Gamma Knife Radiosurgery in Pediatric Patients: Indications and Evolution over Twenty Years of Experience

Keywords

pediatric - neuro-oncology - arteriovenous malformation - Gamma Knife radiosurgery

Radiation therapy is commonly used in pediatric neuro-oncology, delivering a short multifraction treatment for tumor control, while giving appropriate recovery time for the surrounding normal tissue. Long-term complications such as secondary tumors and detrimental impacts on neurodevelopment and cognition are still the main concerns.

Gamma Knife radiosurgery (GKRS) can deliver a highly conformal dose while minimizing normal tissue dose, leading to wide acceptance in the adult population. It has been used for benign and malignant tumors, arteriovenous malformations (AVMs), and functional disorders like tremors and pain. The proven safety and efficacy of GKRS in adult populations has encouraged its use in the pediatric population. We aimed to evaluate our 22 years of GKRS experience in patients younger than 18 years and report how the treatment and delivery have changed with subsequent iterations of GKRS technology.

Method

We conducted a retrospective chart review of all patients younger than 18 years who underwent GKRS from 1999 to 2020 and collected follow-up data through 2023 at Roswell Park Comprehensive Cancer Center, Buffalo, NY. Data collected included the primary pathology, age, dose, lesion volume, use of rigid frame (RF) versus thermoplastic mask (TPM), single session versus hypofractionation, and model of GKRS technology.

Results

A total of 55 patients underwent 80 treatments, with ages ranging from 2.8 to 18 years, with 27 (49%) between 15 and 18 years old. Thirty patients (55%) were treated for a variety of tumors, and 25 patients (45%) were treated for AVMs. Treatment dose varied according to tumor type, volume, location, and previous radiation treatment. During this period, three models of GKRS were used: Gamma Knife Model 4C, Perfexion, and Icon (Elekta AB, Sweden).

Oncology

A total of 30 patients were treated for benign and malignant tumors, including primary and secondary brain tumors. Most oncologic patients were referred from other institutions, which limited our access to their outcome data. In [Table 1], we present the cases for which we had proper follow-up information on demographics, treatment characteristics, and outcomes. Tumor control, defined as a reduction or stable volume in benign pathologies and volume reduction in malignant diseases, was observed in 61.5%. None have developed secondary tumors during this period. Two patients experienced transitory treatment-related symptoms immediately after GKRS. Delayed symptoms were related to disease progression ([Table 2]).

Table 1 Oncological patients who presented adequate follow-up: patient's demographics, treatment doses, fixation type, additional treatments, and outcomes

