Treatment of Stages I–III Squamous Cell Anal Cancer: A Systematic Review
Authors: Parikh Romil R. , Troester Alexander , Southwell Bronwyn , Ester Elizabeth , Sultan Shahnaz , Claussen Amy M. , Greeno Edward , Arsoniadis Elliot , Church Timothy R. , Wilt Timothy J. , Goffredo Paolo , Butler Mary 
Published: October 2024

Objectives. To evaluate the comparative effectiveness and harms of initial treatment and posttreatment surveillance strategies for stages I–III squamous cell anal cancer. Data sources. MEDLINE®, Embase®, Cochrane Register of Controlled Trials, and ClinicalTrials.gov from January 2000 through March 2024; reference lists of systematic reviews and included studies; and a Federal Register notice. Review methods. Using predefined criteria and dual review, we selected randomized controlled trials (RCTs) and nonrandomized studies of interventions (NRSIs) comparing strategies for chemotherapy, radiation therapy (RT), and surgery; modalities, doses, volumes, and fractionation schema for RT; dose de-escalation or escalation in chemoradiation (CRT); immunotherapy; and posttreatment surveillance. We evaluated risk of bias (RoB) using the RoB2 tool for RCTs and the ROBINS-I tool for NRSIs and strength of evidence (SOE) using Agency for Healthcare Research and Quality Evidence-based Practice Center Program methods for prespecified outcomes (PROSPERO registration number CRD42023456886). Results. We included 33 articles from 8 RCTs (6 with low to moderate RoB and 2 with high RoB) and 20 NRSIs (all with serious to critical RoB). Compared with RT alone, doublet CRT with 5-fluorouracil (5FU) plus mitomycin C (MMC) showed lower locoregional failure rate (LRF) and greater disease-specific and colostomy-free survival (CFS) (moderate to low SOE), greater hematologic toxicity (low SOE), greater overall acute harms (moderate SOE), and no difference in late harms (low SOE). Doublet CRT with 5FU plus MMC showed lower LRF (low SOE) and greater CFS and disease-free survival (DFS) (low SOE) than CRT with 5FU, and evidence was insufficient to compare harms. Compared with CRT with 5FU plus MMC, CRT with 5FU plus cisplatin did not improve several effectiveness outcomes up to 5 years, or overall acute or late harms (moderate to low SOE), showed lower hematologic toxicity (moderate SOE), and had conflicting, insufficient evidence for CFS. Triplet CRT with paclitaxel plus capecitabine plus MMC showed greater CFS, DFS, overall survival, and overall acute harms than doublet CRT with capecitabine plus MMC (low SOE). Remaining comparisons had insufficient evidence. Patients with older age, immunocompromised status, or minoritized racial/ethnic identities were underrepresented in included studies. Conclusions. Doublet CRT is likely more effective but may have greater hematologic toxicity compared with RT alone or CRT with 5FU. Adding paclitaxel to doublet CRT may increase treatment efficacy and toxicity. Evidence is insufficient for optimal posttreatment surveillance strategies, quality of life, and other patient-reported outcomes. Future RCTs should increase inclusion of historically underrepresented patients, and future real-world evidence generation must prioritize methodological rigor.