- Email: [email protected]
Safety of Everolimus in Patients Younger than 3 Years of Age: Results from EXIST-1, a Randomized, Controlled Clinical Trial
Safety of Everolimus in Patients Younger than 3 Years of Age: Results from EXIST-1, a Randomized, Controlled Clinical Trial Sergiusz Jozwiak, MD1,2, Katarzyna Kotulska, MD2, Noah Berkowitz, MD3, Thomas Brechenmacher, MSc4, and David Neal Franz, MD5 Objectives To assess the long-term safety of everolimus in young children with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA). Study design EXamining everolimus In a Study of Tuberous Sclerosis Complex-1 (EXIST-1) was a multicenter, randomized, double-blind phase 3 study with an open-label extension evaluating the efficacy and tolerability of everolimus in patients with TSC-associated SEGA. Everolimus was initiated at 4.5 mg/m2/day and titrated to blood trough levels of 5-15 ng/mL. Post hoc analysis of safety data (adverse events [AEs]) was performed in a subgroup of patients aged <3 years at everolimus initiation. Results Eighteen patients (median age 1.82 years) were included; 16 were still receiving everolimus at the analysis cut-off date of January 11, 2013. Median everolimus exposure was 31.1 months (range, 11.5-39 months). One patient discontinued treatment because of AEs (ie, Acinetobacter bacteremia, increased blood alkaline phosphatase, and viral infection). AEs were reported in all patients, but events were mostly grade 1/2 in severity; 12 patients (66.7%) experienced grade 3 events, and 2 patients (11.1%) reported grade 4 events. The most common AEs were stomatitis, cough, pharyngitis, and pyrexia; no new safety issues were identified in this population. Serious AEs were reported in 50% of patients; these were suspected to be medication related in 4 patients (22.2%). Conclusions Everolimus appears to be a safe therapeutic option for patients aged <3 years with TSC-associated SEGA. The small sample size in this subpopulation limits interpretation of the results; additional studies in the pediatric population are needed and are underway. (J Pediatr 2016;-:---). Trial registration ClinicalTrials.gov: NCT00789828.
T
uberous sclerosis complex (TSC) is a multisystem disorder characterized by the growth of nonmalignant tumors (hamartomas) in various organs.1 TSC can manifest in utero and affect individuals throughout their lifetime.2 In the brain, subependymal giant cell astrocytoma (SEGA) occurs in up to 20% of patients with TSC.3-5 SEGAs typically appear during the first 20 years of life and on occasion have been detected prenatally.6-9 They are slow-growing tumors composed of astrocytes, spindle cells, and giant cells.6,10 Although SEGAs are often asymptomatic, their clinical consequences can be grave because of their close proximity to the foramen of Monro. As SEGAs grow, there is the potential for obstruction of cerebrospinal fluid flow, possibly leading to hyFrom the Department of Pediatric Neurology, Warsaw drocephalus and increased intracranial pressure, which may result in death.4,7,11 Medical University; Department of Neurology and Treatment of SEGA includes surgery and pharmacotherapy with mammalian Epileptology, The Children’s Memorial Health Institute, Warsaw, Poland; Department of Oncology, Novartis target of rapamycin (mTOR) inhibitors.12 Surgical resection of SEGA, recommenPharmaceuticals Corporation, Florham Park, NJ; 12 Department of Oncology, Novartis Pharmaceuticals ded in patients with acute symptoms, can be curative, but there are risks and a S.A.S., Rueil-Malmaison, France; and Department of potential for postoperative and long-term complications. Postoperative complicaNeurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH tions include hemiparesis, development of new seizures, cognitive impairment, hyFunded by Novartis Pharmaceuticals Corporation. S.J. 6,7,11,13 drocephalus, infections, and even death. In the largest reported series to date has received speaking and advisory board honoraria from Novartis Pharmaceuticals Corporation. K.K. has of surgically resected SEGAs, including 64 surgeries in 57 patients, complications received speaking honoraria from Novartis. D.F. has 14 received support from Novartis for other research at his were most frequent in children aged <3 years than in older patients. Furthermore, institution; has served as a consultant to Novartis (with payments going to Cincinnati Children’s Hospital Mediif gross total resection is not achieved, there is the potential for SEGA regrowth, cal Center); has received honoraria from Novartis and necessitating additional surgical interventions and/or therapy.7,11,13,14 Lundbeck Pharmaceuticals; has been reimbursed by Novartis and Lundbeck Pharmaceuticals for travel costs A multicenter, randomized, double-blind, placebo-controlled phase 3 study, for lectures; and has performed legal work in reviewing medical malpractice cases and occasionally in giving EXamining everolimus In a Study of Tuberous Sclerosis Complex-1 (EXIST-1) 1
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AE EXIST-1 mTOR SAE SEGA TSC
Adverse event EXamining everolimus In a Study of Tuberous Sclerosis Complex-1 Mammalian target of rapamycin Serious AE Subependymal giant cell astrocytoma Tuberous sclerosis complex
expert testimony for various attorneys. The other authors are employees of Novartis. Novartis was responsible for the study design, conduct, and data collection and participated in data analysis and interpretation; all authors had full access to the study report and had final responsibility for the decision to submit for publication. Writing and editorial assistance provided by ApotheCom (Yardley, PA), which was funded by Novartis Pharmaceuticals Corporation, and performed under the direction of the authors.
0022-3476/$ - see front matter. Copyright ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2016.01.027
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(NCT00789828) evaluated everolimus for the treatment of TSC-associated SEGA in 117 patients irrespective of age.15,16 Short- and long-term evaluation of their therapy is promising. Everolimus is the only mTOR inhibitor evaluated in a randomized, placebo-controlled clinical trial for patients with TSC and SEGA. It was initially approved for use in patients aged $3 years. Data for mTOR inhibitors from other indications in patients aged <3 years are also limited. In TSC, some manifestations are present at birth or soon after,2 and given the increasing body of evidence that mTOR inhibition may be beneficial not only for SEGA, but also epilepsy, neuropsychiatric problems, skin lesions, and other manifestations,17-20 a significant number of patients are candidates for medical treatment as infants or toddlers. Here we report the results of a post hoc analysis focusing on the safety and tolerability of everolimus in the subgroup of EXIST-1 patients aged <3 years when everolimus was initiated, using long-term data with a cut-off date of January 11, 2013.
