Tolerability of intensified intravenous interferon alfa-2b versus the ECOG 1684 schedule as adjuvant therapy for stage III melanoma: a randomized phase III Italian Melanoma Inter-group trial (IMI - Mel.A.) [ISRCTN75125874]

Abstract

Background: High-dose interferon alfa-2b (IFNalfa-2b), according to the ECOG 1684 schedule, is the only approved adjuvant treatment for stage III melanoma patients by the FDA and EMEA. However, the risk/benefit profile has been questioned limiting its world-wide use. In the late nineties, the Italian Melanoma Inter-group started a spontaneous randomized clinical trial (RCT) to verify if a more intense, but shorter than the ECOG 1684 regimen, could improve survival without increasing the toxicity profile. The safety analysis in the first 169 patients who completed the treatment is here described.

Methods: Stage III melanoma patients were randomized to receive IFNalfa-2b 20 MU/m2/d intravenously (IV) 5 days/week x 4 weeks, repeated for three times on weeks 9 to 12, 17 to 20, 25 to 28 (Dose-Dense/Dose-Intense, DD/DI, arm), or IFNalfa-2b 20 MU/m2/d IV 5 days/week x 4 weeks followed by 10 MU/m2 subcutaneously (SC) three times per week x 48 weeks (High Dose Interferon, HDI, arm). Toxicity was recorded and graded, according to the WHO criteria, as the worst grade that occurred during each cycle.

Results: The most common toxicities in both arms were flu-like and gastrointestinal symptoms, leukopenia, liver and neuro-psychiatric morbidities; with regard to severe toxicity, only leukopenia was statistically more frequent in DD/DI arm than in HDI arm (24% vs 9%) (p = 0.0074), yet, this did not cause an increase in the infection risk. Discontinuation of treatment, due to toxicity, was observed in 13 and 17% of the patients in the DD/DI and HDI arm, respectively. The median actual dose intensity delivered in the DD/DI arm (36.4 MU/m2/week) was statistically higher than that delivered in the HDI arm (30.7 MU/m2/week) (p = 0.003).

Conclusion: Four cycles of intravenous high-dose IFNalfa-2b can be safely delivered with an increase in the median dose intensity. Efficacy results from this trial are eagerly awaited.

Figure 1

Computed tomography scan during the interferon treatment. Computed tomography scan, performed after the 20^th week for DD/DI patient (left) and during the 52^nd week for HDI patient (right), confirmed mild ground-glass opacities in both lungs with bronchial wall and interstitial thickening. Sputum cultures were negative for bacteria, fungi, and acid-fast bacilli.

Figure 2

Computed tomography scan after the end of the interferon treatment. Computed tomography scan for DD/DI patient (left) and HDI patient (right) performed after the end of treatment showed the disappearance of radiographic infiltrates.