Hyperthermia is one of the most powerful anticancer, antiviral, and antibacterial therapies available, yet it is underutilized and largely unknown in North America. Hyperthermia treatment involves raising the temperature of the whole body, or of local areas of the body to 39 to 43 degrees C (102 F to 109 F). Research has shown that high temperatures stimulate cellular immunity and can damage cancer cells, usually with minimal injury to normal tissues.1, 2, 3, 4, 5 By damaging proteins and structures within cancer cells, hyperthermia may shrink tumors.6 In general, malignant cells are more sensitive to heat than are normal cells in the range of 41-45°C. In addition, most clinically apparent tumors (above 1-cm diameter) have blood perfusion rates less than 1/5 that of surrounding normal tissue, meaning that they may be preferentially heated. In Europe, hyperthermia is considered the 4th major modality of cancer therapy along with surgery, chemotherapy, and radiation. And in Europe, hyperthermia is often utilized as an adjunctive therapy with various conventional cancer treatments, such as chemotherapy and radiotherapy, but in some clinics, is also used alongside biological regulatory therapies.7 As hyperthermia is non-myelosuppressive and can potentiate the tumoricidal effects of biological regulatory therapies, its use as part of a multimodality treatment approach is attractive. The positive results of randomized trials have established hyperthermia alone, or in combination with biological regulatory therapies, as an effective clinical modality for the treatment of cancer.
Temperature is a highly conserved and important parameter in all living systems. In mammalians, particularly in humans, a narrow range of 37.0 – 37.5 °C is attempted to be maintained by regulation. In this range, the complicated cellular and physiological processes work most efficiently. Under stress conditions, e.g. infectious diseases, fever is a reaction of the organism to better handle external attacks. Hence, fever is a natural defense reaction of the human body. The immune system’s defense cells work best at a temperature above 39 degrees Celsius (102 F.). At this temperature, all metabolic and detoxification processes are intensely stimulated. This helps overcome infections, inflammations and pain much quicker and more effectively. During fever, the build-up of perspiration activates the excretion of toxic substances. This purifies the body and improves metabolism and after the fever subsides, the body relaxes, and the pain disappears.
The following are complementary effects of fever:
Increase in blood circulation and oxygenation of tissues
Acceleration of metabolism, detoxification, and excretion processes
Relaxation of muscle tension
Increased stimulus conduction of nerve fibers
Stimulation of cellular immune defenses
Inactivation of chronic bacteria and viruses
Hyperthermia treatment may be local (tumor only), regional (e.g., a limb), or whole body. Physical techniques for hyperthermia include metabolic heat containment, conduction through the skin (e.g., hot water bath), perfusion of externally heated blood, heated intravenous fluids and anesthetic gases, ultrasound, and electro-magnetic EM coupling modalities. Thermometric requirements vary with the treatment modality and clinical situation. Until the late 1990s, the use of radiant whole-body hyperthermia (WBHT) was restricted to a few specialized treatment centers worldwide. During the last decade, a larger number of WBHT-devices were put into operation particularly in Germany. Worldwide, hyperthermia is becoming more utilized clinically, due to the substantial technical improvements made in achieving selected increase of temperatures in superficial and deep-seated tumors. In North America, however, it is rarely used, and then only as part of an alternative cancer treatment protocol or research project.
History of Hyperthermia
Fever as the imminent sign of infectious diseases has been used as a diagnostic indicator since ancient times. The effectiveness of heat as a therapy against disease is believed to be known since 3000 B.C.8 Parmenides, a Greek physician and philosopher 2500 years ago said, “Give me a chance to create a fever and I will cure any disease.” Fever is one of the body’s best defensive and healing forces, created and sustained for the purpose of restoring health. Belief in the curative effect of fever was also shared by Celsus, a Roman author of the first systematic treatise on medicine "De Medicina," and Rufus of Ephesus, a Greek physician who lived at the turn of the 1st and 2nd century. Celsus described the hot baths as a tool in the treatment of various diseases.
There has been a historic, cross-cultural recognition of the benefit of fever and heat therapy. The healing effect of heat was first mentioned in the early civilizations of ancient Egypt, where baths in hot desert sand were prescribed for the ill. Doctors of ancient Greece started using this therapeutic approach and named it “overheating” (in Greek: hyperthermia). Other examples are the Roman sulfur hot baths, Finnish saunas, Japanese hot baths, Native American sweat lodges, and the many therapeutic hot springs in Europe, Iceland and in the Americas. Saunas and hot baths do not significantly increase core body temperature enough to have an anti-cancerous effect, but they have been shown to stimulate the immune system. More technologically innovative approaches have developed that increase core temperature or local temperature of tumor tissue to levels that damage or destroy cancer cells.