Methods The methods used in EXIST-1 have been previously published.15,16 Patients, irrespective of age, with TSC-associated SEGA and radiologic evidence of $1 of 3 conditions (serial SEGA growth, presence of a new SEGA lesion, and/or new or worsening hydrocephalus) were randomly assigned 2:1 to receive double-blinded treatment with either everolimus or placebo. Randomization was stratified by the use of enzyme-inducing antiepileptic medications. Patients received oral everolimus initiated at 4.5 mg/m2/d (titrated to attain blood trough levels of 5-15 ng/mL) or placebo. Protocolspecified dose modifications were permitted if treatmentrelated toxic effects occurred.15,16 In cases of treatment interruption, study medication was resumed if the toxicity recovered to grade #1 within 6 weeks. Treatment was generally reintroduced at the initial dose in cases of grade 1-3 toxicity, except with grade 3 stomatitis or pneumonitis, platelets <50 000/mm3, absolute neutrophil count <500/mm3, or febrile neutropenia for which treatment was restarted at a lower dose level. The patient was discontinued from the study if treatment was interrupted for $6 weeks or if grade 4 toxicity was experienced. The protocol was approved by the institutional review board/ethics committee at each center, and the study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. Safety data were reviewed every 6 months by an independent data-monitoring committee, and all patients provided written informed consent. For participants aged <18 years, written informed consent was obtained from a legally acceptable representative (eg, a parent), and verbal assent was obtained if the patient was able. The primary efficacy endpoint in the core phase of the study was SEGA response rate (as determined by independent central radiology review). SEGA response was defined 2
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as (1) a $50% reduction in SEGA volume relative to baseline (where SEGA volume was the sum of all target SEGA lesion volumes identified at baseline); and (2) no unequivocal worsening of nontarget SEGA lesions, no new SEGA lesions ($1 cm in longest diameter), and no new or worsening hydrocephalus.15,16 Safety and tolerability were assessed throughout the study according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Rate, severity, and causal relationship of adverse events (AEs) and serious AEs (SAEs) to treatment were recorded. Patients also underwent regular monitoring of hematology, blood clinical chemistry, and urine, as well as regular assessments of vital signs and physical condition. The core phase of the study was the period lasting from randomization of the first patient until the last randomly assigned patient was treated with everolimus or placebo for 6 months. Because superiority of everolimus was shown during the core treatment phase, a prespecified open-label extension phase was launched wherein all patients, including those originally randomized to receive placebo, who were still in the study at that time or who were being followed up for posttreatment evaluation, were offered the possibility of receiving open-label everolimus. Statistical Analyses All analyses are reported for the subset of patients aged <3 years at the time they began receiving everolimus. Numbers and percentages of patients with AEs were summarized. Statistical analyses were performed with SAS software version 9.2 (SAS Institute Inc, Cary, North Carolina).
Results The EXIST-1 study enrolled 117 patients from 24 centers in 10 countries between August 2009 and September 2010.15,16 Of these, 78 patients received everolimus and 39 received placebo. The patient flow and disposition are outlined in the Figure (available at www.jpeds.com). The overall median patient age at entry into the double-blind phase was 9.5 years (range, 0.8-26.6 years). In total, 111 patients received at least 1 dose of everolimus; 18 patients were aged <3 years at the start of everolimus treatment. Of these 18 patients, 13 (72.2%) were initially randomized to receive everolimus, and 5 (27.8%) were originally randomized to receive placebo but switched to everolimus during the extension phase of the study. At the data cut-off date of January 11, 2013, 16 patients (88.9%) were still receiving everolimus, and 2 (11.1%) had discontinued treatment; 1 patient discontinued because of AEs (Acinetobacter bacteremia, increased blood alkaline phosphatase, and viral infection), and the other was lost to follow-up. Table I shows the baseline demographics and characteristics of the 18 patients aged <3 years at everolimus initiation. The majority of patients (66.7%) were male, and the median age was 1.82 years (range, 1.1-3.0 years). Onehalf of the patients (50.0%) had 1 target SEGA lesion, and the other one-half had 2 target lesions. The median sum of zwiak et al Jo
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Table I. Patient baseline demographics and characteristics Everolimus, N = 18 Age, y Mean (SD) Median (range) Sex, n (%) Male Female Body weight, kg Mean (SD) Median (range) Height, cm Mean (SD) Median (range) Body surface area*, m2 Mean (SD) Median (range) Race, n (%) White Black/African American
2.06 (0.64) 1.82 (1.1-3.0) 12 (66.7) 6 (33.3) 13.91 (3.44) 13.45 (9.0-20.5) 90.78 (8.44) 92.00 (76.0-104.0) 0.58 (0.09) 0.57 (0.4-0.7) 17 (94.4) 1 (5.6)
*Body surface area was calculated using the formula of Dubois and Dubois (1916).21
volumes of target SEGA lesions at baseline was 0.90 cm3 (range, 0.28-3.59 cm3). SEGA were bilateral in 15 (83.3%) patients and unilateral in 3 (16.7%) patients. Parenchymal invasion was superficial in 16 (88.9%) patients and deep in 2 (11.1%) patients. Summary of AEs in Patients Aged <3 Years The median duration of exposure to everolimus was 31.1 months (range, 11.5-39 months), and the median dose intensity was 5.86 mg/m2/d (range, 2.5-9.5 mg/m2/d). AEs were reported in all 18 patients (100%) and were consistent with those previously observed with everolimus. The majority of AEs were considered by the investigator to be grade 1 (mild) or grade 2 (moderate) in severity. The most common AEs regardless of relationship to study medication were stomatitis, cough, pharyngitis, and pyrexia (Table II). Suspected treatment-related AEs were Table II. AEs, regardless of relationship to study medication, by preferred term occurring in >20% of patients aged <3 years Preferred term*, n (%)
Everolimus, N = 18
Any Stomatitis Cough Pharyngitis Pyrexia Nasopharyngitis Pneumonia Bronchitis Convulsion Diarrhea Otitis media Ear infection Laryngitis Rhinitis Upper respiratory tract infection Vomiting
18 (100.0) 12 (66.7) 8 (44.4) 8 (44.4) 8 (44.4) 7 (38.9) 7 (38.9) 5 (27.8) 5 (27.8) 5 (27.8) 5 (27.8) 4 (22.2) 4 (22.2) 4 (22.2) 4 (22.2) 4 (22.2)
*Only AEs occurring on or after the start of everolimus and no more than 28 days after the discontinuation of everolimus are summarized.
