Dynamic Changes in Arteriovenous Malformations (AVMs): Spontaneous Growth and Resolution of AVM-Associated Aneurysms in Two Pediatric Patients.

Arteriovenous malformations (AVMs) of the central nervous system are dynamic lesions that can change with time. One of the most clinically important concerns is the development and potential rupture of AVM-associated aneurysms. In this report, we review pediatric cases of de novo development of AVM-associated aneurysms in 2 children and present the relevant clinical and radiographic records. These 2 cases, coupled with a review of the current literature, offer insight into the risks of AVMs in children and underline the importance of timely treatment of appropriate cases.

Adjuvant Radiation Therapy Versus Surveillance After Surgical Resection of Atypical Meningiomas.

PURPOSE: The optimal timing of adjuvant radiation therapy (RT) in the management of atypical meningiomas remains controversial. We compared the outcomes of atypical meningiomas managed with upfront adjuvant RT versus postoperative surveillance. METHODS AND MATERIALS: Patients with intracranial atypical meningiomas who underwent resection between 2000 and 2015 at a single institution were identified. Patients receiving adjuvant RT (n = 51), defined as RT within the first year of surgery before tumor progression/recurrence (P/R), were compared with those undergoing initial surveillance (n = 179). The primary endpoints were radiographic evidence of P/R and time to P/R from surgery. RESULTS: A total of 230 patients were identified. Fifty-one (22%) patients received upfront adjuvant RT, and 179 (78%) underwent surveillance. Compared with the surveillance group, patients who received adjuvant RT had larger tumors (5.2 cm vs 4.6 cm; P = .04), were more likely to have undergone subtotal resection (65% vs 26%; P < . 01), and more often had bone invasion (18% vs 7%; P = .02). On multivariable analysis, receipt of adjuvant RT was associated with a lower risk of P/R compared with surveillance (hazard ratio, 0.21; 95% confidence interval, 0.11-0.41; P < .01). Patients who initially underwent surveillance and then received salvage RT at time of P/R had a shorter median time to local progression after RT compared with patients who developed local P/R after upfront adjuvant RT (19 vs 64 months, respectively; P < . 01). CONCLUSION: Upfront adjuvant RT was associated with improved local control in atypical meningiomas irrespective of extent of initial resection compared with surveillance. Early adjuvant RT should be strongly considered after gross total resection of atypical meningiomas.

Outcome and Toxicity of Proton Therapy for Vestibular Schwannoma: A Cohort Study.

OBJECTIVE: To assess the efficacy and toxicity of proton radiotherapy in vestibular schwannoma. STUDY DESIGN: Retrospective chart review and volumetric MRI-analyses. SETTING: Tertiary referral center. PATIENTS: Vestibular schwannoma patients treated with protons between 2003 and 2018. INTERVENTION: Proton radiotherapy. MAIN OUTCOME MEASURES: Tumor control was defined as not requiring salvage treatment. Progressive hearing loss was defined as a decrease in maximum speech discrimination score below the 95% critical difference in reference to the pretreatment score. Hearing assessment includes contralateral hearing and duration of follow-up. Dizziness and/or unsteadiness and facial and trigeminal nerve function were scored. Patients who had surgery prior to proton radiotherapy were separately assessed. RESULTS: Of 221 included patients, 136 received single fraction and 85 fractionated proton radiotherapy. Actuarial 5-year local control rate was 96% (95% CI 90-98%). The median radiological follow-up was 4.5 years. Progressive postirradiation speech discrimination score loss occurred in 42% of patients with audiometric follow-up within a year. Facial paresis was found in 5% (usually mild), severe dizziness in 5%, and trigeminal neuralgia in 5% of patients receiving protons as primary treatment. CONCLUSIONS: Proton radiotherapy achieves high tumor control with modest side effects aside from hearing loss in vestibular schwannoma patients. Limited and heterogeneous outcome reporting hamper comparisons to the literature. Potential sequelae of radiation therapy impacting vestibular function, cognitive function, and quality of life warrant further evaluation. Subgroups that benefit most from proton radiotherapy should be identified to optimize allocation and counterbalance its costs.

Multimodal cerebral arteriovenous malformation treatment: a 12-year experience and comparison of key outcomes to ARUBA.

