Therapeutic hyperthermia
Therapeutic hyperthermia (Greek for overheating ) is what medicine calls a treatment in which the temperature of the body tissue is artificially increased. It is a part of thermotherapy . There is overheating of the whole body and that of regions or individual organs. The name does not include the simple external heat applications, which above all increase the temperature of the skin layers ( fango , infrared treatment ), etc.
With overheating therapy , in contrast to fever therapy, the body's heat emission is artificially restricted, for example through baths or heat-accumulating compresses. Basically all those procedures are called hyperthermia in which the overheating of the body or the tumor area is caused by micro waves or radio waves, or by infrared emitters from the outside.
History of therapeutic hyperthermia
The healing effect of heat was mentioned for the first time in the ancient Egyptian civilizations (2400 BC), but it was not until ancient Greece that doctors consistently applied, recognized and named this therapeutic approach: overheating (Greek: hyperthermia). For example, in the Corpus Hippocraticum in The Epidemic Diseases, quartana malaria is reported to have a healing effect on epilepsy . A healing fever is also described in literature at the beginning of the 13th century.
Various areas of application have been found over the centuries. For example, in the fight against infectious diseases, the artificial generation of fever with the aid of pyrogenic substances was common as fever therapy (fever caused for therapeutic purposes). These interventions in the organism and body functions can be referred to as active hyperthermia and are also called therapeutic fever . Passive hyperthermia, on the other hand, describes the increase in body temperature by using external equipment. Today it is mainly used in cancer treatment .
Julius Wagner von Jauregg can be regarded as a pioneer of modern “fever therapy” . First von Jauregg accidentally observed a cure for generalized paralysis in systemic syphilis in a patient with erysipelas ; later he developed fever therapy using malaria-infected blood, also known as malaria therapy . Von Jauregg received the 1927 Nobel Prize in Physiology or Medicine for the treatment of syphilis using fever therapy. The procedure has lost its importance with the advent of antibiotic therapy.
Hyperthermia in cancer treatment
Note: A form of hyperthermia that has been further developed with regard to cancer treatment is sometimes also referred to as oncothermia or oncothermia (combined with the term oncology ).
Whole body hyperthermia
In 1886 the German surgeon Wilhelm Busch published an article "on the effects that violent erysipelas (which are accompanied by a high fever) have on malignant neoplasms". Initially, attempts were made to cure malignant tumors with artificially generated fever. In the first two decades of the 20th century, more and more devices were used. In the early 1960s, this already known and applied method was rediscovered as whole body hyperthermia. Interest is thereby general increase in performance, increase of the immune defense, supplement of cancer therapies. In alternative cancer therapy, hyperthermia is used particularly for relapses, metastases and tumors and as an accompanying therapy during and after conventional medical treatment as a therapy with few side effects. Studies on this form of therapy have been ongoing since the 1970s. In East Germany it was above all the physicist and cancer researcher Manfred von Ardenne who developed whole-body hyperthermia. He achieved high penetration depth with long-wave infrared light . In the absence of precise control over internal body temperature, it was initially difficult to optimize the method. To support it, it is usually combined with other therapies, for example almost always with oxygen inhalation, analogous to the use of oxygen in evidence-based medicine . He therefore combined this infrared light therapy with his oxygen multi-step therapy for cancer multi-step therapy - including increased intake of glucose in order to make use of the cancer cells' deviating behavior in terms of metabolism , as the "glycolysis metabolism " in these cases dominates. The modern device technology developed primarily by his institute or the corresponding successor company enables good control of overheating and thus facilitates use in medical practice. Von Ardenne has never been able to provide clinical evidence of cancer efficacy through double-blind studies of any inhalation- related therapy. In animal experiments there are tests that have been positive. The described successes of the oxygen multi-step therapy and the cancer multi-step therapy have been the subject of discussions. In this sense, both methods can currently be assigned to alternative medicine (alternative cancer therapy - complementary oncology). The healing effect of overheating in the form of fever and the artificially induced so-called "healing fever" is undisputed. Hyperthermia mimics and uses a principle that is given by nature.
In a modern version, which is of interest for whole-body hyperthermia (Ardenne), the heat is supplied as filtered infrared radiation. Some of the heat radiation is absorbed by a layer of circulating water before it reaches the patient. The advantage is that the radiation penetrates relatively evenly, so overheating of the skin layers is largely avoided. The patient lies on his back on an IR-permeable mat. The heat radiation comes from below and is reflected on the top of the body. The reflection takes place on a thin metal foil (similar to a rescue blanket) with which the patient is covered. It makes it possible to make better use of the IR radiation, it passes through the body twice. As an alternative to the open application, there are also systems in which the patient is (also in a lying position) in an insulated chamber that is electrically heated. The head is outside the heating zone (advantage = this system is technically easier to implement and therefore cheaper). Whole body hyperthermia is used in two forms. A distinction is made between the extreme at temperatures of 41.8 ° C and the moderate at 40.5 ° C.
