Hyperthermia may act additively or synergistically with a majority of clinically useful chemotherapeutic agents in vitro. In some cases enhanced responses are essentially linear at temperatures from 39 to 43 degrees C (
thiotepa, the nitrosoureas,
cisplatin), while other drugs become more effective only at 42 to 43 degrees (
doxorubicin,
bleomycin,
amphotericin B). Synergism has been observed in vivo with
methotrexate,
cyclophosphamide, the nitrosoureas,
doxorubicin,
bleomycin, and
cisplatin. Optimum enhancement occurs when heat and
drug are given simultaneously. Clinical studies employing WBH at 41 to 41.8 degrees C have shown evidence of potential usefulness, but have been limited by high toxicity and a low benefit-to-risk ratio. Regional perfusion of metastatic
melanoma of the extremity treated with
L-phenylalanine mustard at 40 to 41 degrees C was significantly better than when treated with the
drug alone, but some investigations suggest that heat alone may be just as effective. Localized
hyperthermia combined with nearly all the standard types and doses of single and combination agents has shown objective responses in about one third of patients treated, without evidence of increased
drug toxicity by either the IV or IA route. Responses appear to be thermal-dose related. Maximum enhancement appears at about 40 to 43 degrees C and prior drug resistance does not appear to confer heat resistance. The lack of enhanced
drug toxicity with loco-regional
hyperthermia with potential improvement in response of advanced disease suggests that thermochemotherapy is a viable and important option to
drug treatment alone. Further in vitro, in vivo, and clinical studies are needed to increase our understanding of
drug-heat interactions for the optimization of
therapy.