Optic pathway glioma: current treatment approaches and ongoing clinical trials—a review article

Optic pathway glioma: current treatment approaches and ongoing clinical trials—a review article | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report Optic pathway glioma: current treatment approaches and ongoing clinical trials—a review article Osama Elzaafarany, MD, Sarah Elhomosany, MD, Alexandra Rincones, MD, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6882947/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 20 Aug, 2025 Read the published version in Brain Sciences → Version 1 posted You are reading this latest preprint version Abstract Optic pathway glioma (OPG) is a rare pediatric low-grade glioma, frequently associated with neurofibromatosis type 1 (NF-1), that presents unique therapeutic challenges due to its anatomical location and its potential to impair vision, endocrine function, and developmental trajectories. Current clinical management prioritizes a multidisciplinary, patient-specific approach aimed at tumor control while preserving long-term quality of life. Strategies vary based on clinical presentation, ranging from observation in asymptomatic cases to chemotherapy for progressive or symptomatic tumors. Surgical and radiation options are limited due to potential risks and complications. In recent years, advances in molecular characterization have guided the development of targeted therapies, particularly MEK inhibitors, which demonstrate encouraging efficacy and reduced toxicity profiles. In parallel, investigational therapies including immunotherapy and precision medicine-based approaches are under clinical evaluation. This review synthesizes current standard practices and recent progress in targeted treatment development. Actively recruiting clinical trials are also cataloged to inform both clinicians and families about available therapeutic options. To conduct this review, we searched PubMed, ClinicalTrials.gov, and Scopus for English-language articles published between 2010 and 2025 using terms such as “optic pathway glioma,” “NF1,” “MEK inhibitors,” and “targeted therapy.” Studies were selected based on relevance to treatment strategies, trial design, and clinical applicability. Data extraction focused on trial outcomes, therapeutic mechanisms, and patient-centered considerations. Through integrating clinical evidence and ongoing research, this review aims to provide a comprehensive update on current and emerging treatment strategies for OPG and to support informed, evidence-based care planning. Oncology neurofibromatosis type 1 optic pathway glioma brain/orbit MRI clinical trials Figures Figure 1 Figure 2 Figure 3 Introduction Optic pathway glioma (OPG) are rare, low-grade astrocytic tumors that occur in the optic nerve, chiasm, or both, most commonly affecting children under 10 years old. Most cases are associated with neurofibromatosis type 1 (NF-1), an autosomal-dominant genetic disorder caused by mutations in the NF1 gene, leading to abnormal regulation of cell growth. NF-1 is characterized by skin manifestations (eg, café-au-lait spots, neurofibromas), learning difficulties, and predisposition to tumors such as OPG [ 1 ]. While many OPG are indolent and can remain stable without immediate intervention, others may cause significant morbidity, particularly through visual impairment, proptosis, or even neurological decline [ 2 ]. Managing OPG poses a unique challenge, requiring a delicate balance between tumor control and preservation of vision and quality of life. Treating OPG is influenced by factors such as tumor size, growth rate, patient age, tumor location in the optic pathway, visual status, and the presence of NF-1 diagnosis. Traditional management strategies include observation for asymptomatic or stable tumors, chemotherapy for symptomatic cases, and surgery or radiation for more aggressive lesions. Chemotherapy protocols like carbo-vincristine, vinblastine single agent, and thioguanine, procarbazine, lomustine (CCNU) and vincristine (TPCV) protocol have proven effective in stabilizing or reducing tumor size, particularly for pediatric patients [ 3 , 4 ]. Surgical resection is reserved for certain indications but carries risks of vision loss and neurological complications [ 5 ]. Radiation therapy (RT) is avoided for young children, particularly those younger than 5 years old, because of its long-term developmental effects. RT is also avoided in NF-1 patients due to risk of secondary malignancies in this patient population [ 6 ]. Despite these options, treating OPG remains challenging because of issues such as treatment resistance, side effects, and long-term complications. Advances in molecular genetics and targeted therapies offer hope for more effective, personalized approaches [ 7 ]. Ongoing clinical trials are exploring innovative treatments, including new drug combinations, targeted agents, and immunotherapies, aiming to improve tumor control, minimize side effects, and enhance long-term outcomes. This review highlights the current treatment landscape and emerging therapeutic options, focusing on clinical trials that represent the future of OPG management. Methods This review was conducted through a systematic search and synthesis of peer-reviewed literature and registered clinical trials related to optic pathway glioma (OPG) and neurofibromatosis type 1 (NF1). Databases searched included PubMed, Scopus, and ClinicalTrials.gov, covering publications from January 2010 to May 2025. Search terms included combinations of "optic pathway glioma," "NF1," "low-grade glioma," "MEK inhibitors," "targeted therapy," "clinical trials," and "pediatric glioma." Inclusion criteria encompassed original clinical studies, review articles, and trial protocols that focused on therapeutic strategies, emerging molecular targets, and active clinical investigations. Articles not written in English or lacking sufficient clinical detail were excluded. Data were extracted based on study type, population characteristics, treatment interventions, outcomes (e.g., tumor progression, vision preservation), and relevance to current or investigational management strategies. Clinical trials were included if they were active, recruiting, or recently completed, with a focus on relevance to pediatric populations. Quality and applicability of sources were assessed through publication type, citation relevance, and methodological transparency. Findings were synthesized narratively, emphasizing advancements in therapy and their implications for clinical practice. Current Standard Treatment Approaches for OPG The standard treatment options for OPG include observation, chemotherapy, RT, and surgery. Treatment decisions should be made by a multidisciplinary team, including pediatric oncologists, neuro-oncologists, neurosurgeons, ophthalmologists, and radiation oncologists, to ensure comprehensive care and minimize long-term adverse effects. Screening for NF-1 is essential for patients diagnosed with OPG. Figure 1 shows a suggested algorithm for treating OPG. Observation Observation is reserved for patients who are asymptomatic or have mild symptoms, especially for patients with NF-1. Observation may be recommended to avoid treatment-related morbidity. This approach is often chosen when the tumor is not causing immediate threats to vision or other neurological functions. Scheduling observation visits is advised for every 3 to 6 months. These visits usually involve clinical assessments and imaging tests, such as magnetic resonance imaging MRI, to monitor for any changes in the tumor that could require treatment. The specific frequency of visits may differ based on the patient’s individual circumstances and the judgment of the treating physician. Additionally, regular ophthalmological assessments are an integral part of observation for early detection of visual changes. The natural course of OPG among children is highly unpredictable. While some tumors remain stable for years or even regress spontaneously, other tumors grow progressively. Treatment is typically reserved for patients experiencing progressive vision loss or those with existing visual impairment who are at high risk of further deterioration, regardless of substantial tumor progression on MRI. Tumor growth alone is not a criterion for initiating therapy. Nicolin et al reported that approximately 48% of patients do not require immediate treatment. However, these patients still need regular neuroradiological and ophthalmological monitoring, with intervals determined by factors such as tumor location, symptoms, and the presence or absence of NF-1 association [ 8 , 9 ]. Chemotherapy Chemotherapy is typically the first-line treatment for symptomatic OPG, particularly for young children. Although many OPGs appear benign histologically, chemotherapy surprisingly yields high response rates. Consequently, chemotherapy is frequently chosen as the initial treatment over radiation, particularly for children under 5 years old, as radiotherapy can significantly harm cognitive development. By using chemotherapy, the need for radiation can often be delayed, which may lessen neurocognitive side effects without compromising the survival rates [ 10 ]. The most used frontline chemotherapy regimen available for treating OPG is the combination of vincristine and carboplatin which is the preferred first-line therapy, achieving a 3-year progression-free survival (PFS) rate of 77% and 5-year PFS rate of 69% [ 11 ]. Vinblastine single agent is widely used frontline chemotherapy protocol in Canada. A multicenter study led by Institut Gustave Roussy in France, involving 85 children with progressive OPGs (median age, 33 months), demonstrated the effectiveness of using chemotherapy as an initial treatment to delay the need for RT. The children were treated with alternating chemotherapy regimens every 3 weeks, such as procarbazine and carboplatin, etoposide and cisplatin, and vincristine and cyclophosphamide. This strategy successfully deferred the need for RT among 75% of cases at 3 years old and 61% at 5 years old. For the 25 children who eventually required RT, the median interval from the start of treatment to the commencement of RT was 35 months. Postponing RT did not adversely affect outcomes, as the 5-year overall survival rate was 89%. This result of postponed radiation was similar to that achieved with initial radiation, and visual results were comparable [ 12 ]. Between 40% and 60% of patients eventually progress after chemotherapy and require further salvage therapies [ 13 ]. These may include RT, bevacizumab with or without irinotecan, BRAF and/or MEK inhibitors, immunotherapy, and participation in clinical trials. The benefits of chemotherapy come with significant risks, as its side effects can be serious, including severe bone marrow suppression. Table 1 shows the most common chemotherapy regimens used in treating OPG, including the dosage and potential side effects. Table 1 Carboplatin Vincristine Chemotherapy Protocol Details Drug Mechanism of action Dosage Administration schedule Common side effects Serious side effects Carboplatin Alkylating agent that causes DNA cross-linking, leading to apoptosis of cancer cells. 