Prognostic Factors Influencing Tumor Response, Locoregional Control and Survival, in Melanoma Patients with Multiple Limb In-transit Metastases Treated with TNF alpha-based Isolated Limb Perfusion

Abstract

Background: In isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNF alpha) and interferon (IFN)-gamma, pioneered by Lienard and Lejenne in 1988, TNF alpha was empirically employed at a dosage (3-4 mg) ten times higher than the systemic maximum tolerable close (MTD). We previously conducted a phase I/II study in 20 patients with in-transit melanoma metastases, using a combination of melphalan and TNF alpha at dosages ranging from 0.5 to 3.3 mg. The dose of 1 mg of TNFa was identified as optimal in terms of both efficacy and toxicity. The aim of the present study was to describe our experience with 113 stage IIIA/IIIAB melanoma patients treated with a TNF alpha-based ILP and identify prognostic factors for response, locoregional control and survival. Patients and Methods: Patients at stage IIIA-IIIAB (presence of in-transit metastases and/or regional node involvement) were considered eligible. The disease was bulky (>= 10 nodules :53 cm or fewer nodules with a diameter > 3 cm) in 42.5% of the patients and unresectable in 33%. Forty patients were treated with a TNFa dosage of > 1 mg and 73 with 1 mg. Patients with tumors in the tipper and lower limbs were submitted to ILP via axillary and iliac vessels, respectively. TNF alpha was injected in the arterial line of an extracorporeal circuit at the pre-established close, followed by melphalan (13 and 10 mg/l of limb volume for the upper and lower limbs, respectively) 30 minutes later. Results: Complete responses (CR) and partial responses (PR) were 63% and 24.5%, respectively, with an objective response (OR) of 87.5%. No change (NC) was observed in only 12.5% of the patients. Upon multivariate analysis, only bulky disease maintained its independent value for tumor response with an odds ratio of 4.07 and a p-value of 0.02. The 5-year locoregional disease-free survival was 42.7%. Upon multivariate analysis, the only prognostic factors were stage, age and bulky disease. The 5-year overall survival was 49%. Multivariate analysis showed that only, sex, stage and CR maintained their independent values. Conclusion: TNF alpha-based ILP was proven to be an effective treatment for melanoma patients with in-transit metastases. The TNF alpha dosage of 1 mg was as effective as 3-4 mg, with lower toxicity and cost. We propose that TNF alpha and melphalan-based ILP should be employed for bulky tumors or after failure of melphalan-based ILP