Proton versus Photon Radiotherapy in Adults with Primary Brain Tumors Evaluating Functional Survival: A Phase 3 Randomized Controlled Trial Study Protocol (PRIDE)

Proton versus Photon Radiotherapy in Adults with Primary Brain Tumors Evaluating Functional Survival: A Phase 3 Randomized Controlled Trial Study Protocol (PRIDE) | 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 Method Article Proton versus Photon Radiotherapy in Adults with Primary Brain Tumors Evaluating Functional Survival: A Phase 3 Randomized Controlled Trial Study Protocol (PRIDE) Archya Dasgupta, Suman Ghosh, Abhishek Chatterjee, Sadhana Kannan, and 16 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6805126/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Radiation therapy (RT) plays a significant role in the multimodal management of primary brain tumors, improving oncological outcomes. However, despite advances such as Intensity-Modulated Radiation Therapy (IMRT), photon-based RT inevitably exposes normal organs to low-dose radiation, leading to long-term functional morbidities like cognitive decline, neuroendocrine dysfunction, auditory toxicity. These late effects are particularly concerning in patients with favorable prognoses and protracted survival. Proton beam therapy (PBT), owing to its unique physical properties, holds promise for better functional preservation, but robust clinical data in adults are lacking. Methods: The PRIDE study is a prospective, open-label, phase 3 randomized controlled trial enrolling adults aged 18–70 years undergoing focal cranial RT with conventional fractionation for primary brain tumors with expected survival >5 years at Tata Memorial Centre, Mumbai. Participants will be randomized 1:1 to receive either photon-IMRT (standard arm) or PBT (experimental arm), stratified by age, tumor type, proximity to the hypothalamic-pituitary axis, and radiation dose. The primary endpoint is 5-year functional survival, defined as survival without functional deterioration (neurocognitive decline, significant ototoxicity, new or worsening neuroendocrine dysfunction, neurological impairment, severe radio-necrosis, disease progression, or death). Secondary endpoints include patient-reported quality of life and health economic analysis. Statistical Analysis: Survival outcomes will be analyzed using Kaplan-Meier methods with log-rank test. Neurocognitive and quality-of-life data will be evaluated using linear mixed-effects and non-parametric tests. A total of 156 patients will be enrolled, accounting for 20% attrition, to detect a 25% absolute improvement in 5-year functional survival favoring PBT (65% vs 40%, HR 0.47, α=0.05, power=80%). An interim analysis has been planned using the O'Brien-Fleming rule after 50% of the events (n=28). Conclusion: This trial will provide level 1 evidence investigating the role of PBT in functional outcomes among adults with primary brain tumors, guiding future neuro-oncology practice. Ethics and Dissemination : The trial has been approved by the Institutional Ethics Committee of Tata Memorial Centre, Mumbai. Registration: The trial has been registered with the Clinical Trial Registry of India (CTRI/2025/03/082568) and Clinicaltrials.gov (study identifier NCT06831461). Oncology Proton Beam Therapy Brain Tumours Neurocognition Functional Survival Randomized Controlled Trial Figures Figure 1 Figure 2 Figure 3 INTRODUCTION Primary brain tumors account for approximately 2% of all malignancies, with 80% of these occurring in adults 1 . Radiation therapy (RT) plays a critical role in the multimodality management of primary brain tumors, contributing to improved local control and prolonged progression-free survival across a broad range of tumor types, making it an integral part of multimodal management 2 . However, despite advancements like Intensity-Modulated Radiation Therapy (IMRT), modern photon radiation is associated with unavoidable low-dose exposure to normal brain tissues. This can lead to several late side effects that impact the functionality of adult patients with brain tumors, such as cognitive impairment, endocrine dysfunction, and auditory impairment. Although some of the radiation-related side effects are often reversible with rehabilitation, they still contribute to economic toxicity and almost universally lead to a deterioration in overall quality of life (QoL). As the magnitude of late functional effects is dose-dependent, recent advancements in radiation therapy have aimed to increase precision, thereby minimizing damage to surrounding healthy tissues 3 . The efforts to reduce treatment-induced morbidities are of particular interest in patients diagnosed with tumors with good prognosis and, therefore, higher probability of survivorship 4 . Particle beam therapy, such as proton beam therapy (PBT), with its unique physical properties, including a finite range and sharp distal dose fall-off known as the Bragg peak, allows superior dose conformality and reduced total integral dose to OARs. The dose distribution comparing photon and proton therapy has been shown in a patient with right temporal IDH mutant glioma ( Figure 1 ). The corresponding dose-volume parameters demonstrating lower doses received by relevant organs at risk (eye, cochlea, hippocampus) are presented in Figure 2 . The increasing availability of PBT facilities offers an option for further reducing RT-induced late effects. While there is substantial dosimetric evidence supporting the benefits of PBT compared to photon therapy, clinical efficacy in functional preservation has been demonstrated primarily in pediatric populations 5,6 , particularly in the context of whole craniospinal irradiation (CSI). Studies have shown favorable neurocognitive and academic outcomes with PBT compared to photon therapy in children 7 . In adults, the evidence is limited to dosimetric studies, and the extent of its clinical benefit remains uncertain. Existing clinical and dose-modeling reports often used older passive scattering techniques, while newer technologies, such as pencil beam scanning, offer greater potential for functional sparing 8 . Overall, there is currently no high-quality, randomized data comparing the outcomes of proton versus photon therapy in adults with primary brain tumors. To address this knowledge gap, the current randomized controlled trial compares PBT with standard photon therapy, focusing on cognitive and functional preservation in adults undergoing focal cranial irradiation. STUDY METHODOLOGY A. Study design/ Population: This is an open-label, prospective, superiority, 2-arm, phase 3 randomized controlled trial. Patients will be screened from the neuro-radiation oncology clinic at Tata Memorial Centre, Mumbai. Patients aged 18 to 70 years who are planned for focal cranial radiotherapy for primary CNS tumors meeting eligibility criteria will be considered for the study. Indications for radiation will be as per standard institutional practice, primarily decided by histology, tumor grade, molecular features (as appropriate for selected histologies), type of tumor resection, and extent of disease. Patients with an expected life expectancy of more than 5 years, as per published literature and institutional data, will be considered eligible for the study. This will include but is not limited to the diagnosis of low-grade glial/ glioneural tumors, IDH-mutant grade 2/3 gliomas (astrocytoma and oligodendroglioma), ependymoma, meningioma, pituitary tumor, craniopharyngioma, schwannoma. In some instances, which are treated based on a radiological diagnosis (without needing a histopathological diagnosis), like schwannoma, meningioma, will be eligible for the study. The trial (protocol version 1.0) has been approved by the Institutional Ethics Committee of Tata Memorial Centre, Mumbai. The trial has been registered with the Clinical Trial Registry of India (CTRI/2025/03/082568, dated 18.03.2025) and Clinicaltrials.gov (study identifier NCT06831461, dated 18.02.2025). Inclusion criteria: Primary brain tumors Age at irradiation: 18 to 70 years Karnofsky Performance Status ≥ 60 Diagnosis (histopathological/ radiological) of primary brain tumor with an expected survival of >5 years (e.g., grade 2-3 diffuse glioma, low-grade glial/ glioneuronal tumors, ependymoma, meningioma, pituitary tumors, schwannoma, craniopharyngioma, etc.) Planned for focal cranial radiotherapy Informed consent taken Exclusion Criteria Re-irradiation Palliative radiotherapy Multifocal or multicentric disease Planned for whole brain irradiation or craniospinal irradiation Planned for hypo-fractionated or stereotactic radiotherapy B. Study intervention: After meeting study eligibility and discussion with patients and caregivers by the study investigators, consent forms will be served and accrued in the study once a signed consent form is obtained. Participants will be randomized in one of the two arms (standard arm or experimental arm) in a 1:1 ratio via computerized software using a permuted block design, accounting for the following stratification factors: Diagnosis of tumor type on histopathology/radiology (diffuse glioma vs. others) Age during radiation (18-39 vs ≥ 40 years) Proximity to the hypothalamic-pituitary axis (tumor within 1 cm vs > 1cm of hypothalamic-pituitary axis) Radiation dose (≤54 Gy vs > 54 Gy) Treatments : Patients in the standard arm will undergo focal cranial radiotherapy using photons (X-rays) with image guidance using IMRT, VMAT, or helical intensity-modulated techniques. The patients in the experimental arm will undergo focal radiotherapy to an equivalent dose using protons (Cobalt Gray Equivalent) with pencil beam scanning or volumetric modulated proton arc therapy. The radiation dose and volumes will be guided by tumor type and molecular features without any influence from the current study on radiation protocols. Baseline workup investigations for diagnosis and treatment plan will be undertaken per standard practice, including histopathological evaluation, molecular evaluation, blood analysis, and imaging with magnetic resonance imaging (MRI) brain tumor protocol. Patients will be simulated in a supine position and immobilized using head-neck thermoplastic masks fitted to a Universal Base Plate according to the institutional protocol. Radiation planning non-contrast computed tomography (NCCT) scan will be acquired from the top of the vertex to the clavicle with a slice thickness of 1.25-2.5 mm. Planning MRI of the brain will be done per institutional practice, including 3D sequences of T1-contrast, 3D T2-weighted propellor, 3D T2-FLAIR sequences, and additional sequences like FIESTA or CISS as indicated (for skull base targets) is needed within 4 weeks from starting radiation. Planning PET scans will be done in patients with tumor diagnoses of meningioma, schwannoma, and pituitary tumors as clinically indicated. The contouring of target volumes will be done by the radiation oncologists using registrations of appropriate planning imaging to delineate gross tumor volume (GTV), clinical target volume (CTV), and planning target volumes (PTV) as applicable for the tumor type without any influence of the study arm. Organs at risk (OAR) like the hippocampus, temporal lobes, amygdala, brainstem, optic nerves and optic chiasm, pituitary gland, cochlea, oral cavity, eye, lens, etc., will be contoured for the plan as per institutional practice. Dose prescriptions will be done as per standard practice. Typically, the target volume dose prescriptions currently for the common histologies likely to be included in the study are as follows: diffuse gliomas (55.8 Gy-59.4 Gy using 1.8 Gy per fraction depending upon subtype i.e., oligodendroglioma vs. astrocytoma); ependymoma (59.4 Gy using 1.8 Gy per fraction), meningioma (54 Gy to 60 Gy using 1.8/2 Gy per fraction depending upon grade, location, molecular features); craniopharyngioma, schwannoma (54 Gy in 30 fractions); circumscribed glioma, low-grade glioma (50 Gy to 54 Gy in 1.67/ 1.8 Gy depending upon location); pituitary tumors (45 Gy in 25 fractions). To avoid any potential bias from the study arm, the dose fractionation needs to be defined before randomization, which also serves as a stratification factor. The OAR tolerance will be used as per standard practice and existing literature. The radiation plan will be made in the Treatment Planning System (TPS) by designated medical physicists and reviewed by the responsible radiation oncologist. Given the diverse location of the target volumes for patients accrued in the study, no predefined dose-volume constraints are mandated. However, the principle