Cognitive Function, Quality of Life, and Survival Outcomes in Patients with Lower Grade Gliomas Treated with Proton Radiation Therapy: A Phase II study.

BACKGROUND Lower grade gliomas (LGGs) are associated with long survival and frequently affect young adults; as such, treatment-related toxicities and quality of life are of particular concern. Proton therapy may reduce the risks of these toxicities by minimizing radiation exposure to healthy brain and pituitary tissue. This study evaluates the safety and efficacy of proton therapy in LGG patients, focusing on neurocognitive, neuroendocrine, and quality-of-life (QOL) outcomes. METHODS A single-institution, prospective phase 2 trial enrolled 60 patients with WHO grade 1-2 gliomas or IDH-mutant grade 3 gliomas. Proton therapy was delivered to a dose of 54 Gy(RBE) or 59.4 Gy(RBE) based on tumor grade. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), neurocognitive and neuroendocrine function, and QOL. Neurocognitive testing occurred at baseline and biennially utilizing clinical trials’ battery composite (CTBC). QOL was assessed using the FACT-Brain questionnaire. Toxicities were graded per CTCAE v4.0. RESULTS The median follow-up was 7.0 years, 5-year PFS and OS were 79.1% and 85.6%, respectively. PFS was highest in IDH-mutant, 1p/19q co-deleted gliomas (100%) and lowest in IDH-wildtype tumors (62.5%). The incidence of neurocognitive decline at 5 years was 6%. Neuroendocrine dysfunction occurred in 5.3%, with only one case attributed to radiation. QOL decline peaked at 6 months with 29% showing clinically meaningful decline, then improved and remained stable at approximately 15% from years 2 to 7. No late grade 3 toxicities were observed; one case of grade 4 radionecrosis occurred. CONCLUSIONS Proton therapy for LGG provides effective disease control with modest long-term toxicity. These findings support its use as a standard radiation modality and highlight the need for comparative trials with photon therapy.

Despite technological advances in radiation therapy (RT) and cancer treatment, patients still experience adverse effects. Proton therapy (PT) has emerged as a valuable RT modality that can improve treatment outcomes. Normal tissue injury is an important determinant of the outcome; therefore, for this review, we analyzed 2 databases: (1) clinical trials registered with ClinicalTrials.gov and (2) the literature on PT in PubMed, which shows a steady increase in the number of publications. Most studies in PT registered with ClinicalTrials.gov with results available are nonrandomized early phase studies with a relatively small number of patients enrolled. From the larger database of nonrandomized trials, we listed adverse events in specific organs/sites among patients with cancer who are treated with photons and protons to identify critical issues. The present data demonstrate dosimetric advantages of PT with favorable toxicity profiles and form the basis for comparative randomized prospective trials. A comparative analysis of 3 recently completed randomized trials for normal tissue toxicities suggests that for early stage non-small cell lung cancer, no meaningful comparison could be made between stereotactic body RT and stereotactic body PT due to low accrual (NCT01511081). In addition, for locally advanced non-small cell lung cancer, a comparison of intensity modulated RTwith passive scattering PT (now largely replaced by spot-scanned intensity modulated PT), PT did not provide any benefit in normal tissue toxicity or locoregional failure over photon therapy. Finally, for locally advanced esophageal cancer, proton beam therapy provided a lower total toxicity burden but did not improve progression-free survival and quality of life (NCT01512589). The purpose of this review is to inform the limitations of current trials looking at protons and photons, considering that advances in technology, physics, and biology are a continuum, and to advocate for future trials geared toward accurate precision RT that need to be viewed as an iterative process in a defined path toward delivering optimal radiation treatment. A foundational understanding of the radiobiologic differences between protons and photons in tumor and normal tissue responses is fundamental to, and necessary for, determining the suitability of a given type of biologically optimized RT to a patient or cohort.

