- Email: [email protected]
III Rectal Cancer
Original Study
Phase II Study of Bevacizumab and Chemoradiation in the Preoperative or Adjuvant Treatment of Patients With Stage II/III Rectal Cancer David R. Spigel,1,2 Johanna C. Bendell,1,2 Michael McCleod,3 Dianna L. Shipley,2 Edward Arrowsmith,4 E. Kirk Barnes,2 Jeffrey R. Infante,1,2 Howard A. Burris, III,1,2 F. Anthony Greco,1,2 John D. Hainsworth1,2 Abstract Sixty-six patients with rectal cancer received bevacizumab in addition to chemotherapy and radiation. This trial sought to determine if adding bevacizumab would produce a benefit for patients before or after surgery. Some patients’ cancer improved but there were side effects, some severe. Patients should be cautioned about risks associated with adding bevacizumab to this type of therapy, particularly after surgery. Background and Purpose: We wanted to evaluate the efficacy, defined as 2-year disease-free survival (DFS), and safety of bevacizumab/chemoradiation in preoperative and adjuvant settings for patients with stage II/III rectal cancer. Patients and Methods: Eligible patients had stage II/III rectal adenocarcinoma, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1, and adequate organ function, and received preoperative (cohort A) or adjuvant (cohort B) treatment at physician discretion. Patients received 5-fluorouracil (5-FU) as an intravenous infusion (IVCI) 225 mg/m2/d on days 1-42, bevacizumab 5 mg/kg intravenously (I.V.) on days 1 and 15 (cohort A), or every 2 weeks (cohort B), with radiation therapy to 50.4 Gy. After surgery (cohort A) or chemoradiation (cohort B), FOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) and bevacizumab were administered for 4 months and then bevacizumab was given alone for up to 1 year. Results: Sixty-six patients (cohort A ⫽ 35; cohort B ⫽ 31) were enrolled from August 2006-April 2009: median age was 57 years; male patients, 62%; ECOG PS 0, 75%; stage II/III, 31%/69%. In cohort A, the complete pathologic response (pCR) rate was 29% (11% microscopic residual disease, 49% gross disease). Four patients did not undergo surgery (toxicity, 2 patients; progressive disease, 1 patient; patient decision, 1 patient). One- and 2-year DFS for cohorts A/B were 85%/not reached and 97%/89%, respectively (median survival not reached for either cohort). Frequent grade 3/4 toxicity included diarrhea (A cohort, 14%; B cohort, 29%), neutropenia (A cohort, 14%, B cohort, 23%), mucositis (A cohort, 23%, B cohort, 0%), and fatigue (A cohort, 6%, B cohort, 10%). Other serious toxicity included bowel perforation and pelvic infection (cohort A, 1 patient each), bowel perforation (2 patients), anal wound dehiscence (1 patient), perianal infection (2 patients), and rectovaginal fistula (1 patient) (cohort B), without treatment-related death in either cohort. Conclusions: Bevacizumab can be added to standard preoperative and adjuvant chemoradiation in most patients with expected and manageable toxicity and may increase treatment efficacy. Clinical Colorectal Cancer, Vol. 11, No. 1, 45-52 © 2012 Elsevier Inc. All rights reserved. Keywords: Adjuvant, Bevacizumab, Chemoradiation, Preoperative, Rectal cancer
Preliminary data presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, January 22-24, 2010, Orlando, FL 1
Sarah Cannon Research Institute, Nashville, TN 2 Tennessee Oncology, PLLC, Nashville, TN 3 Florida Cancer Specialists, Fort Myers, FL 4 Chattanooga Oncology and Hematology Associates, PC, Chattanooga, TN
1533-0028/$ - see frontmatter © 2012 Elsevier Inc. All rights reserved. doi: 10.1016/j.clcc.2011.04.002
Submitted: Feb 14, 2011; Revised: Mar 25, 2011; Accepted: Apr 12, 2011 Address for correspondence: David R. Spigel, MD, Sarah Cannon Research Institute, 250 25th Avenue North, Suite 110, Nashville, TN 37203 Fax: 615-340-1535; e-mail contact: [email protected]
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Preop/Adj Chemo/Rad/Bev in Stage II/III Rectal Ca Introduction
Study Design and Treatment
More than 40,000 patients a year are diagnosed with rectal cancer.1 Combined modality therapy with surgery and chemoradiation is standard treatment for patients with stage II/III disease, resulting in a 5-year survival rate of 75%.2-4 Preoperative chemoradiation is superior to adjuvant treatment in reducing pelvic recurrence and treatment-related toxicity but has no survival advantage. An optimal treatment strategy in rectal cancer would maximize tumor killing locally while also addressing micrometastatic systemic disease. Bevacizumab is a monoclonal antibody to vascular endothelial growth factor (VEGF) used in the treatment of advanced colorectal cancer. Bevacizumab and 5-fluorouracil (5-FU)-based chemotherapy improved survival in patients with metastatic colorectal cancer compared with chemotherapy alone.5 Preclinical models suggest that angiogenesis is a mechanism of radiation resistance.6-8 Bevacizumab and chemoradiation for rectal cancer may improve both local and distant disease control. Based on reports of preliminary antitumor activity and safety9,10 of bevacizumab and chemoradiation in rectal cancer, we conducted a multicenter phase II trial of preoperative or adjuvant bevacizumab and chemoradiation in patients with locally advanced disease.
This study was nonrandomized. Treatment in the preoperative or adjuvant cohorts was at physician discretion. Surgery was performed according to institutional guidelines. Bevacizumab was provided by Genentech. Chemotherapy was obtained from commercial supplies. Each patient enrolled in the preoperative cohort (cohort A) received 5-FU 225 mg/m2 as a continuous infusion (IVCI) on days 1-42 through a portable infusion pump and central venous catheter. Bevacizumab 5 mg/kg was administered intravenously (I.V.) on days 1 and 15. Additionally these patients received radiation to 50.4 Gy (1.8 Gy/day or 28 fractions) Monday through Friday during weeks 1-6. Radiation therapy fields included the tumor (with 2- to 5-cm margins), the presacral nodes, and the internal iliac nodes. Multiple radiation therapy fields were used (eg, 3- or 4-field techniques). Positioning and other techniques to minimize the volume of small bowel in the fields were encouraged. Patients in cohort A underwent resection 2-8 weeks after completion of 5-FU/radiation. At least 8 weeks after surgery, patients in cohort A began 4 months of chemotherapy and bevacizumab. This adjuvant treatment consisted of 5-FU 400 mg/m2 I.V. bolus over 2-4 minutes followed by 2400 mg/m2 IVCI over 46 hours, leucovorin 350 mg as a 2-hour infusion, oxaliplatin 85 mg/m2 I.V. (modified FOLFOX6), and bevacizumab 5 mg/kg I.V., all on days 1 and 15 of each cycle. After 4 treatment cycles and in the absence of disease progression, patients were able to continue single-agent bevacizumab to complete a total of 1 year of treatment. Patients enrolled in the adjuvant cohort (cohort B) received 5-FU 225 mg/m2 IVCI on days 1-42. Bevacizumab was administered at 5 mg/kg IV on day 1 every 2 weeks. These patients also received radiation to 50.4 Gy (1.8 Gy/day or 28 fractions) Monday through Friday during weeks 1-6. For patients treated by abdominoperineal resection, the perineal wound was included within the radiation field. Six weeks after the completion of adjuvant 5-FU/radiation, patients in cohort B began treatment with chemotherapy and bevacizumab, using an identical regimen as described for cohort A. After 4 cycles of this treatment, patients without disease progression could continue single-agent bevacizumab to complete a total of 1 year of treatment. The dose of 5-FU was not modified based on myelosuppression during chemoradiation. Patients in whom grade 3/4 mucositis or diarrhea developed had 5-FU, bevacizumab, and radiation discontinued for 1 week or until the toxicity decreased to grade ⬍ 2. 5-FU was then resumed with a 25% dose reduction. If radiation therapy required interruption, bevacizumab and 5-FU were held as well. Bevacizumab was discontinued for grade ⱖ 2 pulmonary or central nervous system hemorrhage, any grade 4 hemorrhage, grade 4 proteinuria, grade 4 congestive heart failure, fistula development, thromboemboli, wound dehiscence, or reversible posterior leukoencephalopathy. Bevacizumab was held for surgical procedures, other proteinuria, hypertension, other hemorrhage, or other congestive heart failure for up to 4 weeks, or the bevacizumab was discontinued. Patients could continue chemotherapy if bevacizumab was discontinued. Dose modifications during FOLFOX and bevacizumab were based on standard practice. Once an agent was reduced, its dose
Patients and Methods This open-label phase II study of bevacizumab and combined modality therapy for rectal cancer was designed by the Sarah Cannon Research Institute (SCRI) and was performed at selected sites in the SCRI Oncology Research Consortium, a community-based clinical trial organization (Appendix). The protocol was approved by the institutional review boards at all participating institutions, and all patients provided written informed consent.
