Generality
"Give me a fever and I will cure any disease": this statement, attributed to the Greek physician Hippocrates (400 BC), shows how man has long ago sensed the therapeutic potential of heat.
The first documentary evidence on the possible curative effect of high temperatures in the treatment of tumors date back to 1866, when the German doctor Busch observed the complete remission of a sarcoma in the face of a patient after repeated attacks of high fever.
Today, due to the potential therapeutic benefits of this technique, hyperthermia is recognized as the fourth column of oncology.
What is oncological hyperthermia?
Oncological hyperthermia is a clinical treatment for the treatment of malignant tumors, which can be used alone or more frequently in combination with radiotherapy and chemotherapy treatments. Currently, in fact, this technique is not used as an alternative, but as an adjunct to other anticancer treatments; this association allows a mutual enhancement of therapeutic efficacy. Furthermore, the association with hyperthermia reduces the doses of chemotherapy and radiation, with a significant reduction in the side effects associated with standard therapies.
Types of Hyperthermia
The therapeutic effect of hyperthermia for the treatment of tumors can be exploited by using different approaches and technologies.
Tumor forms that have shown a good response to hyperthermia:
- Melanoma and other forms of skin cancer
- Breast cancer
- Soft tissue sarcoma
- Bladder cancer
- Carcinomas of the head and neck
- Cervical and ovarian cancer
- Prostate cancer
- Rectal cancer
- Axillary or thoracic wall carcinomas
The temperature and duration of exposure to heat are the two fundamental quantities to be calibrated to obtain the desired therapeutic result. However, in addition to the extent of the temperature reached and the heat application time, it is very important to evaluate the source that generates the heating and its application site. For example, micro-waves, radiofrequencies, nanoparticles, ultrasounds, lasers, etc., can be used externally or internally in the body.
All these variables are chosen by the oncologist based on the characteristics of the different clinical cases.
Results
In oncology the chances of recovering from a malignant tumor depend on many factors, such as the type and stage of the tumor, its size and its location, the age and general health conditions of the patient.
With all this in mind, several studies have shown that hyperthermia represents an excellent adjuvant to the classic techniques of cure for tumors, presenting few contraindications for patients.
For some types of tumors, associating radiotherapy (and / or chemotherapy) with hyperthermia, a 30-100% increase in complete remission and / or 2 and 5-year survival rates was achieved, compared to to the use of radiotherapy alone (and / or chemotherapy). For some cancers, such as rectal cancer, the results of treatment have proved even more encouraging (up to + 500% of the survival rate at five years).
Classical hyperthermia 41-45 ° C
Classic oncological hyperthermia aims to warm tumor cells without damaging surrounding healthy tissues.
- If the temperatures reached are between 41-43 ° C ( mild hyperthermia ) the main purpose is to increase the susceptibility of the neoplasm to radiotherapy and / or chemotherapy treatments.
- If the temperatures reached are between 43 and 46 ° C, the direct effect of heat on the killing of cancer cells becomes more important.
Depending on the case, the classic hyperthermia treatment lasts on average from 40 to 60 minutes and is repeated two to three times a week . More frequent treatments would tend to induce thermoresistance (or thermotolerance, if you prefer ) in cancer cells, making them able to better withstand high temperatures.
Depending on the case, the heat source can have different dimensions and be placed at different depths, in different organs or anatomical parts of the human body. For example, among modern hyperthermia techniques there is also the possibility of directly implanting microwave antennas in the subcutis.
How does it work
DIRECT DAMAGE TO TUMOR CELLS
The efficacy of oncological hyperthermia is based on the chaotic angiogenesis of tumor tissues. In essence, the tumor microenvironment almost always presents a chaotic and disorganized vascular scaffold; as a result, large tumor areas (especially the central mass) receive insufficient amounts of blood and oxygen. Because of these alterations in blood vessels, the neoplastic mass is unable to dissipate heat like normal tissues ; in other words, tumors tend to suffer much more heat than healthy tissues, because some of their areas receive little blood (which acts as a real cooling liquid); for the same reason, these areas are already suffering from the lack of oxygen and nutrients and the abundance of waste products (hyper acidification).
The heat administered by hyperthermia causes damage to the plasma membrane, the cellular skeleton and the nucleus; if the magnitude and duration of hyperthermia is sufficient, this damage leads directly to the death of the cancer cell. The direct damage becomes significant at temperatures> 43 ° C: the indirect one, which we will see shortly, is instead typical of the so-called "mild hyperthermia" (42-43 ° C).
INDIRECT DAMAGE: ADIUVANT HYPERTHERMIA
Our body reacts to the rise in local temperature by increasing the blood flow to the affected area. In this way the greater quantities of circulating blood "absorb" heat, preserving the tissues from thermal damage. This response also occurs at the tumor level, so - within the limits of the peculiar vascular disorganization - the tumor cells subjected to a slight rise in temperature receive greater quantities of blood and oxygen :
- in the blood antitumor drugs may be present, which thanks to the vasodilation induced by hyperthermia can more easily reach the less vascularized neoplastic areas; the action of these drugs could also be facilitated by cellular alterations (increased permeability of the plasma membrane) and enzymatic (protein denaturation) induced by heat.
When the temperatures in the tumor mass exceed 43 ° C, there is instead a decrease in tumor blood flow, with consequent "entrapment" of the drug molecules.
