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FROM THE LITERATURE
MELANOMA:
Improved Outcome for Locally Advanced Disease
The final results of EORTC 18991, a randomized phase III trial evaluating adjuvant
therapy with pegylated interferon alfa-2b versus observation alone in resected stage
III melanoma were published in a recent issue of The Lancet along with
an editorial. The aim of the trial was to determine whether pegylated interferon
(pegIFN) alfa-2b can facilitate prolonged exposure (a maximum of 5 years) while
maintaining patient tolerability. Patients (N=1256) were randomized to observation
(N=629) or pegIFN alfa-2b (N=627) 6mcg/kg per week for 8 weeks (induction) then
3mcg/kg per week (maintenance) for an intended duration of 5 years and stratified
for microscopic (N1) vs macroscopic (N2) nodal involvement, number of positive nodes,
ulceration and tumor thickness. Primary endpoint was recurrence-free survival (RFS).
Median length of treatment with pegIFN alfa-2b was 12 months. At 3.8 years median
follow-up there were 328 recurrences in pegIFN group vs 368 in observation group
(HR 0.82; p=0.01); the 4-year rate of RFS was 45.6% in the IFN groups vs 38.9% in
the observation groups. There was no difference in OS between the groups. Grade
3 adverse events (A/E) occurred in 40% of patients receiving IFN vs 10% A/E in the
observation group; grade 4 A/Es were seen in 5% of the IFN group vs 2% in observation
group. Most common Grade 3 or 4 A/Es in pegIFN alfa-2b group were fatigue (16%),
hepatotoxicity (11%), and depression (6%). Treatment with pegIFN was discontinued
due to toxicity in 31% of patients.
Interpretation (of authors): Adjuvant pegIFN alfa-2b for stage III melanoma has
a significant, sustained effect on RFS.
Discussion (authors):
- Toxicity did not seem to increase with longer duration of treatment.
- In the N1 (microscopic nodal disease) population, the Kaplan-Meier
curves for RFS in the IFN and observation groups separate from one another increasingly
over time, suggesting that prolonged administration of pegIFN alfa-2b could be of
value.
Editorial Comments:
- More and more patients with stage III melanoma are now diagnosed
worldwide with N1 disease and these findings represent a very relevant subset for
therapy.
- The observation that primary tumor ulceration was associated with
benefit from pegylated IFN is particularly intriguing, and must be evaluated.
- In the near future, the prospects of combining pegIFN alfa-2b with
other agents in the adjuvant setting and evaluating it for maintenance use are real
possibilities.
- Further follow-up might show a significant survival advantage for
the N1 population; that would represent the real advance we have been waiting for.
Eggermont AMM, Suciu S, Santinami M, et al. Adjuvant therapy
with pegylated interferon alfa-2b versus observation alone in resected stage III
melanoma: final results of EORTC 18991, a randomised phase III trial. Lancet.
2008;372:117-126.
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