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Nasser Mohammed, Dale Ding, Yi-Chieh Hung, Zhiyuan Xu, Cheng-Chia Lee, Hideyuki Kano, Roberto Martínez-Álvarez, Nuria Martínez-Moreno, David Mathieu, Mikulas Kosak, Christopher P. Cifarelli, Gennadiy A. Katsevman, L. Dade Lunsford, Mary Lee Vance and Jason P. Sheehan

OBJECTIVE

The role of primary stereotactic radiosurgery (SRS) in patients with medically refractory acromegaly who are not operative candidates or who refuse resection is poorly understood. The aim of this multicenter, matched cohort study was to compare the outcomes of primary versus postoperative SRS for acromegaly.

METHODS

The authors reviewed an International Radiosurgery Research Foundation database of 398 patients with acromegaly who underwent SRS and categorized them into primary or postoperative cohorts. Patients in the primary SRS cohort were matched, in a 1:2 ratio, to those in the postoperative SRS cohort, and the outcomes of the 2 matched cohorts were compared.

RESULTS

The study cohort comprised 78 patients (median follow-up 66.4 months), including 26 and 52 in the matched primary and postoperative SRS cohorts, respectively. In the primary SRS cohort, the actuarial endocrine remission rates at 2 and 5 years were 20% and 42%, respectively. The Cox proportional hazards model showed that a lower pre-SRS insulin-like growth factor–1 level was predictive of initial endocrine remission (p = 0.03), whereas a lower SRS margin dose was predictive of biochemical recurrence after initial remission (p = 0.01). There were no differences in the rates of radiological tumor control (p = 0.34), initial endocrine remission (p = 0.23), biochemical recurrence after initial remission (p = 0.33), recurrence-free survival (p = 0.32), or hypopituitarism (p = 0.67) between the 2 matched cohorts.

CONCLUSIONS

Primary SRS has a reasonable benefit-to-risk profile for patients with acromegaly in whom resection is not possible, and it has similar outcomes to endocrinologically comparable patients who undergo postoperative SRS. SRS with medical therapy in the latent period can be used as an alternative to surgery in selected patients who cannot or do not wish to undergo resection.

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I. Jonathan Pomeraniec, Davis G. Taylor, Or Cohen-Inbar, Zhiyuan Xu, Mary Lee Vance and Jason P. Sheehan

OBJECTIVE

Gamma Knife radiosurgery (GKRS) provides a safe and effective management option for patients with all types of pituitary adenomas. The long-term adverse effects of targeted radiation to the hypothalamic-pituitary axis in relationship to radiation dose remain unclear. In this retrospective review, the authors investigated the role of differential radiation doses in predicting long-term clinical outcomes and pituitary function after GKRS for pituitary adenomas.

METHODS

A cohort of 236 patients with pituitary tumors (41.5% nonfunctioning, 58.5% functioning adenomas) was treated with GKRS between 1998 and 2015. Point dosimetric measurements, with no minimum volume, to 14 consistent points along the hypothalamus bilaterally, pituitary stalk, and normal pituitary were made. Statistical analyses were performed to determine the impact of doses to critical structures on clinical, radiological, and endocrine outcomes.

RESULTS

With a median follow-up duration of 42.9 months, 18.6% of patients developed new loss of pituitary function. The median time to endocrinopathy was 21 months (range 2–157 months). The median dose was 2.1 Gy to the hypothalamus, 9.1 Gy to the pituitary stalk, and 15.3 Gy to the normal pituitary. Increasing age (p = 0.015, HR 0.98) and ratio of maximum dose to the pituitary stalk over the normal pituitary gland (p = 0.013, HR 0.22) were independent predictors of new or worsening hypopituitarism in the multivariate analysis. Sex, margin dose, treatment volume, nonfunctioning adenoma status, or ratio between doses to the pituitary stalk and hypothalamus were not significant predictors.

CONCLUSIONS

GKRS offers a low rate of delayed pituitary insufficiency for pituitary adenomas. Doses to the hypothalamus are low and generally do not portend endocrine deficits. Patients who are treated with a high dose to the pituitary stalk relative to the normal gland are at higher risk of post-GKRS endocrinopathy. Point dosimetry to specific neuroanatomical structures revealed that a ratio of stalk-to-gland radiation dose of 0.8 or more significantly increased the risk of endocrinopathy following GKRS. Improvement in the gradient index toward the stalk and normal gland may help preserve endocrine function.

