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Background Advanced pelvic radiotherapy techniques aim to reduce late bowel toxicity which can severely impact the lives of pelvic cancer survivors. Although advanced techniques have been largely adopted worldwide, to achieve their aim, knowledge of which dose-volume parameters of which components of bowel predict late bowel toxicity is crucial to make best use of these techniques. The rectum is an extensively studied organ at risk (OAR), and dose-volume predictors of late toxicity for the rectum are established. However, for other components of bowel, there is a significant paucity of knowledge. The Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) reviews recommend dose-volume constraints for acute bowel toxicity for peritoneal cavity and bowel loops, although no constraints are recommended for late toxicity, despite its relevance to our increasing number of survivors. This systematic review aims to examine the published literature to seek dose-volume predictors and constraints of late bowel toxicity for OARs (apart from the rectum) for use in clinical practice. Methods A systematic literature search was performed using Medline, Embase, Cochrane Library, Web of Science, Cinahl and Pubmed. Studies were screened and included according to specific pre-defined criteria. Included studies were assessed for quality against QUANTEC-defined assessment criteria. Results 101 studies were screened to find 30 relevant studies. Eight studies related to whole bowel, 11 to small bowel, and 21 to large bowel (including 16 of the anal canal). The anal canal is an important OAR for the development of late toxicity, and we recommend an anal canal Dmean <40Gy as a constraint to reduce late incontinence. For other components of bowel (sigmoid, large bowel, intestinal cavity, bowel loops), although individual studies found statistically significant parameters and constraints these findings were not corroborated in other studies. Conclusions The anal canal is an important OAR for the development of late bowel toxicity symptoms. Further validation of the constraints found for other components of bowel is needed. Studies that were more conclusive included those with patient-reported data, where individual symptom scores were assessed rather than an overall score, and those that followed statistical and endpoint criteria as defined by QUANTEC.

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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 will analyse one of the largest available cross-institutional cohorts of patients with anal cancer treated with chemoradiotherapy. The analysis aims to provide information on current international clinical practice outcomes and may aid the personalisation and design of future anal cancer clinical trials through contributing to a better understanding of patient risk stratification.