Erasmus MC : Facts hyperthermia

Introduction
There is a clear rationale for using hyperthermia in cancer treatment. Treatment at temperatures between 40 and 44°C is cytotoxic for cells in the parts of the tumour with an insufficient blood perfusion. Under such conditions radiotherapy is less effective, and systemically applied drugs will reach such areas in lower concentrations than in well perfused areas. Further, recent animal studies have shown that hyperthermia (42°C) blocks the repair of the radiation-induced damage to cells, i.e. DNA double strand-breaks. Overall, the addition of hyperthermia to radiotherapy or chemotherapy results in additive effects. Moreover, the effects of both radiotherapy and many drugs are enhanced at an increased temperature in all areas, resulting in supra-additive effects.

Techniques and technology
Hyperthermia can be applied by several methods. The most common method is to apply hyperthermia locally using electromagnetic energy (microwaves) to heat the tumours located at various part of the body. Excellent hyperthermia systems are available to heat tumours extending from the skin to a depth of 4 cm and for tumours situated deeper in the pelvic and intestinal region as well as in the head and neck area. At this moment, most advances are being made on improving heating technology, thermometry, the development of hyperthermia treatment planning models and, most recently, drug targeting using thermosensitive drug-carriers (liposomes). Finally, the understanding of the biological effects involved is growing, i.e. heat shock proteins, anti-cancer immune responses and the role of hyperthermia in gene therapy.

Clinical evidence
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 many randomized 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 melanoma1,2,3,4,5. 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. Importantly, when heat is combined with radiotherapy, radiation toxicity is not increased. Whether toxicity from chemotherapy is enhanced depends on sequence of the two modalities, and on which tissues are heated. Toxicity from hyperthermia alone cannot always be avoided, but is usually of limited clinical relevance.

Summary
Superficial hyperthermia
Five randomized trials, addressing the value of hyperthermia in the treatment of advanced primary or recurrent breast cancer, were analysed. The combined result of the five trials demonstrated the efficacy of hyperthermia as an adjunct to radiotherapy for treatment of recurrent breast cancer. The implication of this result is that hyperthermia has an important role in the clinical management of this disease.

Deep-hyperthermia
Twelve year follow-up of the Dutch Deep Hyperthermia trial 2. This trial showed a significant better response for the combination of radiation and heat compared to radiation alone and no increase in acute or late toxicity. This graph shows that after twelve years, the relations remains proving that hyperthermia is an effective addition to hyperthermia.

Dose-effect relation
Retrospective analysis of 431 patients that were treated for advanced cervical cancer were treated with standard radiotherapy plus up to five treatments of hyperthermia for 90 minutes.  The analysis revealed a strong thermal dose effect relation 6. The relation remained significant in multi-variate analysis adding to the strength of the relation. This figure further shows a 5% increase in probability of complete response when adding a hyperthermia treatment.

Impressions

movie DHT

movie DHTcervix

movie HH

Clinical hyperthermia in the Netherlands
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. At this moment in the Netherlands, evidence based hyperthermia is being applied by three clinics: AMC (Amsterdam), Institute Verbeeten (Tilburg) and Erasmus MC – Daniel den Hoed Cancer Center (Rotterdam).

References

• Van der Zee, J., González González, D., Van Rhoon, G.C., Van Dijk, J.D.P., Van Putten, W.L.J. and Hart, A.A.M. Prospective randomised multicentre trial comparing radiation alone to radiation plus hyperthermia in locally advanced pelvic tumours. The Lancet, (2000) April, 1119-1125.
• Franckena M, Stalpers LJ, Koper PC, Wiggenraad RG, Hoogenraad WJ, van Dijk JD, Wárlám-Rodenhuis CC, Jobsen JJ, van Rhoon GC, van der Zee J. Long-term improvement in treatment outcome after radiotherapy and hyperthermia in locoregionally advanced cervix cancer: an update of the Dutch Deep Hyperthermia Trial. Int J Radiat Oncol Biol Phys. 15 (2008) Mar, 1176-82.
• Vernon, C.C., Hand, J.W., Field, S.B., Machin, D., Whaley, J.B., Van der Zee, J., van Putten, W.L., Van Rhoon, G.C., van Dijk, J.D., González González, D., Liu, F.F., Goodman, P. and Sherar, M. Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials. Int J Radiat Oncol Biol Phys, 35 (1996) 731-744.
• Jones EL, Oleson JR, Prosnitz LR, Samulski TV, Vujaskovic Z, Yu D, Sanders LL, Dewhirst MW. Randomized trial of hyperthermia and radiation for superficial tumors. J Clin Oncol 23 (2005) 3079–85.
• Issels RD, Lindner LH, Verweij J, Wust P, Reichardt P, Schem BC, Abdel-Rahman S, Daugaard S, Salat C, Wendtner CM, Vujaskovic Z, Wessalowski R, Jauch KW, Dürr HR, Ploner F, Baur-Melnyk A, Mansmann U, Hiddemann W, Blay JY, Hohenberger P; European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group (EORTC-STBSG); European Society for Hyperthermic Oncology (ESHO). Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study. Lancet Oncol. 11 (2010) Jun, 561-70.
• Franckena M, Fatehi D, de Bruijne M, Canters RA, van Norden Y, Mens JW, van Rhoon GC, van der Zee J. Hyperthermia dose-effect relationship in 420 patients with cervical cancer treated with combined radiotherapy and hyperthermia. Eur J Cancer. 45 (2009) Jul, 1969-78.

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