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Management of bevacizumab-associated bowel perforation: a case series and review of the literature
original article
Annals of Oncology 19: 577–582, 2008 doi:10.1093/annonc/mdm508 Published online 16 November 2007
Management of bevacizumab-associated bowel perforation: a case series and review of the literature B. D. Badgwell1, E. R. Camp1, B. Feig1, R. A. Wolff2, C. Eng2, L. M. Ellis1,3 & J. N. Cormier1* 1
Department of Surgical Oncology; 2Department of Medical Oncology; 3Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
Received 27 July 2007; revised 26 September 2007; accepted 1 October 2007
bevacizumab over a 2-year period (January 2004 to October 2006). Medical records of these patients were examined for reports of confirmed bowel perforation or fistula, associated clinicopathological factors, treatment, and outcomes. Results: We identified 1442 patients who had been treated with bevacizumab over the study period with perforation occurring in 24 (1.7%). The breakdown of these 24 patients by disease site was as follows: ovarian (3 of 50, 6%), gastroesophageal (2 of 38, 5.3%), pancreatic (7 of 141, 5%), unknown primary (1 of 60, 1.7%), lung (1 of 67, 1.5%), colorectal (6 of 478, 1.3%), and renal cell (4 of 269, 1.5%). The majority of patients (n = 19, 79%) were initially managed nonoperatively. Only five (21%) patients ultimately underwent surgical exploration, with a subsequent anastomotic leak developing in one patient. The overall 30-day mortality rate was 12.5%. Conclusions: Bevacizumab-associated bowel perforation occurs in patients with various malignancies, with an incidence of 1.7%. Nonoperative treatment is a viable approach to management in selected patients. Key words: avastin, bevacizumab, complication, GI perforation, toxicity
introduction Targeting vascular endothelial growth factor (VEGF) and its receptors has been shown to be efficacious in a number of disease types either as a single agent or in combination with chemotherapy. The efficacy of bevacizumab, a humanized mAb to VEGF (Avastin; Genentech, San Francisco, CA), when used in combination with chemotherapy has been demonstrated in several prospective, randomized phase III studies [1–3]. For example, in a phase III trial in patients with metastatic colon cancer, bevacizumab in combination with standard chemotherapy was found to increase overall and progressionfree survival and response rates when compared with chemotherapy plus placebo [1]. Because of this and the results from other trials, bevacizumab has become widely used for the treatment of colorectal cancer and non-small-cell lung cancer and is being studied as part of the treatment regimen in a wide range of malignancies [4–8]. Bevacizumab has now become part of the armamentarium of targeted therapies for cancer [9, 10]. Bevacizumab is generally well tolerated and has an acceptable toxicity profile consisting primarily of hypertension and proteinuria. Other rare but important adverse effects, however, *Correspondence to: Dr J. N. Cormier, Department of Surgical Oncology, Unit 444, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Tel: +1-713-792-6949; Fax: +1-713-745-1921; E-mail: [email protected]
include delayed wound healing, arterial thrombosis, and bleeding [11]. Another potentially serious adverse effect of bevacizumab is gastrointestinal (GI) perforation [12]. GI perforation was found to be an uncommon but welldocumented side-effect of treatment in the phase III trials of bevacizumab, as well as in subsequent surveillance trials, with a reported incidence of 1% to 2% [1, 2, 4, 13, 14]. Although infrequent, this potentially life-threatening complication has generated significant clinical interest, including a follow-up analysis that examined potential risk factors as well as associated findings in patients with GI perforation [15]. It is not clear from the current body of literature, however, how these patients, many of whom have advanced malignancies, should be managed. The purpose of this study was to assess the presentation, management, and outcome of patients presenting with bevacizumab-associated bowel perforation.
patients and methods Patients were identified from the pharmaceutical database at The University of Texas M. D. Anderson Cancer Center by querying for all patients who had received bevacizumab from January 2004 through October 2006. Medical records for all identified patients were reviewed, and tumor histology findings were obtained from our institutional tumor registry. Since the half-life of bevacizumab is 20 days, we sought to identify patients with bowel perforation occurring within 7 weeks of their last
ª The Author 2007. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please e-mail: [email protected]
original article
outcomes in patients with bevacizumab-associated bowel perforation at a tertiary cancer center.
Patients and methods: Our institutional pharmacy database was searched to identify all patients who had received
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Background: This study examined the various approaches to the management of perforation and the associated
original article treatment. For those patients who had undergone recent surgery, bevacizumab was not started until 4 weeks postoperatively. We defined bowel perforation as the finding of i.p. air and/or GI/enterocutaneous fistula that was confirmed by computed tomography (CT) imaging of the abdomen/pelvis. The study was approved by the Institutional Review Board at our institution.
patient demographics and presentation
management and outcome The treatment strategy for bevacizumab-associated perforation was categorized as either surgical or nonoperative management. Nonoperative management included the placement of a percutaneous intra-abdominal catheter. For those managed surgically, the operative records were reviewed to determine the intra-operative findings, including the type of operation carried out and the need for a stoma. Outcome data included treatmentassociated complications as well as postperforation 30- and 60-day mortality. Survival was defined as the time from the diagnosis of perforation to death. Probabilities for overall survival were determined using the method of Kaplan and Meier [17]. Computations were carried out using NCSS software (version 2004; NCSS Institute, Kaysville, UT).
results patient demographics and presentation Of the 1442 patients treated with bevacizumab at our institution from January 2004 through October 2006, 24 patients (1.7%) were identified as having evidence of posttreatment bowel perforation. Nineteen patients displayed i.p. air with or without fistula formation, while five patients were found to have a GI/enterocutaneous fistula only. Perforation rates by disease site were as follows: ovarian carcinoma (3 of 50, 6%), pancreatic carcinoma (7 of 141, 5%), gastroesophageal carcinoma (2 of 38, 5.3%), unknown primary (1 of 60, 1.7%), colorectal carcinoma (6 of 478, 1.3%), lung carcinoma (1 of 67, 1.5%), and renal cell carcinoma (4 of 269, 1.5%). The remaining 339 patients, who had a variety of malignancies, had no evidence of perforation.
578 | Badgwell et al.
