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OBJECTIVE High-resolution double-dose gadolinium-enhanced Gamma Knife (GK) radiosurgery-planning MRI (GK MRI) on the day of GK treatment can detect additional brain metastases undiagnosed on the prior diagnostic MRI scan (dMRI), revealing increased intracranial disease burden on the day of radiosurgery, and potentially necessitating a reevaluation of appropriate management. The authors identified factors associated with detecting additional metastases on GK MRI and investigated the relationship between detection of additional metastases and postradiosurgery patient outcomes. METHODS The authors identified 326 patients who received GK radiosurgery at their institution from 2010 through 2013 and had a prior dMRI available for comparison of numbers of brain metastases. Factors predictive of additional brain metastases on GK MRI were investigated using logistic regression analysis. Overall survival was estimated by Kaplan-Meier method, and postradiosurgery distant intracranial failure was estimated by cumulative incidence measures. Multivariable Cox proportional hazards model and Fine-Gray regression modeling assessed potential risk factors of overall survival and distant intracranial failure, respectively. RESULTS The mean numbers of brain metastases (SD) on dMRI and GK MRI were 3.4 (4.2) and 5.8 (7.7), respectively, and additional brain metastases were found on GK MRI in 48.9% of patients. Frequencies of detecting additional metastases for patients with 1, 2, 3-4, and more than 4 brain metastases on dMRI were 29.5%, 47.9%, 55.9%, and 79.4%, respectively (p < 0.001). An index brain metastasis with a diameter greater than 1 cm on dMRI was inversely associated with detecting additional brain metastases, with an adjusted odds ratio of 0.57 (95% CI 0.4-0.9, p = 0.02). The median time between dMRI and GK MRI was 22 days (range 1-88 days), and time between scans was not associated with detecting additional metastases. Patients with additional brain metastases did not have larger total radiosurgery target volumes, and they rarely had an immediate change in management (abortion of radiosurgery or addition of whole-brain radiation therapy) due to detection of additional metastases. Patients with additional metastases had a higher incidence of distant intracranial failure than those without additional metastases (p = 0.004), with an adjusted subdistribution hazard ratio of 1.4 (95% CI 1.0-2.0, p = 0.04). Significantly worse overall survival was not detected for patients with additional brain metastases on GK MRI (log-rank p = 0.07), with the relative adjusted hazard ratio of 1.07, (95% CI 0.81-1.41, p = 0.65). CONCLUSIONS Detecting additional brain metastases on GK MRI is strongly associated with the number of brain metastases on dMRI and inversely associated with the size of the index brain metastasis. The discovery of additional brain metastases at time of GK radiosurgery is very unlikely to lead to aborting radiosurgery but is associated with a higher incidence of distant intracranial failure. However, there is not a significant difference in survival. ▪ CLASSIFICATION OF EVIDENCE Type of question: prognostic; study design: retrospective cohort trial; evidence: Class IV.

