Treatment Of Pediatric Low-grade Gliomas Research Articles

Beyond hand-crafted features for pretherapeutic molecular status identification of pediatric low-grade gliomas

The use of targeted agents in the treatment of pediatric low-grade gliomas (pLGGs) relies on the determination of molecular status. It has been shown that genetic alterations in pLGG can be identified non-invasively using MRI-based radiomic features or convolutional neural networks (CNNs). We aimed to build and assess a combined radiomics and CNN non-invasive pLGG molecular status identification model. This retrospective study used the tumor regions, manually segmented from T2-FLAIR MR images, of 336 patients treated for pLGG between 1999 and 2018. We designed a CNN and Random Forest radiomics model, along with a model relying on a combination of CNN and radiomic features, to predict the genetic status of pLGG. Additionally, we investigated whether CNNs could predict radiomic feature values from MR images. The combined model (mean AUC: 0.824) outperformed the radiomics model (0.802) and CNN (0.764). The differences in model performance were statistically significant (p-values < 0.05). The CNN was able to learn predictive radiomic features such as surface-to-volume ratio (average correlation: 0.864), and difference matrix dependence non-uniformity normalized (0.924) well but was unable to learn others such as run-length matrix variance (− 0.017) and non-uniformity normalized (− 0.042). Our results show that a model relying on both CNN and radiomic-based features performs better than either approach separately in differentiating the genetic status of pLGGs, and that CNNs are unable to express all handcrafted features.

Advances in the Treatment of Pediatric Low-Grade Gliomas.

Pediatric low-grade gliomas (pLGGs) often result in significant long-term morbidities despite high overall survival rates. This review aims to consolidate the current understanding of pLGG biology and molecular features and provide an overview of current and emerging treatment strategies. Surgical resection remains a primary treatment modality, supplemented by chemotherapy and radiotherapy in specific cases. However, recent advances have elucidated the molecular underpinnings of pLGGs, revealing key genetic abnormalities such as BRAF fusions and mutations and the involvement of the RAS/MAPK and mTOR pathways. Novel targeted therapies, including MEK, BRAF and pan-RAF inhibitors, have shown promise in clinical trials, demonstrating significant efficacy and manageable toxicity. Understanding of pLGGs has significantly improved, leading to more personalized treatment approaches. Targeted therapies have emerged as effective alternatives, potentially reducing long-term toxicities. Future research should focus on optimizing therapy sequences, understanding long-term impacts, and ensuring global accessibility to advanced treatments.

Role of surgery in the treatment of pediatric low-grade glioma with various degrees of brain stem involvement

ObjectivePosterior fossa pediatric low-grade glioma involving the brainstem and cerebellar peduncles (BS-pLGG) are a subgroup with higher risks at surgery. We retrospectively analyzed the role of surgery in the interdisciplinary armamentarium of treatment options in our institutional series of BS-pLGG with various degrees of brainstem involvement.Material and methodsWe analyzed data of 52 children with BS-pLGG after surgical intervention for clinical/molecular characteristics, neurological outcome, factors influencing recurrence/progression pattern, and tumor volumetric analysis of exclusively surgically treated patients to calculate tumor growth velocity (TGV). Tumors were stratified according to primary tumor origin in four groups: (1) cerebellar peduncle, (2) 4th ventricle, (3) pons, (4) medulla oblongata.ResultsThe mean FU was 6.44 years. Overall survival was 98%. The mean PFS was 34.07 months. Two patients had biopsies only. Fifty-two percent of patients underwent remission or remained in stable disease (SD) after initial surgery. Patients with progression underwent further 23 resections, 15 chemotherapies, 4 targeted treatments, and 2 proton radiations. TGV decreased after the 2nd surgery compared to TGV after the 1st surgery (p < 0.05). The resection rates were significantly higher in Groups 1 and 2 and lowest in medulla oblongata tumors (Group 4) (p < 0.05). More extended resections were achieved in tumors with KIAA1549::BRAF fusion (p = 0.021), which mostly occurred in favorable locations (Groups 1 and 2). Thirty-one patients showed postoperatively new neurological deficits. A total of 27/31 improved within 12 months. At the end of FU, 6% had moderate deficits, 52% had mild deficits not affecting activities, and 36% had none. Fifty percent of patients were free of disease or showed remission, 38% were in SD, and 10% showed progression.ConclusionThe first surgical intervention in BS-pLGG can control disease alone in overall 50% of cases, with rates differing greatly according to location (Groups 1 > 2 > 3 > 4), with acceptable low morbidity. The second look surgery is warranted except in medullary tumors. With multimodality treatments almost 90% of patients can obtain remission or stable disease after > 5 years of follow-up. An integrated multimodal and multidisciplinary approach aiming at minimal safe residual disease, combining surgery, chemo-, targeted therapy, and, as an exception, radiation therapy, is mandatory.

