NEOADJUVANT BEVACIZUMAB, OXALIPLATIN, 5-FLUOROURACIL, AND RADIATION FOR RECTAL CANCER

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1 doi: /j.ijrobp Int. J. Radiation Oncology Biol. Phys., Vol. 82, No. 1, pp , 2012 Copyright Ó 2012 Elsevier Inc. Printed in the USA. All rights reserved /$ - see front matter CLINICAL INVESTIGATION Gastrointestinal Cancer NEOADJUVANT BEVACIZUMAB, OXALIPLATIN, 5-FLUOROURACIL, AND RADIATION FOR RECTAL CANCER TOM DIPETRILLO, M.D., VICTOR PRICOLO, M.D., JORGE LAGARES-GARCIA, M.D., MATT VREES, M.D., ADAM KLIPFEL, M.D., TOM CATALDO, M.D., WILLIAM SIKOV, M.D., BRENDAN MCNULTY, M.D., JOSHUA SHIPLEY, M.D., ELLIOT ANDERSON, M.D., HUMERA KHURSHID, M.D., BRIGID OCONNOR, M.D., NICKLAS B. E. OLDENBURG, M.D., KATHY RADIE-KEANE, M.D., SYED HUSAIN, M.D., AND HOWARD SAFRAN, M.D. From the Brown University Oncology Group, Providence, RI, USA Purpose: To evaluate the feasibility and pathologic complete response rate of induction bevacizumab + modified infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) 6 regimen followed by concurrent bevacizumab, oxaliplatin, continuous infusion 5-fluorouracil (5-FU), and radiation for patients with rectal cancer. Methods and Materials: Eligible patients received 1 month of induction bevacizumab and mfolfox6. Patients then received 50.4 Gy of radiation and concurrent bevacizumab (5 mg/kg on Days 1, 15, and 29), oxaliplatin (50 mg/ m 2 /week for 6 weeks), and continuous infusion 5-FU (200 mg/m 2 /day). Because of gastrointestinal toxicity, the oxaliplatin dose was reduced to 40 mg/m 2 /week. Resection was performed 4 8 weeks after the completion of chemoradiation. Results: The trial was terminated early because of toxicity after 26 eligible patients were treated. Only 1 patient had significant toxicity (arrhythmia) during induction treatment and was removed from the study. During chemoradiation, Grade 3/4 toxicity was experienced by 19 of 25 patients (76%). The most common Grade 3/4 toxicities were diarrhea, neutropenia, and pain. Five of 25 patients (20%) had a complete pathologic response. Nine of 25 patients (36%) developed postoperative complications including infection (n = 4), delayed healing (n = 3), leak/abscess (n = 2), sterile fluid collection (n = 2), ischemic colonic reservoir (n = 1), and fistula (n = 1). Conclusions: Concurrent oxaliplatin, bevacizumab, continuous infusion 5-FU, and radiation causes significant gastrointestinal toxicity. The pathologic complete response rate of this regimen was similar to other fluorouracil chemoradiation regimens. The high incidence of postoperative wound complications is concerning and consistent with other reports utilizing bevacizumab with chemoradiation before major surgical resections. Ó 2012 Elsevier Inc. Rectal cancer, Neoadjuvant, Bevacizumab, Oxaliplatin. INTRODUCTION There were 40,870 new cases of rectal cancer diagnosed in the United States in 2009 (1). Stage-for-stage, recurrence rates are higher in rectal cancer in comparison to colon cancer and the site of first failure for patients undergoing surgery may be local, within the pelvis, or distant, such as the liver or lungs (2). Preoperative fluorouracil and concurrent radiation is the standard of care for T3-T4 rectal cancer based on the Phase III trial by the German Rectal Cancer Study Group. Preoperative chemoradiation improves local control and is associated with reduced toxicities as compared with postoperative chemoradiation. Pathologic complete response rates for 5-fluorouracil (5-FU) and radiation range from 7% to 29% (2 10). To attempt to increase pathologic complete response rates and reduce local and distant relapses, several strategies have been evaluated. These strategies include the addition of other chemotherapeutic agents and targeted therapies to 5-FU and radiation, as well as the use of induction chemotherapy before concurrent chemoradiation. The addition of oxaliplatin to standard therapy is supported by trials using various infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) regimens that have shown improvements in survival in both the metastatic and adjuvant settings (11 13). The addition of oxaliplatin to preoperative 5-FU/radiation has been reported in rectal cancer (14 16).In Reprint requests to: Howard Safran, M.D., Department of Medicine, The Miriam Hospital, 164 Summit Ave., Providence, RI Tel: (401) ; Fax: (401) ; hsafran@lifespan.org Presented at the Annual Meeting of the American Society of Clinical Oncology, Orlando FL, May 29-June 2, Supported in part by Genentech and Sanofi-Aventis Conflict of interest: none. Received Oct 29, 2009, and in revised form June 10, Accepted for publication Aug 9, 2010.

