Adenocarcinoma of the Rectum, Stage III Rectal Cancer, Stage II Rectal Cancer
Conditions
Keywords
Rectal cancer, Bevacizumab
Brief summary
Drugs used in chemotherapy, such as oxaliplatin, leucovorin, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving more than one drug (combination chemotherapy) together with bevacizumab after surgery may kill any tumor cells that remain after surgery. It is not yet known whether oxaliplatin, leucovorin, and fluorouracil is more effective with or without bevacizumab in treating rectal cancer. This randomized phase III trial is studying combination chemotherapy to see how well it works with or without bevacizumab in treating patients who have had surgery for stage II or stage III rectal cancer.
Detailed description
PRIMARY OBJECTIVES: I. Compare the overall survival of patients who have undergone prior surgery and neoadjuvant chemoradiotherapy for clinical stage II or III rectal cancer treated with adjuvant oxaliplatin, leucovorin calcium, fluorouracil with vs without bevacizumab. SECONDARY OBJECTIVES: I. Evaluate tolerance of treatment, patterns of failure, and disease-free survival in patients treated with these regimens EXPLORATORY OBJECTIVES: I. Assess long-term rectal function using the Patient Bowel Function/Uniscale questionnaire and the Functional Assessment of Cancer (FACT)-Diarrhea subscale in patients treated with these regimens. II. Validate the FACT-Diarrhea subscale. III. Assess long-term symptoms of oxaliplatin-related neurotoxicity using the FACT/Gynecologic Oncology Group (GOG)-Neurotoxicity subscale in patients treated with these regimens. IV. Correlate TS, DPD and TP expression (key targets for fluorouracil); retention of chromosome 18q alleles and microsatellite instability (MSI) with TGFβ1RII mutation (markers for fluorouracil efficacy); ERCC1, ERCC2, and XPF expression (participants in repair of adducts from oxaliplatin); and p53 gene mutation and possibly other molecular markers pertinent to vascular endothelial growth factor in tumor tissue specimens with treatment efficacy in these patients. V. Correlate tumor molecular prognostic markers (chromosome 18q allelic loss and MSI) with survival in patients treated with this regimen. OUTLINE: This is a randomized study. Patients are stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1), clinical staging (high risk \[T3, N+, M0 or T4, any N, M0\] vs low risk \[T1-2, N+, M0 or T3, N0, M0\]), prior pre-operative oxaliplatin (yes vs no), and prior radiotherapy dose (40-50 Gy vs \> 50-55.8 Gy). Patients are randomized to 1 of 2 treatment arms in a 1:1 ratio. ARM I: Patients receive oxaliplatin intravenously (IV) over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV on day 1 followed by fluorouracil IV continuously over 46 hours on days 1 and 2. Treatment repeats every 2 weeks for up to 12 courses\* in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive bevacizumab\*\* IV over 30-90 minutes on day 1. Patients also receive oxaliplatin, leucovorin calcium, and fluorouracil as in arm I\*. \[Note: \*Patients who received prior neoadjuvant oxaliplatin including patients on protocol NSABP-R-04 receive up to 9 courses of treatment followed by leucovorin calcium IV and fluorouracil IV with (arm II) or without (arm I) bevacizumab for up to 3 courses.\] \[Note: \*\*Patients no longer receive bevacizumab as of 4/29/2009 when accrual was terminated due to slow accrual for the study)\] Patients complete 10-15 minute questionnaires about bowel function at randomization, end of treatment, 12 months post-treatment and then annually to 5 years post-treatment. After completion of study treatment, patients are followed periodically for approximately 10 years. PROJECTED ACCRUAL: 2100 patients
Interventions
DRUGoxaliplatin
Given IV
DRUGfluorouracil
Given IV
DRUGleucovorin calcium
Given IV
DRUGbevacizumab
Given IV
Sponsors
National Cancer Institute (NCI)
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
