Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Related Information
Registry Information

Alternate Title

Combination Chemotherapy With or Without Bevacizumab in Treating Patients Who Have Had Surgery for Stage II or Stage III Rectal Cancer

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III Biomarker/Laboratory analysis, Treatment Active 18 and over NCI ECOG-E5204 E5204, NSABP-ECOG-E5204, NCCTG-ECOG-E5204, NCT00303628

Special Category: NCI Web site featured trial, NCI - CMS pilot project trial

Objectives

Primary

1. 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 postoperative bevacizumab.

Secondary

1. Evaluate tolerance of treatment, patterns of failure, and disease-free survival in patients treated with these regimens.
2. 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.
3. Validate the FACT-Diarrhea subscale.
4. Assess long-term symptoms of oxaliplatin-related neurotoxicity using the FACT/GOG-Neurotoxicity subscale in patients treated with these regimens.
5. 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.
6. Correlate tumor molecular prognostic markers (chromosome 18q allelic loss and MSI) with survival in patients treated with this regimen.

Entry Criteria

Disease Characteristics:

• 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 CT scan or 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
  • No evidence of metastatic disease on the surgical/intraoperative examination



• Must have undergone concurrent neoadjuvant chemoradiotherapy*
  • Must have undergone prior radiotherapy at a dose of 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
    • Oxaliplatin and capecitabine OR a continuous infusion of fluorouracil and oxaliplatin received on protocol NSABP-R-04

   [Note: *Neoadjuvant chemoradiotherapy received on protocol NSABP-R-04 allowed provided it met these criteria]

   [Note: **Intensity-modulated radiotherapy allowed]




• No evidence of metastatic disease confirmed by CT scan, MRI, or ultrasound of the liver or chest CT scan or chest x-ray within the past 6 months



• No evidence of tumor outside of the pelvis, including liver metastases, peritoneal seeding, or metastatic inguinal lymphadenopathy

Prior/Concurrent Therapy:

• See Disease Characteristics
• No other prior chemotherapy or pelvic radiotherapy except as neoadjuvant treatment for current diagnosis of rectal cancer
• No 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
• No concurrent major surgery
• Concurrent participation on protocol NSABP-R-04 allowed

Patient Characteristics:

• ECOG performance status 0-1
• Platelet count ≥ 100,000/mm³
• Absolute granulocyte count ≥ 1,500/mm³
• 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 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
• 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
• Not pregnant or nursing
• 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
• No active bleeding not related to the primary rectal tumor within the past 6 months
• No active inflammatory bowel disease or other serious medical illness which might limit the ability of the patient to receive protocol therapy
• No active gastroduodenal ulcer determined by endoscopy
• No serious or nonhealing wound, skin ulcer, or bone fracture
• No clinically significant peripheral sensory or motor neuropathy ≥ grade 2
• No 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
• No transient ischemic attack or cerebrovascular accident
• No arterial thromboembolic event, unstable angina, or myocardial infarction within the past 12 months
• No significant peripheral vascular disease
• No psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude study requirements
• Patients with a history of hypertension must have blood pressure < 150/90 mm Hg AND be on a stable regimen of antihypertensive therapy
• No significant traumatic injury within the past 28 days
• No known allergy to platinum compounds

Expected Enrollment

A total of 2,100 patients will be accrued for this study.

Outcomes

Overall survival

Tolerability
Patterns of failure (local/regional and distant recurrence)
Disease-free survival

Outline

This is a randomized study. Patients are stratified according to 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 pre-operatively). Patients are randomized to 1 of 2 treatment arms.

• Arm I: 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* 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.]

Patients complete 10-15 minute questionnaires about bowel function 4 times during study treatment.

After completion of study treatment, patients are followed periodically for approximately 10 years.