2 Bevacizumab Rectal Cancer d T. DIPETRILLO et al. 125 randomized trials, the addition of oxaliplatin to capecitabine and concurrent radiation did not statistically increase pathologic complete response but was associated with increased gastrointestinal (GI) toxicities (15, 16). Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, increases survival when combined with chemotherapy for patients with advanced colorectal cancer (17). There is strong rationale to initiate vascular endothelial growth factor inhibition with chemoradiation because these modalities are synergistic in preclinical models (18 20). The addition of bevacizumab to 5-FU/radiation has been described, with complete response rates ranging from 8% to 32%, with an acceptable toxicity profile (21 24). The administration of chemotherapy before neoadjuvant chemoradiation has the theoretical advantages of downstaging a locally advanced tumor, eliminating micrometastatic disease, and improving tolerance to chemotherapy when compared with its administration in the adjuvant setting. A randomized Phase II study of induction chemotherapy administered before chemoradiation and surgery revealed similar pathologic complete response rates and R0 resections, but with improved toxicity and compliance as compared with adjuvant chemotherapy after surgery (25). The purpose of this prospective, Phase II study was to evaluate the pathologic complete response rate, safety, and tolerability of a regimen of induction chemotherapy with two cycles of bevacizumab + modified infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) 6 regimen, followed by neoadjuvant concurrent radiation/5-fu/oxaliplatin/ bevacizumab. Another six cycles of bevacizumab + mfol- FOX6 were planned to be administered after surgery. PATIENTS AND METHODS Patient eligibility Eligible patients included those with pathologically documented adenocarcinoma of the rectum with no evidence of distant metastasis. Required pretreatment staging studies included a computed tomography (CT) scan or magnetic resonance imaging of the abdomen and pelvis and chest CT or chest x-ray or positron emission tomography/ct scan. Patients were required to have clinical Stage II or III rectal adenocarcinoma, T3-T4, N0, M0 or T1-T4, N1-2, M0. Transrectal ultrasound was performed whenever possible. Patients were required to have an Eastern Cooperative Oncology Group performance status of 0 1. Required laboratory parameters included granulocytes $1,500/mL, platelets $100,000/mL, total bilirubin #2.0 mg/dl or direct bilirubin #1.0 mg/dl, alkaline phosphatase #3 Upper Limit of Normal (ULN), alanine transaminase (ALT) #3 ULN, creatinine #1.5 ULN, and urine protein creatinine ratio <1.0. A complete history and physical examination were performed on all patients before treatment. Patients with a history of stroke or myocardial infarction in past 6 months, clinically significant congestive heart failure, peripheral vascular disease, or bleeding diathesis were ineligible for the study. Uncontrolled hypertension $150/100 or >Grade 1 neuropathy were also exclusion criteria. The study was approved by the institutional review boards of all participating hospitals, and all patients gave written informed consent according to federal and institutional guidelines. Chemotherapy Each patient received 1 month of induction treatment with biweekly bevacizumab (5 mg/kg) and mfolfox6 (bevacizumab 5 mg/kg intravenously [IV] over 90 min, followed by oxaliplatin 85 mg/m 2 IVover 2 h with concurrent Leucovorin 400 mg/m 2 IV over 2 h, followed by 5-FU 400 mg/m 2 IV push, followed by 5-FU 2400 mg/m 2 IVover 46 h infusion). Patients then received 50.4 Gy of radiation with concurrent bevacizumab (5 mg/kg on Days 1, 15, and 29), oxaliplatin (50 mg/m 2 /week Days 1, 8, 15, 22, 29, 36), and 5-FU (200 mg/m 2 /day) as a continuous IV infusion throughout radiation. Because of GI toxicity experienced by the first 3 patients in the study, the oxaliplatin dose was reduced to 40 mg/m 2 / week. All patients were premedicated before chemotherapy treatment to minimize nausea and vomiting, usually with 5-HT3 receptor antagonists. Adjuvant chemotherapy was started after 4 but less than 12 weeks after surgical resection and consisted of six biweekly treatments of mfolfox6 and bevacizumab. Radiation therapy All patients received pelvic radiation therapy with