Incidence Of Gastrointestinal Perforation Research Articles

Impact on the incidence of gastrointestinal perforation during the COVID-19 pandemic in the Costa del Sol healthcare system area

Introduction and aimsGastrointestinal perforation is a surgical emergency that is associated with a high mortality rate and requires special care. During the pandemic, there has been competition with COVID-19 patients for health resources, especially ICU bed availability. The primary aim of our study was to compare the incidence of gastrointestinal perforation during the COVID-19 pandemic, with cases registered before the pandemic. Materials and methodsA retrospective, observational, single center, cohort study was conducted that included patients that underwent emergency surgery for gastrointestinal perforation in the periods during the pandemic (6 months) and before the pandemic (12 months). Sociodemographic characteristics, comorbidities, duration of hospital and ICU stay, status at discharge, and perforation site were compared. ResultsThe study included 67 subjects (33 in the pre-pandemic period and 34 in the pandemic period). There were no significant differences regarding sex, age, or comorbidity. The perforation rate per emergency intervention was 4-times higher during the pandemic. There was an increase in the number of patients that were foreigners (4 [11%]) and nonresidents (6 [17%]). ICU admissions decreased (6 [19%]) but ICU stay increased to 137 h. Hospital stay increased by 5 days and delay in care increased 4.5 h. The number of deaths was higher (from 5 [15.2%] to 10 [29.4%]). Four patients with perforations were positive for COVID-19, were admitted to the ICU, and died. ConclusionsDuring the COVID-19 pandemic there was an increase in the incidence of gastrointestinal perforations at our healthcare system area; symptoms were more advanced, and mortality was higher.

An Audit on Gastrointestinal Perforation in a Tertiary Care Teaching Hospital Based in Northern Part of India: A Study of 100 Cases

Background: A prospective study was conducted on 100 patients of perforation peritonitis: To find out the incidence of gastro intestinal perforation in various age groups, sex, riral or urban, socio economic status, To find out the various causes and sites of gastra intestinal perforartions, To determine various types of procedures being done to treat gastro intestinal perforations.Methods:The study population consisted of 100 patients of perforation peritonitis admitted at surgical wards of Rajindra Hospital, Patiala. Patients underwent necessary investigations such as Blood counts, biochemical analysis and urine analysis. X-ray Abdomen and chest / USG Abdomen/Pelvis CT-Abdomen (as and when required). All diagnosed patients were subjected to surgery. In all cases, operative findings and postoperative course were followed up for three months. Final outcome was evaluated on the basis of clinical, operative and radiological findings. In pre-pyloric and duodenal perforation, GRAHAM’S PATCH REPAIR carried out. In Ileal and Jejunal perforations, primary closure or exteriorization done depending upon the condition of the gut and duration of the symptoms. The patient outcome was assessed by duration of hospital stay, wound infection, wound dehiscence, leakage/entero-cutaneous fistula, intra-abdominal collection/abscess, ileostomy related complications and reoperation. Wound infection was graded as per SSI grading.Results:Most common age group for perforation was 21-40 years (50%) followed by 41-60 (33%) years in present study. Mean age of the patients is 37.91 + 13.15 years with male predominance (78%) in our study. 4% of the patients were of upper socio-economic status while 32% of the patients were of middle and 64% of the patients were of lower socio-economic status.Abdominal pain was seen in 100% of the patients while abdominal distension was present in 69% of the patients. Nausea/Vomiting was seen in 61% of the patients while Fever and Constipation was seen in 53% and 86% of the patients respectively. Diarrhoea was seen in 3% of the patients. Tenderness, guarding & rigidity, distension, obliteration of liver dullness and evidence of free fluid were present in 100% of the patients. Bowel sounds were not detected in all the patients. Most common perforations were Duodena(37%), Ileal (25%), Gastric (25%) followed by Appendicular (9%), Jejunal (4%) and Colonic perforation (2%). The most common etiology of gastrointestinal perforations was Peptic ulcer followed by Typhoid, Appendicitis, Tuberculosis, Trauma, Malignancy and non-specific infection.In Gastric perforations, Peptic ulcer was the most common cause of perforation followed by Trauma. In Ileal perforations, Typhoid was the most common cause of perforation followed by Tuberculosis and non-specific infection. In Appendicular perforations, most common cause was Appendicitis. In Jejunal perforations, most common cause was Trauma. In Colonic perforations, most common cause was Malignancy.Conclusions:The incidence of gastrointestinal perforations was common in 21-40 years age group followed by 41-60 years age group with male preponderance in our study. The most common site of perforations was Gastro-duodenal followed by Ileal perforations and the most common cause for these perforations was peptic ulcer followed by typhoid. The most common procedure done to treat gastrointestinal perforations was primary closure, resection and anastomosis, appendectomy and stoma formation. However, small sample size and short follow up period were the limitations of the present study.

