Trifiletti, Daniel M.

Abstract Background The current treatment of glioblastoma involves resection followed by radiotherapy (RT) and temozolomide. Rapid early progression (REP) of tumor in the surgery-to-radiotherapy interval (SRI) has been described using categorical or semi-quantitative assessments and is associated with inferior clinical outcomes. This study seeks to establish and validate a quantitative definition for REP and examine how REP could inform future therapy. Methods Volumes of tumor and resection cavity at 3 time points—preoperative, postoperative and RT-planning (pre-RT)—were contoured among patients who had undergone standard of care. A minimal, but clinically appreciable, threshold for defining REP based on change in tumor volume was established, validated, and subsequently used to assess actionable predictors of REP and its prognostic value. Results An increase of >2 cc in volume or a new satellite tumor between the post-operative to planning MRI was found to be a sensitive, pragmatic, and statistically significant cutoff for REP (P = .002). Actionable predictors such as SRI of 6 weeks and a > 5 cc residual immediate post-operative tumor volume were found to be statistically significant predictors of REP. REP was also found to be a statistically significant prognostic indicator for overall survival (P = .002) and progression-free survival. Conclusion These findings support that an increase in tumor volume between post-operative and pre-RT MRI of >2 cc is the ideal working definition of REP in this clinical setting. Furthermore, REP could serve as a prognostic ­biomarker to track treatment response. Additionally, 2 actionable predictors of REP, post-op residual tumor volume and SRI, are identified.

TPS2103 Background: Treatment for newly diagnosed IDH-mutant astrocytoma, WHO grade 3, is based on the results of the CATNON study, demonstrating benefit of radiotherapy followed by 12 months of adjuvant temozolomide. While temozolomide and radiotherapy significantly improved survival, the prognosis for these patients remains limited and more effective therapies are required. This trial will evaluate the benefit of the addition of the IDH1 and IDH-2 inhibitor vorasidenib to adjuvant temozolomide versus placebo following standard radiotherapy to evaluate possible improvement in outcomes. Methods: Alliance A072301 (NCT07215910) is a multicenter, double-blinded phase 3 randomized study to determine if the addition of vorasidenib to adjuvant temozolomide significantly improves progression-free survival (PFS), based on blinded central review in patients with newly diagnosed, IDH-mutant astrocytoma, WHO grade 3. Key inclusion criteria include age ≥ 12 years old, histological confirmation of astrocytoma (absence of 1p/19q codeletion), WHO grade 3, presence of any IDH mutation, plan for radiation and chemotherapy and surgery within 6 months. The presence of CDKN2A/B homozygous deletion, spinal or leptomeningeal disease, as well as prior chemotherapy, cranial irradiation or IDH inhibitor therapy, is exclusionary. 408 patients will be randomized 1:1 to receive vorasidenib 40 mg or placebo daily with 12 cycles of temozolomide following radiotherapy and then continued as monotherapy until disease progression or unacceptable toxicity. Stratification factors include age (< 40 years old vs ≥ 40 years old) and residual disease (< 2 cm vs ≥ 2 cm). Tumor assessments with MRI will be every three months for the first two years, every four months for the next two years and then every six months thereafter as per blinded independent central review using the Response Assessment in Neuro-Oncology (RANO) 2.0 criteria. Key secondary endpoints include PFS by local review, time to next treatment, safety and tolerability, quality of life measures. Exploratory measures will include seizure frequency. The trial will have 85% power to detect a hazard ratio of 0.625 with one-sided type I error rate of 0.025. Enrollment for the trial commenced February 2026. Support: U10CA180821, U10CA180882, U24CA196171. https://acknowledgments.alliancefound.org.