concurrent chemotherapy. Treatments were given with a linear accelerator with a minimum energy of 10MeV. The total dose of radiation therapy was 50.4 Gy. Patients underwent CT simulation with oral contrast to visualize the small bowel. All patients underwent three-dimensional conformal radiation treatment planning. The intent of treatment was to include the tumor bed (gross tumor volume) with a margin, the internal iliac nodes, and the presacral nodes (the external iliac nodes were also included if a structure was invaded that drained to the external iliacs) to a total dose of 45 Gy. This was delivered at 1.8 Gy per day, 5 days per week, or 25 fractions over 5 weeks. A minimum tumor boost of 540 cgy, given at 1.8 cgy per fraction, was required for all patients and was given to the gross tumor volume with a 1-cm margin. Normal tissue sparing techniques were employed so that no portion of the small bowel received more than 4500 cgy and less than 10% of the bladder receive greater than 5000 cgy. Surgery Resection was performed 4 8 weeks after the completion of chemoradiotherapy. A total mesorectal excision was the recommended operation for mid and distal rectal tumors. Abdominoperineal resections were done for tumors with sphincter involvement or very distal locations preventing coloanal anastomosis. Complications after surgery were recorded. Assessments Toxicity was graded according to the National Cancer Institute s Common Toxicity Criteria (version 3.0). Patients

3 126 I. J. Radiation Oncology d Biology d Physics Volume 82, Number 1, 2012 were assessed before each treatment during the induction phase. Weekly toxicity assessments were accomplished during the chemoradiation phase. Pathologic response was assessed in all patients undergoing resection of the tumor. A complete pathologic response was defined as no evidence of malignancy on the specimen. Statistical analysis The primary objective was to determine the complete pathologic response rate as determined by surgical resection. Secondary objectives were to determine the safety and tolerability of the treatment regimen. We hypothesized that a complete response rate of 30% would be clinically meaningful. Our accrual goal was 29 evaluable patients. The treatment regimen was to be accepted if at least 6 pathologic complete response rates were observed from the 29 patients. Accrual was stopped after 26 patients when the Brown University Oncology Group data safety monitoring board reviewed the surgical morbidity of this trial. RESULTS Patient characteristics Between April 2005 and July 2008, 26 patients with locally advanced rectal cancer were treated on the study. Table 1 lists the patient characteristics. The median age was 50 years (range, 39 75). Sixteen patients had nodal involvement. Three patients had anal sphincter involvement at presentation. Toxicities: induction chemotherapy One patient experienced a Grade 4 arrhythmia during induction chemotherapy and was withdrawn from the study. Retrospectively, this patient had prolonged QT syndrome at study entry, and the arrhythmia was probably related to the additional effects of diphenhydramine and prochlorperazine. No other Grade 3 or 4 events occurred during induction chemotherapy. Table 1. Patient characteristics (n = 25) Median age 50 (39 75) Stage T2 2 T3 20 T4 3 Node 7 Node + 16 Nx 2 Distance from anal sphincter: Invades sphincter 3 <2 cm cm 7 5cm 13 Surgical procedure Low anterior resection 19 Abdominoperineal resection 6 Toxicities: chemoradiation Acute Grade 2 4 toxicities for all patients are listed in Table 2. Multiple toxicities in the same patient are scored as separate events. Any Grade 3 or 4 toxicities were experienced by 19 of 25 (76%) patients. Grade 3 nonhematologic toxicities included diarrhea (40%), pain (16%), fatigue (8%), nausea (8%), radiation dermatitis (8%), and bleeding with menstruation (4%). Grade 3 hematologic toxicities included neutropenia (16%) and anemia (8%). Grade 4 toxicities included anemia (4%), neutropenia (4%), sepsis (4%), and nausea/diarrhea/weight loss (4%). Because of toxicity, 10 patients (40%) were unable to complete the intended chemotherapy. Hospitalizations occurred in 5 patients (25%) from diarrhea/dehydration (n = 4) and a port infection (n = 1). One patient had a rectovaginal fistula identified incidentally at the time of surgical