7 (21 patients), 6 cycles of FOLFIRI being administered thereafter. Results: All but one patient underwent curative surgery and two pts refused post-opera-

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tive chemotherapy. Tolerance was generally good. The most relevant toxicities were grade 3–4 neutropenia and thrombocytopenia, observed in 12 patients (25%), without any febrile neutropenia or bleeding event. No toxic death occurred. Two pathologically confirmed complete responses and 15 partial responses (overall response rate of 80%, CI: 69–88) occurred with FOLFOX-7 for the 21 patients receiving this regimen before surgery. The 2-year overall survival rate was 88%. The two year recurrence free survival was 51%. Conclusion: The MIROX strategy is feasible and well tolerated in patients with resectable metastatic colorectal cancer. Progression free and overall survivals, with a 25 months median follow up, are similar to those observed with the best therapeutic strategies currently available, though a longer follow-up is needed to confirm these results. This regimen is currently compared to a LV5-FU2 regimen in a randomized phase III study.

3593

Triplet therapy with oxaliplatin, irinotecan, 5-fluorouracil and folinic acid within a combined modality approach in patients with liver metastases from colorectal cancer J. De La Cámara, J. Rodriguez, F. Rotellar, A. Viudez, J. GarcíaFoncillas, F. Pardo, I. Gíl-Bazo, A. Chopitea, S. Martín-Algarra Clínica Universitaria.University of Navarra, Pamplona, Spain

Background: Although surgical resection remains the treatment of choice for liver metastases from colorectal cancer, only a minority of pts are suitable for surgery. Preoperative chemotherapy allows secondary liver resection and subsequent long-term survival in some patients (pts)with unresectable CCR liver metastases Methods: The aim of this study was to evaluate the safety and efficacy of oxaliplatin 120 mg/m2 day 1, CPT-11 150 mg/m2 day 1 and 14, fluorouracil 2600 mg/m2 days 1 and 14 and folinic acid 500 mg/m2 days 1 and 14, every four weeks, in metastasic liver CCR patients either technically unresectable or with known poor prognostic factors for long term survival after surgery. Results: 39 pts (M/F: 30/9), median age 55 (28–77), median ECOG 1 (0–2) were included. Mean number of liver nodes and mean size were 6.7 and 6.1 cm, respectively. 22 pts (56.4%) were initially unresectable while 17 (43.6%) had poor prognostic factors including large tumor size (52.9%), multinodular (23.5%), ill-located (23.5) and/or bilobar metastases (35.3%).Overall response rate to induction chemotherapy was 64%, 3 pts (7.7%) progressed while ontherapy. 23 pts underwent secondary surgery, including hepatectomy (52.2%) and wedge resections (47.8%), with (n=10) or without radiofrequency. An R0 resection was achieved in 84% of pts, with margins 70% liver or 6 segments. Optimal type (5FU/LV, oxaliplatin, irinotecan) and sequences of chemotherapy pre and post resectability were evaluated. Other specific data relating to CLM (number and size of mets, resection margin, portal nodes) will be presented. Conclusions: This validated decision model tool would help healthcare providers to analyse the appropriateness of liver resection alone or in association with optimal chemotherapeutic sequence based upon individual patient and tumour characteristics. This tool will be available on academic website.

effects were seldom recorded in this 3 months regime and consisted of PNP III in 16%, diarrhea III and IV in 12%, nausea III in 8%; hematologic side effects grade III and IV were neutropenia in 2%, thrombocytopenia in in 6% and anemia in 2%. The achieved response rates were 2 complete responses, 33 partial responses, 11 stable diseases and 4 progressions; leading to an ORR of 70% and a progression under treatment of 8%. None of the progredient patients became inoperable after CTX. Tumor marker response correlated with radiologic response, 15% of the responding patients obtained a normalization of their tumor marker. The extent of the liver resection could be substantially reduced in responding patients. The perioperative mortality was 0% and the morbidity was 4% (1 bile leak, 1 biloma). At the time of this analysis 48% of the patients are alive without recurrence, 34% have recurrence and 18% died after tumor recurrence. Conclusions: Oxaliplatin based chemotherapy demonstrates a high response rate given preoperatively without increasing the perioperative morbidity. No patient demonstrated with nonresectable disease after CTX. The extend of the intended liver resection was considerably reduced in responders. Survival outcome measurements appear promising and further exploration of preoperative CTX is highly recommended.

3613

Resection of previously unresectable liver metastases from colorectal cancer (LMCRC) after chemotherapy (CT) with CPT-11/L-OHP/LV5FU (Folfirinox): A prospective phase II trial F. Quenet, B. Nordlinger, M. Rivoire, J. R. Delpero, G. Portier, D. Mery-Mignard, E. Magherini, S. Payrard, M. Ychou Centre Val d’aurelle, Montpellier, France; Hopital Ambroise Paré, Boulogne Billancourt, France; Centre Léon Bérard, Lyon, France; Institut Paoli Calmette, Marseille, France; Hopital Purpan, Toulouse, France; Laboratoire Aventis, Paris, France

Background: Curative liver resection remains the best treatment option for colorectal liver metastases (CRCLM). Overall survival is still limited due to high recurrence rates. Adjuvant chemotherapy was ineffective in reducing recurrence, therefore neoadjuvant treatment was explored. Methods: During the last two years 50 patients were treated with 6 cycles of neoadjuvant chemotherapy prior to liver resection for CRCLM. Chemotherapy consisted of Oxaliplatin/5FU/LV according to FOLFOX4 regimen or Oxaliplatin (130 mg/m2 d1) and Xeloda (2000 mg/m2 d1–7) q14 over a 3 month period. Primary endpoint of these early results were side effects, radiologic and tumor marker response (CEA, CA 19–9), extend of liver resection and perioperative morbidity/mortality. Results: Grad III and IV side

Background: 5 year-survival after LMCRC resection is 30–35%. Folfiri and Folfox are standard regimens in MCRC. The triple combination Folfirinox as induction CT could improve tumor shrinkage and therefore could allow resection of LM in unresectable patients (pts). Methods: Based on a multidisciplinary consensus, unresectability is defined as follows: LM in right or left lobe in contact of controlateral liver pedicle; LM in contact of veina cava or involving 2 hepatic veins and in contact with the third; liver remaining mass less than 25–30% of functional liver; no initial forseen optimal resection, but susceptible to become resectable after shrinkage. Biweekly 48h-cycles (Cy): L-OHP 85 mg/m2, CPT-11 180 mg/m2, LV5FU were administered. An Independent Committee (IC) reviewed pts eligibility and RR. The primary endpoint was resectability R0 defined as R0= margin ≥2mm, R1=margin 50% in 7 (PR, 39%). Lung Prog occurred in 8 pts, resulting in a 33% objective response rate. PS remained stable in all Stab or PR pts. Median Prog free survival is 6 months and median survival is not reached at 12 months (6 pts alive at 20+ months). Conclusions: Three-drug HACI displayed good tolerability and activity in heavily pretreated MCC patients. Avoidance of extrahepatic progression may require alternating systemic chemotherapy. Such combined modality deserves testing as neoadjuvant therapy of unresectable MCC confined to the liver. Support: ARTBC, Hôp P Brousse, Villejuif (F)

3776

Laparoscopic radiofrequency ablation and systemic chemotherapy for colorectal liver metastases D. A. McCain Hackensack University Medical Center, Hackensack, NJ

Background: Evaluation of 38 patients with colorectal liver metastases(164 lesions) from 11/2000 to12/2003 treated with systemic chemotherapy and laparoscopic radiofrequency ablation. Methods: All patients were treated with standardized systemic regimens of 5-FU, irinotecan and oxaliplatinum with laparoscopic radiofrequency ablation. Results: Median follow up was 16 months (range 3–36 months) with a 78.6% survival at 16 months. Survival by KaplanMeier actuarial survival analyis was 84.7% at 1 year and 52.3% at two yearswith improved disease free survival seen in patients with lesions 50%.The 2-step modified Gehan design was used for sample size determination. Results: 26 pts were enrolled; median age 31 yrs (range 18–46); PS 0/1:13/13; 18 had non seminoma (among whom 5 mediastinal primaries), 2 seminoma and 6 mixed GCT; 16 pts were REF and 10 pts were REL; 22, 3 and one pts had previously received 2, 3 and 5 lines of CDDP based CT. A total of 87 cycles (median 4, range 1–7) were administered. The worst toxicity (NCI-CTC) consist-

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ed in: grade (G) 3 and 4 neutropenia (N) in 3 and 4 pts respectively, G 3 anemia in 3 pts, G 3 thrombocytopenia in one pt, G 3 neuropathy in one pt and G3 infection without N in one pt. One Partial Response with normal TM (lasting 18+ mos) and 4 TMD >90% and 3 TMD >50% were observed. Median Time to Tumor Progression and Overall Survival (months) were 2.0 [95% CI:1.5–2.5] and 8.8 [95% CI: 5–12] respectively. However 2 pts were eventually salvaged by surgical exeresis of limited disease and are alive free of disease progression at 13+ and 23+ months respectively. Conclusions: Ox-Px Combination is safe and looks active in refractory and relapsed GCT, it warrants further developments within the treatment strategy in these patients.

