Advertisement

Melanoma pp 483-498 | Cite as

Adjuvant Therapy of Melanoma

  • Elisabeth Eapen Paul
  • Sanjiv S. Agarwala
Chapter

Abstract

This chapter presents and discusses the historical perspective on adjuvant therapy for surgically resected melanoma.

While doing this, key aspects connected with adjuvant therapy such as the definition of “high-risk” melanoma, which patients would benefit from adjuvant therapy, and how perception of this has developed over time, are also analyzed.

Prognosis of melanoma is heavily dependent upon stage at diagnosis. Within the group thought to benefit from adjuvant treatment, those with “high-risk disease,” stage IIB–IIIC, the prognosis varies greatly. The evolution of stage III melanoma is discussed, as well as the newer tools such as Sentinel Lymph Node biopsies and tumor ulceration as a predictor of disease progression and response to adjuvant therapy.

The pivotal trials that first showed treatment benefit of adjuvant treatment are put into the context of staging techniques used at the time trials were performed.

Trials involving different IFN-α-2b regimens are discussed in depth as well as PEG-IFN-α-2b, with a description of the controversies surrounding both of these adjuvant treatments. The different regimens of interferon utilized in clinical trials, including high dose, low dose, intermediate dose, and pulsed doses, as well as abbreviated regimens are also explored.

Although interferon dominated the field of adjuvant treatment for melanoma for decades, a new treatment option is now available in the CTLA-4 inhibitor Ipilimumab. The trial leading up to FDA approval of this treatment as well as toxicities and side effects are reviewed.

Finally the future of adjuvant therapy of melanoma is considered, with a presentation of ongoing trials involving other checkpoint inhibitors such as the anti PD-1 agents Nivolumab and Pembrolizumab as well as targeted therapy with the BRAF-inhibitors Dabrafenib in combination with the MEK inhibitor Trametinib.

Keywords

Adjuvant Melanoma IFN-α-2b PEG IFN-α-2b Ipilimumab Checkpoint inhibitors BRAF inhibitors 

