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REVIEW

Bevacizumab-Induced Bowel Perforation


Sarunas Sliesoraitis, DO, PharmD
Bernard Tawfik, MD

Bevacizumab has shown efficacy in many different malig- In patients with pneumoperitoneum (a sign of bowel perfo-
nancies and is approved by the US Food and Drug Admin- ration in radiologic tests), mortality rates have been reported
istration for advanced colon and lung cancers. As beva- as high as 15%.4 In the present report, we review the current
cizumab use is expanding, the number of reports of serious knowledge regarding bowel perforation as an adverse effect
adverse effects from the drug are growing. Bowel perforation of bevacizumab, including mechanisms of perforation, risk
is a rare but often fatal event that leads the list of dangerous factors, presentation, and management.
adverse effects. It has been frequently reported in ovarian
cancer trials, with early closure of some trials because of the Mechanism of Perforation
high incidence of bowel perforation. Physicians should be Several mechanisms of action have been described to explain
familiar with not only the presentation of bowel perfora- the development of bowel perforation as a result of beva-
tion, but also with the risk factors, considerations for surgery, cizumab. In the first mechanism, the inhibition of VEGF by
and management of perforation in selected patient popula- bevacizumab could cause thrombosis of smaller splanchnic or
tions. The authors review the current knowledge on beva- mesenteric vessels, leading to bowel ischemia and ultimately
cizumab-induced bowel perforation. bowel perforation.5,6 Vascular endothelial growth factor is
J Am Osteopath Assoc. 2011;111(7):437-441 involved in cytoprotection, proliferation of endothelial cells, and
increased synthesis of nitric oxide and prostacyclin, as well as
tissue plasminogen activator and urokinase. It also induces
evacizumab is a monoclonal immunoglobulin G1 anti-
B body directed against vascular endothelial growth factor
(VEGF) that inhibits new blood vessel formation and growth.1
factor III, von Willebrand factor, and plasminogen activator
inhibitor, which are all important in clotting and thrombosis.7
Bevacizumab inhibits these factors when it inhibits VEGF,
Bevacizumab was initially approved in 2004 by the US Food which may lead to thrombosis or bleeding, depending on the
and Drug Administration (FDA) for use in metastatic colon delicate balance of these factors in an individual. Increased
cancer. Since then, it has also been approved by the European clot formation and vasoconstriction of the splanchnic vascu-
Medical Agency, and it is now FDA-approved for the man- lature could lead to bowel ischemia, which could in turn cause
agement of nonsmall cell lung cancer, renal cell carcinoma, bowel perforation.5
and recurrent glioblastoma, with several other indications The second possible mechanism is related to bowel
pending and under research.2 mucosa. Constant bowel wall proliferation and healing is
With increased use of bevacizumab, serious adverse effects dependent on microcirculation, protection with nitrous oxide,
are being reported more frequently, including hypertension, prostacyclin, and normal platelet function, all of which depend
proteinuria, hemorrhage, thrombosis, fistula formation, and on VEGF. Intestinal healing after damage such as surgery is also
bowel perforation.1,3 The reported incidence rate of bowel dependent on all of these processes. Even without prior
perforation has ranged from 0.3% to 2.4% in the clinical trials.2 damage, the intestinal mucosa could be susceptible to ulcers
and even perforation as a result of VEGF inhibition by beva-
cizumab, especially with the use of nonsteroidal anti-inflam-
matory drugs (NSAIDs).7 Decreased prostacyclin levels can
lead to decreased gastric protective secretions, which can cause
increased damage to the intestinal wall and ulcers.7
From Wake Forest University in Winston-Salem, North Carolina. The third possible mechanism involves the mucosal inva-
Financial Disclosures: None reported.
Address correspondence to Sarunas Sliesoraitis, DO, PharmD, Wake Forest
sion of tumor. Tumor structure may provide some stability to
Baptist Medical Center, Medical Center Boulevard, Winston-Salem, NC 27157- the intestinal wall itself, and tumor death creates an area of dis-
0001. ruption susceptible to perforation.5,6,8
E-mail: ssliesor@wfubmc.edu
Finally, the fourth possible mechanism, which has been
Submitted February 23, 2011; revision received March 15, 2011; accepted observed in animal models, is the regression of normal blood
March 28, 2011. vessels.9 When tissue is deprived of adequate blood supply,

