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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
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 7 ( 2 0 1 3 ) 4 7 9 e4 8 5
Official Journal of the European Paediatric Neurology Society
Original article
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 Katarzyna Kotulska a,b,*, Dariusz Chmielewski a, Julita Borkowska a, ski a, Tomasz Kmiec a, _ Elzbieta Jurkiewicz c, Dariusz Kuczyn b zwiak a Barbara Łojszczyk , Dorota Dunin-Wa˛sowicz a, Sergiusz Jo´ a
Department of Science, The Children’s Memorial Health Institute, Warsaw, Poland Department of Neurology, The Children’s Memorial Health Institute, Warsaw, Poland c Department of Radiology, The Children’s Memorial Health Institute, Warsaw, Poland b
article info
abstract
Article history:
Background: Tuberous sclerosis complex (TSC) is a genetic disorder characterized by
Received 9 December 2012
increased mammalian target of rapamycin (mTOR) activation and growth of benign tumors
Received in revised form
in several organs throughout the body. In young children with TSC, drug-resistant epilepsy
6 March 2013
and subependymal giant cell astrocytomas (SEGAs) present the most common causes of
Accepted 11 March 2013
mortality and morbidity. There are also some reports on the antiepileptic and antiepileptogenic potential of mTOR inhibitors in TSC. However, the data on everolimus effi-
Keywords:
cacy and safety in young children are very limited.
TSC
Aims: To show the long-term safety data and the effect of everolimus treatment on epilepsy
Epilepsy
in children under the age of 3 who received everolimus for SEGAs associated with TSC.
SEGA
Methods: We present the results of everolimus treatment in 8 children under the age of 3
Everolimus
who participated in EXIST-1 study. Five patients presented with active, drug-resistant
Adverse events
epilepsy at baseline. The mean follow-up is 35 months (33e38 months) and all children
Safety
are still on treatment.
Young children
Results: In 6 out of 8 children, at least a 50% reduction in SEGA volume was observed. In 1 child with drug-resistant epilepsy, everolimus treatment resulted in cessation of seizures and in 2 other children, at least a 50% reduction in the number of seizures was noted. The incidence of adverse events (AE) was similar to that observed in older children and adults. Conclusions: This study suggests that everolimus is effective and safe in infants and young children with epilepsy and SEGA associated with TSC and offers a valuable treatment option. ª 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Department of Neurology and Epileptology, The Children’s Memorial Health Institute, Al. Dzieci Polskich 20, 04730 Warsaw, Poland. Tel.: þ48 22 8157404; fax: þ48 22 8157402. E-mail addresses: [email protected], [email protected] (K. Kotulska). 1090-3798/$ e see front matter ª 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejpn.2013.03.002
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1.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 7 ( 2 0 1 3 ) 4 7 9 e4 8 5
Introduction
Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder occurring in approximately 1 in 6000 live births.1 It is characterized by the development of benign, highly vascular, hamartomatic growth in various tissues and organs, including the brain, kidneys, heart, liver, lungs, retina, and skin.2 TSC is caused by the mutation of either of two genes: TSC1 encoding hamartin and TSC2 encoding tuberin.1,3 Both proteins interact to inhibit the activity of mammalian target of rapamycin (mTOR).3,4 In the absence of active tuberin/hamartin complex, mTOR is stimulated to promote protein synthesis and cell growth.1,3 Hyperactivation of mTOR is a common finding in TSC-related tumors and was shown to be pivotal for the development of most disease-related symptoms, including epilepsy, developmental malformations, and tumor growth.2,5 In the brain, cortical and subcortical tubers, subependymal nodules, and subependymal giant cell astrocytomas (SEGAs) are hallmarks of the disease.6 SEGA is a rare low-grade brain tumor occurring almost exclusively in TSC patients and affecting approximately 20% of them.7 SEGAs usually develop in the first two decades of life, and in children and adolescents with TSC, they present the major cause of morbidity and mortality.7,8 SEGAs usually grow in the vicinity of the foramen of Monro and therefore may obstruct cerebrospinal fluid pathways, causing hydrocephalus.9 Until recently, surgical resection has been the only available treatment for SEGAs producing these clinical symptoms. However, SEGA surgery was associated with distinct morbidity and mortality of up to 30% in different pediatric patient series.9,10 Moreover, early SEGA growth symptoms can be easily overlooked, especially in young children and individuals with learning disabilities, and by the time the symptoms are recognized, they are often irreversible even by immediate surgical intervention.10 Epilepsy is the most common TSC symptom appearing in 80e90% of patients, mainly in the first year of life.11 Epilepsy in TSC is often intractable, with a poor response to anticonvulsant medications, and is commonly associated with mental retardation.11e13 The accumulating data implicate the mTOR pathway as mediating epileptogenesis in TSC, and indicate that mTOR inhibitors may have antiepileptogenic and antiepileptic properties in patients with TSC.14e17 Recently, everolimus was approved by United States Food and Drug Administration and European Medicines Agency to treat adults and children aged 3 years and above with TSC who have SEGA that requires therapeutic intervention but cannot be curatively resected. Everolimus is also approved for adults with renal angiomyolipoma and TSC, not requiring immediate surgery. Everolimus is an orally bioavailable derivate of rapamycin, which selectively inhibits mTOR activity, targeting the mTOR-raptor signal transduction complex (mTORC1).18 Everolimus is already used as an immunosuppressant in solid organ transplantation for the prevention of organ rejection in patients with renal and cardiac transplants.18,19 Currently, clinical trials aimed at studying the potential use of everolimus in epilepsy are planned or already ongoing. The adverse events and safety profile of everolimus in adult patients and older children was established in a number of clinical trials settings.18e22 However, the safety of
everolimus treatment in young children has not yet been reported. Of utmost importance, there are concerns about whether everolimus could adversely affect growth and development in children. Given that SEGAs can be found as early as in utero and that some infants could benefit from mTOR inhibitors, the assessment of safety of everolimus in this group of patients is urgently needed. The EXIST-1 (Everolimus in the Treatment of Subependymal Giant Cell Astrocytomas (SEGAs) Associated With Tuberous Sclerosis Complex) trial is the first prospective, double-blind, parallel-group, placebo-controlled, multicenter phase 3 study evaluating everolimus in patients with SEGA associated with TSC.23 At the Department of Neurology and Epileptology, The Children’s Memorial Health Institute, Warsaw, Poland, 20 patients were enrolled in the study. Eight of them began treatment with everolimus before the age of 3 years and have been treated for at least 33 months. The aim of this study was to analyze the effect of everolimus on epilepsy and long-term safety in infants and young children with TSC.
2.
Material and methods
2.1.