Patients Patients 18 years of age or older with documented pathologic evidence of stage II (T3N0M0, T4N0M0) or III (T1-4N1M0, any TN2M0) adenocarcinoma of the rectum and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible. All patients were required to be candidates for definitive surgical resection. Patients enrolling in the adjuvant cohort must have undergone surgical resection of the primary rectal tumor between 4 and 8 weeks before study treatment. Eligible patients had adequate bone marrow and organ function and no previous chemotherapy or radiation for rectal cancer. Patients receiving therapeutic anticoagulation were eligible but must have been on a stable dosing schedule before enrollment. Exclusion criteria included any hemoptysis within 4 weeks before enrollment; significant cardiovascular disease, including unstable angina, myocardial infarction, or stroke within 6 months of enrollment; major surgery within 28 days of enrollment; ventricular arrhythmias requiring medication; or uncontrolled hypertension (defined as systolic blood pressure ⬎ 150 mm Hg and/or diastolic blood pressure ⬎ 100 mm Hg despite antihypertensive therapy). Patients with previous malignancies were excluded with the exception of nonmelanoma skin cancer, carcinoma in situ of the cervix, or low-grade localized prostate cancer with a disease-free survival of ⱖ 5 years after definitive local therapy.
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David R. Spigel et al Figure 1 CONSORT Diagram
CONSORT Flow Diagram Phase II Study of Bevacizumab and Chemoradiation in the Preoperative or Adjuvant Treatment of Patients with Stage II/III Rectal Cancer
Analysis
Follow-up
Allocation
Enrollment
Assessed for Eligibility (N = 66)
Eligible (N = 66)
Preoperative Combined Modality Treatment (n = 35) Completed and proceeded to surgery (n = 31) Did not complete combined modality (n = 4) Disease progression (n = 1) Patient request (n = 1) Intercurrent illness (n = 2)
Adjuvant Combined Modality Treatment (n = 31) Completed combined modality (n = 29) Did not complete combined modality (n = 2) Treatment-related toxicity (n = 2)
Postsurgical Chemotherapy and Bevacizumab Began postsurgical treatment (n = 20) Did not begin postsurgical treatment (n = 11) Treatment-related toxicity (n = 5) Patient request (n = 4) Disease progression (n = 1) Patient noncompliance (n = 1)
Chemotherapy and Bevacizumab Began chemotherapy and bevacizumab (n = 26) Did not begin chemotherapy and bevacizumab (n = 3) Patient request (n = 1) Physician discretion (n = 1) Treatment-related toxicity (n = 1)
Bevacizumab Maintenance Treatment Began maintenance treatment (n = 6)
Bevacizumab Maintenance Treatment Began maintenance treatment (n = 10)
Analyzed (n = 35)
Analyzed (n = 31)
Excluded from analysis (n = 0)
Excluded from analysis (n = 0)
could not be increased. In the case of unacceptable toxicity or intolerance to 5-FU/leucovorin, oxaliplatin, or bevacizumab, the agent responsible could be stopped and the patient could continue with the other study medications. However bevacizumab had to be given in the presence of 5-FU, and if FOLFOX was stopped the patient had to discontinue the study. The primary endpoint was to evaluate the 2-year disease-free survival (DFS) in patients with stage II/III rectal cancer after preoperative or adjuvant treatment with this regimen. Secondary endpoints included assessment of overall toxicity, the incidence of pelvic recurrence and overall survival, and in the preoperative cohort, the patho-
logic complete response (pCR) rate and sphincter preservation rate. Outcomes were assessed for each cohort separately. Because patients were not randomized, this trial was not intended to compare preoperative vs. adjuvant treatment. Toxicity was assessed according to the National Cancer Institute Common Toxicity Criteria, version 3.0.11
Assessments Each patient underwent laboratory testing (including carcinoembryonic antigen [CEA] level), urinalysis, and history taking and physical examination within 7 days before treatment initiation. Baseline tumor staging was performed within 28 days of starting therapy,
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Preop/Adj Chemo/Rad/Bev in Stage II/III Rectal Ca Figure 3 Overall Survival Cohorts A and B (N ⴝ 66)
Preoperative cohort Adjuvant cohort A (n ⴝ 35) B (n ⴝ 31)
Characteristic Median age, years (range)
57 (26-82)
56 (31-76)
Male
26 (74%)
15 (48%)
Female
9 (26%)
16 (52%)
26 (74%)
24 (78%)
Gender
ECOG Performance Status 0 1
9 (26%)
7 (22%)
1
Overall Survival Probability
Table 1 Baseline Demographics (N ⴝ 66)
0.8 0.6 0.4 0.2 0
0
Race White
Adjuvant Cohort Preoperative Cohort
Log-rank P = .3667
10
20
30
Time (months)
33 (94%)
31 (100%)
2 (6%)
0 (0%)
II
11 (31%)
8 (26%)
III
24 (69%)
23 (74%)
polyps were not seen. For patients who had never had a colonoscopy at time of diagnosis, a colonoscopy was performed 3-6 months after finishing treatment.
African-American Stage at Enrollment
Distal Tumor Edge Upper rectum
3 (9%)
12 (39%)
Statistical Plan
Midrectum
11 (31%)
8 (26%)
Lower rectum
21 (60%)
11 (35%)
Based on data from historical controls, a 2-year DFS of ⬎ 85% would justify further study of this regimen. The sample size required to adequately assess DFS of ⬎ 85%, with an alpha of 0.05 and a power of 80% was a total of 65 patients. Secondary study endpoints include toxicity, rate of pelvic recurrence, and overall survival. For patients in the preoperative cohort A, sphincter preservation rate and pCR were also assessed.
Abbreviation: ECOG ⫽ Eastern Cooperative Oncology Group.
