Assessing the effectiveness of rapamycin on angiomyolipoma in tuberous sclerosis: a two years trial

Abstract

BackgroundTuberous sclerosis (TS) is a rare autosomal dominant systemic disease with an estimated prevalence of 1/6000. Renal angiomyolipoma (AML) is a benign tumour with high morbidity frequently present in TS. The aim of the study was to test the effect of rapamycin in reducing the volume of AML in TS.MethodsTwenty four-month prospective open-label, single arm, unicentre Phases II andIII study. The primary endpoint was to evaluate the effect of treatment on the reduction of at least 50% AML volume from baseline at 24 months. The secondary endpoints were: average tumour reduction, surgical complications, skin lesions and drug safety.The study population comprised 17 patients, aged >10 years who were diagnosed with TS and had ≥1 renal AML >2 cm of diameter and had a serum creatinine < 2mg/dl and urine protein/creatinine ratio < 22.6 mg/mmol. The trial was conducted at Fundació Puigvert. Rapamycin was given to achieve stable plasma levels between 4 and 8 ng/ml. AML volume was estimated using orthogonal measurements by MRI at baseline, 6, 12 and 24 months.ResultsTen out of 17 patients were success responders for the main outcome −58.8%, 95%CI: 32.9% to 81.6%-. After 6 months of therapy, the mean volume decrease was 55.18% (5.01 standard error (SE); p<0.001) and 66.38% (4.41 SE; p<0.001) at year 1. There was no significant decrease between year 1 and 2. According to RECIST criteria, all patients achieved a partial response at year 1 and all but two had already achieved this partial response after 6 months.The main analysis was performed according to the intention-to-treat principle analysis. Tumour volume was analyzed over time by means of mixed models for repeated measurement analysis. We used the baseline tumour volume as a covariate for the absolute change and percentage change from baseline data. The analysis was performed using SAS version 9.2 software, and the level of significance was established at 0.05 (two-sided).ConclusionsThis study show that mTOR inhibitors are a relatively safe, efficacious and less aggressive alternative than currently available options in the management of AML in TS.Trial registrationEudraCT number: 2007-005978-30, ClinicalTrials.gov number: NCT0121712

Review of the Tuberous Sclerosis Renal Guidelines from the 2012 Consensus Conference: Current Data and Future Study

“…table 2). Four small, open-label studies showed the effectiveness of sirolimus in the management of renal angiomyolipoma [14,15,16,17]. …”

Transarterial Embolization of Angiomyolipoma: A Systematic Review

“…The tumour biology in these patients demonstrate over-activation mTOR complex 1 (mTORC1), and mTor inhibitors have demonstrated size-reduction in TSC-associated angiomyolipomata. 13,14 The use of chemotherapy, however, is not widely employed in the more common, sporadic form of AML. Future advances may exploit the recently proven over-expression of selective hormonal receptors through hormonal regulation.…”

Recent Strategies for the Management of Renal Angiomyolipoma: A Review of Diagnostic and Therapeutic Approaches

“…Moreover, some serious adverse effects were documented: diarrhea, pyelonephritis, stomatitis, and respiratory infections (47). Grade 1 or 2 adverse events including mouth ulcers, hyperlipidemia, and peripheral edema were observed in 13 patients treated with sirolimus for up to 1 year (49). Nevertheless, the safety and efficacy of sirolimus were proved in long-term trials (49).…”

“…Grade 1 or 2 adverse events including mouth ulcers, hyperlipidemia, and peripheral edema were observed in 13 patients treated with sirolimus for up to 1 year (49). Nevertheless, the safety and efficacy of sirolimus were proved in long-term trials (49). In a multicenter, randomized, double-blind, placebocontrolled trial, everolimus, another rapamycin derivative, caused a higher response rate as compared to placebo (42% vs. 0%) and reduced tumor volume in 80% of patients with TSC or sporadic lymphangioleiomyomatosis AML on Week 24.…”