Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Cytotoxic chemotherapy for metastatic melanoma

Jeffrey A Sosman, MD
Section Editor
Michael B Atkins, MD
Deputy Editor
Michael E Ross, MD


Although the incidence of malignant melanoma is increasing, most cases are diagnosed at an early stage. Surgical excision is curative in most cases of early stage disease, and patients at high risk of developing metastatic disease may benefit from adjuvant therapy with interferon alfa (IFNa) or ipilimumab [1]. (See "Initial surgical management of melanoma of the skin and unusual sites" and "Adjuvant therapy for cutaneous melanoma".)

Most patients with stage IV disease require systemic treatment (table 1A-B and table 2A-B). For patients with extracranial metastatic melanoma, cytotoxic chemotherapy historically was widely used in patients who were not candidates for therapy with high-dose interleukin-2 (IL-2), although this approach was never demonstrated to improve survival. However, with the development of new immunotherapy approaches and targeted therapy for BRAF-mutated tumors, chemotherapy is now generally limited to second- or third-line settings and is frequently omitted altogether.

The clinical role of cytotoxic chemotherapy, administered as a single agent, in combination chemotherapy regimens, or in combination with biological agents (IL-2, IFNa), will be reviewed here. An overview of the management of advanced melanoma is presented separately. (See "Overview of the management of advanced cutaneous melanoma".)


Approaches that have been shown to provide clinically important benefit for patients with disseminated melanoma in appropriately selected patients include immunotherapy with checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) or programmed cell death receptor 1 (PD-1), immunotherapy with high-dose interleukin-2 (IL-2), and therapy targeting the mitogen-activated protein (MAP) kinase pathway with BRAF and MEK inhibitors in patients whose tumors contain a V600 mutation in the BRAF gene (figure 1).

