Hyperthermia Research Information
Overview of Hyperthermia:
Hyperthermia is heat treatment. The temperature of the tissue is elevated artificially with the aim of receiving therapeutic benefits. Hyperthermia is considered an adjunct to other treatments in this country, but has been recognized abroad as a stand-alone therapy as well, sometimes superior to chemo.
One problem with treating cancer successfully is the fact that cancerous cells are very difficult to target specifically. In most respects, they are like normal cells, and even if they are not, they can hide the differences. But malignant cells are reliably more sensitive to heat than normal cells. Raising the temperature of the tumor is one way to selectively destroy cancer cells.
There are two ways to do heat therapy.
One is external, where devices like heating rods, microwaves, radiofrequencies, ultrasound, thermal blankets and lasers are applied to the body. The other is internal, where substances called pyrogens are administered to the patient in order to induce fever. As far as I can tell, pyrogens are used to some extent in Europe and China, while U.S. doctors favor external devices. (Some sources prefer to speak of “fever therapy” as opposed to hyperthermia which is defined as treatment that elevates the body temperature without increasing the set point of the hypothalamus.) Hyperthermia is usually classified as local, regional or whole body.
It has been known for many centuries that heat helps the body against cancer. Unfortunately, the enthusiasm of modern cancer research for this modality has been sporadic until recently. It has been the alternative health community that has kept the access open for patients, particularly in other countries. In the 1960s, some researchers confirmed that cancer cells are more vulnerable to heat than their normal counterparts. In the U.S., the hegemony of the three official modalities — surgery, radiation and chemo — lasted until the 70s, when hyperthermia was taken off the ACS blacklist (Unproven Therapies List). In late 70s and early 80s several trials had shown that hyperthermia combined with radiation produced superior results over radiation alone. However, a U.S. phase III trial subsequently did not confirm these results, and interest waned. Hyperthermia has since inhabited a strange in-between land of having its value recognized, and being used sporadically in some cancer centers, while ignored or underutilized by most oncologists around the country, and largely unknown to the public. That situation is beginning to change. It has been admitted that the U.S. study which showed negative results in the past was flawed on account of inadequate equipment and quality assurance procedures. And recently, the results of three European and one American phase III trials have become available. All these trials were well controlled, showing that the use of hyperthermia in combination with radiation therapy results in superior tumor response, tumor control, and survival as compared with radiation therapy alone. Some studies have claimed three-fold improvement in results, and positive results have even been noted with very difficult cancers like brain, liver and advanced kidney. Hyperthermia is particularly suitable in treating small superficial tumo rs (within 7 cm under the surface).
Summary of benefits.
Hyperthermia can be used by itself, and results in impressive shrinkage and even complete eradication (10-15%) of tumors. However, these results usually don’t last, and the tumors regrow. (In some animal experiments, cures were effected by hyperthermia. For example, in an animal experiment on transplanted mammary carcinoma, radiation alone produced no cures, heat alone produced 22% cures, and combined modality produced 77% cures.)
The synergistic effects of hyperthermia combined with radiation have been studied the most. Hyperthermia has been used for the treatment of resistant tumors of many kinds, with very good results. Combined hyperthermia and radiation has been reported to yield higher complete and durable responses than radiation alone in superficial tumors. In deep seated tumors, the effect of combined treatment is still under research. One source says “An extensive clinical experience has been accumulated with hyperthermia as a radiation enhancing agent. In regions where the heat can effectively penetrate the lesion, the results have been impressive.”
Another source claims that “in all clinical studies hyperthermia has been shown to improve local control to some extent and has never worsened it.” Despite difficulties in increasing human tumor temperatures, recent clinical trials have shown that a combination of hyperthermia with radiation is superior to radiation alone in controlling many human tumors.
It is unfortunate that patients usually come to hyperthermia when other modalities have been exhausted. But even in these circumstances, hyperthermia allows reradiating tissue that has already received the maximum dose. Rates of response in these patients is generally high (one source reports impressive 93%!). Hyperthermia is one way to overcome the radioresistance of tumor cells. It is possible to combine hyperthermia safely with further low dose radiation in situation where a radical dose has already been delivered.
In addition, there seems to be evidence that whole body hyperthermia provides a measure of protection against radiation-induced thrombocytopenia. (And experiments in mice have shown an increase in platelet count 8 days after the administration of hyperthe rmia. The current theory states that whole body hyperthermia induces platelet stimulating hormonal factors.)
