Everolimus for subependymal giant cell astrocytoma

Everolimus for subependymal giant cell astrocytoma

As a result of a trial, the US Food and Drug Administration (FDA) approved everolimus for patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex who are not candidates for curative surgical resection.

Patients ≥ 3 years of age with increasing size of SEGA lesions have had a sustained reduction of SEGA volume on everolimus 1).

A retrospective study included TSC patients being treated with oral everolimus for subependymal giant cell astrocytomas (SEGAs) and angiomyolipomas (AMLs). We recorded the changes in facial angiofibroma. Changes in the Angiofibroma Grading Scale (AGS) indicators were recorded according to erythema, average lesion size, lesion density, and percent involvement on the forehead, nose, cheeks, and chin. The scores were recorded before and after the administration of oral everolimus.

Twenty-one patients being treated with oral everolimus were enrolled in this study. The mean age was 20.5 years (range 11-44 years, 4 males, and 17 females). The mean dose of oral everolimus was 3.6 mg/day. Clinically meaningful and statistically significant improvement was observed in erythema (p = 0.001), average lesion size (p < 0.001), lesion density (p < 0.001), and percent involvement (p < 0.001). Changes in the AGS findings were statistically significant on the forehead (p = 0.001), nose (p < 0.001) cheeks (p < 0.001), and chin (p = 0.004).

Everolimus shows evident improvement and is approved for TSC-associated SEGAs and AMLs. The current study demonstrated the efficacy of oral everolimus in reducing facial angiofibromas, showing the parallel benefits of the treatment protocol for TSC 2).

Case reports

A 21-year female patient with large bilateral angiomyolipoma (AML) in both kidneys with the longest diameter more than 12.3 cm and subependymal giant cell astrocytoma (SEGA). Treatment with everolimus (EVE) was initiated at a dose of 10.0 mg/day and continued during the following 3 years. Magnetic resonance imaging (MRI) was performed before treatment with everolimus was initiated, and consequently at 12 and 36 months for follow-up of the efficacy of the treatment. After 3 years, the total size of the largest AML decreased by ~24.0% in the longest diameter. A reduction in the total size of SEGA was also observed. The most common adverse effect of treatment was stomatitis grades 3 to 4 and one febrile episodes associated with a skin rash that required a reduced dose of EVE. In conclusion, the everolimus treatment improved even such a large renal AML and the effect persisted during the long-term administration with a small number of adverse effects. A positive effect was observed on the brain tumor as well 3).


A case of a woman with TSC and Multifocal micronodular pneumocyte hyperplasia (MMPH) who received everolimus, for the treatment of a subependymal giant cell astrocytoma (SEGA). After 3 months of therapy, a remarkable decrease in density of all pulmonary MMPH lesions was observed, without any change in size. This shows that everolimus is active on MMPH similarly to its effects on SEGA, renal angiomyolipomas, and pulmonary lymphangioleiomyomatosis in TSC, and suggests that the dysregulated activation of mTOR which characterizes TSC also plays a role in the pathogenesis of MMPH 4).


The aim of a study was to evaluate the efficacy of oral everolimus for TSC-associated angiofibromas.

This retrospective study included TSC patients being treated with oral everolimus for subependymal giant cell astrocytomas (SEGAs) and angiomyolipomas (AMLs). We recorded the changes in facial angiofibromas. Changes in the Angiofibroma Grading Scale (AGS) indicators were recorded according to erythema, average lesion size, lesion density, and percent involvement on the forehead, nose, cheeks, and chin. The scores were recorded before and after the administration of oral everolimus.

Twenty-one patients being treated with oral everolimus were enrolled in this study. The mean age was 20.5 years (range 11-44 years, 4 males, and 17 females). The mean dose of oral everolimus was 3.6 mg/day. Clinically meaningful and statistically significant improvement was observed in erythema (p = 0.001), average lesion size (p < 0.001), lesion density (p < 0.001), and percent involvement (p < 0.001). Changes in the AGS findings were statistically significant on the forehead (p = 0.001), nose (p < 0.001) cheeks (p < 0.001), and chin (p = 0.004).

Everolimus shows evident improvement and is approved for TSC-associated SEGAs and AMLs. The study demonstrated the efficacy of oral everolimus in reducing facial angiofibromas, showing the parallel benefits of the treatment protocol for TSC 5).