Applications of machine learning to MR imaging of pediatric low-grade gliomas.

Machine learning (ML) shows promise for the automation of routine tasks related to the treatment of pediatric low-grade gliomas (pLGG) such as tumor grading, typing, and segmentation. Moreover, it has been shown that ML can identify crucial information from medical images that is otherwise currently unattainable. For example, ML appears to be capable of preoperatively identifying the underlying genetic status of pLGG. In this chapter, we reviewed, to the best of our knowledge, all published works that have used ML techniques for the imaging-based evaluation of pLGGs. Additionally, we aimed to provide some context on what it will take to go from the exploratory studies we reviewed to clinically deployed models. Multiple studies have demonstrated that ML can accurately grade, type, and segment and detect the genetic status of pLGGs. We compared the approaches used between the different studies and observed a high degree of variability throughout the methodologies. Standardization and cooperation between the numerous groups working on these approaches will be key to accelerating the clinical deployment of these models. The studies reviewed in this chapter detail the potential for ML techniques to transform the treatment of pLGG. However, there are still challenges that need to be overcome prior to clinical deployment.

LGG-54. PEDIATRIC LOW-GRADE GLIOMAS TREATED WITH MEK INHIBITORS

Abstract BACKGROUND Low-grade gliomas (LGG) represent the most common brain tumor in children. It is well known that these tumors present mutations involving the BRAF gene, causing activation of the MAPK/ERK pathway. MEK inhibitors have now become an important treatment option over the recent years, slowing the growth of cancer cells. METHODS Retrospective analysis of 23 patients with LGG that were treated with MEK inhibitors at Nicklaus Children’s Hospital between 2015-2022. RESULTS Of the 23 patients; 6 were males and 17 were females, with a median age at diagnosis of 9.5 years of age. BRAF V600E mutation was present in 52% of patients (9/17). Other mutations found were: BRAF, BRAF KIAA1549, p.Q61K, and FGFR. Six patients had known associations with NF1. 7 of 23 patients had not received any prior treatment before MEK therapy, 8 underwent partial or total resection only prior, 4 had previous chemotherapy treatment, 3 underwent resection with chemotherapy, and 1 patient had both chemotherapy and proton radiation prior to MEK therapy. Targeted therapies included Trametinib (17/23), Dabrafenib (9/23), Selumetinib (5/23), and Binimetinib (1/23). Of the 9 patients with BRAF V600E mutation, 7/9 were given dual targeted therapies whereas only two were treated with only one inhibitor. The average length of therapy was one year. Most reported side effects were dermatologic manifestations such as dry skin or acne (9/23). Five patients showed objective improvement, 16 patients had stable residual disease, one had local recurrence, and one patient expired. Currently 12 patients are off therapy and 10 remain on treatment. Of the patients with BRAF V600E mutation, 4 had clinical and/or radiologic response, 1 patient expired due to disease progression and 1 has stable disease. CONCLUSION MEK inhibitors as a treatment of pediatric low-grade gliomas demonstrated promise as a therapeutic approach, so far proving to slow progression of disease in some cases. However, long-term side effects and toxicity remain unknown. Further large-scale prospective analysis would be helpful in future studies.

Surgical treatment of pediatric low-grade glioma in developing countries.