* Histologically confirmed adenocarcinoma of the rectum meeting 1 of the following clinical (e.g., before neoadjuvant therapy) or pathologic staging criteria: * T3, N+, M0 * T3, N0, M0 * T4, N0, M0 * Any T, N1-2, M0 * T4, N0-2, M0 disease must meet 1 of the following criteria: * Clinically fixed tumor on rectal examination with tumor adherent to the pelvic sidewall or sacrum * Hydronephrosis on Computed Tomography (CT) scan or Intravenous Pyelogram (IVP) * Ureteric or bladder invasion as documented by cystoscopy and cytology or biopsy * Invasion into prostate * Vaginal or uterine involvement * Must have undergone complete tumor resection \>= 28 days ago and able to begin treatment by day 56 * Must have undergone concurrent neoadjuvant chemoradiotherapy\* * NOTE: \*Neoadjuvant chemoradiotherapy received on protocol NSABP-R-04 allowed provided it met these criteria * Must have undergone prior radiotherapy at 40-55.8 Gy\*\* AND received 1 of the following chemotherapy regimens: * Continuous infusion of fluorouracil with or without oxaliplatin; fluorouracil and leucovorin calcium * Capecitabine with or without oxaliplatin; capecitabine with or without oxaliplatin OR a continuous infusion of fluorouracil with or without oxaliplatin received on protocol NSABP-R-04 * NOTE: \*\*Intensity-modulated radiotherapy allowed * ECOG performance status 0-1 * Platelet count \>= 100,000/mm\^3 * Absolute granulocyte count \>= 1,500/mm\^3 * Bilirubin normal (unless chronic grade 1 bilirubin elevation due to Gilbert's disease or similar syndrome due to slow conjugation of bilirubin) * Alkaline phosphatase (AP) \< 2.5 times upper limit of normal (ULN) and aspartate aminotransferase (AST) \< 1.5 times ULN * Hepatitis B and C negative (for patients with AP \> normal) unless previously vaccinated * Serum creatinine =\< 1.5 times ULN * Urine protein:creatinine (UPC) ratio \< 1.0 OR urine protein \< 1 g on 24-hour urine collection * International Normalized Ratio (INR) =\< 1.5 * INR \> 1.5 allowed provided patient is on full-dose anticoagulants AND meets all of the following criteria: * In-range INR (i.e., between 2 and 3) on a stable dose of warfarin or low molecular weight heparin * No active bleeding or pathological condition that is associated with a high risk of bleeding * Negative pregnancy test * Fertile patients must use effective contraception during and for at least 3 months after study treatment * No other previous or concurrent malignancy except nonmelanoma skin cancer, breast cancer in situ, carcinoma in situ of the cervix, or previously treated nonpelvic cancer that has been disease-free for \> 5 years * Patients with a history of breast cancer (without evidence of disease) who remain on hormonal therapy for \> 5 years are eligible * Patients with a history of hypertension must have blood pressure \< 150/90 mm Hg AND be on a stable regimen of antihypertensive therapy * No other prior chemotherapy or pelvic radiotherapy except as neoadjuvant treatment for current diagnosis of rectal cancer * Concurrent participation on protocol NSABP-R-04 allowed
Exclusion criteria
* Pregnant or nursing * Evidence of metastatic disease on the surgical/intraoperative examination * Evidence of metastatic disease confirmed by CT scan, Magnetic resonance imaging (MRI), or ultrasound of the liver or chest CT scan or chest x-ray within the past 6 months * Evidence of tumor outside of the pelvis, including liver metastases, peritoneal seeding, or metastatic inguinal lymphadenopathy * Concurrent major surgery * Active bleeding not related to the primary rectal tumor within the past 6 months * Active inflammatory bowel disease or other serious medical illness which might limit the ability of the patient to receive protocol therapy * Active gastroduodenal ulcer determined by endoscopy * Serious or nonhealing wound, skin ulcer, or bone fracture * Clinically significant peripheral sensory or motor neuropathy \>= grade 2 * Nonmalignant systemic disease (e.g., cardiovascular, renal, or hepatic) that would preclude study treatment including, but not limited to, any of the following: * New York Heart Association class III or IV congestive heart failure * Concurrent symptomatic arrhythmia * Transient ischemic attack or cerebrovascular accident * Arterial thromboembolic event, unstable angina, or myocardial infarction within the past 12 months * Significant peripheral vascular disease * Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude study requirements * Significant traumatic injury within the past 28 days * Known allergy to platinum compounds * Prior invasive procedure, including either of the following: * Major surgical procedure or open biopsy within the past 28 days * Core biopsy or other minor procedure, except placement of a vascular access device, within the past 7 days
