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Adjuvant therapy remains important option for high-risk melanoma patients

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NEW YORK — Adjuvant therapy remains an important treatment option for those who are at high risk for progression to metastatic melanoma, according to a presentation at the HemOnc Today Melanoma and Cutaneous Malignancies Meeting.

Even if adjuvant therapy does not cure a patient, the potential to delay relapse can yield significant clinical benefit, said Sanjiv S. Agarwala, MD, a HemOnc Today Editorial Board member and course director of the HemOnc Today Melanoma and Cutaneous Malignancies meeting.

“I would argue that’s much more relevant today, considering there are patients I treated with adjuvant therapy who might relapse in 2012 as opposed to early 2011, when I didn’t have treatments like the BRAF inhibitors or ipilimumab or some of the other drugs in development,” said Agarwala, professor of medicine at Temple University School of Medicine and chief of oncology and hematology at St. Luke’s Cancer Center in Bethlehem, Pa.

“The gold standard of any therapy is OS,” Agarwala said. “However, if I tell a patient, ‘I can’t cure you, but I might delay your relapse by ‘X’ amount of time’ and I go through the data with them, most are very accepting of that, provided their quality of life on the treatment isn’t miserable … OS is what you want, but RFS is still better than nothing, in my opinion.”

Clinical trials have shown interferon to be the most effective agent for adjuvant therapy, but only high-dose regimens — IV induction of 20 MIU/m² five times weekly for 4 weeks, followed by 11 months of maintenance in which patients receive 10 MIU/m² three times weekly — have demonstrated clinical benefit in disease-free survival and OS.

The ECOG 1684 trial compared adjuvant therapy with high-dose interferon alpha-2b to observation in 287 patients following surgery for deep primary (T4) or regionally metastatic (N1) melanoma. The results showed 51 of the 146 patients (34.9%) assigned to high-dose interferon experienced relapse-free survival through a median follow-up of 12.6 years.

Some researchers hypothesized that much of the benefit of high-dose interferon arose from the 1 month of IV induction.

Agarwala and colleagues conducted the randomized E1697 trial to compare short-duration intensive therapy (n=565) — high-dose interferon alfa-2b for 4 weeks induction only — with observation (n=546). Eighty percent of patients had node-negative disease, the majority of melanomas were 2 mm to 4 mm thick, and ulceration was present in about one-third of patients.

The results, which Agarwala presented at the 2011 ASCO Annual Meeting, showed 4 weeks of adjuvant therapy with the induction phase only did not improve RFS or OS.

“If you are going to use high-dose interferon with the IV induction, you have to add the 11 months of subcutaneous therapy,” Agarwala said. “Do not shorten it to 4 weeks … It is not effective.”

Another trial conducted by Eggermont and colleagues — derived from the hypothesis that less intensive therapy given for a longer duration could yield clinical benefit — evaluated the effectiveness of pegylated interferon alpha.

Researchers randomized 1,256 node-positive patients to either pegylated IFN — induction with 6 μg/kg weekly for 8 weeks, followed by 3 μg/kg weekly for up to 5 years — or observation. Study results showed an RFS advantage for pegylated IFN after about 9 years of follow-up (HR=0.87; 95% CI, 0.76-1.00; P=.05) but no OS advantage.

“At least there is RFS,” Agarwala said. “If RFS is sustained — and this is long follow-up — that is certainly something that is valuable for patients.”

More details about the potential benefits of adjuvant therapy for melanoma are expected to emerge soon.

A recently completed EORTC trial (18871) compared ipilimumab with placebo for patients with resected stage III melanoma. Another trial (18881) due to be initiated in June will compare pegylated interferon vs. observation with patients with ulcerated melanomas greater than 1 mm in thickness (T2-T4). The ECOG trial E1609, which is under way, will evaluate ipilimumab vs. standard high-dose interferon. Results of a trial comparing biochemotherapy with high-dose interferon will be presented at the 2012 ASCO Annual Meeting in June.

“Certainly there could be some subsets of patients who benefit more than others, but that must be prospectively validated in clinical trials,” Agarwala said.

Disclosure: Dr. Agarwala was a consultant for Merck & Co. Inc. He also served on the speakers’ bureaus for Bristol-Myers Squibb and Genentech.