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Gastrointestinal Perforation Due to Bevacizumab in Colorectal Cancer

Yale Cancer Center, Yale University School of Medicine, Divisions of Medical and Surgical Oncology, 333 Cedar Street, FMP 116, New Haven, Connecticut 06520, USA

Correspondence: Address correspondence and reprint requests to: Muhammad Wasif Saif, MD, MBBS; E-mail: wasif.saif{at}yale.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS GASTROINTESTINAL PERFORATION CONCLUSIONS REFERENCES

 
Bevacizumab is the first U.S. Food and Drug Association-approved vascular endothelial growth factor-targeted agent that greatly increases progression-free and overall survival in combination with standard chemotherapy regimens in patients with metastatic colorectal cancer. Although bevacizumab is generally well tolerated, some serious adverse events have occurred in some patients in clinical trials, including arterial thromboembolism and gastrointestinal (GI) perforation. GI perforation was first observed in the pivotal phase 3 trial, in which six events occurred in bevacizumab group (1.5%), compared with no events in the control group. Since then, similar rates of GI perforation have been observed in other large trials. Typical presentation was abdominal pain associated with constipation and vomiting. Such events occurred throughout treatment and were not correlated with duration of exposure. No difference in rate of GI perforations was found in patients who did and did not have a baseline history of peptic ulcer disease, diverticulosis, and history of chronic use of non-steroidal anti-inflammatory drugs. However, the incidence of GI perforation seemed to be higher in patients with primary tumor intact, recent history of sigmoidoscopy or colonoscopy, or previous adjuvant radiotherapy, but it is necessary to confirm these preliminary findings by multivariate analyses. The mechanism responsible for causing GI perforation is not known and may be multifactorial. Bevacizumab should be permanently discontinued in patients who develop GI perforation. This article reviews the incidence, presentation, pathogenesis, risk factors, and management of GI perforation in patients with colorectal cancer who are treated with bevacizumab.

Key Words: Bevacizumab • Colorectal cancer • Gastrointestinal perforation

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS GASTROINTESTINAL PERFORATION CONCLUSIONS REFERENCES

 
Excluding skin cancers, colorectal cancer (CRC) is the third most common malignancy in the United States. After lung cancer, it is the second leading cause of cancer death in both men and women in the United States.¹ The American Cancer Society estimates that 146,940 new cases of CRC will be diagnosed in the United States in 2006, eventually resulting in 56,730 deaths.¹ Chemotherapy is used palliatively in patients with stage 4 and recurrent CRC. Regimens combining fluorouracil (5-FU) and leucovorin (LV) with irinotecan (FOLFIRI, IFL) or oxaliplatin (FOLFOX4, FOLFOX6) are considered to be standard. Novel targeted agents such as inhibitors of vascular endothelial growth factor (VEGF) and epidermal growth factor receptor are also increasingly combined with these regimens. The National Comprehensive Cancer Network has recently recommended bevacizumab, a monoclonal antibody against VEGF, in combination with 5-FU–based regimens as the standard of care for first-line treatment of metastatic CRC (mCRC).²

The growth and metastasis of tumors requires the development of new blood vessels; the tumor vasculature is thus a good target for therapy. VEGF, a potent angiogenic factor, is overexpressed in many human tumors, and its overexpression is associated with tumor progression and poor prognosis;³ inhibition of VEGF therefore represents a promising therapeutic approach.^4–6 Therapies that inhibit the VEGF pathway have been shown in preclinical models to slow tumor growth,⁷ with enhanced activity being observed when these therapies are combined with chemotherapy⁸ or radiotherapy.⁹

Bevacizumab is a recombinant, humanized monoclonal antibody that binds to VEGF with high specificity and affnity, inhibiting binding of VEGF to its receptors and attenuating downstream signaling events in the VEGF pathway.¹⁰ In the pivotal phase 3 trial, patients with mCRC receiving bevacizumab plus IFL chemotherapy experienced statistically significant improvements in median overall survival (20.3 vs. 15.3 months, P < .001), median progression-free survival (10.6 vs. 6.2 months, P < .001), and rate of objective tumor response (45% vs. 35%, P = .004) relative to patients receiving IFL alone.¹¹