Patients
Eight children under the age of 3 years from our department participated in the EXIST-1 study and received everolimus. The mean follow-up of these children is to date 35 months (range from 33 to 38). All children met the clinical criteria for TSC diagnosis and all fulfilled the inclusion criteria for the EXIST-1 study. All children presented with a history of epilepsy. In three children, epilepsy was well controlled with one or two antiepileptic drugs and they were seizure free at screening. Five children had active drug-resistant epilepsy with at least one seizure per week, despite the use of two or three antiepileptic drugs. In three children, adrenocorticotropic hormone (ACTH) therapy for infantile spasms was completed before enrollment in the EXIST-1 study. In all three of these children, the infantile spasms were well controlled, but they continued to suffer from partial seizures. The study was approved by The Children’s Memorial Health Institute Ethics Committee. Written informed consent was obtained from the parents of all enrolled children before performing any trial procedure.
2.2.
Study design
Patients with definite clinical diagnosis of TSC and a serially growing SEGA exceeding 1 cm in diameter were eligible for the study (for details, see Franz et al., 201223). Patients had to be medically stable and unlikely to require SEGA-related surgery. After the screening period, the patients were randomized to either a placebo or everolimus arm. The blinded core phase of the treatment was followed by an extension phase, which is still ongoing. In the extension phase, all patients were offered open-label everolimus, as the results of the core phase favored everolimus. All children in our department under 3 years of age were randomized to the everolimus group and all are
Table 1 e Clinical characteristics of the patients. Age at treatment onset
Epilepsy status at screening
Neuropsychological evaluation at screening
Follow-up
Initial everolimus dose (mg/m2)
Actual everolimus dose (mg/m2)
1
F
20 mo
63
38 months
4.5
2.53
Stable disease
71
Seizure free on 2 AED
2
F
21 mo
Drug-resistant epilepsy, requiring 3 AED þ ACTH, daily partial (some secondarily generalized) seizures Seizure free on 1 AED
90
36 months
4.5
2.53
88
3
M
35 mo
Seizure free on 2 AED
69
36 months
4.5
3.38
4
M
29 mo
42
35 months
4.5
4.5
Seizure free on 1 AED Seizure free on 1 AED 1 seizure per week on 3 AED
5
M
14 mo
68
35 months
4.5
4.5
Stable disease
72
1e2 partial seizure per week, on 3 AED
6
M
28 mo
Drug-resistant epilepsy, 1 seizure per week on 3 AED þ ACTH Drug-resistant epilepsy, requiring 3 AED, 3e5 partial seizures per week Seizure free on 1 AED
>50% tumor size regression >50% tumor size regression >50% tumor size regression
28
33 months
4.5
8.0
27
7
M
34 mo
67
33 months
4.5
6.0
8
M
12 mo
71
33 months
4.5
4.5
>50% tumor size regression >50% tumor size regression >50% tumor size regression
Seizure free on 1 AED 1 seizure per week on 2 AED 1 partial seizure per week on 3 AED
Daily seizures on 3 AED þ ACTH 1 partial seizure per week on 2 AED
AED, antiepileptic drug; ACTH, adrenocorticotropic hormone.
SEGA response
Neuropsychological outcome
50 41
64 84
Epilepsy outcome
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Sex
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interrupted until resolution to grade 1. The medication was resumed at the dose used prior to interruption in cases of grade 2 toxicity, and at the lower dose level in cases of grade 3 toxicity. Grade 4 toxicity or any toxicity requiring interruption of everolimus for more than 6 weeks resulted in permanent treatment discontinuation. The primary endpoint was the proportion of patients with confirmed SEGA response, defined as a reduction in the sum of the volumes of all target SEGA lesions of 50% relative to baseline, in the absence of worsening of non-target SEGA lesions, new SEGA lesions 1 cm in diameter, and new/worsening hydrocephalus.23 At our Department, annual neuropsychological evaluation by means of PsycheeCattell test was scheduled beyond the protocol. Moreover, in addition to adherence to the protocol procedures, the caregivers of the patients were asked to maintain seizure diaries and to report all seizures daily. Patients were seen every 2 weeks during the first 2 months of the blinded phase and every 12 weeks thereafter. Height and weight were measured every 3 months, after a detailed history of the measurements had been collected before patients entered the study. The results were compared with Polish growth charts,24 in which the height and weight measurements of Polish boys and girls are divided into following percentile intervals: under 3, 3e10, 10e25, 25e50, 50e75, 75e90, 90e97, above 97. The results of height and weight measurements in this study of children were referenced against age and sex matched children in Polish study.24 Adverse events were assessed according to the Common Terminology Criteria for Adverse Events, version 3.0.25
3.
Fig. 1 e Decrease of SEGA diameter on everolimus treatment. A e brain MRI performed at baseline in 35month-old child. B e brain MRI performed after 6 months of everolimus treatment in the same child.
continuing everolimus treatment in the extension phase of the study. The starting dose of everolimus was 4.5 mg per square meter of body surface area and was subsequently adjusted to attain a whole-blood through everolimus concentration of 5e15 ng/mL. The dose levels for dose adjustment were as follows: 2.53 mg every other day, 2.5 mg, 3.38 mg, 4.5 mg, 6.0 mg, 8.0 mg, 10.67 mg, and 14.22 mg. Dose modifications were allowed when treatment-related toxic effects occurred. When grade 2 or 3 toxicity was reported, everolimus was
Results
Eight children (two girls and six boys) under 3 years of age from our department were included in the EXIST-1 study. In all of them, everolimus treatment was introduced before 3 years of age (range from 12 to 35 months; mean 24.1 months), at a dose of 4.5 mg/m2 and then adjusted according to pharmacokinetic analysis and/or tolerability. The age of the children at treatment onset and the follow-up duration as of November 23, 2012, as well as actual dose levels are presented in Table 1. In six of eight children, at least a 50% reduction in SEGA volume was observed (Fig. 1), and no SEGA progression was observed in any of the children. Since no child in the study presented with renal angiomyolipoma or facial angiofibroma at screening, angiomyolipoma and skin lesion response rate assessment was not performed. Seizure diaries were available for all patients. Three children who were seizure free at baseline, remained seizure free throughout the study and in one, the number of antiepileptic drugs was reduced from 2 to 1. One child with severe drugresistant epilepsy, who experienced daily partial seizures before entering the study, had complete and permanent cessation of seizures after everolimus treatment. The patient started to be seizure free 2 months after the introduction of everolimus. Two additional children with drug-resistant epilepsy had at least a 50% decrease in the number of seizures in the first 6 months of everolimus treatment and this effect was stable. In one child, the number of seizures decreased markedly during the first year of treatment and then increased, requiring
483
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75 1, F 2, F 3, M 4, M 5, M 6, M 7, M 8, M
50
25
0
-36 -30 -24 -18 -12 -6 0 6 Months
12 18 24 30 36
Fig. 2 e Impact of everolimus treatment on height. The results of height measurement are referred to the standardized Polish charts.24 Month “0” indicates the enrollment of patients into EXIST-1 trial.
