Phase II Study of Preoperative Radiation With Concurrent Capecitabine, Oxaliplatin and Bevacizumab Followed by Surgery and Postoperative 5-FU, Leucovorin, Oxaliplatin (FOLFOX) and Bevacizumab in Patients With Locally Advanced Rectal Cancer
Overview
- Phase
- Phase 2
- Intervention
- Capecitabine
- Conditions
- Rectal Adenocarcinoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 57
- Locations
- 107
- Primary Endpoint
- Pathologic Complete Response Rate
- Status
- Completed
- Last Updated
- 7 years ago
Overview
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.
Investigators
Eligibility Criteria
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
Exclusion Criteria
- Not provided
Arms & Interventions
Treatment (bevacizumab and chemoradiotherapy)
See Detailed Description
Intervention: Capecitabine
Treatment (bevacizumab and chemoradiotherapy)
See Detailed Description
Intervention: Bevacizumab
Treatment (bevacizumab and chemoradiotherapy)
See Detailed Description
Intervention: Fluorouracil
Treatment (bevacizumab and chemoradiotherapy)
See Detailed Description
Intervention: Leucovorin Calcium
Treatment (bevacizumab and chemoradiotherapy)
See Detailed Description
Intervention: Oxaliplatin
Treatment (bevacizumab and chemoradiotherapy)
See Detailed Description
Intervention: Radiation Therapy
Treatment (bevacizumab and chemoradiotherapy)
See Detailed Description
Intervention: Therapeutic Conventional Surgery
Outcomes
Primary Outcomes
Pathologic Complete Response Rate
Time Frame: 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 Outcomes
- Resection Rate for T3 Rectal Cancers(Assessed at surgery time)
- Resection Rate for T4 Rectal Cancers(Assessed at surgery time)
- 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)
- 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)