Adjuvant therapy with pegylated interferon alfa-2b (36 months) versus low-dose interferon alfa-2b (18 months) in melanoma patients without macro-metastatic nodes: EADO trial.

Abstract

LBA8506 Background: Adjuvant therapy with low-dose adjuvant interferon alfa-2b (IFN) as well as with pegylated interferon alfa-2b (PEG-IFN) were both shown to be superior to observation in melanoma (M) patients (pts) without macro-metastatic nodes. However, the two strategies have never been assessed head to head. Weekly injection of PEG-IFN facilitates a longer duration of treatment which may be critical for benefit. We thus compared adjuvant therapy of flat low-dose PEG-IFN (36 months) versus low-dose IFN (18 months) in intermediate-risk M pts without macro-metastatic nodes. Methods: In this multicenter, open-label, prospective randomized phase III trial, pts with resected M ≥ 1.5 mm in thickness and without clinically detectable nodes were randomized either to IFN (3 MU subcutaneously [sc] 3 times a week for 18 months) or to PEG-IFN (100 mcg sc once weekly for 36 months). Sentinel node procedure (SNP) was not a standard in 2003 and thus was optional. Approach was consistent by center. Randomization was stratified for centers and SNP procedure. Primary endpoint was relapse-free survival (RFS), and secondary were distant metastasis-free survival (DMFS), overall survival (OS), and grade 3-4 severe adverse events (SAE). Sample size (890 pts) was calculated to detect a 10% difference (power >80%, type I error of 5%, 2-sided) for RFS. Analysis describes 5-year probability of survival. Comparisons were done by intent-to-treat using Cox proportional models. Results: Of 898 pts enrolled, 896 (443 PEG vs 453 IFN) were eligible for evaluation after a median follow-up of 4.7 years. SLNB was performed in 68.2% of pts. Neither RFS (PEG-IFN 66.2% vs IFN 64.8%, p=0.43; HR, 0.91; 95% CI, 0.73 to 1.15) nor DMFS (71.3% vs 72.6%, p=0.86; HR, 1.02; 95% CI, 0.80 to 1.32) or OS (77.0% vs 78.4%, p=0.55; HR, 1.09; 95% CI, 0.82 to 1.45) showed statistical difference. There was an excess of SAE grade 3-4 in PEG-IFN arm (44.6% vs 26.6% in the first 18 months) which impacted on median duration of treatment (17.8 months in IFN arm; 19.2 in PEG-IFN arm, with only 28% completing 36 months treatment). Conclusions: Flat low-dose PEG-IFN did not show superiority over conventional low dose IFN. Attempts to increase benefit by prolonging treatment with PEG-IFN over 3 years were hampered by a high rate of treatment discontinuation possibly linked to SAEs with PEG-IFN. [Table: see text]

Real-life Experience With Pegylated Interferon and Conventional Interferon in Adjuvant Melanoma Therapy

“…21 Our toxicity data suggests that the dose of 100 mg/wk peg-IFN represents a higher dose than LDI, explaining the higher incidence of side effects/dose reductions in patients treated with peg-IFN. 21,23 The pharmacokinetic studies of peg-IFN versus IFN in hepatitis C demonstrated a dose of 0.25 mg/kg/wk of peg-IFN results in a similar exposure to 3 Â3 MIU/wk of conventional IFN. 24,25 This is far less than the dose that most of the patients in this or other studies received 12,14,23 and hence can explain the higher incidence of side effects seen in real-life and in clinical trial settings leading to discontinuation of peg-IFN.…”

“…Moreover, the conclusion was made that "it is hard to compete with standard LDI in a population that it is validated in." 23 The EORTC 18991 trial where peg-IFN (6 mg/kg/wk for 8 wk followed by 3 mg/ kg/wk for 60 mo) was compared with observation, the median treatment duration was 16.3 months for the intended to treat population. 21 Our toxicity data suggests that the dose of 100 mg/wk peg-IFN represents a higher dose than LDI, explaining the higher incidence of side effects/dose reductions in patients treated with peg-IFN.…”

Adjuvant Treatment of Melanoma

“…In summary, low doses of PEG-IFN were no better than low doses of conventional IFN α -2b. Trying to increase the benefits of PG-IFN by increasing the length of the treatment to three years is not easy because of the high numbers of patients not completing the full treatment due to the side effects and therefore not solving the clinical needs of them [60]. Advocating the use of IFN in melanomas, a new meta-analysis has recently been published with a large number of patients reviewing the adjuvant treatment with IFN- α in high risk cases, in relation to DFS and OS, and also the effect of the doses and the length of the treatment has been studied.…”

Adjuvante systemische Therapie des Melanoms

“…IE/Woche) bei 890 Patienten mit einer Tumordicke von mindestens 1,5 mm ohne klinischen Nachweis von Lymphknotenmetastasen verglichen. Weder für das rezidivfreie (PegIntron®, 66,2% vs. Intron A® 64,8%, p=0,43; HR, 0,91; 95%-KI 0,73-1,15) noch für die Zeit bis zu einer Fernmetastasierung (71,3% vs. 72,6%; p=0,86; HR 1,02; 95%-KI 0,80-1,32) oder das Gesamtüberleben (77,0% vs. 78,4%; p=0,55; HR 1,09; 95%-KI 0,82-1,45) ergab sich ein statistisch signifikanter Unterschied [33].…”