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 5-year Overall Survival Rate | Follow-up assessments performed every 3 months for patients < 2 years from randomization, every 6 months for patients 2-5 years from randomization, and every 12 months for patients 5-10 years from randomization | Overall survival (OS) was defined as time from randomization to date of death from any cause. Patients who were still alive were censored at last date of known alive. Kaplan-Meier method was used to estimate the 5-year OS rate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 5-year Disease-free Survival Rate | Follow-up assessments performed every 3 months for patients < 2 years from randomization, every 6 months for patients 2-5 years from randomization, and every 12 months for patients 5-10 years from randomization | Disease-free survival (DFS) was defined as time from randomization to recurrence, second invasive primary cancer or death, 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. Kaplan-Meier method was used to estimate 5-year DFS rate. |
| Patterns of Failure | Follow-up assessments performed every 3 months for patients < 2 years from randomization, every 6 months for patients 2-5 years from randomization, and every 12 months for patients 5-10 years from randomization | Failure included recurrence, second primary cancer and death without recurrence. |
| Proportion of Patients Who Completed 12 Cycles of Treatment | assessed at the end of treatment | In the study, treatment was repeated every 2 weeks for a total of 12 cycles on both arms. The total number of cycles of treatment patient received until going off treatment due to any reason was recorded. It was a measure of the tolerance of the therapy. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Rectal Function Between Baseline and 12 Months | assessed at baseline and 12 months after randomization | Change in rectal function between baseline and 12 months was measuring the long-term rectal function among the patients. Rectal function was measured using the Bowel Function Questionnaire at baseline and 12 months after randomization. The total score of the questionnaire was calculated as the number of problems with bowel function (score range 0-11). Change in rectal function between baseline and 12 months= total score at 12 months - total score at baseline. A negative value indicated improved rectal function. This change in score was calculated for each individual patient who had the data. |
| Change in Oxaliplatin-related Neurotoxicity Between Baseline and 12 Months | assessed at baseline and 12 months after randomization | Change in oxaliplatin-related neurotoxicity between baseline and 12 months was measuring the long-term symptom of oxaliplatin-related neurotoxicity among the patients. Oxaliplatin-related neurotoxicity was measured using the FACT/GOG-Ntx subscale at baseline and 12 months after randomization. The range of the total score of the scale was between 0 and 44, and lower values indicate higher neurotoxicity. Change in oxaliplatin-related neurotoxicity between baseline and 12 months= total score at 12 months - total score at baseline. A negative value indicated worsened symptom. This change in score was calculated for each individual patient who had the data. |
Countries
Canada, Peru, Puerto Rico, United States
Participant flow
Recruitment details
The study was activated on February 17, 2006 and accrued its first patient on May 11, 2006. Due to slow accrual, it was terminated on April 29, 2009 before reaching its accrual goal with final accrual of 355 patients.
