Single-arm confirmatory trial of total neoadjuvant therapy and watch-and-wait strategy for patients with low rectal cancer: Japan Clinical Oncology Group study (JCOG2010, TOWARd study).

TPS269 Background: Radical surgery is the standard treatment for advanced lower rectal cancer, but postoperative complications and sequelae are major problems. Recently, some patients treated with preoperative chemoradiotherapy (CRT) have been reported to achieve a clinical complete response (cCR) and be cured with a subsequent watch-and-wait strategy (W&W) without surgery. Moreover, the introduction of total neoadjuvant therapy (TNT) consisting of CRT and systemic chemotherapy has increased proportion of cCR. However, most previous studies on W&W have reported cases in which cCR was achieved incidentally as a result of preoperative CRT or TNT for advanced lower rectal cancer. It is unclear whether combining TNT that is highly effective in early stage rectal cancer and subsequent W&W without surgery is an effective intention-to-cure treatment for advanced lower rectal cancer when cCR is obtained after TNT. The purpose of this single-arm confirmatory trial is to evaluate the efficacy and safety of TNT and intended W&W for cT2-T3 advanced lower rectal cancer with a tumor diameter of 5 cm or less. Methods: Key eligibility criteria include low rectal adenocarcinoma with tumor diameter 5 cm or less, cT2 or cT3 tumor depth, no lymph node metastasis, no distant metastasis, no history of pelvic irradiation or rectal surgery, age 18-75 years, and sufficient organ function. Eligible patients are receiving TNT. CRT consists of the standard dose of capecitabine (1650 mg/m 2 /day) and radiotherapy (45 Gy/25 fractions to whole pelvis plus boost of 5.4 Gy/3 fractions to primary tumor). Consolidation chemotherapy consists of 4 courses of CAPOX (oxaliplatin 130 mg/m 2 on day1 and capecitabine 2000 mg/m 2 /day on day1-14). After completing TNT, patients will be re-staged according to Memorial Sloan Kettering Cancer Center Criteria. Patients with cCR at the primary site will move to W&W, patients with a near complete response will move to either W&W or undergo local resection, and patients with an incomplete response will undergo total mesorectal excision. All patients will be followed every 3 months for 2 years after re-staging, and every 6 months for 3 years after that. The primary endpoint in phase II is the proportion of cCR at re-staging by central review and in phase III is 5-year overall survival (OS). In the phase II part, 40 patients were required with a one-sided alpha of 5%, power of 80%, a threshold value of 20%, and an expected value of 40%. Based on the results of previous studies, we set the threshold 5-year OS at 87% in the phase III part. The sample size was calculated as 105 including the phase II part with a one-sided alpha of 5%, power of 80%, and the expected 5-year OS of 95%. The first patient was enrolled in September 2022. Clinical trial information: jRCTs031220288 .