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Biochemotherapy offers potential alternative to interferon for high-risk melanoma
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NEW YORK — Biochemotherapy may be a viable alternative to interferon in adjuvant therapy for high-risk melanoma patients, according to a presenter at the HemOnc Today Melanoma and Cutaneous Malignancies meeting.
Prior studies have shown that the use of interferon in the adjuvant setting extends DFS and OS in high-risk patient populations. Still, at least 50% of patients with stage III, high-risk disease treated with high-dose interferon (HDI) experience disease progression and die, Lawrence E. Flaherty, MD, of the Barbara Ann Karmanos Cancer Institute at Wayne State University in Detroit, said during a presentation.
“There have been numerous modifications to the dose, duration and administration of interferon that have not led to better outcomes, and it has been difficult to combine with other agents,” Flaherty said. “A brief, more intense therapy made up of agents that possibly could be replaced in the future as the field evolves and develops was sought.”
Biochemotherapy seemed to fit that need. Research conducted in the 1990s involving patients with stage IV disease showed that biochemotherapy (BCT) with interleukin-2 (IL-2) and interferon induced response rates ranging from 40% to 60%, durable complete remissions in 10% of patients, and responses in patients who underwent prior adjuvant therapy with interferon.
In the phase 3 SWOG S0008 study — results of which were presented at the ASCO Annual Meeting last year — Flaherty and colleagues compared HDI with BCT in 402 patients with stage III disease.
Investigators assigned 203 patients to 12 months of HDI, which included standard induction and maintenance.
The other 199 patients were assigned to a 2-month BCT regimen that included cisplatin, vinblastine, IL-2 as a 96-hour infusion, and interferon every 3 weeks. Week 2 of each 3-week cycle included interferon and granulocyte colony–stimulating factor.
Patients in both study arms were well matched for age, sex, race and other features, Flaherty said. Tumor characteristics — including number of positive nodes, nodal status and ulceration of primary site — also were well balanced.
OS and RFS served as co-primary endpoints. Median follow-up was 6.25 years.
Patients assigned to BCT achieved longer median RFS (4.31 years vs. 1.90 years; P=.017) and a higher rate of 5-year RFS (47% vs. 39%; HR=0.76; 95% CI, 0.58-0.98). The findings distinguished the BCT regimen as the only therapy to demonstrate a statistically significant improvement in RFS compared with HDI in patients with high-risk, stage III disease, Flaherty said.
However, BCT was not associated with improved OS (HR=1.02; 95% CI, 0.76-1.37). The investigators reported 5-year survival of 56% in both study arms.
Patients assigned to BCT experienced higher rates of grade 4 toxicities, including neutropenia (26% vs. 4%; P<.01), thrombocytopenia (14% vs. 0%; P<.01) and leukopenia (13% vs. 1%; P<.01). BCT was associated with significantly higher overall rates of grade 3 and 4 hematologic, metabolic and gastrointestinal toxicities, but significantly lower rates of grade 3 and 4 neurological/psychological and hepatic toxicities.
Despite higher rates of toxicities, a larger percentage of patients assigned to BCT completed a full course of therapy (80% vs. 43%), and fewer patients stopped treatment due to toxicity (15% vs. 19%).
One death occurred in each group. Both were due to cardiovascular events.
The researchers conducted an exploratory analysis to investigate why the robust difference in RFS between the two arms did not translate to a comparable difference in OS.
When they investigated differences in the site of relapses between the two arms, results showed more patients assigned to HDI experienced both regional progression (49 vs. 37) and distant progression (73 vs. 56).
When they further examined initial sites of progression, data showed patients assigned to HDI had higher incidence of local (17 vs. 11), in-transit (13 vs. 10) and regional nodal progression (22 vs. 16).
The researchers also determined patients assigned to HDI experienced longer OS after progression (HR=1.44; 95% CI, 1.06-1.96).
The trial design did not require data on post-relapse treatment. Based on information that clinical research associates voluntarily entered into the record, patients assigned to HDI were reported to have received more treatment at relapse than patients who underwent BCT.
The findings also showed patients assigned to HDI who relapsed within the first year experienced slightly better outcomes than patients who relapsed after 1 year.
“Whether that is due to additional therapy applied in those circumstances is unclear,” Flaherty said. “That is the data we’re missing that we would love to have.”
The researchers will continue to monitor OS curves long term, Flaherty said.
“Without an overall survival benefit, I don’t think we can say that biochemotherapy replaces interferon as the standard of care, but it certainly may be an attractive alternative,” he said. “I also think we have an opportunity to build on this. There are five drugs in this regimen that can be replaced with other new and promising agents as they appear on the melanoma scene.”
For more information:
Flaherty LE. Does biochemotherapy have a role in adjuvant therapy? Presented at: HemOnc Today Melanoma and Cutaneous Malignancies; March 22-23, 2013; New York.
Flaherty LE. Abstract #8504. Presented at: ASCO Annual Meeting; June 1-5, 2012; Chicago.
Mocellin S. J Natl Cancer Inst. 2010;102:493-501.
Disclosure: Flaherty reports consulting roles with Genomic Health and Merck; fees for non-CME services from Genentech and Roche; and contracted research with Bristol-Myers Squibb, Genentech and Roche.