OBJECTIVE The aim of this study was to evaluate freedom from tumor progression and clinical outcomes in older adults with small- to medium-sized vestibular schwannoma (VS) managed by observation versus stereotactic radiosurgery (SRS) to better inform optimal management in this patient population. METHODS In this international multicenter study, patients aged ≥ 60 years with Koos grade I or II VS managed by observation or SRS were retrospectively reviewed. Propensity score matching was conducted using patient characteristics, tumor size, and hearing assessments. Outcome measures of freedom from tumor progression, serviceable hearing preservation (SHP), and neurological function (tinnitus, vestibulopathy, House-Brackmann grade, and trigeminal nerve function) were assessed for both groups. RESULTS The observation and SRS groups each comprised 51 matched patients (median age 68 years for both). Ipsilateral serviceable hearing was observed at presentation for 35 patients in each group. The median follow-up duration was 39 months in the observation group versus 27 months in the SRS group (p = 0.5). Tumor progression was significantly lower with SRS than with observation (2% vs 52.9%, p < 0.001). The rate of 5-year freedom from tumor progression was 100% in the SRS group versus 43% (95% CI 29%–64%) in the observation group. The rate of 10-year freedom from tumor progression was 90% (95% CI 73%–100%) in the SRS group versus 20% (95% CI 8.5%–49%) in the observation group. At the last follow-up, hearing loss occurred in 42.9% of the observation group and 51.4% of those who underwent SRS (p = 0.5). The 3-year SHP rate was 68% (95% CI 53%–88%) versus 65% (95% CI 49%–85%) (p = 0.8), and the 5-year SHP rate was 53% in both groups (95% CI 36%–78% in the observation group and 95% CI 35%–79% in the SRS group, p = 0.8). The composite endpoint of tumor progression and/or worsened neurological outcome, including hearing loss, tinnitus, vestibulopathy, facial nerve dysfunction (House-Brackmann grade), or trigeminal dysfunction, demonstrated a significantly lower rate in the SRS group (17.6%) compared with the observation group (66.7%) (p < 0.001). CONCLUSIONS SRS in older patients for management of Koos grade I or II VS resulted in significantly superior rates of freedom from tumor progression, comparable hearing preservation rates, and significantly higher rates of favorable overall radiographic and neurological outcomes than observation alone. Compared with observation, SRS might be the preferred management option in this patient population.

PURPOSE Although outcomes for nonmetastatic cancers have improved since the 1970s, it remains uncertain whether long-term survival has improved among patients presenting with de novo metastatic disease, defined as cancer presenting with distant metastases at the time of initial diagnosis. This study evaluated changes in 5-year survival among patients with de novo metastatic cancer diagnosed in 1976 versus 2015, with a minimum 5-year follow-up through 1981 and 2020, respectively. METHODS Population-based data were obtained from the SEER database. Patients diagnosed with de novo metastatic cancer in 1976 (n = 11,864) and 2015 (n = 26,324) were included. Five-year overall survival (OS) was compared between cohorts, and multivariable logistic regression identified demographic and clinical factors associated with survival. RESULTS The 5-year OS increased significantly from 10.6% in 1976-1981 to 23.6% in 2015-2020 ( P < .001). Survival gains were largest in breast cancer (12.6%-34.2%; P < .001), ovarian cancer (14.4%-32.5%; P < .001), colorectal cancer (3.7%-15.0%; P < .001), and hematologic malignancies (24.3%-53.9%; P < .001). Minimal improvement occurred in pancreatic cancer (0.25%-1.6%; P = .007) and small cell lung cancer (0.8%-3.1%; P = .008). Multivariable analysis demonstrated that older age, male sex, and Black race were associated with lower odds of 5-year survival (all P < .01) CONCLUSION Over the past four decades, long-term survival among patients with de novo metastatic cancer has more than doubled; however, progress remains uneven across cancer types. Gains appear concentrated in malignancies with substantial therapeutic advances, whereas others show persistently poor outcomes. Continued efforts are needed to address disparities and improve survival in resistant cancer types.

