Rectal Mucinous Adenocarcinoma, Rectal Signet Ring Cell Adenocarcinoma, Recurrent Rectal Carcinoma, Stage IIA Rectal Cancer AJCC v7, Stage IIB Rectal Cancer AJCC v7, Stage IIC Rectal Cancer AJCC v7, Stage IIIA Rectal Cancer AJCC v7, Stage IIIB Rectal Cancer AJCC v7, Stage IIIC Rectal Cancer AJCC v7, Stage IVA Rectal Cancer AJCC v7, Stage IVB Rectal Cancer AJCC v7
Conditions
Keywords
rectal cancer, chemotherapy, irinotecan, oxaliplatin
Brief summary
This randomized phase III trial is comparing the effectiveness of three adjuvant combination chemotherapy regimens in treating patients who are receiving radiation therapy and fluorouracil either before or after surgery for stage II or stage III rectal cancer. Drugs used in chemotherapy, such as irinotecan, fluorouracil, leucovorin, and oxaliplatin, 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 adjuvant combination chemotherapy regimen is more effective in treating patients who are receiving radiation therapy and fluorouracil either before or after surgery for rectal cancer.
Detailed description
PRIMARY OBJECTIVES: I. To compare the overall survival of patients treated with irinotecan, 5-FU and leucovorin versus those treated with oxaliplatin, leucovorin and 5-FU versus those treated with leucovorin and 5-FU for patients with stage II and III rectal cancer. SECONDARY OBJECTIVES: I. To determine sphincter preservation, tolerance of treatment and patterns of failure. II. To describe patterns of failures OTHER PRE-SPECIFIED OBJECTIVES: I.To prospectively assess rectal function using the Patient Bowel Function/Uniscale questionnaire and the FACT Diarrhea Subscale in patients treated with an adjuvant program of pelvic radiation therapy and chemotherapy. II. To correlate expression of key targets for 5-FU, leucovorin, oxaliplatin and irinotecan from tumor tissue biopsies with treatment efficacy III. To correlate tumor molecular prognostic markers with survival. IV. To determine physician preference in regard to the radiation-chemotherapy sequence in the Intergroup. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to ECOG performance status (0 vs 1), chemotherapy/radiotherapy sequence (preoperative vs postoperative), and risk group (high risk \[T3, N+, M0 or T4, any N, M0\] vs low risk \[T1-2, N+, M0 or T3, N0, M0\]). Patients are treated in 1 of 2 groups according to physician preference and then randomized to 1 of 3 treatment arms. GROUP I (preoperative chemoradiotherapy and additional adjuvant chemotherapy): Preoperative chemoradiotherapy: Patients receive 1 of 3 treatment regimens, determined by the treating physician. REGIMEN A (radiotherapy and fluorouracil): Patients undergo external beam radiotherapy once daily 5 days a week for 5 1/2 weeks (total of 28 fractions). Patients also receive concurrent fluorouracil intravenously (IV) continuously 7 days a week for 5 1/2 weeks. REGIMEN B (radiotherapy, fluorouracil, and leucovorin calcium): Patients undergo external beam radiotherapy as in regimen A. Patients also receive concurrent fluorouracil IV and leucovorin calcium IV continuously for 4 days on weeks 1 and 5. REGIMEN C (radiotherapy and capecitabine)\*: Patients undergo external beam radiotherapy as in regimen A. Patients also receive concurrent oral capecitabine twice daily for 5 1/2 weeks. NOTE: \*Regimen C is allowed only for patients enrolled on protocol NSABP-R-04. Surgery: Within 21-56 days after the completion of chemoradiotherapy, patients undergo surgical resection. Additional adjuvant chemotherapy: Within 21-56 days after complete surgical resection, patients are randomized to 1 of 3 treatment arms. ARM I: Patients receive irinotecan IV over 90 minutes and leucovorin calcium IV over 2 hours followed immediately by fluorourcil IV bolus on day 1. Patients also receive fluorouracil IV continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for 8 courses. ARM II: Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours followed immediately by fluorourcil IV bolus on day 1. Patients also receive fluorouracil IV continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for 8 courses. ARM III: Patients receive leucovorin calcium IV over 2 hours and fluorouracil IV over 1 hour on days 1, 8, 15, 22, 29, and 36. Treatment repeats every 8 weeks for 3 courses. In all arms, treatment continues in the absence of disease progression or unacceptable toxicity. GROUP 2 (postoperative chemoradiotherapy and additional adjuvant chemotherapy): Within 21-56 days after complete surgical resection, patients are randomized to 1 of 3 treatment arms. ARM I: Patients receive irinotecan, leucovorin calcium, and fluorouracil as in group 1, arm I for 4 courses. ARM II: Patients receive oxaliplatin, leucovorin calcium, and fluorouracil as in group 1, arm II for 4 courses. ARM III: Patients receive leucovorin calcium and fluorouracil as in group 1, arm III for 1 course. Within 4 weeks after the completion of chemotherapy, all patients undergo concurrent pelvic chemoradiotherapy as described in group 1 preoperative chemoradiotherapy Regimen A, B, or C, followed 4-6 weeks later by 4 additional courses of adjuvant chemotherapy for arms I and II and 2 additional courses of adjuvant chemotherapy for arm III. Treatment continues in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 3 years, every 6 months for 2 years, and then annually for 5 years.
