Intergroup Randomized Phase III Study of Postoperative Oxaliplatin, 5-Fluorouracil and Leucovorin vs Oxaliplatin, 5-Fluorouracil, Leucovorin and Bevacizumab for Patients With Stage II or III Rectal Cancer Receiving Pre-operative Chemoradiation
Intergroup Randomized Phase III Study of Postoperative Oxaliplatin, 5-Fluorouracil and Leucovorin vs Oxaliplatin, 5-Fluorouracil, Leucovorin and Bevacizumab for Patients With Stage II or III Rectal Cancer Receiving Pre-operative Chemoradiation
Drugs used in chemotherapy, such as oxaliplatin, leucovorin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving more than one drug (combination chemotherapy) together with bevacizumab after surgery may kill any tumor cells that remain after surgery. It is not yet known whether oxaliplatin, leucovorin, and fluorouracil is more effective with or without bevacizumab in treating rectal cancer. This randomized phase III trial is studying combination chemotherapy to see how well it works with or without bevacizumab in treating patients who have had surgery for stage II or stage III rectal cancer.
PRIMARY OBJECTIVES:
I. Compare the overall survival of patients who have undergone prior surgery and neoadjuvant chemoradiotherapy for clinical stage II or III rectal cancer treated with adjuvant oxaliplatin, leucovorin calcium, fluorouracil with vs without bevacizumab.
SECONDARY OBJECTIVES:
I. Evaluate tolerance of treatment, patterns of failure, and disease-free survival in patients treated with these regimens
EXPLORATORY OBJECTIVES:
I. Assess long-term rectal function using the Patient Bowel Function/Uniscale questionnaire and the Functional Assessment of Cancer (FACT)-Diarrhea subscale in patients treated with these regimens.
II. Validate the FACT-Diarrhea subscale. III. Assess long-term symptoms of oxaliplatin-related neurotoxicity using the FACT/Gynecologic Oncology Group (GOG)-Neurotoxicity subscale in patients treated with these regimens.
IV. Correlate TS, DPD and TP expression (key targets for fluorouracil); retention of chromosome 18q alleles and microsatellite instability (MSI) with TGFβ1RII mutation (markers for fluorouracil efficacy); ERCC1, ERCC2, and XPF expression (participants in repair of adducts from oxaliplatin); and p53 gene mutation and possibly other molecular markers pertinent to vascular endothelial growth factor in tumor tissue specimens with treatment efficacy in these patients.
V. Correlate tumor molecular prognostic markers (chromosome 18q allelic loss and MSI) with survival in patients treated with this regimen.
OUTLINE:
This is a randomized study. Patients are stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1), clinical staging (high risk [T3, N+, M0 or T4, any N, M0] vs low risk [T1-2, N+, M0 or T3, N0, M0]), prior pre-operative oxaliplatin (yes vs no), and prior radiotherapy dose (40-50 Gy vs > 50-55.8 Gy). Patients are randomized to 1 of 2 treatment arms in a 1:1 ratio.
ARM I: Patients receive oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV on day 1 followed by fluorouracil IV continuously over 46 hours on days 1 and 2. Treatment repeats every 2 weeks for up to 12 courses* in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive bevacizumab** IV over 30-90 minutes on day 1. Patients also receive oxaliplatin, leucovorin calcium, and fluorouracil as in arm I*.
[Note: *Patients who received prior neoadjuvant oxaliplatin including patients on protocol NSABP-R-04 receive up to 9 courses of treatment followed by leucovorin calcium IV and fluorouracil IV with (arm II) or without (arm I) bevacizumab for up to 3 courses.]
[Note: **Patients no longer receive bevacizumab as of 4/29/2009 when accrual was terminated due to slow accrual for the study)]
Patients complete 10-15 minute questionnaires about bowel function at randomization, end of treatment, 12 months post-treatment and then annually to 5 years post-treatment.
After completion of study treatment, patients are followed periodically for approximately 10 years.
PROJECTED ACCRUAL: 2100 patients
Inclusion Criteria:
Histologically confirmed adenocarcinoma of the rectum meeting 1 of the following clinical (e.g., before neoadjuvant therapy) or pathologic staging criteria:
T4, N0-2, M0 disease must meet 1 of the following criteria:
Must have undergone complete tumor resection >= 28 days ago and able to begin treatment by day 56
Must have undergone concurrent neoadjuvant chemoradiotherapy*
Must have undergone prior radiotherapy at 40-55.8 Gy** AND received 1 of the following chemotherapy regimens:
ECOG performance status 0-1
Platelet count >= 100,000/mm^3
Absolute granulocyte count >= 1,500/mm^3
Bilirubin normal (unless chronic grade 1 bilirubin elevation due to Gilbert's disease or similar syndrome due to slow conjugation of bilirubin)
Alkaline phosphatase (AP) < 2.5 times upper limit of normal (ULN) and aspartate aminotransferase (AST) < 1.5 times ULN
Hepatitis B and C negative (for patients with AP > normal) unless previously vaccinated
Serum creatinine =< 1.5 times ULN
Urine protein:creatinine (UPC) ratio < 1.0 OR urine protein < 1 g on 24-hour urine collection
International Normalized Ratio (INR) =< 1.5
INR > 1.5 allowed provided patient is on full-dose anticoagulants AND meets all of the following criteria:
Negative pregnancy test
Fertile patients must use effective contraception during and for at least 3 months after study treatment
No other previous or concurrent malignancy except nonmelanoma skin cancer, breast cancer in situ, carcinoma in situ of the cervix, or previously treated nonpelvic cancer that has been disease-free for > 5 years
Patients with a history of breast cancer (without evidence of disease) who remain on hormonal therapy for > 5 years are eligible
Patients with a history of hypertension must have blood pressure < 150/90 mm Hg AND be on a stable regimen of antihypertensive therapy
No other prior chemotherapy or pelvic radiotherapy except as neoadjuvant treatment for current diagnosis of rectal cancer
Concurrent participation on protocol NSABP-R-04 allowed
Exclusion Criteria:
Pregnant or nursing
Evidence of metastatic disease on the surgical/intraoperative examination
Evidence of metastatic disease confirmed by CT scan, Magnetic resonance imaging (MRI), or ultrasound of the liver or chest CT scan or chest x-ray within the past 6 months
Evidence of tumor outside of the pelvis, including liver metastases, peritoneal seeding, or metastatic inguinal lymphadenopathy
Concurrent major surgery
Active bleeding not related to the primary rectal tumor within the past 6 months
Active inflammatory bowel disease or other serious medical illness which might limit the ability of the patient to receive protocol therapy
Active gastroduodenal ulcer determined by endoscopy
Serious or nonhealing wound, skin ulcer, or bone fracture
Clinically significant peripheral sensory or motor neuropathy >= grade 2
Nonmalignant systemic disease (e.g., cardiovascular, renal, or hepatic) that would preclude study treatment including, but not limited to, any of the following:
Transient ischemic attack or cerebrovascular accident
Arterial thromboembolic event, unstable angina, or myocardial infarction within the past 12 months
Significant peripheral vascular disease
Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude study requirements
Significant traumatic injury within the past 28 days
Known allergy to platinum compounds
Prior invasive procedure, including either of the following:
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