the introduction of a third antiepileptic drug. In one child, no impact of everolimus on seizure frequency was noted. The type of seizures did not change in any of the children during the study. Neuropsychological evaluation did not show any significant changes between baseline and follow-up (Table 1). A total of 142 adverse events were noted in all patients; of these, 74 were assessed to be drug related. All adverse events were more frequent in the first year of treatment. The vast majority (127/142) of adverse events were grade 1 and 2. Fifteen grade 3 adverse events and no grade 4 adverse events were observed. Dose reductions due to an adverse event were necessary in 7 patients. Every patient experienced at least one adverse event. The most frequent adverse event was aphthous stomatitis. It was observed in seven of eight patients throughout the follow-up. Grade 1 stomatitis was reported 29 times, mostly (19 times) in the first year of treatment. Grade 2 stomatitis or mouth ulcers were reported 25 times in five of eight patients and were slightly more frequent in the first year of treatment (10 times) than in the second (8 times) and third (7 times) year of treatment. Grade 3 stomatitis was observed in 5 of 8 patients, 4 times in the first year, 4 times in the second year, and once in the third year of treatment. In three patients, grade 2 and grade 3 stomatitis was observed when the dose level was increased to 6 mg/m2 or 10.67 mg/m2, respectively. After dose reductions, no further episodes of stomatitis were noted in these patients. In two patients, grade 2 and 3 stomatitis were observed at the dose level of 4.5 mg/m2 and 3.38 mg/m2, respectively. After dose reductions, stomatitis did not occur. All stomatitis episodes resolved completely. There was no association between the younger age of the child and a higher frequency of stomatitis. At least one upper respiratory tract infection was noted in all patients, but the investigators did not assess any as drug related. All infections were grade 1 or 2, and resolved without sequelae. Upper respiratory infections developed more frequently in the first (31 episodes) than in the second (16 episodes) and third (9 episodes) year of treatment. Upper respiratory tract infections were more common in children
under 2 years of age (35 episodes in four patients) than in older children (21 episodes in four children). Skin rash or eczema was observed in four patients. In one of them, due to grade 2 rash, the dose level of everolimus was reduced twice, but was increased after a few months to 4.5 mg/m2 and no further skin symptoms were seen thereafter. In three patients, skin rash was mild and resolved spontaneously. Four patients experienced mild gastrointestinal disturbances, including vomiting and diarrhea, as well as transient constipation; however, these adverse events were not assessed as related to treatment. Increased total cholesterol concentration was observed in three (37.5%) patients. In all 3 cases, it was determined to be grade 1 hypercholesterolemia, which is ongoing, but not requiring treatment other than dietary modifications. Additionally, grade 1 hypertriglyceridemia was observed in one patient, but does not require any extra treatment. Decreased plasma fibrinogen concentration was observed in two patients, in one of whom, grade 3 and subsequently grade 2 low fibrinogen were noted. No clinical signs of this laboratory abnormality were reported in either of the children. Plasma fibrinogen returned to normal spontaneously in both children within 3 months. Decreased white blood cell count was observed in two patients. In one, grade 3 leukopenia was observed. After dose level reduction, the white blood cell count returned to normal. In the other patient, grade 2 leukopenia resolved after temporary cessation of treatment. Other less frequent and mild adverse events included urinary tract infection, conjunctivitis, delayed wound healing after accidental skin injury, and grade 1 increase in serum alkaline phosphatase in one patient each. One girl was diagnosed with allergic asthma, which was mild and not related to the study treatment. In the patient who experienced accidental skin injury, delayed wound healing was observed and everolimus was discontinued for 1 week enabling the wound to be healed completely.
100
Weight Percentile
Height Percentile
100
75 1, F 2, F 3, M 4, M 5, M 6, M 7, M 8, M
50
25
0
-36 -30 -24 -18 -12 -6 0 6 Months
12 18 24 30 36
Fig. 3 e Impact of everolimus treatment on weight. The results of weight measurement are referred to the standardized Polish charts.24 Month “0” indicates the enrollment of patients into EXIST-1 trial.
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One patient experienced significant loss of appetite in the first and second year of treatment. This adverse event was assessed as drug related and resulted in a temporary decrease in growth rate in this boy. Before enrollment, his height measured between the 75th and 90th percentiles. After everolimus initiation, his height was in the 50th percentile after 12 months, between the 25th and 50th percentiles after 22 months, and between the 50th and 75th percentile after 33 months. Except for this one child, no impact of everolimus treatment on growth rate was observed. Based on the detailed history of height and weight available for each child, results showed that children were growing and gaining weight with at least the same velocity as observed before everolimus introduction. The height and weight measurements of all study children referred to the height and weight charts24 are presented in Figs. 2 and 3, respectively.
4.
Discussion
This is the first study reporting on the safety of everolimus in young children under the age of 3 years with solid tumors. Eight children under 3 years of age with TSC-associated SEGA were treated with everolimus for at least 33 months. Everolimus therapy was associated with at least a 50% reduction in SEGA volume in six of eight (75%) patients. No patient had tumor progression or worsening hydrocephalus. In the blinded phase of the EXIST-1 trial, the overall SEGA response rate was 35% in the everolimus arm versus 0% in the placebo arm.23 Few studies have reported on the efficacy of mTOR inhibitors in children with TSC-associated SEGA. In the study of Franz et al., published in 2006, rapamycin resulted in significant SEGA volume reduction in three children with TSC.26 Rapamycin also appeared to be effective in three pediatric TSC patients with SEGA reported by Lam et al.27 In their study, rapamycin caused a 50e65% regression of SEGA after 3 months of treatment. An open-label, prospective study of everolimus (Certican) for SEGA in TSC patients was published in 2010 by Krueger et al.21 Twenty-eight patients included in this study were 3 years of age or older and presented with serial growth of SEGA on at least two successive MRI scans. In 75% of these patients, everolimus treatment resulted in tumor reduction by at least 30%. In 32% of patients, the reduction was 50% or more. Recently, the potential use of mTOR inhibitors in epilepsy treatment has been widely discussed.14 In mouse models of TSC, mTOR inhibitors prevent the development of epilepsy and underlying brain abnormalities associated with epileptogenesis.14 Accumulating evidence suggests that mTOR inhibition by rapamycin or everolimus might also reduce epilepsy severity in TSC patients.16,17 In the children in our study, everolimus resulted in permanent seizure cessation in one child with severe drug-resistant epilepsy and in at least a 50% reduction in the number of seizures in two other children. However, in another child, the seizure frequency decreased markedly in the first year of treatment, which enabled the reduction in the number of antiepileptic drugs, but then increased again. In one child with active epilepsy, treatment with everolimus showed no impact on seizure frequency. These results indicate that further studies are needed to clarify the effect of mTOR inhibition on epilepsy.
