Heterogeneity of chemosensitivity of metastatic cutaneous melanoma

Advanced melanoma has a poor prognosis and chemotherapy provides little ben efit for most patients. This may be related to heterogeneity of chemosensit ivity as well as frequent constitutive resistance to individual cytotoxic d rugs. We have therefore examined the heterogeneity of chemosensitivity in m etastatic cutaneous melanoma specimens using an ex vivo ATP-based chemosens itivity assay (ATP-TCA). Melanoma deposits (n=55) in skin or lymph node wer e tested using the ATP-TCA, performed in three separate laboratories. Analy sis of the data collected (based on an arbitrary sensitivity index < 300) s hows considerable heterogeneity of chemosensitivity. The most active single cytotoxic agents in the assay were identified as cisplatin, treosulfan, pa clitaxel, vinblastine, gemcitabine and mitoxantrone, There was also a limit ed direct inhibition of melanoma cell growth by interferon-alpha 2b, althou gh this agent is known to have a number of indirect biological antitumor ef fects. Exposure of tumor cells to combinations of drugs at the concentratio ns tested as single agents showed the most active combinations to be treosu lfan+gemcitabine, cisplatin+paclitaxel and vinblastine+paclitaxel. There wa s considerable heterogeneity of chemosensitivity: some tumors responded wel l to one agent or combination, while others showed no response to this and instead responded to one of the alternatives tested. Occasional highly resi stant tumors showed no response to any of the single agents or combinations tested. The degree of heterogeneity observed suggests that the ATP-TCA cou ld be used to select patients who might benefit from specific chemotherapeu tic agents alone or in combination, This provides the rationale for future randomized controlled trials of ATP-TCA-directed chemotherapy versus physic ian's choice to determine whether assay-directed chemotherapy can improve p atient response and survival. [(C) 1999 Lippincott Williams & Wilkins.].