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Therapeutic Advances in Urology Aug 2016Renal angiomyolipomata associated with tuberous sclerosis complex are often bilateral, multiple and progressive. They cause significant morbidity and mortality in older... (Review)
Review
Renal angiomyolipomata associated with tuberous sclerosis complex are often bilateral, multiple and progressive. They cause significant morbidity and mortality in older children and adults. Surveillance and pre-emptive treatment reduce this risk. Recent research suggests treatment with mammalian target of rapamycin inhibitors is better at preventing bleeding, recurrence, and preserving renal function than percutaneous embolization.
PubMed: 27928430
DOI: 10.1177/1756287216641353 -
The Cochrane Database of Systematic... Jul 2016Previous studies have shown potential benefits of rapamycin or rapalogs for treating people with tuberous sclerosis complex. Although everolimus (a rapalog) is currently... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Previous studies have shown potential benefits of rapamycin or rapalogs for treating people with tuberous sclerosis complex. Although everolimus (a rapalog) is currently approved by the FDA (U.S. Food and Drug Administration) and the EMA (European Medicines Agency) for tuberous sclerosis complex-associated renal angiomyolipoma and subependymal giant cell astrocytoma, applications for other manifestations of tuberous sclerosis complex have not yet been established. A systematic review is necessary to establish the clinical value of rapamycin or rapalogs for various manifestations in tuberous sclerosis complex.
OBJECTIVES
To determine the effectiveness of rapamycin or rapalogs in people with tuberous sclerosis complex for decreasing tumour size and other manifestations and to assess the safety of rapamycin or rapalogs in relation to their adverse effects.
SEARCH METHODS
Relevant studies were identified by authors from the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, and clinicaltrials.gov. Relevant resources were also searched by the authors, such as conference proceedings and abstract books of conferences, from e.g. the Tuberous Sclerosis Complex International Research Conferences, other tuberous sclerosis complex-related conferences and the Human Genome Meeting. We did not restrict the searches by language as long as English translations were available for non-English reports.Date of the last searches: 14 March 2016.
SELECTION CRITERIA
Randomized or quasi-randomized studies of rapamycin or rapalogs in people with tuberous sclerosis complex.
DATA COLLECTION AND ANALYSIS
Data were independently extracted by two authors using standard acquisition forms. The data collection was verified by one author. The risk of bias of each study was independently assessed by two authors and verified by one author.
MAIN RESULTS
Three placebo-controlled studies with a total of 263 participants (age range 0.8 to 61 years old, 122 males and 141 females, with variable lengths of study duration) were included in the review. We found high-quality evidence except for response to skin lesions which was judged to be low quality due to the risk of attrition bias. Overall, there are 175 participants in the treatment arm (rapamycin or everolimus) and 88 in the placebo arm. Participants all had tuberous sclerosis complex as proven by consensus diagnostic criteria as a minimum. The quality in the description of the study methods was mixed, although we assessed most domains as having a low risk of bias. Blinding of treatment arms was successfully carried out in all of the studies. However, two studies did not report allocation concealment. Two of the included studies were funded by Novartis Pharmaceuticals.Two studies (235 participants) used oral (systemic) administration of everolimus (rapalog). These studies reported response to tumour size in terms of the number of individuals with a reduction in the total volume of tumours to 50% or more relative to baseline. Significantly more participants in the treatment arm (two studies, 162 participants, high quality evidence) achieved a 50% reduction in renal angiomyolipoma size, risk ratio 24.69 (95% confidence interval 3.51 to 173.41) (P = 0.001). For the sub-ependymal giant cell astrocytoma, our analysis of one study (117 participants, high quality evidence) showed significantly more participants in the treatment arm achieved a 50% reduction in tumour size, risk ratio 27.85 (95% confidence interval 1.74 to 444.82) (P = 0.02). The proportion of participants who showed a skin response from the two included studies analysed was significantly increased in the treatment arms, risk ratio 5.78 (95% confidence interval 2.30 to 14.52) (P = 0.0002) (two studies, 224 participants, high quality evidence). In one study (117 participants), the median change of seizure frequency was -2.9 in 24 hours (95% confidence interval -4.0 to -1.0) in the treatment group versus -4.1 in 24 hour (95% confidence interval -10.9 to 5.8) in the placebo group. In one study, one out of 79 participants in the treatment group versus three of 39 in placebo group had increased blood creatinine levels, while the median percentage change of forced expiratory volume at one second in the treatment arm was -1% compared to -4% in the placebo arm. In one study (117 participants, high quality evidence), we found that those participants who received treatment had a similar risk of experiencing adverse events compared to those who did not, risk ratio 1.07 (95% confidence interval 0.96 - 1.20) (P = 0.24). However, as seen from two studies (235 participants, high quality evidence), the treatment itself led to significantly more adverse events resulting in withdrawal, interruption of treatment, or reduction in dose level, risk ratio 3.14 (95% confidence interval 1.82 to 5.42) (P < 0.0001).One study (28 participants) used topical (skin) administration of rapamycin. This study reported response to skin lesions in terms of participants' perception towards their skin appearance following the treatment. There was a tendency of an improvement in the participants' perception of their skin appearance, although not significant, risk ratio 1.81 (95% confidence interval 0.80 to 4.06, low quality evidence) (P = 0.15). This study reported that there were no serious adverse events related to the study product and there was no detectable systemic absorption of the rapamycin during the study period.
