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Skin Cancer pp 461-474 | Cite as

Systemic Therapy in Melanoma

  • Carmen Nuzzo
  • Maria Simona Pino
  • Francesco CognettiEmail author
Chapter
Part of the Current Clinical Pathology book series (CCPATH)

Abstract

The incidence of malignant melanoma (MM) is continuously rising, representing today the second most common cancer in women and the third in men younger than 40 years. Excisional surgery represents the primary treatment for MM. Adjuvant treatment for melanoma at high risk of recurrence is still debated. Interferon, observation, and inclusion in clinical trials are all valid options. Although several systematic reviews have shown that in patients at high risk of relapse therapy with INF produces a benefit in terms of disease-free survival (DFS) and overall survival (OS), the inclusion of these patients in clinical trials should be a priority. In the absence of such study protocols, the decision about the appropriateness of administering high-dose INF should be taken on individual basis after discussion of the potential benefits and side effects of the treatment. The prognosis of metastatic melanoma remains poor. Different chemotherapeutic agents, such as dacarbazine, temozolomide, and fotemustine, have shown clinical activity when used as single agent. No combination regimens have shown, in controlled, randomized studies, to hold a significant benefit in survival compared with single agents. More recently new molecules, such as inhibitors of BRAF (PLX4032, GSK2118438), and the anti-CTLA-4 monoclonal antibody, ipilimumab, have shown for the first time in 30 years of clinical trials to increase survival. Numerous other molecules are still under study, but the results are to be confirmed.

Keywords

Overall Survival Metastatic Melanoma Melanoma Patient BRAF Mutation Advanced Melanoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Glossary

Adjuvant therapy

is a treatment that is given in addition to the primary, main or initial treatment.

BRAF

is a human gene that makes a protein called B-Raf. The gene is also referred to as proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B1, while the protein is more formally known as serine/threonine-protein kinase B-Raf.

Interferon-alpha

is a pleiotropic cytokine belonging to type I IFN, currently used in cancer patients.