Hyperthermia improves the therapeutic index of TBI (total body irradiation), not only by increased neoplastic cell kill, but also by inhibiting the expression of radiation induced damage to the normal cell population. Some have experimented with hyperthermia as part of BMTs. Whole body hyperthermia results in early engraftment during BMT (there is up to 4-fold increase in GM-CSF and a 15-fold increase in IL-3).
When it comes to chemotherapy, there are indications that some chemo can be potentiated by hyperthermia. This can, in some agents, increase toxicities and the incidence of damage associated with them at the usual doses, or it can be taken advantage of in the sense of getting the same results with lower doses of the drug. In combination with chemo, the type of drug, dose, temperature and time of administration all play a role. Vinca alkaloids and methotrexate exhibit only some additive cytotoxicity. AMSA and Ara-C are inhibited by higher temperatures. Doxorubicin and dactinomycin are potentiated if heat follows, but inhibited if heat precedes them. Synergistic, supra-additive effects between heat and drug have been observed in bleomycin, BCNU, cisplatin, cyclophosphamide, melphalan, mitoxantrone, mitomycin C, thiotepa, misonidazole, and 5-thi-Dglucose. Some agents not cytotoxic at normal temperature show cell killing abilities at higher temperatures: alcohols, amphotericin B, cysteine, cysteamine and AET. Drugs showing no enhancement are the antimetabolites (mixed results with 5FU and methotrexate) and taxanes.
One source says: “The increased effect seen by combining cytotoxic agents with hyperthermia is complex, but may be due to altered drug pharmakinetics such as increased solubility (e.g. nitrosureas and alkylating agents), altered plasma protein binding (e.g. cisplatinum) and activation of enzymatic processes (e.g. anthracyclines). The new agents interferon, TNF and lonidamine and some hypoxic cell sensitizers are all potentiated by heat.” Hyperthermia can augment the cytotoxicity without increasing myelosuppression, and reverse drug resistance to chemo agents.
I am very excited to find out that “it has recently been recognized that hyperthermia may also provide additional advantages in regard to drug delivery, particularly when the drugs of their carriers are relatively large. It has been shown in several studies that the use of hyperthermia can enhance the delivery of monoclonal antibodies to tumors with resultant improvement in antitumor effects. The spread into tissues of liposome-carried chemo drugs increases considerably compared to that under normal temperature.” And interesting information has emerged from hyperthermia studies that may become valuable in the future — a certain heat shock protein seems to be expressed on the surface of malignant cells after hyperthermia, and is absent in normal cells. This creates the possibility that monoclonal antibodies can be designed to home in just on the malignant cells.
Hyperthermia is also an immune system enhancer, and very effective in providing pain relief, controlling bleeding, and useful in other conditions such as prostatic hypertrophy and psoriasis.
Summary of risks:
Hyperthermia’s side effects for the external methods include pain, unpleasant sensations and burns in a small percentage of patients. In the case of the internal pyrogens, which are sometimes bacterial toxins, the situation is more complicated, as bacterial toxins can induce serious, even fatal reactions in humans, depending on dosage. (I have not seen a study evaluating pyrogens’ side effects at safe doses.) Ultrasound hyperthermia in areas where the tumor is over a bone will cause bone pain. Whole body hyperthermia can result in neuropathies.
Extracorporeal systemic hyperthermia is another mode, where the blood is routed from the body as in dialysis, for example, and is heated before returning to the body. It has two advantages — higher possible temperatures, and more homogeneous heating. The side effects, however, have been considerable – frequent persistent peripheral neuropathies, abnormal (and sometimes lethal) blood coagulation, some damage to liver and kidneys, and brain hemorrhaging and seizures. For this reason, one source says that the role of perfusion-induced hyperthermia may be in doubt. I recently noted that one alternative clinic (Innovative Care Medical) in the U.S. offers this treatment for cancer. Their brochure says that “medical studies have revealed no adverse effects to the blood or body from the elevated temperatures.” Beware.
Hyperthermia should be administered to patients who are awake and can report any problems as they experience them. Analgesics can be administered if a patient has difficulty lying still for the duration of the session. Patient’s vital signs must be monitored frequently during the session. Cardiovascular disease and sometimes pace makers (dep. on the heat delivery method) are a contraindication for the treatment.