Disease-free Survival Probability
Figure 2 Disease-Free Survival Cohorts A and B (N ⴝ 66)
Results
1
Patients
0.8 0.6 0.4 0.2 0
Adjuvant Cohort Preoperative Cohort
Log-rank P = .1136
0
10
20
30
Time (months)
and included computed tomography (CT) scans of the abdomen/ pelvis and a chest roentgenogram or CT scan of the chest. Female patients of child-bearing potential underwent a serum pregnancy test. Patients in cohort A underwent imaging again after chemoradiation. All patients underwent imaging after surgery and 4 cycles of chemotherapy and bevacizumab (or sooner if therapy was stopped because of toxicity). Determination of CEA levels and imaging were repeated at the end of all treatment, then every 6 months for years 1-2, and annually during years 3-5. Colonoscopy was performed within 1 year of treatment ending and at least every 2-3 years if
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Between August 2006 and April 2009, a total of 66 patients were enrolled: 35 patients in the preoperative cohort A and 31 patients in the adjuvant cohort B (Figure 1). Detailed baseline patient characteristics are summarized in Table 1. The median age for the entire sample was 57 years; 65% of the patients were male patients, and 76% had an ECOG PS of 0. Among cohort A patients, 31 (89%) completed combined 5-FU/ radiation/bevacizumab and proceeded to surgery. Ten of these patients underwent total mesorectal excision. The 4 preoperative patients who did not complete combined modality therapy discontinued study participation early for the following reasons: disease progression, patient request, coagulopathy, and small bowel perforation (1 patient each). Twenty (65%) of the 31 patients in cohort A who underwent surgery then proceeded to postoperative treatment with chemotherapy and bevacizumab. Eleven patients did not begin postoperative treatment for the following reasons: treatment-related toxicity (5 patients), patient request (4), disease progression (1), and patient noncompliance (1). Among cohort B patients, 29 (94%) completed combined 5-FU/ radiation/bevacizumab. Two patients in cohort B were removed from the study for nausea/vomiting and dehydration (1 patient each). Of the 29 patients in cohort B who completed combined modality therapy, 26 (90%) began treatment with chemotherapy and bevacizumab. Three patients did not receive chemotherapy/be-
David R. Spigel et al Table 2 Cohort A Treatment-Related Toxicity (n ⴝ 35) Grade 1
2
3
4
Total
Anemia
11 (31%)
7 (20%)
0
0
18 (51%)
Leukopenia
11 (31%)
5 (14%)
0
0
16 (46%)
Neutropenia
3 (9%)
2 (6%)
1 (3%)
0
6 (17%)
Preoperative Chemoradiation (n ⴝ 35)
Thrombocytopenia
0
0
0
3 (9%)
3 (9%)
Diarrhea
11 (31%)
10 (29%)
2 (6%)
0
23 (66%)
Fatigue
11 (31%)
7 (20%)
1 (3%)
0
19 (54%)
2 (6%)
8 (23%)
0
0
3 (9%)
1 (3%)
0
4 (11%)
Stomatitis/mucositis 4 (11%) Dehydration
14 (40%)
Chemotherapy/Bevacizumab (n ⴝ 20) Anemia
14 (70%)
1 (5%)
0
0
15 (75%)
Leukopenia
7 (35%)
6 (30%)
4 (20%)
0
17 (85%)
Neutropenia
4 (20%)
2 (10%)
1 (5%)
3 (15%)
10 (50%)
Thrombocytopenia
8 (40%)
0
0
0
8 (40%)
Diarrhea
1 (5%)
7 (35%)
3 (15%)
0
11 (55%)
0
1 (5%)
2 (10%)
1 (5%)
4 (20%)
Thrombosis/embolism Postoperative infection
0
0
1 (5%)
2 (10%)
3 (15%)
Hypertension
0
2 (10%)
1 (5%)
0
3 (15%)
2 (10%)
0
0
0
2 (10%)
Wound complication Maintenance Bevacizumab (n ⴝ 6) Anemia
3 (50%)
0
0
0
3 (50%)
Leukopenia
0
4 (67%)
0
0
4 (67%)
Neutropenia
1 (17%)
1 (17%)
0
0
2 (34%)
Thrombocytopenia
2 (34%)
0
0
0
2 (34%)
Hypertension
1 (17%)
2 (34%)
1 (17%)
0
4 (67%)
Fatigue
1 (17%)
2 (34%)
0
0
3 (50%)
Diarrhea
1 (17%)
1 (17%)
0
0
2 (34%)
vacizumab for the following reasons: patient request, treatment-related toxicity, and physician discretion (1 patient each). At the time of this analysis, 17 (55%) patients left the study before planned treatment had been completed. Reasons for treatment discontinuation included intercurrent illness (6 patients), treatment-related toxicity (5 patients), patient preference (3 patients), physician preference (2 patients), and disease progression (1 patient). After treatment with chemotherapy/bevacizumab, a total of 16 patients began bevacizumab maintenance treatment (cohort A, 6 patients; cohort B,10 patients). One patient from cohort A and 1 patient from cohort B did not complete bevacizumab maintenance treatment. At the time of this analysis 3 patients remained on bevacizumab maintenance treatment.
Efficacy Among the 35 patients who enrolled in cohort A, 10 (29%) achieved a pCR; 6 of these patients had stage III disease at baseline. Four patients (all stage III at baseline) had microscopic residual disease (⬍ 1 cm), whereas 17 patients (stage II, 6 patients; stage III, 11
patients) had macroscopic residual disease. Twelve of the 31 (39%) patients had sphincter preservation. After a median follow-up of 14.8 months (range, 6.5-37.5 months), 92% of patients remained alive, and 58 (88%) patients remained free of disease. DFS for each cohort are cohort A, median not reached; 1-year, 85% (95% [confidence interval [CI], 67%93%); 2-year, not reached; cohort B, median not reached; 1-year, 97% (95% CI, 79%-100%); 2-year, 89% (95% CI, 60%-97%) (Figure 2). The median survival has not been reached for either cohort (Figure 3).
Safety The preoperative and adjuvant regimens were generally safe and well tolerated, although 8 (23%) patients in cohort A and 5 (16%) patients in cohort B discontinued the treatment course prematurely because of related toxicity. Treatment-related toxicity for all phases of treatment is summarized in Table 2 (cohort A) and Table 3 (cohort B). Grade 3/4 hematologic toxicity was relatively uncommon in cohort A, with 5 (14%) patients experiencing severe neutropenia. Neu-
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Preop/Adj Chemo/Rad/Bev in Stage II/III Rectal Ca Table 3 Cohort B Treatment-Related Toxicity (n ⴝ 31) Grade 1
2
3
4
Total
Anemia
10 (32%)
2 (6%)
0
0
12 (39%)
Leukopenia
12 (39%)
3 (10%)
0
0
15 (48%)
Neutropenia
3 (10%)
1 (3%)
0
0
4 (13%)
Thrombocytopenia
8 (26%)
0
0
0
8 (26%)
Diarrhea
4 (13%)
13 (42%)
8 (26%)
0
25 (81%)
Fatigue
9 (29%)
6 (19%)
1 (3%)
0
16 (52%)
Rash/desquamation
2 (6%)
3 (10%)
4 (13%)
0
9 (29%)
Adjuvant Chemoradiation (n ⴝ 31)
Dehydration
0
6 (19%)
2 (6%)
0
8 (26%)
5 (16%)
4 (13%)
2 (6%)
0
11 (35%)
Anemia
10 (38%)
2 (8%)
0
0
12 (46%)
Leukopenia
5 (19%)
8 (31%)
4 (15%)
0
17 (65%)
Neutropenia
2 (8%)
4 (15%)
6 (23%)
1 (4%)
13 (50%)
Mucositis/stomatitis Chemotherapy/Bevacizumab (n ⴝ 26)
Thrombocytopenia
8 (31%)
1 (4%)
1 (4%)
0
10 (38%)
Diarrhea
11 (42%)
6 (23%)
1 (4%)
0
18 (69%)
Fatigue
8 (31%)
6 (23%)
2 (8%)
0
16 (62%)
Bleeding events
0
0
3 (12%)
0
3 (12%)
GI perforation
0
0
1 (4%)
1 (4%)
2 (8%)
Maintenance Bevacizumab (n ⴝ 10) Anemia
5 (50%)
0
0
0
5 (50%)
Leukopenia
3 (30%)
2 (20%)
0
0
5 (50%)
Neutropenia
2 (20%)
1 (10%)
0
0
3 (30%)
Thrombocytopenia
3 (30%)
0
0
0
3 (30%)
0
1 (10%)
1 (10%)
1 (10%)
3 (30%)
1 (10%)
1 (10%)
0
0
2 (20%)
Hypertension Proteinuria
tropenia was the only grade 3/4 hematologic toxicity observed in cohort B (7 [23%] patients). There were no episodes of neutropenic fever, and no patients were required to discontinue treatment because of neutropenia. Additionally there were no cases of grade 3/4 anemia or thrombocytopenia in either cohort. In terms of severe nonhematologic toxicity, diarrhea (cohort A, 14%; cohort B, 29%), fatigue (cohort A, 6%; cohort B, 10%, and stomatitis/mucositis (cohort A, 23%; cohort B, 0%) were the only toxicities seen in more than 2 patients. Grade 3/4 hypertension was rare, and although 28 bleeding events were reported, the majority of these episodes were limited to grade 1/2 epistaxis, with the exception of 1 grade 4 postoperative rectal bleeding episode in cohort A and 2 patients with grade 3 rectal bleeding in cohort B. Other serious toxicity included bowel perforation (1 patient) and pelvic infection (1 patient) in cohort A, and anal wound dehiscence (1 patient), bowel perforation (2 patients), perianal infection (2 patients), and rectovaginal fistula (1 patient) in cohort B. Despite these serious events, there were no treatmentrelated deaths in either cohort.