Clinicopathological factors including bevacizumab-related risk factors in the patients who experienced perforation are summarized in Table 1. The tumors most commonly associated with perforation were pancreatic (n = 7), colorectal (n = 6), renal cell (n = 4), and ovarian (n = 3) carcinomas. Seventy-one percent of patients (n = 17) had distant metastatic (stage IV) disease. The single patient with stage II disease had colorectal cancer and was receiving bevacizumab in the adjuvant setting for lymphovascular invasion. Bowel perforation occurred at a median of 71 days (range 3–512 days) after the initiation of therapy and 14 days (range 2–49) after the last dose of bevacizumab. Twenty-three patients (96%) were receiving concomitant systemic chemotherapy. The most common regimens include capecitabine (n = 8), FOLFOX/FOLFIRI (n = 5), gemcitabine (n = 4), and paclitaxel/docetaxel (with or without carboplatin, n = 4). Twenty-two patients had at least one potential baseline risk factor for perforation on the basis of the findings from a recent, large observational study of patients with colorectal cancer receiving bevacizumab [15]. In particular, 11 patients (46%) had an intact primary tumor while undergoing bevacizumab treatment; nine patients had undergone abdominal
Table 1. Clinicopathological factors in patients with bevacizumabassociated bowel perforation Variable
Patients (N = 24)
Days from bevacizumab initiation to perforation, median (range) Days from last bevacizumab infusion to perforation, median (range) Baseline risk factors Intact primary Abdominal irradiation NSAID use Diverticulosis Recent endoscopy Disease site Pancreatic Colorectal Renal cell Ovarian Gastroesophageal Lung Unknown primary Stage I II III IV Associated findings Tumor at perforation site Gastrointestinal obstruction Abscess/fluid at perforation site Carcinomatosis Diverticulitis Perforation at anastomotic site
71 (3–512)
%
14 (2–49)
11 9 7 7 3
46 38 29 29 13
7 6 4 3 2 1 1
29 25 17 13 8 4 4
0 1 6 17
4 25 71
9 4 16 8 2 4
38 17 67 33 8 17
NSAID, nonsteroidal anti-inflammatory drug.
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Clinicopathological factors collected for patients with confirmed bevacizumab-associated perforation included tumor stage, the treatment rendered, and bevacizumab-related factors (i.e. treatment start date, duration, date of last administration, and if treatment was resumed after management of perforation). Also collected were data pertaining to potential baseline risk factors for bevacizumab-associated perforation [1, 15], such as intact primary tumor, endoscopy carried out within 1 month before initiating treatment, prior adjuvant radiotherapy, long-term nonsteroidal anti-inflammatory drug (NSAID) therapy (‡1 month of use), peptic ulcer disease, diverticulosis, and previous surgery. Patient records were also reviewed for information on the symptoms and signs at the time of bevacizumab-associated perforation. Due to the inherent limitation in documented symptoms on retrospective analysis, we limited symptom evaluation to the presence or absence of abdominal pain and nausea/emesis. Fever was defined as a temperature ‡38.0C, tachycardia as pulse ‡110 beats per minute, and hypotension as a systolic blood pressure <90 mmHg or blood pressure requiring vasopressor support. Patients were evaluated for the presence of sepsis according to the guidelines formulated at the 2001 International Sepsis Definitions Conference [16]. Leukocytosis and leukopenia were defined by a white blood cell count of ‡11 000 and <4000 per U/l, respectively. Neutropenia was defined as an absolute neutrophil count of <500 per U/l.
Annals of Oncology
original article
Annals of Oncology
Volume 19 | No. 3 | March 2008
failed nonoperative treatment consisting of drainage and antibiotics for a perforated diverticulitis with abscess formation. This patient ultimately developed a fistula and abscess that extended to the lower abdominal wall. Colon resection, colostomy placement, and abdominal wall debridement were required to manage this case. The remaining 19 patients did not undergo any surgical intervention within 60 days of diagnosis. Four patients (1–4) were treated with immediate surgical exploration. Two of these patients had a perforated appendicitis, with one undergoing appendectomy and the other an ileocecectomy for an associated gangrenous-appearing cecum. The latter patient subsequently developed a postoperative leak from the bowel anastomosis requiring a second operation that included a completion right colectomy with end ileostomy. This patient’s postoperative course was further complicated after discharge by the development of a right lower quadrant abscess that required readmission and by dehydration with renal failure that required another readmission. Patient 3, who developed a perforation at the site of a primary tumor at the gastroesophageal junction, underwent a gastrectomy with cervical esophagostomy that was accompanied by minimal postoperative complications including a symptomatic pleural effusion requiring thoracentesis. The fourth patient developed a perforation in the setting of ovarian carcinomatosis requiring a diverting loop jejunostomy. The 30-day postperforation mortality rate was 12.5% (n = 3/24), and the 60-day mortality rate was 25% (n = 6/24) in this patient cohort. None of the patients undergoing surgical treatment died within 60 days of the diagnosis of perforation. All three patients who died within 30 days were treated nonoperatively and were not surgical candidates because of advanced carcinomatosis. Three additional deaths occurred in the nonoperatively managed patients from 30 to 60 days after the diagnosis. These deaths, however, were not directly attributable to perforation as all patients were in stable condition without signs of infection or sepsis and were discharged to hospice care. With a median follow-up of 3.8 months, the median overall survival time after bevacizumabassociated perforation was 12.5 months (Figure 1). Four patients were able to resume bevacizumab therapy at a median of 51 days (range 35–135 days) after the management of their perforation.
discussion The overall incidence of bevacizumab-associated GI perforation in patients in our study cohort was 1.7%, but the incidence varied among malignancies, with pancreatic, ovarian, and gastroesophageal carcinoma associated with the highest percentage of bowel perforations. It is important to recognize that the number of patients in certain diseases, however, was small. Interestingly, colorectal cancer was associated with one of the lower incidences of perforation at 1.3%. The median time to perforation after the initiation of bevacizumab treatment was 71 days. The presenting signs and symptoms of these patients are fairly typical of patients with intra-abdominal inflammation, although three patients were asymptomatic at
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radiotherapy; seven patients were regular NSAID users; seven patients had diverticulosis confirmed by colonoscopy and CT imaging; and three patients had undergone either upper or lower endoscopy within 1 month before starting treatment, but none of the patients in our cohort had a history of peptic ulcer disease. At the time of the diagnosis of perforation, tumor was present at the site of perforation in nine patients, and eight patients had carcinomatosis. Four patients presented with GI obstruction, and two patients were diagnosed with diverticulitis. Seven patients had clear radiographic signs of an abscess, and an additional nine patients had fluid present at the site of perforation that did not meet the radiographic criteria for abscess. Four patients developed a perforation at the site of a previous surgical anastomosis. In one patient, the site was at a prior gastrojejunostomy that had been carried out during a pancreaticoduodenectomy 1.5 years prior. In the second patient, the perforation site involved an ileocolonic anastomosis from a right hemicolectomy performed 6 months prior. A presacral fistula developed 3 months following a low anterior resection in a third patient, and an anastomotic leak developed in a fourth patient 4 months after esophagectomy. The clinical findings at the time of presentation of bevacizumab-associated perforation included abdominal pain in 20 patients (83%) and nausea or emesis in seven patients (29%). Physical examination demonstrated fever in six patients (25%), while abdominal tenderness was documented in 18 patients (75%). Twelve patients (50%) demonstrated leukocytosis, and only one patient (4%) presented with leukopenia and neutropenia. Four patients (17%) presented with tachycardia, and only one patient (4%) presented with signs of sepsis which included mental status changes, fever, tachycardia >120 beats per minute, and leukocytosis. Three patients (12.5%) were asymptomatic and were determined to have perforation at the time of surveillance imaging, and one patient (4%) presented with increasing abdominal distention. Twenty-two patients had CT findings indicating perforation, one patient required a fistulogram in addition to a CT scan to confirm perforation, and one patient died shortly after presentation, with perforation confirmed on autopsy. Perforation was identified by radiography in the remaining two patients. Six patients initially underwent plain abdominal radiography, and 23 patients ultimately underwent CT during the initial evaluation. The clinical details, including the perforation site, treatment rendered, morbidities, and outcomes for the 24 patients with bevacizumab-associated perforation, are summarized in Table 2. Twenty patients initially underwent nonoperative treatment that included hospitalization in 14 patients; six were managed solely in the outpatient setting. Seven of the hospitalized patients underwent percutaneous i.p. catheter placement carried out by an interventional radiologist. There were no immediate complications, such as bleeding or adjacent organ injury, in the patients undergoing a drainage procedure. Inpatient treatment also consisted of i.v. antibiotics and a period of bowel rest. Total parenteral nutrition was administered in three patients, and two patients required a nasogastric tube to relieve obstructive symptoms. Of the patients initially managed nonoperatively, only one (patient 5)
original article
Annals of Oncology
Table 2. Management and outcome of patients with bowel perforation while on bevacizumab-containing regimens Patient no.
