A Phase II Study of Total Neoadjuvant Therapy for High-risk Locally Advanced Rectal Cancer

Recommended treatment of patients with locally advanced rectal cancer (LARC) includes preoperative chemoradiation (CRT), total mesorectal excision (TME) and postoperative adjuvant chemotherapy (ACT). However, treatments fail to show an improved therapeutic effect on high-risk patients now. Total neoadjuvant therapy (TNT) is a new try for rectal cancer treatment,and this trial aims to identify and select the more promising TNT sequence.

This trail is a multicenter, randomized, phase II trial . Eligible patients age from 18 to 75 years with histologically confirmed rectal adenocarcinoma. MRI is mandatory, and patients of stage II or III rectal cancer are eligible if any of the following criteria are fulfilled: Categories T4,Categories N2, MRF involvement, EMVI positive, and lateral lymph node involvement. Patients are randomly assigned to 3 groups, group 1: concurrent chemoradiotherapy → TME → adjuvant chemotherapy (control group);or group 2: concurrent chemoradiotherapy → consolidation chemotherapy → TME (CNCT group);Or group 3: induction chemotherapy → concurrent chemoradiotherapy →TME ( INCT group).The primary end point is the rate of tumor down-staging, which is defined as stage yp0-II after surgery,and watch-and-wait strategy after complete clinical response (cCR) was allowed. Secondary end points include acute toxicity, compliance with TNT, surgical complications, 3-year overall survival (3yOS),3-year disease free survival (3yDFS),3-year distant metastatic free survival(3yDMFS),3-year locoregional recurrence-free survival(3yLRRFS) and quality of life.

Inclusion criteria:

1. 18-75 years old, regardless of gender
2. Histologically confirmed rectal adenocarcinoma;
3. Up to 12 cm above the anal verge on the basis of rigid rectoscopy.
4. MRI of the rectum is acceptable;
5. Patients in stage II or III rectal cancer are eligible if any of the following criteria are fulfilled: Categories T4,Categories N2, MRF involvement, EMVI positive, and lateral lymph node involvement.
6. ECOG score 0-1 or KPS score ≥80.

Exclusion Criteria:

1. History of malignant tumor in other parts;
2. Cannot complete MRI; Allergic to 5-fu drugs; Allergic to platinum drugs;
3. During thrombolytic and anticoagulant therapy, the patient has bleeding diathesis or coagulation dysfunction; Or aneurysm, stroke, transient ischemic attack, arteriovenous malformation in the past year;
4. History of kidney, urine test found proteinuria or clinical renal function was significantly abnormal;
5. History of digestive tract fistula, perforation or severe ulcer;
6. Active infection is present; Clinically obvious heart disease; New York heart association (NYHA) of Ⅱ level or congestive heart failure; Unstable symptomatic arrhythmia or peripheral vascular disease ≥ grade II; Myocardial infarction and cerebrovascular accident occurred within 6 months before enrollment.