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Discussion Antiangiogenic therapy has been an important strategy in cancer treatment since bevacizumab was first approved for the treatment of metastatic colorectal cancer in 2004. Bevacizumab and 5-FU– based therapy improved overall survival in patients with advanced disease compared with chemotherapy alone.5 Emerging data showed that bevacizumab’s antitumor effects extended to other solid tumor settings, including rectal cancer.9,12-14 Moreover antiangiogenic therapy appears to augment radiation’s effect on tumors.6-8 Willet et al first reported on a phase I trial of bevacizumab (5 and 10 mg/kg cohorts of 6 and 5 patients, respectively, days 1, 15, 29, and 43) in combination with preoperative 5-FU (225 mg/m2 IVCI days 15-52) and radiation (50.4 Gy in 28 fractions days 15 to 52). Surgery was scheduled 7-9 weeks later.9,10 In the high-dose cohort, 2 pCRs were seen, but at a cost of dose-limiting toxicity defined as diarrhea and colitis. Molecular analysis of the specimens revealed increased tumor apoptosis, suggesting that bevacizumab may sensitize rectal tumors to chemotherapy and radiation, a finding supported preclinically.15
David R. Spigel et al Crane et al recently reported results from a phase II trial of neoadjuvant bevacizumab, capecitabine, and radiation in 25 patients with locally advanced rectal cancer.16 The pCR rate was 32%, and an additional 24% of patients had near-complete responses (⬍ 10% viable tumor cells remaining). Toxicity was generally mild, although wound dehiscence was seen in 12%, requiring a second operation. The 2-year pelvic recurrence rate was 6.2%. We conducted this multicenter phase II study to further understand the role of bevacizumab in the treatment of locally advanced rectal cancer. The 5 mg/kg dose of bevacizumab was chosen based on the toxicity observed in the Willet et al study. This trial was initially designed as an adjuvant trial; however because many physicians preferred a preoperative option, the study was amended to allow for a preoperative cohort. Pelvic toxicity is relatively common with rectal cancer treatment. In a randomized trial comparing preoperative and postoperative chemoradiotherapy, postoperative complications, including anastomotic leakage, delayed wound healing, bleeding, and ileus were seen in 36% and 34% of patients, respectively. In a trial comparing radiation and surgery with surgery alone, fistula formation occurred in 1.6% and 1% of patients, respectively, and bowel obstruction was seen in 7% and 3%, respectively.17 We demonstrated that bevacizumab could be safely incorporated into modern chemoradiation schedules in either the preoperative or adjuvant setting. Toxicities were expected and manageable. The most serious toxicities were wound dehiscence, pelvic infection, bowel perforation, and fistula formation. Although these toxicities can be seen with rectal cancer treatment, they have also been consistently associated with bevacizumab in the treatment of advanced colon cancer as well as in other solid tumors. Our center recently reported fistula formation in patients with lung cancer treated with bevacizumab and radiation.18 The 2-year DFS in the adjuvant cohort exceeded the planned estimate of 85%. The 2-year DFS has not been reached for the preoperative cohort; however the 1-year DFS was 85%. Additional follow-up is needed to better assess DFS and overall survival. The pCR rate of 29% was exceptionally high, compared with a rate of 8% in the pivotal randomized trial by Sauer at al, in which patients received 5-FU and radiation (50.4 Gy), and more recently 14% and 19% in patients treated with capecitabine/radiation or capecitabine/ oxaliplatin/radiation, respectively.4,19 The sphincter preservation rate of 39% was consistent with other studies. This trial has several limitations, foremost of which is the small size of each cohort. The CIs for DFS are wide and could overestimate the treatment effect. Additionally the small size makes any comparisons between cohorts difficult. It is important to point out that cohort selection was at the discretion of the physician, which potentially introduces selection bias. Recently Willet et al at reported results from an expanded phase II cohort treated with preoperative bevacizumab (5 mg/kg), 5-FU, and radiation.20 Adjuvant therapy was at physician discretion but did not include bevacizumab. Among 32 patients the pCR was 16%, the actuarial 5-year local control was 100%, and the actuarial 5-year DFS and overall survival were 75% and 100%, respectively. Importantly, delayed wound healing, pelvic infection, and perforation (ileostomy/ stent) were observed. Several potential biomarkers predictive of re-
sponse were identified, including VEGF, placental-derived growth factor, and interleukin 6, but require prospective validation. Bevacizumab’s role in the treatment of locally advanced rectal cancer is unclear. Our trial supports additional investigation of bevacizumab in rectal cancer given the preliminary efficacy as evidenced by pCR and DFS. However the recent results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-08 trial, in which bevacizumab in combination with FOLFOX6 did not improve DFS in the adjuvant setting in patients with stage II/III colon cancer, suggests that bevacizumab’s efficacy may be maximal in a setting of more advanced disease.21 The difference in rectal cancer may be the synergy of bevacizumab and radiation, which may eradicate local cancer disease effectively while still treating systemic occult metastases. However prolonging patient exposure to maintenance bevacizumab may not be necessary in this setting. Identifying predictive biomarkers for antiangiogenic treatment could help select patients for combination therapy. Future work must also include additional study of safety given the potential for enhanced perioperative toxicity.
Clinical Practice Points ●
●
●
Optimal management of patients with locally advanced rectal cancer includes combined modality treatment with chemoradiation and surgery. Chemoradiotherapy delivered in the preoperative setting is superior to postsurgical therapy in reducing the risk of pelvic recurrence although no survival advantage has been appreciated with traditional therapeutic agents. Bevacizumab interrupts the VEGF signaling pathway to inhibit tumor angiogenesis, which preclinical models suggest is a mechanism of radiation resistance. This trial added bevacizumab to traditional therapy with 5-FU and radiation for patients with stage II/III rectal cancer in either the neoadjuvant or adjuvant settings. Thirty-five patients were treated in the neoadjuvant cohort with 31 treated post-surgically. The pCR rate for the neoadjuvant cohort was 29% and the 1-year disease-free survival (DFS) rates were 85% and 97% for the neoadjuvant and adjuvant cohorts, respectively. Two-year DFS exceeded the planned estimate of 85% in the adjuvant cohort at a rate of 89%. This study was limited by the small sample sizes in each cohort and the inability of most patients (76%, both cohorts) to receive maintenance bevacizumab. Severe bevacizumab-related toxicity occurred in 12% of patients (both cohorts) but was manageable and reversible. A larger randomized study would be required to assess the role of bevacizumab in the treatment of rectal cancer.
Acknowledgments This trial was supported in part by Genentech, Inc, San Francisco, CA.
Appendix: Sarah Cannon Research Institute Participating Sites Tennessee Oncology, PLLC, Nashville, TN Florida Cancer Specialists, Fort Myers, FL Chattanooga Oncology Hematology Associates, Chattanooga, TN Peninsula Cancer Institute, Newport News, VA Northeast Alabama Medical Center, Anniston, AL Northeast Arkansas Clinic, Jonesboro, AK
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Preop/Adj Chemo/Rad/Bev in Stage II/III Rectal Ca Spartanburg Regional Medical Center, Spartanburg, SC Wellstar Cancer Research, Marietta, GA Baptist East Hospital, Louisville, KY South Texas Oncology Hematology, San Antonio, TX Northeast Georgia Medical Center, Gainesville, GA Integrated Community Oncology Network, Jacksonville, FL Watson Clinic for Cancer Research, Lakeland, FL
References 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin 2009; 59:225-49. 2. Bosset J-F, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. Engl J Med 2006; 355:1114-23. 3. Gerard J-P, Conroy T, Bonnetain F, et al. Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in t3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 2006; 24:4620-25. 4. Sauer R, Becker H, Hohenberger W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351:1731-40. 5. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350:2335-42. 6. Geng L, Donnelly E, McMahon G, et al. Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. Cancer Res 2001; 61:2413-9. 7. Gorski DH, Beckett MA, Jaskowiak NT, et al. Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res 1999; 59:3374-8. 8. Lee CG, Heijn M, di Tomaso E, et al. Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 2000; 60:5565-70. 9. Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004; 10:145-7.