Pediatric low-grade gliomas constitute the most common brain tumors worldwide, though with some peculiarities in the presentation and surgical care in different parts of the world. The symptomatology in developing countries is likely to be over longer periods with a tendency to delayed diagnosis due to cultural, religious beliefs, manpower, and infrastructural deficits. Thus, the children present with large tumors with attendant morbidities and an increased risk of mortalities from surgery. Surgery is mainly by "general" neurosurgeons due to the paucity of trained pediatric neurosurgeons. The pre-operative imaging may be limited to anatomic MR imaging, and in some cases, CT scans, without expansive neuropsychological evaluation. The armamentarium available to the neurosurgeon may warrant large openings to access the tumor, and there may be limited possibility for intra-operative mapping of "eloquent" brain functions when this is deemed necessary. Complicating pre-operative acute hydrocephalus can result in two operations that further worsen the catastrophic spending associated with brain tumor surgeries in these climes. While these challenges appear daunting but certainly have not been enough to deter the "can do" spirit of neurosurgeons in developing countries, it is essential to strengthen the training of pediatric neurosurgeons in LMICs and provide a platform for the advocacy of better infrastructure for the surgical management of these tumors.

Impact of trametinib on the neuropsychological profile of NF1 patients.

The use of trametinib in the treatment of pediatric low-grade gliomas (PLGG) and plexiform neurofibroma (PN) is being investigated in an ongoing multicenter phase II trial (NCT03363217). Preliminary data shows potential benefits with significant response in the majority of PLGG and PN and an overall good tolerance. Moreover, possible benefits of MEK inhibitor therapy on cognitive functioning in neurofibromatosis type 1 (NF1) were recently shown which supports the need for further evaluation. Thirty-six patients with NF1 (age range 3-19 years) enrolled in the phase II study of trametinib underwent a neurocognitive assessment at inclusion and at completion of the 72-week treatment. Age-appropriate Wechsler Intelligence Scales and the Trail Making Test (for children over 8 years old) were administered at each assessment. Paired t-tests and Reliable Change Index (RCI) analyses were performed to investigate change in neurocognitive outcomes. Regression analyses were used to investigate the contribution of age and baseline score in the prediction of change. Stable performance on neurocognitive tests was revealed at a group-level using paired t-tests. Clinically significant improvements were however found on specific indexes of the Wechsler intelligence scales and Trail Making Test, using RCI analyses. No significant impact of age on cognitive change was evidenced. However, lower initial cognitive performance was associated with increased odds of presenting clinically significant improvements on neurocognitive outcomes. These preliminary results show a potential positive effect of trametinib on cognition in patients with NF1. We observed significant improvements in processing speed, visuo-motor and verbal abilities. This study demonstrates the importance of including neuropsychological evaluations into clinical trial when using MEK inhibitors for patients with NF1.

DDDR-11. IDENTIFYING NEW VULNERABILITIES TO TARGET PEDIATRIC LOW-GRADE GLIOMA

Abstract Pediatric low-grade gliomas (pLGGs) are the most common solid tumors in children and are associated with devastating lifelong morbidities and mortality. Recent genomic profiling efforts have revealed that these tumors are largely driven by single-driver events that activate MAPK signaling. These insights have led to early clinical trials evaluating the role of MAPK inhibitors for these children with promising initial results. However, pLGGs are not cured by MAPK inhibitors, and tumors often rapidly rebound upon cessation of treatment. Therefore, continuous dosing of these inhibitors is required throughout a child’s development–often with significant and potentially permanent toxicities. In addition, 30-40% of tumors do not respond to MAPK inhibition, indicating primary resistance. We hypothesized that pediatrlc low-grade gliomas may also harbor additional dependencies beyond the MAPK pathway that may represent potential therapeutic targets. To address this, we generated isogenic neural stem cell models that expressed pLGG relevant oncogenes (BRAF family members, FGFR family members and MYB transcription factors, and subjected them to genome-scale CRISPR-cas9 screens. Compared to vector controls, pLGG models exhibited genetic dependencies on pathways that included regulators of cell-cycle and differentiation, in addition to genes involved in regulating the mTOR and MAPK pathways. Cell lines expressing MYB family transcription factors also harbored dependencies on genes involved in the DREAM complex. Together, these genes and pathways represent potential targets for combination treatments with MAPK pathway inhibitors for the treatment of pediatric low-grade gliomas.