Trial Contact Information

Trial Lead Organizations

Eastern Cooperative Oncology Group

Al Benson, MD, FACP, Protocol chair		Ph: 312-695-6180
Neal Meropol, MD, Protocol co-chair		Ph: 215-728-2450; 888-369-2427

National Surgical Adjuvant Breast and Bowel Project

Nicholas Petrelli, MD, Protocol chair		Ph: 302-623-4500 Email: npetrelli@christianacare.org

North Central Cancer Treatment Group

Frank Sinicrope, MD, Protocol chair		Ph: 507-538-7623 Email: cancerclinicaltrials@mayo.edu

NCIC-Clinical Trials Group

J. D. Brierley, MD, Protocol chair		Ph: 416-946-2124 Email: james.brierly@rmp.uhn.on.ca

U.S.A.
Alabama
	Mobile
	Providence Cancer Center at Providence Hospital
		Paul Schwarzenberger, MD	Ph:  251-544-1013
Alaska
	Anchorage
	Providence Cancer Center
		Clinical Trials Office - Providence Cancer Center	Ph:  907-261-3109
Arizona
	Scottsdale
	Mayo Clinic Scottsdale
		Clinical Trials Office - All Mayo Clinic Locations	Ph:  507-538-7623
Arkansas
	Jonesboro
	Ben E. Owens Cancer Treatment Center at St. Bernard's Medical Center
		Clinical Trials Office - Ben E. Owens Cancer Treatment Center at St. Bernard's Medical Center	Ph:  870-972-4100
California
	Berkeley
	Alta Bates Summit Comprehensive Cancer Center
		Clinical Trials Office - Alta Bates Summit Comprehensive Cancer Center	Ph:  510-204-3428
	Burbank
	Providence Saint Joseph Medical Center - Burbank
		Clinical Trials Office - Providence Saint Joseph Medical Center - Burbank	Ph:  818-847-3220
	Burlingame
	Peninsula Medical Center
		David Irwin, MD	Ph:  510-204-1591
	Castro Valley
	East Bay Radiation Oncology Center
		James Feusner, MD	Ph:  510-428-3689
	Valley Medical Oncology Consultants - Castro Valley
		James Feusner, MD	Ph:  510-428-3689
	Concord
	Cancer Care Center at John Muir Health - Concord Campus
		Clinical Trials Office - Cancer Care Center at John Muir Health - Concord Campus	Ph:  925-674-2580
	Fremont
	Kaiser Permanente - Fremont
		Louis Fehrenbacher, MD	Ph:  707-651-2577
	Valley Medical Oncology
		James Feusner, MD	Ph:  510-428-3689
	Fresno
	Cancer Care Associates
		Steven Hager, DO	Ph:  559-326-1222
	Fullerton
	Virginia K. Crosson Cancer Center at St. Jude Medical Center
		Clinical Trials Office - Virginia K. Crosson Cancer Center	Ph:  714-446-5642
	Glendale
	Glendale Memorial Hospital Comprehensive Cancer Center
		Clinical Trials Office - Glendale Memorial Hospital Comprehensive Cancer Center	Ph:  818-409-7653
	Greenbrae
	Marin Cancer Institute at Marin General Hospital
		David Irwin, MD	Ph:  510-204-1591
	Sutter Health - Western Division Cancer Research Group
		David Irwin, MD	Ph:  510-204-1591
	Hayward
	Kaiser Permanente Medical Center - Hayward
		Louis Fehrenbacher, MD	Ph:  707-651-2577
	La Jolla
	Rebecca and John Moores UCSD Cancer Center
		Clinical Trials Office - Rebecca and John Moores UCSD Cancer Center	Ph:  858-822-5354
			Email: cancercto@ucsd.edu
	Loma Linda
	Loma Linda University Cancer Institute at Loma Linda University Medical Center