OBJECTIVE: Curative treatment of unruptured brain arteriovenous malformations (AVMs) remains controversial after the only randomized controlled trial, A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA), was halted prematurely because interim analysis revealed superiority of the medical management group. In contrast, meta-analyses of retrospective cohorts suggest that intervention is much safer than was found in ARUBA. METHODS: The authors retrospectively analyzed 318 consecutive adult patients with brain AVMs treated at their institution with embolization, surgery, and/or proton beam radiosurgery. Analysis was performed in 142 ARUBA-eligible patients (baseline modified Rankin Scale [mRS] score 0-1, no history of hemorrhage), and results were compared to primary and secondary outcomes from ARUBA, as well as to natural history cohorts. RESULTS: The annualized stroke rate (hemorrhagic or ischemic) in this cohort was 1.8%, 4.9% in the first 12 months and 0.8% after the first 12 months, which was lower than in natural history studies and the ARUBA medical management arm (p = 0.001). The primary ARUBA endpoint of symptomatic stroke was reached in 13 patients (9.2%), which compares favorably to the ARUBA intervention arm (39.6%, p = 0.0001) and is similar to the ARUBA medical management arm (9.2%, p = 1.0). The secondary ARUBA endpoint (mRS score ≥ 2 at 5 years of follow-up) was reached in 14.3% of patients, compared to 40.5% in the ARUBA intervention arm (p = 0.002) and 16.7% in the ARUBA medical management arm (p = 0.6). CONCLUSIONS: This multimodal approach to the selection and treatment of patients with brain AVMs yields good clinical outcomes with key safety endpoints (stroke, death, and mRS score 0-1) better than the ARUBA intervention arm and similar to the ARUBA medical arm at 5 years of follow-up. Results compare favorably to natural history cohorts at longer follow-up times. This suggests that tertiary care centers with integrated programs, expertise in patient selection, and individualized treatment approaches may allow for better clinical outcomes than reported in ARUBA. It supports current registry studies and merits consideration of future randomized controlled trials in patients with brain AVMs.

Proton Stereotactic Radiosurgery for Brain Metastases: A Single-Institution Analysis of 370 Patients.

PURPOSE: To report the first series of proton stereotactic radiosurgery (SRS) for the treatment of patients with single or multiple brain metastases, including failure patterns, survival outcomes, and toxicity analysis. METHODS AND MATERIALS: This was a single-institution, retrospective study of 815 metastases from 370 patients treated with proton SRS between April 1991 and November 2016. Cumulative incidence estimates of local failure, distant brain failure, and pathologically confirmed radionecrosis and Kaplan-Meier estimates of overall survival were calculated. Fine and Gray and Cox regressions were performed to ascertain whether clinical and treatment factors were associated with the described endpoints. RESULTS: The median follow-up from proton SRS was 9.2 months. The 6- and 12-month estimates of local failure, distant brain failure, and overall survival were 4.3% (95% confidence interval [CI] 3.0%-5.9%) and 8.5% (95% CI 6.7%-10.6%), 39.1% (95% CI 34.1%-44.0%) and 48.2% (95% CI 43.0%-53.2%), and 76.0% (95% CI 71.3%-80.0%) and 51.5% (95% CI 46.3%-56.5%), respectively. The median survival was 12.4 months (95% CI 10.8-14.0 months) after proton SRS. The most common symptoms were low-grade fatigue (12.5%), headache (10.0%), motor weakness (6.2%), seizure (5.8%), and dizziness (5.4%). The rate of pathologically confirmed radionecrosis at 12 months was 3.6% (95% CI 2.0%-5.8%), and only target volume was associated on multivariate analysis (subdistribution hazard ratio 1.13, 95% CI 1.0-1.20). CONCLUSIONS: To the best of our knowledge, this is the first reported series of proton SRS for the management of brain metastases. Moderate-dose proton SRS is well tolerated and can achieve good local control outcomes, comparable to those obtained with conventional photon SRS strategies. Although proton SRS remains resource-intensive, future strategies evaluating its selective utility in patients who would benefit most from integral dose reduction should be explored.

Modified Park Bench Position for Superior Vermian Arteriovenous Malformations and Dural Fistulas.

OBJECTIVES: Arteriovenous malformations (AVMs) of the superior cerebellar vermis and dural arteriovenous fistulas (dAVFs) draining into tentorial venous structures are uncommon lesions. Various surgical approaches and positions have been used to gain access. METHODS: We present our experience with 10 superior vermian AVMs and 3 dAVFs with retrograde transverse sinus or torcular drainage, each resected through a supracerebellar infratentorial approach in the park bench position with modification of the neck and head position (vertex tilt-up instead of down). RESULTS: All 13 patients were treated surgically, with 4 receiving adjunctive endovascular embolization. Postoperative digital subtraction angiography confirmed complete resection of lesion in all. One patient experienced superficial wound infection treated by oral antibiotics, and another presented with a cerebrospinal fluid collection due to delayed hydrocephalus requiring insertion of a ventriculoperitoneal shunt. The median modified Rankin Scale score at last follow-up was 1. There were no surgical complications at the time of last follow-up. CONCLUSIONS: Our series shows that for superior vermian AVMs or dAVFs with retrograde transverse sinus or torcula venous drainage, the supracerebellar infratentorial approach in a modified vertex tilt-up park bench position is a safe and effective surgical approach.