Incidence of gastrointestinal perforation associated with bevacizumab in combination with neoadjuvant chemotherapy as first-line treatment of advanced ovarian, fallopian tube, or peritoneal cancer: analysis of a Japanese healthcare claims database.

To assess the incidence of bevacizumab-associated gastrointestinal (GI) perforation during first-line treatment of patients with ovarian, fallopian tube, or peritoneal cancer receiving neoadjuvant chemotherapy (NAC) in Japanese real-world clinical practice. A retrospective study was conducted using a healthcare claims database owned by Medical Data Vision Co., Ltd. (study period, 2008-2020). Patients who initiated first-line treatment of ovarian, fallopian tube, or peritoneal cancer were identified and divided into NAC and primary debulking surgery (PDS) groups. The incidence of bevacizumab-associated GI perforation was compared within the NAC group and between the groups. Paclitaxel + carboplatin (TC) was most commonly used as first-line treatment (39.5% and 59.6% in the NAC and PDS groups, respectively). TC + bevacizumab was used in 9.3% and 11.6% of patients in the NAC and PDS groups, respectively. In the NAC group receiving TC, the proportion of patients with risk factors for GI perforation was lower among patients with versus without concomitant bevacizumab. The incidence of GI perforation in the NAC group was 0.38% (1/266 patients) in patients receiving TC + bevacizumab and 0.18% (2/1,131 patients) in patients receiving TC without bevacizumab (risk ratio=2.13; 95% confidence interval [CI]=0.19 to 23.36; risk difference=0.20; 95% CI=-0.58 to 0.97). None of the 319 patients in the PDS group receiving TC + bevacizumab had GI perforation. No notable increase was observed in GI perforation associated with NAC containing bevacizumab. We conclude that bevacizumab is prescribed with sufficient care in Japan to avoid GI perforation.

EP.WE.829Does Covid-19 increase the risk of gastrointestinal perforation? A preliminary UK-based multicentre cohort study

Abstract Aims Recent case reports have described occult gastrointestinal perforation secondary to Covid-related microcirculatory thromboembolic phenomena. This study aims to evaluate the effect of Covid-19 on the incidence of gastrointestinal perforations across South West London (SWL). Methods A retrospective cohort study included all patients with gastrointestinal perforations presenting to three SWL-based NHS hospitals from 01/04/2020-31/12/2020 (i.e. “pandemic” cohort; from the first national lockdown), versus a representative “pre-pandemic” cohort (01/04/2019-31/12/2019). Data was extracted from the hospital coding records, patient case-notes, and the NELA database, and analysed by two independent clinicians. Results A total of 448 patients were included. 9.3% more (214 vs. 234, p = 0.286) gastrointestinal perforations presented during the pandemic period than beforehand. Comparing both periods, there were no significant differences between the numbers of colonic diverticular perforations (183 vs. 185), gastrojejunal ulcer perforations (1 per period), and terminal ileal perforations (1 per period). There were 78% more peptic ulcer perforations (9 vs. 16) and 55% more gallbladder perforations (20 vs. 31) during the pandemic period, although no overall significant difference was derived at the 95% confidence interval (Χ2=3.458, p = 0.484). Conclusions While there was no significant overall increase in spontaneous gastrointestinal perforation during Covid-19, this study clearly suggests increased rates of peptic and gallbladder perforations. Larger-scale epidemiological data are warranted to ascertain whether this is secondary to increased consumption of alcohol, non-steroidal anti-inflammatory medication or other pro-ulcerative drug regimes during the pandemic. Further data will also be vital to highlight delays in investigation and/or presentation resulting in these increased perforation rates.

