Abstract
BackgroundLymphangioleiomyomatosis (LAM) is a rare, low-grade multisystem neoplastic disease. Most LAM patients are at a high risk of losing lung function at an accelerated rate and developing progressive dyspnea. Recently, several studies have reported their experience with pharmacological treatments for LAM. Therefore, we conducted a systematic review and meta-analysis to assess the efficacy and safety of these therapies.MethodsPubMed (Medline), EMBASE, Cochrane Library, Web of Science and EBSCO Host were searched (until March 31, 2019) for eligible prospective studies regarding LAM patients treated with pharmacological treatments. Random effect models were used for quantitative analysis.ResultsFourteen prospective studies regarding five pharmacological treatments (including sirolimus, everolimus, doxycycline, triptorelin, and a combination therapy of sirolimus and hydroxychloroquine) were enrolled in our systematic review, and ten of them were used for the meta-analysis. Seven prospective studies reported that sirolimus was effective at improving or stabilizing lung function and alleviating renal angiomyolipoma (AML) in LAM patients. Subsequent quantitative analyses showed that during sirolimus treatment, the pooled values of lung function and 6-min walk distance (6MWD) were not significantly changed (P > 0.05), with the pooled response rate of AML being 0.62 (95% confidence intervals [CIs]: 0.43 to 0.82, I2 = 65%). Regarding everolimus, three prospective studies reported similar effects to those of sirolimus with regard to preserving lung function and reducing AMLs. The meta-analysis showed that the changes in lung function during everolimus treatment were not statistically significant (P > 0.05), while the pooled response rate of AML was 0.78 (95% CI: 0.68 to 0.88, I2 = 8%). Neither the qualitative nor the quantitative results confirmed the benefits of doxycycline or triptorelin treatment, and the effects of the combination therapy were unclear in LAM patients. Most of the adverse events during pharmacological treatments were low or moderate grade and tolerable.ConclusionsOverall, sirolimus and everolimus were recommended for the treatment of LAM because they could stabilize lung function and alleviate renal AML. Doxycycline and triptorelin were not recommended for the treatment of LAM because no beneficial outcomes were consistently observed. The efficacy and safety of combination therapy remain to be further explored.
Highlights
Lymphangioleiomyomatosis (LAM) is a rare, low-grade multisystem neoplastic disease
Loss of tuberous sclerosis complex (TSC) gene function activates the mammalian target of rapamycin signaling pathway, which is a key regulator of cell growth, motility, and survival, resulting in the proliferation of LAM cells [14]
Only 14 studies met the inclusion criteria for the systematic review, including 3 Randomized controlled trial (RCT) [23, 25, 33] and 11 single-arm trials [9, 20, 22, 24, 34,35,36,37,38,39,40], of which ten studies were included in the meta-analysis [22,23,24,25, 33,34,35,36, 39, 40]
Summary
Lymphangioleiomyomatosis (LAM) is a rare, low-grade multisystem neoplastic disease. Lymphangioleiomyomatosis (LAM) is a rare, low-grade multisystem neoplastic disease characterized by cystic lung destruction, chylous fluid accumulation (pleural or ascitic), angiomyolipomas (AMLs) and lymphangioleiomyomas [1, 2]. LAM occurs sporadically (sLAM) or is associated with tuberous sclerosis complex (TSC). LAM may recur in transplanted lungs [10, 11], and patients with AML often develop new lesions and relapse after treatment [12]. Loss of TSC gene function activates the mammalian target of rapamycin (mTOR) signaling pathway, which is a key regulator of cell growth, motility, and survival, resulting in the proliferation of LAM cells [14]. The lungs and lymphatics of LAM patients are infiltrated with LAM cells [15]. LAM cells can express vascular endothelial growth factor D (VEGFD), which may facilitate the migration of LAM cells to lymphatic vessels and promote metastatic spread [17, 18]
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