Risk Of Gastrointestinal Perforation Research Articles

Bevacizumab-induced intestinal perforation in a patient with inoperable breast cancer: a case report and review of the literature

BackgroundGastrointestinal perforation is known as a serious adverse event, but, for breast cancer, there are very few reports of gastrointestinal perforation. This report highlights gastrointestinal perforation caused by bevacizumab for breast cancer, which is of special interest because gastrointestinal perforations caused by bevacizumab are very rare in breast cancer.Case presentationWe describe the case of 54-year-old Japanese woman. She was diagnosed as having inoperable breast cancer T2 N1 M1 (pleura, peritoneum), Stage IV, and received chemotherapy by paclitaxel. There was reduction in the primary tumor and disappearance of the pleural effusion; however, the ascites did not change. We performed diagnostic laparoscopy which revealed that her whole peritoneum was thickened, and her small intestine, colon, and her omentum were grouped and formed an omental cake. We submitted a part of her peritoneum to pathological examination and diagnosed the peritoneum dissemination of breast cancer. On the basis of these results, paclitaxel and bevacizumab combination chemotherapy was started, and a decrease in ascites was seen. However, a gastrointestinal perforation occurred on 26th day of second cycle of bevacizumab + paclitaxel, and we performed an emergency operation. In the operation, the omental cake was resolved, and we could search the full length of the gastrointestinal tract. Two small perforations of her small intestine were seen. We performed simple closures for perforations, and peritoneal lavage and drainage. She was in a state of septic shock, but it improved. It was thought that the small intestinal perforations were caused by the bevacizumab-additional chemotherapy which was very effective.ConclusionsWe report a very rare and valuable case. This case suggests that the risk of gastrointestinal perforation must be considered in a case of bevacizumab administration, and it is necessary to determine carefully the patient administered bevacizumab, regardless of the type of cancer.

Risk of gastrointestinal perforation in cancer patients receiving ramucirumab: a meta-analysis of randomized controlled trials

Purpose: Although existing evidence from clinical trials has demonstrated manifestation of gastrointestinal perforation with the use of ramucirumab, overall risks have yet to be reported. Therefore, we performed a meta-analysis of published randomized controlled trials (RCTs) to get a better understanding of the overall incidence and risk of gastrointestinal perforation associated with ramucirumab. Methods: The PubMed and Web of Science databases as well as abstracts presented at American Society of Clinical Oncology conferences were searched to identify relevant studies published up to 01 May 2015. Eligible studies included randomized trials of ramucirumab either alone or in combination with another agent compared with the control arm without ramucirumab and that reported gastrointestinal perforation event. Overall incidence, relative risk (RR) and 95% confidence intervals (CI) were computed using fixed- or random-effects models depending on the heterogeneity of the included studies. Results: A total of 4579 patients with a variety of solid malignancies from six RCTs were included in our meta-analysis. The incidence of gastrointestinal perforation related to ramucirumab was 1.5% (95% CI 1.1–2.1%) with a mortality of 29.8% (95% CI 14.9–50.7%). The RR of gastrointestinal perforation associated with ramucirumab was 2.56 (95% CI 1.29–5.09; P = 0.007). Conclusions: Treatment with the ramucirumab is associated with a significant increase in risk of gastrointestinal perforation in cancer patients.

Comment on: Risk of gastrointestinal perforation in cancer patients receiving ramucirumab: a meta-analysis of randomized controlled trials

To the editor:A meta-analysis recently published in The Journal of Chemotherapy concluded treatment with ramucirumab is associated with a significant increase in risk of gastrointestinal (GI) perfo...