1)

Franz DN, Agricola K, Mays M, Tudor C, Care MM, Holland-Bouley K, Berkowitz N, Miao S, Peyrard S, Krueger DA. Everolimus for subependymal giant cell astrocytoma: 5-year final analysis. Ann Neurol. 2015 Dec;78(6):929-38. doi: 10.1002/ana.24523. Epub 2015 Nov 9. PMID: 26381530; PMCID: PMC5063160.
2)

Wei CC, Hsiao YP, Gau SY, Wu YT, Wu CT, Wu MH, Tsai JD. The Efficacy of Everolimus for Facial Angiofibromas in Tuberous Sclerosis Complex Patients Treated for Renal Angiomyolipoma/Subependymal Giant Cell Astrocytoma. Dermatology. 2020 Oct 8:1-6. doi: 10.1159/000510222. Epub ahead of print. PMID: 33032292.
3)

Rambabova Bushljetik I, Lazareska M, Barbov I, Stankov O, Filipce V, Spasovski G. Bilateral Renal Angiomyolipomas and Subependymal Giant Cell Astrocytoma Associated with Tuberous Sclerosis Complex: a Case Report and Review of The Literature. Balkan J Med Genet. 2021 Mar 23;23(2):93-98. doi: 10.2478/bjmg-2020-0017. PMID: 33816078; PMCID: PMC8009567.
4)

Daccord C, Nicolas A, Demicheli R, Chehade H, Hottinger AF, Beigelman C, Lazor R. Effect of everolimus on multifocal micronodular pneumocyte hyperplasia in tuberous sclerosis complex. Respir Med Case Rep. 2020 Nov 25;31:101310. doi: 10.1016/j.rmcr.2020.101310. PMID: 33312857; PMCID: PMC7720070.
5)

Wei CC, Hsiao YP, Gau SY, Wu YT, Wu CT, Wu MH, Tsai JD. The Efficacy of Everolimus for Facial Angiofibromas in Tuberous Sclerosis Complex Patients Treated for Renal Angiomyolipoma/Subependymal Giant Cell Astrocytoma. Dermatology. 2020 Oct 8:1-6. doi: 10.1159/000510222. Epub ahead of print. PMID: 33032292.

Giant Hypothalamic Hamartoma

Giant Hypothalamic Hamartoma

Giant hypothalamic hamartomas (GHH) are extremely rare lesions in infants and usually intrinsically epileptogenic.

Giant HH is an exceptionally difficult neurological disease. Primary hypofractionated GKRS may be an alternative approach as mono/multitherapy with promising results and minimal complication 1).

Although the exploration of epileptic activity and the extent of ablation are limited by the number of SEEG electrodes for the complete disconnection. One-stage high-density focal stereo-array SEEG-guided radiofrequency was safe and effective for treating pediatric giant HH patients. It can be an alternative method to treat giant HHs where LITT is unavailable 2).

Stereotactic radiofrequency thermocoagulation (SRT) provided minimal invasiveness and excellent seizure outcomes even in patients with giant HHs 3).

Three pediatric patients (age range 17-65 mo) underwent primary hypofractionated GKRS in 2-3 consecutive days with an interfraction interval of 24 h. All patients had precocious puberty and were on GnRH analog. Frame-based GKRS was done with 8.1-9.2 Gy radiation per fraction at 50% isodose in 2-3 fractions targeting the entire hamartoma volume. The mean target volume was 5.67 cc (4.45-7.39 cc). The authors followed these patients for clinical and endocrinological assessment at every 6 mo interval while the repeat MRI has done at 6 mo and then annually. The seizure outcome analysis was done using the Engel Epilepsy Surgery Outcome Scale.

At a mean follow up of 27 mo (24-30 mo), 2 patients became Engel class 3 while one achieved Engel class 1 control. 2 patients showed halted pubertal growth with no additional hormonal aberration. 2 patients showed significant volumetric reduction (48% and 32%) and patchy necrosis inside the hypothalamic hamartoma (HH). There was no deficit in visual function, memory and cognition. One patient showed reduction in aggressiveness.