Treatment of Pediatric Low-Grade Gliomas.

Pediatric low-grade gliomas and glioneuronal tumors (pLGG) account for approximately 30% of pediatric CNS neoplasms, encompassing a heterogeneous group of tumors of primarily glial or mixed neuronal-glial histology. This article reviews the treatment of pLGG with emphasis on an individualized approach incorporating multidisciplinary input from surgery, radiation oncology, neuroradiology, neuropathology, and pediatric oncology to carefully weigh the risks and benefits of specific interventions against tumor-related morbidity. Complete surgical resection can be curative for cerebellar and hemispheric lesions, while use of radiotherapy is restricted to older patients or those refractory to medical therapy. Chemotherapy remains the preferred first-line therapy for adjuvant treatment of the majority of recurrent or progressive pLGG. Technologic advances offer the potential to limit volume of normal brain exposed to low doses of radiation when treating pLGG with either conformal photon or proton RT. Recent neurosurgical techniques such as laser interstitial thermal therapy offer a "dual" diagnostic and therapeutic treatment modality for pLGG in specific surgically inaccessible anatomical locations. The emergence of novel molecular diagnostic tools has enabled scientific discoveries elucidating driver alterations in mitogen-activated protein kinase (MAPK) pathway components and enhanced our understanding of the natural history (oncogenic senescence). Molecular characterization strongly supplements the clinical risk stratification (age, extent of resection, histological grade) to improve diagnostic precision and accuracy, prognostication, and can lead to the identification of patients who stand to benefit from precision medicine treatment approaches. The success of molecular targeted therapy (BRAF inhibitors and/or MEK inhibitors) in the recurrent setting has led to a gradual and yet significant paradigm shift in the treatment of pLGG. Ongoing randomized trials comparing targeted therapy to standard of care chemotherapy are anticipated to further inform the approach to upfront management of pLGG patients.

MR Imaging of Pediatric Low-Grade Gliomas: Pretherapeutic Differentiation of BRAF V600E Mutation, BRAF Fusion, and Wild-Type Tumors in Patients without Neurofibromatosis-1.

The prognosis and treatment of pediatric low-grade gliomas is influenced by their molecular subtype. MR imaging remains the mainstay for initial work-up and surgical planning. We aimed to determine the relationship between imaging patterns and molecular subtypes of pediatric low-grade gliomas. This was a retrospective bi-institutional study for patients diagnosed from 2004 to 2021 with pathologically confirmed pediatric low-grade gliomas molecularly defined as BRAF fusion, BRAF V600E mutant, or wild-type (which is neither BRAF V600E mutant nor BRAF fusion). Two neuroradiologists, blinded, independently reviewed imaging parameters from diagnostic MRIs, and discrepancies were resolved by consensus. Bivariate analysis was used followed by pair-wise comparison of the Dwass-Steel-Critchlow-Fligner method to compare the 3 molecular subtypes. Interreader agreement was assessed using κ. We included 70 patients: 30 BRAF fusion, 19 BRAF V600E mutant, and 21 wild-type. There was substantial agreement between the readers for overall imaging variables (κ = 0.75). BRAF fusion tumors compared with BRAF V600E and wild-type tumors were larger (P = .0022), and had a greater mass effect (P = .0053), increased frequency of hydrocephalus (P = .0002), and diffuse enhancement (p <.0001). BRAF V600E mutant tumors were more often hemispheric (P < .0001), appeared more infiltrative (P = .0002), and, though infrequent, were the only group demonstrating diffusion restriction (qualitatively; P = .0042) with a lower ADC ratio (quantitatively) (P = .003). BRAF fusion and BRAF V600E mutant pediatric low-grade gliomas have unique imaging features that can be used to differentiate them from each other and wild-type pediatric low-grade glioma using a standard radiology review with high interreader agreement. In the era of targeted therapy, these features can be useful for therapeutic planning before surgery.