Bacteria Induced Fever Therapy - William Coley and Coley’s Toxins
The history of bacteria induced fever therapy (fever induction therapy) began in the mid-19th century by several European physicians. One of the first papers on hyperthermia was published in 1866 by a German surgeon Carl D. W. Busch. He described the case of a 43-year-old woman with advanced sarcoma on her face. After the tumor was removed, the patient fell ill with erysipelas. The disease induced high temperature which led to tumor regression for over two years. Busch’s discovery was fundamental because it was the first reported case showing that high temperature can selectively kill cancerous cells while not affecting normal cells.9 Along that time others reported that cancer patients who experienced a feverish period after surgery survived significantly longer than patients without fever. In 1882, Fehleisen discovered the erysipelas causative organism as Streptococcus pyogenes. He inoculated these live bacteria to seven cancer patients and achieved complete remission in 3 cases.10 In the second half of the 19th century, the practice of infectious febrile therapy was quite common not only in Germany and France, but also in Russia, and it was used to treat a wide range of diseases.
The American surgeon William Coley (1862-1936) also observed that cancer patients often recovered from their cancer if they had suffered a severe post-surgical infection of the wound accompanied by high fever. Coley developed the theory that it was the fever from the infection which had helped patients to recover from their cancer. So, he began to treat patients by injecting a Streptococcus pyogenes directly into inoperable tumors. He found the treatment was most effective when it provoked a fever and a full-blown infection. This led physicians to understand that the increase in body temperature not only mobilized the body’s own immune system, thus fighting off the infection, but also destroyed the tumor at the same time.
Later Dr. Coley decided to use a mixture of dead Streptococcus pyogenes and dead Serratia marcescens bacteria. This was subsequently termed “Coley’s Toxin”. In 1893, the first patient to receive Coley’s Toxin was John Ficken, a sixteen-year-old boy with a massive abdominal tumor. Every few days, Coley injected this bacterium directly into the tumor mass and produced the symptoms of an infectious disease, but did not produce the disease itself. On each injection, there was a dramatic rise in body temperature and chills. The tumor gradually diminished in size, and after four months of intensive treatment, the tumor was a fifth its original size. Later that year the remains of the growth were barely perceptible.11 The boy received no further anticancer treatment and remained in good health until he died of a heart attack 26 years later.
Over the next 40 years, as head of the Bone Tumor Service at Memorial Hospital in New York, Coley injected more than 1000 cancer patients with bacteria or bacterial products. By the end of his career, Coley had written over 150 papers on this subject.12, 13, 14 Coley mainly used his toxins on patients with inoperable bone and soft-tissue sarcomas, observing that this treatment was less effective on other types of cancer such as melanomas and carcinomas. Beginning in 1899, Parke Davis and Company had begun to prepare the Coley’s Toxins, so they were available for all physicians. They were widely used for the next 30 years.
In the first half of the 20th century, different formulas of Coley’s Toxins were manufactured by several drug companies in the U.S. These formulations were used to treat patients with a variety of types of cancer until the early 1950s, when other forms of cancer treatment became more widely used, such as radiotherapy. Despite his reported positive results, Coley's Toxin came under a great deal of criticism because many doctors did not believe it possible. Medicine has always been, and still is, ruled by belief.
Additional controversies surrounding Coley's work reflect the field of oncology struggling to stabilize its understanding of how to treat cancer. For example, James Ewing, perhaps the most famous cancer pathologist in the country, was a leading opponent of Coley's work. This was a problem for Coley because Ewing was Medical Director of Memorial Hospital, and for many years was Coley's boss. Their memos to one another reflect constant interpersonal animosity. Ewing himself had become a fanatical supporter of radiation therapy for the treatment of all bone tumors and repudiated any other theories for the treatment of cancer. Ewing therefore refused Coley permission to use his toxins at Memorial Hospital. This was ironic, because Coley had more experience than any other surgeon in the country in treating the small round blue cell sarcoma that still carries Ewing's name.
Skepticism and criticism, along with the development of radiation therapy and chemotherapy, caused Coley's Toxin to gradually disappear from use in the U.S. By 1952, the Park Davis Company no longer produced Coley's Toxin, and, in 1962 the FDA refused to acknowledge Coley's Toxin as a proven drug.15 Thus, in 1962 it became illegal to use Coley's Toxin for the treatment of cancer in the United States. However, in Europe, Australia and Asia, bacteria induced hyperthermia continued in certain medical circles, and has become an advanced immunotherapy. In retrospect, William Coley's intuitions were correct. Using fever induction therapy to stimulate the immune system is effective in treating cancer. Coley was a model of the clinician-scientist, treating patients and using his practice to initiate research and build theories. But he was a man before his time, and he met with severe criticism.
