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| Ahead of print
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Role of gamma knife radiosurgery in the management of intracranial pathologies of pediatric population: Current concepts, limitations, and future directions
Harsh Deora1, Soumyata Tripathi2, Nagarjun Ballari3, Manjul Tripathi4
1 Department of Neurosurgery, National Institute of Mental Health and Neurosciences, Bengaluru, India
2 Department of Pediatrics, Consultant, Apollo Clinics, Chandigarh, India
3 Department of Radiation Oncology, Postgraduate Institute of Medical Education & Research, Chandigarh, India
4 Department of Neurosurgery, Post Graduate Institute of Medical Education and Research, Chandigarh, India
| Date of Submission | 03-Mar-2021 |
| Date of Decision | 29-Apr-2021 |
| Date of Acceptance | 19-Nov-2021 |
| Date of Web Publication | 12-Jul-2022 |
Correspondence Address:
Manjul Tripathi,
Department of Neurosurgery, Post Graduate Institute of Medical Education and Research, Chandigarh 160012
India
 Source of Support: None, Conflict of Interest: None DOI: 10.4103/jpn.JPN_51_21
 Abstract | | |
The aim of treating pediatric brain tumors is not only tumor control but also preservation of the quality of life. To safeguard the neurocognitive outcome, progression-free survival, and overall survival, the field of radiotherapy has strived for better conformality, precision, and accuracy while mitigating the extracranial dose distribution. Stereotactic radiosurgery and in particular, Gamma Knife radiosurgery, has been a significant advancement in this direction with a gradually expanding horizon of its indications. Gamma Knife radiosurgery has been instrumental in changing the paradigm in the management of the disorders of the tender age group. In this review article, we tried to encompass all the spheres of application of Gamma Knife radiosurgery in pediatric cases highlighting the limitations and frontiers of the current practice in the field of radiosurgery pertinent to the pediatric population. While the traditional indications have been reviewed in depth and a bird's eye view of the possible future applications has also been presented.
Keywords: Arteriovenous malformation, gamma knife, pediatrics, radiosurgery
How to cite this URL:
Deora H, Tripathi S, Ballari N, Tripathi M. Role of gamma knife radiosurgery in the management of intracranial pathologies of pediatric population: Current concepts, limitations, and future directions. J Pediatr Neurosci [Epub ahead of print] [cited 2023 May 27]. Available from: https://www.pediatricneurosciences.com/preprintarticle.asp?id=350286 |
| Introduction | |  |
In the search for safer and sophisticated treatments, microneurosurgery has undergone a sea change in the last five decades. The development of stereotactic radiosurgery (SRS) has been a breakthrough. It remains especially interesting as SRS reached beyond the limits of microneurosurgery, in the traditional remote areas of the skull base, in between critical neurovascular neighborhoods, and at eloquent areas of the brain. Being a primary radiation tool, radiosurgery was initially viewed with much suspicion and skepticism. The major concerns were radiation-induced long-term side effects, tolerability, and patient safety. Authors have been practicing SRS at leading gamma knife radiosurgery (GKRS) centers of India and have faced unique challenges while managing the pediatric population.
Today most pediatric cerebral and skull base tumors are treated with multimodal management. For many pathologies, complete resection is difficult without the risk of significant side effects. Chemotherapy has well-known systemic toxicity, and its efficiency in most pediatric brain tumors has been disappointing.[1] However, both extensive surgery and conventional radiotherapy and chemotherapy may have an untoward impact on the growing child’s development. There arises a need for alternative or adjuvant methods of treatment.[2],[3],[4],[5] With wider applicability in the adult population, GKRS is now applied for similar and some specific indications in the pediatric age group albeit with certain differences.
