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Dose fractionation in stereotactic radiotherapy for parasellar meningiomas: radiobiological considerations of efficacy and optic nerve tolerance

Dennis C. Shrieve, Lisa Hazard, Kenneth Boucher, and Randy L. Jensen

Object. Benign meningiomas have been shown to be equally well controlled with single-dose radiosurgery (15 Gy) and fractionated doses of 54 Gy in 30 fractions after adequate follow up. For a subset of patients with meningioma, the optic apparatus is dose limiting when considering single-dose stereotactic radiosurgery, with tolerance estimated to be 8 to 10 Gy. Recently, hypofractionated regimens have been used to treat benign meningiomas with a small number of fractions. An analysis of the expected efficacy of hypofractionation compared with the estimated optic tolerance to fractionated radiotherapy was undertaken.

Methods. Using the assumption that 15 Gy in one fraction and 54 Gy in 30 fractions are isoeffective for control of benign meningioma, an α/β for meningioma is calculated to be 3.28 Gy. Invoking a 10% error for these doses (15 Gy ± 10% is equivalent to 54 Gy ± 10%) results in upper and lower limits of the estimate for α/β of 3.85 Gy and 2.7 Gy. Using these estimates, isoeffect curves for control of meningioma were constructed for fraction numbers of one to 45. Best estimates of optic nerve/chiasm tolerance to single doses of radiation are 8 to 10 Gy, with the reported incidence of optic neuropathy increasing significantly at higher doses. This is consistent with the optic ret model, which also predicts for optic tolerance following fractionated radiotherapy. Comparison of optic tolerance and estimates of efficacious doses at fraction numbers between one and 30 were made. Statistical estimates of patient numbers and duration of follow up required to rule out optic neuropathy following radiotherapy were made. Single doses of radiation required to treat benign meningioma optimally (13.5–16.5 Gy) clearly exceed the estimated and reported clinical tolerance of the optic nerves and chiasm. The application of equivalent biological doses in a small number of fractions continues to exceed optic tolerance until at least 25 fractions are applied.

Conclusions. The use of small numbers of fractions to treat patients with meningioma when portions of optic nerve or chiasm receive full dose may result in undertreatment of the tumor and/or exceeding optic nerve tolerance. In such cases standard fractionation is recommended. Ruling out a low, yet unacceptable, risk of optic neuropathy may require the close study of many patients with long-term follow-up evaluation.

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Anaplastic meningioma: an analysis of the National Cancer Database from 2004 to 2012

Andrew Orton, Jonathan Frandsen, Randy Jensen, Dennis C. Shrieve, and Gita Suneja

OBJECTIVE

Anaplastic meningiomas represent 1%–2% of meningioma diagnoses and portend a poor prognosis. Limited information is available on practice patterns and optimal management. The purpose of this study was to define treatment patterns and outcomes by treatment modality using a large national cancer registry.

METHODS

The National Cancer Database was used to identify patients diagnosed with anaplastic meningioma from 2004 to 2012. Log-rank statistics were used to compare survival outcomes by extent of resection, use of adjuvant radiotherapy (RT), and use of adjuvant chemotherapy. Least-squares linear regression was used to evaluate the utilization of RT over time. Logistic regression modeling was used to identify predictors of receipt of RT. Cox proportional hazards modeling was used to evaluate the effect of RT, gross-total resection (GTR), and chemotherapy on survival.

RESULTS

A total of 755 adults with anaplastic meningioma were identified. The 5-year overall survival rate was 41.4%. Fifty-two percent of patients received RT, 7% received chemotherapy, and 58% underwent GTR. Older patients were less likely to receive RT (OR 0.98, p < 0.01). Older age (HR 1.04, p < 0.01), high comorbidity score (HR 1.33, p = 0.02), and subtotal resection (HR 1.57, p = 0.02) were associated with increased risk of death on multivariate modeling, while RT receipt was associated with decreased risk of death (HR 0.79, p = 0.04). Chemotherapy did not have a demonstrable effect on survival (HR 1.33, p = 0.18).

CONCLUSIONS

Anaplastic meningioma portends a poor prognosis. Gross-total resection and RT are associated with improved survival, but utilization of RT is low. Unless medically contraindicated, patients with anaplastic meningioma should be offered RT.