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Oxaliplatin, Fluorouracil, Leucovorin) Patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and fluorouracil IV on day 1 followed by fluorouracil IV continuously over 46 hours on days 1 and 2. Treatment repeats every 2 weeks for up to 12 courses.
oxaliplatin: Given IV
fluorouracil: Given IV
leucovorin calcium: Given IV | 176 |
| Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) Patients receive bevacizumab IV over 30-90 minutes on day 1. Patients also receive oxaliplatin, leucovorin calcium, and fluorouracil as in arm I.
oxaliplatin: Given IV
fluorouracil: Given IV
leucovorin calcium: Given IV
bevacizumab: Given IV | 179 |
| Total | 355 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 26 | 36 |
| Overall Study | Alternative therapy | 2 | 0 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Disease progression | 0 | 1 |
| Overall Study | Not start protocol therapy | 3 | 5 |
| Overall Study | Other | 8 | 9 |
| Overall Study | Other complicating disease | 0 | 1 |
| Overall Study | Withdrawal by Subject | 11 | 20 |
Baseline characteristics
| Characteristic | Arm I (Oxaliplatin, Fluorouracil, Leucovorin) | Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) | Total |
|---|---|---|---|
| Age, Continuous | 54 Years | 53 Years | 53 Years |
| Sex: Female, Male Female | 62 Participants | 67 Participants | 129 Participants |
| Sex: Female, Male Male | 114 Participants | 112 Participants | 226 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 154 / 173 | 155 / 174 |
| serious Total, serious adverse events | 119 / 173 | 123 / 174 |
Outcome results
Primary
5-year Overall Survival Rate
Overall survival (OS) was defined as time from randomization to date of death from any cause. Patients who were still alive were censored at last date of known alive. Kaplan-Meier method was used to estimate the 5-year OS rate.
Time frame: Follow-up assessments performed every 3 months for patients < 2 years from randomization, every 6 months for patients 2-5 years from randomization, and every 12 months for patients 5-10 years from randomization
Population: All randomized patients (intent-to-treat population)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Oxaliplatin, Fluorouracil, Leucovorin) | 5-year Overall Survival Rate | 0.883 proportion of participants |
| Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) | 5-year Overall Survival Rate | 0.837 proportion of participants |
p-value: 0.876Log Rank
Secondary
5-year Disease-free Survival Rate
Disease-free survival (DFS) was defined as time from randomization to recurrence, second invasive primary cancer or death, 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. Kaplan-Meier method was used to estimate 5-year DFS rate.
Time frame: Follow-up assessments performed every 3 months for patients < 2 years from randomization, every 6 months for patients 2-5 years from randomization, and every 12 months for patients 5-10 years from randomization
Population: All randomized patients (intent-to-treat population)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Oxaliplatin, Fluorouracil, Leucovorin) | 5-year Disease-free Survival Rate | 0.712 proportion of participants |
| Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) | 5-year Disease-free Survival Rate | 0.765 proportion of participants |
p-value: 0.299Log Rank
Secondary
Patterns of Failure
Failure included recurrence, second primary cancer and death without recurrence.
Time frame: Follow-up assessments performed every 3 months for patients < 2 years from randomization, every 6 months for patients 2-5 years from randomization, and every 12 months for patients 5-10 years from randomization
Population: all randomized patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm I (Oxaliplatin, Fluorouracil, Leucovorin) | Patterns of Failure | DFS event | 52 participants |
| Arm I (Oxaliplatin, Fluorouracil, Leucovorin) | Patterns of Failure | Distant recurrence | 24 participants |
| Arm I (Oxaliplatin, Fluorouracil, Leucovorin) | Patterns of Failure | Local/regional recurrence | 6 participants |
| Arm I (Oxaliplatin, Fluorouracil, Leucovorin) | Patterns of Failure | Mutiple recurrence | 5 participants |
| Arm I (Oxaliplatin, Fluorouracil, Leucovorin) | Patterns of Failure | Unknown site | 1 participants |
| Arm I (Oxaliplatin, Fluorouracil, Leucovorin) | Patterns of Failure | Death without recurrence | 5 participants |
| Arm I (Oxaliplatin, Fluorouracil, Leucovorin) | Patterns of Failure | Second invasive primary cancer | 12 participants |
| Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) | Patterns of Failure | DFS event | 41 participants |
| Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) | Patterns of Failure | Unknown site | 1 participants |
| Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) | Patterns of Failure | Distant recurrence | 20 participants |
| Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) | Patterns of Failure | Second invasive primary cancer | 4 participants |
| Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) | Patterns of Failure | Local/regional recurrence | 5 participants |
| Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) | Patterns of Failure | Death without recurrence | 6 participants |
| Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) | Patterns of Failure | Mutiple recurrence | 8 participants |
Secondary
Proportion of Patients Who Completed 12 Cycles of Treatment
In the study, treatment was repeated every 2 weeks for a total of 12 cycles on both arms. The total number of cycles of treatment patient received until going off treatment due to any reason was recorded. It was a measure of the tolerance of the therapy.