Stereotactic radiation is either delivered in a single fraction as in stereotactic radiosurgery (SRS) or as hypo-fractionated radiosurgery (hfSRS), in which up to five fractions are administered over five days with an inter-fraction interval of 24 hours.[1] Most pediatric patients may not be well suited to standard radiotherapy with poor long-term neurological and cognitive outcomes.[6] On the other hand, SRS is designed to precisely deliver a high dose of hypofractionated radiation therapy with minimal radiation spillage. In this review, we detail the evolving trend of SRS for the pediatric subset, its implications with traditional and new challenges.
| Radiobiology of Gamma Knife Radiosurgery In Paediatric Population | | |
GKRS does not follow the conventional 5Rs (repair, redistribution, repopulation, reoxygenation, and radiosensitivity) of radiotherapy. It is not based on variable tissue response to fractionated radiation. Irrespective of radiosensitivity, it provides a high control over the targeted volume, as it does not depend on the stage of a cell cycle for radiation to impart its effect. High-dose radiosurgery’s predominant action is due to endothelial cells’ sensitivity to radiation-induced apoptosis.[2],[3] Radiation doses greater than 10 Gy lead to indirect tumor cell death due to vascular damage.[4] The most recent theory points to the “abscopal effect”.[5],[6] It refers to immune-mediated killing of cells at a distant metastatic site due to irradiation of the tumor.[7]
Linear-quadratic (LQ) model has traditionally explained the relation of cell kill with radiation dose, but this only holds for conventionally fractionated radiotherapy. In the dose fractionation regimen used for SRS, the LQ model overestimates the dose’s potency per fraction. Hence, Park et al. formulated the universal cell survival curve (USC) that combines the LQ model for conventional fractionation (shoulder) along with the multitarget model for SRS.[8] As per USC, a transition dose from the LQ model to the multitarget model can be calculated. From this model, biological effective dose (BED) and single fraction equivalent dose (SFED) can be determined. If the dose is below transition dose, the LQ model calculates BED and the USC model for doses above the transition dose. SFED is the dose delivered in a single fraction, which has the same biological effect as the reported dose fractionation regimen. The incidence and severity of the late effects depend upon the age at the time of irradiation, the dose-volume relationship, and the total dose delivered. Another aspect is to evaluate the alpha-beta ratio for early responding and late responding tissues.
Gamma-knife’s high conformality gives it the theoretical advantage, especially in a pediatric population, to prevent damage to the normally developing brain. The chances of collateral damage by radiation to the neighboring structures are minimized by rapid dose fall out, high precision, and conformality offered by the advanced versions of the gamma knife machine (Leksell Perfexion and ICON model) and planning software while maintaining reasonable target control.[9] With improved immobilization, utilization of high-definition imaging, daily image guidance, and beam arrangements, GKRS may reduce the chances of delayed neurocognitive decline,[10],[11] radiation necrosis,[12] endocrine dysfunction,[13],[14] and secondary malignancies.[15],[16],[17],[18],[19]
| Indications of Radiosurgery and Current Evidence | | |
Arteriovenous malformations (AVMs)
AVMs are the most common cause of intracranial hemorrhage (ICH) in the pediatric population that constitutes 50% of pediatric hemorrhagic strokes.[20],[21],[22] Pediatric AVMs are also more likely to present with ICH than their adult counterparts.[23] However, the mortality with pediatric hemorrhage is 22%,[24] in addition to the lifetime risk of morbidity and mortality. AVMs in the deep or eloquent area may lead to 70–90% morbidity if operated and are suitable candidates for GKRS.[25],[26],[27],[28],[29] The International Gamma-Knife research foundation (IGKRF),[30] in their pooled analysis, included 357 patients (aged <18 years; mean age 12.6 years). 69% of these had presented with bleeding, and 77% were located in eloquent areas. They reported and a 63% obliteration rate at a mean follow-up of 92 months with a 3% permanent damage risk with radiation [Figure 1].[29],[31-33] A dose-response relationship was observed in this series, with a marginal radiosurgery dose of 22 Gy or higher being associated with a significantly higher probability of a favorable outcome (78% versus 47%) and AVM obliteration (81.6% versus 51.4%). In their unpublished results, authors have found a 76% rate of complete obliteration in 110 pediatric patients, with a 3% incidence of rebleed at a median follow-up of 5.6 years. 4% of patients suffered from temporary radiation insult with no long-term complication. | Figure 1: Eight years old boy with ruptured Posterior fossa AVM. Complete nidus obliteration after two years of Gamma Knife Radiosurgery (by MT)
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Further, it has been shown that the response to radiation is better in children than in their adult counterparts.[34],[35] Nicolato et al.[36] and the UK cohort by Dinca et al.[35] have achieved 88% and 70% obliteration rate, with an 11% permanent complication rate and 1.1% risk of radiation necrosis, respectively. Smaller AVM with volume less than 10cc is associated with higher obliteration rate with a reduced risk of radiation necrosis.