Interventions
RADIATIONRadiotherapy
Undergo external beam radiation therapy
DRUGFluorouracil
Given IV
DRUGLeucovorin Calcium
Given IV
DRUGOxaliplatin
Given IV
DRUGIrinotecan
Given IV
Sponsors
National Cancer Institute (NCI)
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
1. Group I (Pre-operative) Registration Inclusion Criteria: * Patients must have histologically proven adenocarcinoma of the rectum with no distant metastases. Clinical staging is required (T3N0M0, T4N0M0, TanyN1-3M0). * Patients must not have evidence of tumor outside of the pelvis including liver metastases, peritoneal seeding, or metastatic inguinal lymphadenopathy. * The distal border of the tumor must be at or below the peritoneal reflection, defined as within 12 cm of anal verge by proctoscopic examination. In addition, patients who have had a portion of their tumors confirmed to be below the peritoneal reflection at the time of surgery are eligible regardless of the distance determined by endoscopy. * Transmural penetration of tumor through the muscularis propria must be demonstrated by CT scan, endo-rectal ultrasound or MRI. * Tumors must be defined prospectively by the surgeon as clinically resectable or not. * Clinically resectable tumors will be defined by the surgeon as not fixed and completely resectable with negative margins based on the routine examination of the non-anesthetized patient. * Before pre-op treatment, the surgeon should estimate and record the type of resection anticipated: APR, LAR or LAR/coloanal anastomosis. * The tumor may be clinically fixed or initially not completely resectable, clinical stage T4 N0-2 M0 based on the presence of at least one of the following criteria: * Clinically fixed tumors on rectal examination with tumor adherent to the pelvic sidewall or sacrum. * Hydronephrosis on CT scan or IVP or ureteric or bladder invasion as documented by cystoscopy and cytology or biopsy, or invasion into prostate. * Vaginal or uterine involvement. * Patients must not have a previous or concurrent malignancy, with the exception of: * Nonmelanoma skin cancer or in situ cervical cancer. * Treated non-pelvic cancer from which the patient has been continuously disease-free for \>5 years. * Patients must have ECOG performance status 0-1. * Patients must be \> 18 years of age. * All females of childbearing potential must have a blood or urine test within 2 weeks prior to registration to rule out pregnancy. * Sexually-active women of childbearing potential and sexually active males are strongly advised to use an accepted and effective method of contraception
Exclusion criteria
* Patients have received prior chemotherapy or pelvic irradiation therapy. * Female patients must not be pregnant or breast-feeding. * Patients have an active inflammatory bowel disease or other serious medical illness which might limit the ability of the patient to receive protocol therapy. 2. Group II (Post-operative) Registration Inclusion Criteria: * Patients must have had histologically proven adenocarcinoma of the rectum with no distant metastases. Pathologic staging is required (T3N0M0, T4N0M0, TanyN1-3M0). * Patients must not have evidence of tumor outside of the pelvis including liver metastases, peritoneal seeding, or metastatic inguinal lymphadenopathy. * The distal border of the tumor must have been at or below the peritoneal reflection, defined as within 12 centimeters of anal verge by proctoscopic examination. In addition, patients who have had a portion of their tumors confirmed to be below the peritoneal reflection at the time of the surgery are eligible regardless of the distance determined by endoscopy. * Patients must not have received prior chemotherapy or pelvic irradiation therapy. * Patients must not have a previous or concurrent malignancy, with the exception of: * Non-melanoma skin cancer or in situ cervical cancer. * Treated non-pelvic cancer from which the patient has been continuously disease-free for \>5 years. * Patients must have ECOG performance status 0-1. * Patients must be \> 18 years of age. * All females of childbearing potential must have a blood or urine test within 2 weeks prior to registration to rule out pregnancy. * Sexually active women of childbearing potential and sexually active males are strongly advised to use an accepted and effective method of contraception.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 3-year Overall Survival Rate | assessed every 3 months withihn 2 years of study entry, every 6 monhts between years 3-5 and then annually for 5 years, estimated at 3 years | Overall survival (OS) was defined as time from randomization to death from any cause. 3-year OS rate was estimated using Kaplan-Meier method. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 3-year Disease Free Survival | assessed every 3 months withihn 2 years of study entry, every 6 monhts between years 3-5 and then annually for 5 years, estimated at 3 years | Disease free survival (DFS) was defined as time from randomization to recurrence, second invasive primary cancer and death from any cause, whichever occurred first. 3-year DFS rate was estimated using Kaplan-Meier method. |