560 mg/m² IV every 4 weeks. Administered as i.v. infusion over 15–60 min. Nausea, vomiting, myelosuppression (anemia, neutropenia, thrombocytopenia), and fatigue. Nephrotoxicity, ototoxicity, hypersensitivity reactions, and severe myelosuppression. Vincristine Inhibits microtubule formation in the mitotic spindle, arresting cell division in metaphase. 1.5 mg/m² IV weekly (maximum dose of 2 mg per dose). Administered as a short i.v. infusion (1–2 min). Constipation, peripheral neuropathy, jaw pain, and hair loss. Severe neurotoxicity, including peripheral neuropathy and autonomic dysfunction. Radiation Therapy Radiation therapy is reserved for children older than 8–10 years or those whose tumors are resistant to chemotherapy because of its potential long-term complications such as cognitive impairment, secondary malignancies, and vascular injury. Radiation therapy is avoided for patients with NF-1 because of increased risks of developing secondary malignancies. The typical RT dose ranges from 45 Gy to 54 Gy, delivered in 1.8 Gy to 2 Gy per fraction. Radiation therapy can halt the progression of visual decline, though the full impact of RT may take years to manifest. In a retrospective analysis involving 42 patients with OPG, with a median age of 6.6 years (1.25–19 years), 29 patients received radiation because of disease progression. Tumor reduction was noted for 18% of patients at 24 months and 46% at 60 months, with a median response time of 62 months. Additionally, vision stabilization or improvement was achieved among 81% of cases. The rate of freedom from disease progression at 10 years was 89%, and the rate of overall survival at 10 years was 100% [ 14 ]. Surgery Surgery is not commonly used as a primary treatment but may be considered for specific cases, such as patients with single-nerve involvement causing progressive proptosis and blindness, patients with exophytic tumors involving the optic chiasm that cause mass effect or hydrocephalus. Furthermore, surgical debulking may be performed to relieve symptoms or improve vision, but complete resection is rarely possible without significant neurological injury [ 15 ]. Promising Treatment Options Mitogen-Activated Protein Kinase– (MAPK-) Pathway Inhibitors Targeting the MAPK pathway has emerged as a promising strategy for treating OPG; however, the optimal timing for its implication remains controversial; some pediatric oncologists advocate for using it as a first-line therapy, while others recommend it after failure of chemotherapy or RT. Therefore, participation in clinical trials is highly encouraged [ 10 , 16 ]. The rationale for using this approach is that the overwhelming majority of OPG are pilocytic astrocytoma which frequently exhibit BRAF alterations. Furthermore, the Pediatric Brain Tumor Consortium (PBTC) data looking at MEKi and OPGs illustrated that even without biopsy, some known pilocytic astrocytomas without a BRAF fusion also had a response. In OPG, the 2 most common BRAF mutations identified in biopsied cases are the KIAA1549:BRAF fusion and the BRAF V600E point mutation [ 17 ]. These mutations activate the MAPK pathway, a key regulator of cell growth and proliferation. Figure 2 provides a simplified illustration of the MAPK pathway and its inhibitors [ 18 ]. Interestingly, several MAPK pathway inhibitors have demonstrated activity against OPG, including trametinib and selumetinib (MEK1/MEK2 inhibitors), vemurafenib and dabrafenib (type I rapidly accelerated fibrosarcoma [RAF] inhibitors), and tovorafenib (a type II RAF inhibitor). Typically, RAF inhibitors are combined with MEK inhibitors to avoid paradoxical MAPK pathway activation. Table 2 demonstrates a clear overview of the mechanisms, dosages, and side effects for each drug, highlighting their clinical considerations and potential adverse effects. Table 2 MAPK Pathway Inhibitors Mechanism of Action, Dosage, Common Side Effects, and Serious Side Effects Drug Mechanism of action Dosage Common side effects Serious side effects Selumetinib Inhibits MEK1/MEK2, preventing phosphorylation and activation of ERK1/ERK2 in the MAPK pathway. 25 mg/m² orally 2× daily. Rash, diarrhea, nausea, vomiting, fatigue, and peripheral edema. Cardiomyopathy, ocular toxicity, interstitial lung disease, and elevated liver enzymes. Vemurafenib Inhibits mutated BRAF V600E kinase, blocking MAPK pathway activation. 960 mg orally 2× daily. Arthralgia, rash, photosensitivity, alopecia, and fatigue. Cutaneous squamous cell carcinoma, liver enzyme elevation, QT prolongation, and uveitis. Dabrafenib Inhibits mutated BRAF V600E kinase, blocking MAPK pathway activation. 150 mg orally 2× daily. Hyperkeratosis, headache, pyrexia, arthralgia, and alopecia. Febrile drug reaction, cutaneous squamous cell carcinoma, hyperglycemia, and uveitis. Tovorafenib (DAY101) Inhibits RAF dimer-driven MAPK pathway activation. 420 mg orally 1× weekly. Fatigue, nausea, vomiting, diarrhea, and elevated liver enzymes. QT prolongation, severe skin reactions, and hepatotoxicity. Abbreviation: MAPK, mitogen-activated protein kinase. Evidence Supporting MAPK Pathway Inhibitors Selumetinib Selumetinib, a MEK1/MEK2 inhibitor approved for NF-1-associated plexiform neurofibromas, has demonstrated efficacy in both NF-1-associated and sporadic OPG. In a phase II trial by the Pediatric Brain Tumor Consortium, a total of 25 eligible and evaluable patients were included in the study, with a median of four prior treatment regimens (ranging from 1 to 11). Among them, 24% (6 patients) achieved a partial response, 56% (14 patients) maintained stable disease, and 20% (5 patients) experienced disease progression during therapy. The median number of treatment cycles administered was 26 (range: 2–26), and over half (14 of 25) completed the full course. The two-year progression-free survival (PFS) rate was 78% (± 8.5%). Of the 19 patients assessable for visual acuity, 21% (4 patients) showed improvement, 68% (13 patients) remained stable, and 11% (2 patients) experienced deterioration. Visual field enhancement was observed in 26% (5 patients), while 74% (14 patients) had no change. The most frequently reported adverse effects were mild to moderate (grade 1/2) and included elevated creatine phosphokinase (CPK), anemia, gastrointestinal symptoms (diarrhea, nausea/vomiting), fatigue, headaches, liver enzyme elevations (AST, ALT), hypoalbuminemia, and dermatologic reactions such as rash. [ 19 , 20 ]. Tovorafenib Tovorafenib is a type II RAF inhibitor, which was approved by the FDA in 2024 for children 6 months and older with relapsed/refractory low-grade gliomas harboring BRAF V600E mutations or fusions. In the phase II FIREFLY-1 trial (n = 137), tovorafenib achieved an objective response rate of 67% (Response Assessment in Neuro-Oncology criteria) and a median duration of response of 16.6 months. Common adverse events included hair-color changes, elevated creatine phosphokinase, and anemia, with toxicities of grade 3 or higher among 42% of patients [ 21 ]. However, Tovorafenib should not be used for NF1 mutated tumors as there is a FDA package insert warning against using it for NF-1 patients. Dabrafenib Plus Trametinib This combination is FDA-approved for BRAF V600E-mutant low-grade gliomas among children 1 year and older. A randomized phase II trial demonstrated its superiority over carboplatin/vincristine, with significant activity in tumors involving the optic pathway or hypothalamus [ 22 ]. Other Treatment Options Bevacizumab Bevacizumab is an anti-VEGF (vascular endothelial growth factor) monoclonal antibody that has a significant role in managing brain tumors such as recurrent high-grade gliomas. Several reports have documented qualitative improvements in vision among children with OPG following bevacizumab-based treatment [ 23 ]. Multiple retrospective studies consistently show that bevacizumab, either as a stand-alone treatment or in combination with therapies like irinotecan, can lead to significant visual improvement and radiological responses among 50–70% of children with recurrent OPGs, regardless of NF-1 status. Even though bevacizumab shows effectiveness and manageable toxicity, such as systemic hypertension and proteinuria, it has decreased efficacy with prolonged treatment beyond 12 months. Furthermore, over 40% of children experience recurrence within a few months after discontinuation of bevacizumab, indicating that its effects are not long-lasting [ 24 ]. Lenalidomide Researchers are investigating immune modulators like lenalidomide among pediatric patients whose conditions have worsened despite standard treatments. In a phase II study involving 74 children with pilocytic astrocytoma or OPG, both high-dose and low-dose lenalidomide were tested, resulting in 4 partial responses in each group. The low-dose treatment was found to be better tolerated by the children [ 25 ]. Pegylated Interferon α-2b Pegylated interferon α-2b works by binding to and activating