INTRODUCTION Insular gliomas are challenging tumors to surgically resect due to the anatomy surrounding them. This study evaluates the role of extent of resection (EOR) and molecular markers on surgical outcome and survival for insular gliomas. METHODS Seventy-four patients who had undergone an initial resection for an insular glioma by the same surgeon from 2006 to 2016 were analyzed. Low(grade II) and high(grade III/IV) grade gliomas were analyzed for the prognostic role of volumetric EOR and molecular markers (IDH1 mutation, 1p/19q codeletion) on patient survival outcomes. RESULTS >The cohort includes 25 low grade gliomas (LGGs) patients(33.8%), and 49 high grade glioma(HGGs) patients(66.2%). The median EOR was 91.7% (range 10–100%). New permanent postoperative deficits were found in 2.7% of patients. LGG patients with a = 90% EOR had a 5-year survival rate of 100% and patients with a <90% EOR had 5-year survival of 80%. HGG patients with a = 90% EOR had a 2-year survival rate of 83.7%, and patients with a <90% EOR had 2-year survival of 43.8%. For LGGs, accounting for EOR, IDH1 mut, 1p/19 codeletion, the EOR was predictive of OS(P = 0.017), progression free survival (PFS, P = 0.039), and malignant progression free survival (MPFS, P = 0.014), while the 1p/19q co-deletion was predictive for PFS (P = 0.014). For HGGs, the EOR was predictive of OS (P = 0.020) and PFS(P = 0.024). Preoperative tumor volume was a factor that most significantly affected the EOR for insular gliomas (R2 = 0.053, P = 0.048). CONCLUSION Extensive resections of insular gliomas can be achieved with low morbidity and can improve OS and PFS. In this series of low-grade gliomas, EOR was associated with longer MPFS, and the 1p/19q co-deletion was predictive of PFS.

ObjectiveA prospective multi-institutional registry study (Proton Net) has been conducted since May 2016, enrolling all patients undergoing proton therapy. Registered cases receive treatment in accordance with the guidelines established by the Japanese Society for Radiation Oncology, allowing evaluation of the safety and efficacy of proton therapy. This study reports treatment outcomes of glioma cases treated with proton therapy under advanced medical care up to June 2023.MethodsWe analyzed overall survival (OS), progression-free survival (PFS), and late adverse events in glioblastoma (GBM, n = 28), high-grade glioma (HGG, n = 17), and low-grade glioma (LGG, n = 9) cases registered in Proton Net. A systematic review comparing reported outcomes of proton vs. photon therapy was also conducted.ResultsThe median observation period (months) for GBM, HGG, and LGG was 59.3, 54.6, and 41.2, respectively. In GBM, median OS/PFS was 21. 3/10. 9 months; the 1-/3-year OS rates were 81.5%/21.7%, and PFS rates were 41.1%/11.4%. In HGG, median OS/PFS was 54. 2/30.1 months; 1-/3-year OS rates were 88. 2%/53. 5%, and PFS rates were 76. 0%/29. 0%. All LGG patients remained alive and progression-free during the observation period. Late adverse events were observed in one GBM and one HGG case; the 3-year incidence of late toxicity was 4.4%, 6.6%, and 0% for GBM, HGG, and LGG, respectively. The systematic review of 14 articles suggested comparable efficacy and safety between proton and photon therapies across glioma types, although the observation period may be insufficient for LGG evaluation.ConclusionShort-term outcomes of proton therapy for gliomas appear comparable to those of photon therapy. Continued long-term follow-up and evaluations incorporating predictive models for adverse event risk are warranted.

Proceedings to the 7th Annual Conference of the Particle Therapy Cooperative Group North America (PTCOG-NA)

PURPOSE To report preliminary results on outcomes of patients with lower grade gliomas (LGG) treated with proton therapy. METHODS Patients with grade II or IDH mutant grade III glioma and indications for radiation therapy were enrolled in a prospective single arm trial of proton therapy (PRT), receiving a dose of 54 Gy(RBE) or 59.4 Gy(RBE), respectively. Comprehensive baseline and regular post-treatment evaluations of neuroendocrine function, neurocognitive functions (NCF), quality of life (QOL), and progression-free survival (PFS) were performed. RESULTS Among 60 patients (median age 40.8) who received PRT, 28 (47%) were men, and 39 (65%) were WHO grade II. Eighteen patients (30%) were IDH mutant+1p/19q co-deleted, 36 (60%) were IDH mutant astrocytoma, and 6 (10%) were IDH wildtype. Treatment was at initial diagnosis (41; 68%) or progression (19; 32%). Median follow-up after PRT was 4.1 years. All current data are reported for 3 years from PRT. PFS at 3 years was 86% for all patients, 84% for grade II (n = 39), and 90% for favorable grade III gliomas (n = 21). PFS was 83% for IDH mutant astrocytoma, and 94% for IDH mutant+1p/19q co-deleted oligodendrogliomas. New endocrine dysfunction was detected in 3 patients (5%). There was one grade 4 case of brain necrosis (2%) but no grade 3 toxicities. NCF decline, defined by Z-score drop of >/= 1SD on clinical trials battery composite, occurred in 7% (n = 3/43). QOL assessment by FACT-Brain showed 16% with decline of >/= 10 points (n = 7/43). CONCLUSIONS At 3 years post-treatment, LGG patients receiving PRT have a high PFS, similarly to previous reports on photon therapy, few new neuroendocrine deficiencies, modest treatment toxicities, and minimal decline in NCF or QOL. These positive outcomes may be attributable to limited integral dose to the brain by use of PRT, demonstrating its value in treatment of LGG patients with long survival expectations.

