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Medical Specialties

Integrative Medicine. Hyperthermia

Hyperthermia is also called thermotherapy. This non-invasive form of therapy involves exposing the entire body or certain areas of the body to high temperatures for therapeutic purposes. In the past few years, this therapy has started being increasingly used as a complementary form in treating cancer.
Currently, general (systemic) and local hyperthermia are commonly used in several university medical centers in Europe and the United States.

 

Currently, general (systemic) and local hyperthermia are commonly used in several university medical centers in Europe and the United States.

 

Procedure

In this form of therapy, ultrasounds or low frequency electrical currents are directed, in a controlled and targeted manner, by means of special devices, towards the organ or tissue affected by the tumor. The energy thus produced is absorbed by the extracellular environment where the tumor cells are located, consequently increasing their temperature and producing the intended effects.

 

The devices that are used transmit the dose of energy in a controlled manner, causing the tissue to heat up to 42.5˚C. Biophysics and cell biology tests have shown that, in tumor areas where cell activity is more intense, a higher ionic concentration is recorded. Therefore, the conductivity and permittivity of the extracellular matrix of malignant tissue becomes higher than in the healthy tissue. This difference facilitates the almost exclusive damage of the malignant cells in a tumor that also contains healthy cells. This natural selection is further accentuated by the individual behavior of the tumor cells, while also stimulating the immune response of the body.

 

Recommendations

Clinical trials (phases II and III) have proven that regional hyperthermia is recommended for solid tumors, both primary and metastatic. The therapy is able to increase the patient's survival rate and quality of life. It may also be applied for palliative purposes, when conventional therapies are no longer indicated or efficient.

 

Oncothermia is used in a large number of cancers, such as breast cancer, prostate cancer, cancers with abdominal localization (stomach, intestine, liver, pancreas), lung cancer, lymphatic cancer and various other metastases.

Clinical experience has shown that local hyperthermia, especially when performed before or after tumor tissue removal surgery, improves patient recovery parameters and decreases the chances of subsequent metastasis occurrence.

 

The frequency and duration of hyperthermia application depends entirely on the specific condition of the patient. Generally, therapy is extremely well tolerated. Usually, there are no side effects, even when used concomitantly with other therapies. The heat is applied locally, directly to the affected tissue or organ. During the session, which lasts for approximately 60 minutes, the patient is placed on a special bed, under the continuous observation of the medical staff.

 

Benefits

The following benefits of local hyperthermia have been demonstrated:

 

Chemosensitization. Local therapy, applied in addition to conventional chemotherapy, sensitizes the tumors to this treatment, by affecting the integrity of the tumor cell membrane and increasing the permeability and structural dysfunction, thus increasing the rate of absorption of the administered chemicals. The results of the clinical trials, phases II/III, proved that local hyperthermia, associated with chemotherapy, is a more precise way of targeted administering of antitumor drugs in the tumor.

 

Radiosensitization. Local hyperthermia sensitizes the tumor to radiotherapy when it is administered complementarily (there is an increase in oxygen supply to the cells). Regional hyperthermia carried out during radiotherapy treatments improves patients' response to treatment and their chances of survival. Hyperthermia increases oxygenation and thus reduces hypoxia, amplifying the cytotoxic effect of radiation. It also inhibits the processes of recovery of tumor cells affected by radiation.

 

The immune response. Local hyperthermia activates antigen expression as a result of impaired tumor cell membrane. Most notably, the release of heat shock proteins (HSPs) that support the emergence of a tumor destruction immune response. The release, by the affected tumor cells, of the B1 proteins (HMGB1), ATP and HSP stimulates the body's immune response and thus contributes to the antitumor effect. Local hyperthermia also stimulates the restoration of inter-cellular and intermolecular connections necessary to trigger apoptosis (programmed cell death) and to stop the migration processes of tumor cells in the body.

 

Gene damage. Studies have shown that local hyperthermia activates the p53 suppressor tumor gene, which plays a role in lowering the rate of division and in facilitating apoptosis.