Spatiotemporal Fractionation Schemes for Irradiating Large Cerebral Arteriovenous Malformations.

PURPOSE: To optimally exploit fractionation effects in the context of radiosurgery treatments of large cerebral arteriovenous malformations (AVMs). In current practice, fractionated treatments divide the dose evenly into several fractions, which generally leads to low obliteration rates. In this work, we investigate the potential benefit of delivering distinct dose distributions in different fractions. METHODS AND MATERIALS: Five patients with large cerebral AVMs were reviewed and replanned for intensity modulated arc therapy delivered with conventional photon beams. Treatment plans allowing for different dose distributions in all fractions were obtained by performing treatment plan optimization based on the cumulative biologically effective dose delivered at the end of treatment. RESULTS: We show that distinct treatment plans can be designed for different fractions, such that high single-fraction doses are delivered to complementary parts of the AVM. All plans create a similar dose bath in the surrounding normal brain and thereby exploit the fractionation effect. This partial hypofractionation in the AVM along with fractionation in normal brain achieves a net improvement of the therapeutic ratio. We show that a biological dose reduction of approximately 10% in the healthy brain can be achieved compared with reference treatment schedules that deliver the same dose distribution in all fractions. CONCLUSIONS: Boosting complementary parts of the target volume in different fractions may provide a therapeutic advantage in fractionated radiosurgery treatments of large cerebral AVMs. The strategy allows for a mean dose reduction in normal brain that may be valuable for a patient population with an otherwise normal life expectancy.

Proton beam stereotactic radiosurgery of vestibular schwannomas.

PURPOSE: The proton beam's Bragg peak permits highly conformal radiation of skull base tumors. This study, prompted by reports of transient (30% each) and permanent (10% each) facial and trigeminal neuropathy after stereotactic radiosurgery of vestibular schwannomas with marginal doses of 16-20 Gy, assessed whether proton beam radiosurgery using a marginal dose of only 12 Gy could control vestibular schwannomas while causing less neuropathy. METHODS AND MATERIALS: Sixty-eight patients (mean age 67 years) were treated between 1992 and 1998. The mean tumor volume was 2.49 cm(3). The dose to the tumor margin (70% isodose line) was 12 Gy. The prospectively specified follow-up consisted of neurologic evaluation and MRI at 6, 12, 24, and 36 months. RESULTS: After a mean clinical follow-up of 44 months and imaging follow-up of 34 months in 64 patients, 35 tumors (54.7%) were smaller and 25 (39.1%) were unchanged (tumor control rate 94%; actuarial control rate 94% at 2 years and 84% at 5 years). Three tumors enlarged: one shrank after repeated radiosurgery, one remained enlarged at the time of unrelated death, and one had not been imaged for 4 years in a patient who remained asymptomatic at last follow-up. Intratumoral hemorrhage into one stable tumor required craniotomy that proved successful. Thus, 97% of tumors required no additional treatment. Three patients (4.7%) underwent shunting for hydrocephalus evident as increased ataxia. Of 6 patients with functional hearing ipsilaterally, 1 improved, 1 was unchanged, and 4 progressively lost hearing. Cranial neuropathies were infrequent: persistent facial hypesthesia (2 new, 1 exacerbated; 4.7%); intermittent facial paresthesias (5 new, 1 exacerbated; 9.4%); persistent facial weakness (2 new, 1 exacerbated; 4.7%) requiring oculoplasty; transient partial facial weakness (5 new, 1 exacerbated; 9.4%), and synkinesis (5 new, 1 exacerbated; 9.4%). CONCLUSION: Proton beam stereotactic radiosurgery of vestibular schwannomas at the doses used in this study controls tumor growth with relatively few complications.

Second tumors after radiosurgery: tip of the iceberg or a bump in the road?