| Proportion of Sphincter Preservation | assessed at primary surgery time | Proportion of sphincter preservation was defined as number of patients with sphincter preservation divided by total number of patients randomized to the arm |
| Failure Pattern | assessed every 3 months withihn 2 years of study entry, every 6 monhts between years 3-5 and then annually for 5 years | Type of failures (local/regional recurrence vs. distant recurrence vs. concurrent recurrence vs. second primary cancer vs. deaths) in the analysis population |
Countries
United States
Participant flow
Recruitment details
This study was activated on October 15, 2003. Accrual was suspended on November 26, 2004 and subsequently closed on October 25, 2005 with total accrual of 225 patients to step 1 and 179 patients to step 2.
Participants by arm
| Arm | Count |
|---|---|
| Irinocetan (Arm I) The study was not designed to look at the treatment regimen separately in the two groups. I in Group I and Group II are combined. Patients in this group received irinocetan plus 5-FU and leucovorin, | 59 |
| Oxaliplatin (Arm II) The study was not designed to look at the treatment regimen separately in the two groups. I in Group I and Group II are combined. Patients in this group received oxaliplatin plus 5-FU and leucovorin. | 58 |
| Control (Arm III) The study was not designed to look at the treatment regimen separately in the two groups. I in Group I and Group II are combined. Patients in this group only received 5-FU and leucovorin. | 62 |
| Total | 179 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Step 1: Registration | Adverse Event | 7 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Step 1: Registration | Alternative therapy | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Step 1: Registration | Complicating disease | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Step 1: Registration | Death | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Step 1: Registration | Disese progression/relapse | 5 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Step 1: Registration | Not eligible | 6 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Step 1: Registration | Not start protocol therapy | 3 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Step 1: Registration | Other | 2 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Step 1: Registration | Protocol Violation | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Step 1: Registration | Registered but not randomized | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Step 1: Registration | Withdrawal by Subject | 11 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Step 2: Randomization | Adverse Event | 0 | 0 | 4 | 2 | 2 | 3 | 4 | 4 |
| Step 2: Randomization | alternative therapy | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 |
| Step 2: Randomization | Death | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 |
| Step 2: Randomization | Disesae progression/replase | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 |
| Step 2: Randomization | never start protocol therapy | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 |
| Step 2: Randomization | Other | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 |
| Step 2: Randomization | Physician Decision | 0 | 0 | 0 | 1 | 1 | 0 | 0 | 0 |
| Step 2: Randomization | Withdrawal by Subject | 0 | 0 | 4 | 6 | 3 | 2 | 0 | 3 |
Baseline characteristics
| Characteristic | Irinocetan (Arm I) | Oxaliplatin (Arm II) | Control (Arm III) | Total |
|---|---|---|---|---|
| Age, Continuous | 58 years | 56 years | 58 years | 57 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 1 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 56 Participants | 57 Participants | 58 Participants | 171 Participants |
| Sex: Female, Male Female | 19 Participants | 22 Participants | 19 Participants | 60 Participants |
| Sex: Female, Male Male | 40 Participants | 36 Participants | 43 Participants | 119 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 123 | 8 / 27 | 12 / 22 | 11 / 28 | 11 / 31 | 9 / 33 | 10 / 32 |
| other Total, other adverse events | 27 / 123 | 7 / 27 | 3 / 22 | 3 / 28 | 6 / 31 | 6 / 33 | 12 / 32 |
| serious Total, serious adverse events | 62 / 123 | 11 / 27 | 14 / 22 | 10 / 28 | 21 / 31 | 23 / 33 | 23 / 32 |
Outcome results
Primary
3-year Overall Survival Rate
Overall survival (OS) was defined as time from randomization to death from any cause. 3-year OS rate was estimated using Kaplan-Meier method.