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Sciatic nerve sarcoidosis: utility of magnetic resonance peripheral nerve imaging and treatment with radiation therapy

Case report

Andrew T. Dailey, Matthew T. Rondina, Jeannette J. Townsend, Dennis C. Shrieve, J. Richard Baringer, and Kevin R. Moore

✓ Sarcoidosis may involve both the central and peripheral nervous system, although peripheral nerve manifestations are usually seen late in the disease. In this report, the authors describe a case of sarcoidosis in a 22-year-old woman who presented with a foot drop. Although results of conventional lumbar magnetic resonance (MR) imaging were normal, MR peripheral nerve imaging of the thigh showed a mass in the sciatic nerve indicating tumor. An intraoperative biopsy sample revealed noncaseating granulomas consistent with sarcoid. The patient was treated with steroid drugs to control the manifestations of her disease but exhibited early signs of femoral bone necrosis, which required discontinuation of the steroids. She was then treated with local radiation therapy. At her 2-year follow-up visit the patient demonstrated relief of her symptoms and improvement on MR peripheral nerve imaging. This case demonstrates that sarcoidosis may present with peripheral nerve manifestations. The appearance of a diffusely swollen nerve on MR imaging should prompt clinicians to include sarcoidosis in the differential diagnosis and plan surgery accordingly. Patients who are not responsive to or who are unable to tolerate medical therapy may be treated with radiation therapy.

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Treatment of patients with primary glioblastoma multiforme with standard postoperative radiotherapy and radiosurgical boost: prognostic factors and long-term outcome

Dennis C. Shrieve, Eben Alexander III, Peter McL. Black, Patrick Y. Wen, Howard A. Fine, Hanne M. Kooy, and Jay S. Loeffler

Object. To assess the value of stereotactic radiosurgery (SRS) as adjunct therapy in patients suffering from glioblastoma multiforme (GBM), the authors analyzed their experience with 78 patients.

Methods. Between June 1988 and January 1995, 78 patients underwent SRS as part of their initial treatment for GBM. All patients had undergone initial surgery or biopsy confirming the diagnosis of GBM and received conventional external beam radiotherapy. Stereotactic radiosurgery was performed using a dedicated 6-MV stereotactic linear accelerator. Thirteen patients were alive at the time of analysis with a median follow-up period of 40.8 months. The median length of actuarial survival for all patients was 19.9 months. Twelve- and 24-month survival rates were 88.5% and 35.9%, respectively. Patient age and Radiation Therapy Oncology Group (RTOG) class were significant prognostic indicators according to univariate analysis (p < 0.05). Twenty-three patients aged younger than 40 years had a median survival time of 48.6 months compared with 55 older patients who had 18.2 months (p < 0.001). Patients in this series fell into RTOG Classes III (27 patients), IV (29 patients), or V (22 patients). Class III patients had a median survival time of 29.5 months following diagnosis; this was significantly longer than median survival times for Classes IV and V, which were 19.2 and 18.2 months, respectively (p = 0.001). Only patient age (< 40 years) was a significant prognostic factor according to multivariate analysis. Acute complications were unusual and limited to exacerbation of existing symptoms. There were no new neuropathies secondary to SRS. Thirty-nine patients (50%) underwent reoperation for symptomatic necrosis or recurrent tumor. The rate of reoperation at 24 months following SRS was 54.8%.

Conclusions. The addition of a radiosurgery boost appears to confer a survival advantage to selected patients.

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Local control after stereotactic radiosurgery for brain metastases in patients with melanoma with and without BRAF mutation and treatment

David Ly, Hilary P. Bagshaw, Christopher J. Anker, Jonathan D. Tward, Kenneth F. Grossmann, Randy L. Jensen, and Dennis C. Shrieve

OBJECT

BRAF inhibitors improve progression-free and overall survival in patients with metastatic melanoma. Brain metastases are common, and stereotactic radiosurgery (SRS) has been used, resulting in excellent local control. Because BRAF inhibitors are associated with intracranial responses, the authors hypothesized that BRAF inhibitors would improve local control in patients with melanoma who are receiving SRS for brain metastases.

METHODS

The authors retrospectively identified patients with metastatic melanoma who had been tested for BRAF mutation and treated with SRS for brain metastases. Patients with previous resection, multiple brain metastases, or multiple courses of SRS were eligible. SRS was delivered in a single fraction to a median dose of 2000 cGy. Patients with a BRAF mutation were treated with a BRAF inhibitor on the basis of physician preference.

RESULTS

The authors identified 52 patients who were treated in 82 treatment sessions for 185 brain metastases and 13 tumor beds. At a median follow-up of 10.5 months, the 1-year local control rate was 69.2%. At 1 year, the local control rate for brain metastases in patients with BRAF mutation with BRAF treatment was 85.0%, and the local control rate for brain metastases in those without BRAF treatment was 51.5% (p = 0.0077). The rates of distant brain failure, freedom from whole-brain radiation, and overall survival were not different on the basis of BRAF mutation status or inhibitor therapy. The number of new intratumoral hemorrhages after SRS was increased significantly in patients with BRAF treatment.

CONCLUSIONS

Treatment with BRAF inhibitors was associated with improved local control after SRS in patients with melanoma and brain metastases. An increased number of intratumoral hemorrhages was associated with BRAF inhibitor therapy.