Gastric perforation leading to the diagnosis of classic Ehlers\u2013Danlos syndrome: a case report

BackgroundEhlers–Danlos syndrome is a clinically and genetically heterogeneous group of heritable connective tissue disorders caused by a defect in collagen synthesis and structure. The vascular subtype (Ehlers–Danlos syndrome IV) is reported to be associated with a higher incidence of gastrointestinal perforations. The most reported site of perforation is the colon, followed by the small bowel. Perforation of the stomach is very rare, and there are no reported cases to date of classic types I and II.Case presentationWe present the case of a 14-year-old Saudi girl who visited our emergency department with abdominal pain and vomiting. Initially, she was diagnosed with gastroenteritis and discharged once her condition stabilized. After 48 hours, she developed severe abdominal pain with recurrent vomiting and peritonitis evident on clinical examination. Initial abdominal x-ray failed to show any free air; however, enhanced computed tomography revealed free air and contrast extravasation in the proximal gut. During exploratory laparotomy, a large perforation was found on the anterior wall of the stomach due to the underlying ischemia. The posterior wall had ischemic mucosa with an intact healthy serosa. A free-hand partial gastrectomy was performed to resect all ischemic parts of the stomach. Detailed examinations and laboratory workup were carried out after the surgery to figure out the possible underlying cause. The clinical findings during the physical examination supported marfanoid features. Marfan’s syndrome and related disorders sequencing panel was requested, and Deoxyribonucleic acid (DNA) samples were sent. Given results were supporting the diagnosis of classical Ehlers–Danlos syndrome, the patient was labeled as a case of Ehlers–Danlos syndrome. During the postoperative period, she developed a wound infection that was managed successfully with vacuum-assisted closure dressing. She recovered well without gastrointestinal sequelae in the 4 years of follow-up.ConclusionsHeritable systemic connective tissue diseases must be given serious consideration in young patients with unusual spontaneous perforation. Such patients might develop life-threatening conditions that require immediate intervention. Hence, correct and timely diagnosis is important to prepare for the anticipated complications.

The Efficacy and Safety of Methylnaltrexone for the Treatment of Postoperative Ileus.

Postoperative ileus (POI) is a surgical complication resulting in increased morbidity and length of stay (LOS). Usual care for POI includes bowel rest and gastric decompression. It has been questioned if methylnaltrexone (MNTX), a peripheral opioid antagonist, could be used as treatment for POI. The purpose of this study was to determine if MNTX is effective and safe for POI treatment. This single-center, retrospective cohort study included patients ⩾ 18years with a POI. Patients with acute colonic pseudo-obstruction, small bowel obstruction, and gastrointestinal malignancy were excluded. The intervention was MNTX administration. The primary outcome was time to ileus resolution. Secondary outcomes included LOS, duration of nasogastric tube, total parenteral nutrition requirement, and incidence of gastrointestinal perforations. 110 patients were included in the analysis; 28 received MNTX. Time to ileus resolution was 9.9days for the MNTX group and 11.4days for the control group (P = .38). Duration of gastric decompression was 4.6days for the MNTX group and 4.2days for the control group (P = .71). Length of stay was 19.9days for the MNTX group and 19.7days for the control group (P = .96). The percentage of TPN requirement was 17.9% in the MNTX group and 22.0% in the control group (P = .65). No gastrointestinal perforations were observed in either group. For the treatment of POI, MNTX did not significantly reduce time to resolution of ileus, LOS, duration of gastric decompression, or TPN requirements. However, no gastrointestinal perforations were seen, indicating that MNTX may be safely used in these patients.