It was once believed that hyperthermia damages tumor vasculature, but more recent experiences have shown that human tumor vasculature is more resistant to damage than that of rodents — this is good news in respect to heat treatment because the damage to vasculature would interfere with heat transfer to the tumor.
How hyperthermia works?
Hyperthermia exerts its beneficial effect in several ways, according to the current understanding.
Several studies have shown increased apoptosis in response to heat. Hyperthermia damages the membranes, cytoskeleton, and nucleus functions of malignant cells. It causes irreversible damage to cellular perspiration of these cells.
Heat above 41 C also pushes cancer cells toward acidosis (decreased cellular pH) which decreases the cells’ viability and transplantability.
Hyperthermia activates the immune system. One source says: “Heat has a well known stimulatory effect on the immune system causing both increased production of interferon alpha, and increased immune surveillance.” Another source mentions the release of lys osomes.
Tumors have a tortuous growth of vessels feeding them blood, and these vessels are unable to dilate and dissipate heat as normal vessels do. So tumors take longer to heat, but then concentrate the heat within themselves. Tumor blood flow is increased by hyperthermia despite the fact that tumor-formed vessels do not expand in response to heat. Normal vessels are incorporated into the growing tumor mass and are able to dilate in response to heat, and to channel more blood into the tumor.
Tumor masses tend to have hypoxic (oxygen deprived) cells within the inner part of the tumor. These cells are resistant to radiation, but they are very sensitive to heat. This is why hyperthermia is an ideal companion to radiation: radiation kills the oxygenated outer cells, while hyperthermia acts on the inner low-oxygen cells, oxygenating them and so making them more susceptible to radiation damage. It is also thought that hyperthermia’s induced accumulation of proteins inhibits the malignant cells from repairing the damage sustained.
One source puts it thus: “It can be hypothesized that hypoxic cells in the center of a tumor are relatively radioresistant but thermosensitive, whereas wellvascularized peripheral portions of the tumor are more sensitive to irradiation. This supports the use of combined radiation and heat; hyperthermia is especially effective against centrally located hypoxic cells, and irradiation eliminates the tumor cells in the periphery of the tumor, where heat would be less effective.”
Hyperthermia is considered a modifier of radiation response. “Heat selectively kills cells that are chronically hypoxic and nutritionally deficient and have a low pH — characteristics shared by tumor cells in comparison with the better oxygenated and better nourished normal cells. Furthermore, heat preferentially kills cells in the S phase of the proliferative cycle, which are known to be resistant to irradiation.” Another source notes that “marked complementary synergism across the cell cycle was observed when heat and radiation were combined.”
As the research gains momentum, more reasons for the use of hyperthermia are continuously being identified.
How it is administered?
The researchers are still working out the various practical details — the best machinery, the best way to measure the “dose” and the heat within the tumor, and so on, as well as the optimal sequencing of the treatment and its duration. The cytotoxicity of hyperthermia is dependent on both temperature and time. Whole body hyperthermia is done at 41.8° C with the Aquatherm radiant heat device invented by Dr Robins, and in use now in several centers.
The number of hyperthermia treatments patients should ideally receive is still being studied. Many sources recommend 2 treatments per week, but this recommendation is based in part on the concern over thermotolerance, which may be unnecessary. Most advocate about 40 min. to an hour, within 30 min. after radiation. Some have recommended up to 25 treatments overall. Tumor regression continues for several months after treatment. Effects may be seen for up to 6 months afterwards.
Desired, uniform temperatures throughout the tumor are difficult to attain, but one source says “failure to achieve the desired temperature should not discourage the physician from the use of this … modality as it appears to enhance radiation effects even at the lower temperatures.”
Some sources recommend doing hyperthermia as soon as possible after radiation, and interest is increasing in trying simultaneous treatment for the two modalities. There is also interest in low-temperature, long-duration hyperthermia, and Myerson et al (below) say the preliminary studies have been promising.
The development of thermotolerance was noted in animal experiments and this is why it was not recommended to treat more often than twice a week. The development of thermotolerance in humans has, however, not been a problem so far. (Thermotolerance, when it does develop, begins to wear off as soon as the heat treatment stops, and does not persist.)
