Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Trial Contact Information
Registry Information

Alternate Title

Chemotherapy Plus Radiation Therapy in Treating Patients With Rectal Cancer That Has Been Surgically Removed

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase III Treatment Closed over 18 NCI SWOG-9304 CAN-NCIC-CO11, CLB-9491, E-S9304, NCCTG-934751, RTOG-9403, CLB-C9491, INT-0144, NCT00002551, CO11

Objectives

I.  Compare the overall and relapse free survival of patients with stage II or 
III rectal cancer treated with one of the following three regimens:  bolus 
injections of fluorouracil (5-FU) prior to and following pelvic irradiation 
plus protracted venous infusion (PVI) 5-FU radiosensitization vs PVI 5-FU 
prior to and following pelvic irradiation plus PVI 5-FU radiosensitization vs 
bolus 5-FU with leucovorin calcium and levamisole prior to and following 
pelvic irradiation.

II.  Describe relapse patterns and tolerance associated with these regimens in 
these patients.

Entry Criteria

Disease Characteristics:

Histologically proven stage II or III adenocarcinoma of the rectum
 Tumor extends through the bowel wall and into perirectal fat or soft tissue
  (TNM T3-4, N0, M0)
 Nodes are involved with tumor (TNM T1-4, N1-3, M0)

Tumor completely resected en bloc with no gross or microscopic evidence of
residual disease
 Circumferential (radial) margins of resected adherent tumors must be
  specifically documented free of disease (with the sole exception of
  extraperitoneal serosal margins)

No evidence of metastasis
 No regional nodal metastases (metastases outside of the pelvis) that cannot
  be resected en bloc with the primary lesion

 No distant peritoneal metastases (metastases that are not a direct extension
  from the primary tumor) even if grossly resected (direct extension into
  another structure permitted)

Abdominopelvic CT required unless:
 Bilirubin, SGOT, and alkaline phosphatase are within normal limits, AND
 Operative report describes liver as normal on exploration

No tumors of colonic origin, i.e.:
 Lower edge of the tumor is below the peritoneal reflection or a portion of
  the tumor is retroperitoneally located (usually posteriorly) as defined by
  the surgeon at laparotomy OR
 Lower margin of the tumor is 12 cm or less from the anal verge by
  proctoscopic exam

No prior history of rectal cancer

No stage II or III cancers of the extrapelvic colon within the past 5 years
 Complete surgical resection at least 5 years prior to protocol registration
  allowed provided no other therapy was administered

Synchronous modified stage I or IIa colorectal cancer (no nodal
involvement or penetration through the muscularis propria) that has been
completely resected allowed

Registration between 20 and 70 days after the definitive surgical procedure
required
 Chemotherapy must begin no later than day 70 following surgery

Concurrent registration on protocol SWOG-9419 allowed for patients with
adequate tissue samples

Prior/Concurrent Therapy:

Biologic therapy:
 No prior immunotherapy

Chemotherapy:
 No prior chemotherapy

Endocrine therapy:
 Not specified

Radiotherapy:
 No prior radiotherapy

Surgery:
 See Disease Characteristics

Other:
 No other concurrent antineoplastic therapy

Patient Characteristics:

Age:
 Over 18

Performance status:
 SWOG 0-2

Hematopoietic:
 WBC at least 4,000/mm3
 Platelet count normal

Hepatic:
 Bilirubin no greater than 2 times upper limit of normal (ULN)
 SGOT no greater than 2 times ULN
 Alkaline phosphatase no greater than 2 times ULN

Renal:
 Not specified

Other:
 No chronic ulcerative colitis
 No other serious medical illness that would preclude protocol therapy
 No psychiatric condition that would preclude informed consent
 No noncolorectal malignancy within 5 years except:
  Adequately treated nonmelanomatous skin cancer
  Adequately treated carcinoma in situ of the cervix
 Not pregnant or nursing
 Negative pregnancy test 
 Fertile patients must use effective contraception

Expected Enrollment

A total of 1,800 patients (600 per arm) will be accrued for this study.

Outline

This is a randomized, multicenter study. Patients are stratified according to 
type of prior surgery (abdominoperineal resection vs anterior resection), 
nodal status (N0 vs N1 vs N2-3), depth of tumor invasion (T1-2 vs T3 vs T4a vs 
T4b), time from surgery to study entry (20-45 days vs 46-70 days), 
participating center, and performance status (0-1 vs 2).  Patients are 
randomized to one of three treatment arms.

Arm I:  Patients receive fluorouracil (5-FU) IV on days 1-5 and 29-33.  5-FU 
is then given as a continuous infusion beginning on day 57 and continuing 
concurrently with radiotherapy for 5 weeks.  Following a 28 day break from 
treatment patients receive 5-FU IV on days 1-5 of a 28 day course.  
Postradiotherapy treatment repeats for a total of 2 courses in the absence of 
disease progression or unacceptable toxicity.