AUTHORS' CONCLUSIONS
We found evidence that oral everolimus significantly increased the proportion of people who achieved a 50% reduction in the size of sub-ependymal giant cell astrocytoma and renal angiomyolipoma. Although we were unable to ascertain the relationship between the reported adverse events and the treatment, participants who received treatment had a similar risk of experiencing adverse events as compared to those who did not receive treatment. Nevertheless, the treatment itself significantly increased the risk of having dose reduction, interruption or withdrawal. This supports ongoing clinical applications of oral everolimus for renal angiomyolipoma and subependymal giant cell astrocytoma. Although oral everolimus showed beneficial effect on skin lesions, topical rapamycin only showed a non-significant tendency of improvement. Efficacy on skin lesions should be further established in future research. The beneficial effects of rapamycin or rapalogs on tuberous sclerosis complex should be further studied on other manifestations of the condition.
Topics: Administration, Oral; Administration, Topical; Angiolipoma; Astrocytoma; Brain Neoplasms; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Male; Randomized Controlled Trials as Topic; Seizures; Sirolimus; Skin Diseases; Tuberous Sclerosis; Tumor Burden
PubMed: 27409709
DOI: 10.1002/14651858.CD011272.pub2 -
Journal of the European Academy of... Apr 2016Tuberous sclerosis complex (TSC) is a genetic multisystem disorder associated with constitutive overactivation of the mammalian target of rapamycin (mTOR) pathway and... (Review)
Review
Tuberous sclerosis complex (TSC) is a genetic multisystem disorder associated with constitutive overactivation of the mammalian target of rapamycin (mTOR) pathway and characterized by development of benign tumours in various organs. mTOR inhibitors have proven to be effective in the targeted therapy of certain TSC-associated pathologies such as subependymal giant cell astrocytomas (SEGAs) and renal angiomyolipomas (AMLs). Accumulating experimental and clinical data suggest that mTOR inhibitors might have a systemic, disease-modifying influence on affected individuals. This systematic review provides an analysis of available clinical data concerning systemic effect of mTOR inhibitors and the influence of mTOR inhibition on different manifestations of TSC in individual patients.
Topics: Humans; TOR Serine-Threonine Kinases; Tuberous Sclerosis
PubMed: 26403211
DOI: 10.1111/jdv.13356 -
Orphanet Journal of Rare Diseases Aug 2015Rapamycin has gained significant attention for its potential activity in reducing the size of TSC-associated tumors, thus providing alternative to surgery. This study... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Rapamycin has gained significant attention for its potential activity in reducing the size of TSC-associated tumors, thus providing alternative to surgery. This study aimed at determining the efficacy of rapamycin and rapalogs for reducing the size of TSC-associated solid tumors in patients with Tuberous Sclerosis Complex (TSC).
METHODS
Our data sources included electronic searches of the PubMed. We included into our meta-analysis any type of non-randomized study that reported the use of rapamycin and rapalogs for reducing the size of TSC-associated solid tumors in patients with TSC. Data was entered into Cochrane Review Manager Version 5.3 and analyzed.
RESULTS
Four case reports and 4 clinical trials were included. Five patients from the case reports (all with SEGA) and 91 patients from the clinical trials (41 with SEGA, 63 with kidney angiomyolipoma and 5 with liver angiomyolipoma) were included into the analysis. Volume and diameter of SEGAs were significantly reduced by mean difference of 1.23 cc (95 % CI -2.32 to -0.13; p = 0.03) and 7.91 mm (95 % CI -11.82 to -4.01; p < 0.0001), respectively. Volume and mean of sum of longest diameter of kidney angiomyolipomas were significantly reduced by mean difference of 39.5 cc (95 % CI -48.85 to -30.15; p <0.00001) and 69.03 mm (95 % CI -158.05 to 12.65; p = 0.008), respectively. In liver angiomyolipomas, however, reduction in tumor size was not evident. Sum of longest diameter of liver angiomyolipomas in 4 patients were enlarged by 2.7 mm (95 % CI 28.42 to -23.02) by the end of treatment, though not significant (p = 0.84).
CONCLUSIONS
Rapamycin and rapalogs showed efficacy towards reducing the size of SEGA and kidney angiomyolipoma but not liver angiomyolipomas. This finding is strengthening the conclusion of our Cochrane systematic review on the randomized trials.