OBJECTIVE: Radiosurgery-associated second tumors have been reported in four isolated patients during the past 2 years. In our own experience, we are aware of two additional patients. The purpose of this report is to call attention to this potentially emerging problem. METHODS: A review of the English-language literature concerning patients with radiosurgery-associated second tumors was performed. In addition, we report on two patients in our own practice who were treated in the past year. RESULTS: Four patients were found in the literature, and two additional patients were seen by the authors. Malignant tumors occurred as early as 6 years after radiosurgery. The pathological findings in three of these four malignant tumors were glioblastoma multiforme. Benign tumors developed between 16 and 19 years later. Tumors developed both within the full-dose prescription volume and in the lower-dose periphery. Of interest, three of the six patients experienced complications of the radiosurgery treatment before developing second tumors. CONCLUSION: Although patients will increasingly be reported with second tumors after radiosurgery in the future, the overall incidence seems quite low and should not alter current radiosurgical practice. However, continual surveillance of treated patients should be considered.

Far posterior subtemporal approach to the dorsolateral brainstem and tentorial ring: technique and clinical experience.

OBJECTIVE: Surgical access to the posterolateral mesencephalon or tentorial ring can be problematic, depending on the angle of the tentorium and associated venous structures. A far posterior subtemporal approach was developed that uses the wide opening of the tentorium and the option of supratentorial retraction of the cerebellum to provide an excellent angle of approach to this region. Details of this technique and a series of eight patients with lesions treated by this approach are presented. METHODS: Seven cavernous malformations and one dural arteriovenous malformation were approached in eight patients. In this far posterior subtemporal approach, a horseshoe incision is centered slightly behind the ear, with the caudal extent of the craniotomy defined by the temporal fossa floor. The entry of the vein of Labbé into transverse sinus is identified intradurally. If the vein enters anteriorly in the exposure, it is mobilized. Retractors are then placed, and the tentorium is visualized and opened laterally, avoiding the trochlear nerve. A thin, tapered retractor can be used to retract the cerebellum posterolaterally away from the brainstem. RESULTS: This approach was used to treat eight patients, and their lesions were successfully resected. Seven patients experienced good outcomes, and one patient, who presented with Hunt-Hess Grade IV subarachnoid hemorrhage from a dural arteriovenous malformation, experienced a fair outcome. CONCLUSION: The far posterior subtemporal approach is effective for approaching carefully selected lesions of the posterolateral mesencephalon and tentorial ring.

The relationship between occlusive hyperemia and complications associated with the radiosurgical treatment of arteriovenous malformations: report of two cases.

OBJECTIVE AND IMPORTANCE: It has been suggested that impaired venous drainage of normal brain after surgical removal of an arteriovenous malformation (AVM) may cause perinidal edema and hemorrhage. The term occlusive hyperemia has been proposed for this phenomenon. There is evidence that occlusive hyperemia also may occur after radiosurgical treatment of AVMs. The purpose of this article is to lend further support to the concept that venous occlusion may be responsible for some complications observed after AVM radiosurgery. CLINICAL PRESENTATION: We report two patients with unusual radiosurgery-associated complications, and we examine the evidence for venous occlusion as the mechanism underlying the observed clinical sequelae in each patient. INTERVENTION: Patient 1 had a large parietal venous infarct remote from her frontal AVM site 11 months after radiosurgery. At that time, the AVM was confirmed by angiography to have been obliterated. During the next 4 years, the patient experienced persistent posterior hemispheric edema with recurrent focal hemorrhages until the patient's death from massive swelling and uncal herniation. During this period, radiographic studies, including repeat angiography, demonstrated sequential cortical venous occlusions and findings most consistent with venous insufficiency. Postmortem examination revealed no evidence of radionecrosis. Patient 2 exhibited a biphasic pattern of neurological deterioration at 3 and 6 years after radiosurgery. Associated with this unusual phenomenon, there was radiographic evidence of venous outflow obstruction of her thalamic AVM with prominent perinidal edema and progressive occlusion of the nidus. CONCLUSION: We conclude that occlusive hyperemia is responsible for some cases of neurological deterioration after AVM radiosurgery, especially in a setting for which the time course or other clinical features are not as might be expected from a radiobiological perspective. The two patients we describe in this report suggest that manifestations may vary.

Results of multimodality treatment for 141 patients with brain arteriovenous malformations and seizures: factors associated with seizure incidence and seizure outcomes.