4535

Oxaliplatin and irinotecan plus granulocyte-colony stimulating factor (G-CSF) as third-line treatment in relapsed or cisplatin-refractory germ-cell tumor (GCT) patients: A phase II study D. Farmakis, D. Pectasides, M. Pectasides, M. Nikolaou, M. Koumpou, A. Gaglia, A. Koumarianou, G. Aravantinos, T. Economopoulos Metaxas Memorial Cancer Hospital, Piraeus, Greece; Attikon University Hospital, Athens, Greece; Ag. Anargiri Cancer Hospital, Athens, Greece

Background: Oxaliplatin is an active agent in patients with cisplatinrefractory GCT, while the combination of irinotecan with platinum compounds has also induced responses in such patients. Given the synergistic activity of the two agents, we investigated the efficacy and tolerability of their combination in patients with relapsed or cisplatinrefractory GCT. Methods: Eighteen patients with relapsed or cisplatin-refractory GCT were treated with oxaliplatin 85 mg/m2 (days 1, 15) and irinotecan 80 mg/m2 (days 1, 8, 15) every 4 weeks for a maximum of 6 cycles. Results: All patients were assessable for response and toxicity. Seven patients (40%) achieved a favorable response (4 complete and 3 partial responses). One of the complete responders relapsed after 2.5 months and, despite treatment with high dose chemotherapy, he died 2 months later; the rest 3 patients are continuously disease-free for 11+, 14+ and 19+ months. The partial responders progressed subsequently and died after 2, 3 and 4.5 months, respectively. None of the patients with extragonadal mediastinal GCT responded to chemotherapy. The regimen had a good tolerance. Neutropenia (grade 3/4, 17%), neutropenic infections and sepsis were not common probably due to prophylactic G-CSF administration. Thrombocytopenia and anemia were not a serious problem. Grade 3/4 diarrhea and nausea/vomiting were noted in 22% and 28% of patients, respectively. Oxaliplatin-associated neurotoxicity was rather low; grade 3 peripheral sensory neuropathy was recorded in 11%. Conclusions: The combination of oxaliplatin and irinotecan is feasible and associated with significant clinical antitumor activity, mild and manageable toxicity and easy outpatient administration in patients with relapsed or cisplatin-refractory GCT. This combination offered a possibility for long-term disease-free status (17%), despite the poor prognostic features of the study group.

4544

Gemcitabine and oxaliplatin combination: A multicenter phase II trial in unfit patients with locally advanced or metastatic urothelial cancer A. Font, E. Esteban, J. Carles, M. A. Climent, J. L. Gonzalez-Larriba, A. Berrocal, J. Bellmunt, I. Garcia-Ribas, X. Marfa, X. Fabregat Hospital Germans Trias i Pujol, Badalona, Spain; Hospital General de Asturias, Oviedo, Spain; Hospital del Mar, Barcelona, Spain; Instituto Valenciano de Oncologia, Valencia, Spain; Hospital Clinico San Carlos, Madrid, Spain; Hospital General de Valencia, Valencia, Spain; Hospital Valle de Hebron, Barcelona, Spain; Eli Lilly & Co, Alcobendas, Spain; Sanofi Sinthelabo, Barcelona, Spain

Background: Although cisplatin is considered the cornerstone for the treatment of advanced bladder cancer, up to 50% of the patients (pts) cannot receive it because they are considered unfit mainly due to poor renal function. New non nephrotoxic regimens are needed. Gemcitabine and oxaliplatin are active, non-nephrotoxic and with non-overlapping toxicity and therefore being attractive to be studied in combination for unfit bladder cancer patients. Methods: Thirty-six pts unfit (mainly due to renal function, creatinine clearance 5 days, 1 grade 3 diarrhea) resulting in dose reduction for vinorelbine (20 mg/m2) and oxaliplatin (40 mg/m2). In the next 10 pts only 2 DLTs (febrile neutropenia and grade 4 neutropenia lasting >5 days) were observed and the study is ongoing as phase II. All pts were evaluable for toxicity and 29 (19 CDDP-refractory; 10 CDDP-sensitive) for response (2 too early, 1 protocol violation, 1 lost to follow up). Three complete (CR) and 2 partial responses (PR) were seen in the CDDP-refractory group (ORR 23.8%; 95%CI: 5.6–42.0%) and 4 CR with 5 PR in the CDDP-sensitive group (ORR 90%; 95%CI: 71.4–100%). Median duration of response was 5.2 months (range 1–6) for CDDP-refractory and 6.6 (range 1–10) for CDDP-sensitive; median time to progression was 4.1 months (range 1–14) and 8.6 (range 1–12), respectively. So far 8 pts have died (7 disease progression; 1 pulmonary embolism), 14 had disease progression, and 11 continue treatment. 134 cycles have been administered: median 3 (range 1–9) cycles per pt. 2oxicity included grade 3/4 neutropenia each in 8 (24%) pts, febrile neutropenia 4 (12%), grade 3 anemia 1 (3%), grade 3 diarrhea 3 (9%), neurotoxicity 1 (3%), rash 1 (3%) and transaminase elevation 1 (3%). Conclusions: The concurrent administration of gefitinib with vinorelbine and oxaliplatin is feasible and shows promising activity in pretreated pts with AOC.

5023

Phase II trial of oxaliplatin (OXA) combined with paclitaxel (P) inplatinum + taxanes sensitive advanced ovarian cancer (AOC) patients: Final results P. Viens, T. Petit, A. Yovine, P. Bougnoux, G. Deplanque, P. Cottu, R. Delva, J. P. Lotz, J. S. Van Belle, J. M. Extra Paoli-Calmettes, Marseille, France; Centre Paul Strauss, Strasbourg, France; CAC, Le Kremlin-Bicêtre, France; Hôpital Bretonneau, Tours, France; Institut Claude Bernard, Metz, France; Hôpital St Louis, Paris, France; Centre Paul Papin, Angers, France; Hôpital Tenon, Paris, France; UZ-Gent, Gent, Belgium; Institut Curie, Paris, France

Background: OXA is active in mismatch repair (MMR) deficient cells, a condition prevalent in pretreated AOC. OXA/P shows high activity in investigator initiated studies (Faivre et al, Ann Oncol 10:1125, 1999). We evaluated efficacy and safety of OXA/P in AOC pts with clinically evaluable disease pretreated with 1 platinum based regimen ± taxanes and a progression-platinum-free interval (PPFI) ≥6 months (mo). Methods: From Dec 99 to Apr 02, 105 pts, 14 centres received P 175 mg/m2, 3h iv followed by OXA 130 mg/m2, 2h iv, every 3 weeks, for up to 9 cycles (cy) without G-CSF. Median (m) age: 58 years (range 37–83), 96% PS 0/1. PPFI: 69 pts >12 mo, 34 pts 6–12 mo; 80 pts (76%) taxane-pretreated. Results: 708 cy administered; m 7 cy/pt (1–9). Relative dose intensity: OXA 0.95, P 0.97. Efficacy: 98 pts eligible, 7 noneligible (3 bowel occlusion, 3 >1 prior platinum-based chemotherapy, 2 PPFI not determinable). 98 pts evaluable for response (see table) ORR: 81% (95%CI 71–88), all but 3 responses third party reviewed; 90 pts evaluable for biological response (baseline CA125 ≥50 UI/ml): 89% response (decrease >75% or CA125 normalization >1 mo). Combined RECIST /biological response: 88% (95%CI 80–94). M followup: 27 mo (14–48); m PFS: 10.2 mo; projected OS >28 mo (44 events). Safety (NCI-CTC): % pts with grade (gr) 3/4: neutropenia 21/46; thrombocytopenia 15/1; nausea-vomiting 9/2; asthenia 7/1; allergic reaction: 1/1; cumulative reversible neurotoxicity gr 2/3 (OXA specific scale): 50/25 after a m 7 cy (3–9); febrile neutropenia: 9 episodes/8 pts; 4% cy required G-CSF; no treatment-related deaths. Conclusion: The OXA/P combination shows the highest level of efficacy in platinumsensitive third party reviewed large phase II studies in platinum/taxane pretreated AOC pts with PPFI >6 mo, and can be administered in an outpatient setting without special safety measures.

Abstracts

Response (RECIST)   Prior taxanes No prior taxanes Total N=75 (%) N=23 (%) PPFI (mo) CR+PR SD PD

6–12 N=28 24 (86) 2 (7) 2 (7)

>12 N=47 35 (74) 8 (17) 4 (9)

6–12 N=2 1 (50) 1 (50) –

>12 N=21 19 (90) 2 (10) –

79 (81) 13 (13) 6 (6)

5034

Gemcitabine and oxaliplatin followed by paclitaxel and carboplatin as first line therapy for patients with advanced epithelial ovarian cancer. A phase II trial of sequential doublets. (GO-FIRST) K. Chrystal, C. B. Steer, K. A. Cheong, E. Galani, A. Strickland, F. Lofts, C. Gallagher, H. Thomas, P. Harper Guys Hospital, London; St Georges Hospital, London; St Bartholomew’s Hospital, London; Royal Surrey County Hospital, London

Background: Gemcitabine and oxaliplatin are active in epithelial ovarian cancer with minimal overlapping toxicity, and in pre-clinical studies have shown synergy. The primary objective of this prospective phase II study is to evaluate the response rate (RR) and toxicity of gemcitabine and oxaliplatin (GO) administered sequentially with paclitaxel and carboplatin (PC). Secondary objectives were time to progression, quality of life outcomes and overall survival. Methods: Patients with histologically proven epithelial ovarain cancer, FIGO stage II–IV, measurable disease (RECIST), and PS 0–2 were eligible. Treatment consisted of gemcitabine 1250 mg/m2 D1, D8 and oxaliplatin 135 mg/m2 D8 q21days for 4 cycles followed by carboplatin AUC6 and paclitaxel 175 mg/m2 D1 q21days for 4 cycles. Interval debulking was permitted after 4 cycles. Results: 20 patients are enrolled. Median age 62 yrs (range 39–78), FIGO III–IV (16/4). 12/20 pts were only able to have an initial biopsy and of these, 7 were subsequently debulked. 4 cycles of GO were given prior to the planned 4 cycles of PC. The RR to 4 cycles of GO was 80% (CR4/PR12). With subsequent debulking surgery and further chemotherapy (PC) the final RR was 85% (13 CR/4 PR). One pt died of a PE and one progressed on GO and died. At a median F/U of 21 mths 15 pts are still alive, 6 without progression. The median TTP was 15.2 mths. Grade 3/4 toxicities for GO: nausea and vomiting 4pts (20%), neutropenia 4pts (20%). PC: alopecia 14 (70%), neutropenia 2 (10%), thrombocytopenia 1 (5%). Peripheral neuropathy was the major toxicity. 4 pts developed G2 and a further 1pt G3 on GO. With sequential PC, 8 pts developed G2 and 5 pts G3 neuropathy requiring dose reduction in 3 pts and cessation of paclitaxel in 6 pts. Conclusions: GO is a new doublet with activity in ovarian cancer, but sequential PC should not be used given the cumulative neurotoxicity.