the human type 1 interferon receptors, causing them to dimerize, and this activates the JAK/STAT pathway. Peginterferon α-2b may also activate the nuclear factor κB pathway. A phase II clinical trial of pegylated interferon α-2B for patients with unresectable juvenile pilocytic astrocytomas and OPG enrolled 9 subjects with a median age of 11 years. The trial demonstrated prolonged stable disease among 2 patients (75 + and 66 + months) and event-free survival rates of 76.2% at 12 and 24 months, with median event-free survival and overall survival not reached. Side effects were mostly mild (grade 1–2), with no severe drug-related events reported. While the treatment showed safety and potential for delaying disease progression in select cases, its overall efficacy as a therapeutic option remains uncertain because of the lack of significant tumor responses [ 26 ]. Immunotherapy To date, no compelling evidence supports immunotherapy as a treatment for OPG. However, there are ongoing clinical trials testing the PD1/PD-L1 inhibitors and CART in gliomas [ 27 ]. Current immunotherapy approaches for glioma are summarized in Fig. 3 [28]. Ongoing Actively Recruiting Clinical Trials These are examples of actively recruiting clinical trials that will assist physicians, patients, and their families in making treatment decisions. These clinical trials were divided into 3 categories: systemic therapy trials, vision-improvement trials, and CAR T-cell therapy trials as follows. Systemic Therapy Trials Selumetinib Three phase III clinical trials are investigating selumetinib for low-grade glioma (LGG) at multiple locations in the United States. NCT04166409 compares the efficacy of selumetinib to the standard chemotherapy combination of carboplatin and vincristine (CV) for patients with newly diagnosed LGG that lacks the BRAFV600E mutation and is not linked to NF-1. The trial aims to determine whether selumetinib can provide comparable or improved outcomes, including tumor control and quality of life, compared with CV [29]. NCT04576117 examines the addition of vinblastine to selumetinib in treating recurrent or progressive LGG. This trial seeks to determine whether the combination therapy is more effective than selumetinib alone [30]. Similarly, NCT03871257 evaluates selumetinib vs CV for treating LGG for patients with NF-1, focusing on tumor control and its potential to improve vision for those patients with OPG [31]. Tovorafenib Tovorafenib is being compared with chemotherapy in an ongoing 2-arm, randomized, open-label, multicenter, global, phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy vs standard-of-care chemotherapy among patients with pediatric LGG harboring an activating RAF alteration requiring front-line systemic therapy ( NCT05566795 ) [32]. Avutometinib NCT06104488 is multicenter phase I dose-escalation study of avutometinib, a RAF/MEK clamp, in pediatric patients with refractory or recurrent solid tumors harboring activating MAPK pathway alterations [33]. Vision-Improvement Trials The NCT05278715 trial evaluates a modified chemotherapy regimen combining increased-dose carboplatin (220 mg/m²), vincristine, and recombinant human endostatin (rh-ES). The trial includes pediatric and adult patients and focuses on visual acuity improvement and response rates over 3 years [34]. Meanwhile, the NCT05733572 trial assesses the safety and efficacy of CHF6467, a recombinant mutated nerve growth factor, for improving visual function among OPG patients. This randomized, double-blind, placebo-controlled study uses CHF6467 eye drops and measures visual-field and visual-evoked potentials over 6 months. The trial targets children (ages 6–17 years) and young adults (ages 18–39 years) [35]. CAR T-cell Therapy Trials Three innovative clinical trials are investigating CAR T-cell therapy in gliomas. The first trial ( NCT06355908 ) is a phase I study assessing the safety and feasibility of IL13Ra2-targeted CAR T cells in patients with recurrent or refractory glioma [36]. This trial is focusing on glioma-specific CAR T-cell therapies. Similarly, the second trial ( NCT04099797 ) explores C7R-GD2 CAR T cells for treating GD2-expressing brain tumors, including diffuse intrinsic pontine glioma, high-grade glioma, and medulloblastoma [37]. This phase I study combines i.v. and intracranial infusions to determine the largest safe dose while enhancing T-cell survival with cytokine support. The third trial ( NCT06640582 ) is a phase I/II study which investigates a combination of tumor-infiltrating lymphocytes therapy with pembrolizumab in advanced brain cancers, including glioblastoma and meningioma [38]. Conclusion and Future Directions Managing OPGs is challenging because of their complex location, association with NF-1, and diverse clinical progression. Current treatments, including chemotherapy, targeted therapy, and RT, provide reasonable control in many cases but are limited by issues such as treatment resistance, long-term toxicities, and variability in outcomes. Emerging strategies, including bevacizumab for symptom control and MEK inhibitors for NF-1-associated gliomas, show promise, while immunotherapy and CAR T-cell therapy hold potential to transform the therapeutic landscape. However, the safety and efficacy of these treatments, particularly among pediatric populations, require further investigation. Future research should focus on developing durable therapies to reduce relapse risk, minimizing toxicities through targeted approaches, and identifying predictive biomarkers for personalized treatment. Integrative care models that address the multifaceted needs of OPG patients and the expansion of clinical trials exploring next-generation therapeutics, such as immune-based therapies and gene-editing techniques, are vital. Collaborations among researchers, clinicians, and patient-advocacy groups will be essential to translating preclinical advancements into effective clinical practices, improving outcomes and quality of life for OPG patients. References Donahue BS, Sun M, Patel P, et al. Optic nerve gliomas: a comprehensive review. J Neuro-Oncol . 2019;141(2):271–279. doi:10.1007/s11060-019-03153-9. Walker RD, Thompson J, Greenfield JP, et al. 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Bevacizumab for optic pathway glioma with worsening visual field in absence of imaging progression: 2 case reports and literature review. Childs Nerv Syst . 2020;36(3):635–639. doi:10.1007/s00381-019-04407-6. Epub November 7, 2019. PMID:31701281. Cassina M, Frizziero L, Opocher E, Parrozzani R, et al. Optic Pathway Glioma in Type 1 Neurofibromatosis: Review of Its Pathogenesis, Diagnostic Assessment, and Treatment Recommendations. Cancers (Basel). 2019 Nov 14;11(11):1790. doi: 10.3390/cancers11111790. PMID: 31739524; PMCID: PMC6896195.Warren KE, Vezina G, Krailo M, et al. Phase II randomized trial of lenalidomide in children with pilocytic astrocytomas and optic pathway gliomas: a report from the Children’s Oncology Group. J Clin Oncol . 2023;41(18):3374–3383. doi:10.1200/JCO.22.01777. Epub May 1, 2023. PMID:37126770; PMCID: PMC10414716. Warren, K. E., Vezina, G., Krailo, M., Springer, L., Reddy, A. T., et al. (2023). 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A study of the drugs selumetinib vs. carboplatin and vincristine in patients with low-grade glioma [Internet]. clinicaltrials.gov; 2023 [accessed December 1, 2024]. Available from: https://clinicaltrials.gov/ct2/show/NCT04166409 NCT04576117. A study to compare treatment with the drug selumetinib alone versus selumetinib and vinblastine in patients with recurrent or progressive low-grade glioma [Internet]. clinicaltrials.gov; 2023 [accessed December 1, 2024]. Available from: https://clinicaltrials.gov/ct2/show/NCT04576117 NCT03871257. A study of the drugs selumetinib versus carboplatin/vincristine in patients with neurofibromatosis and low-grade glioma [Internet]. clinicaltrials.gov; 2023 [cited 2024 Dec 1]. Available from: https://clinicaltrials.gov/ct2/show/NCT03871257 DAY101 vs. standard of care chemotherapy in pediatric patients with low-grade glioma requiring first-line systemic therapy (LOGGIC/FIREFLY-2) [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT05566795 32 [updated November 1, 2024; accessed December 1, 2024]. Available from: https://www.clinicaltrials.gov/study/NCT05566795 NCT06104488. A study of avutometinib for people with solid tumor cancers [Internet]. clinicaltrials.gov; 2023 [accessed December 1, 2024]. Available from: https://clinicaltrials.gov/ct2/show/NCT06104488 NCT05278715. Modified CV regimen in optic pathway glioma [Internet]. clinicaltrials.gov; 2023 [cited December 1, 2024]. Available from: https://clinicaltrials.gov/ct2/show/NCT05278715 NCT05733572. Safety and Efficacy of the PAINLESS nerve growth factor CHF6467 in optic pathway glioma [Internet]. clinicaltrials.gov; 2023 [accessed December 1, 2024]. Available from: https://clinicaltrials.gov/ct2/show/NCT05733572 NCT06355908. IL13Rα2 CAR-T for patients with r/r glioma [Internet]. clinicaltrials.gov; 2023 [accessed December 1, 2024]. Available from: https://clinicaltrials.gov/ct2/show/NCT06355908 NCT04099797. C7R-GD2.CAR T Cells for GD2-Expressing Brain Tumors [Internet]. clinicaltrials.gov; 2023 [accessed December 1, 2024]. Available from: https://clinicaltrials.gov/ct2/show/NCT04099797 NCT06640582. TIL Therapy + pembrolizumab for advanced brain cancer [Internet]. clinicaltrials.gov; 2023 [accessed December 1, 2024]. Available from: https://clinicaltrials.gov/ct2/show/NCT06640582 Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Published Journal Publication published 20 Aug, 2025 Read the published version in Brain Sciences → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6882947","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":470559347,"identity":"e97f7ade-8202-408a-96a0-b954a6c70fd9","order_by":0,"name":"Osama