	METHODS

TOP ABSTRACT INTRODUCTION METHODS GASTROINTESTINAL PERFORATION CONCLUSIONS REFERENCES

 
The major trials to date evaluating bevacizumab in patients with mCRC are listed in Table 1. These include the phase 3 trial of IFL with or without bevacizumab¹¹; a randomized phase 2 study comparing 5-FU–LV with and without bevacizumab in patients who were not candidates for first-line irinotecan;¹² the phase 2 TREE-2 study, which evaluated bevacizumab in combination with oxaliplatin-containing regimens as first-line treatment;¹³ the Eastern Cooperative Oncology Group (ECOG) 3200 phase 3 study, which compared FOLFOX4, FOLFOX4 plus bevacizumab, and bevacizumab alone as second-line therapy in patients with recurrent advanced-stage CRC;¹⁴ and the phase 2 BOND-2 trial evaluating bevacizumab and cetuximab with or without irinotecan.¹⁵ In addition, two community-based observational studies—the BRiTE study^16–18 and the First BEATrial^19,20—continue to provide new data on the safety of bevacizumab in large, community-based patient populations.

However, subsequent studies showed that there is an increase in arterial thromboembolic events (total incidence, 0%–3%), but there is no increase in venous thromboembolic events when bevacizumab is added to treatment. The rate of hypertension in bevacizumab-containing regimens ranges from 0% to 18%, but most hypertension observed has been grade 3 and has been readily managed with antihypertensive medication. These events do not overlap with chemotherapy-associated events and therefore do not preclude the concomitant use of bevacizumab and chemotherapy. In addition bevacizumab-related toxicities do not seem to overlap with those of cetuximab,¹⁵ suggesting that combining bevacizumab with targeted therapies will not present new safety concerns.

GI perforation is a serious adverse event that in rare cases has resulted in death. Thus, the early identification of and treatment of GI perforation is important in the safe use of bevacizumab. This article reviews the incidence, presentation, pathogenesis, risk factors, and management of GI perforations in patients with CRC who are treated with bevacizumab.

	GASTROINTESTINAL PERFORATION

TOP ABSTRACT INTRODUCTION METHODS GASTROINTESTINAL PERFORATION CONCLUSIONS REFERENCES

 
CRC generally presents with nonspecific signs and symptoms, the most common complaint being abdominal pain that may itself follow a wide variety of patterns, both localized and generalized.²³ Colicky pain may arise from a lesion that causes partial obstruction. Localized pain may indicate a localized perforation, and generalized pain may suggest peritonitis associated with a perforation. Perforations and partial or complete bowel obstructions are not uncommon presenting features of CRC.²³

The incidence of GI perforation in the setting of workup and evaluation for CRC is 1.96 per 1000 procedures for colonoscopy and .88 for sigmoidoscopy.²⁴ Perforation from either procedure occurs more frequently in older patients and in patients with comorbidities. Among patients with resected primary tumors, these procedures reveal peritonitis in 2.4% of patients (95% confidence interval [95% CI], .3–8.5), fistula formation in 3.7% (95% CI, .8–10.3), and intestinal hemorrhage in 3.7% (95% CI, .8–10.3). These values do not differ greatly from those in patients in whom the primary tumor was not resected.²⁴

Major studies evaluating bevacizumab in combination with 5-FU–based regimens such as IFL, 5-FU–LV, and FOLFOX have revealed GI perforation rates of 0% to 3.3% (Table 2),^11–14,21 which are roughly similar to historical rates seen in mCRC patients receiving chemotherapy alone (GI perforation, abscess, or fistula in 2%–5% of patients). The reasons for increased rates of GI perforation in patients with CRC are not clear. Aside from ovarian carcinoma, these complications are not as commonly seen in other tumor types; they may therefore arise from the use of GI-toxic regimens in the treatment of CRC, which, by causing more diarrhea, bowel inflammation, and inflammatory wound-healing responses, may predispose CRC patients to GI perforation.

