Background
The outcomes of patients with surgery- and radiation-refractory meningiomas treated with medical therapies are poorly defined. Published reports are limited by small patient numbers, ...selection bias, inclusion of mixed histologic grades and stages of illness, and World Health Organization (WHO) criteria changes. This analysis seeks to define outcome benchmarks for future clinical trial design.
Methods
A PubMed literature search was performed for all English language publications on medical therapy for meningioma. Reports were tabulated and analyzed for number of patients, histologic grade, prior therapy, overall survival, progression-free survival (PFS), and radiographic response.
Results
Forty-seven publications were identified and divided by histology and prior therapies, including only those that treated patients who were surgery and radiation refractory for further analysis. This included a variety of agents (hydroxyurea, temozolomide, irinotecan, interferon-α, mifepristone, octreotide analogues, megestrol acetate, bevacizumab, imatinib, erlotinib, and gefitinib) from retrospective, pilot, and phase II studies, exploratory arms of other studies, and a single phase III study. The only outcome extractable from all studies was the PFS 6-month rate, and a weighted average was calculated separately for WHO grade I meningioma and combined WHO grade II/III meningioma. For WHO I meningioma, the weighted average PFS-6 was 29% (95% confidence interval CI: 20.3%–37.7%). For WHO II/III meningioma, the weighted average PFS-6 was 26% (95% CI: 19.3%–32.7%).
Conclusions
This comprehensive review confirms the poor outcomes of medical therapy for surgery- and radiation-refractory meningioma. We recommend the above PFS-6 benchmarks for future trial design.
Abstract
Meningiomas are the most common primary brain tumor, subsequent tumor progression can be problematic for surgical treatment options based upon location. Currently there is limited activity ...of various single agent medical therapies. We evaluated a combined treatment modality in recurrent Meningiomas. Patients were consented to NOC study protocol JWCI-17–0401 in this retrospective analysis. Treatment consisted of combination Octreotide LAR, Everolimus, Hydroxyurea, and Mifepristone. Patient characteristics in the combined treatment meningioma group (n=12) had a median age 60, 50% male, 47% WHO grade I, 37% WHO grade II, 11% WHO grade III, 67% skull base location, median number of recurrences is 2.2, with median number of surgeries of 1.7. Total comparison meningioma patients (n=19) with median age 62, 42% male, 42% WHO grade I, 50% WHO grade II, 17% WHO grade III, 58% skull base location, median number of recurrences is 2.2, with median number of surgeries of 2.2. Median PFS in recurrence prior to initiation of multimodal combined therapy, mPFS=283 days. Median PFS with subsequent multimodal combined therapy, mPFS=318 days. Multimodal therapy may prolong mPFS in recurrent meningiomas. Our pilot data supports further clinical trials in combined multimodal treatments.
Abstract
BACKGROUND
Women ages 35–44 have three-fold higher risk of meningioma compared to men. Epidemiologic studies have implicated exogenous hormone use, but endogenous hormonal factors are ...inconsistently associated. Elevated body mass index (BMI) is consistently associated with meningioma risk in both men and women, and personal history of breast cancer has also been associated with meningioma risk. Recent genome-wide association studies (GWAS) have identified a meningioma risk locus on chromosome 10p12 near previous GWAS hits for breast and ovarian cancers.
METHODS
To elucidate the pleiotropic role of 10p12 variation in predisposition to diverse tumors - possibly via a common mediating factor - we performed imputation‐based fine‐mapping in three case-control datasets of meningioma (927 cases, 790 controls), female breast cancer (28108 cases, 22209 controls), and ovarian cancer (25509 cases, 40941 controls). Analyses were stratified by sex (meningioma), estrogen receptor status (breast), and histotype (ovarian), then combined using ASSET meta-analysis. Lead variants were queried for association with >700 additional traits to identify potential effect-mediators.
