Clinical and Translational Oncology

, Volume 14, Issue 5, pp 325–332 | Cite as

Advances in cutaneous melanoma

  • Enrique EspinosaEmail author
  • Alfonso Berrocal
  • José Antonio López Martín
  • María González Cao
  • Pablo Cerezuela
  • José Ignacio Mayordomo
  • Salvador Martín Algarra
Educational Series Advances in Translational Oncology


After several decades of slow progress in the field of melanoma, significant advances have been reported in recent years. These include a better understanding of the molecular biology of the tumour, a new staging classification system, insights into the patterns of relapse in early stage, and new drugs for the treatment of advanced disease. Ipilimumab and vemurafenib have just been approved and provide a survival benefit in stage IV. Both compounds are under evaluation in the adjuvant setting, where interferon remains the only drug with proven efficacy. Further investigation is required to treat patients with primary or secondary resistance to new drugs.


Melanoma BRAF mutation Interferon Ipilimumab Vemurafenb 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    MacKie RM, Hauschild A, Eggermont AM (2009) Epidemiology of invasive cutaneous melanoma. Ann Oncol 20[Suppl 6]:vi1–7PubMedCrossRefGoogle Scholar
  2. 2.
    Balch CM, Gershenwald JE, Soong SJ et al (2009) Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 27:6199–6206PubMedCrossRefGoogle Scholar
  3. 3.
    Lin WM, Baker AC, Beroukhim R et al (2008) Modeling genomic diversity and tumor dependency in malignant melanoma. Cancer Res 68:664–673PubMedCrossRefGoogle Scholar
  4. 4.
    Edlundh-Rose E, Egyhazi S, Omholt K et al (2006) NRAS and BRAF mutations in melanoma tumours in relation to clinical characteristics: a study based on mutation screening by pyrosequencing. Melanoma Res 16:471–478PubMedCrossRefGoogle Scholar
  5. 5.
    Gorden A, Osman I, Gai W et al (2003) Analysis of BRAF and N-RAS mutations in metastatic melanoma tissues. Cancer Res 63:3955–3957PubMedGoogle Scholar
  6. 6.
    Maldonado JL, Fridlyand J, Patel H et al (2003) Determinants of BRAF mutations in primary melanomas. J Natl Cancer Inst 95:1878–1890PubMedCrossRefGoogle Scholar
  7. 7.
    Handolias D, Salemi R, Murray W et al (2010) Mutations in KIT occur at low frequency in melanomas arising from anatomical sites associated with chronic and intermittent sun exposure. Pigment Cell Melanoma Res 23:210–215PubMedCrossRefGoogle Scholar
  8. 8.
    Harbour JW, Onken MD, Roberson ED et al (2010) Frequent mutation of BAP1 in metastasizing uveal melanomas. Science 330:1410–1413PubMedCrossRefGoogle Scholar
  9. 9.
    Romano E, Scordo M, Dusza SW et al (2010) Site and timing of first relapse in stage III melanoma patients: implications for follow-up guidelines. J Clin Oncol 28:3042–3047PubMedCrossRefGoogle Scholar
  10. 10.
    Turner RM, Bell KJ, Morton RL et al (2011) Optimizing the frequency of follow-up visits for patients treated for localized primary cutaneous melanoma. J Clin Oncol 29:4641–4646PubMedCrossRefGoogle Scholar
  11. 11.
    Wheatley K, Ives N, Hancock B et al (2003) Does adjuvant interferon-alpha for high-risk melanoma provide a worthwhile benefit? A meta-analysis of the randomised trials. Cancer Treat Rev 29:241–252PubMedCrossRefGoogle Scholar
  12. 12.
    Mocellin S, Pasquali S, Rossi CR, Nitti D (2010) Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst 102:493–501PubMedCrossRefGoogle Scholar
  13. 13.
    Pirard D, Heenen M, Melot C, Vereecken P (2004) Interferon alpha as adjuvant postsurgical treatment of melanoma: a meta-analysis. Dermatology 208:43–48PubMedCrossRefGoogle Scholar
  14. 14.
    Hauschild A, Weichenthal M, Rass K et al (2010) Efficacy of low-dose interferon {alpha}2a 18 versus 60 months of treatment in patients with primary melanoma of >=1.5 mm tumor thickness: results of a randomized phase III DeCOG trial. J Clin Oncol 28:841–846PubMedCrossRefGoogle Scholar
  15. 15.
    Eggermont AM, Suciu S, Santinami M et al (2008) 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 372:117–126PubMedCrossRefGoogle Scholar
  16. 16.
    Eggermont AM, Suciu S, Testori A et al (2012) Ulceration and stage are predictive of interferon efficacy in melanoma: results of the phase III adjuvant trials EORTC 18952 and EORTC 18991. Eur J Cancer 48:218–225PubMedCrossRefGoogle Scholar
  17. 17.
    Eggermont AM, Suciu S, MacKie R et al (2005) 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 366:1189–1196PubMedCrossRefGoogle Scholar
  18. 18.
