International Commission on Non-Ionizing Radiation Protection.
Quote: "The medical use of infrared radiation has a long history. It has been widely used in physical medicine for treatment of sports injuries, muscle aches, pain, and some chronic diseases (Licht 1967; Vaupel and Kruger 1992, 1995). In recent years there has been an interest in the use of IR-A sources for hyperthermic treatment of cancers (von Ardenne 1994, 1997; Vaupel and Kruger 1995; Wehner et al. 2001). Because of the deeper penetration of IR-A, this is used almost exclusively, and water filtering of IR to achieve pure IR-A has been recommended in therapeutics. There are also special IR-A therapeutic apparatuses that have been used for hyperthermic treatment of cancers and Raynaud's syndrome (i.e., white finger disease). The typical treatment irradiance of several therapeutic IR devices fall in the range of 800 W m_2. A German standard (DIN 5031-10; DIN 2000) limits IR-A to 1,200 W m_2 in therapeutic equipment."
Ishibashi J, Yamashita K, Ishikawa T, Hosokawa H, Sumida K, Nagayama M, Kitamura S.
Department of Oral and Maxillofacial Anatomy, Medical Science for Oral and Maxillofacial Regeneration, Graduate School of Health Biosciences, University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8504, Japan.
We developed a tissue culture incubator that can continuously irradiate cells with far-infrared radiation (FIR) of wavelengths between 4 and 20 microm with a peak of 7-12 microm, and found that FIR caused different inhibiting effects to five human cancer cell lines, namely A431 (vulva), HSC3 (tongue), Sa3 (gingiva), A549 (lung), and MCF7 (breast). Then, in order to make clear the control system for the effect of FIR, the gene expression concerned to the inhibition effect by FIR were analyzed. In consequence, basal expression level of HSP70A mRNA was higher in A431 and MCF7 cells than in the FIR-sensitive HSC3, Sa3, and A549 cells. Also, the over expression of HSP70 inhibited FIR-induced growth arrest in HSC3 cells, and an HSP70 siRNA inhibited the proliferation of A431 cells by irradiation with FIR. These results indicate that the effect of a body temperature range of FIR suppressing the proliferation of some cancer cells is controlled by the basal expression level of heat shock protein (HSP) 70A. This finding suggested that FIR should be very effective medical treatment for some cancer cells which have a low level of HSP70. Still more, if the level of HSP70 in any cancer of a patient was measured, the effect of medical treatment by FIR can be foreseen for the cancer.
Yamada Y, Itoh Y, Aoki S, Nakamura K, Taki T, Naruse K, Tobiume M, Zennami K, Katsuda R, Kato Y, Watanabe M, Nishikawa G, Minami M, Nakahira M, Ukai S,Sawada M, Kitamura A, Honda N.
Department of Urology, Aichi Medical University School of Medicine, Nagakute, Aichi 480-1195, Japan.
OBJECTIVE: We evaluated the efficacy and safety of M-VAC chemotherapy combined with mild hyperthermia, a new therapeutic strategy for advanced metastatic transitional cell carcinoma of the urothelium. SUBJECTS AND METHODS: The subjects were 12 patients diagnosed with advanced metastatic transitional cell carcinoma of the urothelium. For mild hyperthermia, the patients' oral temperature was elevated to about 38 degrees C by heating for 20 min and retaining the heat for 20 min with a far-infrared heater. The antitumor effect was evaluated according to the RECIST, while adverse drug reactions were assessed based on the NCI-CTC. RESULTS: The antitumor effect was rated as partial remission (PR) in 10 of the 12 patients and stable disease in 2 patients, with an efficacy rate of 83% (10/12). All 10 patients who had achieved PR received three courses of treatment. Of the 12 patients, 5 died during the observation period, with survival for 9-23 months (mean: 15.6 months). Adverse drug reactions included myelosuppression in all patients (Grade 3 in 4 patients, Grade 4 in 8), and gastrointestinal toxicity, such as nausea or vomiting, which was mild (Grade 0 in 2 patients, Grade 1 in 8, Grade 2 in 1, Grade 3 in 1). CONCLUSIONS: The results of the present study suggest that M-VAC chemotherapy combined with mild hyperthermia, which potentiates the anticancer effect and reduces adverse drug reactions such as gastrointestinal symptoms, is a useful and safe method for the treatment of advanced transitional cell carcinoma of the urothelium.
Hattori T, Kokura S, Okuda T, Okayama T, Takagi T, Handa O, Naito Y, Yoshida N, Yoshikawa T.