 

Side effects and contraindications

The therapy has minimal risks during administration, and side effects are limited and rare. The application of high temperature to the tumor has minimal effects on the neighboring healthy tissues.

 

From among side effects, the most common is the slight reddening of the area where the treatment was applied, but the effect disappears by itself due to the function of the highly branched and efficient blood system from healthy tissues. This does not happen in the tumor, as it is irrigated by a deficient capillary system.

 

The therapy is effective in all forms of cancer, but it is not recommended to be applied in areas where there is a pacemaker or metal stents placed in parallel to the electrode, as well as metal prostheses. Therapy may be applied from the distance of approximately 10-20 cm from these areas.

 

Total hyperthermia

 

Procedure

 

The objective of systemic hyperthermia is to induce the beneficial effects that fever has on the body. Usually, during 3 hours, the temperature of 40-41˚C is induced, with the possibility of maintaining it at 38-40˚C for 4-8 hours.

 

By applying heat to the entire body, general hyperthermia treats systemic diseases, including cancer. As a result of abnormal vascularization, anaerobic metabolism and nutrient depletion, tumors have a higher thermal sensitivity than healthy tissues.

 

The patient is placed on a special bed, adjustable throughout the procedure, which may last for several hours, to ensure patient comfort throughout the session. Body temperature is increased by applying infrared radiation (IR-A). The patient makes minimal effort during this procedure, he relaxes in a pleasant and comfortable environment, during the several hours of temperature application. Throughout the entire procedure, body temperature, heart rate, oxygenation, blood pressure, EKG, respiratory rate are constantly monitored.

 

Total hyperthermia is administered in cycles of 4-6-8-10-12 sessions, consecutively carried out, one week apart from one another.

 

Recommendations

Treatment with hyperthermia may be applied in all stages of cancer.

 

Countless clinical trials have studied the effects of combined hyperthermia treatment with radiotherapy or chemotherapy. These studies focused on treating several types of cancer, such as sarcomas, melanoma, head and neck cancer, brain, lung, esophageal, breast, urinary bladder, anal, liver, cervical, peritoneal cancer. Many of these studies showed a significant reduction in tumor volume, when hyperthermia was combined with other forms of treatment.

 

The main reasons for using general/systemic hyperthermia are the following:

-compared to healthy cells, cancer cells become more sensitive, even developing an intolerance to the effects of excessive heat,

• because the tumors do not have the capacity to adapt their blood circulation to the effects of the high temperatures, a decrease in their blood supply is registered,

• temperatures higher than 41° C cause the appearance of acidosis in cancer cells, which decreases their viability and division capacity,

• high temperatures cause activation of the body's immune system, with increased interferon production. Renowned German doctor Rolf Issels has noticed that hyperthermia increases the concentration of heat shock proteins (HSPs) on the surface of cancer cells, thus making them prone to the attacks of the immune system,

• systemic hyperthermia may be successfully used for metastatic cancers.

 

The tumor mass, at its core, contains the cells that live in a state of hypoxia (with little oxygen). These cells have resistance to radiation treatment, but they are very sensitive to heat. Researchers believe that radiation therapy destroys normally oxygenated cells in the upper layers of the tumor, while hyperthermia acts on those within, greatly decreasing the overall resistance of the tumor to radiation or drug treatment.

 

Benefits

Clinical experience has shown that one of the greatest benefits of systemic hyperthermia is the increased efficiency of other forms of cancer treatment. Heating the cells at temperatures higher than the physiological ones makes them susceptible to radiation and chemotherapy treatment.

 

Specialized research has shown that (general) systemic hyperthermia can cause:

• maturation of dendritic cells in the brain,

• increased immune response (through the interaction of dendritic cells with CD8 T cells),

• prolonged activation of immune T cells,

• activation of monocytes and macrophages,

• release of tumor necrosis factor (TNFα),

• increased number of T lymphocytes and natural killer cells (NK),

• general stimulation of the body's immune response.

Moreover, under the influence of heat, tumor cells produce heat shock proteins (HSPs), specific to damaged cells in the body; their synthesis makes them susceptible to destruction by the immune system. Thus, hyperthermia stimulates the immune system to fight the tumor.

