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

Abstract

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, I² = 0%) and 0.22 L (95%: 0.11 to 0.32, P < 0.01, I² = 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, I² = 0%) nor 6-min walking distance (WMD: 5.29 m, 95%CI: -18.01 to 28.59, P = 0.66, I² = 1%). The weighted partial response rate was 0.68 (95%CI: 0.53 to 0.84, P < 0.01, I² = 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.

Trial registration: PROSPERO registration number: CRD42018085470. Registered 22 January 2018.

Keywords: Lymphangioleiomyomatosis; Meta-analysis; mTOR inhibitors.

Fig. 1

Study selection flow diagram

Fig. 2

Forest plot for the weighted mean difference of FEV₁ and FVC with 95% confidence interval in the random effects model

Fig. 3

Forest plot for the weighted-pooled proportion of renal angiomyolipoma partial response with 95% confidence interval in the random effects model

Fig. 4

Forest plot for the weighted mean difference of VEGF-D levels with 95% confidence interval in the random effects model

Fig. 5

Forest plot for the weighted-pooled proportions of adverse events in patients receiving sirolimus or everolimus including the 95% confidence interval from random effect model and number of included study(n)