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Originally published as JCO Early Release 10.1200/JCO.2009.23.0334 on July 27 2009 © 2009 American Society of Clinical Oncology.
Duration of High-Dose Interferon Alfa-2b Regimen for Resected High-Risk MelanomaUniversity of Pennsylvania, Philadelphia, and St Luke's Cancer Center, Bethlehem, PA
Dana-Farber Cancer Institute and Harvard University, Boston, MA
Clinical Drug Development Biologic Therapy, Sarcoma/Melanoma, GU Clinics Roswell Park Cancer Institute, Buffalo, NY To the Editor: In the recently published Hellenic Cooperative Oncology Group trial, Pectasides et al1 report no observed differences in relapse-free survival (RFS) and overall survival with 1 month versus 1 year of adjuvant high-dose interferon alfa-2b (HDI) therapy in patients with resected, high-risk (stage IIb to III) melanoma. We have two main concerns regarding the design of this noninferiority study, which are mentioned by the authors in the article but not given the appropriate weight—the noninferiority margin used was not appropriate; and the dose used was not the conventional high-dose interferon alfa-2b (HDI) regimen approved by the US Food and Drug Administration for high-risk melanoma. The US Food and Drug Administration has provided guidance for the design of noninferiority trials. An acceptable noninferiority margin is defined by taking into account historical data and relevant clinical and statistical considerations. Specifically, "The margin chosen for a noninferiority trial cannot be greater than the smallest effect size that the active drug would be reliably expected to have compared with placebo in the setting of the planned trial."2 Indeed, in practice, the noninferiority margin is usually smaller than the smallest expected effect size of the active control, ensuring a clinically acceptable effect size. The Hellenic study group set their noninferiority margin at 15%. This raises several issues. The difference in 5-year RFS previously observed between US Food and Drug Administration–approved HDI regimens and observation only was 9% and 11%.3,4 Smaller differences in RFS were observed at 3 years. The statistical precision of these estimates also needs to be considered,5 and the prior data definitively establish only a somewhat smaller benefit. Therefore, a 15% difference between two active treatment arms is an unrealistic expectation, particularly with lower doses. Furthermore, in the Hellenic study, the upper 95% confidence limit for the primary end point of RFS at 3 years was 9.8%, indicating that a treatment difference of less than 9.8% would not be detected. Although this is stated as a limitation and illustrated by reductions in the hazard ratio and loss of significance when smaller noninferiority margins were applied, the reliability of the conclusion depends on an active treatment difference of at least 9% to 10%, an unrealistic goal based on historical data. It is clear, therefore, that a much larger study would be required to demonstrate noninferiority at the appropriate margin for these two study arms; the Hellenic study was grossly underpowered to detect appropriate differences between the two active treatment arms. To place this in context, the Eastern Cooperative Oncology Group (ECOG) designed a trial in 2004 to attempt to answer the same question posed by the Hellenic Oncology Group. In the design of that trial, the noninferiority margin was set at lower than 5%. The group decided to abandon efforts to conduct this trial due to the large sample size of 3,000 patients required for what was not even an equivalence study. The second major issue with the Hellenic study is the dose of HDI actually utilized. The induction therapy dose was 15 x 106 U/m2/d intravenously (IV) for 5 of 7 days for 4 weeks, whereas the standard HDI dose on the ECOG trials is 20 x 106 U/m2/d. This was followed by a flat dose of 10 x 106 U subcutaneously (SC) 3 times per week for 48 weeks (as compared to the standard HDI dose of 10 x 106 U/m2 3 times per week for 48 weeks). Even if one allowed for dose reductions during the induction phase of the ECOG studies to match the lower prescribed dose on the Hellenic trial, the maintenance-phase dose is problematic. The latter has already been shown to be ineffective compared with observation in a large randomized European Organisation for Research and Treatment of Cancer trial (18952)6 where 10 x 106 U administered SC for 1 year was found to be no better than observation alone. In effect, this nullifies any effect of the SC maintenance phase of the Hellenic trial and reduces this study to a comparison of "induction versus induction," with all the additional caveats previously discussed. Since adjuvant therapy is given with curative intent, any change in its administration can have significant impact on patients. It is our contention, therefore, that the results of the Hellenic trial cannot and should not be considered conclusive and that the 1-year HDI regimen remain the standard of care for patients with high-risk melanoma as defined in the ECOG trials. The ongoing, high-priority ECOG 1697 trial we are conducting is randomly assigning 1,420 patients with intermediate- and high-risk melanoma to 1 month of IV induction at full standard dosages or to observation, and will shed more light on the issue of whether the induction therapy alone is sufficient for patients in the adjuvant setting. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Sanjiv S. Agarwala, Schering Plough (C); Michael K.K. Wong, Schering Plough (C), Pfizer (C), Novartis (C) Stock Ownership: None Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None Acknowledgment Supported by Grant No. CA-23318 from the National Institutes of Health to the Eastern Cooperative Oncology Group Statistical Center. REFERENCES
1. Pectasides D, Dafni U, Bafaloukos 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 27:939–944, 2009. 2. Guidance for Industry. E 10 Choice of Control Group and Related Issues in Clinical Trials. Rockville, MD: US Dept of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER), 2001. 3. 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 14:7–17, 1996.[Abstract] 4. 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 18:2444–2458, 2000. 5. Dahlberg SE, Gray RJ, Johnson BE: Gefitinib for recurrent non–small-cell lung cancer: All things are not created equal. J Clin Oncol 26:4233–4235, 2008. 6. Eggermont AM, Suciu S, MacKie R, 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 366:1189–1196, 2005.[CrossRef][Medline]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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