Adjuvant Therapy of Melanoma: At What Cost?
Authors: Lynn E. Spitler, John M. Kirkwood
Journal: Journal of Clinical Oncology (2001)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2001.19.4.1226 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11181688 Adjuvant Therapy of Melanoma: At What Cost? Lynn E. SpitlerxLynn E. SpitlerSearch for articles by this author John M. KirkwoodxJohn M. KirkwoodSearch for articles by this author , for the authorship of the E1694 and E1690 trials, including J. Ibrahim, V. Sondak, J. Sosman, J. Richards, M. Ernstoff, L. Flaherty, S. Agarwala, U. Rao, T. Smith, M. Steel, and R. BlumxSearch for articles by this author Show More Northern California Melanoma Center, San Francisco, CAUniversity of Pittsburgh Cancer Institute, Pittsburgh, PA https://doi.org/10.1200/JCO.2001.19.4.1226 First Page Full Text PDF Figures and Tables © 2001 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse15022001In Reply:We write in response to the letter of L.E. Spitler regarding the role of high-dose interferon alfa-2b (IFNα2B) in stage III melanoma and our recent publication of the E1690/S9111/C9190 study in the June issue of the Journal of Clinical Oncology.1 Several important points are raised that bear discussion. The prognosis of node-positive melanoma is suggested to be more favorable than would warrant adjuvant therapy for patients with nodal micrometastases, and it is suggested that 79% of patients with disease detected by sentinel node mapping may be disease-free at 3 years without adjuvant therapy. The category of patients with microscopic disease in a single node, designated N1a in the recently proposed American Joint Committee on Cancer (AJCC) staging system for melanoma,2 is suggested to have a prognosis that is so good that high-dose IFN may be excessive relative to the therapeutic benefit. Toxicity of high-dose IFN is suggested to be different than previously reported, especially for low-dose IFN events noted in a preliminary abstract regarding our recently published study E1690/S9111/C9190 as posted on the Eastern Cooperative Oncology Group Web site. The benefit of high-dose IFNα2b is suggested to be too little and too uncertain to warrant treatment of patients with microscopic nodal involvement as a compelling standard, given the more favorable prognosis suggested by Spitler and the toxicity. We take strong exception to all three of these points, and submit the following: There is no mature evidence that supports the suggestion of a relapse rate of 21% for patients with microscopic nodal metastases. In fact, the AJCC melanoma subcommittee has recently reviewed outcome data for 17,653 cases of melanoma with 5- to 10-year follow-up from major centers and groups involved with the AJCC. These data demonstrate quite a different picture: relapse and death in occurred in 39% of patients with microscopic involvement of one node by melanoma, and in 46% of patients with microscopic involvement of two or three lymph nodes. This prognosis is certainly better than for that for patients with macroscopic involvement; corresponding figures are 5-year mortality of 54%, 62%, and 73% for patients with macroscopic involvement of one, two, or three nodes, respectively. Melanoma is a long-term threat to patients with nodal involvement, and at 10 years, the prognosis for patients with microscopic disease is even more ominous, with mortality in 49%, 53%, and 59% of those with microscopic involvement of one, two, or three nodes, respectively. There is nothing in the literature or our experience to justify the suggestion of Dr. Spitler that microscopic disease should be considered relatively innocent, or less appropriate for adjuvant therapy, with an agent that has shown relapse prevention in five separate multicenter randomized controlled trials and has proven and recently confirmed highly significant survival advantages: high-dose IFNα2 (see item no. 3 below). The toxicity of high-dose IFNα2b reported in the intergroup E1690/S9111/C9190 trial was noted to be very similar to that reported in detail 5 years ago for trial E1684,3 except that the broader national experience using high-dose IFNα2b has been associated with greater safety since the trials of the early 1980s, and no lethal toxicity has been noted.1 Spitler cites two deaths among low-dose IFN recipients reported in a preliminary abstract presented 2 years ago, but these were in the final analysis as published1 and attributed to progression of tumor. The toxicity of IFNα2b is now the subject of multiple textbooks,4,5 and the recent trial experience did not, therefore, detail these toxicities, which have previously been published. The risk-to-benefit analysis for high-dose IFNα2b is the subject of ongoing intergroup randomized controlled trials, which have recently been reported. We have just completed two further trials, including an intergroup study in which accrual to high-dose IFNα2b was two-fold larger than in either of the E1684/E1690 experiences.3,6 The Intergroup E1694/S9512/C509801 trial has revealed such overwhelming evidence of