Bevacizumab, Radiation Therapy, and Combination Chemotherapy in Treating Patients Who Are Undergoing Surgery for Locally Advanced Nonmetastatic Rectal Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00321685
• Collaborator: (none)
• Enrollment: 57
• Locations: 107
• Arm: 1
• Actual Duration (Months): 150.6
• Patients Per Site: 0.5
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Rectal Adenocarcinoma; Stage II Rectal Cancer AJCC v7; Stage III Rectal Cancer AJCC v7	Biological: Bevacizumab; Drug: Capecitabine; Drug: Fluorouracil; Drug: Leucovorin Calcium; Drug: Oxaliplatin; Radiation: Radiation Therapy; Procedure: Therapeutic Conventional Surgery	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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).

2. 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).

3. To make preliminary observations of patient survival and patterns of recurrence for this treatment combination.

4. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 57 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Jul 25, 2006
• Actual Primary Completion Date: Aug 12, 2013
• Actual Study Completion Date: Feb 11, 2019

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (bevacizumab and chemoradiotherapy) See Detailed Description

Biological: Bevacizumab; Given IV; Other Names: Anti-VEGF Anti-VEGF Humanized Monoclonal Antibody Anti-VEGF rhuMAb Avastin Bevacizumab Biosimilar BEVZ92 Bevacizumab Biosimilar BI 695502 Bevacizumab Biosimilar CBT 124 Bevacizumab Biosimilar FKB238 Bevacizumab Biosimilar MIL60 Bevacizumab Biosimilar QL 1101 BEVACIZUMAB, LICENSE HOLDER UNSPECIFIED Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer Recombinant Humanized Anti-VEGF Monoclonal Antibody rhuMab-VEGF ; Drug: Capecitabine; Given PO; Other Names: Ro 09-1978/000 Xeloda ; Drug: Fluorouracil; Given IV; Other Names: 5-Fluoro-2,4(1H, 3H)-pyrimidinedione 5-Fluorouracil 5-Fluracil 5-FU AccuSite Carac Fluoro Uracil Fluouracil Flurablastin Fluracedyl Fluracil Fluril Fluroblastin Ribofluor Ro 2-9757 Ro-2-9757 ; Drug: Leucovorin Calcium; Given IV; Other Names: Adinepar Calcifolin Calcium (6S)-Folinate Calcium Folinate Calcium Leucovorin Calfolex Calinat Cehafolin Citofolin Citrec citrovorum factor Cromatonbic Folinico Dalisol Disintox Divical Ecofol Emovis Factor, Citrovorum Flynoken A Folaren Folaxin FOLI-cell Foliben Folidan Folidar Folinac Folinate Calcium folinic acid Folinic Acid Calcium Salt Pentahydrate Folinoral Folinvit Foliplus Folix Imo Lederfolat Lederfolin Leucosar leucovorin Rescufolin Rescuvolin Tonofolin Wellcovorin ; Drug: Oxaliplatin; Given IV; Other Names: 1-OHP Ai Heng Aiheng Dacotin Dacplat Diaminocyclohexane Oxalatoplatinum Eloxatin Eloxatine JM-83 Oxalatoplatin Oxalatoplatinum RP 54780 RP-54780 SR-96669 ; Radiation: Radiation Therapy; Undergo radiotherapy; Other Names: Cancer Radiotherapy Irradiate Irradiated irradiation Radiation Radiotherapeutics RADIOTHERAPY RT Therapy, Radiation ; Procedure: Therapeutic Conventional Surgery; Undergo surgical resection

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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

2. 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

3. 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.

4. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama	United States	35233
2	The Hospital of Central Connecticut	New Britain	Connecticut	United States	06050
3	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia	United States	30322
4	Atlanta VA Medical Center	Decatur	Georgia	United States	30033
5	Medical Center of Central Georgia	Macon	Georgia	United States	31201
6	Rush - Copley Medical Center	Aurora	Illinois	United States	60504
7	MacNeal Hospital and Cancer Center	Berwyn	Illinois	United States	60402
8	Hematology and Oncology Associates	Chicago	Illinois	United States	60611
9	Northwestern University	Chicago	Illinois	United States	60611
10	Jesse Brown Veterans Affairs Medical Center	Chicago	Illinois	United States	60612
11	Mercy Hospital and Medical Center	Chicago	Illinois	United States	60616
12	Swedish Covenant Hospital	Chicago	Illinois	United States	60625
13	Presence Saint Joseph Hospital-Chicago	Chicago	Illinois	United States	60657
14	Saint Anthony Memorial Hospital	Effingham	Illinois	United States	62401
15	Hematology Oncology Associates of Illinois-Highland Park	Highland Park	Illinois	United States	60035
16	Hinsdale Hematology Oncology Associates Incorporated	Hinsdale	Illinois	United States	60521
17	Midwest Center for Hematology Oncology	Joliet	Illinois	United States	60432
18	Joliet Oncology-Hematology Associates Limited	Joliet	Illinois	United States	60435
19	NorthShore Hematology Oncology-Libertyville	Libertyville	Illinois	United States	60048
20	Garneau, Stewart C MD (UIA Investigator)	Moline	Illinois	United States	61265
21	Porubcin, Michael MD (UIA Investigator)	Moline	Illinois	United States	61265
22	Sharis, Christine M MD (UIA Investigator)	Moline	Illinois	United States	61265
23	Spector, David MD (UIA Investigator)	Moline	Illinois	United States	61265
24	Stoffel, Thomas J MD (UIA Investigator)	Moline	Illinois	United States	61265
25	Trinity Medical Center	Moline	Illinois	United States	61265
26	Vigliotti, Antonio, P.G. M.D. (UIA Investigator)	Moline	Illinois	United States	61265
27	DuPage Medical Group-Ogden	Naperville	Illinois	United States	60563
28	Illinois Cancer Specialists-Niles	Niles	Illinois	United States	60714
29	Edward H Kaplan MD and Associates	Skokie	Illinois	United States	60076
30	Hematology Oncology Associates of Illinois - Skokie	Skokie	Illinois	United States	60076
31	Carle Cancer Center	Urbana	Illinois	United States	61801
32	Franciscan Saint Anthony Health-Michigan City	Michigan City	Indiana	United States	46360
33	Constantinou, Costas L MD (UIA Investigator)	Bettendorf	Iowa	United States	52722
34	Siouxland Regional Cancer Center	Sioux City	Iowa	United States	51101
35	Mercy Medical Center-Sioux City	Sioux City	Iowa	United States	51102
36	Saint Luke's Regional Medical Center	Sioux City	Iowa	United States	51104
37	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
38	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007
39	Borgess Medical Center	Kalamazoo	Michigan	United States	49048
40	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
41	Mercy Hospital	Coon Rapids	Minnesota	United States	55433
42	Fairview-Southdale Hospital	Edina	Minnesota	United States	55435
43	Unity Hospital	Fridley	Minnesota	United States	55432
44	Hutchinson Area Health Care	Hutchinson	Minnesota	United States	55350
45	Meeker County Memorial Hospital	Litchfield	Minnesota	United States	55355
46	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota	United States	55109
47	Saint John's Hospital - Healtheast	Maplewood	Minnesota	United States	55109
48	Abbott-Northwestern Hospital	Minneapolis	Minnesota	United States	55407
49	Virginia Piper Cancer Institute	Minneapolis	Minnesota	United States	55407
50	Hennepin County Medical Center	Minneapolis	Minnesota	United States	55415
51	North Memorial Medical Health Center	Robbinsdale	Minnesota	United States	55422
52	Metro Minnesota Community Oncology Research Consortium	Saint Louis Park	Minnesota	United States	55416
53	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota	United States	55416
54	Regions Hospital	Saint Paul	Minnesota	United States	55101
55	Saint Joseph's Hospital - Healtheast	Saint Paul	Minnesota	United States	55102
56	United Hospital	Saint Paul	Minnesota	United States	55102
57	Saint Francis Regional Medical Center	Shakopee	Minnesota	United States	55379
58	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
59	Minnesota Oncology Hematology PA-Woodbury	Woodbury	Minnesota	United States	55125
60	Woodwinds Health Campus	Woodbury	Minnesota	United States	55125
61	Nebraska Cancer Research Center	Lincoln	Nebraska	United States	68510
62	Missouri Valley Cancer Consortium	Omaha	Nebraska	United States	68106
63	Alegent Health Immanuel Medical Center	Omaha	Nebraska	United States	68122
64	Alegent Health Bergan Mercy Medical Center	Omaha	Nebraska	United States	68124
65	Creighton University Medical Center	Omaha	Nebraska	United States	68131
66	Virtua Memorial	Mount Holly	New Jersey	United States	08060
67	Sparta Cancer Treatment Center	Sparta	New Jersey	United States	07871
68	Virtua Voorhees	Voorhees	New Jersey	United States	08043
69	Inspira Medical Center Woodbury	Woodbury	New Jersey	United States	08096
70	Montefiore Medical Center-Wakefield Campus	Bronx	New York	United States	10466
71	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
72	Summa Akron City Hospital/Cooper Cancer Center	Akron	Ohio	United States	44304
73	Summa Barberton Hospital	Barberton	Ohio	United States	44203
74	Mary Rutan Hospital	Bellefontaine	Ohio	United States	43311
75	Adena Regional Medical Center	Chillicothe	Ohio	United States	45601
76	Riverside Methodist Hospital	Columbus	Ohio	United States	43214
77	Grant Medical Center	Columbus	Ohio	United States	43215
78	Mount Carmel Health Center West	Columbus	Ohio	United States	43222
79	Doctors Hospital	Columbus	Ohio	United States	43228
80	Grady Memorial Hospital	Delaware	Ohio	United States	43015
81	Fairfield Medical Center	Lancaster	Ohio	United States	43130
82	Saint Rita's Medical Center	Lima	Ohio	United States	45801
83	Marietta Memorial Hospital	Marietta	Ohio	United States	45750
84	Licking Memorial Hospital	Newark	Ohio	United States	43055
85	Springfield Regional Medical Center	Springfield	Ohio	United States	45505
86	Saint Ann's Hospital	Westerville	Ohio	United States	43081
87	Genesis Healthcare System Cancer Care Center	Zanesville	Ohio	United States	43701
88	Natalie Warren Bryant Cancer Center at Saint Francis	Tulsa	Oklahoma	United States	74136
89	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania	United States	18103
90	Mercy Fitzgerald Hospital	Darby	Pennsylvania	United States	19023-1291
91	Pocono Medical Center	East Stroudsburg	Pennsylvania	United States	18301
92	Ephrata Cancer Center	Ephrata	Pennsylvania	United States	17522
93	Riddle Memorial Hospital	Media	Pennsylvania	United States	19063
94	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
95	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
96	Aria Health-Torresdale Campus	Philadelphia	Pennsylvania	United States	19114
97	Einstein Medical Center Philadelphia	Philadelphia	Pennsylvania	United States	19141
98	Hematology and Oncology Associates of North East Pennsylvania	Scranton	Pennsylvania	United States	18508
99	Associates In Hematology Oncology PC-Upland	Upland	Pennsylvania	United States	19013
100	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota	United States	57104
101	Avera Cancer Institute	Sioux Falls	South Dakota	United States	57105
102	Avera McKennan Hospital and University Health Center	Sioux Falls	South Dakota	United States	57105
103	Medical X-Ray Center	Sioux Falls	South Dakota	United States	57105
104	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
105	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
106	Gundersen Lutheran Medical Center	La Crosse	Wisconsin	United States	54601
107	Froedtert and the Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Jerome C Landry, ECOG-ACRIN Cancer Research Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00321685
• Other Study ID Numbers: NCI-2009-01081; NCI-2009-01081; CDR0000471148; ECOG-E3204; E3204; E3204; U10CA180820; U10CA021115
• First Posted: May 4, 2006
• Last Update Posted: Mar 27, 2019
• Last Verified: Mar 1, 2019

