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Background: Anal cancer is a rare cancer with rising incidence. Despite the relatively good outcomes conferred by state-of-the-art chemoradiotherapy, further improving disease control and reducing toxicity has proven challenging. Developing and validating prognostic models using routinely collected data may provide new insights for treatment development and selection. However, due to the rarity of the cancer, it can be difficult to obtain sufficient data, especially from single centres, to develop and validate robust models. Moreover, multi-centre model development is hampered by ethical barriers and data protection regulations that often limit accessibility to patient data. Distributed (or federated) learning allows models to be developed using data from multiple centres without any individual-level patient data leaving the originating centre, therefore preserving patient data privacy. This work builds on the proof-of-concept three-centre atomCAT1 study and describes the protocol for the multi-centre atomCAT2 study, which aims to develop and validate robust prognostic models for three clinically important outcomes in anal cancer following chemoradiotherapy. Methods: This is a retrospective multi-centre cohort study, investigating overall survival, locoregional control and freedom from distant metastasis after primary chemoradiotherapy for anal squamous cell carcinoma. Patient data will be extracted and organised at each participating radiotherapy centre (n = 18). Candidate prognostic factors have been identified through literature review and expert opinion. Summary statistics will be calculated and exchanged between centres prior to modelling. The primary analysis will involve developing and validating Cox proportional hazards models across centres for each outcome through distributed learning. Outcomes at specific timepoints of interest and factor effect estimates will be reported, allowing for outcome prediction for future patients. Discussion: The atomCAT2 study

Intensity-modulated radiotherapy (IMRT) for gynaecological malignancies aims to reduce toxicity and improve tumour control. However, there are several barriers to its uptake in clinical practice. Amongst these are that of pelvic organ motion, whereby due to motion of the target organs on treatment there is a risk of geographical miss with IMRT. Secondly, although new IMRT techniques may improve bowel toxicity there is limited knowledge about dose-volume constraints for bowel, making it difficult to assess whether new techniques are likely to translate into clinical improvements. The purpose of this thesis is to address these problems. Methods Dose-volume constraints for late bowel toxicity are investigated initially through systematic review, followed by a dose-volume study based on toxicity data from pelvic radiotherapy patients. Pelvic organ motion is assessed in a systematic review examining organ motion patterns and potential strategies to account for this. Population-based and adaptive margin strategies are investigated in modelling studies for both definitive cervical cancer patients and post-hysterectomy patients. Results Initial systematic review of the literature, followed by the analysis of the toxicity and dosevolume data of 203 pelvic radiotherapy patients highlighted anal canal, bowel loops, bowel bag, sigmoid and large bowel as important organs at risk (OARs) for bowel toxicity. Dosevolume constraints were derived for these organs. Pelvic organ motion was found to be a significant problem for gynaecological IMRT. Adaptive margin strategies, such as plan-of-the-day, were demonstrated to achieve both CTV coverage whilst reducing dose to the OARs compared to standard margins and population-based margins. Conclusions Dose-volume constraints derived for late bowel toxicity, if validated with independent data, may be used to reduce bowel toxicity in future patients, and as a benchmark to assess the efficacy of new IMRT techniques. Adaptive strategies for gyn

Intensity-modulated radiotherapy (IMRT) for gynaecological malignancies aims to reduce toxicity and improve tumour control. However, there are several barriers to its uptake in clinical practice. Amongst these are that of pelvic organ motion, whereby due to motion of the target organs on treatment there is a risk of geographical miss with IMRT. Secondly, although new IMRT techniques may improve bowel toxicity there is limited knowledge about dose-volume constraints for bowel, making it difficult to assess whether new techniques are likely to translate into clinical improvements. The purpose of this thesis is to address these problems. Methods Dose-volume constraints for late bowel toxicity are investigated initially through systematic review, followed by a dose-volume study based on toxicity data from pelvic radiotherapy patients. Pelvic organ motion is assessed in a systematic review examining organ motion patterns and potential strategies to account for this. Population-based and adaptive margin strategies are investigated in modelling studies for both definitive cervical cancer patients and post-hysterectomy patients. Results Initial systematic review of the literature, followed by the analysis of the toxicity and dosevolume data of 203 pelvic radiotherapy patients highlighted anal canal, bowel loops, bowel bag, sigmoid and large bowel as important organs at risk (OARs) for bowel toxicity. Dosevolume constraints were derived for these organs. Pelvic organ motion was found to be a significant problem for gynaecological IMRT. Adaptive margin strategies, such as plan-of-the-day, were demonstrated to achieve both CTV coverage whilst reducing dose to the OARs compared to standard margins and population-based margins. Conclusions Dose-volume constraints derived for late bowel toxicity, if validated with independent data, may be used to reduce bowel toxicity in future patients, and as a benchmark to assess the efficacy of new IMRT techniques. Adaptive strategies for gyn