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Does Adjuvant Vaccine Therapy Really Have Activity in Malignant Melanoma?

Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, United Kingdom

Paul Lorigan

Christie Hospital National Health Service Trust, Manchester, United Kingdom

To the Editor:

Mitchell et al¹ interpret their trial of high-dose interferon (IFN) versus low-dose IFN plus allogeneic melanoma lysate vaccine as representing "the first time a randomized large-scale trial of a vaccine regimen has demonstrated ... activity" in the adjuvant melanoma setting, and suggest that "low-dose IFN was probably not solely responsible" for any activity observed. However, since publication, an individual patient data meta-analysis presented recently at the 2007 Annual Meeting of the American Society of Clinical Oncology (ASCO; Chicago, IL)² provides no evidence that low-dose IFN is any less effective than high-dose. The hazard ratio (HR) for high-dose IFN is 0.90 (95% CI, 0.80 to 1.02; P = .1), and the HR for low-dose IFN is also 0.90 (95% CI, 0.80 to 1.01; P = .07). Nor is this finding new. While Mitchell et al quote two qualitative systematic reviews in their discussion, they fail to mention a quantitative published data meta-analysis from 2003,³ which also showed no dose effect on overall survival (high-dose HR = 0.90, low-dose HR = 0.90). Thus, it is entirely plausible that the "indistinguishable" survival of patients in the high-dose IFN and low-dose IFN plus vaccine arms of their study is due to the similar efficacy of low-dose and high-dose IFN, with the vaccine making no contribution. Furthermore, at the 2007 Annual Meeting of ASCO, a trial of a vaccine in stage III melanoma patients reported adverse survival in the vaccine arm (P = .04).⁴ We therefore consider that caution should be exercised in interpreting the trial by Mitchell and colleagues as providing any evidence of benefit for adjuvant vaccine therapy in melanoma.

Also, as the authors point out, the trial was not large enough to demonstrate equivalence, but no idea (ie, HR with CI) of the range of uncertainty of the treatment effect is presented. We calculate them to be, approximately, HR of 0.92 with a 95% CI of 0.70 to 1.22, meaning that the observed result is compatible with a reasonably large survival benefit for either arm. It would be helpful if a point estimate of the treatment effect (eg, hazard ratio, odds ratio), with an indication of the degree of uncertainty surrounding this (eg, a CI), was given for all major end points when randomized trials are being reported, as per the CONSORT statement.⁵

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Mitchell MS, Abrams J, Thompson JA, et al: Randomized trial of an allogeneic melanoma lysate vaccine with low-dose interferon alfa-2b compared with high-dose interferon alfa-2b for resected stage III cutaneous melanoma. J Clin Oncol 25:2078-2085, 2007[Abstract/Free Full Text]

2. Wheatley K, Ives N, Eggermont A, et al: Interferon- as adjuvant therapy for melanoma: An individual patient data meta-analysis of randomised trials. J Clin Oncol 25:478s, 2007 (suppl; abstr 8526)

3. Wheatley K, Ives N, Hancock B, et al: Does adjuvant interferon-alpha for high-risk melanoma provide a worthwhile benefit? A meta-analysis of the randomised trials. Cancer Treat Rev 29:241-252, 2003[CrossRef][Medline]

4. Morton DL, Mozzillo N, Thompson JF, et al: An international randomized, phase III trial of bacillus Calmette-Guerin (BCG) plus allogeneic melanoma vaccine (MCV) or placebo after complete resection of melanoma metastatic to regional or distant sites. J Clin Oncol 25:474s, 2007 (suppl, abstr 8508)

5. Moher D, Schulz KF, Altman D: The CONSORT statement: Revised recommendations for improving the quality of reports of parallel-group randomized trials. JAMA 285:1987-1991, 2001[Abstract/Free Full Text]

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