Perforation site
Management of perforation
Morbidity
Postperforation survival
1
Appendix
Ileocecectomy
Alive at 5 months after perforation
2 3
Appendix Gastroesophageal junction at site of primary tumor Unclear, unable to identify source in pelvis due to carcinomatosis Colonic diverticulitis
Appendectomy Gastrectomy, cervical esophagostomy Diverting loop jejunostomy, drain placement
Anastomotic leak requiring right colectomy and ileostomy on postoperative day 16, intraabdominal abscess, and admission for dehydration and renal failure None Symptomatic pleural effusion requiring thoracentesis None
4
6 7 8 9 10 11
Gastrojejunostomy after Whipple procedure Duodenum at site of primary tumor Small bowel, likely duodenum Colon at site of right hemicolectomy Unclear, likely small bowel Unclear, likely small bowel
Alive at 2.4 months after perforation
Failed nonoperative management and drainage, sigmoid colectomy and ostomy Nonoperative
Open wound with delayed healing
Alive at 5.6 months after perforation
None
Dead at 18 months after perforation
Nonoperative with percutaneous drain Nonoperative with drain Nonoperative
Drain developed into enterocutaneous fistula None None
Dead at 2.5 months after perforation
Nonoperative Nonoperative
Alive at 6.1 months after perforation Alive at 3.5 months after perforation
Dead at 1.2 months after perforation Alive at 5.5 months after perforation
Small bowel at site of tumor Duodeno-pancreatic fistula at site of tumor Rectal perforation at site of low anterior resection Unclear Small bowel
Nonoperative Nonoperative
None Requiring TPN and multiple courses of antibiotics None None
Nonoperative
None
Dead at 12 months after perforation
Nonoperative Nonoperative with drain
Death same day as diagnosis Alive at 6.5 months after perforation
17 18
Small bowel at site of tumor Colonic perforation adjacent to cholecystitis
Nonoperative Nonoperative with drain
19
Nonoperative Nonoperative with drain Nonoperative
None None
Dead at 19 days after perforation Alive at 4.6 months after perforation
Nonoperative
None
Dead at 1.3 months after perforation
23
Duodeno-pancreatic fistula at site of tumor Unclear Gastroesophageal at site of resection and healed anastomotic leak Rectal perforation at site of tumor Unclear
None Chronic enterocutaneous and enterovesicular fistula requiring TPN None Chronic chole-colonic fistula requiring right hemicolectomy 2.5 months after diagnosis None
Nonoperative
None
24
Colonic diverticulitis
Nonoperative with drain
Abscess
Dead at time of diagnosis, also found to have large saddle pulmonary embolus Alive at 3.1 months after perforation
12 13 14 15 16
20 21
22
Dead at 14 months after perforation Dead at 1.7 months after perforation
Alive at 3.2 months after perforation Alive at 13.5 months after perforation
Dead at 9 months after perforation
TPN, total parenteral nutrition.
presentation. The management of perforation in this cohort of patients was distinctly atypical, however, in that 19 patients were managed nonoperatively. This finding reflects the
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complex clinical decision making required in patients with advanced cancer, including the reluctance to operate in the setting of bevacizumab treatment. It also shows, however,
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5
Dead at 3.8 months after perforation Alive at 3.3 months after perforation
Annals of Oncology
that there can be a positive outcome from nonoperative treatment. Our findings are similar to those in the existing literature on bevacizumab-associated bowel perforation with respect to the incidence, associated findings, and possible risk factors. In one study, a phase III study conducted by Hurwitz et al. [1] that included 402 patients with metastatic colorectal cancer, a total of six patients (1.5%) developed bowel perforation. Of these, one patient died as a direct result of the perforation and the remaining five recovered, with three patients able to resume treatment. Although these authors identified colon surgery within 2 months as a risk factor, they also found a history of peptic ulcer disease and a partial (30% decrease in tumor size) or complete response (disappearance of tumor) to therapy as potential risk factors for perforation. The interval from surgical intervention to perforation in our study also tended to be longer than the 2-month interval noted in that study. In an observational study of 1960 patients with unresectable colorectal cancer receiving bevacizumab and first-line chemotherapy, Hedrick et al. [13] found that 33 (1.7%) experienced GI perforation, an incidence similar to the 1.3% observed in this patient group in our study and identical with the overall incidence we observed. Potential risk factors identified in that study consisted of an intact primary tumor, colonoscopy or sigmoidoscopy carried out within 1 month of starting bevacizumab therapy, and prior adjuvant radiotherapy, which were similar to the factors identified in our study [13]. Indeed, we noted that all our patients except two had at least one of the risk factors identified by Sugrue et al. [15]. The study of Sugrue et al., analyzing the same registry as Hedrick et al., also showed at least one of the following associated findings in 67% of the patients with GI perforation: tumor at the site of perforation, obstruction, intra-abdominal abscess, carcinomatosis, and acute diverticulitis, which were likewise similar to those observed in our study. In addition, in a case report series of patients treated with bevacizumab for colorectal, lung, renal cell, and unknown primary cancer, ischemic bowel complications were more frequent in patients with a history of pelvic irradiation [12]. Although this series consisted of only 33 patients, three bowel complications (two
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episodes of ischemic colitis and one episode of perforation) occurred in the three patients who had received infradiaphragmatic irradiation but in none of the 30 remaining patients who had not undergone irradiation. As in our study, a varying incidence of bevacizumabassociated GI perforation has also been observed in patients with malignancies other than colorectal cancer. For example, in a phase II study of the combination of bevacizumab and gemcitabine in patients with advanced pancreatic cancer, the incidence of visceral perforation was 8% (n = 4) [7]. These perforations included a Mallory–Weiss tear, a perforation following sigmoid stent placement, an unclear source of perforation that was the cause of patient death, and, similar to our study finding, a perforation at a gastrojejunostomy anastomosis. In a phase I trial of bevacizumab and capecitabine with radiotherapy in patients with pancreatic cancer done at our institution, 2 of 48 patients treated developed bowel perforation [18]. In a study of bevacizumab treatment in patients with recurrent, refractory ovarian cancer, bowel perforation occurred in 9% (n = 2) [19]. In addition, a phase II study of bevacizumab in patients with ovarian cancer resistant to platinum-based therapy was halted after 5 of 44 (11%) patients developed GI perforations [20]. We, too, observed bevacizumab-associated perforation in patients with cancer at various sites, with the highest incidence in patients with pancreatic, ovarian, and gastroesophageal cancers, a finding that was in agreement with these published findings. A potentially important contribution of the current study are the details regarding the clinical presentation, treatment, and outcomes of patients with bevacizumab-associated perforation. In general, patients displayed the signs, symptoms, and leukocytosis frequently seen in patients presenting with a serious intra-abdominal process. Few patients, however, displayed tachycardia, hypotension, or sepsis, which may be the result of heightened awareness and the prompt recognition of complications in these high-risk patients. Another significant finding in our study was the success of the nonoperative management of bowel perforation in most patients, which conflicts with the traditional view that bowel perforation constitutes a surgical emergency [21]. This treatment strategy is the outgrowth of multidisciplinary discussions that include the medical oncologist, surgical oncologist, interventional radiologist, ancillary staff, family members, and the patient regarding the best palliative measures in the setting of incurable cancer. The success of this conservative approach to treatment is borne out by the fact that four of the patients in our study cohort who underwent nonoperative management were discharged to a hospice with resolution of their acute symptoms. While these patients ultimately died of tumor progression, they were spared the morbidity and potential mortality of a surgical procedure that might have hastened their demise. Another important concern to weigh when considering surgery in such patients is the increased likelihood of surgical complications in patients receiving bevacizumab treatment, as described in the literature. For example, Scappaticci et al. [22] reported a wound healing complication rate of 13% in 75 patients who underwent surgery during study treatment. Of 10 patients with complications, a fistula formed in two and an
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Figure 1. Overall survival following bevacizumab-associated bowel perforation.
