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Heating the patient: a promising approach?

  • J. van der Zee
    Correspondence
    Correspondence to: Dr J. van der Zee, Department of Radiation Oncology, Hyperthermia Unit, Erasmus Medical Center–Daniel den Hoed Cancer Center, PO Box 5201, 3008 AE Rotterdam, The Netherlands. Tel: +31-10-4391-498; Fax: +31-10-4391-022;
    Affiliations
    Erasmus Medical Center–Daniel den Hoed Cancer Center, Department of Radiation Oncology, Hyperthermia Unit, Rotterdam, The Netherlands
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      Abstract

      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.

      Keywords

      Introduction

      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 [
      • Seegenschmiedt M.H.
      • Seegenschmiedt M.H.
      • Fessenden P.
      • Vernon C.C.
      Thermoradiotherapy and Thermochemotherapy.
      ].
      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 [
      • Reinhold H.S.
      • Endrich B.
      Tumour microcirculation as a target for hyperthermia.
      ,
      • Song V.E.
      • Choi I.B.
      • Nah B.S.
      • Seegenschmiedt M.H.
      • Fessenden P.
      • Vernon C.C.
      • et al.
      Thermoradiotherapy and Thermochemotherapy.
      ,
      • Vaupel P.W.
      • Kelleher D.K.
      • Seegenschmiedt M.H.
      • Fessenden P.
      • Vernon C.C.
      Thermoradiotherapy and Thermochemotherapy.
      ], 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 [
      • Raaphorst G.P.
      • Field S.B.
      • Hand J.W.
      An Introduction to the Practical Aspects of Clinical Hyperthermia.
      ]. Most normal tissues are undamaged by treatment for 1 h at a temperature of up to 44°C [
      • Fajardo L.F.
      Pathological effects of hyperthermia in normal tissues.
      ]. Only nervous tissues appear more sensitive. For the central nervous tissue, irreversible damage was found after treatment at42–42.5°C for longer than 40–60 min [
      • Sminia P.
      • Van der Zee J.
      • Wondergem J.
      • Haveman J.
      Effect of hyperthermia on the central nervous system: a review.
      ]. 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 [
      • Wondergem J.
      • Haveman J.
      • Rusman V.
      • et al.
      Effects of local hyperthermia on the motor function of the rat sciatic nerve.
      ]. 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 [
      • Streffer C.
      • Seegenschmiedt M.H.
      • Fessenden P.
      • Vernon C.C.
      Thermoradiotherapy and Thermochemotherapy.
      ].

       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 [
      • Raaphorst G.P.
      • Field S.B.
      • Hand J.W.
      An Introduction to the Practical Aspects of Clinical Hyperthermia.
      ]. Hyperthermia may cause an increased blood flow, which may result in an improvement in tissue oxygenation, which then results in a temporally increased radiosensitivity [
      • Song C.W.M.
      • Shakil A.
      • Griffin R.J.
      • Okajima K.
      Improvement of tumor oxygenation status by mild temperature hyperthermia alone or in combination with carbogen.
      ]. 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 [
      • Kampinga H.H.
      • Dikomey E.
      Hyperthermic radiosensitization: mode of action and clinical relevance.
      ]. 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 [
      • Stewart F.A.
      • Denekamp J.
      The therapeutic advantage of combined heat and X-rays on a mouse fibrosarcoma.
      ,
      • Marino C.
      • Cividalli A.
      Combined radiation and hyperthermia: effects of the number of heat fractions and their interval on normal and tumour tissues.
      ]. 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 [
      • Horsman M.R.
      • Overgaard J.
      • Hyperthermia Interstitial
      Handl-Zeller L.
      ]. 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 [
      • Dahl O.
      Interaction of heat and drugs in vitro and in vivo.
      ]. For the combination of hyperthermia and chemotherapy, spatial cooperation can again explain the additive effects. Drug concentrationwill 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 [
      • Skibba J.L.
      • Jones F.E.
      • Condon R.E.
      Altered hepatic disposition of doxorubicin in the perfused rat liver at hyperthermic temperatures.
      ,
      • Ostrow S.
      • Van Echo D.
      • Egorin M.
      • et al.
      Cyclophosphamide pharmacokinetics in patients receiving whole-body hyperthermia.
      ,
      • Honess D.J.
      • Donaldson J.
      • Workman P.
      • Bleehen N.M.
      The effect of systemic hyperthermia on melphalan pharmocokinetics in mice.
      ].
      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 [
      • Skibba J.L.
      • Jones F.E.
      • Condon R.E.
      Altered hepatic disposition of doxorubicin in the perfused rat liver at hyperthermic temperatures.
      ]. 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.