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Robert M. Starke, David J. McCarthy, Ching-Jen Chen, Hideyuki Kano, Brendan J. McShane, John Lee, Mohana Rao Patibandla, David Mathieu, Lucas T. Vasas, Anthony M. Kaufmann, Wei Gang Wang, Inga S. Grills, Christopher P. Cifarelli, Gabriella Paisan, John Vargo, Tomas Chytka, Ladislava Janouskova, Caleb E. Feliciano, Nanthiya Sujijantarat, Charles Matouk, Veronica Chiang, Judith Hess, Rafael Rodriguez-Mercado, Daniel A. Tonetti, L. Dade Lunsford and Jason P. Sheehan

OBJECTIVE

The authors performed a study to evaluate the hemorrhagic rates of cerebral dural arteriovenous fistulas (dAVFs) and the risk factors of hemorrhage following Gamma Knife radiosurgery (GKRS).

METHODS

Data from a cohort of patients undergoing GKRS for cerebral dAVFs were compiled from the International Radiosurgery Research Foundation. The annual posttreatment hemorrhage rate was calculated as the number of hemorrhages divided by the patient-years at risk. Risk factors for dAVF hemorrhage prior to GKRS and during the latency period after radiosurgery were evaluated in a multivariate analysis.

RESULTS

A total of 147 patients with dAVFs were treated with GKRS. Thirty-six patients (24.5%) presented with hemorrhage. dAVFs that had any cortical venous drainage (CVD) (OR = 3.8, p = 0.003) or convexity or torcula location (OR = 3.3, p = 0.017) were more likely to present with hemorrhage in multivariate analysis. Half of the patients had prior treatment (49.7%). Post-GRKS hemorrhage occurred in 4 patients, with an overall annual risk of 0.84% during the latency period. The annual risks of post-GKRS hemorrhage for Borden type 2–3 dAVFs and Borden type 2–3 hemorrhagic dAVFs were 1.45% and 0.93%, respectively. No hemorrhage occurred after radiological confirmation of obliteration. Independent predictors of hemorrhage following GKRS included nonhemorrhagic neural deficit presentation (HR = 21.6, p = 0.027) and increasing number of past endovascular treatments (HR = 1.81, p = 0.036).

CONCLUSIONS

Patients have similar rates of hemorrhage before and after radiosurgery until obliteration is achieved. dAVFs that have any CVD or are located in the convexity or torcula were more likely to present with hemorrhage. Patients presenting with nonhemorrhagic neural deficits and a history of endovascular treatments had higher risks of post-GKRS hemorrhage.

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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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Robert M. Starke, David J. McCarthy, Ching-Jen Chen, Hideyuki Kano, Brendan McShane, John Lee, David Mathieu, Lucas T. Vasas, Anthony M. Kaufmann, Wei Gang Wang, Inga S. Grills, Mohana Rao Patibandla, Christopher P. Cifarelli, Gabriella Paisan, John A. Vargo, Tomas Chytka, Ladislava Janouskova, Caleb E. Feliciano, Rafael Rodriguez-Mercado, Daniel A. Tonetti, L. Dade Lunsford and Jason P. Sheehan

OBJECTIVE

In this multicenter study, the authors reviewed the results obtained in patients who underwent Gamma Knife radiosurgery (GKRS) for dural arteriovenous fistulas (dAVFs) and determined predictors of outcome.

METHODS

Data from a cohort of 114 patients who underwent GKRS for cerebral dAVFs were compiled from the International Gamma Knife Research Foundation. Favorable outcome was defined as dAVF obliteration and no posttreatment hemorrhage or permanent symptomatic radiation-induced complications. Patient and dAVF characteristics were assessed to determine predictors of outcome in a multivariate logistic regression analysis; dAVF-free obliteration was calculated in a competing-risk survival analysis; and Youden indices were used to determine optimal radiosurgical dose.

RESULTS

A mean margin dose of 21.8 Gy was delivered. The mean follow-up duration was 4 years (range 0.5–18 years). The overall obliteration rate was 68.4%. The postradiosurgery actuarial rates of obliteration at 3, 5, 7, and 10 years were 41.3%, 61.1%, 70.1%, and 82.0%, respectively. Post-GRKS hemorrhage occurred in 4 patients (annual risk of 0.9%). Radiation-induced imaging changes occurred in 10.4% of patients; 5.2% were symptomatic, and 3.5% had permanent deficits. Favorable outcome was achieved in 63.2% of patients. Patients with middle fossa and tentorial dAVFs (OR 2.4, p = 0.048) and those receiving a margin dose greater than 23 Gy (OR 2.6, p = 0.030) were less likely to achieve a favorable outcome. Commonly used grading scales (e.g., Borden and Cognard) were not predictive of outcome. Female sex (OR 1.7, p = 0.03), absent venous ectasia (OR 3.4, p < 0.001), and cavernous carotid location (OR 2.1, p = 0.019) were predictors of GKRS-induced dAVF obliteration.

