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ARTICLES -
Hyperthermia Therapy

BIOREGULATORY MEDICINE

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Atanackovic D, et al. 41.8 degrees C whole body hyperthermia as an adjunct to chemotherapy induces prolonged T cell activation in patients with various malignant diseases. Cancer Immunol Immunother Epub 2002 Oct 18 2002;51(11-12):603.

Baronzio GF, Hager ED. Hyperthermia in Cancer Treatment: A Primer; Medical Intelligence Unit. 2006. ISBN: 978-0-387- 33440-0.

Dayanc BE, Beachy SH, Ostberg JR, Repasky EA: Dissecting the role of hyperthermia in natural killer cell mediated anti-tumor responses. Int J Hyperthermia, 24: 41-56, 2008.

Dewhirst MW, Gibbs FA Jr, Roemer RB, Samulski TV. Hyperthermia. In: Gunderson LL, Tepper JE, editors. Clinical Radiation Oncology. 1st ed. New York, NY: Churchill Livingstone, 2000.

Dinarello CA. Thermoregulation and the pathogenesis of fever. Infect Dis Clin North Am.1996;10(2):433–49.

Hildebrandt B, Wust P, Ahlers O, et al. The cellular and molecular basis of hyperthermia. Critical Reviews in Oncology/Hematology 2002; 43(1):33–56.

Kerner, T., et al. Whole body hyperthermia: a secure procedure for patients with various malignancies? Intensive care medicine 25.9 (1999): 959-965.

Kong G, Braun RD, Dewhirst MW. Characterization of the effect of hyperthermia on nanoparticle extravasation from tumor vasculature. Cancer Res 2001; 61:3027 – 3032.

Manjili MH, et al. Subjeck, Cancer immunotherapy: stress proteins and hyperthermia. Int J Hyperthermia 2002;18(6): 506-520.

Owens, S. D., and P. W. Gasper. Hyperthermic therapy for HIV infection. Medical hypotheses 44.4 (1995): 235-242.

Pettigrew, R. T., et al. Clinical effects of whole-body hyperthermia in advanced malignancy. Br Med J 4.5946 (1974): 679-682.

Robins, H. Ian, et al. A nontoxic system for 41.8 C whole-body hyperthermia: results of a phase I study using a radiant heat device. Cancer Research 45.8 (1985): 3937-3944.

Robins, H. Ian. Role of whole-body hyperthermia in the treatment of neoplastic disease: its current status and future prospects. Cancer research 44.10 Supplement (1984): 4878s-4883s.

van der Zee J, Gonzalez DG, van Rhoon GC, et al: Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: A prospective, randomised, multicenter trial. Lancet 355:1119-1125, 2010.

van der Zee J. Heating the patient: a promising approach? Annals of Oncology 2002; 13(8):1173–1184.

Vertrees, Roger A., et al. Whole-body hyperthermia: a review of theory, design and application. Perfusion 17.4 (2002): 279-290. 50. Larkin, James M., et al. "Systemic thermotherapy: description of a method and physiologic tolerance in clinical subjects." Cancer 40.6 (1977): 3155-3159.

Wust P, Hildebrandt B, Sreenivasa G, et al. Hyperthermia in combined treatment of cancer. The Lancet Oncology 2002; 3(8):487– 497.

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Hyperthermia.