       Local 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) [
      • Myerson R.J.
      • Moros E.
      • Roti Roti JL.
      • Perez C.A.
      • Brady L.W.
      Hyperthermia.
      ]. 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.
      Figure 1
      Figure 1Example of a clinical hyperthermia treatment set-up for a patient with recurrent breast cancer on the chest wall. Hyperthermia is applied using 433 MHz through four (custom-built) Lucite Cone waveguide applicators. The power output can be adjusted for each applicator separately. Optical fibre thermometry probes, which are not disturbed by electromagnetic radiation, are placed interstitially within catheters and on the skin. A perfused water bolus bag is placed between applicators and skin.
      Figure 2
      Figure 2Example of a patient during deep hyperthermia treatment in the BSD-2000 system (BSD Medical Corporation, Salt Lake City, UT). Eight radiating antennae are built-in in the wall of the cylinder-shaped applicator surrounding the pelvic area of the patient. The space between applicator and skin is filled with water in a bolus bag. Thermometry probes are placed interstitially and intraluminally within catheters, and on the skin. This system is placed in a room shielded from electromagnetic radiation.

       Regional hyperthermia

      Regional hyperthermia is applied by perfusion of a limb, organ or body cavity with heated fluids [
      • Coit D.G.
      Hyperthermic isolation limb perfusion for malignant melanoma: a review.
      ,
      • Ceelen W.P.
      • Hesse U.
      • De Hemptinne B.
      • Pattyn P.
      Hyperthermic intraperitoneal chemoperfusion in the treatment of locally advanced intra-abdominal cancer.
      ]. 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.

       Whole-body hyperthermia

      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 [
      • Robins H.I.
      on behalf of SHOWG members. Meeting report. Systemic Hyperthermia Oncological Working Group.
      ,
      • Robins H.I.
      • Dennis W.H.
      • Neville A.J.
      • et al.
      A nontoxic system for 41.8°C whole-body hyperthermia: results of a phase I study using a radiant heat device.
      ]. 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 [
      • Bull J.C.M.
      Clinical practice of whole-body hyperthermia: new directions.
      ].

      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 [
      • Cavaliere R.
      • Ciocatto E.C.
      • Giovanella B.C.
      • et al.
      Selective heat sensitivity of cancer cells. Biochemical and clinical studies.
      ], whole-body hyperthermia in patients for whom no standard treatments were available [
      • Pettigrew R.T.
      • Galt J.M.
      • Ludgate C.M.
      • Smith A.N.
      Clinical effects of whole-body hyperthermia in advanced malignancy.
      ] or hyperthermia combined with low doses of radiotherapy [
      • Kim J.H.
      • Hahn E.W.
      • Tokita N.
      • Nisce L.Z.
      Local tumor hyperthermia in combination with radiation therapy. 1. Malignant cutaneous lesions.
      ,
      • González González D.
      • Van Dijk J.D.P.
      • Blank L.E.C.M.
      • Rümke P.H.
      Combined treatment with radiation and hyperthermia in metastatic malignant melanoma.
      ]. 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% [
      • Hetzel F.W.
      • Mattiello J.
      • Paliwal B.R.
      • Hetzel F.W.
      • Dewhirst M.W.
      Medical Physics Monograph no. 16. Biological, Physical and Clinical Aspects of Hyperthermia.
      ]. Three additional studies report complete response rates of 11%, 16% and 18% [
      • Manning M.R.
      • Cetas T.C.
      • Miller R.C.
      • et al.
      Clinical hyperthermia: results of a phase I trial employing hyperthermia alone or in combination with external beam or interstitial radiotherapy.
      ,
      • Dunlop P.R.C.
      • Hand J.W.
      • Dickinson R.J.
      • Field S.B.
      An assessment of local hyperthermia in clinical practice.
      ,
      • Gabriele P.
      • Orecchia R.
      • Ragona R.
      • et al.
      Hyperthermia alone in the treatment of recurrences of malignant tumors.
      ]. A drawback of the use of hyperthermia alone is that in general the duration of response is short, with a median of only6 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% [
      • Van der Zee J.
      • Treurniet-Donker A.D.
      The SK et al. Low dose reirradiation in combination with hyperthermia: a palliative treatment for patients with breast cancer recurring in previously irradiated areas.
      ]. 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 [
      • Overgaard J.
      The current and potential role of hyperthermia in radiotherapy.
      ,
      • Van der Zee J.
      • Vernon C.C.
      Thermoradiotherapy for advanced and recurrent breast tumours.
      ]. 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 [
      • Van der Zee J.
      • Van der Holt B.
      • Rietveld P.J.M.
      • et al.
      Reirradiation combined with hyperthermia in recurrent breast cancer results in a worthwhile local palliation.
      ].
      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 [
      • Rietbroek R.C.
      • Schilthuis M.S.
      • Bakker P.J.M.
      • et al.
      Phase II trial of weekly locoregional hyperthermia and cisplatin in patients with a previously irradiated recurrent carcinoma of the uterine cervix.
      ,
      • De Wit R.
      • Van der Zee J.
      • Van der Burg M.E.L.
      • et al.
      A phase I/II study of combined weekly systemic cisplatin and locoregional hyperthermia in patients with previously irradiated recurrent carcinoma of the uterine cervix.
      ], 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 [
      • Issels R.D.
      • Abdel-Rahman S.
      • Wendtner C.-M.
      • et al.
      Neoadjuvant chemotherapy combined with regional hyperthermia (RHT) for locally advanced primary or recurrent high-risk adult soft-tissue sarcomas (STS) of adults long-term results of a phase II study.
      ,
      • Wendtner C.-M.
      • Abdel-Rahman S.
      • Baumert J.
      • et al.
      Treatment of primary, recurrent or inadequately resected high-risk soft-tissue sarcomas (STS) of adults: results of a phase II pilot study (RHT-95) of neoadjuvant chemotherapy combined with regional hyperthermia.
      ]. Another study [
      • Westermann A.M.
      • Grosen E.A.
      • Katschinski D.M.
      • et al.
      A pilot study of whole body hyperthermia and carboplatin in platinum-resistant ovarian cancer.
      ] 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 [
      • Wiedemann G.J.
      • Robins H.I.
      • Gutsche S.
      • et al.
      Ifosfamide, carboplatin and etoposid (ICE) combined with 41.8°C whole body hyperthermia in patients with refractory sarcoma.
      ].
      The experience with hyperthermia in children is limited, although both regional and whole-body hyperthermia appear feasible [
      • Van Heek R.
      • D’Oleire F.
      • Havers W.
      • Seegenschmiedt M.H.
      • Fessenden P.
      • Vernon C.C.
      Thermoradiotherapy and Thermochemotherapy.
      ]. 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 [
      • Wessalowski R.
      • Ruck H.
      • Pape H.
      • et al.
      Hyperthermia for the treatment of patients with malignant germ cell tumors. A phase I/II study in ten children and adolescents with recurrent or refractory tumors.
      ].