• Additional relevant MeSH terms: Rectal Neoplasms; Calcium, Dietary; Leucovorin; Folic Acid; Bevacizumab; Antineoplastic Agents, Immunological; Fluorouracil; Capecitabine; Oxaliplatin; Endothelial Growth Factors; Antibodies; Immunoglobulins; Antibodies, Monoclonal; Immunoglobulin G; Calcium; Levoleucovorin

Study Results

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.

Arm/Group Title	Arm I
Arm/Group Description	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 4-12 weeks after surgery, patients receive oxaliplatin IV over 2 hours, leucovorin calcium IV over 2 hours, 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. radiation therapy: Patients undergo 3-dimensional conformal radiation therapy once daily 5 days
Period Title: Overall Study
STARTED	57
Eligible	55
Started Protocol Therapy	55
Eligible and Treated	53
COMPLETED	18
NOT COMPLETED	39

Baseline Characteristics

Arm/Group Title	Arm I
Arm/Group Description	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.
Overall Participants	53
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	54
Sex: Female, Male (Count of Participants)
Female	17 32.1%
Male	36 67.9%
Clinical T stage (participants) [Number]
T3	49 92.5%
T4	4 7.5%

Outcome Measures

1. Primary Outcome

Title	Pathologic Complete Response Rate
Description	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

