Hyperthermia, i.e. thermal cancer therapy, is increasingly (re)gaining ground as a treatment option. Encouraging results from phase I, II, and III clinical trials and positive meta-analyses for common adult cancers support the position that hyperthermia in combination with radiotherapy and/or chemotherapy is indeed a promising alternative to either of these treatment approaches administered individually, as hyperthermia remains the most potent biological sensitiser. However, continuous progress at all levels is mandatory to expand our understanding of biological and physiological mechanisms even further, and breakthroughs are still needed both at the bench to develop improved hardware and treatment planning software, and at the bedside for improved design, implementation, and interpretation of clinical trials. Essential to achieving meaningful progress is an effective dialogue between the diverse members of the hyperthermia community and a mutual understanding of the strengths and limitations of all professionals – i.e. clinicians, physicists, engineers, and biologists – responsible for implementing hyperthermia in the clinical setting.
In Europe the European Society for Hyperthermic Oncology (ESHO) has been instrumental in building up a strong hyperthermia community, and various national initiatives (e.g. the formation of an active multi-centre and multi-disciplinary hyperthermia network group in Switzerland) and European initiatives (e.g. research networks COST EMF-MED, a European network for innovative uses of electromagnetic fields in biomedical applications, and COST RADIOMAG, a European network on multifunctional nanoparticles for magnetic hyperthermia and indirect radiation therapy) illustrate the commitment of the European hyperthermia research community to provide new and more effective treatment options to cancer patients. Since its establishment in 1987, the ESHO has strived to promote fundamental and applied research in all scientific areas related to the use of hyperthermia in cancer therapy, and to facilitate the integration and exchange of information pertinent to the study of the biological effects of heat in the treatment of cancer. Among its numerous commitments, ESHO has been (co-)organising conferences to facilitate the dialogue between the diverse members of the hyperthermia community.
ESHO 2015, the 30th ESHO annual meeting, held in June 2015 in Switzerland, was co-organised by Stephan Bodis of the Kantonsspital Aarau (KSA) and Niels Kuster of the IT’IS Foundation for Research on Information Technologies in Society (IT’IS), two important players in the hyperthermia community. As in previous years, the 2 days of plenary meeting held in Zurich were preceded by an educational day in the clinic, organised by KSA, and which included a visit to the VetSuisse facilities in Zurich. The Department of Radio-Oncology at VetSuisse in Zurich, led by Carla Rohrer-Bley, was the first European centre to perform radiation therapy in animals and has been performing animal hyperthermia treatments combined with radiotherapy since early 2015. In overall structure, the meeting revolved around three main topics – hyperthermia in the clinic, the biology of hyperthermia, and hyperthermia from a physics and engineering perspective, and targeted all members of the hyperthermia community, including veterinarians. As a European conference, most of the > 150 participants of ESHO 2015 had European affiliations, including Scandinavian and Turkish. Some ESHO members and key players in hyperthermic oncology, including the chief editor of this journal – Mark Dewhirst – joined from the USA and India, and this year’s invitations were also extended to clinical researchers from Russia and Korea who have collected especially exciting hyperthermia treatment data from patients with various types of cancer.
Among the various highlights of this anniversary edition of the ESHO annual meeting is this journal’s special issue, which consists of nine selected papers recapitulating recent achievements in hyperthermia cancer treatment, major progress in our understanding of the biology of hyperthermia, and future research directions.
In the first contribution, Dewhirst et al., summarise 40 years of research on hyperthermia biology to identify research future directions and priorities and present readers with a vision for the field. Specifically, by searching the Web of Science and cross-referencing search terms the authors home in on a limited subset of publications about the effect of hyperthermia on specific features of the tumour microenvironment and evaluate these studies to formulate new hypothesis and questions. This first paper is an important source of information and of inspiration for novel project ideas and an elegant introduction to subsequent papers. An additional quality is that it readily overcomes a slight disconnection between the oncology research community at large and the hyperthermia community by focusing on the concept of ‘tumour microenvironment’, which has been widely recognised as a cornerstone of tumorigenesis and is increasingly adopted in the context of hyperthermia. Dewhirst and co-authors tackle hyperthermia both alone and in combination with radio- and/or chemotherapy, and much of the discussion concentrates on biological mechanisms and how much still needs to be understood.