experienced by 17 (94.4%) patients. The most common AEs (frequency >10%) with a suspected relationship to study medication were stomatitis in 12 patients (66.7%); decreased blood fibrinogen and cough in 3 patients (16.7%) each; and neutropenia, aphthous stomatitis, mouth ulceration, bronchitis, otitis media, pneumonia, upper respiratory tract infection, viral infection, increased blood alkaline phosphatase, decreased neutrophil count, decreased appetite, and hypercholesterolemia in 2 patients (11.1%) each. Oral ulcers were generally transient and resolved with treatment in the majority of patients. Of the 12 patients with stomatitis-related AEs, 11 patients received medication (mostly topical antifungals, steroids, and rinses) to manage the AE. All stomatitis events resolved over time, with the exception of 2 events (both grade 1, not requiring dose adjustment) that were ongoing at the cut-off date. Fourteen patients (77.8%) experienced grade 3 or 4 AEs, which were suspected to be study medication-related in 11 patients (61.1%). Grade 3 AEs irrespective of relationship to study medication occurred in 12 patients (66.7%), and only 2 patients (11.1%) reported grade 4 AEs. The most frequent (>10%) grade 3 AEs were stomatitis, pyrexia, and bronchitis in 4 patients (22.2%) each; convulsion in 3 patients (16.7%); and neutropenia, pneumonia, and decreased blood fibrinogen in 2 patients (11.1%) each. Convulsions were reported in patients with a history of epilepsy preceding the start of everolimus treatment and included febrile seizure in 1 patient, single epileptic seizure in 1 patient, and increased number of seizures in 1 patient with severe drug-resistant epilepsy. None of the grade 3 convulsions were considered by the investigators to be related to everolimus; convulsions resolved after concomitant medication for 2 patients, but an increased number of seizures reported in 1 patient remained at the data cut-off. Grade 4 AEs irrespective of study medication relationship were infrequent and consisted of pneumonia, upper respiratory tract infection, febrile infection, and gastroenteritis and were reported in 1 patient (5.6%) each. SAEs were reported in one-half of the patients (50.0%). SAEs that were suspected by the investigator to be study medication-related occurred in 4 patients (22.2%). SAEs irrespective of relationship to study medication occurring in >10% of patients consisted of pneumonia in 3 patients (16.7%) and pyrexia, bronchitis, upper respiratory tract infection, and convulsion in 2 patients each (11.1%). Infections and infestations occurred in all patients (100.0%), followed by stomatitis and related events, which occurred in 12 patients (66.7%), and cytopenia, which occurred in 5 patients (27.8%) (Table II). Dose was reduced or interrupted in 17 patients (94.4%), and all patients (100.0%) required additional therapy because of AEs. Fifteen patients (83.3%) had a dose reduction; 12 patients (66.7%) had >1 dose reduction. A reduction in everolimus dose was needed following an AE in 7 patients (38.9%), a dosing error in 1 patient (5.6%), and a change in body surface area in 3 patients (16.7%). Sixteen patients (88.9%) had $1 dose interruption, with
Safety of Everolimus in Patients Younger than 3 Years of Age: Results from EXIST-1, a Randomized, Controlled Clinical Trial
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the main reasons being AEs in 16 patients (88.9%), dosing errors in 3 patients (16.7%), laboratory test abnormalities in 2 patients (11.1%), and scheduling conflict in 1 patient (5.6%). AEs requiring dose reduction or interruption occurring in >10% of patients were stomatitis in 7 patients (38.9%), cough and pyrexia in 5 patients (27.8%) each, pneumonia in 4 patients (22.2%), bronchitis in 3 patients (16.7%), and decreased blood fibrinogen, diarrhea, ear infection, neutropenia, otitis media, upper respiratory tract infection, and viral infection in 2 patients (11.1%) each. The median duration of dose interruption because of an AE was 10 days (range, 1-47 days). There were no deaths.
Discussion Everolimus is approved for the treatment of pediatric and adult patients with SEGA who are candidates for therapy but not surgical resection.22 Recently updated guidelines recommend medical therapy with mTOR inhibitors or surgery in patients with growing asymptomatic SEGA, with the decision to treat with either pharmacotherapy or surgery based on the benefits and risks of each and evaluated in the whole context of the patient.12,23,24 Thus, the safety profile of everolimus is an important consideration when making treatment decisions in children. The safety and tolerability profile observed in patients aged <3 years at the start of everolimus treatment are consistent with the overall EXIST-1 trial population; the type and severity of AEs were comparable with those seen in the overall study population, albeit with somewhat different frequencies,15,16 and with those reported in the subgroup of 8 patients aged <3 years treated at a single institute.25 No AEs were reported that had not been previously observed in TSC-associated clinical settings with everolimus, which included a large clinical trial in an adult population.26 No new safety issues arose out of this analysis; however, the small sample size may limit interpretation of the results. Stomatitis, a known and identified risk of everolimus treatment,22 was one of the most common AEs in the overall study population15,16 and the most common AE in patients aged <3 years at the start of everolimus treatment, both in this analysis and in the single-institute analysis.25 It was also the most common reason for everolimus dose reduction or interruption in both populations. Stomatitis and related events can generally be successfully managed with dose adjustment and/or medication. In fact, dose reduction or interruption and medication were common methods for management of AEs in general. Furthermore, data from the full population of EXIST-1 showed that the total number of new-onset treatment-related AEs and SAEs decreased over time,16 suggesting that many AEs can be successfully managed by close supervision, medication adjustment, and concomitant medication. Although convulsion was listed as a grade 3 AE for 3 patients, epilepsy is also a common disease-related symptom 4
Volume in patients with TSC, and seizures are often resistant to treatment.12,27 A phase III clinical trial is underway (EXIST-3) to investigate the antiepileptic potential of everolimus in patients with TSC with partial-onset seizures. Most AEs were grade 1 (mild) or grade 2 (moderate) in severity; grade 3 and 4 AEs were not common. AEs leading to discontinuation (in 1 patient) were Acinetobacter bacteremia, increased blood alkaline phosphatase, and viral infection. Some of the most important clinical AEs and toxicities associated with everolimus treatment are related to its immunosuppressive properties, with opportunistic infections, stomatitis, and noninfectious pneumonitis all known risks of everolimus treatment.22,28 Infections and stomatitis were common among patients <3 years of age, but no patients developed noninfectious pneumonitis, which occurs primarily in adults, or opportunistic infections such as pneumocystis pneumonia or bacterial sepsis. There are limited safety data on mTOR inhibitors in young children, regardless of the indication for the treatment. However, available data in pediatric transplant recipients indicate that everolimus has manageable tolerability similar to that seen in TSC indications, despite it being administered in combination with additional immunosuppressive drugs. Three-year results of a study of everolimus in combination with low-dose cyclosporine and low-dose prednisone demonstrated an acceptable incidence of infections (mostly urinary tract infection and viral infection/reactivation) and no apparent effects of everolimus on growth in 41 de novo pediatric recipients of renal transplant (mean age, 9.1 years).29 A recent review of data by a panel of experts from this and other studies in pediatric solid organ transplantation confirmed a relatively low risk for infections and a possible improvement in long-term growth but cautioned that, because of sparse data, growth and development must be monitored when mTOR inhibitors are used in children.30 The dosing strategy used in the study appears to be suitable for ensuring minimization of toxicity. The recommended starting dose and subsequent requirement for therapeutic drug monitoring to achieve and maintain trough concentrations of 5-15 ng/mL are the same for adult and pediatric patients with SEGA. According to the prescribing information, everolimus clearance normalized to body surface area was higher in pediatric patients than in adults with SEGA. The geometric mean minimum plasma concentration values normalized to mg/m2 dose in patients aged <10 years and aged 10-18 years were lower by 54% and 40%, respectively, than those observed in adults (aged >18 years).15,16 This analysis demonstrated that everolimus is a safe longterm therapy for patients aged <3 years with TSC and SEGA not requiring immediate surgery. Data on the safety of everolimus in patients aged <3 years are limited; additional studies in children are needed and are underway. n We would like to thank the patients, study investigators, and study site personnel involved in the EXIST-1 trial; Scott Segal, MD (Novartis Pharmaceuticals Corporation), for contributing to the manuscript and data review; and Andrea Bothwell, BSc, and Traci Stuve, MA zwiak et al Jo
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(ApotheCom, funded by Novartis Pharmaceuticals Corporation), for assistance with medical writing and the preparation of the manuscript. Submitted for publication Aug 17, 2015; last revision received Nov 13, 2015; accepted Jan 8, 2016. zwiak, MD, Department of Pediatric Neurology, Reprint requests: Sergiusz Jo Warsaw Medical University, Ul.Zwirki i Wigury 61, 02-091 Warsaw, Poland. E-mail: [email protected]
References 1. Northrup H, Krueger DA. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013;49: 243-54. 2. Staley BA, Vail EA, Thiele EA. Tuberous sclerosis complex: diagnostic challenges, presenting symptoms, and commonly missed signs. Pediatrics 2011;127:e117-25. 3. Adriaensen ME, Schaefer-Prokop CM, Stijnen T, Duyndam DA, Zonnenberg BA, Prokop M. Prevalence of subependymal giant cell tumors in patients with tuberous sclerosis and a review of the literature. Eur J Neurol 2009;16:691-6. 4. Shepherd CW, Gomez MR, Lie JT, Crowson CS. Causes of death in patients with tuberous sclerosis. Mayo Clin Proc 1991;66:792-6. 5. Dabora SL, Jozwiak S, Franz DN, Roberts PS, Nieto A, Chung J, et al. Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet 2001;68:64-80. 6. Cuccia V, Zuccaro G, Sosa F, Monges J, Lubieniecky F, Taratuto AL. Subependymal giant cell astrocytoma in children with tuberous sclerosis. Childs Nerv Syst 2003;19:232-43. 7. Goh S, Butler W, Thiele EA. Subependymal giant cell tumors in tuberous sclerosis complex. Neurology 2004;63:1457-61. 8. Hussain N, Curran A, Pilling D, Malluci CL, Ladusans EJ, Alfirevic Z, et al. Congenital subependymal giant cell astrocytoma diagnosed on fetal MRI. Arch Dis Child 2006;91:520. 9. Kotulska K, Borkowska J, Mandera M, Roszkowski M, Jurkiewicz E, Grajkowska W, et al. Congenital subependymal giant cell astrocytomas in patients with tuberous sclerosis complex. Childs Nerv Syst 2014;30: 2037-42. 10. Crino PB. Evolving neurobiology of tuberous sclerosis complex. Acta Neuropathol 2013;125:317-32. 11. de Ribaupierre S, Dorfmuller G, Bulteau C, Fohlen M, Pinard JM, Chiron C, et al. Subependymal giant-cell astrocytomas in pediatric tuberous sclerosis disease: when should we operate? Neurosurgery 2007; 60:83-9. 12. Krueger DA, Northrup H. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013;49: 255-65. 13. Sun P, Kohrman M, Liu J, Guo A, Rogerio J, Krueger D. Outcomes of resecting subependymal giant cell astrocytoma (SEGA) among patients with SEGA-related tuberous sclerosis complex: a national claims database analysis. Curr Med Res Opin 2012;28:657-63. 14. Kotulska K, Borkowska J, Roszkowski M, Mandera M, Daszkiewicz P, Drabik K, et al. Surgical treatment of subependymal giant cell astrocytoma in tuberous sclerosis complex patients. Pediatr Neurol 2014;50: 307-12.
15. Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2013;381: 125-32. 16. Franz DN, Belousova E, Sparagna S, Bebin EM, Frost M, Kuperman R, et al. Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study. Lancet Oncol 2014;15:1513-20. 17. Kotulska K, Borkowska J, Jozwiak S. Possible prevention of tuberous sclerosis complex lesions. Pediatrics 2013;132:e239-42. 18. Tiberio D, Franz DN, Phillips JR. Regression of a cardiac rhabdomyoma in a patient receiving everolimus. Pediatrics 2011;127:e1335-7. 19. Aguilera D, Flamini R, Mazewski C, Schniederjan M, Hayes L, Boydston W, et al. Response of subependymal giant cell astrocytoma with spinal cord metastasis to everolimus. J Pediatr Hematol Oncol 2013;36:e448-51. 20. Cappellano AM, Senerchia AA, Adolfo F, Paiva PM, Pinho R, Covic A, et al. Successful everolimus therapy for SEGA in pediatric patients with tuberous sclerosis complex. Childs Nerv Syst 2013;29:2301-5. 21. Du Bois D, Du Bois EF. A formula to estimate the approximate surface area if height and weight be known. 1916. Nutrition 1989;5:303-11. 22. Novartis Pharmaceuticals Corporation. Afinitor (everolimus tablets for oral administration) Afinitor Disperz (everolimus tablets for oral suspension) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015. 23. Roth J, Roach ES, Bartels U, J ozwiak S, Koenig MK, Weiner HL, et al. Subependymal giant cell astrocytoma: diagnosis, screening, and treatment. Recommendations from the International Tuberous Sclerosis Complex Consensus Conference 2012. Pediatr Neurol 2013;49:439-44. 24. Jozwiak S, Nabbout R, Curatolo P , participants of the TSC Consensus meeting for SEGA and Epilepsy Management. Management of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC): clinical recommendations. Eur J Paediatr Neurol 2013; 17:348-52. 25. Kotulska K, Chmielewski D, Borkowska J, Jurkiewicz E, Kuczy nski D, Kmiec T, et al. Long-term effect of everolimus on epilepsy and growth in children under 3 years of age treated for subependymal giant cell astrocytoma associated with tuberous sclerosis complex. Eur J Paediatr Neurol 2013;17:479-85. 26. Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, et al. Everolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: extension of a randomized controlled trial. Nephrol Dial Transplant 2016;31:111-9. 27. Kotulska K, Jurkiewicz E, Domanska-Pakiela D, Grajkowska W, Mandera M, Borkowska J, et al. Epilepsy in newborns with tuberous sclerosis complex. Eur J Paediatr Neurol 2014;18:714-21. 28. Porta C, Osanto S, Ravaud A, Climent MA, Vaishampayan U, White DA, et al. Management of adverse events associated with the use of everolimus in patients with advanced renal cell carcinoma. Eur J Cancer 2011;47:1287-98. 29. Ferraresso M, Belingheri M, Ginevri F, Murer L, Dello Strologo L, Cardillo M, et al. Three-year safety and efficacy of everolimus and low-dose cyclosporine in de novo pediatric kidney transplant patients. Pediatr Transplant 2014;18:350-6. 30. Ganschow R, Pape L, Sturm E, Bauer J, Melter M, Gerner P, et al. Growing experience with mTOR inhibitors in pediatric solid organ transplantation. Pediatr Transplant 2013;17:694-706.
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Figure. CONSORT diagram.
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T
uberous sclerosis complex (TSC) is a multisystem disorder characterized by the growth of nonmalignant tumors (hamartomas) in various organs.1 TSC can manifest in utero and affect individuals throughout their lifetime.2 In the brain, subependymal giant cell astrocytoma (SEGA) occurs in up to 20% of patients with TSC.3-5 SEGAs typically appear during the first 20 years of life and on occasion have been detected prenatally.6-9 They are slow-growing tumors composed of astrocytes, spindle cells, and giant cells.6,10 Although SEGAs are often asymptomatic, their clinical consequences can be grave because of their close proximity to the foramen of Monro. As SEGAs grow, there is the potential for obstruction of cerebrospinal fluid flow, possibly leading to hyFrom the Department of Pediatric Neurology, Warsaw drocephalus and increased intracranial pressure, which may result in death.4,7,11 Medical University; Department of Neurology and Treatment of SEGA includes surgery and pharmacotherapy with mammalian Epileptology, The Children’s Memorial Health Institute, Warsaw, Poland; Department of Oncology, Novartis target of rapamycin (mTOR) inhibitors.12 Surgical resection of SEGA, recommenPharmaceuticals Corporation, Florham Park, NJ; 12 Department of Oncology, Novartis Pharmaceuticals ded in patients with acute symptoms, can be curative, but there are risks and a S.A.S., Rueil-Malmaison, France; and Department of potential for postoperative and long-term complications. Postoperative complicaNeurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH tions include hemiparesis, development of new seizures, cognitive impairment, hyFunded by Novartis Pharmaceuticals Corporation. S.J. 6,7,11,13 drocephalus, infections, and even death. In the largest reported series to date has received speaking and advisory board honoraria from Novartis Pharmaceuticals Corporation. K.K. has of surgically resected SEGAs, including 64 surgeries in 57 patients, complications received speaking honoraria from Novartis. D.F. has 14 received support from Novartis for other research at his were most frequent in children aged <3 years than in older patients. Furthermore, institution; has served as a consultant to Novartis (with payments going to Cincinnati Children’s Hospital Mediif gross total resection is not achieved, there is the potential for SEGA regrowth, cal Center); has received honoraria from Novartis and necessitating additional surgical interventions and/or therapy.7,11,13,14 Lundbeck Pharmaceuticals; has been reimbursed by Novartis and Lundbeck Pharmaceuticals for travel costs A multicenter, randomized, double-blind, placebo-controlled phase 3 study, for lectures; and has performed legal work in reviewing medical malpractice cases and occasionally in giving EXamining everolimus In a Study of Tuberous Sclerosis Complex-1 (EXIST-1) 1
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Adverse event EXamining everolimus In a Study of Tuberous Sclerosis Complex-1 Mammalian target of rapamycin Serious AE Subependymal giant cell astrocytoma Tuberous sclerosis complex
expert testimony for various attorneys. The other authors are employees of Novartis. Novartis was responsible for the study design, conduct, and data collection and participated in data analysis and interpretation; all authors had full access to the study report and had final responsibility for the decision to submit for publication. Writing and editorial assistance provided by ApotheCom (Yardley, PA), which was funded by Novartis Pharmaceuticals Corporation, and performed under the direction of the authors.
0022-3476/$ - see front matter. Copyright ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2016.01.027
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(NCT00789828) evaluated everolimus for the treatment of TSC-associated SEGA in 117 patients irrespective of age.15,16 Short- and long-term evaluation of their therapy is promising. Everolimus is the only mTOR inhibitor evaluated in a randomized, placebo-controlled clinical trial for patients with TSC and SEGA. It was initially approved for use in patients aged $3 years. Data for mTOR inhibitors from other indications in patients aged <3 years are also limited. In TSC, some manifestations are present at birth or soon after,2 and given the increasing body of evidence that mTOR inhibition may be beneficial not only for SEGA, but also epilepsy, neuropsychiatric problems, skin lesions, and other manifestations,17-20 a significant number of patients are candidates for medical treatment as infants or toddlers. Here we report the results of a post hoc analysis focusing on the safety and tolerability of everolimus in the subgroup of EXIST-1 patients aged <3 years when everolimus was initiated, using long-term data with a cut-off date of January 11, 2013.
Methods The methods used in EXIST-1 have been previously published.15,16 Patients, irrespective of age, with TSC-associated SEGA and radiologic evidence of $1 of 3 conditions (serial SEGA growth, presence of a new SEGA lesion, and/or new or worsening hydrocephalus) were randomly assigned 2:1 to receive double-blinded treatment with either everolimus or placebo. Randomization was stratified by the use of enzyme-inducing antiepileptic medications. Patients received oral everolimus initiated at 4.5 mg/m2/d (titrated to attain blood trough levels of 5-15 ng/mL) or placebo. Protocolspecified dose modifications were permitted if treatmentrelated toxic effects occurred.15,16 In cases of treatment interruption, study medication was resumed if the toxicity recovered to grade #1 within 6 weeks. Treatment was generally reintroduced at the initial dose in cases of grade 1-3 toxicity, except with grade 3 stomatitis or pneumonitis, platelets <50 000/mm3, absolute neutrophil count <500/mm3, or febrile neutropenia for which treatment was restarted at a lower dose level. The patient was discontinued from the study if treatment was interrupted for $6 weeks or if grade 4 toxicity was experienced. The protocol was approved by the institutional review board/ethics committee at each center, and the study was conducted in accordance with the principles of Good Clinical Practice and the Declaration of Helsinki. Safety data were reviewed every 6 months by an independent data-monitoring committee, and all patients provided written informed consent. For participants aged <18 years, written informed consent was obtained from a legally acceptable representative (eg, a parent), and verbal assent was obtained if the patient was able. The primary efficacy endpoint in the core phase of the study was SEGA response rate (as determined by independent central radiology review). SEGA response was defined 2
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as (1) a $50% reduction in SEGA volume relative to baseline (where SEGA volume was the sum of all target SEGA lesion volumes identified at baseline); and (2) no unequivocal worsening of nontarget SEGA lesions, no new SEGA lesions ($1 cm in longest diameter), and no new or worsening hydrocephalus.15,16 Safety and tolerability were assessed throughout the study according to National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. Rate, severity, and causal relationship of adverse events (AEs) and serious AEs (SAEs) to treatment were recorded. Patients also underwent regular monitoring of hematology, blood clinical chemistry, and urine, as well as regular assessments of vital signs and physical condition. The core phase of the study was the period lasting from randomization of the first patient until the last randomly assigned patient was treated with everolimus or placebo for 6 months. Because superiority of everolimus was shown during the core treatment phase, a prespecified open-label extension phase was launched wherein all patients, including those originally randomized to receive placebo, who were still in the study at that time or who were being followed up for posttreatment evaluation, were offered the possibility of receiving open-label everolimus. Statistical Analyses All analyses are reported for the subset of patients aged <3 years at the time they began receiving everolimus. Numbers and percentages of patients with AEs were summarized. Statistical analyses were performed with SAS software version 9.2 (SAS Institute Inc, Cary, North Carolina).
Results The EXIST-1 study enrolled 117 patients from 24 centers in 10 countries between August 2009 and September 2010.15,16 Of these, 78 patients received everolimus and 39 received placebo. The patient flow and disposition are outlined in the Figure (available at www.jpeds.com). The overall median patient age at entry into the double-blind phase was 9.5 years (range, 0.8-26.6 years). In total, 111 patients received at least 1 dose of everolimus; 18 patients were aged <3 years at the start of everolimus treatment. Of these 18 patients, 13 (72.2%) were initially randomized to receive everolimus, and 5 (27.8%) were originally randomized to receive placebo but switched to everolimus during the extension phase of the study. At the data cut-off date of January 11, 2013, 16 patients (88.9%) were still receiving everolimus, and 2 (11.1%) had discontinued treatment; 1 patient discontinued because of AEs (Acinetobacter bacteremia, increased blood alkaline phosphatase, and viral infection), and the other was lost to follow-up. Table I shows the baseline demographics and characteristics of the 18 patients aged <3 years at everolimus initiation. The majority of patients (66.7%) were male, and the median age was 1.82 years (range, 1.1-3.0 years). Onehalf of the patients (50.0%) had 1 target SEGA lesion, and the other one-half had 2 target lesions. The median sum of zwiak et al Jo
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Table I. Patient baseline demographics and characteristics Everolimus, N = 18 Age, y Mean (SD) Median (range) Sex, n (%) Male Female Body weight, kg Mean (SD) Median (range) Height, cm Mean (SD) Median (range) Body surface area*, m2 Mean (SD) Median (range) Race, n (%) White Black/African American
2.06 (0.64) 1.82 (1.1-3.0) 12 (66.7) 6 (33.3) 13.91 (3.44) 13.45 (9.0-20.5) 90.78 (8.44) 92.00 (76.0-104.0) 0.58 (0.09) 0.57 (0.4-0.7) 17 (94.4) 1 (5.6)
*Body surface area was calculated using the formula of Dubois and Dubois (1916).21
volumes of target SEGA lesions at baseline was 0.90 cm3 (range, 0.28-3.59 cm3). SEGA were bilateral in 15 (83.3%) patients and unilateral in 3 (16.7%) patients. Parenchymal invasion was superficial in 16 (88.9%) patients and deep in 2 (11.1%) patients. Summary of AEs in Patients Aged <3 Years The median duration of exposure to everolimus was 31.1 months (range, 11.5-39 months), and the median dose intensity was 5.86 mg/m2/d (range, 2.5-9.5 mg/m2/d). AEs were reported in all 18 patients (100%) and were consistent with those previously observed with everolimus. The majority of AEs were considered by the investigator to be grade 1 (mild) or grade 2 (moderate) in severity. The most common AEs regardless of relationship to study medication were stomatitis, cough, pharyngitis, and pyrexia (Table II). Suspected treatment-related AEs were Table II. AEs, regardless of relationship to study medication, by preferred term occurring in >20% of patients aged <3 years Preferred term*, n (%)
Everolimus, N = 18
Any Stomatitis Cough Pharyngitis Pyrexia Nasopharyngitis Pneumonia Bronchitis Convulsion Diarrhea Otitis media Ear infection Laryngitis Rhinitis Upper respiratory tract infection Vomiting
18 (100.0) 12 (66.7) 8 (44.4) 8 (44.4) 8 (44.4) 7 (38.9) 7 (38.9) 5 (27.8) 5 (27.8) 5 (27.8) 5 (27.8) 4 (22.2) 4 (22.2) 4 (22.2) 4 (22.2) 4 (22.2)
*Only AEs occurring on or after the start of everolimus and no more than 28 days after the discontinuation of everolimus are summarized.