 

Currently, systemic hyperthermia is officially recognized as a classic, effective method of treating different forms of cancer.

 

 

Side effects and contraindications

 

Contraindications depend on the degree of elevation of the proposed temperature and are oriented according to the negative load exerted on the circulatory system and to the possibility of creating an unwanted activation of inflammation, as well as of destabilizing the hormonal and metabolic labile constellations:

• acute infections,

• excessive dehydration with disturbances of the hydro-electrolyte balance in the body, anhidrosis,

• heart failure (degree > 2),

• advanced atherosclerosis, myocardial infarction; heart rhythm disorders - (prior to the hyperthermic treatment, cardiac tests are required),

• extreme deficient cerebral circulation, brain tumors, possibly cerebral edema; as regards those disorders that have an intense rate of cancer metastasis, a medical examination is required prior to the hyperthermic therapy (the onset of convulsions during the oncological hyperthermic treatment indicates the existence of the brain cancer metastases that have not been diagnosed yet, which entails the immediate interruption of the therapeutic sessions).

• manifest insufficiency of internal organs such as lungs, liver, kidneys, bone marrow regarding obstructive neoplasms or destructive inflammatory processes,

• diagnosed or suspected thrombosis, the anticoagulant drug Marcumar, peripheral arterial occlusive disease (in case of venous varicose veins, the patient's legs will be suspended and covered),

• for diseases with strong episodes, where treatments have unsatisfactory results, such as multiple sclerosis,

• for episodes of primary-evolutionary chronic polyarthritis (rheumatoid arthritis),

• hormonal and metabolic crises such as hyperthyroidism and porphyria,

• sugar diabetes (Diabetes Mellitus) and muscle hypertonia require a permanent discontinuation in advance,

• oxygen saturation below 92%,

• poor condition of general health of the patient in the advanced stages of a present disease (WHO 3rd or 4th degree),

• limit psychiatric situations,

• pregnancy and breastfeeding,

• a diagnosed lymphedema may be intensified after the hyperthermic treatment due to the vasodilation that occurs. In order to start a hyperthermic treatment, aware of the aforementioned risks, the patient must be informed about the seriousness of this decision. When affirmative, the hyperthermic process will be joined by adjuvant medications such as (enzyme therapy).

 

The main adverse reactions are:

 

• overloading of the circulatory system and of the regulation of the central body temperature in situations where it is forced to increase the temperature from the reference value of 370C to a much higher real value,

• thermal overloading of the main arteries affected by malperfusion (ischemia) or that have other special properties,

• unwanted effects of immune system stimulation and coronary perfusion.


 

 

Procedure
In this form of therapy, ultrasounds or low frequency electrical currents are directed, in a controlled and targeted manner, by means of special devices, towards the organ or tissue affected by the tumor. The energy thus produced is absorbed by the extracellular environment where the tumor cells are located, consequently increasing their temperature and producing the intended effects.

The devices that are used transmit the dose of energy in a controlled manner, causing the tissue to heat up to 42.5˚C. Biophysics and cell biology tests have shown that, in tumor areas where cell activity is more intense, a higher ionic concentration is recorded. Therefore, the conductivity and permittivity of the extracellular matrix of malignant tissue becomes higher than in the healthy tissue. This difference facilitates the almost exclusive damage of the malignant cells in a tumor that also contains healthy cells. This natural selection is further accentuated by the individual behavior of the tumor cells, while also stimulating the immune response of the body.

Recommendations
Clinical trials (phases II and III) have proven that regional hyperthermia is recommended for solid tumors, both primary and metastatic. The therapy is able to increase the patient's survival rate and quality of life. It may also be applied for palliative purposes, when conventional therapies are no longer indicated or efficient.

Oncothermia is used in a large number of cancers, such as breast cancer, prostate cancer, cancers with abdominal localization (stomach, intestine, liver, pancreas), lung cancer, lymphatic cancer and various other metastases.
Clinical experience has shown that local hyperthermia, especially when performed before or after tumor tissue removal surgery, improves patient recovery parameters and decreases the chances of subsequent metastasis occurrence.

