The efficacy and adverse events of mTOR inhibitors in lymphangioleiomyomatosis: systematic review and meta-analysis

Background: Lymphangioleiomyomatosis (LAM) is a rare lung disease and the mammalian target of the rapamycin (mTOR) inhibitors has been used as an effective therapy. Here we conducted a systematic review and meta-analysis with the aims to quantify the efficacy and safety of mTOR inhibitors in LAM patients. Methods: The following databases were searched for clinical trials regarding LAM patients treated with mTOR inhibitors until December 2017: Pubmed, Embase, Cochrane Library and OVID medicine. Random effect models were used for the quantitative analysis. Results: Nine eligible studies were included in our systematic review, 7 of which were used for the meta-analysis. In LAM patients, mTOR inhibitors improved forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) significantly, with the weighted mean difference (WMD) 0.15 L (95% CI: 0.08 to 0.22, P < 0.01, I-2 = 0%) and 0.22 L (95%: 0.11 to 0.32, P < 0.01, I-2 = 0%) respectively. There was no significant change in neither the diffusing capacity for carbon monoxide (WMD: 0.51 ml/mm Hg/min, 95% CI: -0.48 to 1.49, P = 0.31, I-2 = 0%) nor 6-min walking distance (WMD: 5.29 m, 95% CI: -18.01 to 28.59, P = 0.66, I-2 = 1%). The weighted partial response rate was 0.68 (95% CI: 0.53 to 0.84, P < 0.01, I-2 = 72%) for renal angiomylipoma. The cumulative incidence rates of common safety events were 50, 40, 23, 20 and 19% for oral mucositis, hyperlipidemia, headache, bone marrow suppression, and diarrhea, respectively. And most events were low grade and tolerant. Conclusions: In LAM patients, there are improvements of FEV1 and FVC after the application of mTOR inhibitors and over a half achieved the shrinkage of renal angiomyolipoma.