Golfinos, John G.

2090 Background: A subset of meningiomas has an aggressive clinical course requiring multimodal therapies. Yet, treatment options beyond surgery and radiation are limited. Somatostatin receptor 2 (SSTR2) is uniformly expressed in meningiomas and can be targeted by the radiopharmaceutical agent [ 177 Lu]Lu-DOTA-TATE ( 177 Lu-Dotatate). [ 68 Ga]Ga-DOTA-TATE ( 68 Ga-Dotatate) PET is emerging as a promising imaging modality to assess treatment response in SSTR2-expressing tumors. However, prospective clinical data supporting the use of 177 Lu-Dotatate and 68 Ga-Dotatate in treatment-refractory meningiomas is limited. Methods: In this multicenter, open-label, phase 2 clinical study (NCT03971461), adult patients with progressive intracranial meningiomas received 177 Lu-Dotatate at 7.4 GBq (200 mCi) every 8 weeks for 4 doses. The primary endpoint was 6-month progression-free survival (PFS-6). Up to 5 meningioma lesions per patient were assessed by gadolinium-enhanced T1 MRI every 12 weeks. 68 Ga-Dotatate PET was obtained before/after 177 Lu-Dotatate treatments. Lesional 68 Ga-Dotatate PET activity was assessed relative to liver/spleen or superior sagittal sinus (SSS). Results: 32 patients (female = 21, male = 11) with progressive meningiomas (WHO grade 1 = 7, grade 2 = 24, grade 3 = 1) were enrolled. Median age was 65.5 (range 41-78) years. All patients had at least one prior tumor surgery and at least one course of radiation. Overall, 177 Lu-Dotatate was well tolerated and the most common grade 3/4 adverse events were transient cytopenia in 15 patients (47%). One patient (3%) discontinued treatment due to grade 4 thrombocytopenia. PFS-6 was reached in 22 patients (69%), which includes 5 of 7 (71%) with grade 1 and 17 of 24 (71%) with grade 2 meningiomas. Best radiographic response by MRI was partial response (PR) in 5 (16%) and stable disease (SD) in 20 (63%) patients. Eight patients (16 lesions) were evaluable by paired MRI and 68 Ga-Dotatate PET pre- and post-treatment. Referenced to SSS, 68 Ga-Dotatate avidity reduced by ≥50% in 2 lesions (PR), 25-49% (minor response, MR) in 3 lesions and remained stable ( < 25% reduction and < 25% increase) in 11 lesions. Using liver/spleen as a reference (6 patients, 14 lesions), 68 Ga-Dotatate uptake was reduced in 9 lesions and stable in 5 lesions. 68 Ga-Dotatate PET assessments were generally concordant with MRI-based treatment response assessments. Conclusions: The primary endpoint (PFS-6) was met in this phase 2 study with 69% of patients achieving PFS-6, thereby surpassing established historical benchmarks. 177 Lu-Dotatate was generally well tolerated and deserves further study in patients with advanced meningiomas. Exploratory 68 Ga-DOTATATE PET studies showed decreased uptake in a subset of lesions and bears promise as an imaging biomarker to assess treatment response. Clinical trial information: NCT03971461 .