Elzaafarany, MD","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABOklEQVRIiWNgGAWjYBACfigtAyI+gJnsDQwMFTYSOLVINkBoHiBmnAFhHmBgOJMmgVOPwQEMLRIJIC0MuLWcP/x0ww8GGx759sMPG37uscszuPk68cGBBIs6Bvbexy+wabmRZnazhyGNh7EnzbCx51lyscHt3M0GBxKADuM5bmaBVQuD2Q0ehsM8zAwJ5g94DjAnbridu0364w+gFok0NgOsDjv+7eYfhv88bPzPPzb+OVCfuOHm2W0SYFtwaTmQY3abh+EAD49EjmEzz4HDiRtu8MK1MD/AokVyRk7ZbRmDZB4JiTeFzTIHjifOPAPxi2QbzzE2bCHGz3982803FXZy8v3pGxvfHKhO7Dt+diMwxOr4+dnbmD/gCmkGZCcrHIAygFaw4U4DyEC+AcHGY8soGAWjYBSMIAAAiz9sl3XsV5cAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-3842-9825","institution":"Moffitt Cancer Center","correspondingAuthor":true,"prefix":"","firstName":"Osama","middleName":"","lastName":"Elzaafarany","suffix":"MD"},{"id":470560897,"identity":"babdde58-653d-4a87-9cfe-70f0295f3c66","order_by":1,"name":"Sarah Elhomosany, MD","email":"","orcid":"","institution":", Faculty of Medicine Alexandria University, Alexandria, Egypt","correspondingAuthor":false,"prefix":"","firstName":"Sarah","middleName":"","lastName":"Elhomosany","suffix":"MD"},{"id":470560898,"identity":"783bc5e0-c90a-4376-a9e8-6fff9167c174","order_by":2,"name":"Alexandra Rincones, MD","email":"","orcid":"","institution":"University of South Florida, Tampa, FL, USA","correspondingAuthor":false,"prefix":"","firstName":"Alexandra","middleName":"","lastName":"Rincones","suffix":"MD"},{"id":470560899,"identity":"6c55ba65-f74d-4146-962e-638e00966d70","order_by":3,"name":"Vincent Dlugi","email":"","orcid":"","institution":"Moffitt Cancer Center, Tampa, FL, USA","correspondingAuthor":false,"prefix":"","firstName":"Vincent","middleName":"","lastName":"Dlugi","suffix":""},{"id":470560902,"identity":"ac9f217e-32d2-4acd-a9fb-e84ed246e111","order_by":4,"name":"Sepideh Mokhtari, MD","email":"","orcid":"","institution":"Moffitt Cancer Center, Tampa, FL, USA","correspondingAuthor":false,"prefix":"","firstName":"Sepideh","middleName":"","lastName":"Mokhtari","suffix":"MD"}],"badges":[],"createdAt":"2025-06-12 19:59:40","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-6882947/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6882947/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.3390/brainsci15080894","type":"published","date":"2025-08-21T00:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":84678933,"identity":"931d0236-6a51-4422-8acf-1fa37dcfee73","added_by":"auto","created_at":"2025-06-16 08:03:30","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":52110,"visible":true,"origin":"","legend":"\u003cp\u003eSuggested algorithm for treating OPGs. Abbreviations: NF1, neurofibromatosis type 1; OPGs, optical pathway gliomas.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6882947/v1/f12354801ed59efc9eced07a.jpg"},{"id":84678419,"identity":"e0b9d8d0-a33f-453f-b2d5-297a6afac0b2","added_by":"auto","created_at":"2025-06-16 07:55:30","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":191541,"visible":true,"origin":"","legend":"\u003cp\u003eTargeting the hyperactive Ras/RAF/MEK/ERK (MAPK) signaling pathway is a promising approach for cancer therapy. This signaling cascade operates downstream of RTKs. When RTKs bind to their ligands, they activate guanine exchange factors, such as Sos proteins, which facilitate the loading of GTP onto Ras GTPases. The GTP-bound Ras GTPases then recruit RAF/MEK heterodimers from the cytosol to the plasma membrane, where RAFs form transient tetramers through side-to-side dimerization. This dimerization activates RAFs, disrupts the RAF/MEK heterodimers, and promotes MEK homodimerization on the RAF dimer surface, leading to MEK activation by RAFs. Once activated, MEKs phosphorylate ERKs, which in turn phosphorylate various downstream effectors. In cancer cells, this pathway can become hyperactive due to mutations in Ras GTPases and BRAF. Such hyperactivity can be targeted with small molecule inhibitors that specifically inhibit Ras G12C, BRAF(V600E), MEK, and ERK [18]. Abbreviations: MAPK, mitogen-activated protein kinase; RAF, rapidly accelerated fibrosarcoma; RTKs, receptor tyrosine kinases.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6882947/v1/53acb7414bddc1d39f19d0ec.jpg"},{"id":84678935,"identity":"06e617bc-6321-4690-84f5-09d61c5f1521","added_by":"auto","created_at":"2025-06-16 08:03:30","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":218546,"visible":true,"origin":"","legend":"\u003cp\u003eOncolytic viruses have the ability to lyse glioma cells and subsequently release progeny viruses, which further assist in eradicating residual tumor masses. The tumor lysate released in this process can be identified by DCs, which are integral to DC vaccines. Dendritic cells are highly effective in presenting antigens and can activate CTLs, which then target and eliminate glioma cells. Glioma cells frequently evade immune detection by expressing immune checkpoint ligands such as PD-1, CTLA-4, and IDO. Blocking these checkpoints can significantly disrupt this immune evasion. Cytokines like IFN-γ and IL-2 are capable of activating Th1 cells, thereby enhancing CTL-mediated antitumor responses. Additionally, IFN-α and IFN-β can activate NK cells, which target tumor cells through ADCC. Glioma-associated antigens such as IL-13Rα2, EGFRvIII, and CD70 are expressed on tumor cell surfaces and can be recognized by CTLs with the enhancement of MHC-1 expression. Genetically engineered CAR T cells are targeting these antigens. Moreover, TAMs stimulated by CSF-1 and CCL2 can produce MMP-9 and TGF-β1, promoting glioma cell invasion. Inhibiting these pathways can help reduce glioma cell invasiveness [27]. Abbreviations: ADCC, antibody-dependent cellular cytoxicity; CAR, chimeric antigen receptor; CTLs, cytotoxic T lymphocytes; DCs, dendritic cells; IDO, Indoleamine 2,3-Dioxygenase; NK, natural killer; TAMs, tumor-associated macrophages.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6882947/v1/6336cf381ff137502d43e4b5.jpg"},{"id":89691086,"identity":"775bfd15-386c-4c95-a343-3ae24ad5bfa8","added_by":"auto","created_at":"2025-08-22 16:47:51","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1216982,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6882947/v1/0d1e59b9-c45a-44e9-80c0-33b28b02656a.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eOptic pathway glioma: current treatment approaches and ongoing clinical trials—a review article\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOptic pathway glioma (OPG) are rare, low-grade astrocytic tumors that occur in the optic nerve, chiasm, or both, most commonly affecting children under 10 years old. Most cases are associated with neurofibromatosis type 1 (NF-1), an autosomal-dominant genetic disorder caused by mutations in the NF1 gene, leading to abnormal regulation of cell growth. NF-1 is characterized by skin manifestations (eg, caf\u0026eacute;-au-lait spots, neurofibromas), learning difficulties, and predisposition to tumors such as OPG [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. While many OPG are indolent and can remain stable without immediate intervention, others may cause significant morbidity, particularly through visual impairment, proptosis, or even neurological decline [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Managing OPG poses a unique challenge, requiring a delicate balance between tumor control and preservation of vision and quality of life.\u003c/p\u003e \u003cp\u003eTreating OPG is influenced by factors such as tumor size, growth rate, patient age, tumor location in the optic pathway, visual status, and the presence of NF-1 diagnosis. Traditional management strategies include observation for asymptomatic or stable tumors, chemotherapy for symptomatic cases, and surgery or radiation for more aggressive lesions. Chemotherapy protocols like carbo-vincristine, vinblastine single agent, and thioguanine, procarbazine, lomustine (CCNU) and vincristine (TPCV) protocol have proven effective in stabilizing or reducing tumor size, particularly for pediatric patients [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Surgical resection is reserved for certain indications but carries risks of vision loss and neurological complications [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Radiation therapy (RT) is avoided for young children, particularly those younger than 5 years old, because of its long-term developmental effects. RT is also avoided in NF-1 patients due to risk of secondary malignancies in this patient population [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eDespite these options, treating OPG remains challenging because of issues such as treatment resistance, side effects, and long-term complications. Advances in molecular genetics and targeted therapies offer hope for more effective, personalized approaches [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Ongoing clinical trials are exploring innovative treatments, including new drug combinations, targeted agents, and immunotherapies, aiming to improve tumor control, minimize side effects, and enhance long-term outcomes. This review highlights the current treatment landscape and emerging therapeutic options, focusing on clinical trials that represent the future of OPG management.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis review was conducted through a systematic search and synthesis of peer-reviewed literature and registered clinical trials related to optic pathway glioma (OPG) and neurofibromatosis type 1 (NF1). Databases searched included PubMed, Scopus, and ClinicalTrials.gov, covering publications from January 2010 to May 2025. Search terms included combinations of \"optic pathway glioma,\" \"NF1,\" \"low-grade glioma,\" \"MEK inhibitors,\" \"targeted therapy,\" \"clinical trials,\" and \"pediatric glioma.\" Inclusion criteria encompassed original clinical studies, review articles, and trial protocols that focused on therapeutic strategies, emerging molecular targets, and active clinical investigations. Articles not written in English or lacking sufficient clinical detail were excluded.