of low as reasonably achievable (ALARA) will be followed by practicing reasonable dose-volume constraints as per current literature and institutional practice. As a part of quality assurance, the radiation target volume and plan will be individually reviewed in the radiation-planning review meeting, comprising radiation oncologists, medical physicists, neuroradiologists, and radiation therapy technologists. Treatment will be delivered on photon or proton facilities equipped with image guidance platforms. All patients will be reviewed on a weekly basis by radiation oncologists to monitor for acute radiation-related toxicities using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 scales. All toxicities occurring within 60 days from the completion of radiotherapy and directly ascribed from the radiation treatment will be labeled as acute radiation effects. Interval imaging and adaptive planning will be done as per standard practice in both study arms without any influence from the study participation. Chemotherapy (concurrent or adjuvant) will be given as indicated (IDH-mutant glioma). Follow-up : After completion of radiotherapy, patients will undergo scheduled regular clinical and radiological follow-ups as per standard practice without any influence from the study. The first imaging after radiation for IDH-mutant gliomas is done 1-month post-radiotherapy, before starting adjuvant chemotherapy, and after that during adjuvant chemotherapy and at the conclusion. Otherwise, for high-grade tumors (not planned for adjuvant chemotherapy) treated with radiation, the first imaging is done 1-2 months, while for low-grade and benign tumors, it is done 2-3 months after completion of radiotherapy. As per standard practice, after completing all scheduled treatments (including chemotherapy), patients will undergo scheduled clinical evaluation every 3-6 months for the initial 2 years and every 6 months after that. Institutional protocols include surveillance imaging every 6-12 months or as per clinical indication (during new symptoms), which will apply to the current study. Any disease recurrence or complications arising from treatments will be treated per standard practice and discussed in the multidisciplinary joint neuro-oncology clinic as required. Functional assessments: Neurocognitive evaluation using age-appropriate tests by psychologists will include the Wechsler Adult Intelligence Scale test, which provides the Full-Scale Intelligence Quotient (FSIQ) and other subdomains as the Verbal Quotient (VQ), Performance Quotient (PQ). Neurocognitive assessment will be done before starting radiotherapy (baseline), post-radiotherapy 6 months, 1 year, and annually after that. To evaluate the endocrine function, the pituitary profile will be tested, which includes thyroid-stimulating hormone, free T4, T3, insulin-like growth factor (IGF)-1, growth hormone (GH), estrogen, testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), adrenocorticotropic hormone (ACTH), cortisol, and prolactin levels. The auditory function will be tested using pure tone audiometry. Endocrinal and auditory assessments will be done before starting radiation and annually after that. Patient-reported outcomes will be recorded using the European Organisation For Research and Treatment of Cancer (EORTC) QLQ core (C-30) and brain (BN-20) modules for quality-of-life assessment before starting radiation, once during mid-radiotherapy (3 rd to 4 th week), at conclusion, 1-3 months after completion (during 1 st follow-up visit after radiotherapy), 6 months, 1 year after completion, and annually after that. The sleep and dream will be assessed through the PSQI and MADRE questionnaires, respectively. The time points of assessment will be similar to QOL assessments. All pre-radiation (baseline) investigations are required to be done within 1 month before the start of the radiotherapy. The study workflow has been summarized in Figure 3 . Oncological and toxicity assessments : The assessment of disease status and radiation-induced toxicity in the form of radio-necrosis will be done by serial clinical and imaging surveillance, as outlined earlier. In equivocal cases of radio-necrosis, additional imaging with amino acid PET will be done and discussed in the multidisciplinary joint neuro-oncology meeting. Disease progression will be defined by the response assessment in neuro-oncology (RANO) 2.0 criteria. C. Statistical considerations: The hypothesis of the study is Proton beam therapy (experimental arm) is superior in functional preservation compared to photon therapy (standard arm) in adults with primary brain tumours receiving focal radiotherapy with conventional fractionation. Outcome measures: The study's primary and secondary outcome measures of interest have been summarized in Table 1. The primary endpoint of the study is the 5-year rate of overall survival without functional deterioration (functional survival=fS), calculated from the date of randomization. An event concerning the primary endpoint will include (See Table 1 for definitions) Neurocognitive decline, CTCAE grade 2 ototoxicity, new neuroendocrine axis dysfunction or worsening of pre-existing dysfunction, neurological and functional impairment, CTCAE gr 3 radio-necrosis, disease progression, and all-cause mortality. Sample size calculation: The sample size calculation is based on the primary endpoint of functional survival at 5 years. The 5-year functional survival rate is considered to be 40% in photon radiotherapy (standard arm). To demonstrate the superiority of proton beam therapy, the 5-year functional survival needs to be 65% (hazard ratio 0.47, two-sided α=0.05, power=80%), 65 patients need to be randomized in each arm (35 and 21 events in the standard and experimental arms, respectively). Accounting for a 20% attrition rate, the final sample size will be 156. Statistical analysis: Primary endpoint: Functional survival will be tested using the Kaplan-Meier method, and differences between the treatment arms will be compared using the log-rank test. The date of randomization will be considered the baseline for survival analysis, and a p-value of 0.048 (two-sided) will be regarded as statistically significant during the final analysis. Patients lost to follow-up will be censored for the assessment of functional survival, while death from any cause will be considered as an event as defined in the functional survival (in either arm). Secondary and tertiary endpoints: The survival analysis of overall survival (OS) and progression-free survival (PFS) will be tested using the Kaplan-Meier method, and differences between the treatment arms will be compared using the log-rank test. The date of randomization will be considered the baseline, with the date of death considered an event for OS, while the date of radiological progression will be regarded as an event for PFS. Patients who are lost to follow-up will be censored. The slope of FSIQ and other domains of neurocognition between the two study arms at different time points will be compared using linear mixed-effect regression models. Endocrine and auditory function will be analyzed using the Wilcoxon Rank Sum test for numerical data and the Fisher’s Exact test or the chi-square test for categorical data, as applicable. Toxicity will be documented using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and compared between the groups using the Chi-square test or Fisher exact test as appropriate. Summary scores for QLQ-C30 and BN20 will be calculated from raw scores as per the EORTC scoring manual, ranging from 0 to 100, with 0 being the worst and 100 being the best possible score. Shapiro-Wilks normality test will be used to assess the normality of data, with data being considered skewed if p<0.05. For non-normally distributed data, related samples two-way Friedman test, the non-parametric equivalent of repeated measures analysis of variance will be used to analyze differences in paired summary scores at any time point compared to baseline. Cost-effectiveness analysis will be measured using the Markov model. The cost-benefit analysis will be done by accounting for the direct and indirect costs associated with radiation treatment, the cost of toxicity management, and survival outcomes. The sleep and dream scores will be calculated using the PSQI and MADRE questionnaires, with composite and the subdomains computed using the manual. The scores between the two treatment arms and other clinical factors will be compared using Mann Whitney U test and independent t-test as appropriate. Interim analysis: An interim analysis using the O'Brien-Fleming rule will be planned after 50% of the events (n=28), which is estimated to happen around 4.4 years from the start of accrual. To demonstrate the superiority of proton beam therapy over photon radiotherapy during interim analysis, the p-value is required to be <0.005, and if the trial continues after the interim analysis, the p-value for the final analysis will be 0.048. DISCUSSION Advancements in cancer-directed therapies have consistently improved disease-related outcomes. Patients with certain histologies (e.g., low-grade gliomas, meningiomas, craniopharyngioma, and pituitary tumors) exhibit prolonged survival, with 10-year survival rates ranging from 80-100% following multimodality treatment. These improved outcomes have encouraged researchers to focus more on functional preservation, particularly in long-term survivors. Recent progresses in radiation therapy have aimed to increase precision, thereby minimizing damage to surrounding healthy tissues 3 . The routine use of multiparametric imaging like magnetic resonance imaging (MRI) and positron emission tomography (PET) for target volume and organ-at-risk (OAR) delineation, volumetric modulation of radiation beam intensity, inverse planning algorithms with specific dosimetric objectives for targets and OARs, and three-dimensional image guidance during delivery now represent the standard of care in neuro-oncology practice. These refinements have been gradually incorporated into clinical practice, supported by evidence of both dosimetric and clinical benefits 4,9 . Particle therapy, such as proton beam therapy, has been available for clinical use in Western countries for several decades but is a relatively recent addition to the Indian healthcare system. The depth-dose distribution of a proton beam, characterized by the Bragg peak, offers a key advantage over conventional photon therapy by minimizing radiation exposure to surrounding healthy tissues. The Bragg peak allows reduced radiation exposure to tissues located upstream of the tumor and completely spares tissues downstream of the target. Along with its favorable physical properties, the technological aspects of proton therapy are also evolving. Intensity-modulated proton therapy (IMPT), using spot scanning, allows for dose painting and image guidance during delivery, increasing the accuracy of radiation delivery and potentially reducing the margins required for treatment 10,11 . Thus, modern proton therapy represents one of the most conformal radiation techniques currently available, offering the most optimal sparing of organs at risk. The hypothesis that PBT can reduce toxicity is based on the fact that the majority of radiation-induced long-term effects are deterministic, with a finite threshold, and the severity is dose-dependent. Although this hypothesis is primarily based on retrospective dosimetric correlations, the proof of concept comes from clinical investigations that have shown reduced late effects with better sparing of the OARs. However, despite the clear dosimetric advantages, proving that technological advancements translate into significant clinical benefits in terms of efficacy and long-term side effects has often been challenging. The key domains of radiation-induced functional toxicity impacting the QoL of adults with primary brain tumors, particularly in the context of focal irradiation, are discussed below. Long-term cognitive function in brain tumor survivors is a major concern in clinical practice. Cognitive decline in these patients is multifactorial, influenced by age, tumor location (especially in the temporal and frontal lobes), hydrocephalus, antiepileptic drugs, chemotherapy, and radiation dose to critical neural structures 12–17 . Radiotherapy has been associated with impairments in processing speed and executive function 18–20 , with the reported prevalence of cognitive deficits ranging from 19% to 83% in adult brain tumor patients 14,21 . The hypothesized mechanism for radiation-induced