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Melanoma: Adjuvant therapy and other treatment options

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Opinion statement

Melanoma, diagnosed and treated at its earliest stages, can be successfully cured by surgery alone. However, when metastatic beyond the regional nodes, it is almost uniformly deadly. Adjuvant therapy targeted toward the treatment of microscopic residual disease after surgical resection is the subject of intense scientific investigation because this is the stage at which it is possible to have the greatest impact on diseasefree and overall survival. However, standard therapies commonly used for other solid tumors have had disappointing results in the treatment of melanoma in the adjuvant setting. These disappointing results have led researchers and clinicians to work to develop innovative treatment strategies for this disease, most of which center on the use of immunotherapy. The realm of cancer immunotherapy is broad and rapidly expanding; it encompasses strategies using immunomodulating agents, such as interferon and interleukin-2, in addition to a wide range of novel vaccination strategies for the induction of active antitumor immune responses. Although clinical trials continue to be conducted to sort out the safety and efficacy of a myriad of new treatment modalities and novel combinations of the old and the new, data indicate that high-dose interferonalfa2b should be offered to appropriately selected intermediate- and high-risk patients with melanoma not involved in an experimental protocol.

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References and Recommended Reading

  1. Sondak VK, Wolfe JA: Adjuvant therapy for melanoma. Curr Opin Oncol 1997, 9:189–204.

    Article  PubMed  CAS  Google Scholar 

  2. Ang KK, Peters LJ, Weber RS, et al.: Postoperative radiotherapy for cutaneous melanoma of the head and neck region. Int J Radiat Oncol Biol Phys 1994, 30:795–798.

    PubMed  CAS  Google Scholar 

  3. O’Brien CJ, Petersen-Schaefer K, Stevens GN, et al.: Adjuvant radiotherapy following neck dissection and parotidectomy for metastatic malignant melanoma. Head Neck 1997, 19:589–594.

    Article  PubMed  CAS  Google Scholar 

  4. Shen P, Wanek LA, Morton DL: Is adjuvant radiotherapy necessary after positive lymph node dissection in head and neck melanomas? Ann Surg Oncol 2000, 7:554–559.

    Article  PubMed  CAS  Google Scholar 

  5. Strom EA, Ross MI: Adjuvant radiation therapy after axillary lymphadenectomy for metastatic melanoma: toxicity and local control. Ann Surg Oncol 1995, 2:445–449.

    Article  PubMed  CAS  Google Scholar 

  6. Corry J, Smith JG, Bishop M, et al.: Nodal radiation therapy for metastatic melanoma. Int J Radiat Oncol Biol Phys 1999, 44:1065–1069.

    Article  PubMed  CAS  Google Scholar 

  7. Creagan ET, Cupps RE, Ivins JC, et al.: Adjuvant radiation therapy for regional nodal metastases from malignant melanoma. Cancer 1978, 42:2206–2210.

    Article  PubMed  CAS  Google Scholar 

  8. Meyskens FL Jr, Liu PY, Tuthill RJ, et al.: Randomized trial of vitamin A versus observation as adjuvant therapy in high-risk primary malignant melanoma: a Southwest Oncology Group study. J Clin Oncol 1994, 12:2060–2065.

    PubMed  Google Scholar 

  9. Creagan ET, Ingle JN, Schutt AJ, et al.: A prospective, randomized controlled trial of megestrol acetate among high-risk patients with resected malignant melanoma. Am J Clin Oncol 1989, 12:152–155.

    Article  PubMed  CAS  Google Scholar 

  10. Markovic S, Suman VJ, Dalton RJ, et al.: Randomized, placebo-controlled, phase III surgical adjuvant clinical trial of megestrol acetate (Megace) in selected patients with malignant melanoma. Am J Clin Oncol 2002, 25:552–556.

    Article  PubMed  Google Scholar 

  11. Morton DL, Eilber FR, Malmgren RA, et al.: Immunological factors which influence response to immunotherapy in malignant melanoma. Surgery 1970, 68:158–164.

    PubMed  CAS  Google Scholar 

  12. Morton DL, Eilber FR, Holmes EC, et al.: BCG immunotherapy of malignant melanoma: summary of a sevenyear experience. Ann Surg 1974, 180:635–643.

    Article  PubMed  CAS  Google Scholar 

  13. Ariyan S, Kirkwood JM, Mitchell MS, et al.: Intralymphatic and regional surgical adjuvant immunotherapy in high-risk melanoma of the extremities. Surgery 1982, 92:459–463.