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5075

Phase II trial of oxaliplatin (OXA) combined with paclitaxel (P) as first-line chemotherapy for patients (pts) with advanced ovarian cancer (AOC): Preliminary results G. Deplanque, A. Goupil, M. Fabbro, E. Levy, O. Rixe, B. Benettaib, E. Cvitkovic Clinique Cluade Bernard, Metz, France; Centre René Huguenin, St Cloud, France; CRLC Val d’Aurelle, Montpellier, France; Hôpital European Georges Pompidou, Paris, France; Hôpital de la PitiéSalpétrière, Paris, France; CAC, Le Kremlin-Bicêtre, France

Background: Despite the introduction of paclitaxel/platinum combinations in first line treatment of AOC, a small proportion of patients fail to respond. This has been linked to genetic or epigenetic deficiency in activity in mismatch repair (MMR; MLH1, MSH2). OXA has activity in MMR deficient cells and the OXA/ P combination has been shown to be safe and highly active in pre-treated AOC pts (Faivre et al. Ann Oncol 10:1125, 1999). This motivated the present phase II study in first line AOC. Methods: AOC pts with histologically proven stage IIc or IIIa-c after maximal debulking surgery (microscopic disease or macroscopic disease ≤2 cm) performed 2–7 weeks before study treatment start, received 175 mg/m2 P, 3-hour intravenous infusion, followed by 130 mg/m2 OXA, 2-hour intravenous infusion, every 3 weeks, on an outpatient basis, without G-CSF. A maximum of 6 cycles were administered before evaluation by second look laparoscopy or laparotomy. Pts with positive histology after second look surgery could receive up to 2 further cycles; pts with pathological complete response received no further treatment. Results: Between Aug 2001 and Jan 2003, 17 pts were entered in 9 centres (49 planned), 14 eligible, 3 ineligible (2 colorectal cancer with peritoneal presentation, 1 pre-treated with OXA/cisplatin/P). Median age 59 years (range 40–68); Performance status 0/1/2: 10/3/1; histology serous: 11, other: 3; FIGO stage IIIb: 5, IIIc: 9; microscopic residual disease: 3, macroscopic: 11. Patients received a median of 6 cycles (6–8). Efficacy: Of 13 pts evaluable for pathological response, 8 had complete response (62%) and 5 stable disease. With a median follow-up of 14 months (6–24), only 2 pts with macroscopic residual disease progressed. Median PFS: 14 months (5–22), 9 out of 12 patients have an ongoing PFS >12 months. Safety (NCI-CTC; 91 cycles) % by pts: neutropenia grade (Gr) 3/4: 7%/14%; febrile neutropenia: 7%, reversible neurosensory toxicity (OXA specific scale) ≥Gr2: 21%. Conclusion: The OXA/P combination shows high antitumor activity and a safe toxicity profile in first-line treatment for AOC.

5078

Phase II study of oxaliplatin (OXA) and docetaxel (DTX) in recurrent platinum-sensitive ovarian cancer G. Ferrandina, M. Ludovisi, G. Dagostino, D. Lorusso, A. Naldini, A. C. Testa, I. Paris, V. Gallotta, C. Pozzo, G. Scambia Catholic University of the Sacred Heart, Roma, Italy; Catholic University of the Sacred Heart, Campobasso, Italy

Background: We conducted a phase II study in order to evaluate the efficacy and safety of the combination of OXA and DTX in recurrent platinum-sensitive ovarian cancer patients. Methods: Patients received DTX 75 mg/m2 (60-min i.v.) on day 1, followed by OXA 100 mg/m2 (120-min i.v.) on day 1 every 21 days. Results: Between October 2002 and December 2003, 14 Caucasian patients (median age: 55.5 yrs; range, 39–68) were enrolled. At first diagnosis 1 (7.1%) patient had FIGO stage I ovarian cancer, 12 (85.8%) had FIGO stage III and 1 (7.1%) had FIGO stage IV disease. Sites of relapse were as follows: liver/spleen = 3 cases (21.4%), pelvis = 3 cases (21.4%), lym-

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phnodes = 4 cases (28.6%), peritoneal = 3 cases (21.4%) and multiple sites = 1 case (7.2%). The median platinum-free-interval was 23.5 months (range 13–58). At recurrence the median CA125 was 324.5 U/ml (range 21–5596 U/ml). Of the 13 patients evaluable, 4 (30.8%) had complete response and 3 (23.1%) had partial response to OXA/DTX with an overall response rate of 53.9%. The median time to response was 10 wks (range 5–32) and the median duration of response was 16 wks (range 6–31). Five (38.5%) patients had stable disease (median duration of stabilization: 21 wks, range 12–40). One (7.7%) patient progressed while on treatment. Therefore, an overall clinical benefit was observed in 92.3% of patients. All patients were evaluable for toxicity. A total of 81 courses were given, with a median of 5.5 cycles per patient (range 1–10). Severe toxicities (Grade 3–4 NCI-CTC) included: neutropenia in 33.3% of cycles; severe anemia and thrombocytopenia were not observed. Grade 3–4 neurotoxicity and alopecia were detected in 4.9% and 24.7% of cycles respectively. Allergic reaction was observed only in one case. Doses were reduced by 20% in 13.5% of cycles due to neurological toxicity. Conclusions: In recurrent platinum-sensitive ovarian cancer patients the OXA/DTX combination is highly active with acceptable toxicity, thus making it an attractive regimen which warrants the prosecution of the study.

5104

Bi-weekly oxaliplatin (oxa) and gemcitabine (gem) in cisplatin pretreated patients with relapsed ovarian cancer (roc): Preliminary data of a phase II trial D. Germano, D. Bilancia, A. Di Nota, A. M. Dello Russo, R. Romano, G. Rosati, F. Giotta, L. Manzione San Carlo Hospital, Potenza, Italy; Oncology Institute, Bari, Italy

Background: Both OXA and GEM have shown single agent activity in pts with ROC. Responce rates to second-line therapies remain low and there is a need to develop more effective regimens. In view of the synergistic effect using the sequence GEM followed by OXA (Faivre S, Cancer Chemother Pharmacol 1999, 44(2): 117–23), we studied these agents in pts with ROC heavely pretreated. The aim of the study was to evaluate the efficacy and toxicity of combination of GEM 1000 mg/m2 D1 IV and OXA 100 mg/m2 in 2h infusion D2, treatment was repeated every 2 weeks until progression of desease or intollerable toxicity Methods: The study was monoinstitutional and started in November 2002.To date 15 patients, median age 66 years (range 52–82) have been treated. Median Karnofski Performance Status was 70% (range 60–90), all had at least 1 prior platinum based chemotherapy and 11 had received a taxane Results: At November 2003 of 15 patients entered onto study, 13 were assesable. Pts received a median of 6 cycles of treatment (range 4–11). There was 1 patient (7.7%) with complete response, 3 patients (23%) achieved a partial response. Using the technique of Rustin et al. (JCO 1996, 14:5; 1545–1551) Ca 125 responses occurred in 3 of the 4 responding patients. As concerns toxicity, a low profile (grade 1 –2, WHO criteria) was observed: nausea 38.5%, trombocytopenia 30.7%, neuropaty 38.5%. Conclusions: The GEMOX combination is extremely well tolerated and even in this small pts group encouraging responses have been documented. Recruitment continues and further data will be presented.