In the second contribution, Horsman concentrates specifically on thermoradiotherapy (i.e. the combination of hyperthermia and radiation therapy) and on how to improve its efficiency by disrupting specific features of tumour biology using additional ‘agents’ (including drugs and nanoparticles). In short, Horsman identifies specific cellular, microenvironmental, and vascular factors that are potential targets for improving thermoradiotherapy by means of what he calls ‘alternative approaches’ and offers a suite of well-founded arguments for why a better therapeutic response should be expected. This paper, however, is especially valuable for its discussion of the importance of normal tissue studies. Whereas synergetic effects are indeed appealing, they present no advantage if the increase in efficiency comes with a comparable increase in normal tissue damage. Hence the importance of Horsman’s take-home message that preclinical studies need to be performed in view of quantifying the absolute benefit associated with combining therapeutic approaches.
In Werthmöller et al. the combined effect of hyperthermia and radiotherapy on tumour immunity is discussed with an example at hand. Using both in vitro and in vivo experiments the authors conclude that hyperthermia in combination with radiotherapy has immune-stimulating potential that might result in anti-tumour immunity. Besides performing well-designed experiments in a very relevant study system, the authors offer a solid discussion of their results in view of both the specific mechanisms and actors involved in the immune response and the exposure protocols required to achieve clinically relevant results, and conclude with a number of pertinent research directions based on their findings.
Another piece of evidence in favour of thermoradiotherapy, as opposed to radiotherapy alone, is the contribution by Datta et al. on head and neck cancer treatment. Based on a systematic and stringent review of the literature and a meta-analysis of selected studies, the authors make a case for combined therapy by showing that it significantly increases the likelihood of complete response. Performing a meta-analysis on clinical trials spanning 27 years and using methodologies and treatment protocols that are not even fully standardised to date is not a trivial task. However, the strength of this paper resides not only in the meta-analysis per se but also in the meticulous discussion of the various factors likely to influence its overall outcomes as well as clinical outcomes, including patient selection, the definition of end points, the exposure hardware and protocols, and appropriate treatment planning.
Treatment planning for thermoradiotherapy is the topic of the next contribution by Crezee and colleagues. Crezee concludes that thermoradiotherapy planning is feasible (and a necessity) – and for good reasons, since a first tool to model the combined effects of hyperthermia and radiotherapy (accounting for inhibition of DNA damage repair) has been developed and implemented. Yet the bulk of the paper consists of a very informed and informative description of the known but often poorly quantified variables that contribute to a realistic patient-specific thermoradiotherapy treatment plan, a concise introduction to specific modelling paradigms currently applied in dose estimation, and an extensive section on future research and prospects. As in Datta et al., the length of the discussion is indicative of the amount of work that remains to be performed. However, as shown in subsequent contributions by von Rhoon and Winter et al. for instance, many of the key variables and concepts underlying the accurate modelling of radiosensitisation, including dose–effect relations, sequence and time intervals, and normal tissue thresholds, are maturing. Additionally, data, such as oxygenation status and tissue properties, and methods for real-time temperature monitoring, imaging and segmentation are also becoming available and will greatly contribute to improving the planning tools and accelerating their clinical adoption.
The concept of thermal dose discussed by von Rhoon has been a subject of controversy since the early days of hyperthermia and remains a topic of debate. The need for it is obvious but how to define it is less so, in particular in view of the complexity of the biological and physiological response to heat, the complex nature of cancer, and the importance of treatment history and protocol. Von Rhoon offers a comprehensive and well-documented review of the strengths and limitations of CEM43 (cumulative equivalent minutes at 43 °C) and does a remarkable job in summarising the biological, physiological, clinical, and technological knowledge that is available, needed and still missing to make an informed decision about the applicability of any dose parameter. This summary makes it very clear that progress in dosimetry, and hence in treatment planning and clinical outcomes, still requires breakthroughs in real-time temperature measurement, better designed clinical trials, and a better understanding of the spatio-temporal response of healthy and diseased tissues to heat and radiation. Yet, von Rhoon drives home an additional and equally important message, which is that progress in the definition of a robust thermal dose concept requires the input from and the collaboration of all professionals involved in hyperthermia cancer treatment.
