Copyright 2009 by the Society for Neuro-Oncology
Colon perforation during antiangiogenic therapy for malignant glioma
Division of Neuro-Oncology, Department of Neurology, Brigham and Women's Hospital, Boston, MA (A.D.N., J.D., S.K., P.Y.W.); Center for Neuro-Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA (A.D.N., J.D., A.S.C., L.D., D.C.L., S.K., P.Y.W.); Harvard Medical School, Boston, MA, (A.D.N., J.D., S.K., P.Y.W.); USA
Address correspondence to Andrew D. Norden, Center for Neuro-Oncology, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115, USA (anorden{at}partners.org).
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Abstract |
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Antiangiogenic drugs have emerged as effective treatment options for patients with recurrent malignant gliomas (MGs). Though this class of drugs is generally well tolerated, rare life-threatening complications, including thromboembolism, hemorrhage, and gastrointestinal (GI) perforation, are reported. We describe six cases of GI perforation among 244 glioma patients (2.5%) during treatment with antiangiogenic agents in combination with chemotherapy and corticosteroids. Two patients succumbed to this complication, and the others recovered. Because GI perforation is a life-threatening yet treatable complication, neurooncologists must have a low threshold to consider it in patients on antiangiogenic drug therapy who present with abdominal pain and other GI complaints.
Keywords: antiangiogenic drugs, bevacizumab, gastrointestinal perforation, malignant glioma
Received March 25, 2008; Accepted July 8, 2008
Recently, antiangiogenic drugs for recurrent malignant gliomas (MGs) have emerged as effective treatment options. Earlier studies of ineffective chemotherapy agents found that the 6-month progression-free survival (PFS6) for recurrent glioblastoma (GBM) was only 15% and for anaplastic glioma (AG), 31%.1 In a phase II trial, 32 patients with recurrent MG were treated with bevacizumab (Avastin; Genentech, South San Francisco, CA, USA), a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), and irinotecan (Camptosar; Pfizer, New York, NY, USA). PFS6 for recurrent GBM was 30%, and for AG, 56%.2 A larger phase II study found a PFS6 of 51% for GBM patients in first or second recurrence who were treated with the same combination.3,4 The small-molecule pan-VEGF receptor (VEGFR) inhibitor cediranib (AZD2171, Recentin; AstraZeneca, London, UK) also appears to be active against recurrent GBM, with PFS6 of 27% in a phase II trial.5
Antiangiogenic agents are generally well tolerated. Frequently observed adverse effects include hypertension and proteinuria without the nausea, vomiting, and myelosuppression that cytotoxic chemotherapy may cause. Inhibitors of VEGF and VEGFR, however, are associated with small risks of life-threatening complications, including arterial thromboembolism, hemorrhage, and gastrointestinal (GI) perforation. In the definitive phase III trial that led to FDA approval of bevacizumab for metastatic colon cancer, the rate of GI perforation was 1.5% in patients treated with bevacizumab and chemotherapy, compared with 0.0% for patients treated with chemotherapy alone.6 For unclear reasons, GI perforation appears to be more common among bevacizumab-treated patients with colorectal and ovarian cancers compared with patients with other solid tumors.7 With the increasing use of bevacizumab and other antiangiogenic therapies in recurrent MG patients, we have observed six cases of GI perforation among 244 patients treated with antiangiogenic drugs at our institution.
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Methods |
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After obtaining institutional review board approval, we reviewed medical and pharmacy records from January 1, 2003, through April 30, 2008, to identify all glioma patients who were treated at our institution with antiangiogenic drug therapies. We subsequently identified the subset of patients who experienced GI perforation and obtained detailed information from their medical records, including demographics, brain tumor treatment history, corticosteroid use, treatment for GI perforation, pathology, and outcome.
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Results |
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Antiangiogenic drug treatments included the VEGF inhibitors bevacizumab and aflibercept (VEGF-Trap, Regeneron; Tarrytown, NY, USA; Sanofi-Aventis, Paris, France) and the VEGFR inhibitors cediranib (AZD2171, Recentin; AstraZeneca, London, UK), pazopanib (GW786034; GlaxoSmithKline, London, UK)), sorafenib (Nexavar; Bayer AG, Leverkusen, Germany), sunitinib (Sutent; Pfizer, New York, NY, USA), vandetanib (ZD6474, Zactima; AstraZeneca, London, UK), and vatalanib (PTK787; Novartis, Basel, Switzerland). The total numbers of patients treated with each agent are presented in Table 1. There were six cases of GI perforation. Among patients treated with anti-VEGF therapy, the risk of GI perforation was 5 of 170 (2.9%). Among patients treated with anti-VEGFR therapy, the risk of GI perforation was 1 of 74 (1.4%). The overall risk among patients treated with antiangiogenic therapy was 6 of 244 (2.5%).