cognitive impairment involves the progressive depletion of neural stem cells in the hippocampus and dentate gyrus, regions critical for learning and memory 22,23 . Additionally, radiation-induced brain injury is linked to neuroinflammatory cascades, including disruption of the blood-brain barrier (BBB), decreased hippocampal neurogenesis, and increased astrocytic senescence 24 . Dosimetric studies have consistently shown that higher RT doses to the left temporal lobe, hippocampus, and thalamus correlate with declines in verbal memory, executive function, and processing speed 25–27 . High-precision conformal radiotherapy has been proven to improve neurocognitive outcomes in pediatric patients with low-grade glioma and benign tumors in a prospective randomized trial 4 . Even with proton beam therapy, studies have clinically meaningful differences in cognitive outcomes with sparing the left temporal lobe and hippocampus in childhood brain cancers 28 . However, most prospective data of cognition sparing still come from younger, more vulnerable populations, where preserving critical brain structures is particularly important due to ongoing neurodevelopment and neuroplasticity. In contrast, studies involving adult patients—such as the NOA-07 trial in adult medulloblastoma and other glioma cohorts—suggest that long-term neurocognitive function can remain relatively preserved after radiotherapy 29,30 . Evidence of proton therapy for preserving neurocognitive functioning in adults is limited to single-arm prospective studies, showing encouraging results 31 . Robust clinical evidence supporting cognitive preservation with proton therapy over IMRT remains lacking. A dosimetric modeling study from the Princess Margaret Cancer Centre estimated only modest improvements in verbal fluency 32 . Despite convincing dosimetric superiority, clinically meaningful cognitive benefits of proton therapy over photon therapy are yet to be firmly established. Endocrine dysfunction in brain tumor survivors is closely associated with the proximity of the tumor (or radiation target) to the hypothalamic-pituitary axis (HPA). The incidence of endocrine deficiencies increases with time since radiotherapy and the dose delivered to the HPA and decreases with older age at the time of treatment 33 . In tumors such as pituitary adenomas and craniopharyngiomas, endocrine dysfunction requiring long-term hormonal replacement is observed in over 80–90% of patients. However, hypopituitarism is also common in non-pituitary brain tumors, with reported incidences ranging from 41% to 66% in adult patients 34 . The analysis of endocrine outcomes from the current study will provide information related to the role of PBT in preserving endocrine dysfunction. Auditory dysfunction, particularly sensorineural hearing loss (SNHL), is an understudied late effect of cranial RT in adults. Most available data come from head and neck cancers, particularly nasopharyngeal carcinoma, where outcomes are confounded by concurrent chemotherapy and higher radiation doses, limiting applicability to primary brain tumors. Factors such as younger age at the time of RT and higher cochlear doses (>30-35 Gy) significantly increase the risk of SNHL in patients with primary CNS tumor 35,36 . In proton therapy, mean cochlear dose has also been linked to mild hearing loss at 24 months in NTCP modeling studies 8 . The risk of radiation-induced hearing impairment largely depends on tumor location, especially when involving the posterior fossa, sella, or basal temporal lobe. The only evidence of benefit of PBT in this context is a dose-modelling study by Dennis et al., which demonstrated that passive-scanning PBT reduced NTCP by 5-10% for the cochlea and 4% for the pituitary gland in adults with low-grade gliomas 37 . Proton beam therapy clearly offers superior dose conformity and delivers a lower total integral dose to surrounding tissues due to its physical properties. The assumption that PBT can reduce toxicity is supported by substantial evidence of a dose-response relationship for many radiation-induced toxicities. However, despite the dosimetric advantages of proton therapy, the extent of its clinical benefit in adult patients remains uncertain, especially in adults. Age at the time of radiation has been identified as one of the most important predictors of cognitive and endocrine outcomes 13,28 . The evidence gathered in the pediatric population for proton therapy should not be directly extrapolated to adult patients as the impact of neurocognitive decline post-radiation is often less pronounced in adults. Therefore, a randomized trial comparing standard-of-care IMRT with IMPT in adults receiving partial brain radiotherapy is highly desirable. Ongoing trials with similar designs often include a single histological diagnosis, such as low-grade glioma or cavernous hemangioma, providing high-quality evidence of PBT in the forthcoming years ( Table 2 ) 38,39 . However, we believe a basket trial including mixed histologies with good prognosis will facilitate recruitment and also offer an answer to the common endpoint of functional preservation, which is primarily influenced by factors such as patient age, tumor location, use of chemotherapy, and radiotherapy dose, leading to more generalized applicability of PBT in clinical practice. Since these variables will be incorporated as stratification factors during randomization, the results should remain interpretable and clinically meaningful. Post-radiation functional impairments are multifactorial, with several other factors besides radiation dose influencing outcomes. Reported rates of radiation-related toxicities with photon therapy vary widely due to confounding factors, making it difficult to establish a standard historical control as a comparator. Most studies have attempted to capture the differential benefit of proton therapy in specific functional domains, but we believe that each functional impairment—whether in cognition, hormonal balance, hearing, or performance status—constitutes a clinically meaningful event that impacts QoL. Therefore, we propose using a composite endpoint for efficacy analysis, a similar approach to that adopted in the ongoing IMPROVE-CODEL trial 40 . This approach allows for exploring the relevant benefits of proton therapy and accounts for toxicity and tumor control. Proton beam therapy (PBT) is a relatively expensive form of radiation therapy (RT), and concerns about its cost remain at the forefront 41 . The cost of proton therapy varies globally, impacting either the patient or the healthcare system. This emphasizes the need for a clear understanding of the clinical utility of proton therapy and its potential to offer meaningful benefits. Currently, along with cost, the availability of proton therapy is limited. However, the use of PBT is constantly increasing, with new facilities opening worldwide. As the technology matures, long-term costs relative to photon therapy may decrease as demand grows and the longer life cycle of PBT machines compared to linear accelerators becomes evident 11 . Conclusion The PRIDE study is an open-label, phase 3 randomized controlled trial designed to assess whether proton therapy offers superior neurological functional preservation compared to photon therapy in adults with primary brain tumours. Patients aged 18–70 years undergoing focal cranial radiotherapy with conventional fractionation are randomized to either the standard arm (IMRT) or the experimental arm (IMPT). The primary endpoint is the 5-year rate of overall survival without functional deterioration (functional survival). Secondary endpoints include specific domains of functional survival such as neurocognitive decline, ototoxicity, endocrine dysfunction, overall and progression-free survival, and quality of life. If proven superior, the trial will provide level 1 evidence supporting the clinical use of proton therapy in adults with supratentorial brain tumors and a favourable prognosis. Declarations Ethics approval and consent to participate The study is being conducted in accordance with ICMR (2017) “National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, International Conference on Harmonization Good Clinical Practice (ICH-GCP) guidelines, Good Clinical Practice and the principles of the Declaration of Helsinki. The study, including all the study-related documents, has obtained approval from the Ethics Committee prior to the enrolment of participants. The trial has been registered with the Clinical Trial Registry of India (CTRI/2025/03/082568 dated 18.03.2025) and Clinicaltrials.gov (study identifier NCT06831461 dated 18.02.2025). Consent for Publication: Not applicable. Conflict Of Interest (COI) All the study investigators declare no conflict of interest in the conduct or outcome of the study. Availability of data and materials Data will be provided upon reasonable request to the principal investigator, following the guidelines by the institutional ethics committee. Funding: The study is funded by an Intra-mural research grant (IRG) from Tata Memorial Centre. The funding agency had no role in study conduct, study design, or analysis. Author contributions: Study concept and design: Archya Dasgupta, Tejpal Gupta, Suman Ghosh Study conduct and data collection: All authors Statistical analysis: Sadhana Kannan, Archya Dasgupta, Tejpal Gupta, Writing manuscript and approval: All authors Funding acquisition: Archya Dasgupta Study administration: Archya Dasgupta Acknowledgments: We acknowledge the participants and their caregivers for participation in the study. References Miller KD, Ostrom QT, Kruchko C, et al. Brain and other central nervous system tumor statistics, 2021. CA: A Cancer Journal for Clinicians . 2021;71(5):381-406. doi:10.3322/caac.21693 Stieber VW, Mehta MP. Advances in Radiation Therapy for Brain Tumors. Neurologic Clinics . 2007;25(4):1005-1033. doi:10.1016/j.ncl.2007.07.005 Baumert BG, Norton IA, Lomax AJ, Davis JB. Dose conformation of intensity-modulated stereotactic photon beams, proton beams, and intensity-modulated proton beams for intracranial lesions. 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Predicting the risk of neurocognitive decline after brain irradiation in adult patients with a primary brain tumor. Neuro-Oncology . 2024;26(8):1467-1478. doi:10.1093/neuonc/noae035 Jalali R, Mallick I, Dutta D, et al. Factors Influencing Neurocognitive Outcomes in Young Patients With Benign and Low-Grade Brain Tumors Treated With Stereotactic Conformal Radiotherapy. International Journal of Radiation Oncology*Biology*Physics . 2010;77(4):974-979. doi:10.1016/j.ijrobp.2009.06.025 van Kessel E, Baumfalk AE, van Zandvoort MJE, Robe PA, Snijders TJ. Tumor-related neurocognitive dysfunction in patients with diffuse glioma: a systematic review of neurocognitive functioning prior to anti-tumor treatment. J Neurooncol . 2017;134(1):9-18. doi:10.1007/s11060-017-2503-z Merchant TE, Schreiber JE, Wu S, Lukose R, Xiong X, Gajjar A. Critical combinations of radiation dose and volume predict intelligence quotient and academic achievement scores after craniospinal irradiation in children with medulloblastoma. Int J Radiat Oncol Biol Phys . 2014;90(3):554-561. doi:10.1016/j.ijrobp.2014.06.058 Ruben JD, Dally M, Bailey M, Smith R, McLean CA, Fedele P. Cerebral radiation necrosis: incidence, outcomes, and risk factors with emphasis on radiation parameters and chemotherapy. Int J Radiat Oncol Biol Phys . 2006;65(2):499-508. doi:10.1016/j.ijrobp.2005.12.002 Habets EJJ, Hendriks EJ, Taphoorn MJB, et al. Association between tumor location and neurocognitive functioning using tumor localization maps. J Neurooncol . 2019;144(3):573-582. doi:10.1007/s11060-019-03259-z Haldbo-Classen L, Amidi A, Wu LM, et al. Long-term cognitive dysfunction after radiation therapy for primary brain tumors. Acta Oncologica . 2019;58(5):745-752. doi:10.1080/0284186X.2018.1557786 Douw L, Klein M, Fagel SS, et al. Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: long-term follow-up. Lancet Neurol . 2009;8(9):810-818. doi:10.1016/S1474-4422(09)70204-2 Surma-aho O, Niemelä M, Vilkki J, et al. Adverse long-term effects of brain radiotherapy in adult low-grade glioma patients. Neurology . 2001;56(10):1285-1290. doi:10.1212/wnl.56.10.1285 van Loon EMP, Heijenbrok-Kal MH, van Loon WS, et al. Assessment methods and prevalence of cognitive dysfunction in patients with low-grade glioma: A systematic review. J Rehabil Med . 2015;47(6):481-488. doi:10.2340/16501977-1975 Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ. Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci . 1999;2(3):260-265. doi:10.1038/6365 van Praag H, Schinder AF, Christie BR, Toni N, Palmer TD, Gage FH. Functional neurogenesis in the adult hippocampus. Nature . 2002;415(6875):1030-1034. doi:10.1038/4151030a Turnquist C, Harris BT, Harris CC. Radiation-induced brain injury: current concepts and therapeutic strategies targeting neuroinflammation. Neuro-Oncology Advances . 2020;2(1):vdaa057. doi:10.1093/noajnl/vdaa057 Gondi V, Hermann BP, Mehta MP, Tomé WA. Hippocampal Dosimetry Predicts Neurocognitive Function Impairment After Fractionated Stereotactic Radiotherapy for Benign or Low-Grade Adult Brain Tumors. International Journal of Radiation Oncology, Biology, Physics . 2013;85(2):348-354. doi:10.1016/j.ijrobp.2012.11.031 Jalali R, Maitre M, Gupta T, et al. Dose-Constraint Model to Predict Neuroendocrine Dysfunction in Young Patients With Brain Tumors: Data From a Prospective Study. Practical Radiation Oncology . 2019;9(4):e362-e371. doi:10.1016/j.prro.2019.02.011 Goda JS, Dutta D, Krishna U, et al. Hippocampal radiotherapy dose constraints for predicting long-term neurocognitive outcomes: mature data from a prospective trial in young patients with brain tumors. Neuro Oncol . 2020;22(11):1677-1685. doi:10.1093/neuonc/noaa076 Greenberger BA, Pulsifer MB, Ebb DH, et al. Clinical Outcomes and Late Endocrine, Neurocognitive, and Visual Profiles of Proton Radiation for Pediatric Low-Grade Gliomas. International Journal of Radiation Oncology*Biology*Physics . 2014;89(5):1060-1068. doi:10.1016/j.ijrobp.2014.04.053 Dirven L, Luerding R, Beier D, et al. Neurocognitive functioning and health-related quality of life in adult medulloblastoma patients: long-term outcomes of the NOA-07 study. J Neurooncol . 2020;148(1):117-130. doi:10.1007/s11060-020-03502-y Pertz M, Schlömer S, Seidel C, et al. Long-term neurocognitive function and quality of life after multimodal therapy in adult glioma patients: a prospective long-term follow-up. J Neurooncol . 2023;164(2):353-366. doi:10.1007/s11060-023-04419-y Dutz A, Agolli L, Bütof R, et al. Neurocognitive function and quality of life after proton beam therapy for brain tumour patients. Radiotherapy and Oncology . 2020;143:108-116. doi:10.1016/j.radonc.2019.12.024 Petruccelli M, Parent A, Holwell M, et al. Estimating Potential Benefits to Neurocognition with Proton Therapy in Adults with Brain Tumors. Int J Part Ther . 2023;9(4):261-268. doi:10.14338/IJPT-22-00024.1 Vatner RE, Niemierko A, Misra M, et al. Endocrine Deficiency As a Function of Radiation Dose to the Hypothalamus and Pituitary in Pediatric and Young Adult Patients With Brain Tumors. JCO . 2018;36(28):2854-2862. doi:10.1200/JCO.2018.78.1492 Agha A, Sherlock M, Brennan S, et al. Hypothalamic-Pituitary Dysfunction after Irradiation of Nonpituitary Brain Tumors in Adults. The Journal of Clinical Endocrinology & Metabolism . 2005;90(12):6355-6360. doi:10.1210/jc.2005-1525 Huang Y, Zhou H, An F, et al. The relevance of ototoxicity induced by radiotherapy. Radiat Oncol . 2023;18(1):95. doi:10.1186/s13014-023-02268-7 Gehin W, Chastagner P, Mansuy L, Bernier-Chastagner V. Dosimetric analysis of hearing loss after cranial radiation therapy in children: A single-institution study from the French national registry PediaRT. Radiotherapy and Oncology . 2024;197:110346. doi:10.1016/j.radonc.2024.110346 Dennis ER, Bussière MR, Niemierko A, et al. A Comparison of Critical Structure Dose and Toxicity Risks in Patients with Low Grade Gliomas Treated with IMRT versus Proton Radiation Therapy. Technol Cancer Res Treat . 2013;12(1):1-9. doi:10.7785/tcrt.2012.500276 Heggebø LC, Borgen IMH, Rylander H, et al. Investigating survival, quality of life and cognition in PROton versus photon therapy for IDH-mutated diffuse grade 2 and 3 GLIOmas (PRO-GLIO): a randomised controlled trial in Norway and Sweden. BMJ Open . 2023;13(3):e070071. doi:10.1136/bmjopen-2022-070071 Lesueur P, Clarisse B, Lequesne J, et al. Proton therapy versus conventional radiotherapy for the treatment of cavernous sinus benign meningioma, a randomized controlled phase III study protocol (COG-PROTON-01). BMC Cancer . 2024;24(1):1594. doi:10.1186/s12885-024-13353-9 Wick A, Sander A, Koch M, et al. Improvement of functional outcome for patients with newly diagnosed grade 2 or 3 gliomas with co-deletion of 1p/19q - IMPROVE CODEL: the NOA-18 trial. BMC Cancer . 2022;22(1):645. doi:10.1186/s12885-022-09720-z Kahan J, Martinez C, Tsien C. Critical Appraisal of Proton Therapy for Patients with Central Nervous System (CNS) Malignancies. Curr Treat Options in Oncol . 2023;24(8):988-1003. doi:10.1007/s11864-023-01097-w Tables Table 1: Objectives and endpoints of the study Study Objective To compare the clinical utility of proton therapy versus photon therapy in preservation of neurological functions in adult patients with brain tumours receiving focal radiotherapy. Study Endpoints Primary Endpoint 5-year rate of functional survival (overall survival without functional deterioration) defined as the time from randomization to any of the following events: Cognitive decline A drop of 10% from baseline (pre-radiotherapy) in the FSIQ or any sub-domains of the neurocognition test. CTCAE v.5 gr 2 ototoxicity Threshold shift of >25 dB averaged at 2 or more contiguous test frequencies in at least one ear, or profound bilateral loss (absolute threshold >80 dB HL at 2 kHz and above, or hearing loss limiting instrumental ADL, or needing a hearing aid or intervention. In patients with pre-existing hearing loss because of tumor location (e.g., acoustic neuroma) or as a comorbidity, a decline of hearing loss by one grade in the CTCAE scale is required to be considered as an event. Also, in some instances where radiation dose to the cochlea is clinically insignificant (e.g., high frontal, parietal location) and future development of hearing loss cannot be related to the radiotherapy (e.g., age-related or other cause assigned after detailed auditory evaluation by a specialist) will be reviewed by study investigators and will be not be defined as an event for the study. Endocrinal dysfunction: Significant decline in one or multiple pituitary axes and/or starting/increasing doses of hormone supplements. Neurological impairment A decrease in the NPS by 2 points or KPS by at least 30 points from pre-radiation status will be considered as an event. Fulfilling one of these criteria will be regarded as an event unless temporal causation is directly attributable to other non-neurological causes. CTCAE v.5 gr ≥3 radio-necrosis A disorder characterized by a necrotic process occurring in the brain and/or spinal cord causing severe symptoms; intravenous medical intervention indicated; excluding corticosteroid. Disease progression In cases of glioma, the progression of the disease will be defined by RANO 2.0 criteria, which integrate MRI changes, clinical findings, and changes in steroid use (54). All-cause mortality Death from disease progression or any other cause, including toxicity, will be considered as an event. Secondary Endpoints 1. Overall survival and Progression-free survival. 2. Radiation-induced acute toxicity (during and within 60 days of completion of radiotherapy, using CTCAE v.5). 3. Cumulative incidence of sub-domains of functional survival. 4. Quality of Life (patient-reported outcomes). 5. Post hoc analysis per stratification factors. Tertiary endpoints 1. Cost-effectiveness analysis. 2. Cost-benefit analysis. 3. Sleep scores using Pittsburg Sleep Quality Index (PSQI). 4. Dream analysis using the Mannheim Dream questionnaire (MADRE). Table 2: Ongoing randomized controlled trials of proton beam therapy in adults with primary brain tumors Study Population Sample size Arms Primary Endpoint Timeline NRG BN-005 ( NCT03180502) IDH mutant low-intermediate grade gliomas 120 IMPT vs IMRT Neurocognition Accrual completed in March 2024 PRO-GLIO ( NCT05190172) IDH mutant grade 2-3 gliomas 225 IMPT vs IMRT 2-year first intervention-free survival Expected accrual completion in 2027 COG-PROTON-01 ( NCT05895344) Grade 1 Cavernous sinus meningiomas 160 IMPT vs IMRT 5-year neurocognitive outcomes Expected completion in 2032 Current study (PRIDE) ( NCT06831461) Primary brain tumors with expected survival >5 years 156 VMAT vs IMPT 5-year functional survival (composite endpoint) Expected completion 2032 IMPT: Intensity-modulated proton therapy, IMRT: Intensity-modulated radiotherapy, VMAT: Volumetric modulated arc therapy Additional Declarations The authors declare potential competing interests as follows: None of the authors has any conflicts of interest to disclose. Supplementary Files PISandICFPRIDEstudy.pdf PRIDEstudyprotocolv1.0.pdf Cite Share Download PDF Status: Posted 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6805126","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Method Article","associatedPublications":[],"authors":[{"id":465471089,"identity":"20f6e995-5ffa-44b9-a67b-52e7382cdd02","order_by":0,"name":"Archya 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The orange, cyanide, and green regions denote the 95%, 50%, and 25% dose regions, demonstrating proton beam therapy associated with a lower dose spillage to the surrounding region (right cochlea, right eye, brainstem).\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-6805126/v1/bca24cef2553508835aa1025.png"},{"id":84337792,"identity":"857a66d7-c7f8-48ab-b0ca-96a3ecc5106a","added_by":"auto","created_at":"2025-06-10 18:02:25","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":183437,"visible":true,"origin":"","legend":"\u003cp\u003eThe dose-volume parameters for the above patient for the clinical target volume (demonstrating better coverage), right cochlea, right eye, and left hippocampus. Kindly note that proton beam therapy delivered no dose to the left hippocampus.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-6805126/v1/ac6ead224ecf49a33d1d6d89.png"},{"id":84337794,"identity":"2660708c-9b7c-4588-96a0-779c4a3f3475","added_by":"auto","created_at":"2025-06-10 18:02:25","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":209688,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic workflow of the study showing the scheduled assessments at different time points.\u003c/p\u003e","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-6805126/v1/b1a6d9808b9d3c085749e3a3.png"},{"id":84340738,"identity":"8524fc3a-8508-471e-b135-843989a44b19","added_by":"auto","created_at":"2025-06-10 18:26:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1754193,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6805126/v1/371eba47-3a65-465c-b984-4a2ae63e812b.pdf"},{"id":84338910,"identity":"d38fab58-956e-4387-967f-116717e9f46e","added_by":"auto","created_at":"2025-06-10 18:10:25","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":282948,"visible":true,"origin":"","legend":"","description":"","filename":"PISandICFPRIDEstudy.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6805126/v1/399188f96350eed7e8f376a3.pdf"},{"id":84337788,"identity":"557bdb57-c7ed-4dd2-8cde-b7611689b951","added_by":"auto","created_at":"2025-06-10 18:02:25","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":551134,"visible":true,"origin":"","legend":"","description":"","filename":"PRIDEstudyprotocolv1.0.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6805126/v1/21f497dee34ff216ddd419c5.pdf"}],"financialInterests":"The authors declare potential competing interests as follows: None of the authors has any conflicts of interest to disclose.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eProton versus Photon Radiotherapy in Adults with Primary Brain Tumors Evaluating Functional Survival: A Phase 3 Randomized Controlled Trial Study Protocol (PRIDE)\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003ePrimary brain tumors account for approximately 2% of all malignancies, with 80% of these occurring in adults\u003csup\u003e1\u003c/sup\u003e. Radiation therapy (RT) plays a critical role in the multimodality management of primary brain tumors, contributing to improved local control and prolonged progression-free survival across a broad range of tumor types, making it an integral part of multimodal management\u003csup\u003e2\u003c/sup\u003e. However, despite advancements like Intensity-Modulated Radiation Therapy (IMRT), modern photon radiation is associated with unavoidable low-dose exposure to normal brain tissues. This can lead to several late side effects that impact the functionality of adult patients with brain tumors, such as cognitive impairment, endocrine dysfunction, and auditory impairment. Although some of the radiation-related side effects are often reversible with rehabilitation, they still contribute to economic toxicity and almost universally lead to a deterioration in overall quality of life (QoL).