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Kevin T. Nead, Allen Haas, LiJin Joo, and Mackenzie R. Wehner

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Roman O. Kowalchuk, Ajay Niranjan, Judith Hess, Joseph P. Antonios, Michael Y. Zhang, Steve Braunstein, Richard B. Ross, Stylianos Pikis, Christopher P. Deibert, Cheng-chia Lee, Huai-che Yang, Anne-Marie Langlois, David Mathieu, Selcuk Peker, Yavuz Samanci, Chad G. Rusthoven, Veronica Chiang, Zhishuo Wei, L. Dade Lunsford, Daniel M. Trifiletti, and Jason P. Sheehan

OBJECTIVE

Stereotactic radiosurgery (SRS) is an effective treatment for intracranial metastatic disease, but its role in triple-negative breast cancer requires further study. Herein, the authors report overall survival (OS) and local tumor control in a multiinstitutional cohort with triple-negative breast cancer metastases treated with SRS.

METHODS

Patients treated from 2010 to 2019 at 9 institutions were included in this retrospective study if they had biopsy-proven triple-negative breast cancer with intracranial metastatic lesions treated with SRS. Patients were excluded if they had undergone prior SRS, whole-brain radiation therapy, or resection of the metastatic lesions. A retrospective chart review was conducted to determine OS, local control, and treatment efficacy.

RESULTS

Sixty-eight patients with 315 treated lesions were assessed. Patients had a median Karnofsky Performance Status of 80 (IQR 70–90) and age of 57 years (IQR 48–67 years). Most treated patients had 5 or fewer intracranial lesions, with 34% of patients having a single lesion. Treated lesions were small, having a median volume owf 0.11 cm3 (IQR 0.03–0.60 cm3). Patients were treated with a median margin dose of 18 Gy (IQR 18–20 Gy) to the median 71% isodose line (IQR 50%–84%). Overall, patients had a 1-year OS of 43% and 2-year OS of 20%. Most patients (88%) were followed until death, by which time local tumor progression had occurred in only 7% of cases. Furthermore, 76% of the lesions demonstrated regression. Tumor volume was correlated with local tumor progression (p = 0.012). SRS was very well tolerated, and only 3 patients (5%) developed symptomatic radiation necrosis.

CONCLUSIONS

SRS is a safe and efficacious treatment for well-selected patients with triple-negative breast cancer, especially for those with a favorable performance status and small- to moderate-volume metastatic lesions.

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Georgios Mantziaris, Stylianos Pikis, Tomas Chytka, Roman Liščák, Kimball Sheehan, Darrah Sheehan, Selcuk Peker, Yavuz Samanci, Shray K. Bindal, Ajay Niranjan, L. Dade Lunsford, Rupinder Kaur, Renu Madan, Manjul Tripathi, Dhiraj J. Pangal, Ben A. Strickland, Gabriel Zada, Anne-Marie Langlois, David Mathieu, Ronald E. Warnick, Samir Patel, Zayda Minier, Herwin Speckter, Zhiyuan Xu, Rithika Kormath Anand, and Jason P. Sheehan

OBJECTIVE

Radiological progression occurs in 50%–60% of residual nonfunctioning pituitary adenomas (NFPAs). Stereotactic radiosurgery (SRS) is a safe and effective management option for residual NFPAs, but there is no consensus on its optimal timing. This study aims to define the optimal timing of SRS for residual NFPAs.

METHODS

This retrospective, multicenter study involved 375 patients with residual NFPAs managed with SRS. The patients were divided into adjuvant (ADJ; treated for stable residual NFPA within 6 months of resection) and progression (PRG) cohorts (treated for residual NFPA progression). Factors associated with tumor progression and clinical deterioration were analyzed.