Background: Atypical and malignant meningiomas can recur despite resection and radiation., Objective: To determine outcomes of patients with recurrent atypical or malignant meningioma treated with repeat resection and permanent iodine-125 ( 125 I) brachy-therapy., Methods: Charts of patients who underwent surgical resection and 125 I brachyther-apy implantation for atypical and malignant meningiomas between 1988 and 2013 were retrospectively reviewed. The Kaplan-Meier actuarial method was used to calculate progression-free and overall survival. The log-rank test was used to compare groups. Significance was set at P < .05., Results: Forty-two patients underwent 50 resections with 125 I brachytherapy im-plantations. All patients had undergone previous resections and 85% had previously undergone radiation. Median follow-up was 7.5 years after diagnosis and 2.3 years after brachytherapy. Median time to progression after resection with 125 I brachytherapy was 20.9 months for atypical meningioma, 11.4 months for malignant meningioma, and 11.4 months for the combined groups. Median survival after re-resection and 125 I brachytherapy was 3.5 years for atypical meningioma, 2.3 years for malignant menin-gioma, and 3.3 years for all subjects. Median overall survival after diagnosis was 11.1 years for atypical meningioma, 9.1 years for malignant meningioma, and 9.4 years for all subjects. Complications occurred in 17 patients and included radiation necrosis (n = 8, 16%), wound breakdown (n = 6, 12%), hydrocephalus (n = 4, 8%), infection (n = 3, 6%), and a pseudomeningocele (n = 2, 5%)., Conclusion: This is the largest experience with adjuvant 125 I brachytherapy for recurrent high-grade meningiomas. The outcomes support the use of adjuvant brachytherapy as an option for these aggressive tumors., (Copyright © 2017 by the Congress of Neurological Surgeons)

Background: Pineal parenchymal tumors (PPTs) are rare neoplasms of the central nervous system, and data concerning clinical outcomes are limited. The purpose of this study was to define the clinical behavior of PPT according to current histopathologic criteria and identify prognostic factors to guide therapeutic decisions., Methods: Seventy-five patients treated for PPT at a single institution between 1992 and 2015 were retrospectively identified. Forty-five resection specimens were available and re-reviewed. Freedom from progression (FFP) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using log-rank tests., Results: Median follow-up was 4.1 years. All patients initially underwent surgery; 78% of patients with PPT of intermediate differentiation (PPTID) and all patients with pineoblastoma received adjuvant therapy. Pathologic re-review refined classification in 27% of cases, with the majority of these being adult patients with pineal tumors originally classified as pineoblastomas that more accurately resembled PPTID based on the 2007 WHO classification., Classification: Our histologic review also identified that PPTIDs can be classified into small-cell and large-cell morphologic subtypes, which have distinct clinical outcomes. Tumor grade, extent of resection, and neuraxis spread were prognostic for FFP. PPTID subtype, extent of resection, and neuraxis spread were prognostic for OS. Genetic analysis of a pineoblastoma case identified somatic mutations of DICER1, ARID1A, and KDM5C genes., Conclusions: PPTIDs can be classified into 1 of 2 novel morphologic subtypes that are associated with distinct clinical outcomes. Tumor grade, neuraxis spread, and extent of resection also influence outcome for patients with PPT., (Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Purpose: Various cochlear dose surrogates have been reported as associated with hearing outcome in studies of stereotactic radiosurgery (SRS) for vestibular schwannomas. In this study, we investigated whether an inherent functional relationship exists among these reported surrogates., Methods and Materials: A cohort of 85 serial patient cases treated with single-fraction stereotactic radiosurgery from 1997 through 2013 at our institution was analyzed. For all the cases, the mean prescription dose was 12.5 ± 0.3 Gy (range, 12-13 Gy) and mean target volume 1.32 ± 1.51 mL (range, 0.80-8.77 mL). The mean cochlea volume was 0.078 ± 0.016 mL (range, 0.048-0.131 mL; median, 0.076 mL). Correlation analysis among mean cochlear dose, point maximum dose and modiolus dose was performed and also parameterized with new variables such as the effective dose radius (EDR) as derived from a general dose fall-off model., Results: Weak correlation via linear