Changes in the management of children with pre-school high-grade gliomas—a narrative review of four decades of multi-disciplinary and multi-institutional collaboration

Introduction

High-grade gliomas (HGGs) comprise of approximately 8-12% of all central nervous system (CNS) tumors in children with the most common histologic diagnosis of anaplastic astrocytoma (AA) [World Health Organization (WHO) grade III] and glioblastoma (WHO grade IV) (1). These tumors occur most commonly within the brainstem and the supratentorial region, accounting for approximately 60% of all HGGs (2). Historically, treatment regimens for young children (aged 3 years or younger) have been similar to those of adolescents and young adults comprising primarily maximal safe surgical resection and radiotherapy (RT). However, as early as the 1970s, it was abundantly clear that the outcome of pediatric patients with HGG was dismal even with these treatment modalities with 5-year overall survival (OS) less than 20% (3-5). Brainstem glioma (BSG) had an even worse prognosis with 5-year OS of less than 5%. The median survival of such patients, including the youngest children, was less than 1 year following diagnosis (6).

To improve survival, the Children’s Cancer Group (CCG) initiated and conducted the first phase III prospective randomized clinical trial (CCG-943) testing the addition of chemotherapy during and following irradiation to standard surgical resection and RT (7). This was followed by CCG-945 which utilized prolonged, intensive multi-agent chemotherapy administered in a pre-irradiation “window” as well as post-irradiation (8-10).

It was also clear that the use of RT resulted in miserable quality of life outcomes for these children. The youngest especially, suffered from neuropsychological and cognitive problems, endocrinopathies, vasculopathy with stroke and secondary malignancies (11). Two trials conducted by the Pediatric Oncology Group (Baby POG I and II) in children under 3 years of age at diagnosis attempted to delay RT until 3 years of age [and for gross totally resected (GTR), non-metastatic patients on Baby POG II, avoid RT] with prolonged intravenous multi-agent chemotherapy (12-15). The French Society of Paediatric Oncology (SFOP) conducted a prospective multi-center “baby brain” trial of chemotherapy alone (BBSFOP) which utilized multi-agent chemotherapy with the intent to avoid RT until relapse (16). The United Kingdom Children’s Cancer Group (UKCCSG) and the International Society of Paediatric Oncology (SIOP) collaborated on CNS9204 which added intravenous high-dose methotrexate to the multi-agent chemotherapy ‘backbone’ to avoid irradiation until relapse (17).

The “Head Start” (HS) consortium has conducted three sequential irradiation-avoiding clinical trials for children less than 6 years of age with HGG and BSG between 1990 and 2009. These trials utilized induction chemotherapy followed by a single cycle of marrow-ablative chemotherapy and autologous hematopoietic cell rescue (AuHPCR) (18,19). Finally, the recently published multi-center trial (SJYC07) from the St. Jude Children’s Research Hospital was a risk-adapted trial utilizing multi-agent induction chemotherapy followed by non-myeloablative consolidation chemotherapy (20).

Although the results of these clinical trials have been published and reviewed previously, literature is scarce about the outcomes of HGG/BSG in young children specifically. The aim of this article is to detail the evolution in the management strategies and outcomes for each of these trials, including neuropsychological and quality of life measures, in the youngest children. Potentials avenues for achieving further progress in this modern era of molecular profiling of tumors with resultant risk-stratification and potentially targeted biological therapies will be discussed. We present this article in accordance with the Narrative Review reporting checklist (available at https://pm.amegroups.com/article/view/10.21037/pm-24-47/rc).