OBJECTIVE: Previous reports of seizure outcomes after arteriovenous malformation (AVM) treatment have involved single-treatment modality (surgery, radiosurgery, or embolization) series. Such series reflect only selected lesions, of certain sizes, locations, and other clinical and anatomic characteristics, that are amenable to the single therapy, limiting the analysis of those factors. We report the results of AVM treatment using a multimodality approach that we think encompasses a broader spectrum of treatable brain AVMs. We tested for factors associated with seizure presentation and seizure outcomes. METHODS: Between 1991 and 1999, the multidisciplinary neurovascular unit at Massachusetts General Hospital treated 424 patients with brain AVMs. Treatment consisted of surgical resection, radiosurgery, or embolization, either alone or in combination. One hundred forty-one patients (33%) experienced seizures before treatment. We studied the following factors: sex, age, AVM size, AVM location, occurrence of intracranial hemorrhage, seizure type, duration of seizure history, treatment modality, and AVM obliteration. We tested for statistical associations between these factors and seizure presentation and outcomes. Clinical follow-up monitoring was via mailed questionnaires. RESULTS: When we compared the 141 patients with seizures with the 283 patients who did not experience seizures (total of 424 patients), male sex, age of less than 65 years, AVM size of more than 3 cm, and temporal lobe AVM location were statistically associated with seizures (P < 0.01, P < 0.05, P < 0.0001, and P < 0.01, respectively). Posterior fossa and deep locations were statistically associated with no seizures (P < 0.0001). One hundred ten (78%) of the 141 patients who experienced seizures before treatment responded to the mailed questionnaires, with a mean follow-up period of 2.9 years. A detailed comparison of responders and nonresponders demonstrated no statistically significant differences in pertinent characteristics. As determined with the Engel Seizure Outcome Scale, there were 73 (66%) Class I (free of disabling seizures), 11 (10%) Class II (rare disabling seizures), 1 (0.9%) Class III (worthwhile improvement), and 22 (20%) Class IV (no worthwhile improvement) outcomes. Three patients died during the follow-up period. We tested for factors associated with Engel Class I outcomes. Sex, age, and AVM size were not associated with Class I outcomes. Short seizure history, association of seizures with intracranial hemorrhage, generalized tonicoclonic seizure type, deep and posterior fossa AVM locations, surgical resection, and complete AVM obliteration were statistically associated with Class I outcomes (P < 0.0001, P < 0.05, P < 0.05, P < 0.05, P < 0.001, and P < 0.001, respectively). When only completely obliterated AVMs were considered, there were no statistically significant differences between surgery, radiosurgery, and embolization. CONCLUSION: Certain factors, as identified in an analysis of a wide spectrum of treatable brain AVMs, can facilitate predictions of the incidence of seizure presentation with AVMs, as well as seizure outcomes after multimodality treatment.

Radiosurgery of the rat hippocampus: magnetic resonance imaging, neurophysiological, histological, and behavioral studies.

OBJECTIVE: To explore the histological, electrophysiological, radiological, and behavioral effects of radiosurgery using a new model of proton beam radiosurgery (PBR) of the rodent hippocampus. METHODS: Forty-one rats underwent PBR of the right hippocampus with nominal doses of 5 to 130 cobalt Gray equivalents (CGE). Three control animals were untreated. Three months after PBR, 41 animals were evaluated with the Morris water maze, 23 with T2-weighted magnetic resonance imaging, and 22 with intrahippocampal microelectrode recordings. Animals that were studied physiologically were killed, and their brains were examined with Nissl staining and immunocytochemical staining for glutamic acid decarboxylase, heat shock protein 72 (HSP-72), parvalbumin, calmodulin, calretinin, calbindin, and somatostatin. RESULTS: Ninety and 130 CGE resulted in decreased performance in the Morris water maze, increased signal on T2-weighted magnetic resonance imaging, diminished granule cell field potentials, and tissue necrosis, which was restricted to the irradiated side. These doses also resulted in ipsilateral up-regulation of calbindin and HSP-72. Parvalbumin was down-regulated at 130 CGE. The 30 and 60 CGE animals displayed a marked increase in HSP-72 staining on the irradiated side but no demonstrable cell loss. No asymmetries were noted in somatostatin, calretinin, and glutamic acid decarboxylase staining. Normal physiology was found in rats receiving up to 60 CGE. CONCLUSION: This study expands our understanding of the effects of radiosurgery on the mammalian brain. Three months after PBR, the irradiated rat hippocampus demonstrates necrosis at 90 CGE, but not at 60 CGE, with associated abnormalities in magnetic resonance imaging, physiology, and memory testing. HSP-72 was up-regulated at nonnecrotic doses.

Proton beam radiosurgery for vestibular schwannoma: tumor control and cranial nerve toxicity.

