Impact of Total Neoadjuvant Therapy vs. Standard Chemoradiotherapy in Locally Advanced Rectal Cancer: A Systematic Review and Meta-Analysis of Randomized Trials

SIMPLE SUMMARY: Multimodality therapy is the standard of care for patients with locally advanced rectal cancer (LARC). The optimal treatment sequence is, however, a matter of debate. Neoadjuvant radiotherapy with concurrent fluoropyrimidines followed by surgery and adjuvant chemotherapy has been the standard treatment for the past years. Alternative therapeutic strategies such as total neoadjuvant treatment (TNT) are gaining momentum, although results from individual clinical trials are not conclusive regarding its impact on survival. In this context, we aimed to systematically review available evidence from randomized trials comparing different sequencing strategies. The results from our meta-analysis show that TNT not only provides increased complete pathological response rates, but also improves disease-free and overall survival at 3 years compared to standard neoadjuvant chemoradiotherapy, with no substantial increase in severe adverse events. These results support the use of induction or consolidation chemotherapy before surgery in LARC and TNT as a valuable treatment strategy in these patients. ABSTRACT: Multimodality treatment is a standard of care for LARC, but the optimal sequencing of the treatment modalities remains unclear. Several randomized clinical trials (RCTs) compared total neoadjuvant treatment (TNT) vs. standard neoadjuvant chemoradiotherapy (CRT) with inconsistent results. A systematic review and meta-analysis was performed to evaluate the efficacy of TNT in terms of complete pathological response (pCR) rate, disease-free and overall survival vs. standard CRT in LARC. A systematic search was performed through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and meeting abstracts up to May 2020. RCTs comparing CRT vs. TNT followed by surgery in LARC were eligible for the study. Study selection and data extraction were done following PRISMA guidelines by two independent reviewers. The Mantel–Haenzel method was used to obtain a fixed-effects model of pooled odds or hazard ratios for the main outcomes. Eight RCTs, including 2301 patients, met the eligibility criteria. TNT significantly improved pCR rate (OR = 1.99, 95% confidence interval (CI) 1.59–2.49; p < 0.001), 3-year disease-free-survival (DFS) (HR = 0.82, 95%CI 0.71–0.95; p = 0.01) and 3-year overall survival (OS) (hazard ratio (HR) = 0.81, p = 0.04). Grade 3–4 adverse events were not significantly different in both strategies (OR = 1.58; p = 0.14). An improved pCR rate was documented regardless of the type of radiotherapy administered (long vs. short fractionation schedules). No significant heterogeneity was found. The results of this meta-analysis show that TNT improves pCR and survival rates vs. standard preoperative CRT in patients with LARC. TNT may become a new standard of care in LARC, although longer follow-up is needed to properly assess its long-term impact on survival.