Abstracts

5111

Gemcitabine (GEM) + oxaliplatin (OX) in patients (pts) with stage III/IV ovarian cancer following 3 cycles of carboplatin (CB) + paclitaxel (PAC): Preliminary report of a phase II study R. Arca, J. Ibarra, G. Lerzo, M. Mandachain, E. Mickievicz, J. Perez, E. Richardet, J. Rodger, M. Van Kooten, M. Orlando Hospital Urquiza, Concepcion del Uruguay-Entre Rios, Argentina; COIR, Mendoza, Argentina; LUCEN, Buenos Aires, Argentina; Instituto Alexander Fleming, Buenos Aires, Argentina; Hospital Roffo, Buenos Aires, Argentina; Hospital Penna B. Blanca, Bahia Blanca, Argentina; Hospital Italiano de Cordoba, Cordoba, Argentina; Eli Lilly, Buenos Aires, Argentina

Background: GEM is active in recurrent epithelial ovarian cancer. OX activity in ovarian cancer is similar to cisplatin in first-line therapy and PAC in nonrefractory relapses. This multicenter, prospective phase II study combines GEM/OX as first-line sequential therapy for advanced ovarian cancer in pts after 3 cycles of CB/PAC. Primary endpoint is time to disease progression; secondary endpoints are CA 125 response rate, objective response, response duration, overall survival, correlation between expression of MMR and p53 and efficacy, and toxicity. Methods: Pts with confirmed histologic diagnosis of stage III/IV epithelial ovarian carcinoma, initial surgery including anexohysterectomy + omentectomy, 3 cycles of CB ≥AUC 5 and PAC ≥175 mg/m2, no other prior chemotherapy, and adequate organ and marrow function were enrolled. Three to 4 weeks after CB/PAC, pts received GEM 1000 mg/m2 on days (d) 1,15 (100-minute infusion) and OX 85 mg/m2 on d2,16 (120-minute infusion), q28d. Results: To date, 18 pts (median age 57 [range 42–73]; Zubrod performance status 0/1 [10/8 pts]) have been enrolled. 8 pts had stage IIIB; 7, stage IIIC; 3, stage IV. At baseline, median CA 125 level was 777 ng/ml (range 27–9330). Of 13 evaluable for CA 125 response, 12 had complete response and 1 progressed; 3 were evaluable for objective response (1 complete and 2 partial). Total number GEM/OX cycles was 51 (median 2.83 [range 1–3]). All intended doses given as planned; only 5.8% were delayed due to insufficient hematologic recovery. All were evaluable for toxicity. Grade (G) 3 anemia occurred in 2 cycles (3.9%); G3 neutropenia, in 1 cycle (1.9%); mild thrombocytopenia (G1), in 4 cycles (7.8%). G3 nausea occurred in 1 cycle (1.9%); G3 vomiting, in 2 cycles (3.9%). Reversible G1/2 sensory neuropathy occurred in 9 (17.6%) and 3 cycles (5.9%), respectively. No treatmentrelated deaths occurred. Conclusions: GEM/OX following CB and PAC is feasible, with minimal and manageable toxicity, in pts with ovarian cancer. Updated results of survival and pharmacology will be presented. Supported by Eli Lilly, Debiopharm.

well-tolerated salvage therapies with minimal toxicities are needed. Methods: We designed the R-GEMOX regimen, with rituximab 375 mg/m2 d1, gemcitabine 1000 mg/m2 d2 and oxaliplatin 100 mg/m2 d2 (recycling on d15). Between January 2002 and August 2003, 24 patients with refractory/relapsing B-cell lymphoma not eligible for HDT were enrolled in an open unicenter pilot study whose primary objective was to determine the overall response rate (ORR) after 4 cycles of R-GEMOX. Patients were planned to receive 8 cycles if a good response (at least PR) was observed after 4 cycles. Median age was 64 years (range: 43–77) and histological subtypes were: diffuse large Bcell lymphoma (n=16), follicular (n=6) and mantle cell (n=2). Prior treatment included anthracyclin (n=22), rituximab (n=11) and HDT (n=6). The median number of prior treatments was 2 (range: 1 to 5) and 8 patients had received at least 3 prior regimens. Results: 172 cycles were given. The dose administered was 100% of the intended dose for the three drugs in all patients but 4, for whom the dose of oxaliplatin was reduced due to neurotoxicity (n=3) or preexisting renal insufficiency (n=1). Two patients progressed after 3 cycles. After 4 cycles, observed responses were: 6 CR, 4 CRu, 11 PR and 1 failure resulting in an ORR of 88%. Among the 21 responders after 4 cycles, 17 achieved CR or CRu, 2 remained in PR after completion of 8 cycles. Treatment was stopped after 5 cycles in 2 patients because of physician decision. As of December 2003, 22 patients are alive, 15 in continuous complete remission, 3 in CRu, 2 in PR and 2 in progression. NCIC grade 3–4 neutropenia and thrombocytopenia were reported in 50% and 21% of cycles. Two patients developed a grade 4 infection. There was no renal toxicity. Conclusion: The R-GEMOX regimen shows promising activity with an acceptable toxicity. It is evaluated in an ongoing multicentric phase II study.

6681

Dexamethasone, high-dose cytarabine, and oxaliplatin (DHAOx), and rituximab plus DHAOx (R-DHAOx) for treatment of patients with B-cell non-Hodgkin’s lymphoma: Results from two consecutive phase II studies D. Machover, B. Delmas-Marsalet, Y. Gumus, S. C. Misra, A. Ulusakarya, N. Brahimi, E. Goldschmidt, N. Frenoy, C. Guettier Paul Brousse Hospital, Villejuif, France

Background: High-dose therapy with autologous stem cell support (HDT) is now an established treatment for chemosensitive relapse in aggressive lymphoma. However, not all patients are candidates for HDT because of age, comorbidities or previous HDT. Effective and

Background: To determine, from two consecutive phase II studies, the efficacy of oxaliplatin (L-OHP), cytarabine (ara-C), and dexamethasone (DHAOx), and DHAOx plus rituximab (R-DHAOx), in patients with non-Hodgkin’s lymphoma (NHL). Methods: In Study I, treatment consisted of DHAOx (dexamethasone, 40 mg/day, days 1 to 4; L-OHP, 130 mg/m2, day 1; and ara-C, 2,000 mg/m2, every 12 hrs, day 2). In Study II, treatment consisted of R-DHAOx (DHAOx plus rituximab, on day 1, 375 mg/m2). Courses were repeated every 21 days. Patients had failed to achieve a complete response (CR) with initial chemotherapy, were in relapse, or could not receive standard treatment. Results: Response to therapy: Study I: Eight patients (61.5%) achieved a CR, and 1 (8%) had a PR. None of the complete responders has relapsed; they had a median disease-free survival (DFS) of 44.6 months. Study II: Fifteen patients (68%) achieved a CR, and 3 (13.5%) had a PR. None of the complete responders has relapsed; they had a median DFS of 19.8 months. Responses were obtained in lymphomas of follicular, marginal-zone, mantle-cell, and diffuse large B-cell subtypes, and in patients with or without resistance to prior chemotherapy. Disappearance of molecular markers occurred in all of the complete responders whose tumor cells carried markers. Toxicity: Myelosuppression and dose-related peripheral neuropathy were the most prominent toxic effects. Conclusions: DHAOx and RDHAOx are highly active for salvage treatment of patients with Bcell NHLs, and possess toxicity characteristics which compare favorably to those reported with ara-C plus cisplatin-containing regimens.

Abstracts

Onkologie 2004;27(suppl 1):12–58

Adult Leukemia, Lymphoma and Transplantation 6592

Rituximab, gemcitabine and oxaliplatin (R-GEMOX): A promising regimen for refractory/relapsed B-cell lymphoma T. El Gnaoui, B. Joly, J. Dupuis, K. Belhadj, A. Rahmouni, C. Copie-Bergman, A. Allain, I. Tabah-Fisch, F. Reyes, C. Haioun Hôpital Henri Mondor, Créteil, France; Sanofi-Synthelabo, Paris, France

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Lung Cancer 7250

Chemotherapy with gemcitabine and oxaliplatin in 13 malignant pleural mesothelioma (MPM): A monocenter experience J.-M. Brechot, J.-F. Morère, G. Des Guetz, K. Chouahnia, J.-L. Breau Hôpital Avicenne, Bobigny, France

Background: A wide range of chemotherapic agents used singly or in combination have been evaluated in MPM. Doublets with gemcitabine and a platinum salt emerge as one of the most promising regimen. The combination of gemcitabine and oxaliplatin (GEMOX) has a very good toxicity profile. This chemotherapy has been administered in clinical practice in our department for 2 years. Methods: We have rewieved the data of consecutive non pretreated MPM patients (pts) treated with GEMOX between October 2001 and October 2003 at our department. Results: 13 pts (9 males, 4 females), mean age 62y (50–74), PS 0–1 12 pts, PS 2 1 pt, with a MPM diagnosed by pleuroscopy (9), thoracotomy (1) or blind pleural biopsy (3), with epithelial (4), mixed (4) and unspecified (5) histological subtype, all stage III or IV, received as outpatient treatment an association of gemcitabine 1000 mg/m2 D1 and oxaliplatin 100 mg/m2 D2 every 2 weeks with a mean of 8 cycles. In 9 evaluable pts, 2 PR, 6 SD and 1PD were observed. Median time to progression (TTP) was 7,5 months. Median survival is 12 months. Seven pts died, all in progressive disease. No grade 3 or 4 hematologic toxicities were observed. In 5 cases, treatment was discontinued because of non hematologic toxicities (allergia grade 3 in 2 pts at the 6th and 7th cycles, peripheral neurotoxicity in 3 pts (at the 6th and 10th cycles). Conclusion: GEMOX is a well tolerated and active chemotherapy regimen in MPM. It could be recommended in clinical practice.

7263

A multicenter phase II trial with gemcitabine plus oxaliplatin as second line treatment in patients with advanced non-small cell lung cancer (NSCLC) C. Kouroussis, K. Syrigos, A. Potamianou, N. Ziras, P. Ziotopoulos, J. Stergiou, P. Ginopoulos, E. Tselepatiotis, V. Biozionelou, V. Georgoulias For the Lung Cancer Working Group, of the Hellenic Oncology Research Group (HORG), Greece

Background: Gemcitabine and Oxaliplatin have shown activity in NSCLC even in pretreated patients (pts). We conducted a phase II study to determine the activity of this combination as second line treatment in NSCLC. Methods: Patients were eligible if they had confirmed NSCLC, measurable or evaluable disease, performance status (ECOG) 0–2 and adequate hepatic, renal and bone marrow function. Gemcitabine dose was 1500 mg/m2 (30 minute infusion) on days 1 and 8, and Oxaliplatin 130 mg/m2 (2–6 hour infusion) on day 8. Cycles were administered every 3 weeks. Results: 24 pts were enrolled, 21 males and 3 females. Median age was 61.5 years (range 42–72); 83% had PS 0 or 1 and 17% PS 2; 12 pts had received 2 lines of treatment. All pts were evaluable for toxicity and 23 for response. Three pts achieved partial response (13%; 95% c.i 0.72%–26.81%) and 6 (26%) stable disease. The median time to progression was 3 months (range 1–12.7) and the median survival 5.6 months (range, 1–14). A total of 84 cycles were administered (median number/patient: 3) and the median dose administered was 85% for Gemcitabine and 81% for Oxaliplatin. No grade IV or febrile neutropenia occurred. Grade 3 neutropenia occurred in 4 (17%) pts, grade 3 anemia in 3 (12.5%) and grade 3 thrombocytopenia in 2 (8%). Non-hematological toxicity was

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mild and not clinically relevant. The only grade 3 non-hematological toxicity was neurotoxicity in 2 (8%) pts which was reversible with the discontinuation of treatment. Conclusions: The Gemcitabine plus Oxaliplatin is a well tolerated but marginally active regimen in pretreated pts with advanced NSCLC.