Bevacizumab-related gastrointestinal perforation in patients with three or more prior chemotherapy regimens: A real-world experience

ObjectiveAssociations between the number of prior chemotherapy (CT) regimens and gastrointestinal (GI) perforation in patients receiving bevacizumab treatment has not been fully investigated. The aim of the study was to investigate the impact of ≥3 prior CT regimens on GI perforation. Materials and methodsWe retrospectively investigated the medical records of 133 patients with gynecological cancer who received bevacizumab-containing treatment. Bevacizumab was intravenously administered at a dose of 15 mg/kg every 4 weeks. Incidence of GI perforation was compared between ≤2 and ≥3 prior CT groups. ResultsTwenty-three (17.3%) patients had a history of ≥3 CT; these patients received bevacizumab at 4-week intervals. The percentage of patients with prior surgery was significantly higher in the ≥3 prior CT group (95.7% vs. 70.0%, P = 0.008), while those with prior bowel resection was significantly higher in the ≥3 prior CT group (30.4% vs. 12.7%, P = 0.034). There was no significant difference in the mean number of bevacizumab cycles between the two groups (10.7 vs. 8.9, P = 0.19). While GI perforation was observed in three (2.7%) patients in the ≤2 prior CT group, no GI perforation was found in the ≥3 prior CT group (P > 0.99). ConclusionA history of ≥3 prior CT did not increase the risk for GI perforation when bevacizumab is administered at a dose of 15 mg/kg every 4 weeks in our cases.

Brief Report: Risk of Gastrointestinal Perforation Among Rheumatoid Arthritis Patients Receiving Tofacitinib, Tocilizumab, or Other Biologic Treatments.

To evaluate gastrointestinal (GI) perforation in rheumatoid arthritis (RA) patients receiving tofacitinib, tocilizumab, or other biologic agents. Using health plan data from 2006 through 2014, RA patients without prior GI perforation were identified. Those in whom treatment with tofacitinib or a biologic agent was being initiated were followed up for incident GI perforation with hospitalization. Crude incidence rates were calculated by exposure. Adjusted Cox proportional hazards models were used to evaluate the association between GI perforation and exposures. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated. A cohort of 167,113 RA patients was analyzed. Among them, 4,755 began treatment with tofacitinib, 11,705 with tocilizumab, 115,047 with a tumor necrosis factor inhibitor (TNFi), 31,214 with abatacept, and 4,392 with rituximab. Compared to TNFi recipients, abatacept recipients were older, tofacitinib and rituximab recipients were younger, and tocilizumab recipients were similar in age. Patients beginning treatment with a non-TNFi agent were more likely to have previously received biologic agents than patients beginning treatment with a TNFi. The incidence of GI perforation per 1,000 patient-years was 0.86 (tofacitinib), 1.55 (tocilizumab), 1.07 (abatacept), 0.73 (rituximab), and 0.83 (TNFi). Most perforations occurred in the lower GI tract: the incidence of lower GI tract perforation per 1,000 patient-years was 0.86 (tofacitinib), 1.26 (tocilizumab), 0.76 (abatacept), 0.48 (rituximab), and 0.46 (TNFi). Lower GI tract perforation risk was significantly elevated with tocilizumab treatment, and numerically elevated with tofacitinib treatment, versus treatment with TNFi. Adjusted HRs were 2.51 (95% CI 1.31-4.80) for tocilizumab and 1.94 (95% CI 0.49-7.65) for tofacitinib. Older age (HR 1.16 per 5 years [95% CI 1.10-1.22]), diverticulitis/other GI conditions (HR 3.25 [95% CI 1.62-6.50]), and prednisone use at >7.5 mg/day (HR 2.29 [95% CI 1.39-3.78]) were associated with lower GI tract perforation. The incidence of upper GI tract perforation was similar among all drug exposures. The risk of lower GI tract perforation associated with tocilizumab treatment, and possibly tofacitinib treatment, is elevated compared to that associated with TNF blockade.