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REVIEW

there is an increased possibility of cell damage, necrosis, and the potential to produce lesions that can lead to perforation.
perforation. Although NSAIDs and steroids have been associated with
peptic ulcer disease, whether the risk of peptic ulcers adds to
Risk Factors the risk off bowel perforation when combined with steroids or
Several risk factors for bowel perforation have been identi- NSAIDs remains to be assessed in future trials.
fied in clinical trials and case reports (Figure 1). Some of the most Certain types of cancer may also be risk factors for bowel
frequently reported established risks for perforation include his- perforation. Results of trials have reported bowel perforation
tory of bowel surgery, ulcers, and certain types of cancer. rates as high as 8% in patients being treated for pancreatic
Evidence has shown that peptic ulcers may be a clini- tumor20 and as high as 15.4% in patients being treated for
cally significant risk factor for perforation.15 Bevacizumab is ovarian primary tumors,6 compared with rates of less than
associated with ulcers through its inhibition of VEGF. In a 2.5% in other trials.15,2 The ORBIT trial,21 which sought to
Dutch Colorectal Cancer Group phase III study with 755 evaluate bevacizumab for ovarian cancer, was closed early
patients (oxaliplatin, capecitabine, and bevacizumab vs the after 5 of 44 treated patients developed bowel perforations. All
same regimen with the addition of cetuximab), Tol et al15 of the patients had platinum-resistant disease and bowel metas-
reported 12 patients who had bowel perforation and 4 patients tasis. In addition, it has been postulated that erlotinib, a drug
who had gastric ulcers and bowel perforation. The authors for the treatment of locally advanced or metastatic nonsmall
recommended using endoscopic evaluation to screen patients cell lung cancer, may interact with bevacizumab to cause per-
receiving bevacizumab for potential ulcers, as they may have foration.22 However, only 1 case of bowel perforation associ-
ated with both drugs has been reported in the medical litera-
Conditions ture.22 In that case report, nonsmall cell lung cancer had
Bowel obstruction5,10 metastasized to the bowel, which could have contributed to the
Chemotherapy-induced colitis10,11 weakening of the bowel wall.10 The stage of disease and
Diverticulitis10,12,13,14 number of prior chemotherapy treatments may be a factor in
Peptic ulcer disease10,13,15 perforation risk.18
Rectovaginal nodularity3 Surgery may also increase the risk of bowel perforation.
Tumor Several cases15 of reported perforation occurred years after
Intact primary tumor5,9,12,16 surgery and at the site of anastomosis, which may be because
Tumor necrosis10 of incompletely healed bowel. Other potential risk factors for
Transmural tumor17 bowel perforation, like the increased number of pretreatments
Cancer (ie, chemotherapy), have not shown a clear relationship.3 A
Abdominal carcinomatosis10 high rate of perforation occurred when bevacizumab was
Pancreatic primary cancer15 used after surgery in patients with pancreatic cancer.15
Ovarian primary cancer,6 especially with: With careful patient screening and selection, future trials
Bowel obstruction symptoms or small bowel may report lower rates of bevacizumab-associated bowel per-
obstruction17,18 foration.
Rectosigmoid involvement18
Bowel involvement on computed tomography scan17 Presentation and Diagnosis
Bowel wall thickening18 Badgwell et al12 reported the largest retrospective case series
Pretreatment with 3 or more regimens18 (N=24) to date on bevacizumab-associated bowel perforation
Platinum-resistant disease18 (Figure 2). Most patients (n=20) presented with abdominal
Treatments pain, 1 had sepsis, and 3 were asymptomatic but had perfo-
Abdominal irradiation9,10,12,14,16,19 rations detected during surveillance imaging. Six patients had
Bowel surgery12,15,20 initial plain abdominal radiographs, the results of which
Drugs showed intraperitoneal air and fistulas. Twenty-two bowel
NSAID9,15,20 perforations were diagnosed by means of computed tomog-
Steroids11,15 raphy (CT) scan, 1 was diagnosed by means of fistulogram, and
Erlotinib1 1 was diagnosed postmortem by means of autopsy (the patient
Sigmoidoscopy or colonoscopy,9,11,12,16 died quickly after initial presentation). Imaging results showed
19 patients had intraperitoneal air and 5 had a gastrointestinal
or enterocutaneous fistula only.12
Figure 1. Risk factors known or suspected to contribute to beva- Symptoms of bowel perforation, if present, are highly
cizumab-induced bowel perforation. Abbreviation: NSAID, nonsteroidal dependent on the site of involvement.15 Although 50% of
anti-inflammatory drug. bowel perforations that occur in patients with intact primary

