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Update on Adjuvant Interferon Therapy for High-Risk Melanoma

Update on Adjuvant Interferon Therapy for High-Risk Melanoma

Two of the most important predictors of relapse (and, therefore, survival) in
patients with melanoma are the Breslow thickness of the primary melanoma and
regional lymph node involvement. Patients with melanomas greater than 4 mm in
thickness have approximately a 50% risk of recurrence, and those with lymph node
involvement have a 50% to 85% risk of recurrence depending on the number of
lymph nodes involved. Thus, a group of patients can be identified who are at
high risk of death from melanoma and are, therefore, appropriate candidates for
postsurgical adjuvant therapy.

Over the past 20 years, numerous agents have been evaluated in a series of
nonrandomized and randomized adjuvant therapy trials in melanoma patients. Many
of these trials suffered from serious methodologic problems, (such as inadequate
statistical power, use of inappropriate controls, and lack of stratification for
known prognostic factors). However, the major obstacle to the success of
adjuvant therapy for melanoma has been the lack of active agents. Agents tested,
with little or no benefit, include bacillus Calmette-Guérin (BCG), levamisole (Ergamisol),
interferon gamma-1b (Actimmune), interleukin-2, retinoids, dacarbazine (DTIC-Dome),
and megestrol acetate.

Drs. Agarwala and Kirkwood thoroughly review the completed and ongoing trials
of interferon-alpha as postsurgical adjuvant treatment of melanoma patients.
Although clinicians generally agree with most of the conclusions reached by the
authors, the role of high-dose interferon in patients with high-risk melanoma
remains controversial. Drs. Agarwala and Kirkwood conclude that high-dose
interferon is the standard of care for patients with high-risk melanoma and,
therefore, is the most appropriate control for future adjuvant clinical trials.
However, there is considerable discussion and debate as to whether high-dose
interferon improves overall survival in patients with high-risk melanoma.

ECOG Trial E1684

The data from the clinical trials reviewed by Drs. Agarwala and Kirkwood
consistently demonstrate that high-dose interferon is associated with
improvement in disease-free survival. Multiple randomized trials have shown that
high-dose interferon alfa-2b for 1 year improves relapse-free survival compared
with observation. However, in terms of overall survival, the only clinical trial
of high-dose interferon that has demonstrated an improvement in overall survival
is the Eastern Cooperative Oncology Group (ECOG) study E1684. In that trial,
patients with high-risk melanoma were randomized to either high-dose interferon
alfa-2b (Intron A) therapy for 1 year or observation after surgery. As
reported, the median survival was increased by 1 year in the treatment arm,
and there was a 10% increase in the 5-year overall survival rate (46% for
interferon vs 37% for observation, one-sided P = .0237).

Does this result justify the use of interferon, and are the differences
between the two arms statistically significant? Only a one-sided test was
reported: Had the results been reported with a more standard and appropriate
two-sided test, the resulting P value would have been greater and barely
statistically significant. Use of the less stringent measure is appropriate when
one assumes only a benefit for the experimental therapy and no possible harm. In
fact, when a two-sided test was performed by Cole et al in a later
quality-of-life study using the same data set, there was no statistically
significant difference between the treatment and observation arms in terms of
overall survival (P = .07).[1]

Moreover, an updated analysis of E1684 by Kirkwood no longer showed a
survival advantage at a median 12.6 years of follow-up: The high-dose
interferon arm had 93 deaths in 146 patients, whereas the observation arm had 95
deaths in 140 patients. Although a trend toward improved overall survival in the
interferon-treated patients remains, the one-sided log-rank test showed a P
value of .09.[2]

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