Hyperthermia therapy
Intervention
Whole-body suit used in hyperthermia therapy.
ICD-10-PCS	6A3
ICD-9-CM	93.35, 99.85
MeSH	D006979
OPS-301 code:	8-60

Hyperthermia therapy is a type of medical treatment in which body tissue is exposed to slightly higher temperatures to damage and kill cancer cells or to make cancer cells more sensitive to the effects of radiation and certain anti-cancer drugs.^[1] When combined with radiation therapy, it is called thermoradiotherapy.

Local hyperthermia for certain small tumors is generally accepted, similar to surgically removing a tumor. Whole-body hyperthermia is generally considered to be a promising experimental cancer treatment.

Hyperthermia is only useful for certain kinds of cancer, and is not in widespread use. Hyperthermia is most effective when used alongside other therapies, so it is almost always used as an adjuvant therapy.^[2][3] The most effective uses are currently being studied.

Mechanism [edit]

Patient undergoing whole-body hyperthermia with doctors looking on.

During treatment the body temperature reaches a level between 39.5°C and 40.5°C.

^[4]

Hyperthermia may kill or weaken tumor cells, and is controlled to limit effects on healthy cells. Tumor cells, with a disorganized and compact vascular structure, have difficulty dissipating heat. Hyperthermia may therefore cause cancerous cells to undergo apoptosis in direct response to applied heat, while healthy tissues can more easily maintain a normal temperature. Even if the cancerous cells do not die outright, they may become more susceptible to ionizing radiation therapy or to certain chemotherapy drugs, which may allow such therapy to be given in smaller doses.

Intense heating will cause denaturation and coagulation of cellular proteins, rapidly killing cells within a tumor. More prolonged moderate heating to temperatures just a few degrees above normal can cause more subtle changes. A mild heat treatment combined with other stresses can cause cell death by apoptosis. There are many biochemical consequences to the heat shock response within the cell, including slowed cell division and increased sensitivity to ionizing radiation therapy.

Hyperthermia can kill cells directly, but its more important use is in combination with other treatments for cancer.^[5] Hyperthermia increases blood flow to the warmed area, perhaps doubling perfusion in tumors, while increasing perfusion in normal tissue by ten times or even more.^[5] This enhances the delivery of medications. Hyperthermia also increases oxygen delivery to the area, which may make radiation more likely to damage and kill cells, as well as preventing cells from repairing the damage induced during the radiation session.^[6]

Cancerous cells are not inherently more susceptible to the effects of heat.^[5] When compared in in vitro studies, normal cells and cancer cells show the same responses to heat. However, the vascular disorganization of a solid tumor results in an unfavorable microenvironment inside tumors. Consequently, the tumor cells are already stressed by low oxygen, higher than normal acid concentrations, and insufficient nutrients, and are thus significantly less able to tolerate the added stress of heat than a healthy cell in normal tissue.^[5]

Mild hyperthermia, which provides temperatures equal to that of a naturally high fever, may stimulate natural immunological attacks against the tumor. However it is also induces a natural physiological response called thermotolerance, which tends to protect the treated tumor.^[5]

Moderate hyperthermia, which heats cells in the range of 40 to 42 °C, damages cells directly, in addition to making the cells radiosensitive and increasing the pore size to improve delivery of large-molecule chemotherapeutic and immunotherapeutic agents (molecular weight greater than 1,000 Daltons), such as monoclonal antibodies and liposome-encapsulated drugs.^[5] Cellular uptake of certain small molecule drugs is also increased.^[5] Most local and regional cancer treatments are in this temperature range.

Very high temperatures, above 50 °C (122 °F), are used for ablation (direct destruction) of some tumors.^[6] This generally involves inserting a metal tube directly into the tumor, and heating the tip until the tissue next to the tube has been killed.

Heat sources [edit]

There are many techniques by which heat may be delivered. Some of the most common involve the use of focused ultrasound (FUS or HIFU), infrared sauna, microwave heating, induction heating, magnetic hyperthermia, infusion of warmed liquids, or direct application of heat such as through sitting in a hot room or wrapping a patient in hot blankets.

Types [edit]

Patient is undergoing local hyperthermia treatment for head and neck cancer.

The computer-controlled short waves are bundled in the tumor or the tumor bed and heated to between 42°C and a maximum of 44°C.