Cavernous malformations
Cavernous malformations in eloquent areas of the brain such as the thalamus and brain stem are suitable candidates for GKRS.[37],[38],[39],[40] Arguably surgery remains the treatment of choice for the management of cavernous malformation, as it immediately mitigates the chances of rebleed and improves seizure control. Excision of the associated hemosiderin rim significantly improves the epilepsy profile. However, surgery done in the deep-seated eloquent locations carry a risk of significant morbidity and mortality, which may be permanent in 15–35% of patients. GKRS, if given to the complete lesion without radiation spillage to the surrounding hemosiderin ring and with avoidance of the developmental venous anomaly (DVA), leads to a remarkable decrease in the risk of rebleed after two years of the treatment.[41] GKRS has also been found to lead to an improvement in epilepsy control.[42]
Craniopharyngioma
Craniopharyngiomas are benign, slow-growing, locally invasive intracranial tumors that can cause considerable morbidity, and recurrences are often challenging to manage.[39] Radical excision may not always be possible.[43] Even with radical excision, a 20–27% recurrence rate has been reported. Given its proximity to the pituitary and optic apparatus, there is an increased risk of hormonal disturbances, visual deterioration, cognitive decline with an aggressive surgical approach.[44],[45]
Consequently, cyst aspiration with Ommaya placement[37] and limited excision with radiotherapy has resulted in better cognitive, ophthalmic, and endocrine outcomes.[38],[46],[47] Kobayashi et al.[48] have the largest reported series of 98 cases of craniopharyngioma treated with GKRS with a minimum of 6 months follow-up and a median follow-up of 63 months. 38/98 cases were 15 years or younger. The mean margin dose used was 11.5 Gy. The 5- and 10-year progression-free survival was 60.8% and 53.8%, respectively. 6.1% suffered a deterioration in either vision or endocrine function. The control rates in other radiosurgery with at least four years of follow-up ranged from 67% to 100%.[49],[50],[51],[52],[53] Solid lesions respond better than cystic, and dosing is always decided on the optic apparatus tolerance.
Various series reported deterioration in 0–8%.[49],[50],[51],[52],[53] Although not specific for craniopharyngioma, an analysis of 1578 skull base tumors (including pituitary adenomas, cavernous sinus meningiomas, and craniopharyngioma, among others) evaluated the risks for radiation-induced optic neuropathy.[53] Prior radiation therapy, more than 12 Gy in a single session, 20 Gy in three sessions, and 25 Gy in five sessions were all predictive of increased risk of optic neuropathy. Hypothalamic dysfunction ranges from 2–8%[49],[50],[51],[52],[53] in radiosurgery. The common deficiencies in conventional radiotherapy are growth hormonal deficiency (45–100%), followed by gonadotropin deficiency (30% of patients), TSH deficiency (6–25% of patients), and ACTH deficiency (22% of patients).[53] This emphasizes the increased role of GKRS in these cases; thus higher number of prospective studies are needed to validate and better quantify the results. In perioptic lesions and hypo-fractionated GKRS has proven valuable as the same radiation is delivered in 2–5 sessions preserving the organs at risk from radiation injury mitigating the complications of conventional radiation therapies.