During the second half of the 20th century, which is characterized by heavy use of antibiotics, fever was regarded by mainstream medicine as an unnecessary, weakening state which should be suppressed or prevented. The situation today has not changed much. The immune system is constantly repressed with anti-microbials and even mild fever is suppressed with anti-febriles.
The Modern Development of Hyperthermia
Fever induction therapy today involves the injection of specific bacterial lysates, which induce the release of cytokines, and bring about a fever reaction. The immunological response of cytokine release with underlying fever has been extensively researched over the last several decades. Direct endogenous pyrogens, or proteins that produce fever, are associated with IL-1alpha, IL-1beta, TNF-alpha, TNF-beta (lymphotoxin-alpha), IL-6, macrophage inflammatory protein 1, and IFN-alpha.16, 17, 18 Indirect fever inducers are considered to be IL-2 and IFN-gamma.19 Most fever response usually only reaches a maximum of around 39°C (102°F), which is not sufficient to induce enough thermal damage within cancerous tissue. However, the immunological effect of this treatment can greatly improve the general condition of the patient through stimulating the immunity, resulting in a positive response.20, 21
Within the last century, hyperthermia has been shown to be of great use in treating cancer. Such techniques as immersion in heated water, artificial fever production by toxins, and fever cabinets have been used historically. In September 1965, the physicist and cancer researcher Manfred von Ardenne (1907-1997) presented in the Heidelberg Cancer Research Centre the concept of his so-called systemic Cancer Multistep Therapy - a combined modality treatment including whole-body hyperthermia. At the time, whole-body hyperthermia was attained by a warm water bath plus induced hyperglycemia and a high dosage application of oxygen. Since hyperthermia treatment was a very strenuous procedure, Ardenne supplied oxygen to the patients in support of the treatment. At first he had difficulty optimizing the treatment, since there was no way to exactly control the internal temperature of the body.22 Dr. von Ardenne was the first person to specifically treat cancer patients with the help of hyperthermia by using long-wave infrared light. Over the years, however, more technologically advanced equipment guaranteed better control of the overheating process and made widespread use of hyperthermia in clinics possible.
Types of External Hyperthermia
To reach the temperatures necessary to disrupt cancer cell growth, today externally induced hyperthermia procedures are used. These involve ultrasound, microwave, radio wave technology, or by infrared light. This differs from induced fever therapy, by which body temperature increase is induced with a bacterial protein. The high-tech science of external hyperthermia has greatly evolved in the precise control of the therapeutic application of heat. Numerous devices have now been developed to produce elevated temperatures of the body, by a variety of physical means. After a shift in focus to local and regional hyperthermia, there is now a resurgence of interest in systemic hyperthermia or whole-body hyperthermia (WBHT) for treatment of cancer as well as other systemic diseases.
Apart from the induction of biological fever by pathogens or toxins, all methods of external hyperthermia involve transfer of heat into the body from an external energy source. The administration of a hyperthermia treatment requires technology to heat the tissues as well as technology to monitor, control and evaluate the thermal or other parameters involved in the heat treatment. External hyperthermia is basically divided into three types: local hyperthermia, regional hyperthermia and whole-body hyperthermia.23, 24 Because of the different routes and different range of heating temperature, the treatment scopes are also different. Local hyperthermia is appropriate for small tumors, such as breast, whereas, the regional and whole-body variant is used for metastatic tumors.
Local hyperthermia is performed with superficial applicators (microwave, radio wave, ultrasound) of different kinds (waveguide, spiral, current sheet etc.). These applicators are positioned upon superficial tumors coupled to the tissue by water bags or a water bolus. The penetration depth depends on the frequency and size of the applicator, and typically the clinical range is not more than 3 – 4 cm. A system for local hyperthermia consists of a generator, the control computer, the applicator and the possibility to measure temperature in the tumor. Then the power is increased until the desired temperature is achieved. Indications for local hyperthermia include chest wall recurrences, superficial malignant melanoma lesions, lymph node metastases of head and neck tumors.
