Rectal Adenocarcinoma, Stage III Rectal Cancer AJCC v7, Stage II Rectal Cancer AJCC v7
Conditions
Brief summary
This phase II trial studies how well giving bevacizumab, radiation therapy, and combination chemotherapy works in treating patients who are undergoing surgery for locally advanced nonmetastatic rectal cancer. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some find tumor cells and kill them or carry tumor-killing substances to them. Others interfere with the ability of tumor cells to grow and spread. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs, such as capecitabine, may make tumor cells more sensitive to radiation therapy. Drugs used in chemotherapy, such as capecitabine, oxaliplatin, fluorouracil, and leucovorin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving bevacizumab together with radiation therapy and combination chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving bevacizumab together with combination chemotherapy after surgery may kill any tumor cells that remain after surgery.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the pathological complete response rate in patients with T3 and T4 rectal cancers when treated preoperatively with capecitabine, oxaliplatin, bevacizumab, and concurrent radiotherapy (XRT). II. To evaluate the resection rate for T3 and T4 rectal cancers and the expected versus actual type of resection (abdominoperinal resection \[APR\] vs. low anterior resection \[LAR\] vs. LAR/coloanal anastomosis). III. To make preliminary observations of patient survival and patterns of recurrence for this treatment combination. IV. To gain additional experience regarding the toxicity and tolerability of this preoperative and postoperative regimen. OUTLINE: PREOPERATIVE CHEMORADIOTHERAPY: Patients undergo radiotherapy (total dose to the tumor bed was 5040 cGy) once daily (QD) 5 days a week and receive capecitabine 825 mg/m\^2 orally (PO) twice daily (BID) 5 days a week for 5.5 weeks. Patients also receive oxaliplatin 50 mg/m\^2 intravenously (IV) over 2 hours on days 1, 8, 15, 22, and 29 and bevacizumab 5 mg/kg IV over 30-90 minutes on days 1, 15, and 29 during radiotherapy. SURGERY: Approximately 6-8 weeks after completion of chemoradiotherapy, patients undergo surgical resection. Patients whose tumors are not completely resected or who have metastatic disease discontinue protocol therapy. POSTOPERATIVE CHEMOTHERAPY: Approximately 4-12 weeks after surgery, patients receive oxaliplatin IV over 2 hours, leucovorin calcium 400 mg/m\^2 IV over 2 hours, and bevacizumab 5 mg/kg IV over 30-90 minutes on day 1. Patients also receive fluorouracil 2400 mg/m\^2 IV continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for 9 courses in the absence of disease progression or unacceptable toxicity. Patients then receive up to 3 additional courses of leucovorin calcium, fluorouracil, and bevacizumab. After completion of study treatment, patients are followed up periodically for 10 years.
Interventions
BIOLOGICALBevacizumab
Given IV
DRUGCapecitabine
Given PO
DRUGFluorouracil
Given IV
DRUGLeucovorin Calcium
Given IV
DRUGOxaliplatin
Given IV
RADIATIONRadiation Therapy
Undergo radiotherapy
PROCEDURETherapeutic Conventional Surgery
Undergo surgical resection
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically confirmed, locally advanced, non-metastatic primary T3 or T4 adenocarcinoma of the rectum * Patients must not have evidence of tumor outside of the pelvis including liver metastases, peritoneal seeding, or metastatic inguinal lymphadenopathy * Patients must not have intra-operative radiotherapy (IORT) or brachytherapy treatment to the pelvis * The distal border of the tumor must be at or below the peritoneal reflection, defined as within 12 centimeters of the anal verge by proctoscopic examination * Transmural penetration of tumor through the muscularis propria must be demonstrated by either of the following: computed tomography (CT) scan plus endorectal ultrasound, or a magnetic resonance imaging (MRI); an endorectal coil or pelvic MRI is allowed * For the patient to be eligible, the surgeon must prospectively define the tumor as either initially resectable or potentially resectable after pre-operative chemoradiation; clinically resectable tumors are defined as completely resectable with negative margins based on routine examination of the non-anesthetized patient; patients whose tumors are not resectable are not eligible; before pre-operative (op) treatment, the surgeon should estimate and record the type of resection anticipated: pelvic exenteration, posterior pelvic exenteration, APR, LAR, or LAR/coloanal anastomosis * Patients with tumors that are clinically fixed, clinical stage T4N0-2, M0 are eligible if it is believed that their tumors are potentially resectable after chemoradiation; based on the following: * Clinically fixed tumors on rectal examination with tumor adherent to the pelvic sidewall or sacrum * Sciatica attributed to sacral root invasion with CT scan/MRI evidence of the lack of clear tissue plane will be considered evidence of fixation * Hydronephrosis on CT scan or intravenous pyelogram (IVP) or ureteric or bladder invasion as documented by cystoscopy and cytology or biopsy, or invasion into prostate * Vaginal or uterine involvement * Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * A surgical evaluation must confirm patient's ability to tolerate the proposed surgical procedure * Patients must have a caloric intake \> 1500 kilocalories/day (d) * Within 4 weeks prior to registration, the patient's absolute neutrophil count (ANC) level must be \>= 1,500/mm\^3 * Within 4 weeks prior to registration, the patients platelet level must be \>= 100,000/mm\^3 * Within 4 weeks prior to registration, serum creatinine must be \< 1.5 X upper limit of normal (ULN); if serum creatinine \> 1.5 x ULN, then creatinine clearance must be \>= 50 mL/mm * Within 4 weeks