The effect of everolimus on renal angiomyolipoma in patients with tuberous sclerosis complex being treated for subependymal giant cell astrocytoma: subgroup results from the randomized, placebo-controlled, Phase 3 trial EXIST-1

Kingswood, J. Chris; Jóźwiak, Sergiusz; Ed, Belousova; Frost, Michael; Kuperman, Rachel; Bebin, E. Martina; Korf, Bruce R.; Flamini, J. Robert; Kohrman, Michael; Sparagana, Steven; Wu, Joyce; Brechenmacher, Thomas; Stein, Karen; Berkowitz, Noah; Bissler, John J.; Franz, David Neal

doi:10.1093/ndt/gfu013

Cited by 78 publications

(58 citation statements)

References 17 publications

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“…The striking adverse effects in this case involve stomatitis, nasopharyngitis, and acne-like skin lesions (50). In another trial on TSC AML in patients with subependymal giant cell astrocytoma (SEGA), everolimus caused a decline of more than 50% in the tumor volume (51). Both these studies confirmed the efficiency and safety of everolimus (50,51).…”

Section: Treatmentsupporting

confidence: 53%

“…In another trial on TSC AML in patients with subependymal giant cell astrocytoma (SEGA), everolimus caused a decline of more than 50% in the tumor volume (51). Both these studies confirmed the efficiency and safety of everolimus (50,51). All in all, according to the international TSC consensus group, recent recommendations for the treatment of AML patients with TSC, particularly in case of acute hemorrhage, include embolization and corticosteroids; as for asymptomatic lesions with a size larger than 3 cm, the administration of mTOR inhibitors followed by selective arterial emobilization or partial resection is recommended (36).…”

Section: Treatmentmentioning

confidence: 99%

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

et al. 2017

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Recent prophylactic treatment options and diagnostic tools show a suboptimal improvement in patients with renal angiomyolipoma (AML). This study was an attempt to review management strategies applied before invasive options. An extensive research on medical databases such as PubMed and Scopus was performed from 1999 to 2016 using the following keywords: 'kidney', 'renal', and 'angiomyolipoma'. All related studies on patients treating with conservative or minimally-invasive procedures were included. However, reports on surgical treatments were excluded. Treatment strategies have been selected based on outcomes resulting from computed tomography (CT) and magnetic resonance (MR) imaging. Fat content and tumor size are the most common used indications for AMLs. Unenhanced CT and chemical shift imaging provide good evidence in case of fat-poor AMLs. Chemical analysis and percutaneous biopsy are recommended in case of a diagnostic challenge. A tumor size of 6 cm or larger in diameter might necessitate invasive treatment, while AMLs patients with tumors around 4 cm may require prophylactic treatment. Of all treatment options, embolization indicated a high risk of reintervention. Moreover, everolimus and sirolimus as 2 inhibitors of mammalian target of rapamycin (mTOR) have been evaluated in clinical trials and demonstrated promising outcomes. In conclusion, advances in imaging techniques along with mTOR inhibitors and embolic materials potentiate functional outcomes in AMLs.

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Section: Treatmentsupporting

confidence: 53%

Section: Treatmentmentioning

confidence: 99%

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

et al. 2017

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“…The first mTOR inhibitor tried was sirolimus, also known as rapamycin, initially developed as an immunosuppressive agent in solid organ transplantations. Everolimus is a rapamycin derivative that has been recently studied with data from two randomized controlled trials suggesting safety and efficacy (72,73). EXIST-2, a double-blind-randomized controlled trial that included 118 patients with 3 cm or larger AMLs in the setting of TSC, randomized everolimus and placebo (67).…”

Section: Discussionmentioning

confidence: 99%

Selective arterial embolization of symptomatic and asymptomatic renal angiomyolipomas: a retrospective study of safety, outcomes and tumor size reduction

Bardin¹,

Chevallier²,

Bertaut³

et al. 2017

Quant. Imaging Med. Surg.

