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Hyperthermia Treatment at BCI:
- Gentle heat + low dose radiation
- Effective pain reduction
- Low side effects
- Scientifically based, FDA approved modality
- Accepted by most insurance
- Statistically proven successful results
Features and Benefits of Hyperthermia
Hyperthermia (also called hyperthermia therapy, thermal therapy or thermotherapy) is an acute condition which occurs when the body produces or absorbs more heat than it can dissipate. It is usually caused by prolonged exposure to high temperatures. The heat-regulating mechanisms of the body eventually become overwhelmed and unable to effectively deal with the heat, causing the body temperature to climb uncontrollably.
Hyperthermia can also be created artificially by drugs or medical devices. In these instances it may be used to treat cancer and other conditions. Cancer cells are more heat-sensitive than healthy cells and their structure reacts differently to overheating. In 1910 the possibility of overheating in order to increase the radiation effect on malicious tumors was described for the first time. This already well-known and applied method was rediscovered as so called “whole body hyperthermia” in the beginning of the 1960s. Since the 70s a number of studies were run to further investigate this therapy form.
Research has shown that high temperatures (up to 44°C) can damage and kill cancer cells, usually with minimal injury to normal tissues. By killing cancer cells and damaging proteins and structures within cells, hyperthermia may shrink tumors.
Hyperthermia is almost always used with other forms of cancer therapy, such as radiation therapy and chemotherapy. Hyperthermia may make some cancer cells more sensitive to radiation or harm other cancer cells that radiation cannot damage. When hyperthermia and radiation therapy are combined, they are often given within an hour of each other. Hyperthermia can also enhance the effects of certain anticancer drugs, which is mutually strengthened thereby and a healing more likely – the so-called synergistic effect of hyperthermia. It was found out that cytostatic drugs (chemotherapy substances) clearly act more aggressively at temperatures over 40° C than within the range of the normal body temperature.
The healing effect of heat treatment was already mentioned in the advanced cultures of the old Egypt (2400 B.C.), but only the medical professionals of the Greek Antique used this therapeutic approach consistently, acknowledged it and called it over-warming (in Greek: Hyperthermia). “Give me the power to produce fever and I heal every illness”, said Parmenides, Greek physician, 540-480 B.C.
Click on the files names below to read about hyperthermia machines used at Bicher Cancer Institute.
- Sonotherm 1000 ultrasound hyperthermia system
- Hyperthermia system 100A
- Bicher, James Haim, MD., Wolfstein, Ralf, M.D. Thermoradiotherapy with curative intent – breast, head and neck and prostate tumors. Deutsche Zeitschrift für Onkologie (German Journal of Oncology) 2006, 38: 116-122.
- Bicher HI, McLaren JR, Pigliucci GM, (eds). Consensus on Hyperthermia for the 1990s. Clinical Practice in Cancer Treatment. Plenum Press, New York and London, 1990.
- Bicher HI, Hetzel FW, Sandhu TS. Physiology and Morphology of Tumor Microcirculation on Hyperthermia. Chapter 9. Ed. K Storm, K Hall Publisher, New York, 1982.
- Bicher HI, Hetzel FW, D'Agostino L, Johnson RJ. Changes in tumor tissue oxygenation induced by microwave hyperthermia. Int J. Radiat Oncol Biol Phys 1977, S2:157.
- Bicher HI, Hetzel FW, Mitagvaria N, O'hara M. Reoxygenation induced by localized microwave hyperthermia as an adjuvant to radiation therapy. 6th International Congress of Radiation Research, 1979, 5:171-175.
- Bicher HI, Hetzel FW, Sandhu TS, Frinak S, Vaupel P, O'Hara MD, O'Brien T. Effects of hyperthermia on normal and tumor microenviroment. Radiology 1980, 137:523530.
- James Haim Bicher, M.D. The physiological effects of hyperthermia. Radiology; 1980:511513.
- Sandhu TS, Bicher HI, Hetzel FW. A thermal dosimetry system with blood flow simulation. Journal of National Cancer Institute, 6:361-363.
- Bicher HI, Sandhu TS, Vaupel P, Hetzel FW. The effect of localized microwave hyperthermia on physiological responses. Journal of National Cancer Institute, 6:375-377.
- Bicher HI, Sandhu TS, Hetzel FW. Inhomogenities in oxygen and pH distributions in tumors. Radiat Res 1980, 83376.
- Hetzel FW, Kaufman N, Brown M, Bicher HI. Indirect sensitization by drug induced reoxygenation in spheroids. Radiat Res 1980, 83:375376.
- Bicher HI, Sandhu TS, Vaupel P, Hetzel FW. Physiological mechanisms of action of localized microwave hyperthermia. Presented at the Third International Symposium on Cancer Therapy by Hyperthermia, Drugs and Radiation. Fort Collins, Colorado, June 1920, 1980.
- Bicher HI, Sandhu TS, Hetzel FW, Matvia F. An effective fractionation protocol for the clinical use of hyperthermia with adjuvant radiation. Presented at the Second Meeting of the European Group on Hyperthermia in Radiation. Rome, Italy, September 1920, 1980.
- Bicher HI, Vaupel P, O'Hara MD, O'Brien T, Mitagvaria N. Tissue oxygenation in normal and hyperthermic conditions. In proceedings of the XXVIIIth International Congress of Physiological Sciences. Budapest, Hungary, July 1318, 1980. Akademial Kiado Publishers: Adv. Physiol Sci. 1981, 25:215233.
- Bicher HI, Hetzel FW, Vaupel P, Sandhu TS. Microcirculation modification by localized microwave hyperthermia and hematoporphyrin phototherapy. Bibl Anat 1981, 20:628632.
- James Haim Bicher, M.D., Nodar Mitagvaria Circulatory responses of malignant tumors during hyperthermia. Microvascular Research 1981, 21:1926.
- Bicher HI, Sandhu TS, Vaupel P, Hetzel FW. Effect of localized microwave hyperthermia on physiological responses. Natl Inst Drug Abuse Res Monogr Ser 1982, 61:217219.
- Vaupel P, Frinak S, MuellerKlieser W, Bicher HI. Impact of localized hyperthermia on the cellular microenvironment in solid tumors. Natl Inst Drug Abuse Res Monogr Ser 1982, 61:207209.
- Bicher HI. Impact of microcirculation and physiologic considerations on clinical hyperthermia. Proceedings 13th International Cancer Congress, 235245, Alan R Liss Inc., New York, 1983.
- Bicher HI, Mitagvaria NP. Changes in tumor tissue oxygenation during microwave hyperthermia clinical relevance. Advances in Experimental Medicine and Biology, 180: 190905, 1985.
- Mitagvaria NP, Bicher HI. Effect of microwave radiation on local blood flow and tissue oxygenation in the brain. Bulletin of Experimental Biology and Medicine, 98:895897, 1984.
- Bicher HI, Shani J, Reesman KJ. Use of non perturbing thermocouples (NPT's) for hyperthermia clinical thermometry. Int. J. Hyperthermia, 3:550551, 1987. (Abst) and J. Microwave power 22: 173, 1987, (Abst).
- Bicher HI, Wolfstein RS. Local Hyperthermia of tumors at moderate depth using POPAS: Results by site (Abstract). 36th Annual Meeting of the Radiation Research Society, 4:1621, 1988.
- Bicher HI, Shani J, Reesman KJ. Use of nonperturbing thermocouple for clinical hyperthermia thermometry (Abstract). 36th Annual Meeting of the Radiation Research Society, 4:1621, 1988.
- Bicher HI, Wolfstein RS. Treatment of intratoracic lesions. Preliminary results (Abstract). 37th Annual Meeting of the Radiation Research Society. 3:1823, 1989.
- Bicher HI, Reesman KJ, Afuwape SA. A target triapplicator system with nonperturbing thermocouples thermometry. Hyperthermic Oncology 1988, Taylor and Francis, 1:778779, 1989.