切除不能進行再発大腸癌に対するBevacizumab併用化学療法における消化管穿孔危険因子の検討

目的：Bevacizumab併用化学療法を行った切除不能進行再発大腸癌症例を対象に，消化管穿孔の危険因子を検討する．方法：2007年7月から2012年12月までに当院でBevacizumab併用化学療法を開始した切除不能進行再発大腸癌症例195例をレトロスペクティブに解析した．消化管穿孔の危険因子を単変量，多変量ロジスティック回帰分析により検索した．結果：消化管穿孔は7例（3.6%）に認めた．単変量解析では，直腸癌（オッズ比4.933，95%信頼区間1.061～22.947），放射線照射既往（オッズ比39.120，95%信頼区間4.518～338.691）の二つの因子が統計学的有意（P<0.05）に消化管穿孔の発生と関連していた．多変量解析では，放射線照射既往のみが独立して有意な因子であり，照射既往ありの調整オッズ比は34.831（95%信頼区間3.566～340.204）であった．結語：放射線照射症例に対するBevacizumab投与は慎重に行われるべきであると考えられた．

Risk of gastrointestinal perforation in cancer patients treated with aflibercept: a systematic review and meta-analysis.

Gastrointestinal (GI) perforation is a serious adverse event associated with aflibercept, a novel vascular endothelial growth factor (VEGF)-targeted agent currently approved as second-line treatment for previously treated metastatic colorectal cancer, but the incidence and risk of GI perforation associated with aflibercept has not been well determined. We thus conducted this meta-analysis to investigate the overall incidence and risk of developing GI perforation associated with aflibercept. Databases from PubMed, Web of Science, and abstracts presented at American Society of Clinical Oncology (ASCO) and European Society of Medical Oncology (ESMO) meeting up to January, 2014 were searched to identify relevant studies. Eligible studies included prospective phase II and III trials evaluating aflibercept in cancer patients with adequate data on GI perforation. Statistical analyses were conducted to calculate the summary incidence, odds ratio, and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of included studies. A total of 4,101 patients with a variety of solid tumors from eight clinical trials were included in our analysis. The incidence of GI perforation associated with aflibercept was 1.9% (95%CI, 1.0-3.8%), with a mortality of 10.8% (95%CI, 4.1-25.5%). In addition, patients treated with aflibercept had a significantly increased risk of developing all-grade (OR 3.76; 95%CI, 1.94-7.25; p < 0.001) and high-grade GI (OR 4.14; 95%CI; 2.12-8.06; p < 0.001) perforation compared with patients treated with control medication. No evidence of publication bias was observed. The use of aflibercept is associated with a significantly increased risk of GI perforation compared to controls.

The risk of gastrointestinal perforations in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the BSRBR-RA

ObjectivesTo evaluate the risk of gastrointestinal perforation (GIP) in subjects with rheumatoid arthritis (RA) treated with antitumour necrosis factor (anti-TNF) therapy compared with non-biological disease-modifying antirheumatic drugs (nbDMARDs).MethodsUsing data from...

Risk of gastrointestinal perforation in patients with metastatic breast cancer treated with bevacizumab: A meta-analysis.

1091 Background: Bevacizumab, a vascular endothelial growth factor inhibitor, has shown to be active in patients with metastatic breast cancer (MBC) as first or second line therapy. In some tumor types, the addition of bevacizumab to chemotherapy increase the risk of gastrointestinal (GI) perforation compared with controls. The aim of this systematic review and meta-analysis of randomized trials was to assess the overall risk of GI perforation associated with bevacizumab in MBC. Methods: We selected all randomized trials which compared chemotherapy with or without bevacizumab in MBC. For the analysis, we used a fixed-effects and random effects models to calculate the pooled event-based relative risk ratios (RR) with 95% confidence interval (CI). The Cochran's Q statistic and I2 statistics were first calculated to assess the heterogeneity among the proportions of the included trials. For this study, we collected all events as reported in these trials. We did not consider differences in grade or outcomes. Results: Five trials were included in the meta-analysis: E2100, AVADO, RIBBON-1, RIBBON-2, and AVF-2119g. In total, 2,368 patients received bevacizumab-based therapy and 1,416 chemotherapy alone. GI perforation was reported in 9 and 3 patients, respectively. There was no statistical heterogeneity (p=0.532) considering all trials, so the fixed-effects model was used. Patients treated with bevacizumab-containing regimens had a RR for GI perforation, of 1.172 (95% CI, 0.342-4.016; p=0.801). Conclusions: GI perforation is an uncommon finding in patients with MBC treated with chemotherapy in the first or second line. According to this meta-analysis, the addition of bevacizumab to chemotherapy was not associated with a significant increase risk of GI perforation in this population. No significant financial relationships to disclose.