      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 [
      • Perez C.A.
      • Gillespie B.
      • Pajak T.
      • et al.
      Quality assurance problems in clinical hyperthermia and their impact on therapeutic outcome: a report by the Radiation Therapy Oncology Group.
      ,
      • Perez C.A.
      • Pajak T.
      • Emami B.
      • et al.
      Randomized phase III study comparing irradiation and hyperthermia with irradiation alone in superficial measurable tumors. Final report by the Radiation Therapy Oncology Group.
      ,
      • Emami B.
      • Scott C.
      • Perez C.A.
      • et al.
      Phase III study of interstitial thermoradiotherapy compared with interstitial radiotherapy alone in the treatment of recurrent or persistent human tumors: a prospectively controlled randomized study by the Radiation Therapy Oncology Group.
      ]. 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 [
      • Valdagni R.
      • Amichetti M.
      • Pani G.
      Radical radiation alone versus radical radiation plus microwave hyperthermia for N3 (TNM-UICC) neck nodes: a prospective randomized clinical trial.
      ,
      • Valdagni R.
      • Amichetti M.
      Report of long-term follow-up in a randomized trial comparing radiation therapy and radiation therapy plus hyperthermia to metastatic lymphnodes in stage IV head and neck patients.
      ], and on malignant melanoma [
      • Overgaard J.
      • González González D.
      • Hulshof M.C.C.M.
      • et al.
      Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma.
      ], breast cancer [
      • Vernon C.C.
      • Hand J.W.
      • Field S.B.
      • et al.
      Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials.
      ], glioblastoma multiforme [
      • Sneed P.K.
      • Stauffer P.R.
      • McDermott W.
      • et al.
      Survival benefit of hyperthermia in a prospective randomized trial of brachytherapy boost ± hyperthermia for glioblastoma multiforme.
      ] and pelvic tumours [
      • Van der Zee J.
      • González González D.
      • Van Rhoon G.C.
      • et al.
      for the Dutch Deep Hyperthermia Group. Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial.
      ], which were performed in Europe and North America. Patients with cervical lymph nodes were randomised to radiotherapy to a total dose of64–70 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% [
      • Valdagni R.
      • Amichetti M.
      • Pani G.
      Radical radiation alone versus radical radiation plus microwave hyperthermia for N3 (TNM-UICC) neck nodes: a prospective randomized clinical trial.
      ,
      • Valdagni R.
      • Amichetti M.
      Report of long-term follow-up in a randomized trial comparing radiation therapy and radiation therapy plus hyperthermia to metastatic lymphnodes in stage IV head and neck patients.
      ]. 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% [
      • Overgaard J.
      • González González D.
      • Hulshof M.C.C.M.
      • et al.
      Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma.
      ]. 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 the3 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% [
      • Vernon C.C.
      • Hand J.W.
      • Field S.B.
      • et al.
      Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials.
      ]. 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 [
      • Sneed P.K.
      • Stauffer P.R.
      • McDermott W.
      • et al.
      Survival benefit of hyperthermia in a prospective randomized trial of brachytherapy boost ± hyperthermia for glioblastoma multiforme.
      ]. 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% [
      • Van der Zee J.
      • González González D.
      • Van Rhoon G.C.
      • et al.
      for the Dutch Deep Hyperthermia Group. Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial.
      ].
      Table 1Summary of randomised trials showing significantly better results following a combination of radiotherapy (RT), chemotherapy (CT) or RT plus CT with hyperthermia (HT), compared with the same treatment without HT
      Ref no.TumourTreatmentPatients(lesions)End pointEffect withHTEffect withoutHT
      [
      • Valdagni R.
      • Amichetti M.
      • Pani G.
      Radical radiation alone versus radical radiation plus microwave hyperthermia for N3 (TNM-UICC) neck nodes: a prospective randomized clinical trial.
      ,
      • Valdagni R.
      • Amichetti M.
      Report of long-term follow-up in a randomized trial comparing radiation therapy and radiation therapy plus hyperthermia to metastatic lymphnodes in stage IV head and neck patients.
      ]
      Lymphnodes of head and neck tumoursRT41 [44]CR rate83%41%
      5-year local control69%24%
      5-year survival53%0%
      [
      • Overgaard J.
      • González González D.
      • Hulshof M.C.C.M.
      • et al.