The frequency and duration of hyperthermia application depends entirely on the specific condition of the patient. Generally, therapy is extremely well tolerated. Usually, there are no side effects, even when used concomitantly with other therapies. The heat is applied locally, directly to the affected tissue or organ. During the session, which lasts for approximately 60 minutes, the patient is placed on a special bed, under the continuous observation of the medical staff.

Benefits
The following benefits of local hyperthermia have been demonstrated:

Chemosensitization. Local therapy, applied in addition to conventional chemotherapy, sensitizes the tumors to this treatment, by affecting the integrity of the tumor cell membrane and increasing the permeability and structural dysfunction, thus increasing the rate of absorption of the administered chemicals. The results of the clinical trials, phases II/III, proved that local hyperthermia, associated with chemotherapy, is a more precise way of targeted administering of antitumor drugs in the tumor.

Radiosensitization. Local hyperthermia sensitizes the tumor to radiotherapy when it is administered complementarily (there is an increase in oxygen supply to the cells). Regional hyperthermia carried out during radiotherapy treatments improves patients' response to treatment and their chances of survival. Hyperthermia increases oxygenation and thus reduces hypoxia, amplifying the cytotoxic effect of radiation. It also inhibits the processes of recovery of tumor cells affected by radiation.

The immune response. Local hyperthermia activates antigen expression as a result of impaired tumor cell membrane. Most notably, the release of heat shock proteins (HSPs) that support the emergence of a tumor destruction immune response. The release, by the affected tumor cells, of the B1 proteins (HMGB1), ATP and HSP stimulates the body's immune response and thus contributes to the antitumor effect. Local hyperthermia also stimulates the restoration of inter-cellular and intermolecular connections necessary to trigger apoptosis (programmed cell death) and to stop the migration processes of tumor cells in the body.

Gene damage. Studies have shown that local hyperthermia activates the p53 suppressor tumor gene, which plays a role in lowering the rate of division and in facilitating apoptosis.

Side effects and contraindications
The therapy has minimal risks during administration, and side effects are limited and rare. The application of high temperature to the tumor has minimal effects on the neighboring healthy tissues.

From among side effects, the most common is the slight reddening of the area where the treatment was applied, but the effect disappears by itself due to the function of the highly branched and efficient blood system from healthy tissues. This does not happen in the tumor, as it is irrigated by a deficient capillary system.

The therapy is effective in all forms of cancer, but it is not recommended to be applied in areas where there is a pacemaker or metal stents placed in parallel to the electrode, as well as metal prostheses. Therapy may be applied from the distance of approximately 10-20 cm from these areas.

Whole body hyperthermia

 

Procedure

The objective of systemic hyperthermia is to induce the beneficial effects that fever has on the body. Usually, during 3 hours, the temperature of 40-41˚C is induced, with the possibility of maintaining it at 38-40˚C for 4-8 hours.
By applying heat to the entire body, general hyperthermia treats systemic diseases, including cancer. As a result of abnormal vascularization, anaerobic metabolism and nutrient depletion, tumors have a higher thermal sensitivity than healthy tissues.

The patient is placed on a special bed, adjustable throughout the procedure, which may last for several hours, to ensure patient comfort throughout the session. Body temperature is increased by applying infrared radiation (IR-A). The patient makes minimal effort during this procedure, he relaxes in a pleasant and comfortable environment, during the several hours of temperature application. Throughout the entire procedure, body temperature, heart rate, oxygenation, blood pressure, EKG, respiratory rate are constantly monitored.

Total hyperthermia is administered in cycles of 4-6-8-10-12 sessions, consecutively carried out, one week apart from one another.

Recommendations
Treatment with hyperthermia may be applied in all stages of cancer.

Countless clinical trials have studied the effects of combined hyperthermia treatment with radiotherapy or chemotherapy. These studies focused on treating several types of cancer, such as sarcomas, melanoma, head and neck cancer, brain, lung, esophageal, breast, urinary bladder, anal, liver, cervical, peritoneal cancer. Many of these studies showed a significant reduction in tumor volume, when hyperthermia was combined with other forms of treatment.