    Lawson D, Lee S, Tarhini AA et al (2010) E4697: phase III cooperative group study of yeast-derived granulocyte macrophage colony-stimulating factor (GM-CSF) versus placebo as adjuvant treatment of patients with completely resected stage III–IV melanoma. In: Proc Am Soc Clin Oncol abs 8504Google Scholar
  19. 19.
    Tsao H, Atkins MB, Sober AJ (2004) Management of cutaneous melanoma. N Engl J Med 351:998–1012PubMedCrossRefGoogle Scholar
  20. 20.
    Lee ML, Tomsu K, Von Eschen KB (2000) Duration of survival for disseminated malignant melanoma: results of a meta-analysis. Melanoma Res 10:81–92PubMedGoogle Scholar
  21. 21.
    Patel PM, Suciu S, Mortier L et al (2011) Extended schedule, escalated dose temozolomide versus dacarbazine in stage IV melanoma: final results of a randomised phase III study (EORTC 18032). Eur J Cancer 47:1476–1483PubMedCrossRefGoogle Scholar
  22. 22.
    Avril MF, Aamdal S, Grob JJ et al (2004) Fotemustine compared with dacarbazine in patients with disseminated malignant melanoma: a phase III study. J Clin Oncol 22:1118–1125PubMedCrossRefGoogle Scholar
  23. 23.
    Hersh EM, O’Day SJ, Ribas A et al (2010) A phase 2 clinical trial of nab-paclitaxel in previously treated and chemotherapy-naive patients with metastatic melanoma. Cancer 116:155–163PubMedGoogle Scholar
  24. 24.
    Atkins MB, Hsu J, Lee S et al (2008) 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 26:5748–5754PubMedCrossRefGoogle Scholar
  25. 25.
    Kottschade LA, Suman VJ, Amatruda T 3rd et al (2011) A phase II trial of nab-paclitaxel (ABI-007) and carboplatin in patients with unresectable stage IV melanoma: a North Central Cancer Treatment Group Study, N057E(1). Cancer 117: 1704–1710PubMedCrossRefGoogle Scholar
  26. 26.
    Robert C, Ghiringhelli F (2009) What is the role of cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma? Oncologist 14:848–861PubMedGoogle Scholar
  27. 27.
    Peggs KS, Quezada SA, Korman AJ, Allison JP (2006) Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. Curr Opin Immunol 18:206–213PubMedCrossRefGoogle Scholar
  28. 28.
    Hodi FS, O’Day SJ, McDermott DF et al (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363: 711–723PubMedCrossRefGoogle Scholar
  29. 29.
    Robert C, Thomas L, Bondarenko I et al (2011) Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 364: 2517–2526PubMedCrossRefGoogle Scholar
  30. 30.
    Wolchok JD, Hoos A, O’Day S et al (2009) Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 15:7412–7420PubMedCrossRefGoogle Scholar
  31. 31.
    Ribas A (2010) Clinical development of the anti-CTLA-4 antibody tremelimumab. Semin Oncol 37:450–454PubMedCrossRefGoogle Scholar
  32. 32.
    Tarhini AA (2010) Phase II evaluation of tremelimumab (Treme) combined with high-dose interferon alpha-2b (HDI) for metastatic melanoma. In: Proc Am Soc Clin Oncol abs 8524Google Scholar
  33. 33.
    Eggermont AM, Robert C (2011) New drugs in melanoma: it’s a whole new world. Eur J Cancer 47:2150–2157PubMedCrossRefGoogle Scholar
  34. 34.
    Brahmer JR, Drake CG, Wollner I et al (2010) Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 28:3167–3175PubMedCrossRefGoogle Scholar
  35. 35.
    Lee JT, Li L, Brafford PA et al (2010) PLX4032, a potent inhibitor of the B-Raf V600E oncogene, selectively inhibits V600E-positive melanomas. Pigment Cell Melanoma Res 23:820–827PubMedCrossRefGoogle Scholar
  36. 36.
    Yang H, Higgins B, Kolinsky K et al (2010) RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res 70:5518–5527PubMedCrossRefGoogle Scholar
  37. 37.
    Ribas A (2010) BRIM-2: an open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAF V600E mutation-positive metastatic melanoma. In Proc Am Soc Clin Oncol abs 8509Google Scholar
  38. 38.
    Sosman JA, Kim K, Schuchter L et al (2012) Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N Egl J Med 366:707–714CrossRefGoogle Scholar
  39. 39.
    Chapman PB, Hauschild A, Robert C et al (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364:2507–2516PubMedCrossRefGoogle Scholar
  40. 40.
    Kefford R (2010) Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumors. In Proc Am Soc Clin Oncol abs 8503Google Scholar
  41. 41.
    Wagle N, Emery C, Berger MF et al (2011) Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J Clin Oncol 29:3085–3096PubMedCrossRefGoogle Scholar
  42. 42.
    Nazarian R, Shi H, Wang Q et al (2010) Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468:973–977PubMedCrossRefGoogle Scholar
  43. 43.