Gastrointestinal perforation during regorafenib administration in a case with hepatic metastases of colon cancer

Although common side effects of regorafenib include hand-and-foot syndrome and diarrhoea, the incidence of gastrointestinal perforation is reportedly unknown. We describe our experience with the case of a 65-year-old woman treated with regorafenib as a third-line therapy for progressive caecal cancer with multiple hepatic metastases after 4 and 6 courses of systemic mFOLFOX6 + bevacizumab (BV) and FOLFIRI + BV chemotherapy, respectively. The patient used regorafenib for 32 days but visited our hospital with abdominal pain during the second course. She was diagnosed with acute appendicitis and treated conservatively with antibiotics. The abdominal findings did not improve, and a computed tomography evaluation on day 4 of hospitalization revealed free air lateral to the caecal tumour, liver surface, and epigastric region. The patient underwent same-day emergency surgery based on a diagnosis of gastrointestinal perforation with generalized peritonitis. Upon observing digestive fluid leakage into the peri-ileocaecal area and a 5-mm perforation in the appendix, the patient was diagnosed with peritonitis due to gastrointestinal perforation. Ileocaecal resection with D2 debridement was performed, and a colostomy was opened into the ileum and ascending colon. We conclude that our patient developed gastrointestinal perforation during regorafenib therapy and note that clinicians should be aware of this possible complication in patients with a history of prior treatment with BV.

Incidence of Gastrointestinal Perforations in Patients with Rheumatoid Arthritis Treated with Tocilizumab from Clinical Trial, Postmarketing, and Real-World Data Sources.

IntroductionThe aim of this study was to use multiple data sources to update information on gastrointestinal perforations (GIPs) during tocilizumab (TCZ) treatment in patients with rheumatoid arthritis (RA).MethodsReporting rates of GIP events were estimated from three distinct patient data sets: a TCZ-IV RA clinical trial all-exposure population, a global TCZ postmarketing safety database population, and a US healthcare claims database population of patients with RA, including patients who received TCZ, anti-tumor necrosis factor (aTNF) agents, or abatacept.ResultsThe clinical trial, global postmarketing, and healthcare claims populations provided 17,906, 382,621, and 3268 patient-years (PYs) of TCZ exposure, respectively. GIP incidence rates [95% confidence interval (CI)] were 1.9 (1.3–2.7), 1.2 (1.1–1.3), and 1.8 (0.7–4.0; specific definition) to 2.8 (1.3–5.2; sensitive definition) per 1000 PYs for the clinical trial, postmarketing, and healthcare claims populations, respectively. The GIP incidence rate (95% CI) for the comparator aTNF healthcare claims population ranged from 0.6 (0.3–1.2) to 0.9 (0.5–1.5) per 1000 PYs, for an absolute rate difference between TCZ and aTNFs of 1.2 (−0.3 to 2.5) to 1.9 (0.0–3.7) per 1000 PYs, corresponding to a number needed to harm between 533 and 828.ConclusionThe TCZ GIP event rates from multiple data sources were consistent with previously reported rates, did not increase over time, and were significantly associated with the number of prior biologics. Comparison of GIP incidence rates among patients with prior biologic exposure suggests that, for every 1000 patients treated with TCZ per year, an additional 1–2 GIP events might occur compared with patients treated with aTNFs.FundingRoche.

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.

The incidence of gastrointestinal perforations among rheumatoid arthritis patients.