BACKGROUND AND OBJECTIVES: Stereotactic radiosurgery (SRS) for brain arteriovenous malformations (AVMs) can cause radiation-induced changes (RIC), but its interactions with AVM embolization are not well established. The aim of this study was to assess the effect of previous embolization on RIC in SRS-treated AVM patients. METHODS: Data of AVM patients treated with single-session SRS from 1987 to 2018 were retrieved from the International Radiosurgery Research Foundation. Univariable and stepwise backward logistic regression models were used to identify RIC predictors. Patients were stratified into those who received pre-SRS embolization (E + SRS) vs those who did not (SRS-only). Radiologic RIC (rRIC) was the primary end point. Secondary outcomes included symptomatic RIC (sRIC) and permanent symptomatic RIC (pRIC). RESULTS: Among 1187 AVM patients, the mean age was 36.4 years (SD 16.8), with 50.4% female patients. AVMs had a mean untreated AVM volume of 5.2 cm 3 . A total of 130 patients (11%) underwent neoadjuvant embolization (E + SRS). The overall rRIC and sRIC rates were 32.8% and 12.1%, respectively, with time to rRIC and sRIC being significantly longer in the E + SRS vs SRS-only cohorts (103.6 ± 339.4 vs 11.3 ± 12.5 and 60.4 ± 262.9 vs 9.5 ± 9.0 months, respectively). Seizures at presentation and ≥3-cm untreated AVM volume significantly correlated with a higher likelihood of rRIC (adjusted odds ratio [aOR] 2.32 [1.25-4.30] and aOR 2.77 [1.24-6.16], respectively). Age and pre-SRS embolization were associated with a significantly lower risk of rRIC (aOR 0.97 [0.96-0.99] and aOR 0.32 [0.13-0.74], respectively). The E + SRS cohort had significantly reduced odds of rRIC (aOR = 0.37 [0.15-0.89]) and pRIC (aOR = 0.04 [0.00-0.30]) after adjusting for significant covariates. CONCLUSION: Seizures at presentation and larger untreated AVM volume were independently associated with an increased risk of rRIC, whereas older age and pre-SRS embolization were protective. Notably, patients who underwent embolization before SRS had lower odds of rRIC and pRIC, with delayed onset of complications compared with SRS-only.

Abstract BACKGROUND Glioblastoma (GBM) is highly aggressive with poor prognosis, especially in recurrent cases where treatments are limited. Intra-arterial (IA) Yttrium-90 (Y90) microsphere therapy, FDA-approved for hepatocellular carcinoma, offers the potential for targeted radiotherapy in recurrent GBM (rGBM). The FRONTIER trial evaluated the safety and feasibility of IA Y90-glass microsphere treatment for rGBM under an FDA Investigational Device Exemption. Materials and METHODS This prospective, single-arm, multi-center study included patients with rGBM in non-dominant, non-eloquent regions. The primary endpoint was 30-day incidence of treatment-related limiting toxicities (primarily ≥grade 3 non-hematologic, with exclusions). Secondary endpoints included adverse event (AE) rate, neurological changes, technical success (PET absorbed dose within ±20% of target), and efficacy. Treatment regions, defined via cerebral angiography-MRI fusion to cover the recurrent lesion, were targeted with 40±4Gy. Post-treatment evaluations included MRI, Y90-PET, and neurological assessments. RESULTS The procedure was well-tolerated by all twelve subjects and discharge occurred the following day with no decline in neurologic status. No limiting toxicities or device-related AEs were reported. Five patients experienced 8 procedure-related AEs (6 Grade 1, 2 Grade 3). Technical success was 100%, with post-treatment Y90-PET derived median absorbed dose of 41.5 Gy to the treatment region (median volume 80.3 cc). The median tumor absorbed dose was considerably higher at 124.2 Gy (median tumor volume 5.8 cc), indicating preferential tumor perfusion. At 2 months, 67% had stable disease, and 33% showed reduced T1-contrast enhancing volume within the treated area. Median progression-free survival was 3.1 (95% CI 0.92-NE) and overall survival (OS) was 9.3 months (95% CI 5.0-NE) from Y90 treatment. Exploratory analysis revealed a significant OS benefit for patients receiving a tumor absorbed dose above the median (11.9 vs 5.7 months, p=0.0073). CONCLUSION Results from this initial cohort suggest IA Y90-microsphere therapy is technically feasible and well-tolerated in rGBM. Further investigation is warranted.