The risk of gastrointestinal perforation and/or fistula in patients with recurrent ovarian cancer receiving bevacizumab compared to standard chemotherapy: A retrospective cohort study

Objective To determine the rate of gastrointestinal perforation and/or fistula in patients with recurrent ovarian cancer treated with and without bevacizumab. Methods A retrospective chart review from January 2004 to August 2007 identified two cohorts of patients with recurrent ovarian cancer: 1) patients who were receiving bevacizumab either alone or in combination with standard chemotherapy; 2) patients who were receiving standard chemotherapy alone. Gastrointestinal toxicity (perforation and fistula) was assessed using NCI Common Toxicity Criteria. Relative risk and 95% confidence intervals were calculated. Chi square test and student's t test were used for statistical analysis. Results Sixty-eight patients receiving bevacizumab for recurrent ovarian cancer were identified. 67% of these patients received chemotherapy in combination with bevacizumab. For comparison, 195 patients receiving standard chemotherapy alone for recurrent ovarian cancer were identified. A history of previous gastrointestinal resection (40% vs. 37%; p = 0.79) and gastrointestinal obstruction (30% vs. 27%; p = 0.74) was similar in both cohorts. Five patients (7.2%) developed a gastrointestinal perforation and/or fistula in the bevacizumab cohort compared to 13 patients (6.5%) in the chemotherapy alone cohort. The relative risk for developing a perforation and/or fistula is 1.09 (95% CI, 0.40 to 2.96). Conclusions Although a substantial number of patients with recurrent ovarian cancer experience gastrointestinal obstruction, the rate of gastrointestinal perforation and/or fistula is relatively low. Treatment with bevacizumab does not significantly increase gastrointestinal toxicity compared to standard salvage chemotherapy.

Risk of bevacizumab-associated gastrointestinal perforation in patients with colorectal cancer and noncolorectal cancer

9622 Background: Bevacizumab is a recombinant humanized monoclonal antibody that inhibits vascular endothelial growth factor. It is a widely used angiogenesis inhibitor in the treatment of colorectal cancer (CRC) and other solid tumors. Gastrointestinal (GI) perforation is a potentially fatal adverse event associated with bevacizumab, but the risk unclear. This study was conducted to determine the risk of developing GI perforation among CRC and non-CRC patients receiving bevacizumab. Methods: Databases from PUBMED and the Web Science from January 1966 until July 2008 and abstracts presented at the American Society of Clinical Oncology conferences from January 2000 to through July 2008 were searched to identify relevant studies. Eligible studies included prospective phase III clinical trials in which standard anti-neoplastic therapy was administered with and without the use of bevacizumab with available data for GI perforation. Summary incidence rate, relative risk (RR), and 95% confidence interval (CI) were calculated using fixed or random effect models based upon the heterogeneity of the included studies. Results: A total of 12084 patients with various solid tumors from 14 phase III trials were included for analysis. Among patients receiving bevacizumab, the incidence of GI perforation was 0.8% (95% CI: 0.6–1.1%), and RR was 2.0 (95% CI: 1.1–3.8, p = 0.028) in compared with controls. The risk of GI perforation was significantly increased in patients receiving bevacizumab at 5 mg/kg/week (RR 2.6, 95% CI: 1.0–6.6, p=0.04), but not at 2.5 mg/kg/week (RR=1.5, 95%CI: 0.7–3.3, p=0.3). Among 2151 patients with CRC, the incidence of GI perforation was 0.8% (95% CI: 0.5–1.6%); while for 2.999 patients with non-CRC malignancies, the incidence of GI perforation was 0.7% (95% CI: 0.5–1.1%); The relative risk of GI perforation varied with tumor type, with significantly increased risk observed in patients with CRC (RR = 3.1, 95% CI: 1.2–8.2, p&lt;0.023), but not non-CRC (RR=1.5, 95% CI: 0.67–3.4, p=0.3). Conclusions: There is a significant difference in the risk of developing GI perforation in CRC and non-CRC patients receiving bevacizumab with a higher relative risk in patients with CRC. Further investigation into the etiology of this difference is recommended. No significant financial relationships to disclose.