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10. Willett CG, Boucher Y, Duda DG, et al. Surrogate markers for antiangiogenic therapy and dose-limiting toxicities for bevacizumab with radiation and chemotherapy: continued experience of a phase I trial in rectal cancer patients. J Clin Oncol 2005; 23:8136-9. 11. National Cancer Institute: Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Available at http://ctep.cancer.gov/protocolDevelopment/electronic_ applications/ctc.htm. Accessed May 20, 2011. 12. Czito BG, Bendell JC, Willett CG, et al. Bevacizumab, oxaliplatin, and capecitabine with radiation therapy in rectal cancer: phase I trial results. Int J Radiat Oncol Biol Phys 2007; 68:472-8. 13. Escudier B, Bellmunt J, Negrier S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol 2010; 28:2144-50. 14. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006; 355:2542-50. 15. Pidgeon GP, Barr MP, Harmey JH, et al. Vascular endothelial growth factor (VEGF) upregulates BCL-2 and inhibits apoptosis in human and murine mammary adenocarcinoma cells. Br J Cancer 2001; 85:273-8. 16. Crane CH, Eng C, Feig BW, et al. Phase II trial of neoadjuvant bevacizumab, capecitabine, and radiotherapy for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2010; 76:824-30. 17. Birgisson H, Pahlman L, Gunnarsson U, et al. Adverse effects of preoperative radiation therapy for rectal cancer: long-term follow-up of the Swedish Rectal Cancer Trial. J Clin Oncol 2005; 23:8697-705. 18. Spigel DR, Hainsworth JD, Yardley DA, et al. Tracheoesophageal fistula formation in patients with lung cancer treated with chemoradiation and bevacizumab. J Clin Oncol 2010; 28:43-8. 19. Gerard J-P, Azria D, Gourgou-Bourgade S, et al. Comparison of two neoadjuvant chemoradiotherapy regimens for locally advanced rectal cancer: results of the phase III trial ACCORD 12/0405-Prodige 2. J Clin Oncol 2010; 28: 1638-44. 20. Willett CG, Duda DG, di Tomaso E, et al. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol 2009; 27:3020-6. 21. Allegra CJ, Yothers G, O’Connell MJ, et al. Initial safety report of NSABP C-08: a randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer. J Clin Oncol 2009; 27:3385-90.
Phase II Study of Bevacizumab and Chemoradiation in the Preoperative or Adjuvant Treatment of Patients With Stage II/III Rectal Cancer David R. Spigel,1,2 Johanna C. Bendell,1,2 Michael McCleod,3 Dianna L. Shipley,2 Edward Arrowsmith,4 E. Kirk Barnes,2 Jeffrey R. Infante,1,2 Howard A. Burris, III,1,2 F. Anthony Greco,1,2 John D. Hainsworth1,2 Abstract Sixty-six patients with rectal cancer received bevacizumab in addition to chemotherapy and radiation. This trial sought to determine if adding bevacizumab would produce a benefit for patients before or after surgery. Some patients’ cancer improved but there were side effects, some severe. Patients should be cautioned about risks associated with adding bevacizumab to this type of therapy, particularly after surgery. Background and Purpose: We wanted to evaluate the efficacy, defined as 2-year disease-free survival (DFS), and safety of bevacizumab/chemoradiation in preoperative and adjuvant settings for patients with stage II/III rectal cancer. Patients and Methods: Eligible patients had stage II/III rectal adenocarcinoma, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1, and adequate organ function, and received preoperative (cohort A) or adjuvant (cohort B) treatment at physician discretion. Patients received 5-fluorouracil (5-FU) as an intravenous infusion (IVCI) 225 mg/m2/d on days 1-42, bevacizumab 5 mg/kg intravenously (I.V.) on days 1 and 15 (cohort A), or every 2 weeks (cohort B), with radiation therapy to 50.4 Gy. After surgery (cohort A) or chemoradiation (cohort B), FOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) and bevacizumab were administered for 4 months and then bevacizumab was given alone for up to 1 year. Results: Sixty-six patients (cohort A ⫽ 35; cohort B ⫽ 31) were enrolled from August 2006-April 2009: median age was 57 years; male patients, 62%; ECOG PS 0, 75%; stage II/III, 31%/69%. In cohort A, the complete pathologic response (pCR) rate was 29% (11% microscopic residual disease, 49% gross disease). Four patients did not undergo surgery (toxicity, 2 patients; progressive disease, 1 patient; patient decision, 1 patient). One- and 2-year DFS for cohorts A/B were 85%/not reached and 97%/89%, respectively (median survival not reached for either cohort). Frequent grade 3/4 toxicity included diarrhea (A cohort, 14%; B cohort, 29%), neutropenia (A cohort, 14%, B cohort, 23%), mucositis (A cohort, 23%, B cohort, 0%), and fatigue (A cohort, 6%, B cohort, 10%). Other serious toxicity included bowel perforation and pelvic infection (cohort A, 1 patient each), bowel perforation (2 patients), anal wound dehiscence (1 patient), perianal infection (2 patients), and rectovaginal fistula (1 patient) (cohort B), without treatment-related death in either cohort. Conclusions: Bevacizumab can be added to standard preoperative and adjuvant chemoradiation in most patients with expected and manageable toxicity and may increase treatment efficacy. Clinical Colorectal Cancer, Vol. 11, No. 1, 45-52 © 2012 Elsevier Inc. All rights reserved. Keywords: Adjuvant, Bevacizumab, Chemoradiation, Preoperative, Rectal cancer
Preliminary data presented at the American Society of Clinical Oncology Gastrointestinal Cancers Symposium, January 22-24, 2010, Orlando, FL 1
Sarah Cannon Research Institute, Nashville, TN 2 Tennessee Oncology, PLLC, Nashville, TN 3 Florida Cancer Specialists, Fort Myers, FL 4 Chattanooga Oncology and Hematology Associates, PC, Chattanooga, TN
1533-0028/$ - see frontmatter © 2012 Elsevier Inc. All rights reserved. doi: 10.1016/j.clcc.2011.04.002
Submitted: Feb 14, 2011; Revised: Mar 25, 2011; Accepted: Apr 12, 2011 Address for correspondence: David R. Spigel, MD, Sarah Cannon Research Institute, 250 25th Avenue North, Suite 110, Nashville, TN 37203 Fax: 615-340-1535; e-mail contact: [email protected]
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Preop/Adj Chemo/Rad/Bev in Stage II/III Rectal Ca Introduction
Study Design and Treatment
More than 40,000 patients a year are diagnosed with rectal cancer.1 Combined modality therapy with surgery and chemoradiation is standard treatment for patients with stage II/III disease, resulting in a 5-year survival rate of 75%.2-4 Preoperative chemoradiation is superior to adjuvant treatment in reducing pelvic recurrence and treatment-related toxicity but has no survival advantage. An optimal treatment strategy in rectal cancer would maximize tumor killing locally while also addressing micrometastatic systemic disease. Bevacizumab is a monoclonal antibody to vascular endothelial growth factor (VEGF) used in the treatment of advanced colorectal cancer. Bevacizumab and 5-fluorouracil (5-FU)-based chemotherapy improved survival in patients with metastatic colorectal cancer compared with chemotherapy alone.5 Preclinical models suggest that angiogenesis is a mechanism of radiation resistance.6-8 Bevacizumab and chemoradiation for rectal cancer may improve both local and distant disease control. Based on reports of preliminary antitumor activity and safety9,10 of bevacizumab and chemoradiation in rectal cancer, we conducted a multicenter phase II trial of preoperative or adjuvant bevacizumab and chemoradiation in patients with locally advanced disease.