The main reasons for using general/systemic hyperthermia are the following:
-compared to healthy cells, cancer cells become more sensitive, even developing an intolerance to the effects of excessive heat,
• because the tumors do not have the capacity to adapt their blood circulation to the effects of the high temperatures, a decrease in their blood supply is registered,
• temperatures higher than 41° C cause the appearance of acidosis in cancer cells, which decreases their viability and division capacity,
• high temperatures cause activation of the body's immune system, with increased interferon production. Renowned German doctor Rolf Issels has noticed that hyperthermia increases the concentration of heat shock proteins (HSPs) on the surface of cancer cells, thus making them prone to the attacks of the immune system,
• systemic hyperthermia may be successfully used for metastatic cancers.

The tumor mass, at its core, contains the cells that live in a state of hypoxia (with little oxygen). These cells have resistance to radiation treatment, but they are very sensitive to heat. Researchers believe that radiation therapy destroys normally oxygenated cells in the upper layers of the tumor, while hyperthermia acts on those within, greatly decreasing the overall resistance of the tumor to radiation or drug treatment.

Benefits
Clinical experience has shown that one of the greatest benefits of systemic hyperthermia is the increased efficiency of other forms of cancer treatment. Heating the cells at temperatures higher than the physiological ones makes them susceptible to radiation and chemotherapy treatment.

Specialized research has shown that (general) systemic hyperthermia can cause:
• maturation of dendritic cells in the brain,
• increased immune response (through the interaction of dendritic cells with CD8 T cells),
• prolonged activation of immune T cells,
• activation of monocytes and macrophages,
• release of tumor necrosis factor (TNFα),
• increased number of T lymphocytes and natural killer cells (NK),
• general stimulation of the body's immune response.
Moreover, under the influence of heat, tumor cells produce heat shock proteins (HSPs), specific to damaged cells in the body; their synthesis makes them susceptible to destruction by the immune system. Thus, hyperthermia stimulates the immune system to fight the tumor.

Currently, systemic hyperthermia is officially recognized as a classic, effective method of treating different forms of cancer.


Side effects and contraindications
Contraindications depend on the degree of elevation of the proposed temperature and are oriented according to the negative load exerted on the circulatory system and to the possibility of creating an unwanted activation of inflammation, as well as of destabilizing the hormonal and metabolic labile constellations:
• acute infections,
• excessive dehydration with disturbances of the hydro-electrolyte balance in the body, anhidrosis,
• heart failure (degree > 2),
• advanced atherosclerosis, myocardial infarction; heart rhythm disorders - (prior to the hyperthermic treatment, cardiac tests are required),
• extreme deficient cerebral circulation, brain tumors, possibly cerebral edema; as regards those disorders that have an intense rate of cancer metastasis, a medical examination is required prior to the hyperthermic therapy (the onset of convulsions during the oncological hyperthermic treatment indicates the existence of the brain cancer metastases that have not been diagnosed yet, which entails the immediate interruption of the therapeutic sessions).
• manifest insufficiency of internal organs such as lungs, liver, kidneys, bone marrow regarding obstructive neoplasms or destructive inflammatory processes,
• diagnosed or suspected thrombosis, the anticoagulant drug Marcumar, peripheral arterial occlusive disease (in case of venous varicose veins, the patient's legs will be suspended and covered),
• for diseases with strong episodes, where treatments have unsatisfactory results, such as multiple sclerosis,
• for episodes of primary-evolutionary chronic polyarthritis (rheumatoid arthritis),
• hormonal and metabolic crises such as hyperthyroidism and porphyria,
• sugar diabetes (Diabetes Mellitus) and muscle hypertonia require a permanent discontinuation in advance,
• oxygen saturation below 92%,
• poor condition of general health of the patient in the advanced stages of a present disease (WHO 3rd or 4th degree),
• limit psychiatric situations,
• pregnancy and breastfeeding,
• a diagnosed lymphedema may be intensified after the hyperthermic treatment due to the vasodilation that occurs. In order to start a hyperthermic treatment, aware of the aforementioned risks, the patient must be informed about the seriousness of this decision. When affirmative, the hyperthermic process will be joined by adjuvant medications such as (enzyme therapy).

