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European Journal of Nuclear and Molecular Imaging (2019) 46:1588–1590 https://doi.org/10.1007/s00259-019-04334-3

LETTER TO THE EDITOR

Call to arms: need for radiobiology in molecular therapy

Samantha Y. A. Terry1 & Julie Nonnekens2,3 & An Aerts4 & Sarah Baatout4 & Marion de Jong2 & Bart Cornelissen5 & Jean-Pierre Pouget6,7,8,9

Received: 4 April 2019 /Accepted: 10 April 2019 /Published online: 8 May 2019 # Springer-Verlag GmbH Germany, part of Springer Nature 2019

Dear Sir, vector, radionuclide, combinations, and patient selection. Now is an extraordinarily exciting time for the multidisci- The frequent ambiguity in predicting treatment outcome and plinary field of molecular radionuclide therapy (MRT) [1–3]. inflexibility in altering set treatment regimens could lead to More patients than ever before are being treated with recurrence and avoidable treatment-related side effects radiolabelled compounds, and an increasing number of phar- that worsen quality of life. For example, it is becoming in- maceutical companies incorporate into creasingly clear that some patients are being overtreated their portfolios. (resulting in high levels of toxicity), while some may be MRT allows specific irradiation of localised and dissemi- undertreated (no tumour regression) [1, 3]. In the NETTER I nated disease, with potentially fewer side effects than external trial, for instance, although most of the patients showed stable beam radiotherapy (EBRT). However, aside from obvious im- disease, very few complete responses were observed [1]. provements in radiochemistry, radiopharmacy, and Delivering a sufficient dose is necessary, but this of MRT agents, a better understanding of the radiobiology, i.e. dose parameter alone may not always best predict treatment of the biological effects of ionising radiation of MRTagents, is efficacy and toxicity [4]. More specifically, a multiparametric needed. approach has to be considered in order to propose Radiobiology has been key in establishing optimal treat- personalised treatments [5]. ment regimens for EBRT whilst protecting healthy tissues. It is now understood that extrapolation of the radiobiology The paradigm of radiobiology is that tumour control probabil- of EBRT to MRT is not straightforward, not only because of ity and side effects are proportional to absorbed radiation differences in dose-rate effects, which would give cells more dose; radiobiology is thus deeply connected with dosimetry. time to repair lesions, but also because of activation of differ- However, breakthroughs in EBRT effectiveness also required ent molecular and cellular signalling pathways inducing dif- an understanding of concepts that purely fall under ferent biological responses [6]. As an MRT radiobiological radiobiology. community, we therefore propose to further deepen our under- Radiobiology of MRT is necessary to devise an optimised standing for each therapeutic of the fol- approach of use with regard to activity, therapy interval, lowing topics:

Julie Nonnekens and An Aerts contributed equally to this work.

* Samantha Y. A. Terry 4 Radiobiology Unit, Interdisciplinary Biosciences, Institute for [email protected] Environment, Health and Safety, SCK•CEN, Belgian Nuclear Research Centre, Mol, Belgium 5 1 Department of Imaging Chemistry and Biology, School of CRUK/MRC Oxford Institute for Radiation Oncology, Department Biomedical Engineering & Imaging Sciences, King’sCollege of Oncology, University of Oxford, Old Road Campus Research London, 4th floor Lambeth Wing, St Thomas’ Hospital, London SE1 Building, Off Roosevelt Drive, Oxford OX3 7LJ, UK 7EH, UK 6 IRCM, Institut de Recherche en Cancérologie de Montpellier, F-34298 Montpellier, France 2 Department of and , Erasmus MC, 7 INSERM U1194, F-34298 Montpellier, France Rotterdam, Netherlands 8 Université de Montpellier, F-34298 Montpellier, France 3 Department of , Erasmus MC, 9 Institut régional du de Montpellier, Rotterdam, Netherlands F-34298 Montpellier, France Eur J Nucl Med Mol Imaging (2019) 46:1588–1590 1589