      Randomised trial of hyperthermia as adjuvant to radiotherapy for recurrent or metastatic malignant melanoma.
      ]
      MelanomaRT70 (138)CR rate62%35%
      2-year local control46%28%
      [
      • Vernon C.C.
      • Hand J.W.
      • Field S.B.
      • et al.
      Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials.
      ]
      BreastRT306CR rate59%41%
      [
      • Sneed P.K.
      • Stauffer P.R.
      • McDermott W.
      • et al.
      Survival benefit of hyperthermia in a prospective randomized trial of brachytherapy boost ± hyperthermia for glioblastoma multiforme.
      ]
      Glioblastoma multiformeSurgery, RT68Median survival85 weeks76 weeks
      2-year survival31%15%
      [
      • Van der Zee J.
      • González González D.
      • Van Rhoon G.C.
      • et al.
      for the Dutch Deep Hyperthermia Group. Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial.
      ]
      Bladder, cervix and rectumRT298CR rate55%39%
      3-year survival30%24%
      [
      • Berdow B.A.
      • Menteshashvili G.Z.
      Thermoradiotherapy of patient with locally advanced carcinoma of the rectum.
      ]
      RectumRT, surgery1155-year survival36%7%
      [
      • Colombo R.
      • Da Pozzo L.F.
      • Gev A.
      • et al.
      Neoadjuvant combined microwave induced local hyperthermia and topical chemotherapy versus chemotherapy alone for superficial bladder cancer.
      ]
      BladderCT52pCR66%22%
      [
      • Datta N.R.
      • Bose A.K.
      • Kapoor H.K.
      Thermoradiotherapy in the management of carcinoma cervix (stage IIIb): a controlled clinical study.
      ]
      CervixRT64CR55%31%
      [
      • Egawa S.
      • Tsukiyama I.
      • Watanabe S.
      • et al.
      A randomized clinical trial of hyperthermia and radiation versus radiation alone for superficially located cancers.
      ]
      VariousRT92Response82%63%
      [
      • Engelhardt R.
      • Neumann H.
      • Sugahara T.
      • Saito M.
      • Müller U.
      • Löhr G.W.
      Hyperthermic Oncology.
      ]
      LungCT44Response68%36%
      [
      • Harima Y.
      • Nagata K.
      • Harima K.
      • et al.
      A randomized clinical trial of radiation therapy versus thermoradiotherapy in stage IIIb cervical carcinoma.
      ]
      CervixRT40CR85%50%
      [
      • Kakehi M.
      • Ueda K.
      • Mukojima T.
      • et al.
      Multi-institutional clinical studies on hyperthermia combined with radiotherapy or chemotherapy in advanced cancer of deep-seated organs.
      ]
      RectumRT14Response100%20%
      [
      • Kitamura K.
      • Kuwano H.
      • Watanabe M.
      • et al.
      Prospective randomized study of hyperthermia combined with chemoradiotherapy for esophageal carcinoma.
      ]
      OesophagusRT, CT66CR25%6%
      [
      • Kohno I.
      • Kaneshige E.
      • Fujiwara K.
      • Sekiba K.
      • Overgaard J.
      Hyperthermic Oncology.
      ]
      Vulva/vaginaCT65Response59%19%
      [
      • Strotsky A.V.
      • Fradkin S.Z.
      • Zhavrid E.A.
      • Karpovich U.A.
      Combined therapy of bladder cancer with the use of hyperthermia.
      ]
      BladderRT, surgery1023-year survival94%67%
      [
      • Sugimachi K.
      • Kitamura K.
      • Baba K.
      • et al.
      Hyperthermia combined with chemotherapy and irradiation for patients with carcinoma of the oesophagus: a prospective randomized trial.
      ]
      OesophagusRT, CT, surgery53Palliation70%8%
      [
      • Wang J.
      • Li D.
      • Chen N.
      Intracavitary microwave hyperthermia combined with external irradiation in the treatment of esophageal cancer.
      ]
      OesophagusRT1253-year survival42%24%
      [
      • You Q.-S.
      • Wang R.-Z.
      • Suen G.-Q.
      • et al.
      Combination preoperative radiation and endocavitary hyperthermia for rectal cancer: long-term results of 44 patients.
      ]
      RectumRT, surgery122pCR23%5%
      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) [
      • Berdow B.A.
      • Menteshashvili G.Z.
      Thermoradiotherapy of patient with locally advanced carcinoma of the rectum.
      ,
      • Colombo R.
      • Da Pozzo L.F.
      • Gev A.
      • et al.
      Neoadjuvant combined microwave induced local hyperthermia and topical chemotherapy versus chemotherapy alone for superficial bladder cancer.
      ,
      • Datta N.R.
      • Bose A.K.
      • Kapoor H.K.
      Thermoradiotherapy in the management of carcinoma cervix (stage IIIb): a controlled clinical study.
      ,
      • Egawa S.
      • Tsukiyama I.
      • Watanabe S.
      • et al.
      A randomized clinical trial of hyperthermia and radiation versus radiation alone for superficially located cancers.
      ,
      • Engelhardt R.
      • Neumann H.
      • Sugahara T.
      • Saito M.
      • Müller U.
      • Löhr G.W.
      Hyperthermic Oncology.
      ,
      • Harima Y.
      • Nagata K.
      • Harima K.
      • et al.
