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Current and novel practice of stereotactic radiosurgery

JNSPG 75th Anniversary Invited Review Article

Douglas Kondziolka

Stereotactic radiosurgery emerged as a neurosurgical discipline in order to utilize energy for the manipulation of brain or nerve tissue, with the goal of minimal access and safe and effective care of a spectrum of neurosurgical disorders. Perhaps no other branch of neurosurgery has been so disruptive across the entire discipline of brain tumor care, treatment of vascular disorders, and management of functional problems. Radiosurgery is mainstream, supported by thousands of peer-reviewed outcomes reports. This article reviews current practice with a focus on challenges, emerging trends, and areas of investigation.

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Ching-Jen Chen, Kathryn N. Kearns, Dale Ding, Hideyuki Kano, David Mathieu, Douglas Kondziolka, Caleb Feliciano, Rafael Rodriguez-Mercado, Inga S. Grills, Gene H. Barnett, L. Dade Lunsford and Jason P. Sheehan

OBJECTIVE

Arteriovenous malformations (AVMs) of the basal ganglia (BG) and thalamus are associated with elevated risks of both hemorrhage if left untreated and neurological morbidity after resection. Therefore, stereotactic radiosurgery (SRS) has become a mainstay in the management of these lesions, although its safety and efficacy remain incompletely understood. The aim of this retrospective multicenter cohort study was to evaluate the outcomes of SRS for BG and thalamic AVMs and determine predictors of successful endpoints and adverse radiation effects.

METHODS

The authors retrospectively reviewed data on patients with BG or thalamic AVMs who had undergone SRS at eight institutions participating in the International Gamma Knife Research Foundation (IGKRF) from 1987 to 2014. Favorable outcome was defined as AVM obliteration, no post-SRS hemorrhage, and no permanently symptomatic radiation-induced changes (RICs). Multivariable models were developed to identify independent predictors of outcome.

RESULTS

The study cohort comprised 363 patients with BG or thalamic AVMs. The mean AVM volume and SRS margin dose were 3.8 cm3 and 20.7 Gy, respectively. The mean follow-up duration was 86.5 months. Favorable outcome was achieved in 58.5% of patients, including obliteration in 64.8%, with rates of post-SRS hemorrhage and permanent RIC in 11.3% and 5.6% of patients, respectively. Independent predictors of favorable outcome were no prior AVM embolization (p = 0.011), a higher margin dose (p = 0.008), and fewer isocenters (p = 0.044).

CONCLUSIONS

SRS is the preferred intervention for the majority of BG and thalamic AVMs. Patients with morphologically compact AVMs that have not been previously embolized are more likely to have a favorable outcome, which may be related to the use of a higher margin dose.

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Jason P. Sheehan, Inga Grills, Veronica L. Chiang, Huamei Dong, Arthur Berg, Ronald E. Warnick, Douglas Kondziolka and Brian Kavanagh

OBJECTIVE

Stereotactic radiosurgery (SRS) is increasingly used for the treatment of brain metastasis. To date, most studies have focused on survival, radiological response, or surrogate quality endpoints such as Karnofsky Performance Scale status or neurocognitive indices. The current study prospectively evaluated pre-procedural factors impacting quality of life in brain metastasis patients undergoing SRS.

METHODS

Using a national, cloud-based platform, patients undergoing SRS for brain metastasis were accrued to the registry. Quality of life prior to SRS was assessed using the 5-level EQ-5D (EQ5D-L) validated tool; additionally, patient and treatment attributes were collected. Patient quality of life was assessed as part of routine follow-up after SRS. Factors predicting a difference in the aggregate EQ5D-L score or the subscores were evaluated. Pre-SRS covariates impacting changes in EQ5D-L were statistically evaluated. Statistical analyses were conducted using multivariate linear regression models.

RESULTS

EQ5D-L results were available for 116 patients. EQ5D-L improvement (average of 0.387) was noted in patients treated with earlier SRS (p = 0.000175). Worsening overall EQ5D-L (average of 0.052 per lesion) was associated with an increased number of brain metastases at the time of initial presentation (p = 0.0399). Male sex predicted a risk of worsening (average of 0.347) of the pain and discomfort subscore at last follow-up (p = 0.004205). Baseline subscores of pain/discomfort were not correlated with pain/discomfort subscores at follow-up (p = 0.604), whereas baseline subscores of anxiety/depression were strongly positively correlated with the anxiety/depression follow-up subscores (p = 0.0039).