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs the magnitude of late functional effects is dose-dependent, recent advancements in radiation therapy have aimed to increase precision, thereby minimizing damage to surrounding healthy tissues\u003csup\u003e3\u003c/sup\u003e. The efforts to reduce treatment-induced morbidities are of particular interest in patients diagnosed with tumors with good prognosis and, therefore, higher probability of survivorship\u003csup\u003e4\u003c/sup\u003e. Particle beam therapy, such as proton beam therapy (PBT), with its unique physical properties, including a finite range and sharp distal dose fall-off known as the Bragg peak, allows superior dose conformality and reduced total integral dose to OARs. The dose distribution comparing photon and proton therapy has been shown in a patient with right temporal IDH mutant glioma (\u003cstrong\u003eFigure 1\u003c/strong\u003e). The corresponding dose-volume parameters demonstrating lower doses received by relevant organs at risk (eye, cochlea, hippocampus) are presented in \u003cstrong\u003eFigure 2\u003c/strong\u003e. The increasing availability of PBT facilities offers an option for further reducing RT-induced late effects.\u003c/p\u003e\n\u003cp\u003eWhile there is substantial dosimetric evidence supporting the benefits of PBT compared to photon therapy, clinical efficacy in functional preservation has been demonstrated primarily in pediatric populations\u003csup\u003e5,6\u003c/sup\u003e, particularly in the context of whole craniospinal irradiation (CSI). Studies have shown favorable neurocognitive and academic outcomes with PBT compared to photon therapy in children\u003csup\u003e7\u003c/sup\u003e. In adults, the evidence is limited to dosimetric studies, and the extent of its clinical benefit remains uncertain. Existing clinical and dose-modeling reports often used older passive scattering techniques, while newer technologies, such as pencil beam scanning, offer greater potential for functional sparing\u003csup\u003e8\u003c/sup\u003e. Overall, there is currently no high-quality, randomized data comparing the outcomes of proton versus photon therapy in adults with primary brain tumors. To address this knowledge gap, the current randomized controlled trial compares PBT with standard photon therapy, focusing on cognitive and functional preservation in adults undergoing focal cranial irradiation.\u003c/p\u003e"},{"header":"STUDY METHODOLOGY","content":"\u003cp\u003e\u003cstrong\u003eA. Study design/ Population:\u0026nbsp;\u003c/strong\u003eThis is an open-label, prospective, superiority, 2-arm, phase 3 randomized controlled trial. Patients will be screened from the neuro-radiation oncology clinic at Tata Memorial Centre, Mumbai. Patients aged 18 to 70 years who are planned for focal cranial radiotherapy for primary CNS tumors meeting eligibility criteria will be considered for the study. Indications for radiation will be as per standard institutional practice, primarily decided by histology, tumor grade, molecular features (as appropriate for selected histologies), type of tumor resection, and extent of disease. Patients with an expected life expectancy of more than 5 years, as per published literature and institutional data, will be considered eligible for the study. This will include but is not limited to the diagnosis of low-grade glial/ glioneural tumors, IDH-mutant grade 2/3 gliomas (astrocytoma and oligodendroglioma), ependymoma, meningioma, pituitary tumor, craniopharyngioma, schwannoma. In some instances, which are treated based on a radiological diagnosis (without needing a histopathological diagnosis), like schwannoma, meningioma, will be eligible for the study. The trial (protocol version 1.0) has been approved by the Institutional Ethics Committee of Tata Memorial Centre, Mumbai. The trial has been registered with the Clinical Trial Registry of India (CTRI/2025/03/082568, dated 18.03.2025) and Clinicaltrials.gov (study identifier NCT06831461, dated 18.02.2025).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion criteria:\u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003ePrimary brain tumors\u003c/li\u003e\n \u003cli\u003eAge at irradiation: 18 to 70 years\u003c/li\u003e\n \u003cli\u003eKarnofsky Performance Status\u0026nbsp;\u0026ge; 60\u003c/li\u003e\n \u003cli\u003eDiagnosis (histopathological/ radiological) of primary brain tumor with an expected survival of \u0026gt;5 years (e.g., grade 2-3 diffuse glioma, low-grade glial/ glioneuronal tumors, ependymoma, meningioma, pituitary tumors, schwannoma, craniopharyngioma, etc.)\u003c/li\u003e\n \u003cli\u003ePlanned for focal cranial radiotherapy\u003c/li\u003e\n \u003cli\u003eInformed consent taken \u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion Criteria\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eRe-irradiation\u003c/li\u003e\n \u003cli\u003ePalliative radiotherapy\u003c/li\u003e\n \u003cli\u003eMultifocal or multicentric disease\u003c/li\u003e\n \u003cli\u003ePlanned for whole brain irradiation or craniospinal irradiation\u003c/li\u003e\n \u003cli\u003ePlanned for hypo-fractionated or stereotactic radiotherapy\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eB. Study intervention:\u0026nbsp;\u003c/strong\u003eAfter meeting study eligibility and discussion with patients and caregivers by the study investigators, consent forms will be served and accrued in the study once a signed consent form is obtained. Participants will be randomized in one of the two arms (standard arm or experimental arm) in a 1:1 ratio via computerized software using a permuted block design, accounting for the following stratification factors:\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eDiagnosis of tumor type on histopathology/radiology (diffuse glioma vs. others)\u003c/li\u003e\n \u003cli\u003eAge during radiation (18-39 vs \u0026ge; 40 years)\u003c/li\u003e\n \u003cli\u003eProximity to the hypothalamic-pituitary axis (tumor within 1 cm vs \u0026gt; 1cm of hypothalamic-pituitary axis)\u003c/li\u003e\n \u003cli\u003eRadiation dose (\u0026le;54 Gy vs \u0026gt; 54 Gy)\u0026nbsp;\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eTreatments\u003c/strong\u003e: Patients in the standard arm will undergo focal cranial radiotherapy using photons (X-rays) with image guidance using IMRT, VMAT, or helical intensity-modulated techniques. The patients in the experimental arm will undergo focal radiotherapy to an equivalent dose using protons (Cobalt Gray Equivalent) with pencil beam scanning or volumetric modulated proton arc therapy. The radiation dose and volumes will be guided by tumor type and molecular features without any influence from the current study on radiation protocols. Baseline workup investigations for diagnosis and treatment plan will be undertaken per standard practice, including histopathological evaluation, molecular evaluation, blood analysis, and imaging with magnetic resonance imaging (MRI) brain tumor protocol. Patients will be simulated in a supine position and immobilized using head-neck thermoplastic masks fitted to a Universal Base Plate according to the institutional protocol. Radiation planning non-contrast computed tomography (NCCT) scan will be acquired from the top of the vertex to the clavicle with a slice thickness of 1.25-2.5 mm. Planning MRI of the brain will be done per institutional practice, including 3D sequences of T1-contrast, 3D T2-weighted propellor, 3D T2-FLAIR sequences, and additional sequences like FIESTA or \u0026nbsp;CISS as indicated (for skull base targets) is needed within 4 weeks from starting radiation. Planning PET scans will be done in patients with tumor diagnoses of meningioma, schwannoma, and pituitary tumors as clinically indicated.\u003c/p\u003e\n\u003cp\u003eThe contouring of target volumes will be done by the radiation oncologists using registrations of appropriate planning imaging to delineate gross tumor volume (GTV), clinical target volume (CTV), and planning target volumes (PTV) as applicable for the tumor type without any influence of the study arm. Organs at risk (OAR) like the hippocampus, temporal lobes, amygdala, brainstem, optic nerves and optic chiasm, pituitary gland, cochlea, oral cavity, eye, lens, etc., will be contoured for the plan as per institutional practice. Dose prescriptions will be done as per standard practice. Typically, the target volume dose prescriptions currently for the common histologies likely to be included in the study are as follows: diffuse gliomas (55.8 Gy-59.4 Gy using 1.8 Gy per fraction depending upon subtype i.e., oligodendroglioma vs. astrocytoma); ependymoma (59.4 Gy using 1.8 Gy per fraction), meningioma (54 Gy to \u0026nbsp;60 Gy using 1.8/2 Gy per fraction depending upon grade, location, molecular features); craniopharyngioma, schwannoma (54 Gy in 30 fractions); circumscribed glioma, low-grade glioma (50 Gy to 54 Gy in 1.67/ 1.8 Gy depending upon location); pituitary tumors (45 Gy in 25 fractions). To avoid any potential bias from the study arm, the dose fractionation needs to be defined before randomization, which also serves as a stratification factor. The OAR tolerance will be used as per standard practice and existing literature. \u0026nbsp; The radiation plan will be made in the Treatment Planning System (TPS) by designated medical physicists and reviewed by the responsible radiation oncologist. Given the diverse location of the target volumes for patients accrued in the study, no predefined dose-volume constraints are mandated. However, the principle of low as reasonably achievable (ALARA) will be followed by practicing reasonable dose-volume constraints as per current literature and institutional practice. As a part of quality assurance, the radiation target volume and plan will be individually reviewed in the radiation-planning review meeting, comprising radiation oncologists, medical physicists, neuroradiologists, and radiation therapy technologists. \u0026nbsp; Treatment will be delivered on photon or proton facilities equipped with image guidance platforms. All patients will be reviewed on a weekly basis by radiation oncologists to monitor for acute radiation-related toxicities using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 scales. All toxicities occurring within 60 days from the completion of radiotherapy and directly ascribed from the radiation treatment will be labeled as acute radiation effects. Interval imaging and adaptive planning will be done as per standard practice in both study arms without any influence from the study participation. Chemotherapy (concurrent or adjuvant) will be given as indicated (IDH-mutant glioma).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFollow-up\u003c/strong\u003e: After completion of radiotherapy, patients will undergo scheduled regular clinical and radiological follow-ups as per standard practice without any influence from the study. The first imaging after radiation for IDH-mutant gliomas is done 1-month post-radiotherapy, before starting adjuvant chemotherapy, and after that during adjuvant chemotherapy and at the conclusion. Otherwise, for high-grade tumors (not planned for adjuvant chemotherapy) treated with radiation, the first imaging is done 1-2 months, while for low-grade and benign tumors, it is done 2-3 months after completion of radiotherapy. As per standard practice, after completing all scheduled treatments (including chemotherapy), patients will undergo scheduled clinical evaluation every 3-6 months for the initial 2 years and every 6 months after that. Institutional protocols include surveillance imaging every 6-12 months or as per clinical indication (during new symptoms), which will apply to the current study. Any disease recurrence or complications arising from treatments will be treated per standard practice and discussed in the multidisciplinary joint neuro-oncology clinic as required.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunctional assessments:\u0026nbsp;\u003c/strong\u003eNeurocognitive evaluation using age-appropriate tests by psychologists will include the Wechsler Adult Intelligence Scale test, which provides the Full-Scale Intelligence Quotient (FSIQ) and other subdomains as the Verbal Quotient (VQ), Performance Quotient (PQ). Neurocognitive assessment will be done before starting radiotherapy (baseline), post-radiotherapy 6 months, 1 year, and annually after that.