regression was found between the point maximum dose and the mean cochlear dose (R 2 = 0.719) as well as the modiolus dose (R 2 = 0.568). However, when parameterized with EDR, a near-perfect correlation (P < .0001) via linear regression was found between the EDR for the point maximum dose and the EDR for the mean cochlear dose (R 2 = 0.996), and with the EDR for the modiolus dose (R 2 = 0.993). Such a result led to a functional formula relating these dose surrogates, yielding dose equivalence results such as: 12-Gy point maximum dose is equivalent to mean cochlear dose of 5.6 ± 0.1 Gy (95% confidence level), or modiolus dose of 6.0 ± 0.2 Gy (95% confidence level)., Conclusions: An inherent functional relationship was found among point maximum, modiolus, and mean cochlear doses for SRS of vestibular schwannomas. As such, clinical hearing outcome can be interchangeably analyzed or reported via any of these dose surrogates., (Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Background: The role of stereotactic radiosurgery (SRS) for recurrent glioblastoma and the radionecrosis risk in this setting remain unclear., Objective: To perform a large retrospective study to help inform proper indications, efficacy, and anticipated complications of SRS for recurrent glioblastoma., Methods: We retrospectively analyzed patients who underwent Gamma Knife SRS between 1991 and 2013. We used the partitioning deletion/substitution/addition algorithm to identify potential predictor covariate cut points and Kaplan-Meier and proportional hazards modeling to identify factors associated with post-SRS and postdiagnosis survival., Results: One hundred seventy-four glioblastoma patients (median age, 54.1 years) underwent SRS a median of 8.7 months after initial diagnosis. Seventy-five percent had 1 treatment target (range, 1-6), and median target volume and prescriptions were 7.0 cm 3 (range, 0.3-39.0 cm 3 ) and 16.0 Gy (range, 10-22 Gy), respectively. Median overall survival was 10.6 months after SRS and 19.1 months after diagnosis. Kaplan-Meier and multivariable modeling revealed that younger age at SRS, higher prescription dose, and longer interval between original surgery and SRS are significantly associated with improved post-SRS survival. Forty-six patients (26%) underwent salvage craniotomy after SRS, with 63% showing radionecrosis or mixed tumor/necrosis vs 35% showing purely recurrent tumor. The necrosis/mixed group had lower mean isodose prescription compared with the tumor group (16.2 vs 17.8 Gy; P = .003) and larger mean treatment volume (10.0 vs 5.4 cm 3 ; P = .009)., Conclusion: Gamma Knife may benefit a subset of focally recurrent patients, particularly those who are younger with smaller recurrences. Higher prescriptions are associated with improved post-SRS survival and do not seem to have greater risk of symptomatic treatment effect., (Copyright © 2016 by the Congress of Neurological Surgeons)

Sharp dose fall-off is the hallmark of brain radiosurgery for the purpose of delivering high dose radiation to the target while minimizing peripheral dose to regional normal brain tissue. In this study, a technique was developed to enhance the peripheral dose gradient by magnifying the total number of beams focused toward each isocenter through pre-programmed patient head tilting. This technique was tested in clinical settings on a dedicated brain radiosurgical system (GKPFX, Gamma Knife Perfexion, Elekta Oncology) by comparing dosimetry as well as delivery efficiency for 20 radiosurgical cases previously treated with the system. The 3-fold beam number enhancement (BNE) treatment plans were found to produce nearly identical target volume coverage (absolute value  <  0.5%, P  >  0.2) and dose conformity (BNE CI  =  1.41  ±  0.22 versus 1.41  ±  0.11, P  >  0.99) as the original treatment plans. The total beam-on time for the 3-fold BNE treatment plans were also found to be comparable (<0.5 min or 2%) with those of the original treatment plans for all the cases. However, BNE treatment plans significantly improved the mean gradient index (BNE GI  =  2.94  ±  0.27 versus original GI  =  2.98  ±  0.28 P  <  0.0001) and low-level isodose volumes, e.g. 20-50% prescribed isodose volumes, by 1.7%-3.9% (P  <  0.03). With further 4-5-fold increase in the total number of beams, the absolute gradient index can decrease by as much as  -0.5 in absolute value or  -20% for a treatment. In conclusion, BNE via patient head tilt has been demonstrated to be a clinically suitable and efficient technique for physically sharpening the peripheral dose gradient for brain radiosurgery.

