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.

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Relationship between thermal dose and outcome in thermoradiotherapy treatments for superficial recurrences of breast cancer: data from a phase III trial Sherar, M.; Liu, F.F.; Pintilie, M.; Levin, W.; Hunt, J.; Hill, R.; Hand, J.; Vernon, C.; van Rhoon, G.; van der Zee, J.; González González, D.; van Dijk, J.D.P.; Whaley, J.; Machin, D. Published in:International Journal of Radiation Oncology Biology Physics DOI:10.1016/S0360-3016(97)00333-7 Link to publicationCitation for published version (APA): Sherar, M., Liu, F. F., Pintilie, M., Levin, W., Hunt, J., Hill, R., ... Machin, D. (1997). Relationship between thermal dose and outcome in thermoradiotherapy treatments for superficial recurrences of breast cancer: data from a phase III trial. International Journal of Radiation Oncology Biology Physics, 39, 371-380. https://doi.org/10.1016/S0360-3016(97)00333-7 General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Purpose: The objective of this study was to determine whether the thermal tmtments and other thermal Pactors correlate with outcome after combined carcinoma recurrences. Data were from the combined hyperthermia and radiation tmktment arms 0Pfour PhaseResuits: Five thermal parameters were tested, ail associated with the iow regions of the measur4 &@&tions. Max(TDmin) and Sum(TDmin) were associated with c rawrs representative of the low end of the measured temperature complete response rate, local disease-free survival, time to local failure and overail survival. 0 1997 Elsevier Science Inc.Hyperthermia, Randomized trial, Thermal dose, Outcome, Breast cancer, Recurrence. INTRODUCTIONWe recently reported that hypeitheimia is an effective adjunct to radiation in the treatment of chest wall recnrrences of breast carcinoma (1 I). This result is consistent with that of a recent trial of the effect of hypertherrnia on the response of malignant melanoma (19) and neck node metastases from head and neck cancer (27). However, other studies have shown no benefit in the addition of hyperthermia to radiation either for the treatment of chest wall recumnces of breast cancer using external heating (22,23), or for interstitial heating of miscellaneous tumors (9)

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The combined result of the five trials has demonstrated the efficacy of hyperthermia as an adjunct to radiotherapy for treatment of recurrent breast cancer. The implication of these encouraging results is that hyperthermia appears to have an important role in the clinical management of this disease, and there should be no doubt that further studies of the use of hyperthermia are warranted.

The purpose of this work was to define all features, and show the potential, of the novel HYPERcollar applicator system for hyperthermia treatments in the head and neck region. The HYPERcollar applicator consists of (1) an antenna ring, (2) a waterbolus system and (3) a positioning system. The specific absorption rate (SAR) profile of this applicator was investigated by performing infra-red measurements in a cylindrical phantom. Mandatory patient-specific treatment planning was performed as an object lesson to a patient with a laryngeal tumour and an artificial lymph node metastasis. Comfort tests with healthy volunteers have revealed that the applicator provides sufficient comfort to maintain in treatment position for an hour: the standard hyperthermia treatment duration in our centre. By phantom measurements, we established that a central focus in the neck can be obtained, with 50% iso-SAR lengths of 3.5 cm in transversal directions (x/y) and 9-11 cm in the axial direction (z). Using treatment planning by detailed electromagnetic simulations, we showed that the SAR pattern can be optimised to enable simultaneous encompassing of a primary laryngeal tumour and a lymph node metastasis at the 25% iso-SAR level. This study shows that the applicator enables a good control, and sufficient possibilities for optimisation, of the SAR pattern. In an ongoing clinical feasibility study, we will investigate the possibilities of heating various target regions in the neck with this apparatus.

The results from experimental studies indicate that hyperthermia is both an effective complementary treatment to, and a strong sensitiser of, radiotherapy and many cytotoxic drugs. Since the first international hyperthermia conference in 1975, Washington DC, techniques to increase tumour temperature have been developed and tested clinically. Hyperthermia can be applied by several methods: local hyperthermia by external or internal energy sources, perfusion hyperthermia of organs, limbs, or body cavities, and whole body hyperthermia. The clinical value of hyperthermia in combination with other treatment modalities has been shown by randomised trials. Significant improvement in clinical outcome has been demonstrated for tumours of the head and neck, breast, brain, bladder, cervix, rectum, lung, oesophagus, for melanoma and sarcoma. The addition of hyperthermia resulted in remarkably higher (complete) response rates, accompanied by improved local tumour control rates, better palliative effects, and/or better overall survival rates. Toxicity from hyperthermia cannot always be avoided, but is usually of limited clinical relevance. In spite of these good clinical results, hyperthermia has received little attention. Problems with acceptance concern the limited availability of equipment, the lack of awareness concerning clinical results, and the lack of financial resources. In this paper the most relevant literature describing the clinical effects of hyperthermia is reviewed and discussed, and means to overcome the lack of awareness and use of this modality is described.