Glioma
Diffuse midline glioma has subtended a grim shadow on pediatric glioma survival.[54] Histone H3 K27M mutations are found in 80% of diffuse pontine gliomas. These variants uniformly have a poor prognosis. Furthermore, recurrence may develop despite the imaging appearance of complete resection, especially in cases of non-pilocytic lesions.
Grabb et al. reported a series of 25 cases with a mean age of 8.5 years with pilocytic astrocytomas as predominant histology.[55] These were treated with a mean peripheral dose of 15.2 Gy (11–20 Gy) with a mean follow-up of 22 months. Investigators reported 100% survival in pilocytic and grade II gliomas, 80% survival in grade III, and 50% survival in GBM cases. Boethius et al. (2002) similarly reported a series of 19 patients with a mean age of 10.6 years, with pilocytic gliomas being the only histopathological diagnosis[56] [Table 1]. These were treated with a mean peripheral dose of 11.3 Gy (9–20 Gy) with a mean follow-up of 5.9 years. The investigators showed a 100% survival with 26% adverse radiation effects (ARE), with one patient requiring re-surgery for radionecrosis, and one symptomatic cyst requiring decompression. Weintraub et al. in 2012 studied 24 cases with a mean age of 11 years with mixed subsets of histology. These were treated with a mean peripheral dose of 15 Gy (4–20 Gy) with a mean follow-up of 5.9 years. They observed 96% survival while 12.5% required repeat resection with larger tumor volume predictive of progression.[57] GKRS offers benefits over both chemotherapy and fractionated radiotherapy. Apart from it, it remains comfortable being a single-day procedure. GKRS seems to be associated with increased progression-free survival rates and complete tumor response when matched with chemotherapy or fractionated radiotherapy.[58],[59],[60] | Table 1: Efficacy of gamma knife radiosurgery in pediatric patients of intracranial gliomas
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Choroid plexus tumors
GKRS is usually offered to cases of partial or subtotal resection of choroid plexus tumors.[61] Their use in pediatric patients is limited by scattered case reports with doses ranging from 14–19 Gy.[62] International Radiosurgery Research Foundation (IRRF) reported positive results of GKRS in 32 patients treated over 25 years.[63] Of the 32 cases, four were pediatric, with the most common location in the fourth ventricle. The median tumor volume was 2.2cc with a median margin dose of 13 Gy (11–25 Gy). 41% of cases needed additional treatment for a new or recurrent disease, with 28% undergoing repeat GKRS. All of this points to the conclusion that while surgery remains the first-line treatment option, GKRS can provide a suitable alternative in cases where the tumor cannot be completely resected.
Vestibular schwannomas
Contrary to the adult population, VS in the pediatric age group is usually syndromic, i.e., Neurofibromatosis type 2 (NF2).[64],[65] The role of SRS in the management of VS of NF 2 is underutilized and maximally a part of multimodality treatment.[66] The long-term results are not as good as for sporadic schwannomas. The pediatric age group’s most extensive published experience reported a three-year tumor control rate of 35%, with a five-year hearing preservation rate of 53%. One needs to adopt a judicious approach with the combined use of microsurgery and radiosurgery to ensure long-term hearing preservation and tumor control; it is reasonable to have a higher threshold before offering radiosurgery. Apart from it, patients suffering from NF2 may have a higher chance of malignant transformation after receiving radiation therapy.[67]
Ependymoma
Ependymoma represents the third most common brain tumor in children,[68] with 90% occurring inside the brain.[69] The standard treatment is maximal safe resection followed by radiotherapy.[70],[71],[72],[73] Interestingly the recurrence has almost always been local.[74] In their series, Stauder et al.[75] reported 26 patients, 12 of whom were aged 18 and younger, treated with a median dose of 18 Gy. At 3 years, local control was 72%, with a median overall survival of 5.5 years. Two patients developed radiation necrosis.