Whole-body hyperthermia is used in a complementary way within evidence-based medicine . The maximum temperatures of 41.8 ° C reached with extreme whole-body hyperthermia increase the risk of complications considerably. In this case, the administration of a sedative may also be necessary. In extreme cases, anesthesia is induced. However, forms of application in which slightly lower temperatures (40.5 ° C) are used are more common. In complementary oncology (alternative cancer medicine), the body reaches temperatures between 39.5 and 40.5 ° C with whole-body hyperthermia. Infrared radiators are used to generate heat. Whole-body hyperthermia is often used in alternative cancer treatment for highly metastatic cancers, as well as for metastases and tumors that cannot be operated on. The overheating usually lasts no more than an hour. The temperature is gradually increased and reduced with constant observation of the patient (pulse, blood pressure, body temperature).
Whole-body hyperthermia is often used in the CIS countries . There, the patient's body temperature is increased to temperatures of up to 43 ° C while the brain is cooled.
Partial body hyperthermia
The application as surface , deep or partial body hyperthermia is being further developed in many places and tested in clinical studies. In loco-regional deep hyperthermia, the body is heated to a limited extent. “First, the region of the body affected by the tumor is fixed with two applicators. Computer-controlled radio waves are then bundled in the tumor or in the tumor bed, and the temperature is raised to 42 to a maximum of 44 ° C. The temperature is maintained in the tumor bed for about 60 to 90 minutes. ”Hyperthermia is almost always combined with radiation or chemotherapy when it comes to cancer. It is mainly used in the treatment of cancer when other procedures ( surgery , radiation therapy or chemotherapy ) no longer promise sufficient success, i.e. when the patient has exhausted the therapy . The effectiveness of chemotherapy or radiation therapy can be improved by combining it with hyperthermia for certain types of cancer. A phase 3 study of hyperthermia in soft tissue sarcoma - which accounts for less than 1% of all cancers - compared the combination of chemotherapy and hyperthermia or chemotherapy alone in 341 high-risk patients. The mean disease-free survival in the combination therapy group was 30 months compared to 16 months in the chemotherapy-only group. Hyperthermia also performed better in the mean local progression-free survival with 38 versus 26 months.
Transurethral hyperthermia
In urology , high-energy microwave therapy is used for benign prostate enlargement (BPH). Using a special treatment method (CoreTherm therapy), the prostate is heated to 55 ° C in a controlled manner in a specific area. This minimally invasive procedure destroys the excess prostate tissue.
In this form of treatment, known as transurethral hyperthermia, an electromagnetic field of radio short waves is built up in addition to the heat, which - in contrast to the microwaves used earlier - have a greater range. In alternative cancer therapy, in transurethral radio frequency hyperthermia (TUR), the therapy electrode is placed directly in the urethra under local anesthesia. A probe sends electromagnetic waves through the prostate tissue, painless for the patient, where they are converted into heat. The probe itself remains cold, so there is no risk of injuring the urethra. The denser the fabric, the more it absorbs the waves and the higher the temperature. In transurethral hyperthermia, this is around 48 to 52 ° C. The heat generated by the electric waves damages the enlarged tissue of the prostate, the electric field acts as a kind of alpha blocker, which means that it "depolarizes" the so-called alpha receptors that are located on the prostate muscles. This relaxes the muscles, improves the flow of urine and makes the prostate smaller. With this method, which is free of side effects, a regression or a complete remission can be achieved in many cases through simultaneous medicinal measures. An operation or radiation can thus be avoided, as can the side effects of incontinence or impotence known from an operation.
Different procedures
The overheating to 40 to 44 ° C is generated specifically in the tumor area, usually from the outside with the help of microwaves , radio waves or ultrasound . Other groups experiment with implanted antennas, magnetically excited thermoseeds or with tubes fed with hot water. Individual organs can be temporarily separated from the bloodstream and flushed with warmed solution. There are also experimental approaches to insert heating coils directly into a tumor or to inject magnetic fluids and then inductively heat them.
A current approach is based e.g. B. on the injection of a suspension of superparamagnetic iron oxide particles with a diameter of about 15 nm and a coating of aminosilanes into the tumor. These particles are taken up relatively selectively by tumor cells and heat up in the alternating magnetic field.
