Optimizing Regional Therapy for Melanoma

In this issue of Annals of Surgical Oncology, Kroon et al. describe the toxicity of isolated limb infusion with melphalan and actinomycin D in their experience with 185 patients over 15 years. This work continues to expand on the group’s notable contributions to regional chemotherapeutics for extremity melanoma including their initial description and utilization of isolated limb infusion (ILI) in the early 1990s. ILI has been explored as a minimally invasive alternative to hyperthermic isolated limb perfusion (HILP) for advanced extremity melanoma whereby placement of percutaneously placed catheters allows delivery of regional chemotherapy to an isolated limb. In the current study, ILI was found to be a safe alternative to HILP with less long-term morbidity than HILP. Previously, the Sydney Melanoma Group has reported response rates that are less than traditional response rates to HILP but certainly not outside the range of reported studies of HILP. Due to the safety and efficacy of the treatment as well as disappointing results of a multicenter HILP trial, ILI is now utilized at several major US centers and has been demonstrated to be a well-tolerated treatment alternative for patients with advanced extremity melanoma. As with any new regional treatment, the goal should be to define the procedure’s therapeutic index, which balances the treatment’s toxicity with its ability to control disease. Results of the current study suggest that there may be additional methods to reduce toxicity from ILI by altering modifiable factors which were found to be predictive of higher grades of toxicity. In addition this study’s results further support a role for ILI as a safe treatment in the armamentarium of therapeutic options for patients with advanced extremity melanoma. ILI is essentially a low-flow HILP performed by insertion of percutaneous catheters in the contralateral limb, in contrast to HILP where open surgical cannulation of the artery and vein are performed. ILI is performed attempting to achieve temperatures in the range 37–38.5 C and the blood is not oxygenated, leading to hypoxia and acidosis in the limb. The hypoxia and acidosis of ILI have previously been suggested to be beneficial in terms of response. In HILP, the catheters are connected to a cardiopulmonary bypass circuit which maintains physiologic oxygenation and pH. Temperatures in HILP generally range from 38.5 C to 40 C. While hyperthermia is well documented to increase the cytotoxicity induced by melphalan, excessive heat can also increase the toxicity of melphalan to normal tissue. ILI also differs from HILP in that ILI uses less melphalan per liter of extremity treated, circulates blood in an isolated extremity at a much slower rate than HILP (50– 100 mL/min in ILI versus 350–1,000 mL/min in HILP), and treatment is only for 30 min as compared with 60 min in HILP. These differences in the method of drug delivery are important to consider when comparing toxicity and response between the two procedures. In both ILI and HILP, there appears to be no relationship between significant limb toxicity and response to treatment. As such, minimizing toxicity from these procedures as discussed by the authors should be a goal of therapy. In the current study, high-grade limb toxicity (Wiberdink toxicity C grade 3) occurred in 42% (n = 77) of patients. Only 3% (n = 5) of patients had grade IV toxicities and there were no grade V toxicities (grade V toxicity is a toxicity necessitating amputation). Systemic toxicities were minimal and melphalan was detected in the systemic circulation in only 6% of patients. There were no systemic effects clearly associated with leakage of the small amounts of melphalan into the systemic circulation. Low circulating volumes seen in ILI were not related to increased limb toxicity. Overall toxicity from this study is in a similar range to the spectrum of toxicity after HILP. However, as the authors point out, long-term morbidity and severe toxicity (grade V) appear to be less with ILI. In a Society of Surgical Oncology 2009