Similarly, Kano et al.[76] reported 21 children who had undergone initial surgery and conventional adjuvant radiation. The median targeted volume was 2.2 cc with a median margin dose of 15 Gy. Three-year progression-free survival was 42%, with only three patients developing radiation necrosis. However, the remote relapse rate was 80.3% at three years. These studies provide clear evidence of the efficacy of GKRS with a risk of distant metastasis at 3 years follow-up. Fourth ventricle location, spine metastasis at presentation, and <18-month interval between radiotherapy and radiosurgery are all predictive of a poor prognosis.[77]
Hodgson et al.[78] reported a series of 90 pediatric patients from Boston treated with radiosurgery for various diagnoses; 28 were treated for ependymoma, either for recurrence (25 cases) or in the upfront setting (3 cases) with a median dose of 12.5 Gy. They had poor outcomes with a median PFS of 8.5 months and 3-year local control of only 29%. Twenty percent of the patients in the overall cohort required surgery for radiation necrosis. Results have been better with focally recurrent ependymoma with durable local control, so it should be a treatment consideration for selected cohort of patients with only focal nodular recurrences.[79],[80]
Medulloblastoma
By far, the most common intracranial tumor[81] in children is medulloblastoma. Maximum resection followed by craniospinal radiation and chemotherapy has an 80% survival at five years for average-risk cases[82] and 70% for high-risk cases. Radiosurgery has been usually reserved for recurrent disease or as an upfront boost. Patrice et al.[83] reported on 11 patients who were treated for recurrence and were three treated with a boost for residual disease. They used a median peripheral dose of 12 Gy and with a median follow-up of 27 months; all patients treated with radiosurgery with intent to boost sites of residual disease were alive and free of disease.
On the other hand, over half of the patients treated with SRS for recurrence were dead due to progressive disease. Of all patients treated, the most common site of failure was distally within the CNS, and there were no local failures. Multiple other series have reported the efficacy of radiosurgery in this population.[84],[85],[86] Local control in these series is generally reasonable, and the pattern of failure is predominantly outside of the SRS volume. In the largest of these series, 16 patients were treated (11 of medulloblastoma), 3-year progression-free survival was only 15%, underlining the importance of optimizing systemic therapy in this population to reduce the incidence of distant metastases and perhaps alter overall survival. Reports of toxicity varied across the multiple published series—in the series with the longest reported follow-up (3 patients with a follow-up of 30, 39, and 48 months),[86] there was no reported toxicity.
Malignant diseases: oligometastatic diseases
To minimize the risk of radiation injury, there is an emerging Role of radiosurgery in treating oligometastatic diseases such as sarcoma (esp. Ewing’s sarcoma and osteosarcoma) and other solid tumors. At present, metastasis is the most common indication for GKRS worldwide. However, its potential has not been checked for the pediatric age group. Theoretically, children should benefit from radiosurgery because of its improved precision conformality and better radiation spillage to the surrounding intricate neurovascular structures. SRS’s superiority has already been proven in the adult population in the domains of the neurocognitive outcome, local control, and comparable overall survival with subtly increased distant failure. The pediatric population needs prospective evaluation of radiosurgery for metastatic diseases.
Inflammatory pathologies
Histiocytosis is a group of inflammatory disorders of clonal cells with neoplastic potential. The management protocols are still evolving, with chemotherapy as the mainstay of treatment. Literature reports successful management of histiocytosis, which includes Langerhans cell histiocytosis (LCH) and Rosai Dorfman disease (RDD). Seven studies[87],[88],[89],[90],[91],[92],[93] reported 18 lesions in 9 patients, followed up for 81.67 patient-years treated with radiosurgery. Out of 18 lesions, 7(39%) disappeared, 8(44.4%) showed radiologic reduction, while 2(11%) remained stable. One lesion(5%) showed an increase in size demanding surgical excision. There were no adverse effects. Patients presenting with the unifocal LCH are potential candidates for SRS. We need to further evaluate concurrent chemotherapy’s role with radiosurgery in prospective trials and compare them with conventional treatment modalities. Radiosurgery may be used to treat focal lesions of the CNS and obtain in-field disease control and prevent out-of-field relapses with chemotherapy.
