Regional therapeutic strategies in melanoma: not just local disease control, but an opportunity to develop novel therapeutic strategies with potential implications for systemic therapy.

Since the initial description of isolated regional chemotherapeutic perfusion therapy in 1958 by Creech et al., there have been surprisingly few modifications to this therapeutic intervention for advanced extremity melanoma over the last 50 years. In this issue of Annals of Surgical Oncology, Kroon et al. publish their manuscript entitled ‘‘Outcomes following isolated limb infusion for melanoma. A 14-year experience,’’ which summarizes the Sydney Melanoma Unit’s experience using melphalan and dactinomycin for regionally advanced melanoma administered through a minimally invasive regional chemotherapy procedure that they developed and initially described. The initial results and subsequent follow-up suggest that isolated limb infusion (ILI) may be a reasonable alternative to hyperthermic isolated limb perfusion (HILP) in the management of regionally advanced melanoma, in the form of intransit disease or local recurrence. However, as with any technique that is initially described in a large single-institutional fashion, care must be taken in defining the place for this treatment modality until its efficacy is tested on a wider scale. ILI differs from HILP in several ways. ILI involves isolating an extremity by placing catheters into the affected extremity percutaneously, in contrast to HILP, which requires an open surgical procedure. ILI has a very small circuit volume and generates flow rates of only 55–75 ml/min. HILP has not only a much larger circuit volume, which usually necessitates priming the circuit with one or two units of packed red blood cells, but is also able to generate much greater flow rates than ILI, usually in the 500– 700 ml/min range. The higher flow rates of HILP probably lead to a wider and more uniform distribution of melphalan throughout the isolated extremity. While both techniques use melphalan as the core chemotherapeutic agent, the melphalan dose used in ILI is approximately 25% lower than that used in HILP. Furthermore, the ILI technique circulates the melphalan for only 30 min, in contrast to HILP where the standard drug circulation time is 60 min. While both techniques involve the addition of hyperthermia, ILI usually initiates treatment at 37 C, while with HILP, the higher flow rates allow the limb to heat up faster and thus treatments are usually started at 38.5 C. The environment in which the melphalan circulates is also different between the two techniques. ILI circulates melphalan in a hypoxic, acidotic environment unlike HILP, where, using the bypass machine, the acid–base status of the treated limb and the oxygenation status are maintained in or above the physiologic range. Despite these marked differences, there is little clear scientific data to determine which technique delivers melphalan in a method that will optimize its effectiveness. As the procedure for ILI is more widely adopted for managing regionally advanced disease, it will be important to examine the results of other centers to determine how reproducible the results of the Sydney Melanoma Unit (SMU) will be. There are currently Published online August 19, 2008. Address correspondence and reprint requests to: Douglas Tyler, MD; E-mail: tyler002@acpub.duke.edu