The main adverse reactions are:
• overloading of the circulatory system and of the regulation of the central body temperature in situations where it is forced to increase the temperature from the reference value of 370C to a much higher real value,
• thermal overloading of the main arteries affected by malperfusion (ischemia) or that have other special properties,
• unwanted effects of immune system stimulation and coronary perfusion.
Short history
Hyperthermia has been used since Ancient Greece, and the Hellenic physicians have recognized, since those times, the therapeutic value of fever. In the 19th century, several German doctors noticed the decrease or healing of sarcomas in patients with infections and who had a fever for extended periods of time. In the same 19th century, the American physician William Coley reported healing cases in cancer patients following the administration of bacterial endotoxins (substances produced by bacteria and which, in the host body, can induce a strong immune response, a specific disease), known today as the "Coley’s mixed bacterial vaccine".

Since 1951, the German doctor Josef M. Issels has started systematically administering this therapy in patients diagnosed with cancer, with extremely encouraging results.

In addition to the controlled induction of fever by pathogens or toxins, all forms of hyperthermia involve the application of heat into/on the body by using external sources. Different forms of energy may be used, such as microwaves, radio frequencies and ultrasounds.

In the first decades of the 20th century, when the biological effects of the controlled increase of body temperature were better understood, several special devices for the therapeutic application of systemic or only local heat were developed and improved. Although local (regional) hyperthermia has been the most commonly used so far (treating a particular tissue, organ or region of the body), there is a growing interest in systemic hyperthermia, due to its various advantages.

In March 2000, The Lancet medical journal revealed the results of a six-year clinical trial carried out in the Netherlands, which compared the efficacy of radiation therapy with the complementarily administered hyperthermia. The trial was randomized, phase III, and included 358 patients diagnosed with various advanced forms of cancer (cervical, urinary bladder, colorectal). The most impressive results were recorded for cervical cancer: complete elimination of the tumor in 83% of the patients who had undergone the combined treatment, compared to 57%, in case of radiotherapy. Moreover, the survival rate for patients treated with hyperthermia and radiotherapy was almost twice as high as for those undergoing radiotherapy only. At the same time, in patients undergoing the combination treatment, no side effects were noticed (dizziness, nausea, requiring hospitalization), as in the case of radiotherapy patients. Following these results, the Dutch government approved the administration of this combined form of treatment.

In 2009, the European Society of Medical Oncology (ESMO), during the Berlin meeting, presented the participants with the results of a randomized trial comparing the efficiency of chemotherapy and chemotherapy administered concomitantly with hyperthermia, showing that the survival rate doubled in the second group, from an average of 18 months to 32 months.

The US National Cancer Institute (NCI) states that "hyperthermia can sensitize certain cells to radiation or affect those resistant to radiation treatment. Hyperthermia allows the successful administration of high doses of chemotherapeutics, without triggering significant side effects”.

How does this therapy work
Hyperthermia is a therapy where the increase of body temperature, by different methods, causes the damage or destruction of cancer cells or increases their susceptibility to the effects of radio- and chemotherapy. According to the US National Cancer Institute (NCI), this noninvasive form of therapy causes tumor shrinkage, with minimal impact on healthy tissues.

Studies have shown that, for malignant tumors:
• heat destroys or weakens the proteins and structure of malignant cells,
• heat increases the blood flow in the affected tumor, thus increasing the penetration power of drugs into the tumor,
• increased body temperature stimulates the immune function,
• destruction of malignant cells as a result of necrobiosis and apoptosis process induction,
• decreased resistance of malignant cells to chemotherapy,
• protection against side effects of chemotherapy, when hyperthermia is co-administered. It also allows reducing the doses of chemotherapy, decreasing the negative effects on the healthy tissues, while maintaining the antineoplastic activity.