CONCLUSIONS

After SRS, quality of life was likely to improve in patients treated early with SRS and worsen in those with a greater number of brain metastases. Sex differences appear to exist regarding pain and discomfort worsening after SRS. Those with high levels of anxiety and depression at SRS may benefit from medical treatment as this particular quality of life factor generally remains unchanged after SRS.

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Caroline Chung, Dheerendra Prasad, Michael Torrens, Ian Paddick, Patrick Hanssens, Douglas Kondziolka and David A. Jaffray

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Zane Schnurman, John G. Golfinos, David Epstein, David R. Friedmann, J. Thomas Roland Jr. and Douglas Kondziolka

OBJECTIVE

Given rising scrutiny of healthcare expenditures, understanding intervention costs is increasingly important. This study aimed to compare and characterize costs for vestibular schwannoma (VS) management with microsurgery and radiosurgery to inform practice decisions and appraise cost reduction strategies.

METHODS

In conjunction with medical records, internal hospital financial data were used to evaluate costs. Total cost was divided into index costs (costs from arrival through discharge for initial intervention) and follow-up costs (through 36 months) for 317 patients with unilateral VSs undergoing initial management between June 2011 and December 2015. A retrospective matched cohort based on tumor size with 176 patients (88 undergoing each intervention) was created to objectively compare costs between microsurgery and radiosurgery. The full sample of 203 patients treated with resection and 114 patients who underwent radiosurgery was used to evaluate a broad range of outcomes and identify cost contributors within each intervention group.

RESULTS

Within the matched cohort, average index costs were significantly higher for microsurgery (100% by definition, because costs are presented as a percentage of the average index cost for the matched microsurgery group; 95% CI 93–107) compared to radiosurgery (38%, 95% CI 38–39). Microsurgery had higher average follow-up costs (1.6% per month, 95% CI 0.8%–2.4%) compared to radiosurgery (0.5% per month, 95% CI 0.4%–0.7%), largely due to costs incurred in the initial months after resection. A major contributor to total cost and cost variability for both resection and radiosurgery was the need for additional interventions in the follow-up period, which were necessary due to complications or persistent functional deficits. Although tumor size was not associated with increased total costs for radiosurgery, linear regression analysis demonstrated that, for patients who underwent microsurgery, each centimeter increase in tumor maximum diameter resulted in an estimated increase in total cost of 50.2% of the average index cost of microsurgery (95% CI 34.6%–65.7%) (p < 0.001, R2 = 0.17). There were no cost differences associated with the proportion of inpatient days in the ICU or with specific surgical approach for patients who underwent resection.

CONCLUSIONS

This study is the largest assessment to date based on internal cost data comparing VS management with microsurgery and radiosurgery. Both index and follow-up costs are significantly higher when tumors were managed with resection compared to radiosurgery. Larger tumors were associated with increased resection costs, highlighting the incremental costs associated with observation as the initial management.

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Diogo Cordeiro, Zhiyuan Xu, Gautam U. Mehta, Dale Ding, Mary Lee Vance, Hideyuki Kano, Nathaniel Sisterson, Huai-che Yang, Douglas Kondziolka, L. Dade Lunsford, David Mathieu, Gene H. Barnett, Veronica Chiang, John Lee, Penny Sneed, Yan-Hua Su, Cheng-chia Lee, Michal Krsek, Roman Liscak, Ahmed M. Nabeel, Amr El-Shehaby, Khaled Abdel Karim, Wael A. Reda, Nuria Martinez-Moreno, Roberto Martinez-Alvarez, Kevin Blas, Inga Grills, Kuei C. Lee, Mikulas Kosak, Christopher P. Cifarelli, Gennadiy A. Katsevman and Jason P. Sheehan

OBJECTIVE

Recurrent or residual adenomas are frequently treated with Gamma Knife radiosurgery (GKRS). The most common complication after GKRS for pituitary adenomas is hypopituitarism. In the current study, the authors detail the timing and types of hypopituitarism in a multicenter, international cohort of pituitary adenoma patients treated with GKRS.

METHODS

Seventeen institutions pooled clinical data obtained from pituitary adenoma patients who were treated with GKRS from 1988 to 2016. Patients who had undergone prior radiotherapy were excluded. A total of 1023 patients met the study inclusion criteria. The treated lesions included 410 nonfunctioning pituitary adenomas (NFPAs), 262 cases of Cushing’s disease (CD), and 251 cases of acromegaly. The median follow-up was 51 months (range 6–246 months). Statistical analysis was performed using a Cox proportional hazards model to evaluate factors associated with the development of new-onset hypopituitarism.