      A randomized clinical trial of radiation therapy versus thermoradiotherapy in stage IIIb cervical carcinoma.
      ,
      • Kakehi M.
      • Ueda K.
      • Mukojima T.
      • et al.
      Multi-institutional clinical studies on hyperthermia combined with radiotherapy or chemotherapy in advanced cancer of deep-seated organs.
      ,
      • Kitamura K.
      • Kuwano H.
      • Watanabe M.
      • et al.
      Prospective randomized study of hyperthermia combined with chemoradiotherapy for esophageal carcinoma.
      ,
      • Kohno I.
      • Kaneshige E.
      • Fujiwara K.
      • Sekiba K.
      • Overgaard J.
      Hyperthermic Oncology.
      ,
      • Strotsky A.V.
      • Fradkin S.Z.
      • Zhavrid E.A.
      • Karpovich U.A.
      Combined therapy of bladder cancer with the use of hyperthermia.
      ,
      • Sugimachi K.
      • Kitamura K.
      • Baba K.
      • et al.
      Hyperthermia combined with chemotherapy and irradiation for patients with carcinoma of the oesophagus: a prospective randomized trial.
      ,
      • Wang J.
      • Li D.
      • Chen N.
      Intracavitary microwave hyperthermia combined with external irradiation in the treatment of esophageal cancer.
      ,
      • You Q.-S.
      • Wang R.-Z.
      • Suen G.-Q.
      • et al.
      Combination preoperative radiation and endocavitary hyperthermia for rectal cancer: long-term results of 44 patients.
      ,
      • Datta N.R.
      • Bose A.K.
      • Kapoor H.K.
      • Gupta S.
      Head and neck cancers: results of thermoradiotherapy versus radiotherapy.
      ,
      • Marmor J.B.
      • Hahn G.M.
      Combined radiation and hyperthermia in superficial human tumors.
      ,
      • Sharma S.
      • Patel F.D.
      • Sandhu A.P.S.
      • et al.
      A prospective randomized study of local hyperthermia as a supplement and radiosensitizer in the treatment of carcinoma of the cervix with radiotherapy.
      ,
      • Shchepotin I.B.
      • Evans S.R.T.
      • Chorny V.
      • et al.
      Intensive preoperative radiotherapy with local hyperthermia for the treatment of gastric carcinoma.
      ,
      • Sugimachi K.
      • Kuwano H.
      • Ide H.
      • et al.
      Chemotherapy combined with or without hyperthermia for patients with oesophageal carcinoma: a prospective randomized trial.
      ]. 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.
      Table 2Summary of randomised trials showing no significant differences between results from treatment with the combination of radiotherapy (RT), chemotherapy (CT), or RT plus CT with hyperthermia (HT), and those of the same treatment without HT
      Ref no.TumourTreatmentPatients (lesions)End pointEffect withHT (%)Effect withoutHT (%)
      [
      • Perez C.A.
      • Gillespie B.
      • Pajak T.
      • et al.
      Quality assurance problems in clinical hyperthermia and their impact on therapeutic outcome: a report by the Radiation Therapy Oncology Group.
      ,
      • Perez C.A.
      • Pajak T.
      • Emami B.
      • et al.
      Randomized phase III study comparing irradiation and hyperthermia with irradiation alone in superficial measurable tumors. Final report by the Radiation Therapy Oncology Group.
      ]
      VariousRT145CR3230
      [
      • Emami B.
      • Scott C.
      • Perez C.A.
      • et al.
      Phase III study of interstitial thermoradiotherapy compared with interstitial radiotherapy alone in the treatment of recurrent or persistent human tumors: a prospectively controlled randomized study by the Radiation Therapy Oncology Group.
      ]
      VariousRT1732-year survival3629
      [
      • Datta N.R.
      • Bose A.K.
      • Kapoor H.K.
      • Gupta S.
      Head and neck cancers: results of thermoradiotherapy versus radiotherapy.
      ]
      Head and neckRT65CR7458
      [
      • Marmor J.B.
      • Hahn G.M.
      Combined radiation and hyperthermia in superficial human tumors.
      ]
      VariousRT15 (30 matched lesions)Better response477
      [
      • Overgaard J.
      The current and potential role of hyperthermia in radiotherapy.
      ]
      BreastRT, surgery5075-year survival7367
      [
      • Sharma S.
      • Patel F.D.
      • Sandhu A.P.S.
      • et al.
      A prospective randomized study of local hyperthermia as a supplement and radiosensitizer in the treatment of carcinoma of the cervix with radiotherapy.
      ]
      CervixRT5018 months local control7050
      [
      • Shchepotin I.B.
      • Evans S.R.T.
      • Chorny V.
      • et al.
      Intensive preoperative radiotherapy with local hyperthermia for the treatment of gastric carcinoma.
      ]
      StomachRT, surgery1935-year survival5145
      [
      • Sugimachi K.
      • Kuwano H.
      • Ide H.
      • et al.
      Chemotherapy combined with or without hyperthermia for patients with oesophageal carcinoma: a prospective randomized trial.
      ]
      OesophagusCT40pCR4119

