The impact of multiple lesions on progression-free survival of meningiomas: a 10-year multicenter experience

J Neurosurg 137:9–17, 2022

Multiple meningiomas (MMs) occur in as many as 18% of patients with meningioma, and data on progression- free survival (PFS) are scarce. The objective of this study was to explore the influence of the number of lesions and clinical characteristics on PFS in patients with WHO grade I meningiomas.

METHODS The authors retrospectively reviewed the records of all adults diagnosed with a meningioma at their three main sites from January 2009 to May 2020. Progression was considered the time from diagnosis until radiographic growth of the originally resected meningioma. A secondary analysis was performed to evaluate the time of diagnosis until the time to second intervention (TTSI). Univariable and multivariable analyses were conducted to assess whether the number of lesions or any associated variables (age, sex, race, radiation treatment, tumor location, and extent of resection) had a significant impact on PFS and TTSI.

RESULTS Eight hundred thirty-eight patients were included. Use of a log-rank test to evaluate PFS and TTSI between a single and multiple lesions showed a significantly shorter progression for MM (p < 0.001 and p < 0.001, respectively). Multivariable Cox regression analysis showed significantly inferior PFS on MM compared to a single lesion (hazard ratio [HR] 2.262, 95% confidence interval [CI] 1.392–3.677, p = 0.001) and a significantly inferior TTSI for patients with MM when compared to patients with a single meningioma (HR 2.377, 95% CI 1.617–3.494, p = 0.001). By testing the number of meningiomas as a continuous variable, PFS was significantly inferior for each additional meningioma (HR 1.350, 95% CI 1.074–1.698, p = 0.010) and TTSI was significantly inferior as well (HR 1.428, 95% CI 1.189–1.716, p < 0.001). African American patients had an inferior PFS when compared to non-Hispanic White patients (HR 3.472, 95% CI 1.083–11.129, p = 0.036).

CONCLUSIONS The PFS of meningiomas appears to be influenced by the number of lesions present. Patients with MM also appear to be more prone to undergoing a second intervention for progressive disease. Hence, a closer follow-up may be warranted in patients who present with multiple lesions. These results show a decreased PFS for each additional lesion present, as well as a shorter PFS for MM compared to a single lesion. When assessing associated risk factors, African American patients showed an inferior PFS, whereas older age and adjuvant therapy with radiation showed an improved PFS.

 

Central Nervous System Plasticity Influences Language and Cognitive Recovery in Adult Glioma

Neurosurgery 89:539–548, 2021

Gliomas exist within the framework of complex neuronal circuitry in which network dynamics influence both tumor biology and cognition. The generalized impairment of cognition or loss of language function is a common occurrence for glioma patients.

The interface between intrinsic brain tumors such as gliomas and functional cognitive networks are poorly understood. The ability to communicate effectively is critically important for receiving oncological therapies and maintaining a high quality of life.

Although the propensity of gliomas to infiltrate cortical and subcortical structures and disrupt key anatomic language pathways is well documented, there is new evidence offering insight into the network and cellular mechanisms underpinning glioma-related aphasia and aphasia recovery.

In this review, we will outline the current understanding of the mechanisms of cognitive dysfunction and recovery, using aphasia as an illustrative model.

Prospective validation of a molecular prognostication panel for clival chordoma

J Neurosurg 130:1528–1537, 2019

There are currently no reliable means to predict the wide variability in behavior of clival chordoma so as to guide clinical decision-making and patient education. Furthermore, there is no method of predicting a tumor’s response to radiation therapy.

METHODS A molecular prognostication panel, consisting of fluorescence in situ hybridization (FISH) of the chromosomal loci 1p36 and 9p21, as well as immunohistochemistry for Ki-67, was prospectively evaluated in 105 clival chordoma samples from November 2007 to April 2016. The results were correlated with overall progression-free survival after surgery (PFSS), as well as progression-free survival after radiotherapy (PFSR).

RESULTS Although Ki-67 and the percentages of tumor cells with 1q25 hyperploidy, 1p36 deletions, and homozygous 9p21 deletions were all found to be predictive of PFSS and PFSR in univariate analyses, only 1p36 deletions and homozygous 9p21 deletions were shown to be independently predictive in a multivariate analysis. Using a prognostication calculator formulated by a separate multivariate Cox model, two 1p36 deletion strata (0%–15% and > 15% deleted tumor cells) and three 9p21 homozygous deletion strata (0%–3%, 4%–24%, and ≥ 25% deleted tumor cells) accounted for a range of cumulative hazard ratios of 1 to 56.1 for PFSS and 1 to 75.6 for PFSR.

CONCLUSIONS Homozygous 9p21 deletions and 1p36 deletions are independent prognostic factors in clival chordoma and can account for a wide spectrum of overall PFSS and PFSR. This panel can be used to guide management after resection of clival chordomas.