Time frame: assessed at the end of treatment
Population: Patients who received at least one cycle of protocol treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Oxaliplatin, Fluorouracil, Leucovorin) | Proportion of Patients Who Completed 12 Cycles of Treatment | 0.722 proportion of participants |
| Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) | Proportion of Patients Who Completed 12 Cycles of Treatment | 0.615 proportion of participants |
Other Pre-specified
Change in Oxaliplatin-related Neurotoxicity Between Baseline and 12 Months
Change in oxaliplatin-related neurotoxicity between baseline and 12 months was measuring the long-term symptom of oxaliplatin-related neurotoxicity among the patients. Oxaliplatin-related neurotoxicity was measured using the FACT/GOG-Ntx subscale at baseline and 12 months after randomization. The range of the total score of the scale was between 0 and 44, and lower values indicate higher neurotoxicity. Change in oxaliplatin-related neurotoxicity between baseline and 12 months= total score at 12 months - total score at baseline. A negative value indicated worsened symptom. This change in score was calculated for each individual patient who had the data.
Time frame: assessed at baseline and 12 months after randomization
Population: Patients with data about their oxaliplatin-related neurotoxicity measured using FACT/GOG Ntx subscale at both baseline and 12 months after randomization. Due to the early termination of the trial, the sample size was quite small for the endpoint. Consequently, it was considered as an exploratory endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Oxaliplatin, Fluorouracil, Leucovorin) | Change in Oxaliplatin-related Neurotoxicity Between Baseline and 12 Months | -8.6 scores on a scale | Standard Deviation 8.1 |
| Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) | Change in Oxaliplatin-related Neurotoxicity Between Baseline and 12 Months | -9.5 scores on a scale | Standard Deviation 7.9 |
Other Pre-specified
Change in Rectal Function Between Baseline and 12 Months
Change in rectal function between baseline and 12 months was measuring the long-term rectal function among the patients. Rectal function was measured using the Bowel Function Questionnaire at baseline and 12 months after randomization. The total score of the questionnaire was calculated as the number of problems with bowel function (score range 0-11). Change in rectal function between baseline and 12 months= total score at 12 months - total score at baseline. A negative value indicated improved rectal function. This change in score was calculated for each individual patient who had the data.
Time frame: assessed at baseline and 12 months after randomization
Population: Patients with data about their rectal function measured using the Bowel Function Questionnaire at both baseline and 12 months after randomization. Due to the early termination of the trial, the sample size was quite small for the endpoint. Consequently, it was considered as an exploratory endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Arm I (Oxaliplatin, Fluorouracil, Leucovorin) | Change in Rectal Function Between Baseline and 12 Months | -1.17 scores on a scale | Standard Deviation 3.19 |
| Arm II (Oxaliplatin, Fluorouracil, Leucovorin, Bevacizumab) | Change in Rectal Function Between Baseline and 12 Months | 1.18 scores on a scale | Standard Deviation 3.09 |