The use of radiotherapy, surgery and chemotherapy in the curative treatment of cancer: results from the FORTY (Favourable Outcomes from RadioTherapY) project.

OBJECTIVES: Radiotherapy, surgery and chemotherapy play key roles in the curative treatment of cancer, alone and in combination. Quantifying their roles is essential for equipment provision and workforce planning. The estimate that 40% of cancer patients are cured by RT has been used extensively to inform and influence policy but is relatively old and warrants review. METHODS: Patient, tumour and treatment event data was obtained for the 5 year period from 2009 to 2013, allowing a further 5 years for survival outcomes to be known. We analysed patient-level data on utilisation of surgery, radiotherapy, and chemotherapy in cancer patients in England. Data were sourced from Public Health England, using National Cancer Registrations, the National Radiotherapy Dataset (RTDS) and the Systemic Anti-Cancer Therapy Dataset (SACT). All tumour sites (excluding C44) and ages were included. We analysed three cohorts: all patients [n = 1,029,569], patients who survived 5 years or more [n = 537,970] and patients who survived <5 years [n = 491,599]. RESULTS: Overall cancer-specific 5-year survival was 52%, and in those patients, surgery was the most common curative treatment, with 80% receiving surgery, alone or in combination; radiotherapy was delivered to 39% and chemotherapy to 29%; 45% received two and 13% all three modalities. CONCLUSIONS: The high proportion receiving multi-modality treatment emphasises the importance of integrated, resourced, multidisciplinary cancer care. Radiotherapy was delivered to almost 40% of patients who survived 5 years which underlines its importance in cancer management. ADVANCES IN KNOWLEDGE: The results are essential in planning cancer services. They also inform the public health narrative.

Mechanistic Modelling of Slow and Fast NHEJ DNA Repair Pathways Following Radiation for G0/G1 Normal Tissue Cells.

Mechanistic in silico models can provide insight into biological mechanisms and highlight uncertainties for experimental investigation. Radiation-induced double-strand breaks (DSBs) are known to be toxic lesions if not repaired correctly. Non-homologous end joining (NHEJ) is the major DSB-repair pathway available throughout the cell cycle and, recently, has been hypothesised to consist of a fast and slow component in G0/G1. The slow component has been shown to be resection-dependent, requiring the nuclease Artemis to function. However, the pathway is not yet fully understood. This study compares two hypothesised models, simulating the action of individual repair proteins on DSB ends in a step-by-step manner, enabling the modelling of both wild-type and protein-deficient cell systems. Performance is benchmarked against experimental data from 21 cell lines and 18 radiation qualities. A model where resection-dependent and independent pathways are entirely separated can only reproduce experimental repair kinetics with additional restraints on end motion and protein recruitment. However, a model where the pathways are entwined was found to effectively fit without needing additional mechanisms. It has been shown that DaMaRiS is a useful tool when analysing the connections between resection-dependent and independent NHEJ repair pathways and robustly matches with experimental results from several sources.

Heavy charged particle beam therapy and related new radiotherapy technologies: The clinical potential, physics and technical developments required to deliver benefit for patients with cancer.

In the UK, one in two people will develop cancer during their lifetimes and radiotherapy (RT) plays a key role in effective treatment. High energy proton beam therapy commenced in the UK National Health Service in 2018. Heavier charged particles have potential advantages over protons by delivering more dose in the Bragg peak, with a sharper penumbra, lower oxygen dependence and increased biological effectiveness. However, they also require more costly equipment including larger gantries to deliver the treatment. There are significant uncertainties in the modelling of relative biological effectiveness and the effects of the fragmentation tail which can deliver dose beyond the Bragg peak. These effects need to be carefully considered especially in relation to long-term outcomes.In 2019, a group of clinicians, clinical scientists, engineers, physical and life scientists from academia and industry, together with funding agency stakeholders, met to consider how the UK should address new technologies for RT, especially the use of heavier charged particles such as helium and carbon and new modes of delivery such as FLASH and spatially fractionated radiotherapy (SFRT).There was unanimous agreement that the UK should develop a facility for heavier charged particle therapy, perhaps constituting a new National Ion Research Centre to enable research using protons and heavier charged particles. Discussion followed on the scale and features, including which ions should be included, from protons through helium, boron, and lithium to carbon, and even oxygen. The consensus view was that any facility intended to treat patients must be located in a hospital setting while providing dedicated research space for physics, preclinical biology and clinical research with beam lines designed for both in vitro and in vivo research. The facility should to be able to investigate and deliver both ultra-high dose rate FLASH RT and SFRT (GRID, minibeams etc.). Discussion included a number of accelerator design options and whether gantries were required. Other potential collaborations might be exploited, including with space agencies, electronics and global communications industries and the nuclear industry.In preparation for clinical delivery, there may be opportunities to send patients overseas (for 12C or 4He ion therapy) using the model of the National Health Service (NHS) Proton Overseas Programme and to look at potential national clinical trials which include heavier ions, FLASH or SFRT. This could be accomplished under the auspices of NCRI CTRad (National Cancer Research Institute, Clinical and Translational Radiotherapy Research Working Group).The initiative should be a community approach, involving all interested parties with a vision that combines discovery science, a translational research capability and a clinical treatment facility. Barriers to the project and ways to overcome them were discussed. Finally, a set of different scenarios of features with different costs and timelines was constructed, with consideration given to the funding environment (prer-Covid-19) and need for cross-funder collaboration.