Arm II:  Patients receive 5-FU IV continuously on days 1-42.  5-FU and 
radiotherapy are then administered as in arm II.

Arm III:  Patients receive leucovorin calcium (CF) IV followed by 5-FU IV on 
days 1-5 and 29-33.  Patients also receive oral levamisole twice daily on days 
1-3, 15-17, 29-31, and 43-45.  CF IV and 5-FU IV are then given on days 57-60 
and 85-88 concurrently with radiotherapy.  Following a 28 day break from 
treatment patients receive CF IV and 5-FU IV on days 1-5 and 29-33 and oral 
levamisole twice daily on days 1-3, 15-17, 29-31, and 43-45 in the absence of 
disease progression or unacceptable toxicity.

All patients receive radiotherapy 5 days per week for 5 weeks starting on day 
57.

Patients are followed every 4 months for 2 years, then every 6 months for 4 
years, and then annually until death.

Ulrich CM, Rankin C, Holmes RS, et al.: Polymorphisms in folate-metabolizing enzymes and response to 5-fluorouracil among stage II or III rectal cancer patients (SWOG 9304). [Abstract] American Society of Clinical Oncology 2008 Gastrointestinal Cancers Symposium, 25-27 January 2008, Orlando, FL. A-309, 2008.

Zhang W, Rankin CJ, Danenberg KD, et al.: An update of pharmacogenetic analysis of adjuvant rectal cancer patients treated with 5-fluorouracil and pelvic radiation in a phase III intergroup trial (INT-0144, SWOG 9304). [Abstract] J Clin Oncol 26 (Suppl 15): A-4115, 2008.

Zhang W, Rankin C, Nagashima F, et al.: Pharmacogenetic analysis of stage II/III rectal cancer patients treated with 5-fluorouracil and pelvic radiation in a phase III intergroup trial (INT-0144, SWOG 9304). [Abstract] American Society of Clinical Oncology 2008 Gastrointestinal Cancers Symposium, 25-27 January 2008, Orlando, FL. A-300, 2008.

Smalley SR, Benedetti JK, Williamson SK, et al.: Phase III trial of fluorouracil-based chemotherapy regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144. J Clin Oncol 24 (22): 3542-7, 2006.[PUBMED Abstract]

Smalley SR, Benedetti J, Williamson S, et al.: Intergroup 0144 - phase III trial of 5-FU based chemotherapy regimens plus radiotherapy (XRT) in postoperative adjuvant rectal cancer. Bolus 5-FU vs prolonged venous infusion (PVI) before and after XRT + PVI vs bolus 5-FU + leucovorin (LV) + levamisole (LEV) before and after XRT + bolus 5-FU + LV. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-1006, 2003.

Trial Contact Information

Trial Lead Organizations

Southwest Oncology Group

Stephen Smalley, MD, Protocol chair(Contact information may not be current)		Ph: 913-588-3610

Eastern Cooperative Oncology Group

Al Benson, MD, FACP, Protocol chair		Ph: 312-695-6180

Radiation Therapy Oncology Group

Jaffer Ajani, MD, Protocol chair		Ph: 713-792-2828; 800-392-1611 Email: jajani@mdanderson.org

North Central Cancer Treatment Group

Michael O'Connell, MD, Protocol chair(Contact information may not be current)		Ph: 507-284-2511

NCIC-Clinical Trials Group

Anthony Fields, MD, FRCPC, Protocol chair		Ph: 780-432-8756 Email: alaf@cancerboard.ab.ca

Cancer and Leukemia Group B

Robert Mayer, MD, FACP, Protocol chair		Ph: 617-632-3474; 866-790-4500

Registry Information
Official Title		POSTOPERATIVE EVALUATION OF 5-FU BY BOLUS INJECTION VS. 5-FU BY PROLONGED VENOUS INFUSION PRIOR TO AND FOLLOWING COMBINED PROLONGED VENOUS INFUSION PLUS PELVIC XRT VS. BOLUS 5-FU PLUS LEUCOVORIN PLUS LEVAMISOLE PRIOR TO AND FOLLOWING COMBINED PELVIC XRT PLUS BOLUS 5-FU PLUS LEUCOVORIN IN PATIENTS WITH RECTAL CANCER, PHASE III
Trial Start Date		1994-03-01
Registered in ClinicalTrials.gov		NCT00002551
Date Submitted to PDQ		1994-03-01
Information Last Verified		2008-06-06
NCI Grant/Contract Number		U10-CA32102