prior to registration, serum bilirubin must be =\< 1.5 X ULN * Within 4 weeks prior to registration, alkaline phosphatase (alk phos) must be \< 2 x ULN * Within 4 weeks prior to registration, serum glutamic oxaloacetic transaminase (SGOT) must be \< 2 x ULN * Carcinoembryonic antigen (CEA) must be determined prior to initiation of therapy * Within 4 weeks prior to registration, urine protein/creatinine (UPC) ratio must be \< 1; patients with a ratio of \>= 1 must undergo a 24-hour urine collection which must be an adequate collection and must demonstrate \< 1 gram (gm) of protein in order to participate * Within 4 weeks prior to registration, albumin must be \>= 2 gm/dl * Absence of clinical evidence of high-grade (lumen diameter \< 1 cm) large bowel obstruction, unless diverting colostomy has been performed * Eligible patients of reproductive potential (both sexes) must agree to use an accepted and effective method of contraceptive during study therapy and for at least 6 months after the completion of bevacizumab * Women must not be pregnant or breast-feeding; all females of childbearing potential must have a serum pregnancy test to rule out pregnancy within 2 weeks of registration * Patients must have had no prior chemotherapy for rectal cancer or pelvic irradiation therapy * Patients with prior malignancies, including pelvic cancer, are eligible if they have been disease free for \> 5 years; patients with prior in situ carcinomas are eligible provided there was complete removal * Patients must have no active inflammatory bowel disease or other serious medical illness or disease that might limit the patient's ability to receive protocol therapy * Patients with a history of cerebrovascular accident (CVA)/transient ischemic attack (TIA) at any time, or myocardial infarction/unstable angina within 12 months of study entry are not eligible * Patients with \> grade 1 peripheral neuropathy are not eligible * Patients must have urine protein/creatinine (UPC) ratio of \< 1.0; patients with a UPC ratio \>= 1.0 must undergo a 24-hour urine collection, which must be an adequate collection and must demonstrate \< 1 gm of protein in order to participate * Patients with a history of hypertension must measure \< 150/90 mmHg and be on a stable regimen of anti-hypertensive therapy * Patients with clinically significant peripheral vascular disease are not eligible * Patients must not have any of the following: * Unstable angina (within 12 months of study entry) * New York Heart Association (NYHA) grade II or higher congestive heart failure * Evidence of bleeding diathesis/coagulopathy * Serious non-healing wound or bone fracture * Patients with a history of the following within 28 days prior to registration are not eligible: * Abdominal fistula * Gastrointestinal perforation * Intrabdominal abscess * Patients with a history of the following within 28 days prior to day 0 (first treatment day) are not eligible: * Major surgical procedure * Open biopsy * Significant traumatic injury * Patients must not have core biopsy within 7 days prior to day 0 (first treatment day) * Patients with prothrombin time (PT) (international normalized ratio \[INR\]) \> 1.5 are not eligible, unless the patient is on full-dose anticoagulants; if so, the following criteria must be met for enrollment: * The subject must have an in-range INR (usually between 2 and 3), be on a stable dose of warfarin or on a stable dose of low molecular weight heparin * The subject must not have active bleeding or a pathological condition that is associated with a high risk of bleeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pathologic Complete Response Rate | Assessed at surgery time | Pathologic complete response to preoperative therapy was determined at the time of surgical resection. Pathologic complete response (pCR) is defined as no evidence of invasive cells on pathologic examination of the primary rectal cancer (or tissue from the area where the tumor had been if there is a complete clinical response). Pathologic complete response rate is calculated as number of patients achieving pathologic complete response divided by all eligible and treated patients |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Resection Rate for T3 Rectal Cancers | Assessed at surgery time | Resection rate is defined as number of patients with T3 rectal cancer who underwent curative surgical resection among all eligible and treated patients with T3 rectal cancers |
| Resection Rate for T4 Rectal Cancers | Assessed at surgery time | Resection rate is defined as number of patients with T4 rectal cancer who underwent curative surgical resection among all eligible and treated patients with T4 rectal cancers |
| 5-year Overall Survival Rate | survival follow-up began after post-operative chemotherapy, assessed every 3 months for patients 3-5 years from registration, every 6 months for patients 5-10 years from registration and every 12 months for patients 10 years from registration | Overall survival is defined as time from registration to death from any cause. 5-year overall survival rate is estimated using Kaplan-Meier method. |
| 5-year Recurrence-free Survival Rate | recurrence follow-up began after post-operative chemotherapy, assessed every 3 months for patients 3-5 years from registration, every 6 months for patients 5-10 years from registration and every 12 months for patients 10 years from registration | Recurrence free survival is defined as time from surgery to disease recurrence or death without recurrence (whichever occurred first) among resected patients. 5-year recurrence-free survival rate is estimated using Kaplan-Meier method, with 90% confidence interval calculated using Greenwood's formula. |
Countries
United States
Participant flow
Recruitment details
This study was activated on July 25, 2006 and terminated on May 26, 2010 with a final accrual of 57 patients from 11 participating sites.