RESULTS

At last follow-up, 248 patients had developed new pituitary hormone deficiency (86 with NFPA, 66 with CD, and 96 with acromegaly). Among these patients, 150 (60.5%) had single and 98 (39.5%) had multiple hormone deficiencies. New hormonal changes included 82 cortisol (21.6%), 135 thyrotropin (35.6%), 92 gonadotropin (24.3%), 59 growth hormone (15.6%), and 11 vasopressin (2.9%) deficiencies. The actuarial 1-year, 3-year, 5-year, 7-year, and 10-year rates of hypopituitarism were 7.8%, 16.2%, 22.4%, 27.5%, and 31.3%, respectively. The median time to hypopituitarism onset was 39 months.

In univariate analyses, an increased rate of new-onset hypopituitarism was significantly associated with a lower isodose line (p = 0.006, HR = 8.695), whole sellar targeting (p = 0.033, HR = 1.452), and treatment of a functional pituitary adenoma as compared with an NFPA (p = 0.008, HR = 1.510). In multivariate analyses, only a lower isodose line was found to be an independent predictor of new-onset hypopituitarism (p = 0.001, HR = 1.38).

CONCLUSIONS

Hypopituitarism remains the most common unintended effect of GKRS for a pituitary adenoma. Treating the target volume at an isodose line of 50% or greater and avoiding whole-sellar radiosurgery, unless necessary, will likely mitigate the risk of post-GKRS hypopituitarism. Follow-up of these patients is required to detect and treat latent endocrinopathies.

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Gary K. Steinberg, Douglas Kondziolka, Lawrence R. Wechsler, L. Dade Lunsford, Anthony S. Kim, Jeremiah N. Johnson, Damien Bates, Gene Poggio, Casey Case, Michael McGrogan, Ernest W. Yankee and Neil E. Schwartz

OBJECTIVE

The aim of this study was to evaluate the safety and clinical outcomes associated with stereotactic surgical implantation of modified bone marrow–derived mesenchymal stem cells (SB623) in patients with stable chronic ischemic stroke.

METHODS

This was a 2-year, open-label, single-arm, phase 1/2a study; the selected patients had chronic motor deficits between 6 and 60 months after nonhemorrhagic stroke. SB623 cells were administered to the target sites surrounding the subcortical stroke region using MRI stereotactic image guidance.

RESULTS

A total of 18 patients were treated with SB623 cells. All experienced at least 1 treatment-emergent adverse event (TEAE). No patients withdrew due to adverse events, and there were no dose-limiting toxicities or deaths. The most frequent TEAE was headache related to the surgical procedure (88.9%). Seven patients experienced 9 serious adverse events, which resolved without sequelae. In 16 patients who completed 24 months of treatment, statistically significant improvements from baseline (mean) at 24 months were reported for the European Stroke Scale (ESS) score, 5.7 (95% CI 1.4–10.1, p < 0.05); National Institutes of Health Stroke Scale (NIHSS) score, −2.1 (95% CI −3.3 to −1.0, p < 0.01), Fugl-Meyer (F-M) total score, 19.4 (95% CI 9.9–29.0, p < 0.01); and F-M motor scale score, 10.4 (95% CI 4.0–16.7, p < 0.01). Measures of efficacy reached plateau by 12 months with no decline thereafter. There were no statistically significant changes in the modified Rankin Scale score. The size of transient lesions detected by T2-weighted FLAIR imaging in the ipsilateral cortex at weeks 1–2 postimplantation significantly correlated with improvement in ESS (0.619, p < 0.05) and NIHSS (−0.735, p < 0.01) scores at 24 months.

CONCLUSIONS

In this completed 2-year phase 1/2a study, implantation of SB623 cells in patients with stable chronic stroke was safe and was accompanied by improvements in clinical outcomes.

Clinical trial registration no.: NCT01287936 (clinicaltrials.gov)

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Hideyuki Kano, Antonio Meola, Huai-che Yang, Wan-Yuo Guo, Roberto Martínez-Alvarez, Nuria Martínez-Moreno, Dusan Urgosik, Roman Liscak, Or Cohen-Inbar, Jason Sheehan, John Y. K. Lee, Mahmoud Abbassy, Gene H. Barnett, David Mathieu, Douglas Kondziolka and L. Dade Lunsford

OBJECTIVE

For some jugular foramen schwannomas (JFSs), complete resection is possible but may be associated with significant morbidity. Stereotactic radiosurgery (SRS) is a minimally invasive alternative or adjunct to microsurgery for JFSs. The authors reviewed clinical and imaging outcomes of SRS for patients with these tumors.