Functional indications
Hypothalamic hamartoma
HH is a rare developmental nonneoplastic lesion with a prevalence of one in 50,000–1,00,000 pediatric population. These patients mostly present with seizures in 61% of cases and precocious puberty in 66% cases, while 25% presents with both. The mean age of presentation is 2.8 years (one month to 15 years). Most of these patients suffer from other complex seizure disorders, behavioral disturbances, cognitive impairment, and hormonal imbalances. The options available for the treatment are open and endoscopic surgical approaches, SRS, stereotactic radiofrequency thermocoagulation, laser interstitial thermal therapy, stereotactic brachytherapy, etc. GKRS has been accepted as a first-line modality in Regis type 1–3 lesions because of its better safety and complication profile among the cafeteria choices. Different radio-surgical series by Abla et al.[94] and the Marseille group have reported improved seizure control in 60–70% of these patients.[95] Abla et al. demonstrated improved quality of life in 90% of cases due to improved seizure control or improvement in short-term memory and behavioral symptomatology.[94] No radio surgical series found any cognitive decline. The hormonal outcome is found to be better with radiosurgery in comparison to other surgical approaches. Authors have recently published their experience of managing large volume HH with primary hypo-fractionated GKRS in 2–3 consecutive days in 3 pediatric patients.[96] The mean target volume was 5.67 cc, and frame-based GKRS was done with 8.1–9.2 Gy marginal dose at 50% isodose in 2–3 fractions targeting the entire hamartoma volume. Authors found significant volumetric reduction (32–48%) and patchy necrosis inside the HH [Figure 2]. Two patients became Engel class 3 while one achieved Engel class one seizure control. There was no deficit in visual function, memory, and cognition. The authors recommend this treatment as an alternative approach as monotherapy or multi-therapy with promising results by showing the feasibility, safety, efficacy, and better complication profile of primary hypo-fractionated GKRS. | Figure 2: Hypothalamic hamartoma (A) at the time of gamma knife; (B) a good volumetric reduction at three years follow-up MRI (by MT)
Click here to view |
Emerging indications
Corpus callosotomy
Corpus callosotomy is an effective treatment of palliative care for drug-resistant epilepsy. Radio surgical callosotomy is a viable alternative to microsurgical callosotomy both as a primary and secondary treatment modality for drug-resistant epilepsy, especially in Lennox Gastaut syndrome and drop attacks. It has a specific advantage of better neuropsychological outcome with comparable seizure control to microsurgical callosotomy. The authors reviewed seven studies detailing 12 patients with a mean age of 22.8 years. 3/12 patients were of the pediatric age group, the youngest being four years of age. Radiosurgery targets a small target volume of anterior 2/3rd of the corpus callosum. It may also serve the purpose of completing callosotomy after partial microsurgical callosotomy in resistant cases. The best indications for radio surgical callosotomy are drop attacks closely followed by GTCS. Absence, myoclonic, and CPS usually do not respond to radiosurgical surgical callosotomy. At present, the role of radio surgical callosotomy is mostly palliative.[97]
Radio surgical third ventriculostomy
Gutierrez- Aceves et al.[98] described the technique of frame-based and frameless radio surgical third ventriculostomy in a case of midbrain glioma with mild obstructive hydrocephalus. The radio surgical lesioning is done on the floor of the third ventricle at the point between the mamillary body and infundibular recess. The prescription isodose is 120 Gy at 100% isodose. The introduction of radio surgical third ventriculostomy is an advent over conventional techniques as it avoids general anesthesia and remains principally noninvasive.