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Background: Angiomyolipoma (AML) is the most common renal benign tumor. Treatment should be considered for symptomatic patients or for those at risk for complications, especially retroperitoneal bleeding which is correlated to tumor size, grade of the angiogenic component and to the presence of tuberous sclerosis complex (TSC). This study reports our single-center experience with the use of selective arterial embolization (SAE) in the management of symptomatic and asymptomatic renal AMLs. Methods:In this retrospective mono-centric study, all demographic and imaging data, medical records, angiographic features, outpatient charts and follow-up visits of patients who underwent prophylactic or emergency SAE for AMLs between January 2005 and July 2016 were reviewed. Tumor size and treatment outcomes were assessed at baseline and after the procedure during follow-up. Computed tomography (CT), magnetic resonance imaging (MRI) or ultrasonography was used to evaluate AML shrinkage. Renal function was measured pre-and post-procedure.Results: Twenty-three patients (18 females, 5 males; median age, 45 years; range, 19-85 years) who underwent SAE either to treat bleeding AML (n=6) or as a prophylactic treatment (n=17) were included.Overall, 34 AMLs were embolized. TSC status was confirmed for 6 patients. Immediate technical success rate was 96% and 4 patients benefitted from an additional procedure. Major complications occurred in 3 patients and minor post-embolization syndrome (PES) in 14 patients. The mean AML size reduction rate was 26.2% after a mean follow-up was 20.5 months (range, 0.5-56 months), and only non-TSC status was significantly associated with better shrinkage of tumor (P=0.022). Intralesional aneurysms were significantly more frequent in patients with hemorrhagic presentation (P=0.008). There was no change in mean creatinine level after SAE.Conclusions: SAE is a safe and effective technique to manage renal AMLs as a preventive treatment as well as in emergency setting, with significant reduction in tumor size during follow-up. A multidisciplinary approach remains fundamental, especially for TSC patients. In addition to size, the presence of intralesional aneurysms should be considered in any prophylactic treatment decision.

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“…Angiomyolipoma volume reductions with everolimus were sustained over 48 weeks of treatment (fig. 2) [20]. In EXIST-2, the primary end point of angiomyolipoma response was achieved in 42% of patients (33 of 79) compared with 0% for placebo (0 of 39, p < 0.0001) after a median everolimus exposure of 8.7 months, and the median time to reach an angiomyolipoma response was 2.9 months [18].…”

Section: Outcome Of Interventionmentioning

confidence: 99%

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

Kingswood

Bissler²,

Budde

et al. 2016

Nephron

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Renal-related disease is the most common cause of tuberous sclerosis complex (TSC)-related death in adults, and renal angiomyolipomas can lead to complications that include chronic kidney disease (CKD) and hemorrhage. International TSC guidelines recommend mammalian target of rapamycin (mTOR) inhibitors as first-line therapy for management of asymptomatic, growing angiomyolipomas >3 cm in diameter. This review discusses data regarding patient outcomes that were used to develop current guidelines for embolization of renal angiomyolipomas and presents recent data on 2 available mTOR inhibitors - sirolimus and everolimus - in the treatment of angiomyolipoma. TSC-associated renal angiomyolipomas can recur after embolization. Both sirolimus and everolimus have shown effectiveness in reduction of angiomyolipoma volume, with an acceptable safety profile that includes preservation of renal function with long-term therapy. The authors propose a hypothesis for mTORC1 haploinsufficiency as an additional mechanism for CKD and propose that preventive therapy with mTOR inhibitors might have a role in reducing the number of angiomyolipoma-related deaths. Because mTOR inhibitors target the underlying pathophysiology of TSC, patients might benefit from treatment of multiple manifestations with one systemic therapy. Based on recent evidence, new guidelines should be considered that support the earlier initiation of mTOR inhibitor therapy for the management of renal angiomyolipomas to prevent future serious complications, rather than try to rescue patients after the complications have occurred.

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The effect of everolimus on renal angiomyolipoma in patients with tuberous sclerosis complex being treated for subependymal giant cell astrocytoma: subgroup results from the randomized, placebo-controlled, Phase 3 trial EXIST-1

Abstract: Everolimus showed efficacy in reducing angiomyolipoma lesion volume in patients with SEGA associated with TSC.The trial is registered with ClinicalTrials.gov, number NCT00789828; http://clinicaltrials.gov/ct2/show/NCT00789828?term=EXIST-1&rank=1.

Cited by 78 publications

References 17 publications

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

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

Selective arterial embolization of symptomatic and asymptomatic renal angiomyolipomas: a retrospective study of safety, outcomes and tumor size reduction

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

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