- Bicher HI, Mitagvaria, N. Oxygen and pH in Human Tumors During Hyperthermia (Abstract). Proceeding of the 1991 International Society on Oxygen Transport to Tissue Meeting (ISSOT). Willemstad, Curaco, Netherlands Antilles, August 24-30, 1991.
- Mitagvaria, N., Bicher HI. Local Blood Flow and PO2 in Rat's Brain During Maze Behavior (Abstract). Proceeding of the 1991 International Society on Oxygen Transport to Tissue Meeting (ISSOT). Willemstad, Curaco, Netherlands Antilles, August 24-30, 1991.
- Bicher HI, Wolfstein RS. Transcranial Treatment of Brain Tumors with Microwave Hyperthermia (Abstract). Proceeding of the 8th Annual Conference of the American Society for Clinical Hyperthermic Oncology (ASCHO). Chicago, Illinois, October 31-November 2, 1991.
- Bicher HI, Mitagvaria N. Oxygen and pH in Human Tumors During Hyperthermia (Paper presented as a poster). Proceeding of the 6th International Congress on Hyperthermic Oncology. Tucson, Arizona, April 26- May 1, 1992.
- Surowiec, A. Bicher HI, Caridad, C. A Comparison of Heating Characteristics of Two Hyperthermia Systems Used for Deep Seated Malignancies BSD-2000 and Tripas (Abstract). Proceeding of the 16th International Symposium on Clinical Hyperthermia (ISCHO). Kyoto, Japan, June 13-16, 1993.
- Bicher HI, Yarmonenko S, Wainson A, Swrowiec I, Metagvaria N. Specific inhibition of L-Glucose cell proliferation. Potentiation of Hyperthermia, Radiation and Chemotherapy effects (Abstract). Proceeding of the 10th Annual Meeting of the American Society Of Clinical Hyperthermic Oncology (ASCHO). Memphis, Tennessee; November 28-30, 1993.
- Surowiec, A, Bicher HI, Intercomparison of Heating Patterns of the BSD-2000 and the Tripas System (Abstract). Proceeding of the 14th Annual Meeting of the North American Hyperthermia Society (NAHS), Nashville, Tennessee, April 29- May 4, 1994.
- Bicher HI, Yarmonenko, S. Wainson, A. Surowiec, I. Mitagvaria, N. Anticancer Effect of L-Glucose In-Vivo Potentiation of Hyperthermia (Abstract). Proceeding of the 17th International Symposium on Clinical Hyperthermia (ISCH). Pavia, Italy, May 1-5, 1994.
- Bicher HI MD., Eva H. Barker, Patrick J. Bolan, Lance delabarre, Hellmuth Merkle, Lenore I. Everson, Michael Garwood. In VIVO Monitoring to Treatment for Breast Cancer Using 4T H MRS. Center for Magnetic Resonance Research, University of Minnesota, 2021 Sixth street SE, Minneapolis, MN. USA;
- H. Bicher, Mitagvaria, I. Kvachadze , T. Khetsuriani, A. Shukakidze, I. Lazrishvili, M. Arabuli, TS.T. Khomeriki, Main factors in development of local hyperthermia-induced morphological changes in cerebral tissue of the rat In Press, Proceedings of Tbilisi State Medical University.
- Hyperthermia in Cancer Treatment: Questions and Answers from The National Cancer Institute (NCI)
- Hyperthermia Treatment Program at Duke University Medical Center
- International Journal of Hyperthermia published by Informa Healthcare
- Hyperthermia as a type of cancer treatment from the American Cancer Society
Heating the patient: a promising approach?
by J. van der Zee from Annals of Oncolofy
There is a clear rationale for using hyperthermia in cancer treatment. Treatment at temperatures between 40 and 44°C is cytotoxic for cells in an environment with a low pO2 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.
Written reports concerning the use of increased temperatures in cancer treatment have existed for many centuries. Probably the oldest report was found in the Egyptian Edwin Smith surgical papyrus, dated around 3000 BC. Hyperthermia researchers like to cite Hippocrates (460–370 BC) in particular, although the method he describes in one of his aphorisms, i.e. hot irons, concerns higher temperatures, such as those used in cauterisation. In the 19th and 20th centuries, fever therapy has been used as a method to increase temperatures, while other investigators started to apply radiofrequency techniques .
A worldwide interest in hyperthermia was initiated by the first international congress on hyperthermic oncology in Washington in 1975. This interest has followed a course that is usual for a new type of treatment. In the first decade there was a growing enthusiasm, reflected by an exponential increase in the number of papers and participants at meetings. Thereafter the interest waned, due to disappointing clinical results from some of the first randomised studies, accompanied by a reluctance among sponsoring authorities and hospital boards to support further research. Nowadays there appears to be a renewed interest, thanks to several randomised studies demonstrating that the improvements in treatment outcome by additional hyperthermia can be very substantial, provided that adequate heating procedures are used.
This report summarises the rationale for the use of hyperthermia in cancer treatment, the methods available to apply and monitor hyperthermia treatments, the first clinical results and the results of randomised trials, and new developments.
Rationale for hyperthermia in cancer treatment
The tumour-selective effect of hyperthermia
Generally, there is no intrinsic difference between hyperthermia sensitivity of normal and tumour cells, except for haematological malignancies. Nevertheless, in vivo a selective tumour cell killing effect is achieved at temperatures between 40 and 44°C, which is related to a characteristic difference between normal and tumour physiology. The architecture of the vasculature in solid tumours is chaotic, resulting in regions with hypoxia and low pH [2–4], which is not found in normal tissues in undisturbed conditions. These environmental factors make cells more sensitive to hyperthermia. The effect of hyperthermia depends on the temperature and the exposure time. At temperatures above 42.5–43°C, the exposure time can be halved with each 1°C temperature increase to give an equivalent cell kill . Most normal tissues are undamaged by treatment for 1 h at a temperature of up to 44°C . Only nervous tissues appear more sensitive. For the central nervous tissue, irreversible damage was found after treatment at 42–42.5°C for longer than 40–60 min . Treatment of peripheral nervous tissue for >30 min at 44°C, or an equivalent ‘dose’, results in temporary functional loss, which recovers within 4 weeks . The main mechanism for cell death is probably protein denaturation, observed at temperatures >40°C, which leads to, among other things, alterations in multimolecular structures like cytoskeleton and membranes, and changes in enzyme complexes for DNA synthesis and repair .
Radiotherapy plus hyperthermia
Several mechanisms are responsible for the supra-additive effect of the combination of radiotherapy and hyperthermia. The additive complementary effect comes from the sensitivity of cells in the hypoxic, low pH areas, and the cells in S-phase, which are both relatively radioresistant . Hyperthermia may cause an increased blood flow, which may result in an improvement in tissue oxygenation, which then results in a temporally increased radiosensitivity . Experimental studies have also shown for almost all cell lines studied that hyperthermia also potentiates radiation effects. The most important mechanism for this interactive effect is that the effect of hyperthermia interferes with the cellular repair of radiation-induced DNA damage, probably by an effect on cellular proteins . The thermal enhancement ratio for radiation-induced cell kill is greater under hypoxic conditions, increases with higher temperatures and longer exposure times, and decreases with longer time-intervals between the two modalities. Maximum thermal enhancement ratios are obtained when radiation and hyperthermia are applied simultaneously, but this has been found for both tumour and normal tissues. In vivo studies have demonstrated that the effect of radiotherapy can be enhanced by a factor of between 1.2 and 5 [12, 13]. When tumour and normal tissue are heated to the same degree, maximum therapeutic gain will be obtained with a time interval between the two treatments . Overall, hyperthermia is probably the most potent radiosensitiser known to date.
