Metastatic melanoma: is biochemotherapy the future?

Current treatment options in metastatic melanoma are of limited efficacy. Achievement of durable responses with biological agents, and the possibility to complement the higher response rate of chemotherapy and combined chemotherapy by prolonged duration of responses, led to development of biochemotherapy. Although a clear improvement in response rate (40-60% OR) resulted in some studies of the combined modality, several phase III studies had mixed results on the duration of survival. Various timeframes between the administration of chemotherapy and biologics have been tested, ranging between concurrent biochemotherapy, 1 d (immediately sequential), and up to 3 wk (long sequence or alternating). An analysis of the trend of responses and survival versus the duration of the chemobiotherapy sequence showed that, as the timeframe between chemo and bio components increases, the overall survival, survival of complete responders, and survival of partial responders appear to increase, but the effect is only present for the chemo-bio, and not for the bio-chemo sequence. Because there is no current explanation for this observation, it appears possible that the interaction between components of biochemotherapy results in a double effect: an increase in the immediate response reflected in the OR, CR, PR on one side, and an increase in survival on the other side. An analysis of mechanisms involved in the response leads us hypothesize that macrophage activation, as measured by the neopterin levels, may correlate with the survival of patients undergoing biochemotherapy, while the generation of nitric oxide, acting synergistically with chemotherapy in producing tumor cell killing, may be reflected in the overall response rate seen with the biochemotherapy combinations.