7348

Preliminary results of phase II trial with combination of gemcitabine and oxaliplatin in elderly patients with advanced NSCLC R. Buosi, S. Poletti, V. Cantele, S. Piazza, R. Torazzo, E. Negru, A. Vandone, O. Alabiso Ospedale Maggiore della Carità, Novara, Italy

Background: Oxaliplatin (L-OHP) is a novel antineoplastic platinum derivative with a DACH carrier ligand. In preclinical studies it appeared to have clinical activity in many tumor cell lines, including some that are resistant to cisplatin and carboplatin. Based upon in vitro studies demonstrating synergistic anti-tumor activity between LOHP and new citotoxyc drugs, as Gemcitabine, we have conduced a phase II study to evaluate the toxicity and potential synergistic effect by combining the two drugs in elderly patients with locally advanced or metastatic NSCLC. Methods: 14 chemotherapy naive patients with stage III B and IV NSCLC were enrolled in the study. The patients show these characteristics: 4 females, 10 males, median age 73 years, range 65–78, 12 patients with ECOG performance status 0, 2 with ECOG 1. Cancer istotype: 2 adenocarcinoma, 10 squamous cell, 1 large cell, 1 in determinated carcinoma. 3 patients have bone metastasis, 4 have lung metastasis and 3 with brain lesion. 4,9 cycles for patient are administered. Treatment schedule: L-OHP 65 mg/mq and Gemcitabine 1000 mg/mq, both drugs are administered at days 1–8, to be repeated every 3 weeks Results: 13/14 patient evaluable for response rate: 6 RO (43%) in which 1 RC and 5 RP, 1 PD (7%) and 6 SD (43%). Only 1 patient had a worsening of PS, 1 patient in RP after 3 cycles is die for unrelated therapy cardiac failure. We observed mild hematological toxicity: 2 pts show grade (Gr) 2 anemia; 3 pts Gr 2 trombocytopenia, and Gr 3 and Gr 4 trombocytopenia we relevate in only 1 pt respectively. Neither Gr 4 neutropenia nor febrile episodes were detected. Also non hematological toxicity is low: nobody experimented Gr >2 nausea and vomiting. Gr. 2 diarrhea and Gr 2 neurotoxicity are manifested in 2 pts and in 4 pts respectively; 1 pt have Gr 2 transaminases increase. The 2 pts with Hb level ≤10 g/dl are treated with recombinant human erythropoietin 10.000 UI s.c. 3 times/wk until to normal Hb level Conclusions: these encouraging results indicate that the GEMOX schedule could be used in treatment of advanced NSCLC and so we advise to use this combination in elderly patients.

Abstracts

8093

Patient Care

Potential prevention and treatment of oxaliplatin associated peripheral neuropathy

8042

Oxaliplatin (with 5FU and leucovorin) in patients above age 70 («elderly») suffering from metastatic colorectal cancer: An observational study B. Exquis, M. Aapro, S. Kohler Groupe Médical Onex, Onex, Switzerland; IMO Clinique de Genolier, Genolier, Switzerland; Sanofi-Synthélabo Suisse, Meyrin, Switzerland

Background: Data on standard chemotherapy in the real elderly are rare. Patients and Methods: We conducted, during 18 months, an observational study of Oxaliplatin in combination with 5-FU and leucovorin (FUFOL) for treatment of metastatic colorectal cancer, in order to assess safety, response rate and exact regimens used in patients below and above 70 years. Twenty-five centres documented 137 patients (57% male, median age 62 years, colon/rectum/other: 64%/30%/6%, ECOG PS 0/1/2/3: 34%/55%/10%/1%, previous chemotherapy: 69%). Total number of administered cycles was 816 (median 6, range 1–23). Results: Regimen used: 71% received Eloxatin at 85 mg/m2 every 2 weeks, 18% at 130 mg/m2 every 3 weeks, and 11% received other regimens. FUFOL regimens were 37% FOLFOX4, 27% simplified 46h infusion, 21% weekly bolus (Roswell Park), 8% daily bolus (Mayo), 7% others. Response rates: CR 4%, PR 21%, SD 37, PD 27%, unknown 11%. ECOG PS before vs. after therapy: 20% of patients improved, 62% stable, 18% deteriorated. Safety: Grade 3/4 toxicities (per cycle) were nausea (0.1%), vomiting (0.5%), diarrhea (2%), stomatitis (0.2%), thrombocytopenia (1%), leucocytopenia (1%), granulocytopenia (0.6%), lymphocytopenia (7.2%). 75% no hair loss, 18% had mild and 7% had grade 2 hair loss. Grade 3 neuropathy (Levy scale) was reported by 3%. These 4 patients had at least tumor stabilisation or partial response. Influence of age: 33 patients were older than 70. Overall response rate was 24% for patients up to 70 years and 27% for older patients. Grade 3/4 toxicities (per cycle) were (≤70/>70 years): nausea 0.3%/0.0%, vomiting 0.7%/0.0%, diarrhea 1.8%/2.8%, stomatitis 0.4%/0.0%, neuropathy 0.7%/0.0%. Conclusion: Combination therapy with Eloxatin as used here is safe and efficacious in daily practice. Elderly patients benefit equally from therapy without increased toxicity.

K. R. Hoffman M.P.H., Totowa, New Jersey, NJ

Background: The major toxicities of oxaliplatin are two different types of peripheral neuropathies, a reversible one related to the drug’s infusion and an irreversible one based on the cumulative dose received. The incidence of onset and the severity of the neuropathy increase as the number of cycles increase as does the prevalence of the toxicity. Gabapentin (Neurontin) and carbamazepine (Tegretol) are two drugs used in the treatment of autonomic dysfunction and peripheral neuropathic pain. Given the similar syndromes, a trial was first conducted to see if the use of these agents could prevent the progression of this oxaliplatin-associated toxicity. A second trial was then begun to see if these agents could totally prevent oxaliplatin-associated neurotoxicity. Methods: 34 consecutive patients receiving oxaliplatin-5-FU-leucovorin rescue chemotherapy for stage IV colon cancer were available for study. Treatment was determined by random drawing of treatment options. Results: In the initial study of 24 patients, grade 1 toxicity had to be reported before treatment was initiated with either drug, usually after the 2nd cycle. Treatment was begun a week before the 3rd cycle. Gabapentin was begun at 900 mg/day and escalated to 2700 mg/day, as needed. Carbamazepine was begun at 400 mg/day and escalated to 800 mg/day, as needed. A success rate for preventing any grade 3 or higher sensory symptomatology occurred in 75% (9/12) in both groups. No life-threatening nor persistent neuropathy occurred. To judge whether these agents could totally prevent the sensory neuropathy, the next 10 patients have been randomized at the start of their treatment to either gabapentin, carbamazepine or nothing. After 3 cycles the 6 treated patients have grade 1 sensory neuropathy while 2 of the 4 non-prophylaxed patients had grade 2 sensory neuropathy and were started on therapy before cycle 3. No drug toxicity associated with either carbamazepine or gabapentin was observed. Conclusions: While a prospective, doubleblinded randomized trial needs to confirm these findings, gabapentin or carbamazepine can be considered as adjuvant therapy to minimize the sensory neuropathic toxicity of oxaliplatin.

Grade 3/4 toxicity (% per cycle)

≤70 years N=104 >70 years N=33

Abstracts

CR + PR

Nausea

Vomiting

Diarrhea

Stomatitis

Haemoglobin

Platelets

Leucocytes

Granulocytes

Lymphocytes

Neuropathy (Levy scale)

24% 27%

0.3 0.0

0.7 0.0

1.8 2.8

0.4 0.0

0.0 0.0

0.0 1.6

1.6 0.0

0.5 0.0

6.3

0.7

Onkologie 2004;27(suppl 1):12–58

57

Tumor Biology / Immunobiology / Human Genetics 9506

Assessment of multiple markers for association with response rate (RR) and failure-free survival (FFS) in patients with advanced colorectal cancer (CRC) treated with chemotherapy in the MRC CR08 (FOCUS) randomized trial J. W. Adlard, S. D. Richman, P. Royston, J. M. Allan, A. Meade, M. Parmar, P. Selby, P. Quirke, M. T. Seymour, on behalf of the FOCUS Trial Collaborators Cancer Research UK, Leeds, United Kingdom; Medical Research Council, London, United Kingdom; University of Leeds, Leeds, United Kingdom

Background: We have assessed potential prognostic and predictive markers of response to fluorouracil (FU) in advanced CRC patients randomized 4:1:1 to FU alone, FU+oxaliplatin, or FU+irinotecan. Methods: Pathology specimens were retrieved from 846 patients in the FOCUS trial. 85% were from the primary site. Normal and tumor DNA and RNA were extracted and tissue microarrays were made for

immunohistochemistry (IHC). The following factors were assessed for effect on FFS and RR to first-line therapy: age; performance status; primary site; liver metastases; serum ALP; grade; mucoid status; IHC for hMLH1, hMSH2, P53, SMAD4, dUTPase, DPD, thymidine phosphorylase (TP), thymidylate synthase (TS); TS mRNA expression; DNA polymorphisms in TS (TSER, TS1494), hMLH1 (–93 G2A), MTHFR (677 C2T). Results: Overall RR and median FFS to first-line therapy were 42% and 8 months respectively. The table shows markers with significant relationships to RR and FFS. Together markers explained 6% of the variability in outcome, with the IHC/histology markers contributing most. DNA polymorphisms showed no clear association with outcomes. Similar associations of marker status were found for patients treated with FU alone or FU+oxaliplatin/irinotecan. Using logistic regression, a predictive algorithm could separate tumors into groups with RR from 15% to 50% for treatment with FU alone and 25% to 70% for treatment with FU+oxaliplatin/irinotecan. Conclusions: Significant differences in RR have been identified for mucoid status, TS IHC and dUTPase IHC scores allowing development of a predictive algorithm for response to FU-containing chemotherapy. Associations with modest differences in FFS were also identified. Ongoing work is looking at markers specific for oxaliplatin or irinotecan benefit.

