Thermal Medicine, or the manipulation of body or tissue temperature for the treatment of disease, can be traced back to the earliest practice of medicine. Cultures from around the world can point to ancient uses of hot and cold therapy for specific medical applications, including cancer. Modern research in thermal medicine aims to understand molecular, cellular and physiological effects of temperature manipulation and the “stress” response, as well as to develop effective and safe equipment for clinical application and temperature monitoring. As a result, today there are a growing number of clinical applications of thermal therapy that benefit patients with a variety of diseases. Here are a few:
· Hyperthermia – historically a major the focus of the Society for Thermal Medicine – is clinically used for cancer treatment, particularly in combination with radiotherapy and chemotherapy. Hyperthermia can also be used to activate cytotoxic effects of chemotherapy within tumors, thereby sparing normal tissue, when the drugs are encapsulated in thermally sensitive nanoparticles.
· Enlarged prostate (benign prostatic hyperplasia) can be clinically treated by hyperthermia that relieves symptoms via shrinking the tissue.
· Thermal ablation, whereby tissue is destroyed by localized heating or freezing, is now used world-wide for cancer treatment and several other important medical applications. Various energy sources including laser, ultrasound, microwaves, and radiofrequency electric current are being investigated as minimally invasive, and potentially non-invasive therapies. In addition, cryogenic freezing is clinically used for localized cancer treatment (cryoablation, cryosurgery).
· Other diseases where ablation is used include: Cardiac catheter thermal ablation is now standard of care for a variety of cardiac arrhythmia types (irregular heart beat rhythm). Endometrial ablation is clinically used to treat endometrial bleeding. Varicose veins can be eliminated by intravascular heating with laser or radiofrequency current.
· Cryopreservation – typically at temperatures below -80 ºC - allows storage of viable cells for extended time periods for future use.
· Excessive subcutaneous fat, which can contribute to obesity and metabolic disorders including diabetes are treated by laser and other thermal methods.
· There is growing research interest in the use of mild hypothermia for treatment of inflammatory disease, brain injuries and stroke.
As a result of these and other clinical applications, combined with a rapidly expanding research base, interest in thermal medicine is rapidly growing, attracting the attention of laboratory and clinical researchers, physicians, engineers, physicists and biotechnologists who are joining the Society for Thermal Medicine. Some examples of major topics discussed at our annual meetings are described below.
Hyperthermia (HT) as an adjuvant to radiation and chemotherapy: Starting in the late 1970s, a major focus of many members of our Society was on achieving focal, cytotoxic temperatures of 42-45 oC within tumors, a strategy which can sensitize tumors to radiation and/or chemotherapy. Remarkable progress in engineering and physics over the past 20 years has led to the implementation of clinical trials that are revealing the true potential of this strategy. Over the past decade, positive clinical data has emerged from trials utilizing HT in the treatment of recurrent chest wall breast cancer, melanoma, esophageal cancer, locally advanced head and neck cancer, locally advanced cervix cancer and gliomas. Today, in some countries such as The Netherlands and Germany, HT is part of standard cancer care. Two recent pivotal trials have demonstrated, for the first time that combination of HT with radiation therapy improves treatment efficacy, improving tumor response and duration of local tumor control. In combination with novel non-invasive thermometry methods using MR imaging, these new trials are driving a renewed research effort designed to optimize the use of HT for cancer treatments, which will facilitate new thermal therapy applications over the next decade.
Thermal Ablation: Image-guided, thermal ablation (e.g. by radiofrequency electric current, microwaves, laser, or ultrasound) has gained significant momentum in the past decade. High temperatures above 50 oC (122 oF) and freezing temperatures used in ablation result in very rapid and localized destruction within defined tissue volumes. Today, about ~100,000 cancer patients (with cancers of the liver, lung, kidney and bone) are annually treated worldwide by this minimally invasive therapy, as it provides local tumor control with minimal side effects. About a dozen FDA approved devices are available, with novel devices in the pipeline. For example, high-intensity focused ultrasound (HIFU) has gained a large amount of interest recently, and allows non-invasive tissue heating with highly spatial accuracy (~mm). HIFU is often combined with MRI-thermometry for non-invasive temperature monitoring and control. Also the combination of thermal ablation with standard cancer therapies such as chemo- or radiation therapy, as well as immunotherapy, is attracting growing clinical interest.