The pivotal phase 3 trial by Hurwitz and colleagues¹¹ randomized 813 chemotherapy-naive patients with mCRC to IFL plus placebo or to IFL plus bevacizumab. Patients receiving bevacizumab exhibited a longer duration of therapy (40.4 weeks vs. 27.6 weeks), longer overall survival (20.3 vs. 15.6 months; P < .001), and longer progression-free survival (10.6 vs. 6.2 months; P < .001).¹¹ Although no GI perforations were observed in patients receiving IFL alone, as shown in Table 2, six such events occurred in patients receiving IFL plus bevacizumab (1.5%).¹¹ Of these six patients, one died, two recovered but discontinued therapy, and three recovered and resumed treatment with IFL plus bevacizumab. Among these six patients, three confirmed complete or partial responses were observed.

A phase 2 study randomized 209 patients who were not candidates for first-line irinotecan (because of inability to tolerate intensive chemotherapy) to 5-FU–LV plus bevacizumab or 5-FU–LV plus placebo.¹² The authors observed a trend toward longer median overall survival (16.6 vs. 12.9 months) and statistically significantly longer progression-free survival (9.2 vs. 5.5 months; P = .0002) among patients treated with bevacizumab plus 5-FU–LV, as well as a trend toward a higher response rate (26% vs. 15%). Two patients in the 5-FU–LV plus bevacizumab group experienced GI perforation (1.9%), compared with none in the 5-FU–LV plus placebo group (Table 2). Both patients had intact primary tumors. The first GI perforation was diagnosed on day 110 of treatment; the patient recovered but discontinued the study. The other perforation was diagnosed on day 338 of treatment; the patient died as a result.¹²

The TREE-2 trial, the first to use bevacizumab with oxaliplatin-based regimens in a first-line setting, randomized 213 patients to one of three treatments: bevacizumab plus modified FOLFOX6, bevacizumab plus bolus 5-FU with oxaliplatin (bFOL), or bevacizumab plus capecitabine and oxaliplatin (CAPOX).¹³ The authors observed an overall confirmed response rate of 53% for patients treated with FOLFOX, 41% for patients treated with bFOL, and 48% for patients treated with CAPOX. The median overall survival across all groups was an unprecedented 24.4 months. Time to tumor progression was 9.9 months for patients treated with FOLFOX, 8.3 months for patients treated with bFOL, and 10.3 months for patients treated with CAPOX. GI perforations occurred in 3 (4.2%) of 71 patients treated with FOLFOX plus bevacizumab, in 2 (2.9%) of 70 patients treated with bFOL, and in 2 (2.8%) of 72 patients treated with CAPOX, for an overall incidence of 3.3% (Table 2).

The phase 3 ECOG E3200 trial evaluated a higher dose of bevacizumab than that used in most other studies—10 mg/kg rather than 5 mg/kg every 2 weeks—in patients with mCRC whose disease had progressed on first-line therapy.¹⁴ A total of 828 patients were randomized to FOLFOX4, FOLFOX4 plus bevacizumab 10 mg/kg every 2 weeks, or bevacizumab monotherapy at the same dose. Accrual to the bevacizumab monotherapy arm was discontinued after an interim analysis showed less clinical activity than for FOLFOX4 alone. Treatment with FOL-FOX4 plus bevacizumab statistically significantly improved median overall survival (12.5 vs. 10.7 months; P = .0024) and median progression-free survival (7.4 vs. 5.5 months; P = .0003) versus FOLFOX4 alone. Despite the higher dose of bevacizumab used in this study, GI perforation occurred at a relatively low rate of 1% in the FOLFOX plus bevacizumab arm, 0% in the FOLFOX arm, and 1.3% of the bevacizumab monotherapy arm (Table 2).¹⁴

