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I. Jonathan Pomeraniec, Zhiyuan Xu, Cheng-Chia Lee, Huai-Che Yang, Tomas Chytka, Roman Liscak, Roberto Martinez-Alvarez, Nuria Martinez-Moreno, Luca Attuati, Piero Picozzi, Douglas Kondziolka, Monica Mureb, Kenneth Bernstein, David Mathieu, Michel Maillet, Akiyoshi Ogino, Hao Long, Hideyuki Kano, L. Dade Lunsford, Brad E. Zacharia, Christine Mau, Leonard C. Tuanquin, Christopher Cifarelli, David Arsanious, Joshua Hack, Ronald E. Warnick, Ben A. Strickland, Gabriel Zada, Eric L. Chang, Herwin Speckter, Samir Patel, Dale Ding, Darrah Sheehan, Kimball Sheehan, Svetlana Kvint, Love Y. Buch, Alexander R. Haber, Jacob Shteinhart, Mary Lee Vance, and Jason P. Sheehan

OBJECTIVE

Stereotactic radiosurgery (SRS) provides a safe and effective therapeutic modality for patients with pituitary adenomas. The mechanism of delayed endocrine deficits based on targeted radiation to the hypothalamic-pituitary axis remains unclear. Radiation to normal neuroendocrine structures likely plays a role in delayed hypopituitarism after SRS. In this multicenter study by the International Radiosurgery Research Foundation (IRRF), the authors aimed to evaluate radiation tolerance of structures surrounding pituitary adenomas and identify predictors of delayed hypopituitarism after SRS for these tumors.

METHODS

This is a retrospective review of patients with pituitary adenomas who underwent single-fraction SRS from 1997 to 2019 at 16 institutions within the IRRF. Dosimetric point measurements of 14 predefined neuroanatomical structures along the hypothalamus, pituitary stalk, and normal pituitary gland were made. Statistical analyses were performed to determine the impact of doses to critical structures on clinical, radiographic, and endocrine outcomes.

RESULTS

The study cohort comprised 521 pituitary adenomas treated with SRS. Tumor control was achieved in 93.9% of patients over a median follow-up period of 60.1 months, and 22.5% of patients developed new loss of pituitary function with a median treatment volume of 3.2 cm3. Median maximal radiosurgical doses to the hypothalamus, pituitary stalk, and normal pituitary gland were 1.4, 7.2, and 11.3 Gy, respectively. Nonfunctioning adenoma status, younger age, higher margin dose, and higher doses to the pituitary stalk and normal pituitary gland were independent predictors of new or worsening hypopituitarism. Neither the dose to the hypothalamus nor the ratio between doses to the pituitary stalk and gland were significant predictors. The threshold of the median dose to the pituitary stalk for new endocrinopathy was 10.7 Gy in a single fraction (OR 1.77, 95% CI 1.17–2.68, p = 0.006).

CONCLUSIONS

SRS for the treatment of pituitary adenomas affords a high tumor control rate with an acceptable risk of new or worsening endocrinopathy. This evaluation of point dosimetry to adjacent neuroanatomical structures revealed that doses to the pituitary stalk, with a threshold of 10.7 Gy, and doses to the normal gland significantly increased the risk of post-SRS hypopituitarism. In patients with preserved pre-SRS neuroendocrine function, limiting the dose to the pituitary stalk and gland while still delivering an optimal dose to the tumor appears prudent.

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Zachary A. Seymour, Jason W. Chan, Michael W. McDermott, Inga Grills, Hong Ye, Hideyuki Kano, Craig A. Lehocky, Rachel C. Jacobs, L. Dade Lunsford, Tomas Chytka, Roman Liščák, Cheng-Chia Lee, Huai-che Yang, Dale Ding, Jason P. Sheehan, Caleb E. Feliciano, Rafael Rodriguez-Mercado, Veronica L. Chiang, Judith A. Hess, Samuel Sommaruga, Brendan McShane, John Y. K. Lee, Lucas T. Vasas, Anthony M. Kaufmann, and Penny K. Sneed

OBJECTIVE

The optimal treatment paradigm for large arteriovenous malformations (AVMs) is controversial. One approach is volume-staged stereotactic radiosurgery (VS-SRS). The authors previously reported efficacy of VS-SRS for large AVMs in a multiinstitutional cohort; here they focus on risk of symptomatic adverse radiation effects (AREs).