Abstract BACKGROUND Glioblastoma (GBM) is highly aggressive with poor prognosis, especially in recurrent cases where treatments are limited. Intra-arterial (IA) Yttrium-90 (Y90) microsphere therapy, CE-marked for hepatic neoplasia, offers the potential for targeted high-dose beta radiation in GBM by leveraging tumor hypervascularity. The FRONTIER trial evaluated the safety and feasibility of IA Y90-glass microsphere treatment for recurrent GBM. MATERIAL AND METHODS FRONTIER is a prospective, single-arm, multi-center study with Investigational Device Exemption approval from the US FDA. This initial cohort included patients with recurrent GBM in non-dominant, non-eloquent regions after 1-2 lines of prior therapy. The primary endpoint was the 30-day incidence of treatment-related toxicities (primarily ≥grade 3 non-hematologic, with exclusions). Secondary endpoints included overall treatment-related adverse events (AE), neurological function changes, technical success, and efficacy measures. Treatment regions, defined via cerebral angiography-MRI fusion to cover the recurrent lesion were targeted with 40±4Gy. Post-treatment evaluations included MRI, Y90-PET for absorbed dose distribution, and serial neurological assessments. Changes in post-contrast T1-enhancing tissue volume (T1C-vol) were tracked longitudinally. RESULTS Twelve subjects (67% male; average age 57 years) were treated. The procedure was well-tolerated with no limiting toxicities reported or device-related AEs reported. Five patients experienced 8 procedure-related AEs (6 Grade 1, 2 Grade 3). At discharge one day after treatment, there was no decline in neurologic status per NIHSS. Technical success was 100%, with post-treatment Y90-PET showing a median absorbed dose of 41.5 Gy (range 39.2-45.4) to the treatment region (median volume 80.3 cc [40.9-118.5]). The median tumor absorbed dose was significantly higher at 124.2 Gy (range 58.5-508.5) within a median tumor volume of 5.8 cc (range 0.5-55.4), indicating preferential tumor perfusion. At 1 month, the best response was partial response in 17% (2/12), stable disease (SD) in 67% (8/12), and progressive disease in 17% (2/12). At 2 months, 73% (8/11 evaluable) had SD, and 33% (4/12) showed reduced T1C-vol within the treated area. Median progression-free survival was 3.0 (95% CI 1.1-3.7) and median overall survival (OS) was 9.3 months (95% CI 5.0-NE) from Y90 treatment. Exploratory analysis revealed a significant OS benefit for patients receiving a tumor absorbed dose above the median (&gt;124 Gy) compared to those below (13.1 vs 5.8 months, p=0.0054). CONCLUSION Results from this initial cohort of the FRONTIER trial suggest IA Y90 glass microsphere therapy is technically feasible and well-tolerated in patients with recurrent GBM. The observed dose-response relationship warrants further investigation of this modality as a potential treatment option.