    Johannessen CM, Boehm JS, Kim SY et al (2010) COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468:968–972PubMedCrossRefGoogle Scholar
  44. 44.
    Poulikakos PI, Persaud Y, Janakiraman M et al (2011) RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 480:387–390PubMedCrossRefGoogle Scholar
  45. 45.
    Villanueva J, Vultur A, Lee JT et al (2010) Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 18:683–695PubMedCrossRefGoogle Scholar
  46. 46.
    Yancovitz M, Litterman A, Yoon J et al (2012) Intra- and inter-tumor heterogeneity of BRAF mutations in primary and metastatic melanoma. PLoS One 7:e29336PubMedCrossRefGoogle Scholar
  47. 47.
    Infante J (2011) Phase I/II study to assess safety, pharmacokinetics, and efficacy of the oral MEK 1/2 inhibitor GSK1120212 dosed in combination with the oral BRAF inhibitor GSK2118436. In Proc Am Soc Clin Oncol abs 8503Google Scholar
  48. 48.
    Beadling C, Jacobson-Dunlop E, Hodi FS et al (2008) KIT gene mutations and copy number in melanoma subtypes. Clin Cancer Res 14:6821–6828PubMedCrossRefGoogle Scholar
  49. 49.
    Guo J, Si L, Kong Y et al (2011) Phase II, openlabel, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol 29:2904–2909PubMedCrossRefGoogle Scholar
  50. 50.
    Carvajal RD, Antonescu CR, Wolchok JD et al (2011) KIT as a therapeutic target in metastatic melanoma. JAMA 305:2327–2334PubMedCrossRefGoogle Scholar
  51. 51.
    Creagan ET, Dalton RJ, Ahmann DL et al (1995) Randomized, surgical adjuvant clinical trial of recombinant interferon alfa-2a in selected patients with malignant melanoma. J Clin Oncol 13:2776–2783PubMedGoogle Scholar
  52. 52.
    Kirkwood JM, Strawderman MH, Ernstoff MS et al (1996) Interferon alfa-2b adjuvant therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology Group Trial EST 1684. J Clin Oncol 14:7–17PubMedGoogle Scholar
  53. 53.
    Kirkwood JM, Ibrahim JG, Sondak VK et al (2000) High- and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol 18:2444–2458PubMedGoogle Scholar
  54. 54.
    Kirkwood JM, Ibrahim JG, Sosman JA et al (2001) 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 19:2370–2380PubMedGoogle Scholar
  55. 55.
    Agarwala SS (2011) Randomized phase III trial of high-dose interferon alfa-2b for 4 weeks induction only in patients with intermediate and high-risk melanoma. In Proc Am Soc Clin Oncol abs 8505Google Scholar
  56. 56.
    Hauschild A, Weichenthal M, Rass K et al (2009) Prospective randomized multicenter adjuvant dermatologic cooperative oncology group trial of low-dose interferon alfa-2b with or without a modified high-dose interferon alfa-2b induction phase in patients with lymph node-negative melanoma. J Clin Oncol 27:3496–3502PubMedCrossRefGoogle Scholar
  57. 57.
    Hansson J, Aamdal S, Bastholt L et al (2011) Two different durations of adjuvant therapy with intermediate-dose interferon alfa-2b in patients with high-risk melanoma (Nordic IFN trial): a randomised phase 3 trial. Lancet Oncol 12:144–152PubMedCrossRefGoogle Scholar
  58. 58.
    Pehamberger H, Soyer HP, Steiner A et al (1998) Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. Austrian Malignant Melanoma Cooperative Group. J Clin Oncol 16:1425–1429PubMedGoogle Scholar
  59. 59.
    Grob JJ, Dreno B, de la Salmoniere P et al (1998) Randomised trial of interferon alpha-2a as adjuvant therapy in resected primary melanoma thicker than 1.5 mm without clinically detectable node metastases. French Cooperative Group on Melanoma. Lancet 351:1905–1910PubMedCrossRefGoogle Scholar
  60. 60.
    Hancock BW, Wheatley K, Harris S et al (2004) 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 22:53–61PubMedCrossRefGoogle Scholar
  61. 61.
    Garbe C, Radny P, Linse R et al (2008) Adjuvant low-dose interferon {alpha}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 19:1195–1201PubMedCrossRefGoogle Scholar
  62. 62.
    Cascinelli N, Belli F, MacKie RM et al (2001) Effect of long-term adjuvant therapy with interferon alpha-2a in patients with regional node metastases from cutaneous melanoma: a randomised trial. Lancet 358:866–869PubMedCrossRefGoogle Scholar

Copyright information

© Feseo 2012

Authors and Affiliations

  • Enrique Espinosa
    • 1
    • 2
    Email author
  • Alfonso Berrocal
    • 2
  • José Antonio López Martín
    • 2
  • María González Cao
    • 2
  • Pablo Cerezuela
    • 2
  • José Ignacio Mayordomo
    • 2
  • Salvador Martín Algarra
    • 2
  1. 1.Service of OncologyHospital La PazMadridSpain
  2. 2.Grupo Español de Melanoma (GEM)MadridSpain

Personalised recommendations