Whole body hyperthermia (WBH) has been used as an adjunct to radio-/chemotherapy in patients with various malignant diseases. Although clear evidence is still missing, it has been hypothesized that an activation of the immune system might contribute to the therapeutic effect of WBH. To examine whether a treatment with 60-minute 41.8°C WBH as an adjunct to chemotherapy (WBH-CT) induces an activation of T cells, blood samples were collected at numerous time points before and up to 48 h post-treatment. The aim of this study was to examine the effect of WBH-CT on the expression of a broad range of activation markers on peripheral blood lymphocytes (PBL), on serum cytokines and intracellular cytokine levels in T cells, and the capacity of these cells to proliferate. Immediately after 41.8 °C WBH-CT treatment, a drastic increase in peripheral natural killer (NK) cells (P<0.05) and CD56+ cytotoxic T lymphocytes (CTL; P<0.01) in the patients' peripheral blood was observed. At 5 h post-treatment, the percentages of both effector cell types had returned to baseline levels. This transient phenomenon was accompanied by a short period of reduced T cell activity, indicated by diminished serum levels of soluble interleukin-2 receptors (sIL-2R) at 3 h post-WBH-CT (P<0.05) and decreased lymphocytic proliferation at the same point in time. This first phase was followed by a marked but short-lived increase in the patients' serum levels of interleukin-6 (IL-6; P<0.01) during the first 5 h following treatment, with a subsequent decrease to baseline levels at 24 h and significantly increased serum levels of tumor necrosis factor-α (TNF-α) at 0 h (P<0.01), 3 h (P<0.05), 5 h (P<0.05) and 24 h (P<0.01) post-WBH-CT. The third phase of the immunological consequences of WBH-CT consisted of an increase in the percentage of peripheral cytotoxic T lymphocytes (CTL) expressing CD56, reaching a maximum at 48 h post-WBH (P<0.01). Furthermore, the percentage of CD4+ T cells expressing the T cell activation marker CD69 increased nearly two-fold over time, reaching its maximum at 48 h (P<0.05). As an additional marker for T cell activation, serum levels of sIL-2R increased markedly (P<0.01), reaching maximum levels at the same point in time. Elevated intracellular concentrations of interferon-gamma (IFN-γ) and/or TNF-α in CD8+ T cells were found in 4 out of 5 patients at 24 h post-WBH-CT. Since similar changes were not observed in patients receiving chemotherapy alone, this is the first study to provide evidence for prolonged WBH-CT-induced activation of human T cells.

In this review, we summarized the historical and experimental basis of cancer immunity and the role of fever and of artificial elevation of temperature on immunity. The interactions of heat in vitro and in vivo on cytotoxicity of immune competent cells are discussed as their positive contribution on the various cancer mmunotherapeutic strategies. Furthermore we have described the link existing among Heat shock proteins, Toll like receptors and innate immunity justifying the use of temperature elevation for treating cancer. The disputed and life-threatening effect of local and whole body hyperthermia on metastasization is also reviewed.

We conclude this review by listing several unresolved questions that should be addressed for a more complete understanding of the molecular mechanisms which underlie the effects of thermal stress on the function of NK cells. Altogether, the available data indicate a strong potential for heat-induced enhancement of NK cell activity in mediating, at least in part, the improved clinical responses seen when hyperthermia is used in combination with other therapies.

The aim of this paper is to give a concise description of hyperthermia and a brief review of its clinical applications.

Pyrogenic substances and the more recent use of whole-body hyperthermia to mimic the physiologic response to fever have successfully been administered in palliative and curative treatment protocols for metastatic cancer. Further research in this area is warranted.

This manuscript deals with discussions concerning the direct cytotoxic effect of heat, heat-induced alterations of the tumor microenvironment, synergism of heat in conjunction with radiation and drugs, as well as, the presumed cellular effects of hyperthermia including the expression of heat-shock proteins (HSP), induction and regulation of apoptosis, signal transduction, and modulation of drug resistance by hyperthermia.

Cancer Multistep Therapy, including whole body hyperthermia, accompanied by suitable anesthesiological management and monitoring, does not lead to any serious or sustained organ dysfunction and can therefore be regarded as a safe therapy.

This study investigates the effects of a range of temperatures (34–42°C) and hyperthermia treatment scheduling (time between hyperthermia and drug administration as well as between consecutive hyperthermia treatments) on the extravasation of nanoparticles (100-nm liposomes) from tumor microvasculature in a human tumor (SKOV-3 ovarian carcinoma) xenograft grown in athymic nude mouse window chambers. The results of this study have implications for the application and scheduling of hyperthermia combined with other therapeutics (e.g., liposomes, antibodies, and viral vectors) for the treatment of cancer.

