Sub theme 3.4
Hyperthermia: a treatment for cancer

Goals of research: general outline
Scientific achievements
Future plans: special goals and approach
Running projects
Associated staff

Goals of research: general outline

Hyperthermia (HT), i.e. heating tissue to 39 - 44 C for 60 to 90 minutes, has a clear role in the treatment of locally or regionally advanced and locally recurrent diseases for which standard of care is unsatisfactory. Hyperthermia results in a cascade of effects, which all augment tumor response to radiotherapy (RT) and chemotherapy (CT). It does this by acutely changing the tumor microenvironment - alterations in perfusion, oxygenation and immunological stimulation. Additional known effects are: inhibition of radiation-induced damage repair, enhancing drug uptake and reversing drug resistance. More recently, hyperthermia has also demonstrated its potential to target drug delivery when used in combination with temperature sensitive liposome drug-carriers. A unique feature of hyperthermia is that normal tissue tolerates a hyperthermic treatment of 1 hour up to 44 C without relevant clinical damage. In summary, hyperthermia is not a stand alone treatment but is a powerful adjuvant that makes standard therapies work better.

All the above makes hyperthermia an ideal complementary treatment to both radiotherapy and chemotherapy and it should be an integral part of a multimodal, oncological strategy. Its efficacy to improve clinical outcome of radiotherapy and chemotherapy has been demonstrated in multiple randomized phase III trials. At present, HT is part of standard therapy for several tumor pathologies in the Netherlands (locally advanced cervical cancer, recurrent breast cancer in earlier irradiated areas, lymph-node metastasis in head and neck cancer, large melanoma). In fact hyperthermia is always indicated in the treatment of recurrent disease in earlier irradiated areas.

The goal of the hyperthermia research program is to establish hyperthermia in combination with radiotherapy or chemotherapy as a high quality cancer therapy, to address diseases where standard of care for local-regional therapy is of limited effectiveness or in instances where local failure following definitive treatment compromises quality of life.

Scientific achievements

The group is internationally recognized for its participation in the coordination clinical trials. Currently we are coordinating a multi-center phase III study on combined radiotherapy and hyperthermia versus combined radiotherapy and cisplatin for the treatment of cervical cancer Figo stage IB-IIA ( 4 cm) and IIB-IVA. Further the group took the initiative and had a guiding position with regard to the recognition of hyperthermia as regular health care within the frame of the Dutch National Health Service. In 2009 these efforts culminated in the admittance of hyperthermia within the Dutch system of reimbursement (DBC-structure).

Concerning the research in hyperthermia physics the group holds an international leading position regarding the development and implementation of technical procedure for quality assurance and the translation of these procedures during the clinical application of hyperthermia. As recognition for these activities the group has been presented three awards for best physics papers published in the international journal of Hyperthermia and has been given the ESHO-BSD award as well.

Besides the positive phase III trials the most appealing results of the research program of the group are

The demonstration of a thermal-dose effect relationship, which amplifies the need for prospective assessment and control of the quality of the hyperthermia treatment delivered.

The translation of hyperthermia treatment planning from the computer monitor towards an on-line tool to optimize the quality of the energy/temperature distribution during the hyperthermia treatment.

The development of the HyperCollar for heating head and neck tumors.

Future plans: special goals and approach

A strong focus of the research program is on the assessment of critical parameters for the application of 3-dimensional treatment planning on-line during loco-regional deep and superficial heating. In direct association to this objective we also invest in research aiming at (quantitative) validation of our treatment planning models for each individual applicator, including the development of new, accurate QA tools and procedures. A new highly compelling part of our research is the development of the controlled delivery of targeted hyperthermia. The result of this research carries a great potential of benefit for the patient as it will enable to focus the sensitizing effects of hyperthermia even more specific at the tumor.

Combined the research of the hyperthermia group and that performed in the Laboratory Experimental Surgical Oncology (LECO) on temperature sensitive liposomes as well as the research within the Molecular Radiation Biology group on how hyperthermia affects DNA repair holds great promises for the future for making cancer treatment highly tumor specific.

Most recent publications
  1. Franckena M, Fatehi D, de Bruijne M, Canters RAM, van Norden Y, Mens JW, van Rhoon GC and van der Zee J. Hyperthermia dose-effect relationship in 420 patients with cervical cancer treated with combined radiotherapy and hyperthermia European J. of Cancer, 2009, epub
  2. Wal E van der, Franckena M, Wielheesen DH, van der Zee J, van Rhoon GC. Steering in locoregional deep hyperthermia: evaluation of common practice with 3D-planning. Int J Hyperthermia. 2008 Dec;24(8):682-93.
  3. Canters RA, Franckena M, van der Zee J, Van Rhoon GC. Complaint-adaptive power density optimization as a tool for HTP-guided steering in deep hyperthermia treatment of pelvic tumors. Phys Med Biol. 2008 Dec 7;53(23):6799-820
  4. Van der Zee J, Kleynen CE, Nuyttens JJ, Ansink AC. Hyperthermia to improve results in vaginal cancer. Radiother Oncol. 2008 Aug;88(2):286-7. Epub 2008 Mar 4. No abstract available.
  5. Franckena M, Stalpers LJ, Koper PC, Wiggenraad RG, Hoogenraad WJ, van Dijk JD, Wrlm-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. 2008 Mar 15;70(4):1176-82.
  6. de Bruijne M, Wielheesen DH, van der Zee J, Chavannes N, van Rhoon GC. Benefits of superficial hyperthermia treatment planning: Five case studies. Int J Hyperthermia. 2007 Aug;23(5):417-29.
  7. Paulides MM, Bakker JF,Van Rhoon GC Electromagnetic Head-and-neck hyperthermia applicator:experimental phantom verification and fdtd model, Int J.Radiation Oncology.Biol. Phys., Vol 68,no.2, 612-620,2007.
  8. Van Rhoon, van der Heuvel DJ, Ameziane A, Rietveld PJM, Volenec K, van der Zee J. Characterization of the SAR-distribution of the Sigma-60 applicator for regional hyperthermia using a Schottky diode sheet. Int J Hyperthermia 2003 Nov-Dec;19(6):642-654.
  9. Lee WM, Ameziane A, Van den Biggelaar MC, Rietveld M, Van Rhoon GC. Stability and accuracy of power and phase measurements of a VVM system designed for online quality control of the BSD-2000 (-3D) DHT system. Int. J. Hyperthermia 2003 Jan-Feb;19(1):74-88.
  10. Zee J van der, Gonzlez Gonzlez D, Rhoon GC van, Dijk JDP van, Putten WLJ van, Hart AAM, for the Dutch Deep Hyperthermia Group. Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial. Lancet. 2000; 355: 1119-1125.