LGG-08. MR Imaging of pediatric low-grade gliomas: Pretherapeutic differentiation ofBRAF V600E mutation,BRAF-Fused and Wild-Type tumors in patients without Neurofibromatosis-1

OBJECTIVE: The prognosis and treatment of pediatric low-grade gliomas (pLGGs) is influenced by their molecular subtype. MRI remains the mainstay for initial work-up and surgical planning. We aimed to determine the relationship between imaging patterns and molecular subtypes of pLGGs. METHODS: This is a bi-institutional retrospective study for patients diagnosed from 2004 to 2021 with pathologically confirmed pLGG, molecularly defined as BRAF fusion (KIAA1549-BRAF), BRAF V600E mutation, or wild-type (negative for both BRAF V600E mutation and BRAF fusion). Two neuroradiologists, blinded, independently reviewed imaging parameters on the initial MRI and discrepancies were solved by consensus. Bivariate analysis was used followed by pairwise comparison of Dwass, Steel, and Critchlow-Fligner methods to compare the 3 molecular subtypes. Agreement between reviewers was assessed using Kappa (k). RESULTS: 70 patients were included: 30 with BRAF fusion, 19 with BRAF V600E mutation, and 21 wild-type. There was substantial agreement between the two readers for overall imaging variables (k=0.75). BRAF fusion tumors compared to V600E and wild-type had larger size (p=0.0022), greater mass effect (p=0.0053), and increased rate of hydrocephalus (p=0.0002). BRAF fusion tumors had increased frequency of diffuse enhancement compared with BRAF V600E and wild-type (p <0.0001). BRAF V600E mutant tumors were more often located in a cerebral hemisphere (p <0.0001). Diffusion restriction (qualitatively) was uncommon but only seen in BRAF V600E (p=0.0042) with lower ADC ratio (quantitatively) (p=0.003). Additionally, BRAF V600E mutant tumors appeared more infiltrative than BRAF fusion and wild-type (p=0.0002). CONCLUSION:BRAF fusion and BRAF V600E mutant pLGG have unique imaging features that can be used to differentiate from each other and wild-type pLGG using standard radiology review with high inter-reader agreement. In the era of targeted therapy, these features can be useful for therapeutic planning prior to surgery.

Medical Treatment of Pediatric Low-Grade Glioma.

Low-grade glioma (LGG) is the most common brain tumor in children and has excellent long-term survival. With an excellent survival rate, the choice of treatment involves careful consideration of minimizing late toxicity from surgery, radiation, and chemotherapy. Surgery, radiation therapy, and chemotherapy can be used as monotherapy or in combination, providing different therapeutic ratios and complications. As a result, establishing the selection of ideal therapies has been a controversial area, presenting challenges. Recent advances in understanding molecular characteristics of pediatric LGG affect classification and treatment approaches. This review aims to overview recent developments in medical treatment in pediatric LGG.

Risk of secondary neoplasms after external-beam radiation therapy treatment of pediatric low-grade gliomas: a SEER analysis, 1973-2015.

Although past studies have associated external-beam radiation therapy (EBRT) with higher incidences of secondary neoplasms (SNs), its effect on SN development from pediatric low-grade gliomas (LGGs), defined as WHO grade I and II gliomas of astrocytic or oligodendrocytic origin, is not well understood. Utilizing a national cancer registry, the authors sought to characterize the risk of SN development after EBRT treatment of pediatric LGG. A total of 1245 pediatric patient (aged 0-17 years) records from 1973 to 2015 were assembled from the Surveillance, Epidemiology, and End Results (SEER) database. Univariable and multivariable subdistribution hazard regression models were used to evaluate the prognostic impact of demographic, tumor, and treatment-related covariates. Propensity score matching was used to balance baseline characteristics. Cumulative incidence analyses measured the time to, and rate of, SN development, stratified by receipt of EBRT and controlled for competing mortality risk. The Fine and Gray semiparametric model was used to estimate future SN risk in EBRT- and non-EBRT-treated pediatric patients. In this study, 366 patients received EBRT and 879 did not. Forty-six patients developed SNs after an LGG diagnosis, and 27 of these patients received EBRT (OR 3.61, 95% CI 1.90-6.95; p < 0.001). For patients alive 30 years from the initial LGG diagnosis, the absolute risk of SN development in the EBRT-treated cohort was 12.61% (95% CI 8.31-13.00) compared with 4.99% (95% CI 4.38-12.23) in the non-EBRT-treated cohort (p = 0.013). Cumulative incidence curves that were adjusted for competing events still demonstrated higher rates of SN development in the EBRT-treated patients with LGGs. After matching across available covariates and again adjusting for the competing risk of mortality, a clear association between EBRT and SN development remained (subhazard ratio 2.26, 95% CI 1.21-4.20; p = 0.010). Radiation therapy was associated with an increased risk of future SNs for pediatric patients surviving LGGs. These data suggest that the long-term implications of EBRT should be considered when making treatment decisions for this patient population.

