Low-intensity induction chemotherapy before chemoradiotherapy for rectal cancer: 10-year overall survival in the LARC-RRP trial

OBJECTIVES: Total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC) often uses intensive oxaliplatin-based chemotherapy alongside standard radiotherapy to prevent metastatic progression. The optimal intensity of the chemotherapy component, given a contribution of radiotherapy to clonogenic cell elimination in the primary tumour, remains uncertain. We aimed to assess long-term outcomes of a TNT regimen with low-intensity induction chemotherapy before chemoradiotherapy, as evaluated in the LARC-RRP trial. METHODS: Between 2005 and 2010, 87 LARC patients (36% with T4 organ-infiltrating tumour) were enrolled in the single-arm trial. Induction chemotherapy was given over four weeks prior to chemoradiotherapy and surgery. We report 10-year overall survival by tumour regression grade (TRG) and performed descriptive comparisons with contemporary trials whose experimental TNT arms used more intensive chemotherapy. RESULTS: At 10 years, overall survival was 83% (95% confidence interval, 71-90) for patients with complete or near-complete tumour cell elimination in the surgical specimen (TRG 1-2; 70% of the cohort) versus 52% (95% confidence interval, 31-69) for others (log-rank p = 0.0005). LARC-RRP survival outcomes were comparable with those reported in more contemporary TNT trials. CONCLUSIONS: The LARC-RRP results raise the possibility that shorter-duration chemotherapy combined with standard radiotherapy may suffice to protect against systemic recurrence of high-risk LARC. ADVANCES IN KNOWLEDGE: These long-term data support investigation of less intensive chemotherapy within TNT regimens and may guide the design of risk-stratified TNT trials.