Outcome Measure Data

Analysis Population Description

Eligible and treated patients

Arm/Group Title	Arm I
Arm/Group Description	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 4-12 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.
Measure Participants	53
Number (90% Confidence Interval) [percentage of participants]	17 32.1%

2. Secondary Outcome

Title	Resection Rate for T3 Rectal Cancers
Description	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

Outcome Measure Data

Analysis Population Description

eligible and treated patients with T3 rectal cancers

Arm/Group Title	Arm I
Arm/Group Description	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 4-12 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.
Measure Participants	49
Number (90% Confidence Interval) [percentage of participants]	92 173.6%

3. Secondary Outcome

Title	Resection Rate for T4 Rectal Cancers
Description	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

Outcome Measure Data

Analysis Population Description

eligible and treated patients with T4 rectal cancers

Arm/Group Title	Arm I
Arm/Group Description	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 4-12 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.
Measure Participants	4
Number (90% Confidence Interval) [percentage of participants]	75 141.5%

4. Secondary Outcome

Title	5-year Overall Survival Rate
Description	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

Outcome Measure Data

Analysis Population Description

Eligible and treated patients

Arm/Group Title	Arm I
Arm/Group Description	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 4-12 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.
Measure Participants	53
Number (90% Confidence Interval) [percentage of participants]	80 150.9%

5. Secondary Outcome

Title	5-year Recurrence-free Survival Rate
Description	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

Outcome Measure Data

Analysis Population Description

Eligible and treated patients who underwent surgery after neoadjuvant therapy

Arm/Group Title	Arm I
Arm/Group Description	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 4-12 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.
Measure Participants	48
Number (90% Confidence Interval) [percentage of participants]	81 152.8%

