Treatment of melanoma in-transit metastases confined to the limb

Background: In-transit metastases develop in 5 to 8% of melanoma patients. They present as single or multiple (sub)cutaneous nodules close by the tumor (satellitosis < 3 cm of the primary tumor; stage II) or scattered over the whole extremity (> 3 cm from the primary tumor; stage IIIA). They can appear synchronously together with the primary tumor or as a regional relapse and precede most often the appearance of systemic metastases. The management of regionally recurrent melanoma remains a challenge at present. Methods: Various locoregional treatments are reviewed. The choice depends primarily on the number and size of the lesions and on the general condition of the patient. Treatments vary from (multiple) excision(s), laser-evaporation, intralesional injection of interferons, regional chemotherapy, e.g. intraarterial chemotherapy, isolated limb infusions and isolated limb perfusions. Results: A single or only a few in-transit metastases are initially usually treated by surgical excision. Carbon dioxide laser management of recurrences has been reported successful only in the management of small nodules (< 1.5 cm). Intralesional injections with interferons (α/β) yields modest response rates of short duration. Intraarterial chemotherapy is ineffective. Isolated limb infusions with application of a tourniquet seems more effective, but experience is very limited. Isolated Limb Perfusion (ILP) using an extracorporeal perfusion circuit is the most effective therapy available for inoperable melanoma, providing excellent local control but no clear survival benefit. However, about 25% of the patients with stage II to IIIA are alive after 5 to 10 years. Thus ILP can be curative. An overall response rate of about 80% (40% CR, 40% PR) can be obtained by a single perfusion with melphalan, the standard drug in this disease. Hyperthermia may improve response rates, but at the cost of increased regional toxicity. Perfusion with the combination of Tumor Necrosis Factor α (TNFα), Interferon-gamma (IFNγ) and melphalan has proven most effective, yielding a 80 to 90% complete response rate, and an overall response rate of 100%. Conclusions: Multiple lesions or rerecurrences in stage II to IIIA/AB are best treated by ILP, in particular ILP with melphalan + TNFα, resulting in 100% response rate. This last treatment is now available in a few perfusion centers in Europe. Reports often do not mention duration of local tumor control after ILP, in spite of the fact that this is the most important measurestick of success. The main issue for the future will be prolongation of the limb recurrence-free interval.