OBJECTIVE: We sought to determine the tumor control rate and cranial nerve function outcomes in patients with vestibular schwannomas who were treated with proton beam stereotactic radiosurgery. METHODS: Between November 1992 and August 2000, 88 patients with vestibular schwannomas were treated at the Harvard Cyclotron Laboratory with proton beam stereotactic radiosurgery in which two to four convergent fixed beams of 160-MeV protons were applied. The median transverse diameter was 16 mm (range, 2.5-35 mm), and the median tumor volume was 1.4 cm(3) (range, 0.1-15.9 cm(3)). Surgical resection had been performed previously in 15 patients (17%). Facial nerve function (House-Brackmann Grade 1) and trigeminal nerve function were normal in 79 patients (89.8%). Eight patients (9%) had good or excellent hearing (Gardner-Robertson [GR] Grade 1), and 13 patients (15%) had serviceable hearing (GR Grade 2). A median dose of 12 cobalt Gray equivalents (range, 10-18 cobalt Gray equivalents) was prescribed to the 70 to 108% isodose lines (median, 70%). The median follow-up period was 38.7 months (range, 12-102.6 mo). RESULTS: The actuarial 2- and 5-year tumor control rates were 95.3% (95% confidence interval [CI], 90.9-99.9%) and 93.6% (95% CI, 88.3-99.3%). Salvage radiosurgery was performed in one patient 32.5 months after treatment, and a craniotomy was required 19.1 months after treatment in another patient with hemorrhage in the vicinity of a stable tumor. Three patients (3.4%) underwent shunting for hydrocephalus, and a subsequent partial resection was performed in one of these patients. The actuarial 5-year cumulative radiological reduction rate was 94.7% (95% CI, 81.2-98.3%). Of the 21 patients (24%) with functional hearing (GR Grade 1 or 2), 7 (33.3%) retained serviceable hearing ability (GR Grade 2). Actuarial 5-year normal facial and trigeminal nerve function preservation rates were 91.1% (95% CI, 85-97.6%) and 89.4% (95% CI, 82-96.7%). Univariate analysis revealed that prescribed dose (P = 0.005), maximum dose (P = 0.006), and the inhomogeneity coefficient (P = 0.03) were associated with a significant risk of long-term facial neuropathy. No other cranial nerve deficits or cancer relapses were observed. CONCLUSION: Proton beam stereotactic radiosurgery has been shown to be an effective means of tumor control. A high radiological response rate was observed. Excellent facial and trigeminal nerve function preservation rates were achieved. A reduced prescribed dose is associated with a significant decrease in facial neuropathy.

Dose-volume prediction of radiation-related complications after proton beam radiosurgery for cerebral arteriovenous malformations.

OBJECT: The use of radiosurgery for the treatment of cerebral arteriovenous malformations (AVMs) and other lesions demands an accurate understanding of the risk of radiation-related complications. Some commonly used formulas for predicting risk are based on extrapolation from small numbers of animal experiments, pilot human treatment series, and theoretical radiobiological considerations. The authors studied the incidence of complications after AVM radiosurgery in relation to dose, volume, and other factors in a large patient series. METHODS: A retrospective review was conducted in 1329 patients with AVM treated by Dr. Raymond Kjellberg at the Harvard Cyclotron Laboratory (HCL) between 1965 and 1993. Dose and volume were obtained from HCL records, and information about patient follow up was derived from concurrent clinical records, questionnaires, and contact with referring physicians. Multivariate logistic regression with bootstrapped confidence intervals was used. Follow up was available in 1250 patients (94%); the median follow-up duration was 6.5 years. The median radiation dose was 10.5 Gy and the median treatment volume was 33.7 cm(3). Twenty-three percent of treated lesions were smaller than 10 cm(3). Fifty-one permanent radiation-related deficits occurred (4.1%). Of 1043 patients treated with a dose predicted by the Kjellberg isoeffective centile curve to have a less than 1% complication risk, 1.8% suffered radiation-related complications. Actual complication rates were 4.7% for 128 patients treated at Kjellberg risk centile doses of 1 to 1.8%, and 34% for 61 patients treated at risk centile doses of 2 to 2.5%. The fitted logistic model showed that complication risk was related to treatment dose and volume, thalamic or brainstem location, and patient age. CONCLUSIONS: The Kjellberg isoeffective risk centile curve significantly underpredicted actual risks of permanent complications after proton beam radiosurgery for AVMs. Actual risks were best predicted using a model that accounted for treatment dose and volume, lesion location, and patient age.

Proton beam stereotactic radiosurgery for pediatric cerebral arteriovenous malformations.