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100
when steroids and NSAIDs are used
Presenting Sign or Symptom together, use of either a proton pump
inhibitor or a prostaglandin agonist
should be considered to prevent peptic
80 ulcer disease, which is an exacerbating
factor to perforation.
Another approach to prevention
involves careful consideration when
60
giving bevacizumab to patients who are
Patients, %

undergoing or have undergone elective


surgery. Current recommendations for
40
elective surgery include a 60-day wait
period after bevacizumab administra-
tion and a 30- to 60-day wait period to
restart bevacizumab therapy after
20 surgery.24 However, several cases of
reported perforation have occurred years
after surgery.10,26 Thus, even a 60-day
wait period may not be enough for some
0 s
ain es sis sis ve
r
rd
ia ion nia is* tic patients with slower healing. Ongoing
alp ern cyto eme Fe y ca ens ope eps oma
in nd ko r ch ist tr S t inflammation and granulation may occur
om al te Leu eao Ta a ld neu y mp
d s n ia / s for years after surgery and may carry a
Ab mi
n
Na
u
omi en
A
do d o p substantial risk for perforation.26
Ab Ab uk
Le Although the average reported beva-
cizumab half-life is 20 days, it can range
Figure 2. Presenting signs and symptoms of bowel perforation in 24 from 11 days to 50 days,2 making a 60-day wait period for
patients treated with bevacizumab.12 *Specific signs included mental elective surgery risky for some patients.9 Another considera-
status changes, fever, tachycardia (120 beats per minute), and tion is that clearance of bevacizumab has been reported to be
leukocytosis. 20% lower in women than in men.2 If at all possible, the wait
period for elective surgery should be at least 3 half-lives of
the drug (or until 87.5% of the drug is eliminated). In most
patients, this period would be about 60 hours (with a 20-hour
tumor involving the bowel will occur at the tumor site,15 any half-life), but in some patients it could be up to 150 days.2
part of the bowel can be involved. Pelvic pain may occur with Abdominal CT scans can be used to assess bowel healing
rectosigmoid colon perforation, while nausea, vomiting, and at a past resection or anastomosis site and to evaluate the pres-
obstipation may occur with bowel obstruction.23 Gastroin- ence of other potential risk factors such as rectovaginal nodu-
testinal complaints should be given careful consideration, as larity, bowel wall thickening, diverticulitis, bowel obstruc-
bowel perforations may be hard to diagnose. tion, and colitis.26 If the benefit of bevacizumab therapy is
In the Dutch Colorectal Cancer Group phase III study,15 relatively low in a patient with multiple risk factors or if inflam-
most cases (89%) of perforation occurred within 15 weeks mation of the bowel wall can be seen on results fro a CT scan,
after the start of bevacizumab treatment and anywhere prior then the risks of surgery may outweigh the benefits. Radiolo-
to the fifth cycle of chemotherapy. This period is when a physi- gists should be asked to focus on the anastomosis site and
cian must have the highest level of suspicion for perforation report any inflammatory changes present, otherwise smaller
and lowest threshold for ordering diagnostic imaging. A radio- important findings may be read as unremarkable. Future trials
graph of the kidneys, ureters, and bladder may show free should assess this approach in high-risk patients such as those
peritoneal air, but CT should be considered the diagnostic with ovarian and pancreatic cancer, and exclude or delay
study of choice because it may reveal pneumoperitoneum, enrollment of patients into bevacizumab protocols with incom-
small bowel loops caused by obstruction, or even pneumatosis pletely healed surgical sites.
intestinalis.24,25 Once bowel perforation does occur in patients receiving
bevacizumab, the perforation is managed conservatively or sur-
Treatment gically. The decision regarding treatment can be complicated
The best approach to bowel perforation in patients receiving because patients typically have a terminal illness and are
bevacizumab is surveillance and prevention. For example, taking a drug that causes poor wound healing and dysfunc-

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tional platelets. The mortality rate for patients with beva- therapy. Previous imaging studies may also be examined to
cizumab-induced bowel perforation has been reported as high identify risk factors, which could help exclude patients from
as 50%.7,12 For this reason, patients with multiple risk factors bevacizumab protocols if they are at increased risk for bowel
(eg, recent surgery, radiologic evidence of incompletely healed perforation. These steps should be taken in future clinical
bowel, presence of a pretreated tumor with multiple trials.
chemotherapy regimens) may be considered for alternative
regimens if the goal is palliation. References
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