Thermal dosimetry is about time and temperature. Whereas recoding time alone is quite straightforward, measuring temperature over time represents a challenge that Winter and colleagues have been tackling for many years and that they describe in the seventh contribution to this special edition. In a few well-formulated pages, Winter and co-authors summarise more than two decades of progress in magnetic resonance (MR) thermometry, providing practical considerations, describing the pitfalls and the technical challenges associated with achieving high measurement accuracy, elaborating on the concepts of spatial and temporal resolution notably in view of the choice of treatment hardware, and reviewing existing evidence in favour of a wider adoption of MR thermometry in the clinical workflow.
Another field in which very exciting progress has been achieved in recent years is that of nanoparticle-based hyperthermia, explored by Krishnan and co-authors in the eighth contribution. After providing a fascinating overview of the specific magnetic nanoparticles commonly used for hyperthermic cancer treatment, Krishnan et al. continue with the potential advantages of nanoparticle-based hyperthermia, as opposed to ‘traditional’ hyperthermia, before naturally concluding with the challenges associated with its wider adoption in the clinical workflow.
Last but not least is the contribution by Issels and co-authors on the future of regional hyperthermia as targeted therapy in the clinic. Issels et al., bring the readers somewhat back to square one by organising their discussion around the same hallmark as Dewhirst and co-authors in the first chapter. Yet Issels and his colleagues concentrate on clinical applications and illustrate with an example at hand how to best capitalise on the pleiotropic effects induced by hyperthermia to design clinical trials and achieve the best possible results. Last of nine, this contribution is a useful reminder that the ultimate goal is to successfully treat, and that any insight that can be gained into why and how hyperthermia works needs to be translated into improved hardware, software, and clinical practice.
As illustrated with this suite of fascinating papers, amazing progress has been achieved over the last 15–20 years in how much of the biology and physiology we understand, in what the physicists and engineers have achieved, and in how hyperthermia is delivered in the clinic. This is without mentioning recent achievements in hardware technologies for heat delivery and ongoing efforts towards in silico clinical trials, which is a concept that remains to be explored in hyperthermia and thermoradiotherapy. Yet the list of open questions remains long, and the hyperthermia community needs to grow and consolidate to maintain the formidable momentum gained over the last two decades. Additionally, with a view to improving visibility, evidence level, quality assurance, and fostering more international collaborations, there is a pressing need to conduct international multicentre phase III randomised trials on common tumours with adequate sample sizes, ultimately performing Environmental Health & Safety Office (Europ. Society of Hyperthermic Oncology)-endorsed studies. High level evidence data from such trials and examples of (published) meta-analysis will also contribute to the integration of oncologic hyperthermia combined with radio- and/or chemotherapy in national cancer treatment programmes and hopefully become eligible for systematic reimbursement.
Glossary
ESHO European Society for Hyperthermic Oncology. www.esho.info
ESHO 2015 Thirtieth annual meeting of the European Society for Hyperthermic Oncology. www.esho2015.org
COST European Cooperation on Science and Technology: means for European researchers, engineers and scholars to jointly develop their own ideas and new initiatives across all fields of science and technology through trans-European networking of nationally funded research activities. http://www.cost.eu/
COST EMF-MED European network for innovative uses of electromagnetic fields in biomedical applications: cooperative framework to support the research on beneficial biological effects of non-ionising electromagnetic fields and their use in biomedical applications. http://cost-emf-med.eu/
COST RADIOMAG European network on multifunctional nanoparticles for magnetic hyperthermia and indirect radiation therapy: the network aims to provide clinicians with the necessary input to trial a novel anti-cancer treatment combining magnetic hyperthermia and radiotherapy, also identifying future research objectives upon appraisal of the obtained results. http://www.cost.eu/COST_Actions/tdp/TD1402