 

Outcomes of stereotactic radiosurgery for foramen magnum meningiomas: an international multicenter study

J Neurosurg 129:383–389, 2018

Meningiomas are the most common benign extramedullary lesions of the foramen magnum; however, their optimal management remains undefined. Given their location, foramen magnum meningiomas (FMMs) can cause significant morbidity, and complete microsurgical removal can be challenging. Anterior and anterolateral FMMs carry greater risks with surgery, but they comprise the majority of these lesions. As an alternative to resection, stereotactic radiosurgery (SRS) has been used to treat FMMs in small case series. To more clearly define the outcomes of SRS and to delineate a rational management paradigm for these lesions, the authors analyzed the safety and efficacy of SRS for FMM in an international multicenter trial.

METHODS Seven medical centers participating in the International Gamma Knife Research Foundation (IGKRF) provided data for this retrospective cohort study. Patients who were treated with Gamma Knife radiosurgery and whose clinical and radiological follow-up was longer than 6 months were eligible for study inclusion. Data from pre- and post- SRS radiological and clinical evaluations were analyzed. Stereotactic radiosurgery treatment variables were recorded.

RESULTS Fifty-seven patients (39 females and 18 males, with a median age of 64 years) met the study inclusion criteria. Thirty-two percent had undergone prior microsurgical resection. Patients most frequently presented with cranial neuropathy (39%), headache (35%), numbness (32%), and ataxia (30%). Median pre-SRS tumor volume was 2.9 cm3. Median SRS margin dose was 12.5 Gy (range 10–16 Gy). At the last follow-up after SRS, 49% of tumors were stable, 44% had regressed, and 7% had progressed. Progression-free survival rates at 5 and 10 years were each 92%. A greater margin dose was associated with a significantly increased likelihood of tumor regression, with 53% of tumors treated with > 12 Gy regressing. Fifty-two percent of symptomatic patients noted some clinical improvement. Adverse radiation effects were limited to hearing loss and numbness in 1 patient (2%).

CONCLUSIONS Stereotactic radiosurgery for FMM frequently results in tumor control or tumor regression, as well as symptom improvement. Margin doses > 12 Gy were associated with increased rates of tumor regression. Stereotactic radiosurgery was generally safe and well tolerated. Given its risk-benefit profile, SRS may be particularly useful in the management of small- to moderate-volume anterior and anterolateral FMMs.

 

The timing of stereotactic radiosurgery for medically refractory trigeminal neuralgia

Acta Neurochirurgica (2018) 160:977–986

Diffusion tensor imaging (DTI) is a novel MRI technique that enables noninvasive evaluation of microstructural alterations in white matter of brain. Initially, DTI was used in intra- or inter-hemispheric association bundles. Recent technical advances are overcoming the challenges of imaging small white matter bundles, such as the cranial nerves. In this study, we use DTI to shed more light on the microstructure changes in long-standing trigeminal neuralgia. We also utilize DTI to study the effect of early stereotactic radiosurgery (SRS) on the microstructures of the trigeminal nerve and to predict the effectiveness of early SRS in the treatment of medically refractory trigeminal neuralgia (TN).

Methods To analyze the presentation of trigeminal nerve, the DTI was reconstructed in 21 cases pre- and post-SRS. DTI parameters recorded include fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), axial diffusivity (AD), linear anisotropy coefficient (Cl), planar anisotropy coefficient (Cp), and spherical anisotropy coefficient (Cs). Comparisons between ipsilateral (symptomatic) and contralateral (asymptomatic) trigeminal nerves and symptomdurations of < 5 and ≧ 5 years were performed.

Results The study cohort comprised 21 patients with TN with a median age of 66 years. Initial adequate facial pain relief (Barrow Neurological Institute facial pain scores I–IIIb) was achieved in 16 (76%) patients. For the pre-SRS DTI findings, ipsilateral trigeminal nerve was associated with higher baseline root entry zone (REZ) Cs compared to contralateral nerve (0.774 vs. 0.743, p = 0.04). Ipsilateral trigeminal nerve with symptoms of < 5 years was associated with higher baseline FA compared to trigeminal nerve with symptoms of ≧ 5 years (0.314 vs. 0.244, p = 0.02). For the post-SRS DTI findings, ipsilateral trigeminal nerves with symptoms of <5 years demonstrated decrease in Cl, while those with symptoms ≧ 5 years demonstrated increase in Cl after SRS at the ipsilateral REZ (− 0.025 vs. 0.018, p = 0.04). At the cisternal segment of ipsilateral trigeminal nerve, symptoms of < 5 years were associated with decreased FA and increased λ2, while symptoms of ≧ 5 years were associated with increased FA and decreased λ2 after SRS (FA − 0.068 vs. 0.031, p = 0.04, λ2 0.0003 vs. − 0.0002, p = 0.02).