METHODS

This is a multicentered retrospective review of patients treated with a planned prospective volume staging approach to stereotactically treat the entire nidus of an AVM, with volume stages separated by intervals of 3–6 months. A total of 9 radiosurgical centers treated 257 patients with VS-SRS between 1991 and 2016. The authors evaluated permanent, transient, and total ARE events that were symptomatic.

RESULTS

Patients received 2–4 total volume stages. The median age was 33 years at the time of the first SRS volume stage, and the median follow-up was 5.7 years after VS-SRS. The median total AVM nidus volume was 23.25 cm3 (range 7.7–94.4 cm3), with a median margin dose per stage of 17 Gy (range 12–20 Gy). A total of 64 patients (25%) experienced an ARE, of which 19 were permanent. Rather than volume, maximal linear dimension in the Z (craniocaudal) dimension was associated with toxicity; a threshold length of 3.28 cm was associated with an ARE, with a 72.5% sensitivity and a 58.3% specificity. In addition, parietal lobe involvement for superficial lesions and temporal lobe involvement for deep lesions were associated with an ARE.

CONCLUSIONS

Size remains the dominant predictor of toxicity following SRS, but overall rates of AREs were lower than anticipated based on baseline features, suggesting that dose and size were relatively dissociated through volume staging. Further techniques need to be assessed to optimize outcomes.

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Akiyoshi Ogino, L. Dade Lunsford, Hao Long, Stephen Johnson, Andrew Faramand, Ajay Niranjan, John C. Flickinger, and Hideyuki Kano

OBJECTIVE

While extensive long-term outcome studies support the role of stereotactic radiosurgery (SRS) for smaller-volume vestibular schwannomas (VSs), its role in the management for larger-volume tumors remains controversial.

METHODS

Between 1987 and 2017, the authors performed single-session SRS on 170 patients with previously untreated Koos grade IV VSs (volumes ranged from 5 to 20 cm3). The median tumor volume was 7.4 cm3. The median maximum extracanalicular tumor diameter was 27.5 mm. All tumors compressed the middle cerebellar peduncle and distorted the fourth ventricle. Ninety-three patients were male, 77 were female, and the median age was 61 years. Sixty-two patients had serviceable hearing (Gardner-Robertson [GR] grades I and II). The median margin dose was 12.5 Gy.

RESULTS

At a median follow-up of 5.1 years, the progression-free survival rates of VSs treated with a margin dose ≥ 12.0 Gy were 98.4% at 3 years, 95.3% at 5 years, and 90.7% at 10 years. In contrast, the tumor control rate after delivery of a margin dose < 12.0 Gy was 76.9% at 3, 5, and 10 years. The hearing preservation rates in patients with serviceable hearing at the time of SRS were 58.1% at 3 years, 50.3% at 5 years, and 35.9% at 7 years. Younger age (< 60 years, p = 0.036) and initial GR grade I (p = 0.006) were associated with improved serviceable hearing preservation rate. Seven patients (4%) developed facial neuropathy during the follow-up interval. A smaller tumor volume (< 10 cm3, p = 0.002) and a lower margin dose (≤ 13.0 Gy, p < 0.001) were associated with preservation of facial nerve function. The probability of delayed facial neuropathy when the margin dose was ≤ 13.0 Gy was 1.1% at 10 years. Nine patients (5%) required a ventriculoperitoneal shunt because of delayed symptomatic hydrocephalus. Fifteen patients (9%) developed detectable trigeminal neuropathy. Delayed resection was performed in 4% of patients.

CONCLUSIONS

Even for larger-volume VSs, single-session SRS prevented the need for delayed resection in almost 90% at 10 years. For patients with minimal symptoms of tumor mass effect, SRS should be considered an effective alternative to surgery in most patients, especially those with advanced age or medical comorbidities.

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Akiyoshi Ogino, L. Dade Lunsford, Hao Long, Stephen Johnson, Andrew Faramand, Ajay Niranjan, John C. Flickinger, and Hideyuki Kano

OBJECTIVE

While extensive long-term outcome studies support the role of stereotactic radiosurgery (SRS) for smaller-volume vestibular schwannomas (VSs), its role in the management for larger-volume tumors remains controversial.