Chemotherapy plus hyperthermia
An extensive review on the combination of hyperthermia with chemotherapy was published in 1995 . For the combination of hyperthermia and chemotherapy, spatial cooperation can again explain the additive effects. Drug concentration will be less in the insufficiently perfused tumour regions. In addition, many drugs are potentiated by heat. Furthermore it has been shown for mitomycin C, nitrosureas, cisplatin, doxorubicin and mitoxantrone that the addition of hyperthermia to chemotherapy can counteract drug resistance. Generally, interaction is only seen when the two treatments are given in close sequence. The most important mechanisms for an interactive effect are an increased intracellular drug uptake, enhanced DNA damage and higher intratumour drug concentrations, resulting from an increase in blood flow. Pharmacodynamics may also play a role, e.g. when doxorubicin, cyclophosphamide and melphalan pharmacokinetics are altered, an increased area under the curve and/or decreased excretion occur. This can be explained by a decrease in biliary excretion, as observed with liver perfusion, or a change in perfusion distribution, as found during whole body hyperthermia [16–18].
An interactive effect was observed for virtually all cell lines treated at temperatures above 40°C for alkylating agents, nitrosureas and platin analogues, with enhancement ratios depending on temperature and exposure time. The effect of these drugs can be enhanced by a factor of between 1.2 to 10, and an extremely high thermal enhancement ratio of 23 was even observed for in vitro application of melphalan to drug-resistant cells at 44°C . In combination with bleomycin, an interactive effect was seen at temperatures >42°C. In the combination with anthracyclins, the results show discrepancies and appear to vary with cell type, growth conditions and drug scheduling. In vivo experiments showed improved results when hyperthermia was combined with doxorubicin and mitoxantrone. With antimetabolites vinblastine, vincristine and etoposide, most experiments did not show an interactive effect. In the case of etoposide, cytotoxicity was even reduced, which was explained by instability of the drug at an increased temperature. Whether the clinical combination of hyperthermia and chemotherapy leads to therapeutic gain will depend on the temperature increase in the organs for which the used drug is toxic, which depends on the heating method (see below). In animal studies, increased toxicities were seen in skin (cyclophosphamide, bleomycin), heart (doxorubin), kidney (cisplatin, with a core temperature >41°C), urinary tract (carmustine, with a core temperature >41°C) and bone marrow (alkylating agents and nitrosureas). Lethal toxicity was enhanced when systemic hyperthermia was applied in combination with cyclophosphamide, methyl-CCNU and carmustine.
Methods to increase tumour temperatures
In the clinical application of hyperthermia, three methods can be distinguished: local, regional and whole-body hyperthermia.
With local hyperthermia, the aim is to increase mainly the tumour temperature. Local hyperthermia can be applied by external, intraluminal or interstitial methods. Electromagnetic or ultrasound energy is directed at the treatment volume. The volume that can be heated depends on the physical characteristics of the energy source and on the type of applicator (array) . Methods for applying hyperthermia externally can be divided into superficial techniques (the energy coming from one direction) and deep, also termed regional hyperthermia (energy directed from around the part of the body in which the target volume is located). Examples of external hyperthermia application are given in Figures 1 and 2. The energy distribution in the tissues strongly depends on tissue characteristics and is thereby inhomogeneous. The temperature distribution is not simply a result of the energy distribution, but also depends on thermal tissue characteristics and blood flow. The reduced blood flow in tumour tissue compared with that in normal tissues is advantageous, since tumour tissue will heat more easily. During local hyperthermia the systemic temperature may also increase; the absolute temperature increase will depend on both the treatment volume to which energy is applied and the measures taken to help the patient lose energy. During local hyperthermia, the tumour temperatures are increased to levels that are as high as possible, as long as the tolerance limits of the surrounding normal tissues are not exceeded.
Regional hyperthermia is applied by perfusion of a limb, organ or body cavity with heated fluids [21, 22]. When regional hyperthermia is applied to limbs, and without a cytotoxic agent, the temperature can be increased to ∼43°C for a duration of 2 h. The temperature must be lower in combination with cytostatic drugs to avoid unacceptable toxicity.
For whole-body hyperthermia, several methods have been used. A common characteristic is that energy is introduced into the body, while at the same time energy losses are minimised. The temperature increase is usually limited to 41.8–42°C. The toxicity of the treatment depends on the procedure used. Recent experience with radiant heat methods, for which the patients need only sedation during the treatment, has shown that this procedure is tolerated very well [23, 24]. A newer approach is to increase the temperature to ∼40°C for a longer period, which, in combination with cytokines and cytotoxic drugs, is expected to lead to a greater therapeutic index than whole-body hyperthermia at the maximum tolerated level .
First clinical results
The first reports on the clinical use of hyperthermia generated great enthusiasm. The results appeared considerably better than without hyperthermia, for example when studying hyperthermic regional isolated perfusion , whole-body hyperthermia in patients for whom no standard treatments were available  or hyperthermia combined with low doses of radiotherapy [28, 29]. Many reports are anecdotal, or compare results of a combined treatment with historic control groups. However, among the many non-randomised studies one can find rather convincing results.
Several groups used hyperthermia alone. A review of 14 such studies including a total of 343 patients reported complete response rates varying from 0% to 40% (overall 13%) and partial response rates from 0% to 56%, with an overall objective response rate of 51% . Three additional studies report complete response rates of 11%, 16% and 18% [31–33]. A drawback of the use of hyperthermia alone is that in general the duration of response is short, with a median of only 6 weeks.
Many studies concerned the combination of hyperthermia with radiotherapy. Several investigators studied the effect of additional hyperthermia in ‘matched lesions’: in patients with more than one tumour lesion, some of the lesions were treated with hyperthermia, while the other(s) received the same radiotherapy without hyperthermia. Such studies consistently show a higher complete response rate for combined treated lesions. A summation of the data from these studies (total 713 lesions) shows an increase in complete response rate from 31% to 67% . Literature reviews concerning complete response rates following the addition of hyperthermia to radiotherapy in breast cancer, malignant melanoma and neck nodes suggest a clinical thermal enhancement ratio of 1.5 to 1.7 [35, 36]. Comparison of results over a longer period revealed that the clinical outcome very much depends on the heating technique used. With recurrences of breast cancer, for example, reirradiation plus hyperthermia resulted in 31% complete response in the initial experience, while the complete response was 67% with a better heating technique .
Experience with a combination of hyperthermia and chemotherapy is more scarce, but again the results are promising. Use of a simultaneous combination of cisplatin and hyperthermia in cervical cancer, recurring following irradiation, resulted in a 50% response rate [38, 39], while without hyperthermia the response rate was expected to be ∼15%. Recently, two phase II studies on hyperthermia in combination with pre- and/or postoperative chemotherapy in high-risk sarcomas have demonstrated quite impressive 5-year overall survival rates. A phase III trial has been started to confirm the value of hyperthermia in the treatment schedule [40, 41]. Another study  evaluated the safety and effectiveness of whole-body hyperthermia at 41.8°C plus carboplatin in 16 patients with platinum-resistant ovarian cancer. Of 12 patients evaluable for response, one had a complete response and four had a partial response. In these studies, the toxicity was not in excess of that expected. Earlier experience with ifosfamide, carboplatin and etoposide and whole-body hyperthermia in patients with sarcomas also suggests that drug resistance can be overcome by hyperthermia at 41.8°C .
The experience with hyperthermia in children is limited, although both regional and whole-body hyperthermia appear feasible . In 10 patients with recurrent or refractory germ cell tumours, regional hyperthermia combined with cisplatin, etoposide and ifosfamide resulted in five complete and two partial responses, again suggesting that hyperthermia counteracts drug resistance .