RESULTS

Following propensity-score matching, each cohort consisted of 130 patients. At last follow-up, tumor control was achieved in 93.1% of patients in the ADJ cohort and in 96.2% of patients in the PRG cohort (HR 1.6, 95% CI 0.55–4.9, p = 0.37). Hypopituitarism was associated with a maximum point dose of > 8 Gy to the pituitary stalk (HR 4.5, 95% CI 1.6–12.6, p = 0.004). No statistically significant difference was noted in crude new-onset hypopituitarism rates (risk difference [RD] = −0.8%, p > 0.99) or visual deficits (RD = −2.3%, p = 0.21) between the two cohorts at the last follow-up. The median time from resection to new hypopituitarism was longer in the PRG cohort (58.9 vs 29.7 months, p = 0.01).

CONCLUSIONS

SRS at residual NFPA progression does not appear to alter the probability of tumor control or hormonal/visual deficits compared with adjuvant SRS. Deferral of radiosurgical management to the time of radiological progression could significantly prolong the time to radiosurgically induced pituitary dysfunction. A lower maximum point dose (< 8 Gy) to the pituitary stalk portended a more favorable chance of preserving pituitary function after SRS.

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Othman Bin-Alamer, Arka N. Mallela, Paolo Palmisciano, Zachary C. Gersey, Turki Elarjani, Mohamed A. Labib, Georgios A. Zenonos, Amir R. Dehdashti, Jason P. Sheehan, William T. Couldwell, L. Dade Lunsford, and Hussam Abou-Al-Shaar

OBJECTIVE

The objective of this retrospective study was to compare the survival of patients with biopsy-proven skull base chordoma who had undergone stereotactic radiosurgery (SRS) with versus without prior fractionated radiation therapy (RT).

METHODS

Relevant articles from database inception to September 2021 were retrieved from the PubMed, Scopus, Web of Science, and Cochrane databases for a systematic review of treatment protocols. Studies were included if they 1) involved adult patients (age ≥ 18 years) with histologically and radiologically confirmed chordomas located within the clival skull base region and treated with SRS; 2) reported data on clinical features, SRS protocols, and outcomes; and 3) were written in the English language. Studies were excluded if they 1) were literature reviews, case reports, technical notes, abstracts, or autopsy reports; 2) did not clearly differentiate the data of patients with chordomas from the data of patients with different tumors or the data of patients with chordomas in locations other than the skull base; or 3) lacked histological confirmation or treatment and outcome data. Extracted data included the following: study author and publication year, patient age and sex, symptoms, cranial nerve involvement, invaded structures, lesion size, treatment modality, surgical details, histopathological type, RT modality, SRS parameters, complications, postradiosurgery outcomes, complications, and survival outcomes.

RESULTS

After the selection process, 15 articles describing 130 patients met the study eligibility criteria, including 94 patients who had undergone postresection SRS (NoRT group) and 36 who had undergone postresection fractionated RT and subsequent SRS (RT group). The NoRT and RT groups were comparable in age (51.3 vs 47.4 years, respectively), sex (57.1% vs 58.3% male), tumor volume (9.5 vs 11.2 cm3), SRS treatment parameters (maximum dose: 35.4 vs 42.2 Gy, marginal dose: 19.6 vs 20.6 Gy, treatment isodose line: 60.2% vs 65.2%), and SRS adverse effects (10.9% vs 17.6%). For the entire cohort, the 3-, 5-, and 10-year progression-free survival (PFS) rates were 23%, 9%, and 3%, respectively, and the overall survival (OS) rates were 94%, 82%, and 76%, respectively. In the NoRT group, SRS was adjuvant treatment after resection in 38 patients (40.4%), salvage treatment for recurrent tumor treated with resection alone in 10 (10.6%), and not specified in 46 (48.9%). In the RT group, SRS was boost treatment in 9 patients (25.0%), salvage treatment after recurrence in 22 (61.1%), and not specified in 5 (13.9%). There was no difference between the two groups in terms of median PFS (24.0 months [Q1 34.0, Q3 15.0] vs 23.8 months [34.0, 18.0], respectively; p = 0.8) or median OS (293.0 months [not reached, 137.4] vs not reached [not reached, 48.0], respectively; p = 0.36). The adverse radiation effect rates were comparable between the groups (10.9% vs 17.6%, respectively; p = 0.4).