Gastrointestinal (GI) perforation has emerged as a novel safety concern in relation to medications used to treat rheumatoid arthritis (RA). This study was undertaken to characterize the incidence and risk factors for GI perforation in RA patients. Using administrative databases of a large US health plan, we identified RA patients treated with biologic agents, methotrexate (MTX), oral glucocorticoids, and nonsteroidal antiinflammatory drugs (NSAIDs). Additional risk factors we evaluated included diverticulitis. Hospitalization with GI perforation was identified using a validated algorithm. Incidence rates and risk factors were evaluated using Cox proportional hazards models. Among 40,841 RA patients, 37 hospitalizations with GI perforation were identified. The rate of GI perforation among patients currently being treated with biologic agents who were also receiving oral glucocorticoids was higher (1.12 per 1,000 person-years [95% confidence interval (95% CI) 0.50-2.49]) than for patients being treated with biologic agents who were not also receiving glucocorticoids (0.47 per 1,000 person-years [95% CI 0.22-0.98]) or for patients being treated with MTX who were also receiving glucocorticoids (0.87 per 1,000 person-years [95% CI 0.36-2.10]). Neither biologic agents nor MTX was significantly associated with GI perforation, in contrast to current treatment with glucocorticoids and NSAIDs together (hazard ratio 4.7 [95% CI 1.9-12.0]) or glucocorticoids alone (hazard ratio 2.8 [95% CI 1.3-6.1]). Diverticulitis also was a strong risk factor (hazard ratio 9.1 [95% CI 3.1-26.4]). Seventy percent of patients with GI perforation received glucocorticoids, had antecedent diverticulitis, or both. GI perforation is an uncommon but serious adverse event among RA patients. Because a majority of patients with GI perforation were being treated with glucocorticoids or had previously experienced diverticulitis, these individuals should be considered at higher risk.

Risk of gastrointestinal perforation in patients with cancer treated with bevacizumab: a meta-analysis

Gastrointestinal perforation is a serious adverse event associated with bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF) widely used in current cancer treatment. The association is highlighted by a black-box warning issued by the US Food and Drug Administration, recommending that bevacizumab be permanently discontinued in patients with gastrointestinal perforation. However, no significant association has yet been established between bevacizumab and gastrointestinal perforation in randomised controlled trials. We did a systematic review and meta-analysis of published randomised controlled trials to assess the overall risk of gastrointestinal perforation associated with bevacizumab treatment. We searched PubMed and Web of Science for articles published between January, 1966, and July, 2008. Additionally, abstracts presented at American Society of Clinical Oncology conferences held between January, 2000, and July, 2008, were searched to identify relevant clinical trials. Eligible studies included prospective randomised controlled trials in which bevacizumab was compared with controls in combination with standard anti-neoplastic therapy. Summary incidence rates, relative risks, and 95% CIs were calculated using a fixed-effects or random-effects model, depending on the heterogeneity of the included studies. 12,294 patients with a variety of solid tumours from 17 randomised controlled trials were included in our analysis. The incidence of gastrointestinal perforation was 0.9% (95% CI 0.7-1.2) among patients receiving bevacizumab, with a mortality of 21.7% (11.5-37.0). Patients treated with bevacizumab had a significantly increased risk of gastrointestinal perforation compared with patients treated with control medication, with a relative risk of 2.14 (95% CI 1.19-3.85; p=0.011). Risk varied with bevacizumab dose and tumour type. Relative risks for patients receiving bevacizumab at 5 and 2.5 mg/kg per week were 2.67 (95% CI 1.14-6.26) and 1.61 (0.76-3.38), respectively. Higher risks were observed in patients with colorectal carcinoma (relative risk 3.10, 95% CI 1.26-7.63) and renal cell cancer (relative risk 5.67, 0.66-48.42). The addition of bevacizumab to cancer therapy significantly increased the risk of gastrointestinal perforation compared with controls. The risk may vary with bevacizumab dose and tumour type. Further studies are recommended to investigate the use of bevacizumab in selected patients who have recovered from gastrointestinal perforation. Stony Brook University Research Foundation.

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<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.

Final safety results of BO17704 (AVAiL): A phase III randomized study of first-line bevacizumab (Bv) and cisplatin/gemcitabine (CG) in patients (pts) with advanced or recurrent nonsquamous non-small cell lung cancer (NSCLC)