original article
original article
acknowledgements We would like to thank Beth Notzen for editorial assistance, Debbie Dunaway for manuscript preparation, and Sarah Taylor for assistance with data acquisition from the tumor registry.
references 1. Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350 (23): 2335–2342. 2. Giantonio BJ, Catalano PJ, Meropol NJ et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007; 25 (12): 1539–1544. 3. 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 (24): 2542–2550.
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4. Yang JC, Haworth L, Sherry RM et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003; 349 (5): 427–434. 5. Johnson DH, Fehrenbacher L, Novotny WF et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-smallcell lung cancer. J Clin Oncol 2004; 22 (11): 2184–2191. 6. Miller KD, Chap LI, Holmes FA et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005; 23 (4): 792–799. 7. Kindler HL, Friberg G, Singh DA et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 2005; 23 (31): 8033–8040. 8. de Gramont A, Van Cutsem E. Investigating the potential of bevacizumab in other indications: metastatic renal cell, non-small cell lung, pancreatic and breast cancer. Oncology 2005; 69 (Suppl 3): 46–56. 9. Keck PJ, Hauser SD, Krivi G et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 1989; 246 (4935): 1309–1312. 10. Leung DW, Cachianes G, Kuang WJ et al. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989; 246 (4935): 1306–1309. 11. Gordon MS, Cunningham D. Managing patients treated with bevacizumab combination therapy. Oncology 2005; 69 (Suppl 3): 25–33. 12. Lordick F, Geinitz H, Theisen J et al. Increased risk of ischemic bowel complications during treatment with bevacizumab after pelvic irradiation: report of three cases. Int J Radiat Oncol Biol Phys 2006; 64 (5): 1295–1298. 13. Hedrick E, Kozloff M, Hainsworth J et al. Safety of bevacizumab plus chemotherapy as first-line treatment of patients with metastatic colorectal cancer: updated results from a large observational registry in the US (BRiTE) [meeting abstracts]. J Clin Oncol 2006; 24 (18 Suppl): (Abstr 3536). 14. Kabbinavar FF, Schulz J, McCleod M et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 2005; 23 (16): 3697–3705. 15. Sugrue M, Kozloff M, Hainsworth J et al. Risk factors for gastrointestinal perforations in patients with metastatic colorectal cancer receiving bevacizumab plus chemotherapy [meeting abstracts]. J Clin Oncol 2006; 24 (18 Suppl): (Abstr 3535). 16. Levy MM, Fink MP, Marshall JC et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003; 31 (4): 1250–1256. 17. Chen HX, Mooney M, Boron M et al. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI Treatment Referral Center Trial TRC-0301. J Clin Oncol 2006; 24 (21): 3354–3360. 18. Crane CH, Ellis LM, Abbruzzese JL et al. Phase I trial evaluating the safety of bevacizumab with concurrent radiotherapy and capecitabine in locally advanced pancreatic cancer. J Clin Oncol 2006; 24 (7): 1145–1151. 19. Wright JD, Hagemann A, Rader JS et al. Bevacizumab combination therapy in recurrent, platinum-refractory, epithelial ovarian carcinoma: a retrospective analysis. Cancer 2006; 107 (1): 83–89. 20 Genentech Press-Release from 9/23/05 http://www.gene.com/gene/news/pressreleases/index.jsp2 January 2007, date last accessed). 21. Mularski RA, Sippel JM, Osborne ML. Pneumoperitoneum: a review of nonsurgical causes. Crit Care Med 2000; 28 (7): 2638–2644. 22. Scappaticci FA, Fehrenbacher L, Cartwright T et al. Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol 2005; 91 (3): 173–180. 23. Heinzerling JH, Huerta S. Bowel perforation from bevacizumab for the treatment of metastatic colon cancer: incidence, etiology, and management. Curr Surg 2006; 63 (5): 334–337.
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anastomotic leak in one. An enterocutaneous fistula was also described in a case report of a single patient undergoing transverse colectomy with primary anastomosis for a bevacizumab-associated perforation [23]. These findings, in addition to our finding of an anastomotic leak, support the growing belief that caution must be exercised when performing a primary anastomosis in a patient with a bevacizumabassociated perforation. We were unable to identify specific risk factors for bevacizumab-associated perforation. The identification of risk factors for bevacizumab-associated perforation will ultimately depend on the maturation of large clinical trials and observational studies. In addition, any disparity between our findings and those of other investigators could stem from a difference in the definition of bowel perforation. While we defined bowel perforation to include a spontaneous fistula, not all physicians might agree with this definition. Better comparison across studies will be possible when there is general agreement on this definition and on the approach to diagnosis. Another aspect that may limit the extent to which these findings can be compared with other centers is the off-label use of bevacizumab in many of our patients. Further reports from other institutions will be required to compare our results pertaining to specific histologic types. In summary, the low incidence of bevacizumab-associated bowel perforation in the present study appears to mirror that seen in earlier trials. Higher rates of perforation can be expected in patients with ovarian, pancreatic, or gastroesophageal cancer, but the number of patients treated with bevacizumab for these diseases is small, and further studies and/or registries may help to better define the true incidence of bowel perforation in these diseases. Nonetheless, this serious adverse event can be managed successfully in selected patients without surgical intervention.