Results of randomised studies
The results of the first two randomised studies performed in the United States were disappointing, as these failed to show a beneficial effect of adding hyperthermia to radiotherapy. Retrospectively, these negative results have been explained by the use of hyperthermia treatment techniques that were inadequate for the patients included in these studies [46–48]. Besides these two studies, at least 24 other randomised trials studying the addition of hyperthermia to radiotherapy and/or chemotherapy have been performed, of which 18 showed significantly better results with the hyperthermia group (Table 1). The best-known randomised trials are those on metastatic lymph nodes of head and neck tumours [49, 50], and on malignant melanoma , breast cancer , glioblastoma multiforme  and pelvic tumours , which were performed in Europe and North America. Patients with cervical lymph nodes were randomised to radiotherapy to a total dose of 64–70 Gy, or the same radiotherapy with twice weekly hyperthermia. The complete response rate improved from 41% to 83%, with 5-year local control increasing from 24% to 69%, and 5-year overall survival increasing from 0% to 53% [49, 50]. In malignant melanoma, the addition of hyperthermia to radiotherapy (three fractions of 8–9 Gy) increased the complete response rate from 35% to 62%, and 2-year local control from 28% to 46% . A combined analysis of the results of five randomised trials in recurrent or advanced breast cancer showed an improvement in complete response rate from 41% to 59% following the addition of hyperthermia to either conventional high-dose radiotherapy or low-dose re-irradiation. The difference in local control was maintained over the 3 years of follow-up. The best results from additional hyperthermia were seen in the two trials where 90–100% of the patients were treated with re-irradiation. These two trials both showed a significant improvement in complete response rate, from 38% to 78% and from 29% to 57% . Patients with glioblastoma multiforme were randomised to receive either interstitial hyperthermia or not in addition to a complex treatment schedule including surgery, external radiotherapy and brachytherapy. With hyperthermia, the median survival time was 85 weeks and the 2-year survival rate 31%, compared with 76 weeks and 15% in the control group . Hyperthermia added to standard radiotherapy in irresectable tumours of bladder, cervix and rectum resulted in overall significantly better local control and survival rates. The effect of hyperthermia appeared especially worthwhile for patients with advanced cervix cancer, where the 3-year local control rate improved from 41% to 61%, and 3-year overall survival from 27% to 51% .
Besides the studies listed above, there are less well-known randomised trials, all showing an improvement in one or more end point (Tables 1 and 2) [55–72]. In 13 studies the improvement with hyperthermia of either response, complete response, palliative effect or overall survival was significant, while in six studies the differences were not significant. Significant improvements were seen for tumours of the rectum (three studies), bladder (two), cervix (two), lung (small cell cancer, one), vulva and vagina (one) and oesophagus (three). Significant improvements were seen when adding hyperthermia to radiotherapy in 13 out of 20 studies, to chemotherapy in three out of four studies, and to radiotherapy plus chemotherapy in two out of two studies.
Normal tissue toxicity will result directly from hyperthermia when the tolerance limits are exceeded. Experimental studies have shown that most normal tissues are not damaged when the temperature over 1 h of treatment does not exceed 44°C . During local hyperthermia, it is not always possible to avoid higher temperatures due to the heterogeneity of the temperature distribution and the limited thermometry. The patient is not always able to feel painful hot spots, e.g. when the target area has been subject to surgery in the past and sensitivity is disturbed. The toxicity from superficial hyperthermia is usually a skin burn (in ∼25% of the patients with recurrent breast cancer [37, 52, 73], healing with conservative treatment). During hyperthermia for deep-seated tumours the skin is extensively cooled, through which the hot spots will develop in deeper tissues. A temperature that is too high in subcutaneous fat or muscle tissue results in a feeling of pressure, which is not always recognised by the patient. As a result of this patients may be reluctant to mention unpleasant sensations. Subcutaneous fat or muscle tissue burns do not usually cause much discomfort: the patient feels a subcutaneous lump, which is tender for a few days to a maximum of a few weeks and then disappears spontaneously. Subcutaneous fat burns were seen in 3–12% of the patients treated with deep hyperthermia. The risk of developing skin burns appears to be higher following treatment with a radiofrequency capacitive heating technique (5–16%) than with a radiative heating technique (0–3%) [54, 74–76]. The randomised studies did not show an increase in acute or late toxicity of radiotherapy. Whether the toxicity of chemotherapy is enhanced will depend on the temperature in the drug-sensitive tissues.
Toxicity from whole-body hyperthermia depends on, besides temperature, the patient’s general condition, condition of organ systems and the physiological conditions during the treatment . Serious toxicity from regional hyperthermic perfusion with modern technology and proper choice of perfusate composition, flow rate and pressure, blood gas values, drug doses, temperature dose and scheduling, is limited . During any application of hyperthermia it is important to avoid pressure sites, since hypoxic normal tissues will be more sensitive to hyperthermia.
The application of hyperthermia is relatively labour intensive. Usually the duration of a treatment is 60 min or longer. With local hyperthermia, the energy distribution and the resulting temperature distribution can only partially be monitored with temperature sensors placed interstitially. During treatment the information given by the patient, especially on (painful) hot spots, is crucial in preventing the development of thermal burns. Clinical staff must remain continuously alert in interpreting both the measured temperature distribution and the symptoms mentioned by the patient, in order to adjust the applied energy distribution appropriately. Both whole-body and regional hyperthermia are also time-consuming procedures, requiring appropriate equipment and skilled personal. Nevertheless, thanks to the large therapeutic gain achieved the cost-effectiveness of hyperthermia appears acceptable. Within, for example, the Dutch randomised trial on intrapelvic tumours, the cost per life-year gained for cervical cancer was less than ı4000 .
Heating technique and thermometry
Research areas in the delivery of local hyperthermia include development of additional techniques for heating, to expand the tumour locations that can be treated adequately, and improvement of existing systems [79–81]. A new method for interstitial hyperthermia is to inject a fluid containing magnetic nanoparticles intratumourally, and than to apply alternating current magnetic fields . Hyperthermia treatment planning systems have been developed [83, 84] and are now clinically verified . Another important development is that of non-invasive thermometry, requiring large technical efforts in combining MRI systems with heating equipment, and programming for data analysis [86, 87]. These tools will contribute to an easier and better controlled application of hyperthermia, and will expand the tumour locations that can be treated adequately.
Targeting drugs to tumours
The old idea of using temperature-sensitive liposomes containing cytotoxic drugs  recently regained interest. In pet animals with soft tissue sarcomas, intratumour liposome accumulation was two to 13 times higher with local hyperthermia than without hyperthermia . In a mouse model, treatment with temperature-sensitive liposomes containing doxorubicin and local hyperthermia resulted in higher intratumour drug concentrations and an improved therapeutic efficacy compared with treatment with either free doxorubicin, or doxorubicin containing liposomes without hyperthermia. None of the treatment regimens caused any obvious signs of morbidity .
Heat shock proteins
Heat shock proteins (HSPs) are synthesised in response to stress such as a hyperthermic treatment. After a non-lethal heat shock, HSPs were found to be expressed on the surface of malignant cells but not on normal cells. HSP-expressing cells are more susceptible to lysis by natural killer effector cells [91, 92]. HSPs are released following necrotic cell death, and released HSPs stimulate macrophages and dendritic cells to secrete cytokines, and activate antigen-presenting cells . Tumour growth in a rat model was significantly inhibited following a pre-implantation heat treatment, while splenic lymphocytes displayed specific cytotoxicity against the implanted cells . In a study comparing radiotherapy with radiotherapy plus hyperthermia in cervical cancer, the percentage of patients with continuing pelvic control developing metastatic disease was significantly lower in the combined treated group than in the radiotherapy-alone group, which may be explained by an effect of HSPs on tumour immunogenicity .