References

  1. 1.
    Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011;61(4):212–36.PubMedCrossRefGoogle Scholar
  2. 2.
    Corona R, Mele A, Amini M, et al. Interobserver variability on the histopathologic diagnosis of cutaneous melanoma and other pigmented skin lesions. J Clin Oncol. 1996;14(4):1218–23.PubMedGoogle Scholar
  3. 3.
    Eggermont AM, Gore M. Randomized adjuvant therapy trials in melanoma: surgical and systemic. Semin Oncol. 2007;34(6):509–15.PubMedCrossRefGoogle Scholar
  4. 4.
    Hauschild A. Adjuvant interferon alfa for melanoma: new evidence based treatment recommendations? Curr Oncol. 2009;16(3):3–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Kirkwood JM, Strawderman MH, Ernstoff MS, et al. Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol. 1996;14:7–17.PubMedGoogle Scholar
  6. 6.
    Kirkwood JM, Ibrahim JG, Sondak VK, et al. High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of inter-group trial E1690/S9111/C9190. J Clin Oncol. 2000;18:2444–58.PubMedGoogle Scholar
  7. 7.
    Kirkwood JM, Ibrahim JG, Sosman JA, et al. High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial E1694/S9512/C509801. J Clin Oncol. 2001;19:2370–80.PubMedGoogle Scholar
  8. 8.
    Eggermont AM, Suciu S, MacKie R, et al. Post-surgery adjuvant therapy with intermediate doses of interferon alfa 2b versus observation in patients with stage IIb/III melanoma (EORTC 18952): randomised controlled trial. Lancet. 2005;366:1189–96.PubMedCrossRefGoogle Scholar
  9. 9.
    Hancock BW, Wheatley K, Harris S, et al. Adjuvant interferon in high-risk melanoma: the AIM HIGH Study–United Kingdom Coordinating Committee on Cancer Research randomized study of adjuvant low-dose extended- duration interferon alfa-2a in high-risk resected malignant melanoma. J Clin Oncol. 2004;22:53–61.PubMedCrossRefGoogle Scholar
  10. 10.
    Cascinelli N, Belli F, MacKie RM, et al. Effect of long-term adjuvant therapy with interferon alpha-2a in patients with regional node metastases from cutaneous melanoma: a randomised trial. Lancet. 2001;358:866–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Cameron DA, Cornbleet MC, MacKie RM, et al. Adjuvant interferon alpha 2b in high risk melanoma—the Scottish study. Br J Cancer. 2001;84:1146–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Garbe C, Radny P, Linse R, et al. Adjuvant low-dose interferon_2a with or without dacarbazine compared with surgery alone: a prospective-randomized phase III DeCOG trial in melanoma patients with regional lymph node metastasis. Ann Oncol. 2008;19:1195–201.PubMedCrossRefGoogle Scholar
  13. 13.
    Eggermont AM, Suciu S, Santinami M, et al. Adjuvant therapy with pegylated interferon alfa-2b versus observation alone in resected stage III melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet. 2008;372:117–26.PubMedCrossRefGoogle Scholar
  14. 14.
    Eggermont AM, Suciu S, Santinami M, et al. EORTC 18911 phase III trial: long-term adjuvant pegylated interferon-α2b (PEG-IFN) versus observation in resected stage III melanoma: long-term results at 7.6 years follow-up. Program and abstracts of the 2011 American Society of Clinical Oncology Annual Meeting. 2011. Chicago. Abstract 8506b.Google Scholar
  15. 15.
    Lens MB, Dawes M. Interferon alpha therapy for malignant melanoma: a systematic review of randomized controlled trials. J Clin Oncol. 2002;20:1818–25.PubMedCrossRefGoogle Scholar
  16. 16.
    Wheatley K, Ives N, Hancock B, et al. Does adjuvant interferon alfa for high-risk melanoma provide a worthwhile benefit? A meta-analysis of the randomized trials. Cancer Treat Rev. 2003;29(4):241–52.PubMedCrossRefGoogle Scholar
  17. 17.
    Kirkwood JM, Manola J, Ibrahim J, et al. A pooled analysis of eastern cooperative oncology group and intergroup trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res. 2004;10:1670–7.PubMedCrossRefGoogle Scholar
  18. 18.
    Verma S, Quirt I, McCready D, et al. Systematic review of systemic adjuvant therapy for patients at high risk for recurrent melanoma. Cancer. 2006;106:1431–42.PubMedCrossRefGoogle Scholar
  19. 19.
    Eggermont AM, Testori A, Marsden J, et al. Utility of adjuvant systemic therapy in melanoma. Ann Oncol. 2009;20 Suppl 6:vi30–4.PubMedCrossRefGoogle Scholar
  20. 20.
    Mocellin S, Pasquali S, Rocci CR, et al. Interferon alpha adjuvant therapy in patients with high risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst. 2010;102:493–501.PubMedCrossRefGoogle Scholar
  21. 21.