Stereotactic radiosurgery provides conformal treatment of intracranial lesions, but when multiple lesions are treated, cumulative dose to structures such as the hippocampi may be increased. We analyzed hippocampal dose for patients treated with radiosurgery for multiple brain metastases. We then investigated a means to minimize hippocampal dose. We randomly selected 8 patients treated with single-session, frame-based radiosurgery for 6 to 12 intracranial metastases. Standard planning was employed to deliver 16 to 20 Gy to each lesion without hippocampal avoidance. Each case was replanned using the software's dynamic shaping function to minimize direct beam hippocampal irradiation, while maintaining conformality and target coverage. With standard planning, the maximum hippocampal dose varied from 0.8 to 9.0 Gy but was >3 Gy only when a lesion was <10 mm from the hippocampus. There was no clear correlation between hippocampal dose and the number or the total volume of lesions. Replanning with direct beam avoidance decreased the mean hippocampal dose by an average of 35% but increased treatment time by a mean of 20%. Sparing was most pronounced when the closest lesion was in close proximity to the hippocampus. This is the first study reporting hippocampal dose for multilesion intracranial radiosurgery. It illustrates that when multiple intracranial targets are treated with radiosurgery, substantial hippocampal dose can result. Active beam shielding and optimization can lower hippocampal dose, especially with lesions <10 mm from the hippocampus. These results raise the prospect that the risk of neurocognitive side effects may be further decreased with a hippocampal-sparing approach., (© The Author(s) 2015.)

To identify parameters that influence local control after stereotactic radiosurgery (SRS) for meningiomas we retrospectively analyzed all meningiomas treated with Gamma Knife SRS at our institution from 1991 to 2007. Endpoints were measured from the date of SRS and estimated using the Kaplan-Meier method; subgroups were compared with log-rank tests. Sex, performance status, age, SRS setting, radiation dose, grade, volume and location were evaluated with univariate and multivariate Cox proportional hazards analyses. Of 280 patients with 438 tumors, 264 patients with clinical follow-up and 406 tumors with imaging follow-up were analyzed (median follow-up: 75.9 months). Thirty-seven percent of the tumors had no tissue diagnosis, 32 % were benign (grade I), 12 % atypical (grade II), and 19 % malignant (grade III). Five-year freedom from progression (FFP) was 97 % for presumed meningiomas, 87 % for grade I tumors, 56 % for grade II tumors, and 47 % for grade III tumors (p < 0.0001). Five-year FFP probabilities for upfront SRS versus SRS at recurrence after surgery versus SRS at recurrence after RT were 97, 86, and 38 %, respectively (p < 0.0001). Univariate analysis revealed that higher grade, larger target volume (median diameter: 2.4 cm) and SRS setting were associated with poorer FFP. Only target volume and SRS setting remained significant on multivariate analysis. Local control of presumed and grade I meningiomas is excellent with Gamma Knife SRS, but is suboptimal with high-grade tumors as well as for those treated at recurrence after RT or of large volume.

Stereotactic radiosurgery (SRS) to a surgical cavity after brain metastasis resection is a promising treatment for improving local control. The optimal timing of adjuvant SRS, however, has yet to be determined. Changes in resection cavity volume and local progression in the interval between surgery and SRS are likely important factors in deciding when to proceed with adjuvant SRS. We conducted a retrospective review of patients with a brain metastasis treated with surgical resection followed by SRS to the resection cavity. Post-operative and pre-radiosurgery magnetic resonance imaging (MRI) was reviewed for evidence of cavity volume changes, amount of edema, and local tumor progression. Resection cavity volume and edema volume were measured using volumetric analysis. We identified 21 consecutive patients with a brain metastasis treated with surgical resection and radiosurgery to the resection cavity. Mean age was 57 yrs. The most common site of metastasis was the frontal lobe (38%), and the most common primary neoplasms were lung adenocarcinoma and melanoma (24% each). The mean postoperative resection cavity volume was 7.8 cm(3) and shrank to a mean of 4.5 cm(3) at the time of repeat imaging for radiosurgical planning (median 41 days after initial post-operative MRI), resulting in a mean reduction in cavity volume of 43%. Patients who underwent pre-SRS imaging within 1 month of their initial post-operative MRI had a mean volume reduction of 13% compared to 61% in those whose pre-SRS imaging was ≥1 month (p=0.0003). Post-resection edema volume was not related to volume reduction (p=0.59). During the interval between MRIs, 52% of patients showed evidence of tumor progression within the resection cavity wall. There was no significant difference in local recurrence if the interval between resection and radiosurgery was <1 month (n=8) versus ≥1 month (n=13, p=0.46). These data suggest that the surgical cavity after brain metastasis resection constricts over time with greater constriction seen in patients whose pre-SRS imaging is ≥1 month after initial post-operative imaging. Given that there was no difference in local recurrence rate, the data suggest there is benefit in waiting in order to treat a smaller resection cavity.