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Adjuvant radiotherapy for atypical meningiomas

Hilary P. Bagshaw, Lindsay M. Burt, Randy L. Jensen, Gita Suneja, Cheryl A. Palmer, William T. Couldwell, and Dennis C. Shrieve

OBJECTIVE

The aim of this paper was to evaluate outcomes in patients with atypical meningiomas (AMs) treated with surgery alone compared with surgery and radiotherapy at initial diagnosis, or at the time of first recurrence.

METHODS

Patients with pathologically confirmed AMs treated at the University of Utah from 1991 to 2014 were retrospectively reviewed. Local control (LC), overall survival (OS), Karnofsky Performance Status (KPS), and toxicity were assessed. Outcomes for patients receiving adjuvant radiotherapy were compared with those for patients treated with surgery alone. Kaplan-Meier and the log-rank test for significance were used for LC and OS analyses.

RESULTS

Fifty-nine patients with 63 tumors were reviewed. Fifty-two patients were alive at the time of analysis with a median follow-up of 42 months. LC for all tumors was 57% with a median time to local failure (TTLF) of 48 months. The median TTLF following surgery and radiotherapy was 180 months, compared with 46 months following surgery alone (p = 0.02). Excluding Simpson Grade IV (subtotal) resections, there remained an LC benefit with the addition of radiotherapy for Simpson Grade I, II, and III resected tumors (median TTLF 180 months after surgery and radiotherapy compared with 46 months with surgery alone [p = 0.002]). Patients treated at first recurrence following any initial therapy (either surgery alone or surgery and adjuvant radiotherapy) had a median TTLF of 26 months compared with 48 months for tumors treated at first diagnosis (p = 0.007). There were 2 Grade 3 toxicities and 1 Grade 4 toxicity associated with radiotherapy.

CONCLUSIONS

Adjuvant radiotherapy improves LC for AMs. The addition of adjuvant radiotherapy following even a Simpson Grade I, II, or III resection was found to confer an LC benefit. Recurrent disease is difficult to control, underscoring the importance of aggressive initial treatment.

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Patterns of care and outcomes in gliosarcoma: an analysis of the National Cancer Database

Jonathan Frandsen, Andrew Orton, Randy Jensen, Howard Colman, Adam L. Cohen, Jonathan Tward, Dennis C. Shrieve, and Gita Suneja

OBJECTIVE

The authors compared presenting characteristics and survival for patients with gliosarcoma (GS) and glioblastoma (GBM). Additionally, they performed a survival analysis for patients who underwent GS treatments with the hypothesis that trimodality therapy (surgery followed by radiation and chemotherapy) would be superior to nontrimodality therapy (surgery alone or surgery followed by chemotherapy or radiation).

METHODS

Adults diagnosed with GS and GBM between the years 2004 and 2013 were queried from the National Cancer Database. Chi-square analysis was used to compare presenting characteristics. Kaplan-Meier, Cox regression, and propensity score analyses were employed for survival analyses.

RESULTS

In total, data from 1102 patients with GS and 36,658 patients with GBM were analyzed. Gliosarcoma had an increased rate of gross-total resection (GTR) compared with GBM (19% vs 15%, p < 0.001). Survival was not different for patients with GBM (p = 0.068) compared with those with GS. After propensity score analysis for GS, patients receiving trimodality therapy (surgery followed by radiation and chemotherapy) had improved survival (12.9 months) compared with those not receiving trimodality therapy (5.5 months). In multivariate analysis, GTR, female sex, fewer comorbidities, trimodality therapy, and age < 65 years were associated with improved survival. There was a trend toward improved survival with MGMT promoter methylation (p = 0.117).

CONCLUSIONS

In this large registry study, there was no difference in survival in patients with GBM compared with GS. Among GS patients, trimodality therapy significantly improved survival compared with nontrimodality therapy. Gross-total resection also improved survival, and there was a trend toward increased survival with MGMT promoter methylation in GS. The major potential confounder in this study is that patients with poor functional status may not have received aggressive radiation or chemotherapy treatments, leading to the observed outcome. This study should be considered hypothesis-generating; however, due to its rarity, conducting a clinical trial with GS patients alone may prove difficult.

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Reliability of contour-based volume calculation for radiosurgery

Laboratory investigation

Lijun Ma, Arjun Sahgal, Ke Nie, Andrew Hwang, Aliaksandr Karotki, Brian Wang, Dennis C. Shrieve, Penny K. Sneed, Michael McDermott, and David A. Larson

Object

Determining accurate target volume is critical for both prescribing and evaluating stereotactic radiosurgery (SRS) treatments. The aim of this study was to determine the reliability of contour-based volume calculations made by current major SRS platforms.