      Toxicity

      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 [
      • Fajardo L.F.
      Pathological effects of hyperthermia in normal tissues.
      ]. 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 [
      • Van der Zee J.
      • Van der Holt B.
      • Rietveld P.J.M.
      • et al.
      Reirradiation combined with hyperthermia in recurrent breast cancer results in a worthwhile local palliation.
      ,
      • Vernon C.C.
      • Hand J.W.
      • Field S.B.
      • et al.
      Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials.
      ,
      • Lee H.K.
      • Antell A.G.
      • Perez C.A.
      • et al.
      Superficial hyperthermia and irradiation for recurrent breast carcinoma of the chest wall: prognostic factors in 196 tumors.
      ], 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%) [
      • Van der Zee J.
      • González González D.
      • Van Rhoon G.C.
      • et al.
      for the Dutch Deep Hyperthermia Group. Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial.
      ,
      • Hiraoka M.
      • Jo S.
      • Akuta K.
      • et al.
      Radiofrequency capacitive hyperthermia for deep-seated tumors II. Effect of thermoradiotherapy.
      ,
      • Lee C.K.
      • Song C.W.
      • Rhee J.G.
      • et al.
      Clinical experience using 8 MHz radiofrequency capacitive hyperthermia in combination with radiotherapy: results of a phase I/II study.
      ,
      • Wust P.
      • Stahl H.
      • Löffel J.
      • et al.
      Clinical, physiological and anatomical determinants for radiofrequency hyperthermia.
      ]. 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 [
      • Bull J.C.M.
      Clinical practice of whole-body hyperthermia: new directions.
      ]. 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 [
      • Cavaliere R.
      • Di Filippo F.
      • Cavaliere F.
      • Seegenschmiedt M.H.
      • Fessenden P.
      • Vernon C.C.
      • et al.
      Thermoradiotherapy and Thermochemotherapy.
      ]. During any application of hyperthermia it is important to avoid pressure sites, since hypoxic normal tissues will be more sensitive to hyperthermia.

      Economic aspects

      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 [
      • Van der Zee J.
      • González González D.
      The Dutch Deep Hyperthermia Trial: results in cervical cancer.
      ].