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo evaluate the endocrine function, the pituitary profile will be tested, which includes thyroid-stimulating hormone, free T4, T3, \u0026nbsp;insulin-like growth factor (IGF)-1, growth hormone (GH), estrogen, testosterone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), adrenocorticotropic hormone (ACTH), cortisol, and prolactin levels. The auditory function will be tested using pure tone audiometry. Endocrinal and auditory assessments will be done before starting radiation and annually after that.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatient-reported outcomes will be recorded using the European Organisation For Research and Treatment of Cancer (EORTC) QLQ core (C-30) and brain (BN-20) modules for quality-of-life assessment before starting radiation, once during mid-radiotherapy (3\u003csup\u003erd\u003c/sup\u003e to 4\u003csup\u003eth\u003c/sup\u003e week), at conclusion, 1-3 months after completion (during 1\u003csup\u003est\u003c/sup\u003e follow-up visit after radiotherapy), 6 months, 1 year after completion, and annually after that. The sleep and dream will be assessed through the PSQI and MADRE questionnaires, respectively. The time points of assessment will be similar to QOL assessments. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll pre-radiation (baseline) investigations are required to be done within 1 month before the start of the radiotherapy. The study workflow has been summarized in \u003cstrong\u003eFigure 3\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOncological and toxicity assessments\u003c/strong\u003e: The assessment of disease status and radiation-induced toxicity in the form of radio-necrosis will be done by serial clinical and imaging surveillance, as outlined earlier. In equivocal cases of radio-necrosis, additional imaging with amino acid PET will be done and discussed in the multidisciplinary joint neuro-oncology meeting. Disease progression will be defined by the response assessment in neuro-oncology (RANO) 2.0 criteria.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eC. Statistical considerations:\u003c/strong\u003e The hypothesis of the study is Proton beam therapy (experimental arm) is superior in functional preservation compared to photon therapy (standard arm) in adults with primary brain tumours receiving focal radiotherapy with conventional fractionation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome measures:\u003c/strong\u003e The study\u0026apos;s primary and secondary outcome measures of interest have been summarized in \u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eThe primary endpoint of the study is the 5-year rate of overall survival without functional deterioration (functional survival=fS), calculated from the date of randomization. An event concerning the primary endpoint will include (See Table 1 for definitions) Neurocognitive decline, CTCAE grade \u003cimg width=\"12\" height=\"20\" src=\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAAwAAAAUCAMAAACOLiwjAAAAAXNSR0IArs4c6QAAADxQTFRFAAAAAAAAAAA6ADpmADqQOgAAOmaQZjoAZpC2kDoAkGY6kLbbtra2ttvb25Bm27aQ29v/2////9u2///bmdM2gwAAAAF0Uk5TAEDm2GYAAAAJcEhZcwAADsQAAA7EAZUrDhsAAAAZdEVYdFNvZnR3YXJlAE1pY3Jvc29mdCBPZmZpY2V/7TVxAAAAQUlEQVQoU2NgoBQI8wgiGcHHysyNxBXiYmTjReLzszNxCCD4QuwsMM0IGSQ9INNgCoR5kDSiOFqYkxEK4KaR5CkA6sQB2qMQntgAAAAASUVORK5CYII=\" alt=\"image\"\u003e2 ototoxicity, new neuroendocrine axis dysfunction or worsening of pre-existing dysfunction, neurological and functional impairment, CTCAE gr\u0026nbsp;\u003cimg width=\"12\" height=\"20\" src=\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAAwAAAAUCAMAAACOLiwjAAAAAXNSR0IArs4c6QAAADxQTFRFAAAAAAAAAAA6ADpmADqQOgAAOmaQZjoAZpC2kDoAkGY6kLbbtra2ttvb25Bm27aQ29v/2////9u2///bmdM2gwAAAAF0Uk5TAEDm2GYAAAAJcEhZcwAADsQAAA7EAZUrDhsAAAAZdEVYdFNvZnR3YXJlAE1pY3Jvc29mdCBPZmZpY2V/7TVxAAAAQUlEQVQoU2NgoBQI8wgiGcHHysyNxBXiYmTjReLzszNxCCD4QuwsMM0IGSQ9INNgCoR5kDSiOFqYkxEK4KaR5CkA6sQB2qMQntgAAAAASUVORK5CYII=\" alt=\"image\"\u003e3 radio-necrosis, disease progression, and all-cause mortality.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size calculation:\u0026nbsp;\u003c/strong\u003eThe sample size calculation is based on the primary endpoint of functional survival at 5 years. The 5-year functional survival rate is considered to be 40% in photon radiotherapy (standard arm). To demonstrate the superiority of proton beam therapy, the 5-year functional survival needs to be 65% (hazard ratio 0.47, two-sided \u0026alpha;=0.05, power=80%), 65 patients need to be randomized in each arm (35 and 21 events in the standard and experimental arms, respectively). Accounting for a 20% attrition rate, the final sample size will be 156.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis:\u003c/strong\u003e\u003c/p\u003e\n\u003cul class=\"decimal_type\" style=\"list-style-type: circle;\"\u003e\n \u003cli\u003e\u003cstrong\u003ePrimary endpoint:\u003c/strong\u003e Functional survival will be tested using the Kaplan-Meier method, and differences between the treatment arms will be compared using the log-rank test. The date of randomization will be considered the baseline for survival analysis, and a p-value of 0.048 (two-sided) will be regarded as statistically significant during the final analysis. Patients lost to follow-up will be censored for the assessment of functional survival, while death from any cause will be considered as an event as defined in the functional survival (in either arm).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eSecondary and tertiary endpoints:\u003c/strong\u003e The survival analysis of overall survival (OS) and progression-free survival (PFS) will be tested using the Kaplan-Meier method, and differences between the treatment arms will be compared using the log-rank test. The date of randomization will be considered the baseline, with the date of death considered an event for OS, while the date of radiological progression will be regarded as an event for PFS. Patients who are lost to follow-up will be censored. The slope of FSIQ and other domains of neurocognition between the two study arms at different time points will be compared using linear mixed-effect regression models. Endocrine and auditory function will be analyzed using the Wilcoxon Rank Sum test for numerical data and the Fisher\u0026rsquo;s Exact test or the chi-square test for categorical data, as applicable. Toxicity will be documented using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and compared between the groups using the Chi-square test or Fisher exact test as appropriate. Summary scores for QLQ-C30 and BN20 will be calculated from raw scores as per the EORTC scoring manual, ranging from 0 to 100, with 0 being the worst and 100 being the best possible score. Shapiro-Wilks normality test will be used to assess the normality of data, with data being considered skewed if p\u0026lt;0.05. For non-normally distributed data, related samples two-way Friedman test, the non-parametric equivalent of repeated measures analysis of variance will be used to analyze differences in paired summary scores at any time point compared to baseline. Cost-effectiveness analysis will be measured using the Markov model. The cost-benefit analysis will be done by accounting for the direct and indirect costs associated with radiation treatment, the cost of toxicity management, and survival outcomes. The sleep and dream scores will be calculated using the PSQI and MADRE questionnaires, with composite and the subdomains computed using the manual. The scores between the two treatment arms and other clinical factors will be compared using Mann Whitney U test and independent t-test as appropriate.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003e\u003cstrong\u003eInterim analysis:\u0026nbsp;\u003c/strong\u003eAn interim analysis using the O\u0026apos;Brien-Fleming rule will be planned after 50% of the events (n=28), which is estimated to happen around 4.4 years from the start of accrual. To demonstrate the superiority of proton beam therapy over photon radiotherapy during interim analysis, the p-value is required to be \u0026lt;0.005, and if the trial continues after the interim analysis, the p-value for the final analysis will be 0.048.\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eAdvancements in cancer-directed therapies have consistently improved disease-related outcomes. Patients with certain histologies (e.g., low-grade gliomas, meningiomas, craniopharyngioma, and pituitary tumors) exhibit prolonged survival, with 10-year survival rates ranging from 80-100% following multimodality treatment. These improved outcomes have encouraged researchers to focus more on functional preservation, particularly in long-term survivors. Recent progresses in radiation therapy have aimed to increase precision, thereby minimizing damage to surrounding healthy tissues\u003csup\u003e3\u003c/sup\u003e. The routine use of multiparametric imaging like magnetic resonance imaging (MRI) and positron emission tomography (PET) for target volume and organ-at-risk (OAR) delineation, volumetric modulation of radiation beam intensity, inverse planning algorithms with specific dosimetric objectives for targets and OARs, and three-dimensional image guidance during delivery now represent the standard of care in neuro-oncology practice. These refinements have been gradually incorporated into clinical practice, supported by evidence of both dosimetric and clinical benefits\u003csup\u003e4,9\u003c/sup\u003e.\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eParticle therapy, such as proton beam therapy, has been available for clinical use in Western countries for several decades but is a relatively recent addition to the Indian healthcare system. The depth-dose distribution of a proton beam, characterized by the Bragg peak, offers a key advantage over conventional photon therapy by minimizing radiation exposure to surrounding healthy tissues. The Bragg peak allows reduced radiation exposure to tissues located upstream of the tumor and completely spares tissues downstream of the target. Along with its favorable physical properties, the technological aspects of proton therapy are also evolving. Intensity-modulated proton therapy (IMPT), using spot scanning, allows for dose painting and image guidance during delivery, increasing the accuracy of radiation delivery and potentially reducing the margins required for treatment\u003csup\u003e10,11\u003c/sup\u003e. Thus, modern proton therapy represents one of the most conformal radiation techniques currently available, offering the most optimal sparing of organs at risk.\u003c/p\u003e\n\u003cp\u003eThe hypothesis that PBT can reduce toxicity is based on the fact that the majority of radiation-induced long-term effects are deterministic, with a finite threshold, and the severity is dose-dependent. Although this hypothesis is primarily based on retrospective dosimetric correlations, the proof of concept comes from clinical investigations that have shown reduced late effects with better sparing of the OARs. However, despite the clear dosimetric advantages, proving that technological advancements translate into significant clinical benefits in terms of efficacy and long-term side effects has often been challenging. The key domains of radiation-induced functional toxicity impacting the QoL of adults with primary brain tumors, particularly in the context of focal irradiation, are discussed below.