Response does not depend only on the energy delivered but also on the intrinsic tissue sensitivity, duration of heating, rate of heating and cooling, pH and nutrient levels, cell cycle distribution etc. There are experiments that focus on the enhancement of the beneficial effect through the addition of supplements; for example, acidification of tissues after the ingestion of glucose, or quercetin to block the formation of heat shock proteins.
The rationale in lymphoma.
Several sources confirm that lymphoma is uniquely responsive to hyperthermia. “The spectrum of tissues susceptible to apoptosis induction by hyperthermia is similar to that for radiation and anticancer drugs: rapidly proliferating normal cell populations, lymphoid organs and solid tumors.” “Malignant lymphoma is very responsive to hyperthermia with radiation.” It has been noted that melanomas and sarcomas have a better response than carcinomas. And there are several studies (see below) where lymphoma patients underwent hyperthermia in combination with other agents with excellent results. Despite the excellent rationale for its use for lymphoma, and the distinctly poor results particularly with low grade lymphomas with current treatments, most oncologists do not seem interested.
There is, however, a trial going on at the University of Texas using whole body hyperthermia in combination with two chemo agents. (Viz the page on experimental therapies.)
It is interesting to note that hyperthermia is being used in some centers for prostate and breast cancer. It seems to me no coincidence that cancer patients with these cancers are the best organized and most vocal.
Why so little interest overall?
The current technology cannot deliver effective heating of all sites, particularly the deeper ones. Research and implementation has also been hampered by lack of noninvasive temperature measuring instruments. In addition, clinical applications apart from radiation have not been explored adequately. And hyperthermia is a procedure that consumes significant amount of time and manpower compared with radiotherapy or chemotherapy. Until recently, it was not possible to write a thermal prescription, but that obstacle has been overcome. Noninvasive thermometry is being developed, and so is the use of computer modeling which helps with directing and controlling the heat. These developments raise the expectations that hyperthermia will likely lead to improved loco-regional control of tumors, extending even to deep seated ones.
RESULTS OF MEDLINE SEARCH (1990-1997) FOR HYPERTHERMIA AND LYMPHOMA (14 items)
1. In one study, dogs with high grade lymphoma were treated with doxorubicin, and those who got a CR were then treated with more doxorubicin plus hyperthermia (half got hyperthermia plus doxo, half got doxo alone). The dogs with hyperthermia did show long er disease free survival, but the study claims it was not statistically significant. There was evidence of greater damage to the heart muscle in the dogs that got both treatments. (Another study describes phase 1 of the same trial.) (NC State U.)
2. A 58-year-old Japanese woman with primary malignant lymphoma of the rectum was treated preoperatively with radiation and intraluminal hyperthermia, after which abdominoperineal rectal amputation (Miles’ operation) was done. The rectal tumor disappeared and there were no lymphoma cells in the resected specimens. The postoperative course was smooth and she is being followed in the outpatient department. At this writing, five years after the surgery, she remains well. (Japan)
3. The effect of interferon (IFN) and tumour necrosis factor (TNF), either alone or combined with hyperthermia, on cell proliferation and expression of idiotype antigen on a murine B-cell lymphoma has been studied. Incubation with same doses of IFN-alpha and IFN-gamma reduced cell proliferation to the same extent. Hyperthermia potentiated the antiproliferative activity of IFN-alpha and IFNgamma. (Stanford)
4. The combination of Radiation Therapy (RT) and Hyperthermia (HT) has proved to be an effective treatment for a wide variety of superficially located recurrences of different tumors, particularly those arising in previously irradiated areas. Few studies on the use of HT in the management of lymphomatous diseases have so far obtained interesting results. Eight patients with Non Hodgkin Lymphomas – 4 with cutaneous lymphomas and 4 with nodal recurrences after RT-Chemotherapy treatment treated in three different Italian institutions with combined RT and HT are here reported. Rt dose ranged from 15 to 40 Gy with different fractionations, on the basis of previously received treatment. Hyperthermia was delivered using 432 or 915 MHz external microwave applicators, according to extension and depth of the lesions and available equipment. All patients tolerated well the HT treatment, and in all cases average intratumoral temperatures were >42 degrees, with 3 out of 10 treated sites achieving the goal of average temperatures >42.5%. One patient, with recurrent NHL, is disease-free after 24 months from completion of combined therapy. Our results seem to confirm previous experiences, suggesting a role of HT/RT not only for palliative purposes in cutaneous lymphomas, but also as an adjunct to radiotherapy alone in selected patients with superficially located recurrences. (Italy)
