Treatment for metastatic malignant melanoma: Old drugs and new strategies
Section snippets
Single agent chemotherapy
Chemotherapeutic agents are cytotoxic anticancer drugs that impair cell division, resulting in the death of rapidly dividing cells. They are widely used in the treatment of malignancies; however, melanoma is resistant to many forms of traditional chemotherapy. A large number of clinical trials have tested different single drug-like alkylating agents, nitrosureas, vinca alkaloids, platinum drugs, taxanes, topoisomerase inhibitors, and anthracyclines (Table 1), but few have shown an objective
Multi-drug combinations
The disappointing results with single agent chemotherapy led to the evaluation of multi-drug combinations regimens in the 1980s in efforts to improve outcome and enhance response rates in patients with metastatic disease. A listing of major randomized studies evaluating DTIC vs drug combination is summarized in Table 2. Initial combinations added nitrosourea, vinka alkaloids, or platinum compounds to DTIC. The majority of those trials have failed to demonstrate any significant benefit for
What about immunotherapies?
The relationship between melanoma and the immune system has been recognized for decades. Case reports of spontaneous tumor regression in patients with metastatic melanoma have suggested that immunotherapy might have a higher impact on the outcome of metastatic melanoma than in other cancers. This has led to intensive studies of immune-based treatment strategies with biologic response modifiers (cytokines) especially interleukin-2 and interferon-α witch have important roles in both adjuvant
Interferon-alpha (IFN-α)
Several studies have demonstrated that IFN-α has antiproliferative and immunomodulatory effects, including the inhibition of angiogenesis [39], the increase of major histocompatability complex class I antigen expression and the infiltration of CD4+ T cells into melanomas [40]. In a metastatic situation, single agent IFN-α showed approximately 15% of responses with less than 5% of complete response rates and median response duration between 6 and 9 months with a maximum of 12 months for the best
Interleukin-2
Initially, IL-2, a natural product secreted by CD4+ T lymphocytes, was described as a T cell growth factor, which plays a central role in immune regulation. However, IL-2 can also modulate immunological effects by stimulating HLA-restricted or non-restricted cytotoxic cell, activate natural killer cells, B lymphocytes, macrophages and induce lymphokine-activated killer cells in vitro as well as the production of other cytokines [43]. In initial clinical studies, a bolus I.V. infusion of
Combination of IFN-α and IL-2
Encouraged by the results of the high-dose IL-2 data, efforts have been made to combine IL-2 with IFN-α. This association did not seem to achieve better results (median response rate of 18% with three complete response) than if these agents were given alone [61], [62], [63]. By contrast, in a small randomized phase III trial comparing continuous infusion IL-2 plus interferon vs continuous infusion decrescendo IL-2 plus interferon, Keilholtz et al. [64], demonstrated improved response rates and
Moving on to biochemotherapy
Because chemotherapy and cytokines have different and perhaps synergistic mechanisms of action and in order to improve response rates and durable remissions, several teams including our group developed in the early 1990s the concept of biochemotherapy, a combination of chemotherapy and biologic response modifiers [67], [68], [69], [70], [71], [72], [73], [74]. A listing of major randomized studies of biochemotherapy is summarized in Table 3.
Dacarbazine/IFN-α combinations are one of the most
Investigational and new agents
A number of new agents and combination have entered clinical trials with promising results in melanoma and we will resume some of them; lenalidomide (initially known as CC-5013; ImiDS or Revlimid) is a thalidomide derivative designed to be more effective and less toxic. In a phase I trial, it was found to be well tolerated in patients with metastatic melanoma and to produce immune activation [82]. Two randomized phase III trials of lenalidomide in patients with metastatic melanoma who had
Take home message
Metastatic melanoma has remained refractory to systemic treatment for decades. It is hoped that the therapeutic strategies for the patients with metastatic melanoma is entering a new era of exploration in the hope of identifying better therapies. To date, there are no markers that can help to evaluate which patients will or will not respond to any of the treatments available. Nevertheless, we are still faced with the need to make choices for care today. We should first consider participation in
Conflict of interest
The authors declare no conflict of interest with this paper is to be disclosed.
Reviewers
Prof. Alexander M.M. Eggermont, University Hospital Rotterdam, Department of Surgical Oncology, 301 Groene Hilledijk, NL-3075 EA Rotterdam, Netherlands.
Prof. Olivier Michielin & Dr. Roger Stupp, University of Lausanne/CHUV, CH-1011 Lausanne, Switzerland.
Acknowledgment
Authors would like to thank Francis CAJFINGER, MD for critical reading of the manuscript.
Dr. Roger Mouawad, was born in Lebanon; he received his Master of Science degree from the University of Paris 7, France. He studied tumor immunology at the IRSC at VilleJuif and obtains his PhD on 1988 from the University of Paris XII. His PhD thesis was on the production and characterization of monoclonal antibodies against cytokeratin and there use on oncology. He is the Professor of Biological Science and Head of Medical Oncology laboratory at the Hospital Pitié-Salpêtrière, Paris, France.