^[7]

• Local hyperthermia heats a very small area, usually the tumor itself. In some instances, the goal is to kill the tumor by heating it, without damaging anything else. The heat may be created with microwave, radiofrequency, ultrasound energy or using magnetic hyperthermia. Depending on the location of the tumor, the heat may be applied to the surface of the body, inside normal body cavities, or deep in tissue through the use of needles or probes. One relatively common type is radiofrequency ablation of small tumors.^[3] This is easiest to achieve when the tumor is on a superficial part of the body, which is called superficial hyperthermia, or when needles or probes are inserted directly into the tumor, which is called interstitial hyperthermia.
• Regional hyperthermia heats a larger part of the body, such as an entire organ or limb. Usually, the goal is to weaken cancer cells so that they are more likely to be killed by radiation and chemotherapeutic medications. This may use the same techniques as local hyperthermia treatment, or it may rely on blood perfusion. In blood perfusion, the patient's blood is removed from the body, heated up, and returned to blood vessels that lead directly through the desired body part. Normally, chemotherapy drugs are infused at the same time. One specialized type of this approach is continuous hyperthermic peritoneal perfusion (CHPP), which is used to treat difficult cancers within the peritoneal cavity (the abdomen), including primary peritoneal mesothelioma and stomach cancer. Hot chemotherapy drugs are pumped directly into the peritoneal cavity to kill the cancer cells.^[3]
• Whole-body hyperthermia heats the entire body to temperatures of about 39 to 41 °C. It is typically used to treat metastatic cancer (cancer that spread to many parts of the body). Techniques include infrared hyperthermia domes which include the whole body apart from the head, putting the patient in a very hot room, or wrapping the patient in hot, wet blankets.^[3]

Treatment [edit]

Moderate hyperthermia treatments usually maintain the temperature for about an hour or so.^[6]

The schedule for treatments depends on the effect desired. After being heated, cells develop resistance to heat, which persists for about three days and reduces the likelihood that they will die from direct cytotoxic effects of the heat.^[5] This suggests a maximum treatment schedule of about twice a week.^[6] However, if the desired goal is increased radiosensitivity in a poorly oxygenated tumor, rather than directly killing the cells, then application of heat with every radiation treatment is acceptable.^[5]

Controlling temperatures [edit]

One of the challenges in thermal therapy is delivering the appropriate amount of heat to the correct part of the patient's body. For this technique to be effective, the temperatures must be high enough, and the temperatures must be sustained long enough, to damage or kill the cancer cells. However, if the temperatures are too high, or if they are kept elevated for too long, then serious side effects, including death, can result. The smaller the place that is heated, and the shorter the treatment time, the lower the side effects.

To minimize damage to healthy tissue and other adverse effects, physicians carefully monitor the temperature of the affected area.^[3] The goal is to keep local temperatures under 44 °C (111 °F) to avoid damage to surrounding tissues, and the whole body temperatures under 42 °C (108 °F), which is the upper limit compatible with life. These temperatures compare to the normal human body temperature, taken internally, of about 37.6 °C (99.6 °F).

A great deal of current research focuses on precisely positioning heat-delivery devices (catheters, microwave and ultrasound applicators, etc.) using ultrasound or magnetic resonance imaging, as well as developing new types of nanoparticles that make them particularly efficient absorbers while offering little or no concerns about toxicity to other tissues. Clinicians also hope to use advanced imaging techniques to monitor heat treatments in real time; heat-induced changes in tissue are sometimes perceptible using these imaging instruments.

The thermoacoustic (TA) effect refers to the generation of acoustic waves by electromagnetic (EM) irradiation, such as optical or microwave/radio frequency waves. In the past ten years, thermoacoustic tomography (TAT) using pulsed EM excitation has undergone tremendous growth. Energy deposition inside biological tissue through the absorption of incident EM pulses will create a transient temperature rise on the order of 10 mK. In the thermoelastic mechanism of acoustic generation, a sound or stress wave is produced as a consequence of the expansion induced by the temperature variation. Thermoacoustic signals are temperature dependent, which is an ideal characteristic for use in monitoring biological tissue temperature. The thermoacoustic pressure has the following expression^[8]

P = µ_aHβc²/c_p,

where µ_a is the microwave absorption coefficient, H is the heating function and can be written as the product of a spatial absorption function and a temporal illumination function, β is the isobaric volume expansion coefficient, c₀ is the speed of sound, c_p is the heat capacity. The thermal expansion coefficient defines the fractional changes in the volume of a material with temperature; normally, its value increases almost linearly with temperature except for the lowest temperatures. Thus, the thermoacoustic pressure can be written in the following form:

P = (A+BT)*P₀

where A and B is a constant, which can be gotten by the linearship between temperature and thermal expansion coefficient. T is the temperature, P₀ is the thermoacoustic pressure at baseline temperature. The equation demonstrates that the thermoacoustic pressure is directly proportional to temperature where its variation is the reaction of sample thermodynamic parameter changes with heat.

This characteristic of thermoacoustic signals that give us a new method to monitor thermotherapy temperature, has the potential to be developed into a viable alternative to current clinical temperature monitoring device for microwave thermotherapy.

