Anti-Tumour Treatment Drug radiotherapy combinations: Review of previous failures and reasons for future optimism Geoff S. Higgins a,b,⇑ , Sean M. O’Cathail b , Ruth J. Muschel a , W. Gillies McKenna a,b a Cancer Research UK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, Department of Oncology, University of Oxford, Oxford, UK b Oxford University Hospitals NHS Trust, Department of Oncology, Churchill Hospital, Oxford, UK article info Article history: Received 10 August 2014 Received in revised form 22 December 2014 Accepted 29 December 2014 Available online xxxx Keywords: Radiosensitisation Tumour hypoxia Chemo-radiotherapy Drug-radiotherapy combinations abstract Combining chemotherapy with radiotherapy has resulted in significant clinical improvements in many different tumour types. However, the non-specific mechanisms by which these drugs exert their effects mean that this is often at the expense of increased side effects. Previous attempts at using targeted drugs to induce more tumour specific radiosensitisation have been generally disappointing. Although cetux- imab, an EGFR monoclonal antibody, resulted in improved overall survival in HNSCC when combined with radiotherapy, it has failed to show benefit when added to chemo-radiotherapy. In addition, our inability to successfully use drug treatments to reverse tumour hypoxia is underlined by the fact that no such treatment is currently in widespread clinical use. The reasons for these failures include the lack of robust biomarkers, and the previous use of drugs with unacceptable side-effect profiles. Despite these disappointments, there is reason for optimism. Our improved understanding of key signal transduction pathways and of tumour specific DNA repair deficiencies has produced new opportunities to specifically radiosensitise tumours. Novel strategies to reduce tumour hypoxia include the use of drugs that cause vascular normalisation and drugs that reduce tumour oxygen consumption. These new strategies, combined with better compounds at our disposal, and an ability to learn from our previous mistakes, mean that there is great promise for future drug-radiotherapy combinations to result in significant clinical benefits. Ó 2014 Elsevier Ltd. All rights reserved. Introduction Radiotherapy (RT) plays a key role in the management of 40% of patients who are cured of cancer [1]. Technical advances in radio- therapy such as image guided radiotherapy (IGRT), and intensity modulated radiotherapy (IMRT) have enabled the delivery of more accurate treatment to tumours whilst sparing radiation dose to healthy, normal tissues [2]. Despite these improvements, radio- therapy treatment often fails to provide local tumour control, and delivering higher doses of radiation alone is unlikely to solve this problem. The greatest potential to increase the effectiveness of radiother- apy lies in combining it with drugs that render tumours more sensitive to radiation, either by molecularly targeting tumour cells directly or by modifying the tumour microenviroment in order to ‘open’ the therapeutic window (Fig. 1). However, previous attempts in this area have met with more failures than successes. This article explores the reasons for these failures, what can be learnt to avoid repeating them, and why there is cause for signifi- cant optimism in the future. Tumour resistance to radiotherapy can be broadly classified as either intrinsic or extrinsic. Intrinsic radioresistance reflects genetic or epigenetic changes that alter the capacity of tumour cells to repair DNA damage and/or avoid mitotic cell death that typically results from cell irradiation [3]. Extrinsic radioresistance occurs due to abnormalities in the tumour microenvironment, par- ticularly tumour hypoxia, which markedly reduces the efficacy of radiotherapy [4]. Previous attempts at altering intrinsic radiosensitivity Arguably the biggest change in radiation oncology practice over the last 20 years has been the evolution of chemo-radiotherapy, which reduces intrinsic radioresistance of tumour cells. Combining radiotherapy with conventional chemotherapies such as cisplatin, 5-FU and temozolomide has resulted in significant clinical improvements in many different tumour types including brain, http://dx.doi.org/10.1016/j.ctrv.2014.12.012 0305-7372/Ó 2014 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Cancer Research UK/MRC Oxford Institute for Radiation Oncology, Gray Laboratories, Department of Oncology, University of Oxford, Oxford, UK. Tel.: +44 1865 617355; fax: +44 1865 617318. E-mail address: geoffrey.higgins@oncology.ox.ac.uk (G.S. Higgins). Cancer Treatment Reviews xxx (2015) xxx–xxx Contents lists available at ScienceDirect Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv Please cite this article in press as: Higgins GS et al. Drug radiotherapy combinations: Review of previous failures and reasons for future optimism. Cancer Treat Rev (2015), http://dx.doi.org/10.1016/j.ctrv.2014.12.012