		Clinical Trials Office - Loma Linda University Cancer Institute	Ph:  909-558-3375
	Los Angeles
	USC/Norris Comprehensive Cancer Center and Hospital
		Clinical Trials Office - USC/Norris Comprehensive Cancer Center and Hospital	Ph:  323-865-0451
	Martinez
	Contra Costa Regional Medical Center
		James Feusner, MD	Ph:  510-428-3689
	Marysville
	Tibotec Therapeutics - Division of Ortho Biotech Products, LP
		Michael Tanaka, MD	Ph:  916-734-3772
	Modesto
	Memorial Medical Center
		Clinical Trials Office - Memorial Medical Center	Ph:  209-572-7116
	Monterey
	Community Hospital of the Monterey Peninsula Comprehensive Cancer Center
		Jerome Rubin, MD	Ph:  831-375-4777
	Mountain View
	Camino Medical Group - Treatment Center
		Peter Yu, MD	Ph:  408-524-5814
	Oakland
	Alta Bates Summit Medical Center - Summit Campus
		Clinical Trials Office - Alta Bates Summit Medical Center - Summit Campus	Ph:  510-204-1414
	Bay Area Breast Surgeons, Incorporated
		James Feusner, MD	Ph:  510-428-3689
	CCOP - Bay Area Tumor Institute
		James Feusner, MD	Ph:  510-428-3689
	Highland General Hospital
		James Feusner, MD	Ph:  510-428-3689
	Kaiser Permanente Medical Center - Oakland
		Louis Fehrenbacher, MD	Ph:  707-651-2577
	Larry G Strieff MD Medical Corporation
		James Feusner, MD	Ph:  510-428-3689
	Tom K Lee, Incorporated
		James Feusner, MD	Ph:  510-428-3689
	Palm Springs
	Desert Regional Medical Center Comprehensive Cancer Center
		Clinical Trials Office - Desert Regional Medical Center Comprehensive Cancer Center	Ph:  760-416-4730
	Palo Alto
	Palo Alto Medical Foundation
		Peter Yu, MD	Ph:  408-524-5814
	Pleasanton
	Valley Care Medical Center
		James Feusner, MD	Ph:  510-428-3689
	Valley Medical Oncology Consultants - Pleasanton
		James Feusner, MD	Ph:  510-428-3689
	Redwood City
	Kaiser Permanente Medical Center - Redwood City
		Louis Fehrenbacher, MD	Ph:  707-651-2577
	Richmond
	Kaiser Permanente Medical Center - Richmond
		Louis Fehrenbacher, MD	Ph:  707-651-2577
	Roseville
	Kaiser Permanente Medical Center - Roseville
		Louis Fehrenbacher, MD	Ph:  707-651-2577
	Sacramento
	Kaiser Permanente Medical Center - Sacramento
		Louis Fehrenbacher, MD	Ph:  707-651-2577
	South Sacramento Kaiser-Permanente Medical Center
		Louis Fehrenbacher, MD	Ph:  707-651-2577
	University of California Davis Cancer Center
		Clinical Trials Office - University of California Davis Cancer Center	Ph:  916-734-3089
	Salinas
	Salinas Valley Memorial Hospital
		Shehzad Aziz, MD	Ph:  831-755-1701
	San Diego
	Kaiser Permanente Medical Office -Vandever Medical Office
		Jonathan Polikoff, MD	Ph:  619-528-5888
	San Francisco
	California Pacific Medical Center - California Campus
		David Irwin, MD	Ph:  510-204-1591
	Kaiser Permanente Medical Center - San Francisco Geary Campus
		Louis Fehrenbacher, MD	Ph:  707-651-2577
	San Jose
	Kaiser Permanente Medical Center - Santa Teresa
		Louis Fehrenbacher, MD	Ph:  707-651-2577
	San Pablo
	Doctors Medical Center - San Pablo Campus
		James Feusner, MD	Ph:  510-428-3689
	San Rafael