Giant HH is an exceptionally difficult neurological disease. Primary hypofractionated GKRS may be an alternative approach as mono/multitherapy with promising results and minimal complication 4)


Wang et al. analyzed the clinical data of six patients with giant HHs (masses with a maximum diameter >30 mm) who underwent stereotactic electrode implantation between November 2017 and April 2019. After a multidisciplinary discussion, we designed a high-density focal stereo-array electrode implantation strategy. SEEG-guided bipolar coagulations were performed between two contiguous contacts of the same electrode, or between two adjacent contacts of different electrodes. Results: Among the six patients, three were male and three were female, with an average age of 5.08 ± 4.73 years (range, 1.4-12 years); the average follow-up duration was 20.17 ± 5.49 months. One patient had previously undergone open surgery. Four patients had gelastic seizures, one had gelastic and tonic seizures, and one had gelastic and generalized tonic-clonic seizures. The number of implanted electrodes ranged from 3 to 7, with an average of 5.33. One patient had transient diabetes insipidus after the operation, and no child had fever or new hormone metabolisms disorder after surgery. Four patients had Engel I classification outcomes (free from disabling seizures), and two patients had Engel II classification outcomes. Conclusion: Although the exploration of epileptic activity and the extent of ablation are limited by the number of SEEG electrodes for the complete disconnection. One-stage high-density focal stereo-array SEEG-guided radiofrequency was safe and effective for treating pediatric giant HH patients. It can be an alternative method to treat giant HHs where LITT is unavailable 5).


Cristobal et al. presented a unique case of an asymptomatic giant hypothalamic hamartoma diagnosed prenatally by fetal magnetic resonance imaging and followed throughout infancy. This case demonstrates the utility of multimetric analysis using difference sequences, including diffuse-weighted imaging, to assess specific properties of intracranial lesions detected in utero and to aid in accurate diagnosis prior to birth 6).


A 10-month-old girl child presenting with drug-resistant seizures and a giant hypothalamic lesion that was confirmed as hamartoma on histopathology. Surgical decompression and disconnection from the hypothalamus was performed with the intent of controlling her seizures. Unfortunately, the patient developed right middle cerebral artery and posterior cerebral artery territory infarction, possibly due to vasospasm or thrombosis of the vessels. The patient had a stormy postoperative course but has recovered well neurologically at the 18-month follow-up. Histopathological examination revealed abnormal clusters of NeuN-positive neurons, which was confirmatory of hypothalamic hamartoma 7).


1) , 4)

Tripathi M, Maskara P, Sankhyan N, Sahu JK, Kumar R, Kumar N, Ahuja CK, Kaur P, Kaur R, Batish A, Mohindra S. Safety and Efficacy of Primary Hypofractionated Gamma Knife Radiosurgery for Giant Hypothalamic Hamartoma. Indian J Pediatr. 2021 Jan 27. doi: 10.1007/s12098-020-03637-w. Epub ahead of print. PMID: 33501606.
2) , 5)

Wang M, Zhou Y, Zhang Y, Shi W, Zhou S, Wang Y, Li H, Zhao R. One-Stage High-Density Focal Stereo-Array SEEG-Guided Radiofrequency Thermocoagulation for the Treatment of Pediatric Giant Hypothalamic Hamartomas. Front Neurol. 2020 Sep 2;11:965. doi: 10.3389/fneur.2020.00965. PMID: 32982954; PMCID: PMC7493627.
3)

Shirozu H, Masuda H, Ito Y, Sonoda M, Kameyama S. Stereotactic radiofrequency thermocoagulation for giant hypothalamic hamartoma. J Neurosurg. 2016 Oct;125(4):812-821. doi: 10.3171/2015.6.JNS15200. Epub 2016 Jan 1. PMID: 26722850.
6)

Cristobal A, Vorona G, Ritter A, Lanni S, Urbine J. Pre- and postnatal MR imaging of an asymptomatic giant hypothalamic hamartoma. Radiol Case Rep. 2020 Jun 16;15(8):1250-1255. doi: 10.1016/j.radcr.2020.05.041. PMID: 32577141; PMCID: PMC7303913.
7)

Kandregula S, Savardekar AR, Nandeesh BN, Arivazhagan A, Rao MB. Giant Hypothalamic Hamartoma in an Infant: A Case Report and Review of the Literature. Pediatr Neurosurg. 2017;52(1):55-61. doi: 10.1159/000448738. Epub 2016 Oct 26. PMID: 27780163.

Subependymal giant cell astrocytoma treatment

Subependymal giant cell astrocytoma treatment

The management of subependymal giant cell astrocytomas (SEGAs) has been traditionally represented by surgical treatment through an open craniotomic approach. Though open surgery still represents a major option in the management of this kind of tumors, the introduction of mTOR inhibitors in the clinical practice, technological advances in neuroendoscopy and the more recent use of Laser interstitial thermal therapy have significantly enlarged the range of available management opportunities.

A thorough review of the literature has been performed. Accordingly, current views in open surgical treatment, medical therapy, endoscopic tumor removal, and new trends (such as laser interstitial thermal therapy) are discussed.

