Neoadjuvant FOLFOXIRI Chemotherapy Alone for Locally Advanced Rectal Cancer

Study Overview
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Brief Summary
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The standard treatment for stage 2/3 rectal cancer is neoadjuvant 5-Fu based chemoradiation. However, preoperative radiation cause kinds of adverse events, some were irreversible. And the survival benefit was not obvious. Whether chemotherapy alone is effective enough in treating rectal cancer is not yet known. Here, the investigators chose all the three active cytotoxic agents (5-FU, Oxaliplatin, Irinotecan) as the neoadjuvant treatment regimen (FOLFOXIRI). The purpose of the study is to evaluate the efficacy of FOLFOXIRI as neoadjuvant regimen in treating patients with locally advanced rectal cancer.

Detailed Description
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Preoperative chemoradiotherapy could improve the local control of locally advanced rectal cancer, but the role was limited, only 5%. The adverse event cause by radiotherapy was severe. This single phase II trial was aimed to evaluate the efficacy of triplet regimen (FOLFOXIRI) in treating patients with locally advanced rectal cancer. All patients will receive the study regimen every 2 weeks for 4-6 cycles. MRI of the pelvic will be performed after 4 cycles of chemotherapy to assess clinical response. If the tumor response over 20% after 4 cycles of treatment, the patient will go to surgery (TME) directly or 2 more cycles of treatment before surgery under the decision of MDT. On the contrary, if the tumor show poor response (<20%), radiotherapy will be performed before operation. After surgery, 6-8 cycles of mFOLFOX6 will be given as adjuvant chemotherapy.

Official Title
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A Phase II Study of Neoadjuvant FOLFOXIRI Chemotherapy Alone in Treating Patients With Locally Advanced Rectal Cancer

Conditions
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Rectal Cancer

Intervention / Treatment
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* Drug: FOLFOXIRI


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Diagnosis of adenocarcinoma of the rectum Age: 18-70 years old Signed informed consent; able to comply with study and/or follow- up procedures Stage of the primary tumor may be determined by ultrasound or MRI Stage II (T3-4, N0 [N0 is defined as all imaged lymph nodes < 1.0 cm]) OR stage III (T1-4, N1-2 [with the definition of a clinically positive lymph node being any node ≥ 1.0 cm] Tumor palpable by digital rectal exam OR accessible by proctoscope or sigmoidoscope Distal border of the tumor must be located < 12 cm from the anal verge Tumor amenable to curative resection Adequate bone marrow, hepatic and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment: Leukocytes ≥ 3.0 x109/ L, absolute neutrophil count (ANC) ≥ 1.5 x109/ L, platelet count ≥ 100 x109/ L, hemoglobin (Hb) ≥ 9g/ dL. Total bilirubin ≤1.5 x the upper limit of normal (ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x ULN. Alkaline phosphatase limit ≤ 5x ULN. Amylase and lipase ≤ 1.5 x the ULN. Serum creatinine ≤ 1.5 x the ULN. Calculated creatinine clearance or 24 hour creatinine clearance ≥ 50 mL/ min. No renal disease that would preclude study treatment or follow-up ECOG status: 0～1 Exclusion Criteria: Hypersensitivity to fluorouracil, oxaliplatin or irinotecan. No More than 4 weeks since prior participation in any investigational drug study More than 4 weeks since prior participation in any investigational drug study Clear indication of involvement of the pelvic side walls by imaging With distant metastasis History of invasive rectal malignancy, regardless of disease-free interval Fertile patients must use effective contraception Uncontrolled hypertension Cardiovascular disease that would preclude study treatment or follow-up Lack of upper gastrointestinal tract integrity or malabsorption syndrome，active upper gastrointestinal tract bleeding Synchronous colon cancer Pregnant or nursing, Fertile patients do not use effective contraception Other malignancy within the past 5 years except effectively treated squamous cell or basal cell skin cancer, melanoma in situ, carcinoma in situ of the cervix, or carcinoma in situ of the colon or rectum No psychiatric or addictive disorders, or other conditions that, in the opinion of the investigator, would preclude study participation patients refused to signed informed consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: FOLFOXIRI<br>patients received FOLFOXIRI alone for 4 cycles before surgery. | Drug: FOLFOXIRI<br>* irinotecan* 165 mg/m² + oxaliplatin 85 mg/m² + leucovorin 200 mg/m² + 5-FU 2800 mg/m² cont. inf. 46h all on day 1 of each 2 weeks cycle<br>* Other names: Irinotecan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The ratio of tumor downstaging to stage 0 and stage I | Tumor downstaging from stage II or III to pathologic complete response (stage 0) and stage I | 2 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average neoadjuvant rectal cancer score | neoadjuvant rectal cancer score (NAR) =[5*pN-3*(cT-pT)+12]^2/9.61 had been proposed and proven to be the surrogate endpoint of overall survival. It refered to the predictive value of lymphnode status and primary tumor downstaging on Overall survival of rectal cancer. | 2 year | 
| the local Recurrence rate | the ratio of patients with local recurrence within 3 years | 3 year | 
| Recurrence free survival | 3 years recurrence free survival of this group of patients | 3 years | 
| Reported Adverse events | Number of patients with adverse events and severity according to NCI CTC 4.0 after treatment with this regimen. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rectal Cancer, Locally advanced rectal cancer, Neoadjuvant, chemotherapy, FOLFOXIRI