Topics: Adolescent; Adult; Female; Humans; Male; Neoplasms; Sirolimus; Tuberous Sclerosis; Young Adult
PubMed: 26259610
DOI: 10.1186/s13023-015-0317-7 -
World Journal of Gastroenterology May 2015A 58-year-old man presented with the chief complaint of abdominal bloating and was incidentally found to have a liver tumor. As diagnostic imaging studies could not rule... (Review)
Review
A 58-year-old man presented with the chief complaint of abdominal bloating and was incidentally found to have a liver tumor. As diagnostic imaging studies could not rule out malignancy, the patient underwent partial resection of segment 3 of the liver. The lesion pathologically showed eosinophilic proliferation, in addition to immunohistochemical positivity for human melanoma black 45 and Melan-A, thereby leading to the diagnosis of a hepatic perivascular epithelioid cell tumor (PEComa). A PEComa arising from the liver is relatively rare. Moreover, the name 'PEComa' has not yet been widely recognized, and the same disease entity has been called epithelioid angiomyolipoma (EAML), further diminishing the recognition of PEComa. In addition, PEComa imaging findings mimic those of malignant liver tumors, and clinically, this tumor tends to enlarge. Therefore, a PEComa is difficult to diagnose. We conducted a systematic review of PEComa and EAML cases and discuss the results, including findings useful for differentiating perivascular epithelioid cell tumors from malignant liver tumors.
Topics: Biomarkers, Tumor; Biopsy; Diffusion Magnetic Resonance Imaging; Hepatectomy; Humans; Immunohistochemistry; Incidental Findings; Liver Neoplasms; Male; Middle Aged; Perivascular Epithelioid Cell Neoplasms; Predictive Value of Tests; Tomography, X-Ray Computed; Treatment Outcome
PubMed: 25954119
DOI: 10.3748/wjg.v21.i17.5432 -
The Journal of Urology Sep 2015Transarterial embolization is increasingly used in the management of renal angiomyolipoma. The level of evidence establishing the safety and efficacy of transarterial... (Review)
Review
INTRODUCTION
Transarterial embolization is increasingly used in the management of renal angiomyolipoma. The level of evidence establishing the safety and efficacy of transarterial embolization has not increased in parallel.
MATERIALS AND METHODS
Using the MOOSE (Meta-analysis Of Observational Studies in Epidemiology) criteria a systematic review of transarterial embolization of angiomyolipoma was performed to establish procedural safety and efficacy. A MEDLINE® PubMed® search revealed 1,739 publications, of which 31 studies met eligibility criteria.
RESULTS
A total of 524 cases of transarterial embolization of angiomyolipoma were included in analysis. Self-limiting post-embolization syndrome developed following 35.9% of embolizations and further morbidity developed in 6.9%. No procedural mortality was reported. At a mean followup of 39 months the mean size reduction was 3.4 cm (-38.3% of angiomyolipoma diameter). Unplanned repeat embolization or surgery was required in 20.9% of cases during this period. The most frequent indications for repeat procedures included angiomyolipoma revascularization in 30.0% of cases, unchanged or increasing size in 22.6%, refractory or recurring symptoms in 16.7% and representation with acute retroperitoneal hemorrhage in 14.3%. Treatment included a combination of 2 or more embolic agents in 46.8% of cases, ethanol monotherapy in 41.7%, coil monotherapy in 6.2% and foam or microparticle monotherapy in 5.2%.
CONCLUSIONS
Transarterial embolization of angiomyolipoma demonstrates low rates of mortality and serious complications. Re-treatment rates and size reduction at a mean followup of 39 months are presented. Longitudinal data assessing long-term size reduction and re-treatment rates are lacking. Recommendations guiding the indications for transarterial embolization and clear followup require further longitudinal data.
Topics: Angiomyolipoma; Arteries; Embolization, Therapeutic; Humans; Kidney Neoplasms
PubMed: 25916674
DOI: 10.1016/j.juro.2015.04.081 -
The Journal of Urology Nov 2014We evaluate the efficacy and safety of sirolimus in the treatment of renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic... (Review)
Review
PURPOSE
We evaluate the efficacy and safety of sirolimus in the treatment of renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis.
MATERIALS AND METHODS
A systematic search of MEDLINE®, Embase®, ACP (American College of Physicians) Journal Club, Cochrane CENTRAL (Central Register of Controlled Trials) and Cochrane Database of Systematic Reviews was performed. A secondary hand search was performed in relevant journals, references and the grey literature. The screening, quality assessment and data extraction of the retrieved articles were independently performed by 2 reviewers in duplicate. Studies that reported an angiomyolipoma response or adverse events after the treatment of sirolimus were included in the analysis.
RESULTS
Four prospective nonrandomized studies involving 94 patients were included in the study. The overall response rate of angiomyolipoma was 46.8% (44 of 94) in the first year. In the second year the angiomyolipoma response rate for those patients still being treated with sirolimus was 43.5% (20 of 46) and the response rate of the patients whose sirolimus treatment was discontinued was 5% (2 of 40). The most common sirolimus related adverse reactions were stomatitis, respiratory infection, skin lesions and hyperlipidemia, while serious adverse reactions were rarely observed.
CONCLUSIONS
This study shows that renal angiomyolipoma shrank during sirolimus therapy but tended to regrow after the therapy was stopped. In general, sirolimus is an effective and safe therapy for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis.
Topics: Angiomyolipoma; Antibiotics, Antineoplastic; Humans; Kidney Neoplasms; Lymphangioleiomyomatosis; Sirolimus; Treatment Outcome; Tuberous Sclerosis
PubMed: 24813310
DOI: 10.1016/j.juro.2014.04.096