Colorectal Cancer
Conditions
Keywords
stage II colon cancer, stage III colon cancer
Brief summary
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.
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.
Interventions
DRUGfluorouracil
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
DRUGleucovorin calcium
given after surgery at dose of 20mg/m\^2 IV push on days 1-5
Sponsors
National Cancer Institute (NCI)
SWOG Cancer Research Network
Cancer and Leukemia Group B
American College of Surgeons
NSABP Foundation Inc
ECOG-ACRIN Cancer Research Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 5-year Overall Survival Rate in Patients With Dukes' B3/C Disease | every 3 months for 2 years, then every 6 months for 2 years, and then annually until year 15 after randomization | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 5-year Disease-free Survival Rate in Patients With Dukes' B3/C Disease | every 3 months for 2 years, then every 6 months for 2 years, and then annually until year 15 after randomization | 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. |
| 5-year Overall Survival Rate in Patients With Dukes' B2 Disease | every 3 months for 2 years, then every 6 months for 2 years, and then annually until year 15 after randomization | 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 |
| 5-year Disease-free Survival Rate in Patients With Dukes' B2 Disease | every 3 months for 2 years, then every 6 months for 2 years, and then annually until year 15 after randomization | 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. |
Countries
United States
Participant flow
Recruitment details
This study was activated on August 20, 1993 and was terminated on May 19, 2000 before reaching its accrual goal due slow accrual. The first accrual was on October 1, 1993. The final accrual for the study was 859 patients.
Participants by arm
| Arm | Count |
|---|---|
| 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
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
leucovorin calcium: given after surgery at dose of 20mg/m\^2 IV push on days 1-5 | 156 |
| 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
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
leucovorin calcium: given after surgery at dose of 20mg/m\^2 IV push on days 1-5 | 158 |
| Total | 314 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 36 | 0 |
| Overall Study | Death | 5 | 0 |
| Overall Study | Duke's A, B1, D disease | 92 | 0 |
| Overall Study | Error | 6 | 0 |
| Overall Study | Never start protocol therapy | 8 | 0 |
| Overall Study | Other | 26 | 0 |
| Overall Study | Other complicating disease | 1 | 0 |
| Overall Study | Start non-protocol therapy | 1 | 0 |
| Overall Study | Withdrawal by Subject | 11 | 0 |
Baseline characteristics
| Characteristic | Perioperative 5-FU | No Perioperative 5-FU | Total |
|---|---|---|---|
| Age, Continuous | 63 Years | 66 Years | 65 Years |
| Sex/Gender, Customized Female | 57 participants | 61 participants | 118 participants |
| Sex/Gender, Customized Male | 99 participants | 96 participants | 195 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 236 / 418 | 9 / 422 | 167 / 171 | 58 / 61 |
| serious Total, serious adverse events | 75 / 418 | 4 / 422 | 76 / 171 | 32 / 61 |
Outcome results
Primary
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
Time frame: every 3 months for 2 years, then every 6 months for 2 years, and then annually until year 15 after randomization
Population: All randomized patients with Dukes' B3 and C disease
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Perioperative 5-FU | 5-year Overall Survival Rate in Patients With Dukes' B3/C Disease | 0.666 proportion of participants |
| No Perioperative 5-FU | 5-year Overall Survival Rate in Patients With Dukes' B3/C Disease | 0.612 proportion of participants |
p-value: 0.178Log Rank
Secondary
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.
Time frame: every 3 months for 2 years, then every 6 months for 2 years, and then annually until year 15 after randomization
Population: All randomized patients with Dukes' B2 disease who had complete disease assessment data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Perioperative 5-FU | 5-year Disease-free Survival Rate in Patients With Dukes' B2 Disease | 0.749 proportion of participants |
| No Perioperative 5-FU | 5-year Disease-free Survival Rate in Patients With Dukes' B2 Disease | 0.724 proportion of participants |
Secondary
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.
Time frame: every 3 months for 2 years, then every 6 months for 2 years, and then annually until year 15 after randomization
Population: All randomized patients with Dukes' B3 and C disease who had complete disease assessment data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Perioperative 5-FU | 5-year Disease-free Survival Rate in Patients With Dukes' B3/C Disease | 0.582 proportion of participants |
| No Perioperative 5-FU | 5-year Disease-free Survival Rate in Patients With Dukes' B3/C Disease | 0.543 proportion of participants |
p-value: 0.847Log Rank
Secondary
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
Time frame: every 3 months for 2 years, then every 6 months for 2 years, and then annually until year 15 after randomization
Population: All randomized patients with Dukes' B2 disease
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Perioperative 5-FU | 5-year Overall Survival Rate in Patients With Dukes' B2 Disease | 0.851 proportion of participants |
| No Perioperative 5-FU | 5-year Overall Survival Rate in Patients With Dukes' B2 Disease | 0.780 proportion of participants |