METHODS

Between 1987 and 2017, the authors performed single-session SRS on 170 patients with previously untreated Koos grade IV VSs (volumes ranged from 5 to 20 cm3). The median tumor volume was 7.4 cm3. The median maximum extracanalicular tumor diameter was 27.5 mm. All tumors compressed the middle cerebellar peduncle and distorted the fourth ventricle. Ninety-three patients were male, 77 were female, and the median age was 61 years. Sixty-two patients had serviceable hearing (Gardner-Robertson [GR] grades I and II). The median margin dose was 12.5 Gy.

RESULTS

At a median follow-up of 5.1 years, the progression-free survival rates of VSs treated with a margin dose ≥ 12.0 Gy were 98.4% at 3 years, 95.3% at 5 years, and 90.7% at 10 years. In contrast, the tumor control rate after delivery of a margin dose < 12.0 Gy was 76.9% at 3, 5, and 10 years. The hearing preservation rates in patients with serviceable hearing at the time of SRS were 58.1% at 3 years, 50.3% at 5 years, and 35.9% at 7 years. Younger age (< 60 years, p = 0.036) and initial GR grade I (p = 0.006) were associated with improved serviceable hearing preservation rate. Seven patients (4%) developed facial neuropathy during the follow-up interval. A smaller tumor volume (< 10 cm3, p = 0.002) and a lower margin dose (≤ 13.0 Gy, p < 0.001) were associated with preservation of facial nerve function. The probability of delayed facial neuropathy when the margin dose was ≤ 13.0 Gy was 1.1% at 10 years. Nine patients (5%) required a ventriculoperitoneal shunt because of delayed symptomatic hydrocephalus. Fifteen patients (9%) developed detectable trigeminal neuropathy. Delayed resection was performed in 4% of patients.

CONCLUSIONS

Even for larger-volume VSs, single-session SRS prevented the need for delayed resection in almost 90% at 10 years. For patients with minimal symptoms of tumor mass effect, SRS should be considered an effective alternative to surgery in most patients, especially those with advanced age or medical comorbidities.

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Akiyoshi Ogino, L. Dade Lunsford, Hao Long, Stephen Johnson, Andrew Faramand, Ajay Niranjan, John C. Flickinger, and Hideyuki Kano

OBJECTIVE

This report evaluates the outcomes of stereotactic radiosurgery (SRS) as the first-line treatment of intracanalicular vestibular schwannomas (VSs).

METHODS

Between 1987 and 2017, the authors identified 209 patients who underwent SRS as the primary intervention for a unilateral intracanalicular VS. The median patient age was 54 years (range 22–85 years); 94 patients were male and 115 were female. Three patients had facial neuropathy at the time of SRS. One hundred fifty-five patients (74%) had serviceable hearing (Gardner-Robertson [GR] grades I and II) at the time of SRS. The median tumor volume was 0.17 cm3 (range 0.015–0.63 cm3). The median margin dose was 12.5 Gy (range 11.0–25.0 Gy). The median maximum dose was 24.0 Gy (range 15.7–50.0 Gy).

RESULTS

The progression-free survival rates of all patients with intracanalicular VS were 97.5% at 3 years, 95.6% at 5 years, and 92.1% at 10 years. The rates of freedom from the need for any additional intervention were 99.4% at 3 years, 98.3% at 5 years, and 98.3% at 10 years. The serviceable hearing preservation rates in GR grade I and II patients at the time of SRS were 76.6% at 3 years, 63.5% at 5 years, and 27.3% at 10 years. In univariate analysis, younger age (< 55 years, p = 0.011), better initial hearing (GR grade I, p < 0.001), and smaller tumor volumes (< 0.14 cm3, p = 0.016) were significantly associated with improved hearing preservation. In multivariate analysis, better hearing (GR grade I, p = 0.001, HR 2.869, 95% CI 1.569–5.248) and smaller tumor volumes (< 0.14 cm3, p = 0.033, HR 2.071, 95% CI 1.059–4.047) at the time of SRS were significantly associated with improved hearing preservation. The hearing preservation rates of patients with GR grade I VS were 88.1% at 3 years, 77.9% at 5 years, and 38.1% at 10 years. The hearing preservation rates of patients with VSs smaller than 0.14 cm3 were 85.5% at 3 years, 77.7% at 5 years, and 42.6% at 10 years. Facial neuropathy developed in 1.4% from 6 to 156 months after SRS.