The significant increase of temperature in the cancerous tissue produces different effects on the tumor microenvironment. It is well known that cancer cells have a very high metabolic activity (required for fast division); however, the supply of cells through the tumor capillaries is deficient. This situation has fatal consequences on the tumor cells when the area is heated, particularly if this heating occurs suddenly. The increase of temperature entails the decrease of oxygen and nutrient intake in the target tissue, which affects the metabolic processes and, consequently, the capacity for growth and division of the tumor. Proteins and cellular structures are irreversibly affected by heat. Thus, hyperthermia opens the way to the onset of processes preceding cell death. Moreover, studies have shown that, in the capillaries of the tissues subjected to hyperthermia, a concentration of the immune system cells takes place.

The antitumor effect of hyperthermia
Hyperthermia entails numerous changes at cell level, changes that determine the alteration of cellular homeostasis. One of the most relevant effects that can occur is that of protein denaturation and aggregation, which further causes cell cycle blockage, inactivation of protein synthesis and inhibition of DNA repair processes. Other biochemical effects caused by hyperthermia are: inhibition of DNA synthesis, of transcription and of translation; amplification of the processes of protein degradation, through lysosomal and proteosomal pathways; impairment of membrane cytoskeleton integrity; metabolic changes (e.g. impairment of oxidative phosphorylation processes), causing the decrease of ATP levels; alterations of membrane permeability, causing the increase of intracellular flow of Na+, H+ and Ca2+.

Studies have shown that changes in membrane viscosity are followed by an increase in the activity of the sodium-potassium-ATP-dependent pump, which maintains the membrane level of Na+ and of K+ at values opposite the concentration gradient. During hyperthermia treatment, the membrane permeability to certain compounds is altered (e.g. polyamines, glucose and chemotherapeutics).

Despite the significant number of studies conducted on cellular changes that occur during hyperthermia, the nature of the lesions that cause cell death is still poorly understood. It appears that proteins are the first to be affected by hyperthermia (39-45°C). Alteration of cellular homeostasis occurs after the exposure to high temperatures causes a series of translational changes such as glycosylation, acylation, phosphorylation and ubiquitination. Several studies have reported DNA fragmentation and the formation of double-strand breaks following hyperthermia. However, it appears that nuclear protein damage is the key effect of therapy, not direct DNA damage. Nuclear proteins, particularly, seem to be highly sensitive to high temperatures, undergoing aggregation processes very quickly. Laboratory studies have shown that nuclear protein aggregation causes inhibition of DNA transcription and replication. Thus, cell division and tumor growth are stopped.

High temperatures are able to increase the incidence of biochemical reactions, with increased cellular metabolism, thus increasing oxidative stress as well. Studies have shown that the level of reactive oxygen species (ROS) have grown following the exposure to lethal (≥42°C) or non-lethal (40°C) temperatures. This ROS growth is more particularly associated with the increased generation of superoxide radical and hydrogen peroxide (H2O2) as a result of mitochondrial respiratory chain impairment. Other sources of ROS are the NADPH enzymes, oxidase and xanthine oxidase, as their activity is stimulated once the temperature rises. Likewise, hyperthermia also determines a higher reactivity of ROS - researchers have noticed an increase of cytotoxicity caused by H2O2, once the temperature rises from physiological values (37°C) to abnormal values (41°C - 43°C).

One of the consequences of these cellular disorders is the impairment of mitosis, the permanent arrest in G1 and the loss of clonogenic or reproductive cell capacity. Cell death can be induced by processes such as apoptosis and/or necrosis, depending on the cell type, but also on the temperature and duration of heat exposure. Another consequence is the sensitization of cells to classical antitumor treatment, such as radiation. Centrosome and mitotic dysfunctions are reported as a result of thermo-radiosensitization.

In rats with fibrosarcoma and colon cancer treated with systemic hyperthermia (41.5°C for 2 h), a variation was noticed, both in magnitude, and in the kinetics of apoptosis thus induced. In addition, the induction of apoptosis was noticed to be more intense in tumor tissues, compared to healthy ones. Most of the studies that have investigated the mechanisms of cytotoxicity induction following exposure to high temperatures have concluded that apoptosis is the main antitumor effect recorded in this therapy.