Table. Markers associated with adverse RR/FFS. n/s=not significant. *=significant in multivariate analysis. Marker associated with adverse RR/FFS

p-value for RR

Odds ratio (OR) for RR

95% C.I. for OR

Absolute difference in RR (%)

p-value for FFS

Hazard ratio (HR) for FFS

95% C.I. for HR

Difference in median FFS (months)

Mucoid tumor* High TS IHC* High dUTPase (*for FFS only) High TS mRNA* Grade 3* Low DPD* Liver secondaries present* High ALP

0.0001 0.0001 0.052

2.64 1.85 1.39

1.58–4.42 1.38–2.49 1.01–1.91

21.3 15.0 8.0

n/s 0.0001 0.002

n/s 1.37 1.32

n/s 1.17–1.62 1.11–1.56

n/s 1.6 1.1

n/s n/s n/s n/s n/s

n/s n/s n/s n/s n/s

n/s n/s n/s n/s n/s

n/s n/s n/s n/s n/s

0.004 0.013 0.014 0.021 0.046

1.42 1.27 1.24 1.26 1.18

1.12–1.81 1.05–1.53 1.04–1.47 1.03–1.38 1.01–1.38

0.5 1.6 1.5 1.1 1.1

58

Onkologie 2004;27(suppl 1):12–58

Abstracts

Dokumentation und Evaluation der Weiterbildung Autorenindex Dokumentation und Evaluation der Weiterbil Onkologie 2004;27(suppl 1):59–60

Aapro, M. 57 Abad, A. 29 Achille, E. 25 Adam, R. 35, 37, 40 Adlard, J.W. 58 Advani, R.H. 17 Agafitei, R.D. 27 Airoldi, M. 44 Alabiso, O. 56 Albertotti, C. 51 Alberts, S.R. 27 Algeri, R. 42 Allain, A. 55 Allan, J.M. 58 Allegrini, G. 36, 38 Alonso, V. 42 André, T. 16, 19, 23, 25, 25, 38, 45 Andreuccetti, M. 38 Anton, A. 42 Anton, L.M. 48 Antón-Aparicio, L. 31 Aparicio, J. 24 Aravantinos, G. 52 Arca, R. 55 Arcara, C. 12 Arkenau, H.-T. 22 Arland, M. 28 Arnold, D. 50 Artioli, F. 47 Artru, P. 22, 38 Aschele, C. 42 Asensio, D. 24 Asnaghi, D. 43 Athanasiadis, A. 20, 30, 52 Avallone, A. 44 Avenin, D. 23 Azarnia, N. 33 Azoulay, D. 37 Badalamenti, G. 12 Badarinath, S. 20 Bae, S.H. 32 Balart, J. 43 Baltesgard, L. 35 Barbara, C. 36 Baron, M.G. 48 Bartel, C. 24 Barugel, M. 32 Basaran, G. 37 Bastian, G. 13 Battistini, G. 42 Bauer, J. 46 Beale, P. 26 Beasley, S. 36 Behrens, R. 45 Beijnen, J.H. 13 Belda, C. 43 Belhadj, K. 55 Bellmunt, J. 52 Belón, J. 24 Benettaib, B. 54 Bennouna, J. 22 Benson, A.I.B. 14 Berdzik, J. 46 Bernabé, R. 24 Bernuzzi, P. 47 Berrocal, A. 52 Bertè, R. 47 Bidin, L. 47 Biffi, A. 31 Bilancia, D. 54 Binda, G.A. 42 Biozionelou, V. 56 Bismuth, H. 37 Bjarnason, G. 19 Blanco, G. 29 Blumgart, L. 34 Boige, V. 44, 47, 50 Bolaños, M. 24, 29, 48 Bonetti, A. 12, 16 Boni, C. 12, 16 Bonnay, M. 44 Bonyhay, L. 50 Bordonaro, R. 29 Borgonovo, K. 43 Boron, M. 33 Botto, H.G. 30 Botturi, M. 43 Bouchahda, M. 35, 40

Bougnoux, P. 53 Brahimi, N. 55 Breau, J.-L. 13, 56 Brechot, J.-M. 56 Brell, J.M. 14 Brennscheidt, U. 26 Brezault Bonnet, C. 35, 40 Brienza, S. 12 Brunetti, I. 36, 38 Bu, Z.D. 47 Budillon, A. 44 Buechner-Steudel, P. 45 Bugat, R. 22, 26 Bui, B. 51 Buosi, R. 56 Burkart, C. 50 Busquier, I. 24 Butts, C. 23 Buzaid, A.C. 51 Buzzi, F. 32 Campana, F. 33 Campos, J.M. 24 Canon, J.-L. 40 Cantele, V. 56 Cantore, M. 45 Carles, J. 52 Carola, E. 25 Caroti, C. 42 Carraro, S. 32 Carreca, I. 44 Casado, E. 43 Cascinu, S. 48 Caspar, C.B. 30 Cassidy, J. 23 Castaing, D. 37, 40 Castelo, B. 43 Catalano, G. 48 Catalano, P.J. 14 Catalano, V. 48 Catot, S. 29 Cattel, L. 44 Cavanna, L. 47 Ceccarelli, C. 40 Cerri, E. 36, 38 Cervantes, A. 17, 19, 49 Chacón, J.I. 48 Chacon, M. 32 Chacon, R. 32 Chang, I.Y. 28 Chatta, G. 16 Chatzichristou, A. 30 Chen, H.X. 14, 33 Chen, J.-S. 49 Chen, T.T. 20 Cheng, C. 28 Cheong, K.A. 53 Chevreau, C. 51 Chirivella, I. 25, 25 Cho, C.D. 17 Chopitea, A. 38 Chouahnia, K. 13, 56 Christakis, C. 30 Chrystal, K. 53 Cicero, G. 12 Clark, J.W. 35 Clark, K. 46 Clarke, S. 26 Clemens, M. 46 Climent, M.A. 52 Clingan, P. 16 Coche, J.-C. 40 Cognetti, F. 31 Cohn, A.L. 33 Cola, B. 40 Colin, P. 25 Comella, P. 32, 44 Conill, C. 49 Conroy, T. 23, 47 Constantin, C. 34 Constela, M. 31 Copie-Bergman, C. 55 Cordio, S. 29 Cornelis, M. 39 Coronado, C. 32 Corretgé, S. 17 Cortés-Funes, H.G. 26 Costa, F.P. 51 Costa, O.F. 51

© 2004 S. Karger GmbH, Freiburg Fax +49 761 4 52 07 14 E-mail [email protected] www.karger.com

Accessible online at: www.karger.com/onk

Costa, P.A. 51 Coster, B. 40 Cottu, P. 53 Coudert, B. 19 Coviello, K.M. 14 Creaven, P.J. 16 Cupini, S. 36, 38 Cvitkovic, E. 33, 54 Cvitkovic, F. 33 D’Amico, M. 42 Dagostino, G. 54 Dane, F. 37 D’Angelica, M. 34 De Baere, T. 50 De Braud, F. 23, 45 De Castro, J. 31, 43 De Gramont, A. 16, 17, 19, 23, 25, 38, 45 De la Cámara, J. 38 De Vita, F. 32 Decian, F. 42 Deguetz, G. 13 Del Mastro, L. 12 Delaloge, S. 12 Delgado, M. 50 Dello Russo, A.M. 54 Delmas-Marsalet, B. 55 Delord, J.P. 22, 26, 51 Delpero, J.R. 39 Delrio, P. 44 Delva, R. 53 Delvart, V. 37 Dematteo, R. 34 Demols, A. 46 Den Boer, S.S. 13 Deplanque, G. 53, 54 Des Guetz, G. 56 Di Costanzo, F. 31 Di Nota, A. 54 Di Seri, M. 48 Díaz-Rubio, E. 23 Dietrich, G. 34 Dimopoulos, A. 52 Dixon, J. 43 Dogliotti, L. 19 Doroshow, J. 51 Dorta, F. 31 Douillard, J.-Y. 17, 22 Dowlati, A. 14 Duck, L.R. 40 Ducreux, M. 44, 45, 47, 50 Dupuis, J. 55 Eckardt, J.R. 14 Economopoulos, T. 52 Efstathiou, E. 52 Egorin, M.J. 14, 16 Ekenel, M. 37 El Gnaoui, T. 55 Elfring, G.L. 17 Elias, D. 44 Emanuel, D. 21 Enzinger, P.C. 35 Escribano, A. 43 Escudero, P. 29, 42, 48 Esteban, B. 26 Esteban, E. 52 Etienne, P.-L. 19 Exquis, B. 57 Extra, J.M. 53 Fabbro, M. 54 Fabregat, X. 52 Falcone, A. 36, 38 Falk, S. 41 Farmakis, D. 52 Farris, A. 32 Fasolo, A. 43 Feliú, J. 29, 43, 48 Fernandez-Martos, C. 24 Ferrandina, G. 54 Ferrarato, E. 44 Ferraresi, V. 31 Fettner, S. 26 Feyereislova, A. 26 Figer, A. 16, 19, 23, 25, 25 Filippelli, G. 32 Findlay, B. 19 Findlay, B.P. 27 Fisher, G.A. 17