LGG-30. TRAMETINIB-ASSOCIATED HYPONATREMIA IN A CHILD WITH LOW GRADE GLIOMA IS NOT SEEN FOLLOWING TREATMENT WITH ALTERNATIVE MEK INHIBITOR

Molecularly targeted therapy with MEK inhibitors is increasingly being incorporated into the treatment of pediatric low-grade gliomas (LGGs). Trametinib is an orally available MEK1/2 inhibitor that has demonstrated tumor control in LGGs with BRAF alterations. Safe expansion of MEK inhibitor therapy within the pediatric patient population demands adequate understanding of and surveillance for potential MEK-inhibitor specific toxicities, especially among young children. Hyponatremia has been reported in adult patients receiving BRAF/MEK inhibitor combination treatment as well as in two pediatric patients with known diabetes insipidus treated with trametinib monotherapy. To our knowledge, single-agent trametinib has not previously been reported to be associated with hyponatremia in children in the absence of an underlying endocrinopathy. We present a case of hyponatremia associated with trametinib use in an infant with progressive LGG without known endocrine dysfunction, which recurred after significant dose reduction. Therapy with an alternative MEK1/2 inhibitor, binimetinib, provided excellent tumor response without hyponatremia. Hyponatremia is a rare but serious side effect of trametinib, even without underlying pituitary dysfunction. Infants and patients lacking the ability to quickly regulate fluid intake in response to osmolality changes are at particular risk of suffering severe consequences from hyponatremia and should be monitored closely with initiation of trametinib. Switching to a different drug within the same class may offer an alternative to significant dose reduction or discontinuation due to this toxicity.

Current Salvage Treatment Strategies for Younger Children (

Pediatric low-grade gliomas (LGGs) are the most common brain tumors in children. Treatment of pediatric LGG can often be challenging, particularly when not resectable and refractory or recurrent following standard chemotherapy regimens. There is no current accepted standard of care salvage regimen for progressive LGG after the failure of first-line chemotherapy. A web-based survey was distributed to pediatric cancer centers throughout North America to inquire regarding institutional preferences of salvage treatment strategies after initial chemotherapy for LGG in children less than 10 years of age, as well as molecular testing preferences. Highlights from the survey results were as follows: vincristine/carboplatin (VC) and vinblastine (VBL) were the top 2 preferred salvage regimens for non-BRAF-altered pediatric LGG. BRAF and MEK inhibitors were the most preferred salvage regimens for BRAF V600e-mutated and BRAF fusion-positive pediatric LGG, respectively. VC ranked second. As high as 47.8% of North American centers would use conformal radiation for younger children with non-neurofibromatosis type 1 LGG after failing 2 to 3 chemotherapy regimens. Overall, 87% (87%) of North American institutions obtain some type of routine molecular testing for non-neurofibromatosis type 1-associated pediatric LGG cases. Less than 60% of centers obtain routine H3 K27M molecular testing for pediatric LGG with a midline location.