CONCLUSIONS

SRS provided sustained tumor control in more than 90% of patients with intracanalicular VS at 10 years and freedom from the need for additional intervention in more than 98% at 10 years. Patients with initially better hearing and smaller VSs had enhanced serviceable hearing preservation during an observation interval up to 10 years after SRS.

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Adomas Bunevicius, Mohand Suleiman, Samir Patel, Roberto Martínez Álvarez, Nuria E. Martinez Moreno, Roman Liscak, Jaromir Hanuska, Anne-Marie Langlois, David Mathieu, Christine Mau, Catherine Caldwell, Leonard C. Tuanquin, Brad E. Zacharia, James McInerney, Cheng-Chia Lee, Huai-Che Yang, Jennifer L. Peterson, Daniel M. Trifiletti, Akiyoshi Ogino, Hideyuki Kano, Ronald E. Warnick, Anissa Saylany, Love Y. Buch, John Y. K. Lee, Ben A. Strickland, Gabriel Zada, Eric L. Chang, L. Dade Lunsford, and Jason Sheehan

OBJECTIVE

Radiation-induced meningiomas (RIMs) are associated with aggressive clinical behavior. Stereotactic radiosurgery (SRS) is sometimes considered for selected RIMs. The authors investigated the effectiveness and safety of SRS for the management of RIMs.

METHODS

From 12 institutions participating in the International Radiosurgery Research Foundation, the authors pooled patients who had prior cranial irradiation and were subsequently clinically diagnosed with WHO grade I meningiomas that were managed with SRS.

RESULTS

Fifty-two patients underwent 60 SRS procedures for histologically confirmed or radiologically suspected WHO grade I RIMs. The median ages at initial cranial radiation therapy and SRS for RIM were 5.5 years and 39 years, respectively. The most common reasons for cranial radiation therapy were leukemia (21%) and medulloblastoma (17%). There were 39 multiple RIMs (35%), the mean target volume was 8.61 ± 7.80 cm3, and the median prescription dose was 14 Gy. The median imaging follow-up duration was 48 months (range 4–195 months). RIM progressed in 9 patients (17%) at a median duration of 30 months (range 3–45 months) after SRS. Progression-free survival at 5 years post-SRS was 83%. Treatment volume ≥ 5 cm3 predicted progression (HR 8.226, 95% CI 1.028–65.857, p = 0.047). Seven patients (14%) developed new neurological symptoms or experienced SRS-related complications or T2 signal change from 1 to 72 months after SRS.

CONCLUSIONS

SRS is associated with durable local control of RIMs in the majority of patients and has an acceptable safety profile. SRS can be considered for patients and tumors that are deemed suboptimal, poor surgical candidates, and those whose tumor again progresses after removal.

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Monica Mureb, Danielle Golub, Carolina Benjamin, Jason Gurewitz, Ben A. Strickland, Gabriel Zada, Eric Chang, Dušan Urgošík, Roman Liščák, Ronald E. Warnick, Herwin Speckter, Skyler Eastman, Anthony M. Kaufmann, Samir Patel, Caleb E. Feliciano, Carlos H. Carbini, David Mathieu, William Leduc, DCS, Sean J. Nagel, Yusuke S. Hori, Yi-Chieh Hung, Akiyoshi Ogino, Andrew Faramand, Hideyuki Kano, L. Dade Lunsford, Jason Sheehan, and Douglas Kondziolka

OBJECTIVE

Trigeminal neuralgia (TN) is a chronic pain condition that is difficult to control with conservative management. Furthermore, disabling medication-related side effects are common. This study examined how stereotactic radiosurgery (SRS) affects pain outcomes and medication dependence based on the latency period between diagnosis and radiosurgery.

METHODS

The authors conducted a retrospective analysis of patients with type I TN at 12 Gamma Knife treatment centers. SRS was the primary surgical intervention in all patients. Patient demographics, disease characteristics, treatment plans, medication histories, and outcomes were reviewed.