Adverse Events

Time Frame	Assessed at the completion of Pre-Operative Chemoradiation, at the end of every cycle during PostOperative Chemotherapy, and at 30 days after the end of treatment
Adverse Event Reporting Description	Prior to diagnosis of progression/relapse, any severe (Grade ≥ 3) long term toxicity that has not been previously reported were collected using the Long-term follow up form.
Arm/Group Title	Arm I
Arm/Group Description	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.
All Cause Mortality
	Arm I
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Arm I
	Affected / at Risk (%)	# Events
Total	39/55 (70.9%)
Blood and lymphatic system disorders
Anemia	5/55 (9.1%)
DIC	1/55 (1.8%)
Gastrointestinal disorders
Constipation	1/55 (1.8%)
Diarrhea w/o prior colostomy	7/55 (12.7%)
Distention/bloating, abdominal	1/55 (1.8%)
Enteritis	1/55 (1.8%)
Fistula, Rectum	1/55 (1.8%)
Ileus	2/55 (3.6%)
Nausea	3/55 (5.5%)
Proctitis	1/55 (1.8%)
Vomiting	3/55 (5.5%)
Oral cavity, hemorrhage	1/55 (1.8%)
Abdomen, pain	5/55 (9.1%)
Intestine, pain	1/55 (1.8%)
Rectum, pain	9/55 (16.4%)
General disorders
Fatigue	9/55 (16.4%)
Hypothermia	1/55 (1.8%)
Death NOS	1/55 (1.8%)
Pain-other	1/55 (1.8%)
Immune system disorders
Allergic reaction	1/55 (1.8%)
Infections and infestations
Infection Gr0-2 neut, anal/perianl	1/55 (1.8%)
Infection Gr0-2 neut, muscle	1/55 (1.8%)
Infection Gr0-2 neut, pelvis NOS	1/55 (1.8%)
Infection Gr0-2 neut, rectum	1/55 (1.8%)
Infection Gr0-2 neut, wound	2/55 (3.6%)
Infection w/ unk ANC anal/perianal	2/55 (3.6%)
Infection w/ unk ANC wound	1/55 (1.8%)
Injury, poisoning and procedural complications
Chemoradiation dermatitis	1/55 (1.8%)
Wound - non-infectious	2/55 (3.6%)
Investigations
Leukocytes decreased	8/55 (14.5%)
Lymphopenia	8/55 (14.5%)
Neutrophils decreased	10/55 (18.2%)
Platelets decreased	3/55 (5.5%)
Weight loss	2/55 (3.6%)
Coagulation-other	1/55 (1.8%)
Alkaline phosphatase increased	1/55 (1.8%)
Aspartate aminotransferase increased	1/55 (1.8%)
Metabolic/Laboratory-other	1/55 (1.8%)
Metabolism and nutrition disorders
Anorexia	2/55 (3.6%)
Dehydration	5/55 (9.1%)
Acidosis	1/55 (1.8%)
Hypoalbuminemia	2/55 (3.6%)
Hypocalcemia	1/55 (1.8%)
Hyperglycemia	2/55 (3.6%)
Hypophosphatemia	1/55 (1.8%)
Hyperkalemia	2/55 (3.6%)
Hyponatremia	1/55 (1.8%)
Musculoskeletal and connective tissue disorders
Bone, pain	1/55 (1.8%)
Nervous system disorders
CNS, hemorrhage	1/55 (1.8%)
Neuropathy-motor	1/55 (1.8%)
Neuropathy-sensory	5/55 (9.1%)
Renal and urinary disorders
Incontinence urinary	1/55 (1.8%)
Renal failure	1/55 (1.8%)
Urinary retention	1/55 (1.8%)
Reproductive system and breast disorders
Perineum, pain	1/55 (1.8%)
Erectile impotence	1/55 (1.8%)
Respiratory, thoracic and mediastinal disorders
Aspiration	1/55 (1.8%)
Skin and subcutaneous tissue disorders
Rash/desquamation	2/55 (3.6%)
Skin-other	1/55 (1.8%)
Vascular disorders
Thrombosis/thrombus/embolism	2/55 (3.6%)
Other (Not Including Serious) Adverse Events
	Arm I
	Affected / at Risk (%)	# Events
Total	53/55 (96.4%)
Blood and lymphatic system disorders
Anemia	33/55 (60%)
Gastrointestinal disorders
Constipation	9/55 (16.4%)
Diarrhea w/o prior colostomy	27/55 (49.1%)
Dry mouth	3/55 (5.5%)
Dyspepsia	5/55 (9.1%)
Incontinence, anal	3/55 (5.5%)
Muco/stomatitis (symptom) oral cavity	7/55 (12.7%)
Nausea	23/55 (41.8%)
Proctitis	5/55 (9.1%)
Vomiting	13/55 (23.6%)
Rectum, hemorrhage	4/55 (7.3%)
Abdomen, pain	9/55 (16.4%)
Rectum, pain	14/55 (25.5%)
General disorders
Fatigue	31/55 (56.4%)
Fever w/o neutropenia	5/55 (9.1%)
Rigors/chills	3/55 (5.5%)
Injury, poisoning and procedural complications
Wound - non-infectious	6/55 (10.9%)
Investigations
Leukocytes decreased	23/55 (41.8%)
Lymphopenia	7/55 (12.7%)
Neutrophils decreased	17/55 (30.9%)
Platelets decreased	22/55 (40%)
Weight loss	17/55 (30.9%)
Alkaline phosphatase increased	3/55 (5.5%)
Alanine aminotransferase increased	5/55 (9.1%)
Aspartate aminotransferase increased	11/55 (20%)
Metabolic/Laboratory-other	3/55 (5.5%)
Metabolism and nutrition disorders
Anorexia	17/55 (30.9%)
Dehydration	5/55 (9.1%)
Hypoalbuminemia	4/55 (7.3%)
Hypocalcemia	7/55 (12.7%)
Hyperglycemia	5/55 (9.1%)
Hypokalemia	6/55 (10.9%)
Hyponatremia	4/55 (7.3%)
Musculoskeletal and connective tissue disorders
Back, pain	3/55 (5.5%)
Nervous system disorders
Taste disturbance	4/55 (7.3%)
Dizziness	3/55 (5.5%)
Neuropathy-sensory	28/55 (50.9%)
Head/headache	5/55 (9.1%)
Psychiatric disorders
Insomnia	5/55 (9.1%)
Depression	3/55 (5.5%)
Renal and urinary disorders
Urinary hemorrhage NOS	3/55 (5.5%)
Urinary frequency/urgency	6/55 (10.9%)
Respiratory, thoracic and mediastinal disorders
Nose, hemorrhage	3/55 (5.5%)
Dyspnea	5/55 (9.1%)
Voice changes/dysarthria	3/55 (5.5%)
Skin and subcutaneous tissue disorders
Sweating	4/55 (7.3%)
Dry skin	3/55 (5.5%)
Alopecia	4/55 (7.3%)
Hyperpigmentation	3/55 (5.5%)
Rash/desquamation	7/55 (12.7%)
Hand-foot reaction	3/55 (5.5%)
Vascular disorders
Hypotension	4/55 (7.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.