Time frame: assessed every 3 months withihn 2 years of study entry, every 6 monhts between years 3-5 and then annually for 5 years, estimated at 3 years
Population: All randomized patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Irinocetan (Arm I) | 3-year Overall Survival Rate | 0.965 proportion of patients |
| Oxaliplatin (Arm II) | 3-year Overall Survival Rate | 0.843 proportion of patients |
| Control (Arm III) | 3-year Overall Survival Rate | 0.870 proportion of patients |
p-value: 0.35Log Rank
p-value: 0.69Log Rank
Secondary
3-year Disease Free Survival
Disease free survival (DFS) was defined as time from randomization to recurrence, second invasive primary cancer and death from any cause, whichever occurred first. 3-year DFS rate was estimated using Kaplan-Meier method.
Time frame: assessed every 3 months withihn 2 years of study entry, every 6 monhts between years 3-5 and then annually for 5 years, estimated at 3 years
Population: All randomized patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Irinocetan (Arm I) | 3-year Disease Free Survival | 0.670 proportion of patients |
| Oxaliplatin (Arm II) | 3-year Disease Free Survival | 0.717 proportion of patients |
| Control (Arm III) | 3-year Disease Free Survival | 0.704 proportion of patients |
Secondary
Failure Pattern
Type of failures (local/regional recurrence vs. distant recurrence vs. concurrent recurrence vs. second primary cancer vs. deaths) in the analysis population
Time frame: assessed every 3 months withihn 2 years of study entry, every 6 monhts between years 3-5 and then annually for 5 years
Population: All randomized patients
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Irinocetan (Arm I) | Failure Pattern | Local/regional recurrence only | 3 Participants |
| Irinocetan (Arm I) | Failure Pattern | Any recurrence | 20 Participants |
| Irinocetan (Arm I) | Failure Pattern | Both local/regional and distant recurrence | 2 Participants |
| Irinocetan (Arm I) | Failure Pattern | Death | 19 Participants |
| Irinocetan (Arm I) | Failure Pattern | Second primary cancer | 3 Participants |
| Irinocetan (Arm I) | Failure Pattern | Distant recurrence only | 15 Participants |
| Oxaliplatin (Arm II) | Failure Pattern | Any recurrence | 20 Participants |
| Oxaliplatin (Arm II) | Failure Pattern | Local/regional recurrence only | 5 Participants |
| Oxaliplatin (Arm II) | Failure Pattern | Distant recurrence only | 11 Participants |
| Oxaliplatin (Arm II) | Failure Pattern | Both local/regional and distant recurrence | 4 Participants |
| Oxaliplatin (Arm II) | Failure Pattern | Second primary cancer | 5 Participants |
| Oxaliplatin (Arm II) | Failure Pattern | Death | 21 Participants |
| Control (Arm III) | Failure Pattern | Local/regional recurrence only | 5 Participants |
| Control (Arm III) | Failure Pattern | Death | 21 Participants |
| Control (Arm III) | Failure Pattern | Second primary cancer | 2 Participants |
| Control (Arm III) | Failure Pattern | Any recurrence | 16 Participants |
| Control (Arm III) | Failure Pattern | Both local/regional and distant recurrence | 1 Participants |
| Control (Arm III) | Failure Pattern | Distant recurrence only | 10 Participants |
Secondary
Proportion of Sphincter Preservation
Proportion of sphincter preservation was defined as number of patients with sphincter preservation divided by total number of patients randomized to the arm
Time frame: assessed at primary surgery time
Population: All randomized patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Irinocetan (Arm I) | Proportion of Sphincter Preservation | 0.814 proportion of patients |
| Oxaliplatin (Arm II) | Proportion of Sphincter Preservation | 0.724 proportion of patients |
| Control (Arm III) | Proportion of Sphincter Preservation | 0.655 proportion of patients |