PDTC-17. A RETROSPECTIVE STUDY OF RECOMBINANT HUMAN ENDOSTATIN COMBINED WITH CARBOPLATIN AND VINCRISTINE FOR PEDIATRIC LOW-GRADE GLIOMAS

Abstract OBJECTIVE To analyze the response and toxicity of recombinant human endostatin (rh-ES) combined with carboplatin and vincristine (CV) chemotherapy regimen for pediatric low-grade gliomas (LGGs). METHODS Retrospectively reviewed the clinical data of the patients who were received rh-ES with CV chemotherapy regimen at Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University from October 2014 to October 2018. Carboplatin was administrated at a dose of 200~300 mg/m2 and the vincristine dose was 1.5 mg/m2 (maximum dose: 2 mg). Rh-ES was administrated 15 mg/d, daily for 14 days of each 28-day treatment cycle. RESULTS 26 patients were enrolled. By the time of the last follow-up, 14 patients had completed the treatment and 6 were still in treatment. Of the 26 patients, 14 had partial response (PR), 12 had stable disease (SD), and the objective response rate (ORR) was 53.8%. Of the 14 patients who completed all the treatment, 10 achieved PR, 4 got SD, and the ORR was 71.4%. The median time interval to response was 3.3 months (range 2–12.6 months). The main adverse reactions were myelosuppression and allergy to carboplatin. Three patients were terminated in the consolidation phase due to adverse reactions. CONCLUSIONS The rh-ES combined with CV regimen is effective in the treatment of pediatric LGGs and had a rapid time interval to response, which is conducive to the rapid relief of brain stem or visual function damage.

A Pilot Study of MR-Guided Mid-Treatment Adaptive Proton Therapy for Pediatric Low-Grade Gliomas

Intensity-modulated proton therapy (IMPT) is associated with reduced integral brain dose compared to photon therapy in the treatment of pediatric low-grade gliomas (pLGG). Mid-treatment imaging and response evaluation may allow for further reductions in dose to organs at risk (OAR) and improvement of the therapeutic ratio. This study investigates potential dosimetry advantages to MRI-guided mid-treatment adaptive planning for patients treated using IMPT. From 2006 to 2017, patients less than 21 years of age with intact pLGGs were treated with definitive radiotherapy and underwent mid-treatment MRI. Clinically delivered regimens were 54Gy/30 fractions (n=26) or 52.2GyRBE/29 fractions (n=2). Simulated initial IMPT plans were created with prescribed dose of 52.2GyRBE/29 fractions. Target volumes and OARs were retrospectively contoured on mid-treatment MRI. Tumors with mid-treatment response (>20% reduction in GTV) were replanned using the response-based contours. Coverage, dose constraints, and robust optimization parameters were identical for the initial and adapted plans. The initial and adapted plans were compared for OAR sparing. Mid-treatment imaging response was observed in 6/28 (21%) patients: five were located in the diencephalon/optic pathway region and one in the brainstem. Mean (± SD) GTV reduction was 32%±8%. Mean reduction in the volume of the brainstem receiving 40 GyRBE (V40GyRBE), V45GyRBE and V50GyRBE was 9.3%±4.1%, 8.2%±3.8%, and 5.5±5.1% respectively. Four of six adapted plans showed reductions in right and left cochlea V25GyRBE (right cochlea mean reduction: 29.6%±15.6%, left cochlea mean reduction: 20.9%±21.8%). Two of six adapted plans showed reductions in optic chiasm V50GyRBE (mean reduction: 9.8%±5.4%). Based on mid-treatment response to IMPT, MRI-guided adaptive planning may allow for reductions in brainstem V40GyRBE-V50GyRBE. Select patients may benefit from reductions in optic chiasm V50GyRBE and cochlea V25GyRBE. Prospective evaluation of adaptive therapy in pLGG is warranted to avoid late brainstem and optic nerve toxicities.