Hyperthermia and gene therapy
Gene expression with a heat shock promoter can be elevated to adequate levels by hyperthermia treatment. The enhancement can be as great as many thousand-fold over background. Otherwise, gene-infected cells were found to be more sensitive to hyperthermia [95–97]. In a murine system, intratumourally injected viral gene therapy encoding for interleukin-12, controlled with a heat shock promoter and followed by hyperthermia was shown to be feasible and therapeutically effective, with no apparent systemic toxicity .
Bone marrow purging
The clinical trial data concerning bone marrow purging for patients undergoing autologous bone marrow transplantation have as yet failed to show a survival benefit, which may be explained by the fact that purging techniques are still not good enough . Murine and human leukemic bone marrow-derived stem cells have been shown to be much more sensitive than their normal counterparts [100–102]. The addition of drugs that protect the normal cells can enhance further the therapeutic index to values of >5000 . To date, purging by hyperthermia has not been tested clinically.
Targeting tumour vasculature
Several drugs decrease tumour blood perfusion and thereby may secondarily induce tumour cell kill. Drugs like KB-R8498, flavone acetic acid, vinblastin and combretastatin have been studied in combination with hyperthermia. In the animal models investigated, all drugs induced a temporary reduction in tumour blood flow but generally, following a single application, had no effect on tumour growth. In combination with hyperthermia at 41.5–44°C, significant tumour responses were observed [104–107].
There is an increasing interest in the clinical application of trimodality treatment, in which radiotherapy, chemotherapy and hyperthermia are combined. Japanese colleagues were probably the first to test trimodality treatment in patients , and in the meantime have demonstrated the value of additional hyperthermia in patients with oesophageal cancer [62, 65]. More recent studies on preoperative treatment in rectal cancer, on head and neck tumours and recurrent breast cancer have made it clear that trimodality treatment is feasible and appears effective [109–113].
Discussion and conclusions
The results from experimental studies indicate that hyperthermia is both the ideal complementary treatment to, and a strong sensitiser of, radiotherapy and many cytotoxic drugs. Results from clinical studies have confirmed the expectations raised by the laboratory studies. In spite of the remarkable therapeutic gain that has now been demonstrated in patients, hyperthermia still is not widely recognised as a useful treatment. There are several reasons for this lack of acceptance.
First, many years have passed since the first anecdotal reports of results that were better than expected in patients, and the publication of positive results from randomised clinical trials. This can be explained by the limited availability of treatment techniques, which were being developed during the first clinical studies. The first randomised studies performed in the United States failed to show evidence of a beneficial effect from hyperthermia due to the use of inadequate treatment techniques. This initial result has had a strong negative impact on further interest for this treatment. Over the years, it has become clearer how important it is to use adequate heating equipment. In the study by Perez et al. [46, 47], for example, the more easily heated lesions (<3 cm in diameter) did show a difference in complete response rate (52% compared with 39%), while the larger lesions did not (25% compared with 27%). A study on recurrent breast cancer showed that the complete response rate in tumours >3 cm increased from 31% to 65% by using a better heating technique . A further study  has shown that the energy distribution in the target area is an important prognostic factor for complete response.
Secondly, most of the positive randomised trials have been relatively small and/or were performed in Asia and Russia and have therefore received less attention than the North American studies. Altogether, however, both non-randomised and randomised clinical studies have shown how remarkable the improvement can be by adding hyperthermia to other treatment modalities. It is therefore peculiar that, in general, the oncology community still appears hesitant to start using it. The application of hyperthermia is mainly performed by a small group of dedicated institutes. What can the further obstacles be?
While hyperthermia requires investments in equipment and personnel training, the same is true for other types of cancer treatment, such as radiotherapy or bone marrow transplantation. In spite of the required investments, the economic evaluation of hyperthermia in cervical cancer has made clear that the cost-effectiveness can be within an acceptable range. Another obstacle for the acceptance of hyperthermia may be that it lacks public awareness . Hyperthermia used as single modality resulted in an overall complete response of 13%. Hyperthermia added to radiotherapy or chemotherapy results in up to a doubling of complete response rate. In selected patient groups, a substantial gain in overall survival was found. If a drug were to achieve similar successes, its corporate sponsor would have announced it as a new breakthrough in cancer treatment, and it would have received extensive attention from the media. Hyperthermia equipment is manufactured by a few relatively small organisations that lack the finances for mass media promotion and support of clinical trials.
Hyperthermia is not yet a fully developed modality; there are still problems with its routine clinical application, and there is still room for further technological improvements. Most of the clinical studies are on its combination with radiotherapy. However, the experimental and the few clinical results with combined chemotherapy and hyperthermia make clear that this combination is also worth testing further. With the presently available equipment for local hyperthermia, only a limited number of tumour sites can be treated adequately. It may not seem a sensible approach to combine systemic chemotherapy with local hyperthermia, but for patients who are palliatively treated for a tumour in an accessible location, the addition of hyperthermia can be valuable. Whole-body hyperthermia can be applied only to patients in a good general condition, and when combined with drugs the first step must evidently be to demonstrate its safety, but patients in a good general condition do exist and there is room for improvement of the efficacy of chemotherapy. The more recent findings on hyperthermia used in drug targeting, gene therapy and stem cell purging, and on its effect on tumour immunogenicity or in combination with drugs targeting tumour vasculature, make it an even more interesting treatment modality. It would be to the benefit of present and future patients if more institutes would invest in hyperthermia equipment and personnel. All patients with a tumour for which a beneficial effect of hyperthermia has been clearly shown should have access to the treatment. Only when hyperthermia is available more widely can larger studies be performed to learn how to fully exploit its therapeutic effect.
Radiation oncologists have been exploring heat therapy as an adjunct to radiation for at least 40 years. Hyperthermia, however, seems to have retained its novelty—a perpetual newcomer in a world where surgery, radiotherapy and chemotherapy are the much more established players.
Hyperthermia, as a radiosensitizer, is used in treating a few cancers in some radiation oncology departments. It is not often considered a standard adjunct, like chemotherapy, and, up until now, national guidelines for treating specific tumors have not included hyperthermia.
A randomized trial published last May in the Journal of Clinical Oncology demonstrated that hyperthermia combined with radiation significantly improved response rates in breast cancer patients who had recurring tumors on the chest wall. In August, researchers reported in the journal Cancer that hyperthermia produced impressive response rates when combined with radiation and chemotherapy in advanced cervical cancer.
These gains, plus improvements in equipment, are spurring new interest in radiation oncology departments and optimism among hyperthermia researchers that heat may, at last, be living up to its early promise.
In the first trial, conducted at Duke University Medical Center, hyperthermia given before radiation therapy eradicated tumors in 66 percent of the patients, most of whom had post-mastectomy chest wall recurrences of breast cancer. By comparison, radiation therapy alone destroyed tumors in just 42 percent of patients.
These results could change the standard of care nationally for patients with chest wall tumors. Duke is already using hyperthermia as standard therapy, said principal investigator Ellen L. Jones, M.D., and it has been approved for Medicare and Medicaid patients.
In addition, the National Comprehensive Cancer Network is considering a recommendation that hyperthermia be used for chest wall recurrences in the next edition of its breast cancer guidelines.
The cervical cancer trial combined data from three separate but very similar trials in the United States, Norway and The Netherlands. The trial, led by Anneke M. Westermann, M.D., Ph.D., from the Academic Medical Center in Amsterdam, involved radiotherapy, chemotherapy and hyperthermia in the treatment of 68 patients with cancer, spread beyond the cervix. Patients received external radiotherapy and brachytherapy, plus four courses of chemotherapy, which included the drug Cisplatin, plus four sessions of hyperthermia using focused microwave energy.
The researchers found that 61 patients (90 percent) achieved complete remission. After two years of follow up, 71.6 percent were still in remission. The two-year overall survival rate was 78.5 percent.