\u003c/p\u003e\n\u003cp\u003eLong-term cognitive function in brain tumor survivors is a major concern in clinical practice. Cognitive decline in these patients is multifactorial, influenced by age, tumor location (especially in the temporal and frontal lobes), hydrocephalus, antiepileptic drugs, chemotherapy, and radiation dose to critical neural structures\u003csup\u003e12\u0026ndash;17\u003c/sup\u003e. Radiotherapy has been associated with impairments in processing speed and executive function\u003csup\u003e18\u0026ndash;20\u003c/sup\u003e, with the reported prevalence of cognitive deficits ranging from 19% to 83% in adult brain tumor patients\u003csup\u003e14,21\u003c/sup\u003e. The hypothesized mechanism for radiation-induced cognitive impairment involves the progressive depletion of neural stem cells in the hippocampus and dentate gyrus, regions critical for learning and memory\u003csup\u003e22,23\u003c/sup\u003e. Additionally, radiation-induced brain injury is linked to neuroinflammatory cascades, including disruption of the blood-brain barrier (BBB), decreased hippocampal neurogenesis, and increased astrocytic senescence\u003csup\u003e24\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eDosimetric studies have consistently shown that higher RT doses to the left temporal lobe, hippocampus, and thalamus correlate with declines in verbal memory, executive function, and processing speed\u003csup\u003e25\u0026ndash;27\u003c/sup\u003e. High-precision conformal radiotherapy has been proven to improve neurocognitive outcomes in pediatric patients with low-grade glioma and benign tumors in a prospective randomized trial\u003csup\u003e4\u003c/sup\u003e. Even with proton beam therapy, studies have clinically meaningful differences in cognitive outcomes with sparing the left temporal lobe and hippocampus in childhood brain cancers\u003csup\u003e28\u003c/sup\u003e. However, most prospective data of cognition sparing still come from younger, more vulnerable populations, where preserving critical brain structures is particularly important due to ongoing neurodevelopment and neuroplasticity. In contrast, studies involving adult patients\u0026mdash;such as the NOA-07 trial in adult medulloblastoma and other glioma cohorts\u0026mdash;suggest that long-term neurocognitive function can remain relatively preserved after radiotherapy\u0026nbsp;\u003csup\u003e29,30\u003c/sup\u003e. Evidence of proton therapy for preserving neurocognitive functioning in adults is limited to single-arm prospective studies, showing encouraging results\u003csup\u003e31\u003c/sup\u003e. Robust clinical evidence supporting cognitive preservation with proton therapy over IMRT remains lacking. A dosimetric modeling study from the Princess Margaret Cancer Centre estimated only modest improvements in verbal fluency\u003csup\u003e32\u003c/sup\u003e. Despite convincing dosimetric superiority, clinically meaningful cognitive benefits of proton therapy over photon therapy are yet to be firmly established.\u003c/p\u003e\n\u003cp\u003eEndocrine dysfunction in brain tumor survivors is closely associated with the proximity of the tumor (or radiation target) to the hypothalamic-pituitary axis (HPA). The incidence of endocrine deficiencies increases with time since radiotherapy and the dose delivered to the HPA and decreases with older age at the time of treatment\u003csup\u003e33\u003c/sup\u003e. In tumors such as pituitary adenomas and craniopharyngiomas, endocrine dysfunction requiring long-term hormonal replacement is observed in over 80\u0026ndash;90% of patients. However, hypopituitarism is also common in non-pituitary brain tumors, with reported incidences ranging from 41% to 66% in adult patients\u003csup\u003e34\u003c/sup\u003e. The analysis of endocrine outcomes from the current study will provide information related to the role of PBT in preserving endocrine dysfunction.\u003c/p\u003e\n\u003cp\u003eAuditory dysfunction, particularly sensorineural hearing loss (SNHL), is an understudied late effect of cranial RT in adults. Most available data come from head and neck cancers, particularly nasopharyngeal carcinoma, where outcomes are confounded by concurrent chemotherapy and higher radiation doses, limiting applicability to primary brain tumors. Factors such as younger age at the time of RT and higher cochlear doses (\u0026gt;30-35 Gy) significantly increase the risk of SNHL in patients with primary CNS tumor\u003csup\u003e35,36\u003c/sup\u003e. In proton therapy, mean cochlear dose has also been linked to mild hearing loss at 24 months in NTCP modeling studies\u003csup\u003e8\u003c/sup\u003e. The risk of radiation-induced hearing impairment largely depends on tumor location, especially when involving the posterior fossa, sella, or basal temporal lobe. The only evidence of benefit of PBT in this context is a dose-modelling study by Dennis et al., which demonstrated that passive-scanning PBT reduced NTCP by 5-10% for the cochlea and 4% for the pituitary gland in adults with low-grade gliomas\u003csup\u003e37\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eProton beam therapy clearly offers superior dose conformity and delivers a lower total integral dose to surrounding tissues due to its physical properties. The assumption that PBT can reduce toxicity is supported by substantial evidence of a dose-response relationship for many radiation-induced toxicities. However, despite the dosimetric advantages of proton therapy, the extent of its clinical benefit in adult patients remains uncertain, especially in adults. Age at the time of radiation has been identified as one of the most important predictors of cognitive and endocrine outcomes\u0026nbsp;\u003csup\u003e13,28\u003c/sup\u003e. The evidence gathered in the pediatric population for proton therapy should not be directly extrapolated to adult patients as the impact of neurocognitive decline post-radiation is often less pronounced in adults. Therefore, a randomized trial comparing standard-of-care IMRT with IMPT in adults receiving partial brain radiotherapy is highly desirable. Ongoing trials with similar designs often include a single histological diagnosis, such as low-grade glioma or cavernous hemangioma, providing high-quality evidence of PBT in the forthcoming years (\u003cstrong\u003eTable 2\u003c/strong\u003e)\u0026nbsp;\u003csup\u003e38,39\u003c/sup\u003e. However, we believe a basket trial including mixed histologies with good prognosis will facilitate recruitment and also offer an answer to the common endpoint of functional preservation, which is primarily influenced by factors such as patient age, tumor location, use of chemotherapy, and radiotherapy dose, leading to more generalized applicability of PBT in clinical practice. Since these variables will be incorporated as stratification factors during randomization, the results should remain interpretable and clinically meaningful.\u003c/p\u003e\n\u003cp\u003ePost-radiation functional impairments are multifactorial, with several other factors besides radiation dose influencing outcomes. Reported rates of radiation-related toxicities with photon therapy vary widely due to confounding factors, making it difficult to establish a standard historical control as a comparator. Most studies have attempted to capture the differential benefit of proton therapy in specific functional domains, but we believe that each functional impairment\u0026mdash;whether in cognition, hormonal balance, hearing, or performance status\u0026mdash;constitutes a clinically meaningful event that impacts QoL. Therefore, we propose using a composite endpoint for efficacy analysis, a similar approach to that adopted in the ongoing IMPROVE-CODEL trial\u003csup\u003e40\u003c/sup\u003e. This approach allows for exploring the relevant benefits of proton therapy and accounts for toxicity and tumor control.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eProton beam therapy (PBT) is a relatively expensive form of radiation therapy (RT), and concerns about its cost remain at the forefront\u003csup\u003e41\u003c/sup\u003e. The cost of proton therapy varies globally, impacting either the patient or the healthcare system. This emphasizes the need for a clear understanding of the clinical utility of proton therapy and its potential to offer meaningful benefits. Currently, along with cost, the availability of proton therapy is limited. However, the use of PBT is constantly increasing, with new facilities opening worldwide. As the technology matures, long-term costs relative to photon therapy may decrease as demand grows and the longer life cycle of PBT machines compared to linear accelerators becomes evident\u003csup\u003e11\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe PRIDE study is an open-label, phase 3 randomized controlled trial designed to assess whether proton therapy offers superior neurological functional preservation compared to photon therapy in adults with primary brain tumours. Patients aged 18\u0026ndash;70 years undergoing focal cranial radiotherapy with conventional fractionation are randomized to either the standard arm (IMRT) or the experimental arm (IMPT). The primary endpoint is the 5-year rate of overall survival without functional deterioration (functional survival). Secondary endpoints include specific domains of functional survival such as neurocognitive decline, ototoxicity, endocrine dysfunction, overall and progression-free survival, and quality of life. If proven superior, the trial will provide level 1 evidence supporting the clinical use of proton therapy in adults with supratentorial brain tumors and a favourable prognosis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study is being conducted in accordance with ICMR (2017) \u0026ldquo;National Ethical Guidelines for Biomedical and Health Research Involving Human Participants, International Conference on Harmonization Good Clinical Practice (ICH-GCP) guidelines, Good Clinical Practice and the principles of the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003eThe study, including all the study-related documents, has obtained approval from the Ethics Committee prior to the enrolment of participants. The trial has been registered with the Clinical Trial Registry of India (CTRI/2025/03/082568 dated 18.03.2025) and Clinicaltrials.gov (study identifier NCT06831461 dated 18.02.2025).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication:\u0026nbsp;\u003c/strong\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict Of Interest (COI)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the study investigators declare no conflict of interest in the conduct or outcome of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData will be provided upon reasonable request to the principal investigator, following the guidelines by the institutional ethics committee.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThe study is funded by an Intra-mural research grant (IRG) from Tata Memorial Centre.\u0026nbsp;The funding agency had no role in study conduct, study design, or analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy concept and design:\u0026nbsp;\u003c/strong\u003eArchya Dasgupta, Tejpal Gupta, Suman Ghosh\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy conduct and data collection:\u0026nbsp;\u003c/strong\u003eAll authors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis:\u0026nbsp;\u003c/strong\u003eSadhana Kannan,\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eArchya Dasgupta, Tejpal Gupta,\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWriting manuscript and approval:\u0026nbsp;\u003c/strong\u003eAll authors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding acquisition:\u0026nbsp;\u003c/strong\u003eArchya Dasgupta\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStudy administration:\u0026nbsp;\u003c/strong\u003eArchya Dasgupta\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eWe acknowledge the participants and their caregivers for participation in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMiller KD, Ostrom QT, Kruchko C, et al. 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Investigating survival, quality of life and cognition in PROton versus photon therapy for IDH-mutated diffuse grade 2 and 3 GLIOmas (PRO-GLIO): a randomised controlled trial in Norway and Sweden. \u003cem\u003eBMJ Open\u003c/em\u003e. 2023;13(3):e070071. doi:10.1136/bmjopen-2022-070071\u003c/li\u003e\n\u003cli\u003eLesueur P, Clarisse B, Lequesne J, et al. Proton therapy versus conventional radiotherapy for the treatment of cavernous sinus benign meningioma, a randomized controlled phase III study protocol (COG-PROTON-01). \u003cem\u003eBMC Cancer\u003c/em\u003e. 2024;24(1):1594. doi:10.1186/s12885-024-13353-9\u003c/li\u003e\n\u003cli\u003eWick A, Sander A, Koch M, et al. Improvement of functional outcome for patients with newly diagnosed grade 2 or 3 gliomas with co-deletion of 1p/19q - IMPROVE CODEL: the NOA-18 trial. \u003cem\u003eBMC Cancer\u003c/em\u003e. 2022;22(1):645. doi:10.1186/s12885-022-09720-z\u003c/li\u003e\n\u003cli\u003eKahan J, Martinez C, Tsien C. Critical Appraisal of Proton Therapy for Patients with Central Nervous System (CNS) Malignancies. \u003cem\u003eCurr Treat Options in Oncol\u003c/em\u003e. 2023;24(8):988-1003. doi:10.1007/s11864-023-01097-w\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1: Objectives and endpoints of the study\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eStudy Objective\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 469px;\"\u003e\n \u003cp\u003eTo compare the clinical utility of proton therapy versus photon therapy in preservation of neurological functions in adult patients with brain tumours receiving focal radiotherapy.