Methods

A literature search was performed using PubMed, and Cochrane library for published, peer-reviewed, prospective clinical trials involving patients with HGG and BSG conducted from the mid-1970s to May 31, 2024. A keyword search was undertaken using the search terms ‘high grade glioma’ AND each of the following search terms: ‘young children’, ‘infants’, ‘newly diagnosed’, and ‘clinical trials’. Search results were limited to publications in the English language and human-only studies. Clinical trials which included young children, 6 years of age or younger, conducted in North America and Europe were included. Clinical trials which excluded children less than 36 months of age were excluded from this review. Review articles and published abstracts based on oral, or poster presentations have also been excluded. Lastly, manuscripts that were in preparation or in press at the time of preparation and submission of this manuscript were excluded. Table 1 summarizes the search strategy. The data included have been drawn entirely from peer-reviewed published manuscripts based upon prospective multi-institutional trials.

Quantitative trial data has been tabulated in a systematic manner to differentiate protocols used in the management of these young children. Qualitative trial data, including neuropsychological and quality of life outcomes, have been described.

Results

This review highlights the prospective clinical trials for management of young children with HGG/BSG.

The CCG 943 and 945 trials were conducted from 1976 to 1992. CCG-943 was the first randomized phase III trial for children with HGG. All patients with biopsy-proven intracranial HGG were eligible. Patients with brainstem and spinal cord tumors were not eligible. Following initial surgical resection and central pathologic confirmation of diagnosis, patients were randomized to RT alone or RT with 6 weeks of weekly vincristine followed by 6-week cycles of chemotherapy with prednisone, lomustine (CCNU) and vincristine (PCV) for 58 weeks. All patients greater than 3 years old received RT doses of 52.5 Gy and patients 2 to 3 years old received decreased doses of 45 Gy. Nineteen patients (33%) enrolled were 6 years of age or younger. Eleven patients received RT only and 8 were randomized to RT with chemotherapy. Although specific age-related outcomes were not published, age was not associated with event-free-survival (EFS) or OS. The 5-year EFS and OS for the entire RT-only arm was 18% and 17% respectively compared to a 5-year EFS and OS of 46% and 43% respectively for the entire RT plus chemotherapy arm (Table 2) (7). CCG-943 highlighted the importance of chemotherapy with irradiation in the treatment of children with HGG. Additionally, this study showed that extent of resection was the single most important predictor of outcome.

The subsequent CCG trial (CCG-945) enrolled patients with HGG including spinal cord and brainstem tumors (provided, for the latter, the predominant location was outside the brainstem). Following surgical resection, patients 36 months old or younger were non-randomly assigned to 6-week cycles of the “eight-drugs-in-one-day” chemotherapy regimen, consisting of vincristine, carmustine (BCNU), procarbazine, hydroxyurea, cisplatin, cytosine arabinoside, dacarbazine (DTIC) and methylprednisolone for 48 weeks. Patients could receive RT (as per investigator preference) after completion of two cycles administered just 2 weeks apart, or else continued with the chemotherapy cycles every 4 to 6 weeks for a total of ten cycles. Patients older than 36 months were randomized to 54 Gy focal RT followed by 48 weeks of maintenance chemotherapy with PCV or the “eight-drugs-in-one-day” regimen administered both prior to and following RT (8). Eighty-three children were less than 6 years of age (33.1% of all enrolled). Forty-nine children were less than 36 months of age and had 10-year EFS of 29% and 10-year OS of 37.5%. The 10-year EFS and OS for the 34 children aged 3 to 6 years old was 35% and 36% respectively (Table 2). There was no statistically significant difference between the age groups with respect to EFS (P=0.70) and OS (P=0.83) (10). Additionally, the 5-year progression-free survival (PFS) was not statistically different for patients who underwent randomization; 26% for those treated with PCV compared to 33% for those who received “eight-drugs-in-one-day” (P=0.52) with median time to progression of 14 months for both arms (9). Extent of resection, defined as greater or less than 90%, did not statistically impact PFS for patients younger than 24 months of age (5). However, older patients had improved PFS with resection greater than 90% (P=0.02). Patients with AA had higher PFS than those with glioblastoma multiforme (GBM) at all ages (9). All children 3 to 6 years old received RT while 13 of 49 (26.5%) children less than 36 months ultimately received irradiation; eight patients less than 36 months old received RT prior to progression. There was no survival advantage in children less than 3 years old who received RT, with 10-year OS of 31% compared to 40% for those who did not receive RT. Twenty-four patients are long-term survivors, with 10 patients less than 36 months old and 14 patients 3 to 6 years old at diagnosis. Ninety percent of survivors less than 36 months of age did not receive RT. On measures of intelligence, visual-motor integration, visual memory and processing speed, the patients less than 36 months performed below the mean of the 3 to 6 years old cohort. However, the self-report quality of life measures were similar for both cohorts (10).