Fizazi, K. 51 Flechon, A. 51 Fleig, W.E. 45 Flesch, M. 19, 25, 25 Focan, C. 19 Fong, Y. 34 Fonseca, E. 31, 48 Font, A. 52 Fontana, E. 36, 38 Forstbauer, H. 34 François, E. 47 Frankel, P. 51 Fraschini, F. 31 Freidank, A. 28 Freier, W. 22 Frenoy, N. 55 Fuchs, C.S. 19, 27, 35 Fulfaro, F. 12 Gabriele, A. 31 Gaglia, A. 52 Galán, A. 29 Galani, E. 53 Galassi, B. 43 Gallagher, C. 53 Gallego, R. 49 Gallo, L. 42 Gallotta, V. 54 Gallurt, P. 24 Gamelin, E. 25 Gamucci, T. 31 Gandara, D. 51 Ganem, G. 23 García-Foncillas, J. 38 García-Girón, C. 26, 31 García-Olmo, D. 43 Garcia-Ribas, I. 52 García-Rico, E. 26 Garriga, J. 43 Garufi, C. 19 Gascón, P. 49 Gay, F. 46 Gebauer, B. 36 Gebbia, N. 12 Gelibter, A. 31 Gentile, A.L. 40 Geoffrois, L. 51 Georgoulias, V. 20, 52, 56 Germano, D. 54 Gholam, D. 35, 40 Giacchetti, S. 19, 35, 40 Giaccone, G. 27 Giachetti, S. 37 Giannakakis, T. 20 Giantonio, B.J. 14 Gíl-Bazo, I. 38 Gil-Delgado, M. 13 Ginopoulos, P. 56 Giornelli, G. 32 Giotta, F. 54 Giovannini, M. 47 Giulianotti, P.C. 42 Glasgow, S.C. 13 Glimelius, B. 35 Glynne-Jones, R. 41, 43 Gold, P.J. 33 Goldberg, R.M. 19, 27 Goldschmidt, E. 55 Golf, A. 46 Gollasch, H. 36 Gómez-Reina, M.J. 24 González, D. 43 González, E. 24 González-Barón, M. 29, 31, 43 Gonzalez-Larriba, J.L. 52 Gordon, M. 18 Goupil, A. 54 Gövercin, M. 49 Graeven, U. 22 Graham, C.D. 20 Grandez, R. 42 Grandinetti, C. 33 Grávalos, C. 26 Graziano, F. 48 Greco, A.O. 14 Greco, W. 46 Green, E. 19 Gregor, M. 50 Griffing, S. 18

Grochow, L. 33 Groshen, S. 27 Grothey, A. 18, 22, 34 Gruenberger, T. 39 Gruia, G. 17 Guallar, J. 43 Guercovich, A. 32 Guettier, C. 55 Guimaraes, R. 37 Gumus, Y. 55 Guo, Y. 48 Haase, C.G. 15 Habib, F. 12 Haioun, C. 55 Haller, D. 39 Halsey, J. 17 Hammel, P. 45 Hansen, V.L. 20 Harper, P. 53 Harris, R. 34 Harrison, M. 43 Hart, L. 21 Hartmann, J.-T. 50 Hata, T. 15 Headlee, C. 36 Hebbar, M. 23, 25, 38 Hedrick, E.E. 18 Heinemann, V. 46 Helm, A. 49 Henderson, C.A. 20 Hendlisz, A. 46 Hickish, T. 16 Hilbig, A. 49 Hilger, R.A. 15 Hinke, A. 46 Hirawat, S. 17 Ho, P. 13 Hochhaus, A. 50 Hochster, H. 21 Hoeffkes, H.-G. 28 Hoffman, K. 57 Hofheinz, R. 50 Höhler, T. 46 Hollis, D. 41 Honhon, B. 40 Hoppel, C.L. 14 Hospers, G. 21 Huang, J.-S. 49 Hukunaga, H. 15 Humblet, Y. 17, 40 Hurwitz, H. 18 Husseini, F. 22 Hyun, M. 32 Iacobelli, S. 19 Iacopino, B. 40 Ibarra, J. 55 Ibeas, R. 28 Ikeda, M. 15 Imadalou, K. 22 Ingalls, S.T. 14 Iqbal, S. 27 Ivy, S.P. 14 Iyikesici, M.S. 37 Jackson, D. 36 Jambalos, C.N. 17 Jarnagin, W. 34 Jasmin, C. 35, 40 Jennis, A. 20 Ji, J.-F. 47 Jin, W. 48 Jirau-Lucca, G. 21 Johnson-Buarque, E.J. 50 Joly, B. 55 Jordan, K. 34 Junker, U. 24 Kahan, J. 39 Kakolyris, S. 20 Kalbakis, K. 20 Kalykaki, A. 52 Kamentsidis, P. 30 Kaplan, R.S. 33 Kastritis, E. 52 Kellner, O. 34 Kemeny, N. 34 Kerbrat, P. 51 Kerger, J. 40 Khayat, D. 13 Kimminau, C. 14

Kleber, G. 45 Klump, B. 50 Koch, K. 13 Kohler, S. 57 Kornek, G. 39 Koumarianou, A. 52 Koumpou, M. 52 Kouroussis, C. 56 Kretzschmar, A. 36 Krishnamurthi, S.S. 14 Kroening, H. 34 Kubicka, S. 22 Kulke, M.H. 35 Kunslinger, F. 37, 40 Kuo, T. 17 Kupsch, P. 15 Kuss, O. 45 Labianca, R. 45 Lakhai, W.S. 13 Lambea, J. 42 Landi, B. 25 Langer, C. 20 Lasser, P. 44 Lastoria, S. 44 Laurent, D. 24 Laurent, S. 25 Lawrence, D. 46 Lazzaro, A. 47 Lebwohl, D. 24 Lee, H.I. 32 Lee, J.L. 32 Lee, K.H. 32 Leichman, C.G. 46 Leichman, L.P. 46 Lenz, H. 51 Lenz, H.J. 18, 27, 33, León, A.I. 26 Leonard, G.D. 34 Leong, L. 51 Lerzo, G. 55 Lévi, F.A. 19, 35, 37, 40 Levy, E. 54 Li, X. 14 Liau, C.-T. 49 Lim, D. 51 Lin, C.-P. 28 Lin, Y.-C. 49 Linehan, D.C. 13 Llaurado, J. 43 Lledo, G. 19, 25, 25, 45 Llorca, C. 24 Lofts, F. 53 Löhr, J.M. 46 Lomas, M. 31 López-Gómez, L. 29 Lordick, F. 46 Lorusso, D. 54 Losa, F. 29 Lotz, J.P. 51, 53 Lou, F. 48 Lou, H.-Z. 48 Louvet, C. 38, 45 Ludovisi, M. 54 Mabro, M. 23 Machiels, J.-P. 40 Machover, D. 25, 55 Maestu, I. 24 Magherini, E. 39, 44 Mahyaoui, S. 39 Maindrault-Goebel, F. 23, 38 Maiorino, L. 32 Makowski, M. 50 Makrantonakis, N. 30 Makris, A. 43 Malka, D. 44 Mallik, N. 18 Maluf, F. 51 Mancarella, S. 32 Mandachain, M. 55 Mansourbakht, T. 50 Mantovani, L. 34 Manzano, H. 49 Manzano, J.L. 29 Manzione, L. 29, 54 Marcucci, L. 36, 38 Marcuello, E. 43 Marechal, R. 46 Marfà, X. 49, 52 Marijken, M. 46 Marone, P. 44 Marques, R. 51 Martin, A. 43 Martín-Algarra, S. 38 Martinelli, G.N. 40 Martínez, A. 43 Martinez, F. 28 Martinez-Balibrea, E. 29

