Compliance and Toxicity of Total Neoadjuvant Therapy in Locally Advanced Rectal Cancer: A Systematic Review and Network Meta-analysis

PurposeThe individual chemotherapy- and radiotherapy-related toxicities between induction (iTNT) and consolidation total neoadjuvant therapy (cTNT) remain unclear. This network meta-analysis (NMA) comparing iTNT, cTNT, and traditional neoadjuvant chemoradiation (nCRT) evaluated the comparative treatment-related toxicities and compliance of the TNT schemas.MethodsA systematic review of randomized clinical trials and nonrandomized studies of interventions was performed as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-NMA guidelines. A Bayesian NMA was conducted, and odds ratios (OR) with 95% credible intervals (CrI) are reported for all outcomes.ResultsEighteen studies including 5730 patients were identified. iTNT ranked highest on rate of rectal bleeding (cTNT: OR 0.23 95% CrI 0.05-0.93; nCRT: OR 0.33, 95% CrI 0.09-0.96), proctitis (cTNT: OR 0.2, 95% CrI 0.06-0.55; nCRT: OR 0.2, 95% CrI 0.06-0.51), and postoperative diarrhea (cTNT: OR 0.37, 95% CrI 0.18-0.73; nCRT: OR 0.33, 95% CrI 0.15-0.71); cTNT ranked highest on rate of vomiting (iTNT: OR 0.24, 95% CrI 0.05-0.96; nCRT: OR 0.29, 95% CrI 0.06-0.89) and a higher rate of lymphopenia than iTNT (iTNT: OR 0.56, 95% CrI 0.34-0.99). Radiotherapy compliance was highest in cTNT (iTNT: OR 0.23, 95% CrI 0.05-0.72; nCRT: OR 0.18, 95% CrI 0.04-0.58). There was no difference in overall toxicity and mortality, chemotherapy compliance, and remaining individual system-based toxicities and postoperative complications.ConclusionsAcross all treatment strategies, iTNT had higher radiation-related gastrointestinal toxicities and postoperative diarrhea; cTNT had higher vomiting and lymphopenia rates. While no treatment strategy was superior in chemotherapy compliance, radiotherapy compliance was ranked highest in cTNT.