From laboratory studies to clinical trials: Past benefits and future directions in hyperthermia

Abstract

Three examples of clinical research trials that were direct outgrowths of hyperthermia laboratory investigations performed at Stanford University, as well as elsewhere, are reviewed and directions for future studies presented. The first series of laboratory—clinical studies investigated the influence of the number of hyperthermia treatments on tumour response in combined radiotherapy-hyperthermia regimens. A prospective randomized clinical trial was performed and showed no difference in response rate or duration of local control in combined radiation therapy-hyperthermia regimens comparing two versus six hyperthermia treatments. The results were in agreement with the laboratory studies in RIF murine tumours which suggested that persistent thermotolerance limited the effectiveness of multiple heat treatments in fractionated hyperthermia treatment regimens. The second prospective clinical trial was undertaken to investigate the influence of pretreatment tumour temperatures on subsequent response to radiotherapy and hyperthermia. In agreement with the laboratory studies, low (< 37°C) pretreatment temperatures sensitized superficially located tumours to subsequent hyperthermia treatment. Lower pretreatment temperatures and larger differentials between minimum treatment temperatures and pretreatment maximum or mean temperatures were correlated with the duration of local control. The final studies investigated thermosensitizing agents, agents which were non-toxic at 37°C but became cytotoxic at elevated temperatures. Thermosensitizers such as sulphhydryl compounds have demonstrated up to 10 000-fold enhancement of cell killing at exposure to 43°C for 1 h and may be considered for tumour sensitization. However, normal tissue may also be sensitized as was noted for topical anaesthetics such as lidocaine. These investigations demonstrate the value 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.

Key Words:

• Clinical hyperthermia
• number of treatments
• pretreatment temperatures
• thermal sensitizers