Heat shock proteins (hsps) can induce anti-cancer immune responses by targeting associated tumour antigens to the immune system. Hyperthermia has been shown to have important stimulatory effects on several cellular and organismal endpoints related to the immune system. This review highlights advantages and disadvantages of various ways of using stress proteins in cancer immunotherapy. It also overviews the interaction of hyperthermia with heat shock protein therapy and the related effects on the host's immune response.

The objective of this paper is to review what is known about the antiviral effects of fever and to highlight the scientific evidence supporting the hypothesis that hyperthermic therapy may prove to be a beneficial treatment modality for persons infected with HIV. Our hyperthermic hypothesis is based upon the mutant escape, quasispecies theory of HIV antigenic diversity. We propose that, if initiated during the asymptomatic stage of HIV infection, hyperthermia may prove to decrease the number of mutant HIV strains arising due to evolutionary pressures created by the patient's immune system, with a resultant prolongation of the asymptomatic period of infection. A review of the literature from three areas of investigation: the immune response to fever, heat as a tumor killing agent, and preliminary studies with fever and retroviral infections, strongly suggests that there is a good scientific basis for the use of hyperthermic therapy in a multimodal treatment approach to HIV infection.

Fifty-one patients in the terminal stages of cancer have been treated with whole-body hyperthermia either alone (38 cases) or in combination with chemotherapy (13 cases). Altogether 227 treatment sessions were held averaging four hours each. The most sensitive tumours were those of the gastrointestinal tract and sarcomas. Breast and genitourinary tumours did not respond, and lung tumours and melanomas were only partially responsive. Major complications were remarkably few.

We conclude the radiant-heat device coupled with a defined pharmacological approach to WBH with appropriate patient screening yields a system for 41.8Â°C WBH which is safe and efficient, is not labor intensive, and does not require general anesthesia and endotracheal intubation. This system is appropriate for a multimodality approach to various systemic cancers.

The potential of hyperthermia as a treatment modality for cancer was first predicted following observations that several types of cancer cells were more sensitive to temperatures in excess of 41° C. than were their normal cell counterparts. Beyond these studies, there now is preclinical evidence as well as the clinical suggestion that hyperthermia potentiates radiation and/ or drugs for the treatment of cancer. As most cancers refractory to conventional therapy are systemic diseases, the proposal that whole-body hyperthermia in combination with other therapies be used to treat metastatic disease is an inherently attractive approach. The basis and the practicality of this proposal is presented here with suggestions for its application to current pre-clinical and clinical research.

Hyperthermia in addition to standard radiotherapy may be especially useful in locally advanced cervical tumours. Studies of larger numbers of patients are needed for other pelvic tumour sites before practical recommendations can be made.

These findings justify using hyperthermia as part of standard treatment in tumour sites for which its efficacy has been proven and, furthermore, to initiate new studies with other tumours. Hyperthermia is certainly a promising approach and deserves more attention than it has received until now.

Our group has developed an extracorporeal method, veno-venous perfusion-induced systemic hyperthermia, that was used first to safely heat swine homogenously to an average body temperature of 43°°C for 2 h. More recently, a Phase I clinical trial has been completed in which all patients were safely heated to 42 or 42.5°°C for 2 h and survived the 30-day study period. We have been sufficiently encouraged by these results and are continuing to develop this technology.

Several phase III trials comparing radiotherapy alone or with hyperthermia have shown a beneficial effect of hyperthermia (with existing standard equipment) in terms of local control (eg, recurrent breast cancer and malignant melanoma) and survival (eg, head and neck lymph-node metastases, glioblastoma, cervical carcinoma).

Click here for
Dr. Odell's chapter on Hyperthermia.