A Phase II/III Trial of Neoadjuvant FOLFOX With Selective Use of Combined Modality Chemoradiation Versus Preoperative Combined Modality Chemoradiation for Locally Advanced Rectal Cancer Patients Undergoing Low Anterior Resection With Total Mesorectal Excision
Trial status: Open for Enrollment
Why is this study being done?
OUTLINE: This is a multicenter, phase II/III study. Patients are stratified according to ECOG performance status (0 or 1 vs 2) and randomized to 1 of 2 treatment regimens. Patients will receive full supportive care while on this study.
1. Phase II component: To assure that neoadjuvant FOLFOX followed by selective use of 5FUCMT group (Group 1) maintains the current high rate of pelvic R0 resection and is consistent with non-inferiority for time to local recurrence (TLR).
2. Phase III component: To compare neoadjuvant FOLFOX followed by selective use of 5FUCMT (Group 1) to standard 5FUCMT (Group 2) with respect to the co-primary endpoints of the Time to Local Recurrence (TLR) and Disease-Free Survival (DFS).
1. To determine if the neoadjuvant FOLFOX followed by selective use of 5FUCMT (Group 1) is non-inferior to the standard group 5FUCMT (Group 2) with respect to the proportion of patients who achieve a pathologic complete response (pCR) at the time of surgical resection.
2. To determine if the neoadjuvant FOLFOX followed by selective use of 5FUCMT (Group 1) is non-inferior to the standard 5FUCMT (Group 2) with respect to overall survival.
3. To evaluate and compare the adverse event profile and surgery complications between two groups.
4. To estimate the proportion of patients in the selective group (Group 1) who receive: 1) pre-operative 5FUCMT; 2) post-operative 5FUCMT; 3) either pre- or post-operative 5FUCMT.
Event monitoring of patients will continue up to 8 years post randomization.
Who is eligible to participate?
Registration Inclusion Criteria:
1. Age ≥ 18 years at diagnosis
2. Diagnosis of rectal adenocarcinoma
3. Radiologically measurable or clinically evaluable disease as defined in the protocol
4. ECOG Performance Status (PS): 0, 1 or 2
5. For this patient, the standard treatment recommendation in the absence of a clinical trial would be combined modality neoadjuvant chemoradiation followed by curative intent surgical resection
6. Candidate for sphincter-sparing surgical resection prior to neoadjuvant therapy according to the primary surgeon
7. Primary surgeon is credentialed or is willing to be credentialed in Total Mesorectal Excision (TME), which entails submission of photos of a single TME specimen either before enrolling the first patient or by using the surgeon's 1st accrued case.
8. Clinical Stage: T2N1, T3N0, T3N1. Clinical staging should be estimated based on the combination of the following assessments: physical exam by the primary surgeon, CT scan of the chest/abdomen/pelvis and either a pelvic MRI or an ultrasound (ERUS).
Clinical stage N2 disease is to be estimated as four or more lymph nodes that are ≥ 10mm.
9. Preoperative proctoscopy with distal end of tumor tissue evident between 5 and 12 cm from the anal verge, inclusive. Tumors should not extend below 5cm. Tumors may extend above 12 cm provided distal tumor is located between 5-12 cm.
10. The following laboratory values obtained ≤ 28 days prior to registration:
- Absolute neutrophil count (ANC) ≥ 1500/mm^3
- Platelet count ≥ 100,000/mm^3
- Hemoglobin > 8.0 g/dL
- Total bilirubin ≤ 1.5 x upper limit of normal (ULN)
- SGOT (AST) ≤ 3 x ULN
- SGPT (ALT) ≤ 3 x ULN
- Creatinine ≤1.5 x ULN
11. Negative pregnancy test done ≤ 7 days prior to registration, for women of childbearing potential only.
12. Patient of child-bearing potential is willing to employ adequate contraception.
13. Provide informed written consent
14. Willing to return to enrolling medical site for all study assessments
Registration Exclusion Criteria:
1. Clinical T4 tumors
2. Primary surgeon indicates need for abdominoperineal (APR) at baseline
3. Evidence that tumor is adjacent to (defined as within 3 mm of) the mesorectal fascia on pre-operative MRI or ERUS/pelvic CT scan.
4. Tumor is causing symptomatic bowel obstruction (patients who have had a temporary diverting ostomy are eligible).
5. Chemotherapy within 5 years prior to registration. Hormonal therapy is allowable if the disease free interval is ≥ 5 years.
6. Any prior pelvic radiation
7. Other invasive malignancy ≤ 5 years prior to registration. Exceptions are colonic polyps, non-melanoma skin cancer or carcinoma in-situ of the cervix.
8. Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects.
- Pregnant women
- Nursing women
- Men or women of childbearing potential who are unwilling to employ adequate contraception
9. Co-morbid illnesses or other concurrent disease which, in the judgment of the clinician obtaining informed consent, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.