CONCLUSIONS

The role of SRS in the management of skull base chordomas is still evolving. This systematic literature review of biopsy-proven chordoma revealed that tumor control and survival rates for SRS alone after chordoma surgery were not inferior to those encountered after SRS plus fractionated RT.

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Eric J. Lehrer, Manmeet S. Ahluwalia, Jason Gurewitz, Kenneth Bernstein, Douglas Kondziolka, Ajay Niranjan, Zhishuo Wei, L. Dade Lunsford, Kareem R. Fakhoury, Chad G. Rusthoven, David Mathieu, Claire Trudel, Timothy D. Malouff, Henry Ruiz-Garcia, Phillip Bonney, Lindsay Hwang, Cheng Yu, Gabriel Zada, Samir Patel, Christopher P. Deibert, Piero Picozzi, Andrea Franzini, Luca Attuati, Rahul N. Prasad, Raju R. Raval, Joshua D. Palmer, Cheng-Chia Lee, Huai-Che Yang, Brianna M. Jones, Sheryl Green, Jason P. Sheehan, and Daniel M. Trifiletti

OBJECTIVE

Immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS) are commonly utilized in the management of brain metastases. Treatment-related imaging changes (TRICs) are a frequently observed clinical manifestation and are commonly classified as imaging-defined radiation necrosis. However, these findings are not well characterized and may predict a response to SRS and ICIs. The objective of this study was to investigate predictors of TRICs and their impact on patient survival.

METHODS

This retrospective multicenter cohort study was conducted through the International Radiosurgery Research Foundation. Member institutions submitted de-identified clinical and dosimetric data for patients with non–small cell lung cancer (NSCLC), melanoma, and renal cell carcinoma (RCC) brain metastases that had been treated with SRS and ICIs. Data were collected from March 2020 to February 2021. Univariable and multivariable Cox and logistic regression analyses were performed. The Kaplan-Meier method was used to evaluate overall survival (OS). The diagnosis-specific graded prognostic assessment was used to guide variable selection. TRICs were determined on the basis of MRI, PET/CT, or MR spectroscopy, and consensus by local clinical providers was required.

RESULTS

The analysis included 697 patients with 4536 brain metastases across 11 international institutions in 4 countries. The median follow-up after SRS was 13.6 months. The median age was 66 years (IQR 58–73 years), 54.1% of patients were male, and 57.3%, 36.3%, and 6.4% of tumors were NSCLC, melanoma, and RCC, respectively. All patients had undergone single-fraction radiosurgery to a median margin dose of 20 Gy (IQR 18–20 Gy). TRICs were observed in 9.8% of patients. The median OS for all patients was 24.5 months. On univariable analysis, Karnofsky Performance Status (KPS; HR 0.98, p < 0.001), TRICs (HR 0.67, p = 0.03), female sex (HR 0.67, p < 0.001), and prior resection (HR 0.60, p = 0.03) were associated with improved OS. On multivariable analysis, KPS (HR 0.98, p < 0.001) and TRICs (HR 0.66, p = 0.03) were associated with improved OS. A brain volume receiving ≥ 12 Gy of radiation (V12Gy) ≥ 10 cm3 (OR 2.78, p < 0.001), prior whole-brain radiation therapy (OR 3.46, p = 0.006), and RCC histology (OR 3.10, p = 0.01) were associated with an increased probability of developing TRICs. The median OS rates in patients with and without TRICs were 29.0 and 23.1 months, respectively (p = 0.03, log-rank test).

CONCLUSIONS

TRICs following ICI and SRS were associated with a median OS benefit of approximately 6 months in this retrospective multicenter study. Further prospective study and additional stratification are needed to validate these findings and further elucidate the role and etiology of this common clinical scenario.

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Stylianos Pikis, Georgios Mantziaris, Purushotham Ramanathan, Zhiyuan Xu, and Jason P. Sheehan

OBJECTIVE

The purpose of this retrospective, single-institution study was to evaluate radiological and clinical outcomes of patients managed with repeat stereotactic radiosurgery (SRS) for residual cerebral arteriovenous malformation (AVM) after prior SRS.

METHODS

The authors evaluated the clinical and radiological outcomes of consecutive patients treated with repeat single-session SRS for a residual brain AVM from 1989 to 2021.