Heat-activated drug delivery: An exciting new generation of clinical trials is now harnessing drug-containing thermosensitive liposomes, and other nanoparticle drug carriers, that release contained chemotherapy agents upon heating above ~40 ºC. Combined with localized heating methods as described above, this allows for targeted chemotherapy delivery to tumors. Thermal ablation or hyperthermia can be combined with heat-activated drug carriers to selectively deposit chemotherapy in the heated area. Initial clinical trial results suggest patient benefits from this combination and thus there is considerable excitement among members of our Society in this approach.
Study of basic biological impact of temperature on cellular function: Many members of our society are interested in learning about direct and indirect effects of temperature on the stress response, gene-expression, and metabolic, vascular and immunological parameters of the tumor microenvironment. In addition to cytotoxic temperature shifts, researchers in our Society have begun to study the very mild hyperthermia associated with natural fever during infection or inflammation. New discoveries on the role of the stress or heat shock protein (HSP) response on the immune system, metabolism and immunotherapy have made their way into the field of thermal medicine and are fundamentally changing the underlying paradigms and are leading to new clinical applications. Multiple facets of tumor growth and the tumor microenvironment, including vascular perfusion, heat shock protein expression, endothelial/stromal cells, hypoxia, immune cells, pro-inflammatory cytokines, are impacted by heat and these effects may underlie remarkable successes being obtained in new clinical trials throughout the world.
While interest in the heat shock response has always been of interest to members of this Society, principles that have been learned over many years in this area have now guided the development of new cancer vaccines based upon the “chaperone” function of HSPs which are now entering clinical trials. Moreover, development of HSP-targeted drugs and small-molecular inhibitors of molecular chaperone expression have entered clinical trial stage and there will continue to be new discoveries made which will help us to understand the physiological functions and regulatory mechanisms of the cellular stress response.
In summary: From our historical roots to the present day, members of the Society for Thermal Medicine continue to make new discoveries in basic, translational and clinical research that break new barriers to achieving improved therapy for patients with cancer and other diseases. At each annual meeting of our Society, members learn about new ideas and strategies involving thermal biology and of new clinical opportunities. New heating, cooling and imaging platforms and drug/radiation-enhancing nanoparticles, heat-driven vaccine development and gene-expression, as well as mild (fever-range) and high temperature, MR-guided therapies are rapidly evolving into new clinical trial opportunities.
For more information regarding the theory and practice of Thermal Medicine, please refer to the references below which can be found in the Society’s Journal, The International Journal of Hyperthermia.
Hyperthermia and the Immune System. Inter. J. Hyperthermia. Vol.18, No. 6 November 2002
Guest Editors: Elizabeth Repasky and Rolf Issels
Radiosensitization by hyperthermia. Int. J. Hyperthermia. Vol. 20, No. 3 May 2004
Guest Editor: Joseph Roti Roti
Thermal Ablation Therapy. Int. J. Hyperthermia. Vol. 20, No. 7 November 2004
Guest Editors: Paul Stauffer and Nahum Goldberg
Non-invasive thermometry for thermotherapy Int. J. Hyperthermia. Vol. 21, No. 6 September 2005. Guest Editors: Gerard van Rhoon and Peter Wust
Thermal Medicine, Heat Shock Proteins and Cancer. Int. J. Hyperthermia. Volume 21, Number 8 December 2005. Guest Editors: Peter Corry and Mark Dewhirst
High intensity focused ultrasound. Int. J. Hyperthermia. Volume 23, No. 2 March 2007
Guest editors: Gail ter Haar and Constantin Coussios
Cellular and vascular effects of hyperthermia. Int. J. Hyperthermia. Volume 24, No.1 February 2008. Guest Editors: Valeria Milani and Michael Horsman
Regional Therapy of the extremities for Cancer. Int. J. Hyperthermia. Volume 24, No. 3 May 2008. Guest Editors: Douglas Tyler and Merrick Ross
Hyperthermia and Nanotechnology. Int. J. Hyperthermia. Volume 24, No 6, 2008 Editor: Mark Dewhirst
Tumor Perfusion and Associated Physiology. Int. J. Hyperthermia. Volume 26, No 3, 2010 Guest Editors: Michael Horsman and Peter Vaupel