\u003c/p\u003e \u003cp\u003eData were extracted based on study type, population characteristics, treatment interventions, outcomes (e.g., tumor progression, vision preservation), and relevance to current or investigational management strategies. Clinical trials were included if they were active, recruiting, or recently completed, with a focus on relevance to pediatric populations. Quality and applicability of sources were assessed through publication type, citation relevance, and methodological transparency. Findings were synthesized narratively, emphasizing advancements in therapy and their implications for clinical practice.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eCurrent Standard Treatment Approaches for OPG\u003c/h2\u003e \u003cp\u003eThe standard treatment options for OPG include observation, chemotherapy, RT, and surgery. Treatment decisions should be made by a multidisciplinary team, including pediatric oncologists, neuro-oncologists, neurosurgeons, ophthalmologists, and radiation oncologists, to ensure comprehensive care and minimize long-term adverse effects. Screening for NF-1 is essential for patients diagnosed with OPG. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows a suggested algorithm for treating OPG.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eObservation\u003c/h3\u003e\n\u003cp\u003eObservation is reserved for patients who are asymptomatic or have mild symptoms, especially for patients with NF-1. Observation may be recommended to avoid treatment-related morbidity. This approach is often chosen when the tumor is not causing immediate threats to vision or other neurological functions. Scheduling observation visits is advised for every 3 to 6 months. These visits usually involve clinical assessments and imaging tests, such as magnetic resonance imaging MRI, to monitor for any changes in the tumor that could require treatment. The specific frequency of visits may differ based on the patient\u0026rsquo;s individual circumstances and the judgment of the treating physician. Additionally, regular ophthalmological assessments are an integral part of observation for early detection of visual changes.\u003c/p\u003e \u003cp\u003eThe natural course of OPG among children is highly unpredictable. While some tumors remain stable for years or even regress spontaneously, other tumors grow progressively. Treatment is typically reserved for patients experiencing progressive vision loss or those with existing visual impairment who are at high risk of further deterioration, regardless of substantial tumor progression on MRI. Tumor growth alone is not a criterion for initiating therapy. Nicolin et al reported that approximately 48% of patients do not require immediate treatment. However, these patients still need regular neuroradiological and ophthalmological monitoring, with intervals determined by factors such as tumor location, symptoms, and the presence or absence of NF-1 association [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eChemotherapy\u003c/h3\u003e\n\u003cp\u003eChemotherapy is typically the first-line treatment for symptomatic OPG, particularly for young children. Although many OPGs appear benign histologically, chemotherapy surprisingly yields high response rates. Consequently, chemotherapy is frequently chosen as the initial treatment over radiation, particularly for children under 5 years old, as radiotherapy can significantly harm cognitive development. By using chemotherapy, the need for radiation can often be delayed, which may lessen neurocognitive side effects without compromising the survival rates [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe most used frontline chemotherapy regimen available for treating OPG is the combination of vincristine and carboplatin which is the preferred first-line therapy, achieving a 3-year progression-free survival (PFS) rate of 77% and 5-year PFS rate of 69% [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Vinblastine single agent is widely used frontline chemotherapy protocol in Canada.\u003c/p\u003e \u003cp\u003eA multicenter study led by Institut Gustave Roussy in France, involving 85 children with progressive OPGs (median age, 33 months), demonstrated the effectiveness of using chemotherapy as an initial treatment to delay the need for RT. The children were treated with alternating chemotherapy regimens every 3 weeks, such as procarbazine and carboplatin, etoposide and cisplatin, and vincristine and cyclophosphamide. This strategy successfully deferred the need for RT among 75% of cases at 3 years old and 61% at 5 years old. For the 25 children who eventually required RT, the median interval from the start of treatment to the commencement of RT was 35 months. Postponing RT did not adversely affect outcomes, as the 5-year overall survival rate was 89%. This result of postponed radiation was similar to that achieved with initial radiation, and visual results were comparable [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBetween 40% and 60% of patients eventually progress after chemotherapy and require further salvage therapies [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. These may include RT, bevacizumab with or without irinotecan, BRAF and/or MEK inhibitors, immunotherapy, and participation in clinical trials.\u003c/p\u003e \u003cp\u003eThe benefits of chemotherapy come with significant risks, as its side effects can be serious, including severe bone marrow suppression. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the most common chemotherapy regimens used in treating OPG, including the dosage and potential side effects.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCarboplatin Vincristine Chemotherapy Protocol Details\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrug\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMechanism of action\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDosage\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdministration schedule\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCommon side effects\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSerious side effects\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCarboplatin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAlkylating agent that causes DNA cross-linking, leading to apoptosis of cancer cells.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e560 mg/m\u0026sup2; IV every 4 weeks.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdministered as i.v. infusion over 15\u0026ndash;60 min.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNausea, vomiting, myelosuppression (anemia, neutropenia, thrombocytopenia), and fatigue.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNephrotoxicity, ototoxicity, hypersensitivity reactions, and severe myelosuppression.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVincristine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInhibits microtubule formation in the mitotic spindle, arresting cell division in metaphase.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.5 mg/m\u0026sup2; IV weekly (maximum dose of 2 mg per dose).\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdministered as a short i.v. infusion (1\u0026ndash;2 min).\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eConstipation, peripheral neuropathy, jaw pain, and hair loss.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSevere neurotoxicity, including peripheral neuropathy and autonomic dysfunction.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e\n\u003ch3\u003eRadiation Therapy\u003c/h3\u003e\n\u003cp\u003eRadiation therapy is reserved for children older than 8\u0026ndash;10 years or those whose tumors are resistant to chemotherapy because of its potential long-term complications such as cognitive impairment, secondary malignancies, and vascular injury. Radiation therapy is avoided for patients with NF-1 because of increased risks of developing secondary malignancies. The typical RT dose ranges from 45 Gy to 54 Gy, delivered in 1.8 Gy to 2 Gy per fraction.\u003c/p\u003e \u003cp\u003eRadiation therapy can halt the progression of visual decline, though the full impact of RT may take years to manifest. In a retrospective analysis involving 42 patients with OPG, with a median age of 6.6 years (1.25\u0026ndash;19 years), 29 patients received radiation because of disease progression. Tumor reduction was noted for 18% of patients at 24 months and 46% at 60 months, with a median response time of 62 months. Additionally, vision stabilization or improvement was achieved among 81% of cases. The rate of freedom from disease progression at 10 years was 89%, and the rate of overall survival at 10 years was 100% [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eSurgery\u003c/h3\u003e\n\u003cp\u003eSurgery is not commonly used as a primary treatment but may be considered for specific cases, such as patients with single-nerve involvement causing progressive proptosis and blindness, patients with exophytic tumors involving the optic chiasm that cause mass effect or hydrocephalus. Furthermore, surgical debulking may be performed to relieve symptoms or improve vision, but complete resection is rarely possible without significant neurological injury [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003ePromising Treatment Options\u003c/h2\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003eMitogen-Activated Protein Kinase\u0026ndash; (MAPK-) Pathway Inhibitors\u003c/h2\u003e \u003cp\u003eTargeting the MAPK pathway has emerged as a promising strategy for treating OPG; however, the optimal timing for its implication remains controversial; some pediatric oncologists advocate for using it as a first-line therapy, while others recommend it after failure of chemotherapy or RT. Therefore, participation in clinical trials is highly encouraged [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe rationale for using this approach is that the overwhelming majority of OPG are pilocytic astrocytoma which frequently exhibit BRAF alterations. Furthermore, the Pediatric Brain Tumor Consortium (PBTC) data looking at MEKi and OPGs illustrated that even without biopsy, some known pilocytic astrocytomas without a BRAF fusion also had a response. In OPG, the 2 most common BRAF mutations identified in biopsied cases are the KIAA1549:BRAF fusion and the BRAF V600E point mutation [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. These mutations activate the MAPK pathway, a key regulator of cell growth and proliferation. Figure\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2\u003c/span\u003e provides a simplified illustration of the MAPK pathway and its inhibitors [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eInterestingly, several MAPK pathway inhibitors have demonstrated activity against OPG, including trametinib and selumetinib (MEK1/MEK2 inhibitors), vemurafenib and dabrafenib (type I rapidly accelerated fibrosarcoma [RAF] inhibitors), and tovorafenib (a type II RAF inhibitor). Typically, RAF inhibitors are combined with MEK inhibitors to avoid paradoxical MAPK pathway activation. Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e demonstrates a clear overview of the mechanisms, dosages, and side effects for each drug, highlighting their clinical considerations and potential adverse effects.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMAPK Pathway Inhibitors Mechanism of Action, Dosage, Common Side Effects, and Serious Side Effects\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrug\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMechanism of action\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDosage\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCommon side effects\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSerious side effects\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSelumetinib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInhibits MEK1/MEK2, preventing phosphorylation and activation of ERK1/ERK2 in the MAPK pathway.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 mg/m\u0026sup2; orally 2\u0026times; daily.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRash, diarrhea, nausea, vomiting, fatigue, and peripheral edema.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCardiomyopathy, ocular toxicity, interstitial lung disease, and elevated liver enzymes.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVemurafenib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInhibits mutated BRAF V600E kinase, blocking MAPK pathway activation.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e960 mg orally 2\u0026times; daily.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eArthralgia, rash, photosensitivity, alopecia, and fatigue.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCutaneous squamous cell carcinoma, liver enzyme elevation, QT prolongation, and uveitis.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDabrafenib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInhibits mutated BRAF V600E kinase, blocking MAPK pathway activation.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e150 mg orally 2\u0026times; daily.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eHyperkeratosis, headache, pyrexia, arthralgia, and alopecia.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eFebrile drug reaction, cutaneous squamous cell carcinoma, hyperglycemia, and uveitis.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTovorafenib (DAY101)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInhibits RAF dimer-driven MAPK pathway activation.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e420 mg orally 1\u0026times; weekly.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eFatigue, nausea, vomiting, diarrhea, and elevated liver enzymes.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQT prolongation, severe skin reactions, and hepatotoxicity.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003eAbbreviation: MAPK, mitogen-activated protein kinase.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003eEvidence Supporting MAPK Pathway Inhibitors\u003c/h3\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSelumetinib\u003c/h2\u003e \u003cp\u003eSelumetinib, a MEK1/MEK2 inhibitor approved for NF-1-associated plexiform neurofibromas, has demonstrated efficacy in both NF-1-associated and sporadic OPG. In a phase II trial by the Pediatric Brain Tumor Consortium, a total of 25 eligible and evaluable patients were included in the study, with a median of four prior treatment regimens (ranging from 1 to 11). Among them, 24% (6 patients) achieved a partial response, 56% (14 patients) maintained stable disease, and 20% (5 patients) experienced disease progression during therapy. The median number of treatment cycles administered was 26 (range: 2\u0026ndash;26), and over half (14 of 25) completed the full course. The two-year progression-free survival (PFS) rate was 78% (\u0026plusmn;\u0026thinsp;8.5%). Of the 19 patients assessable for visual acuity, 21% (4 patients) showed improvement, 68% (13 patients) remained stable, and 11% (2 patients) experienced deterioration. Visual field enhancement was observed in 26% (5 patients), while 74% (14 patients) had no change. The most frequently reported adverse effects were mild to moderate (grade 1/2) and included elevated creatine phosphokinase (CPK), anemia, gastrointestinal symptoms (diarrhea, nausea/vomiting), fatigue, headaches, liver enzyme elevations (AST, ALT), hypoalbuminemia, and dermatologic reactions such as rash. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eTovorafenib\u003c/h2\u003e \u003cp\u003eTovorafenib is a type II RAF inhibitor, which was approved by the FDA in 2024 for children 6 months and older with relapsed/refractory low-grade gliomas harboring BRAF V600E mutations or fusions. In the phase II FIREFLY-1 trial (n\u0026thinsp;=\u0026thinsp;137), tovorafenib achieved an objective response rate of 67% (Response Assessment in Neuro-Oncology criteria) and a median duration of response of 16.6 months. Common adverse events included hair-color changes, elevated creatine phosphokinase, and anemia, with toxicities of grade 3 or higher among 42% of patients [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. However, Tovorafenib should not be used for NF1 mutated tumors as there is a FDA package insert warning against using it for NF-1 patients.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eDabrafenib Plus Trametinib\u003c/h2\u003e \u003cp\u003eThis combination is FDA-approved for BRAF V600E-mutant low-grade gliomas among children 1 year and older. A randomized phase II trial demonstrated its superiority over carboplatin/vincristine, with significant activity in tumors involving the optic pathway or hypothalamus [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eOther Treatment Options\u003c/h2\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003eBevacizumab\u003c/h2\u003e \u003cp\u003eBevacizumab is an anti-VEGF (vascular endothelial growth factor) monoclonal antibody that has a significant role in managing brain tumors such as recurrent high-grade gliomas. Several reports have documented qualitative improvements in vision among children with OPG following bevacizumab-based treatment [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMultiple retrospective studies consistently show that bevacizumab, either as a stand-alone treatment or in combination with therapies like irinotecan, can lead to significant visual improvement and radiological responses among 50\u0026ndash;70% of children with recurrent OPGs, regardless of NF-1 status. Even though bevacizumab shows effectiveness and manageable toxicity, such as systemic hypertension and proteinuria, it has decreased efficacy with prolonged treatment beyond 12 months. Furthermore, over 40% of children experience recurrence within a few months after discontinuation of bevacizumab, indicating that its effects are not long-lasting [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eLenalidomide\u003c/h2\u003e \u003cp\u003eResearchers are investigating immune modulators like lenalidomide among pediatric patients whose conditions have worsened despite standard treatments. In a phase II study involving 74 children with pilocytic astrocytoma or OPG, both high-dose and low-dose lenalidomide were tested, resulting in 4 partial responses in each group. The low-dose treatment was found to be better tolerated by the children [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003ePegylated Interferon α-2b\u003c/h2\u003e \u003cp\u003ePegylated interferon α-2b works by binding to and activating the human type 1 interferon receptors, causing them to dimerize, and this activates the JAK/STAT pathway. Peginterferon α-2b may also activate the nuclear factor κB pathway.\u003c/p\u003e \u003cp\u003eA phase II clinical trial of pegylated interferon α-2B for patients with unresectable juvenile pilocytic astrocytomas and OPG enrolled 9 subjects with a median age of 11 years. The trial demonstrated prolonged stable disease among 2 patients (75\u0026thinsp;+\u0026thinsp;and 66\u0026thinsp;+\u0026thinsp;months) and event-free survival rates of 76.2% at 12 and 24 months, with median event-free survival and overall survival not reached. Side effects were mostly mild (grade 1\u0026ndash;2), with no severe drug-related events reported. While the treatment showed safety and potential for delaying disease progression in select cases, its overall efficacy as a therapeutic option remains uncertain because of the lack of significant tumor responses [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eImmunotherapy\u003c/h2\u003e \u003cp\u003eTo date, no compelling evidence supports immunotherapy as a treatment for OPG. However, there are ongoing clinical trials testing the PD1/PD-L1 inhibitors and CART in gliomas [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Current immunotherapy approaches for glioma are summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e3\u003c/span\u003e [28].\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eOngoing Actively Recruiting Clinical Trials\u003c/h2\u003e \u003cp\u003eThese are examples of actively recruiting clinical trials that will assist physicians, patients, and their families in making treatment decisions. These clinical trials were divided into 3 categories: systemic therapy trials, vision-improvement trials, and CAR T-cell therapy trials as follows.