Prospectively Randomized Control Clinical Trial of FOLFOXIRI Preoperative Chemotherapy Alone on Rectal Cancer in Local Advance Comparing to Oral Capecitabine Combined With Long-term Radiation

Preoperative radiation and chemotherapy is the standard treatment for local advanced rectal cancer. The addition of oxaliplatin to capecitabine combined with radiotherapy does not improve local control and long-term survival. Most importantly,chemoradiotherapy significantly increased surgical complication and poor long-term quality of life .In the absence of effective measures of predicting chemo-sensitivity, there is considerable risk of using any two-drug regimen for neoadjuvant therapy. Simultaneous use of the three chemotherapeutic drugs may be able to reduce the likelihood of resistance to both dual drug regimen and single drug regimen. The purpose of this study is to compare the efficacy and safety of three chemotherapeutic regimen known as FOLFOXIRI (the drug 5-fluorouracil, oxaliplatin, Irinotecan) with standard radiotherapy combined with capecitabine in neoadjuvant therapy for local advanced rectal cancer. The drugs in the FOLFOXIRI regimen are all FDA(Food and Drug Administration) approved and have been used routinely to treat patients with advanced colorectal cancer.

Outline: This is a multicenter,prospectively,randomized control ,phase III clinical study.Patients are stratified according to the distance from the tumor to the anal margin（≤5cm，\>5cm） and randomized to 1 of 2 treatment regimen.Patients will receive full supportive care while on this study.

Objectives：

Primary: To compare neoadjuvant chemotherpay of FOLFOXIRI with conventional capecitabine single-agent radiotherapy in local advanced rectal cancer with respect to 3-year disease free survival rate (DFS) .

Secondary:

1. To compare postoperative 3-year local recurrence rate, 3-year distance metastasis free survival rate, 3-year overall survival between neoadjuvant FOLFOXIRI with capecitabine single-agent radiotherapy groups.
2. To compare R0 Resection rate and surgical complication between the two groups.
3. To evaluate the tumor regression grade(TRG) between the two groups.
4. To evaluate the adverse event profile and Long term quality of life between the two groups.

Eligibility Criteria:
Inclusion Criteria:

* 1）Age: 18 to 75 years old;
* 2）Histological diagnosis of rectal adenocarcinoma;
* 3）Distance form anal margin ≤ 5cm: cT3-4aN + M0, there is no distant metastasis, lymph node positive, or the tumor breaking through the muscular layer, no invasion of the adjacent organs , positive MRF, it is estimated that R0 resection can be performed;
* 4）From the anal margin\>5cm: cT3c-4aN+M0, there is no distant metastasis, lymph node positive, or the tumor breaking through the muscular layer with invading the mesorectum more than 5mm, no invasion of the adjacent organs, positive MRF, it is estimated that R0 resection can be performed;
* 5）Preoperative staging method: All patients undergoing anal examination, high-resolution MRI and/or EUS for preoperative staging. The diameter of parenteral lymph node ≥10mm, lymph node shape or the MRI characteristics is consistent with typical lymph node metastasis. If combined with EUS, the material should be submitted to the central assessment team for judgment when there is a contradiction in the staging method. Preoperative chest and abdomen CT, pelvic MRI are used for excluding distant metastasis;
* 6）Confirmed as the lower edge of tumor is located within 12 cm from the anal margin by MRI examination
* 7）There is no signs of intestinal obstruction, or obstruction of intestinal after treating with proximal colostomy has been relieved;
* 8）Patients did not previously receive rectal surgery, chemotherapy or radiation therapy , biological treatment , except for endocrine therapy;
* 9）ECOG Performance Status :0-1
* 10）Life expectancy: more than 2 years;
* 11）Laboratory values：Hematology: white blood cell count\>4000/mm3; Platelet count\>100000/mm3; Hemoglobin \>10g/dL; Liver function: SGOT and SGPT \< 1.5 upper limit of normal(ULN); Bilirubin\< 1.5mg/dL; Renal function :Creatinine \<1.8mg/dL.

Exclusion Criteria:

* 1）Tumor invasion of surrounding tissue organs (T4b) by preoperative staging assessment;
* 2）Obturator lymph node metastasis;
* 3）Arrhythmia requires treatment with antiarrhythmia (except for beta-blockers or digoxin), symptomatic coronary artery disease, myocardial ischemia (myocardial infarction within the last 6 months) or congestive heart failure exceeding NYHA class II;
* 4）Severe hypertension with poor control;
* 5）History of HIV infection or active phase of chronic hepatitis B or C infection with high copy viral DNA;
* 6）Other active serious infections according to NCI-CTC version 4.0;
* 7）There is preoperative evidence for distant metastasis outside pelvis;
* 8）Cachexia and organ function decompensation
* 9）History of pelvic or abdominal radiotherapy;
* 10）Multiple primary cancer;
* 11）Patients with epilepcy requiring treatment ( steroids or antiepileptic treatment);
* 12）History of other malignant tumors within 5 years, except for cured cervical carcinoma in situ or skin basal cell carcinoma;
* 13）Drug abuse and medical, psychological or social conditions interfering patient participation in research or the evaluation of research results;
* 14）Any allergy to clinical research drugs or any drugs associated with this study;
* 15）Any unstable condition or condition that may endanger safety and compliance of patients;
* 16）Pregnancy or the lactating female without adequate contraception.