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Dr. Roger Mouawad, was born in Lebanon; he received his Master of Science degree from the University of Paris 7, France. He studied tumor immunology at the IRSC at VilleJuif and obtains his PhD on 1988 from the University of Paris XII. His PhD thesis was on the production and characterization of monoclonal antibodies against cytokeratin and there use on oncology. He is the Professor of Biological Science and Head of Medical Oncology laboratory at the Hospital Pitié-Salpêtrière, Paris, France. His main research interests include predictive factors of response to immunotherapy in melanoma patients and the development of phases I studies testing new agents in different tumors, including breast, colorectal, lung cancers and melanoma. He is working on the development of surrogate markers for new drugs in order to personalize patients treatments. He is the member of several scientific societies, including the European Tissue Culture Society, The FASEB, the American Society of Immunology and the World Immunological Society. He published over 40 papers in immunology and oncology, has made several oral presentations and is a very active poster presenter at different meetings including AACR, ASCO and FASEB societies.
Dr. Marie Sebert, was born in France and studied medicine at the University of Pierre et Marie Curie in Paris. She is currently doing a specialization in medical haematology/oncology at the Medical Oncology Department of the Salpetriere Hospital, in Paris.
Dr. Judith Michels, was born in France and studied medicine at the University of Pierre et Marie Curie in Paris. She is currently doing a specialization in medical haematology/oncology at the Medical Oncology Department of the Salpetriere Hospital, in Paris.
Dr. Joel Bloch was born in France and gained his medical degree at the University of Nice and went on to become an intern and resident in surgery. Currently he is responsible of the Clinical Research Unity at the Medical Oncology Department at the Salpetriere Hospital. His main interests include the development of phases I, II and III studies testing new agents in different tumors. He is working on the development of new imaging methodology.
Pr. Spano is currently Professor in the Department of Medical Oncology of Pr. David Khayat at the Pitie-Salpetriere Hospital in Paris, France. He holds a medical oncology fellowship from the Internat des hôpitaux de Paris, and has worked at the Curie Institute, the Rothschild Hospital, the Gustave-Roussy Institute, and St. Louis Hospital in Paris. He also participated in a clinical exchange program with the MD Anderson Cancer Center in Houston, Texas. President of the Association of fellows in Oncology (AERIO) in France, which he founded in 1996, and is also a member of several well-known oncology societies, including the American Association for cancer Research (AACR), the European Society for Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO). He is also active in the scientific committees of EUROCANCER and the International Congress of Anti-Cancer Treatment (ICACT). He also belongs to the JCO editorial committee and to the Bulletin of Cancer. Pr. Spano has published over 60 papers in haematology and oncology, has made several oral presentations at medical congresses, and is a very active poster presenter at the aforementioned medical societies. Pr. Spano obtained a PhD degree at the University of Paris in 2004. His PhD thesis was on EGFR, CXCR4 and PTEN as prognostic and predictive factors of metastases in oncogenesis. The title of his MD thesis is “Factors predictive of disease progression and death in aids-related Kaposi's sarcoma. His title of Professor of the Pierre et Marie Curie University was obtained in 2006.
David Khayat is Professor of Medicine and Head of Medical Oncology at the Hospital Pitié-Salpêtrière, Paris, France. He gained his medical degree at the University of Nice and went on to become intern and resident in oncology at the Paris hospitals. Professor Khayat also gained a Master of Science in tumor immunology from the University of Paris and went on to complete his PhD in tumor immunology at the University Pierre and Marie Curie, Paris. In addition to his current position, he is also Adjunct Professor of Medicine in the Department of Breast Diseases at the MD Anderson Cancer Center, University of Texas, Houston, United States. He was the President of the French National Cancer Institute (INCa) from December 2004 to August 2006 and is now Honorary President of this Institute. In 1998, he organised the French Federation of Medical Oncologists (FFOM) and was elected its first President, a post he held until 2001. He set up the Master of Excellence of Medicine in Oncology programme. Professor Khayat was one of the organisers of the World Summit Against Cancer, 2000 and 2001, and the Charter of Paris Against Cancer, 2000. He is member of several scientific societies, including the steering committee of the World Alliance of Cancer Research organisations and has been a member of the American Society of Clinical Oncology (ASCO) since 1987. He is Professor Emeritus of several institutions, including the Suzhou Institute for Onco-haematology in China and the Matsumoto University in Japan. Professor Khayat received the American Association for Cancer Research public service award in 2000 and was elected for a research grant from the Bristol–Myers–Squibb Foundation in 2000. He is a member of several editorial boards and is the associate editor of the Journal of Clinical Oncology and of Cancer.