Total Neoadjuvant Treatment vs. Chemoradiotherapy in Local Advanced Rectal Cancer With High Risk Factors

Total Neoadjuvant Treatment Versus Conventional Neo-chemoradiotherapy in Locally Advanced Rectal Cancer With High Risk Factors: a Multicenter Randomized Phase III Clinical Study.

Purpose:To compare the efficacy and the safety of total neoadjuvant chemotherapy + TME with standard neoadjuvant concurrent chemoradiotherapy + TME + adjuvant chemotherapy for locally advanced rectal cancer patients with high risk factors of recurrence.

Evaluation indexes: (1) the primary evaluation index: disease-free survival (disease free survival, DFS); (2) the secondary evaluation indexes: pathological complete remission rate (pCR), the 3 year overall survival (overall survival, OS); R0 dissection rate; distant metastasis free survival (DMFS); local recurrence free survival rate (LRRFS); tumor regression grade (TRG, tumor regression grade) and the adverse reaction rate during the chemotherapy, the operation safety index; quality of life; psychological and cognitive effects, assessment of nutritional status.

Safety evaluation indexes: including all adverse events observed during the experiment.

Number of patients: 458 cases Study design: patients will be randomly assigned into the total neoadjuvant treatment group (experimental group, TNT) and neoadjuvant concurrent chemotherapy group (control group, CRT) in the ratio of 1: 1. The patients of experimental group will be given 1 cycle of induction CAPOX (Oxaliplatin 130mg/m2 d1, Capecitabine 1000mg/m2, bid, d1-14) prior to radiotherapy. Then pelvic IMRT/VMAT (50-50.4Gy/25-28f) and two cycles of concurrent chemotherapy (Oxaliplatin 130mg/m2, d1, d 22, Capecitabine 825mg/m2, bid, 5d/w, 25-28d) are performed. And three cycles of consolidation chemotherapy (CAPOX) are delivered after concurrent chemoradiotherapy. Total mesorectal excision (TME) is performed after completion of the whole neoadjuvant treatment. The patients of control group will receive standard concurrent neoadjuvant chemoradiotherapy with capecitabine (825mg/m2, bid, 5d/w) followed by TME 6-8 weeks after the end of concurrent chemoradiotherapy. Then, patients are treated with another 6 cycles of CAPOX.

Schedule: Investigators plan to finish the study in 4 years and write the related work within 2 years after the completion of this study.

Inclusion Criteria:（1）Age: 18 ~ 70 years old; sex is not limited. （2）Patients with stage II/III rectal cancer staged under MRI or endoscopic ultrasonography and have at least one risk factor: cT4a-b(resectable)；cT3c-d with EMVI+ (Extramural venous invasion)；cN2；MRF+ (MRI in evaluating the mesorectal fascia).（According to the 2010 AJCC cancer staging system, the seventh edition）. The preoperative T stage is referred to endoscopic ultrasonography or rectal MRI. The N stage is referred to abdominal CT. The M stage is referred to abdominal and thoracic CT. If symptoms occur, other appropriate imaging examinations are needed（cranial MRI or ECT）.

（3）The lower edge of lesion is less than 12cm from anal verge according to rigid sigmoidoscopy or rectal digital examination.

（4）No distant metastasis after a thorough examination . （5）Pathological diagnosis of rectal adenocarcinoma. （6）ECOG score: 0-1. （7）Patients with primary rectal cancer who had not received surgery prior to surgery (except for palliative ileostomy or colostomy), radiotherapy, systemic chemotherapy or other anti-tumor therapy.

（8）The main organ function is normal, including the following characteristics:

• Blood routine examination: HB ≥9g/dL, WBC ≥ 3.5/4.0×109/L，PLT≥ 100×109/L

  • Biochemical examination：Crea and BIL ≤ 1.0 upper normal limit（ULN），ALT and AST≤ 2.5 upper normal limit（ULN）.

    （9）Not allergic to 5-Fu or Platinum. （10）The site of radiotherapy had not previously received radiation. （11）If female and of childbearing potential, have a negative result on a pregnancy test performed a maximum of 7 days before initiation of study treatment. If female and of childbearing potential, or if male, agree to use adequate contraception (eg, abstinence, intrauterine device, oral contraceptive, or double-barrier method) based on the judgment of the investigator or a designated associate from the date on which the ICF (Informed Consent Form) is signed until 8 weeks after the last dose of study drug.

    （12）Participants are volunteered to participate in this study, sign informed consent, good compliance, cooperation with follow-up.

Exclusion Criteria:（1）Have had prior or concurrent cancer distinct in primary site or histology EXCEPT for curatively treated cervical cancer in situ, Basal cell carcinoma of skin.

（2）Pregnant or lactating women. （3）Patients with severe cardiovascular disease and poorly controlled diabetes. （4）Mental disorder. （5）Severe infection. （6）Patients who can't finish MRI examination. （7）Patients were treated with thrombolytic therapy and anticoagulant therapy, either with bleeding diathesis or coagulopathy, or aneurysm, stroke, transient ischemic attack, arteriovenous malformation in the past year.

（8）The past history of kidney disease, urine or urine protein found in clinical renal abnormalities.

（9）The digestive tract fistula, perforation or serious ulcer disease. （10）Be allergic to 5-Fu or Platinum. （11）The presence of severe gastrointestinal diseases that affecting the absorption of oral chemotherapy drugs.

（12）Additional clinical trials were attended within 4 weeks before treatment initiation.