Participants by arm
| Arm | Count |
|---|---|
| Arm I Preoperative radiation therapy: Patients undergo radiotherapy once daily 5 days a week.
Preoperative chemotherapy: Patients receive oral capecitabine twice daily 5 days a week for 5.5 weeks. Patients also receive oxaliplatin IV over 2 hours on days 1, 8, 15, 22, and 29 and bevacizumab IV over 30-90 minutes on days 1, 15, and 29 during radiotherapy.
Surgery: Approximately 6-8 weeks after completion of chemoradiotherapy, patients undergo surgical resection.
Postoperative chemotherapy: Approximately 4-8 weeks after surgery, patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, and bevacizumab IV over 30-90 minutes on day 1. Patients also receive fluorouracil (5-FU) IV continuously over 46 hours beginning on day 1. Treatment repeats every 2 weeks for 9 courses. Patients then receive up to 3 additional courses of leucovorin calcium, 5-FU, and bevacizumab. | 53 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 18 |
| Overall Study | Alternative therapy | 1 |
| Overall Study | Complicating disese | 1 |
| Overall Study | Death | 2 |
| Overall Study | Ineligible | 2 |
| Overall Study | Not start protocol therapy | 2 |
| Overall Study | Other | 5 |
| Overall Study | Withdrawal by Subject | 8 |
Baseline characteristics
| Characteristic | Arm I |
|---|---|
| Age, Continuous | 54 years |
| Clinical T stage T3 | 49 participants |
| Clinical T stage T4 | 4 participants |
| Sex: Female, Male Female | 17 Participants |
| Sex: Female, Male Male | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 53 / 55 |
| serious Total, serious adverse events | 39 / 55 |
Outcome results
Primary
Pathologic Complete Response Rate
Pathologic complete response to preoperative therapy was determined at the time of surgical resection. Pathologic complete response (pCR) is defined as no evidence of invasive cells on pathologic examination of the primary rectal cancer (or tissue from the area where the tumor had been if there is a complete clinical response). Pathologic complete response rate is calculated as number of patients achieving pathologic complete response divided by all eligible and treated patients
Time frame: Assessed at surgery time
Population: Eligible and treated patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I | Pathologic Complete Response Rate | 17 percentage of participants |
Secondary
5-year Overall Survival Rate
Overall survival is defined as time from registration to death from any cause. 5-year overall survival rate is estimated using Kaplan-Meier method.
Time frame: survival follow-up began after post-operative chemotherapy, assessed every 3 months for patients 3-5 years from registration, every 6 months for patients 5-10 years from registration and every 12 months for patients 10 years from registration
Population: Eligible and treated patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I | 5-year Overall Survival Rate | 80 percentage of participants |
Secondary
5-year Recurrence-free Survival Rate
Recurrence free survival is defined as time from surgery to disease recurrence or death without recurrence (whichever occurred first) among resected patients. 5-year recurrence-free survival rate is estimated using Kaplan-Meier method, with 90% confidence interval calculated using Greenwood's formula.
Time frame: recurrence follow-up began after post-operative chemotherapy, assessed every 3 months for patients 3-5 years from registration, every 6 months for patients 5-10 years from registration and every 12 months for patients 10 years from registration
Population: Eligible and treated patients who underwent surgery after neoadjuvant therapy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I | 5-year Recurrence-free Survival Rate | 81 percentage of participants |
Secondary
Resection Rate for T3 Rectal Cancers
Resection rate is defined as number of patients with T3 rectal cancer who underwent curative surgical resection among all eligible and treated patients with T3 rectal cancers
Time frame: Assessed at surgery time
Population: eligible and treated patients with T3 rectal cancers
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I | Resection Rate for T3 Rectal Cancers | 92 percentage of participants |
Secondary
Resection Rate for T4 Rectal Cancers
Resection rate is defined as number of patients with T4 rectal cancer who underwent curative surgical resection among all eligible and treated patients with T4 rectal cancers
Time frame: Assessed at surgery time
Population: eligible and treated patients with T4 rectal cancers
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I | Resection Rate for T4 Rectal Cancers | 75 percentage of participants |