BACKGROUND: For cerebral arteriovenous malformations (AVMs) determined to be high risk for surgery or endovascular embolization, stereotactic radiosurgery (SRS) is considered the mainstay of treatment. OBJECTIVE: To determine the outcomes of pediatric patients with AVMs treated with proton SRS. METHODS: We reviewed the records of 44 consecutively treated pediatric patients (younger than 18 years of age) who underwent proton SRS at our institution from 1998 to 2010. The median target volume was 4.5 ± 5.9 mL (range, 0.3-29.0 mL) and the median maximal diameter was 3.6 ± 1.5 cm (range, 1-6 cm). Radiation was administered with a median prescription dose of 15.50 ± 1.87 CGE to the 90% isodose. RESULTS: At a median follow-up of 52 ± 25 months, 2 patients (4.5%) had no response, 24 patients (59.1%) had a partial response, and 18 patients (40.9%) experienced obliteration of their AVM. The median time to obliteration was 49 ± 26 months, including 17 patients who underwent repeat proton radiosurgery. Four patients (9%) experienced hemorrhage after treatment at a median time of 45 ± 15 months. Univariate analysis identified modified AVM scale score (P = .045), single fraction treatment (0.04), larger prescription dose (0.01), larger maximum dose (<0.001), and larger minimum dose (0.01) to be associated with AVM obliteration. CONCLUSION: High-risk AVMs can be safely treated with proton radiosurgery in the pediatric population. Because protons deposit energy more selectively than photons, there is the potential benefit of protons to lower the probability of damage to healthy tissue in the developing brain.

Single-fraction proton beam stereotactic radiosurgery for cerebral arteriovenous malformations.

PURPOSE/OBJECTIVE(S): To evaluate the obliteration rate and potential adverse effects of single-fraction proton beam stereotactic radiosurgery (PSRS) in patients with cerebral arteriovenous malformations (AVMs). METHODS AND MATERIALS: From 1991 to 2010, 248 consecutive patients with 254 cerebral AVMs received single-fraction PSRS at our institution. The median AVM nidus volume was 3.5 cc (range, 0.1-28.1 cc), 23% of AVMs were in critical/deep locations (basal ganglia, thalamus, or brainstem), and the most common prescription dose was 15 Gy(relative biological effectiveness [RBE]). Univariable and multivariable analyses were performed to assess factors associated with obliteration and hemorrhage. RESULTS: At a median follow-up time of 35 months (range, 6-198 months), 64.6% of AVMs were obliterated. The median time to total obliteration was 31 months (range, 6-127 months), and the 5-year and 10-year cumulative incidence of total obliteration was 70% and 91%, respectively. On univariable analysis, smaller target volume (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.86-0.93, P<.0001), smaller treatment volume (HR 0.93, 95% CI 0.90-0.96, P<.0001), higher prescription dose (HR 1.16, 95% CI 1.07-1.26, P=.001), and higher maximum dose (HR 1.14, 95% CI 1.05-1.23, P=.002) were associated with total obliteration. Deep/critical location was also associated with decreased likelihood of obliteration (HR 0.68, 95% CI 0.47-0.98, P=.04). On multivariable analysis, critical location (adjusted HR [AHR] 0.42, 95% CI 0.27-0.65, P<.001) and smaller target volume (AHR 0.81, 95% CI 0.68-0.97, P=.02) remained associated with total obliteration. Posttreatment hemorrhage occurred in 13 cases (5-year cumulative incidence of 7%), all among patients with less than total obliteration, and 3 of these events were fatal. The most common complication was seizure, controlled with medications, both acutely (8%) and in the long term (9.1%). CONCLUSIONS: The current series is the largest modern series of PSRS for cerebral AVMs. PSRS can achieve a high obliteration rate with minimal morbidity. Post-treatment hemorrhage remains a potentially fatal risk among patients who have not yet responded to treatment.

Outcomes of proton therapy for patients with functional pituitary adenomas.

PURPOSE/OBJECTIVE(S): This study evaluated the efficacy and toxicity of proton therapy for functional pituitary adenomas (FPAs). METHODS AND MATERIALS: We analyzed 165 patients with FPAs who were treated at a single institution with proton therapy between 1992 and 2012 and had at least 6 months of follow-up. All but 3 patients underwent prior resection, and 14 received prior photon irradiation. Proton stereotactic radiosurgery was used for 92% of patients, with a median dose of 20 Gy(RBE). The remainder received fractionated stereotactic proton therapy. Time to biochemical complete response (CR, defined as ≥ 3 months of normal laboratory values with no medical treatment), local control, and adverse effects are reported. RESULTS: With a median follow-up time of 4.3 years (range, 0.5-20.6 years) for 144 evaluable patients, the actuarial 3-year CR rate and the median time to CR were 54% and 32 months among 74 patients with Cushing disease (CD), 63% and 27 months among 8 patients with Nelson syndrome (NS), 26% and 62 months among 50 patients with acromegaly, and 22% and 60 months among 9 patients with prolactinomas, respectively. One of 3 patients with thyroid stimulating hormone-secreting tumors achieved CR. Actuarial time to CR was significantly shorter for corticotroph FPAs (CD/NS) compared with other subtypes (P=.001). At a median imaging follow-up time of 43 months, tumor control was 98% among 140 patients. The actuarial 3-year and 5-year rates of development of new hypopituitarism were 45% and 62%, and the median time to deficiency was 40 months. Larger radiosurgery target volume as a continuous variable was a significant predictor of hypopituitarism (adjusted hazard ratio 1.3, P=.004). Four patients had new-onset postradiosurgery seizures suspected to be related to generously defined target volumes. There were no radiation-induced tumors. CONCLUSIONS: Proton irradiation is an effective treatment for FPAs, and hypopituitarism remains the primary adverse effect.

