Patient Outcomes With Dose Escalation Using Modern Radiotherapy Techniques: A Retrospective Review of Anal Cancer Treated at a Large Academic Institution Between 2010 and 2016

Introduction: The use of modern radiotherapy techniques (MRTs) has contributed to reduced treatment-related toxicities through better avoidance of normal structures and dose tapering, and has enabled the delivery of higher doses continuously. The purpose of this study was to review retrospectively (1) outcomes for anal cancer treated at BC Cancer (Canada) using MRT, and (2) the utilization and effect of dose escalation on cancer-related outcomes. Methods: Patients between 2010 and 2016 with biopsy-proven anal cancer, aged >18 years, and treated with primary curative-intent chemoradiation using intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT) were included. Primary end points included overall survival (OS), relapse-free survival (RFS), and colostomy-free survival (CFS). Kaplan-Meier curves were created for prognostic factors, as well as dose escalation (>54 Gy vs. ≤54 Gy). Univariate and multivariate analyses were performed to evaluate predictors of the outcome. Results: A total of 273 patients were assessed. The median age was 61 years with 70% being female, 6% HIV positive, and 68% with locally advanced cancer (T3-4, or node positive). The median follow-up time was 41.3 months. Time from diagnosis to treatment was 60 days, and treatment duration 42 days. Dose escalation was prescribed for 22, of whom 15 were locally advanced cases. A total of 97% completed their radiation, including all who were dose-escalated; 11% required unplanned treatment breaks, with over half of breaks <5 days. More than 90% completed at least half of their chemotherapy; 41% had pre-treatment, and 34% post-treatment positron emission tomography (PET) scans. For primary tumor response, 88% were complete and 10% partial; 23% relapsed, with 15% locoregional, 5% distant, and 3% both, and 12% had salvage surgery. The colostomy rate was 15%, with 4% pre-treatment, 10% relapse related, and only 1% treatment-toxicity related. On univariate analysis, male sex was associated with a higher risk of death (p=0.02) and relapse (p=0.041). Non-squamous histology was consistently a strong predictor of all outcomes (OS, p=0.0089; RFS, p<0.0001; CFS, p<0.0001) as was advanced T stage (OS, p=0.0075; RFS, p=0.0019; CFS, p=0.0099), and node positivity (OS, p=0.0014; RFS, p=0.001; CFS, p=0.0071). Age, HIV status, grade, longer treatment times (>42-day median), and lack of a pre- or post-treatment PET scan were not associated with the outcome. Dose escalation beyond 54 Gy was not significant, even among locally advanced tumors. On multivariate analysis, non-squamous histology (OS, p=0.043; RFS, p<0.001; CFS, p=0.01), T4 (OS, p=0.049; RFS, p=0.026; CFS, p=0.042) and node positivity (OS, p=0.05; RFS, p=0.006) remained significant predictors of the outcome, although node positivity was no longer significant for CFS (p=0.10). Conclusion: BC Cancer outcomes for anal cancer treated with MRTs are comparable to what has been previously reported. Unplanned breaks were notably few, and short. Treatment-related colostomies were rare. Dose-escalated regimens were infrequently prescribed, appeared tolerable, but more often required a break. Prospective trials are needed to clarify efficacy of such regimens.