ASCO 2010-PERCUTANEOUS HEPATIC PERFUSION FOR MELANOMA METASTASES

June 5, 2010 (Chicago, Illinois) — For patients with hepatic metastases from primary melanoma, a new minimally invasive regional therapy significantly improved hepatic progression-free survival. Compared with patients who received conventional treatment, those treated with melphalan (Alkeran, GlaxoSmithKline) using the Delcath Percutaneous Hepatic Perfusion system had a 54% reduction in time to tumor progression or death.

According to the study results presented here at the American Society of Clinical Oncology 2010 Annual Meeting, patients who received the novel therapy achieved a median hepatic progression-free survival of 245 days (95% confidence interval [CI],136 - 267), whereas those who received the current standard of care achieved a median of 49 days (95% CI, 43 - 68; P < .001).

However, Dirk Schadendorf, MD, from University Hospital Essen in Germany, noted that a major problem with the study is that it did not try to demonstrate an overall survival benefit.

"A substantial number of patients crossed over, and the overall survival is very close between the 2 groups," said Dr. Schadendorf, who served as a discussant for the study. "This may be due to crossover."

More Options Needed

Only about 25% of patients with liver cancer are eligible for resection, and current treatments for patients with unresectable tumors are limited, the authors note. The median survival for patients with hepatic metastases from primary melanoma is between 6 and 9 months, and few available treatment strategies have a meaningful impact on outcome.

A large number of melanomas will recur, explained lead author James F. Pingpank, MD, FACS, associate professor of surgery at the University of Pittsburgh School of Medicine in Pennsylvania. "The liver is the sole or dominant site of disease in over 80% of cases."

Systemic chemotherapy or immunotherapy often does not halt disease progression. However, regional therapy allows dose escalation to the cancer-bearing region or organ while minimizing systemic exposure and toxicity, said Dr. Pingpank during his presentation. "The delivery of clinically relevant levels of hyperthermia or biologic agents is possible. Regional therapy also eliminates or reduces systemic toxicity."

In this phase 3 study, the authors examined the effectiveness of delivering high doses of melphalan to the liver by hepatic arterial infusion. This trial was initiated after a phase 1 dose-escalation study was conducted. "We saw that we were able to have good delivery to the liver with minimal delivery to general circulation," said Dr. Pingpank.

Progression-Free Survival Improved

From February 2006 to October 2009, 93 patients with hepatic metastases from malignant melanoma were randomized to receive percutaneous hepatic perfusion with melphalan (n = 44) or the standard of care (n = 49), which includes supportive care, systemic or regional chemotherapy, and any appropriate therapy administered at the discretion of the physician.

The mean age of the cohort was 54.8 years, and the majority of patients had not received previous therapy. The trial started as a single-institution study, transitioned to a multicenter trial, and was ultimately conducted in 10 centers.

The primary end point of the study was hepatic progression-free survival, and crossover to the experimental group was permitted at hepatic progression. Secondary end points included assessment of response rate, duration of response, and overall survival.

The regimen consisted of 4 to 6 percutaneous hepatic perfusions at 28- to 35-day intervals, delivering 3.0 mg/kg melphalan in a 30-minute hepatic-artery infusion using a percutaneously placed catheter with hepatic venous hemofiltration and a retrohepatic double-balloon catheter.

There was an overall response rate of 34.1% (n = 15) for patients receiving experimental therapy, and of 2.0% (n = 1) for those receiving standard care (P < .001). No complete responses were observed. A total of 27 (55%) patients who were randomized to standard care crossed over to percutaneous hepatic perfusion upon hepatic progression.

Other Limitations

Dr. Schadendorf pointed out the study had limitations. There are relevant data missing, he said; it is unclear which patients had metastases only to the liver and which had metastasis to other sites.

"Clinical benefits, aside from local control, are also missing," he said. "Crossover, in my view, is a sign of bias, so we don't know the full benefit to the patient."

The study was funded by Delcath Systems. Dr. Pingpank and coauthor J.S. Zager, MD, from the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Florida, report serving on the scientific advisory board of Delcath Systems.

American Society of Clinical Oncology (ASCO) 2010 Annual Meeting: Abstract LBA8512. Presented June 5, 2010.