Abstract BACKGROUND [68Ga]Ga-DOTA-TATE (68Ga-Dotatate) PET is a promising imaging modality for post-operative meningioma delineation and outcome assessments following stereotactic radiosurgery. However, its utility for response assessment following other meningioma therapies, including somatostatin receptor 2 (SSTR2) targeting [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) therapy is insufficiently understood. Here we report the 68Ga-Dotatate PET results, prospectively obtained in patients with treatment-refractory meningioma who enrolled in a phase 2, open-label clinical trial (NCT03971461) evaluating the radiopharmaceutical 177Lu-Dotatate. METHODS Patients underwent 68Ga-Dotatate PET during screening and 24±2 weeks following treatment with 177Lu-Dotatate at 7.4 GBq (200 mCi) every 8 weeks for 4 doses. Up to 5 meningioma lesions per patient were assessed by gadolinium-enhanced T1 MRI and 68Ga-Dotatate PET using lesional Krenning score and lesional to superior sagittal sinus (SSS) maximum standardized uptake value (SUVmax) ratio (SUVR (lesion/SSS)). RESULTS Eight patients with 16 lesions were assessed. By RANO criteria, the best radiographic response was stable disease (SD) in 7 patients (14 lesions) and partial response (PR) in 1 patient (2 lesions). Krenning score was assessed in 14 lesions (Krenning 4/3/2/1 in 3/4/5/2 lesions). Following 177Lu-Dotatate, Krenning score was reduced by ≥1 point in 9 and remained stable in 5 lesions. SUVR (lesion/SSS) was evaluated in 16 lesions. Compared to baseline, SUVR (lesion/SSS) at 6 months was partially reduced (PR, ≥50%) in 2 lesions, minimally reduced (MR, &lt;50% and ≥25%) in 3 lesions, and stable (SD, &lt;25% reduction and &lt;25% increase) in 11 lesions. CONCLUSIONS 68Ga-Dotatate PET is a promising imaging biomarker in patients with advanced meningioma. Treatment with 177Lu-Dotatate led to substantial reduction in SUVR (lesion/SSS) in a subset of patients. In contrast to other reports, 68Ga-Dotatate assessments were generally concordant with post-gad T1 based MRI assessments per RANO. Updated results in an expanded group of patients will be presented.

Abstract BACKGROUND Most meningiomas are considered benign tumors, however, a subset of meningiomas are characterized by a more aggressive clinical course and require multimodal treatment. Beyond surgery and radiation, there are no effective medical treatments available. Somatostatin receptor 2 (SSTR2) is expressed by the majority of meningiomas. [177Lu]Lu-DOTA-TATE (177Lu-Dotatate) is a SSTR2-targeting radioligand therapeutic agent that has been successful in other oncological entities, including neuroendocrine tumors. Here we report the results of a phase 2 clinical trial (NCT03971461) evaluating 177Lu-Dotatate in patients with advanced and treatment-refractory intracranial meningiomas. METHODS In this multicenter, open-label, phase 2 study, adults with advanced intracranial meningiomas received 177Lu-Dotatate at 7.4 GBq (200 mCi) every eight weeks for four doses. [68Ga]Ga-DOTA-TATE (68Ga-Dotatate) PET was performed before and at the end of treatment. The primary endpoint was progression-free survival at 6 months (PFS-6). Correlative studies evaluated the association of PFS-6, objective response rate, progression-free survival, overall survival with radiographic tumor measurements, and 68Ga-Dotatate uptake on PET. RESULTS Thirty-two patients (F=21, M=11) with progressive meningiomas (WHO 1=7, WHO 2=24, WHO 3=1) were enrolled. Median age was 65.5 (range 41-78) years. All patients previously underwent tumor resection and at least one course of radiation. Three patients (9%) had received medical therapy. Treatment with 177Lu-Dotatate was well tolerated, no treatment-limiting toxicities were observed. Of 29 evaluable patients at the data cutoff, 19 patients (66%) had achieved PFS-6 (WHO 1=4, WHO 2=15). Radiographically, the best response was partial response (PR) in 2 patients (6%) and stable disease (SD) in 20 patients (63%). CONCLUSIONS Treatment with SSTR2-targeting 177Lu-Dotatate is well tolerated and 66% of patients achieved PFS-6, comparing favorably to historical benchmarks, 177Lu-Dotatate therefore may be a useful new therapeutic modality for patients with advanced meningiomas and will be further explored in MOMENTUM-1 (NCT#06955169), an open-label, randomized, phase 2 trial.