References

  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30.CrossRefGoogle Scholar
  2. 2.
    Balch CM, et al. Multivariate analysis of prognostic factors among 2,313 patients with stage III melanoma: comparison of nodal micrometastases versus macrometastases. J Clin Oncol. 2010;28(14):2452–9.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Agarwala SS. An update on pegylated IFN-α2b for the adjuvant treatment of melanoma. Expert Rev Anticancer Ther. 2012;12(11):1449–59.CrossRefPubMedGoogle Scholar
  4. 4.
    Balch CM, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009;27(36):6199–206.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Buzaid AC, et al. Critical analysis of the current American Joint Committee on Cancer staging system for cutaneous melanoma and proposal of a new staging system. J Clin Oncol. 1997;15(3):1039–51.CrossRefPubMedGoogle Scholar
  6. 6.
    Balch CM, et al. A multifactorial analysis of melanoma: III. Prognostic factors in melanoma patients with lymph node metastases (stage II). Ann Surg. 1981;193(3):377.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Balch CM. Cutaneous melanoma: prognosis and treatment results worldwide. In: Seminars in surgical oncology. Wiley Online Library; 1992.CrossRefPubMedGoogle Scholar
  8. 8.
    Calabro A, Singletary SE, Balch CM. Patterns of relapse in 1001 consecutive patients with melanoma nodal metastases. Arch Surg. 1989;124(9):1051–5.CrossRefPubMedGoogle Scholar
  9. 9.
    Gershenwald J, et al. The prognostic significance of microscopic tumor burden in 925 melanoma patients undergoing sentinel lymph node biopsy. Proc Am Soc Clin Oncol. 2000;19:551a.Google Scholar
  10. 10.
    Morton DL, et al. Improved long-term survival after lymphadenectomy of melanoma metastatic to regional nodes. Analysis of prognostic factors in 1134 patients from the John Wayne Cancer Clinic. Ann Surg. 1991;214(4):491.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Coit DG, Rogatko A, Brennan MF. Prognostic factors in patients with melanoma metastatic to axillary or inguinal lymph nodes. A multivariate analysis. Ann Surg. 1991;214(5):627.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Bevilacqua RG, et al. Axillary dissection in melanoma. Prognostic variables in node-positive patients. Ann Surg. 1990;212(2):125.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Drepper H, et al. The prognosis of patients with stage III melanoma prospective long-term study of 286 patients of the fachklinik hornheide. Cancer. 1993;71(4):1239–46.CrossRefPubMedGoogle Scholar
  14. 14.
    Cascinelli N, et al. Prognosis of skin melanoma with regional node metastases (stage II). J Surg Oncol. 1984;25(4):240–7.CrossRefPubMedGoogle Scholar
  15. 15.
    Balch CM, et al. Prognostic factors analysis of 17,600 melanoma patients: validation of the American Joint Committee on Cancer melanoma staging system. J Clin Oncol. 2001;19(16):3622–34.CrossRefPubMedGoogle Scholar
  16. 16.
    Eilber FR, et al. Adjuvant immunotherapy with BCG in treatment of regional-lymph-node metastases from malignant melanoma. N Engl J Med. 1976;294(5):237–40.CrossRefPubMedGoogle Scholar
  17. 17.
    Isaacs A, Lindenmann J. Virus interference. I. The interferon. Proc R Soc Lond B Biol Sci. 1957;147(927):258–67.CrossRefGoogle Scholar
  18. 18.
    Pestka S. The human interferons—from protein purification and sequence to cloning and expression in bacteria: before, between, and beyond. Arch Biochem Biophys. 1983;221(1):1–37.CrossRefPubMedGoogle Scholar
  19. 19.
    Moschos SJ, et al. Neoadjuvant treatment of regional stage IIIB melanoma with high-dose interferon alfa-2b induces objective tumor regression in association with modulation of tumor infiltrating host cellular immune responses. J Clin Oncol. 2006;24(19):3164–71.CrossRefPubMedGoogle Scholar
  20. 20.
    Wang W, et al. Impact of IFNα2b upon pSTAT3 and the MEK/ERK MAPK pathway in melanoma. Cancer Immunol Immunother. 2008;57(9):1315–21.CrossRefPubMedGoogle Scholar
  21. 21.
    Kortylewski M, Jove R, Yu H. Targeting STAT3 affects melanoma on multiple fronts. Cancer Metastasis Rev. 2005;24(2):315–27.CrossRefPubMedGoogle Scholar
  22. 22.
    Kirkwood JM, 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(1):7–17.CrossRefPubMedGoogle Scholar
  23. 23.
    Kirkwood JM, 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(5):1670–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Kirkwood JM, et al. High-and low-dose interferon alfa-2b in high-risk melanoma: first analysis of intergroup trial E1690/S9111/C9190. J Clin Oncol. 2000;18(12):2444–58.CrossRefPubMedGoogle Scholar
  25. 25.
    Livingston PO, et al. Improved survival in stage III melanoma patients with GM2 antibodies: a randomized trial of adjuvant vaccination with GM2 ganglioside. J Clin Oncol. 1994;12(5):1036–44.CrossRefPubMedGoogle Scholar
  26. 26.
    Livingston PO, et al. Characterization of IgG and IgM antibodies induced in melanoma patients by immunization with purified GM2 ganglioside. Cancer Res. 1989;49(24 Part 1):7045–50.PubMedGoogle Scholar
  27. 27.
    Kirkwood JM, 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(9):2370–80.CrossRefPubMedGoogle Scholar