Annals of Oncology
Annals of Oncology 19: 577–582, 2008 doi:10.1093/annonc/mdm508 Published online 16 November 2007
Management of bevacizumab-associated bowel perforation: a case series and review of the literature B. D. Badgwell1, E. R. Camp1, B. Feig1, R. A. Wolff2, C. Eng2, L. M. Ellis1,3 & J. N. Cormier1* 1
Department of Surgical Oncology; 2Department of Medical Oncology; 3Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
Received 27 July 2007; revised 26 September 2007; accepted 1 October 2007
bevacizumab over a 2-year period (January 2004 to October 2006). Medical records of these patients were examined for reports of confirmed bowel perforation or fistula, associated clinicopathological factors, treatment, and outcomes. Results: We identified 1442 patients who had been treated with bevacizumab over the study period with perforation occurring in 24 (1.7%). The breakdown of these 24 patients by disease site was as follows: ovarian (3 of 50, 6%), gastroesophageal (2 of 38, 5.3%), pancreatic (7 of 141, 5%), unknown primary (1 of 60, 1.7%), lung (1 of 67, 1.5%), colorectal (6 of 478, 1.3%), and renal cell (4 of 269, 1.5%). The majority of patients (n = 19, 79%) were initially managed nonoperatively. Only five (21%) patients ultimately underwent surgical exploration, with a subsequent anastomotic leak developing in one patient. The overall 30-day mortality rate was 12.5%. Conclusions: Bevacizumab-associated bowel perforation occurs in patients with various malignancies, with an incidence of 1.7%. Nonoperative treatment is a viable approach to management in selected patients. Key words: avastin, bevacizumab, complication, GI perforation, toxicity
introduction Targeting vascular endothelial growth factor (VEGF) and its receptors has been shown to be efficacious in a number of disease types either as a single agent or in combination with chemotherapy. The efficacy of bevacizumab, a humanized mAb to VEGF (Avastin; Genentech, San Francisco, CA), when used in combination with chemotherapy has been demonstrated in several prospective, randomized phase III studies [1–3]. For example, in a phase III trial in patients with metastatic colon cancer, bevacizumab in combination with standard chemotherapy was found to increase overall and progressionfree survival and response rates when compared with chemotherapy plus placebo [1]. Because of this and the results from other trials, bevacizumab has become widely used for the treatment of colorectal cancer and non-small-cell lung cancer and is being studied as part of the treatment regimen in a wide range of malignancies [4–8]. Bevacizumab has now become part of the armamentarium of targeted therapies for cancer [9, 10]. Bevacizumab is generally well tolerated and has an acceptable toxicity profile consisting primarily of hypertension and proteinuria. Other rare but important adverse effects, however, *Correspondence to: Dr J. N. Cormier, Department of Surgical Oncology, Unit 444, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Tel: +1-713-792-6949; Fax: +1-713-745-1921; E-mail: [email protected]
include delayed wound healing, arterial thrombosis, and bleeding [11]. Another potentially serious adverse effect of bevacizumab is gastrointestinal (GI) perforation [12]. GI perforation was found to be an uncommon but welldocumented side-effect of treatment in the phase III trials of bevacizumab, as well as in subsequent surveillance trials, with a reported incidence of 1% to 2% [1, 2, 4, 13, 14]. Although infrequent, this potentially life-threatening complication has generated significant clinical interest, including a follow-up analysis that examined potential risk factors as well as associated findings in patients with GI perforation [15]. It is not clear from the current body of literature, however, how these patients, many of whom have advanced malignancies, should be managed. The purpose of this study was to assess the presentation, management, and outcome of patients presenting with bevacizumab-associated bowel perforation.
patients and methods Patients were identified from the pharmaceutical database at The University of Texas M. D. Anderson Cancer Center by querying for all patients who had received bevacizumab from January 2004 through October 2006. Medical records for all identified patients were reviewed, and tumor histology findings were obtained from our institutional tumor registry. Since the half-life of bevacizumab is 20 days, we sought to identify patients with bowel perforation occurring within 7 weeks of their last
ª The Author 2007. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please e-mail: [email protected]
original article
outcomes in patients with bevacizumab-associated bowel perforation at a tertiary cancer center.
Patients and methods: Our institutional pharmacy database was searched to identify all patients who had received
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Background: This study examined the various approaches to the management of perforation and the associated
original article treatment. For those patients who had undergone recent surgery, bevacizumab was not started until 4 weeks postoperatively. We defined bowel perforation as the finding of i.p. air and/or GI/enterocutaneous fistula that was confirmed by computed tomography (CT) imaging of the abdomen/pelvis. The study was approved by the Institutional Review Board at our institution.
patient demographics and presentation
management and outcome The treatment strategy for bevacizumab-associated perforation was categorized as either surgical or nonoperative management. Nonoperative management included the placement of a percutaneous intra-abdominal catheter. For those managed surgically, the operative records were reviewed to determine the intra-operative findings, including the type of operation carried out and the need for a stoma. Outcome data included treatmentassociated complications as well as postperforation 30- and 60-day mortality. Survival was defined as the time from the diagnosis of perforation to death. Probabilities for overall survival were determined using the method of Kaplan and Meier [17]. Computations were carried out using NCSS software (version 2004; NCSS Institute, Kaysville, UT).
results patient demographics and presentation Of the 1442 patients treated with bevacizumab at our institution from January 2004 through October 2006, 24 patients (1.7%) were identified as having evidence of posttreatment bowel perforation. Nineteen patients displayed i.p. air with or without fistula formation, while five patients were found to have a GI/enterocutaneous fistula only. Perforation rates by disease site were as follows: ovarian carcinoma (3 of 50, 6%), pancreatic carcinoma (7 of 141, 5%), gastroesophageal carcinoma (2 of 38, 5.3%), unknown primary (1 of 60, 1.7%), colorectal carcinoma (6 of 478, 1.3%), lung carcinoma (1 of 67, 1.5%), and renal cell carcinoma (4 of 269, 1.5%). The remaining 339 patients, who had a variety of malignancies, had no evidence of perforation.
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Clinicopathological factors including bevacizumab-related risk factors in the patients who experienced perforation are summarized in Table 1. The tumors most commonly associated with perforation were pancreatic (n = 7), colorectal (n = 6), renal cell (n = 4), and ovarian (n = 3) carcinomas. Seventy-one percent of patients (n = 17) had distant metastatic (stage IV) disease. The single patient with stage II disease had colorectal cancer and was receiving bevacizumab in the adjuvant setting for lymphovascular invasion. Bowel perforation occurred at a median of 71 days (range 3–512 days) after the initiation of therapy and 14 days (range 2–49) after the last dose of bevacizumab. Twenty-three patients (96%) were receiving concomitant systemic chemotherapy. The most common regimens include capecitabine (n = 8), FOLFOX/FOLFIRI (n = 5), gemcitabine (n = 4), and paclitaxel/docetaxel (with or without carboplatin, n = 4). Twenty-two patients had at least one potential baseline risk factor for perforation on the basis of the findings from a recent, large observational study of patients with colorectal cancer receiving bevacizumab [15]. In particular, 11 patients (46%) had an intact primary tumor while undergoing bevacizumab treatment; nine patients had undergone abdominal
Table 1. Clinicopathological factors in patients with bevacizumabassociated bowel perforation Variable
Patients (N = 24)
Days from bevacizumab initiation to perforation, median (range) Days from last bevacizumab infusion to perforation, median (range) Baseline risk factors Intact primary Abdominal irradiation NSAID use Diverticulosis Recent endoscopy Disease site Pancreatic Colorectal Renal cell Ovarian Gastroesophageal Lung Unknown primary Stage I II III IV Associated findings Tumor at perforation site Gastrointestinal obstruction Abscess/fluid at perforation site Carcinomatosis Diverticulitis Perforation at anastomotic site
71 (3–512)
%
14 (2–49)
11 9 7 7 3
46 38 29 29 13
7 6 4 3 2 1 1
29 25 17 13 8 4 4
0 1 6 17
4 25 71
9 4 16 8 2 4
38 17 67 33 8 17
NSAID, nonsteroidal anti-inflammatory drug.