      Further developments

       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 [
      • Wust P.
      • Fahling H.
      • Helzel T.
      • et al.
      Design and test of a new multi-amplifier system with phase and amplitude control.
      ,
      • Van Rhoon G.C.
      • Rietveld P.C.M.
      • Van der Zee J.
      A 433 MHz Lucite Cone waveguide applicator for superficial hyperthermia.
      ,
      • Rietveld P.J.M.
      • Van Putten W.L.J.
      • Van der Zee J.
      • Van Rhoon G.C.
      Comparison of the clinical effectiveness of the 433 MHz Lucite Cone applicator with that of a conventional waveguide applicator in applications of superficial hyperthermia.
      ]. A new method for interstitial hyperthermia is to inject a fluid containing magnetic nanoparticles intratumourally, and than to apply alternating current magnetic fields [
      • Jordan A.
      • Scholz R.
      • Maier-Hauff K.
      • et al.
      Presentation of a new magnetic field therapy system for the treatment of human solid tumors with magnetic fluid hyperthermia.
      ]. Hyperthermia treatment planning systems have been developed [
      • Wust P.
      • Seebass M.
      • Nadobny J.
      • et al.
      Simulation studies promote technological development of radiofrequency phased array hyperthermia.
      ,
      • Lagendijk J.J.W.
      Hyperthermia treatment planning.
      ] and are now clinically verified [
      • Gellermann J.
      • Wust P.
      • Stalling D.
      • et al.
      Clinical evaluation and verification of the hyperthermia treatment planning system Hyperplan.
      ]. 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 [
      • Carter D.L.
      • MacFall J.R.
      • Clegg S.T.
      • et al.
      Magnetic resonance thermometry during hyperthermia for human high-grade sarcoma.
      ,
      • Hentschel M.
      • Dreher W.
      • Wust P.
      • et al.
      Fast spectroscopic imaging for non-invasive thermometry using the Pr[MOE-DO3A] complex.
      ]. 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 [
      • Yatvin M.B.
      • Mühlensiepen H.
      • Porschen W.
      • et al.
      Selective delivery of liposome-associated cis-Dichlorodiammineplatinum(II) by heat and its influence on tumor drug uptake and growth.
      ] 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 [
      • Matteucci M.L.
      • Anyarambhatla G.
      • Rosner G.
      • et al.
      Hyperthermia increases accumulation of Technetium-99M-labeled liposomes in feline sarcomas.
      ]. 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 [
      • Kong G.
      • Anyarambhatla G.
      • Petros W.P.
      • et al.
      Efficacy of liposomes and hyperthermia in a human tumor xenograft model: importance of triggered drug release.
      ].

       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 [
      • Multhoff G.
      • Botzler C.
      • Wiesnet M.
      • et al.
      A stress-indcible 72-kDa heat-shock protein (HSP72) is expressed on the surface of human tumor cells, but not on normal cells.
      ,
      • Multhoff G.
      • Botzler C.
      • Wiesnet M.
      • et al.
      CD-3 large granular lymphocytes recognize a heat-inducible immunogenic determinant associated with the 72-kD heat shock protein on human sarcoma cells.
      ]. HSPs are released following necrotic cell death, and released HSPs stimulate macrophages and dendritic cells to secrete cytokines, and activate antigen-presenting cells [
      • Basu S.
      • Binder R.J.
      • Suto R.
      • et al.
      Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-κB pathway.
      ]. 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 [
      • Ito A.
      • Shinkai M.
      • Honda H.
      • et al.
      Augmentation of MHC class I antigen presentation via heat shock protein expression by hyperthermia.
      ]. 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 [
      • Van der Zee J.
      • González González D.
      The Dutch Deep Hyperthermia Trial: results in cervical cancer.
      ].

       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 [
      • Gerner E.W.
      • Hersh E.M.
      • Pennington M.
      • et al.
      Heat-inducible vectors for use in gene therapy.
      ,
      • Huang Q.
      • Hu J.K.
      • Lohr F.
      • et al.
      Heat-induced gene expression as a novel targeted cancer gene therapy strategy.
      ,
      • Okamota K.
      • Shinoura N.
      • Egawa N.
      • et al.
      Adnovirus-mediated transfer of p53 augments hyperthermia-induced apoptosis in U251 glioma cells.
      ]. 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 [
      • Lohr F.
      • Hu K.
      • Huang Q.
      • et al.
      Enhancement of radiotherapy by hyperthermia-regulated gene therapy.
      ].