Topic 1: Investigate the consequences of physical common practice, and several recent (preclinical) studies parameters on the tumour and normal tissue response. have shown that MRT effects can be similarly amplified This includes the role of absorbed radiation dose as- [10]. sessment as a prerequisite for establishing tumour con- Topic 6: Determine effects of MRT on healthy tissues, trol and normal tissue complication probability dose– both in the short and long term. Radiopharmaceuticals effect curves, just as they exist for EBRT. Dose assess- accumulate not only in tumour cells, but also in healthy ment on the tissue and (sub)cellular scale is essential tissues via normal physiological excretion routes and/or for determining the role of dose rate, dose fraction- receptor expression on healthy cells. For example, the ation, and dose distribution [7]. This challenge covers majority of radiopharmaceuticals are cleared from the a hugely valuable field, which requires optimisation body by the kidneys, and radiolabelled prostate-specific and standardisation, especially in of the recent membrane antigen (PSMA)-targeting agents accumulate EU directive (European Council Directive 2013/59 not only in prostate cancer cells but also in salivary and Euratom [7, 8]). lacrimal glands. Topic 2: Determine the role of radiopharmaceutical and target distribution at both the subcellular and tissue level. This includes determining target expression using imaging, (micro-) autoradiography, and other techniques, which is a prerequisite for estimating radiotherapy effica- Our plan of action cy and toxicity. Non-uniformity of the may lead to increased damage within these subcompartments, We think that a better understanding of the radiobiology of resulting in organ failure. Tissue and subcellular distribu- MRT is needed to optimise existing and new MRT strategies tion of the radiopharmaceuticals also affects the choice of to their maximal clinical potential, efficacious in tumour cure vector (e.g. internalising or not), as well as the subcellular whilst simultaneously safe for normal organs. While this in- target (e.g. nucleus, cell membrane, mitochondria) and cludes optimisation of target and vector choice, radiochemis- radionuclide (e.g. short or long particle/ range, try, and dosimetry physics, we aim to expand the field of high or low linear energy transfer [LET]). radiobiology of MRT and form a large collaborative group Topic 3: Determine the role of the tumour microenvi- to ensure clinical impact sooner rather than later. Now is the ronment and systemic reactions during MRT. As for time to set up national initiatives and create a solid network EBRT, bystander effects and systemic effects involving that connects these at an international level. Hence, this call to the immune system (both innate and acquired) may con- arms. tribute to MRT effectiveness. Bystander effects include So, calling all researchers in radiobiology and MRT, if you intercellular communication between targeted tumour are interested in helping to establish a tight community with cells (including cancer stem cells) and neighbouring cells the aim of increasing the input of radiobiology in existing and including other tumour cells, cancer-associated fibro- new MRT, we invite you to join our working group (www. blasts, and endothelial cells [9]. Those effects will lead mrtradiobiology.com), which will foster radiobiology- to modifications in extracellular matrix structure and in oriented research in MRT by launching new funded research perfusion, with consequences on vector distribution and programs, organising symposia together with educational oxygen levels. training. Topic 4: Identify biomarkers of therapy response. Partners for whom this would be interesting include Every patient is unique, and tumour characteristics will radiobiologists, medical physicists, radiochemists, vary between patients, but also between different meta- radiopharmacists, nuclear medicine clinicians, radiation static sites within one patient. Currently, every patient oncologists, technologists, referring clinicians, radiation receives the same MRT regimen based on their cancer protection advisors, radioactive waste advisors, societies type. To optimise treatment outcome, biomarkers should (European Association of Nuclear Medicine [EANM], be identified. These can be simple markers such as target- European Radiation Research Society [ERRS]), industry level expression or proliferation, or can be more specific partners, and funding bodies where radiobiology is markers such as anomalies in cellular pathways altering highlighted as a priority research area. the of the tumour or healthy tissues (e.g. To conclude, let us invest time, effort, and money into this DNA damage repair defects). very essential area of nuclear medicine research together. Topic 5: Determine optimal combination therapies,in particular, combinations of MRT with chemotherapy, im- Acknowledgements The authors would like to acknowledge Mark munotherapy, hormone therapy, or radiosensitisers. Konijnenberg, Emmanuel Deshayes, and Fijs van Leeuwen for their com- Combination of EBRT with a variety of these agents is ments during preparation of this letter. 1590 Eur J Nucl Med Mol Imaging (2019) 46:1588–1590

Compliance with ethical standards 5. Del Prete M, et al. Personalized 177Lu-octreotate peptide receptor radionuclide therapy of neuroendocrine tumours: initial results from the P-PRRT trial. Eur J Nucl Med Mol Imaging. 2019;46(3):728– Conflict of interest Author ST declares that she has no conflict of inter- 42. est. Author JN has an investigator-initiated project contract with Advanced Accelerator Applications, a Novartis company. Author AA 6. Pouget JP, et al. Introduction to radiobiology of targeted radionu- declares that she has no conflict of interest. Author SB declares that she clide therapy. Front Med. 2015;2:12. has no conflict of interest. Author MdJ has an investigator-initiated pro- 7. European Association of Nuclear Medicine ject contract with Advanced Accelerator Applications, a Novartis com- Task Force Report, Treatment planning for molecular radiotherapy: pany. Author BC is a paid consultant for Molecular Targeted potential and prospects. Flux G, Stokke C., editors. 2017. Radiopharmaceuticals. Author J-PP declares that he has no conflict of 8. European Council Directive. 2013/59/Euratom of 5 December interest. 2013 laying down basic safety standards for protections against the dangers arising from exposure to ionising radiation, and Ethical approval This article does not contain any studies with human repealing Directives 89/618/Euratom, 90/641/Euratom, 96/29/ participants or animals performed by any of the authors. Euratom, 97/43/Euratom and 2003/122/Euratom. Off J Eur Union. 2014. 9. Prise KM, O’Sullivan JM. Radiation-induced bystander signalling – References in cancer therapy. Nat Rev Cancer. 2009;9(5):351 60. 10. Nonnekens J, et al. Potentiation of peptide receptor radionuclide therapy by the PARP inhibitor olaparib. Theranostics. 2016;6(11): 1. Strosberg J, et al. Phase 3 trial of 177Lu-Dotatate for midgut neu- 1821–32. roendocrine tumors. N Engl J Med. 2017;376(2):125–35. 2. Parker C, et al. Alpha emitter -223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213–23. 3. Verheijen RH, et al. Phase III trial of intraperitoneal therapy with yttrium-90-labeled HMFG1 murine monoclonal antibody in pa- tients with epithelial ovarian cancer after a surgically defined com- Publisher’snoteSpringer Nature remains neutral with regard to jurisdic- plete remission. J Clin Oncol. 2006;24(4):571–8. tional claims in published maps and institutional affiliations. 4. Bodei L, et al. Long-term tolerability of PRRT in 807 patients with neuroendocrine tumours: the value and limitations of clinical fac- tors. Eur J Nucl Med Mol Imaging. 2015;42(1):5–19.