Ophthalmic indications
Ophthalmologists are now increasingly interested in uveal melanoma, and most interestingly pediatric glaucoma. Pediatric glaucoma is a functional indication in which GKRS irradiates the ciliary bodies; intraocular pressure may be brought down to within normal limits. It cures pain and allows the patient to retain the eyes.
Movement disorders
Radiosurgical management of movement disorders aims at neuromodulation or lesioning. Radio surgical thalamotomy is a valuable tool for Holmes’s tremor, posttraumatic tremor, etc.[99] Radio surgical pallidotomy has gone into disrepute due to the higher and unpredictable response of iron-rich globus pallidus interna and the network of lenticulostriate arteries in this zone.[100]
Anesthetic considerations for pediatric population
A pediatric patient deserves particular concern and merit as far as painful parts of the procedure such as fixation of the frame end immobilization are concerned for a long duration. Frame-based stereotaxy demands 4 point pin fixation, rigid immobilization, and fixed position in the gamma couch for the course of treatment. The role of anesthesia is to ensure patient immobilization during image acquisition and radiation delivery while ensuring an awake, neurologically accessible patient at the end of the radiosurgery [Figure 3]. Radiosurgery poses a unique challenge to anesthesia goals.[101] A patient undergoing radiosurgery goes through various places in hospital, which involve separate rooms for frame fixation, image acquisition, patient waiting area (during the planning of the treatment), and gamma gantry.[102] The radiation delivery time with GKRS is more than other radiosurgery techniques such as cyberknife, LINAC radiosurgery, etc.[103] We need to ensure anesthetic equipment in various locations and transport the patient to and from different areas. The frame should be fixed under short general anesthesia for a pediatric patient. One needs to be cautious with pediatric patients as thinner skull thickness compared to the adults makes fixation of the frame more difficult because of concern for the pins’ penetrance.[104] Most of the patients undergo the treatment under subtle sedation with chloralhydrate. If necessary, there should be arrangements for general anesthesia and ventilation. In the author’s personal experience most of the patients above ten years of age cooperate as an adult.[105] | Figure 3: (A) Frame fixation under short general anesthesia; and (B) Patient receiving treatment under influence of Chloralhydrate (by MT)
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Radiation toxicity
Radiation-induced malignancies secondary to SRS for benign conditions, particularly in the pediatric age group, are a concern given these patients’ long-life expectancy. The likelihood of developing second malignancies is related to several factors such as age, sex, the volume of low dose radiation-exposed area, genomic instability, etc. A study found that the risk of SRS-induced neoplasm was 0.04% at 15 years based on an estimation of the total worldwide number of patients treated with SRS for the benign disease.[6] Another international pooled analysis of 5000 patients treated with SRS for benign disease calculated a 0.0006% risk of malignant transformation and 0.0002% risk of radiation-induced malignancy.[8] Thus, it can be seen that the risk of RISM is very low when weighed against the benefits. A recent publication comparing GKRS and LINAC-based SRS revealed an increased relative risk of radiation-induced secondary malignancies when treated using LINAC-based SRS. Paddick et al.[106] demonstrated that GKRS had the lowest lifetime excess risk: 0.06–0.88% for females and 0.03–0.29% for males aged 5–45 years treated with 12.5–25 Gy SRS. With LINAC radiosurgery, the risk was 0.78–11% and 1.3–18% (females), and 0.36–3.6% and 0.61–6.0% (males) respectively. For Cyber Knife, the excess risk was 3.8–39% (females) and 2.2–15% (males). These observations may help in formulating age-specific recommendations for pediatric SRS, where children are expected to survive longer and can face long-term complications.[106]
The aim of SRS in malignant and benign tumors is local growth control with either unchanged or decreased tumor volume. GKRS has advantages compared to LINAC radiosurgery because of its potential for better demarcation between the area destined for irradiation and the normal surrounding tissues. GKRS offers a steeper fall in radiation at the periphery of the treated area compared to LINAC radiosurgery.[107] When normal cerebral tissue is subjected to heavy-dose irradiation, parenchymal white matter demyelination and small-vessel occlusion ensue.[108]
