SWOG-9304 Chemotherapy Plus Radiation Therapy in Treating Patients With Rectal Cancer That Has Been Surgically Removed

Sponsor

Southwest Oncology Group (Other)

Overall Status

Completed

CT.gov ID

NCT00002551

Collaborator

National Cancer Institute (NCI) (NIH), Eastern Cooperative Oncology Group (Other), Radiation Therapy Oncology Group (Other), North Central Cancer Treatment Group (Other), NCIC Clinical Trials Group (Other), Cancer and Leukemia Group B (Other)

1,917

Enrollment

Locations

Arms

175

Duration (Months)

51.8

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. It is not yet known which treatment regimen is more effective for rectal cancer.

PURPOSE: Randomized phase III trial to compare the effectiveness of different regimens of combination chemotherapy plus radiation therapy in treating patients who have rectal cancer that has been surgically removed.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer	Drug: fluorouracil Drug: leucovorin calcium Drug: levamisole hydrochloride Radiation: radiation therapy	Phase 3

Detailed Description

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.

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.

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

Study Design

Study Type:

Interventional

Actual Enrollment :

1917 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Study Start Date :

Mar 1, 1994

Actual Primary Completion Date :

Aug 1, 2006

Actual Study Completion Date :

Oct 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bolus 5-FU, Pelvic XRT + PVI 5-FU, Bolus 5-FU Bolus 5-FU (fluorouracil) (500mg/m2/day on days 1-5, 29-33), Pelvic XRT + PVI 5-FU, Bolus 5-FU (450mg/m2/day for 5 days beginning 28 days after RT, for 2 cycles on days 1-5 of a 28 days cycle).	Drug: fluorouracil See arm assignments. Other Names: 5-FU Radiation: radiation therapy See arm assignments.
Experimental: PVI 5-FU+Pelvic XRT+PVI 5-FU+PVI 5-FU 5-FU (fluorouracil) 300mg/m2/day for 42 days followed by 2 week interruption, Day 57 through XRT will receive 225mg/m2/day of 5-FU followed by 1 month interruption, 4 weeks after completion of XRT 1 8wk cycle of 5-FU 300mg/m2/day.	Drug: fluorouracil See arm assignments. Other Names: 5-FU Radiation: radiation therapy See arm assignments.
Experimental: Bol 5-FU+LV+LEV+Pel XRT+Bol 5-FU+LV Bol 5-FU + LV + LEV 5-FU (fluorouracil) 425/mg/m2/day Days 1-5,29-33; LV (leucovorin calcium) 20mg/m2/day Days 1-5,29-33; LEV (levamisole hydrochloride) 150mg/day (50mg TID) for 3 days every 14 days starting after each course of 5-FU. During RT: 5-FU and LV 4 days on wk 1 and wk 5 of RT. LV 20 mg/m2/day IV bolus within 2hrs after completion of that day's radiation therapy, for four days in each cycle. Followed immediately by 5- FU 400 mg/m2/day IV bolus. Treatment will be given on days 57 - 60 and 85 - 88.Treatment post-RT-chemotherapy 28 days after completion of RT consist of 5 days of chemotherapy in 28 day cycles. 5-FU, 380 mg/m2/day on days 1 - 5 and LV given at a dose of 20 mg/m2/day on days 1 - 5 with the 5-FU given immediately after the LV. For 2 post-radiation cycles on days 1 - 5 of a 28 day cycle. Levamisole will be given orally at a dose of 150 mg/day (50 mg tid) for 3 days every 14 days during the 1st 3 days of each cycle of 5-FU, and again 14 days after starting each course of 5-FU.	Drug: fluorouracil See arm assignments. Other Names: 5-FU Drug: leucovorin calcium See arm assignments. Other Names: leucovorin LV Drug: levamisole hydrochloride See arm assignments. Other Names: LEV Radiation: radiation therapy See arm assignments.

Arm

Intervention/Treatment

Experimental: Bolus 5-FU, Pelvic XRT + PVI 5-FU, Bolus 5-FU

Bolus 5-FU (fluorouracil) (500mg/m2/day on days 1-5, 29-33), Pelvic XRT + PVI 5-FU, Bolus 5-FU (450mg/m2/day for 5 days beginning 28 days after RT, for 2 cycles on days 1-5 of a 28 days cycle).

Drug: fluorouracil

See arm assignments.

Other Names:

5-FU

Radiation: radiation therapy

See arm assignments.

Experimental: PVI 5-FU+Pelvic XRT+PVI 5-FU+PVI 5-FU

5-FU (fluorouracil) 300mg/m2/day for 42 days followed by 2 week interruption, Day 57 through XRT will receive 225mg/m2/day of 5-FU followed by 1 month interruption, 4 weeks after completion of XRT 1 8wk cycle of 5-FU 300mg/m2/day.

Drug: fluorouracil

See arm assignments.

Other Names:

5-FU

Radiation: radiation therapy

See arm assignments.

