Treatment of Locally Advanced Rectal Cancer in the Era of Total Neoadjuvant Therapy: A Systematic Review and Network Meta-Analysis

Abstract

Importance: Treatment of locally advanced rectal cancer (LARC) involves neoadjuvant chemoradiotherapy plus total mesorectal excision and adjuvant chemotherapy. However, total neoadjuvant therapy (TNT) protocols (ie, preoperative chemotherapy in addition to radiotherapy) may allow better adherence and early treatment of distant micrometastases and may increase pathological complete response (pCR) rates.

Objective: To assess the efficacy and tolerability of TNT protocols for LARC.

Data sources: MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science Core Collection electronic databases and ClinicalTrials.gov for unpublished studies were searched from inception to March 2, 2024.

Study selection: Randomized clinical trials including adults with LARC who underwent rectal resection as a final treatment were included. Studies including nonoperative treatment (watch-and-wait strategy), treatments other than rectal resection, immunotherapy, or antiangiogenic agents were excluded. Among the initially identified studies, 2.9% met the selection criteria.

Data extraction and synthesis: Two authors independently screened the records and extracted data. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)-compliant pairwise and network meta-analyses with a random-effects model were performed in a frequentist framework, and the certainty of evidence was assessed according to the confidence in network meta-analysis approach.

Main outcomes and measures: The primary outcome was pCR, defined as the absence of residual tumor at pathological assessment after surgery. Secondary outcomes included tolerability, toxic effects, perioperative outcomes, and long-term survival.

Results: Of 925 records identified, 27 randomized clinical trials, including 13 413 adults aged 18 years or older (median age, 60.0 years [range, 42.0-63.5 years]; 67.2% male) contributed to the primary network meta-analysis. With regard to pCR, long-course chemoradiotherapy (L-CRT) plus consolidation chemotherapy (relative risk [RR], 1.96; 95% CI, 1.25-3.06), short-course radiotherapy (S-RT) plus consolidation chemotherapy (RR, 1.76; 95% CI, 1.34-2.30), and induction chemotherapy plus L-CRT (RR, 1.57; 95% CI, 1.09-2.25) outperformed standard L-CRT with single-agent fluoropyrimidine-based chemotherapy. Considering 3-year disease-free survival, S-RT plus consolidation chemotherapy (RR, 1.08; 95% CI, 1.01-1.14) and induction chemotherapy plus L-CRT (RR, 1.12; 95% CI, 1.01-1.24) outperformed L-CRT, in spite of an increased 5-year locoregional recurrence rate of S-RT plus consolidation chemotherapy (RR, 1.65; 95% CI, 1.03-2.63).

Conclusions and relevance: In this systematic review and network meta-analysis, 3 TNT protocols were identified to outperform the current standard of care in terms of pCR rates, with good tolerability and optimal postoperative outcomes, suggesting they should be recognized as first-line treatments.

Figure 1.. Network Plot Comparing Each Treatment With the Common Comparator Long-Course Chemoradiotherapy With Single-Agent Fluoropyrimidine (L-CRT1) for Primary Outcome Pathological Complete Response

The thickness of lines is proportional to the number of studies comparing the 2 treatments, and the size of circles is proportional to the number of individuals for each treatment. CHT indicates chemotherapy; induction + L-CRT, induction CHT plus consolidation L-CRT; L-CRT + consolidation, L-CRT plus consolidation CHT; L-CRT2, L-CRT with duplex CHT drug (fluoropyrimidine plus oxaliplatin); L-RT, long-course radiotherapy; S-RT + consolidation, short-course RT plus consolidation CHT; S-RTdelayed, S-RT plus delayed rectal resection; S-RTearly, S-RT plus early rectal resection.

Figure 2.. League Table for the Primary Outcome of Pathological Complete Response

Treatments included in the analysis are shown in boldface on a diagonal in alphabetical order. Results of the network meta-analysis are reported in the lower left part of the matrix, and results from the pairwise meta-analysis are reported in the upper right matrix of the table. Each cell presents the relative risk (RR) and the corresponding 95% CI, and RRs greater than 1 favor the column-defining treatment (ie, the left-most cell on the diagonal). ^aSignificant RR (95% CI).

Figure 3.. Forest Plot Comparing Each Treatment With the Common Comparator Long-Course Chemoradiotherapy With Single-Agent Fluoropyrimidine (L-CRT1) for the Primary Outcome Pathological Complete Response

Relative risks (RRs) greater than 1 favor the treatment over L-CRT1. Squares indicate RRs; horizontal lines, 95% CIs for RRs. CHT indicates chemotherapy; CINeMA, confidence in network meta-analysis; induction + L-CRT, induction CHT plus consolidation long-course chemoradiotherapy; L-CRT + consolidation, L-CRT plus consolidation CHT; L-CRT2, L-CRT with duplex CHT drug (fluoropyrimidine plus oxaliplatin); L-RT, long-course radiotherapy; NNT, number needed to treat (for details, see eAppendix 4 in Supplement 1); S-RT + consolidation, short-course RT plus consolidation CHT; S-RTdelayed, S-RT plus delayed rectal resection; S-RTearly, S-RT plus early rectal resection.