Roadmap for research on individual radiosensitivity and radiosusceptibility – the MELODI view on research needs

The aim of the European MELODI Association is to coordinate and promote research on effects and risks associated with low-dose and low-dose rate exposures to ionizing radiation low dose and low-dose rate exposures to ionizing radiation. This MELODI Special Issue on Radiosensitivity and Radiosusceptibility reviews the current knowledge on this topic and gives recommendations for future research. The review articles are based on presentations and discussions during the MELODI workshop on ‘Individual Radiosensitivity and Radiosusceptibility’ organized by MELODI together with the European Joint Program CONCERT in Saint Julians, Malta on 12–14 March 2018. Around 40 experts from more than 10 countries reviewed the present state of research, determined open scientific questions and discussed recommendations for future research on variations in individual radiation sensitivity (i.e. tissue reactions induced by ionizing radiation, IR) and radiation susceptibility (i.e. cancer risk from IR). The workshop covered three topics: (1) Clinical and epidemiological observations, (2) Mechanisms involved in individual radiation response, and (3) Tests for individual radiosensitivity/susceptibility to identify sensitive and susceptible subgroups both for cancer and non-cancer diseases. The objective was to provide input for the European roadmap for research in these areas, summarizing the research needs, required resources anticipated and the expected timespan for studies that could be expected to yield considerable progress in this area. Furthermore, the ethical issues related to the use of such information were thoroughly discussed, along with potential impact on the system of radiation protection.

There has been a recent recommendation to define and distinguish radiosensitivity and radiosusceptibility (Foray et al. 2016; Foray and Bourguignon 2019). Here, we follow this proposal and define radiosensitivity as any enhanced tissue or cell reaction following exposure to IR compared to that of most individuals, classified as normal responding individuals. The above classification is based largely on tissue reactions, which include inflammation and fibrosis. IR-induced heart disease, cognitive decline and cataracts are additional well-reported consequences of IR with reference to radiosensitivity (Averbeck et al. 2018). We use the term radiosusceptibility in relation to increased stochastic effects in some subpopulations compared to the average risk in the general population, of which some IR-induced cancers are an important example. Radiosusceptible individuals, therefore, represent those with an elevated risk of IR-induced cancer. Although these terms distinguish events arising after distinct doses and with different kinetics, and thus likely represent mechanistically distinct processes, there is likely to be an overlap since some exposures and outcomes (such as cataracts or heart disease) do not neatly fall into one or other category. Although this terminology clearly has limitations (Wojcik et al. 2018), we use it here as a useful, current working terminology.

The first paper (Seibold et al. 2019) provides an overview on clinical and epidemiological observations on radiation sensitivity and susceptibility in studies after exposures in radiotherapy, diagnostic procedures, environmental and occupational settings. Studies reporting criteria for defining radiosensitivity were reviewed, and the occurrence of variations in radiosensitivity and radiosusceptibility as well as influencing factors were evaluated. In addition, the clinical relevance and consequences of individual differences in radiosensitivity were explored. An important part for future studies will be the identification of suitable cohorts and biobanks for these research questions and to illustrate methodological considerations such as statistical power.

The second paper (Averbeck et al. 2019) considers mechanisms of radiosensitivity and radiosusceptibility, with special focus on the genetic predisposition. The IR-induced DNA damage response has been well characterized. Patients with mutations in these response pathways have been identified and display a marked radiosensitivity but they represent only a small percentage of the radiotherapy (RT) patients with adverse reactions. The authors review the impacting mechanisms and additional factors influencing radiosensitivity/-susceptibility and discuss possible genetic backgrounds for either or both. As a recommendation, the authors propose that a prospective study should be established to assess the genetic background for radiosensitivity and secondary cancers following radiotherapy. The study should include detailed information on tumor pathology and site as well as encompass a well-defined grading system. Predictive assays should be independently validated. Detailed analysis of the inflammatory, stress and immune responses, mitochondrial function and life style factors should be included. Existing cohorts should also be optimally exploited.