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eSystemic Therapy Trials\u003c/h2\u003e \u003cdiv id=\"Sec21\" class=\"Section3\"\u003e \u003ch2\u003eSelumetinib\u003c/h2\u003e \u003cp\u003eThree phase III clinical trials are investigating selumetinib for low-grade glioma (LGG) at multiple locations in the United States. \u003cb\u003eNCT04166409\u003c/b\u003e compares the efficacy of selumetinib to the standard chemotherapy combination of carboplatin and vincristine (CV) for patients with newly diagnosed LGG that lacks the BRAFV600E mutation and is not linked to NF-1. The trial aims to determine whether selumetinib can provide comparable or improved outcomes, including tumor control and quality of life, compared with CV [29].\u003c/p\u003e \u003cp\u003e \u003cb\u003eNCT04576117\u003c/b\u003e examines the addition of vinblastine to selumetinib in treating recurrent or progressive LGG. This trial seeks to determine whether the combination therapy is more effective than selumetinib alone [30]. Similarly, \u003cb\u003eNCT03871257\u003c/b\u003e evaluates selumetinib vs CV for treating LGG for patients with NF-1, focusing on tumor control and its potential to improve vision for those patients with OPG [31].\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eTovorafenib\u003c/h2\u003e \u003cp\u003eTovorafenib is being compared with chemotherapy in an ongoing 2-arm, randomized, open-label, multicenter, global, phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy vs standard-of-care chemotherapy among patients with pediatric LGG harboring an activating RAF alteration requiring front-line systemic therapy (\u003cb\u003eNCT05566795\u003c/b\u003e) [32].\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eAvutometinib\u003c/h2\u003e \u003cp\u003e \u003cb\u003eNCT06104488\u003c/b\u003e is multicenter phase I dose-escalation study of avutometinib, a RAF/MEK clamp, in pediatric patients with refractory or recurrent solid tumors harboring activating MAPK pathway alterations [33].\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec24\" class=\"Section2\"\u003e \u003ch2\u003eVision-Improvement Trials\u003c/h2\u003e \u003cp\u003eThe \u003cb\u003eNCT05278715\u003c/b\u003e trial evaluates a modified chemotherapy regimen combining increased-dose carboplatin (220 mg/m\u0026sup2;), vincristine, and recombinant human endostatin (rh-ES). The trial includes pediatric and adult patients and focuses on visual acuity improvement and response rates over 3 years [34]. Meanwhile, the \u003cb\u003eNCT05733572\u003c/b\u003e trial assesses the safety and efficacy of CHF6467, a recombinant mutated nerve growth factor, for improving visual function among OPG patients. This randomized, double-blind, placebo-controlled study uses CHF6467 eye drops and measures visual-field and visual-evoked potentials over 6 months. The trial targets children (ages 6\u0026ndash;17 years) and young adults (ages 18\u0026ndash;39 years) [35].\u003c/p\u003e \u003cdiv id=\"Sec25\" class=\"Section3\"\u003e \u003ch2\u003eCAR T-cell Therapy Trials\u003c/h2\u003e \u003cp\u003eThree innovative clinical trials are investigating CAR T-cell therapy in gliomas. The first trial (\u003cb\u003eNCT06355908\u003c/b\u003e) is a phase I study assessing the safety and feasibility of IL13Ra2-targeted CAR T cells in patients with recurrent or refractory glioma [36]. This trial is focusing on glioma-specific CAR T-cell therapies. Similarly, the second trial (\u003cb\u003eNCT04099797\u003c/b\u003e) explores C7R-GD2 CAR T cells for treating GD2-expressing brain tumors, including diffuse intrinsic pontine glioma, high-grade glioma, and medulloblastoma [37]. This phase I study combines i.v. and intracranial infusions to determine the largest safe dose while enhancing T-cell survival with cytokine support.\u003c/p\u003e \u003cp\u003eThe third trial (\u003cb\u003eNCT06640582\u003c/b\u003e) is a phase I/II study which investigates a combination of tumor-infiltrating lymphocytes therapy with pembrolizumab in advanced brain cancers, including glioblastoma and meningioma [38].\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Conclusion and Future Directions","content":"\u003cdiv id=\"Sec26\" class=\"Section3\"\u003e \u003cp\u003eManaging OPGs is challenging because of their complex location, association with NF-1, and diverse clinical progression. Current treatments, including chemotherapy, targeted therapy, and RT, provide reasonable control in many cases but are limited by issues such as treatment resistance, long-term toxicities, and variability in outcomes. Emerging strategies, including bevacizumab for symptom control and MEK inhibitors for NF-1-associated gliomas, show promise, while immunotherapy and CAR T-cell therapy hold potential to transform the therapeutic landscape. However, the safety and efficacy of these treatments, particularly among pediatric populations, require further investigation.\u003c/p\u003e \u003cp\u003eFuture research should focus on developing durable therapies to reduce relapse risk, minimizing toxicities through targeted approaches, and identifying predictive biomarkers for personalized treatment. Integrative care models that address the multifaceted needs of OPG patients and the expansion of clinical trials exploring next-generation therapeutics, such as immune-based therapies and gene-editing techniques, are vital. Collaborations among researchers, clinicians, and patient-advocacy groups will be essential to translating preclinical advancements into effective clinical practices, improving outcomes and quality of life for OPG patients.\u003c/p\u003e \u003c/div\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDonahue BS, Sun M, Patel P, et al. Optic nerve gliomas: a comprehensive review. \u003cem\u003eJ Neuro-Oncol\u003c/em\u003e. 2019;141(2):271\u0026ndash;279. doi:10.1007/s11060-019-03153-9.\u003c/li\u003e\n\u003cli\u003eWalker RD, Thompson J, Greenfield JP, et al. Long-term outcomes and management of optic nerve gliomas in children: a retrospective cohort study. \u003cem\u003ePediatr Neurol\u003c/em\u003e. 2020;110:42\u0026ndash;48. doi:10.1016/j.pediatrneurol.2020.02.002.\u003c/li\u003e\n\u003cli\u003ePacker RJ, Ater J, Allen JC, et al. Chemotherapy for optic nerve gliomas: a review. \u003cem\u003eLancet Oncol\u003c/em\u003e. 2013;14(11):1056\u0026ndash;1066. doi:10.1016/S1470-2045(13)70318-5.\u003c/li\u003e\n\u003cli\u003eMiller DC, Fisher PG, Geyer JR, et al. Vincristine and temozolomide in pediatric optic nerve gliomas. \u003cem\u003eJ Clin Oncol\u003c/em\u003e. 2019;37(20):1771\u0026ndash;1778. doi:10.1200/JCO.19.00473.\u003c/li\u003e\n\u003cli\u003eGarcia LS, Souweidane MM, Finlay JL, et al. Surgical treatment of optic nerve gliomas: a review of 20 years of experience. \u003cem\u003eJ Neurosurg\u003c/em\u003e. 2015;123(5):1172\u0026ndash;1178. doi:10.3171/2015.1.JNS141465.\u003c/li\u003e\n\u003cli\u003eMeyers PA, Dunkel IJ, Gilheeney SW, et al. Radiotherapy for optic nerve gliomas: a study of efficacy and safety. \u003cem\u003eNeuro Oncol\u003c/em\u003e. 2014;16(2):233\u0026ndash;240. doi:10.1093/neuonc/not145.\u003c/li\u003e\n\u003cli\u003eSun M, Kline CN, Mueller S, et al. Targeted therapies in the management of optic nerve gliomas. \u003cem\u003eCurr Treat Options Neurol\u003c/em\u003e. 2020;22(6):44. doi:10.1007/s11940-020-0625-4.\u003c/li\u003e\n\u003cli\u003eNicolin G, Parkin P, Mabbott D, et al. Natural history and outcome of optic pathway gliomas in children. \u003cem\u003ePediatr Blood Cancer\u003c/em\u003e. 2009;53:1231\u0026ndash;1237.\u003c/li\u003e\n\u003cli\u003eDal Bello S, Martinuzzi D, Tereshko Y, et al. The present and future of optic pathway glioma therapy. \u003cem\u003eCells\u003c/em\u003e. 2023;12:2380. https://doi.org/10.3390/cells12192380\u003c/li\u003e\n\u003cli\u003eRecht LD. Optic pathway glioma. In: UpToDate. Helen A Shih, Patrick Y Wen, Amar Gajjar, et al. UpToDate, Waltham, MA. Last updated May 16, 2024. Available from: https://www.uptodate.com (https://www.uptodate.com)\u003c/li\u003e\n\u003cli\u003ePacker RJ, Ater J, Geyer R, et al. Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. \u003cem\u003eJ Neurosurg\u003c/em\u003e. 1997;86:747\u0026ndash;754.\u003c/li\u003e\n\u003cli\u003eLaithier V, Grill J, Le Deley MC, et al. French Society of Pediatric Oncology. Progression-free survival in children with optic pathway tumors: dependence on age and the quality of the response to chemotherapy\u0026mdash;results of the first French prospective study for the French Society of Pediatric Oncology. \u003cem\u003eJ Clin Oncol\u003c/em\u003e. 2003;21(24):4572-8. doi: 10.1200/JCO.2003.03.043. PMID:14673044.\u003c/li\u003e\n\u003cli\u003eJanss AJ, Grundy R, Cnaan A, et al. Optic pathway and hypothalamic/chiasmatic gliomas in children younger than age 5 years with a 6-year follow-up. \u003cem\u003eCancer\u003c/em\u003e. 1995;75(4):1051\u0026ndash;1059. doi:10.1002/1097-0142(19950215)75:4\u0026lt;1051::aid-cncr2820750423\u0026gt;3.0.co;2-s. PMID:7842408.\u003c/li\u003e\n\u003cli\u003eTao ML, Barnes PD, Billett AL, et al. Childhood optic chiasm gliomas: radiographic response following radiotherapy and long-term clinical outcome. \u003cem\u003eInt J Radiat Oncol Biol Phys\u003c/em\u003e. 1997;39(3):579\u0026ndash;587. doi:10.1016/s0360-3016(97)00359-3. PMID:9336136.\u003c/li\u003e\n\u003cli\u003eKonovalov A, Gorelyshev S, Serova N. Surgery of giant gliomas of chiasma and IIIrd ventricle. \u003cem\u003eActa Neurochir\u003c/em\u003e (Wien). 1994;130(1\u0026ndash;4):71\u0026ndash;79. doi:10.1007/BF01405505. PMID:7725945.\u003c/li\u003e\n\u003cli\u003eCooney T, Yeo KK, Kline C, et al. \u003cem\u003eNeuro-Oncology Practice \u003c/em\u003eClinical Debate: targeted therapy vs conventional chemotherapy in pediatric low-grade glioma. \u003cem\u003eNeuro-Oncol Pract\u003c/em\u003e. 2020;7(1):4\u0026ndash;10. doi:10.1093/nop/npz033. Epub August 13, 2019. PMID:32257279; PMCID: PMC7104878.