RESULTS

Overall, 404 patients were included. The mean patient age at SRS was 70 years, and 60% of the population was female. The most common indication for SRS was pain refractory to medications (81%). The median maximum radiation dose was 80 Gy (range 50–95 Gy), and the mean follow-up duration was 32 months. The mean number of medications between baseline (pre-SRS) and the last follow-up decreased from 1.98 to 0.90 (p < 0.0001), respectively, and this significant reduction was observed across all medication categories. Patients who received SRS within 4 years of their initial diagnosis achieved significantly faster pain relief than those who underwent treatment after 4 years (median 21 vs 30 days, p = 0.041). The 90-day pain relief rate for those who received SRS ≤ 4 years after their diagnosis was 83.8% compared with 73.7% in patients who received SRS > 4 years after their diagnosis. The maximum radiation dose was the strongest predictor of a durable pain response (OR 1.091, p = 0.003). Early intervention (OR 1.785, p = 0.007) and higher maximum radiation dose (OR 1.150, p < 0.0001) were also significant predictors of being pain free (a Barrow Neurological Institute pain intensity score of I–IIIA) at the last follow-up visit. New sensory symptoms of any kind were seen in 98 patients (24.3%) after SRS. Higher maximum radiation dose trended toward predicting new sensory deficits but was nonsignificant (p = 0.075).

CONCLUSIONS

TN patients managed with SRS within 4 years of diagnosis experienced a shorter interval to pain relief with low risk. SRS also yielded significant decreases in adjunct medication utilization. Radiosurgery should be considered earlier in the course of treatment for TN.

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Rebecca M. Burke, Ching-Jen Chen, Dale Ding, Thomas J. Buell, Jennifer D. Sokolowski, Cheng-Chia Lee, Hideyuki Kano, Kathryn N. Kearns, Shih-Wei Tzeng, Huai-che Yang, Paul P. Huang, Douglas Kondziolka, Natasha Ironside, David Mathieu, Christian Iorio-Morin, Inga S. Grills, Caleb Feliciano, Gene H. Barnett, Robert M. Starke, L. Dade Lunsford, and Jason P. Sheehan

OBJECTIVE

Stereotactic radiosurgery (SRS) is a treatment option for pediatric brain arteriovenous malformations (AVMs), and early obliteration could encourage SRS utilization for a subset of particularly radiosensitive lesions. The objective of this study was to determine predictors of early obliteration after SRS for pediatric AVMs.

METHODS

The authors performed a retrospective review of the International Radiosurgery Research Foundation AVM database. Obliterated pediatric AVMs were sorted into early (obliteration ≤ 24 months after SRS) and late (obliteration > 24 months after SRS) responders. Predictors of early obliteration were identified, and the outcomes of each group were compared.

RESULTS

The overall study cohort was composed of 345 pediatric patients with obliterated AVMs. The early and late obliteration cohorts were made up of 95 (28%) and 250 (72%) patients, respectively. Independent predictors of early obliteration were female sex, a single SRS treatment, a higher margin dose, a higher isodose line, a deep AVM location, and a smaller AVM volume. The crude rate of post-SRS hemorrhage was 50% lower in the early (3.2%) than in the late (6.4%) obliteration cohorts, but this difference was not statistically significant (p = 0.248). The other outcomes of the early versus late obliteration cohorts were similar, with respect to symptomatic radiation-induced changes (RICs), cyst formation, and tumor formation.

CONCLUSIONS

Approximately one-quarter of pediatric AVMs that become obliterated after SRS will achieve this radiological endpoint within 24 months of initial SRS. The authors identified multiple factors associated with early obliteration, which may aid in prognostication and management. The overall risks of delayed hemorrhage, RICs, cyst formation, and tumor formation were not statistically different in patients with early versus late obliteration.

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Michael M. McDowell, Nitin Agarwal, Gordon Mao, Stephen Johnson, Hideyuki Kano, L. Dade Lunsford, and Stephanie Greene

OBJECTIVE

The study of pediatric arteriovenous malformations (pAVMs) is complicated by the rarity of the entity. Treatment choice has often been affected by the availability of different modalities and the experience of the providers present. The University of Pittsburgh experience of multimodality treatment of pAVMs is presented.