A clinical workflow was developed for urgent palliative radiotherapy treatments that integrates patient simulation, planning, quality assurance, and treatment in one 30-minute session. This has been successfully tested and implemented clinically on a linac with MV CBCT capabilities. To make this approach available to all clin-ics equipped with common imaging systems, dose calculation accuracy based on treatment sites was assessed for other imaging units. We evaluated the feasibility of palliative treatment planning using on-board imaging with respect to image quality and technical challenges. The purpose was to test multiple systems using their commercial setup, disregarding any additional in-house development. kV CT, kV CBCT, MV CBCT, and MV CT images of water and anthropomorphic phantoms were acquired on five different imaging units (Philips MX8000 CT Scanner, and Varian TrueBeam, Elekta VersaHD, Siemens Artiste, and Accuray Tomotherapy linacs). Image quality (noise, contrast, uniformity, spatial resolution) was evaluated and compared across all machines. Using individual image value to density calibrations, dose calculation accuracies for simple treatment plans were assessed for the same phantom images. Finally, image artifacts on clinical patient images were evaluated and compared among the machines. Image contrast to visualize bony anatomy was sufficient on all machines. Despite a high noise level and low contrast, MV CT images provided the most accurate treatment plans relative to kV CT-based planning. Spatial resolution was poorest for MV CBCT, but did not limit the visualization of small anatomical structures. A comparison of treatment plans showed that monitor units calculated based on a prescription point were within 5% difference relative to kV CT-based plans for all machines and all studied treatment sites (brain, neck, and pelvis). Local dose differences > 5% were found near the phantom edges. The gamma index for 3%/3 mm criteria was ≥ 95% in most cases. Best dose calculation results were obtained when the treatment isocenter was near the image isocenter for all machines. A large field of view and immediate image export to the treatment planning system were essential for a smooth workflow and were not provided on all devices. Based on this phantom study, image quality of the studied kV CBCT, MV CBCT, and MV CT on-board imaging devices was sufficient for treatment planning in all tested cases. Treatment plans provided dose calculation accuracies within an acceptable range for simple, urgently planned palliative treatments. However, dose calculation accuracy was compromised towards the edges of an image. Feasibility for clinical implementation should be assessed separately and may be complicated by machine specific features. Image artifacts in patient images and the effect on dose calculation accuracy should be assessed in a separate, machine-specific study.

OBJECT Large arteriovenous malformations (AVMs) remain difficult to treat, and ideal treatment parameters for volume-staged stereotactic radiosurgery (VS-SRS) are still unknown. The object of this study was to compare VS-SRS treatment outcomes for AVMs larger than 10 ml during 2 eras; Era 1 was 1992-March 2004, and Era 2 was May 2004-2008. In Era 2 the authors prospectively decreased the AVM treatment volume, increased the radiation dose per stage, and shortened the interval between stages. METHODS All cases of VS-SRS treatment for AVM performed at a single institution were retrospectively reviewed. RESULTS Of 69 patients intended for VS-SRS, 63 completed all stages. The median patient age at the first stage of VS-SRS was 34 years (range 9-68 years). The median modified radiosurgery-based AVM score (mRBAS), total AVM volume, and volume per stage in Era 1 versus Era 2 were 3.6 versus 2.7, 27.3 ml versus 18.9 ml, and 15.0 ml versus 6.8 ml, respectively. The median radiation dose per