This study was nonrandomized. Treatment in the preoperative or adjuvant cohorts was at physician discretion. Surgery was performed according to institutional guidelines. Bevacizumab was provided by Genentech. Chemotherapy was obtained from commercial supplies. Each patient enrolled in the preoperative cohort (cohort A) received 5-FU 225 mg/m2 as a continuous infusion (IVCI) on days 1-42 through a portable infusion pump and central venous catheter. Bevacizumab 5 mg/kg was administered intravenously (I.V.) on days 1 and 15. Additionally these patients received radiation to 50.4 Gy (1.8 Gy/day or 28 fractions) Monday through Friday during weeks 1-6. Radiation therapy fields included the tumor (with 2- to 5-cm margins), the presacral nodes, and the internal iliac nodes. Multiple radiation therapy fields were used (eg, 3- or 4-field techniques). Positioning and other techniques to minimize the volume of small bowel in the fields were encouraged. Patients in cohort A underwent resection 2-8 weeks after completion of 5-FU/radiation. At least 8 weeks after surgery, patients in cohort A began 4 months of chemotherapy and bevacizumab. This adjuvant treatment consisted of 5-FU 400 mg/m2 I.V. bolus over 2-4 minutes followed by 2400 mg/m2 IVCI over 46 hours, leucovorin 350 mg as a 2-hour infusion, oxaliplatin 85 mg/m2 I.V. (modified FOLFOX6), and bevacizumab 5 mg/kg I.V., all on days 1 and 15 of each cycle. After 4 treatment cycles and in the absence of disease progression, patients were able to continue single-agent bevacizumab to complete a total of 1 year of treatment. Patients enrolled in the adjuvant cohort (cohort B) received 5-FU 225 mg/m2 IVCI on days 1-42. Bevacizumab was administered at 5 mg/kg IV on day 1 every 2 weeks. These patients also received radiation to 50.4 Gy (1.8 Gy/day or 28 fractions) Monday through Friday during weeks 1-6. For patients treated by abdominoperineal resection, the perineal wound was included within the radiation field. Six weeks after the completion of adjuvant 5-FU/radiation, patients in cohort B began treatment with chemotherapy and bevacizumab, using an identical regimen as described for cohort A. After 4 cycles of this treatment, patients without disease progression could continue single-agent bevacizumab to complete a total of 1 year of treatment. The dose of 5-FU was not modified based on myelosuppression during chemoradiation. Patients in whom grade 3/4 mucositis or diarrhea developed had 5-FU, bevacizumab, and radiation discontinued for 1 week or until the toxicity decreased to grade ⬍ 2. 5-FU was then resumed with a 25% dose reduction. If radiation therapy required interruption, bevacizumab and 5-FU were held as well. Bevacizumab was discontinued for grade ⱖ 2 pulmonary or central nervous system hemorrhage, any grade 4 hemorrhage, grade 4 proteinuria, grade 4 congestive heart failure, fistula development, thromboemboli, wound dehiscence, or reversible posterior leukoencephalopathy. Bevacizumab was held for surgical procedures, other proteinuria, hypertension, other hemorrhage, or other congestive heart failure for up to 4 weeks, or the bevacizumab was discontinued. Patients could continue chemotherapy if bevacizumab was discontinued. Dose modifications during FOLFOX and bevacizumab were based on standard practice. Once an agent was reduced, its dose
Patients and Methods This open-label phase II study of bevacizumab and combined modality therapy for rectal cancer was designed by the Sarah Cannon Research Institute (SCRI) and was performed at selected sites in the SCRI Oncology Research Consortium, a community-based clinical trial organization (Appendix). The protocol was approved by the institutional review boards at all participating institutions, and all patients provided written informed consent.
Patients Patients 18 years of age or older with documented pathologic evidence of stage II (T3N0M0, T4N0M0) or III (T1-4N1M0, any TN2M0) adenocarcinoma of the rectum and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible. All patients were required to be candidates for definitive surgical resection. Patients enrolling in the adjuvant cohort must have undergone surgical resection of the primary rectal tumor between 4 and 8 weeks before study treatment. Eligible patients had adequate bone marrow and organ function and no previous chemotherapy or radiation for rectal cancer. Patients receiving therapeutic anticoagulation were eligible but must have been on a stable dosing schedule before enrollment. Exclusion criteria included any hemoptysis within 4 weeks before enrollment; significant cardiovascular disease, including unstable angina, myocardial infarction, or stroke within 6 months of enrollment; major surgery within 28 days of enrollment; ventricular arrhythmias requiring medication; or uncontrolled hypertension (defined as systolic blood pressure ⬎ 150 mm Hg and/or diastolic blood pressure ⬎ 100 mm Hg despite antihypertensive therapy). Patients with previous malignancies were excluded with the exception of nonmelanoma skin cancer, carcinoma in situ of the cervix, or low-grade localized prostate cancer with a disease-free survival of ⱖ 5 years after definitive local therapy.
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David R. Spigel et al Figure 1 CONSORT Diagram
CONSORT Flow Diagram Phase II Study of Bevacizumab and Chemoradiation in the Preoperative or Adjuvant Treatment of Patients with Stage II/III Rectal Cancer
Analysis
Follow-up
Allocation
Enrollment
Assessed for Eligibility (N = 66)
Eligible (N = 66)
Preoperative Combined Modality Treatment (n = 35) Completed and proceeded to surgery (n = 31) Did not complete combined modality (n = 4) Disease progression (n = 1) Patient request (n = 1) Intercurrent illness (n = 2)
Adjuvant Combined Modality Treatment (n = 31) Completed combined modality (n = 29) Did not complete combined modality (n = 2) Treatment-related toxicity (n = 2)
Postsurgical Chemotherapy and Bevacizumab Began postsurgical treatment (n = 20) Did not begin postsurgical treatment (n = 11) Treatment-related toxicity (n = 5) Patient request (n = 4) Disease progression (n = 1) Patient noncompliance (n = 1)
Chemotherapy and Bevacizumab Began chemotherapy and bevacizumab (n = 26) Did not begin chemotherapy and bevacizumab (n = 3) Patient request (n = 1) Physician discretion (n = 1) Treatment-related toxicity (n = 1)
Bevacizumab Maintenance Treatment Began maintenance treatment (n = 6)
Bevacizumab Maintenance Treatment Began maintenance treatment (n = 10)
Analyzed (n = 35)
Analyzed (n = 31)
Excluded from analysis (n = 0)
Excluded from analysis (n = 0)
could not be increased. In the case of unacceptable toxicity or intolerance to 5-FU/leucovorin, oxaliplatin, or bevacizumab, the agent responsible could be stopped and the patient could continue with the other study medications. However bevacizumab had to be given in the presence of 5-FU, and if FOLFOX was stopped the patient had to discontinue the study. The primary endpoint was to evaluate the 2-year disease-free survival (DFS) in patients with stage II/III rectal cancer after preoperative or adjuvant treatment with this regimen. Secondary endpoints included assessment of overall toxicity, the incidence of pelvic recurrence and overall survival, and in the preoperative cohort, the patho-
logic complete response (pCR) rate and sphincter preservation rate. Outcomes were assessed for each cohort separately. Because patients were not randomized, this trial was not intended to compare preoperative vs. adjuvant treatment. Toxicity was assessed according to the National Cancer Institute Common Toxicity Criteria, version 3.0.11
Assessments Each patient underwent laboratory testing (including carcinoembryonic antigen [CEA] level), urinalysis, and history taking and physical examination within 7 days before treatment initiation. Baseline tumor staging was performed within 28 days of starting therapy,
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Preop/Adj Chemo/Rad/Bev in Stage II/III Rectal Ca Figure 3 Overall Survival Cohorts A and B (N ⴝ 66)
Preoperative cohort Adjuvant cohort A (n ⴝ 35) B (n ⴝ 31)
Characteristic Median age, years (range)
57 (26-82)
56 (31-76)
Male
26 (74%)
15 (48%)
Female
9 (26%)
16 (52%)
26 (74%)
24 (78%)
Gender
ECOG Performance Status 0 1
9 (26%)
7 (22%)
1
Overall Survival Probability
Table 1 Baseline Demographics (N ⴝ 66)
0.8 0.6 0.4 0.2 0
0
Race White
Adjuvant Cohort Preoperative Cohort
Log-rank P = .3667
10
20
30
Time (months)
33 (94%)
31 (100%)
2 (6%)
0 (0%)
II
11 (31%)
8 (26%)
III
24 (69%)
23 (74%)
polyps were not seen. For patients who had never had a colonoscopy at time of diagnosis, a colonoscopy was performed 3-6 months after finishing treatment.
African-American Stage at Enrollment
Distal Tumor Edge Upper rectum
3 (9%)
12 (39%)
Statistical Plan
Midrectum
11 (31%)
8 (26%)
Lower rectum
21 (60%)
11 (35%)
Based on data from historical controls, a 2-year DFS of ⬎ 85% would justify further study of this regimen. The sample size required to adequately assess DFS of ⬎ 85%, with an alpha of 0.05 and a power of 80% was a total of 65 patients. Secondary study endpoints include toxicity, rate of pelvic recurrence, and overall survival. For patients in the preoperative cohort A, sphincter preservation rate and pCR were also assessed.
Abbreviation: ECOG ⫽ Eastern Cooperative Oncology Group.
