The current and potential role of hyperthermia in radiotherapy.

Current clinical experience strongly suggests that hyperthermia will become an important modality as an adjuvant to radiotherapy in the treatment of locally advanced solid tumors. Hyperthermia must therefore be considered a topic of general interest. Biologically, hyperthermia has two different types of interactions with radiation. Firstly, heat has a radiosensitizing effect. This is most prominent with simultaneous application, but is of the same magnitude in both tumor and normal tissue and will not improve the therapeutic ratio unless the tumor is heated to a higher temperature than the normal tissue. Secondly, hyperthermia exhibits a direct cytotoxic effect, and a moderate heat treatment alone can almost selectively destroy tumor cells in a nutritionally deprived chronically hypoxic and acidic environment. Because such cells are the most radioresistant, a smaller radiation dose is needed to control the remaining more radiosensitive cells. If critical, irradiated normal tissues are also heated, the cytotoxicity is best utilised if heat is given at least 3-4 hours after irradiation. The magnitude of both the sensitizing and the cytotoxic effect depends on temperature and heating time. Clinically, heating of superficial tumors (e.g. breast, neck nodes and malignant melanoma) has confirmed the biological rationale for using hyperthermia as an adjuvant to radiotherapy. An overview of available data gives thermal enhancement ratios of approximately 1.5 in several superficial tumor sites after external heating. From a practical point of view, true simultaneous treatment is almost impossible using external heating, and the major effect of the combined treatment will have to rely on hyperthermic cytotoxicity. This makes the design of clinical schedules less complicated since only a few heat fractions may be needed to achieve an optimal effect. On this basis, several randomized clinical trials have been activated with the aim to evaluate the role of adjuvant hyperthermia in the primary treatment of advanced (superficial) tumors. In addition, studies are underway to specifically elucidate the clinical relevance of thermotolerance and other biological issues. So far, the clinical evaluation has almost solely been limited to superficial tumors, or to situations where interstitial heating is feasible. External heating of "deep" seated tumors is still preliminary, and most studies are in Phase I-II, with emphasis on toxicity and feasibility. The initial results are promising with regard to improved tumor control and acceptable toxicity.