CONCLUSIONS

GKRS for cerebral dAVFs achieved obliteration and avoided permanent complications in the majority of patients. Those with cavernous carotid location and no venous ectasia were more likely to have fistula obliteration following radiosurgery. Commonly used grading scales were not reliable predictors of outcome following radiosurgery.

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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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Alana Tooze and Jason P. Sheehan

OBJECTIVE

Pituitary adenomas and the treatment required for the underlying neuropathology have frequently been associated with cognitive dysfunction. However, the mechanisms for these impairments remain the subject of much debate. The authors evaluated cognitive outcomes in patients treated with or without Gamma Knife radiosurgery (GKRS) for an underlying pituitary adenoma.

METHODS

This was a retrospective, institutional review board–approved, single-institution study. A total of 51 patients (23 male, 28 female) treated for pituitary adenoma were included in this neurocognitive study. Twenty-one patients underwent GKRS following transsphenoidal surgery, 22 patients were treated with transsphenoidal surgery alone, and eight patients were conservatively managed or were treated with medical management alone. Comparisons using psychometric tests of general intellectual abilities, memory, and executive functions were made between the treatment groups, between male and female patients, and between patients with Cushing’s disease and those with nonfunctioning adenoma (NFA).

RESULTS

The entire patient sample, the NFA group, and the GKRS group scored significantly below expected on measures of both immediate and delayed memory, particularly for visually presented information (p ≤ 0.05); however, there were no significant differences between the patients with Cushing’s disease and those with NFA (t ≤ 0.56, p ≥ 0.52). In those who underwent GKRS, memory scores were not significantly different from those in the patients who did not undergo GKRS (t ≤ 1.32, p ≥ 0.19). Male patients across the sample were more likely to demonstrate impairments in both immediate memory (t = −3.41, p = 0.003) and delayed memory (t = −3.80, p = 0.001) than were female patients (t ≤ 1.09, p ≥ 0.29). There were no impairments on measures of general intellectual functioning or executive functions in any patient group. The potential contributions of tumor size and hormone levels are discussed.

CONCLUSIONS

Overall, pituitary adenoma patients demonstrated relative impairment in anterograde memory. However, GKRS did not lead to adverse effects for immediate or delayed memory in pituitary adenoma patients. Cognitive assessment of pituitary adenoma patients is important in their longitudinal care.

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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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I. Jonathan Pomeraniec, Dale Ding, Robert M. Starke, Kenneth C. Liu, E. Kelly Mrachek, M. Beatriz Lopes and Jason P. Sheehan

OBJECTIVE

Stereotactic radiosurgery (SRS) is a commonly employed treatment modality for brain arteriovenous malformations (AVMs). However, due to the low frequency of delayed cyst formation after AVM SRS, as well as the prolonged time interval between treatment and its occurrence, the characteristics of post-SRS cyst formation are not well defined. Therefore, the aims of this retrospective cohort study are to determine the rate of cyst formation after SRS for AVMs, identify predictive factors, and evaluate the clinical sequelae of post-SRS cysts.

METHODS

The authors analyzed an SRS database for AVM patients who underwent SRS at the University of Virginia and identified those who developed post-SRS cysts. Statistical analyses were performed to determine predictors of post-SRS cyst formation and the effect of cyst formation on new or worsening seizures after SRS.

RESULTS

The study cohort comprised 1159 AVM patients treated with SRS; cyst formation occurred in 17 patients (post-SRS cyst rate of 1.5%). Compared with patients who did not develop post-SRS cysts, those with cyst formation were treated with a greater number of radiosurgical isocenters (mean 3.8 vs 2.8, p = 0.047), had a longer follow-up (mean 132 vs 71 months, p < 0.001), were more likely to develop radiological radiation-induced changes (RIC) (64.7% vs 36.1%, p = 0.021), and had a longer duration of RIC (57 vs 21 months, p < 0.001). A higher number of isocenters (p = 0.014), radiological RIC (p = 0.002), and longer follow-up (p = 0.034) were found to be independent predictors of post-SRS cyst formation in the multivariate analysis. There was a trend toward a significant association between cyst formation and new or worsening seizures in univariate analysis (p = 0.054).

CONCLUSIONS

Patients with greater nidal complexity appear to be more prone to post-SRS cyst formation. The findings of this study emphasize the importance of long-term follow-up for patients who have undergone AVM SRS, even after nidal obliteration is achieved. Post-SRS cysts may be epileptogenic, although seizure outcomes after AVM SRS are multifactorial.