Everolimus treatment was well-tolerated overall in the children in our study. No grade 4 toxicities or toxicities lasting for more than 6 weeks, which would require treatment discontinuation, were observed. The most frequent adverse events were mild and included stomatitis, upper respiratory tract infections, skin rash, decreased white blood cell count, decreased plasma fibrinogen, and hyperlipidemia. Less frequently, everolimus treatment was associated with diarrhea, loss of appetite, hypertriglyceridemia, impaired wound healing, and increase in serum alkaline phosphatase. The spectrum of everolimus-related adverse events in young children is very similar to that observed in adults and older children with TSC-associated SEGAs.21,23,27 Twenty-eight patients with TSC-associated SEGA, aged from 3 to 34 years, were enrolled in the study reported by Krueger et al.21 In their study, all patients had at least one adverse event, with grade 1 or grade 2 selflimiting infections and stomatitis accounting for the majority. Four patients developed serious adverse reactions, and one patient discontinued treatment because of drug toxicity. In the phase II study of Franz et al.,26 in which three children and one adult with TSC receiving rapamycin for treatment of symptomatic and growing SEGA were included, the most frequent adverse events included oral mucositis, upper respiratory tract infections, and skin rash. A phase I study of everolimus in pediatric patients with refractory solid tumors also included patients older than 3 years.28 In this study, the most frequent adverse events included stomatitis, diarrhea, and elevation of alanine aminotransferase. Similar adverse events were reported in studies of children receiving everolimus after kidney and liver transplantations,19,20 in which the overall tolerance of everolimus was good and the most frequent adverse events included stomatitis, various infections, hypercholesterolemia, and problems with wound healing. The only adverse event observed in our group that was not reported in the previous studies was decreased plasma fibrinogen, which was observed in 2 patients, neither of whom presented with any clinical symptoms. In both patients, plasma fibrinogen returned to normal spontaneously and the reaction was considered unrelated to everolimus. However, the effect of everolimus on plasma fibrinogen requires further elucidation. Many adverse events were reported more frequently in the first 12 months of treatment than in the second year of the study, particularly upper respiratory tract infections, which were twice as frequent in the first year than in the second year of the study, and stomatitis. This phenomenon was also noted in the previous studies of everolimus in TSC-associated SEGAs.1 The potential impact of mTOR inhibitors on the physical development of young children poses a major concern about such treatment. Growth inhibition has been reported in kidneytransplanted pediatric patients receiving sirolimus.29,30 In our study, seven children experienced no change in height and weight gain velocity because of treatment. A temporary decrease in growth velocity was observed in only one child, who experienced significant loss of appetite during the study. These data indicate that the antiproliferative effects of everolimus did not appear to negatively affect growth in most patients. There are two important limitations of our study. First, the study group was relatively small. Second, we compared the growth velocity before enrollment in the study and during at least 33 months of everolimus treatment, but did not match the
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 7 ( 2 0 1 3 ) 4 7 9 e4 8 5
patients to untreated controls. The trial was randomized and placebo-controlled but it happened by chance that all of our youngest patients were randomized to the everolimus arm. Therefore, the results obtained in this subgroup could not be compared with placebo controls from the EXIST-1 study. The discrepancy between the impact of mTOR inhibition on children’s growth in our study and in kidney-transplanted patients may also result from the genetic differences between the groups of patients. Our patients had TSC, characterized by constitutive mTOR hyperactivation in many organs, and thus their growth might not have been compromised by mTOR inhibition. Finally, it cannot be ruled out that the impact of sirolimus and everolimus on growth is different between the two drugs. This hypothesis is supported by the study of Pape et al., who analyzed the growth of children who received everolimus after kidney transplantation.20 They did not see the negative effect of everolimus on growth rate during the 3-year observation period, but the results could have been biased by treatment with steroids and other immunosuppressive agents in their study. The effect of everolimus on the physical development of young children requires further studies, but our results indicate that in TSC patients, everolimus treatment is not associated with significant growth inhibition. Given the efficacy and well-tolerated profile of everolimus in our study, everolimus may represent a rational treatment option in infants and young children with TSC-associated epilepsy and SEGA.
references
1. Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet 2008;372:657e68. 2. Borkowska J, Schwartz RA, Kotulska K, Jozwiak S. Tuberous sclerosis complex: tumors and tumorigenesis. Int J Dermatol 2011;50:13e20. 3. Kwiatkowski DJ, Manning BD. Tuberous sclerosis: a GAP at the crossroads of multiple signaling pathways. Hum Mol Genet 2005;14:251e8. 4. Chan JA, Zhang H, Roberts PS, et al. Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J Neuropathol Exp Neurol 2004;63:1236e42. 5. Tyburczy ME, Kotulska K, Pokarowski P, et al. Novel proteins regulated by mTOR in subependymal giant cell astrocytomas of patients with tuberous sclerosis complex and new therapeutic implications. Am J Pathol 2010;176:1878e90. 6. Grajkowska W, Kotulska K, Jurkiewicz E. Brain lesions in tuberous sclerosis complex. Review Folia Neuropathol 2010;48:139e49. 7. Adriaensen ME, Schaefer-Prokop CM, Stijnen T, et al. Prevalence of subependymal giant cell tumors in patients with tuberous sclerosis and a review of the literature. Eur J Neurol 2009;16:691e6. 8. Shepherd CW, Gomez MR, Lie JT, et al. Causes of death in patients with tuberous sclerosis. Mayo Clin Proc 1991;66:792e6. 9. Kim SK, Wang KC, Cho BK, et al. Biological behavior and tumorigenesis of subependymal giant cell astrocytomas. J Neurooncol 2001;52:217e25. 10. de Ribaupierre S, Dorfmu¨ller G, Bulteau C, et al. Subependymal giant-cell astrocytomas in pediatric tuberous sclerosis disease: when should we operate? Neurosurgery 2007;60:83e9.