ABSTRACT Introduction Sinonasal sarcomas are exceedingly rare entities, constituting less than 7% of head and neck sarcomas. Their complex histology needs specialized treatment, which is often based on multimodal approaches including surgery, radiation therapy, and/or chemotherapy. This manuscript aims to gather expert opinions to establish common management principles for sinonasal sarcomas. Methods This international consensus followed a modified Delphi method in seven steps, including statements definition by the core group, expert panel recruitment, and a two‐round survey. Sixty‐two statements on sinonasal sarcoma management were developed. Experts from multiple continents participated, and results were anonymized and analyzed between March and May 2025. Results A total of 44 invited experts were recruited, 43.2% otorhinolaryngologists/head and neck surgeons, 31.8% medical oncologists, and 25% radiation oncologists. Participants varied in age and experience, representing Europe (70.5%), North America (18.2%), South America (6.8%), and Asia (4.5%). Among all histologies, biphenotypic sarcoma, chondrosarcoma, leiomyosarcoma, and myofibrosarcoma are principally treated with an upfront surgical management, differently from Ewing sarcoma and rhabdomyosarcoma in which chemotherapy, eventually associated with radiotherapy, is often chosen. In the remaining histologies (angiosarcoma, liposarcoma, malignant peripheral nerve sheath tumor [MPNST], osteosarcoma, and synovial sarcoma), a precise multimodal treatment is less standardized and needs to be discussed on a case‐by‐case basis. Conclusion Sinonasal sarcomas require a histology‐driven approach to determine upfront treatment, whether surgical, medical, or multimodal. Despite this structured strategy, prognosis remains highly variable across subtypes. Multidisciplinary evaluation and individualized management in referral centers are crucial to address the biological diversity and anatomical complexity of these rare malignancies.

BACKGROUND AND OBJECTIVES: The therapeutic approach for small- and medium-sized vestibular schwannoma (VS) with normal hearing function remains controversial, with limited comparative data regarding hearing outcomes after stereotactic radiosurgery (SRS) or observation (OBS). We evaluated the serviceable hearing preservation, loss of American Academy of Otolaryngology-Head and Neck Surgery class A hearing, and tumor control (TC) across individuals with Koos grade I and II VSs and normal hearing at presentation who underwent SRS or OBS. METHODS: In this multicenter international study, we retrospectively analyzed the hearing, radiological, and neurological outcomes of patients who underwent SRS (SRS group) or OBS (OBS group). The cohorts were matched using propensity scores based on age, sex, tumor volume, pure-tone average, and speech discrimination score at a 1:1 ratio without replacement. RESULTS: After matching, each group comprised 57 patients. The median follow-up was 49 and 37 months for the SRS and the OBS groups, respectively ( P = .3). The 5- and 9-year serviceable hearing preservation rates in the SRS group were 76.2% and 42.4% vs 56.1% and 16.8% in the OBS group ( P = .17). Class A preservation occurred in 57.9% (33/57) of the SRS and 52.6% (30/57) of the OBS cohorts ( P = .70). Regarding the TC rates, SRS was associated with significantly higher TC rates ( P < .0001). CONCLUSION: We found that SRS is significantly superior regarding TC and provided noninferior hearing outcomes compared with OBS in VS patients with American Academy of Otolaryngology-Head and Neck Surgery class A hearing at presentation. Therefore, we suggest performing SRS in individuals with VS and normal hearing function.

This study evaluated the effectiveness of using a traditional computed tomography (CT) simulation scan in the Leksell Gamma Knife® Icon™ workflow for stereotactic radiosurgery. We compared two workflows, one involving a traditional CT simulation co-registered with the magnetic resonance imaging (MRI) and cone-beam CT (CBCT) (MRI-CT-CBCT) and another without the CT scan, co-registering the MRI directly with CBCT (MRI-CBCT). The cohort included 50 frame-based (54 targets) and 55 frameless (124 targets) patients treated between August 2020 and December 2022. Target coverage was assessed by the percentage of each target covered by the prescription isodose line. The mean coverage differences for the frame-based and frameless cohorts were −1.20% ± 1.43% and −1.06% ± 1.51%, respectively, with 95% confidence intervals of −1.59, −0.81 and −1.32, −0.79. The MRI-CBCT workflow was deemed noninferior to the MRI-CT-CBCT workflow. Our data indicate that both workflows yield similar results, suggesting that a traditional CT simulation scan is unnecessary.