Total neoadjuvant therapy followed by a watch-and-wait strategy for patients with rectal cancer (TOWARd): protocol for single-arm phase II/III confirmatory trial (JCOG2010)

BACKGROUND: Radical surgery is the standard treatment for rectal cancer, but can impact quality of life. Recently, the concept of total neoadjuvant therapy with a watch-and-wait strategy has been proposed in which patients with a cCR after total neoadjuvant therapy do not proceed to surgery. However, most investigations of a watch-and-wait strategy have reported cases where cCR was achieved coincidentally via total neoadjuvant therapy. The aim is to assess whether total neoadjuvant therapy is effective in early-stage rectal cancer in patients that achieve cCR and are offered a watch-and-wait strategy. METHODS: JCOG2010 (TOWARd) is a multi-institutional, single-arm phase II/III confirmatory investigation of the safety and efficacy of total neoadjuvant therapy followed by a watch-and-wait strategy for rectal cancer. Key eligibility criteria include cT2–3 N0 M0 rectal adenocarcinoma, tumour diameter less than or equal to 5 cm, age 18–75 years, performance status 0–1, and no history of pelvic irradiation or rectal surgery. Total neoadjuvant therapy involves neoadjuvant chemoradiotherapy (capecitabine and radiotherapy: 45 Gy/25 fractions to the whole pelvis plus boost of 5.4 Gy/3 fractions to the primary tumour) followed by consolidation chemotherapy (four cycles of capecitabine/oxaliplatin). Patients will be re-staged every 8 weeks after total neoadjuvant therapy, and those who achieve cCR will undergo a watch-and-wait strategy, those with near complete response will undergo a watch-and-wait strategy or local resection, and those with an incomplete response will undergo radical surgery. The primary endpoint is the cCR rate in phase II and 5-year overall survival in phase III. Secondary endpoints include postoperative anal, urinary, and sexual function. A total of 105 patients (phase II, 40 patients; phase III, 65 patients) will be enrolled over 3.5 years. CONCLUSION: This trial will determine whether total neoadjuvant therapy and a watch-and-wait strategy is an effective alternative to radical surgery for early-stage rectal cancer in patients with cT2–3 N0 M0 and tumour size less than or equal to 5 cm. REGISTRATION NUMBER: jRCTs031220288 (https://jrct.niph.go.jp/en-latest-detail/jRCTs031220288).