Adverse effects [edit]

External application of heat may cause blisters, which generally heal quickly, and burns, which do not.^[6] All techniques may result in pain or fatigue. Perfusion and moderate or high levels of hyperthermia can cause swelling, blood clots, and bleeding.^[5] Whole-body hyperthermia, which is the riskiest treatment, usually results in diarrhea, nausea, vomiting, fatigue, and other symptoms of sunstroke; it may also cause cardiovascular problems.^[3]

Effectiveness [edit]

By itself, hyperthermia is generally ineffective, with only small numbers of patients receiving lasting benefit.^[6] However, it may significantly increase the effectiveness of other treatments.^[6]

When combined with radiation, hyperthermia is particularly effective at increasing the damage to acidic, poorly oxygenated parts of a tumor,^[5] and cells that are preparing to divide.^[6] Hyperthermia treatment is most effective when provided at the same time, or within an hour, of the radiation.^[6]

Irradiation alone produces a complete response in about 30% of patients. Combining irradiation and hyperthermia increases the complete response rate to about 70% of patients.^[9] In the past decade hyperthermia treatments in conjunction with radiation have been used with curative intent in patients with early stage cancers of the breast, head and neck, and prostate. In his observations, James Bicher, M.D., recorded complete response rates were 82% for breast patients, 88% for head and neck, and 93% for prostate patients.^[10] Projected 5 year survival rates were 80% for breast patients, 88% for head and neck, 87% for prostate patients.^[10]

Whole-body hyperthermia cannot safely reach the temperatures necessary to improve the effectiveness of radiation, and thus is not used with radiation,^[5] but it may be useful for chemotherapy and immunotherapy.^[6]

The purpose of overheating the tumor cells is to create a lack of oxygen so that the heated tumor cells become overacidified, which leads to a lack of nutrients in the tumor. This in turn disrupts the metabolism of the cells so that cell death (apoptosis) can set in. In certain cases chemotherapy or radiation that has previously not had any effect can be made effective. Because Hyperthermia alters the cell walls by means of so-called heat shock proteins, cancer cells then react very much more effectively to the cytostatics and radiation. If hyperthermia is used conscientiously it has no serious side effects. However whole body hyperthermia or local hyperthermia has better results when associated with infusion therapies (like Vitamin C, mandelonitrile (B17), Oxygen) and can be combined with an insulin potentiation therapy as a way to administrate a low dose chemotherapy.^[11]

Research in Russia has shown interesting results with extreme hyperthermia (body temperatures of 43,5°C to 44°C) where hyperthermia is used in cancer therapy, HIV therapy and Virus and Immune system illnesses. In a clinical trial, 30 patients received 4 extreme hyperthermia sessions within 70 days and 200 days later. All 30 patients showed less viruses (1,76 logs) and an increase in CAD4+ (45%), which is 20 times higher when compared with the HAART Therapy.^[12]

History [edit]

The application of heat to treat certain conditions, including possible tumors, has a long history. Ancient Greeks, Romans, and Egyptians used heat to treat breast masses; this is still a recommended self-care treatment for breast engorgement. Medical practitioners in ancient India used regional and whole-body hyperthermia as treatments.^[13]

During the 19th century, tumor shrinkage after a high fever due to infection had been reported in a small number of cases.^[6] Typically, the reports documented the rare regression of a soft tissue sarcoma after erysipelas (an acute streptococcus bacterial infection of the skin; a different presentation of an infection by "flesh-eating bacteria") was noted. Efforts to deliberately recreate this effect led to the development of Coley's toxin.^[13] A sustained high fever after induction of illness was considered critical to treatment success.^[13] This treatment is generally considered both less effective than modern treatments and, when it includes live bacteria, inappropriately dangerous.

Around the same period Westermark used localized hyperthermia to produce tumor regression in patients.^[14] Encouraging results were also reported by Warren when he treated patients with advanced cancer of various types with a combination of heat, induced with pyrogenic substance, and x-ray therapy. Out of 32 patients, 29 improved for 1 to 6 months.^[15]

Properly controlled clinical trials on deliberately induced hyperthermia began in the 1970s.^[6]

Future directions [edit]

Hyperthermia may be combined with gene therapy, particularly using the heat shock protein 70 promoter.^[5]

Two major technological challenges make hyperthermia therapy complicated: the ability to achieve a uniform temperature in a tumor, and the ability to precisely monitor the temperatures of both the tumor and the surrounding tissue.^[5] Advances in devices to deliver uniform levels of the precise amount of heat desired, and devices to measure the total dose of heat received, are hoped for.^[5]

In locally advanced adenocarcinoma of middle and lower rectum, regional hyperthermia added to chemoradiotherapy achieved good results in terms of rate of sphincter sparing surgery.^[16]

See also [edit]

• Microwave thermotherapy, use of microwave heating to treat cancer
• Photothermal Therapy, use of infrared radiation to treat cancer
• Photodynamic therapy, which uses light but not heat
• Thermotherapy, use of heat for treating other conditions
• Coley's Toxins, a bacteria mixture used to generate fevers as an alternative cancer treatment
• Tronado Machine, a device that uses microwave radiation to generate hypothermia for cancer treatment

References [edit]

External links [edit]

• Information from the American Cancer Society
• Transurethral Microwave Thermotherapy of the Prostate (TUMT) at eMedicine
• Hyperthermia — Cancer therapy hots up article on physics.org