Results of a Randomized Controlled Multicenter Phase III Trial of Percutaneous Hepatic Perfusion Compared with Best Available Care for Patients with Melanoma Liver Metastases

Abstract

Purpose: There is no consensus for the treatment of melanoma metastatic to the liver. Percutaneous hepatic perfusion with melphalan (PHP-Mel) is a method of delivering regional chemotherapy selectively to the liver. In this study, we report the results of a multicenter, randomized controlled trial comparing PHP-Mel with best alternative care (BAC) for patients with ocular or cutaneous melanoma metastatic to the liver.

Patients and methods: A total of 93 patients were randomized to PHP-Mel (n = 44) or BAC (n = 49). On the PHP-Mel arm, melphalan was delivered via the hepatic artery, and the hepatic effluent captured and filtered extracorporeally prior to return to the systemic circulation via a venovenous bypass circuit. PHP-Mel was repeatable every 4-8 weeks. The primary endpoint was hepatic progression-free survival (hPFS), and secondary endpoints included overall PFS (oPFS), overall survival (OS), hepatic objective response (hOR), and safety.

Results: hPFS was 7.0 months for PHP-Mel and 1.6 months for BAC (p < 0.0001), while oPFS was 5.4 months for PHP-Mel and 1.6 months for BAC (p < 0.0001). Median OS was not significantly different (PHP-Mel 10.6 months vs. BAC 10.0 months), likely due to crossover to PHP-Mel treatment (57.1 %) from the BAC arm, and the hOR was 36.4 % for PHP-Mel and 2.0 % for BAC (p < 0.001). The majority of adverse events were related to bone marrow suppression. Four deaths were attributed to PHP-Mel, three in the primary PHP-Mel group, and one post-crossover to PHP-Mel from BAC.

Conclusion: This randomized, phase III study demonstrated the efficacy of the PHP-Mel procedure. hPFS, oPFS, and hOR were significantly improved with PHP-Mel. PHP with melphalan should provide a new treatment option for unresectable metastatic melanoma in the liver.

FIG. 1

Consort flow diagram of phase III trial of PHP (melphalan) compared with BAC. PHP percutaneous hepatic perfusion, BAC best alternative care, Mel melphalan

FIG. 2

ITT intention-to-treat, CI confidence interval, PFS progression-free survival, BAC best alternative care, PHP percutaneous hepatic perfusion

FIG. 3

Maximum percent change in hepatic tumor size by treatment in the phase III study. ITT intention-to-treat, BAC best alternative care, PHP percutaneous hepatic perfusion

FIG. 4

Metastatic ocular melanoma. Baseline and post-treament scans on a patient with ocular melanoma with bilobar liver metastases treated with PHP-mel. Treatment response correlates with decrease in LDH. Patient was successfully retreated with melphalan via IHP at disease recurrence within the liver.