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Journal of Clinical Oncology, Vol 23, No 10 (April 1), 2005: pp. 2431-2432 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.226
In Reply:University of Pittsburgh Cancer Institute, Pittsburgh, PA
University of Pennsylvania, Philadelphia, PA The comments of Hancock et al regarding our editorials1,2 on the negative AIM HIGH study3 are remarkable. We would specifically respond to the minor statistical details of their previous meta-analysis,4 which do not alter our conclusions. The first issue relates to the termination of the AIM HIGH trial before reaching the targeted accrual goal and the lack of sufficient evidence of benefit. Futility analysis is conducted by data monitoring committees to stop trials where further accrual is unlikely to change final conclusions, and in this case occurred when no benefit of low-dose interferon (LDI) was observed worthy of completing the planned trial. We find it provocative that the authors have reported the largest and most recent of a series of seven negative phase III trials of LDI for adjuvant therapy of high-risk melanoma and yet suggest that the results of meta-analyses preserve some hope for efficacy with this modality. These authors take issue with the common point of our and Dr Schuchter's editorials, which was that the only significant impact on survival of melanoma has, to date, been observed with high-dose interferon (HDI), as it has been tested in two separate, individually significant, randomized phase III trials. It appears from this letter that a methodology that approximates the weighted average of individual log-rank data was utilized to draw the conclusions in their prior report, in contrast to the formal log-rank analysis of all data that was performed in each of the trials concerned.4 However, estimates of the log hazard ratio and its variance are difficult when numbers of events are not consistently reported in the studies as they were conducted over time. These reporting inconsistencies and requirements for assumptions render conclusions from such meta-analyses less robust than prospective trials analyzed by log-rank methods.5 Meta-analysis of individual patient data is a better option, as Hancock et al have suggested. We have conducted and published an individual patient data meta-analysis for the four relevant trials of HDI conducted in the US Cooperative Groups, where HDI, LDI, and a ganglioside have been rigorously tested over the past 20 years.6 Regarding the continuing controversy on the adjuvant use of interferon (and in particular, HDI) for melanoma, we think that the design of future adjuvant trials and the current therapy of patients with melanoma is best based on level I evidence derived from prospective randomized phase III multicenter studies. Meta-analyses and other collective analyses provide lower levels of evidence that are often marshaled for decision-making when higher-level evidence does not exist, or where, as in the case of LDI, the original trials have uniformly failed to achieve durable relapse-free survival and overall survival benefits. The positive Eastern Cooperative Oncology Group trial E1684 and Intergroup trial E1694 have been published and recently analyzed together with all the currently available evidence regarding HDI in the adjuvant therapy of high-risk melanoma. We submit that the results of these mature and significant trials offer the highest level of evidence for decision-making in regard to the adjuvant therapy of high-risk resected melanoma patients. We have tested HDI on four separate occasions, twice in relation to observation and once each in relation to low-dose IFN, and most recently, a ganglioside vaccine that had suggested benefit in a smaller single-institution trial (GM2-KLH-QS21; Progenics, Tarrytown, NY), and therefore disagree with Hancock et al that there is no direct evidence that HDI is more effective than LDI in reducing recurrence and death as a result of melanoma. The data gained from meta-analyses may be utilized to augment the interpretation of individual mature phase III trials, and has previously been of use in the assessment of multiple negative or borderline trials that were individually underpowered to assess small benefits of therapies for other solid tumors. However, these data from meta-analyses ought not to supplant the highest-level evidence for decision-making when this exists (as it does for HDI), namely the disease-free survival benefit reported for all four trials of HDI and the overall survival benefit that has emerged from two of the three major phase III trials of this therapy. Where properly conducted randomized controlled trials have failed to demonstrate survival benefits of LDI, meta-analyses may serve to guide further efforts and to compare various trials. To use meta-analyses over the primary level I evidence does a disservice to the precepts of evidence-based medicine. 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. Consultant: John M. Kirkwood, Schering-Plough. Honoraria: John M. Kirkwood, 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 therapy of 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-1a 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- 5. Parmar MK, Torri V, Stewart L: Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 17:2815-2834, 1998[CrossRef][Medline]
6. Kirkwood JM, Manola J, Ibrahim J, et al: A pooled analysis of Eastern Cooperative Oncology Group and interferon trials of adjuvant high-dose interferon for melanoma. Clin Cancer Res 10:1670-1677, 2004
Related Correspondence
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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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for high-risk melanoma provide a worthwhile benefit? A meta-analysis of the randomized trials. Cancer Treat Rev 29:241-252, 2003
