Info

T4, N1

IFN-2b 20MU/m2/day IV x 1 month (induction phase) then 10MU/m2 SC TIW x 11 months (maintenance phase) versus GM2-KLH/QS-21 vaccine

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TIW, three times per week; BIW, twice a week.

TIW, three times per week; BIW, twice a week.

sis of these four trials was that all four demonstrated a relapse-free survival benefit for high-dose interferon, but any overall survival benefit was unclear and could only unequivocally be claimed for the trial with the most premature follow-up.

A meta-analysis of the randomized high-dose interferon trials has been conducted to increase the number of patients accrued and the statistical power to perceive small differences in survival.55 The results of that meta-analysis indicate that the relapse-free survival advantage of high-dose interferon is significant and reproducible but that the data suggesting a survival advantage are much weaker. This brings us to the EORTC 18902 trial, in which patients with high-risk disease were randomly assigned to receive an intermediate-dose induction regimen of interferon. The induction consisted of 10 million units/m2 of interferon administered subcuta-neously every day for 4 weeks, followed by 1 year of 10 million units/m2 three times a week, compared with 5 million units/m2 three times a week for 2 years. The results of that study have been presented publicly, first at ASCO in 2001, with the final summary presented in 2003.56 The data do not suggest that there is any difference in overall survival between the groups, although a modest difference in relapse-free survival was observed. If the high-dose regimen of EST 1684 truly resulted in a significant overall survival difference, why would that difference not be seen with a similarly dose intense, although subcutaneous regimen, in the EORTC 18902 trial? The answer is likely that there is no reproducible, significant, and biologically important overall survival difference for high-risk melanoma patients who receive the highdose interferon regimen. Significant differences in relapse-free survival were observed in all four trials and were maintained in the meta-analysis after adjustment for prognostic variables, suggesting that the difference is genuine.

What conclusions can be drawn about recommending high-dose interferon to patients with resected high-risk melanoma? One is that it is likely to confer a moderate benefit in relapse-free survival, postponing the time to disease recurrence but not changing overall survival significantly. Is the acknowledged toxicity and cost of the year-long regimen justified by the relapse-free survival benefit? Admittedly, the Q-TWIST quality of life analysis, which assumed the level of survival benefit found in the EST 1684 trial, indicated that in spite of the side effects the use of high-dose interferon was justified.57 However, the relapse-free survival advantage without the likelihood of ever observing a clear overall survival benefit renders interferon an acceptable but hardly desirable option. It should be offered to patients with resected high-risk melanoma but should not be a clearly superior option to a well-designed randomized Phase III or even a Phase II study. Given the difficulty and lack of acceptance of a randomized trial in high-risk melanoma that includes an observation arm, high-dose interferon is a reasonable and proper control arm against which new therapies in development may be measured.

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