The advantages of the hyperthermia-chemotherapy association have been confirmed by several studies. Anticancer drugs such as Melphalan, Bleomycin, Adriamycin, Mitomycin C, Nitrosuree, Cisplatin are most effective when given during hyperthermia. In this regard, however, it should be emphasized that not all known chemotherapeutic drugs find an increase in their effectiveness if used in a hyperthermic environment.
- The increased supply of oxygen to the tumor tissue amplifies the effects of radiotherapy, which are based above all on DNA damage induced by reactive oxygen species (free radicals) generated by radiation. As seen for chemotherapy, the activity of radiotherapy is also facilitated by neoplastic cellular impairment linked to the damage previously inflicted by hyperthermia.
The mutual completion and reinforcement of action between hyperthermia and radiotherapy derives from the fact that:
- the damage induced by hyperthermia is greater in areas of low vascularization (which cannot effectively dissipate heat), such as the hypoxygenated central nucleus of the neoplastic nodule;
- the damage induced by radiotherapy is instead greater in areas of high vascularization (richer in oxygen), such as the peripheral areas of the tumor nodule;
- the two treatments exert their maximum efficacy damaging the tumor in different phases of the cell cycle, resulting complementary also in this sense.
The maximum therapeutic gain seems to be obtained by practicing hyperthermic treatment within one or two hours after the radiotherapy session. As far as thermo-chemotherapy is concerned, however, the two treatments can also be performed simultaneously.
Oncological hyperthermia can contribute to the reduction of the tumor mass in view of a surgical removal operation. There are also benefits in terms of analgesic effect (reduction of pain triggered by tissue compression by the neoplastic mass).
Other forms of hyperthermia
TOTAL-BODY HYPERTHERMIA
As the name suggests, this form of hyperthermia involves heating the entire body. The aim, in this case, is not to directly destroy the tumor mass, but to determine its indirect remission by means of an enhancement of the immune system . The latter, in fact, has an intrinsic capacity to destroy cancer cells, and this capacity increases enormously under conditions of high body temperature.
The purpose of total-body hyperthermia is to induce an artificial fever, simulating a fever attack around 39-41 ° Celsius. In this regard, thermal or water-covered chambers can be used.
The use of the total-body is mostly confined to the experimental setting for the treatment of widespread metastases . The technique requires close monitoring of the patient to avoid damage from hyperthermia, which can also be very serious. It is also an adjuvant therapy, to be used therefore in association with other anticancer therapies.
INTERSTITIAL HYPERTHERMIA
As seen for brachytherapy - in which small radioactive sources are implanted in the target tissue - interstitial hyperthermia involves the implantation of devices capable of generating local hyperthermia. In this regard, antennas are used which heat thanks to the supply of microwaves.
INFUSION HYPERTHERMIA AND HYPERTHERMIA IN PERFUSION
Intraperitoneal infusion hyperthermia is based on the use of peritoneal washings with medicated solutions at high temperatures. It is used in cases of difficult peritoneal neoplasms, such as peritoneal mesothelioma and stomach cancer. On the same principle, other hyperthermia techniques are based on the infusion of therapeutic solutions heated in other cavities, such as the pleural or bladder.
In perfusion hyperthermia recourse is had to extracorporeal circulation, with heating of part of blood and re-introduction of the same with addition of chemotherapeutic drugs, so as to obtain high concentrations of drug in the perfused tissue.
ABLATIVE HYPERTHERMIA
In this case the temperatures are much higher (50-100 ° C), but they are applied only for a few minutes. Similar temperatures can produce immediate and total necrosis of the treated tissues. The heat is generated by the application of an alternating electric current through electrodes or through the use of lasers or electromagnetic radiations, applied directly on the tumor mass (invasive treatment). The greatest difficulty lies in preserving the healthy tissues surrounding the tumor.
Although this technique exploits the therapeutic effect of heat, due to the mechanism of action it is beyond what is the traditional concept of hyperthermia.
NEW DEVELOPMENTS WITHIN THE HYPERTERMIA
The science of hyperthermia is constantly evolving, to develop increasingly selective treatments in order to destroy cancer cells without damaging healthy ones.
The most recent developments concern non-invasive thermometry with the use of magnetic resonance scanners (to assess the temperature in different tumor areas), the magneto-fluid hyperthermia and the use of thermosensitive liposomes. The latter are drugs enclosed in lipid vesicles, stable at normal body temperatures but capable of releasing their contents at temperatures of about 40-43 ° C; these drugs therefore represent the ideal combination with regional hyperthermia treatments.
Limitations
Understanding the mechanisms of action of hyperthermia and the consequent potential benefits in the treatment of tumors could lead to excessive reader's enthusiasm for this type of treatment.
Although it is supported by discrete evidence of efficacy, the application of hyperthermia in the oncology field preserves some critical points. First of all in clinical practice there may be contraindications or limits that make the intervention impractical; some techniques, for example, involve more or less invasive surgical procedures; others are still mostly confined to the experimental setting. It is also necessary to overcome the technical limitations connected to the emission of heat, the depth of penetration, the homogeneity of the thermal fields and the need for a correct thermal dosage to avoid damage to healthy tissues. In this regard, further studies and technological developments are desirable to develop effective and standardized protocols to be adopted in the various clinical situations.