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Clinicopathological factors collected for patients with confirmed bevacizumab-associated perforation included tumor stage, the treatment rendered, and bevacizumab-related factors (i.e. treatment start date, duration, date of last administration, and if treatment was resumed after management of perforation). Also collected were data pertaining to potential baseline risk factors for bevacizumab-associated perforation [1, 15], such as intact primary tumor, endoscopy carried out within 1 month before initiating treatment, prior adjuvant radiotherapy, long-term nonsteroidal anti-inflammatory drug (NSAID) therapy (‡1 month of use), peptic ulcer disease, diverticulosis, and previous surgery. Patient records were also reviewed for information on the symptoms and signs at the time of bevacizumab-associated perforation. Due to the inherent limitation in documented symptoms on retrospective analysis, we limited symptom evaluation to the presence or absence of abdominal pain and nausea/emesis. Fever was defined as a temperature ‡38.0C, tachycardia as pulse ‡110 beats per minute, and hypotension as a systolic blood pressure <90 mmHg or blood pressure requiring vasopressor support. Patients were evaluated for the presence of sepsis according to the guidelines formulated at the 2001 International Sepsis Definitions Conference [16]. Leukocytosis and leukopenia were defined by a white blood cell count of ‡11 000 and <4000 per U/l, respectively. Neutropenia was defined as an absolute neutrophil count of <500 per U/l.
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failed nonoperative treatment consisting of drainage and antibiotics for a perforated diverticulitis with abscess formation. This patient ultimately developed a fistula and abscess that extended to the lower abdominal wall. Colon resection, colostomy placement, and abdominal wall debridement were required to manage this case. The remaining 19 patients did not undergo any surgical intervention within 60 days of diagnosis. Four patients (1–4) were treated with immediate surgical exploration. Two of these patients had a perforated appendicitis, with one undergoing appendectomy and the other an ileocecectomy for an associated gangrenous-appearing cecum. The latter patient subsequently developed a postoperative leak from the bowel anastomosis requiring a second operation that included a completion right colectomy with end ileostomy. This patient’s postoperative course was further complicated after discharge by the development of a right lower quadrant abscess that required readmission and by dehydration with renal failure that required another readmission. Patient 3, who developed a perforation at the site of a primary tumor at the gastroesophageal junction, underwent a gastrectomy with cervical esophagostomy that was accompanied by minimal postoperative complications including a symptomatic pleural effusion requiring thoracentesis. The fourth patient developed a perforation in the setting of ovarian carcinomatosis requiring a diverting loop jejunostomy. The 30-day postperforation mortality rate was 12.5% (n = 3/24), and the 60-day mortality rate was 25% (n = 6/24) in this patient cohort. None of the patients undergoing surgical treatment died within 60 days of the diagnosis of perforation. All three patients who died within 30 days were treated nonoperatively and were not surgical candidates because of advanced carcinomatosis. Three additional deaths occurred in the nonoperatively managed patients from 30 to 60 days after the diagnosis. These deaths, however, were not directly attributable to perforation as all patients were in stable condition without signs of infection or sepsis and were discharged to hospice care. With a median follow-up of 3.8 months, the median overall survival time after bevacizumabassociated perforation was 12.5 months (Figure 1). Four patients were able to resume bevacizumab therapy at a median of 51 days (range 35–135 days) after the management of their perforation.
discussion The overall incidence of bevacizumab-associated GI perforation in patients in our study cohort was 1.7%, but the incidence varied among malignancies, with pancreatic, ovarian, and gastroesophageal carcinoma associated with the highest percentage of bowel perforations. It is important to recognize that the number of patients in certain diseases, however, was small. Interestingly, colorectal cancer was associated with one of the lower incidences of perforation at 1.3%. The median time to perforation after the initiation of bevacizumab treatment was 71 days. The presenting signs and symptoms of these patients are fairly typical of patients with intra-abdominal inflammation, although three patients were asymptomatic at
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radiotherapy; seven patients were regular NSAID users; seven patients had diverticulosis confirmed by colonoscopy and CT imaging; and three patients had undergone either upper or lower endoscopy within 1 month before starting treatment, but none of the patients in our cohort had a history of peptic ulcer disease. At the time of the diagnosis of perforation, tumor was present at the site of perforation in nine patients, and eight patients had carcinomatosis. Four patients presented with GI obstruction, and two patients were diagnosed with diverticulitis. Seven patients had clear radiographic signs of an abscess, and an additional nine patients had fluid present at the site of perforation that did not meet the radiographic criteria for abscess. Four patients developed a perforation at the site of a previous surgical anastomosis. In one patient, the site was at a prior gastrojejunostomy that had been carried out during a pancreaticoduodenectomy 1.5 years prior. In the second patient, the perforation site involved an ileocolonic anastomosis from a right hemicolectomy performed 6 months prior. A presacral fistula developed 3 months following a low anterior resection in a third patient, and an anastomotic leak developed in a fourth patient 4 months after esophagectomy. The clinical findings at the time of presentation of bevacizumab-associated perforation included abdominal pain in 20 patients (83%) and nausea or emesis in seven patients (29%). Physical examination demonstrated fever in six patients (25%), while abdominal tenderness was documented in 18 patients (75%). Twelve patients (50%) demonstrated leukocytosis, and only one patient (4%) presented with leukopenia and neutropenia. Four patients (17%) presented with tachycardia, and only one patient (4%) presented with signs of sepsis which included mental status changes, fever, tachycardia >120 beats per minute, and leukocytosis. Three patients (12.5%) were asymptomatic and were determined to have perforation at the time of surveillance imaging, and one patient (4%) presented with increasing abdominal distention. Twenty-two patients had CT findings indicating perforation, one patient required a fistulogram in addition to a CT scan to confirm perforation, and one patient died shortly after presentation, with perforation confirmed on autopsy. Perforation was identified by radiography in the remaining two patients. Six patients initially underwent plain abdominal radiography, and 23 patients ultimately underwent CT during the initial evaluation. The clinical details, including the perforation site, treatment rendered, morbidities, and outcomes for the 24 patients with bevacizumab-associated perforation, are summarized in Table 2. Twenty patients initially underwent nonoperative treatment that included hospitalization in 14 patients; six were managed solely in the outpatient setting. Seven of the hospitalized patients underwent percutaneous i.p. catheter placement carried out by an interventional radiologist. There were no immediate complications, such as bleeding or adjacent organ injury, in the patients undergoing a drainage procedure. Inpatient treatment also consisted of i.v. antibiotics and a period of bowel rest. Total parenteral nutrition was administered in three patients, and two patients required a nasogastric tube to relieve obstructive symptoms. Of the patients initially managed nonoperatively, only one (patient 5)
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Annals of Oncology
Table 2. Management and outcome of patients with bowel perforation while on bevacizumab-containing regimens Patient no.
