Title

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
  • Phase

    Phase 3
  • Study Type

    Interventional
  • Study Participants

    859
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.
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 Started
Aug 31
1993
Primary Completion
Feb 28
2015
Study Completion
Apr 30
2015
Results Posted
Jul 20
2016
Estimate
Last Update
Aug 29
2016
Estimate

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: 5-formyl tetrahydrofolate, LV, LCV, Leucovorin, Wellcovorin, Citrovorum factor, Folinic acid

No perioperative 5-FU Active Comparator

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

Perioperative 5-FU Experimental

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

Criteria

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).

Summary

Arm I (Perioperative 5-FU)

Arm II (No Perioperative 5-FU)

Adjuvant Chemotherapy-- 5-FU+Levamisolem

Adjuvant Chemotherapy-- 5-FU+Leucovovin

All Events

Event Type Organ System Event Term Arm I (Perioperative 5-FU) Arm II (No Perioperative 5-FU) Adjuvant Chemotherapy-- 5-FU+Levamisolem Adjuvant Chemotherapy-- 5-FU+Leucovovin

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

Perioperative 5-FU

0.666
proportion of participants
95% Confidence Interval: 0.585 to 0.735

No Perioperative 5-FU

0.612
proportion of participants
95% Confidence Interval: 0.53 to 0.683

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.

Perioperative 5-FU

0.582
proportion of participants
95% Confidence Interval: 0.486 to 0.668

No Perioperative 5-FU

0.543
proportion of participants
95% Confidence Interval: 0.442 to 0.634

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

Perioperative 5-FU

0.851
proportion of participants
95% Confidence Interval: 0.783 to 0.899

No Perioperative 5-FU

0.78
proportion of participants
95% Confidence Interval: 0.701 to 0.841

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.

Perioperative 5-FU

0.749
proportion of participants
95% Confidence Interval: 0.66 to 0.818

No Perioperative 5-FU

0.724
proportion of participants
95% Confidence Interval: 0.626 to 0.801

Total

314
Participants

Age, Continuous

65
Years (Median)
Full Range: 25.0 to 89.0

Gender

Overall Study

Perioperative 5-FU

No Perioperative 5-FU

Drop/Withdrawal Reasons

Perioperative 5-FU