The First BEATrial recently provided a preliminary analysis of bevacizumab safety in a large community population.¹⁹ In this study, patients are eligible if they have mCRC and are chemotherapy naive. The choice of chemotherapy to combine with bevacizumab is determined by the treating physician. Patients are treated to progression and are seen every 3 months as well as 30 days after their last bevacizumab treatment. Up to 2000 patients will be enrolled onto the study. In a preliminary analysis of 1603 patients (94% of whom had been followed for >60 days), 24 GI perforations (1.5%) occurred (Table 2). An analysis of GI perforation by primary tumor resection status suggested that an intact primary tumor may be a risk factor for GI perforation. Of the 1373 patients with resected primary tumors whose data were available, 1.2% had GI perforation. Of the 223 patients with their primary tumor intact, 3.6% of patients had a GI perforation. Associated clinicopathologic findings in the eight patients with intact primary tumors who experienced GI perforation were tumor at the site of GI perforation (n = 3), GI obstruction (n = 2), abdominal carcinomatosis (n = 2), and history of abdominal pelvic radiation (n = 1). Not all patients had an associated finding, and some patients had more than one associated finding.

Most recently, preliminary data from the community-based BRiTE study were presented at the 2006 American Society for Clinical Oncology meeting.^16–18 These data provide the most detailed analysis to date of GI perforation with bevacizumab-containing therapy. In this study, patients with mCRC being treated in the first-line setting are eligible. The bevacizumab dose, bevacizumab schedule, and chemotherapy are determined by the physician. Observational data are collected quarterly, and patients will be followed for up to 3 years. To date, 1960 patients have been followed for up to 3 years (median, 12.9 months). The most frequently used therapies include FOLFOX (56%), FOLFIRI (14.3%), IFL (9.7%), and bolus 5-FU–LV (6.8%), all in combination with bevacizumab (5 mg/kg every 2 weeks in 95% of patients).¹⁷

To date, 33 patients (1.7%) have experienced GI perforations,¹⁸ a rate similar to that seen in randomized clinical trials in more selected patient populations.^11,12,14 GI perforations occurred early in treatment, with most occurring within the first 6 months of treatment (52% in the first 3 months and an additional 27% in the next 3 months). To determine potential risk factors for GI perforation, the relationship of baseline medical characteristics to the incidence of GI perforation was assessed. Patients with primary tumor intact (3.3% vs. 1.4%), recent history of sigmoidoscopy or colonoscopy (2.6% vs. 1.5%), or previous adjuvant radiotherapy (2.3% vs. 1.6%) seemed to have a slightly higher incidence of GI perforation. Patients with chronic aspirin or use of nonsteroidal anti-inflammatory drugs (0% vs. 1.7%), history of peptic ulcer disease (1.8% vs. 1.7%), or diverticulosis (1.8% vs. 1.7%) do not seem to be at higher risk for GI perforation. However, multivariate analyses are necessary to validate these findings. Sixty-seven percent of patients with GI perforation exhibited at least one clinicopathologic finding on surgery, the most common being tumor at site of perforation (33%) and GI obstruction (18%).¹⁸

Differential Diagnosis
Although abdominal pain commonly occurs from a variety of causes, particularly in patients with CRC, acute and severe pain nearly always accompanies intra-abdominal disease, and this pain may be the sole indicator of the need for urgent surgery.^23,25 The decision of whether or not surgery is indicated must occur quickly, before possible harmful sequelae occur. For example, gangrene and perforation of the gut can occur within as little as 6 hours after interruption of the intestinal blood supply from an obstruction or arterial embolus. In contrast, initial therapy for chronic abdominal pain almost never requires surgery.²⁵

For purposes of differentiating the two situations, the following conditions generally require surgery: perforated or obstructing diverticulum, postoperative perforated anastomosis, volvulus (cecal, sigmoidal), primary malignancy, intussusception, colonic obstruction, adhesions, abscess, peritonitis or hemoperitoneum from unknown cause, fissure, and fistula. Nonsurgical (i.e., medical) therapy can generally be used to manage abdominal pain that arises from ulcerative colitis, Crohn disease, primary peritonitis, hemoperitoneum resulting from therapy with anticoagulants, burning pain (except for peptic ulcer), diverticulitis (mild), fecal impaction, functional colonic pain, motility disturbances, diarrhea, constipation, or ileus.²⁵