Perforation site
Management of perforation
Morbidity
Postperforation survival
1
Appendix
Ileocecectomy
Alive at 5 months after perforation
2 3
Appendix Gastroesophageal junction at site of primary tumor Unclear, unable to identify source in pelvis due to carcinomatosis Colonic diverticulitis
Appendectomy Gastrectomy, cervical esophagostomy Diverting loop jejunostomy, drain placement
Anastomotic leak requiring right colectomy and ileostomy on postoperative day 16, intraabdominal abscess, and admission for dehydration and renal failure None Symptomatic pleural effusion requiring thoracentesis None
4
6 7 8 9 10 11
Gastrojejunostomy after Whipple procedure Duodenum at site of primary tumor Small bowel, likely duodenum Colon at site of right hemicolectomy Unclear, likely small bowel Unclear, likely small bowel
Alive at 2.4 months after perforation
Failed nonoperative management and drainage, sigmoid colectomy and ostomy Nonoperative
Open wound with delayed healing
Alive at 5.6 months after perforation
None
Dead at 18 months after perforation
Nonoperative with percutaneous drain Nonoperative with drain Nonoperative
Drain developed into enterocutaneous fistula None None
Dead at 2.5 months after perforation
Nonoperative Nonoperative
Alive at 6.1 months after perforation Alive at 3.5 months after perforation
Dead at 1.2 months after perforation Alive at 5.5 months after perforation
Small bowel at site of tumor Duodeno-pancreatic fistula at site of tumor Rectal perforation at site of low anterior resection Unclear Small bowel
Nonoperative Nonoperative
None Requiring TPN and multiple courses of antibiotics None None
Nonoperative
None
Dead at 12 months after perforation
Nonoperative Nonoperative with drain
Death same day as diagnosis Alive at 6.5 months after perforation
17 18
Small bowel at site of tumor Colonic perforation adjacent to cholecystitis
Nonoperative Nonoperative with drain
19
Nonoperative Nonoperative with drain Nonoperative
None None
Dead at 19 days after perforation Alive at 4.6 months after perforation
Nonoperative
None
Dead at 1.3 months after perforation
23
Duodeno-pancreatic fistula at site of tumor Unclear Gastroesophageal at site of resection and healed anastomotic leak Rectal perforation at site of tumor Unclear
None Chronic enterocutaneous and enterovesicular fistula requiring TPN None Chronic chole-colonic fistula requiring right hemicolectomy 2.5 months after diagnosis None
Nonoperative
None
24
Colonic diverticulitis
Nonoperative with drain
Abscess
Dead at time of diagnosis, also found to have large saddle pulmonary embolus Alive at 3.1 months after perforation
12 13 14 15 16
20 21
22
Dead at 14 months after perforation Dead at 1.7 months after perforation
Alive at 3.2 months after perforation Alive at 13.5 months after perforation
Dead at 9 months after perforation
TPN, total parenteral nutrition.
presentation. The management of perforation in this cohort of patients was distinctly atypical, however, in that 19 patients were managed nonoperatively. This finding reflects the
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complex clinical decision making required in patients with advanced cancer, including the reluctance to operate in the setting of bevacizumab treatment. It also shows, however,
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5
Dead at 3.8 months after perforation Alive at 3.3 months after perforation
Annals of Oncology
that there can be a positive outcome from nonoperative treatment. Our findings are similar to those in the existing literature on bevacizumab-associated bowel perforation with respect to the incidence, associated findings, and possible risk factors. In one study, a phase III study conducted by Hurwitz et al. [1] that included 402 patients with metastatic colorectal cancer, a total of six patients (1.5%) developed bowel perforation. Of these, one patient died as a direct result of the perforation and the remaining five recovered, with three patients able to resume treatment. Although these authors identified colon surgery within 2 months as a risk factor, they also found a history of peptic ulcer disease and a partial (30% decrease in tumor size) or complete response (disappearance of tumor) to therapy as potential risk factors for perforation. The interval from surgical intervention to perforation in our study also tended to be longer than the 2-month interval noted in that study. In an observational study of 1960 patients with unresectable colorectal cancer receiving bevacizumab and first-line chemotherapy, Hedrick et al. [13] found that 33 (1.7%) experienced GI perforation, an incidence similar to the 1.3% observed in this patient group in our study and identical with the overall incidence we observed. Potential risk factors identified in that study consisted of an intact primary tumor, colonoscopy or sigmoidoscopy carried out within 1 month of starting bevacizumab therapy, and prior adjuvant radiotherapy, which were similar to the factors identified in our study [13]. Indeed, we noted that all our patients except two had at least one of the risk factors identified by Sugrue et al. [15]. The study of Sugrue et al., analyzing the same registry as Hedrick et al., also showed at least one of the following associated findings in 67% of the patients with GI perforation: tumor at the site of perforation, obstruction, intra-abdominal abscess, carcinomatosis, and acute diverticulitis, which were likewise similar to those observed in our study. In addition, in a case report series of patients treated with bevacizumab for colorectal, lung, renal cell, and unknown primary cancer, ischemic bowel complications were more frequent in patients with a history of pelvic irradiation [12]. Although this series consisted of only 33 patients, three bowel complications (two
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episodes of ischemic colitis and one episode of perforation) occurred in the three patients who had received infradiaphragmatic irradiation but in none of the 30 remaining patients who had not undergone irradiation. As in our study, a varying incidence of bevacizumabassociated GI perforation has also been observed in patients with malignancies other than colorectal cancer. For example, in a phase II study of the combination of bevacizumab and gemcitabine in patients with advanced pancreatic cancer, the incidence of visceral perforation was 8% (n = 4) [7]. These perforations included a Mallory–Weiss tear, a perforation following sigmoid stent placement, an unclear source of perforation that was the cause of patient death, and, similar to our study finding, a perforation at a gastrojejunostomy anastomosis. In a phase I trial of bevacizumab and capecitabine with radiotherapy in patients with pancreatic cancer done at our institution, 2 of 48 patients treated developed bowel perforation [18]. In a study of bevacizumab treatment in patients with recurrent, refractory ovarian cancer, bowel perforation occurred in 9% (n = 2) [19]. In addition, a phase II study of bevacizumab in patients with ovarian cancer resistant to platinum-based therapy was halted after 5 of 44 (11%) patients developed GI perforations [20]. We, too, observed bevacizumab-associated perforation in patients with cancer at various sites, with the highest incidence in patients with pancreatic, ovarian, and gastroesophageal cancers, a finding that was in agreement with these published findings. A potentially important contribution of the current study are the details regarding the clinical presentation, treatment, and outcomes of patients with bevacizumab-associated perforation. In general, patients displayed the signs, symptoms, and leukocytosis frequently seen in patients presenting with a serious intra-abdominal process. Few patients, however, displayed tachycardia, hypotension, or sepsis, which may be the result of heightened awareness and the prompt recognition of complications in these high-risk patients. Another significant finding in our study was the success of the nonoperative management of bowel perforation in most patients, which conflicts with the traditional view that bowel perforation constitutes a surgical emergency [21]. This treatment strategy is the outgrowth of multidisciplinary discussions that include the medical oncologist, surgical oncologist, interventional radiologist, ancillary staff, family members, and the patient regarding the best palliative measures in the setting of incurable cancer. The success of this conservative approach to treatment is borne out by the fact that four of the patients in our study cohort who underwent nonoperative management were discharged to a hospice with resolution of their acute symptoms. While these patients ultimately died of tumor progression, they were spared the morbidity and potential mortality of a surgical procedure that might have hastened their demise. Another important concern to weigh when considering surgery in such patients is the increased likelihood of surgical complications in patients receiving bevacizumab treatment, as described in the literature. For example, Scappaticci et al. [22] reported a wound healing complication rate of 13% in 75 patients who underwent surgery during study treatment. Of 10 patients with complications, a fistula formed in two and an
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Figure 1. Overall survival following bevacizumab-associated bowel perforation.