Bevacizumab and oxaliplatin-based chemotherapy in metastatic colorectal cancer

In metastatic colorectal cancer disease progression correlates with serum VEGF levels. The importance of VEGF in tumor-induced angiogenesis is well described in preclinical models. In this review we discuss the role of anti-VEGF therapy in combination with oxaliplatin-based chemotherapy for the treatment of metastatic colorectal cancer. A recent Phase III clinical trial in patients with metastatic colorectal cancer demonstrated the efficacy of FOLFOX4 in combination with bevacizumab, a recombinant humanized monoclonal antibody with high binding specificity for VEGF, to improve median overall survival when used as second-line therapy. The major adverse events associated with bevacizumab include grade III hypertension, bleeding and the risk of gastrointestinal perforation. Combining bevacizumab with oxaliplatin-based chemotherapy as first-line treatment for patients with metastatic colorectal cancer improves progression-free survival, as seen in the NO16966 and Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) studies, when compared with placebo and historical controls, respectively. Future research will need to focus on the mechanisms whereby bevacizumab enhances the benefit of chemotherapy to identify predictive markers that better define which patient populations will benefit the most from treatment.

Bevacizumab in the treatment of ovarian cancer

Current treatment for epithelial ovarian cancer involves a combination of surgery and chemotherapy with platinum- and taxane-based chemotherapy. With the recent approval of the anti-VEGF antibody bevacizumab by several regulatory bodies in colorectal and non-small-cell lung cancers, interest has developed regarding the potential role of bevacizumab therapy in ovarian cancer. Several case series and Phase II studies indicate that in ovarian cancer bevacizumab is active as a single agent or in combination with other drugs. Currently, ongoing Phase III trials are testing bevacizumab in front-line adjuvant therapy with carboplatin and paclitaxel. Bevacizumab has been generally well tolerated in ovarian cancer patients, but recent reports on increased risk of gastrointestinal perforations have gained attention. Bevacizumab offers a novel therapeutic modality in the treatment of epithelial ovarian cancers.