5. A study evaluates the effects of hyperthermia on a high grade and low grade mouse lymphoma cells. The findings were that the high grade cells were more sensitive to the heat. (Israel)
6. Another study with mouse cell lines showed that when hypothermia was used alone or with adriamycin, it was more effective with metastatic tumor cells than primary tumor cells. Fluorescent microscopy and cytofluorometry showed that the increased effect of adriamycin by hyperthermia was due to an increased drug uptake at the supranormal temperature. (Israel)
7. A study examined the effect of heat on B cell lymphoma, and noted significant cell destruction at 42-43 degree Celsius. It recommends the application of hyperthermia to purging of cells prior to BMTs. (Japan)
8. Three adult T-cell leukemia/lymphoma-derived cell lines, were investigated to determine how they responded to hyperthermia, lymphokine-activated killer (LAK) cells, or a combination of both in vitro. All three cell lines showed a similar sensitivity to LAK cells, but revealed varying degrees of sensitivity to hyperthermia. Hyperthermia did not cause immediate cell death, but did cause substantial decreases in the numbers of heated cells within 2 days. When the cells were heated at 39-43 degrees C for 1-3 hr and then interacted with various LAK cell/ATL cell (E/T) ratios at 37 degrees C for 4 hr, total cytolysis of the cells increased in a synergistic and/or additive manner over that of the cells without hyperthermia. This augmentation of cytolysis by LAK cells after hyperthermia was not seen in normal peripheral lymphocytes. These results suggest that the combination therapy of hyperth ermia and LAK cells may be more specific, useful, and effective for treating malignant lymphoma. (Japan)
9. Another study looking at lymphoma and melanoma cells and their vulnerability to hyperthermia. Interestingly, low grade lymphoma is more resistant to heat, but low grade melanoma is less resistant. Also, the results suggest that drug resistance in late stages of tumor progression can be overcome by an agent acting on the cell membrane (e.g., hyperthermia). (Israel)
10. The results of three completed clinical studies and complementary laboratory investigations are reviewed to illustrate an innovative approach to the nodular lymphomas and chronic lymphocytic leukemia. The clinical trials summarized include: A) the combination of 41.8 degrees C whole body hyperthermia (WBH) and the chemotherapeutic drug lonidamine; B) the use of total body irradiation (TBI) (12.5 cGy twice a week, every other week–total planned dose 150 cGy) and daily oral lonidamine; C) the juxtapositioning of TBI (with the same fraction schema) and 41.8 degrees C WBH x 75 min–initiated 10 min after TBI. Also presented is the laboratory rationale and early clinical results for combining lonidamine, TBI, and WBH. Abstract does not summarize results. (U. of Wisconsin Madison)
11. Hyperthermia (42 – 44 degrees C for 30 min to 1 h) can induce apoptosis in a variety of cell types and tumour cell lines. This process is usually, but not invariably unaffected by RNA and protein synthesis inhibition. C-fos expression has been implicated in the regulation of apoptosis occurring under diverse circumstances. By heating a Burkitt lymphoma cell line, for 43 degrees C for 30 min, approximately 60% of cells underwent apoptosis within 6h of treatment. (Australia)
12. Three cell line were tested to see if they can develop tolerance to heat. All three lines could develop thermotolerance, but the persistence of tolerance was less than can be measured in nonlymphoid cell lines. (Stanford)
13. Adjunctive therapy (whole body hyperthermia versus lonidamine) to total body irradiation for the treatment of favorable B-cell neoplasms: a report of two pilot clinical trials and laboratory investigations. (by H.I. Robins, et al; Address: done at University of Wisconsin Clinical Cancer Center, Madison; published in Int J Radiat Oncol Biol Phys, Apr 1990, vol.18, pp 909-920.)
