Phase II Pilot Study Does Not Support Phase III Investigation of IV High-Dose Interferon Without Maintenance in Resected Melanoma
There is evidence that high-dose interferon alfa-2b consisting of 4 weeks of daily intravenous interferon alfa-2b followed by 48 weeks of subcutaneous maintenance interferon alfa-2b three times per week reduces risk of recurrence of resected melanoma and that response may depend on the early higher-dose intravenous component of the regimen. In a phase II pilot trial reported in the Journal of Clinical Oncology, Payne et al compared a high-dose 4-week intravenous regimen with the same regimen followed by 48 weeks of subcutaneous maintenance therapy in patients with resected melanoma. The longer regimen was associated with nonsignificantly better relapse-free survival and a significant overall survival advantage. The investigators stated that the outcome does not support examination of the shorter regimen in a phase III trial.
Study Details
In the trial, 194 patients with stage IIB, IIC, IIIB, or IIIC resected melanoma were randomly assigned between 2003 and 2009 to receive intravenous interferon alfa-2b at 20 MIU/m2 daily 5 days per week for 4 weeks (n = 96) or the same regimen followed by subcutaneous interferon alfa-2b 10 MIU/m2 three times per week for 48 weeks (n = 98). The high-dose and high-dose/maintenance groups were generally balanced for age (median, 53 and 48 years, range, 20–78 and 17–75 years), sex (52% and 58% female), primary tumor site (eg, trunk in 38.5% and 48%, limbs in 44% and 39%), Breslow thickness (1.1–2.0 mm in 23% and 32%, 2.1–4.0 mm in 28% and 25.5%, > 4.0 mm in 22% and 25.5%), ulceration (32% and 42%), lymph node involvement (77% and 77.5%), and stage (III in 80% and 83%).
Survival Outcomes
After median follow-up of 39.5 months, relapse-free survival was 22.7 months in the high-dose group vs 33.3 months in the high-dose/maintenance group (P = .28). The proportions of patients free of relapse at 2 years were 50.0% vs 54.1% (hazard ratio [HR] = 0.89 for high-dose/maintenance vs high-dose group, P = .569). Median overall survival was 41.5 months vs not reached (P = .05).
On multivariate analysis adjusting for age, sex, performance status, primary site, tumor thickness, ulceration, and disease stage, the high-dose/maintenance group had nonsignificantly longer relapse-free survival (HR = 0.72, P = .09) and significantly longer overall survival (HR = 0.59, P = .02). Tumor thickness and nodal status were significant predictors of both relapse-free survival and overall survival.
The mean delivered intravenous dose did not differ between the high-dose and high-dose/maintenance groups (78% of planned dose in both). Reduction of intravenous dose occurred in 39% and 34% of patients. Subcutaneous dose reduction occurred in 35% of patients and mean subcutaneous dose was 42% of the planned dose.
Toxicities
The majority of adverse events were grade 1 or 2, with neutropenia, leukopenia, nausea, hepatotoxicity, flu-like symptoms, and fatigue being the most common in both groups. Grade 3 or 4 fatigue was significantly more common in the high-dose/maintenance group (35% vs 16%, P = .002). The most common grade 3 or 4 adverse events other than fatigue were neutropenia (30% in high-dose group vs 26.5% in high-dose/maintenance group) and transaminitis (28% vs 31%).
The investigators concluded, “Clinical outcomes were better in patients who had the longer regimen. Our results do not support either the use of a month of [intravenous high-dose interferon alfa-2b] alone in place of the year-long regimen or the initiation of a larger trial on this question.”
Mark R. Middleton, MD, PhD, of Oxford Cancer Centre, is the corresponding author for the Journal of Clinical Oncology article.
For full disclosures of the study authors, visit jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