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy Endpoints\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrimary Endpoint\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 469px;\"\u003e\n \u003cp\u003e5-year rate of functional survival (overall survival without functional deterioration) defined as the time from randomization to any of the following events:\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003col\u003e\n \u003cli\u003eCognitive decline\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 469px;\"\u003e\n \u003cp\u003eA drop of 10% from baseline (pre-radiotherapy) in the FSIQ or any sub-domains of the neurocognition test.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003col start=\"2\"\u003e\n \u003cli\u003eCTCAE v.5 gr \u003cimg width=\"12\" height=\"20\" src=\"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAAwAAAAUCAMAAACOLiwjAAAAAXNSR0IArs4c6QAAADxQTFRFAAAAAAAAAAA6ADpmADqQOgAAOmaQZjoAZpC2kDoAkGY6kLbbtra2ttvb25Bm27aQ29v/2////9u2///bmdM2gwAAAAF0Uk5TAEDm2GYAAAAJcEhZcwAADsQAAA7EAZUrDhsAAAAZdEVYdFNvZnR3YXJlAE1pY3Jvc29mdCBPZmZpY2V/7TVxAAAAQUlEQVQoU2NgoBQI8wgiGcHHysyNxBXiYmTjReLzszNxCCD4QuwsMM0IGSQ9INNgCoR5kDSiOFqYkxEK4KaR5CkA6sQB2qMQntgAAAAASUVORK5CYII=\" alt=\"image\"\u003e2 ototoxicity\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 469px;\"\u003e\n \u003cp\u003eThreshold shift of \u0026gt;25 dB averaged at 2 or more contiguous test frequencies in at least one ear, or profound bilateral loss (absolute threshold \u0026gt;80 dB HL at 2 kHz and above, or hearing loss limiting instrumental ADL, or needing a hearing aid or intervention.\u003c/p\u003e\n \u003cp\u003eIn patients with pre-existing hearing loss because of tumor location (e.g., acoustic neuroma) or as a comorbidity, a decline of hearing loss by one grade in the CTCAE scale is required to be considered as an event. Also, in some instances where radiation dose to the cochlea is clinically insignificant (e.g., high frontal, parietal location) and future development of hearing loss cannot be related to the radiotherapy (e.g., age-related or other cause assigned after detailed auditory evaluation by a specialist) will be reviewed by study investigators and will be not be defined as an event for the study.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003col start=\"3\"\u003e\n \u003cli\u003eEndocrinal dysfunction:\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 469px;\"\u003e\n \u003cp\u003eSignificant decline in one or multiple pituitary axes and/or starting/increasing doses of hormone supplements.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003col start=\"4\"\u003e\n \u003cli\u003eNeurological impairment\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 469px;\"\u003e\n \u003cp\u003eA decrease in the NPS by 2 points or KPS by at least 30 points from pre-radiation status will be considered as an event. Fulfilling one of these criteria will be regarded as an event unless temporal causation is directly attributable to other non-neurological causes. \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003col start=\"5\"\u003e\n \u003cli\u003eCTCAE v.5 gr \u0026ge;3 radio-necrosis\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 469px;\"\u003e\n \u003cp\u003eA disorder characterized by a necrotic process occurring in the brain and/or spinal cord causing severe symptoms; intravenous medical intervention indicated; excluding corticosteroid.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003col start=\"6\"\u003e\n \u003cli\u003eDisease progression\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 469px;\"\u003e\n \u003cp\u003eIn cases of glioma, the progression of the disease will be defined by RANO 2.0 criteria, which integrate MRI changes, clinical findings, and changes in steroid use (54).\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003col start=\"7\"\u003e\n \u003cli\u003eAll-cause mortality\u003c/li\u003e\n \u003c/ol\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 469px;\"\u003e\n \u003cp\u003eDeath from disease progression or any other cause, including toxicity, will be considered as an event.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSecondary Endpoints\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 469px;\"\u003e\n \u003cp\u003e1. Overall survival and Progression-free survival.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2. Radiation-induced acute toxicity (during and within 60 days of completion of radiotherapy, using CTCAE v.5).\u003c/p\u003e\n \u003cp\u003e3. Cumulative incidence of sub-domains of functional survival.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4. Quality of Life (patient-reported outcomes).\u003c/p\u003e\n \u003cp\u003e5. Post hoc analysis per stratification factors.\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTertiary endpoints\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 469px;\"\u003e\n \u003cp\u003e1. Cost-effectiveness analysis.\u003c/p\u003e\n \u003cp\u003e2. Cost-benefit analysis.\u003c/p\u003e\n \u003cp\u003e3. Sleep scores using Pittsburg Sleep Quality Index (PSQI).\u003c/p\u003e\n \u003cp\u003e4. Dream analysis using the Mannheim Dream questionnaire (MADRE).\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2: Ongoing randomized controlled trials of proton beam therapy in adults with primary brain tumors\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStudy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePopulation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eSample size\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eArms\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 141px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrimary Endpoint\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTimeline\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eNRG BN-005\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(\u003c/strong\u003eNCT03180502)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eIDH mutant low-intermediate grade gliomas\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e120\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003eIMPT vs IMRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 141px;\"\u003e\n \u003cp\u003eNeurocognition\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eAccrual completed in March 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePRO-GLIO\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(\u003c/strong\u003eNCT05190172)\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eIDH mutant grade 2-3 gliomas\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e225\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003eIMPT vs IMRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 141px;\"\u003e\n \u003cp\u003e2-year first intervention-free survival\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eExpected accrual completion in 2027\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCOG-PROTON-01\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(\u003c/strong\u003eNCT05895344)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eGrade 1 Cavernous sinus meningiomas\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e160\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003eIMPT vs IMRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 141px;\"\u003e\n \u003cp\u003e5-year neurocognitive outcomes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eExpected completion in 2032\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 165px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCurrent study (PRIDE)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(\u003c/strong\u003eNCT06831461)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003ePrimary brain tumors with expected survival \u0026gt;5 years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e156\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 71px;\"\u003e\n \u003cp\u003eVMAT vs IMPT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 141px;\"\u003e\n \u003cp\u003e5-year functional survival (composite endpoint)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eExpected completion 2032\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIMPT: Intensity-modulated proton therapy, IMRT: Intensity-modulated radiotherapy, VMAT: Volumetric modulated arc therapy\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[{"identity":"ba3078fa-e98e-46fb-b49c-75d62afe3591","identifier":"10.13039/501100010476","name":"Tata Memorial Centre","awardNumber":"Intramural Grant","order_by":0}],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Advanced Centre for Treatment, Research and Education in Cancer","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"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":"Proton Beam Therapy, Brain Tumours, Neurocognition, Functional Survival, Randomized Controlled Trial","lastPublishedDoi":"10.21203/rs.3.rs-6805126/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6805126/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eRadiation therapy (RT) plays a significant role in the multimodal management of primary brain tumors, improving oncological outcomes. However, despite advances such as Intensity-Modulated Radiation Therapy (IMRT), photon-based RT inevitably exposes normal organs to low-dose radiation, leading to long-term functional morbidities like cognitive decline, neuroendocrine dysfunction, auditory toxicity. These late effects are particularly concerning in patients with favorable prognoses and protracted survival. Proton beam therapy (PBT), owing to its unique physical properties, holds promise for better functional preservation, but robust clinical data in adults are lacking.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThe PRIDE study is a prospective, open-label, phase 3 randomized controlled trial enrolling adults aged 18–70 years undergoing focal cranial RT with conventional fractionation for primary brain tumors with expected survival \u0026gt;5 years at Tata Memorial Centre, Mumbai. Participants will be randomized 1:1 to receive either photon-IMRT (standard arm) or PBT (experimental arm), stratified by age, tumor type, proximity to the hypothalamic-pituitary axis, and radiation dose. The primary endpoint is 5-year functional survival, defined as survival without functional deterioration (neurocognitive decline, significant ototoxicity, new or worsening neuroendocrine dysfunction, neurological impairment, severe radio-necrosis, disease progression, or death). Secondary endpoints include patient-reported quality of life and health economic analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis:\u003c/strong\u003e Survival outcomes will be analyzed using Kaplan-Meier methods with log-rank test. Neurocognitive and quality-of-life data will be evaluated using linear mixed-effects and non-parametric tests. A total of 156 patients will be enrolled, accounting for 20% attrition, to detect a 25% absolute improvement in 5-year functional survival favoring PBT (65% vs 40%, HR 0.47, α=0.05, power=80%). An interim analysis has been planned using the O'Brien-Fleming rule after 50% of the events (n=28).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eThis trial will provide level 1 evidence investigating the role of PBT in functional outcomes among adults with primary brain tumors, guiding future neuro-oncology practice.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics and Dissemination\u003c/strong\u003e: The trial has been approved by the Institutional Ethics Committee of Tata Memorial Centre, Mumbai.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRegistration:\u003c/strong\u003eThe trial has been registered with the Clinical Trial Registry of India (CTRI/2025/03/082568) and Clinicaltrials.gov (study identifier NCT06831461).\u003c/p\u003e","manuscriptTitle":"Proton versus Photon Radiotherapy in Adults with Primary Brain Tumors Evaluating Functional Survival: A Phase 3 Randomized Controlled Trial Study Protocol (PRIDE)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-10 18:02:20","doi":"10.21203/rs.3.rs-6805126/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":"e7a2f2cd-607c-4606-84d4-3c5ed7af4112","owner":[],"postedDate":"June 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":49415461,"name":"Oncology"}],"tags":[],"updatedAt":"2025-06-10T18:02:20+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-10 18:02:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6805126","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6805126","identity":"rs-6805126","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}