METHODS

Nine participating centers of the International Gamma Knife Research Foundation identified 92 patients who underwent SRS between 1990 and 2013. Forty-one patients had prior subtotal microsurgical resection. The median interval between previous surgery and SRS was 15 months (range 0.5–144 months). Eighty-four patients had preexisting cranial nerve (CN) symptoms and signs. The median tumor volume was 4.1 cm3 (range 0.8–22.6 cm3), and the median margin dose was 12.5 Gy (range 10–18 Gy). Patients with neurofibromatosis were excluded from this study.

RESULTS

The median follow-up was 51 months (range 6–266 months). Tumors regressed in 47 patients, remained stable in 33, and progressed in 12. The progression-free survival (PFS) was 93% at 3 years, 87% at 5 years, and 82% at 10 years. In the entire series, only a dumbbell shape (extension extracranially via the jugular foramen) was significantly associated with worse PFS. In the group of patients without prior microsurgery (n = 51), factors associated with better PFS included tumor volume < 6 cm3 (p = 0.037) and non–dumbbell-shaped tumors (p = 0.015). Preexisting cranial neuropathies improved in 27 patients, remained stable in 51, and worsened in 14. The CN function improved after SRS in 12% of patients at 1 year, 24% at 2 years, 27% at 3 years, and 32% at 5 years. Symptomatic adverse radiation effects occurred in 7 patients at a median of 7 months after SRS (range 5–38 months). Six patients underwent repeat SRS at a median of 64 months (range 44–134 months). Four patients underwent resection at a median of 14 months after SRS (range 8–30 months).

CONCLUSIONS

Stereotactic radiosurgery proved to be a safe and effective primary or adjuvant management approach for JFSs. Long-term tumor control rates and stability or improvement in CN function were confirmed.

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Kyung-Jae Park, Hideyuki Kano, Aditya Iyer, Xiaomin Liu, Daniel A. Tonetti, Craig Lehocky, Andrew Faramand, Ajay Niranjan, John C. Flickinger, Douglas Kondziolka and L. Dade Lunsford

OBJECTIVE

The authors of this study evaluate the long-term outcomes of stereotactic radiosurgery (SRS) for cavernous sinus meningioma (CSM).

METHODS

The authors retrospectively assessed treatment outcomes 5–18 years after SRS in 200 patients with CSM. The median patient age was 57 years (range 22–83 years). In total, 120 (60%) patients underwent Gamma Knife SRS as primary management, 46 (23%) for residual tumors, and 34 (17%) for recurrent tumors after one or more surgical procedures. The median tumor target volume was 7.5 cm3 (range 0.1–37.3 cm3), and the median margin dose was 13.0 Gy (range 10–20 Gy).

RESULTS

Tumor volume regressed in 121 (61%) patients, was unchanged in 49 (25%), and increased over time in 30 (15%) during a median imaging follow-up of 101 months. Actuarial tumor control rates at the 5-, 10-, and 15-year follow-ups were 92%, 84%, and 75%, respectively. Of the 120 patients who had undergone SRS as a primary treatment (primary SRS), tumor progression was observed in 14 (11.7%) patients at a median of 48.9 months (range 4.8–120.0 months) after SRS, and actuarial tumor control rates were 98%, 93%, 85%, and 85% at the 1-, 5-, 10-, and 15-year follow-ups post-SRS. A history of tumor progression after microsurgery was an independent predictor of an unfavorable response to radiosurgery (p = 0.009, HR = 4.161, 95% CI 1.438–12.045). Forty-four (26%) of 170 patients who had presented with at least one cranial nerve (CN) deficit improved after SRS. Development of new CN deficits after initial microsurgical resection was an unfavorable factor for improvement after SRS (p = 0.014, HR = 0.169, 95% CI 0.041–0.702). Fifteen (7.5%) patients experienced permanent CN deficits without evidence of tumor progression at a median onset of 9 months (range 2.3–85 months) after SRS. Patients with larger tumor volumes (≥ 10 cm3) were more likely to develop permanent CN complications (p = 0.046, HR = 3.629, 95% CI 1.026–12.838). Three patients (1.5%) developed delayed pituitary dysfunction after SRS.

CONCLUSIONS

This long-term study showed that Gamma Knife radiosurgery provided long-term tumor control for most patients with CSM. Patients who underwent SRS for progressive tumors after prior microsurgery had a greater chance of tumor growth than the patients without prior surgery or those with residual tumor treated after microsurgery.

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Michael J. Link, Douglas Kondziolka and Madjid Samii