RESULTS

In total, 170 patients underwent repeat SRS for AVM (90 [52.9%] females; median [interquartile range] age at the first SRS procedure 28 [21.5] years; median [interquartile range] age at the second SRS procedure 32 [22.5] years). After repeat SRS, the actuarial 3-, 5-, and 10-year AVM obliteration rates were 37.6%, 57.3%, and 80.9%, respectively. Higher obliteration rates were associated with margin dose ≥ 19 Gy (p = 0.001). After the second SRS procedure, hemorrhage occurred in 8.2% of patients and was lethal in 1 patient. The risk factors of intracranial hemorrhage were age < 18 years (p = 0.03) and residual AVM diameter > 20 mm (p = 0.004). Lower obliteration rates were noted in patients with residual AVM diameter > 20 mm (p = 0.04) and those < 18 years of age (p = 0.04). Asymptomatic, symptomatic, and permanent radiation-induced changes (RICs) after the second SRS procedure occurred in 25.9%, 8.8%, and 5.3% of patients, respectively, and were associated with RIC after the first SRS procedure (p = 0.006). There was 1 case of a radiation-induced meningioma 12 years after SRS.

CONCLUSIONS

Repeat SRS is a reasonable therapeutic option, in particular for patients with residual AVM. Repeat SRS was associated with more favorable outcomes in adult patients and those with residual AVM smaller than 20 mm in maximum diameter. To increase the rate of residual AVM obliteration, a prescription dose ≥ 19 Gy should ideally be used for repeat SRS.

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Stylianos Pikis, Georgios Mantziaris, Rithika Kormath Anand, Ahmed M. Nabeel, Darrah Sheehan, Kimball Sheehan, Wael A. Reda, Sameh R. Tawadros, Khaled Abdelkarim, Amr M. N. El-Shehaby, Reem Emad Eldin, Selcuk Peker, Yavuz Samanci, Tehila Kaisman-Elbaz, Herwin Speckter, Wenceslao Hernández, Julio Isidor, Manjul Tripathi, Renu Madan, Brad E. Zacharia, Lekhaj C. Daggubati, Nuria Martínez Moreno, Roberto Martínez Álvarez, Anne-Marie Langlois, David Mathieu, Christopher P. Deibert, Vivek R. Sudhakar, Christopher P. Cifarelli, Denisse Arteaga Icaza, Daniel T. Cifarelli, Zhishuo Wei, Ajay Niranjan, Gene H. Barnett, L. Dade Lunsford, Greg N. Bowden, and Jason P. Sheehan

OBJECTIVE

Though stereotactic radiosurgery (SRS) is an established safe treatment for small- and medium-sized vestibular schwannomas (VSs), its role in the management of Koos grade IV VS is still unclear. In this retrospective multicenter study, the authors evaluated tumor control and the patient outcomes of primary, single-session SRS treatment for Koos grade IV VS.

METHODS

This study included patients treated with primary, single-session SRS for Koos grade IV VS at 10 participating centers. Only those patients presenting with non–life-threatening or incapacitating symptoms and at least 12 months of clinical and neuroimaging follow-up were eligible for inclusion. Relevant data were collected, and the Kaplan-Meier method was used to perform time-dependent analysis for post-SRS tumor control, hearing preservation, and facial nerve function preservation. Univariate and multivariate analyses were performed for outcome measures using Cox regression analysis.