Methods

Spheres ranging in diameter from 6.4 to 38.2 mm were scanned and then delineated on imaging studies. Contour data sets were subsequently exported to 6 SRS treatment-planning platforms for volume calculations and comparisons. This procedure was repeated for the case of a patient with 12 metastatic lesions distributed throughout the brain. Both the phantom and patient datasets were exported to a stand-alone workstation for an independent volume-calculation analysis using a series of 10 algorithms that included approaches such as slice stacking, surface meshing, point-cloud filling, and so forth.

Results

Contour data–rendered volumes exhibited large variations across the current SRS platforms investigated for both the phantom (−3.6% to 22%) and patient case (1.0%–10.2%). The majority of the clinical SRS systems and algorithms overestimated the volumes of the spheres, compared with their known physical volumes. An independent algorithm analysis found a similar trend in variability, and large variations were typically associated with small objects whose volumes were < 0.4 cm3 and with those objects located near the end-slice of the scan limits.

Conclusions

Significant variations in volume calculation were observed based on data obtained from the SRS systems that were investigated. This observation highlights the need for strict quality assurance and benchmarking efforts when commissioning SRS systems for clinical use and, moreover, when conducting multiinstitutional cross-SRS platform clinical studies.

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Dual isotope single-photon emission computerized tomography used for prediction of histology and survival in patients after high-dose radiotherapy for malignant astrocytoma

Richard B. Schwartz, B. Leonard Holman, Basem M. Garada, Paulo A. Carvalho, Rebecca Folkerth, Marc S. Schwartz, Jay S. Loeffler, Dennis C. Shrieve, Joseph F. Polak, Peter McL. Black, and Eben Alexander III

This study was conducted to determine the sensitivity of dual-isotope single-photon emission computerized tomography (SPECT) in predicting tumor recurrence and survival in patients treated with high-dose radiotherapy for malignant gliomas.

Studies using SPECT with thallium-201 (Tl-201) and technetium-99m (Tc-99m) hexamethypropyleneamine oxime (HMPAO) in 50 consecutive patients with malignant astrocytomas treated by surgery and high-dose radiotherapy were performed 1 day before reoperation. Maximum uptake of Tl-201 in the lesion was expressed as a ratio to that of the contralateral scalp, and uptake of Tc-99m HMPAO was expressed as a ratio to that of the cerebellar cortex. Patients were stratified into groups based on maximum radioisotope uptake values in their tumor beds. Differences in tumor histopathology at reoperation and 1-year survival between SPECT groups were determined by using chi-square analysis.

The majority of patients in Group IA (Tl-201 ratio less than 2 or Tc-99m HMPAO ratio less than 0.5) showed radiation changes in their biopsy specimens (85.7%); they had an 85.7% 1-year survival rate. Group II (Tl-201 ratio between 2 and 3.5) had predominantly infiltrating tumor (78.6%); they had a 42% 1-year survival rate. Almost all of the patients in Group III (Tl-201 ratio greater than 3.5) had solid tumor (93.3%) and they had a 6.7% 1-year survival. Survival and pathological data differed significantly among groups (p less than 0.009).

Dual-isotope SPECT data correlates with histological findings on reoperation and postoperative survival in patients with malignant gliomas.

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Apparatus dependence of normal brain tissue dose in stereotactic radiosurgery for multiple brain metastases

Technical note

Lijun Ma, Paula Petti, Brian Wang, Martina Descovich, Cynthia Chuang, Igor J. Barani, Sandeep Kunwar, Dennis C. Shrieve, Arjun Sahgal, and David A. Larson

Object

Technical improvements in commercially available radiosurgery platforms have made it practical to treat a large number of intracranial targets. The goal of this study was to investigate whether the dose to normal brain when planning radiosurgery to multiple targets is apparatus dependent.

Methods

The authors selected a single case involving a patient with 12 metastatic lesions widely distributed throughout the brain as visualized on contrast-enhanced CT. Target volumes and critical normal structures were delineated with Leksell Gamma Knife Perfexion software. The imaging studies including the delineated contours were digitally exported into the CyberKnife and Novalis multileaf collimator–based planning systems for treatment planning using identical target dose goals and dose-volume constraints. Subsets of target combinations (3, 6, 9, or 12 targets) were planned separately to investigate the relationship of number of targets and radiosurgery platform to the dose to normal brain.

Results

Despite similar target dose coverage and dose to normal structures, the dose to normal brain was strongly apparatus dependent. A nonlinear increase in dose to normal brain volumes with increasing number of targets was also noted.

Conclusions

The dose delivered to normal brain is strongly dependent on the radiosurgery platform. How general this conclusion is and whether apparatus-dependent differences are related to differences in hardware design or differences in dose-planning algorithms deserve further investigation.