Baby POG I, conducted between 1986 and 1990, enrolled 18 children less than 36 months of age with HGG, and 14 children with BSG. The goal of the study was to delay RT utilizing chemotherapy for up to 2 years for children less than 24 months of age and up to 1 year for children 2 to 3 years old. The chemotherapy regimen consisted of two monthly cycles of vincristine, and cyclophosphamide alternating with one cycle of cisplatin and etoposide. Sixty percent of patients with HGG had partial radiographic responses after two cycles of chemotherapy with vincristine and cyclophosphamide compared to no responses for BSG patients. The 2-year PFS and OS for patients with HGG was 54% and 65% compared with 28% and 42% for patients with BSG (Table 2) (12). Interestingly, four patients (22%) with HGG did not receive RT after completion of 2 years of chemotherapy and are long-term survivors without recurrence. The degree of surgical resection, metastatic status and pathologic diagnosis did not influence survival (13,14).

After the success of Baby POG I, Baby POG II was conducted between 1992 and 1998 to evaluate the impact of dose-intensification on survival. Patients less than 36 months with HGG including BSG were randomized to either the Baby POG I regimen or to a regimen with 1.8 times the dose-intensification with the same agents. Patients with residual tumor (R+) or presence of metastatic disease (M+) at diagnosis received RT at the completion of chemotherapy. Twenty children were enrolled of whom 50% were long-term survivors (Table 2). Given the small accrual numbers, prognostic factors including extent of resection, use of RT or specific chemotherapy regimen were not evaluated. As similar outcomes were achieved with the standard regimen, dose-intensification did not prove superior (15).

The BBSFOP HGG trial for young children was conducted between 1990 and 2002 and enrolled 21 patients less than 5 years of age, all with localized disease. Five of 21 patients had BSG. Patients received two-drug courses every 21 days consisting of carboplatin and procarbazine, followed by etoposide and cisplatin, followed by vincristine and cyclophosphamide for 16 months. The 5-year PFS was 35.3% and 5-year OS was 58.8% for the entire cohort. Of the 5 patients with BSG, time to relapse was reported in only 3 and occurred at less than 5-years in all with 5-year PFS of 0%. Five-year OS for these patients was approximately 40% (Table 2). Two patients achieved partial responses, one achieved a minor response and one patient had disease stabilization. Ten patients (47.6%) remained alive without treatment with RT. Fourteen patients had progression or relapse, four of whom had midline tumors. Although not statistically significant, children less than 2 years old had better outcome with 54% remaining alive compared to 20% of those older than 2 years. Additionally, AA histology and GTR demonstrated superior although not statistically significant outcomes (P value not reported). At last follow-up, 73% of the 11 evaluable patients demonstrated normal neurodevelopmental outcomes. This study concluded that RT can be avoided in some children with HGG (16).

CNS9204 was the UKCCSG/SIOP co-operative trial conducted between 1992 and 2003, during which 19 children with HGG and seven with BSG, less than 3 years of age, were enrolled. Treatment consisted of 1 year of alternating marrow-suppressive and non-marrow-suppressive chemotherapy administered every 14 days in 56-day cycles. Patients received carboplatin and vincristine followed by methotrexate and vincristine, followed by cyclophosphamide and vincristine and finally cisplatin. RT was administered only for progressive disease. Three patients had M+ disease at diagnosis. For the HGG cohort, the 5-year EFS and OS were 18.1% and 34.7% (Table 2). Only one of the long-term survivors had achieved a GTR and only one received RT. The 1-year EFS was 0% for the BSG cohort with a median PFS of 0.21 years (0.10–0.53 years), while the 1-year and 3-year OS was 14.3% and 0% (17).