RESULTS

Six hundred twenty-seven patients (344 females, median patient age 54 [IQR 22] years) treated with primary SRS were included in this study. The median tumor volume was 8.7 (IQR 5) cm3. Before SRS, serviceable hearing, facial nerve weakness (House-Brackmann grade > I), and trigeminal neuropathy were present in 205 (33%), 48 (7.7%), and 203 (32.4%) patients, respectively. The median prescription dose was 12 (IQR 1) Gy. At a median radiological follow-up of 38 (IQR 54) months, tumor control was achieved in 94.1% of patients. Early tumor expansion occurred in 67 (10.7%) patients and was associated with a loss of tumor control at the last follow-up (p = 0.001). Serviceable hearing preservation rates at the 5- and 10-year follow-ups were 65% and 44.6%, respectively. Gardner-Robertson class > 1 (p = 0.003) and cochlear dose ≥ 4 Gy (p = 0.02) were risk factors for hearing loss. Facial nerve function deterioration occurred in 19 (3.0%) patients at the last follow-up and was associated with margin doses ≥ 13 Gy (p = 0.03) and early tumor expansion (p = 0.04). Post-SRS, 33 patients developed hydrocephalus requiring shunting. Adverse radiation effects occurred in 92 patients and were managed medically or surgically in 34 and 18 cases, respectively.

CONCLUSIONS

SRS is a safe and effective method of obtaining tumor control in patients with Koos grade IV VS presenting with non–life-threatening or debilitating symptoms, especially those with surgical comorbidities that contraindicate resection. To decrease the incidence of post-SRS facial palsy, a prescription dose < 13 Gy is recommended.

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Shervin R. Dashti, Robert J. Kadner, Bradley S. Folley, Jason P. Sheehan, Dong Y. Han, Richard J. Kryscio, Mary B. Carter, Lisa B. E. Shields, Brian M. Plato, Renato V. La Rocca, Aaron C. Spalding, Tom L. Yao, and Justin F. Fraser

OBJECTIVE

There is an unmet need for safe and rapidly effective therapies for refractory brain radiation necrosis (RN). The aim of this prospective single-arm phase II trial was to evaluate the safety and efficacy of a single low-dose targeted bevacizumab infusion after blood-brain barrier disruption (BBBD) in adult patients with steroid-refractory brain RN.

METHODS

Ten adults with steroid-refractory, imaging-confirmed brain RN were enrolled between November 2016 and January 2018 and followed for 12 months after treatment. Bevacizumab 2.5 mg/kg was administered as a one-time targeted intra-arterial infusion immediately after BBBD. Primary outcomes included safety and > 25% decrease in lesion volume. Images were analyzed by a board-certified neuroradiologist blinded to pretrial diagnosis and treatment status. Secondary outcomes included changes in headache, steroid use, and functional status and absence of neurocognitive sequelae. Comparisons were analyzed using the Fisher exact test, Mann-Whitney U-test, linear mixed models, Wilcoxon signed-rank test, and repeated-measures 1-way ANOVA.

RESULTS

Ten adults (mean ± SD [range] age 35 ± 15 [22–62] years) participated in this study. No patients died or exhibited serious adverse effects of systemic bevacizumab. At 3 months, 80% (95% CI 44%–98%) and 90% (95% CI 56%–100%) of patients demonstrated > 25% decrease in RN and vasogenic edema volume, respectively. At 12 months, RN volume decreased by 74% (median [range] 76% [53%–96%], p = 0.012), edema volume decreased by 50% (median [range] 70% [−11% to 83%], p = 0.086), and headache decreased by 84% (median [range] 92% [58%–100%], p = 0.022) among the 8 patients without RN recurrence. Only 1 (10%) patient was steroid dependent at the end of the trial. Scores on 12 of 16 (75%) neurocognitive indices increased, thereby supporting a pattern of cerebral white matter recovery. Two (20%) patients exhibited RN recurrence that required further treatment at 10 and 11 months, respectively, after bevacizumab infusion.

CONCLUSIONS

For the first time, to the authors’ knowledge, the authors demonstrated that a single low-dose targeted bevacizumab infusion resulted in durable clinical and imaging improvements in 80% of patients at 12 months after treatment without adverse events attributed to bevacizumab alone. These findings highlight that targeted bevacizumab may be an efficient one-time treatment for adults with brain RN. Further confirmation with a randomized controlled trial is needed to compare the intra-arterial approach with the conventional multicycle intravenous regimen.

