HAMBURG, GermanyAttempts to improve on interferon-based
regimens for melanoma with alternative immuno-stimulant strategies
are proving less successful than originally hoped, according to
presentations at the 25th Congress of the European Society of Medical
Adding high-dose interleukin-2 (IL-2) to a regimen of dacarbazine,
cisplatin (Platinol), and interferon-alfa-2b (IFN, Intron A) has no
significant effect on response rate or overall survival in patients
with advanced melanoma, according to the first analysis of a trial
conducted by the European Organization for Research and Treatment of
The EORTC trial, which involved 363 patients, ranks as the largest
randomized study ever performed in metastatic melanoma.
Study enrollees received up to four cycles of dacarbazine (250
mg/m² on days 1 to 3), cisplatin (30 mg/m² on days 1 to 3),
and IFN (10 MIU/m² on days 1 to 5), with or without intravenous
IL-2, given according to a decrescendo schedule on days 4 to 9. Most
of the participants had visceral metastases, and half had impaired
The response rate according to World Health Organization
criteria was rather low, noted Ulrich Keilholz, MD, of Berlin,
whose group developed the IL-2 decrescendo regimen. Objective
responses were achieved in 24% of patients without IL-2 and 22% of
patients with IL-2, so there was clearly no difference he
Dr. Keilholz stressed that the report is a first analysis, and,
because of time pressure, approximately 20% of responses have not yet
been verified by central review.
Disappointingly, after a median follow-up of 2.3 years, overall
survival was the same in both treatment arms. Median survival in the
EORTC study was 8.2 months.
However, a provocative finding emerged from an analysis of the
survival data according to performance status, which was a
prerandomization stratification variable. In patients with a baseline
Karnofsky score of 100%indicating no impairment in performance
statusthe survival data revealed a trend favoring IL-2.
We need further follow-up in this group to see whether this
trend may translate into a significant difference within the next 6
to 9 months, Dr. Keilholz said. He stressed that multivariate
analysis is the only way to confirm whether IL-2 affords any
advantage in the good-prognosis subgroup. The EORTC will be pursuing
additional studies of the potential role of IL-2 in advanced melanoma
patients with unimpaired performance status.
Vaccine No Substitute for IFN
Vaccination with an antibody against GM2 ganglioside, a well-defined
melanoma antigen, has failed to displace high-dose interferon-alfa-2b
as the gold standard for high-risk resected stage IIB-III melanoma,
said John Kirkwood, MD, of the University of Pittsburgh Cancer
Institute. He reported the results of a recent US Intergroup phase
The trial randomized 880 patients with T4 or node-positive disease to
receive the so-called GMK vaccine, administered weekly for 4 weeks
and thereafter every 12 weeks for 96 weeks, or high-dose IFN, given 5
days a week for 4 weeks and thereafter every other day for 48 weeks.
Although the GMK vaccine induced IgM antibodies in 87% of patients
and IgG antibodies in 33%, immunologic efficacy did not translate
into clinical benefit. Review of the data after 16 months of
follow-up revealed significantly superior relapse-free survival and
overall survival among patients on high-dose IFN.
With 774 eligible patients, in this, our largest trial of
high-dose IFN to date, 39% of patients on the vaccine relapsed vs 25%
of those in the IFN group, Dr. Kirkwood said. Mortality was
20.8% among the vaccine patients, compared with 13.5% among
IFN-treated patients, he added.
The advantage of IFN relative to the vaccine was significant across
all treatment strata, but was greatest in patients without nodal
involvement. On the positive side, the GMK vaccine was considerably
less toxic than IFN, and there was no evidence to suggest that it had
any adverse effect on patient outcome.
High-dose IFN is therefore reaffirmed as the standard of
adjuvant therapy, as it has been in the United States for the last 5
years, Dr. Kirkwood said.