BACKGROUND AND OBJECTIVES: Surgery in NF2-related schwannomatosis (NF2-SWN) vestibular schwannoma (VS) carries a higher risk of facial nerve damage, hearing loss, and partial resection, than in sporadic cases. Radiosurgery is also associated with higher failure compared with sporadic schwannomas. Nowadays, bevacizumab (BEV) is frequently considered in the NF2-SWN population. However, some patients experience progression despite treatment. Among other surgical risks, in BEV-treated patients, hemorrhage and impaired healing are specific considerations. These concerns have led manufacturers to recommend stopping BEV 6 to 8 weeks preoperatively. The aim of our multicentric study was to assess the perioperative bleeding risk and postoperative outcomes in NF2-SWN patients undergoing VS surgery after preoperative BEV treatment. METHODS: Our retrospective analysis included medical and surgical records along with imaging reviews from 4 high-volume tertiary academic referral centers for NF2-SWN and VS. RESULTS: A total of 21 patients met the inclusion criteria. VS had a mean volume of 13.2 ±7.6 cm 3 corresponding to 1 KOOS III and 20 KOOS IV. BEV was stopped at a mean of 5.8 ± 4.0 months before surgery with a total mean treatment duration of 33.7 ± 20.7 months and a monthly dose of 10.2 ± 4.1 mg/kg. Intraoperatively, the tumor was assessed to be bloody by the operating surgeons in 7 patients. Late BEV discontinuation and high cumulative dose independently predicted perioperative bleeding and longer surgery duration. No other complication such as wound dehiscence was reported. CONCLUSION: Our findings suggest that a higher cumulative BEV dose (∼600 mg/kg) and a longer interval between BEV discontinuation and surgery (∼8 months) are associated with a modest but statistically significant increase in intraoperative bleeding risk. Based on these observations, a BEV-free window between 6 weeks and 6 months (depending on the clinical scenario) before tumor resection seems optimal, particularly for patients with high cumulative exposure.

AbstractObjectiveLimited evidence guides the optimal timing of treatment after the detection of tumor growth during the observation of sporadic vestibular schwannoma (VS). The current work aimed to inform the timing of radiosurgical intervention based on an analysis of patient outcomes among those who ultimately failed stereotactic radiosurgery (SRS) and underwent salvage microsurgery.Study DesignA historical cohort study.SettingSeven centers across the United States and Norway.MethodsAdults with sporadic VS who underwent salvage microsurgery following failed primary SRS were included. The primary outcome of interest was the association between tumor size at the time of primary SRS and the ability to achieve gross total resection (GTR) and maintain postoperative House–Brackmann (HB) facial nerve grade I at the last follow‐up after salvage microsurgery.ResultsAmong 96 patients, the median (interquartile range [IQR]) cerebellopontine angle (CPA) tumor size at primary SRS was 14.5 mm (10.0‐19.0). Each 1‐mm increase in CPA tumor size at the time of primary SRS was associated with a 13% increased likelihood of near‐total/subtotal resection or most recent postoperative HB grade >I (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.05‐1.21, P = .001), with an optimal tumor size threshold to distinguish this outcome of 12 mm of CPA extension (c‐index 0.73). Similarly, for each 1‐mm increase in CPA tumor size at the time of primary SRS, a 9% increase in any postoperative complication with salvage microsurgery was observed (OR 1.09, 95% CI 1.02‐1.15, P = .009).ConclusionCorroborated by size threshold surveillance data informing the timing of primary microsurgical resection, the current study suggests that VS outcomes are optimized when primary radiosurgical intervention is undertaken on growing tumors when they harbor 10–15 mm of cerebellopontine angle extension or less.

Objective To describe outcomes of patients with sporadic vestibular schwannoma (VS) who underwent repeat stereotactic radiosurgery (SRS) after primary SRS failure. Study Design Multi-institutional historical cohort study. Setting Five tertiary care referral centers. Patients Adults ≥18 years old with sporadic VS. Intervention Primary and repeat treatment with SRS. Main Outcome Measure Microsurgery-free survival after repeat SRS. Results Across institutions, 32 patients underwent repeat SRS after primary SRS. Most patients (74%) had tumors with cerebellopontine angle extension at primary SRS (median size, 13.5 mm [interquartile range, 7.5–18.8] mm). After primary SRS, patients underwent repeat SRS at a median of 4.8 years (interquartile range, 3.2–5.7 yr). For treatment modality, 30 (94%) patients received gamma knife for primary treatment and 31 (97%) patients received gamma knife as their repeat treatment. Median tumor volume increased from 0.970 cm3 at primary SRS to 2.200 cm3 at repeat SRS. Facial nerve function worsened in two patients after primary SRS and in two patients after repeat SRS. There were no instances of intracranial complications after repeat SRS. Microsurgery-free survival rates (95% confidence interval; number still at risk) at 1, 3, and 5 years after repeat SRS were 97% (90–100%, 24), 84% (71–100%, 13), and 68% (48–96%, 6), respectively. There was one occurrence of malignancy diagnosed after repeat radiosurgery. Conclusion Overall, repeat SRS for sporadic VS has comparable risk profile, but lower rates of tumor control, compared with primary SRS.

