Standardizing Regional Therapy: Developing a Consensus on Optimal Utilization of Regional Chemotherapy Treatments in Melanoma

Abstract

In this issue of Annals of Surgical Oncology, Huismans et al. describe their extensive experience with isolated limb infusion (ILI) in the treatment of 185 patients with intransit melanoma over a 15-year period (1992–2007). The group initially described and introduced the technique of ILI in the early 1990s as a minimally invasive alternative to hyperthermic isolated limb perfusion (HILP) whereby placement of percutaneously placed catheters allows delivery of regional chemotherapy (usually melphalan plus dactinomycin) to an isolated limb. Because of the safety and efficacy of the treatment as well as disappointing results of a multicenter HILP trial, ILI is now utilized at several major U.S. centers and has been demonstrated to be a well-tolerated treatment alternative for patients with advanced extremity melanoma. As with any new technique, evidenceand observationbased modifications have been applied to ILI with the goal of maximizing response in conjunction with minimizing toxicity from the procedure. In this study, the authors compare outcomes after initial ILI from their early experience (1992–1999) in 94 patients to their subsequent, or late, experience in 91 patients after several modifications were incorporated into the ILI protocol (2000–2007). The authors conclude that the study’s results support the use of the modifications, although no significant changes in response or toxicity were seen with the modifications. Despite the lack of change, the underlying response rates over the entire period still support a role for ILI as a safe treatment in the armamentarium of therapeutic options for patients with advanced extremity melanoma. There are many aspects of ILI in need of standardization, as is shown in Table 1. Some of these issues revolve around the following: optimal method of drug dosing, technical aspects of performing the ILI procedure, and how best to define toxicity and response after the procedure. Currently, theoretical evidence suggests that the hypoxia and acidosis of ILI may be beneficial by optimizing how melphalan is metabolized and leads to an antitumor response. Hyperthermia is also thought to improve clinical response induced by alkylating agents like melphalan, but within a narrow therapeutic window such that excessive heat may increase the toxicity of melphalan to normal tissue. Finally, papaverine is thought to improve response by maximizing subcutaneous vasodilation and thereby improving melphalan delivery to the tumor, as was suggested in a U.S. multicenter analysis. In the current study, modifications to the ILI protocol included increasing drug circulation time from 20 to 30 min, the use of a hot air blanket cocoon and a radiant overhead heater to achieve more efficient limb warming, use of a higher melphalan dose (5–7 mg/l for early vs. 7–8 mg/l for late), and routine use of papaverine. These changes did result in some not unexpected measurable differences between the early and late groups, including median difference in PCO2 in the limb blood between the start and the end of the procedure, which increased from 8.8 to 14.7 mm Hg (P 0.0001), and an increase in peak subcutaneous temperature (37.7 vs. 38.7) (P 0.0001). These changes, however, did not appear to significantly affect overall tumor response or limb toxicity. There was no significant difference between complete or partial response (PR) in the early versus late group with a trend toward a lower complete response (CR) rate (36%, 38 Society of Surgical Oncology 2011