60

Martinez-Cardus, A. 29 Martins, S. 51 Martoni, A. 40 Masi, G. 36, 38 Masri-Zada, R. 45 Masseroni, S. 31 Massidda, B. 32 Maughan, T. 41 Maurel, J. 26, 49 Mavroudis, D. 52 Mayer, I. 51 Mayer, R.J. 33, 41 Mazzocchi, M. 47 McCain, D.A. 40 McDonald, A. 41 McLeod, H.L. 13 Meade, A. 58 Mel Lorenzo, J.R. 25, 48 Meropol, N.J. 14 Mery-Mignard, D. 39 Metges, J.P. 47 Meyerhardt, J.A. 19, 35 Micari, C. 44 Michel, F. 23 Michelini, A. 35 Mickievicz, E. 55 Miedema, B.E. 41 Milaki, G. 52 Miller, L.L. 17 Mineur, L. 19, 23 Minni, F. 40 Mira, M. 42 Mirtsching, B.C. 33, 36 Misra, S.C. 55 Misset, J.L. 33 Mitchell, E.P. 20 Moehler, M. 45 Monden, M. 15 Montalar, J. 31 Monzo, M. 28 Mooney, M. 33 Moreno, I. 28 Moreno, J. 28 Moreno-Nogueira, J.A. 24 Morère, J.-F. 56 Morgan, B. 24 Morgan, R. 51 Mortensen, J.P. 35 Morton, R.F. 27 Mosby, K. 33 Moshidis, A. 30 Motwani, M.V. 15 Moukhtar, R. 23 Mueser, M. 17 Murad, M. 37 Murias, A. 26 Myint, S. 43 Naldini, A. 54 Nardoni, C. 31 Natale, D. 32 Natsiopoulos, I. 30 Nava, E. 46 Nava, H. 46 Navarro, A. 28 Navarro, M. 16 Needle, M.N. 33 Negru, E. 56 Nehls, O. 50 Neri, S. 40 Niedzwiecki, D. 41 Nikolaou, M. 52 Noordhuis, P. 27 Nordlinger, B. 39 Novotny, W. 18 Nuñez, L. 29 O’Connor, J. 32 O’Dwyer, P.J. 14 Oettle, H. 49, 50 Ogreid, D. 35 Ohue, M. 15 Onida, F. 43 Oprea, C. 44 Orlando, M. 55 Ourives, N. 37 Paillot, B. 22 Palladino, M. 47 Pan, H.-M. 48 Pandite, L. 13 Parc, R. 38 Pardo, F. 38 Paris, I. 54 Park, D. 18 Park, K.U. 32 Parmar, M. 58 Pascal, G. 37 Passarge, K. 15 Passera, R. 44

Onkologie 2004;27(suppl 1):59–60

Paty, P. 34 Paule, B. 13, 37 Paye, F. 38 Payrard, S. 39 Pecci, A.P. 42 Pectasides, D. 52 Pectasides, M. 52 Pederiva, S. 30 Peeters, M. 46 Pelzer, U. 49 Pendyala, L. 46 Pera, M. 49 Perez, J. 55 Perez, N. 25 Perillo, F. 42 Pernas, J. 43 Perrier, H. 22 Peters, G.J. 27 Petit, T. 53 Petrillo, A. 44 Pétriz, L. 43 Pfeiffer, P. 35 Phan, S. 16 Piazza, S. 56 Pinedo, H.M. 27 Pink, D. 36 Pinto, C. 40 Pinuaga, M. 28 Pippas, A.W. 33 Pirovano, M. 31 Pissanidis, N. 30 Pitot, H.R. 27 Pizza, C. 29 Pocard, M. 44 Poletti, S. 56 Pollak, M. 19 Pollera, C.F. 31 Polus, M. 46 Polyzos, A. 20, 52 Porschen, R. 22 Portier, G. 39 Poston, G. 39 Potamianou, A. 56 Pou, E. 28 Poynard, T. 50 Pozzo, C. 54 Press, O. 18 Priou, F. 22 Proulx, G. 46 Quenet, F. 39 Quinaux, E. 19 Quinn, S. 25 Quintè, A. 31 Quirke, P. 58 Racanelli, A. 15 Rahmouni, A. 55 Rakhit, A. 26 Ramanathan, R.K. 19, 21, 27 Ramnath, N. 16 Ranze, O. 28 Rau, K.-M. 49 Ravo, E. 44 Raymond, E. 33 Redondo, A. 43 Reggiardo, G. 29 Reichardt, P. 22 Reina, J.J. 24 Remick, S.C. 14 Reyes, F. 55 Ricci, P. 42 Ricci, S. 36, 38 Richardet, E. 55 Richel, D.J. 13 Richly, H. 15 Richman, S.D. 58 Riess, H. 49 Rinaldi, G. 12 Rivera, F. 25 Rivoire, M. 39 Rixe, O. 54 Rizzi, A. 47 Robert, R.V. 17 Roca, E. 32 Rodger, J. 55 Rodriguez, J. 38 Roll, L. 49 Romanelli, A. 31 Romano, R. 54 Romero, R. 24 Rosati, G. 29, 54 Rotellar, F. 38 Rovej, R. 43 Royston, P. 58 Ruiz de Lobera, A. 42 Russ, G. 19 Russo, A. 12 Ryan, D.P. 35, 41

Ryoo, H.-M. 32 Saenz, J.A.G. 48 Saintini, P. 13 Salazar, R. 49 Saleh, M. 30 Saltz, L.B. 17 Salud, A. 26, 29, 42 Samuel, L. 43 Sanchez, B. 43 Sánchez-Rovira, P. 24 Sancho, F. 43 Santini, D. 48 Santoro, A. 12 Sargent, D.J. 19, 27 Saridaki, Z. 52 Sarkar, S. 18 Sastre, J. 17 Sbrana, F. 42 Sburlati, P. 43 Scaglione, F. 31 Scalabrini-Neto, A.O. 37 Scalliet, P. 40 Scambia, G. 54 Scanni, A. 43 Schaapveld, M. 21 Scheithauer, W. 39 Schellens, J. 13 Schemerling, R. 51 Scheulen, M.E. 15 Schiaroli, G. 42 Schlichting, C. 34 Schmalenberg, H. 45 Schmidt, A.M. 14 Schmoll, H.-J. 22, 34 Schneider, S. 27 Schöffski, P. 23 Schuell, B. 39 Schwartz, B. 15 Schwartz, E.J. 17 Schwartz, G.K. 15 Schwartz, L. 34 Sebag-Montefiore, D. 41, 43 Sedeki, I. 47 Seeber, S. 15 Seipelt, G. 46 Seitz, J. 47 Sekimoto, M. 15 Selby, P. 58 Sempoux, C. 40 Sereno, M. 43 Seshimo, I. 15 Sestini, S. 31 Seufferlein, T. 22 Sevilla, I. 26 Seymour, M.T. 58 Shibata, S. 51 Shpilsky, A. 21 Signorelli, C. 31 Siragusa, A. 42 Sjak-Shie, N.N. 14 Smaaland, R. 19 Smorenburg, C.H. 27 Sole Monne, J. 28 Sørbye, H. 35 Souglakos, J. 20 Soulié, P. 17, 25 Spalletta, S. 48 Spano, J.-P. 13 Spinnato, F. 12 Starkhammar, H. 35 Stauch, M. 46 Steer, C.B. 53 Stella, P.J. 33 Stergiou, J. 56 Steward, W.P. 24 Stieler, J.M. 49 Strickland, A. 53 Stroszczynski, C. 36 Strumberg, D. 15 Sturm, I. 36 Sverdlin, R. 35 Syrigos, K. 56 Tabah-Fisch, I. 55 Tabernero, J. 16, 17, 23 Tabiadon, D. 31 Tafuto, S. 32 Taïeb, J. 38 Taieb, J. 50 Takayama, O. 15 Tanaka, K. 40 Taron, M. 29 Tatangelo, F. 44 Tecimer, C. 37 Teel, C. 36 Tejpar, S. 25 Tepper, J.E. 41 Testa, A.C. 54

Autorenindex

Testa, E. 48 Theodore, C. 51 Thomas, A. 24, 35 Thomas, H. 53 Thuss-Patience, P. 36 Tomirotti, M. 43 Tonini, G. 48 Topham, C. 16 Torazzo, R. 56 Tournigand, C. 25, 38 Trarbach, T. 24 Tres, A. 42 Tsavdaridis, D. 30 Tselepatiotis, E. 20, 56 Tubiana-Hulin, M. 12 Tubiana-Mathieu, N. 19 Tucci, A. 29 Tucci, E. 42 Turhal, N.S. 37 Tveit, K.M. 35 Twelves, C. 23 Ugolini, G. 40 Ulusakarya, A. 25, 55 Urien, S. 13 Valencia, J. 42 Valerio, M.R. 12 Valsecchi, R. 31 Van Belle, J.S. 53 Van Cutsem, E. 17, 23, 25, 26, 33 Van Groeningen, C.J. 27 Van Kooten, M. 55 Van Laethem, J.-L. 17, 46 Van Riel, J.M. 27 Vandone, A. 56 Vanhoefer, U. 24 Vardakis, N. 20 Vauthier, J.M. 25 Vena, D. 33 Verslype, C. 26 Versola, M. 13 Vicent, J. 31 Vicent, J.M. 24, 29, 48 Viens, P. 53 Vila, J.M. 28 Vincenzi, B. 48 Vincitore, M. 35 Vitali, M.L. 42 Viudez, A. 38 Vizzini, L. 12 Wadler, S. 41 Wagman, L. 51 Wagner, D. 45 Wakelee, H.A. 17 Wang, H.-M. 49 Wang, W.-Y. 28 Wang, Y. 47 Wardley, A. 12 Wasserman, E. 32 Watson, M.A. 13 Wein, A. 45 Welles, L. 21 Westermann, A.M. 13 White, L.A. 14 Wiedenmann, B. 24 Wiesemann, K. 15 Williamson, S.K. 19, 27 Wong, L. 21 Wu, Q. 47 Wu, X.J. 47 Xhu, A. 35 Yamamoto, H. 15 Yang, D. 18, 27 Yang, T.-S. 49 Yasui, M. 15 Yataghene, Y. 47, 51 Ychou, M. 39, 47 Yen, Y. 51 Yovine, A. 53 Yu, J. 13 Yu, Z. 47 Yubero, A. 29 Yumuk, P.F. 37 Yun, J. 18 Zacharchuk, C. 25 Zambelli, A. 12 Zaniboni, A. 45, 47 Zanon, C. 44 Zeuli, M. 31 Zhang, W. 18 Zheng, Y. 48 Zhong, X.N. 47 Zhu, N. 48 Ziotopoulos, P. 56 Ziras, N. 20, 56 Zwiebel, J. 33