Despite the challenges with hyperthermia delivery in the early 1990s, a number of investigators persevered and phase III trials have since been completed showing benefit, including survival benefit in several instances, with addition of hyperthermia to radiation or chemotherapy. A pooled analysis of 5 breast cancer studies by the Medical Research Council and European Society for Hyperthermic Oncology (ESHO) involving 306 patients showed a significant increase in complete response and local recurrence free progression, particularly for patients for recurrent disease, with the addition of hyperthermia.37 A more recent study at Duke University showed the importance of thermal dose to complete response, again with the greatest benefit shown for patients with recurrent previously irradiated chest disease with a 68% versus 23% complete response noted with versus without hyperthermia.38 In large part, as a result of these findings, hyperthermia has been included in the 2007 NCCN guidelines for treatment of chest wall recurrence of breast cancer.
The impact of hyperthermia on survival has been noted in several studies. In the Dutch Deep Hyperthermia Trial, a survival advantage with hyperthermia, similar to that seen in concurrently performed chemotherapy trials, was noted in addition to radiation for patients with locally advanced cervical cancer. At 3 years, overall survival was 51% versus 31% with versus without hyperthermia.39 As a result of the wide adaptation of cisplatin-based chemotherapy with radiation 2 new phase III studies including an international trial designed to look at the additional benefit of hyperthermia to chemoradiation is now underway. A study at the University of California at San Francisco randomizing patients with glioblastoma to interstitial radiation +/− hyperthermia showed a notable survival advantage for patients receiving hyperthermia. There was a doubling of overall survival at 2 years from 15% to 31% with the addition of hyperthermia.40 An Italian study of hyperthermia for head and neck tumors noted improved local control, which translated into a survival advantage for patients receiving hyperthermia.41 A phase III ESHO study for melanoma revealed improved local control with hyperthermia. The importance of improved local control was noted in the finding that patients experiencing overall complete response enjoyed improved overall survival.42 The benefit of hyperthermia is not limited to radiation. The first report of a completed EORTC/ESHO phase III study of the combination of hyperthermia and chemotherapy for sarcoma was provided at the 2007 ASCO meeting demonstrating a highly significant benefit of hyperthermia in improving progression free survival.
Beyond traditional use of hyperthermia with radiation or chemotherapy there are a number of novel applications emerging for this treatment modality. The use of HSP-based therapies, thermal enhancement of drug delivery, and thoughtful application of the principles of hyperthermia to thermal ablation are all promising avenues for integration of hyperthermia into a widening array of cancer therapies.
Apart from hyperthermia, the broad reaching roles of HSPs in regulation of signal transduction pathways and the immune system are being targeted including HSP-specific inhibitors such as geldanamycin and quercetin and development of HSP-based vaccines.25–28 In regard to drug delivery, thermally sensitive liposomes have been developed so that heat applied to the region of interest results in a highly concentrated release of chemotherapy in proximity to tumor.43 Thermal ablation, the use of heat to destroy tissue, is increasingly being used for oncologic applications. Although the primary goal is direct destruction of tissue, a hyperthermic but nonablated rim of tissue around the kill zone is created providing opportunity to apply the principals of hyperthermia to thermal ablation thereby enhancing the effective zone of ablation.44
There are presently a broad array of reasons why hyperthermia holds promise for improving outcomes for cancer patients: These include:
1. New understandings of thermal biology with a focus on heat shock-regulated signal transduction and immune regulatory pathways.
2. Development of conformal thermal therapy complete with user friendly treatment planning and thermal monitoring capabilities.
3. Mounting evidence from phase III clinical trials for the favorable impact of hyperthermia on treatment outcome.
4. Integration of hyperthermia with emerging and novel treatment strategies.
The present confluence of these factors are compelling reasons to consider how best to integrate hyperthermia into the care of the 21st century cancer patient.
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