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11. Holmes GL, Stafstrom CE., Tuberous Sclerosis Study Group. Tuberous sclerosis complex and epilepsy: recent developments and future challenges. Epilepsia 2007;48:720e31. wiak S, Goodman M, Lamm SH. Poor mental development 12. Jo´z in patients with tuberous sclerosis complex: clinical risk factors. Arch Neurol 1998;55:379e84. ska-Pakieła D, et al. Antiepileptic wiak S, Kotulska K, Doman 13. Jo´z treatment before the onset of seizures reduces epilepsy severity and risk of mental retardation in infants with tuberous sclerosis complex. Eur J Paediatr Neurol 2011;15:424e31. 14. Wong M. Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: from tuberous sclerosis to common acquired epilepsies. Epilepsia 2010;51:27e36. ska-Pakieła D, Kotulska K, Kaczorowska M. 15. Jo´zwiak S, Doman Treatment before seizures: new indications for antiepileptic therapy in children with tuberous sclerosis complex. Epilepsia 2007;48:1632e4. wiak S, Jurkiewicz E, et al. Effective 16. Perek-Polnik M, Jo´z everolimus treatment of inoperable, life-threatening subependymal giant cell astrocytoma and intractable epilepsy in a patient with tuberous sclerosis complex. Eur J Paediatr Neurol 2011;16:83e5. 17. Muncy J, Butler IJ, Koenig MK. Rapamycin reduces seizure frequency in tuberous sclerosis complex. J Child Neurol 2009;24:477. 18. Dancey J. mTOR signaling and drug development in cancer. Nat Rev Clin Oncol 2010;7:209e19. 19. Nielsen D, Briem-Richter A, Sornsakrin M, et al. The use of everolimus in pediatric liver transplants recipients: first experience in a single center. Pediatr Transplant. 2011;15:510e4. 20. Pape L, Offner G, Kreuzer M, et al. De novo therapy with everolimus, low dose ciclosporine A, basiliximab and steroid elimination in pediatric kidney transplantation. Am J Transplant 2010;10:2349e54. 21. Krueger D, Care M, Holland K, et al. Everolimus for subependymal giant cell astrocytomas in tuberous sclerosis. N Engl J Med 2010;363:1801e11. 22. Ferte C, Paci A, Zizi M, et al. Natural history, management and pharmacokinetics of everolimus-induced oral ulcers: insights into compliance issues. Eur J Cancer 2011;47:2249e55. 23. Franz DN, Belousova E, Sparagana S, et al. Efficacy and safety of everolimus for the treatment of subependymal giant-cell astrocytomas associated with tuberous sclerosis complex: a multicentre, randomized, placebo-controlled trial. Lancet 14 November 2012. http://dx.doi.org/10.1016/S0140-6736(12) 61134-9. Early Online Publication. ska A, Jodkowska M, Mikiel-Kostyra K, et al. 24. Oblacin Assessment of physical development of children and adolescents. Part I. Infants and children up to 5 years e national reference values or WHO standards? Med Wieku Rozwoj 2010;14:95e100. 25. The Cancer Therapy Evaluation Program Common Terminology Criteria for Adverse Events, versions 3.0 http:// ctep.cancer.gov/forms. 26. Franz DN, Leonard J, Tudor C, et al. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol 2006;59:490e8. 27. Lam C, Bouffet E, Tabori U, et al. Rapamycin (sirolimus) in tuberous sclerosis associated pediatric central nervous system tumors. Pediatr Blood Cancer 2009;54:476e9. 28. Fouladi M, Laningham F, Wu J, et al. Phase I study of everolimus in pediatric patients with refractory solid tumors. J Clin Oncol 2007;25:4806e12. 29. Gonzalez D, Garcia C, Azocar M, et al. Growth of kidneytransplanted pediatric patients treated with sirolimus. Pediatr Nephrol 2011;26:961e6. 30. Rangel G, Ariceta G. Growth failure associated with sirolimus: case report. Pediatr Nephrol 2009;24:2047e50.
Official Journal of the European Paediatric Neurology Society
Original article
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 Katarzyna Kotulska a,b,*, Dariusz Chmielewski a, Julita Borkowska a, ski a, Tomasz Kmiec a, _ Elzbieta Jurkiewicz c, Dariusz Kuczyn b zwiak a Barbara Łojszczyk , Dorota Dunin-Wa˛sowicz a, Sergiusz Jo´ a
Department of Science, The Children’s Memorial Health Institute, Warsaw, Poland Department of Neurology, The Children’s Memorial Health Institute, Warsaw, Poland c Department of Radiology, The Children’s Memorial Health Institute, Warsaw, Poland b
article info
abstract
Article history:
Background: Tuberous sclerosis complex (TSC) is a genetic disorder characterized by
Received 9 December 2012
increased mammalian target of rapamycin (mTOR) activation and growth of benign tumors
Received in revised form
in several organs throughout the body. In young children with TSC, drug-resistant epilepsy
6 March 2013
and subependymal giant cell astrocytomas (SEGAs) present the most common causes of
Accepted 11 March 2013
mortality and morbidity. There are also some reports on the antiepileptic and antiepileptogenic potential of mTOR inhibitors in TSC. However, the data on everolimus effi-
Keywords:
cacy and safety in young children are very limited.
TSC
Aims: To show the long-term safety data and the effect of everolimus treatment on epilepsy
Epilepsy
in children under the age of 3 who received everolimus for SEGAs associated with TSC.
SEGA
Methods: We present the results of everolimus treatment in 8 children under the age of 3
Everolimus
who participated in EXIST-1 study. Five patients presented with active, drug-resistant
Adverse events
epilepsy at baseline. The mean follow-up is 35 months (33e38 months) and all children
Safety
are still on treatment.
Young children
Results: In 6 out of 8 children, at least a 50% reduction in SEGA volume was observed. In 1 child with drug-resistant epilepsy, everolimus treatment resulted in cessation of seizures and in 2 other children, at least a 50% reduction in the number of seizures was noted. The incidence of adverse events (AE) was similar to that observed in older children and adults. Conclusions: This study suggests that everolimus is effective and safe in infants and young children with epilepsy and SEGA associated with TSC and offers a valuable treatment option. ª 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
* Corresponding author. Department of Neurology and Epileptology, The Children’s Memorial Health Institute, Al. Dzieci Polskich 20, 04730 Warsaw, Poland. Tel.: þ48 22 8157404; fax: þ48 22 8157402. E-mail addresses: [email protected], [email protected] (K. Kotulska). 1090-3798/$ e see front matter ª 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejpn.2013.03.002
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1.
