Conditions: Adenocarcinoma of the Rectum Stage II Rectal Cancer Stage III Rectal Cancer
Keywords: Rectal cancer Bevacizumab
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 355
Healthy volunteers: no

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

Arms:
arm 1: 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. arm 2: Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive oxaliplatin, leucovorin calcium, and fluorouracil as in arm I.

Interventions: intervention 1: oxaliplatin intervention 2: fluorouracil intervention 3: leucovorin calcium intervention 4: bevacizumab
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given IV

Protocol document: