Two of the most important predictors of relapse (and, therefore, survival) in patients with melanoma are the Breslow thickness of the primary melanoma and regional lymph node involvement. Patients with melanomas greater than 4 mm in thickness have approximately a 50% risk of recurrence, and those with lymph node involvement have a 50% to 85% risk of recurrence depending on the number of lymph nodes involved. Thus, a group of patients can be identified who are at high risk of death from melanoma and are, therefore, appropriate candidates for postsurgical adjuvant therapy.
Over the past 20 years, numerous agents have been evaluated in a series of nonrandomized and randomized adjuvant therapy trials in melanoma patients. Many of these trials suffered from serious methodologic problems, (such as inadequate statistical power, use of inappropriate controls, and lack of stratification for known prognostic factors). However, the major obstacle to the success of adjuvant therapy for melanoma has been the lack of active agents. Agents tested, with little or no benefit, include bacillus Calmette-Guérin (BCG), levamisole(Drug information on levamisole) (Ergamisol), interferon gamma-1b (Actimmune), interleukin-2, retinoids, dacarbazine(Drug information on dacarbazine) (DTIC-Dome), and megestrol(Drug information on megestrol) acetate.
Drs. Agarwala and Kirkwood thoroughly review the completed and ongoing trials of interferon-alpha as postsurgical adjuvant treatment of melanoma patients. Although clinicians generally agree with most of the conclusions reached by the authors, the role of high-dose interferon in patients with high-risk melanoma remains controversial. Drs. Agarwala and Kirkwood conclude that high-dose interferon is the standard of care for patients with high-risk melanoma and, therefore, is the most appropriate control for future adjuvant clinical trials. However, there is considerable discussion and debate as to whether high-dose interferon improves overall survival in patients with high-risk melanoma.
ECOG Trial E1684
The data from the clinical trials reviewed by Drs. Agarwala and Kirkwood consistently demonstrate that high-dose interferon is associated with improvement in disease-free survival. Multiple randomized trials have shown that high-dose interferon alfa-2b(Drug information on interferon alfa-2b) for 1 year improves relapse-free survival compared with observation. However, in terms of overall survival, the only clinical trial of high-dose interferon that has demonstrated an improvement in overall survival is the Eastern Cooperative Oncology Group (ECOG) study E1684. In that trial, patients with high-risk melanoma were randomized to either high-dose interferon alfa-2b (Intron A) therapy for 1 year or observation after surgery. As reported, the median survival was increased by 1 year in the treatment arm, and there was a 10% increase in the 5-year overall survival rate (46% for interferon vs 37% for observation, one-sided P = .0237).
Does this result justify the use of interferon, and are the differences between the two arms statistically significant? Only a one-sided test was reported: Had the results been reported with a more standard and appropriate two-sided test, the resulting P value would have been greater and barely statistically significant. Use of the less stringent measure is appropriate when one assumes only a benefit for the experimental therapy and no possible harm. In fact, when a two-sided test was performed by Cole et al in a later quality-of-life study using the same data set, there was no statistically significant difference between the treatment and observation arms in terms of overall survival (P = .07).
Moreover, an updated analysis of E1684 by Kirkwood no longer showed a survival advantage at a median 12.6 years of follow-up: The high-dose interferon arm had 93 deaths in 146 patients, whereas the observation arm had 95 deaths in 140 patients. Although a trend toward improved overall survival in the interferon-treated patients remains, the one-sided log-rank test showed a P value of .09.