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 7 ( 2 0 1 3 ) 4 7 9 e4 8 5
Introduction
Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder occurring in approximately 1 in 6000 live births.1 It is characterized by the development of benign, highly vascular, hamartomatic growth in various tissues and organs, including the brain, kidneys, heart, liver, lungs, retina, and skin.2 TSC is caused by the mutation of either of two genes: TSC1 encoding hamartin and TSC2 encoding tuberin.1,3 Both proteins interact to inhibit the activity of mammalian target of rapamycin (mTOR).3,4 In the absence of active tuberin/hamartin complex, mTOR is stimulated to promote protein synthesis and cell growth.1,3 Hyperactivation of mTOR is a common finding in TSC-related tumors and was shown to be pivotal for the development of most disease-related symptoms, including epilepsy, developmental malformations, and tumor growth.2,5 In the brain, cortical and subcortical tubers, subependymal nodules, and subependymal giant cell astrocytomas (SEGAs) are hallmarks of the disease.6 SEGA is a rare low-grade brain tumor occurring almost exclusively in TSC patients and affecting approximately 20% of them.7 SEGAs usually develop in the first two decades of life, and in children and adolescents with TSC, they present the major cause of morbidity and mortality.7,8 SEGAs usually grow in the vicinity of the foramen of Monro and therefore may obstruct cerebrospinal fluid pathways, causing hydrocephalus.9 Until recently, surgical resection has been the only available treatment for SEGAs producing these clinical symptoms. However, SEGA surgery was associated with distinct morbidity and mortality of up to 30% in different pediatric patient series.9,10 Moreover, early SEGA growth symptoms can be easily overlooked, especially in young children and individuals with learning disabilities, and by the time the symptoms are recognized, they are often irreversible even by immediate surgical intervention.10 Epilepsy is the most common TSC symptom appearing in 80e90% of patients, mainly in the first year of life.11 Epilepsy in TSC is often intractable, with a poor response to anticonvulsant medications, and is commonly associated with mental retardation.11e13 The accumulating data implicate the mTOR pathway as mediating epileptogenesis in TSC, and indicate that mTOR inhibitors may have antiepileptogenic and antiepileptic properties in patients with TSC.14e17 Recently, everolimus was approved by United States Food and Drug Administration and European Medicines Agency to treat adults and children aged 3 years and above with TSC who have SEGA that requires therapeutic intervention but cannot be curatively resected. Everolimus is also approved for adults with renal angiomyolipoma and TSC, not requiring immediate surgery. Everolimus is an orally bioavailable derivate of rapamycin, which selectively inhibits mTOR activity, targeting the mTOR-raptor signal transduction complex (mTORC1).18 Everolimus is already used as an immunosuppressant in solid organ transplantation for the prevention of organ rejection in patients with renal and cardiac transplants.18,19 Currently, clinical trials aimed at studying the potential use of everolimus in epilepsy are planned or already ongoing. The adverse events and safety profile of everolimus in adult patients and older children was established in a number of clinical trials settings.18e22 However, the safety of
everolimus treatment in young children has not yet been reported. Of utmost importance, there are concerns about whether everolimus could adversely affect growth and development in children. Given that SEGAs can be found as early as in utero and that some infants could benefit from mTOR inhibitors, the assessment of safety of everolimus in this group of patients is urgently needed. The EXIST-1 (Everolimus in the Treatment of Subependymal Giant Cell Astrocytomas (SEGAs) Associated With Tuberous Sclerosis Complex) trial is the first prospective, double-blind, parallel-group, placebo-controlled, multicenter phase 3 study evaluating everolimus in patients with SEGA associated with TSC.23 At the Department of Neurology and Epileptology, The Children’s Memorial Health Institute, Warsaw, Poland, 20 patients were enrolled in the study. Eight of them began treatment with everolimus before the age of 3 years and have been treated for at least 33 months. The aim of this study was to analyze the effect of everolimus on epilepsy and long-term safety in infants and young children with TSC.
2.
Material and methods
2.1.
Patients
Eight children under the age of 3 years from our department participated in the EXIST-1 study and received everolimus. The mean follow-up of these children is to date 35 months (range from 33 to 38). All children met the clinical criteria for TSC diagnosis and all fulfilled the inclusion criteria for the EXIST-1 study. All children presented with a history of epilepsy. In three children, epilepsy was well controlled with one or two antiepileptic drugs and they were seizure free at screening. Five children had active drug-resistant epilepsy with at least one seizure per week, despite the use of two or three antiepileptic drugs. In three children, adrenocorticotropic hormone (ACTH) therapy for infantile spasms was completed before enrollment in the EXIST-1 study. In all three of these children, the infantile spasms were well controlled, but they continued to suffer from partial seizures. The study was approved by The Children’s Memorial Health Institute Ethics Committee. Written informed consent was obtained from the parents of all enrolled children before performing any trial procedure.
2.2.
Study design
Patients with definite clinical diagnosis of TSC and a serially growing SEGA exceeding 1 cm in diameter were eligible for the study (for details, see Franz et al., 201223). Patients had to be medically stable and unlikely to require SEGA-related surgery. After the screening period, the patients were randomized to either a placebo or everolimus arm. The blinded core phase of the treatment was followed by an extension phase, which is still ongoing. In the extension phase, all patients were offered open-label everolimus, as the results of the core phase favored everolimus. All children in our department under 3 years of age were randomized to the everolimus group and all are
Table 1 e Clinical characteristics of the patients. Age at treatment onset
Epilepsy status at screening
Neuropsychological evaluation at screening
Follow-up
Initial everolimus dose (mg/m2)
Actual everolimus dose (mg/m2)
1
F
20 mo
63
38 months
4.5
2.53
Stable disease
71
Seizure free on 2 AED
2
F
21 mo
Drug-resistant epilepsy, requiring 3 AED þ ACTH, daily partial (some secondarily generalized) seizures Seizure free on 1 AED
90
36 months
4.5
2.53
88
3
M
35 mo
Seizure free on 2 AED
69
36 months
4.5
3.38
4
M
29 mo
42
35 months
4.5
4.5
Seizure free on 1 AED Seizure free on 1 AED 1 seizure per week on 3 AED
5
M
14 mo
68
35 months
4.5
4.5
Stable disease
72
1e2 partial seizure per week, on 3 AED
6
M
28 mo
Drug-resistant epilepsy, 1 seizure per week on 3 AED þ ACTH Drug-resistant epilepsy, requiring 3 AED, 3e5 partial seizures per week Seizure free on 1 AED
>50% tumor size regression >50% tumor size regression >50% tumor size regression
28
33 months
4.5
8.0
27
7
M
34 mo
67
33 months
4.5
6.0
8
M
12 mo
71
33 months
4.5
4.5
>50% tumor size regression >50% tumor size regression >50% tumor size regression
Seizure free on 1 AED 1 seizure per week on 2 AED 1 partial seizure per week on 3 AED
Daily seizures on 3 AED þ ACTH 1 partial seizure per week on 2 AED
AED, antiepileptic drug; ACTH, adrenocorticotropic hormone.
SEGA response
Neuropsychological outcome
50 41
64 84
Epilepsy outcome
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 7 ( 2 0 1 3 ) 4 7 9 e4 8 5
Sex
481
482
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interrupted until resolution to grade 1. The medication was resumed at the dose used prior to interruption in cases of grade 2 toxicity, and at the lower dose level in cases of grade 3 toxicity. Grade 4 toxicity or any toxicity requiring interruption of everolimus for more than 6 weeks resulted in permanent treatment discontinuation. The primary endpoint was the proportion of patients with confirmed SEGA response, defined as a reduction in the sum of the volumes of all target SEGA lesions of 50% relative to baseline, in the absence of worsening of non-target SEGA lesions, new SEGA lesions 1 cm in diameter, and new/worsening hydrocephalus.23 At our Department, annual neuropsychological evaluation by means of PsycheeCattell test was scheduled beyond the protocol. Moreover, in addition to adherence to the protocol procedures, the caregivers of the patients were asked to maintain seizure diaries and to report all seizures daily. Patients were seen every 2 weeks during the first 2 months of the blinded phase and every 12 weeks thereafter. Height and weight were measured every 3 months, after a detailed history of the measurements had been collected before patients entered the study. The results were compared with Polish growth charts,24 in which the height and weight measurements of Polish boys and girls are divided into following percentile intervals: under 3, 3e10, 10e25, 25e50, 50e75, 75e90, 90e97, above 97. The results of height and weight measurements in this study of children were referenced against age and sex matched children in Polish study.24 Adverse events were assessed according to the Common Terminology Criteria for Adverse Events, version 3.0.25
3.