Inflammation and Immunology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
AIM: Whole body hyperthermia (WBH) has been used clinically as an adjunct to radio- and chemotherapy in patients with various cancers. Recently, it has been reported that an activation of the immune system has recently been reported as a possible contributor to the therapeutic effects of WBH. Conversely, the glycolipid alpha-galactosylceramide (alpha-GalCer) is recognized by natural killer (NK) T cells together with the monomorphic MHC-like antigen, CD1d, in mice and humans. This study investigated the antitumor effects of WBH combined with alpha-GalCer in a mouse subcutaneous tumor model of colon cancer. METHODS: Colon26 cells were inoculated subcutaneously into male BALB/c mice to establish subcutaneous tumor. Colon26-bearing mice were treated with WBH using far infrared rays three times/week. Rectal temperature was maintained for 60 min at 41 degrees C. In some experimental groups, alpha-GalCer was intraperitoneally injected before WBH. We investigated the therapeutic effects of WBH, alpha-GalCer and combined therapy. RESULTS: (1) Compared with controls, WBH alone resulted in significant inhibition of tumor growth. (2) No inhibitory effect on tumor growth was seen with alpha-GalCer. (3) The combination of WBH and alpha-GalCer showed significant inhibition of tumor growth and prolongation of survival. (4) Serum IFN-gamma increased after 3 h and returned to basal levels by 24 h after alpha-GalCer administration. (5) CTL activity was enhanced following combination therapy with WBH and alpha-GalCer. CONCLUSION: WBH showed antitumor effects in a mouse subcutaneous tumor model of colon cancer. Addition of alpha-GalCer increased the efficacy of WBH, probably via enhancement of immune response.
Udagawa Y, Nagasawa H, Kiyokawa S.
Experimental Animal Research Laboratory, Meiji University, Kawasaki, Japan.
To evaluate possible therapeutic benefits of irradiation with far-infrared rays (FIR) on breast cancer, we examined combined effects of the chronic exposure to FIR at ambient temperature (26.5-27.5 degrees C) and the whole-body hyperthermia induced by FIR (WBH) (35-41 degrees C) on the growth of spontaneous mammary tumours of mice. A high mammary tumour strain of SHN virgin mice born on the normal rack or FIR rack were maintained on the respective racks until mammary tumour appearance. When the mammary tumour size reached approximately 7 mm, some mice in each group received no further treatment (Control and FIR groups, respectively) and the remaining mice received 3 hours of WBH each of 5 consecutive days (C + WBH and FIR + WBH groups, respectively). There was little difference between the control and FIR groups in the tumour growth over 10 days of examination. On the other hand, the tumour growth was inhibited significantly in both C + WBH and FIR + WBH groups and the degree of inhibition was similar. The data confirmed that the chronic exposure to FIR at ambient temperature has little effect on the growth of spontaneous mammary tumours in mice. WBH with FIR, however, strongly inhibited the tumour growth without deleterious side-effects, while chronic FIR irradiation itself again had little effect in this process. This WBH regimen may serve as a useful animal model for long-term studies of a noninvasive treatment of breast cancer.
Hildebrandt B, Wust P, Ahlers O, Dieing A, Sreenivasa G, Kerner T, Felix R, Riess H.
Medical Clinic, Department of Hematology and Oncology, Charite Medical School, Humboldt-University, Campus Virchow Clinic, D-13344 Berlin, Germany.
In oncology, the term 'hyperthermia' refers to the treatment of malignant diseases by administering heat in various ways. Hyperthermia is usually applied as an adjunct to an already established treatment modality (especially radiotherapy and chemotherapy), where tumor temperatures in the range of 40-43 degrees C are aspired. In several clinical phase-III trials, an improvement of both local control and survival rates have been demonstrated by adding local/regional hyperthermia to radiotherapy in patients with locally advanced or recurrent superficial and pelvic tumors. In addition, interstitial hyperthermia, hyperthermic chemoperfusion, and whole-body hyperthermia (WBH) are under clinical investigation, and some positive comparative trials have already been completed. In parallel to clinical research, several aspects of heat action have been examined in numerous pre-clinical studies since the 1970s. However, an unequivocal identification of the mechanisms leading to favorable clinical results of hyperthermia have not yet been identified for various reasons. This manuscript deals with discussions concerning the direct cytotoxic effect of heat, heat-induced alterations of the tumor microenvironment, synergism of heat in conjunction with radiation and drugs, as well as, the presumed cellular effects of hyperthermia including the expression of heat-shock proteins (HSP), induction and regulation of apoptosis, signal transduction, and modulation of drug resistance by hyperthermia.
Jia D, Liu J.
Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, PR China.
For late-stage cancer, whole-body hyperthermia (WBH) is highly regarded by physicians as a promising alternative to conventional therapies. Although WBH is still under scrutiny due to potential toxicity, its benefits are incomparable, as diversified devices and very promising treatment protocols in this area are advanced into Phase II and III clinical trials. Following the introduction of the WBH principle, this paper comprehensively reviews the state-of-art high-performance WBH devices based on the heat induction mechanisms - radiation, convection and conduction. Through analyzing each category's physical principle and heat-induction property, the advantages and disadvantages of the devices are evaluated. Technical strategies and critical scientific issues are summarized. For future developments, research directions worth pursuing are presented in this article.
van der Zee J.
Erasmus Medical Center-Daniel den Hoed Cancer Center, Department of Radiation Oncology, Hyperthermia Unit, Rotterdam, The Netherlands.
