Pulmonary complications with the use of mTOR inhibitors in targeted cancer therapy: a systematic review and meta-analysis

Mammalian target of rapamycin (mTOR) inhibitors have gained regulatory approval for use in several cancer types. Pulmonary adverse events associated with mTOR inhibitors are well recognized but their frequency has varied considerably among trials. PubMed and ASCO abstracts were searched to identify clinical trials of mTOR inhibitors in solid tumors. Twenty-two eligible trials on which 4,242 patients were treated met the criteria for inclusion in this systematic review and meta-analysis. Adverse event data were extracted and used to determine the incidence rate and incidence rate ratio for pneumonitis, dyspnea, and cough. The incidence rate of any grade pneumonitis in patients with solid tumors treated with mTOR inhibitors was 0.11 (95 % confidence interval (CI), 0.06–0.17) per patient, while the incidence of grade 3–4 pneumonitis was 0.03 (95 % CI, 0.01–0.04) per patient. The incidence rate ratio (IRR) of any grade pneumonitis with mTOR inhibitors relative to controls was 19.0 (95 % CI, 6.5–55.4), and for grade 3–4 pneumonitis was 8.0 (95 % CI, 2.6–24.1). The incidence rate for any grade and grade 3–4 cough was 0.23 (95 % CI, 0.20–0.27) per patient and 0.01 (95 % CI, 0.00–0.01) per patient, respectively. The incidence rate for any grade and grade 3–4 dyspnea was 0.15 (95 % CI, 0.10–0.21) per patient and 0.03 (95 % CI, 0.02–0.04) per patient, respectively. Compared to control, treatment with mTOR inhibitors were associated with a significant increase in any grade cough [IRR = 1.9 (95 % CI, 1.6–2.4)] and grade 3–4 dyspnea [IRR = 2.0 (95 % CI, 1.2–3.3)]. This study provides an estimation of the risk of pulmonary adverse events in solid tumor patients treated with mTOR inhibitors. While pulmonary adverse events are relatively common with mTOR inhibitors, most are low grade and asymptomatic.