Fig. 1 e Decrease of SEGA diameter on everolimus treatment. A e brain MRI performed at baseline in 35month-old child. B e brain MRI performed after 6 months of everolimus treatment in the same child.
continuing everolimus treatment in the extension phase of the study. The starting dose of everolimus was 4.5 mg per square meter of body surface area and was subsequently adjusted to attain a whole-blood through everolimus concentration of 5e15 ng/mL. The dose levels for dose adjustment were as follows: 2.53 mg every other day, 2.5 mg, 3.38 mg, 4.5 mg, 6.0 mg, 8.0 mg, 10.67 mg, and 14.22 mg. Dose modifications were allowed when treatment-related toxic effects occurred. When grade 2 or 3 toxicity was reported, everolimus was
Results
Eight children (two girls and six boys) under 3 years of age from our department were included in the EXIST-1 study. In all of them, everolimus treatment was introduced before 3 years of age (range from 12 to 35 months; mean 24.1 months), at a dose of 4.5 mg/m2 and then adjusted according to pharmacokinetic analysis and/or tolerability. The age of the children at treatment onset and the follow-up duration as of November 23, 2012, as well as actual dose levels are presented in Table 1. In six of eight children, at least a 50% reduction in SEGA volume was observed (Fig. 1), and no SEGA progression was observed in any of the children. Since no child in the study presented with renal angiomyolipoma or facial angiofibroma at screening, angiomyolipoma and skin lesion response rate assessment was not performed. Seizure diaries were available for all patients. Three children who were seizure free at baseline, remained seizure free throughout the study and in one, the number of antiepileptic drugs was reduced from 2 to 1. One child with severe drugresistant epilepsy, who experienced daily partial seizures before entering the study, had complete and permanent cessation of seizures after everolimus treatment. The patient started to be seizure free 2 months after the introduction of everolimus. Two additional children with drug-resistant epilepsy had at least a 50% decrease in the number of seizures in the first 6 months of everolimus treatment and this effect was stable. In one child, the number of seizures decreased markedly during the first year of treatment and then increased, requiring
483
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 7 ( 2 0 1 3 ) 4 7 9 e4 8 5
75 1, F 2, F 3, M 4, M 5, M 6, M 7, M 8, M
50
25
0
-36 -30 -24 -18 -12 -6 0 6 Months
12 18 24 30 36
Fig. 2 e Impact of everolimus treatment on height. The results of height measurement are referred to the standardized Polish charts.24 Month “0” indicates the enrollment of patients into EXIST-1 trial.
the introduction of a third antiepileptic drug. In one child, no impact of everolimus on seizure frequency was noted. The type of seizures did not change in any of the children during the study. Neuropsychological evaluation did not show any significant changes between baseline and follow-up (Table 1). A total of 142 adverse events were noted in all patients; of these, 74 were assessed to be drug related. All adverse events were more frequent in the first year of treatment. The vast majority (127/142) of adverse events were grade 1 and 2. Fifteen grade 3 adverse events and no grade 4 adverse events were observed. Dose reductions due to an adverse event were necessary in 7 patients. Every patient experienced at least one adverse event. The most frequent adverse event was aphthous stomatitis. It was observed in seven of eight patients throughout the follow-up. Grade 1 stomatitis was reported 29 times, mostly (19 times) in the first year of treatment. Grade 2 stomatitis or mouth ulcers were reported 25 times in five of eight patients and were slightly more frequent in the first year of treatment (10 times) than in the second (8 times) and third (7 times) year of treatment. Grade 3 stomatitis was observed in 5 of 8 patients, 4 times in the first year, 4 times in the second year, and once in the third year of treatment. In three patients, grade 2 and grade 3 stomatitis was observed when the dose level was increased to 6 mg/m2 or 10.67 mg/m2, respectively. After dose reductions, no further episodes of stomatitis were noted in these patients. In two patients, grade 2 and 3 stomatitis were observed at the dose level of 4.5 mg/m2 and 3.38 mg/m2, respectively. After dose reductions, stomatitis did not occur. All stomatitis episodes resolved completely. There was no association between the younger age of the child and a higher frequency of stomatitis. At least one upper respiratory tract infection was noted in all patients, but the investigators did not assess any as drug related. All infections were grade 1 or 2, and resolved without sequelae. Upper respiratory infections developed more frequently in the first (31 episodes) than in the second (16 episodes) and third (9 episodes) year of treatment. Upper respiratory tract infections were more common in children
under 2 years of age (35 episodes in four patients) than in older children (21 episodes in four children). Skin rash or eczema was observed in four patients. In one of them, due to grade 2 rash, the dose level of everolimus was reduced twice, but was increased after a few months to 4.5 mg/m2 and no further skin symptoms were seen thereafter. In three patients, skin rash was mild and resolved spontaneously. Four patients experienced mild gastrointestinal disturbances, including vomiting and diarrhea, as well as transient constipation; however, these adverse events were not assessed as related to treatment. Increased total cholesterol concentration was observed in three (37.5%) patients. In all 3 cases, it was determined to be grade 1 hypercholesterolemia, which is ongoing, but not requiring treatment other than dietary modifications. Additionally, grade 1 hypertriglyceridemia was observed in one patient, but does not require any extra treatment. Decreased plasma fibrinogen concentration was observed in two patients, in one of whom, grade 3 and subsequently grade 2 low fibrinogen were noted. No clinical signs of this laboratory abnormality were reported in either of the children. Plasma fibrinogen returned to normal spontaneously in both children within 3 months. Decreased white blood cell count was observed in two patients. In one, grade 3 leukopenia was observed. After dose level reduction, the white blood cell count returned to normal. In the other patient, grade 2 leukopenia resolved after temporary cessation of treatment. Other less frequent and mild adverse events included urinary tract infection, conjunctivitis, delayed wound healing after accidental skin injury, and grade 1 increase in serum alkaline phosphatase in one patient each. One girl was diagnosed with allergic asthma, which was mild and not related to the study treatment. In the patient who experienced accidental skin injury, delayed wound healing was observed and everolimus was discontinued for 1 week enabling the wound to be healed completely.
100
Weight Percentile
Height Percentile
100
75 1, F 2, F 3, M 4, M 5, M 6, M 7, M 8, M
50
25
0
-36 -30 -24 -18 -12 -6 0 6 Months
12 18 24 30 36
Fig. 3 e Impact of everolimus treatment on weight. The results of weight measurement are referred to the standardized Polish charts.24 Month “0” indicates the enrollment of patients into EXIST-1 trial.