Conclusions SRS provides high rates of initial pain relief with moderate rates of facial hypoesthesia. Ipsilateral trigeminal nerve was associated with higher baseline REZ Cs, and baseline FAwas associated with duration of symptoms. There were significant associations between duration of symptoms and changes in ipsilateral REZ Cl, cisternal segment FA, and cisternal segment λ2 after SRS. These preliminary findings serve as comparisons for future studies investigating the use of DTI in radiosurgical planning for patients with TN.

The Effect of Timing of Concurrent Chemoradiation in Patients With Newly Diagnosed Glioblastoma

Relationship of glioblastoma multiforme to the subventricular zone is associated with survival

Neurosurgery 77:248–253, 2015

The effect of timing of initiation of concurrent radiation and chemotherapy after surgery on outcome of patients with glioblastoma (GBM) remains unclear.

OBJECTIVE: To further explore this issue, we analyzed 4 clinical trials for patients newly diagnosed with GBM receiving concurrent and adjuvant temozolomide.

METHODS: The cohort study included 198 adult patients with newly diagnosed supratentorial GBM who were enrolled from 2004 to 2010 in 4 clinical trials consisting of radiation plus temozolomide and an experimental agent. The interval to initiation of therapy was determined from the time of surgical resection. The partitioning deletion/ substitution/addition algorithm was used to determine the cutoff points for timing of chemoradiation at which there was a significant difference in overall survival (OS) and progression-free survival (PFS).

RESULTS: The median wait time between surgery and initiation of concurrent chemoradiation was 29.5 days (range, 7-56 days). A short delay in chemoradiation administration (at 30-34 days) was predictive of prolonged OS (hazard ratio [HR]: 0.63, P = .03) and prolonged PFS (HR: 0.68, P = .06) compared with early initiation of concurrent chemoradiation (<30 days), after adjusting for protocol and baseline prognostic variables including extent of resection by multivariate analysis. A longer delay to chemoradiation beyond 34 days was not associated with improved OS or PFS compared with early initiation (HR: 0.94, P = .77 and HR: 0.91, P = .63, respectively).

CONCLUSION: A short delay in the start of concurrent chemoradiation is beyond the classic paradigm of 4 weeks post-resection and may be associated with prolonged OS and PFS.

Adverse radiation effect after stereotactic radiosurgery for brain metastases

Adverse radiation effect after stereotactic radiosurgery for brain metastases- incidence, time course, and risk factors

J Neurosurg 123:373–386, 2015

The authors sought to determine the incidence, time course, and risk factors for overall adverse radiation effect (ARE) and symptomatic ARE after stereotactic radiosurgery (SRS) for brain metastases.

Methods All cases of brain metastases treated from 1998 through 2009 with Gamma Knife SRS at UCSF were considered. Cases with less than 3 months of follow-up imaging, a gap of more than 8 months in imaging during the 1st year, or inadequate imaging availability were excluded. Brain scans and pathology reports were reviewed to ensure consistent scoring of dates of ARE, treatment failure, or both; in case of uncertainty, the cause of lesion worsening was scored as indeterminate. Cumulative incidence of ARE and failure were estimated with the Kaplan-Meier method with censoring at last imaging. Univariate and multivariate Cox proportional hazards analyses were performed.

Results Among 435 patients and 2200 brain metastases evaluable, the median patient survival time was 17.4 months and the median lesion imaging follow-up was 9.9 months. Calculated on the basis of 2200 evaluable lesions, the rates of treatment failure, ARE, concurrent failure and ARE, and lesion worsening with indeterminate cause were 9.2%, 5.4%, 1.4%, and 4.1%, respectively. Among 118 cases of ARE, approximately 60% were symptomatic and 85% occurred 3–18 months after SRS (median 7.2 months). For 99 ARE cases managed without surgery or bevacizumab, the probabilities of improvement observed on imaging were 40%, 57%, and 76% at 6, 12, and 18 months after onset of ARE. The most important risk factors for ARE included prior SRS to the same lesion (with 20% 1-year risk of symptomatic ARE vs 3%, 4%, and 8% for no prior treatment, prior whole brain radiotherapy [WBRT], or concurrent WBRT) and any of these volume parameters: target, prescription isodose, 12-Gy, or 10-Gy volume. Excluding lesions treated with repeat SRS, the 1-year probabilities of ARE were < 1%, 1%, 3%, 10%, and 14% for maximum diameter 0.3–0.6 cm, 0.7–1.0 cm, 1.1–1.5 cm, 1.6–2.0 cm, and 2.1–5.1 cm, respectively. The 1-year probabilities of symptomatic ARE leveled off at 13%–14% for brain metastases maximum diameter > 2.1 cm, target volume > 1.2 cm3, prescription isodose volume > 1.8 cm3, 12-Gy volume > 3.3 cm3, and 10-Gy volume > 4.3 cm3, excluding lesions treated with repeat SRS. On both univariate and multivariate analysis, capecitabine, but not other systemic therapy within 1 month of SRS, appeared to increase ARE risk. For the multivariate analysis considering only metastases with target volume > 1.0 cm3, risk factors for ARE included prior SRS, kidney primary tumor, connective tissue disorder, and capecitabine.

