Total neoadjuvant therapy integrating long-course radiotherapy with trifluridine/tipiracil for locally advanced rectal cancer: a single-arm, multicenter phase 2 trial.

BACKGROUND

Total neoadjuvant therapy (TNT) is recommended for locally advanced rectal cancer (LARC) with high-risk factors. The objective of this multi-center phase 2 study is to evaluate the impact of a newly designed TNT consist of TAS-102 concurrent with long-course radiotherapy followed by consolidative TAS-102 and oxaliplatin on the pathological complete response (pCR) rate in patients with LARC.

METHODS

Patients with LARC were to receive a newly designed TNT consisting of radiotherapy (50 Gy/25 fractions) concurrently with oral TAS-102 (35 mg/m2 given twice a day on days 1-5 during the 1st, 3rd and 5th week of radiotherapy) followed by 2 cycles of consolidation chemotherapy (oxaliplatin 85 mg/m2 on day 1 and TAS-102 35 mg/m2 twice a day on days 1-5, repeated on a 14-day cycle), with total mesorectal excision to follow within 7-11 weeks after radiotherapy completion. The primary endpoint was the pCR (ypT0 ypN0) rate. This trial is registered with Chinese Clinical Trial Registry, ChiCTR2200063142.

FINDINGS: From September 1, 2022 through January 11, 2024, 50 patients were enrolled and treated; 44 (88%) received surgery. Among all 50 patients, the overall complete response rate (pCR and clinical complete response [cCR]) was 32% (95% confidence interval [CI] 20-47). Among the 44 patients who underwent surgery, the pCR rate was 32% (95% CI 19-48), exceeding the hypothesized standard pCR rate of 13%. The major pathological regression rate was 52% (95% CI 37-68), and the pathological complete lymph node regression rate was 61% (95% CI 45-76). Of the 6 patients who did not receive surgery, 2 achieved cCR followed by observation, 1 was confirmed to have high microsatellite instability and refused surgery, and 3 refused surgery for personal reasons. Grade 3 hematologic toxicity was recorded in 10 patients (20%) and grade 4 in 3 (6%), consisting largely of myelosuppression. Most patients had mild gastrointestinal toxicity; the most common grade 3 and 4 toxicity was diarrhea (14%). No patients had hand-foot skin reactions.

INTERPRETATION: We found that TAS-102 concurrent with preoperative radiotherapy led to a high pCR rate (32%) with acceptable toxicity among patients with stage Ⅱ/Ⅲ rectal cancer. Prospective randomized controlled trials comparing fluoropyrimidine-based and TAS-102-based TNT are warranted.

FUNDING: National Natural Science Foundation of China and Shandong Provincial Natural Science Foundation.