  28. 28.
    Eggermont AM, et al. Adjuvant ganglioside GM2-KLH/QS-21 vaccination versus observation after resection of primary tumor >1.5 mm in patients with stage II melanoma: results of the EORTC 18961 randomized phase III trial. J Clin Oncol. 2013;31(30):3831–7.CrossRefPubMedGoogle Scholar
  29. 29.
    McMasters KM, et al. Final results of the sunbelt melanoma trial: a multi-institutional prospective randomized phase III study evaluating the role of adjuvant high-dose interferon alfa-2b and completion lymph node dissection for patients staged by sentinel lymph node biopsy. J Clin Oncol. 2016;34(10):1079–86.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Eggermont AM, et al. Long term follow up of the EORTC 18952 trial of adjuvant therapy in resected stage IIB–III cutaneous melanoma patients comparing intermediate doses of interferon-alpha-2b (IFN) with observation: ulceration of primary is key determinant for IFN-sensitivity. Eur J Cancer. 2016;55:111–21.CrossRefPubMedGoogle Scholar
  31. 31.
    Eggermont AM, et al. 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. 2012;48(2):218–25.CrossRefPubMedGoogle Scholar
  32. 32.
    Cascinelli N, 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(9285):866–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Hancock BW, 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(1):53–61.CrossRefPubMedGoogle Scholar
  34. 34.
    Grob JJ, et al. Randomised trial of interferon α-2a as adjuvant therapy in resected primary melanoma thicker than 1· 5 mm without clinically detectable node metastases. Lancet. 1998;351(9120):1905–10.CrossRefPubMedGoogle Scholar
  35. 35.
    Pehamberger H, et al. Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. Austrian Malignant Melanoma Cooperative Group. J Clin Oncol. 1998;16(4):1425–9.CrossRefPubMedGoogle Scholar
  36. 36.
    Pectasides D, et al. Randomized phase III study of 1 month versus 1 year of adjuvant high-dose interferon alfa-2b in patients with resected high-risk melanoma. J Clin Oncol. 2009;27(6):939–44.CrossRefPubMedGoogle Scholar
  37. 37.
    Hauschild A. Adjuvant interferon alfa for melanoma: new evidence-based treatment recommendations. Curr Oncol. 2009;16(3):3–6.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Agarwala SS, Gray RJ, Wong MK. Duration of high-dose interferon alfa-2b regimen for resected high-risk melanoma. J Clin Oncol. 2009;27(25):e82–3.CrossRefPubMedGoogle Scholar
  39. 39.
    Agarwala SS, et al. Phase III Randomized Study of 4 Weeks of High-Dose Interferon-α-2b in Stage T2bNO, T3a-bNO, T4a-bNO, and T1-4N1a-2a (microscopic) Melanoma: A Trial of the Eastern Cooperative Oncology Group–American College of Radiology Imaging Network Cancer Research Group (E1697). J Clin Oncol. 2017;35:885–92.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Mohr P, et al. Intermittent high-dose intravenous interferon alpha 2b (IFNa2b) for adjuvant treatment of stage III malignant melanoma: an interim analysis of a randomized phase III study (NCT00226408). J Clin Oncol. 2008;26(15_suppl):9040.CrossRefGoogle Scholar
  41. 41.
    Chiarion-Sileni V, et al. Intensified high-dose intravenous interferon alpha 2b (IFNa2b) for adjuvant treatment of stage III melanoma: a randomized phase III Italian Melanoma Intergroup (IMI) trial [ISRCTN75125874]. J Clin Oncol. 2011;29(15_suppl):8506.CrossRefGoogle Scholar
  42. 42.
    Chiarion-Sileni V, et al. Tolerability of intensified intravenous interferon alfa-2b versus the ECOG 1684 schedule as adjuvant therapy for stage III melanoma: a randomized phase III Italian Melanoma Inter-group trial (IMI–Mel. A.)[ISRCTN75125874]. BMC Cancer. 2006;6(1):44.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Bukowski RM, et al. Treating cancer with PEG Intron. Cancer. 2002;95(2):389–96.CrossRefPubMedGoogle Scholar
  44. 44.
    Glue P, et al. Pegylated interferon-α2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Clin Pharmacol Ther. 2000;68(5):556–67.CrossRefPubMedGoogle Scholar
  45. 45.
    Daud A, et al. Pharmacokinetic/pharmacodynamic analysis of adjuvant pegylated interferon α-2b in patients with resected high-risk melanoma. Cancer Chemother Pharmacol. 2011;67(3):657–66.CrossRefPubMedGoogle Scholar
  46. 46.
    Herndon TM, et al. US Food and Drug Administration Approval: peginterferon-alfa-2b for the adjuvant treatment of patients with melanoma. Oncologist. 2012;17(10):1323–8.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Eggermont AM, et al. Long-term results of the randomized phase III trial EORTC 18991 of adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma. J Clin Oncol. 2012;30:3810–8.CrossRefPubMedGoogle Scholar
  48. 48.
    Bottomley A, et al. Adjuvant therapy with pegylated interferon alfa-2b versus observation in resected stage III melanoma: a phase III randomized controlled trial of health-related quality of life and symptoms by the European Organisation for Research and Treatment of Cancer Melanoma Group. J Clin Oncol. 2009;27(18):2916–23.CrossRefPubMedGoogle Scholar
  49. 49.