stage was 15.5 Gy in Era 1 and 17.0 Gy in Era 2, and the median clinical follow-up period in living patients was 8.6 years in Era 1 and 4.8 years in Era 2. All outcomes were measured from the first stage of VS-SRS. Near or complete obliteration was more common in Era 2 (log-rank test, p = 0.0003), with 3- and 5-year probabilities of 5% and 21%, respectively, in Era 1 compared with 24% and 68% in Era 2. Radiosurgical dose, AVM volume per stage, total AVM volume, era, compact nidus, Spetzler-Martin grade, and mRBAS were significantly associated with near or complete obliteration on univariate analysis. Dose was a strong predictor of response (Cox proportional hazards, p < 0.001, HR 6.99), with 3- and 5-year probabilities of near or complete obliteration of 5% and 16%, respectively, at a dose < 17 Gy versus 23% and 74% at a dose ≥ 17 Gy. Dose per stage, compact nidus, and total AVM volume remained significant predictors of near or complete obliteration on multivariate analysis. Seventeen patients (25%) had salvage surgery, SRS, and/or embolization. Allowing for salvage therapy, the probability of cure was more common in Era 2 (log-rank test, p = 0.0007) with 5-year probabilities of 0% in Era 1 versus 41% in Era 2. The strong trend toward improved cure in Era 2 persisted on multivariate analysis even when considering mRBAS (Cox proportional hazards, p = 0.055, HR 4.01, 95% CI 0.97-16.59). The complication rate was 29% in Era 1 compared with 13% in Era 2 (Cox proportional hazards, not significant). CONCLUSIONS VS-SRS is an option to obliterate or downsize large AVMs. Decreasing the AVM treatment volume per stage to ≤ 8 ml with this technique allowed a higher dose per fraction and decreased time to response, as well as improved rates of near obliteration and cure without increasing complications. Reducing the volume of these very large lesions can facilitate a surgical approach for cure.

Unlike scheduled radiotherapy treatments, treatment planning time and resources are limited for emergency treatments. Consequently, plans are often simple 2D image-based treatments that lag behind technical capabilities available for nonurgent radiotherapy. We have developed a novel integrated urgent workflow that uses onboard MV CBCT imaging for patient simulation to improve planning accuracy and reduce the total time for urgent treatments. This study evaluates both MV CBCT dose planning accuracy and novel urgent workflow feasibility for a variety of anatomic sites. We sought to limit local mean dose differences to less than 5% compared to conventional CT simulation. To improve dose calculation accuracy, we created separate Hounsfield unit-to-density calibration curves for regular and extended field-of-view (FOV) MV CBCTs. We evaluated dose calculation accuracy on phantoms and four clinical anatomical sites (brain, thorax/spine, pelvis, and extremities). Plans were created for each case and dose was calculated on both the CT and MV CBCT. All steps (simulation, planning, setup verification, QA, and dose delivery) were performed in one 30 min session using phantoms. The monitor units (MU) for each plan were compared and dose distribution agreement was evaluated using mean dose difference over the entire volume and gamma index on the central 2D axial plane. All whole-brain dose distributions gave gamma passing rates higher than 95% for 2%/2 mm criteria, and pelvic sites ranged between 90% and 98% for 3%/3 mm criteria. However, thoracic spine treatments produced gamma passing rates as low as 47% for 3%/3 mm criteria. Our novel MV CBCT-based dose planning and delivery approach was feasible and time-efficient for the majority of cases. Limited MV CBCT FOV precluded workflow use for pelvic sites of larger patients and resulted in image clearance issues when tumor position was far off midline. The agreement of calculated MU on CT and MV CBCT was acceptable for all treatment sites.