ImportanceManagement of sporadic vestibular schwannoma with radiosurgery is becoming increasingly common globally; however, limited data currently characterize patient outcomes in the setting of microsurgical salvage for radiosurgical failure.ObjectiveTo describe the clinical outcomes of salvage microsurgery following failed primary stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) among patients with sporadic vestibular schwannoma.Design, Setting, and ParticipantsThis was a cohort study of adults (≥18 years old) with sporadic vestibular schwannoma who underwent salvage microsurgery following failed primary SRS/FSRT in 7 vestibular schwannoma treatment centers across the US and Norway. Data collection was performed between July 2022 and January 2023, with data analysis performed between January and July 2023.ExposureSalvage microsurgical tumor resection.Main Outcomes and MeasuresComposite outcome of undergoing less than gross total resection (GTR) or experiencing long-term facial paresis.ResultsAmong 126 patients, the median (IQR) age at time of salvage microsurgery was 62 (53-70) years, 69 (55%) were female, and 113 of 117 (97%) had tumors that extended into the cerebellopontine angle at time of salvage. Of 125 patients, 96 (76%) underwent primary gamma knife SRS, while 24 (19%) underwent linear accelerator-based SRS; the remaining patients underwent FSRT using other modalities. Postoperative cerebrospinal fluid leak was seen in 15 of 126 patients (12%), hydrocephalus in 8 (6%), symptomatic stroke in 7 (6%), and meningitis in 2 (2%). Each 1-mm increase in cerebellopontine angle tumor size was associated with a 13% increased likelihood of foregoing GTR (64 of 102 patients [63%]) or long-term postoperative House-Brackmann grade higher than I (48 of 102 patients [47%]) (odds ratio, 1.13; 95% CI, 1.04-1.23). Following salvage microsurgery, tumor growth–free survival rates at 1, 3, and 5 years were 97% (95% CI, 94%-100%), 93% (95% CI, 87%-99%), and 91% (95% CI, 84%-98%), respectively.ConclusionsIn this cohort study, more than half of patients who received salvage microsurgery following primary SRS/FSRT underwent less than GTR or experienced some degree of facial paresis long term. These data suggest that the cumulative risk of developing facial paresis following primary SRS/FSRT by the end of the patient’s journey with treatment approximates 2.5% to 7.5% when using published primary SRS/FSRT long-term tumor control rates.

Objective In certain cases, clinicians may consider continued observation of a vestibular schwannoma after initial growth is detected. The aim of the current work was to determine if patients with growing sporadic vestibular schwannomas could be stratified by the likelihood of subsequent growth based on initial growth behavior. Study Design Slice-by-slice volumetric tumor measurements from 3,505 serial magnetic resonance imaging studies were analyzed from 952 consecutively treated patients. Setting Three tertiary-referral centers. Patients Adults with sporadic vestibular schwannoma. Interventions Wait-and-scan. Main Outcome Measures Composite end point of subsequent growth- or treatment-free survival rates, where growth is defined as an additional increase of at least 20% in tumor volume from the volume at the time of initial growth. Results Among 405 patients who elected continued observation despite documented growth, stratification, of volumetric growth rate into less than 25% (reference: n = 107), 25 to less than 50% (hazard ratio [HR], 1.39; p = 0.06; n = 96), 50 to less than 100% (HR, 1.71; p = 0.002; n = 112), and at least 100% (HR, 2.01; p < 0.001; n = 90) change per year predicted the likelihood of future growth or treatment. Subsequent growth- or treatment-free survival rates (95% confidence interval) at year 5 after detection of initial growth were 31% (21–44%) for those with less than 25% growth per year, 18% (10–32%) for those with 25 to less than 50%, 15% (9–26%) for those with 50 to less than 100%, and 6% (2–16%) for those with at least 100%. Neither patient age (p = 0.15) nor tumor volume at diagnosis (p = 0.95) significantly differed across stratification groups. Conclusions At the time of diagnosis, clinical features cannot consistently predict which tumors will ultimately display aggressive behavior. Stratification by volumetric growth rate at the time of initial growth results in a stepwise progression of increasing likelihood of subsequent growth. When considering continued observation after initial growth detection, almost 95% of patients who have tumors that double in volume between diagnosis and the first detection of growth demonstrate further tumor growth or undergo treatment if observed to 5 years.