Diagnosis and Workup
Because of the time-sensitive nature of the potential disease process, therapy and diagnosis of severe abdominal pain should occur concurrently. A thorough history and physical examination in addition to select laboratory and imaging studies often establishes the cause.²⁵

In patients with CRC, there is the potential for life-threatening GI perforation events in the setting of extensive tumor burden or recent treatment (surgery or chemotherapy). As outlined in Table 3, evaluation of abdominal pain in patients with CRC should focus on key elements of history, symptoms, and presentation to differentiate between the various causes.²⁵

Diagnostic tests should include blood and urine panels for evidence of blood loss. Measurement of D(–)-lactate may be particularly important in diagnosing mesenteric ischemia. One prospective study of 31 patients undergoing laparotomy for abdominal emergencies revealed far higher serum D(–)-lactate levels in patients with mesenteric ischemia (32.4 µg/mL) compared with patients with other forms of acute abdomen (10.6 µg/mL), patients with bowel obstruction (10.7 µg/mL), and control patients with benign abdominal examinations (4.9 µg/mL).²⁶ The sensitivity was 90%, specificity was 87%, negative predictive value was 96%, and positive predictive value was 70%.²⁶

Imaging studies should be completed, including one or more of the following: x-rays of the chest and abdomen, including supine and upright views for free air under the diaphragm; intravenous urography; ultrasound; computed tomography; or arteriography.²⁵ The choice of imaging modality depends on the clinical suspicion for a particular pathologic process. An expeditious exploratory laparotomy may provide the most important diagnostic measure in patients with severe abdominal pain.²⁵

Ultimately, efforts to diagnose or rule out GI perforation must take into account that it represents a wide spectrum of severities and clinical manifestations, including asymptomatic events detected only through imaging, mild events managed medically through intravenous fluids, and life-threatening events requiring immediate surgical intervention (Table 4).

It is possible—particularly given the impact of VEGF inhibition on the capillary beds of small intestinal villi in animal models²⁹—that excessive VEGF inhibition contributes directly to GI perforation by inducing regression of normal blood vessels in the GI tract. This clinical question remains to be answered.

Risk Factors
In the pivotal phase 3 trial by Hurwitz and colleagues,¹¹ GI perforations occurred in 6 (1.5%) of 402 patients treated with bevacizumab. Five patients recovered from this adverse event, and three of them were able to subsequently continue therapy with bevacizumab plus IFL. In the phase 2 trial by Kabbinavar and colleagues,¹² both of the GI perforations involved a perforated diverticulum in the sigmoid colon (one patient died, and the other recovered and remained enrolled onto the study).

The common feature of these GI perforations was intra-abdominal inflammation due to gastric ulcer disease, tumor necrosis, diverticulitis, or chemotherapy-associated colitis.³¹ Consistent with this view, preliminary data from 1960 patients in the BRiTE registry showed that 67% of patients with GI perforation also exhibited one or more clinicopathologic findings such as a tumor at the site of perforation, GI obstruction, abdominal carcinomatosis, or acute diverticulitis (Table 5).¹⁸ However, a medical history of diverticulosis or of peptic ulcer disease did not seem to be associated with increased risk. In addition both the BRiTE study¹⁸ and the First BEATrial¹⁹ suggest that the incidence of GI perforation is higher in patient with their primary tumors intact.

Management of Surgical Patients Treated with Bevacizumab
Surgical patients considered here can be placed in one of two broad categories: those requiring emergent surgery and those eligible for elective surgical procedures.