Object: Stereotactic radiosurgery (SRS) is a potentially important option for patients with skull base chondrosarcomas. The object of this study was to analyze the outcomes of SRS for chondrosarcoma patients who underwent this treatment as a part of multimodality management., Methods: Seven participating centers of the North American Gamma Knife Consortium (NAGKC) identified 46 patients who underwent SRS for skull base chondrosarcomas. Thirty-six patients had previously undergone tumor resections and 5 had been treated with fractionated radiation therapy (RT). The median tumor volume was 8.0 cm3 (range 0.9-28.2 cm3), and the median margin dose was 15 Gy (range 10.5-20 Gy). Kaplan-Meier analysis was used to calculate progression-free and overall survival rates., Results: At a median follow-up of 75 months after SRS, 8 patients were dead. The actuarial overall survival after SRS was 89% at 3 years, 86% at 5 years, and 76% at 10 years. Local tumor progression occurred in 10 patients. The rate of progression-free survival (PFS) after SRS was 88% at 3 years, 85% at 5 years, and 70% at 10 years. Prior RT was significantly associated with shorter PFS. Eight patients required salvage resection, and 3 patients (7%) developed adverse radiation effects. Cranial nerve deficits improved in 22 (56%) of the 39 patients who deficits before SRS. Clinical improvement after SRS was noted in patients with abducens nerve paralysis (61%), oculomotor nerve paralysis (50%), lower cranial nerve dysfunction (50%), optic neuropathy (43%), facial neuropathy (38%), trochlear nerve paralysis (33%), trigeminal neuropathy (12%), and hearing loss (10%)., Conclusions: Stereotactic radiosurgery for skull base chondrosarcomas is an important adjuvant option for the treatment of these rare tumors, as part of a team approach that includes initial surgical removal of symptomatic larger tumors.

Purpose: The purpose of this study was to evaluate workflow and patient outcomes related to frameless stereotactic radiation surgery (SRS) for brain metastases., Methods and Materials: We reviewed all treatment demographics, clinical outcomes, and workflow timing, including time from magnetic resonance imaging (MRI), computed tomography (CT) simulation, insurance authorization, and consultation to the start of SRS for brain metastases., Results: A total of 82 patients with 151 brain metastases treated with SRS were evaluated. The median times from consultation, insurance authorization, CT simulation, and MRI for treatment planning were 15, 7, 6, and 11 days to SRS. Local freedom from progression (LFFP) was lower in metastases with MRI ≥ 14 days before treatment (P = .0003, log rank). The 6- and 12-month LFFP rate were 95% and 75% for metastasis with interval of <14 days from MRI to treatment compared to 56% and 34% for metastases with MRI ≥ 14 days before treatment. On multivariate analysis, LFFP remained significantly lower for lesions with MRI ≥ 14 days at SRS (P = .002, Cox proportional hazards; hazard ratio: 3.4, 95% confidence interval: 1.6-7.3)., Conclusions: Delay from MRI to SRS treatment delivery for brain metastases appears to reduce local control. Future studies should monitor the timing from imaging acquisition to treatment delivery. Our experience suggests that the time from MRI to treatment should be <14 days., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Object: The authors sought to determine the incidence, time course, and risk factors for overall adverse radiation effect (ARE) and symptomatic ARE after stereotactic radiosurgery (SRS) for brain metastases., Methods: All cases of brain metastases treated from 1998 through 2009 with Gamma Knife SRS at UCSF were considered. Cases with less than 3 months of follow-up imaging, a gap of more than 8 months in imaging during the 1st year, or inadequate imaging availability were excluded. Brain scans and pathology reports were reviewed to ensure consistent scoring of dates of ARE, treatment failure, or both; in case of uncertainty, the cause of lesion worsening was scored as indeterminate. Cumulative incidence of ARE and failure were estimated with the Kaplan-Meier method with censoring at last imaging. Univariate and multivariate Cox proportional hazards analyses were performed., Results: Among 435 patients and 2200 brain metastases evaluable, the median patient survival time was 17.4 months and the median lesion imaging follow-up was 9.9 months. Calculated on the basis of 2200 