RESULTS
Two-sided ASSET meta-analysis identified a lead variant near the MLLT10 promoter (P=1.4x10-13) associated with significantly increased risk of meningioma in women (OR=1.42, 95% CI: 1.20–1.69) and non-significantly increased risk in men (OR=1.19, 95% CI: 0.91–1.57). The meningioma risk allele was also associated with ovarian cancer risk (OR=1.09, 95% CI: 1.06–1.12) and ER+ breast cancer risk (OR=1.05, 95% CI: 1.02–1.08), but protected against ER- breast cancer (OR=0.91, 95% CI: 0.86–0.96). The risk allele was associated with higher body fat percentage, waist circumference and BMI at genome-wide levels (P< 5.0x10-8), but mediation analysis adjusting for BMI did not attenuate its association with meningioma risk.
CONCLUSION
We identify a MLLT10 eQTL that confers risk of female meningioma, ER+ breast cancer, ovarian cancer, and obesity, but which protects against ER- breast cancer. Our results implicate a possible estrogenic mechanism underlying meningioma tumorigenesis.
Abstract
BACKGROUND
Adjuvant radiotherapy (RT) in atypical meningioma, especially for gross-totally resected tumors, remains controversial.
METHODS
We retrospectively identified ...histologically-confirmed cases of WHO Grade II atypical meningioma at a large academic institution from 2004–2018. Clinicodemographic, surgical, radiation therapy (RT), and histopathologic data were collected, as well as imaging and clinical outcomes, with a median follow-up time of 26 months (IQR 32). Patients were stratified by resection status and whether or not upfront RT was administered. Additionally, subanalyses were performed to compare external beam RT (EBRT) and stereotactic radiosurgery (SRS). Progression was defined by radiology report.
RESULTS
Of 122 patients, 45 were excluded for lacking adequate records of previous treatment, less than 3 months follow-up, or lacking MR imaging. Of 77 patients analyzed, 57% (44/77) were female; median 59-years-old. 48% (24/50) of gross-total-resections (GTR) received upfront RT – only a single case progressed, at 39 months. Of 26 GTR patients without upfront RT, 8/26 (31%) progressed at median 19.5 months – of these, 2 were lost to follow-up, 5 received salvage RT, and 1 had surgery alone. Adjuvant RT was associated with superior progression free survival (PFS) in GTR (Cox proportional hazard ratio 0.15, likelihood-ratio p=0.025; median PFS not reached). Of 15 subtotal resections (STR) receiving upfront RT, 11 received EBRT and 4 received SRS – 6 progressed (median 37 months), all after EBRT. Upfront SRS demonstrated superior PFS over EBRT following STR (p=0.036). Across the cohort there was one confirmed death, a GTR patient (without RT) who suffered an ischemic stroke at 11 months.
CONCLUSION
This large single-center retrospective analysis indicates adjuvant RT improves PFS in GTR atypical meningiomas, in concordance with prior studies. It is limited by short median follow-up, possibly related to long-term stability in treated patients. In STR tumors, SRS may contribute to improved PFS compared to EBRT.
Abstract
BACKGROUND
Factors associated with meningioma recurrence after postoperative radiotherapy are poorly understood, and the optimal postoperative radiotherapy target delineation for meningioma ...is unknown. The objective of this study was to identify factors influencing meningioma recurrence after postoperative radiotherapy to inform patient selection and treatment design.
METHODS
Medical records were retrospectively reviewed for patients who underwent meningioma resection at a single institution between 1991 and 2015. Patients with sufficient tumor tissue for histologic classification and who received postoperative radiation therapy with external beam radiotherapy (EBRT), stereotactic radiosurgery (SRS) or brachytherapy, were included. Local freedom from recurrence (LFFR) was analyzed according to tumor and treatment characteristics using the Kaplan Meier method.
RESULTS
We identified 86 patients with 96 meningiomas who met inclusion criteria. Nineteen meningiomas (20%) were WHO grade I, 56 (58%) were grade II and 21 (22%) were grade III. Forty-one meningiomas (43%) were recurrent, and 55 (57%) were de novo. The postoperative radiotherapy modality was EBRT for 58 patients (60%), SRS for 20 (21%) patients and brachytherapy for 18 (19%) patients. With a median follow up of 4.3 years (IQR 2.1–8.8 years), there were 48 (50%) local failures that occurred a median of 17 months after immediate prior resection (IQR 9–33 months). WHO grade II/III and recurrent meningiomas had worse LFFR (p< 0.001). The 5-year LFFR was 53% after EBRT (95% CI 41–69%), 53% after SRS (95% CI 34–84%) and 15% after brachytherapy (95% CI 3–74%), although meningiomas that were treated with brachytherapy were significantly more likely to have received prior EBRT or SRS (86% versus 29%, p< 0.001).