Disease-free Survival Probability
Figure 2 Disease-Free Survival Cohorts A and B (N ⴝ 66)
Results
1
Patients
0.8 0.6 0.4 0.2 0
Adjuvant Cohort Preoperative Cohort
Log-rank P = .1136
0
10
20
30
Time (months)
and included computed tomography (CT) scans of the abdomen/ pelvis and a chest roentgenogram or CT scan of the chest. Female patients of child-bearing potential underwent a serum pregnancy test. Patients in cohort A underwent imaging again after chemoradiation. All patients underwent imaging after surgery and 4 cycles of chemotherapy and bevacizumab (or sooner if therapy was stopped because of toxicity). Determination of CEA levels and imaging were repeated at the end of all treatment, then every 6 months for years 1-2, and annually during years 3-5. Colonoscopy was performed within 1 year of treatment ending and at least every 2-3 years if
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Between August 2006 and April 2009, a total of 66 patients were enrolled: 35 patients in the preoperative cohort A and 31 patients in the adjuvant cohort B (Figure 1). Detailed baseline patient characteristics are summarized in Table 1. The median age for the entire sample was 57 years; 65% of the patients were male patients, and 76% had an ECOG PS of 0. Among cohort A patients, 31 (89%) completed combined 5-FU/ radiation/bevacizumab and proceeded to surgery. Ten of these patients underwent total mesorectal excision. The 4 preoperative patients who did not complete combined modality therapy discontinued study participation early for the following reasons: disease progression, patient request, coagulopathy, and small bowel perforation (1 patient each). Twenty (65%) of the 31 patients in cohort A who underwent surgery then proceeded to postoperative treatment with chemotherapy and bevacizumab. Eleven patients did not begin postoperative treatment for the following reasons: treatment-related toxicity (5 patients), patient request (4), disease progression (1), and patient noncompliance (1). Among cohort B patients, 29 (94%) completed combined 5-FU/ radiation/bevacizumab. Two patients in cohort B were removed from the study for nausea/vomiting and dehydration (1 patient each). Of the 29 patients in cohort B who completed combined modality therapy, 26 (90%) began treatment with chemotherapy and bevacizumab. Three patients did not receive chemotherapy/be-
David R. Spigel et al Table 2 Cohort A Treatment-Related Toxicity (n ⴝ 35) Grade 1
2
3
4
Total
Anemia
11 (31%)
7 (20%)
0
0
18 (51%)
Leukopenia
11 (31%)
5 (14%)
0
0
16 (46%)
Neutropenia
3 (9%)
2 (6%)
1 (3%)
0
6 (17%)
Preoperative Chemoradiation (n ⴝ 35)
Thrombocytopenia
0
0
0
3 (9%)
3 (9%)
Diarrhea
11 (31%)
10 (29%)
2 (6%)
0
23 (66%)
Fatigue
11 (31%)
7 (20%)
1 (3%)
0
19 (54%)
2 (6%)
8 (23%)
0
0
3 (9%)
1 (3%)
0
4 (11%)
Stomatitis/mucositis 4 (11%) Dehydration
14 (40%)
Chemotherapy/Bevacizumab (n ⴝ 20) Anemia
14 (70%)
1 (5%)
0
0
15 (75%)
Leukopenia
7 (35%)
6 (30%)
4 (20%)
0
17 (85%)
Neutropenia
4 (20%)
2 (10%)
1 (5%)
3 (15%)
10 (50%)
Thrombocytopenia
8 (40%)
0
0
0
8 (40%)
Diarrhea
1 (5%)
7 (35%)
3 (15%)
0
11 (55%)
0
1 (5%)
2 (10%)
1 (5%)
4 (20%)
Thrombosis/embolism Postoperative infection
0
0
1 (5%)
2 (10%)
3 (15%)
Hypertension
0
2 (10%)
1 (5%)
0
3 (15%)
2 (10%)
0
0
0
2 (10%)
Wound complication Maintenance Bevacizumab (n ⴝ 6) Anemia
3 (50%)
0
0
0
3 (50%)
Leukopenia
0
4 (67%)
0
0
4 (67%)
Neutropenia
1 (17%)
1 (17%)
0
0
2 (34%)
Thrombocytopenia
2 (34%)
0
0
0
2 (34%)
Hypertension
1 (17%)
2 (34%)
1 (17%)
0
4 (67%)
Fatigue
1 (17%)
2 (34%)
0
0
3 (50%)
Diarrhea
1 (17%)
1 (17%)
0
0
2 (34%)
vacizumab for the following reasons: patient request, treatment-related toxicity, and physician discretion (1 patient each). At the time of this analysis, 17 (55%) patients left the study before planned treatment had been completed. Reasons for treatment discontinuation included intercurrent illness (6 patients), treatment-related toxicity (5 patients), patient preference (3 patients), physician preference (2 patients), and disease progression (1 patient). After treatment with chemotherapy/bevacizumab, a total of 16 patients began bevacizumab maintenance treatment (cohort A, 6 patients; cohort B,10 patients). One patient from cohort A and 1 patient from cohort B did not complete bevacizumab maintenance treatment. At the time of this analysis 3 patients remained on bevacizumab maintenance treatment.
Efficacy Among the 35 patients who enrolled in cohort A, 10 (29%) achieved a pCR; 6 of these patients had stage III disease at baseline. Four patients (all stage III at baseline) had microscopic residual disease (⬍ 1 cm), whereas 17 patients (stage II, 6 patients; stage III, 11
patients) had macroscopic residual disease. Twelve of the 31 (39%) patients had sphincter preservation. After a median follow-up of 14.8 months (range, 6.5-37.5 months), 92% of patients remained alive, and 58 (88%) patients remained free of disease. DFS for each cohort are cohort A, median not reached; 1-year, 85% (95% [confidence interval [CI], 67%93%); 2-year, not reached; cohort B, median not reached; 1-year, 97% (95% CI, 79%-100%); 2-year, 89% (95% CI, 60%-97%) (Figure 2). The median survival has not been reached for either cohort (Figure 3).
Safety The preoperative and adjuvant regimens were generally safe and well tolerated, although 8 (23%) patients in cohort A and 5 (16%) patients in cohort B discontinued the treatment course prematurely because of related toxicity. Treatment-related toxicity for all phases of treatment is summarized in Table 2 (cohort A) and Table 3 (cohort B). Grade 3/4 hematologic toxicity was relatively uncommon in cohort A, with 5 (14%) patients experiencing severe neutropenia. Neu-
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49
Preop/Adj Chemo/Rad/Bev in Stage II/III Rectal Ca Table 3 Cohort B Treatment-Related Toxicity (n ⴝ 31) Grade 1
2
3
4
Total
Anemia
10 (32%)
2 (6%)
0
0
12 (39%)
Leukopenia
12 (39%)
3 (10%)
0
0
15 (48%)
Neutropenia
3 (10%)
1 (3%)
0
0
4 (13%)
Thrombocytopenia
8 (26%)
0
0
0
8 (26%)
Diarrhea
4 (13%)
13 (42%)
8 (26%)
0
25 (81%)
Fatigue
9 (29%)
6 (19%)
1 (3%)
0
16 (52%)
Rash/desquamation
2 (6%)
3 (10%)
4 (13%)
0
9 (29%)
Adjuvant Chemoradiation (n ⴝ 31)
Dehydration
0
6 (19%)
2 (6%)
0
8 (26%)
5 (16%)
4 (13%)
2 (6%)
0
11 (35%)
Anemia
10 (38%)
2 (8%)
0
0
12 (46%)
Leukopenia
5 (19%)
8 (31%)
4 (15%)
0
17 (65%)
Neutropenia
2 (8%)
4 (15%)
6 (23%)
1 (4%)
13 (50%)
Mucositis/stomatitis Chemotherapy/Bevacizumab (n ⴝ 26)
Thrombocytopenia
8 (31%)
1 (4%)
1 (4%)
0
10 (38%)
Diarrhea
11 (42%)
6 (23%)
1 (4%)
0
18 (69%)
Fatigue
8 (31%)
6 (23%)
2 (8%)
0
16 (62%)
Bleeding events
0
0
3 (12%)
0
3 (12%)
GI perforation
0
0
1 (4%)
1 (4%)
2 (8%)
Maintenance Bevacizumab (n ⴝ 10) Anemia
5 (50%)
0
0
0
5 (50%)
Leukopenia
3 (30%)
2 (20%)
0
0
5 (50%)
Neutropenia
2 (20%)
1 (10%)
0
0
3 (30%)
Thrombocytopenia
3 (30%)
0
0
0
3 (30%)
0
1 (10%)
1 (10%)
1 (10%)
3 (30%)
1 (10%)
1 (10%)
0
0
2 (20%)
Hypertension Proteinuria
tropenia was the only grade 3/4 hematologic toxicity observed in cohort B (7 [23%] patients). There were no episodes of neutropenic fever, and no patients were required to discontinue treatment because of neutropenia. Additionally there were no cases of grade 3/4 anemia or thrombocytopenia in either cohort. In terms of severe nonhematologic toxicity, diarrhea (cohort A, 14%; cohort B, 29%), fatigue (cohort A, 6%; cohort B, 10%, and stomatitis/mucositis (cohort A, 23%; cohort B, 0%) were the only toxicities seen in more than 2 patients. Grade 3/4 hypertension was rare, and although 28 bleeding events were reported, the majority of these episodes were limited to grade 1/2 epistaxis, with the exception of 1 grade 4 postoperative rectal bleeding episode in cohort A and 2 patients with grade 3 rectal bleeding in cohort B. Other serious toxicity included bowel perforation (1 patient) and pelvic infection (1 patient) in cohort A, and anal wound dehiscence (1 patient), bowel perforation (2 patients), perianal infection (2 patients), and rectovaginal fistula (1 patient) in cohort B. Despite these serious events, there were no treatmentrelated deaths in either cohort.
