Regional treatment strategies for in-transit melanoma metastasis

Abstract

For in-transit melanoma confined to the extremities, regional chemotherapy in the form of hyperthermic isolated limb perfusion and isolated limb infusion are effective treatment modalities carrying superior response rates to current standard systemic therapy. Despite high response rates, most patients will eventually recur, supporting the role for novel research aimed at improving durable responses and minimizing toxicity. Although the standard cytotoxic agent for regional chemotherapy is melphalan, alternative agents such as temozolomide are currently being tested, with promising preliminary results. Current strategies for improving chemosensitivity to regional chemotherapy are aimed at overcoming classic resistance mechanisms such as drug metabolism and DNA repair, increasing drug delivery, inhibiting tumor-specific angiogenesis, and decreasing the apoptotic threshold of melanoma cells. Concurrent with development and testing of these agents, genomic profiling and biomolecular analysis of acquired tumor tissue may define patterns of tumor resistance and sensitivity from which personalized treatment may be tailored to optimize efficacy. In this article rational strategies for treatment of in-transit melanoma are outlined, with special emphasis on current translational and clinical research efforts.

Copyright © 2011 Elsevier Inc. All rights reserved.

Figures

Figure 1. In-transit melanoma metastases

Right leg with advanced, in-transit metastases of melanoma occurring between site of primary on lower leg and draining lymph node basin. Reproduced with permission from Beasley et al. Surg Oncol Clin N Am. 2008 Oct;17(4):731–58.

Figure 2. Schematic of hyperthermic isolated limb perfusion

The affected limb’s main artery and vein are surgically exposed and openly cannulated. Warming blankets maintain hyperthermia and temperature is monitored with temperature probes. The tourniquet is applied proximally and the melphalan chemotherapy perfusate is circulated with heated, high-flow membrane oxygenator to maintain acid-base status of the limb. Reproduced with permission from Muchmore et al., Surg Oncol Clin N Am. 2008 Oct;17(4):709–30, vii.

Figure 3. Schematic of isolated limb infusion

Catheters are percutaneously inserted into the affected limb. Warming blankets are applied to the limb, but the same degree of hyperthermia in HILP cannot be achieved with ILI. The tourniquet is applied proximally and chemotherapy is circulated manually through a blood warmer using a syringe and 3-way stopcock. Reproduced with permission from Brady et al. Ann Surg Oncol. 2006 Aug; 13(8): 1123–9.

Figure 4. Regional treatment algorithm for in-transit extremity melanoma

Patient entry is denoted at the box labeled “IT disease/local recurrence.” IT, in-transit disease; LN, lymph node; HILP, hyperthermic isolated limb perfusion; ILI, isolated limb infusion; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease. Reproduced with permission from Beasley et al. J Am Coll Surg. 2009 May;208(5):706–15;.