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Case histories are summarized in Table 2. Patients ranged in age from 32 to 70 years. Except for patient 2, who had a history of conservatively managed diverticulitis more than 2 years prior to his diagnosis of MG, none of the patients had any known history of GI disorders. All of the patients presented with the acute onset of abdominal pain. One patient had concurrent rectal bleeding. Only one patient reported constipation, and two were taking stool softeners to prevent it. Five patients developed GI perforation during treatment with bevacizumab and concurrent chemotherapy, most frequently irinotecan. Patient 1 was previously treated with sorafenib and temsirolimus (CCI-779, Torisel; Wyeth, Madison, NJ, USA) on a clinical trial for more than 6 months before switching to bevacizumab and irinotecan. Patient 3 was treated for 3 months with aflibercept on a clinical trial, then bevacizumab for 3 months, and then bevacizumab again after a 4-month break in which cytotoxic treatment was provided. Patient 5 developed GI perforation during treatment with vandetanib, a small-molecule inhibitor of VEGFR and the epidermal growth factor receptor (EGFR), in conjunction with temozolomide and radiation therapy as part of a phase I clinical trial. Patient 6 became symptomatic during treatment with bevacizumab, temozolomide, and radiation therapy for a newly diagnosed brainstem glioma. None of the patients used nonsteroidal anti-inflammatory drugs, but all patients were taking dexamethasone at the time of GI perforation. Most had been receiving moderate corticosteroid doses for weeks or months. Four patients underwent exploratory laparotomy with sigmoid colectomy and colostomy; three of these patients recovered and went on to receive additional tumor-directed therapy, but one died of surgical complications. One patient refused operative intervention and subsequently died of peritonitis. Another patient required subtotal colon resection because of extensive pneumatosis discovered at surgery. In two cases, pathology revealed ruptured diverticulitis. In three other cases, pathology revealed acute inflammation with perforation. In one case, there was no evidence of inflammatory change, only pneumatosis. In five cases, the duration of antiangiogenic therapy at the time of GI perforation was brief, between 17 and 68 days. However, two of these patients had been extensively treated with different antiangiogenic therapies prior to starting the treatment that was temporally associated with the perforation. In these two cases, accounting for the time that the first antiangiogenic therapy was started, the duration of treatment at the time of GI perforation increased from 21 and 38 days to 203 and 375 days, respectively. In one patient, continuous biweekly bevacizumab therapy had been administered for more than 1 year at the time of perforation.
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Discussion |
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In a phase III trial in which 402 metastatic colon cancer patients were treated with bevacizumab and chemotherapy, there were only six cases (1.5%) of GI perforation, as opposed to no cases among the patients treated with chemotherapy alone. Patients with ovarian cancer who are treated with bevacizumab and chemotherapy appear to be at an increased risk of approximately 5%–6%.8 Other tumors that may confer an increased perforation with bevacizumab treatment include pancreatic9 and gastroesophageal cancer,10 but cases have been reported in bevacizumab-treated patients with diverse malignancies including renal cell carcinoma, cancer of unknown primary origin, and lung cancer.11 Proposed risk factors for GI perforation in patients treated with bevacizumab include a variety of local phenomena, such as peptic ulcer disease, diverticulitis, necrosis of a primary or metastatic tumor, carcinomatosis, bowel obstruction, chemotherapy-induced colitis, prior bowel irradiation, and bowel ischemia.12 Data from a large, community-based registry that has evaluated 1,968 bevacizumab-treated patients with metastatic colon cancer showed a 1.7% rate of GI perforation. No statistically significant risk factor had been identified at the time of a preliminary report.13
In this series of six glioma patients, only one had a history of diverticulitis that might have increased the risk of GI perforation. The other known risk factor for GI perforation among these patients is corticosteroid use. Patients treated with corticosteroids for a variety of indications are well known to be at increased risk for GI perforation and other GI complications.14–16 Among patients treated with dexamethasone doses of at least 16 mg/day, the risk of GI perforation may approach 3%.15,17 In the largest published series of GI perforation in 125 patients with neurologic disease treated at a large cancer center, only one patient had a primary brain tumor.15 The majority of patients who experienced this complication were treated with dexamethasone doses of 16–100 mg/day for epidural spinal cord compression. In our institutional experience treating approximately 750 glioma patients with cytotoxic chemotherapy over the past 5 years, we are aware of only two cases of GI perforation (0.3%). By comparison to the overall risk of 2.5% reported here, antiangiogenic therapy appears to represent an important risk factor for GI perforation in this population.
In a recent phase II trial of 167 patients with MG in first or second relapse treated with bevacizumab with or without irinotecan, there was a single case of GI perforation in the combination therapy group.3,4 This suggests a much lower risk for GI perforation (0.6%) than our findings indicate. Details regarding steroid dosing in this trial have not yet been reported. However, because the trial restricted eligibility to patients in first or second relapse who were naive to antiangiogenic therapy, it is probable that the cohort reported here was treated with higher steroid doses for longer periods of time. Additionally, some of the patients described here were treated with sequential antiangiogenic drug therapies.
This series includes one patient who experienced GI perforation during treatment with vandetanib, a small-molecule inhibitor of VEGFR and EGFR. We are not aware of any published data regarding the risk of GI perforation among patients treated with VEGFR inhibitors. Although small case numbers preclude any statistically robust conclusions, these results suggest that the risk of GI perforation associated with VEGFR inhibitors (1.4%) could potentially be smaller than the risk associated with VEGF ligand inhibitors (2.9%).
Additional prospective studies of MG patients treated with antiangiogenic therapies will be useful in determining the frequency of and risk factors for GI perforation, a potentially life-threatening complication. On the basis of our experience, it is possible that antiangiogenic therapy increases the risk of GI perforation, even in patients whose tumors are located far from the abdomen. In our population, the majority of proposed risk factors are absent, suggesting that other risk factors such as corticosteroid use may be important. Because GI perforation is a catastrophic and treatable condition, neurooncologists must have a low threshold to consider it in evaluating patients with abdominal pain.
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References |
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- Wong ET, Hess KR, Gleason MJ, et al. Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol. 1999;17: 2572-2578.
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