The risk of significant neurological morbidity (5-50%) complicating open surgery has been for a long time representing a main drawback in the management of SEGAs. More recent series report a significant reduction of morbidity and mortality. The mTOR inhibitors have demonstrated efficacy in both warranting a tumor reduction by up to 60% of the tumor size and helping the control of seizures. However, the reported rate of side effects is as high as 30% and tumor recurrence is a documented occurrence at the time of mTOR inhibitor discontinuation. Endoscopic tumor removal has been more extensively considered an option due to the acquisition of new tools. Limits are still represented by tumor size (< 3 cm) and broad attachment of the tumor to the basal ganglia. Laser interstitial thermal therapy (LITT) is the more recently considered option. Though promising, only short follow-up is available so far, while data on medium- and long-term results of this treatment are completely lacking to date.

Surgical treatment remains a mainstay of the management of SEGAs. The indication for an open craniotomic approach should be balanced with an endoscopic tumor removal or LITT according to patient conditions, the presence or not of active hydrocephalus, and extension of the attachment of the tumor to the basal ganglia. The mTOR inhibitors do have a definite role both as primary and as adjuvant treatment, but consistent limitations are represented up to now by a not negligible rate of complications and the uncertainties related to the possibility of tumor recurrence once the medical treatment is discontinued 1).


Laviv et al.reported two cases of recurrent shunt malfunctions in adult TSC patients with protein-secreting SGCTs and describe the complexity of treating such patients with an emphasis on the role mTOR inhibitors may have in their management 2).


SEGAs have been reported to regrow if mTOR inhibitor therapy is stopped, raising the possibility that long-term medication may be required to prevent tumor growth and hydrocephalus. The question of regrowth following medication withdrawal will need to be addressed in more patients to help establish the optimal duration of therapy. The risks of surgery include acute morbidity and the permanent need for ventriculoperitoneal shunting, which must be balanced against the adverse effects of mTOR inhibitors, including immunosuppression (infections, mouth sores), hypercholesterolemia, and the need for chronic drug monitoring. Some additional benefits of mTOR inhibition in patients with tuberous sclerosis complex, however, may include shrinkage of angiofibromas and angiomyolipomas as well as a possible decrease in seizure burden. Recent reports of successful nonsurgical treatment of SEGAs are promising, and it is hoped that further specifics on dosing, duration, and long-term outcome will help patients and physicians to make informed therapeutic choices.Present treatment recommendations for SEGAs include routine surveillance neuroimaging and close clinical follow-up, paying particular attention to signs and symptoms of acute hydrocephalus. If symptoms arise, or if serial neuroimaging demonstrates tumor growth, neurosurgical intervention is recommended. When gross total resection is impossible, rapamycin and everolimus should be considered, but may not offer a durable response.


In a phase 1–2, open-label study in 28 patients with evidence of serial subependymal giant cell astrocytoma growth, the mTOR inhibitor everolimus (Afinitor, Novartis, East Hanover, NJ) was associated with a reduction in SEGA volume and improved quality of life 3).


Arroyo et al. present a seven-year-old boy with a large, symptomatic SEGA which was treated acutely with everolimus.

Everolimus treatment resulted in rapid reduction in tumor size, symptomatic improvement, and decrease in cerebrospinal fluid protein.

Everolimus can effectively reduce tumor size, decrease cerebrospinal fluid protein, and allow successful ventriculoperitoneal shunt placement without the need for surgical resection of a symptomatic SEGA 4).

References

1)

Frassanito P, Noya C, Tamburrini G. Current trends in the management of subependymal giant cell astrocytomas in tuberous sclerosis. Childs Nerv Syst. 2020 Sep 25. doi: 10.1007/s00381-020-04889-9. Epub ahead of print. PMID: 32978642.
2)

Laviv Y, Jackson S, Rappaport ZH. Persistent communicating hydrocephalus in adult tuberous sclerosis patients: a possible therapeutic role for everolimus. Acta Neurochir (Wien). 2015 Feb;157(2):241-5. doi: 10.1007/s00701-014-2309-0. Epub 2014 Dec 19. PubMed PMID: 25524658.
3)

Krueger DA, Care MM, Holland K, et al. Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med 2010;363:1801–1811
4)

Arroyo MS, Krueger DA, Broomall E, Stevenson CB, Franz DN. Acute Management of Symptomatic Subependymal Giant Cell Astrocytoma With Everolimus. Pediatr Neurol. 2017 Jul;72:81-85. doi: 10.1016/j.pediatrneurol.2017.04.008. Epub 2017 Apr 18. PubMed PMID: 28511812.
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