Type	Age	Gender	Prior treatment	Number of GKRS	Dose (Gy)	Fixation type	Tumor status at last follow-up	Additional treatments
Atypical meningioma	18	M	Partial resection	1	22	RF	Local control, 55% of volume reduction	None
Atypical teratoid rhabdoid tumor of the brain	3	F	Partial surgical resection CSI Chemotherapy	1	17	TPM	Leptomeningeal progression	Chemotherapy
Chordoma	18	M	Gross total resection	1	15	RF	Local control	None
Craniopharyngioma	4	F	Partial resection	1	10	RF	Local control	None
Ependymoma grade II	18	F	Partial resection EBRT	3	15.75 (8–18)a	RF	Progression	None
Ependymoma grade III	8	m	Surgical resection EBRT	1	15 (x2)	RF	Mild disease progression with hemorrhagic components	Bone marrow transplant
Ewing sarcoma	17	F	Chemotherapy	2	15	RF	Local control	Chemotherapy
Glial tumor grade III	15	F	Surgical resection Chemotherapy EBRT	1	16.3 (15–17)[a]	RF	Progression to a multifocal tumor	Surgical resection ×2 Ventricular shunt
Glioblastoma	8	M	Gross total resection EBRT Chemotherapy	1	15	TPM	Tumor progression associated with pseudo-progression	Anti-VEGF-A
Juvenile nasal angiosarcoma	18	M	Subtotal resection	1	20	RF	Local control	None
Juvenile pilocytic astrocytoma	11	F	Subtotal resection CSI Chemotherapy	1	20	TPM	Solid portion with stable volume, an increase in the cyst	Immunotherapy
Medulloblastoma classic	3	M	Gross total resection EBRT	2	15 (14–17)[a]	RF	Tumor progression to multifocal	Autologous stem-cell transplant
Medulloblastoma classic	12	M	Chemotherapy Gross total resection CSI	1	17	TPM	Intraventricular tumor progression	Autologous stem-cell transplant
Medulloblastoma classic	17	M	Chemotherapy Gross total resection CSI	1	16 and 20	RF	Intraventricular tumor progression	Bone marrow transplant
Meningioma NF II	18	F	None	1	15	RF	Local control. Untreated lesions showed progression	None
Metastasis—multiple (Ewing)	13	F	Chemotherapy	2	15 and 17	RF	Local control	Chemotherapy
Metastasis—single (hepatoblastoma)	12	M	Chemotherapy	1	22	RF	Local control	Chemotherapy
Metastasis—single (osteosarcoma)	16	M	Neoadjuvant chemotherapy	1	18	RF	Skull metastasis with local control	Surgery to the primary site Adjuvant chemotherapy
Metastasis—single (melanoma)	18	M	Chemotherapy	1	24	RF	Progression to multiple metastases associated with intratumoral hemorrhage	EBRT to cervical lesion WBRT Intrathecal chemotherapy Immunotherapy
Neuroblastoma	5	M	Surgical resection CSI Chemotherapy	2	13.4 (10–18)[a]	TPM	Progression to multiple metastasis	Chemotherapy
Neuroblastoma	5	F	Surgical resection CSI Chemotherapy	1	18	TPM	Local control	Chemotherapy
Neurocytoma	18	F	Gross total resection	3	12 and 15	RF	Local control. Volume loss and signal changes within the left hippocampus are also stable	Surgical resection ×2 Omaya catheter Chemotherapy
Pituitary adenoma	17	M	Transsphenoidal resection	1	26	RF	No evidence of tumor	None
Pituitary adenoma	18	M	Transsphenoidal resection	1	28	RF	No evidence of tumor	None
Trigeminal schwannoma	17	F	Subtotal resection	1	12	RF	Volume stable with the development of cyst	None
Vestibular schwannoma	17	F	Subtotal resection	2	11 and 10	RF	Local control	Subtotal resection

Abbreviations: CSI, craniospinal irradiation; EBRT, external-beam radiotherapy; F, female; M, male; RF, rigid frame; TPM, thermoplastic mask.

^a Median dose with range.

Table 2 Description of symptoms and neurological deficits at presentation, acute side-effects after GKRS, and outcome at the end of follow-up: They are separated into arteriovenous malformation (AVM) and oncological patients

Symptoms/Deficits	At presentation		Immediate GKRS side-effects		Outcomes at the last follow-up
	AVM	Oncology	AVM	Oncology	AVM	Oncology
Visual	3	3	3	1	4	0
Motor	3	0	1	0	4	0
Seizure	11	2	1	0	4	1
Headache	0	9	1	0	5	2
Hydrocephalus	2	0	1	0	1	0
Cognitive	3	1	1	0	2	0
Nausea/vomiting	0	5	0	0	0	1
Fatigue	0	3	0	0	0	0
Cranial nerve palsy	0	4	0	1	0	0

Six patients were treated using the TPM ([Table 3]), with five requiring sedation and one having hypofractionation for optic chiasm protection. One patient required multiple treatments (four) due to disease progression. The mean age on the day of treatment was 7.33 years (range: 2.8–11.5 years). Their doses ranged from 10 to 20 Gy (mean of 15.8 Gy), the mean volume for individual lesions was 1.0 cc (0.196–8.588 cc), and delivery time ranged from 13.3 to 87.99 minutes (mean of 39.95 minutes). General anesthesia and monitored anesthesia care (MAC) were utilized. One patient required no sedation. The mask fixation with sedation provided sufficient stabilization with the mean deviation from the post-stereotactic registration baseline of 0.09 mm (± 0.13 mm) for translation and 0.04 degrees (± 0.05 degrees) for rotation. All high-definition motion management was set to 1.5 mm ([Fig. 1]).

Fig. 1 The thermoplastic mask can be molded, while warm, to accommodate the endotracheal tube as shown. Once it cools down, it becomes rigid and limits the patient's motion. The anesthetic guarantees minimal patient motion, as seen in the trace on the right, which is indicative of patient motion and is obtained with the high-definition motion management system.