The knowledge about SRS safety in children is limited, but the optic chiasm and the brainstem are considered critical structures. Baumann et al.[109] found no long-term visual symptoms in two patients receiving >8 Gy to the chiasm. Only one out of 16 patients receiving a maximum of 16 Gy to the brainstem developed temporary symptoms of brainstem edema. He observed local tumor control in two out of five patients with malignant gliomas within a follow-up period of 10 months. In an adult population of 88 patients with meningiomas, Morita et al.[110] found that a median dose of 10 Gy and a maximum dose of 16 Gy to a short segment of the anterior optic pathways were tolerable. Larson et al.[111] documented that young age, high initial KPS, and small tumor volume were associated with significantly better results in a multi-institutional study. More promising results were obtained with GKRS than conventional treatment modalities.[112],[113],[114]
Another concern is the differential radiation tolerance and tissue sensitivity in pediatric patients. Apart from it, younger age has been identified as a risk factor for poor neurocognitive outcomes if irradiated. The historical evidence reports intelligence quotient declines if you irradiate at a tender age. Traditional dose-volume relationships may not apply to the pediatric age group, and the literature is not robust with any laboratory or clinical data. Henceforth it is necessary to have prospective validation and ongoing multicentric trials for different indications in this population.[115],[116] A recent study has shown that even with a modest median marginal dose of 15 Gy an obliteration rate of 66.7% after LINAC-based SRS for intracranial AVM can be achieved instead of the traditionally prescribed 18 Gy.[117] While adult equivalent doses lead to higher AVM obliteration rates, there is a concern about their effect on the developing nervous system. Hence, doses tailored to pediatric pathologies should be explored in subsequent studies.
Although there has been concern about the effect of GKRS on cognition, a recent study showed no clinically harmful effect on cognitive and neuropsychological functioning in patients with brain AVM. On the contrary, there is an improvement in majority of patients at 2 years following radiosurgery when nidus is obliterated.[118] Even in cases of Pituitary adenoma those who underwent GKRS, memory scores were not significantly different from those in the patients who did not undergo GKRS (t ≤ 1.32, P ≥0.19).[119] Post-SRS hypopituitarism was the most common treatment-related toxicity observed, with a random-effects estimate of 21.0% (95% CI: 15–27%), whereas visual dysfunction or other cranial nerve injuries were uncommon (range: 0–7%). This is a genuine concern especially in pediatric cases and needs close follow-up with supplementation if need be.[120]
Pediatric radiosurgery: an effective and disruptive management strategy
SRS in pediatric patients is now viewed as a disruptive technology as this is particularly threatening to the existing leaders and concepts and represent a perceived competition from an unexpected direction. Such disruptions are necessary for the development of science, as conventional or in-vogue practices are frequently or sometimes universally met with disappointing consequences. In the turf wars of existing champions and increasing innovations in radiosurgery, the future seems in favor of radiosurgery as it is providing safer outcomes with progression-free survivals and minimized long-term complications. At present, SRS in the pediatric age group is facing unwelcoming glances both from the conventional neurosurgery and radiotherapy acolytes. There are multiple unanswered questions especially related to the radiobiology of the radiosurgery for the pediatric population and heightened perceived risk of side effects given the longer survival. Rather than being the last option, SRS is now the front runner among the cafeteria choices.[121]
| Conclusions | | |
Though an area still evolving, SRS has already proven its value and role in the pediatric population. With its high precision accuracy and conformality, SRS offers a theoretical advantage of sparing normal tissue in a delicate patient population such as the pediatric age group. Long-term prospective randomized multicentric controlled trials are imperative to establish radiosurgery in this sensitive population and expand radiosurgery horizons. A promising research domain is various functional indications and systemic therapy with biologics and immunotherapy to manage oligometastatic disease.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1]
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