Abstract: Based on earlier clinical and preclinical investigations, we designed two different pilot trials for patients with nodular lymphoma or chronic lymphocytic leukemia. These studies evaluated the use of either 41.8 degrees C whole body hyperthermia (WBH), or the nonmyelosuppressive chemotherapeutic drug, lonidamine (LON), as an adjunct to total body irradiation (TBI) (12.5 cGy twice a week, every other week for a planned total dose of 150 cGy). Whole body hyperthermia was initiated approximately 10 min after total body irradiation; lonidamine was administered orally (420 mg/m2) on a daily basis. Although entry to the studies was nonrandomized, the two patient populations were accrued during the same time frame and were comparable in terms of histology, stage of disease, performance status, and prior therapy. Of 8 patients entered on the TBI/WBH study, we observed 3 complete responses (CR), 4 partial responses (PR), and 1 improvement (i.e., a 48% decrease in tumor burden). Of 10 patients entered in the TBI/LON study, there was 1 CR and 4 PR. For the TBI/WBH study, myelosuppression was not treatment-limiting; there were no instances of infection or bleeding and platelet support was never required. The median survival time for the TBI/WBH study is 52.5 months based on Kaplan Meir estimates. Two patients remain in a CR. The median time to treatment failure (MTTF) is 9.4 months (90% confidence interval = 7-15.4 months). In the TBI/LON study, 50% of patients receiving TBI required treatment modification due to platelet-count depression during therapy, but there were no instances of infection or bleeding. Frequently observed LON-related toxicities included myalgias, testicular pain, photophobia and ototoxicity. For the TBI/LON study, median survival is 7.6 months; MTTF was 2.4 months. In analyzing the results of these pilot studies, our subjective clinical impressions lead to the hypothesis that WBH protected against TBI-induced thrombocytopenia during therapy, whereas LON had no effect on TBI-induced myelosuppression. This speculation was tested and confirmed in a series of in vitro and in vivo experiments.
[In brief, this study reports that the patients treated with radiation and hyperthermia had a 100% response rate, compared to a 50% response rate with radiation and chemo. And the median survival time for hyperthermia-treated patients was over 4 years, compared to about 8 months for the chemo-treated group. Pretty amazing.]
14. Therapeutic hyperthermia, Scott K. Alpard et al, Perfusion 1996, 11, 425-435.
15. Clinical experience with hyperthermia in conjunction with radiation therapy. Homayoon Shidnia et al, Oncology 1993, 50, 353-361.
16. Hyperthermic treatment of malignant diseases: current status and a view toward the future. Mark W. Dewhirst et al. Seminars in Oncology, vol. 24, no. 6 (December), 1997, 616-625. This is the best current article for those who only want to read one thing.
17. Chapter on Hyperthermia in Principles and Practice of Radiation Oncology, by Myerson, Moros and Roti Roti, Third edition, 1997.
18. Med J Australia, 1980, 1 (April), 311-313. Microwave adjuvant radiotherapy and chemotherapy for advanced lymphoma. Alan JM Nelson and John AG Holt. Abstract: “Forty patients with intractable, recurrent stage IV lymphoma were treated with application of 434 Mhz microwave radiation which were combined with small doses of cytotoxic drugs and/or supervoltage irradiation on an individual basis. Complete remission in 34 patients, and partial remission in four patients followed the treatment course; only two patients failed to improve. At the time of the writing, 50% of these patients were alive; the average survival period being 47 months. The synergistic effect of the combination of microwave irradiation with conventional therapeutic agents is discussed.”
This study followed patients who were sent to the center in Perth because their tumors were no longer treatable with available strategies. The results are all the more impressive. The amounts of radiation in the study were small, ranging from 3 to 27 Gy (average, 13 Gy, given in fractionated doses.).
Short chapters on heat treatment can be found in Ralph Moss’ Cancer Therapy (1992) and in Definitive Guide to Cancer: Alternative Medicine by Diamond, Cowder, Goldberg et al (1997).
Note: It is my believe that this document will bring enough evidence forward to at least spark the interest of the medical fraternity. This also show evidently that what we are doing is not new or need to be proven. It was already an excellent treatment and proven modality which was practiced for over 1 and a half decades.
For the record: Ozone Transdermal therapy is widely practiced in Europe, Russia, Canada, South Africa and many more with excellent results in many areas. It is the most powerful detoxification therapy known to man kind. The goal of this therapy is to assist the body to rid itself of the 100’s of toxins that we are exposed to everyday that overload, inhibit and or may shut down our lymph system.
The Following document gives an objective view of both sides of the fence with references regarding validity of ozone therapy. This document is compiled by Wikipedia and is a direct copy from their site. Wiki: Ozone therapy (1/3)