These rates compare favorably with those achieved using chemoradiation—chemotherapy and radiation combined—which is now the standard therapy for advanced cervical cancer, said Dr. Jones, who was also involved in this trial at Duke. In fact, the combined results of the three countries’ trials were encouraging enough to justify a larger, randomized study that will compare chemoradiation to chemoradiation plus hyperthermia in advanced cervical cancer.
This phase III trial, launched in May by Duke and the other participants, has already attracted four additional hospitals including Northwestern University Medical Center in Chicago, hospitals in Holland, Amsterdam, Bergen and three large hospitals in Germany. At least two other U.S. institutions are discussing participation, Dr. Jones said.
Hyperthermia Treatment of Yesterday
Why has it taken so long for hyperthermia to get to this point? In a comprehensive review in the Annals of Oncology in October 2002, one of hyperthermia’s major researchers, Jacoba van der Zee, M.D., Ph.D., of the Erasmus Medical Center in The Netherlands, noted that there was a good deal of enthusiasm for hyperthermia in the 1970s and 1980s. It withered in the aftermath of several large randomized trials in which hyperthermia plus radiation did no better than radiation alone. Dr. van der Zee, who was also involved in the Westermann study, traced the failure of these trials to hyperthermia techniques that were inadequate for the patients being treated.
Then in the 1990s, smaller trials with improved equipment began to produce more favorable results, and some radiation oncologists saw good reasons to continue using the technique. William Small Jr., M.D., said that hyperthermia for chest wall recurrences and other tumors close to the surface has always made a lot of sense to him.
“There is a very good risk/benefit ratio with superficial tumors—they are easy to heat and the treatment is tolerated well,” said Dr. Small, who is an associate professor of radiation oncology at Northwestern University and a principal investigator for the Radiation Therapy Oncology Group. He uses hyperthermia in almost everyone with chest wall recurrences and in some pelvic and other superficial tumors. Hyperthermia makes cancer cells more vulnerable to radiation therapy and to many chemotherapy drugs.
Drawbacks to Hyperthermia Treatments
Despite the positive results, hyperthermia is performed mainly by a small group of dedicated institutes. Dr. van der Zee suggested that this may be because many of the trials with positive results have been small and they took place in Russia and Asia.
In addition, hyperthermia faces some logistical and economic hurdles. The specialized equipment, though not expensive compared to radiation therapy equipment, requires additional training for staff and specialized technical support. Heat can be applied in various ways, using microwaves, radiofrequency or ultrasound, and it can be applied locally, regionally or over the entire body. It may involve external or interstitial applicators. Perfusion techniques, in which a patient’s blood is removed, heated and then returned to a limb or organ, are also under study. All of these approaches require variations in equipment and special expertise.
Hyperthermia treatments also tend to be time-consuming. Treatments may take more than an hour compared to only about 15 minutes for a typical radiation therapy session, Dr. Jones said. Hyperthermia treatments are also labor intensive; staff must continually monitor the temperature of the tumor during the session, since reaching and maintaining the optimal temperature—between 40 and 44 degrees centigrade—is crucial to the effectiveness of hyperthermia and to prevent burns.
Hyperthermia equipment continues to evolve. Duke, for example, has an Investigative Device Exemption from the Food and Drug Administration to use MR imaging for non-invasive hyperthermia monitoring. Dr. Jones said her department is now testing the technique in the hyperthermia treatment of extremity sarcomas.
Such improvements, added to good results from phase III trial results, could make hyperthermia a much more practical and widespread adjunct to radiotherapy, she said.
These results could change the standard of care nationally for patients with chest wall tumors.
To read the abstract of the Jones article, “Randomized Trial of Hyperthermia and Radiation for Superficial Tumors,” go to www.jco.org/cgi/content/abstract/23/13/3079. To view the abstract for the
Westermann article, “First Results of Triple-modality Treatment Combining Radiotherapy, Chemotherapy, and Hyperthermia for the Treatment of Patients with Stage IIB, III, and IVA Cervical Carcinoma,” go to www3.interscience.wiley.com/cgi-bin/abstract/110542336/ABSTRACT. To view the full-text of the van der Zee review article, “Heating the Patient: A Promising Approach?” go to annonc.oxfordjournals.org/cgi/content/full/13/8/1173.
Multiple studies highlight the use of hyperthermia therapy to treat prostrate cancer
from BSD Medical
BSD Medical is highlighting four presentations at the International Congress on Hyperthermic Oncology (ICHO) conducted this month in Munich, Germany that show the benefits of using hyperthermia therapy to improve the treatment of pancreatic cancer.
The conference is a combined meeting of the European Society for Hyperthermic Oncology (ESHO), the US Society of Thermal Medicine (STM) and the Asian Society for Hyperthermic Oncology (ASHO).
Pancreatic cancer is the fourth leading cause of cancer death in men and women, with 37,170 new cases projected in the USA this year by the American Cancer Society, and 33,370 deaths from the disease.
Even a small benefit from a new treatment is important for patients faced with this deadly form of cancer. While the use of hyperthermia therapy in treating some other forms of cancer has been heavily researched, little has been known about the potential of the therapy in treating pancreatic cancer patients, a cancer for which better treatment is urgently needed.
The Verona Study
Fifty-seven pancreatic cancer patients were accrued between 2000 and 2006 in a study conducted by the Department of Radiotherapy of the University of Verona in Italy.
Eleven patients were lost at follow up, leaving 46 evaluable patients. Patients were divided into groups A and B. Group A consisted of 25 patients who received chemotherapy and hyperthermia plus radiation (or chemotherapy alone in the case of 5 patients affected by distant metastases wherein radiation was excluded). Group B consisted of 21 patients (none of whom had metastatic disease) who received chemotherapy and radiation without hyperthermia. At 24 months, nine patients (36 percent) were alive in group A, compared to four patients (19 percent) who were alive in group B.
Chemotherapy was well tolerated in both groups, with no more toxicity in group A. The study concluded that hyperthermia is a promising therapeutic modality in the treatment of locally advanced pancreatic cancer, that it does not increase acute or late toxicity of combined treatment, and that it seems to enhance the efficacy of both chemotherapy plus radiation and chemotherapy alone with metastatic disease, as five patients with distant metastases were included in group A.
The Munich Study
Researchers associated with the University of Munich, Germany, reported results after treating 22 pancreatic patients in a difficult stage of the disease (19 metastatic and 3 with locally advanced pancreatic cancer).
Using a combination of gemcitabine plus cisplatin as their chemotherapy drugs combined with hyperthermia therapy, the treatment reached their target for improvement, and based on these data a randomised first-line phase III clinical trial has been initiated. A number of cancer research institutions with BSD-2000 systems have agreed to participate in this government sponsored phase III study.
The study conducted at the Kyoto Prefectural University of Medicine in Japan was a retrospective analysis of patients with advanced inoperable pancreatic cancer who were treated with the sequential combination of chemotherapy (gemcitabine) plus hyperthermia therapy between 2004 and 2007. Patients treated with gemcitabine alone between December 2003 and April 2005 were allocated as a control group (historical control).
Patients in the experimental group received gemcitabine and hyperthermia therapy. The disease control rate was 57.1 percent for the experimental group and 14.3 percent for patients treated with gemcitabine alone (historical control). The one-year overall survival for the control group was 30 percent, compared to 49 percent for the experimental group that received hyperthermia therapy. The study concluded that this combination therapy could be a potential first-line treatment for patients with advanced pancreatic cancer.
A second Kyoto study was also presented, designed to identify some of the mechanisms whereby hyperthermia therapy works in combination with chemotherapy to improve results in killing cancer cells. When cells are attacked by chemotherapy they release a protective protein complex called NF-kB, and this protein induces tumours to become resistant to chemotherapy.
To explore the effects of hyperthermia therapy in the formation of NF-kB, the group treated cultured human pancreatic cancer cells with gemcitabine, inducing the formation of NF-kB. They discovered that hyperthermia inhibited the chemotherapy-induced activation of NF-kB, and thus enhanced cancer cell death through gemcitabine.