Experimental: Bol 5-FU+LV+LEV+Pel XRT+Bol 5-FU+LV Bol 5-FU + LV + LEV

5-FU (fluorouracil) 425/mg/m2/day Days 1-5,29-33; LV (leucovorin calcium) 20mg/m2/day Days 1-5,29-33; LEV (levamisole hydrochloride) 150mg/day (50mg TID) for 3 days every 14 days starting after each course of 5-FU. During RT: 5-FU and LV 4 days on wk 1 and wk 5 of RT. LV 20 mg/m2/day IV bolus within 2hrs after completion of that day's radiation therapy, for four days in each cycle. Followed immediately by 5- FU 400 mg/m2/day IV bolus. Treatment will be given on days 57 - 60 and 85 - 88.Treatment post-RT-chemotherapy 28 days after completion of RT consist of 5 days of chemotherapy in 28 day cycles. 5-FU, 380 mg/m2/day on days 1 - 5 and LV given at a dose of 20 mg/m2/day on days 1 - 5 with the 5-FU given immediately after the LV. For 2 post-radiation cycles on days 1 - 5 of a 28 day cycle. Levamisole will be given orally at a dose of 150 mg/day (50 mg tid) for 3 days every 14 days during the 1st 3 days of each cycle of 5-FU, and again 14 days after starting each course of 5-FU.

Drug: fluorouracil

See arm assignments.

Other Names:

5-FU

Drug: leucovorin calcium

See arm assignments.

Other Names:

leucovorin

Drug: levamisole hydrochloride

See arm assignments.

Other Names:

LEV

Radiation: radiation therapy

See arm assignments.

Outcome Measures

Primary Outcome Measures

Survival and Relapse-free survival [Until death]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

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

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CCOP - Scottsdale Oncology Program	Scottsdale	Arizona	United States	85259-5404
2	CCOP - Colorado Cancer Research Program, Inc.	Denver	Colorado	United States	80209-5031
3	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
4	Robert H. Lurie Comprehensive Cancer Center, Northwestern University	Chicago	Illinois	United States	60611
5	Veterans Affairs Medical Center - Chicago (Lakeside)	Chicago	Illinois	United States	60611
6	CCOP - Evanston	Evanston	Illinois	United States	60201
7	CCOP - Illinois Oncology Research Association	Peoria	Illinois	United States	61602
8	CCOP - Carle Cancer Center	Urbana	Illinois	United States	61801
9	CCOP - Cedar Rapids Oncology Project	Cedar Rapids	Iowa	United States	52403-1206
10	CCOP - Iowa Oncology Research Association	Des Moines	Iowa	United States	50309-1016
11	Siouxland Hematology-Oncology	Sioux City	Iowa	United States	51101-1733
12	CCOP - Ochsner	New Orleans	Louisiana	United States	70121
13	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115
14	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
15	CCOP - Ann Arbor Regional	Ann Arbor	Michigan	United States	48106
16	CCOP - Kalamazoo	Kalamazoo	Michigan	United States	49007-3731
17	CCOP - Duluth	Duluth	Minnesota	United States	55805
18	University of Minnesota Cancer Center	Minneapolis	Minnesota	United States	55455
19	CCOP - Metro-Minnesota	Saint Louis Park	Minnesota	United States	55416
20	CCOP - Missouri Valley Cancer Consortium	Omaha	Nebraska	United States	68131
21	Veterans Affairs Medical Center - East Orange	East Orange	New Jersey	United States	07018-1095
22	CCOP - Northern New Jersey	Hackensack	New Jersey	United States	07601
23	Albert Einstein Comprehensive Cancer Center	Bronx	New York	United States	10461
24	Quain & Ramstad Clinic, P.C.	Bismarck	North Dakota	United States	58501
25	CCOP - Merit Care Hospital	Fargo	North Dakota	United States	58122
26	Altru Health Systems	Grand Forks	North Dakota	United States	58201
27	Ireland Cancer Center	Cleveland	Ohio	United States	44106-5065
28	CCOP - Toledo Community Hospital Oncology Program	Toledo	Ohio	United States	43623-3456
29	CCOP - Geisinger Clinical and Medical Center	Danville	Pennsylvania	United States	17822-2001
30	Hahnemann University Hospital	Philadelphia	Pennsylvania	United States	19102-1192
31	Rapid City Regional Hospital	Rapid City	South Dakota	United States	57709
32	CCOP - Sioux Community Cancer Consortium	Sioux Falls	South Dakota	United States	57105-1080
33	CCOP - Marshfield Medical Research and Education Foundation	Marshfield	Wisconsin	United States	54449
34	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
35	Veterans Affairs Medical Center - Milwaukee (Zablocki)	Milwaukee	Wisconsin	United States	53295
36	Saskatchewan Cancer Agency	Regina	Saskatchewan	Canada	S4S 6X3
37	Pretoria Academic Hospital	Pretoria		South Africa	0001

Sponsors and Collaborators

Southwest Oncology Group
National Cancer Institute (NCI)
Eastern Cooperative Oncology Group
Radiation Therapy Oncology Group
North Central Cancer Treatment Group
NCIC Clinical Trials Group
Cancer and Leukemia Group B

Investigators

Study Chair: Stephen R. Smalley, MD, University of Kansas
Study Chair: Al B. Benson, MD, FACP, Robert H. Lurie Cancer Center
Study Chair: Jaffer A. Ajani, MD, M.D. Anderson Cancer Center
Study Chair: Michael J. O'Connell, MD, Mayo Clinic
Study Chair: Anthony LA Fields, MD, FRCPC, Cross Cancer Institute at University of Alberta
Study Chair: Robert J. Mayer, MD, FACP, Dana-Farber Cancer Institute