Bevacizumab

The tolerability profile of bevacizumab was generally acceptable in clinical trials in patients with advanced colorectal cancer, breast cancer, or NSCLC. In pooled analysis, the most common adverse events of any severity in patients receiving bevacizumab were asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, constipation, upper respiratory infection, epistaxis, dyspnea, exfoliative dermatitis, and proteinuria. Most adverse events were mild to moderate in severity, and events such as hypertension, hemorrhage, or proteinuria were clinically manageable.The most common grade 3 or 4 adverse events in bevacizumab recipients were asthenia, pain, hypertension, diarrhea, and leukopenia. Bevacizumab is associated with an increased risk of gastrointestinal perforations in patients with metastatic colorectal cancer, hemoptysis in patients with advanced NSCLC (particularly those with squamous cell histology), wound healing complications, arterial thromboembolism, sensory neuropathy, and congestive heart failure. Such events have resulted in death, but are relatively uncommon.AbstractBevacizumab is a humanized recombinant antibody that prevents vascular endothelial growth factor (VEGF) receptor binding, and inhibits angiogenesis and tumor growth.In patients receiving an irinotecan plus fluorouracil/leucovorin (IFL) regimen for first-line treatment of metastatic colorectal cancer, the addition of bevacizumab significantly increased overall survival by 4.7 months relative to IFL plus placebo. In the second-line treatment of advanced colorectal cancer, patients who received bevacizumab in combination with a fluorouracil/leucovorin plus oxaliplatin (FOLFOX4) regimen had an overall survival time that was 2 months longer than that in patients receiving FOLFOX4. Preliminary results indicated that bevacizumab significantly extended progression-free survival by 4.9 months in patients receiving paclitaxel for the first-line treatment of locally recurrent or metastatic breast cancer. The addition of bevacizumab to paclitaxel plus carboplatin in the first-line treatment of advanced NSCLC significantly prolonged overall survival by >2 months.Bevacizumab has acceptable tolerability in patients with advanced colorectal cancer, breast cancer, or NSCLC, with the majority of adverse events being generally mild and clinically manageable. Thus, bevacizumab provides a highly effective addition to standard chemotherapeutic regimens for advanced colorectal cancer, breast cancer, and NSCLC.Pharmacological PropertiesBevacizumab binds to soluble VEGF, preventing receptor binding, and inhibits VEGF-induced endothelial cell proliferation and migration in vitro. In vivo in murine xenografts, bevacizumab decreased tumor growth by ≈70–95% compared with control animals. In patients with rectal adenocarcinoma or inflammatory or locally advanced breast cancer, intravenous bevacizumab displayed antiangiogenic and antitumor effects.The single-dose pharmacokinetic profile of bevacizumab 0.1–10 mg/kg is linear, and an accumulation index of 1.4–2.9 has been observed after multiple doses of 3–20 mg/kg. The mean central volume of distribution of bevacizumab was 37.9–48.6 mL/kg during monotherapy, 34.3–56.8 mL/kg during coadministration with other antineoplastic agents, and was 22% greater in males than in females after correction for bodyweight.The clearance of bevacizumab is low (2.8–5.1 mL/kg/day with doses of 0.3–10 mg/kg) and varies with bodyweight, sex, and tumor burden. Bevacizumab 0.3–20 mg/kg has a long terminal elimination half-life (up to 22 day across a range of doses in multiple studies and ≈20 days in a population pharmacokinetic analysis), permitting administration at 2- or 3-week intervals.Therapeutic EfficacyIn chemotherapy-naive patients with metastatic colorectal cancer, the addition of bevacizumab to IFL treatment significantly increased median values for overall survival by 4.7 months, progression-free survival by 4.4 months, and response duration by 3.3 months and the objective response rate (ORR) 1.3-fold relative to IFL plus placebo. In addition, bevacizumab plus fluorouracil/leucovorin significantly improved median progression-free survival, although not overall survival, in patients with a poor prognosis who were unlikely candidates for irinotecan therapy. Bevacizumab combined with FOLFOX4 significantly increased median overall survival by 2 months, median progression-free survival by >2 months, and the ORR by 2-fold relative to FOLFOX4 alone in chemotherapy-experienced patients with advanced colorectal cancer.In preliminary results, first-line therapy with bevacizumab plus paclitaxel in patients with locally recurrent or metastatic breast cancer significantly increased median progression-free survival by 4.9 months and the ORR by almost 2-fold relative to paclitaxel monotherapy. In heavily pretreated patients, however, despite a significant 2-fold increase in ORR, the addition of bevacizumab to capecitabine did not demonstrate any significant increase in median progression-free or overall survival times relative to capecitabine alone.Bevacizumab combined with paclitaxel plus carboplatin significantly increased median overall survival by >2 months, median progression-free survival at 1 year by almost 2 months, and more than doubled the ORR relative to paclitaxel plus carboplatin in chemotherapy-naive patients with advanced nonsquamous cell NSCLC. as|Tolerability

Localization of gastrinomas by selective intra-arterial calcium injection in patients on proton pump inhibitor or H2 receptor antagonist therapy

Preoperative localization is important for the successful treatment of gastrinomas. The aim of this study was to investigate whether selective intra-arterial calcium injection and hepatic venous sampling was able to localize gastrinomas in four patients who remained on proton pump inhibitor or H2 antagonist therapy. Calcium gluconate was injected directly into the arteries supplying the pancreas and liver after standard selective angiography. Gastrin levels were then measured in samples taken from the right hepatic vein. Calcium gluconate produced a diagnostic rise (at least 2-fold) in serum gastrin and unequivocally localized the tumour to a specific vascular territory in each case. One patient did not undergo surgery. In the remaining three patients, surgery confirmed the position and histology of the tumour. This study shows that in four patients with a confirmed gastrinoma we were able to localize the gastrinoma by selective intra-arterial calcium injection and hepatic venous sampling, whilst the patients remained on proton pump inhibitor or H2 antagonist therapy, thereby reducing their risk of gastrointestinal perforation.