Treatment for metastatic malignant melanoma: Old drugs and new strategies

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Abstract

The number of melanoma cases worldwide is increasing faster than any other cancer and remains one of the most treatment-refractory malignancies. Despite decades of clinical trials testing chemotherapy and immunotherapy, a standard first-line treatment for metastatic melanoma has not yet been established; tough single agent dacarbazine represents the most common option. This review will focus on metastatic malignant melanoma treatment from single agent until new therapies. An overview of established chemotherapies and immunotherapies, followed by a summary of trials testing the potential combination and new agent are explored.

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.

References (123)

  • M.R. Middleton et al.

    Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma

    J Clin Oncol

    (2000)
  • E.S. Newlands et al.

    Phase I trial of temozolomide (CCRG 81045: M&B 39831: NSC 362856)

    Br J Cancer

    (1992)
  • D.L. Ahmann

    Nitrosoureas in the management of disseminated malignant melanoma

    Cancer Treat Rep

    (1976)
  • C. Jacquillat et al.

    Final report of the French multicenter phase II study of the nitrosourea fotemustine in 153 evaluable patients with disseminated malignant melanoma including patients with cerebral metastases

    Cancer

    (1990)
  • D. Khayat et al.

    Fotemustine in the treatment of brain primary tumors and metastases

    Cancer Invest

    (1994)
  • M.F. Avril et al.

    Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study

    J Clin Oncol

    (2004)
  • D. Glover et al.

    WR-2721 and high-dose cisplatin: an active combination in the treatment of metastatic melanoma

    J Clin Oncol

    (1987)
  • L.M. Evans et al.

    Phase II trial of carboplatin in advanced malignant melanoma

    Cancer Treat Rep

    (1987)
  • M.Q. Mohammed et al.

    Oxaliplatin is active in vitro against human melanoma cell lines: comparison with cisplatin and carboplatin

    Anticancer Drugs

    (2000)
  • J. Lutzky et al.

    Phase II trial of oxaliplatin in patients with advanced melanoma

    J Clin Oncol

    (2006)
  • J.M. Quagliana et al.

    Vindesine in patients with metastatic malignant melanoma: a Southwest Oncology Group study

    J Clin Oncol

    (1984)
  • A.Y. Bedikian et al.

    Phase II trial of docetaxel in patients with advanced cutaneous malignant melanoma previously untreated with chemotherapy

    J Clin Oncol

    (1995)
  • A.I. Einzig et al.

    A phase II study of taxol in patients with malignant melanoma

    Invest New Drugs

    (1991)
  • S.S. Agarwala et al.

    Results from a randomized phase III study comparing combined treatment with histamine dihydrochloride plus interleukin-2 versus interleukin-2 alone in patients with metastatic melanoma

    J Clin Oncol

    (2002)
  • P. Rumke et al.

    Tamoxifen as a single agent for advanced melanoma in postmenopausal women. A phase II study of the EORTC Malignant Melanoma Cooperative Group

    Melanoma Res

    (1992)
  • J.J. Costanzi et al.

    Combination chemotherapy for disseminated malignant melanoma

    Cancer

    (1975)
  • W.S. Fletcher et al.

    Evaluation of cis-platinum and DTIC combination chemotherapy in disseminated melanoma. A Southwest Oncology Group Study

    Am J Clin Oncol

    (1988)
  • D.A. Vorobiof et al.

    Combination chemotherapy with dacarbazine and vindesine in the treatment of metastatic malignant melanoma

    Cancer Treat Rep

    (1986)
  • S.S. Legha et al.

    A prospective evaluation of a triple-drug regimen containing cisplatin, vinblastine, and dacarbazine (CVD) for metastatic melanoma

    Cancer

    (1989)
  • A.C. Buzaid et al.

    Cisplatin, vinblastine and dacarbazine (CVD) versus dacarbazine alone in metastatic melanoma: preliminary results of a phase II Cancer Community Oncology Program (CCOP) Trial

    J Clin Oncol

    (1993)
  • E.F. McClay et al.

    Tamoxifen delays the development of resistance to cisplatin in human melanoma and ovarian cancer cell lines

    Br J Cancer

    (1994)
  • S.C. Lattanzi et al.

    Dacarbazine, cisplatin and carmustine, with or without tamoxifen, for metastatic melanoma: 5-year follow-up

    Melanoma Res

    (1995)
  • G. Cocconi et al.

    Treatment of metastatic malignant melanoma with dacarbazine plus tamoxifen

    N Engl J Med

    (1992)
  • E.F. McClay et al.

    The importance of tamoxifen to a cisplatin-containing regimen in the treatment of metastatic melanoma

    Cancer

    (1989)
  • E.F. McClay et al.

    Effective combination chemo/hormonal therapy for malignant melanoma: experience with three consecutive trials

    Int J Cancer

    (1992)
  • J.J. Rusthoven et al.

    Randomized, double-blind, placebo-controlled trial comparing the response rates of carmustine, dacarbazine, and cisplatin with and without tamoxifen in patients with metastatic melanoma. National Cancer Institute of Canada Clinical Trials Group

    J Clin Oncol

    (1996)
  • C.I. Falkson et al.

    Phase III trial of dacarbazine versus dacarbazine with interferon alpha-2b versus dacarbazine with tamoxifen versus dacarbazine with interferon alpha-2b and tamoxifen in patients with metastatic malignant melanoma: an Eastern Cooperative Oncology Group study

    J Clin Oncol

    (1998)
  • R.D. Rao et al.

    Combination of paclitaxel and carboplatin as second-line therapy for patients with metastatic melanoma

    Cancer

    (2006)
  • M. Huncharek et al.

    Single-agent DTIC versus combination chemotherapy with or without immunotherapy in metastatic melanoma: a meta-analysis of 3273 patients from 20 randomized trials

    Melanoma Res

    (2001)
  • S.A. Rosenberg et al.

    Cancer immunotherapy: moving beyond current vaccines

    Nat Med

    (2004)
  • J.W. Slaton et al.

    Interferon-alpha-mediated down-regulation of angiogenesis-related genes and therapy of bladder cancer are dependent on optimization of biological dose and schedule

    Clin Cancer Res

    (1999)
  • A. Hakansson et al.

    Effect of IFN-alpha on tumor-infiltrating mononuclear cells and regressive changes in metastatic malignant melanoma

    J Interferon Cytokine Res

    (1998)
  • S.S. Agarwala et al.

    Interferons in melanoma

    Curr Opin Oncol

    (1996)
  • S.S. Agarwala et al.

    Potential uses of interferon alpha 2 as adjuvant therapy in cancer

    Ann Surg Oncol

    (1995)
  • M. Feldmann

    Cell cooperation in the antibody response

  • M.B. Atkins

    Interleukin-2 in metastatic melanoma: establishing a role

    Cancer J Sci Am

    (1997)
  • M.B. Atkins et al.

    High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993

    J Clin Oncol

    (1999)
  • R.O. Dillman et al.

    Long-term survival after continuous infusion interleukin-2

    Cancer Biother Radiopharm

    (1997)
  • D.R. Parkinson et al.

    Interleukin-2 therapy in patients with metastatic malignant melanoma: a phase II study

    J Clin Oncol

    (1990)
  • S.A. Rosenberg et al.

    Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients

    Ann Surg

    (1989)
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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.

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