Table 3 Oncological patients treated with the thermoplastic mask

Diagnosis	Age at treatment (years)	Sex	Number of treatments	Number of treatment sessions	Anesthesia	Complications
Atypical teratoid rhabdoid tumor	2.8	Female	1	1	General	None
Metastatic neuroblastoma to the brain	4.6	Male	1	1	General	None
Metastatic neuroblastoma to the brain	5.3–6.8	Male	4	1	General (2), MAC (2)	None
Glioblastoma	8.6	Male	1	1	None	None
Juvenile pilocytic astrocytoma	11.2	Female	1	5	General (1), MAC (4)	None
Medulloblastoma	11.5	Male	1	1	General	None

Abbreviation: MAC, monitored anesthesia care.

Arteriovenous Malformation

AVMs underwent individualized evaluations and considerations for surgical resection, embolization, and/or radiation. All patients receiving radiation treatment were treated with the Leksell Frame along with same-day digital subtraction angiography (DSA) for proper nidus definition, under sedation for treatment comfort and tolerance. Among the 25 patients in the cohort, the initial presentation included hemorrhage in 14 and seizure in 11. All patients received various initial treatment modalities prior to GK, based on their symptoms and presentations; embolization with coils (16) or onyx (2) was the most common approach (18/25, 72%). Staged embolization was used to reduce the nidus volume before GKRS treatment. Single-session or volume-staged radiosurgery was performed to keep the minimal dose greater than 16 Gy. In the staged modality, an updated DSA is required and performed on the same day after RF application. Tractography was employed to visualize the motor and optic pathways, which were safeguarded in cases where no severe damage was observed in initial imaging or physical examination. The median marginal dose prescribed was 22 Gy (ranging from 18 to 26 Gy), with a median volume of 1.097 cc (ranging from 0.1999 to 14.324). The median follow-up period was 7.7 years (ranging from 1.1 to 17.7), with the number of treatments varying from 1 to 3.

Further resections and embolization were planned for extensive lesions, with GKRS applied to deeper segments of the nidus or its remnant. Two cases presented with hydrocephalus prior to GKRS. One was related to intraventricular hemorrhage and showed improvement after the placement of an external ventricular drain, not requiring a permanent shunt. The second case involved a non-ruptured arteriovenous malformation (AVM) associated with a congenital venous malformation and a progressively worsening hydrocephalus, requiring the placement of a ventricular-peritoneal shunt. A third case had an incidental diagnosis of an unruptured AVM during the investigation for bacterial meningitis and required a shunt placement following GKRS. This was attributed to a delayed complication of the infection since no hemorrhage occurred after GKRS.

Six patients developed acute symptoms after GKRS, some with multiple complaints, and 20 patients were symptom-free at the last follow-up. Eleven patients originally presented seizures, and only one patient developed it after GKRS. At the end of the follow-up, eight remained seizure-free (8/12, 66.6%). Other non-AVM causes of seizures were ruled out at presentation. Patients who experienced seizure improvement initially benefited from their medication management, which was not modified prophylactically after the GKRS treatment. However, further progressive improvement was associated with the circulatory changes caused by the vessel obliterations over time. [Table 2] shows the symptoms at presentation, acute side-effects, and the outcomes at the end of the follow-up.

Patients were monitored with angiography and MRI. On follow-up, 40% of patients had complete angiographic occlusion, and 48% had total occlusion based on MRI ([Table 4]). No bleeding was observed during this period.

Table 4 Imaging findings on the arteriovenous malformations at the last follow-up

Image findings	Number of patients
Angiography
Partial occlusion	15
Total occlusion	10
MRI
Edema	5
Hemorrhage: old/resolving	3
Hemorrhage: new	0
Stroke non-acute	1
Arachnoid cyst	2
Remaining nidus	13
Hydrocephalus	2
Gliosis	8
Flow void	3
No significant change	3

Discussion

GKRS has been used in the pediatric population over the years, but still less frequent than in adults. The use of the rigid frame can have limitations in younger patients because of the relatively thin skull thickness and potential for non-fused sutures, which can lead to skull fracture and intracranial injury. This risk is eliminated by using the TPM as the fixation technique, which has been available since the advent of the Icon model.