    Trask PC, et al. Longitudinal course of depression, fatigue, and quality of life in patients with high risk melanoma receiving adjuvant interferon. Psycho-Oncology. 2004;13(8):526–36.CrossRefPubMedGoogle Scholar
  50. 50.
    Chapman PB. Counterpoint: the case against adjuvant high-dose interferon-α for melanoma patients. J Natl Compr Cancer Netw. 2004;2(1):69–72.CrossRefGoogle Scholar
  51. 51.
    Lens MB, Dawes M. Interferon alfa therapy for malignant melanoma: a systematic review of randomized controlled trials. J Clin Oncol. 2002;20(7):1818–25.CrossRefPubMedGoogle Scholar
  52. 52.
    Mocellin S, et al. Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. J Natl Cancer Inst. 2010;102(7):493–501.CrossRefPubMedGoogle Scholar
  53. 53.
    Kefford R. Adjuvant therapy of cutaneous melanoma: the interferon debate. Ann Oncol. 2003;14(3):358–65.CrossRefPubMedGoogle Scholar
  54. 54.
    Hodi FS, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;2010(363):711–23.CrossRefGoogle Scholar
  55. 55.
    Robert C, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364(26):2517–26.CrossRefGoogle Scholar
  56. 56.
    Lebbé C, et al. Survival follow-up and ipilimumab retreatment of patients with advanced melanoma who received ipilimumab in prior phase II studies. Ann Oncol. 2014;25(11):2277–84.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Eggermont AM, et al. Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy. N Engl J Med. 2016;375(19):1845–55.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. New England Journal of Medicine. 2017 Oct 5;377(14):1345–56.CrossRefPubMedGoogle Scholar
  59. 59.
    Grossmann KF, et al. SWOG S1404: a phase III randomized trial comparing high dose interferon to pembrolizumab in patients with high risk resected melanoma. Am Soc Clin Oncol; 2015Google Scholar
  60. 60.
    Chapman PB, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364(26):2507–16.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Lewis KD, et al. BRIM8: A phase III, randomized, double-blind, placebo-controlled study of vemurafenib adjuvant therapy in patients with surgically resected, cutaneous BRAF-mutant melanoma at high risk for recurrence (NCT01667419). Am Soc Clin Oncol; 2014.Google Scholar
  62. 62.
    Robert C, et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N Engl J Med. 2015;372(1):30–9.CrossRefGoogle Scholar
  63. 63.
    Veronesi U, et al. A randomized trial of adjuvant chemotherapy and immunotherapy in cutaneous melanoma. N Engl J Med. 1982;307(15):913–6.CrossRefPubMedGoogle Scholar
  64. 64.
    Agarwala SS, et al. Mature results of a phase III randomized trial of bacillus Calmette-Guerin (BCG) versus observation and BCG plus dacarbazine versus BCG in the adjuvant therapy of American Joint Committee on Cancer Stage I-III melanoma (E1673): a trial of the Eastern Oncology Group. Cancer. 2004;100(8):1692–8.CrossRefPubMedGoogle Scholar
  65. 65.
    Lejeune F, et al. An assessment of DTIC versus levamisole or placebo in the treatment of high risk stage I patients after surgical removal of a primary melanoma of the skin. A phase III adjuvant study. EORTC protocol 18761. Eur J Cancer Clin Oncol. 1988;24:81–90.Google Scholar
  66. 66.
    Fisher RI, et al. Adjuvant immunotherapy or chemotherapy for malignant melanoma: preliminary report of the National Cancer Institute randomized clinical trial. Surg Clin N Am. 1981;61(6):1267–77.CrossRefPubMedGoogle Scholar
  67. 67.
    Lipton A, et al. Corynebacterium parvum versus bacille Calmette-Guérin adjuvant immunotherapy of stage II malignant melanoma. J Clin Oncol. 1991;9(7):1151–6.CrossRefPubMedGoogle Scholar
  68. 68.
    Spitler LE, et al. Adjuvant therapy of stage III and IV malignant melanoma using granulocyte-macrophage colony-stimulating factor. J Clin Oncol. 2000;18(8):1614–21.CrossRefPubMedGoogle Scholar
  69. 69.
    Grotz TE, et al. Adjuvant GM-CSF improves survival in high risk stage IIIc melanoma: a single center study. Am J Clin Oncol. 2014;37(5):467.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Kleeberg U, et al. Final results of the EORTC 18871/DKG 80-1 randomised phase III trial: rIFN-α2b versus rIFN-γ versus ISCADOR M® versus observation after surgery in melanoma patients with either high-risk primary (thickness >3 mm) or regional lymph node metastasis. Eur J Cancer. 2004;40(3):390–402.CrossRefPubMedGoogle Scholar
  71. 71.
    Creagan ET, et al. Randomized, surgical adjuvant clinical trial of recombinant interferon alfa-2a in selected patients with malignant melanoma. J Clin Oncol. 1995;13(11):2776–83.CrossRefPubMedGoogle Scholar
  72. 72.
    Kirkwood JM, et al. High-dose interferon alfa-2b does not diminish antibody response to GM2 vaccination in patients with resected melanoma: results of the Multicenter Eastern Cooperative Oncology Group Phase II Trial E2696. J Clin Oncol. 2001;19(5):1430–6.CrossRefPubMedGoogle Scholar
  73. 73.
    Eggermont AM, 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(9492):1189–96.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Elisabeth Eapen Paul
    • 1
  • Sanjiv S. Agarwala
    • 1
  1. 1.Department of Hematology and OncologyUniversity Health NetworkBethlehemUSA

Personalised recommendations