    Spitler LE, Grossbard ML, Ernstoff MS. Adjuvant therapy of stage III and IV malignant melanoma using granulocyte-macrophage colony-stimulating factor. J Clin Oncol. 2000;18(8):1614–21.PubMedGoogle Scholar
  22. 22.
    Lawson DH, Lee SJ, Tarhiini AA, et al. Phase III cooperative group study of yeast-derived granulocyte macrophage colony-stimulating factor (GM-CSF) versus placebo as adjuvant treatment of patient with completely resected stage III-IV melanoma. J Clin Oncol (ASCO Annual Meeting Proceedings). 2010;28:abstract 8504.Google Scholar
  23. 23.
    Kruit WH, Suciu S, Dreno B, et al. Immunization with recombinant MAGE-A3 protein combined with adjuvant systems AS15 or AS02B in patients with unresectable and progressive metastatic cutaneous melanoma: a randomized open-label phase II study of the EORTC Melanoma Group (16032–18031). J Clin Oncol (ASCO Annual Meeting Proceedings). 2008;26:abstract 9065.Google Scholar
  24. 24.
    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;22:1118–25.PubMedCrossRefGoogle Scholar
  25. 25.
    Bedikian AY, Millward M, Pehamberger H, et al. Bcl-2 antisense (oblimersen sodium) plus dacarbazine in patients with advanced melanoma: the Oblimersen Melanoma Study Group. J Clin Oncol. 2006;24:4738–45.PubMedCrossRefGoogle Scholar
  26. 26.
    Schadendorf D, Ugurel S, Schuler-Thurner B, et al. Dacarbazine (DTIC) versus vaccination with autologous peptide-pulsed dendritic cells (DC) in first-line treatment of patients with metastatic melanoma: a randomized phase III trial of the DC study group of the DeCOG. Ann Oncol. 2006;17:563–70.PubMedCrossRefGoogle Scholar
  27. 27.
    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(1):158–66.PubMedGoogle Scholar
  28. 28.
    Patel PM, Suciu S, Mortier L, et al. Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV malignant melanoma: final results of the randomised phase III study (EORTC 18032). Ann Oncol. 2008;19:viii3, abstract LBA8.CrossRefGoogle Scholar
  29. 29.
    Margolin K, Atkins B, Thompson A, et al. Temozolomide and whole brain irradiation in melanoma metastatic to the brain: a phase II trial of the Cytokine Working Group. J Cancer Res Clin Oncol. 2002;128(4):214–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Atkins MB, Lotze MT, Dutcher JP, 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;17:2105–16.PubMedGoogle Scholar
  31. 31.
    Atkins MB. Interleukin-2 in metastatic melanoma: what is the current role? Cancer J Sci Am. 2000;6:S8–10.PubMedGoogle Scholar
  32. 32.
    Atkins MB, Kunkel L, Sznol M, et al. High-dose recombinant interleukin-2 therapy in patients with metastatic melanoma: long term survival update. Cancer J Sci Am. 2000;6:S11–4.PubMedGoogle Scholar
  33. 33.
    Peggs KS, Quezada SA, Korman AJ, et al. Principles and use of anti-CTLA4 antibody in human cancer. Curr Opin Immunol. 2006;18:206–13.PubMedCrossRefGoogle Scholar
  34. 34.
    Robert C, Ghiringhelli F. What is the role of cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma? Oncologist. 2009;14:848–61.PubMedGoogle Scholar
  35. 35.
    Read S, Malmstrom V, Powrie F. Cytotoxic T lymphocyte associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med. 2000;192:295–302.PubMedCrossRefGoogle Scholar
  36. 36.
    Tarhini A, Lo E, Monor DR. Releasing the brake on the immune system: ipilimumab in melanoma and other tumor. Cancer Biother Radiopharm. 2010;25:601–13.PubMedCrossRefGoogle Scholar
  37. 37.
    Hersh EM, O’Day SJ, Powderly J, et al. A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma. Invest New Drugs. 2010;29:489–98.PubMedCrossRefGoogle Scholar
  38. 38.
    O’Day SJ, Maio M, Chiarion-Sileni V, et al. Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. Ann Oncol. 2010;21:1712–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Wolchok JD, Neyns B, Linette G, et al. Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study. Lancet Oncol. 2010;11:155–64.PubMedCrossRefGoogle Scholar
  40. 40.
    Hersh EM, O’Day SJ, Powderly J, et al. A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma. Invest New Drugs. 2011;29:489–98.PubMedCrossRefGoogle Scholar
  41. 41.
    Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res. 2009;15:5591–8.PubMedCrossRefGoogle Scholar
  42. 42.
    Maio M, Lebbe´ C, Sileni VC, et al. Long-term survival in advanced melanoma patients treated with ipilimumab at 10 mg/kg: ongoing analyses from completed phase II trials[abstr]. Eur J Cancer. 2009;7(suppl):578, abstract P-9307.Google Scholar
  43. 43.
    Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412–20.PubMedCrossRefGoogle Scholar
  44. 44.
    Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:711–23.PubMedCrossRefGoogle Scholar