Our youngest patient with an RF fixation was 3 years old and presented no complications and excellent treatment tolerance. Since the upgrade to the Icon and, recently, to the Esprit models, all oncological cases have utilized the TPM. This helped minimize the sedation level and time. The intrafraction movement of these patients is minimal, as noted on the co-registration cone beam CT, and the high-definition motion management guarantees adequate treatment delivery.

Since we perform same-day angiography for all AVM cases, the RF with fiducials was used in all treatments. In cases where the AVM target definition is mainly guided by same-day MRI, or the angiographies have their anatomical segmentation processed by compatible software, some centers opt for the use of TPM.[1]

One of the main applications of radiation for pediatric patients is for the treatment of primary brain tumors. In glial tumors, maximal surgical resection followed by radiation and chemotherapy is responsible for the best outcomes. Deora et al[2] evaluated studies from 1996 to 2012 showing local control from 85 to 100% in low grades, with lower response to high grades with GKRS. Meanwhile, Marcus et al,[3] using a linear accelerator (LINAC), were able to achieve a progression-free survival of 65% and overall survival of 82% at 8 years. Stereotactic radiosurgery (SRS) is still used mainly for salvage treatment, and rarely as the primary treatment option.[4] [5] A level 1 study is still needed to show the efficacy of radiosurgery for gliomas, but GKRS with hypofractionation and greater conformal dose can potentially provide optimal treatment.

Another common pediatric tumor is the craniopharyngioma, which in a single session would receive 10 to 15 Gy or could be treated in three fractions to a total of 18 Gy. Tumor control varies from 65 to 85% in 5 years, with a high recurrence rate of 40%.[6] [7] Factors predictive of better radiosurgical response would be the extent of resection, radiation coverage, high marginal dose, small volume, solid lesions, and younger patients. Cystic lesions and proximity to the optic nerve have been related to poorer response.[6] [7] The one case in our series with craniopharyngioma was treated after recurrence of the solid component, without a cyst formation.

Despite a significant disparity between the number of pediatric and adult GKRS articles and studies, a great variety of tumors can be treated with adequate local control,[5] as observed in our results.

In a meta-analysis with 1,212 AVM patients, GKRS was compared with LINAC and proton beam, which reached greater obliteration with lower hemorrhage rates but higher new deficits.[8] In high-grade ruptured AVMs, GKRS has a lower obliteration rate as a single treatment method, but with good results when associated with surgical resection and embolization.[9] Large AVMs can be treated with volume- or dose-staged, the former option having a higher obliteration rate of 41.2% and the latter of 32.3%.[10] A marginal dose of less than 17 Gy in a single session has already been proven to produce lower obliteration.[11] For large AVMs, where single-session SRS is not recommended, a higher initial dose has been related to a greater obliteration rate, justifying the preference of volume-staged treatments in the majority of centers.[12] Seizure response after GKRS tends to be progressive, with higher rates if associated with complete AVM obliteration.[13] [14] The placebo response in epilepsy is highly debatable,[15] with no proper investigation in patients who underwent radiosurgery treatment for AVMs.

With advances in technology, an automated position of the isocenters with the Perfexion model has allowed for faster treatment time. After the release of the Icon and Esprit models, a TPM can be used, providing the ability to fractionate the treatment without the need to reapply the frame. These updates to the GKRS made it more tolerable for the pediatric population.

Another great accomplishment came with the improvement of the planning software. With the inclusion of the Lightning inverse-planner software, multiple targets can now be quickly planned simultaneously. This impact on the planning and delivery times directly improves the workflow and, in cases where anesthesia is needed, the amount of sedation given during the treatment can be reduced. All these improvements contribute to the safety and quality of the treatment.

Conclusion

GKRS is a viable modality for the radiation treatment of tumors and AVMs in the pediatric population. Decision-making involving indications and therapeutic strategy should involve a multidisciplinary team. For younger patients, sedation may be necessary for tolerance and safety.

The evolution of the Gamma Knife machine and software has allowed an improvement in planning and treatment time. The addition of the TPM, ease of fractionation, and its known conformal dose delivery allows an increase in the tolerance and acceptability in pediatric radiation therapy.

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