Safety and Efficacy of a Sandwich Total Neoadjuvant Therapy Strategy for Low‐Risk Distal Locally Advanced Rectal Cancer: Results From the TESS Phase II Trial

ABSTRACT This prospective phase II multicenter study evaluated a novel sandwich total neoadjuvant treatment (TNT) strategy for patients with relatively low‐risk distal locally advanced rectal cancer (LARC). The regimen consisted of two cycles of capecitabine and oxaliplatin (CapeOx) administrated before, during, and after radiotherapy, followed by surgery or a watch‐and‐wait strategy, and two cycles of adjuvant capecitabine chemotherapy. The primary endpoint was the clinical complete response (cCR) rate. All 98 patients completed radiotherapy, and 88.8% received six cycles of neoadjuvant chemotherapy. In the intention‐to‐treat analysis, 46.9% of patients achieved cCR, 7.1% achieved near‐clinical complete response (near‐cCR), and 45.9% had non‐clinical complete response (non‐cCR). In the observed population, the complete response (CR), pathological complete response (pCR), and sphincter‐preservation (SP) rates were 61.2%, 46.4%, and 79.6%, respectively. The local regrowth‐free survival, local recurrence‐free survival, distant metastases‐free survival, and overall survival rates were 89.5%, 100%, 92.9%, and 96.9%, respectively. Overall, this sandwich TNT strategy achieved high rates of cCR, pCR, CR, and SP, with favorable survival outcomes and acceptable toxicity, suggesting a promising organ‐preserving treatment approach for selected patients with distal LARC. Trial Registration: ClinicalTrials.gov identifier: NCT03840239