There is a clear rationale for using hyperthermia in cancer treatment. Treatment at temperatures between 40 and 44 degrees C is cytotoxic for cells in an environment with a low pO(2) and low pH, conditions that are found specifically within tumour tissue, due to insufficient blood perfusion. Under such conditions radiotherapy is less effective, and systemically applied cytotoxic agents will reach such areas in lower concentrations than in well perfused areas. Therefore, the addition of hyperthermia to radiotherapy or chemotherapy will result in at least an additive effect. Furthermore, the effects of both radiotherapy and many drugs are enhanced at an increased temperature. Hyperthermia can be applied by several methods: local hyperthermia by external or internal energy sources, regional hyperthermia by perfusion of organs or limbs, or by irrigation of body cavities, and whole body hyperthermia. The use of hyperthermia alone has resulted in complete overall response rates of 13%. The clinical value of hyperthermia in addition to other treatment modalities has been shown in randomised trials. Significant improvement in clinical outcome has been demonstrated for tumours of the head and neck, breast, brain, bladder, cervix, rectum, lung, oesophagus, vulva and vagina, and also for melanoma. Additional hyperthermia resulted in remarkably higher (complete) response rates, accompanied by improved local tumour control rates, better palliative effects and/or better overall survival rates. Generally, when combined with radiotherapy, no increase in radiation toxicity could be demonstrated. Whether toxicity from chemotherapy is enhanced depends on sequence of the two modalities, and on which tissues are heated. Toxicity from hyperthermia cannot always be avoided, but is usually of limited clinical relevance. Recent developments include improvements in heating techniques and thermometry, development of hyperthermia treatment planning models, studies on heat shock proteins and an effect on anti-cancer immune responses, drug targeting to tumours, bone marrow purging, combination with drugs targeting tumour vasculature, and the role of hyperthermia in gene therapy. The clinical results achieved to date have confirmed the expectations raised by results from experimental studies. These findings justify using hyperthermia as part of standard treatment in tumour sites for which its efficacy has been proven and, furthermore, to initiate new studies with other tumours. Hyperthermia is certainly a promising approach and deserves more attention than it has received until now.
Falk MH, Issels RD.
Medizinische Klinik III, Klinikum Grosshadern, Munich, Germany.
The purpose of this article is to provide an overview on the current clinical application of hyperthermia combined with conventional treatment modalities (e.g. ionizing radiation, chemotherapy) in the treatment of malignant disease. The clinical application of hyperthermia with increase of tissue temperatures (range 40-44 degrees C) has been integrated in multimodal anti-cancer strategies. This review describes selected phase I or II (n = 17) and phase III trials (n = 16) investigating the effect of hyperthermia combined with radiotherapy (n = 10 trials), chemotherapy (n = 15 trials), or both (n = 8 trials) in a total of more than 2200 patients. The trials were performed in a variety of solid tumours (e.g. melanoma, head and neck cancer, breast cancer, cancer of the gastrointestinal or urogenital tract, glioblastoma, sarcoma) in paediatric or adult patients. Profound research has produced a scientific basis for the simultaneous application of hyperthermia in combination with ionizing radiation and/or systemic chemotherapy. Hyperthermia is becoming more accepted clinically, due to the substantial technical improvements made in achieving selected increase of temperatures in superficial and deep-seated tumours. At present, the combination of hyperthermia and chemotherapy or radiochemotherapy is further tested within clinical protocols (phase II/III) in order to improve local tumour control and relapse-free survival in patients with high-risk or advanced tumours of different entities.
Udagawa Y, Ishigame H, Nagasawa H.
We have found that the administration of a diet containing 5% hydroxyapatite (HAP) derived from pig and cattle bones, and exposure to far-infrared rays (FIR) markedly inhibited spontaneous mammary tumorigenesis in SHN mice. Thus, the effect of combined treatment with HAP and FIR on mammary tumorigenesis was examined. The significant inhibition of tumor development by individual treatment with HAP or FIR was not enhanced by combined treatment; instead, the decrease in the inhibitory effect of HAP with age was ameliorated. Associated with this, life span was elongated and a decline in ovarian function was prevented by HAP plus FIR. Normal and preneoplastic growth of mammary glands and plasma component levels were not significantly affected by any treatment. The findings indicate that HAP and FIR have characteristics common to most natural products; in combination with other agents, they have little additive effect, when each is highly active.
Udagawa Y, Nagasawa H.
Based on findings that free access in drinking water of the extract of coffee cherry (CC), the residue left after the removal of coffee beans, and whole-body hyperthermia (WBH) induced by far-infrared ray (FIR) can markedly inhibit the growth of spontaneous mammary tumours of SHN mice, the effects of the combined treatment with these agents were examined in this study. The significant inhibition of tumour growth by single treatment with either CC or WBH was not enhanced by their combination. Meanwhile, the body weight loss during WBH was significantly decreased by CC. Normal and preneoplastic growth of mammary glands and plasma component levels were affected little by either treatment. The findings confirmed the "normalization effects" of CC usually obtained with natural products and stress the need for prudence in the choice of any agent, natural or synthetic, to be applied simultaneously to increase the efficacy of WBH.
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