FROM LABORATORY STUDIES TO CLINICAL-TRIALS - PAST BENEFITS AND FUTURE-DIRECTIONS IN HYPERTHERMIA

Three examples of clinical research trials that were direct outgrowths of hyperthermia laboratory investigations performed at Stanford Unive rsity, as well as elsewhere, are reviewed and directions for future st udies presented. The first series of laboratory-clinical studies inves tigated the influence of the number of hyperthermia treatments on tumo ur response in combined radiotherapy-hyperthermia regimens. A prospect ive randomized clinical trial was performed and showed no difference i n response rate or duration of local control in combined radiation the rapy-hyperthermia regimens comparing two versus six hyperthermia treat ments. The results were in agreement with the laboratory studies in RI F murine tumours which suggested that persistent thermotolerance limit ed the effectiveness of multiple heat treatments in fractionated hyper thermia treatment regimens. The second prospective clinical trial was undertaken to investigate the influence of pretreatment tumour tempera tures on subsequent response to radiotherapy and hyperthermia. In agre ement with the laboratory studies, low (< 37-degrees-C) pretreatment t emperatures sensitized superficially located tumours to subsequent hyp erthermia treatment. Lower pretreatment temperatures and larger differ entials between minimum treatment temperatures and pretreatment maximu m or mean temperatures were correlated with the duration of local cont rol. The final studies investigated thermosensitizing agents, agents w hich were non-toxic at 37-degrees-C but became cytotoxic at elevated t emperatures. Thermosensitizers such as sulphhydryl compounds have demo nstrated up to 10 000-fold enhancement of cell killing at exposure to 43-degrees-C for 1 h and may be considered for tumour sensitization. H owever, normal tissue may also be sensitized as was noted for topical anaesthetics such as lidocaine. These investigations demonstrate the v alue of close cooperation between the laboratory and clinic which was possible at Stanford and suggest the possible utility of this approach in future trial development.