Chemoimmunotherapy with dacarbazine, cisplatin, interferon-alpha2b and interleukin-2 versus two cycles of dacarbazine followed by chemoimmunotherapy in patients with metastatic melanoma: A randomised phase II study of the European Organization for Research and Treatment of Cancer Melanoma Group
Introduction
The prognosis of patients with metastatic melanoma remains poor, with median overall survival times of around 9–11 months. The current reference treatment remains single agent dacarbazine, with response rates of approximately 15%. A benefit on overall survival has never been demonstrated.1 Many efforts have been made to improve on these results. The combined use of chemotherapy and immunotherapy has attracted much interest given the high response rates in small phase II studies at a time when the results of randomised phase III studies of chemotherapy versus chemoimmunotherapy were not yet available. Our group, the European Organization for Research and Treatment of Cancer (EORTC) Melanoma Cooperative Group, had just finished the accrual of a randomised study of dacarbazine, cisplatin, interferon-alpha (IFN-α) with or without interleukin-2 (IL-2),2 and two early conclusions were already possible. Firstly, chemoimmunotherapy regimens were accompanied by an increased toxicity compared to chemotherapy alone, and secondly, a significant part of patients would still not benefit from this treatment since more than one-third of patients discontinued treatment already after two cycles because of progressive disease (PD). We therefore were interested to answer the question whether patients who had a greater likelihood of responding to intensive chemoimmunotherapy could be identified.
This study was designed to evaluate the question whether it is possible to select patients for intensive chemoimmunotherapy by two cycles of dacarbazine monotherapy. This could imply that patients not responding to dacarbazine monotherapy would have a low probability of achieving a response on subsequent chemoimmunotherapy. The study was designed as a randomised phase II study of up to four cycles of chemoimmunotherapy versus two cycles of dacarbazine monotherapy followed irrespective of response by up to four cycles of chemoimmunotherapy.
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Patients and methods
Eligibility criteria and schedule of chemoimmunotherapy have been described elsewhere.2 Briefly, patients were eligible with histologically documented evidence of measurable metastatic cutaneous melanoma not amenable to curative surgery, age 18–70 years, Karnofsky performance status ⩾60%, life expectancy ⩾3 months, no prior therapy for metastatic disease with any of the study drugs, no chemotherapy ⩽3 months prior to study entry, no second malignancy except for adequately treated basal cell
Statistical considerations
The Simon one sample two stage design was used. The following hypothesis was made: 20% is the largest stabilisation rate after four cycles which, if true, implies that the therapeutic activity does not warrant further investigation, 40% is the target stabilisation rate which, if true, implies that the therapeutic activity does warrant further investigation. The statistical errors were α = 0.10, β = 0.05. The first test was performed after 21 patients had been randomised to each arm and were
Results
Between April and December 2000, a total of 46 patients were randomised (22 in arm A and 24 in arm B). At the interim analysis, 5 patients had reached stabilisation in arm A and 4 patients in arm B. Therefore, the accrual was continued as planned. At full accrual (August 2002), a total of 93 patients were entered into the study. Patient characteristics are shown in Table 1. Eighty-nine patients were eligible, 45 in arm A and 44 in arm B. Reasons for ineligibility were site of primary, serious
Discussion
In this study, we investigated whether two cycles of dacarbazine monotherapy could select for the subgroup of patients with metastatic melanoma that would benefit most from more intensive chemoimmunotherapy. As expected, toxicity was much lower for the first two cycles with dacarbazine compared with the 4-drug chemoimmunotherapy regimen.
Pretreatment with two cycles of dacarbazine monotherapy prior to a 4-drug chemoimmunotherapy regimen resulted in a stabilisation rate lower than the pre-set
Conflict of interest statement
Dr. C.J.A. Punt is on advisory boards and has received honoraria of Roche, Pfizer, Sanofi-Aventis and AstraZeneca.
Dr. U. Keilholz has received honoraria from Chiron and ScheringPlough: less than $10.000 and research funding from Chiron: less than $100.000. No stock ownership and others.
Dr. M. Gore has received honoraria for advisory boards and lectures from ScheringPlough.
Dr. A.M.M. Eggermont: none declared, Dr. J. Thomas: none declared, Dr. P. Patel: none declared, Dr. J. Koller: none
Acknowledgements
The following members of the EORTC Melanoma Group participated in this study: Dr. Punt (St. Radboud University Nijmegen Medical Center, Nijmegen), Dr. Gore (Royal Marsden Hospital, London), Dr. Koller (St. Johanns-Spital, Salzbourg), Drs. Kruit and Eggermont (Daniel den Hoed Cancer Center, Erasmus Medical Center Rotterdam), Dr. Keilholz (Hospital La Charité, Free University Berlin), Dr. Thomas (Gasthuisberg, Leuven), Dr. Patel (St. James’s University Hospital, Leeds), Dr. Lienard (Centre
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2014, Cancer Immunology, Immunotherapy
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A.M.M. and U.K. share last authorship.