The clinical testing, mainly in the working group of the Berlin radio-oncologist Peter Wust, has reached the stage of small series and feasibility studies. Depending on the target method used (injection under computed tomography, fluoroscopy or ultrasound) and the location of the tumor, the uneven temperature distribution is still problematic. The most homogeneous possible hyperthermia of 42 ° C in the entire target volume has not yet been achieved.
Proof of effectiveness of the method named by the manufacturer (MagForce AG) nano cancer therapy was provided. The first phase II study with brain tumors was completed in January 2010. In the media, the unspecific term “nanotherapy” is often used for this form of hyperthermia.
In laser-induced thermotherapy (LIT), the tumor is locally overheated using a laser in order to kill the cancer cells. The LIT is prepared and carried out under computer tomographic control. Laser probes are guided to the tumor focus.
Mode of action
The elevated temperatures are intended to promote increased blood flow in the tumor tissue and thus contribute to an improved effect of radiation and chemotherapy. Due to their primitive blood supply, cancer cells are unable to dissipate heat in contrast to healthy tissue. This is related to the fact that tumor cells have a different metabolism and a different vascular supply than healthy cells. This creates a build-up of heat in the cancer cells, which leads to an insufficient supply of oxygen to the tumor cells and to a depletion of nutrients in the tumor. This deficiency symptom leads to disturbances of important metabolic processes in cell division and cell maintenance, whereby repair systems of the cells also fail. Thermal cell components (damaged by hyperthermia) cannot be replaced, which can lead to the death of the tumor cells. The so-called synergistic effect of hyperthermia leads to a potentiation of the effectiveness when combining standard therapies with therapeutic hyperthermia. A current study by the Berlin Charité, which examined rectal cancer patients, also came to the following result: The additional use of hyperthermia in combination with radiation and chemotherapy has a positive effect on the quality of life of cancer patients compared to those who received no treatment with hyperthermia .
It has been found that cytostatics are significantly more aggressive at temperatures above 40 ° C than at normal body temperature. In addition, the thermally damaged tumor cells are easier to fight with radiation therapy because their repair capabilities are reduced. Studies have also shown that when heated to approx. 42 ° C, cancer cells, in contrast to healthy tissue, form special protein structures on their surface. These protein structures, also known as heat shock proteins, are recognized by the immune system as foreign, so that the cancer cells can be destroyed by the immune system.
Hyperthermia is said to work on two fronts: on the one hand through thermal damage, on the other hand through stimulating the immune system.
At temperatures of up to 46 ° C within the tumor, the effect of radiation or chemotherapy applied at the same time is intensified. The increase in effectiveness compared to radiation therapy occurs, for example, through the heat-related loss of function of repair enzymes, which normally repair radiation damage to the DNA and thus enable tumor cells to survive. If these important enzymes are damaged by heat, the tumor cells die with even lower doses of radiation and thus radiation-resistant tumor cells are also covered by the combination treatment. However, heat also affects other proteins, which are responsible, for example, for chemoresistant tumor cells being able to remove the cytostatics that are harmful to them from the cells. If these “pumps” fail due to the effect of heat, even chemoresistant tumor cells die because the active ingredients remain in the cells.
At temperatures above 46 ° C, almost all biomolecules in the cells are affected and the cell dies directly as a result of overheating.
Current status
There are many devices with different functions on the market, but hardly any larger treatment series with real comparability to classic cancer therapies. This explains why hyperthermia treatments are not yet used as standard therapies. With microwave devices operating from Dr. Sennewald Medizintechnik GmbH use several phase-controlled antennas that can control heat locally and are currently only available in oncological centers. There are currently treatment programs at 14 oncological centers in Germany (e.g. Munich / Großhadern, University Clinic Tübingen, Berlin / Charité). Devices from the manufacturer Oncotherm GmbH work with radio waves of the ISM frequency 13.56 MHz ( shortwave , see also shortwave therapy) and power up to 600 W (device EHY-3010) and are mainly used by doctors in private practice, who are mainly cancer patients in the treat later stages of the disease. The German manufacturer Celsius42 from Eschweiler also produces a shortwave device (frequency 13.56 MHz) with outputs of up to 500 W and sells it to private clinics and hospitals.
Hyperthermia has not been a standard benefit of the statutory health insurance in Germany since 2004 , but the costs can be covered there on application as part of an individual case decision.
HIPEC
HIPEC stands for "Hyperthermic intraperitoneal chemotherapy ", English "hyperthermic intraperitoneal chemotherapy". This method is used in the case of peritoneal metastasis of gastrointestinal tumors or gynecological tumors after a cytoreductive operation (CRS, "cytoreductive surgery"). Tumors that have settled on the peritoneum , i.e. the surface of the abdominal organs and the inner abdominal wall, cannot usually be operated on curatively. In CRS, as much tumor tissue as possible is surgically removed. Then the remnants of the tumor are combated with a hyperthermic solution of chemotherapeutic agents , which is applied to the abdominal cavity. The high temperature increases the effect of chemotherapy on the tumor cells. This destroys microscopic tumor residues and reduces the risk of recurrence. Although the method has already delivered good results, it should initially only be used in suitable centers within the framework of studies because the risk of side effects is considerable if used incorrectly and the indication and methodological details have not yet been sufficiently validated.