The third paper (Gomolka et al. 2019) provides an overview on potential screening assays for predictive detection of individuals with an increased potential for moderate to severe early and late radiation reaction or with an increased risk to develop cancer upon radiation exposure. They conclude that it is necessary to separate clearly between tissue reactions and stochastic effects such as cancer when comparing the existing literature to validate various test systems. Requirements for the assays were set up and the literature was reviewed for assays that are reliable and robust. Sensitivity and specificity of the assays are regarded and scrutinized for modifying factors. The accuracy of an assay system required to demonstrate a well balance risks of adverse reactions against risk to fail to cure the cancer should be more than 90%. No such assay/biomarker is currently in routine use. Assays that have shown predictive potential for radiosensitivity include SNPs, the RILA assay and the phosphor ATM assay. A tree of risk guideline for radiooncologists is provided to assist medical treatment decisions. Recommendations for effective research include the setup of common retrospective and prospective cohorts/biobanks to validate current and future tests.

It was recognized by MELODI that there are several ethical questions related to the identification of sensitive or susceptible individuals and the potential use of this information, as discussed in detail by Kalman and Oughton (2019). The International Commission on Radiological Protection (ICRP) recently published a document (Cho et al. 2018). In addition to providing a historical evaluation of the system of protection and the implicit ethical values addressed during its evolution, the publication also highlights the ethical dimension of radiation protection. It proposes four core ethical values underpinning the ICRP system: Beneficence/Non-maleficence, Dignity, Justice and Prudence. These values are, in turn, shared with other well-established medical and public health ethical principles and will be opened up along with examples from medical, occupational and emergency contexts.

The fields of individual radiosensitivity relating to radiotherapy patients, and radiosusceptibility from both medical and occupational ionizing radiation exposures to patients and workers require detailed ethical evaluation, and evidence of compliance with ethical principles, both at the basic research level, and in relation to the development and eventual implementation of systems of protection and regulatory controls. While testing for radiosensitivity and radiosusceptibility has the potential to improve patient treatment and diagnosis, or protect workers, application of the assays raises several ethical and legal challenges. These go beyond the simple question of whether the assay will ‘do more good than harm’ to include, for example, questions about how the costs and benefits might be distributed in society, concerns about privacy and data protection and considerations of the potential for discrimination. Some of these challenges are specific to the type of assay, for example whether the assays were applied for radiosensitivity (i.e. radiotherapy or interventional radiology induced acute or late reactions) or radiosusceptibility (i.e. enhanced primary cancer risk in connection with radiodiagnosis such as CT scans or mammography or for secondary cancers after radiotherapy) (Seibold et al. 2019). Other challenges, such as worker radio-susceptibility, are like those for other types of occupational exposures (e.g. sensitivity to chemical or physical stress).

MELODI developed several recommendations for the way forward in research on radiosensitivity and radiosusceptibility. An important part for the future studies is identifying existing suitable cohorts and biobanks for research questions and illustrate methodological considerations such as statistical power. Well-defined grading system and exposure assessment are essential for any studies on radiosensitivity. Patients with mutations in the DNA damage response pathway display marked radiosensitivity but they represent only a small percentage of the RT patients with adverse reactions. This means that a single assay may not be enough but rather a combination of assays is needed to identify all radiosensitive individuals. Other factors that still need to be validated include inflammatory, stress and immune responses, mitochondrial function and life style factors. For effective research, it is necessary to set up common retrospective and prospective cohorts/biobanks to validate current and future tests. As for the resources required and timespan needed a roadmap is currently being developed by MELODI, from which in addition some general conclusions on feasibility can be drawn. The retrospective studies often have limitations like the lack of biosamples or limitations in dosimetry or diagnostics. Prospective studies, on the other hand, can avoid many of these problems, but it easily takes 2–3 years first to recruit the cohort, collect biosamples, carry out initial biomarker analyses and record early responses, up to 5–7 years to follow up for delayed responses and several decades to find out the health outcome for cancer or the very late non-cancer outcomes such as vascular diseases. The lower the doses, the larger cohorts are needed. Studies looking for susceptibility to cancer take a longer time span than studies looking for radiosensitivity in the clinical context. Well-planned collaborative prospective studies addressing normal tissue responses after moderate doses thus appears to be the most feasible approach for the next years to come.

MELODI wishes to acknowledge the European Joint Program CONCERT (H2020 Euratom grant number 662287) that supported the organization of the MELODI workshop. CONCERT and IJRB jointly sponsored full open access to the articles in this MELODI Special Issue. We hope that this Special Issue will be useful both to scientists and clinicians, as well as for the planning for national and international research programs on low dose risk.

Disclosure statement

No potential conflict of interest was reported by the authors.