Conclusions Although incidence of ARE after SRS was low overall, risk increased rapidly with size and volume, leveling off at a 1-year cumulative incidence of 13%–14%. This study describes the time course of ARE and provides risk estimates by various lesion characteristics and treatment parameters to aid in decision-making and patient counseling.

Outcomes After Surgery and Radiotherapy for Spinal Myxopapillary Ependymoma

Spinal Myxopapillary Ependymoma

Neurosurgery 75:205–214, 2014

The role of radiotherapy after surgery for myxopapillary ependymoma (MPE) is unclear.

OBJECTIVE: To review long-term outcomes after surgery, with or without radiation, for spinal MPE.

METHODS: Fifty-one patients with spinal MPE treated from 1968 to 2007 were included. Associations between clinical variables and overall survival (OS), progressionfree survival (PFS), and local control (LC) were tested with Cox regression analysis.

RESULTS: The median age at diagnosis was 35 years (range, 8-63 years). Twenty patients (39%) had surgery alone, 30 (59%) had surgery plus radiotherapy (RT), and 1 (2%) had RT only. At a median follow-up of 11 years (range, 0.2-37 years), 10-year OS, PFS, and LC for the entire group were 93%, 63%, and 67%, respectively. Nineteen patients (37%) had disease recurrence, and the recurrence was mostly local (79%). Twenty-eight of 50 patients who had surgery (56%) had gross total resection; 10-year LC was 56% after surgery vs 92% after surgery and RT (log-rank P = .14); the median time of LC was 10.5 years for patients receiving gross total resection plus RT, and 4.75 years for gross total resection only (P = .03). Among 16 patients with subtotal resection and follow-up data, 10-year LC was 0% after surgery vs 65% for surgery plus RT (log-rank P = .008). On multivariate analyses adjusting for resection type, age older that 35 years at diagnosis and receipt of adjuvant radiation were associated with improved PFS (hazard ratio [HR]: 0.14, P = .003 and HR: 0.45, P = .009) and LC (HR: 0.22, P = .02 and HR: 0.45, P = .009).

CONCLUSION: Postoperative radiotherapy after resection of MPE was associated with improved PFS and LC.

Long-term Outcomes After Staged-Volume Stereotactic Radiosurgery for Large Arteriovenous Malformations

Neurosurgery 71:632–644, 2012 DOI: 10.1227/NEU.0b013e31825fd247

Stereotactic radiosurgery is an effective treatment modality for small arteriovenous malformations (AVMs) of the brain. For larger AVMs, the treatment dose is often lowered to reduce potential complications, but this decreases the likelihood of cure. One strategy is to divide large AVMs into smaller anatomic volumes and treat each volume separately.

OBJECTIVE: To prospectively assess the long-term efficacy and complications associated with staged-volume radiosurgical treatment of large, symptomatic AVMs.

METHODS: Eighteen patients with AVMs larger than 15 mL underwent prospective staged-volume radiosurgery over a 13-year period. The median AVM volume was 22.9 mL (range, 15.7-50 mL). Separate anatomic volumes were irradiated at 3- to 9-month intervals (median volume, 10.9 mL; range, 5.3-13.4 mL; median marginal dose, 15 Gy; range, 15-17 Gy). The AVM was divided into 2 volumes in 10 patients, 3 volumes in 5 patients, and 4 volumes in 3 patients. Seven patients underwent retreatment for residual disease.

RESULTS: Actuarial rates of complete angiographic occlusion were 29% and 89% at 5 and 10 years. Five patients (27.8%) had a hemorrhage after radiosurgery. Kaplan-Meier analysis of cumulative hemorrhage rates after treatment were 12%, 18%, 31%, and 31% at 2, 3, 5, and 10 years, respectively. One patient died after a hemorrhage (5.6%).

CONCLUSION: Staged-volume radiosurgery for AVMs larger than 15 mL is a viable treatment strategy. The long-term occlusion rate is high, whereas the radiation-related complication rate is low. Hemorrhage during the lag period remains the greatest source of morbidity and mortality.