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One patient experienced significant loss of appetite in the first and second year of treatment. This adverse event was assessed as drug related and resulted in a temporary decrease in growth rate in this boy. Before enrollment, his height measured between the 75th and 90th percentiles. After everolimus initiation, his height was in the 50th percentile after 12 months, between the 25th and 50th percentiles after 22 months, and between the 50th and 75th percentile after 33 months. Except for this one child, no impact of everolimus treatment on growth rate was observed. Based on the detailed history of height and weight available for each child, results showed that children were growing and gaining weight with at least the same velocity as observed before everolimus introduction. The height and weight measurements of all study children referred to the height and weight charts24 are presented in Figs. 2 and 3, respectively.
4.
Discussion
This is the first study reporting on the safety of everolimus in young children under the age of 3 years with solid tumors. Eight children under 3 years of age with TSC-associated SEGA were treated with everolimus for at least 33 months. Everolimus therapy was associated with at least a 50% reduction in SEGA volume in six of eight (75%) patients. No patient had tumor progression or worsening hydrocephalus. In the blinded phase of the EXIST-1 trial, the overall SEGA response rate was 35% in the everolimus arm versus 0% in the placebo arm.23 Few studies have reported on the efficacy of mTOR inhibitors in children with TSC-associated SEGA. In the study of Franz et al., published in 2006, rapamycin resulted in significant SEGA volume reduction in three children with TSC.26 Rapamycin also appeared to be effective in three pediatric TSC patients with SEGA reported by Lam et al.27 In their study, rapamycin caused a 50e65% regression of SEGA after 3 months of treatment. An open-label, prospective study of everolimus (Certican) for SEGA in TSC patients was published in 2010 by Krueger et al.21 Twenty-eight patients included in this study were 3 years of age or older and presented with serial growth of SEGA on at least two successive MRI scans. In 75% of these patients, everolimus treatment resulted in tumor reduction by at least 30%. In 32% of patients, the reduction was 50% or more. Recently, the potential use of mTOR inhibitors in epilepsy treatment has been widely discussed.14 In mouse models of TSC, mTOR inhibitors prevent the development of epilepsy and underlying brain abnormalities associated with epileptogenesis.14 Accumulating evidence suggests that mTOR inhibition by rapamycin or everolimus might also reduce epilepsy severity in TSC patients.16,17 In the children in our study, everolimus resulted in permanent seizure cessation in one child with severe drug-resistant epilepsy and in at least a 50% reduction in the number of seizures in two other children. However, in another child, the seizure frequency decreased markedly in the first year of treatment, which enabled the reduction in the number of antiepileptic drugs, but then increased again. In one child with active epilepsy, treatment with everolimus showed no impact on seizure frequency. These results indicate that further studies are needed to clarify the effect of mTOR inhibition on epilepsy.
Everolimus treatment was well-tolerated overall in the children in our study. No grade 4 toxicities or toxicities lasting for more than 6 weeks, which would require treatment discontinuation, were observed. The most frequent adverse events were mild and included stomatitis, upper respiratory tract infections, skin rash, decreased white blood cell count, decreased plasma fibrinogen, and hyperlipidemia. Less frequently, everolimus treatment was associated with diarrhea, loss of appetite, hypertriglyceridemia, impaired wound healing, and increase in serum alkaline phosphatase. The spectrum of everolimus-related adverse events in young children is very similar to that observed in adults and older children with TSC-associated SEGAs.21,23,27 Twenty-eight patients with TSC-associated SEGA, aged from 3 to 34 years, were enrolled in the study reported by Krueger et al.21 In their study, all patients had at least one adverse event, with grade 1 or grade 2 selflimiting infections and stomatitis accounting for the majority. Four patients developed serious adverse reactions, and one patient discontinued treatment because of drug toxicity. In the phase II study of Franz et al.,26 in which three children and one adult with TSC receiving rapamycin for treatment of symptomatic and growing SEGA were included, the most frequent adverse events included oral mucositis, upper respiratory tract infections, and skin rash. A phase I study of everolimus in pediatric patients with refractory solid tumors also included patients older than 3 years.28 In this study, the most frequent adverse events included stomatitis, diarrhea, and elevation of alanine aminotransferase. Similar adverse events were reported in studies of children receiving everolimus after kidney and liver transplantations,19,20 in which the overall tolerance of everolimus was good and the most frequent adverse events included stomatitis, various infections, hypercholesterolemia, and problems with wound healing. The only adverse event observed in our group that was not reported in the previous studies was decreased plasma fibrinogen, which was observed in 2 patients, neither of whom presented with any clinical symptoms. In both patients, plasma fibrinogen returned to normal spontaneously and the reaction was considered unrelated to everolimus. However, the effect of everolimus on plasma fibrinogen requires further elucidation. Many adverse events were reported more frequently in the first 12 months of treatment than in the second year of the study, particularly upper respiratory tract infections, which were twice as frequent in the first year than in the second year of the study, and stomatitis. This phenomenon was also noted in the previous studies of everolimus in TSC-associated SEGAs.1 The potential impact of mTOR inhibitors on the physical development of young children poses a major concern about such treatment. Growth inhibition has been reported in kidneytransplanted pediatric patients receiving sirolimus.29,30 In our study, seven children experienced no change in height and weight gain velocity because of treatment. A temporary decrease in growth velocity was observed in only one child, who experienced significant loss of appetite during the study. These data indicate that the antiproliferative effects of everolimus did not appear to negatively affect growth in most patients. There are two important limitations of our study. First, the study group was relatively small. Second, we compared the growth velocity before enrollment in the study and during at least 33 months of everolimus treatment, but did not match the
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 7 ( 2 0 1 3 ) 4 7 9 e4 8 5
patients to untreated controls. The trial was randomized and placebo-controlled but it happened by chance that all of our youngest patients were randomized to the everolimus arm. Therefore, the results obtained in this subgroup could not be compared with placebo controls from the EXIST-1 study. The discrepancy between the impact of mTOR inhibition on children’s growth in our study and in kidney-transplanted patients may also result from the genetic differences between the groups of patients. Our patients had TSC, characterized by constitutive mTOR hyperactivation in many organs, and thus their growth might not have been compromised by mTOR inhibition. Finally, it cannot be ruled out that the impact of sirolimus and everolimus on growth is different between the two drugs. This hypothesis is supported by the study of Pape et al., who analyzed the growth of children who received everolimus after kidney transplantation.20 They did not see the negative effect of everolimus on growth rate during the 3-year observation period, but the results could have been biased by treatment with steroids and other immunosuppressive agents in their study. The effect of everolimus on the physical development of young children requires further studies, but our results indicate that in TSC patients, everolimus treatment is not associated with significant growth inhibition. Given the efficacy and well-tolerated profile of everolimus in our study, everolimus may represent a rational treatment option in infants and young children with TSC-associated epilepsy and SEGA.
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