Local hyperthermia is further typed as External, Endoluminal, and Interstitial. Local external approaches are used to treat tumors that are in or just below the skin. External applicators are positioned around or near the appropriate region, and energy is focused on the tumor to raise its temperature. Intraluminal or endocavitary methods may be used to treat tumors within or near body cavities, such as the esophagus or rectum. Probes are placed inside the cavity and inserted into the tumor to deliver energy and heat the area directly. Based on their design the interstitial hyperthermia techniques can be categorized in four groups; radiofrequency, microwave, hot source and ultrasound techniques. The hot source techniques distinguish themselves from the other techniques because the tissue is heated by thermal conduction while the other techniques deposit energy directly in the tissue at a distance from the heating source.
Endoluminal hyperthermia uses natural orifices to position various kinds of endocavitary applicators (microwave, radio wave, ultrasound) in direct contact to a tumor. A counter electrode might be positioned on the body surface to steer the power deposition pattern. By physical reasons, the penetration depth around those endoluminal applicators is limited and of the order of the applicator´s diameter (in the cm-range). Accessible tumors include esophageal carcinoma, prostate carcinoma, rectal and cervical carcinoma.
Interstitial techniques are used to treat tumors deep within the body, such as brain tumors. This technique allows the tumor to be heated to higher temperatures than external techniques. Under anesthesia, probes or needles are inserted into the tumor. Imaging techniques, such as ultrasound or magnetic resonance, may be used to make sure the probe is properly positioned within the tumor. The heat source is then inserted into the probe. For interstitial hyperthermia, an array of interstitial antennas (microwave) or electrodes (radio wave) is implanted in accessible tumors which might be located in deep or superficial tissues. The distance between the antennas must not exceed 1 – 2 cm, and therefore lesions with diameters below 5 cm are suitable (in order to limit the number of puncturing tracks). Interstitial hyperthermia is an invasive procedure. Temperature measurements must be performed at the antennas and between them. In most systems, every single antenna is controlled by its own generator. Dedicated systems have in addition two or more segments per antenna or electrode controlled in phase and/or amplitude. Clinically interstitial hyperthermia has been applied for prostate carcinoma, recurrent breast cancer and malignant brain tumors.
Thermoablation may also be performed with thin laser applicators (laser induced thermotherapy or LITT) and is considered a minimally invasive procedure. The applicators must be implanted in the lesions under computer tomography or magnetic resonance guidance. Achieved temperatures are high (up to 90 °C), but the thermal gradients are quite steep and the effective range is 1 – 2 cm (i.e. lesions with diameters of 3 – 4 cm are the limit using standard techniques). Liver metastases (number up to 4) are probably the most treated condition with LITT.
Another form of local hyperthermia that is growing in popularity, especially in China, is high intensity focused ultrasound (HIFU). HIFU is a hyperthermia procedure that applies precise high-intensity focused ultrasound energy to heat to destroy cancerous and diseased tissue through ablation. When magnetic resonance imaging is used for guidance, the technique is sometimes called magnetic resonance-guided focused ultrasound, often shortened to MRgFUS or MRgHIFU. Magnetic resonance imaging guidance allows the tumor to be visualized and targeted, and in addition provides a means to measure tissue temperatures in real time. HIFU is used often as a solo treatment or sometime used with other treatments. Unlike radiotherapy, HIFU is a non-invasive technique that also leaves healthy tissue next to a tumor undamaged. In China, over the last decade, thousands of patients with breast cancer, liver cancer, pancreatic cancer, bone tumors, renal cancer, prostate cancer and uterine fibroids have been treated with ultrasound imaging-guided HIFU.
In the U.S., HIFU is only approved treat uterine fibroids. However, there is ongoing research in the area of breast cancer with HIFU conducted by Dennis L. Parker, PhD, a professor of Radiology at the University of Utah and Director of the Utah Center for Advanced Imaging Research (UCAIR). Dr. Parker and colleagues at UCAIR are leading in the development of a HIFU system for breast tumors. Now in prototype form, their system has been tested on phantoms and samples. According to Dr. Parker, "From the standpoint of something that could ultimately be used to treat breast cancer, I think this is an excellent, potential device. The advantage of HIFU for breast cancer is that it's totally noninvasive. It has the opportunity eventually to totally eradicate the disease without any surgical intervention at all."25
In regional hyperthermia, interference patterns in deep seated tumors of the pelvis or lower extremities are generated by an array of phase-controlled antennas radiating in the range of 70 – 150 MHz These antennas are surrounding the whole circumference of the cross section, i.e. all possible directions are employed to deposit power into the target volume. The higher the number of antennas (and the higher the frequency), the better the potential to control the patterns. In particular, several rings of antennas in direction of the patient axis are useful to enable the flexibility with respect to the anatomical structures for optimization. A current frequency of clinical interest is 100 MHz. Locally advanced and/or recurrent tumors of the pelvis are the major indications for regional hyperthermia, i.e. rectal carcinoma, cervical carcinoma, bladder carcinoma, prostate carcinoma, or soft tissue sarcoma.