Advancing (Proton) Radiation Therapy

Proton therapy and limited surgery for paediatric and adolescent patients with craniopharyngioma (RT2CR): a single-arm, phase 2 study.

Radiation therapy is often used to treat meningioma with adverse features or when unresectable. Proton therapy has advantages over photon therapy in reducing integral dose to the brain. This study compared the incidence of radiological and clinical adverse events after photon versus proton therapy in the treatment of meningioma. A retrospective review was conducted on patients with meningioma treated with proton or photon therapy at two high-volume tertiary cancer centers. Patients with a history of prior radiation therapy (RT) or less than 3months of follow-up were excluded. Post-RT imaging changes were categorized into abnormal T2 signal intensities (T2 changes) or abnormal T1 post-contrast and T2 signal intensities (T1c+T2 changes) on magnetic resonance imaging (MRI). Clinical outcomes of adverse events and survival were compared between the proton and photon therapies. Among the total of 77 patients, 38 patients received proton therapy and 39 patients received photon therapy. The median age at diagnosis was 55years and median follow-up was 2.2years. No significant differences in symptomatic adverse events were observed between the two groups: grade ≥ 2 adverse events were seen in 4 (10.5%) patients in the proton group and 3 (7.7%) patients in the photon group (p = 0.67). The 2-year cumulative incidences of T2 changes were 38.3% after proton therapy and 47.7% after photon therapy (p = 0.53) and the 2-year cumulative incidences of T1c+T2 changes were 26.8% after proton therapy and 5.3% after photon therapy (p = 0.02). One patient experienced grade ≥ 4 adverse event in each group (p = 0.99). Estimated 2-year progression-free survival was 79.5% (proton therapy 76.0% vs. photon therapy 81.3%, p = 0.66) and 2-year overall survival was 89.7% (proton therapy 86.6% vs. photon therapy 89.3%, p = 0.65). Following RT, high rates of T2 changes were seen in meningioma patients regardless of treatment modality. Proton therapy was associated with significantly higher rates of T1c+T2 changes compared with photon therapy, but severe adverse events were uncommon in both groups and survival outcomes were comparable between the two groups. Future studies will aim at correlating the MRI changes with models that can be incorporated into RT planning to avoid toxicity.

ObjectiveAccording to existing epidemiological evidence, whether proton therapy is more efficacious and safe than photon therapy in the treatment of craniopharyngioma (CP) remains controversial. This study aimed to evaluate whether proton therapy exhibits better efficacy and safety in terms of survival outcomes and toxic effects than photon therapy.MethodsAn extensive search of pertinent articles published between 1990 and February 2025 was performed in the following four databases: PubMed, Web of Science, Embase, and the Cochrane Library. Original studies investigating the efficacy and safety of proton or photon therapy in patients with CP were included. This meta-analysis is reported following the PRISMA reporting guidelines, and data were pooled using a random effects model.ResultsA total of 43 studies on 2784 patients were included in the meta-analysis. The pooled analysis favored proton therapy over photon therapy in terms of 3-year progression-free survival, 5-year progression-free survival, 5-year overall survival, 3-year local control and 5-year local control but not 3-year overall survival. In the safety analysis, compared with photon therapy, proton therapy was associated with reduced probabilities of visual, neurological, cognitive, and other miscellaneous toxicities, whereas the opposite trend was observed for endocrine toxicity. Subgroup analysis indicated that conventional radiation therapy had superior survival outcomes than stereotactic radiosurgery.ConclusionsCompared with photon therapy, proton therapy may be associated with improved survival outcomes and reduced incidence of toxic effects in CP patients. Conventional radiation therapy appears to be more effective than stereotactic radiosurgery.Supplementary InformationThe online version contains supplementary material available at 10.1007/s11102-025-01578-1.