CONCLUSIONS
These data provide a foundation for understanding patterns of meningioma recurrence after postoperative radiotherapy. Ongoing analyses aim to quantify the relationships between postoperative radiotherapy dose, target delineation and local control of meningioma.
Abstract
Meningiomas are the most frequent primary CNS tumors, usually benign (WHO grade I), but in the 25–30% more aggressive tumors (grade II-III). Histopathological criteria (WHO 2016) are ...unsatisfactory to recognize meningiomas with tendency to recur. Recent studies have identified some mutations associated with histological features and location (i.e. BAP1 mutation in rhabdoid subtype), while risk stratification schemes based on DNA methylation subgroups have been proposed. Epigenetic modifications of histones play a pivotal role in tumorigenesis, the methylation of lysine 27 (K27) of histone H3 controlled by EZH2 subunit of PRC2 complex. BAP1 could be also involved in epigenetic regulation of PRC2 complex. The deregulation of H3K27 methylation has been found associated with recurrence risk in grade II meningiomas. Aim of the present study was to evaluate histone H3 methylation profile in a group of meningiomas of different grade with follow-up longer than 10 years, comparing non-recurrent to recurrent ones. We performed an immunohistochemical study on 145 meningiomas (50 grade I, 80 grade II and 15 grade III), investigating the expression of trimethylated H3K27 (H3K27me3), EZH2 and BAP1. The results were related to clinical data obtained from our Institutional Tumor Registry and evaluation of clinical reports. We observed a loss of H3K27me3 expression only in grade II and III meningiomas in 18% of cases, without correlation with tendency to recur. EZH2 showed increased percentage of positive nuclei related to the grade. In the group of grade I meningioma EZH2 expression was associated to recurrences. We didn’t observe loss of BAP1 expression. In conclusion, our data suggest that immunohistochemical evaluation of H3K27me3 and EZH2 could be a useful tool to better stratify meningioma with high risk of recurrence. Moreover, EZH2 could be of interest as therapeutic target. Molecular investigations in a larger cohort are needed to confirm these results.
Abstract
BACKGROUND
Positron emission tomography (PET) with 3’-deoxy-3’-18F-fluorothymidine (18F-FLT) provides a non-invasive assessment of in vivo tumor proliferation that could be useful for ...predicting growth potential in meningiomas. We aimed to study static and dynamic 18F-FLT PET metrics prospectively to assess metabolic activity of meningioma, and their associations to potential tumor growth on subsequent MRI scans.
METHODS
Between April 2017 and December 2018, 44 patients harboring MRI-suspected (n = 37) and histologically-verified residual meningiomas (n = 7) underwent a 60-minute dynamic 18F-FLT PET prior to imaging surveillance. Maximum and mean standardized uptake values (SUVmax, SUVmean) with/without normalisation to blood radioactivity obtained from a 40-60-minute static PET image and a 60-minute venous blood sampling were calculated. Total volume of distribution (VT) was estimated by kinetic modeling using a two-tissue reversible compartmental model with a fractional blood volume and metabolite-corrected image-derived input function. Tumor growth rate was calculated by volumetric analysis of subsequent MRI scans.
RESULTS
At the time of this writing, a total of 53 follow-up MRI scans from 33 patients were available for review, with a median follow-up time of 11 months (range, 4–22.5 months). Tumor growth/progression was observed in 12 cases with a monthly median growth rate of 0.10 cm3 (range, 0.03–3.41 cm3). All 18F-FLT metrics were significantly higher in patients with radiological progression compared to patients with stable findings with maximum tumor-to-blood-ratio (TBRmax) as the most promising imaging biomarker (4.9 ± 1.4 vs. 3.4 ± 1.0, P = .003; Mann-Whitney) and the strongest predictor for tumor progression (hazard ratio, 3.125; 95% confidence interval, 1.390–7.028; P = .006; univariate binary logistic regression). Age, gender, previous residual remnant(s) and initial tumor volume (median, 3.1 cm3; range, 0.2–55.3 cm3) had no influence.