Cytotoxic chemotherapy does not have an established role in the management of patients with advanced melanoma. However, chemotherapy retains a role as therapy for patients whose disease can no longer be controlled with immunotherapy or targeted agents and who are not eligible or able to enroll in a clinical trial. Although chemotherapy has not been demonstrated to increase overall survival, combination regimens and single-agent chemotherapy have been associated with objective responses in a minority of patients. (See 'Combination regimens' below and 'Single-agent chemotherapy' below.)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Nov 28, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Cole BF, Gelber RD, Kirkwood JM, et al. Quality-of-life-adjusted survival analysis of interferon alfa-2b adjuvant treatment of high-risk resected cutaneous melanoma: an Eastern Cooperative Oncology Group study. J Clin Oncol 1996; 14:2666.
  2. Crosby T, Fish R, Coles B, Mason MD. Systemic treatments for metastatic cutaneous melanoma. Cochrane Database Syst Rev 2000; :CD001215.
  3. Atkins MB. The role of cytotoxic chemotherapeutic agents either alone or in combination with biological response modifiers. In: Molecular Diagnosis, Prevention & Therapy of Melanoma, Kirkwood JK (Ed), Marcel Dekker, New York 1997. p.219.
  4. Houghton AN, Legha S, Bajorin DF. Chemotherapy for metastatic melanoma. In: Cutaneous Melanoma, 2nd, Balch, Houghton, Milton, et al (Eds), JB Lippincott Company, Philadelphia p.498.
  5. Hill GJ 2nd, Krementz ET, Hill HZ. Dimethyl triazeno imidazole carboxamide and combination therapy for melanoma. IV. Late results after complete response to chemotherapy (Central Oncology Group protocols 7130, 7131, and 7131A). Cancer 1984; 53:1299.
  6. Stevens MF, Hickman JA, Langdon SP, et al. Antitumor activity and pharmacokinetics in mice of 8-carbamoyl-3-methyl-imidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (CCRG 81045; M & B 39831), a novel drug with potential as an alternative to dacarbazine. Cancer Res 1987; 47:5846.
  7. Middleton MR, Grob JJ, Aaronson N, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 2000; 18:158.
  8. Patel PM, Suciu S, Mortier L, et al. Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032). Eur J Cancer 2011; 47:1476.
  9. Avril MF, Aamdal S, Grob JJ, et al. Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol 2004; 22:1118.
  10. Leyvraz S, Piperno-Neumann S, Suciu S, et al. Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial. Ann Oncol 2014; 25:742.
  11. Glover D, Glick JH, Weiler C, et al. WR-2721 and high-dose cisplatin: an active combination in the treatment of metastatic melanoma. J Clin Oncol 1987; 5:574.
  12. Evans LM, Casper ES, Rosenbluth R. Phase II trial of carboplatin in advanced malignant melanoma. Cancer Treat Rep 1987; 71:171.
  13. Hersh EM, O'Day SJ, Ribas A, et al. A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma. Cancer 2010; 116:155.
  14. Hersh EM, Del Vecchio M, Brown MP, et al. A randomized, controlled phase III trial of nab-Paclitaxel versus dacarbazine in chemotherapy-naïve patients with metastatic melanoma. Ann Oncol 2015; 26:2267.
  15. Hersh E, et al. A phase III trial of nab-paclitaxel versus dacarbazine in chemotherapy-naive patients with metastatic melanoma: A subanalysis based on BRAF status (abstract 9030). American Society of Clinical Oncology 2013 meeting.
  16. Quagliana JM, Stephens RL, Baker LH, Costanzi JJ. Vindesine in patients with metastatic malignant melanoma: a Southwest Oncology Group study. J Clin Oncol 1984; 2:316.
  17. Aamdal S, Wolff I, Kaplan S, et al. Docetaxel (Taxotere) in advanced malignant melanoma: a phase II study of the EORTC Early Clinical Trials Group. Eur J Cancer 1994; 30A:1061.
  18. Bedikian AY, DeConti RC, Conry R, et al. Phase 3 study of docosahexaenoic acid-paclitaxel versus dacarbazine in patients with metastatic malignant melanoma. Ann Oncol 2011; 22:787.
  19. Chapman PB, Einhorn LH, Meyers ML, et al. Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma. J Clin Oncol 1999; 17:2745.
  20. Flaherty KT, Lee SJ, Zhao F, et al. Phase III trial of carboplatin and paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol 2013; 31:373.
  21. Hauschild A, Agarwala SS, Trefzer U, et al. Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma. J Clin Oncol 2009; 27:2823.
  22. Kim KB, Sosman JA, Fruehauf JP, et al. BEAM: a randomized phase II study evaluating the activity of bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated advanced melanoma. J Clin Oncol 2012; 30:34.
  23. Keilholz U, Goey SH, Punt CJ, et al. Interferon alfa-2a and interleukin-2 with or without cisplatin in metastatic melanoma: a randomized trial of the European Organization for Research and Treatment of Cancer Melanoma Cooperative Group. J Clin Oncol 1997; 15:2579.
  24. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al. Prospective randomized trial of the treatment of patients with metastatic melanoma using chemotherapy with cisplatin, dacarbazine, and tamoxifen alone or in combination with interleukin-2 and interferon alfa-2b. J Clin Oncol 1999; 17:968.
  25. Ridolfi R, Chiarion-Sileni V, Guida M, et al. Cisplatin, dacarbazine with or without subcutaneous interleukin-2, and interferon alpha-2b in advanced melanoma outpatients: results from an Italian multicenter phase III randomized clinical trial. J Clin Oncol 2002; 20:1600.
  26. Keilholz U, Punt CJ, Gore M, et al. Dacarbazine, cisplatin, and interferon-alfa-2b with or without interleukin-2 in metastatic melanoma: a randomized phase III trial (18951) of the European Organisation for Research and Treatment of Cancer Melanoma Group. J Clin Oncol 2005; 23:6747.
  27. Atkins MB, Hsu J, Lee S, et al. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial coordinated by the Eastern Cooperative Oncology Group. J Clin Oncol 2008; 26:5748.
  28. Eton O, Legha SS, Bedikian AY, et al. Sequential biochemotherapy versus chemotherapy for metastatic melanoma: results from a phase III randomized trial. J Clin Oncol 2002; 20:2045.
  29. Sasse AD, Sasse EC, Clark LG, et al. Chemoimmunotherapy versus chemotherapy for metastatic malignant melanoma. Cochrane Database Syst Rev 2007; :CD005413.
  30. Ives NJ, Stowe RL, Lorigan P, Wheatley K. Chemotherapy compared with biochemotherapy for the treatment of metastatic melanoma: a meta-analysis of 18 trials involving 2,621 patients. J Clin Oncol 2007; 25:5426.
  31. Antoine EC, Benhammouda A, Bernard A, et al. Salpêtrière Hospital experience with biochemotherapy in metastatic melanoma. Cancer J Sci Am 1997; 3 Suppl 1:S16.
  32. Legha SS, Ring S, Eton O, et al. Development and results of biochemotherapy in metastatic melanoma: the University of Texas M.D. Anderson Cancer Center experience. Cancer J Sci Am 1997; 3 Suppl 1:S9.
  33. Mousseau M, Khayat D, Benhammouda A, et al. Feasibility study of chemo-immunotherapy (Ch-IM) with cisplatin (CDDP) interleukin-2 (IL-2) and interferon alpha 2a (IFNa) on 14 melanoma brain metastases patients (pts) (abstract). Proc Am Soc Clin Oncol 1997; 16:1773a.
  34. Keilholz U, Conradt C, Legha SS, et al. Results of interleukin-2-based treatment in advanced melanoma: a case record-based analysis of 631 patients. J Clin Oncol 1998; 16:2921.
  35. Atkins MB, O'Boyle KR, Sosman JA, et al. Multiinstitutional phase II trial of intensive combination chemoimmunotherapy for metastatic melanoma. J Clin Oncol 1994; 12:1553.
  36. Tarhini AA, Kirkwood JM, Gooding WE, et al. Durable complete responses with high-dose bolus interleukin-2 in patients with metastatic melanoma who have experienced progression after biochemotherapy. J Clin Oncol 2007; 25:3802.
  37. McDermott DF, Atkins MB. More support for the judicious use of high-dose interleukin-2 in patients with advanced melanoma. J Clin Oncol 2007; 25:3791.
  38. Flaherty LE, Moon J, Atkins MB, et al.Phase III trial of high-dose interferon alpha-2b versus cisplatin, vinblastine, DTIC plus IL-2 and interferon in patients with high-risk melanoma (SWOG S0008): An intergroup study of CALGB, COG, ECOG, and SWOG (Abstract 8504). American Society of Clinical Oncology 2012 meeting.