Web links
- Hyperthermia: heat against cancer , cancer information service of the German Cancer Research Center (DKFZ), Heidelberg. June 30, 2013. Last checked September 4.
- Interdisciplinary Hyperthermia Working Group (IAH) in the German Cancer Society
- Failure of an innovative approach: Manfred von Ardenne and cancer multi-step therapy
- German Society for Hyperthermia
- Decision of the Federal Committee on Hyperthermia (PDF; 360 kB)
- Report of the Federal Committee on Hyperthermia (PDF; 4.69 MB)
Individual evidence
- ↑ Bernhard D. Haage: Heilfieber. In: Encyclopedia of Medical History. 2005, p. 545.
- ↑ Bernhard Dietrich Haage, Gundolf Keil : On the artificially produced therapeutic fever in Wolfram's 'Parzival'. In: Kurt Gärtner , Joachim Heinzle (Ed.): Studies on Wolfram von Eschenbach. Festschrift for Werner Schröder on his 75th birthday. Tübingen 1989, pp. 343-355.
- ↑ Gundolf Keil: Il contromodello: febbre provocata a scopo terapeutico nella medicina Italiana dell'Alto e tardo Medioevo. (Translated by Marco Toni) In: Università degli studi di Padova, Casa della Gioventù Universitaria di Bressanone: European initiatives of the Triangulum Innsbruck - Freiburg i. B. - Padua 2002. Padua 2003, pp. 142-156.
- ^ Gerhard Eis : To the history of the artificial healing fever. (1967) In: Gerhard Eis: Research on professional prose. Bern and Munich 1971, pp. 49 and 367.
- ↑ Bernhard D. Haage: Heilfieber. In: Werner E. Gerabek , Bernhard D. Haage, Gundolf Keil , Wolfgang Wegner (eds.): Enzyklopädie Medizingeschichte. De Gruyter, Berlin / New York 2005, ISBN 3-11-015714-4 , p. 545.
- ↑ Peter Wolf: New ways in cancer therapy. October 2008, p. 34f.
- ↑ RD Issels, LH Lindner u. a .: Neo-adjuvant chemotherapy alone or with regional hyperthermia for localized high-risk soft-tissue sarcoma: a randomized phase 3 multicentre study. In: The Lancet Oncology . Volume 11, Number 6, June 2010, pp. 561-570, ISSN 1474-5488 . doi: 10.1016 / S1470-2045 (10) 70071-1 . PMID 20434400 .
- ↑ Peter Wolf: New ways in cancer therapy . Naturasanitas, Hannover 2008, ISBN 978-3-9812416-0-0 , p. 36.
- ↑ P. Wust et al. a .: Magnetic nanoparticles for interstitial thermotherapy - feasibility, tolerance and achieved temperatures. In: International Journal of Hyperthermia 22/2006, pp. 673-85. PMID 17390997
- ↑ MagForce Nanotechnologies AG receives European approval for Nano-Cancer® therapy. In: MagForce AG. June 28, 2010, accessed October 26, 2011 .
- ^ J. van der Zee: Heating the patient: a promising approach? In: Annals of Oncology . tape 13 , no. 8 , August 1, 2002, ISSN 0923-7534 , p. 1173-1184 , doi : 10.1093 / annonc / mdf280 , PMID 12181239 .
- ↑ T. Schulze, P. Wust, J. Gellermann, B. Hildebrandt, H. Riess: Influence of neoadjuvant radiochemotherapy combined with hyperthermia on the quality of life in rectum cancer patients . In: International Journal of Hyperthermia: The Official Journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group . tape 22 , no. 4 , June 1, 2006, ISSN 0265-6736 , p. 301-318 , doi : 10.1080 / 02656730600665504 , PMID 16754351 .
- ↑ oncotherm.com ( Memento of the original from March 4, 2016 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice.
- ↑ FC Roxan, PA Helderman, Daan R. Löke, H. Petra Kok, Arlene L. Oei, Pieter J. Tanis: Variation in Clinical Application of Hyperthermic Intraperitoneal Chemotherapy: A Review . In: Cancers . tape 11 , no. 1 , January 11, 2019, ISSN 2072-6694 , doi : 10.3390 / cancers11010078 , PMID 30641919 , PMC 6357036 (free full text).
