Postoperative Chemotherapy With or Without Bevacizumab for Patients With Stage II or III Rectal Cancer

Study Overview
=================
Brief Summary
-----------------
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.

Detailed Description
-----------------
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

Official Title
-----------------
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

Conditions
-----------------
Adenocarcinoma of the Rectum, Stage II Rectal Cancer, Stage III Rectal Cancer

Intervention / Treatment
-----------------
* Drug: oxaliplatin
* Drug: fluorouracil
* Drug: leucovorin calcium
* Drug: bevacizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically confirmed adenocarcinoma of the rectum meeting 1 of the following clinical (e.g., before neoadjuvant therapy) or pathologic staging criteria: T3, N+, M0 T3, N0, M0 T4, N0, M0 Any T, N1-2, M0 T4, N0-2, M0 disease must meet 1 of the following criteria: Clinically fixed tumor on rectal examination with tumor adherent to the pelvic sidewall or sacrum Hydronephrosis on Computed Tomography (CT) scan or Intravenous Pyelogram (IVP) Ureteric or bladder invasion as documented by cystoscopy and cytology or biopsy Invasion into prostate Vaginal or uterine involvement Must have undergone complete tumor resection >= 28 days ago and able to begin treatment by day 56 Must have undergone concurrent neoadjuvant chemoradiotherapy* NOTE: *Neoadjuvant chemoradiotherapy received on protocol NSABP-R-04 allowed provided it met these criteria Must have undergone prior radiotherapy at 40-55.8 Gy** AND received 1 of the following chemotherapy regimens: Continuous infusion of fluorouracil with or without oxaliplatin; fluorouracil and leucovorin calcium Capecitabine with or without oxaliplatin; capecitabine with or without oxaliplatin OR a continuous infusion of fluorouracil with or without oxaliplatin received on protocol NSABP-R-04 NOTE: **Intensity-modulated radiotherapy allowed 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: In-range INR (i.e., between 2 and 3) on a stable dose of warfarin or low molecular weight heparin No active bleeding or pathological condition that is associated with a high risk of bleeding 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: New York Heart Association class III or IV congestive heart failure Concurrent symptomatic arrhythmia 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: Major surgical procedure or open biopsy within the past 28 days Core biopsy or other minor procedure, except placement of a vascular access device, within the past 7 days

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I<br>Patients receive oxaliplatin 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. | Drug: oxaliplatin<br>* Given IV<br>* Other names: L-OHP;Drug: fluorouracil<br>* Given IV<br>* Other names: 5-FU;Drug: leucovorin calcium<br>* Given IV<br>* Other names: LV;|
| Experimental: Arm II<br>Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive oxaliplatin, leucovorin calcium, and fluorouracil as in arm I. | Drug: oxaliplatin<br>* Given IV<br>* Other names: L-OHP;Drug: fluorouracil<br>* Given IV<br>* Other names: 5-FU;Drug: leucovorin calcium<br>* Given IV<br>* Other names: LV;Drug: bevacizumab<br>* Given IV<br>* Other names: rhuMAb VEGF;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5-year Overall Survival Rate | Overall survival (OS) was defined as time from randomization to date of death from any cause. Patients who were still alive were censored at last date of known alive. Kaplan-Meier method was used to estimate the 5-year OS rate. | Follow-up assessments performed every 3 months for patients < 2 years from randomization, every 6 months for patients 2-5 years from randomization, and every 12 months for patients 5-10 years from randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 5-year Disease-free Survival Rate | Disease-free survival (DFS) was defined as time from randomization to recurrence, second invasive primary cancer or death, whichever occurred first. Patients who were still alive and had no DFS events were censored at the last disease assessment date known to be free of DFS events. Kaplan-Meier method was used to estimate 5-year DFS rate. | Follow-up assessments performed every 3 months for patients < 2 years from randomization, every 6 months for patients 2-5 years from randomization, and every 12 months for patients 5-10 years from randomization | 
| Patterns of Failure | Failure included recurrence, second primary cancer and death without recurrence. | Follow-up assessments performed every 3 months for patients < 2 years from randomization, every 6 months for patients 2-5 years from randomization, and every 12 months for patients 5-10 years from randomization | 
| Proportion of Patients Who Completed 12 Cycles of Treatment | In the study, treatment was repeated every 2 weeks for a total of 12 cycles on both arms. The total number of cycles of treatment patient received until going off treatment due to any reason was recorded. It was a measure of the tolerance of the therapy. | assessed at the end of treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Rectal cancer, Bevacizumab