8039 Background: AVAiL, an international placebo-controlled phase III trial, showed that Bv-based therapy significantly improved PFS and response rate in patients with advanced/recurrent NSCLC. This report summarizes overall safety findings from AVAiL. Methods: AVAiL randomized 1,043 patients with untreated locally advanced, metastatic or recurrent non-squamous NSCLC to C 80mg/m2 (d1) and G 1,250mg/m2 (d1 and d8) q3w for up to 6 cycles plus either Bv 7.5mg/kg q3w (n=331 with safety data), Bv 15mg/kg q3w (n=329) or placebo (n=326). Bv/placebo was administered until disease progression. Primary endpoint was PFS; secondary endpoints included OS, response rate, and safety. Safety was measured using NCI-CTC version 3.0 criteria for adverse events (AEs). Results: At final analysis, the median/maximum duration of Bv therapy was 4.9/28.5 mo (Bv 7.5) and 4.3/23.4 mo (Bv 15). The most common AEs overall were hematological and gastrointestinal (GI), and occurred in similar proportions of pts in the Bv and placebo arms. Grade ≥3 AEs occurred in 80%, 83%, and 77% of pts in the Bv 7.5, Bv 15 and placebo arms, respectively. The most common grade ≥3 adverse events were hematological, mainly neutropenia and thrombocytopenia. Neutropenia was reported in 43% (Bv 7.5), 40% (Bv 15) and 34% (placebo) of pts. Grade ≥3 AEs of special interest included hypertension (7%, 9% and 2%), proteinuria (2%, 3% and 0%), bleeding (4%, 5% and 2%) and hemoptysis (0.5%, 1.2% and 1.3%). The incidence of grade 5 hemoptysis was low (0.9%, 0.9% and 0% of pts, respectively). The incidence of GI perforations (<1%), thromboembolic events (≤8%), CHF (≤1%) and wound healing complications (<1%) was low and similar between treatment arms. The incidence of serious AEs was 39%, 45% and 36% in the Bv 7.5, Bv 15 and placebo arms, respectively. No new safety signals were reported. Conclusions: After E4599, AVAiL further demonstrated the efficacy of Bv in combination with platinum-based chemotherapy in the treatment of advanced NSCLC. Final safety data confirm the well established and manageable safety profile of Bv-based therapy in pts with advanced NSCLC. [Table: see text]

Gastrointestinal Perforation Due to Bevacizumab in Colorectal Cancer

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 nonsteroidal 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.

A phase II study of outpatient first-line paclitaxel, carboplatin, and bevacizumab for advanced-stage epithelial ovarian, peritoneal, and fallopian tube cancer

The purpose of this study was to assess the response rate and toxicity of paclitaxel, carboplatin, and bevacizumab (PCB) primary induction therapy for the treatment of advanced-stage ovarian carcinoma. Twenty patients were treated with paclitaxel (175 mg/m(2)), carboplatin (AUC of 5 IV), and bevacizumab (15 mg/kg) of body weight; q21 days for six cycles. Bevacizumab was administered at cycles two through six. Patients received 116 cycles of PCB chemotherapy (median = 6, range 2-6) and were evaluable for toxicity assessment. Grade 3 and 4 neutropenia developed in 23.3% and 25% of cycles, with no incidence of grades 3/4 thrombocytopenia or anemia. Prior to cycle six, one patient was removed from the study due to grade 3 neuropathy and another patient was excluded due to clinical deterioration. There was no incidence of gastrointestinal perforations, and only two patients demonstrated grade 3 hypertension (HTN). No grade 4 HTN was observed. Eighteen patients were evaluated for response following induction therapy. Six demonstrated a complete response (30%) and ten exhibited a partial response (50%), resulting in a total response rate of 80%. One patient exhibited stable disease (5%), and one demonstrated disease progression (5%). The lack of bowel perforations and wound complications should mitigate some concerns regarding these side effects. This study suggests that first-line treatment with PCB can be safely administered to previously untreated advanced-stage ovarian carcinoma patients. The favorable toxicity results and reasonable response rate warrant additional study in a larger patient population.