Emergent Surgery
There seems to be no increase in the risk of wound-healing complications or subsequent GI perforation in patients who undergo major surgery at least 1 month before starting treatment with bevacizumab, or in patients who have healed sufficiently to be cleared by their surgeons. Many surgeries, however, occur emergently in the course of treatment for mCRC. Thus, it is of interest to determine the wound healing risks associated with surgery while receiving bevacizumab therapy. A recent analysis³³ of pooled data from randomized studies of bevacizumab in combination with chemotherapy for the first-line treatment of patients with mCRC^11,12 found that in patients undergoing surgery 28 to 60 days before study treatment (chemotherapy alone, n = 516; bevacizumab plus chemotherapy, n = 616), there was no marked increase in wound healing complications. Complications occurred in one patient in the chemotherapy arm and in three patients in the bevacizumab plus chemotherapy arm. There was, however, a marked increase in wound healing complications in patients undergoing surgery after initiating therapy with bevacizumab. One patient (3.4%) in the chemotherapy group (n = 29) and 10 patients (13.4%) in the bevacizumab plus chemotherapy group (n = 75) developed complications. The most frequent wound-healing complications were bowel perforation (n = 2) and abdominal fistula (n = 2). These risks should not deter surgical or interventional management when necessary, but in such cases, bevacizumab should be withheld, and patients should be closely observed for complications.

In this analysis of wound-healing complications,³³ the surgeries that occurred after initiation of bevacizumab-containing therapy were major abdominal surgeries. Recently an analysis of data from the First BEATrial³⁴ assessed whether minor surgery shortly before initiation of bevacizumab therapy was associated with increased risks of wound healing complications. In this study, patients who had a venous access device implanted within 7 days of initiating bevacizumab therapy (n = 182) were compared with patients who had had a venous access device implanted at any time during therapy (n = 534). The rates of wound healing complications (all grade 1) were low overall and were similar between patients who had had the device implanted within 7 days (.5%) and at anytime during therapy (1.1%). Although these data are preliminary, they suggest that bevacizumab therapy may not be associated with wound healing complications after minor surgical procedures.

Elective Surgery
The appropriate interval for withholding bevacizumab before elective surgery has not been established.³² However, determination of this interval should reflect the 20-day half-life of bevacizumab.³² Considering that wound-healing complications have occurred up to 56 days after termination of bevacizumab therapy,³² withholding the drug for 2 to 3 half-lives—approximately 40 to 60 days—may be optimal.

After Surgery
Bevacizumab should be withheld for 30 to 60 days after surgery, and the surgical wound should be completely healed before bevacizumab therapy is resumed.

In all instances, patients must be thoroughly informed of the risks as well as the signs and symptoms of GI complications in treatment with bevacizumab and surgery. Furthermore, clear communication with the surgical team and all other health care providers involved in the patient’s care, with recommendations for follow-up and monitoring, is essential.

	CONCLUSIONS

TOP ABSTRACT INTRODUCTION METHODS GASTROINTESTINAL PERFORATION CONCLUSIONS REFERENCES

 
Bevacizumab is the first VEGF-targeted agent shown to increase survival in patients receiving first-line chemotherapy for mCRC. As the use of bevacizumab expands into a wider range of patient populations, more information will be necessary to determine risk factors for serious complications. GI perforation, the most serious complication, occurs only rarely (1%–3% of patients); however, care must be exercised in the management of patients requiring surgery before, during, or after treatment with bevacizumab. Large, ongoing, community-based studies such as BRiTE and the First BEATrial will continue to clarify the safety profile in the coming years, particularly for rare events such as GI perforation. As VEGF-targeted agents such as bevacizumab become the standard of care for patients with mCRC and possibly other malignancies, the development of detailed guidelines for prevention and management of GI perforation will represent an important step forward. Education of patients, nurses, and other health care providers will also be important. Overall, however, the clear benefits of bevacizumab therapy are likely to outweigh the risks in most patients.

Received for publication October 1, 2006. Accepted for publication December 7, 2006.

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TOP ABSTRACT INTRODUCTION METHODS GASTROINTESTINAL PERFORATION CONCLUSIONS REFERENCES

 

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