The study concluded that hyperthermia inhibited gemcitabine-induced activation of NF-kB and decreased the expression of anti-apoptosis proteins, resulting in the enhancement of the cytotoxicity of gemcitabine.
BSD Medical has welcomed the International Journal of Radiation Oncology, Biology and Physics’ publication of a seven-page report containing the 12-year clinical follow-up data for a landmark study comparing the clinical results for advanced cervical cancer patients treated with radiation and hyperthermia therapy to those for patients treated with radiation alone.
The publication is the official journal of the American Society for Therapeutic Radiology and Oncology (ASTRO), the world’s leading organization devoted to radiation oncology.
The article entitled, ‘Long-Term Improvement in Treatment Outcome after Radiotherapy and Hyperthermia in Loco-regionally Advanced Cervical Cancer: an Update of the Dutch Deep Hyperthermia Trial’, is considered highly relevant by BSD Medical because the follow-up data test the durability of the effect of hyperthermia therapy for cervical cancer patients. The original study was a Phase III clinical trial involving 358 patients with locally advanced pelvic tumours conducted at the University Hospital of Daniel den Hoed Cancer Center in Rotterdam and the Academic Medical Center in Amsterdam. The lead author in this study was Jacoba van der Zee, MD, PhD. The Dutch Health Insurance Council funded the study.
The 114 cervical cancer patients enrolled in the study had tumours that were loco-regionally advanced, and their prognosis was generally grave. The primary endpoints for the study were complete response and local control of the cancer. The secondary endpoints of the study were overall survival and toxic effects from radiation or hyperthermia.
In April 2000 the Lancet published the 3-year data from the study. For the cervical cancer patients, the data showed a complete-response rate of 83 percent for patients receiving both hyperthermia and radiation therapy as compared to 57 percent for those receiving radiation alone (p equals 0.003).
The published article also noted that ‘the improved local-control rates were not accompanied by increased toxic effects from radiation’. Survival follow-up data showed a 51 percent survival rate for patients who received radiation plus hyperthermia therapy, as compared to 27 percent of those who received radiation therapy alone (Lancet vol. 355, pp. 1119-1125).
According to the new publication, after 12 years local control remained significantly better for the cervical cancer patients who received hyperthermia therapy along with radiation - local control of 56 percent for that group as compared to 37 percent for those who received radiation therapy alone (p equals 0.01). After 12 years the survival rate was also persistently better for those patients who received hyperthermia therapy along with radiation, with a 37 percent survival rate for those patients as compared to a 20 percent survival rate for the patients who received radiation alone (p equals0.03). The new article concludes: “For loco-regionally advanced cervical cancer, the addition of hyperthermia therapy to radiation therapy resulted in long-term major improvement in local control and survival without increasing late toxicity.”
The new ASTRO publication offers the following rationale for the use of hyperthermia therapy with radiation therapy: ‘Hyperthermia, the artificial increase in tissue temperature to 40 to 44 degrees C, is an effective cytotoxic agent, especially in cells that are in a hypoxic nutrient-deprived low-pH environment. These conditions are commonly found in malignant tumours and make cells relatively resistant to radiation therapy. In addition to directly killing cells at temperatures of 40 to 44 degrees C, hyperthermia therapy also increases the cytotoxic effect of radiation therapy. Experimental studies show that it interfered with the cellular repair of radiation-induced DNA damage, thereby enhancing the cytotoxic effect of radiation therapy. Hyperthermia also increases blood flow, which may improve tissue oxygenation and make cells more sensitive to radiation therapy’ (see Int J Radiation Oncology Biol Phys, Vol 70, No. 4, pp 1176-1182, 2008).
ESMO recommends that hyperthermia becomes a standard therapy for soft tissue sarcoma from BSD Medical
The addition of hyperthermia to chemotherapy has been recommended as standard therapy for soft tissue sarcoma by the European Society for Medical Oncology (ESMO), the leading European professional medical oncology organization comprising a network of more than 5,000 oncology professionals in over 100 countries.
The use of hyperthermia as standard treatment for soft tissue sarcomas was debated at the 33rd European Society for Medical Oncology (ESMO) Congress, which was held last week in Stockholm, Sweden to determine if the treatment should be approved as standard therapy. The title of the debate was: “Hyperthermia Has Been Shown to Improve Local Control of Soft Tissue Sarcomas: Should This Now Be Standard Therapy?”
Dr Rolf D. Issels, University Hospital Medical Center Grosshadern and Helmholtz Zentrum Munchen-German Research Center for Environmental Health, presented the case for approval based on improved clinical outcomes (response and survival) with the use of regional hyperthermia when combined with chemotherapy in the management of locally advanced, high grade soft tissue sarcomas. T
he results of an EORTC (European Organization for Research and Treatment of Cancer) sponsored Phase III study involving 341 randomized patients with high risk soft tissue sarcomas had demonstrated an approximate doubling of disease-free survival time for patients who received treatments using BSD Medical’s BSD-2000 system to deliver hyperthermia in combination with chemotherapy, surgery and radiation, as compared to those patients who received chemotherapy, surgery and radiation alone.
Dr Issels pointed out that as of May 2008 the mean follow-up time of the sarcoma study patients was 57 months and that the long-term data continues to demonstrate improved clinical outcomes for tumour response and survival from the addition of hyperthermia.
Dr Martin Robinson, Cancer Research Centre, Academic Unit of Clinical Oncology, Weston Park Hospital, Sheffield, Great Britain, presented the case against approval. Dr Robinson did not oppose the use of hyperthermia, but he pointed out some potential problems that a general adoption of hyperthermia might present as an additional treatment mode for soft tissue sarcoma.
After both speakers had concluded their remarks, the physicians voted electronically regarding the approval of hyperthermia as standard therapy in all European countries (population of 450 million). The response was in favour of hyperthermia, with 74 percent of the respondents voting for the adoption of hyperthermia when combined with chemotherapy as standard therapy for the treatment of soft tissue sarcomas.
ESMO constantly strives to address the timely issues that affect the field of oncology. The society’s objective is to provide evidence-based information and treatment requirements for the field of medical oncology and to establish platforms for the dissemination and sharing of knowledge. ESMO releases annual updates of its recommendations for treatment of specific tumors and now recommends in the use of hyperthermia as a treatment for high grade soft tissue sarcoma.
An Italian study of head and neck cancer patients who were treated with radiation alone to those who received hyperthermia therapy plus radiation has been completed.
BSD Medical has concluded an exhibition at the American Brachytherapy Society (ABS) annual conference held in Chicago, Illinois.
The ABS Annual conference provides a forum for reporting developments in brachytherapy.
Brachytherapy is an interstitial form of radiation, administered by placing radioactive material in the cancer.
Head and neck cancers are an important application for brachytherapy, and they were one of the focuses of the meeting.
BSD Medical produces systems that are designed to boost the effectiveness of brachytherapy for certain tumours by providing companion interstitial hyperthermia therapy.
BSD Medical representatives used the conference to emphasise a study conducted by Drs Riccardo Valdagni and Maurizio Amichelli at the Oncology Center of Ospedale Santa Chiara, Trento, Italy, comparing the results for head and neck cancer patients who were treated with radiation alone to those who received hyperthermia therapy plus radiation.
The patients involved had inoperable Stage IV head and neck cancer with metastatic lymph nodes.
The study concluded that hyperthermia added to radiation improved complete response (tumour disappearance) from 41 percent to 83 percent, local relapse-free survival from 24 percent to 68 percent and overall survival at five years from 0 to 53 percent, as compared to radiation treatments alone.
The study, published in the International Journal of Radiation Oncology, Biology, Physics (see Vol 28, pp 163-169), was halted at 41 patients because, due to the strongly favourable results from the addition of hyperthermia therapy to radiation, it was not considered ethical to enroll further patients in the study who would be denied the combined treatment.
