Perioperative Chemotherapy in Treating Patients With Colon Cancer That Can Be Surgically Removed

Phase III Intergroup Prospectively Randomized Trial of Perioperative 5-FU After Curative Resection, Followed by 5-FU/Leucovorin for Patients With Colon Cancer

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug and giving drugs in different ways may kill more tumor cells. It is not yet known if surgery is more effective with or without chemotherapy for colon cancer.

PURPOSE: Randomized phase III trial to evaluate whether perioperative 5-Fluorouracil (5-FU) chemotherapy after curative resection could improve overall survival and disease-free survival in patients with Duke's B3 or C colon cancer.

Study Overview

• Status: Terminated
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: fluorouracil; Drug: leucovorin calcium

Detailed Description

OBJECTIVES:

I. To determine if adjuvant therapy with one week of continuous 5-FU given within 24 hours of a curative colon resection followed by 6 months of 5-FU/leucovorin is effective in prolonging the disease-free survival and increasing overall survival in patients with Dukes' B3 or C colon cancer, when compared to patients who are treated with 5-FU/leucovorin only.

II. 1. To determine if a week of perioperative continuous 5-FU affects disease-free survival and overall survival in patients with Dukes' B2 colon cancer.

OUTLINE: This is an open-label, randomized phase III study. Patients undergo curative colon resection via laparotomy. Patients are randomized to 1 of 2 arms in a 1:1 ratio.

Arm I (Perioperative 5-FU): Within 24 hours of the colon resection, patients receive perioperative 5-fluorouracil (5-FU) intravenously (IV) over 24 hours for 7 days.

Arm II (No perioperative 5-FU): Patients receive no perioperative fluorouracil.

After surgery, patients with stage I, stage IIA, or stage IV colon cancer are immediately removed from study. Patients with stage IIB, IIC, or III colon cancer are re-registered within 35 days postoperatively. Beginning 21-35 days after surgery, patients with stage IIC or III disease receive leucovorin calcium IV bolus immediately followed by 5-FU IV bolus on days 1-5. Courses repeat every 28 days for a total of 6 courses in the absence of disease progression or unacceptable toxicity. Patients with stage IIB disease do not receive adjuvant 5-FU and leucovorin calcium.

Patients are followed every 3 months for 2 years, then every 6 months for 2 years, and then annually until 15 years.

PROJECTED ACCRUAL: A total of 800-2,000 patients (at least 400 per treatment arm) will be accrued for this study over 2-3 years.

• Study Type: Interventional
• Enrollment (Actual): 859
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Eligibility Criteria for Randomization:

Inclusion Criteria:

• Adenocarcinoma of the colon documented by colonoscopy or barium enema
• Tumor either considered resectable or totally resected within 24 hours prior to study
• Randomization within 2 weeks prior to surgery or within 24 hours after surgery required

• Patients randomized after surgery must meet the following criteria:

  • Complete resection performed with no evidence of residual disease or distant metastases
  • Distal margin of tumor above the peritoneal reflection in area of rectum
  • No free perforation Intestinal obstruction allowed
  • Preliminary or complementary colostomy allowed
• Concurrent registration for E3293 strongly recommended
• Age 18 and over
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

• Adequate organ function based on the following tests within 2 weeks prior to randomization

  • White Blood Cell (WBC) at least 3,000/mm^3
  • Platelet count at least 100,000/mm^3
  • Bilirubin no greater than 2.0 mg/dL
  • Creatinine no greater than 2.0 mg/dL
• No second malignancy within 5 years except: superficial non-melanomatous skin cancer and carcinoma in situ of the cervix
• Fertile patients must use adequate contraception

Exclusion Criteria:

• Dual primary tumors
• Prior nonmalignant systemic disease that would preclude use of chemotherapy
• Pregnant or nursing
• Prior fluorouracil
• Other prior or concurrent chemotherapy for this malignancy
• Prior or concurrent radiotherapy for this malignancy

Eligibility Criteria for Re-registration for Patients Randomized Pre-operatively:

• Must have pathologic classification of Dukes' B2, B3, or C disease by the contributing institution.
• Must be re-registered < 35 days after surgery.
• ECOG performance status of 0-2.
• Complete resection must have been performed with no evidence of residual disease or distant metastasis.
• Distal margin of the tumor must not extend below the peritoneal reflection in the area of the rectum.
• Single primary colon carcinoma without free perforation demonstrated. Patients with intestinal obstruction are eligible. Preliminary or complementary colostomy dose not preclude entry of a patient.
• Have WBC > 3000/mm^3, platelets > 100,000/mm^3, adequate renal (serum creatinine <= 2.0mg/dL) and hepatic function (bilirubin <= 2.0mg/dL), within one week prior to beginning adjuvant chemotherapy (For Dukes' B3 and C patients only).

