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
Highlights
Tuberous sclerosis (TS) is a rare autosomal dominant systemic disease with an estimated prevalence of 1/6000
Eligibility The study population comprised 17 patients aged over 10 years who were diagnosed with TS and had at least 1 renal AML > 2 cm in diameter and baseline creatinine < 2 mg/dl
Tumour volume was analyzed over time by means of mixed models for repeated measurement analysis (MMRM) [12], which assumes unmeasured observations to be missing at random (MAR) [13]
Summary
Tuberous sclerosis (TS) is a rare autosomal dominant systemic disease with an estimated prevalence of 1/6000. Tuberous sclerosis (TS), or Bourneville-Pringle disease, is a rare autosomal dominant systemic disease with an estimated prevalence of 1/6000 [1] It manifests on the skin and may show renal, neurological, pulmonary and cardiac symptoms. Renal angiomyolipoma (AML) is a benign tumour formed by abnormal vessels, immature smooth muscle tissue, and adipocytes [2] It is usually bilateral and multiple and its incidence ranges from 55% to 75% among TS patients. As it can lead to spontaneous haemorrhage and, albeit more rarely in very bulky AML, arterial hypertension and kidney failure [3]. This is the most serious manifestation after neurological involvement. The main therapeutic options are embolisation, elective surgery, and emergency nephrectomy in cases of uncontrollable haemorrhage [2]
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