The “Head Start” (HS) I to III trials were conducted between 1991 and 2009, and introduced dose-intense induction chemotherapy followed by marrow ablative high-dose consolidation chemotherapy with AuHPCR, in order to avoid RT. HS I consisted of five cycles of chemotherapy administered every 21 days with cisplatin, cyclophosphamide, etoposide and vincristine (18). In HS II and III, all patients received four cycles of chemotherapy every 28 days with vincristine, carboplatin and temozolomide. In all three trials, induction chemotherapy was followed by a single cycle of consolidation chemotherapy with thiotepa and carboplatin and AuHPCR. Focal RT (54 Gy) was administered following consolidation with R+ disease at entry to consolidation. HS II and III enrolled 13 patients aged 3 to 6 years at diagnosis and nine patients less than 3 years of age, all with HGGs. Patients with predominant brainstem tumors were excluded. Although not statistically significant, patients less than 3 years of age had improved 5-year EFS and OS of 44% and 63% compared to patients 3 to 6 years old (31% and 28%) (P=0.63 and P=0.32) (Table 2). Survival by pathology and extent of resection was not significantly different. Four patients with HGG underwent neuropsychological evaluation at study-mandated time points during and following completion of therapy. Although scores varied from high average to impaired range, results were predominantly consistent between pre-consolidation and following completion of therapy (19). In the HS I and II trials, 12 patients with BSG less than 6 years of age were enrolled. One-year EFS was 31% and 2-year EFS was 0% with median EFS of 6.6 months. One-year and 2-year OS were 38% and 7.7% respectively, with median OS of 8.7 months (Table 2). Due to these disappointing results, BSG patients were excluded from future HS trials (18).

The most recently reported clinical trial for young children with HGG (SJYC07) was conducted between 2007 and 2017 and was a phase II risk-adapted trial for children less than 3 years old. Treatment consisted of four cycles of induction chemotherapy administered every 28 days, comprising of high-dose methotrexate, followed by vincristine and cisplatin, followed by cyclophosphamide for the low-risk (LR) arm (who were patients without metastatic disease). This was followed by two cycles of consolidation with carboplatin, etoposide, and cyclophosphamide. Induction chemotherapy for the high-risk (HR) arm (M+ and R+ patients) comprised of four cycles of induction chemotherapy with the same four-drug regimen with the addition of vinblastine followed by consolidation with two cycles of cyclophosphamide and topotecan. Patients did not receive RT on SJYC07. The outcomes of the protocol patients were compared with similarly treated patients after study closure (between 2017 and 2020) or those who were 3 to 5 years of age grouped as non-protocol tumor patients (NPTP). Forty-one patients were enrolled, and an additional 15 patients were reviewed in the NPTP cohort. Eleven patients (20%) had midline tumors. Seven patients had M+ disease; six patients were treated on the HR arm and one NPTP patient received treatment with molecularly-targeted therapy. Twenty-seven percent of NPTP patients received RT as part of initial treatment and 13 SJYC07 patients received RT after disease progression. The 5-year EFS and OS for the SJYC07 cohort was 51% and 78% respectively (Table 2). There was no difference in the 5-year EFS or OS among the LR (52.78% and 80.56%) and HR arms (40% and 60%). However, NPTP patients treated with other regimens had an inferior EFS of 28.57% at 3 years. Methylation profiling was successfully performed on 61% of patients. Thirty-nine percent of patients (n=22) were found to have infant-type hemispheric glioma (IHG), 11% pediatric type diffuse HGG (n=6), 7% low-grade glioma (LGG) (n=4), and 16% were classified as other CNS tumors (n=9), i.e., BCOR internal tandem duplication, CIC-rearranged sarcoma, FOXR2-activated CNS neuroblastoma, neuroepithelial tumor with PLAGL1-fusion, neuroepithelial tumor with PATZ1 fusion, CNS embryonal tumor with PLAG family amplification, or atypical embryonal tumor with multilayered rosettes, non-C19MC altered. All the patients in the IHG cohort had M0 disease and were younger on average with median age of 0.36 years. Molecular testing confirmed seventy-three percent of the patients had pathogenic RTK gene fusions, 32% had ALK alterations, 23% had alterations in ROS/NTRK and 18% had MET alterations. Eighty-two percent were treated on the LR arm, 13.6% were treated with surgical resection followed by molecularly targeted therapy and only one patient with residual tumor was treated on the HR arm. The median age of the pediatric diffuse type HGG cohort was older at 2.73 years. Sixty-seven percent of the patients in this cohort had midline tumors and one patient had M+ disease. Molecular testing for this cohort confirmed presence of frequent large scale chromosomal gains and losses with focal copy number variations in MYCN and CDKN2A/B. Two patients were treated on the LR arm, two on the HR arm and two received other therapies, details of which were not available. The 5-year EFS for the IHG cohort was significantly higher at 53.13% compared to zero for the HGG cohort (P=0.004). Similarly, the 5-year OS for the IHG cohort was 90.91% compared to 16.7% for the HGG cohort (P<0.001). Within the IHG cohort, extent of resection, type of therapy, and molecular features were not associated with EFS or OS. Neuropsychological testing was performed on 10 IHG patients and 14 non-IHG patients, of whom only four (16.7%) received RT. The entire cohort demonstrated an average progressive decline in IQ of 3.18 points per year with no differences within the rate of decline among the IHG and non-IHG cohorts (P=0.78) (20).