Eligibility Criteria for Re-registration for Patients Randomized Post-operatively:

• Must have pathologic classification of Dukes' B2, B3, or C disease by the contributing institution.
• Patient must be re-registered < 35 days after surgery.
• ECOG performance status of 0-2.
• Started perioperative 5-FU, if assigned, within 24 hours of surgery.
• Have WBC > 3000/mm^3, platelets > 100,000/mm^3, adequate renal (serum creatinine <= 2.0mg/dL) and hepatic function (bilirubin < =2.0mg/dL), within one week prior to beginning adjuvant chemotherapy (For Dukes' B3 and C patients only).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Perioperative 5-FU; Within 24 hours of the colon resection, patients receive perioperative fluorouracil intravenously (IV) over 24 hours for 7 days. After surgery (beginning 21-35 days post-surgery), 5-FU was given at a dose of 425 mg/m^2 IV push on days 1-5, and leucovorin calcium was given at a dose of 20mg/m^2 IV push on days 1-5	Drug: fluorouracil; Perioperative 5-FU: 600 mg/m^2/d x 7 days continuous IV, beginning within 24 hours of surgery After surgery, 5-FU was given 425 mg/m^2 IV push on days 1-5; Other Names: 5-FU; Adrucil; Efudex; Drug: leucovorin calcium; given after surgery at dose of 20mg/m^2 IV push on days 1-5; Other Names: LV; Leucovorin; LCV; Wellcovorin; Folinic acid; 5-formyl tetrahydrofolate; Citrovorum factor
Active Comparator: No perioperative 5-FU; Patients receive no perioperative fluorouracil. After surgery (beginning 21-35 days post-surgery), 5-FU was given at a dose of 425 mg/m^2 IV push on days 1-5, and leucovorin calcium was given at a dose of 20mg/m^2 IV push on days 1-5	Drug: fluorouracil; Perioperative 5-FU: 600 mg/m^2/d x 7 days continuous IV, beginning within 24 hours of surgery After surgery, 5-FU was given 425 mg/m^2 IV push on days 1-5; Other Names: 5-FU; Adrucil; Efudex; Drug: leucovorin calcium; given after surgery at dose of 20mg/m^2 IV push on days 1-5; Other Names: LV; Leucovorin; LCV; Wellcovorin; Folinic acid; 5-formyl tetrahydrofolate; Citrovorum factor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
5-year Overall Survival Rate in Patients With Dukes' B3/C Disease	Overall survival (OS) is defined as time from randomization to death from any cause or last date known alive. Kaplan-Meier method was used to estimate 5-year OS rate	every 3 months for 2 years, then every 6 months for 2 years, and then annually until year 15 after randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
5-year Disease-free Survival Rate in Patients With Dukes' B3/C Disease	Disease-free survival (DFS) was defined as time from randomization to recurrence, second invasive primary cancer, or deaths, 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. Patients without any follow up data were censored at random assignment. Kaplan-Meier method was used to estimate the 5-year DFS rate.	every 3 months for 2 years, then every 6 months for 2 years, and then annually until year 15 after randomization
5-year Overall Survival Rate in Patients With Dukes' B2 Disease	Overall survival (OS) is defined as time from randomization to death from any cause or last date known alive. Kaplan-Meier method was used to estimate 5-year OS rate	every 3 months for 2 years, then every 6 months for 2 years, and then annually until year 15 after randomization
5-year Disease-free Survival Rate in Patients With Dukes' B2 Disease	Disease-free survival (DFS) was defined as time from randomization to recurrence, second invasive primary cancer, or deaths, 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. Patients without any follow up data were censored at random assignment. Kaplan-Meier method was used to estimate the 5-year DFS rate.	every 3 months for 2 years, then every 6 months for 2 years, and then annually until year 15 after randomization

Collaborators and Investigators

• Sponsor: ECOG-ACRIN Cancer Research Group
• Collaborators: National Cancer Institute (NCI); Cancer and Leukemia Group B; NSABP Foundation Inc; American College of Surgeons; SWOG Cancer Research Network
• Investigators: Study Chair: Mary M. Kemeny, MD, FACS, SUNY At Stony Brook

Publications and helpful links

General Publications

• Kemeny M, Ibrahim J, Benson AB, et al.: Post-operative complications of continuous infusion 5 FU following curative resection of colon cancer. [Abstract] Proceedings of the American Society of Clinical Oncology 16: A923, 260a, 1997.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 1993
• Primary Completion (Actual): February 1, 2015
• Study Completion (Actual): April 1, 2015

Study Registration Dates

• First Submitted: November 1, 1999
• First Submitted That Met QC Criteria: April 5, 2004
• First Posted (Estimated): April 6, 2004

Study Record Updates

• Last Update Posted (Actual): June 28, 2023
• Last Update Submitted That Met QC Criteria: June 13, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: stage III colon cancer; stage II colon cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Colorectal Neoplasms; Colonic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Micronutrients; Vitamins; Calcium-Regulating Hormones and Agents; Antidotes; Vitamin B Complex; Fluorouracil; Leucovorin; Calcium; Levoleucovorin; Tetrahydrofolates; Formyltetrahydrofolates
• Other Study ID Numbers: E1292 (Other Identifier: ECOG-ACRIN Cancer Research Group); U10CA023318 (U.S. NIH Grant/Contract); CDR0000078337 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data may be made available upon request as per the ECOG-ACRIN Data Sharing Policy.