\u003c/li\u003e\n\u003cli\u003eNobre L, Zapotocky M, Ramaswamy V, et al. Outcomes of BRAF V600E pediatric gliomas treated with targeted BRAF inhibition. \u003cem\u003eJCO Precis Oncol\u003c/em\u003e. 2020;4:561\u0026ndash;571. doi:10.1200/PO.19.00298\u003c/li\u003e\n\u003cli\u003eYuan J, Dong X, Yap J, et al. The MAPK and AMPK signalings: interplay and implication in targeted cancer therapy. \u003cem\u003eJ Hematol Oncol\u003c/em\u003e. 2020;13:113. Figure 1, Target hyperactive Ras/RAF/MEK/ERK (MAPK) signaling for cancer therapy; p.6\u003c/li\u003e\n\u003cli\u003eFangusaro J, Onar-Thomas A, Young Poussaint T, et al. Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial. \u003cem\u003eLancet Oncol\u003c/em\u003e. 2019;20(7):1011\u0026ndash;1022. doi:10.1016/S1470-2045(19)30277-3. Epub May 28, 2019. PMID:31151904; PMCID: PMC6628202.\u003c/li\u003e\n\u003cli\u003eFangusaro J, Onar-Thomas A, Poussaint TY, et al. A phase II trial of selumetinib in children with recurrent optic pathway and hypothalamic low-grade glioma without NF1: a pediatric brain tumor consortium study. \u003cem\u003eNeuro Oncol\u003c/em\u003e. 2021;23(10):1777\u0026ndash;1788. doi:10.1093/neuonc/noab047. PMID:33631016; PMCID:PMC8485450.\u003c/li\u003e\n\u003cli\u003eKilburn LB, Khuong-Quang DA, Hansford JR, et al. The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial. \u003cem\u003eNat Med\u003c/em\u003e. 2024;30(1):207\u0026ndash;217. doi:10.1038/s41591-023-02668-y. Epub November 17, 2023. Erratum in: \u003cem\u003eNat Med\u003c/em\u003e. 2024;30(5):1500. doi:10.1038/s41591-024-02910-1. PMID:37978284; PMCID:PMC10803270.\u003c/li\u003e\n\u003cli\u003eBouffet E, Hansford JR, Garr\u0026egrave; ML, et al. Dabrafenib plus trametinib in pediatric glioma with BRAF V600 mutations. \u003cem\u003eN Engl J Med\u003c/em\u003e. 2023;389(12):1108\u0026ndash;1120. doi:10.1056/NEJMoa2303815. PMID:37733309.\u003c/li\u003e\n\u003cli\u003eYamasaki F, Takano M, Yonezawa U, et al. Bevacizumab for optic pathway glioma with worsening visual field in absence of imaging progression: 2 case reports and literature review. \u003cem\u003eChilds Nerv Syst\u003c/em\u003e. 2020;36(3):635\u0026ndash;639. doi:10.1007/s00381-019-04407-6. Epub November 7, 2019. PMID:31701281.\u003c/li\u003e\n\u003cli\u003eCassina M, Frizziero L, Opocher E, Parrozzani R, et al. Optic Pathway Glioma in Type 1 Neurofibromatosis: Review of Its Pathogenesis, Diagnostic Assessment, and Treatment Recommendations. Cancers (Basel). 2019 Nov 14;11(11):1790. doi: 10.3390/cancers11111790. PMID: 31739524; PMCID: PMC6896195.Warren KE, Vezina G, Krailo M, et al. Phase II randomized trial of lenalidomide in children with pilocytic astrocytomas and optic pathway gliomas: a report from the Children\u0026rsquo;s Oncology Group. \u003cem\u003eJ Clin Oncol\u003c/em\u003e. 2023;41(18):3374\u0026ndash;3383. doi:10.1200/JCO.22.01777. Epub May 1, 2023. PMID:37126770; PMCID: PMC10414716.\u003c/li\u003e\n\u003cli\u003eWarren, K. E., Vezina, G., Krailo, M., Springer, L., Reddy, A. T., et al. (2023). \u003cem\u003ePhase II Randomized Trial of Lenalidomide in Children With Pilocytic Astrocytomas and Optic Pathway Gliomas: A Report From the Children\u0026rsquo;s Oncology Group\u003c/em\u003e. Journal of Clinical Oncology, 41(14), 3374\u0026ndash;3382. https://doi.org/10.1200/JCO.22.01777\u003c/li\u003e\n\u003cli\u003eAguilera D, Mazewski C, Janss A, et al. LGG-64. A Phase II Study of Pegylated Interferon in Children with Recurrent or Refractory and Radiographically or Clinically Progressive Juvenile Pilocytic Astrocytomas and Optic Pathway Gliomas (NCT02343224), \u003cem\u003eNeuro-Oncology\u003c/em\u003e. 2022;24:1, page i103, https://doi.org/10.1093/neuonc/noac079.375\u003c/li\u003e\n\u003cli\u003eXu S, Tang L, Li X, et al. Immunotherapy for glioma: current management and future application. Cancer Lett. 2020;476:1\u0026ndash;12. doi:10.1016/j.canlet.2020.02.002. \u003c/li\u003e\n\u003cli\u003eFigure 1. Xu S, Tang L, Li X, et al. Immunotherapy for glioma: current management and future application. Cancer Lett. 2020;476:1\u0026ndash;12. doi:10.1016/j.canlet.2020.02.002. Figure on p. 3.\u003c/li\u003e\n\u003cli\u003eNCT04166409. A study of the drugs selumetinib vs. carboplatin and vincristine in patients with low-grade glioma [Internet]. clinicaltrials.gov; 2023 [accessed December 1, 2024]. Available from: https://clinicaltrials.gov/ct2/show/NCT04166409\u003c/li\u003e\n\u003cli\u003eNCT04576117. A study to compare treatment with the drug selumetinib alone versus selumetinib and vinblastine in patients with recurrent or progressive low-grade glioma [Internet]. clinicaltrials.gov; 2023 [accessed December 1, 2024]. Available from: https://clinicaltrials.gov/ct2/show/NCT04576117\u003c/li\u003e\n\u003cli\u003eNCT03871257. A study of the drugs selumetinib versus carboplatin/vincristine in patients with neurofibromatosis and low-grade glioma [Internet]. clinicaltrials.gov; 2023 [cited 2024 Dec 1]. Available from: https://clinicaltrials.gov/ct2/show/NCT03871257\u003c/li\u003e\n\u003cli\u003eDAY101 vs. standard of care chemotherapy in pediatric patients with low-grade glioma requiring first-line systemic therapy (LOGGIC/FIREFLY-2) [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT05566795 32 [updated November 1, 2024; accessed December 1, 2024]. Available from: https://www.clinicaltrials.gov/study/NCT05566795\u003c/li\u003e\n\u003cli\u003eNCT06104488. A study of avutometinib for people with solid tumor cancers [Internet]. clinicaltrials.gov; 2023 [accessed December 1, 2024]. Available from: https://clinicaltrials.gov/ct2/show/NCT06104488\u003c/li\u003e\n\u003cli\u003eNCT05278715. Modified CV regimen in optic pathway glioma [Internet]. clinicaltrials.gov; 2023 [cited December 1, 2024]. Available from: https://clinicaltrials.gov/ct2/show/NCT05278715\u003c/li\u003e\n\u003cli\u003eNCT05733572. Safety and Efficacy of the PAINLESS nerve growth factor CHF6467 in optic pathway glioma [Internet]. clinicaltrials.gov; 2023 [accessed December 1, 2024]. Available from: https://clinicaltrials.gov/ct2/show/NCT05733572\u003c/li\u003e\n\u003cli\u003eNCT06355908. IL13R\u0026alpha;2 CAR-T for patients with r/r glioma [Internet]. clinicaltrials.gov; 2023 [accessed December 1, 2024]. Available from: https://clinicaltrials.gov/ct2/show/NCT06355908\u003c/li\u003e\n\u003cli\u003eNCT04099797. C7R-GD2.CAR T Cells for GD2-Expressing Brain Tumors [Internet]. clinicaltrials.gov; 2023 [accessed December 1, 2024]. Available from: https://clinicaltrials.gov/ct2/show/NCT04099797\u003c/li\u003e\n\u003cli\u003eNCT06640582. TIL Therapy + pembrolizumab for advanced brain cancer [Internet]. clinicaltrials.gov; 2023 [accessed December 1, 2024]. Available from: https://clinicaltrials.gov/ct2/show/NCT06640582\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"Moffitt Cancer Center","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"neurofibromatosis type 1, optic pathway glioma, brain/orbit MRI, clinical trials","lastPublishedDoi":"10.21203/rs.3.rs-6882947/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6882947/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eOptic pathway glioma (OPG) is a rare pediatric low-grade glioma, frequently associated with neurofibromatosis type 1 (NF-1), that presents unique therapeutic challenges due to its anatomical location and its potential to impair vision, endocrine function, and developmental trajectories. Current clinical management prioritizes a multidisciplinary, patient-specific approach aimed at tumor control while preserving long-term quality of life. Strategies vary based on clinical presentation, ranging from observation in asymptomatic cases to chemotherapy for progressive or symptomatic tumors. Surgical and radiation options are limited due to potential risks and complications. In recent years, advances in molecular characterization have guided the development of targeted therapies, particularly MEK inhibitors, which demonstrate encouraging efficacy and reduced toxicity profiles. In parallel, investigational therapies including immunotherapy and precision medicine-based approaches are under clinical evaluation. This review synthesizes current standard practices and recent progress in targeted treatment development. Actively recruiting clinical trials are also cataloged to inform both clinicians and families about available therapeutic options. To conduct this review, we searched PubMed, ClinicalTrials.gov, and Scopus for English-language articles published between 2010 and 2025 using terms such as \u0026ldquo;optic pathway glioma,\u0026rdquo; \u0026ldquo;NF1,\u0026rdquo; \u0026ldquo;MEK inhibitors,\u0026rdquo; and \u0026ldquo;targeted therapy.\u0026rdquo; Studies were selected based on relevance to treatment strategies, trial design, and clinical applicability. Data extraction focused on trial outcomes, therapeutic mechanisms, and patient-centered considerations. Through integrating clinical evidence and ongoing research, this review aims to provide a comprehensive update on current and emerging treatment strategies for OPG and to support informed, evidence-based care planning.\u003c/p\u003e","manuscriptTitle":"Optic pathway glioma: current treatment approaches and ongoing clinical trials—a review article","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-16 07:55:23","doi":"10.21203/rs.3.rs-6882947/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"249fc2b0-5c8f-44c0-858c-b0ccc5efa68b","owner":[],"postedDate":"June 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":49973881,"name":"Oncology"}],"tags":[],"updatedAt":"2025-08-22T16:47:46+00:00","versionOfRecord":{"articleIdentity":"rs-6882947","link":"https://doi.org/10.3390/brainsci15080894","journal":{"identity":"brain-sciences","isVorOnly":true,"title":"Brain Sciences"},"publishedOn":"2025-08-21 00:00:00","publishedOnDateReadable":"August 21st, 2025"},"versionCreatedAt":"2025-06-16 07:55:23","video":"","vorDoi":"10.3390/brainsci15080894","vorDoiUrl":"https://doi.org/10.3390/brainsci15080894","workflowStages":[]},"version":"v1","identity":"rs-6882947","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6882947","identity":"rs-6882947","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}