	Kaiser Foundation Hospital - San Rafael
		Louis Fehrenbacher, MD	Ph:  707-651-2577
	Santa Clara
	Kaiser Permanente Medical Center - Santa Clara Kiely Campus
		Louis Fehrenbacher, MD	Ph:  707-651-2577
	Santa Rosa
	Kaiser Permanente Medical Center - Santa Rosa
		Louis Fehrenbacher, MD	Ph:  707-651-2577
	South San Francisco
	Kaiser Permanente Medical Center - South San Francisco
		Louis Fehrenbacher, MD	Ph:  707-651-2577
	Stockton
	Kaiser Permanente Medical Facility - Stockton
		Louis Fehrenbacher, MD	Ph:  707-651-2577
	Truckee
	Tahoe Forest Cancer Center
		Michael Tanaka, MD	Ph:  916-734-3772
	Vallejo
	Kaiser Permanente Medical Center - Vallejo
		Louis Fehrenbacher, MD	Ph:  707-651-2577
	Sutter Solano Medical Center
		David Irwin, MD	Ph:  510-204-1591
	Walnut Creek
	John Muir/Mt. Diablo Comprehensive Cancer Center
		Clinical Trials Office - John Muir/Mt. Diablo Comprehensive Cancer Center	Ph:  925-941-4246
	Kaiser Permanente Medical Center - Walnut Creek
		Louis Fehrenbacher, MD	Ph:  707-651-2577
Colorado
	Aurora
	Aurora Presbyterian Hospital
		Eduardo Pajon, MD	Ph:  303-399-8020ext2261
	Boulder
	Boulder Community Hospital
		Clinical Trials Office - Boulder Community Hospital	Ph:  303-938-5253
	Colorado Springs
	Penrose Cancer Center at Penrose Hospital
		Clinical Trials Office - Penrose Cancer Center	Ph:  719-776-5275
	Denver
	CCOP - Colorado Cancer Research Program
		Eduardo Pajon, MD	Ph:  303-399-8020ext2261
	Presbyterian - St. Luke's Medical Center
		Clinical Trials Office - Presbyterian - St. Luke's Medical Center	Ph:  303-839-6000
	Rose Medical Center
		Eduardo Pajon, MD	Ph:  303-399-8020ext2261
	St. Anthony Central Hospital
		Eduardo Pajon, MD	Ph:  303-399-8020ext2261
	St. Joseph Hospital
		Eduardo Pajon, MD	Ph:  303-399-8020ext2261
	Englewood
	Swedish Medical Center
		Eduardo Pajon, MD	Ph:  303-399-8020ext2261
	Fort Collins
	Front Range Cancer Specialists
		Robert Marschke, Jr.	Ph:  970-212-7600
	Poudre Valley Hospital
		Clinical Trials Office - Poudre Valley Hospital	Ph:  970-495-8226
	Grand Junction
	St. Mary's Regional Cancer Center at St. Mary's Hospital and Medical Center
		Eduardo Pajon, MD	Ph:  303-399-8020ext2261
	Greeley
	North Colorado Medical Center
		Eduardo Pajon, MD	Ph:  303-399-8020ext2261
	Lone Tree
	Sky Ridge Medical Center
		Eduardo Pajon, MD	Ph:  303-399-8020ext2261
	Longmont
	Hope Cancer Care Center at Longmont United Hospital
		Eduardo Pajon, MD	Ph:  303-399-8020ext2261
	Loveland
	McKee Medical Center
		Eduardo Pajon, MD	Ph:  303-399-8020ext2261
	Pueblo
	St. Mary - Corwin Regional Medical Center
		Eduardo Pajon, MD	Ph:  303-399-8020ext2261
	Thornton
	North Suburban Medical Center
		Eduardo Pajon, MD	Ph:  303-399-8020ext2261
	Wheat Ridge
	Exempla Lutheran Medical Center
		Clinical Trials Office - Exempla Lutheran Medical Center	Ph:  303-403-3605
Connecticut
	Norwich
	Eastern Connecticut Hematology and Oncology Associates
		Dennis Slater, MD	Ph:  860-886-8362
	Stamford
	Carl and Dorothy Bennett Cancer Center at Stamford Hospital