METHODS

The authors conducted a retrospective cohort study examining 212 patients with pAVM presenting to the University of Pittsburgh between 1988 and 2018, during which patients had access to surgical, endovascular, and radiosurgical options. Univariate analysis was performed comparing good and poor outcomes. A poor outcome was defined as a modified Rankin Scale (mRS) score of ≥ 3. Multivariate analysis via logistic regression was performed on appropriate variables with a p value of ≤ 0.2. Seventy-five percent of the cohort had at least 3 years of follow-up.

RESULTS

Five patients (2.4%) did not receive any intervention, 131 (61.8%) had GKRS alone, 14 (6.6%) had craniotomies alone, and 2 (0.9%) had embolization alone. Twenty-two (10.4%) had embolization and Gamma Knife radiosurgery (GKRS); 20 (9.4%) had craniotomies and GKRS; 8 (3.8%) had embolization and craniotomies; and 10 (4.7%) had embolization, craniotomies, and GKRS. Thirty-one patients (14.6%) were found to have poor outcome on follow-up. The multivariate analysis performed in patients with poor outcomes was notable for associations with no treatment (OR 18.9, p = 0.02), hemorrhage requiring craniotomy for decompression alone (OR 6, p = 0.03), preoperative mRS score (OR 2.1, p = 0.004), and Spetzler-Martin score (OR 1.8, p = 0.0005). The mean follow-up was 79.7 ± 62.1 months. The confirmed radiographic obliteration rate was 79.4% and there were 5 recurrences found on average 9.5 years after treatment.

CONCLUSIONS

High rates of long-term functional independence (mRS score of ≤ 2) can be achieved with comprehensive multimodality treatment of pAVMs. At this center there was no difference in outcome based on treatment choice when accounting for factors such as Spetzler-Martin grade and presenting morbidity. Recurrences are rare but frequently occur years after treatment, emphasizing the need for long-term screening after obliteration.

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Adomas Bunevicius, Hideyuki Kano, Cheng-Chia Lee, Michal Krsek, Ahmed M. Nabeel, Amr El-Shehaby, Khaled Abdel Karim, Nuria Martinez-Moreno, David Mathieu, John Y. K. Lee, Inga Grills, Douglas Kondziolka, Roberto Martinez-Alvarez, Wael A. Reda, Roman Liscak, Yan-Hua Su, L. Dade Lunsford, Mary Lee Vance, and Jason P. Sheehan

OBJECTIVE

The optimal time to perform stereotactic radiosurgery after incomplete resection of adrenocorticotropic hormone (ACTH)–producing pituitary adenoma in patients with Cushing’s disease (CD) remains unclear. In patients with persistent CD after resection of ACTH-producing pituitary adenoma, the authors evaluated the association of the interval between resection and Gamma Knife radiosurgery (GKRS) with outcomes.

METHODS

Pooled data from 10 institutions participating in the International Radiosurgery Research Foundation were used in this study.

RESULTS

Data from 255 patients with a mean follow-up of 65.59 ± 49.01 months (mean ± SD) were analyzed. Seventy-seven patients (30%) underwent GKRS within 3 months; 46 (18%) from 4 to 6 months; 34 (13%) from 7 to 12 months; and 98 (38%) at > 12 months after the resection. Actuarial endocrine remission rates were higher in patients who underwent GKRS ≤ 3 months than when treatment was > 3 months after the resection (78% and 65%, respectively; p = 0.017). Endocrine remission rates were lower in patients who underwent GKRS at > 12 months versus ≤ 12 months after the resection (57% vs 76%, respectively; p = 0.006). In multivariate Cox regression analyses adjusted for clinical and treatment characteristics, early GKRS was associated with increased probability of endocrine remission (hazard ratio [HR] 1.518, 95% CI 1.039–2.218; p = 0.031), whereas late GKRS (HR 0.641, 95% CI 0.448–0.919; p = 0.015) was associated with reduced probability of endocrine remission. The incidence of some degree of new pituitary deficiency (p = 0.922), new visual deficits (p = 0.740), and other cranial nerve deficits (p = 0.610) was not significantly related to time from resection to GKRS.

CONCLUSIONS

Early GKRS is associated with an improved endocrine remission rate, whereas later GKRS is associated with a lower rate of endocrine remission after pituitary adenoma resection. Early GKRS should be considered for patients with CD after incomplete pituitary adenoma resection.