    PubMed  CAS  Google Scholar 

  14. Wood WC, Cosimi AB, Carey RW, et al.: Randomized trial of adjuvant therapy for “high risk” primary malignant melanoma. Surgery 1978, 83:677–681.

    PubMed  CAS  Google Scholar 

  15. Balch CM, Smalley RV, Bartolucci AA, et al.: A randomized prospective clinical trial of adjuvant C parvum immunotherapy in 260 patients with clinically localized melanoma (stage I): prognostic factors and preliminary results of immunotherapy. Cancer 1982, 49:1079–1084.

    Article  PubMed  CAS  Google Scholar 

  16. Thatcher N, Mene A, Banerjee SS, et al.: Randomized study of Corynebacterium parvum adjuvant therapy following surgery for (stage II) malignant melanoma. Br J Surg 1986, 73:111–115.

    Article  PubMed  CAS  Google Scholar 

  17. Lipton A, Harvey HA, Lawrence B, et al.: Corynebacterium parvum versus BCG adjuvant immunotherapy in human malignant melanoma. Cancer 1983, 51:57–60.

    Article  PubMed  CAS  Google Scholar 

  18. Lipton A, Harvey HA, Balch CM, et al.: Corynebacterium parvum versus bacille Calmette-Guerin adjuvant immunotherapy of stage II malignant melanoma. J Clin Oncol 1991, 9:1151–1156.

    PubMed  CAS  Google Scholar 

  19. Lejeune FJ, Macher E, Kleeberg U, 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(Suppl 2):S81-S90.

    Google Scholar 

  20. Quirt IC, Shelley WE, Pater JL, et al.: Improved survival in patients with poor-prognosis malignant melanoma treated with adjuvant levamisole: a phase III study by the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1991, 9:729–735.

    PubMed  CAS  Google Scholar 

  21. Spitler LE: A randomized trial of levamisole versus placebo as adjuvant therapy in malignant melanoma. J Clin Oncol 1991, 9:736–740.

    PubMed  CAS  Google Scholar 

  22. Loutfi A, Shakr A, Jerry M, et al.: Double blind randomized prospective trial of levamisole/placebo in stage I cutaneous malignant melanoma. Clin Invest Med 1987, 10:325–328.

    PubMed  CAS  Google Scholar 

  23. Ahmed FY, Leonard GA, A’Hern R, et al.: A randomised dose escalation study of subcutaneous interleukin 2 with and without levamisole in patients with metastatic renal cell carcinoma or malignant melanoma. Br J Cancer 1996, 74:1109–1113.

    PubMed  CAS  Google Scholar 

  24. Creagan ET, Rowland KM Jr, Suman VJ, et al.: Phase II study of combined levamisole with recombinant interleukin-2 in patients with advanced malignant melanoma. Am J Clin Oncol 1997, 20:490–492.

    Article  PubMed  CAS  Google Scholar 

  25. Lawrence HS: The transfer in humans of delayed skin sensitivity to streptococcal M substance and to tuberculin with disrupted leukocytes. J Clin Invest 1955, 34:219–230.

    Article  PubMed  CAS  Google Scholar 

  26. Spitler LE, Levin AS, Wybran J: Combined immunotherapy in malignant melanoma. Cell Immunol 1976, 12:1–19.

    Article  Google Scholar 

  27. Gonzalez RL, Wong P, Spitler LE: Adjuvant immunotherapy with transfer factor in patients with melanoma metastatic to lung. Cancer 1980, 45:57–63.

    Article  PubMed  CAS  Google Scholar 

  28. Miller LL, Spitler LE, Allen RE, et al.: A randomized, double-blind, placebo-controlled trial of transfer factor as adjuvant therapy for malignant melanoma. Cancer 1988, 61:1543–1549.

    Article  PubMed  CAS  Google Scholar 

  29. Bukowski RM, Deodhar S, Hewlett JS, et al.: Randomized controlled trial of transfer factor in stage II malignant melanoma. Cancer 1983, 51:269–272.

    Article  PubMed  CAS  Google Scholar 

  30. 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. The report of the first trial of high-dose interferon, showing a significant improvement in disease-free and overall survival rates to interferon-alfa-2b compared to observation. It was based on this paper that high-dose interferon was approved by the US Food and Drug Administration in the adjuvant treatment of patients with high-risk melanoma.