       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 [
      • Benowitz S.
      Bone marrow experts are still debating the value of purging.
      ]. Murine and human leukemic bone marrow-derived stem cells have been shown to be much more sensitive than their normal counterparts [
      • Moriyama Y.
      • Narita M.
      • Sato K.
      • et al.
      Application of hyperthermia to the treatment of human acute leukemia: purging human leukemic progenitor cells by heat.
      ,
      • Iwasawa T.
      • Hirabayashi Y.
      • Kubota N.
      • et al.
      Hyperthermic purging in vitro of murine leukemia cells (MK-8057): surviving fractions of normal and leukemic stem cells and the long-term survival of mice injected with the post-hyperthermic leukemia cells.
      ,
      • Osman Y.
      • Moriyama Y.
      • Shibata A.
      Enhanced elimination of Ph+ chormosome cells in vitro by combined hyperthermia and other drugs (AZT, IFN-α, TNF, and quercetin): its application to autologous bone marrow transplantation for CML.
      ]. The addition of drugs that protect the normal cells can enhance further the therapeutic index to values of >5000 [
      • Wierenga P.K.
      • Setroikromo R.
      • Vellenga E.
      • Kampinga H.H.
      Purging of acute myeloid leukaemia cells from stem cell grafts by hyperthermia: enhancement of the therapeutic index by the tetrapeptide AcSDKP and the alkyl-lysophospholipid ET-18-OCH[3.
      ]. 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 [
      • Griffin R.J.
      • Ogawa A.
      • Song C.W.
      A novel drug to reduce tumor perfusion: antitumor effect alone and with hyperthermia.
      ,
      • Horsman M.R.
      • Murata R.
      • Overgaard J.
      Improving local tumor control by combining vascular targeting drugs, mild hyperthermia and radiation.
      ,
      • Eikesdal H.P.
      • Bjerkvig R.
      • Dahl O.
      Vinblastine and hyperthermia target the neovasculature in BT4AN rat gliomas: therapeutic implications of the vascular phenotype.
      ,
      • Eikesdal H.P.
      • Bjerkvig R.
      • Mella O.
      • Dahl O.
      Combrestatin A-4 and hyperthermia; a potent combination for the treatment of solid tumors.
      ].

       Trimodality treatment

      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 [
      • Kai H.
      • Matsufuji H.
      • Okudaira Y.
      • Sugimachi K.
      Heat, drugs and radiation given in combination is palliative for unresectable esophageal cancer.
      ], and in the meantime have demonstrated the value of additional hyperthermia in patients with oesophageal cancer [
      • Kitamura K.
      • Kuwano H.
      • Watanabe M.
      • et al.
      Prospective randomized study of hyperthermia combined with chemoradiotherapy for esophageal carcinoma.
      ,
      • Sugimachi K.
      • Kitamura K.
      • Baba K.
      • et al.
      Hyperthermia combined with chemotherapy and irradiation for patients with carcinoma of the oesophagus: a prospective randomized trial.
      ]. 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 [
      • Ohno S.
      • Tomoda M.
      • Tomisaki S.
      • et al.
      Improved surgical results after combining preoperative hyperthermia with chemotherapy and radiotherapy for patients with carcinoma of the rectum.
      ,
      • Rau B.
      • Wust P.
      • Hohenberger P.
      • et al.
      Preoperative hyperthermia combined with radiochemotherapy in locally advanced rectal cancer.
      ,
      • Anscher M.S.
      • Lee C.
      • Hurwitz H.
      • et al.
      A pilot study of preoperative continuous infusion 5-fluorouracil, external microwave hyperthermia, and external beam radiotherapy for treatment of locally advanced, unresectable, or recurrent rectal cancer.
      ,
      • Serin M.
      • Erkal H.S.
      • Cakmak A.
      Radiation therapy, cisplatin and hyperthermia in combination in management of patients with carcinomas of the head and neck with N2 or N3 metastatic cervical lymph nodes.
      ,
      • Feyerabend T.
      • Wiedemann G.J.
      • Jäger B.
      • et al.
      Local hyperthermia, radiation, and chemotherapy in recurrent breast cancer is feasible and effective except for inflammatory disease.
      ].

      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. [
      • Perez C.A.
      • Gillespie B.
      • Pajak T.
      • et al.
      Quality assurance problems in clinical hyperthermia and their impact on therapeutic outcome: a report by the Radiation Therapy Oncology Group.
      ,
      • Perez C.A.
      • Pajak T.
      • Emami B.
      • et al.
      Randomized phase III study comparing irradiation and hyperthermia with irradiation alone in superficial measurable tumors. Final report by the Radiation Therapy Oncology Group.
      ], 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 [
      • Van der Zee J.
      • Van der Holt B.
      • Rietveld P.J.M.
      • et al.
      Reirradiation combined with hyperthermia in recurrent breast cancer results in a worthwhile local palliation.
      ]. A further study [
      • Lee H.K.
      • Antell A.G.
      • Perez C.A.
      • et al.
      Superficial hyperthermia and irradiation for recurrent breast carcinoma of the chest wall: prognostic factors in 196 tumors.
      ] 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 [
      • Hahn GM.
      • Urano M.
      • Douple E.
      Introduction.
      ]. 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.

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