Abstract and Introduction
Background: Bevacizumab is used in the treatment of advanced malignancies and has a "black box" warning for gastrointestinal perforations. Despite this known side effect, there are no large descriptive series of patients who experience bevacizumab-induced gastrointestinal perforations.
Aim: To review and describe post-market cases of bevacizumab-induced gastrointestinal perforation reported by healthcare professionals to the United States Food and Drug Association Adverse Event Reporting System (FAERS) database.
Methods: In total, 74 025 cases of bevacizumab-induced adverse drug reaction were reported to FAERS from January 1 2004 to July 6 2021. We identified 2874 cases of bevacizumab-induced gastrointestinal perforation. A total of 1375 cases were determined to contain complete patient demographic data after the removal of duplicates and were reviewed. Subgroup analysis was completed on gastro-oesophageal perforations given the lack of prior data.
Results: The average patient age was 61.9 ± 11.4 years. A total of 698 cases included descriptive locations of perforations with most occurring in the large intestine (385 cases, 55.2% of specifically described cases). Colorectal cancer was the most common indication for bevacizumab (691 cases, 50.3%) followed by ovarian cancer (197 cases, 14.3%) and non-small cell lung cancer (182 cases, 13.2%). Death was reported in 554 patients (40.3% of cases). Sixty-two cases of gastro-oesophageal perforation were identified.
Conclusions: This is the largest collective descriptive study of bevacizumab-induced gastrointestinal perforations, and sheds light on this often fatal complication. We additionally identified and described a rare subgroup of patients experiencing bevacizumab-induced gastro-oesophageal perforation not previously described.
Bevacizumab is a monoclonal antibody that inhibits vascular endothelial growth factor (VEGF) and is used in the treatment of advanced malignancies. First approved for metastatic colorectal cancer, bevacizumab has since received approval from the United States Food and Drug Administration (FDA) for non-small cell lung cancer (NSCLC), metastatic renal cell carcinoma, glioblastoma, advanced cervical cancer, and, most recently, in combination with atezolizumab for unresectable or metastatic hepatocellular carcinoma (HCC). While elevated blood pressure and proteinuria are commonly experienced side effects of bevacizumab therapy, the medication is associated with three FDA "black box" warnings: gastrointestinal perforations, surgery and wound healing complications, and haemorrhage. Previous clinical trials have indicated an incidence of gastrointestinal (GI) perforations as high as 3.2% for patients on bevacizumab therapy.
While the exact mechanism of GI perforation remains unclear, Sliesoraitis et al hypothesised several plausible processes. The first is due to bevacizumab's prothrombotic properties. Thrombi formation in the small splanchnic or mesenteric vessels could lead to bowel ischaemia and eventually perforation. A second possible mechanism is that VEGF inhibition increases the risk of intestinal ulcer formation through impaired wall proliferation and healing. A third possibility is that these medications decrease normal vasculature supplying the intestinal wall, leading to inadequate blood supply. Lastly, in some cases it is possible that tumour destruction leads to decreased stability in the intestinal wall and, subsequently; this instability increases the risk of perforation. This hypothesis is supported by data from a prior case series that identified nine cases (37.5% of described cases) with tumour at the site of perforation.
Despite the frequency and gravity of bevacizumab-induced intestinal perforations, there have been few descriptive studies to characterise these adverse drug reactions (ADRs). In 2007, Badgwell et al, published a retrospective case series on bevacizumab-induced GI perforations and described 24 cases. In this cohort, the four most common indications for bevacizumab use were: pancreatic cancer (seven cases, 29%), colorectal cancer (six cases, 25%), renal cell carcinoma (four cases, 17%) and ovarian cancer (three cases, 13%). Mortality rate was 12.5%. Hapani et al published a meta-analysis that identified 45 cases of GI perforations from 5591 patients treated with bevacizumab (0.9% incidence rate, 0.7%-1.2% 95% CI). Interestingly, the highest incidence of bevacizumab-induced perforation occurred in patients with renal cell carcinoma (1.1%, 95% CI 0.5%-2.5%) with the lowest incidence in patients with pancreatic cancer (0.6%, 95% CI 0.2%-1.7%). Additional primary malignancies with high relative risk of GI perforation included colorectal cancer and ovarian cancer.
This study consists of reviewing cases of bevacizumab-induced GI perforations from the FDA Adverse Event Reporting System (FAERS), a large database of voluntarily, internationally reported ADRs associated with post-market, FDA-approved medications as well as natural substances, vaccines, and medical devices. The magnitude of ADRs contained within the database lend to its utility and provide a framework for the review of a large number of cases of drug-related side effects, including bevacizumab-induced GI perforations described in this study.
Aliment Pharmacol Ther. 2021;54(10):1290-1297. © 2021 Blackwell Publishing