    PubMed  CAS  Google Scholar 

  31. Kirkwood JM, Ibrahim JG, Sondak VK, 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, 18:2444–2458. The second major ECOG trial, which attempted to confirm the results of ECOG 1684 and evaluate low-dose interferon. It demonstrated a significant improvement in disease-free survival for high-dose interferon, but failed to confirm the overall survival benefit. This sparked the ongoing controversy regarding high-dose interferon in the adjuvant setting.

    PubMed  CAS  Google Scholar 

  32. Livingston PO, Wong GYC, Adluri S, 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, 12:1036–1044.

    PubMed  CAS  Google Scholar 

  33. 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, 19:2370–2380. The third ECOG trial, which demonstrated an improvement in disease-free and overall survival to adjuvant high-dose interferon compared to a promising vaccine. Critics say that without an observation arm, it is difficult to interpret the results.

    PubMed  CAS  Google Scholar 

  34. Creagan ET, Dalton RJ, Ahmann DL, et al.: Randomized, surgical adjuvant clinical trial of recombinant interferon alfa-2a in selected patients with malignant melanoma. J Clin Oncol 1995, 13:2776–2783.

    PubMed  CAS  Google Scholar 

  35. Agarwala SS, Kirkwood JM: Update on adjuvant interferon therapy for high-risk melanoma. Oncology 2002, 16:1177–1187.

    PubMed  Google Scholar 

  36. Cascinelli N, Belli F, MacKie RM, et al.: Effect of longterm adjuvant therapy with interferon alpha-2a in patients with regional node metastases from cutaneous melanoma: a randomised trial. Lancet 2001, 358:866–869.

    Article  PubMed  CAS  Google Scholar 

  37. Rusciani L, Petraglia S, Alotto M, et al.: Postsurgical adjuvant therapy for melanoma. Evaluation of a 3-year randomized trial with recombinant interferona after 3 and 5 years of follow-up. Cancer 1997, 79:2354–2360.

    Article  PubMed  CAS  Google Scholar 

  38. Grob JJ, Dreno B, de la Salmoniere P, et al.: 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 1998, 351:1905–1910.

    Article  PubMed  CAS  Google Scholar 

  39. Pehamberger H, Soyer HP, Steiner A, et al.: Adjuvant interferon alfa-2a treatment in resected primary stage II cutaneous melanoma. J Clin Oncol 1998, 16:1425–1429.

    PubMed  CAS  Google Scholar 

  40. Islam M, Frye RF, Richards TJ, et al.: Differential effect of IFNa-2b on the cytochrome P450 enzyme system: a potential basis of IFN toxicity and its modulation by other drugs. Clin Cancer Res 2002, 8:2480–2487.

    PubMed  CAS  Google Scholar 

  41. Trask PC, Esper P, Riba M, et al.: Psychiatric side effects of interferon therapy: prevalence, proposed mechanisms, and future directions. J Clin Oncol 2000, 18:2316–2326.

    PubMed  CAS  Google Scholar 

  42. Hillner BE, Kirkwood JM, Atkins MB, et al.: Economic analysis of adjuvant interferon alfa-2b in high-risk melanoma based on projections from Eastern Cooperative Oncology Group 1684. J Clin Oncol 1997, 15:2351–2358.

    PubMed  CAS  Google Scholar 

  43. Berd D: M-Vax: an autologous, hapten-modified vaccine for human cancer. Expert Opin Biol Ther 2002, 2:335–342.

    Article  PubMed  CAS  Google Scholar 

  44. Berd D, Sato T, Cohn H, et al.: Treatment of metastatic melanoma with autologous, hapten-modified melanoma vaccine: regression of pulmonary metastases. Int J Cancer 2001, 94:531–539.

    Article  PubMed  CAS  Google Scholar 

  45. Hsueh EC, Essner R, Foshag LJ, et al.: Prolonged survival after complete resection of disseminated melanoma and active immunotherapy with a therapeutic cancer vaccine. J Clin Oncol 2002, 20:4549–4554.

    Article  PubMed  CAS  Google Scholar 

  46. Morton DL, Hsueh EC, Essner R, et al.: Prolonged survival of patients receiving active immunotherapy with Canvaxin therapeutic polyvalent vaccine after complete resection of melanoma metastatic to regional lymph nodes. Ann Surg 2002, 236:438–449. This paper demonstrates the future potential of melanoma vaccines in the adjuvant setting.