resection. Postoperative complications The median time from last dose of bevacizumab and surgery was 8.9 weeks. Two operations, performed by non colorectal surgeons, involved a low anterior resection and primary anastomoses with each case was complicated by an anastomic leak. All other operations were performed by colorectal surgeons and involved 6 patients undergoing abdominoperineal resection and 19 patients undergoing a total mesorectal excision with a low anterior resection and a temporary ostomy. Nine of 25 (36%) patients developed postoperative wound complications including infection (n = 4), delayed healing (n = 3), leak/abscess (n = 2), sterile fluid collection (n = 2), ischemic colonic reservoir (n = 1), and fistula (n = 1). Deep venous thrombosis developed postoperatively in 3 patients. One patient expired suddenly at home approximately 10 days after surgical resection. Autopsy revealed the patient had suffered an acute myocardial infarction and had significant three-vessel coronary artery disease. Table 2. Highest toxicity for each patient during chemoradiation (n = 25) Grade 2 Grade 3 Grade 4 Diarrhea 5 (20%) 10 (40%) 1 (4%) Nausea 2 (8%) 2 (8%) 1 (4%) Dehydration 1 (4%) 2 (8%) Pain 7 (28%) 4 (16%) Bleeding 3 (12%) 1 (4%) Neuropathy 1 (4%) 1 (4%) Radiation dermatitis 4 (16%) 2 (8%) Hypokalemia 1 (4%) 2 (8%) Hypocalcemia 3 (12%) Mucositis 2 (8%) 1 (4%) Neutropenia 1 (4%) 4 (16%) 1 (4%) Anemia 2 (8%) 2 (8%) 1 (4%) Fatigue 6 (24%) 2 (8%) Weight loss 4 (16%) 1 (4%) Infection 2 (8%) 1 (4%) 1 (4%)

4 Bevacizumab Rectal Cancer d T. DIPETRILLO et al. 127 Adjuvant treatment Fifteen of 25 patients (60%) received any adjuvant treatment. Only 6 of 25 patients (25%) were able to complete all six cycles of adjuvant treatment. Response and follow-up Five of 25 patients (20%) had a complete pathologic response. With a median follow-up of 36 months, 5 patients have had disease recurrence, 4 with lung metastases and 1 with a pelvic recurrence. None of the patients with recurrence had a pathologic complete response. Follow up ranged from 8 to 54 months. The disease-free and overall survival curves are included in Fig. 1. Discussion In this prospective trial, two cycles of induction bevacizumab + mfolfox6 were safely administered in patients with rectal cancer. However, the addition of oxaliplatin and bevacizumab to 5-FU and radiation had substantial GI toxicity with 44% of patients developing Grade 3/4 diarrhea. Surgical morbidities were concerning with 9 of 25 (36%) patients developing postoperative wound complications. Because of this toxicity, the Brown University Oncology Group Data Safety Monitoring Board recommended closure of this study. Other trials have demonstrated the addition of oxaliplatin to 5-FU and radiation increases GI toxicities in preoperative treatment of rectal cancer. In a Phase III trial, Gerard reported an increase in diarrhea with preoperative capecitabine, oxaliplatin, and radiation compared to capecitabine and radiation alone (16). Furthermore, in the Studio Terapia Adiuvante Retto - 01 (STAR-01) Phase III trial, Aschele et al. reported an increase in GI toxicity with the addition of oxaliplatin to 5-FU infusion and radiation without an increase in pathologic complete response (16). Willett and colleagues reported the addition of neoadjuvant bevacizumab followed by bevacizumab with continuous infusion 5-FU and radiation for patients with rectal cancer. 21 In this study, which did not use induction chemotherapy before chemoradiation, the regimen of bevacizumab, 5-FU, and radiation appeared to be safe. Surgery Fig. Progression-free survival and overall survival. occurred 7 10 weeks after completion of all therapies as compared with 4 8 weeks in our study. In the Willett study, which included 32 patients, postoperative complications included anastomotic leak with presacral abscess requiring drainage (n = 1), vaginal tear (n = 1), pelvic hematoma (n = 1), and delayed healing of perineal incisions. Five of 32 patients (16%) had a pathologic complete response. This treatment resulted in an actuarial 5-year local control and overall survival of 100%. Actuarial 5-year disease-free survival was 75% and 5 patients developed metastases postsurgery. Postoperative complications have been reported in other studies using major resections after bevacizumab, especially when used in the neoadjuvant setting