experienced by 17 (94.4%) patients. The most common AEs (frequency >10%) with a suspected relationship to study medication were stomatitis in 12 patients (66.7%); decreased blood fibrinogen and cough in 3 patients (16.7%) each; and neutropenia, aphthous stomatitis, mouth ulceration, bronchitis, otitis media, pneumonia, upper respiratory tract infection, viral infection, increased blood alkaline phosphatase, decreased neutrophil count, decreased appetite, and hypercholesterolemia in 2 patients (11.1%) each. Oral ulcers were generally transient and resolved with treatment in the majority of patients. Of the 12 patients with stomatitis-related AEs, 11 patients received medication (mostly topical antifungals, steroids, and rinses) to manage the AE. All stomatitis events resolved over time, with the exception of 2 events (both grade 1, not requiring dose adjustment) that were ongoing at the cut-off date. Fourteen patients (77.8%) experienced grade 3 or 4 AEs, which were suspected to be study medication-related in 11 patients (61.1%). Grade 3 AEs irrespective of relationship to study medication occurred in 12 patients (66.7%), and only 2 patients (11.1%) reported grade 4 AEs. The most frequent (>10%) grade 3 AEs were stomatitis, pyrexia, and bronchitis in 4 patients (22.2%) each; convulsion in 3 patients (16.7%); and neutropenia, pneumonia, and decreased blood fibrinogen in 2 patients (11.1%) each. Convulsions were reported in patients with a history of epilepsy preceding the start of everolimus treatment and included febrile seizure in 1 patient, single epileptic seizure in 1 patient, and increased number of seizures in 1 patient with severe drug-resistant epilepsy. None of the grade 3 convulsions were considered by the investigators to be related to everolimus; convulsions resolved after concomitant medication for 2 patients, but an increased number of seizures reported in 1 patient remained at the data cut-off. Grade 4 AEs irrespective of study medication relationship were infrequent and consisted of pneumonia, upper respiratory tract infection, febrile infection, and gastroenteritis and were reported in 1 patient (5.6%) each. SAEs were reported in one-half of the patients (50.0%). SAEs that were suspected by the investigator to be study medication-related occurred in 4 patients (22.2%). SAEs irrespective of relationship to study medication occurring in >10% of patients consisted of pneumonia in 3 patients (16.7%) and pyrexia, bronchitis, upper respiratory tract infection, and convulsion in 2 patients each (11.1%). Infections and infestations occurred in all patients (100.0%), followed by stomatitis and related events, which occurred in 12 patients (66.7%), and cytopenia, which occurred in 5 patients (27.8%) (Table II). Dose was reduced or interrupted in 17 patients (94.4%), and all patients (100.0%) required additional therapy because of AEs. Fifteen patients (83.3%) had a dose reduction; 12 patients (66.7%) had >1 dose reduction. A reduction in everolimus dose was needed following an AE in 7 patients (38.9%), a dosing error in 1 patient (5.6%), and a change in body surface area in 3 patients (16.7%). Sixteen patients (88.9%) had $1 dose interruption, with
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the main reasons being AEs in 16 patients (88.9%), dosing errors in 3 patients (16.7%), laboratory test abnormalities in 2 patients (11.1%), and scheduling conflict in 1 patient (5.6%). AEs requiring dose reduction or interruption occurring in >10% of patients were stomatitis in 7 patients (38.9%), cough and pyrexia in 5 patients (27.8%) each, pneumonia in 4 patients (22.2%), bronchitis in 3 patients (16.7%), and decreased blood fibrinogen, diarrhea, ear infection, neutropenia, otitis media, upper respiratory tract infection, and viral infection in 2 patients (11.1%) each. The median duration of dose interruption because of an AE was 10 days (range, 1-47 days). There were no deaths.
Discussion Everolimus is approved for the treatment of pediatric and adult patients with SEGA who are candidates for therapy but not surgical resection.22 Recently updated guidelines recommend medical therapy with mTOR inhibitors or surgery in patients with growing asymptomatic SEGA, with the decision to treat with either pharmacotherapy or surgery based on the benefits and risks of each and evaluated in the whole context of the patient.12,23,24 Thus, the safety profile of everolimus is an important consideration when making treatment decisions in children. The safety and tolerability profile observed in patients aged <3 years at the start of everolimus treatment are consistent with the overall EXIST-1 trial population; the type and severity of AEs were comparable with those seen in the overall study population, albeit with somewhat different frequencies,15,16 and with those reported in the subgroup of 8 patients aged <3 years treated at a single institute.25 No AEs were reported that had not been previously observed in TSC-associated clinical settings with everolimus, which included a large clinical trial in an adult population.26 No new safety issues arose out of this analysis; however, the small sample size may limit interpretation of the results. Stomatitis, a known and identified risk of everolimus treatment,22 was one of the most common AEs in the overall study population15,16 and the most common AE in patients aged <3 years at the start of everolimus treatment, both in this analysis and in the single-institute analysis.25 It was also the most common reason for everolimus dose reduction or interruption in both populations. Stomatitis and related events can generally be successfully managed with dose adjustment and/or medication. In fact, dose reduction or interruption and medication were common methods for management of AEs in general. Furthermore, data from the full population of EXIST-1 showed that the total number of new-onset treatment-related AEs and SAEs decreased over time,16 suggesting that many AEs can be successfully managed by close supervision, medication adjustment, and concomitant medication. Although convulsion was listed as a grade 3 AE for 3 patients, epilepsy is also a common disease-related symptom 4
Volume in patients with TSC, and seizures are often resistant to treatment.12,27 A phase III clinical trial is underway (EXIST-3) to investigate the antiepileptic potential of everolimus in patients with TSC with partial-onset seizures. Most AEs were grade 1 (mild) or grade 2 (moderate) in severity; grade 3 and 4 AEs were not common. AEs leading to discontinuation (in 1 patient) were Acinetobacter bacteremia, increased blood alkaline phosphatase, and viral infection. Some of the most important clinical AEs and toxicities associated with everolimus treatment are related to its immunosuppressive properties, with opportunistic infections, stomatitis, and noninfectious pneumonitis all known risks of everolimus treatment.22,28 Infections and stomatitis were common among patients <3 years of age, but no patients developed noninfectious pneumonitis, which occurs primarily in adults, or opportunistic infections such as pneumocystis pneumonia or bacterial sepsis. There are limited safety data on mTOR inhibitors in young children, regardless of the indication for the treatment. However, available data in pediatric transplant recipients indicate that everolimus has manageable tolerability similar to that seen in TSC indications, despite it being administered in combination with additional immunosuppressive drugs. Three-year results of a study of everolimus in combination with low-dose cyclosporine and low-dose prednisone demonstrated an acceptable incidence of infections (mostly urinary tract infection and viral infection/reactivation) and no apparent effects of everolimus on growth in 41 de novo pediatric recipients of renal transplant (mean age, 9.1 years).29 A recent review of data by a panel of experts from this and other studies in pediatric solid organ transplantation confirmed a relatively low risk for infections and a possible improvement in long-term growth but cautioned that, because of sparse data, growth and development must be monitored when mTOR inhibitors are used in children.30 The dosing strategy used in the study appears to be suitable for ensuring minimization of toxicity. The recommended starting dose and subsequent requirement for therapeutic drug monitoring to achieve and maintain trough concentrations of 5-15 ng/mL are the same for adult and pediatric patients with SEGA. According to the prescribing information, everolimus clearance normalized to body surface area was higher in pediatric patients than in adults with SEGA. The geometric mean minimum plasma concentration values normalized to mg/m2 dose in patients aged <10 years and aged 10-18 years were lower by 54% and 40%, respectively, than those observed in adults (aged >18 years).15,16 This analysis demonstrated that everolimus is a safe longterm therapy for patients aged <3 years with TSC and SEGA not requiring immediate surgery. Data on the safety of everolimus in patients aged <3 years are limited; additional studies in children are needed and are underway. n We would like to thank the patients, study investigators, and study site personnel involved in the EXIST-1 trial; Scott Segal, MD (Novartis Pharmaceuticals Corporation), for contributing to the manuscript and data review; and Andrea Bothwell, BSc, and Traci Stuve, MA zwiak et al Jo
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(ApotheCom, funded by Novartis Pharmaceuticals Corporation), for assistance with medical writing and the preparation of the manuscript. Submitted for publication Aug 17, 2015; last revision received Nov 13, 2015; accepted Jan 8, 2016. zwiak, MD, Department of Pediatric Neurology, Reprint requests: Sergiusz Jo Warsaw Medical University, Ul.Zwirki i Wigury 61, 02-091 Warsaw, Poland. E-mail: [email protected]
References 1. Northrup H, Krueger DA. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013;49: 243-54. 2. Staley BA, Vail EA, Thiele EA. Tuberous sclerosis complex: diagnostic challenges, presenting symptoms, and commonly missed signs. Pediatrics 2011;127:e117-25. 3. Adriaensen ME, Schaefer-Prokop CM, Stijnen T, Duyndam DA, Zonnenberg BA, Prokop M. Prevalence of subependymal giant cell tumors in patients with tuberous sclerosis and a review of the literature. Eur J Neurol 2009;16:691-6. 4. Shepherd CW, Gomez MR, Lie JT, Crowson CS. Causes of death in patients with tuberous sclerosis. Mayo Clin Proc 1991;66:792-6. 5. Dabora SL, Jozwiak S, Franz DN, Roberts PS, Nieto A, Chung J, et al. Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet 2001;68:64-80. 6. Cuccia V, Zuccaro G, Sosa F, Monges J, Lubieniecky F, Taratuto AL. Subependymal giant cell astrocytoma in children with tuberous sclerosis. Childs Nerv Syst 2003;19:232-43. 7. Goh S, Butler W, Thiele EA. Subependymal giant cell tumors in tuberous sclerosis complex. Neurology 2004;63:1457-61. 8. Hussain N, Curran A, Pilling D, Malluci CL, Ladusans EJ, Alfirevic Z, et al. Congenital subependymal giant cell astrocytoma diagnosed on fetal MRI. Arch Dis Child 2006;91:520. 9. Kotulska K, Borkowska J, Mandera M, Roszkowski M, Jurkiewicz E, Grajkowska W, et al. Congenital subependymal giant cell astrocytomas in patients with tuberous sclerosis complex. Childs Nerv Syst 2014;30: 2037-42. 10. Crino PB. Evolving neurobiology of tuberous sclerosis complex. Acta Neuropathol 2013;125:317-32. 11. de Ribaupierre S, Dorfmuller G, Bulteau C, Fohlen M, Pinard JM, Chiron C, et al. Subependymal giant-cell astrocytomas in pediatric tuberous sclerosis disease: when should we operate? Neurosurgery 2007; 60:83-9. 12. Krueger DA, Northrup H. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol 2013;49: 255-65. 13. Sun P, Kohrman M, Liu J, Guo A, Rogerio J, Krueger D. Outcomes of resecting subependymal giant cell astrocytoma (SEGA) among patients with SEGA-related tuberous sclerosis complex: a national claims database analysis. Curr Med Res Opin 2012;28:657-63. 14. Kotulska K, Borkowska J, Roszkowski M, Mandera M, Daszkiewicz P, Drabik K, et al. Surgical treatment of subependymal giant cell astrocytoma in tuberous sclerosis complex patients. Pediatr Neurol 2014;50: 307-12.
15. Franz DN, Belousova E, Sparagana S, Bebin EM, Frost M, Kuperman R, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2013;381: 125-32. 16. Franz DN, Belousova E, Sparagna S, Bebin EM, Frost M, Kuperman R, et al. Everolimus for subependymal giant cell astrocytoma in patients with tuberous sclerosis complex: 2-year open-label extension of the randomised EXIST-1 study. Lancet Oncol 2014;15:1513-20. 17. Kotulska K, Borkowska J, Jozwiak S. Possible prevention of tuberous sclerosis complex lesions. Pediatrics 2013;132:e239-42. 18. Tiberio D, Franz DN, Phillips JR. Regression of a cardiac rhabdomyoma in a patient receiving everolimus. Pediatrics 2011;127:e1335-7. 19. Aguilera D, Flamini R, Mazewski C, Schniederjan M, Hayes L, Boydston W, et al. Response of subependymal giant cell astrocytoma with spinal cord metastasis to everolimus. J Pediatr Hematol Oncol 2013;36:e448-51. 20. Cappellano AM, Senerchia AA, Adolfo F, Paiva PM, Pinho R, Covic A, et al. Successful everolimus therapy for SEGA in pediatric patients with tuberous sclerosis complex. Childs Nerv Syst 2013;29:2301-5. 21. Du Bois D, Du Bois EF. A formula to estimate the approximate surface area if height and weight be known. 1916. Nutrition 1989;5:303-11. 22. Novartis Pharmaceuticals Corporation. Afinitor (everolimus tablets for oral administration) Afinitor Disperz (everolimus tablets for oral suspension) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015. 23. Roth J, Roach ES, Bartels U, J ozwiak S, Koenig MK, Weiner HL, et al. Subependymal giant cell astrocytoma: diagnosis, screening, and treatment. Recommendations from the International Tuberous Sclerosis Complex Consensus Conference 2012. Pediatr Neurol 2013;49:439-44. 24. Jozwiak S, Nabbout R, Curatolo P , participants of the TSC Consensus meeting for SEGA and Epilepsy Management. Management of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC): clinical recommendations. Eur J Paediatr Neurol 2013; 17:348-52. 25. Kotulska K, Chmielewski D, Borkowska J, Jurkiewicz E, Kuczy nski D, Kmiec T, et al. Long-term effect of everolimus on epilepsy and growth in children under 3 years of age treated for subependymal giant cell astrocytoma associated with tuberous sclerosis complex. Eur J Paediatr Neurol 2013;17:479-85. 26. Bissler JJ, Kingswood JC, Radzikowska E, Zonnenberg BA, Frost M, Belousova E, et al. Everolimus for renal angiomyolipoma in patients with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis: extension of a randomized controlled trial. Nephrol Dial Transplant 2016;31:111-9. 27. Kotulska K, Jurkiewicz E, Domanska-Pakiela D, Grajkowska W, Mandera M, Borkowska J, et al. Epilepsy in newborns with tuberous sclerosis complex. Eur J Paediatr Neurol 2014;18:714-21. 28. Porta C, Osanto S, Ravaud A, Climent MA, Vaishampayan U, White DA, et al. Management of adverse events associated with the use of everolimus in patients with advanced renal cell carcinoma. Eur J Cancer 2011;47:1287-98. 29. Ferraresso M, Belingheri M, Ginevri F, Murer L, Dello Strologo L, Cardillo M, et al. Three-year safety and efficacy of everolimus and low-dose cyclosporine in de novo pediatric kidney transplant patients. Pediatr Transplant 2014;18:350-6. 30. Ganschow R, Pape L, Sturm E, Bauer J, Melter M, Gerner P, et al. Growing experience with mTOR inhibitors in pediatric solid organ transplantation. Pediatr Transplant 2013;17:694-706.
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Figure. CONSORT diagram.
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