Proton therapy offers dosimetric advantage of decreased dose to non-target tissues. This study explored the potential benefits of proton radiation therapy versus photon based intensity modulated radiation therapy (IMRT) for patients with low grade gliomas (LGG) through dosimetric comparison and biological modeling of potential radiation-induced toxicities. Eleven patients were treated with fractionated proton radiation therapy on a prospective protocol assessing for feasibility and treatment toxicity of proton radiation therapy in patients with LGG. IMRT treatment plans were created for each patient using the same CT planning data set and defined structures. The prescription dose to clinical target volume (CTV) was 54 Gy(RBE). The toxicity risk of IMRT and protons was estimated based upon equivalent uniform dose (EUD) and normal tissue complication probability (NTCP) modeling. The risk of secondary tumors for each modality was estimated. Proton EUD for most immediate normal tissue structures was between 10-20 Gy lower than the EUD delivered by IMRT. However, the difference in NTCP was negligible for both modalities. The mean excess risk of proton radiation-induced second tumor in the brain per 10,000 cases per year is 47 (range 11-83), while the mean risk for IMRT is 106 (range 70-134). The mean ratio of excess risk IMRT/protons is 2.2 (range 1.6-6.5), demonstrating that the risk of secondary tumors is consistently higher for IMRT. Proton therapy effectively reduces the dose to surrounding normal tissues in LGG patients. IMRT has a twofold higher risk of secondary intracranial tumors as compared to proton therapy. In most cases, NTCP is negligible for both modalities. The benefit of proton therapy over IMRT may be more substantial in patients with tumors in proximity to critical structures.

NTCP Modeling of Late Effects for Head and Neck Cancer: A Systematic Review.

Introduction Gliomas are infiltrative neoplasms of a highly invasive nature. Different stages of gliomas feature distinct genomic, genetic, and epigenetic changes. The long noncoding RNA Growth Arrest Specific Transcript 5 (GAS5) is an identified tumour suppressor involved in several cancers. However, the underlying roles of the GAS5 gene in lower-grade glioma (LGG) patients are not clear. Methods Via bioinformatic analysis based on TCGA-LGG and TCGA-GBM data, we explored the mechanisms of GAS5 expression in LGG (grades II and III) and high-grade glioma (glioblastoma multiforme, grade IV). The log-rank test and multivariate Cox analysis were performed to find the association between GAS5 and overall survival (OS) in LGG patients. Weighted gene coexpression network analysis (WGCNA) and RNA-Seq analysis were applied to find the key gene network associated with GAS5. Results We found that GAS5 expression was downregulated in both LGG and glioblastoma multiforme (GBM) compared with normal brain tissue. Low methylation in the GAS5 promoter region was detected in both LGG and GBM tissues. The amplification type was the predominant type of GAS5 gene alteration in both LGG and GBM. High GAS5 expression was more associated with long overall survival (OS) in LGG patients than in GBM patients. The multivariate survival analysis of GAS5 and clinical and molecular characteristics in LGG patients further confirmed the association between GAS5 and OS in LGG patients. We then developed a nomogram for clinical use. WGCNA and RNA-Seq analysis indicated that ribosomal biogenesis and translation initiation were the predominant events regulated by GAS5 in LGG patients. Conclusion Taken together, these results demonstrate that GAS5 expression is associated with OS in LGG patients and that its underlying roles involve the regulation of ribosomal biogenesis and translation initiation, which may aid in identifying a new target for the treatment of LGG.

Proceedings to the 6th Annual Conference of the Particle Therapy Cooperative Group North America (PTCOG-NA): 14-16 October 2019, Hosted by Miami Cancer Institute, part of Baptist Health South Florida, Miami, FL, USA.

Alopecia causes significant distress for patients and negatively impacts quality of life for low-grade glioma (LGG) patients. We aimed to compare and evaluate variations in dose distribution for scalp-sparing in LGG patients with proton therapy and photon therapy, namely intensity-modulated proton therapy (IMPT), intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), and helical tomotherapy (HT). This retrospective study utilized adataset comprising imaging data from 22patients with LGG who underwent postoperative radiotherapy. Treatment plans were generated for each patient with scalp-optimized (SO) approaches and scalp-non-optimized (SNO) approaches using proton techniques and photons techniques; all plans adhered to the same dose constraint of delivering atotal radiation dose of 54.04 Gy to the target volume. All treatment plans were subsequently analyzed. All the plans generated in this study met the dose constraints for the target volume and OARs. The SO plans resulted in reduced maximum scalp dose (Dmax), mean scalp dose (Dmean), and volume of the scalp receiving 30 Gy (V30) and 40 Gy (V40) compared with SNO plans in all radiation techniques. Among all radiation techniques, the IMPT plans exhibited superior performance compared to other plans for dose homogeneity as for SO plans. Also, IMPT showed lower values for Dmean and Dmax than all photon radiation techniques. Our study provides evidence that the SO approach is afeasible technique for reducing scalp radiation dose. However, it is imperative to conduct prospective trials to assess the benefits associated with this approach.