in combination with radiation (22 31). Crane et al. reported a Phase II trial to assess the efficacy and safety of the addition of bevacizumab to concurrent neoadjuvant capecitabinebased chemoradiation in locally advanced rectal cancer (22). Twenty-five patients with clinically staged T3N0-N1 rectal cancer received neoadjuvant therapy with 50.4 Gy radiotherapy with 3 doses of bevacizumab every 2 weeks and capecitabine. Eight (32%) of 25 patients had a pathologic complete response. Three wound complications required surgical intervention (one coloanal anastomotic dehiscence requiring completion abdominal perineal resection and two perineal wound dehiscences after initial abdominal perineal resection APR). Five minor complications occurred that resolved without operative intervention. With a median follow-up of 22.7 months (range, months), all patients were alive; 1 patient has had a recurrence in the pelvis (2-year actuarial rate, 6.2%) and 3 had distant recurrences. The Dutch Colorectal Cancer Group has also evaluated bevacizumab with concurrent capecitabine and radiation in rectal cancer. In a preliminary report of 23 patients, chemoradiation toxicities included 7 patients with Grade 3 toxicities (4 skin, 2 diarrhea, 1 tenesmic) and 1 patient with Grade 4 toxicity (anal mucositis). One patient developed enteritis with diffuse uncontrollable bleeding at the end of the chemoradiation and died before rectal surgery. Two small bowel perforations occurred, with one occurring 70 days after the last administration of bevacizumab. A third patient had an asymptomatic rectal wall perforation at the site of the primary tumor. Surgical complications consisted of one perineal dehiscence, one rectovaginal fistula after a stapling failure, and 1 patient with bleeding (5500 ml). Two of 21 patients had a complete pathologic response. In a trial by Varadhachary evaluating bevacizumab with gemcitabine and radiation as neoadjuvant treatment for pancreatic cancer, major postoperative complications occurred in 5 of the 9 patients (56%) who underwent pancreatic resection including wound dehiscence (n = 3) requiring reoperation, a large ventral hernia related to fascial dehiscence (n = 1), and a biliary anastomotic leak (n =1)(27). After bevacizumab, fewer postoperative complications have been reported in nonirradiated tissues such as resecting liver metastases (31). In our small trial, it is difficult to compare the 20% pathologic complete response rate with other chemoradiation

5 128 I. J. Radiation Oncology d Biology d Physics Volume 82, Number 1, 2012 regimens. Reports of the pathologic complete response rate for 5-FU and radiation have varied widely. For example, the pathologic complete response to fluorouracil and radiation was 5% in the Bosset trial, 8% in the Sauer trial, and 11% in the Gerard trial, respectively (3 5). In Radiation Treatment and Oncology Group 0012, patients with clinical T3/T4 distal rectal cancers were randomly assigned to receive continuous infusion fluorouracil plus pelvic hyperfractionated radiation or continuous infusion fluorouracil and irinotecan. The pathologic complete response rate was 26% in each arm. Furthermore, the impact of bevacizumab and two cycles of induction mfolfox6 and bevacizumab on systemic recurrence cannot be assessed in our trial because the sample size. However, in a large, Phase III randomized trial of 2710 patients with Stage II and Stage III colon cancer, the addition of bevacizumab to mfolfox6 did not significantly prolong disease-free survival compared with mfolfox6 alone (32). It is concerning in our trial that a substantial number of patients did not receive intended postoperative chemotherapy. Fifteen of 25 patients (60%) received any adjuvant treatment and only 6 of 25 patients (25%) were able to complete all six cycles of adjuvant treatment. To improve patient compliance, future Brown University Oncology Group will investigate administering eight cycles of FOLFOX prior to chemoradiation. REFERENCES 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, CA Cancer J Clin 2009;59: Minsky BD, Mies C, Recht A, et al. Resectable adenocarcinoma of the rectosigmoid and rectum. I. Patterns of failure and survival. Cancer 1988;61: Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radiotherapy in rectal cancer. 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