Hyperthermia therapy (focused heating of the cancer) is used in combination with radiation therapies to provide cancer cell kill in addition to radiation, as well as to provide better oxygenation of the tumour by stimulating the blood flow, so that the oxygen radicals necessary to attack cancer cell DNA can be more readily formed by radiation treatments.
The destruction of cancer cells through hyperthermia therapy is attributed to damage of the plasma membrane, the cytoskeleton, and the cell nucleus.
More than 640,000 people worldwide are diagnosed with head and neck cancer every year, and more than 350,000 die from the disease annually.
Head and neck cancer is a group of cancers that include cancers of the mouth, nose and throat.
The treatment of inoperable metastatic lymph nodes in patients with head and neck cancer represents a therapeutic challenge.
Clinical results using radiation therapy alone have been disappointing.
A new article in Current Option in Oncology (Ref 1) has highlighted the use of BSD Medical’s BSD-2000 hyperthermia system in treating patients with high risk soft tissue sarcomas.
Central to the article’s review of sarcoma studies using the BSD-2000 is the results of a phase III study involving 341 randomized patients with high risk soft tissue sarcomas that showed an approximate doubling of disease-free survival time for patients who received treatments using BSD-2000 systems in combination with chemotherapy, surgery and radiation, as compared to those patients who received chemotherapy, surgery and radiation alone.
The additional use of hyperthermia delivered using the BSD-2000 made a difference in patient outcome. The study was conducted under the sponsorship and quality control of the European Organization for Research and Treatment of Cancer (EORTC:62961). Preliminary results of the study were reported at the American Society of Clinical Oncology (ASCO) 2007.
The article entitled “Regional hyperthermia in high-risk soft tissue sarcomas” was authored by Rolf D Issels, MD, PhD of the University Hospital Medical Center Grosshadern and Helmholtz Zentrum Munchen-German Research Center for Environmental Health, Munich, Germany. The author stated that, “The rationale for the combination of cytotoxic drugs with hyperthermia (increase of temperature in the range of 40 to 44 degrees C) is based on experimental and clinical evidence that heat increases killing of cells by direct thermal toxicity and shows thermal enhancement of drug efficacy.”
Ref 1- Current Option in Oncology 2008, 20:pages 438-443.
US cancer institutions report on the use of combined radiation and hyperthermia therapy from BSD Medical
BSD Medical has welcomed a multi-institutional review which has reported on the positive use of combined radiation and hyperthermia therapy for treating recurrent breast cancer.
The review was presented in the official journal of the American Society for Therapeutic Radiology and Oncology (ASTRO).
The review was conducted by participants from Northwestern University, Chicago, Illinois; Duke University Medical Center, Durham, North Carolina; Memorial Sloan-Kettering Cancer Center, New York; Lutheran General Cancer Center, Park Ridge, Illinois; University of Texas M D Anderson Cancer Center, Houston, Texas; Boston University Medical Center, Boston, Massachusetts; Alexian Brothers Hospital, Elk Grove Village, Illinois; and Fox Chase Cancer Center, Philadelphia, Pennsylvania.
The review examines the feasibility of treating recurrent breast and chest wall cancers with radiation. As more than half of the patients from the pooled data received hyperthermia therapy in addition to radiation, this led to an additional comparison of results from radiation treatments with and without hyperthermia therapy.
Recurrent breast cancer is a difficult condition without a clear role for treatment with radiation therapy. The review observes that breast cancer recurrence ‘has classically been considered to confer a poor prognosis’. The review noted that for patients ‘who have undergone previous beast or chest wall radiation therapy, the role of repeat radiation therapy is not clear’.
In conducting this review, 81 recurrent breast cancer patients treated by radiation were identified by the institutions, 44 of who received hyperthermia therapy in addition to radiation. The median follow-up on patients treated was 12 months.
Based on ‘encouraging local response rates’, that is an overall complete response rate (tumour disappearance) of 57 percent for all patients treated with radiation, along with ‘acceptable acute and late morbidity’, the review concluded that ‘repeat radiation therapy of the chest wall for patients with locally recurrent breast cancer is feasible’. However, there was a substantial difference in the complete response rate between the patients who received radiation plus hyperthermia as compared to those who received radiation alone. The review indicated ‘Patients who received hyperthermia had a complete response rate of 67 percent compared with 39 percent for patients who did not receive hyperthermia’.
The review is entitled ‘Multi-Institutional Review of Repeat Radiation of Chest Wall and Breast for Recurrent Breast Cancer’ (see Int J Radiation Oncology Biol. Phys, Vol. 70, No 2, pp. 477-484, 2008).
Hyperthermia study linked to improved cancer survival rates from
Congress in Berlin used to present report linking the use of Hyperthermia and Chemotherapy to prolonged life expectancy in soft tissue cancer patients
BSD Medical reports that significant and “medical practice changing” clinical study results were the subject of a news briefing at Europe’s largest cancer congress, ECCO15 – ESMO34, which is being held September 20 to 24, 2009, in Berlin, Germany. A Phase III study, which utilized the BSD-2000 Hyperthermia System, demonstrated that patients with high risk soft-tissue sarcomas were 30% more likely to be alive and cancer free almost three years after starting treatment if targeted heat therapy (hyperthermia) was added to their chemotherapy treatment.
The press information stated that, “The study, which found that the addition of the innovative heat technique more than doubled the proportion of patients whose tumours responded to chemotherapy without increasing toxicity, is also the first to show that any treatment other than surgery followed by radiation can prolong survival of this type of patient.” The press release also stated that the results increase the case for intensifying the exploration of this type of treatment of other types of cancer. “These findings provide a new standard treatment option and we believe they are likely to change the way many specialists treat these tumours,” said the study’s leader, Professor Rolf Issels, a professor of medical oncology at Klinikum Grosshadern Medical Center at the University of Munich in Germany, who presented the results at the ECCO-ESMO congress.
“But the implications of these findings are more far-reaching,” Prof Issels said. “This is also the first clear evidence that targeted heat therapy adds to chemotherapy. We expect our findings will encourage other researchers to test the approach in other locally advanced cancers. Targeted heat therapy has already shown promise in recurrent breast and locally advanced cervical cancer in combination with radiation and studies combining it with chemotherapy in other localised tumours such as those in the pancreas and rectum are ongoing.”
The Phase III study involved 341 patients who were treated at medical centers in Europe and in the United States. All patients had locally advanced soft tissue sarcomas and were at high risk of recurrence and spread. All patients were given chemotherapy before and after surgery and radiotherapy. Half of the patients were randomly given hyperthermia along with chemotherapy.
“The patients receiving the targeted heat therapy fared better on all outcome measurements,” Prof Issels said. “Almost three years after starting treatment, they were 42% less likely to experience a recurrence of their cancer at the same site or to die than those who were getting chemotherapy alone, surviving an estimated 120 months before local progression of their disease, compared with an estimated 75 months. Similarly, the average length of time that patients remained disease free was 32 months in the group that got both treatments, compared with 18 months in the group that got chemotherapy alone – an improvement of 30%.”
- Cancer: Medical Vocabulary(American Academy of Family Physicians)
Also available in Spanish
- Dictionary of Cancer Terms(National Cancer Institute)
Making a Treatment Decision
- Cancer Treatment Decisions: 5 Steps to Help You Decide(Mayo Foundation for Medical Education and Research)
- Cureious? Ask(Federal Trade Commission)
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- Chemicals in Meat Cooked at High Temperatures and Cancer Risk(National Cancer Institute)
- Known and Probable Human Carcinogens(American Cancer Society)
- Obesity and Cancer: Questions and Answers(National Cancer Institute)
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- Cancer Clusters(National Cancer Institute)
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