Discussion

This review of clinical trials for the treatment of young children with newly-diagnosed HGG/BSG provides analysis of the evolution of multi-agent chemotherapy protocols designed to avoid or delay cranial irradiation and improve PFS.

Briefly, the historic CCG studies were the first to demonstrate the benefit of chemotherapy with irradiation in the survival of young children with HGG. Additionally, these studies identified extent of surgical resection as the single most important prognostic factor. CCG-945 also found that survival in up to 30% of patients was possible without use of RT with chemotherapy alone. Baby POG studies were also instrumental in demonstrating the role for prolonged courses of chemotherapy to delay the use of irradiation. These trials achieved 5-year survival of 40% to 50% in young children with HGG. However, what should not be forgotten is that both CCG-945 and Baby POG II studies showed that the use of further intensive chemotherapy regimens resulted in treatment-related toxicities without added benefit to survival. BBSFOP revealed that a larger subset (almost 50%) of young children with HGG can be cured with irradiation-sparing regimen.

The addition of intravenous and intraventricular methotrexate was revolutionary in catapulting the survival of young children with medulloblastoma to 90% (21,22). Furthermore, the incorporation of marrow-ablative consolidation chemotherapy and AuHPCR as in the “Head Start” trials has led to significant improvement in PFS and OS for medulloblastoma patients (23,24). Disappointingly, the results from CNS9204 and the “Head Start” trials failed to show survival benefit for BSG.

The most recent and groundbreaking work in the outcomes for HGG/BSG in young children comes from the recent publications by St. Jude. This trial followed a review by the St. Jude group of ten patients less than 3 years old with BSG treated at their institution between 1992 and 2007 which found 3-year PFS and OS of 45% and 69%. Treatment was variable and included two patients who received RT only, two who received chemotherapy only and the remaining patients received a combination of RT and chemotherapy and/or molecularly-guided therapy. Chemotherapy included combinations of carboplatin, vincristine, temozolomide, thalidomide or cyclophosphamide in three patients and erlotinib in one patient. Sixty percent of patients survived for at least 2 years. This study concluded that young children with BSG may have a better prognosis than older children potentially due to distinct biological features (25). The results of SJYC07 did not validate this theory as the HGG cohort, 67% of whom harbored midline tumors, had a 5-year OS of only 16%. However, this study did demonstrate an excellent 5-year OS of IHG patients at 90% with all but one patient having received irradiation-sparing therapy. Unexpectedly the neurocognitive outcomes demonstrated an annual decline in IQ in all groups of patients, suggesting that the tumor itself, subsequent resection and medical management may have contributed to this decline.

