Hyperthermia

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.