DR. KIRKWOOD: Interferon benefits make placebo-controls untenable for first-line adjuvant trials...
There are many new alternative therapies that we all hope will alter the outcome of melanoma, including anti-CTLA-4 therapies, vaccines, and new targeted small molecule therapies. But I submit that to date, only interferon has made a significant reproducible impact, and only trials of high-dose interferon have confirmed significant, durable overall and relapse-free survival benefits that are now past 20 years in follow-up.
In the pivotal Eastern Cooperative Oncology Group E1684 trial, use of high-dose interferon reduced mortality and relapse at 5 years by 28% and 38%, respectively (J. Clin. Oncol. 1996;14:7-17). Similar outcomes occurred in the intergroup E1694 trial, in which use of high-dose interferon reduced relapse and mortality at 2 years by 32% and 33%, respectively (J. Clin. Oncol. 2001;19:2370-80).
As for toxicity, E1694 demonstrated that 90% of patients tolerated the medication for 1 year. In addition, the cost per year of life gained is within accepted cost efficacy guidelines for dialysis.
Patients regard toxicity of interferon as far less oppressive than they do the relapse of disease. Indeed, one study found that at least half the patients would be willing to tolerate mild/moderate and severe interferon toxicity for 4% and 10% improvements, respectively, in 5-year, disease-free survival (J. Clin. Oncol. 2001;19:812-23).
Several studies have demonstrated that high-dose interferon is active across the spectrum of disease from microscopic stage IIIA to bulky stage IIIB melanoma, and that it’s equally effective in ulcerated and non-ulcerated forms of disease. Both European (Hellenic Cooperative Oncology Group) and American intergroup studies have shown that high-dose interferon induces autoimmunity in 20-26% of cases. We and other investigators are now looking for the genetic predictors of benefit with interferon, such as major histocompatibility complex profiles and cytokine profiles.
For the time being, high-dose interferon is the standard adjuvant therapy for melanoma. It is unreasonable to force patients into placebo-controlled, first-line studies to gain access to new agents in 2010.
Dr. John M. Kirkwood directs the Melanoma and Skin Cancer Program at the University of Pittsburgh Cancer Institute and is professor and vice chairman for clinical research in the departments of medicine and dermatology at the University of Pittsburgh School of Medicine. He disclosed that he has received an honorarium for his FDA Oncologic Drug Advisory Committee testimony on behalf of Schering.
DR. McMASTERS: Interferon has high toxicity, and survival gains are not consistent across trials...
What about high-dose interferon? E1684 (J. Clin. Oncol. 1996;14:7-17) found a 5-year overall survival rate of 37%, which was significantly higher than 26% in the observation group. However, with longer follow-up, the overall survival advantage of high-dose interferon disappears.
Another intergroup trial, E1690, showed marginal improvement in disease-free survival and no improvement in overall survival (J. Clin. Oncol. 2000;18:2444-58). Patients in the observation group who received salvage therapy with interferon had improved survival compared with those who did not receive interferon. This was a post-hoc analysis of 37 patients out of 642 , however, and subject to selection bias. The proper way to explore the crossover effect would be to exclude crossed-over patients from survival analysis, and see whether overall survival becomes significant. To demonstrate that patients who recurred in the observation arm subsequently treated with interferon did better than those who did not receive interferon does not invalidate a large randomized, controlled trial. E1694 demonstrated improvement in overall survival for interferon, compared with the GMK vaccine—a vaccine since shown in a large randomized trial from the European Organisation for the Research and Treatment of Cancer (EORTC) to have a significant detrimental effect on survival. Therefore, one cannot conclude from E1694 that interferon is beneficial.
The Sunbelt Melanoma Trial, though underpowered to detect small differences in survival, failed to demonstrate a difference in disease-free survival or an advantage in overall survival among patients with a single tumor-positive sentinel lymph node treated with high-dose interferon (J. Clin. Oncol. 2008; May 20 suppl.; abstr. 9003). The recent Dermatologic Cooperative Oncology Group trial of modified high-dose interferon vs. low-dose interferon also failed to show any benefit in relapse-free survival and in overall survival (J. Clin. Oncol. 2009;27:3496-502).