original article
original article
acknowledgements We would like to thank Beth Notzen for editorial assistance, Debbie Dunaway for manuscript preparation, and Sarah Taylor for assistance with data acquisition from the tumor registry.
references 1. Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350 (23): 2335–2342. 2. Giantonio BJ, Catalano PJ, Meropol NJ et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol 2007; 25 (12): 1539–1544. 3. 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 (24): 2542–2550.
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4. Yang JC, Haworth L, Sherry RM et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003; 349 (5): 427–434. 5. Johnson DH, Fehrenbacher L, Novotny WF et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-smallcell lung cancer. J Clin Oncol 2004; 22 (11): 2184–2191. 6. Miller KD, Chap LI, Holmes FA et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005; 23 (4): 792–799. 7. Kindler HL, Friberg G, Singh DA et al. Phase II trial of bevacizumab plus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 2005; 23 (31): 8033–8040. 8. de Gramont A, Van Cutsem E. Investigating the potential of bevacizumab in other indications: metastatic renal cell, non-small cell lung, pancreatic and breast cancer. Oncology 2005; 69 (Suppl 3): 46–56. 9. Keck PJ, Hauser SD, Krivi G et al. Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 1989; 246 (4935): 1309–1312. 10. Leung DW, Cachianes G, Kuang WJ et al. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989; 246 (4935): 1306–1309. 11. Gordon MS, Cunningham D. Managing patients treated with bevacizumab combination therapy. Oncology 2005; 69 (Suppl 3): 25–33. 12. Lordick F, Geinitz H, Theisen J et al. Increased risk of ischemic bowel complications during treatment with bevacizumab after pelvic irradiation: report of three cases. Int J Radiat Oncol Biol Phys 2006; 64 (5): 1295–1298. 13. Hedrick E, Kozloff M, Hainsworth J et al. Safety of bevacizumab plus chemotherapy as first-line treatment of patients with metastatic colorectal cancer: updated results from a large observational registry in the US (BRiTE) [meeting abstracts]. J Clin Oncol 2006; 24 (18 Suppl): (Abstr 3536). 14. Kabbinavar FF, Schulz J, McCleod M et al. Addition of bevacizumab to bolus fluorouracil and leucovorin in first-line metastatic colorectal cancer: results of a randomized phase II trial. J Clin Oncol 2005; 23 (16): 3697–3705. 15. Sugrue M, Kozloff M, Hainsworth J et al. Risk factors for gastrointestinal perforations in patients with metastatic colorectal cancer receiving bevacizumab plus chemotherapy [meeting abstracts]. J Clin Oncol 2006; 24 (18 Suppl): (Abstr 3535). 16. Levy MM, Fink MP, Marshall JC et al. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003; 31 (4): 1250–1256. 17. Chen HX, Mooney M, Boron M et al. Phase II multicenter trial of bevacizumab plus fluorouracil and leucovorin in patients with advanced refractory colorectal cancer: an NCI Treatment Referral Center Trial TRC-0301. J Clin Oncol 2006; 24 (21): 3354–3360. 18. Crane CH, Ellis LM, Abbruzzese JL et al. Phase I trial evaluating the safety of bevacizumab with concurrent radiotherapy and capecitabine in locally advanced pancreatic cancer. J Clin Oncol 2006; 24 (7): 1145–1151. 19. Wright JD, Hagemann A, Rader JS et al. Bevacizumab combination therapy in recurrent, platinum-refractory, epithelial ovarian carcinoma: a retrospective analysis. Cancer 2006; 107 (1): 83–89. 20 Genentech Press-Release from 9/23/05 http://www.gene.com/gene/news/pressreleases/index.jsp2 January 2007, date last accessed). 21. Mularski RA, Sippel JM, Osborne ML. Pneumoperitoneum: a review of nonsurgical causes. Crit Care Med 2000; 28 (7): 2638–2644. 22. Scappaticci FA, Fehrenbacher L, Cartwright T et al. Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol 2005; 91 (3): 173–180. 23. Heinzerling JH, Huerta S. Bowel perforation from bevacizumab for the treatment of metastatic colon cancer: incidence, etiology, and management. Curr Surg 2006; 63 (5): 334–337.
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anastomotic leak in one. An enterocutaneous fistula was also described in a case report of a single patient undergoing transverse colectomy with primary anastomosis for a bevacizumab-associated perforation [23]. These findings, in addition to our finding of an anastomotic leak, support the growing belief that caution must be exercised when performing a primary anastomosis in a patient with a bevacizumabassociated perforation. We were unable to identify specific risk factors for bevacizumab-associated perforation. The identification of risk factors for bevacizumab-associated perforation will ultimately depend on the maturation of large clinical trials and observational studies. In addition, any disparity between our findings and those of other investigators could stem from a difference in the definition of bowel perforation. While we defined bowel perforation to include a spontaneous fistula, not all physicians might agree with this definition. Better comparison across studies will be possible when there is general agreement on this definition and on the approach to diagnosis. Another aspect that may limit the extent to which these findings can be compared with other centers is the off-label use of bevacizumab in many of our patients. Further reports from other institutions will be required to compare our results pertaining to specific histologic types. In summary, the low incidence of bevacizumab-associated bowel perforation in the present study appears to mirror that seen in earlier trials. Higher rates of perforation can be expected in patients with ovarian, pancreatic, or gastroesophageal cancer, but the number of patients treated with bevacizumab for these diseases is small, and further studies and/or registries may help to better define the true incidence of bowel perforation in these diseases. Nonetheless, this serious adverse event can be managed successfully in selected patients without surgical intervention.
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