Early Low-Dose Hydrocortisone in Very Preterm Infants: A Randomized, Placebo-Controlled Trial

Background: Several reports indicate a decreased cortisol response to adrenocorticotropic hormone in preterm infants developing chronic lung disease and in preterm infants with refractory hypotension. Low-dose hydrocortisone (HC) may allow for beneficial effects. Objective: Our aim was to assess whether HC is able to increase survival without chronic lung disease. Methods: We performed a double-blind, randomized, placebo-controlled trial. Fifty mechanically ventilated infants (birth weight: 500–1,249 g) were randomized to receive treatment (HC 0.5 mg/kg/12 h for 9 days, then HC 0.5 mg/kg/24 h for 3 days) or placebo. Major outcome was survival without oxygen dependence at 36 weeks of postconceptional age (O₂-free survival). Results: The basic characteristics were similar between the two groups. O₂-free survival was higher in the HC group (64 vs. 32%). The advantage was particularly evident among infants without antenatal steroids. The mortality rate was 16% in the HC group versus 40% in the control group (difference not significant). Hypotension after recruitment was reduced by HC (0 vs. 30%). The incidence of gastrointestinal perforation and other adverse effects was similar between the two groups. Conclusions: HC prophylaxis improved O₂-free survival and early cardiocirculatory function in our population, without important short-term effects. The neurodevelopmental outcome will be assessed at 2 years.

Risk factors for gastrointestinal perforations in patients with metastatic colorectal cancer receiving bevacizumab plus chemotherapy

3535 Background: Bevacizumab (BV) prolongs overall survival and progression-free survival when added to standard chemotherapy in patients (pts) with metastatic colorectal cancer (mCRC). BRiTE is a large, community-based observational registry of pts with mCRC receiving BV plus first-line chemotherapy (CT). Incidence rate, temporal pattern, and potential risk factors associated with gastrointestinal perforation (GIP) were explored. Methods: Baseline patient characteristics (BC), including prospectively identified potential risk factors for GIP, were collected at study entry. Safety data were collected every 3 months (mo). Logistic regression models, adjusted and unadjusted for treatment assignment, were used to identify BC potentially associated with GIP. Results: 1968 pts were enrolled between Feb 2004 and Jun 2005. Median study follow-up was 10 mo as of Nov 4, 2005. GIPs were observed in 34 pts (1.7%). For pts with GIP, median time to first event was 2.1 mo; the majority of events were non-fatal and occurred within the first 3 mo after starting BV. BC including GI medical history (chronic aspirin or NSAID use, peptic ulcer disease, diverticulosis) were similar in pts with or without GIP and with earlier or later GIP onset (≤ or >3 mo from start of BV). Although adjusted models did not show any significant BC, GIP rates were numerically higher in pts with primary tumor intact (2.6%) vs. resected (1.6%). Furthermore, univariate analyses revealed a significant difference between intact (2.3%) and resected (0.8%) primary tumor for earlier GIP (≤3 mo from start of BV). The majority of pts with GIP had at least one of the following: acute diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, tumor at GIP site, abdominal carcinomatosis, prior abdominal or pelvic radiation therapy. Conclusions: Preliminary analyses indicate the incidence of GIP in this large, community-based observational registry is similar to that previously reported in phase III mCRC trials with BV. No associations between specific BCs and an increased risk of GIP were identified. Patients with primary tumor intact were more likely to incur a GIP within the first 3 mo of starting BV and CT. [Table: see text]

Gastrointestinal perforation in five dogs associated with the administration of meloxicam

AbstractObjective: Five canine cases of gastrointestinal (GI) perforation and septic peritonitis associated with the routine use of meloxicam are reviewed.Series summary: Selective cyclooxygenase‐2 (COX‐2) non‐steroidal anti‐inflammatory drugs (NSAIDs) are being used more extensively and routinely for acute and chronic pain as well as for perioperative management of pain. These medications are safe and effective but can be associated with known GI and renal side effects. The patients in this case series had no significant concurrent illness, were not on any concurrent medication known to potentiate the ulcerogenic effects of NSAIDs, and in most cases did not display clinical signs that were apparent to the owners until the time of perforation.New or unique information provided: Despite the preferential selectivity for COX‐2, newer NSAIDs still carry the risk of GI performation. The incidence of GI perforation may be increased with inappropriate dosing regimens, with use of non‐veterinary products and in animals that are at high risk for toxicity. Early signs of toxicity may include alteration in appetite, and subtle signs of nausea during treatment. Warning owners to monitor their pet for vomiting, melena, and hematemesis may not be sufficient to avoid the potential disastrous consequences of GI ulceration.