benefit with high-dose IFNα2b that the study closed before expectations by the Data Safety Monitoring Board of the Eastern Cooperative Oncology Group. The statistical significance of the benefit of high-dose IFN compared with a vaccine that had been chosen as the experimental arm, measured in terms of overall and relapse-free survival, is compelling, with P = .009 and P = .001, respectively, in 774 eligible patients. This is confirmed in the intent-to-treat analysis (n = 880) and reasserts that high-dose IFNα2b is the standard of care for all patients with high-risk melanoma, including those with deep primary lesions and no known nodal involvement (T4N0) and all groups included with any microscopic or macroscopic evidence of nodal involvement. The hazard ratios for prevention of relapse and prevention of death are 1.47 and 1.52, respectively, in study E1694/S9512/C509801. These ratios are consistent with one another and perfectly corroborate the 1.43 hazard ratio for the relapse-prevention benefit of high-dose IFNα2b reported in E16843,7 with improved quality of life8 and comparable to established adjuvant therapy for other solid tumors.9 The impact of high-dose IFN among patients with regional lymph node metastasis discovered by sentinel lymph node mapping procedures was not possible to analyze in E1690/S9111/C9190, since fewer than 5% of patients who entered that trial had received sentinel node procedures as the basis for their entry onto the study. We are currently analyzing the frequency of sentinel node mapping among participants in E1694/S9512/C509801 and will report these findings to the Presidential Symposium of the European Society of Medical Oncology this month and in further publications on that study. However, the follow-up for currently reported series of patients in whom sentinel node procedures have been performed, including those who entered E1694/S9512/C509801, is relatively short, and prognostic implications are limited by their short median follow-up. The Sunbelt Melanoma Trial has focused specifically on this issue, using sentinel node mapping as the entry point for patients with melanoma studied by routine, immunohistologic, and molecular means. Until mature data from this trial become available, it will be premature to make any firm conclusions in regard to this particular subgroup. Taken together, the data from the aggregate of Eastern Cooperative Oncology Group and Intergroup experience in the mature trials E1684 and E1690, as well as the more recently analyzed E2696 and E1694, reveal a significant benefit of high-dose IFNα2b. This benefit is consistent in terms of relapse and death prevention for all risk groups, including node-negative and node-positive patients. This benefit is best represented in the significantly elevated hazard ratios of 1.47 to 1.52 for relapse and death among patients who are not treated compared with those who are. This indicates a 33% reduction in the risk of relapse and death by IFNα2b. 1. 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 18:: 2444,2000-2458, Link, Google Scholar2. Balch CM, Buzaid AC, Atkins MB, et al: A new American Joint Committee on Cancer staging system for cutaneous melanoma. Cancer 88:: 1484,2000-1491, Crossref, Medline, Google Scholar3. 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 14:: 7,1996-17, Link, Google Scholar4. Kirkwood JM: Interferon-alpha and -beta: Clinical applications—Melanoma, Rosenberg SA (ed): Principles and Practices of the Biologic Therapy of Cancer (ed 3). Philadelphia, PA, Lippincott Williams & Wilkins (in press)in Google Scholar5. Kirkwood JM: Interferons: Rationale for investigation of interferons—Direct regulation of cell growth, differentiation, antigen expression; indirect effects mediated through modulation of the host immune response, DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles & Practice of Oncology (ed 6) Philadelphia, PA, Lippincott Williams & Wilkins, 2000, pp 461-471in Google Scholar6. Kirkwood JM, Ibrahim J, Lawson DH, et al: High-dose interferon alfa-2b does not diminish antibody response to GM2 vaccination in patients with resected melanoma: Results of the multicenter ECOG phase II trial: E2696. J Clin Oncol (in press) Google Scholar7. Kirkwood JM, Ibrahim J, Sondak VK, et al: Relapse-free and overall survival are significantly prolonged by high-dose IFNα2b (HDI) compared to vaccine GM2-KLH with QS21 (GMK, Progenics) for high-risk resected stage IIB-III melanoma: Results of the intergroup phase III study E1694/S9512/C509801. Ann Oncol 11:4, 2000 (suppl 4, abstr 50) Google Scholar8. Cole BF, Gelber RD, Kirkwood JM, et al: A quality-of-life-adjusted survival analysis of interferon alfa-2b adjuvant treatment for high-risk resected cutaneous melanoma: An Eastern Cooperative Oncology Group study (E1684). J Clin Oncol 14:: 2666,1996-2673, Link, Google Scholar9. Hillner BE, Kirkwood JM: Economic analyses of benefit from interferon-alfa2B in high risk melanoma: Tradeoffs between completeness, simplicity, and clarity. Eur J Cancer 33:: 1345,1997-1346, Crossref, Medline, Google Scholar