Objective Spontaneous tumor shrinkage during wait-and-scan management of sporadic vestibular schwannoma is generally considered an uncommon phenomenon. However, most data informing this understanding stem from single-slice linear tumor measurements taken in the axial imaging plane. The objective of the current work was to characterize the regression capacity of sporadic vestibular schwannomas using volumetric tumor measurements. Study Design Retrospective cohort study using slice-by-slice, three-dimensional volumetric tumor measurements. Setting Three tertiary referral centers. Patients Patients with sporadic vestibular schwannoma. Interventions Wait-and-scan. Main Outcome Measures Regression-free survival rates with regression defined as a decrease of at least 20% of the tumor volume. Results Among 952 patients undergoing a total of 3,505 magnetic resonance imaging studies during observation, 123 experienced volumetric tumor regression after diagnosis at a median of 1.2 years (interquartile range, 0.6–2.9 yr). Volumetric regression-free survival rates (95% confidence interval; number still at risk) at 1, 3, and 5 years after diagnosis were 94% (92–95%; 662), 86% (83–89%; 275), and 78% (73–82%; 132), respectively. Among 405 patients who demonstrated an initial period of tumor growth but continued wait-and-scan management, 48 experienced volumetric regression at a median of 1.2 years (interquartile range, 0.8–2.6 yr) after initial growth. Volumetric regression-free survival rates at 1, 3, and 5 years after initial growth were 94% (92–97%; 260), 84% (79–89%; 99), and 75% (67–83%; 43), respectively. Ultimately, only 82 of the 952 patients studied showed exclusively volumetric tumor regression (i.e., without any periods of tumor growth) by the time of last follow-up. Conclusion Spontaneous volumetric tumor shrinkage during wait-and-scan management occurs more frequently than suggested by previous studies using linear tumor measurements and can even occur after previous episodes of documented tumor growth. These data further highlight the dynamic nature of vestibular schwannoma growth. To this end, the application of natural history data to patient management requires a nuanced approach that parallels the complex tumor behavior of vestibular schwannoma.

Abstract Background The current study aims to characterize the natural history of sporadic vestibular schwannoma volumetric tumor growth, including long-term growth patterns following initial detection of growth. Methods Volumetric tumor measurements from 3505 serial MRI studies were analyzed from unselected consecutive patients undergoing wait-and-scan management at three tertiary referral centers between 1998 and 2018. Volumetric tumor growth was defined as a change in volume ≥20%. Results Among 952 patients undergoing observation, 622 experienced tumor growth with initial growth-free survival rates (95% CI) at 1, 3, and 5 years following diagnosis of 66% (63–69), 30% (27–34), and 20% (17–24). Among 405 patients who continued to be observed despite demonstrating initial growth, 210 experienced subsequent tumor growth with subsequent growth-free survival rates at 1, 3, and 5 years following initial growth of 77% (72–81), 37% (31–43), and 24% (18–31). Larger tumor volume at initial growth (HR 1.13, P = .02) and increasing tumor growth rate (HR 1.31; P &lt; .001) were significantly associated with an increased likelihood of subsequent growth, whereas a longer duration of time between diagnosis and detection of initial growth was protective (HR 0.69; P &lt; .001). Conclusions While most vestibular schwannomas exhibit an overall propensity for volumetric growth following diagnosis, prior tumor growth does not perfectly predict future growth. Tumors can subsequently grow faster, slower, or demonstrate quiescence and stability. Larger tumor size and increasing tumor growth rate portend a higher likelihood of continued growth. These findings can inform timing of intervention: whether upfront at initial diagnosis, after detection of initial growth, or only after continued growth is observed.