Clinical trial registration no.: NCT02819479 (ClinicalTrials.gov)

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Georgios Mantziaris, Joshua Diamond, Stylianos Pikis, Farid M. El Hefnawi, Ghusn Al Sideiri, François-Louis Coupé, David Mathieu, Cheng-Chia Lee, Jaromir May, Roman Liščák, Selcuk Peker, Yavuz Samanci, Ajay Niranjan, L. Dade Lunsford, and Jason P. Sheehan

OBJECTIVE

The optimal treatment for recurrent and residual gangliogliomas remains unclear. The aim of this study was to evaluate the safety and efficacy of stereotactic radiosurgery (SRS) in the management of patients with recurrent or residual intracranial ganglioglioma.

METHODS

This retrospective multicenter study involved patients managed with SRS for ganglioglioma. The study endpoints included local tumor control and tumor- or SRS-related neurological morbidity following treatment. Factors associated with tumor progression and neurological morbidity were also analyzed.

RESULTS

The cohort included 20 patients (11 males [55%]) with a median age of 24.5 (IQR 14) years who had been managed with SRS for ganglioglioma. Five-year radiological progression-free survival was 85.6%. After SRS, 2 patients (10%) experienced transient neurological deterioration. At a median clinical follow-up of 88.5 (IQR 112.5) months, 1 patient (5%) experienced seizure worsening and 1 (5%) required further resection of the tumor because of radiological progression. No mortality was noted in this series.

CONCLUSIONS

SRS appears to be a safe and effective treatment option for surgically inaccessible, recurrent, and residual gangliogliomas. In this series, the 5-year progression-free survival rate after SRS was 85.6%. Gross-total resection remains the primary treatment of choice for patients with newly diagnosed or recurrent ganglioglioma. SRS may be considered for patients unfit for surgery and those with surgically inaccessible newly diagnosed, residual, and recurrent lesions.

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Douglas Kondziolka, Kenneth Bernstein, Cheng-Chia Lee, Huai-Che Yang, Roman Liscak, Jaromir May, Roberto Martínez-Álvarez, Nuria Martínez-Moreno, Adomas Bunevicius, and Jason P. Sheehan

OBJECTIVE

Rathke’s cleft cysts (RCCs) are sellar collections from an incompletely regressed Rathke’s pouch. Common symptoms of RCCs can include headaches, visual loss, and endocrinopathy. Surgery is required in some cases of symptomatic or growing RCCs. Recurrence after surgery is common (range 10%–40%). Stereotactic radiosurgery (SRS) has been used in an attempt to control growth and symptoms, but outcomes are not well known. The authors sought to study the outcomes of RCCs following Gamma Knife surgery for both salvage and initial treatment.

METHODS

The outcomes of 25 patients with RCCs who underwent SRS between 2001 and 2020 were reviewed. Four patients received initial SRS and 21 were treated with salvage SRS. Diagnosis was based on imaging or histopathology. Cyst control was defined as stability or regression of the cyst. Kaplan-Meier analysis was used to determine time to recurrence and determine potential factors for recurrence.

RESULTS

The respective median clinical follow-up and margin dose were 6.5 years and 12 Gy. Overall control was achieved in 19 (76%) of 25 patients, and 4 recurrences required further intervention. The average time to recurrence was 35.6 months in those RCCs that recurred. Visual recovery occurred in 14 (93.3%) of 15 patients and no new post-SRS visual deficits occurred. The presence of a pretreatment visual deficit was often an indicator of RCC regrowth. All 3 patients with pretreatment hyperprolactinemia experienced resolution after SRS. New endocrinopathy related to SRS was noted in 5 (20%) of 25 patients, all of which were thyroid and/or cortisol axis related. Upfront SRS was used in 4 patients. No new endocrinopathies or visual deficits developed after upfront SRS, and the 1 patient with a pretreatment visual deficit recovered. One of the 4 patients with upfront SRS experienced a recurrence after 7.5 years.

CONCLUSIONS

SRS produced effective recovery of visual deficits and carries a low risk for new visual deficits. Cyst control was achieved in approximately three-fourths of the patients. Following SRS, patients without pretreatment visual deficits are less likely to have RCC regrowth. Endocrinopathy can occur after SRS, similar to other sellar mass lesions. Initial SRS shows the potential for long-term cyst control, with improvement of symptoms and a low risk for complications.