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Aims Anal cancer is primarily treated using concurrent chemoradiotherapy (CRT), with conformal techniques such as intensity modulated radiotherapy (IMRT) and volumetric arc therapy (VMAT) now being the standard techniques utilised across the world. Despite this, there is still very limited consensus on prognostic factors for outcome following conformal CRT. This systematic review aims to evaluate the existing literature to identify prognostic factors for a variety of oncological outcomes in anal cancer, focusing on patients treated with curative intent using contemporary conformal radiotherapy techniques. Materials and methods A literature search was conducted using Medline and Embase to identify studies reporting on prognostic factors for survival and cancer-related outcomes after conformal CRT for anal cancer. The prognostic factors which were identified as significant in univariable and multivariable analysis, along with their respective factor effects (where available) were extracted. Only factors reported as prognostic in more than one study were included in the final results. Results The results from 19 studies were analysed. In both univariable and multivariable analysis, N stage, T stage, and sex were found to be the most prevalent and reliable clinical prognostic factors for the majority of outcomes explored. Only a few biomarkers have been identified as prognostic by more than one study – pre-treatment biopsy HPV load, as well as the presence of leukocytosis, neutrophilia and anaemia at baseline measurement. The results also highlight the lack of studies with large cohorts exploring the prognostic significance of imaging factors. Conclusion Establishing a set of prognostic and potentially predictive factors for anal cancer outcomes can guide the risk stratification of patients, aiding the design of future clinical trials. Such trials will in turn provide us with greater insight into how to effectively treat this disease using a more personalised approach.

Objectives To assess the effectiveness of fluorine-18 fluorodeoxyglucose (FDG) positron-emission tomography-computed tomography (PET-CT) and magnetic resonance imaging (MRI) for response assessment post curative-intent chemoradiotherapy (CRT) in anal squamous cell carcinoma (ASCC). Methods Consecutive ASCC patients treated with curative-intent CRT at a single centre between January 2018 and April 2020 were retrospectively identified. Clinical meta-data including progression-free survival (PFS) and overall survival (OS) outcomes were collated. Three radiologists evaluated PET-CT and MRI using qualitative response assessment criteria and agreed in consensus. Two-proportion z test was used to compare diagnostic performance metrics (sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), accuracy). Kaplan-Meier analysis (Mantel-Cox log-rank) was performed. Results MRI (accuracy 76%, PPV 44.8%, NPV 95.7%) and PET-CT (accuracy 69.3%, PPV 36.7%, NPV 91.1%) performance metrics were similar; when combined, there were statistically significant improvements (accuracy 94.7%, PPV 78.9%, NPV 100%). Kaplan-Meier analysis demonstrated significant differences in PFS between responders and non-responders at PET-CT ( p = 0.007), MRI ( p = 0.005), and consensus evaluation ( p < 0.001). Cox regression analysis of PFS demonstrated a lower hazard ratio (HR) and narrower 95% confidence intervals for consensus findings (HR = 0.093, p < 0.001). Seventy-five patients, of which 52 (69.3%) were females, with median follow-up of 17.8 months (range 5–32.6) were included. Fifteen of the 75 (20%) had persistent anorectal and/or nodal disease after CRT. Three patients died, median time to death 6.2 months (range 5–18.3). Conclusion Combined PET-CT and MRI response assessment post-CRT better predicts subsequent outcome than either modality alone. This could have valuable clinical benefits by guiding personalised risk-adapted patient follow-up. Key Points • MRI and PET-CT performance metrics for assessing response following chemoradiotherapy (CRT) in patients with anal squamous cell carcinoma (ASCC) were similar. • Combined MRI and PET-CT treatment response assessment 3 months after CRT in patients with ASCC was demonstrated to be superior to either modality alone. • A combined MRI and PET-CT assessment 3 months after CRT in patients with ASCC has the potential to improve accuracy and guide optimal patient management with a greater ability to predict outcome than either modality alone

Anal cancer is a rare disease typically treated with concurrent chemoradiotherapy. Lack of understanding of prognostic factors renders options for treatment individualisation limited. Due to the rarity of the cancer, single-centre data are rarely sufficient for robust prognostic model development. Distributed learning enables the analysis of datasets from multiple centres without exchanging sensitive individual-level patient data. This thesis aimed to determine prognostic factors for patients treated for anal cancer with modern radiotherapy by using distributed learning to analyse real- world data across an international consortium. To achieve this, a local anal cancer data warehouse was established, which includes data for 568 patients treated at Leeds Cancer Centre between 2013 and 2022. The literature was systematically reviewed to identify established prognostic factors for anal cancer outcomes after treatment with conformal radiotherapy. 19 studies were evaluated, and N stage, T stage, and sex were identified as the most prevalent clinical prognostic factors for the majority of outcomes explored. The atomCAT1 three-centre proof-of-concept study was successful in demonstrating the value of distributed learning in outcome modelling for rare cancers. This study guided the expansion of the initial collaboration into an international consortium consisting of 14 radiotherapy treatment centres. Distributed learning was implemented for collaborative prognostic model development and validation across the atomCAT consortium. In the atomCAT2 study, the distributed learning analysis of data from 1,099 patients treated across 12 centres established nodal involvement, male sex, older age, and larger primary tumour size as prognostic for poorer overall survival; male sex, higher T stage, and larger primary tumour size as prognostic for poorer locoregional control; and nodal involvement and larger primary tumour size as prognostic for poorer freedom from distant metastasis. These results may guide the design of future clinical trials in anal cancer and may ultimately aid the personalisation of treatment for future patients.