In contrast to local or regional hyperthermia which heats only one part of the body, namely where the tumor mass is located, whole body hyperthermia (WBHT) heats the entire body. WBHT heats the whole body either up to 42 °C for 60 - 120 minutes (so-called extreme WBHT), or only 39.5 – 41 °C for longer time, e.g. 3 hours (so-called moderate WBHT). Temperature and duration of treatment is usually individually determined depending on the patient’s health condition. Between the heating and cooling phase, the entire procedure may last about 4 to 5 hours. Generally, WBHT in the treatment of metastatic cancer raise the patient’s temperature to 41.6° C. to 41.8° C for 60 to 90 minutes. This is much higher temperature and longer plateau than the WBHT IRB26 research protocols used in the U.S.
For WBHT, the patient is as far as possible thermally isolated, and infra-red radiation with different ranges of wavelengths (for several available systems) is depositing energy in the superficial tissues of the body until the desired temperature is achieved. For extreme WBHT, 60 – 120 minutes are needed until the patient has 42 °C achieved under general anesthesia (plus/minus intubation). For moderate WBHT, often deep sedation is sufficient. In any case, careful monitoring of the systemic parameters are required for any kind of WBHT and an intensive care unit should be available in the background.
WBHT is used principally in advanced stages of cancer and as a metastatic prophylaxis in high risk patients, e.g., young premenopausal women with breast cancer, lymph node involvement and negative hormone receptor status. Up to now, several WBHT-approaches have proved to be safe and associated with acceptable toxicity rates when radiant heat devices are employed. Until the late 1990s, the use of WBHT was restricted to a few specialized treatment centers worldwide. During the last 20 years, a larger number of WBHT-devices have been put into operation throughout Europe and Asia. Because many women diagnosed with invasive breast cancer have undetected occult metastases at the time of their primary tumor diagnosis it may be more desirable to employ WBHT as opposed to local hyperthermia.
In Europe and Asia there are several types of WBHT systems in clinical use. Over the last decade, patient warming with infrared radiation has been established as a standard procedure for WBHT treatment. WBHT systems differ with regard to the spectrum of infrared radiation used and the area of application (front or back of the patient). At the time of this writing some of the more common systems are the Heckel HT-300027, the Oncotherm WBH-200028, the Chinese manufactured Gamma Star GMX-RL-03 WBH system, and the Ballya International Ltd WBH system, only to name a few. The Heckel HT-3000 (Manufactured by: Hydrosun Medizintechnik GmbH, Esslingen, Germany), uses water-filtered infrared radiation (wIRA) delivered by four wIRA emitters to the chest, and two heating elements for warming the air under the tent-like canopy. It features continuous measurement of core temperature, heart rate, oxygen saturation, blood pressure, ECG, respiratory frequency. The OncoTherm WBH-2000 unit is a chamber that encloses all but the patient s head. Special light-emitting diode (LED) radiators deliver computer-generated, alloyﬁltered IRA wave-lengths that penetrate the skin to deliver heat to the capillary bed. The manufacturer claims that these wave-lengths also preferentially stimulate the immune system.
Much of the history and development of hyperthermia is rooted in Europe, and has been fostered by organizations such as the European Society for Hyperthermia Oncology.29 China and Japan have also become world leaders in the clinical use of hyperthermia. In 1978, research on hyperthermia in Japan was started by the Hyperthermia Study Group. Six years later, the Japanese Society of Hyperthermic Oncology (JSHO) was established. Since then hundreds of research articles have been published in China and Japan. It is estimated that more than two hundred hyperthermia units are in use across Japan. Compared to other countries, Japan has the highest number of hyperthermia equipment installed, and the most doctors involved in hyperthermia therapy. The main reasons for the advanced state of hyperthermia research in Japan include the development of excellent heating equipment, high membership in JSHO, grant-in-aid by the Japanese government, and coverage by insurance for this form of therapy.30
In 1981, the North American Hyperthermia Society was founded by those who shared the opinion that hyperthermia continued to show promise as a therapeutic modality, and that the growing numbers of investigators and the amount of data produced required a separate forum for discussion of results and planning future directions of research and application. In 1985 the North American Hyperthermia Society, together with the European Society for Hyperthermic Oncology, and the Japanese Society of Hyperthermic Oncology cooperatively founded the International Journal of Hyperthermia and adopted it as their official journal.31
Despite several decades of ongoing usage in Europe, China and Japan, and numerous human studies, WBHT is still considered ‘exper