Incidence of lung toxicities with bevacizumab
We joined the DRUG (3,875,874 reports), REAC (1,096,193 reports), and DEMO (693,295 patients) tables by ID number. We then removed duplicate data from the DRUG and REAC tables . All AEs classified as “suspected drugs” were extracted totalling 5,273,115 reports that comprise the "data table”.
We analysed this data table and obtained 20,399 reports of AEs caused by bevacizumab. Of these, 1,679 lung toxicities were reportedly associated with bevacizumab (Fig. 1). The patient characteristics are shown in Table 1. Approximately 63.8% of patients were male. According to the age distribution of the study population, lung toxicity was more common among patients in their 70s (33.7%), followed by those in their 60s (34.8%).
Among the types of lung toxicity caused by bevacizumab, reported numbers of cases of interstitial lung disease, pneumonia, pulmonary embolism, pulmonary artery thrombosis, pneumonitis, lung disorder, respiratory failure, dyspnoea, cardio-respiratory arrest, and aspiration pneumonia associated with bevacizumab were 609, 246, 225, 86, 62, 54, 42, 37, 35, and 35, respectively (Table 2). Reporting odds ratios (ROR)s with a lower limit of the 95%CI >1 comprised pulmonary embolism (5.28, 95%CI 4.61–6.05, p<0.001), pulmonary artery thrombosis (14.21, 95%CI 11.30–17.85, p<0.001), pneumonitis (1.85, 95%CI 1.44–2.38, p<0.001), lung disorder (1.37, 95%CI 1.05–1.79, p=0.025), pulmonary haemorrhage (1.97, 95%CI 1.30–2.97, p=0.003), pulmonary infarction (5.63, 95%CI 3.54–8.96, p<0.001), pulmonary thrombosis (8.14, 95%CI 5.02–13.21, p<0.001), pulmonary cavitation (8.24, 95%CI 3.79–17.89, p<0.001), and pulmonary venous thrombosis (13.42, 95%CI 5.23–34.45, p<0.001). Signals were thus detected for these nine lung toxicities with five or more cases reported.
Time to onset of lung toxicities association with bevacizumab
A histogram of times to onset for the nine detected lung toxicity signals showed occurrence from 35 to 238 days after bevacizumab administration (Fig. 2). Median times to onset were 81 days (interquartile range [IQR] 46–161 days) for pulmonary embolism, 93 days (IQR 64–170 days) for pulmonary artery thrombosis, 99 days (IQR 58–175 days) for pneumonitis, 96 days (IQR 29–135 days) for lung disorder, 42 days (IQR 12–113 days) for pulmonary haemorrhage, 78 days (IQR 53–168 days) for pulmonary infarction, 116 days (IQR 57–117 days) for pulmonary thrombosis, 35 days (IQR 35–35 days) for pulmonary cavitation, and 238 days (IQR 2–475 days) for pulmonary venous thrombosis caused by bevacizumab. The Weibull distribution of the histogram for time to onset showed that the ranges of 95%CIs for shape parameter β were < 1 for pulmonary haemorrhage and pulmonary venous thrombosis, approximately 1 for pulmonary embolism and lung disorder, and >1 for the remaining 5 AEs (Table 3).
Outcomes after occurrence of AEs
Percentages of outcomes (recovery, remission, not recovered, with sequelae, death, and unclear) after onset of the nine AEs are shown in Figure 3. Of the nine items for which signals were detected, fatal outcomes were observed in seven AEs. Among these, the AEs showing the highest fatality rates were pulmonary haemorrhage (30.4%), pulmonary infarction (26.3%), and pulmonary thrombosis (22.2%).