Multidisciplinary Treatment of Pediatric Low-Grade Glioma: Experience of Children Cancer Hospital of Egypt; 2007-2012

Abstract Background: Pediatric gliomas comprise a clinically, histologically, and molecularly heterogeneous group of central nervous system tumors. The survival of children with gliomas influenced by histologic subtype, age, and extent of resection. Tumor grade emerged as the most determinant of survival except in the young age groups. The aim of this study was to evaluate the role of multidisciplinary therapeutic approach including surgery and chemotherapy, and their impact on the outcome in pediatric patients with low-grade glioma (LGG). Procedure: Study patients were prospectively enrolled onto the study. All patients were below 18-year-old, diagnosed as LGG between July 2007 and June 2012. Upfront surgical resection was attempted in all tumors other than optic pathway sites. Systemic chemotherapy was given according to CCG-A9952 protocol. Results: Total/near-total resection in 105/227 (46.3%) without adjuvant treatment, while 49/227 patients (21.5%) underwent subtotal tumor resection followed by chemotherapy for big residual (n = 26). Follow-up only was indicated for asymptomatic/small residual (n = 23). The radiological diagnosis was set in 18/227 (7.9%) patients; 13/18 had optic pathway glioma. The 3-year overall survival (OS) was 87.3% versus 65.5% event free survival (EFS) for the whole study patients with a follow-up period of 1–5 years. The OS and EFS for patients who did surgery with no adjuvant treatment (n = 128) were, respectively, 95.2% and 77.3% versus 87.4% and 65.1% for adjuvant chemotherapy group (n = 99); (P = 0.015 and P = 0.016 for OS and EFS, respectively). Conclusion: Pediatric LGGs comprise a wide spectrum of pathological and anatomical entities that carry a high rate of prolonged survival among children and adolescents. Surgical resection is the mainstay of treatment in most of tumors. Combined chemotherapy can be an acceptable alternative when surgery is not safely feasible.

MEK and RAF inhibitors: time for a paradigm shift in the treatment of pediatric low-grade gliomas?

MEK and RAF inhibitors: time for a paradigm shift in the treatment of pediatric low-grade gliomas?

LG-06 * EFFECTS OF TORC1/2 INHIBITOR MLN0128 ALONE AND IN COMBINATION WITH MEK INHIBITION IN BRAF MUTATED GLIOMA CELLS

INTRODUCTION: First generation allosteric inhibitors of mTORC1 have shown clinical benefit for the treatment of pediatric low-grade gliomas (PLGG). MEK inhibition has shown great promise in early phase clinical trials for PLGG with the hypothesis that tumors carrying the KIAA1549:BRAF are particularly sensitive to such treatment. MLN0128, a second-generation, ATP-competitive, pan-mTOR kinase inhibitor, acts on both mTORC1 and mTORC2. Herein we investigate the effects of MLN0128 monotherapy as well as in combination with MEK inhibition in models of PLGG. METHODS: We used human glioma cell lines containing BRAFV600E (AM38), wild-type BRAF (LN229, TN98, SF188) and isogenic systems of KIAA1549:BRAF-expressing NIH3T3 cells. Signaling inhibitors included MLN0128, everolimus, BRAFV600E specific inhibitor PLX4720 and MEK specific inhibitors AZD6244 and GSK1120212. Cell proliferation was determined using an ATP-based assay. Biochemical effects were assessed using western blot analysis. In vivo activity of these inhibitors are ongoing using the BT40 PLGG xenograft mouse model. RESULTS: MLN0128 monotherapy shows stronger anti-proliferative effects compared to everolimus across cell lines independent of BRAF status. As expected, treatment with MLN0128 leads to down-regulation of p-AKT and p-4EBP1, whereas treatment with everolimus only reduces expression of p-S6. MEK inhibition with AZD6244 effectively decreases p-ERK expression in all lines; however, the addition of MLN0128 to AZD6244 causes a rebound in p-ERK expression in BRAFWT gliomas but not in gliomas expression BRAFV600E or KIAA1549:BRAF alterations. In cells carrying either the BRAFV600E or KIAA1549:BRAF alteration, combined treatment with MLN0128 and GSK1120212 or AZD6244 leads to synergistic anti-proliferative effects whereas such synergy is not present in BRAFWT gliomas. In vivo studies in the PLGG xenograft model BT40 are ongoing. CONCLUSION: MLN0128 has synergistic effects with MEK inhibition in gliomas bearing BRAFV600E or KIAA1549:BRAF. In BRAF wild-type cells such synergy is not present, perhaps due to rebound in p-ERK when MLN0128 is combined with AZD6244.