  45. 45.
    Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–26.PubMedCrossRefGoogle Scholar
  46. 46.
    Houben R, Becker JC, Kappel A, et al. Constitutive activation of the Ras-Raf signaling pathway in metastatic melanoma is associated with poor prognosis. J Carcinog. 2004;3:6.PubMedCrossRefGoogle Scholar
  47. 47.
    Long GV, Menzies AM, Nagrial AM, et al. Clinicopathologic correlates of BRAF mutation status in 207 consecutive patients with metastatic melanoma. J Clin Oncol (ASCO Annual Meeting Proceedings). 2010;28:abstract 8548.Google Scholar
  48. 48.
    Eisen T, Ahmand T, Flaherty KT, et al. Sorafenib in advanced melanoma: a phase II randomized discontinuation trial analysis. Br J Cancer. 2006;95:581–6.PubMedCrossRefGoogle Scholar
  49. 49.
    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;27:2823–30.PubMedCrossRefGoogle Scholar
  50. 50.
    Flaherty KT, Lee SJ, Schuchter LM, et al. Final results of E2603: a double-blind, randomized phase III trial comparing carboplatin/paclitaxel with or without sorafenib in metastatic melanoma. J Clin Oncol (ASCO Annual Meeting Proceedings). 2010;28:abstract 8511.Google Scholar
  51. 51.
    Garnett MJ, Marais R. Guilty as charged: B-RAF is a human oncogene. Cancer Cell. 2004;6:313–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809–19.PubMedCrossRefGoogle Scholar
  53. 53.
    Ribas A, Kim KB, Schuchter LM, et al. BRIM-2: an open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAFV600E mutation positive melanoma. J Clin Oncol (ASCO Annual Meeting Proceedings). 2011;29:abstract 8509.Google Scholar
  54. 54.
    Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507–16.PubMedCrossRefGoogle Scholar
  55. 55.
    Kefford RF, Arkenau H, Brown MP, et al. Phase I/II study of GSK 2118436, a selective inhibitor of oncogenic mutant BRAF kinase in patients with metastatic melanoma and other solid tumor. J Clin Oncol (ASCO Annual Meeting Proceedings). 2010;28:abstract 8503.Google Scholar
  56. 56.
    Long GV, Kefford RF, Carr PJA, et al. Phase 1/2 study of GSK2118436, a selective inhibitor of V600 mutant (mut) BRAF kinase: evidence of activity in melanoma brain metastases (mets). Ann Oncol. 2010;21:viii12.CrossRefGoogle Scholar
  57. 57.
    Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, Puzanov I, Hauschild A, Robert C, Algazi A, Mortier L, Tawbi H, Wilhelm T, Zimmer L, Switzky J, Swann S, Martin AM, Guckert M, Goodman V, Streit M, Kirkwood JM, Schadendorf D. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(11):1087–95.PubMedCrossRefGoogle Scholar
  58. 58.
    Poulikakos PI, Rosen N. Mutant BRAF melanomas: dependence and resistance. Cancer Cell. 2011;19:11–5.PubMedCrossRefGoogle Scholar
  59. 59.
    Solit DB, Rosen N. Resistance to B-RAF inhibition in melanoma. N Engl J Med. 2011;364:772–4.PubMedCrossRefGoogle Scholar
  60. 60.
    Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller Jr WH, Kaempgen E, Martín-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380(9839):358–65. doi: 10.1016/S0140-6736(12)60868-X. Epub 2012 Jun 25.PubMedCrossRefGoogle Scholar
  61. 61.
    Kirkwood JM, Bastholt L, Robert C, Sosman J, Larkin J, Hersey P, Middleton M, Cantarini M, Zazulina V, Kemsley K, Dummer R. Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin Cancer Res. 2012;18(2):555–67. doi: 10.1158/1078-0432.CCR-11-1491. Epub 2011 Nov 2. PMID:22048237 [PubMed - indexed for MEDLINE].PubMedCrossRefGoogle Scholar
  62. 62.
    LoRusso PM, Krishnamurthi SS, Rinehart JJ, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers. Clin Cancer Res. 2010;16:1924–37.PubMedCrossRefGoogle Scholar
  63. 63.
    Haura EB, Ricart AD, Larson TG, et al. A phase II study of PD-0325901, an oral MEK inhibitor, in previously treated patients with advanced non-small cell lung cancer. Clin Cancer Res. 2010;16:2450–7.PubMedCrossRefGoogle Scholar
  64. 64.
    Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D, METRIC Study Group. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367(2):107–14.PubMedCrossRefGoogle Scholar
  65. 65.
    Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris 3rd HA, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012;367(18):1694–703. doi: 10.1056/NEJMoa1210093. Epub 2012 Sep 29.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Carmen Nuzzo
    • 1
  • Maria Simona Pino
    • 1
  • Francesco Cognetti
    • 1
    Email author
  1. 1.Division of Medical Oncology “A”, Medical Oncology DepartmentNational Cancer Institute Regina ElenaRomeItaly

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