This special issue of the International Journal of Hyperthermia represents the proceedings of the first ESHO educational symposium on hyperthermia entitled ‘Rationale, indications and translational research’, which was held on 8 June 2005 in Graz, Austria in conjunction with the 22nd Annual Meeting of the European Society of Hyperthermic Oncology (8–11 June 2005), sponsored by ESHO, EMBO and under the auspices of EORTC.
I was motivated to organize this symposium by noticing that many scientists and clinicians coming from different societies and fields still dispute the efficacy and indications for hyperthermia. This is in spite of the fact that we are currently witnessing exciting results in the field of clinical hyperthermia with the involvement of ESHO, STM and EORTC in the implementation of clinical trials. This shows the need to spread the current knowledge on the biological rationale of hyperthermia, its clinical application and indications, to involve more basic researchers and encourage extensive translational research programmes. The multi-disciplinary approach was an important hallmark of this educational symposium.
As a result, this special issue contains 10 articles that cover these various aspects of science related to hyperthermia and is, therefore, designed to meet the needs of scientists coming from different backgrounds.
The first learning objectives were to explain the biological rationale for hyperthermia and compare the benefit of combination of hyperthermia with radiation and/or chemotherapy. Kampinga provides an extensive overview of the last 20 years research on the field of radio- and chemosensitization focusing on the molecular mechanisms of heat-induced damage. He presents compelling evidence that protein damage and consequently protein denaturation and aggregation are the main molecular events underlying the biological effects of hyperthermia in a clinically relevant temperature range (39–45°C). Mechanisms of thermal radiosensitization are due to hyperthermic effects on DNA repair, in particular alteration in the higher order of chromatin organization by nuclear protein aggregation, increasing radiation-induced chromosomal aberration. The major effect is by inhibiting the repolymerization step in the repair of radiation-induced base damage resulting in the formation of secondary toxic DNA double strand breaks. Also, chemosensitization is due to protein damage involved in drug-induced DNA adducts and as well as in drug exclusion and detoxification.
Hyperthermia treatment is known to dramatically influence tumour perfusion and this is utilised to improve drug delivery. More insight into tumour physiology and the response to heat is discussed by Horsman from the effects on the blood flow and tumour oxygenation, vascular permeability and angiogenesis to the bioenergetic and metabolic status. He points out that the most important physiological parameter influencing tissue response to heat is blood flow which is typically transiently increased during heat. If the thermal damage is sufficient, this is followed by vascular collapse and tumour necrosis. High temperatures decrease blood flow and could be used to trap chemotherapeutic drugs in tumours. There is also a decrease in tumour pH and this is known to increase the sensitivity of certain drugs. Mild temperatures increase tumour perfusion and, therefore, also drug delivery.
A major result of the collaboration between basic researchers interested in hyperthermia and clinicians is the implementation of translational research projects and studies. This topic was an important target of this meeting and three contributions in this issue cover disparate approaches of using hyperthermia to improve the efficacy of novel therapeutic strategies. In particular, Ponce, from the group of Dewhirst, provides a newest update on the hyperthermia dependent delivery of liposomal therapeutic agents and the composition of thermosensitive liposomes. She provides evidence that hyperthermia mediated liposomal drug delivery may be an effective means to achieving increased tumour drug concentration and greater clinical response to chemotherapy. Li proposes a novel approach to increase gene delivery to radiosensitize tumours using heat-activated gene-radiotherapy with adenovirus-mediated heat-inducible gene expression. Finally, in the contribution of Parmiani, the mechanisms of induction of a specific anti-tumour immune response of the heat shock protein, gp96, are elucidated. A review of the long experience on the largest clinical trials using gp96 as a cancer vaccine are presented, discussing pros and cons of this immunotherapeutic approach.
Further learning goals were to assess the limitations and complications of hyperthermia and explain the clinical trial evidence supporting the efficacy of combined hyperthermia.
Here, Van der Zee (hyperthermia Dutch study group) was invited to give a critical summary of her study published in Lancet in 2000 and of five further randomized trials on addition of hyperthermia to radiation, showing benefits for thermoradiotherapy vs. radiotherapy alone in terms of therapeutic gain and costs were in cervical tumours.
Clinical evidence of efficacy and positive interaction between hyperthermia and chemotherapeutic agents either applied systemically or in a loco-regional setting is discussed in review articles by Issels and Eggermont. An update on the ongoing phase III randomized clinical trial on high-risk soft tissue sarcomas, investigating the combination of regional hyperthermia with systemic chemotherapy, is provided by Issels. He explains the clinical rationale and clinical setting for this category of patients and makes a detailed analysis of risk stratification. A further approach to increase benefit by enhanced delivery of chemotherapeutic of tumour cells is the use of locoregional treatment methods such as isolated perfusion therapy. Eggermont summarizes the mechanisms of action of vasoactive agents such as TNF, IL2 and histamine and their role together with variation in temperature in changing the pathophysiology of tumour in drug delivery during limb and liver perfusion.
Jones provides evidence that prospectively defined and delivered thermal dose, quantified as CEM43°CT90 derived from intra-tumoural temperature measurements, is related to clinical outcome in canine and in human tumours. This work stresses the importance of accurate thermometry, which is highlighted and summarized in the last contribution of this issue from Wust. By analysing several studies to evaluate thermometry methods he concludes that invasive measurements can be replaced by minimally invasive or non-invasive techniques. These methods provide equivalent or, in the case of non-invasive thermometry, even more complete information. Magnetic resonance-temperature distributions in the target region are better correlated with response than parameters provided by invasive thermometry. These last two articles emphasize that efforts to refine three dimensional thermal dose distributions with non-invasive MR based thermometry may optimize the clinical applications of hyperthermia.
A final round table discussion lead to a number of conclusions, which are currently major topics of research: (i) the p53 status of tumours is highly relevant to the outcome/success of clinical hyperthermia (contribution of Zylicz at the symposium); (ii) the fundamental insights in the cell biology of the heat shock response are relevant to the success of clinical hyperthermia; (iii) hyperthermia influences the pathophysiology of tumour and improves drug delivery; (iv) Hsp-based vaccines should be combined with current hyperthermia techniques; and (v) Online monitoring of treatment temperatures is essential to get hyperthermia accepted in the field of oncology.
As the primary goal of this symposium was educational, this issue provides an updated overview on some of the most important achievements on hyperthermia and is thought to be used to spread this knowledge to scientists not directly involved in this field. The audience of this first ESHO educational symposium was quite heterogeneous; represented by oncologists and basic researchers, such as biochemists and immunologists, followed by physicists and radiation oncologists. This constellation reflects multi-discliplinary scope of hyperthermia which is required for the optimal multi-modal treatment of tumour-bearing patients with this modality.