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Discussion Antiangiogenic therapy has been an important strategy in cancer treatment since bevacizumab was first approved for the treatment of metastatic colorectal cancer in 2004. Bevacizumab and 5-FU– based therapy improved overall survival in patients with advanced disease compared with chemotherapy alone.5 Emerging data showed that bevacizumab’s antitumor effects extended to other solid tumor settings, including rectal cancer.9,12-14 Moreover antiangiogenic therapy appears to augment radiation’s effect on tumors.6-8 Willet et al first reported on a phase I trial of bevacizumab (5 and 10 mg/kg cohorts of 6 and 5 patients, respectively, days 1, 15, 29, and 43) in combination with preoperative 5-FU (225 mg/m2 IVCI days 15-52) and radiation (50.4 Gy in 28 fractions days 15 to 52). Surgery was scheduled 7-9 weeks later.9,10 In the high-dose cohort, 2 pCRs were seen, but at a cost of dose-limiting toxicity defined as diarrhea and colitis. Molecular analysis of the specimens revealed increased tumor apoptosis, suggesting that bevacizumab may sensitize rectal tumors to chemotherapy and radiation, a finding supported preclinically.15
David R. Spigel et al Crane et al recently reported results from a phase II trial of neoadjuvant bevacizumab, capecitabine, and radiation in 25 patients with locally advanced rectal cancer.16 The pCR rate was 32%, and an additional 24% of patients had near-complete responses (⬍ 10% viable tumor cells remaining). Toxicity was generally mild, although wound dehiscence was seen in 12%, requiring a second operation. The 2-year pelvic recurrence rate was 6.2%. We conducted this multicenter phase II study to further understand the role of bevacizumab in the treatment of locally advanced rectal cancer. The 5 mg/kg dose of bevacizumab was chosen based on the toxicity observed in the Willet et al study. This trial was initially designed as an adjuvant trial; however because many physicians preferred a preoperative option, the study was amended to allow for a preoperative cohort. Pelvic toxicity is relatively common with rectal cancer treatment. In a randomized trial comparing preoperative and postoperative chemoradiotherapy, postoperative complications, including anastomotic leakage, delayed wound healing, bleeding, and ileus were seen in 36% and 34% of patients, respectively. In a trial comparing radiation and surgery with surgery alone, fistula formation occurred in 1.6% and 1% of patients, respectively, and bowel obstruction was seen in 7% and 3%, respectively.17 We demonstrated that bevacizumab could be safely incorporated into modern chemoradiation schedules in either the preoperative or adjuvant setting. Toxicities were expected and manageable. The most serious toxicities were wound dehiscence, pelvic infection, bowel perforation, and fistula formation. Although these toxicities can be seen with rectal cancer treatment, they have also been consistently associated with bevacizumab in the treatment of advanced colon cancer as well as in other solid tumors. Our center recently reported fistula formation in patients with lung cancer treated with bevacizumab and radiation.18 The 2-year DFS in the adjuvant cohort exceeded the planned estimate of 85%. The 2-year DFS has not been reached for the preoperative cohort; however the 1-year DFS was 85%. Additional follow-up is needed to better assess DFS and overall survival. The pCR rate of 29% was exceptionally high, compared with a rate of 8% in the pivotal randomized trial by Sauer at al, in which patients received 5-FU and radiation (50.4 Gy), and more recently 14% and 19% in patients treated with capecitabine/radiation or capecitabine/ oxaliplatin/radiation, respectively.4,19 The sphincter preservation rate of 39% was consistent with other studies. This trial has several limitations, foremost of which is the small size of each cohort. The CIs for DFS are wide and could overestimate the treatment effect. Additionally the small size makes any comparisons between cohorts difficult. It is important to point out that cohort selection was at the discretion of the physician, which potentially introduces selection bias. Recently Willet et al at reported results from an expanded phase II cohort treated with preoperative bevacizumab (5 mg/kg), 5-FU, and radiation.20 Adjuvant therapy was at physician discretion but did not include bevacizumab. Among 32 patients the pCR was 16%, the actuarial 5-year local control was 100%, and the actuarial 5-year DFS and overall survival were 75% and 100%, respectively. Importantly, delayed wound healing, pelvic infection, and perforation (ileostomy/ stent) were observed. Several potential biomarkers predictive of re-
sponse were identified, including VEGF, placental-derived growth factor, and interleukin 6, but require prospective validation. Bevacizumab’s role in the treatment of locally advanced rectal cancer is unclear. Our trial supports additional investigation of bevacizumab in rectal cancer given the preliminary efficacy as evidenced by pCR and DFS. However the recent results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-08 trial, in which bevacizumab in combination with FOLFOX6 did not improve DFS in the adjuvant setting in patients with stage II/III colon cancer, suggests that bevacizumab’s efficacy may be maximal in a setting of more advanced disease.21 The difference in rectal cancer may be the synergy of bevacizumab and radiation, which may eradicate local cancer disease effectively while still treating systemic occult metastases. However prolonging patient exposure to maintenance bevacizumab may not be necessary in this setting. Identifying predictive biomarkers for antiangiogenic treatment could help select patients for combination therapy. Future work must also include additional study of safety given the potential for enhanced perioperative toxicity.
Clinical Practice Points ●
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Optimal management of patients with locally advanced rectal cancer includes combined modality treatment with chemoradiation and surgery. Chemoradiotherapy delivered in the preoperative setting is superior to postsurgical therapy in reducing the risk of pelvic recurrence although no survival advantage has been appreciated with traditional therapeutic agents. Bevacizumab interrupts the VEGF signaling pathway to inhibit tumor angiogenesis, which preclinical models suggest is a mechanism of radiation resistance. This trial added bevacizumab to traditional therapy with 5-FU and radiation for patients with stage II/III rectal cancer in either the neoadjuvant or adjuvant settings. Thirty-five patients were treated in the neoadjuvant cohort with 31 treated post-surgically. The pCR rate for the neoadjuvant cohort was 29% and the 1-year disease-free survival (DFS) rates were 85% and 97% for the neoadjuvant and adjuvant cohorts, respectively. Two-year DFS exceeded the planned estimate of 85% in the adjuvant cohort at a rate of 89%. This study was limited by the small sample sizes in each cohort and the inability of most patients (76%, both cohorts) to receive maintenance bevacizumab. Severe bevacizumab-related toxicity occurred in 12% of patients (both cohorts) but was manageable and reversible. A larger randomized study would be required to assess the role of bevacizumab in the treatment of rectal cancer.
Acknowledgments This trial was supported in part by Genentech, Inc, San Francisco, CA.
Appendix: Sarah Cannon Research Institute Participating Sites Tennessee Oncology, PLLC, Nashville, TN Florida Cancer Specialists, Fort Myers, FL Chattanooga Oncology Hematology Associates, Chattanooga, TN Peninsula Cancer Institute, Newport News, VA Northeast Alabama Medical Center, Anniston, AL Northeast Arkansas Clinic, Jonesboro, AK
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Preop/Adj Chemo/Rad/Bev in Stage II/III Rectal Ca Spartanburg Regional Medical Center, Spartanburg, SC Wellstar Cancer Research, Marietta, GA Baptist East Hospital, Louisville, KY South Texas Oncology Hematology, San Antonio, TX Northeast Georgia Medical Center, Gainesville, GA Integrated Community Oncology Network, Jacksonville, FL Watson Clinic for Cancer Research, Lakeland, FL
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