    Article  PubMed  Google Scholar 

  47. Sondak VK, Liu PY, Tuthill RJ, et al.: Adjuvant immunotherapy of resected, intermediate-thickness, nodenegative melanoma with an allogeneic tumor vaccine: overall results of a randomized trial of the Southwest Oncology Group. J Clin Oncol 2002, 20:2058–2066.

    Article  PubMed  CAS  Google Scholar 

  48. Sosman JA, Unger JM, Liu PY, et al.: Adjuvant immunotherapy of resected, intermediate-thickness, nodenegative melanoma with an allogeneic tumor vaccine: impact of HLA class I antigen expression on outcome. J Clin Oncol 2002, 20:2067–2075. This paper demonstrates the importance of a patient’s HLA profile on the effectiveness of melanoma vaccines. This will likely become an important method by which patients are selected for adjuvant therapies.

    Article  PubMed  CAS  Google Scholar 

  49. Mitchell MS, Harel W, Groshen S: Association of HLA phenotype with response to active specific immunotherapy of melanoma. J Clin Oncol 1992, 10:1158–1164.

    PubMed  CAS  Google Scholar 

  50. Tai T, Cahan LD, Tsuchida T, et al.: Immunogenicity of melanoma-associated gangliosides in cancer patients. Int J Cancer 1985, 35:607–612.

    Article  PubMed  CAS  Google Scholar 

  51. Helling F, Zhang S, Shang A, et al.: GM2-KLH conjugate vaccine: increased immunogenicity in melanoma patients after administration with immunological adjuvant QS-21. Cancer Res 1995, 55:2783–2788.

    PubMed  CAS  Google Scholar 

  52. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al.: Impact of cytokine administration on the generation of antitumor reactivity in patients with metastatic melanoma receiving a peptide vaccine. J Immunol 1999, 163:1690–1695.

    PubMed  CAS  Google Scholar 

  53. Rosenberg SA, Yang JC, Schwartzentruber DJ, et al.: Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med 1998, 4:321–327.

    Article  PubMed  CAS  Google Scholar 

  54. Wang F, Bade E, Kuniyoshi C, et al.: Phase I trial of a MART-1 peptide vaccine with incomplete Freund’s adjuvant for resected high-risk melanoma. Clin Cancer Res 1999, 5:2756–2765.

    PubMed  CAS  Google Scholar 

  55. Lee P, Wang F, Kuniyoshi J, et al.: Effects of interleukin-12 on the immune response to a multipeptide vaccine for resected metastatic melanoma. J Clin Oncol 2001, 19:3836–3847.

    PubMed  CAS  Google Scholar 

  56. Weber J, Sondak VK, Scotland R, et al.: Granulocytemacrophage-colony stimulating factor added to a multipeptide vaccine for resected stage II melanoma. Cancer 2003, 97:186–200.

    Article  PubMed  CAS  Google Scholar 

  57. Chang AE, Redman BG, Whitfield JR, et al.: A phase I trial of tumor lysate-pulsed dendritic cells in the treatment of advanced cancer. Clin Cancer Res 2002, 8:1021–1032.

    PubMed  CAS  Google Scholar 

  58. Banchereau J, Palucka AK, Dhodapkar M, et al.: Immune and clinical response in patients with metastatic melanoma to CD34+ progenitor derived dendritic cell vaccine. Cancer Res 2001, 61:6451–6458.

    PubMed  CAS  Google Scholar 

  59. Lau R, Wang F, Jeffery G, et al.: Phase I trial of intravenous peptide-pulsed dendritic cells in patients with metastatic melanoma. J Immunother 2001, 24:66–78.

    Article  PubMed  CAS  Google Scholar 

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  1. University of Michigan Comprehensive Cancer Center, 3304 Cancer Center, 1500 East Medical Center Drive, 48109, Ann Arbor, MI, USA

    Michael S. Sabel MD

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  1. Alicia Terando MD
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  2. Michael S. Sabel MD
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  3. Vernon K. Sondak MD
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Terando, A., Sabel, M.S. & Sondak, V.K. Melanoma: Adjuvant therapy and other treatment options. Curr. Treat. Options in Oncol. 4, 187–199 (2003). https://doi.org/10.1007/s11864-003-0020-0

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