Planned two-fraction proton beam stereotactic radiosurgery for high-risk inoperable cerebral arteriovenous malformations.

PURPOSE: To evaluate patients with high-risk cerebral arteriovenous malformations (AVMs), based on eloquent brain location or large size, who underwent planned two-fraction proton stereotactic radiosurgery (PSRS). METHODS AND MATERIALS: From 1991 to 2009, 59 patients with high-risk cerebral AVMs received two-fraction PSRS. Median nidus volume was 23 cc (range, 1.4-58.1 cc), 70% of cases had nidus volume ≥ 14 cc, and 34% were in critical locations (brainstem, basal ganglia). Median AVM score based on age, AVM size, and location was 3.19 (range, 0.9-6.9). Many patients had prior surgery or embolization (40%) or prior PSRS (12%). The most common prescription was 16 Gy radiobiologic equivalent (RBE) in two fractions, prescribed to the 90% isodose. RESULTS: At a median follow-up of 56.1 months, 9 patients (15%) had total and 20 patients (34%) had partial obliteration. Patients with total obliteration received higher total dose than those with partial or no obliteration (mean dose, 17.6 vs. 15.5 Gy (RBE), p = 0.01). Median time to total obliteration was 62 months (range, 23-109 months), and 5-year actuarial rate of partial or total obliteration was 33%. Five-year actuarial rate of hemorrhage was 22% (95% confidence interval, 12.5%-36.8%) and 14% (n = 8) suffered fatal hemorrhage. Lesions with higher AVM scores were more likely to hemorrhage (p = 0.024) and less responsive to radiation (p = 0.026). The most common complication was Grade 1 headache acutely (14%) and long term (12%). One patient developed a Grade 2 generalized seizure disorder, and two had mild neurologic deficits. CONCLUSIONS: High-risk AVMs can be safely treated with two-fraction PSRS, although total obliteration rate is low and patients remain at risk for future hemorrhage. Future studies should include higher doses or a multistaged PSRS approach for lesions more resistant to obliteration with radiation.

Proton stereotactic radiosurgery for the treatment of benign meningiomas.

PURPOSE: Given the excellent prognosis for patients with benign meningiomas, treatment strategies to minimize late effects are important. One strategy is proton radiation therapy (RT), which allows less integral dose to normal tissue and greater homogeneity than photon RT. Here, we report the first series of proton stereotactic radiosurgery (SRS) used for the treatment of meningiomas. METHODS AND MATERIALS: We identified 50 patients with 51 histologically proven or image-defined, presumed-benign meningiomas treated at our institution between 1996 and 2007. Tumors of <4 cm in diameter and located≥2 mm from the optic apparatus were eligible for treatment. Indications included primary treatment (n=32), residual tumor following surgery (n=8), and recurrent tumor following surgery (n=10). The median dose delivered was 13 Gray radiobiologic equivalent (Gy[RBE]) (range, 10.0-15.5 Gy[RBE]) prescribed to the 90% isodose line. RESULTS: Median follow-up was 32 months (range, 6-133 months). Magnetic resonance imaging at the most recent follow-up or time of progression revealed 33 meningiomas with stable sizes, 13 meningiomas with decreased size, and 5 meningiomas with increased size. The 3-year actuarial tumor control rate was 94% (95% confidence interval, 77%-98%). Symptoms were improved in 47% (16/34) of patients, unchanged in 44% (15/34) of patients, and worse in 9% (3/34) of patients. The rate of potential permanent adverse effects after SRS was 5.9% (3/51 patients). CONCLUSIONS: Proton SRS is an effective therapy for small benign meningiomas, with a potentially lower rate of long-term treatment-related morbidity. Longer follow-up is needed to assess durability of tumor control and late effects.