The importance of molecular subgroups in the survival of young children with HGG has been further elucidated by the Toronto Hospital for Sick Kids; they conducted the largest molecular profiling on a multi-institutional IHG cohort of 118 patients treated for both HGG and LGG. Three distinct molecular subgroups of IHG were identified. Group 1 are hemispheric, RTK-driven tumors which contain alterations in ALK/ROS1/NTRK/MET and are enriched for HGG (82.8%), particularly glioblastoma. Median age at diagnosis is younger—2.8 months (0–12 months). Outcomes were heterogeneous and based on specific alteration with 5-year OS of 53.8% among those with ALK alterations, 42.9% among NTRK fused tumors and 25% among ROS1 tumors. Two patients with NTRK-fused HGG underwent second resections post-chemotherapy displaying lower grade histology, which may suggest an LGG/HGG continuum in these tumors, similar to infant neuroblastoma. Group 2 are hemispheric, RAS/MAPK-driven tumors which are primarily LGG, with 35% harboring non-BRAF RAS/MAPK activating mutations. These tumors had the best outcome of the three subgroups with 10-year OS of 93.3% and were more amenable to GTR and less likely to require a second-line treatment. Group 3 are midline, RAS/MAPK-driven tumors and comprised 75% of all midline infantile gliomas with 97.4% harboring conical BRAF alterations, and were LGG, predominantly pilocytic astrocytoma within the optic chiasm/hypothalamus glioma (OPHG). More importantly, although half of all OPHG contained BRAFV6OOE mutation, no non-OPHG Group 3 tumors harbored this mutation. Five-year PFS for Group 3 tumors was significantly worse (23.4%) compared to non-midline LGG (55.6%) (P=0.01). Additionally, infant OPHG had a poorer outcome with 10-year OS of 57.7% compared to older children (1–18 years) with the same diagnosis treated at Sick Kids (87.1%) (26).

This review represents the first of its kind to detail the management and subsequent improvements in outcomes of young children with newly-diagnosed HGG. Cumulatively, this includes the largest patient numbers as only multi-center clinical trials were included. There are several limitations to the current review. Trials conducted outside of North America and Europe were excluded as the articles were not universally published in English. Long term neurological outcomes were available for 9 of the 11 studies resulting in relatively small patient numbers thereby limiting interpretation of these results.

Conclusions

It is now clear that HGG and BSG in young children are a heterogeneous group of tumors that are distinct from their older counterparts. Information from molecular profiling of such tumors have already provided a rational basis for risk-tailored therapies, as well as for some biologically-targeted therapies. Although survival outcomes for young children with HGG without the use of irradiation have exponentially increased over the last four decades, further research into the epigenetic machinery and the microenvironment of these tumors will be necessary to improve outcomes, especially for children with BSG. Furthermore, targeting the genetic pathways with novel agents will be necessary especially for patients with brainstem tumors.

Acknowledgments

We wish to acknowledge the pivotal contributions of the principal investigators of all of the prospective multi-center cooperative trials detailed in this review: Richard Sposto (CCG-943), Patricia Duffner (Baby POG I), Douglas Strother (Baby POG II), Richard Grundy (UKCCSG/SIOP CNS 9204), Christelle Dufour (BBSFOP), Amar Gajjar and Giles Robinson (SJYC07).

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://pm.amegroups.com/article/view/10.21037/pm-24-47/rc

Peer Review File: Available at https://pm.amegroups.com/article/view/10.21037/pm-24-47/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://pm.amegroups.com/article/view/10.21037/pm-24-47/coif). J.L.F. serves as an unpaid editorial board member of Pediatric Medicine from June 2024 to December 2025. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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