Neoadjuvant Radiotherapy Dose Escalation in Locally Advanced Rectal Cancer: a Systematic Review and Meta-analysis of Modern Treatment Approaches and Outcomes

Abstract

AimsImproving pathological complete response (pCR) rates after neoadjuvant chemoradiotherapy for locally advanced rectal cancer may facilitate surgery-sparing treatment paradigms. Radiotherapy boost has been linked to higher rates of pCR; however, outcomes in moderately escalated inverse-planning studies have not been systematically evaluated. We therefore carried out a systematic review and meta-analysis of radiation dose-escalation studies in the context of neoadjuvant therapy for locally advanced rectal cancer. Materials and methodsA systematic search of Pubmed, EMBASE and Cochrane databases for synonyms of ‘rectal cancer’, ‘radiotherapy’ and ‘boost’ was carried out. Studies were screened for radiotherapy prescription >54 Gy. Prespecified quality assessment was carried out for meta-analysis inclusion suitability. Pooled estimates of pCR, acute toxicity (grade ≥3) and R0 resection rates were determined with random-effects restricted maximum-likelihood estimation. Heterogeneity was assessed with Higgins I2 and Cochran Q statistic. Subset analysis examined outcomes in modern inverse-planning studies. Meta-regression with permutation correction was carried out for each outcome against radiation dose, radiotherapy technique, boost technique, chemotherapy intensification and other patient- and treatment-related cofactors. ResultsForty-nine primary and three follow-up publications were included in the systematic review. Pooled estimates of pCR, toxicity and R0 resection across 37 eligible publications (n = 1817 patients) were 24.1% (95% confidence interval 21.2–27.4%), 11.2% (95% confidence interval 7.2–17.0%) and 90.7% (95% confidence interval 87.9–93.8%). Within inverse-planning studies (17 publications, n = 959 patients), these rates were 25.7% (95% confidence interval 21.0–31.1%), 9.8% (95% confidence interval 4.6–19.7%) and 95.3% (95% confidence interval 91.6–97.4%). Regression analysis did not identify any significant predictor of pCR (P > 0.05). ConclusionsRadiotherapy dose escalation above 54 Gy is associated with high rates of pCR and does not seem to increase the risk of acute grade ≥3 toxicity events. pCR rates approaching 25% may be achievable utilising moderate escalation (54–60 Gy) with modern inverse-planning techniques; however, a clear dose–response relationship was not identified in regression analysis and additional evidence is awaited given the prevalence of heterogenous single-arm studies to date.