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Journal of Clinical Oncology, Vol 23, No 10 (April 1), 2005: pp. 2431 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.99.260
Adjuvant Interferon Therapy for MelanomaUniversity of Sheffield, Sheffield, United Kingdom
University of Birmingham, Birmingham, United Kingdom
Royal Marsden Hospital, London, United Kingdom To the Editor: We would like to comment on some of the issues raised in the editorials1,2 that accompanied our article published in the Journal of Clinical Oncology in January 2004.3 Moschos et al1 are incorrect to state that the AIM HIGH trial was stopped early specifically because of a "lack of sufficient evidence of benefit." As we stated, the decision to end recruitment with 674 patients entered was made largely on the basis that an additional 300 or so patients would not add substantially to the total body of evidence on adjuvant interferon for melanoma, and hence the results should be made public so that they could contribute to this assessment of all the evidence. Moschos et al also claim that our meta-analysis4 did not use log-rank analysis for the high-dose interferon (HDI) trials. This is erroneous since the results used were taken from the published reports using the log-rank statistics presented in these papers. We question the first of Dr Schuchter's2 "top ten conclusions" that HDI is the only treatment showing activity against melanoma in the adjuvant setting. Our meta-analysis4 provides good evidence that low-dose interferon (LDI), at a dose of 3 MU, reduces the risk of recurrence (hazard ratio [HR] = 0.83; 95% CI, 0.75 to 0.93; P = .001). This point estimate of a 17% reduction in the odds of recurrence is smaller than the treatment effect observed for HDI (26% odds reduction; HR = 0.74; 95% CI, 0.63 to 0.86; P = .00009), but it is not quantitatively different (test for heterogeneity: P = .2). Thus, there is no clear evidence that HDI is more effective than LDI in reducing recurrence. We agree with Moschos et al that it is possible that the effect of LDI is more transient than that with HDI, but this hypothesis needs to be confirmed. The best way to do this is through an individual patient data meta-analysis. This would permit the inclusion of data with longer follow-up than in the original trial reports and the analysis of treatment effects over time. We support Dr Schuchter's view that overall survival is the most important end point for an adjuvant therapy, so more importantly, an individual patient data meta-analysis would allow a more precise estimate of the long-term effects on survival, including by dose of interferon, against which to balance toxicity and cost. The two editorials neatly highlight the continuing controversy surrounding the use of adjuvant interferon for melanoma. Dr Schuchter states that "adjuvant trials in patients with high-risk resected melanoma should continue to include a surgery alone control arm"; and Moschos et al assert "HDI remains the standard of care against which any new treatment strategy will ultimately be best compared in randomized controlled trials." Until these disagreements are resolved, some patients will either be denied an effective adjuvant therapy for melanoma or will be subjected to a toxic and expensive treatment of no worthwhile benefit. Authors' Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Research Funding: Martin Gore, Schering-Plough. For a detailed description of these categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosure of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue. REFERENCES
1. Moschos SJ, Kirkwood JM, Konstantinopoulos PA: Present status and future prospects for adjuvant therapy of melanoma: Time to build upon the foundation of high-dose interferon alfa-2b. J Clin Oncol 22:11-14, 2004
2. Schuchter LM: Adjuvant interferon therapy for melanoma: High-dose, low-dose, no dose, which dose? J Clin Oncol 22:7-10, 2004
3. 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 22:53-61, 2004 4. 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 randomised trials. Cancer Treat Rev 29:241-252, 2003[CrossRef][Medline]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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