CONCLUSION
18F-FLT PET imaging could be a valuable tool in designing a patient-tailored surveillance strategy for patients with asymptomatic meningiomas.
Abstract
BACKGROUND
Meningiomas are common intracranial neoplasms with female predominance and sharply rising incidence in the perimenopausal years. As they often express estrogen receptors, hormone ...replacement therapy (HRT) poses a theoretical risk inducing accelerated growth. Although HRT has been linked to slightly increased incidence, its actual effect on meningioma growth-rate had not been studied in a clinical population. AIM: We aimed to retrospectively compare tumor characteristics and grow-rates of incidental meningiomas of those with a ≥6-month history of estrogen-based HRT (e-HRT) before or during surveillance compared to those without (no-HRT).
METHODS
Forty females with e-HRT and 80 age-matched HRT-naïve females were identified from the NorthShore Incidental Meningioma Database. Tumor characteristics and diameters were analyzed on initial and all follow-up MRIs. Progression-free survival (PFS) was assessed.
RESULTS
Twenty-one patients completed e-HRT before, 10 started before and continued during, and 9 started e-HRT during surveillance. Patient and radiographic characteristics were similar between the groups (mean age 62y in both, parity; tumor calcification, T2W-intensity), whereas those with e-HRT had significantly lower body weight (68±16kg vs. 77±21kg; p=0.01) and tended to have longer follow-up (6.7±3.9yrs vs. 5.3±3.9yrs; p=0.07). Those with e-HRT had significantly smaller meningiomas (13±6mm vs. 16±9mm at diagnosis and 15±7mm vs. 19±11mm at end of follow-up; p=0.03 for both), and slower absolute grow-rates (0.5±0.8 vs 1.0±2.1mm/year; p=0.05) than those of no-HRT. Proportional growth-rate differences were not significant (3.3%/year vs. 5.4%/year p >0.05). Subgroup analyses showed no difference between vaginal vs. oral/subcutaneous/transdermal route e-HRT vs. no-HRT. PFS defined by RECIST1.1, RANO and clinical (new symptoms or treatment) criteria were 11.1, 6.6 and 14.7years in e-HRT versus 10.5, 5.4 and 11.4years in no-HRT. None of the differences were significant (log-rank p >0.1).
CONCLUSIONS
In this preliminary analysis, those with e-HRT had smaller tumors that grew slower, suggesting that e-HRT may be safe in incidental meningioma.
Abstract
OBJECTIVE
Texture-related factors such as consistency, vascularity and adherence vary considerably in meningioma and are thought to be linked with surgical resectability and morbidity. ...However, data analyzing the true impact of meningioma texture on the surgical management is sparse.
METHODS
Patients with intracranial meningioma treated between 08/2014-04/2018 were prospectively collected for demographics and surgical treatment with related morbidity and extend of resection (EOR). Tumor characteristics were reported by the surgeon using a standardized questionnaire including items such as tumor rigidity, homogeneity, vascularization and adherence to surrounding neurovascular structure and analyzed for their impact on EOR and neurological outcome using multivariate regression analyses.
RESULTS
296 patients (214 female (72.3%) with intracranial meningiomas were included with a mean age of 60.4 years. 23% of patients had a transient and 6.1% permanent neurological deficits and three patients (1.1%) died. The occurrence of a neurological deficit was associated with duration of surgery (p = 0.013) and tumor adherence to neurovascular structures (p = 0.014). Similar associations were observed in subgroup analyses of different tumor localizations (e.g. convexity and skull base). With regard to EOR, the tumor adherence (p < 0.001) and recurrent surgery (p = 0.001) were found as independent predictors for subtotal resection. Noteworthy, the tumor rigidity had no significant impact on the morbidity or EOR.
CONCLUSION
Our analysis supports the notion that tumor texture has an impact on the surgical management of meningioma and provides sound data that tumor adherence is a significant factor influencing neurological outcome and EOR. In contrast, the influence of tumor rigidity has less impact than previously thought. Preoperative prediction of tumor texture is therefore required for optimized risk assessment.
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