evaluable lesions, the rates of treatment failure, ARE, concurrent failure and ARE, and lesion worsening with indeterminate cause were 9.2%, 5.4%, 1.4%, and 4.1%, respectively. Among 118 cases of ARE, approximately 60% were symptomatic and 85% occurred 3-18 months after SRS (median 7.2 months). For 99 ARE cases managed without surgery or bevacizumab, the probabilities of improvement observed on imaging were 40%, 57%, and 76% at 6, 12, and 18 months after onset of ARE. The most important risk factors for ARE included prior SRS to the same lesion (with 20% 1-year risk of symptomatic ARE vs 3%, 4%, and 8% for no prior treatment, prior whole brain radiotherapy [WBRT], or concurrent WBRT) and any of these volume parameters: target, prescription isodose, 12-Gy, or 10-Gy volume. Excluding lesions treated with repeat SRS, the 1-year probabilities of ARE were < 1%, 1%, 3%, 10%, and 14% for maximum diameter 0.3-0.6 cm, 0.7-1.0 cm, 1.1-1.5 cm, 1.6-2.0 cm, and 2.1-5.1 cm, respectively. The 1-year probabilities of symptomatic ARE leveled off at 13%-14% for brain metastases maximum diameter > 2.1 cm, target volume > 1.2 cm(3), prescription isodose volume > 1.8 cm(3), 12-Gy volume > 3.3 cm(3), and 10-Gy volume > 4.3 cm(3), excluding lesions treated with repeat SRS. On both univariate and multivariate analysis, capecitabine, but not other systemic therapy within 1 month of SRS, appeared to increase ARE risk. For the multivariate analysis considering only metastases with target volume > 1.0 cm(3), risk factors for ARE included prior SRS, kidney primary tumor, connective tissue disorder, and capecitabine., Conclusions: Although incidence of ARE after SRS was low overall, risk increased rapidly with size and volume, leveling off at a 1-year cumulative incidence of 13%-14%. This study describes the time course of ARE and provides risk estimates by various lesion characteristics and treatment parameters to aid in decision-making and patient counseling.

Purpose: To demonstrate the clinical feasibility and potential benefits of sector beam intensity modulation (SBIM) specific to Gamma Knife stereotactic radiosurgery (GKSRS)., Methods and Materials: SBIM is based on modulating the confocal beam intensities from individual sectors surrounding an isocenter in a nearly 2π geometry. This is in contrast to conventional GKSRS delivery, in which the beam intensities from each sector are restricted to be either 0% or 100% and must be identical for any given isocenter. We developed a SBIM solution based on available clinical planning tools, and we tested it on a cohort of 12 clinical cases as a proof of concept study. The SBIM treatment plans were compared with the original clinically delivered treatment plans to determine dosimetric differences. The goal was to investigate whether SBIM would improve the dose conformity for these treatment plans without prohibitively lengthening the treatment time., Results: A SBIM technique was developed. On average, SBIM improved the Paddick conformity index (PCI) versus the clinically delivered plans (clinical plan PCI = 0.68 ± 0.11 vs SBIM plan PCI = 0.74 ± 0.10, P=.002; 2-tailed paired t test). The SBIM plans also resulted in nearly identical target volume coverage (mean, 97 ± 2%), total beam-on times (clinical plan 58.4 ± 38.9 minutes vs SBIM 63.5 ± 44.7 minutes, P=.057), and gradient indices (clinical plan 3.03 ± 0.27 vs SBIM 3.06 ± 0.29, P=.44) versus the original clinical plans., Conclusion: The SBIM method is clinically feasible with potential dosimetric gains when compared with conventional GKSRS., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Object: The surgical treatment of many large arteriovenous malformations (AVMs) is associated with substantial risks, and many are considered inoperable. Furthermore, AVMs larger than 3 cm in diameter are not usually treated with conventional single-session radiosurgery encompassing the entire AVM volume. Volume-staged stereotactic radiosurgery (VS-SRS) is an option for large AVMs, but it has mixed results. The authors report on a series of patients with high-grade AVMs who underwent multiple VS-SRS sessions with resultant downgrading of the AVMs, followed by resection., Methods: A cohort of patients was retrieved from a single-institution AVM patient registry consisting of prospectively collected data. VS-SRS was performed as a planned intentional treatment. Surgery was considered as salvage therapy in select patients., Results: Sixteen AVMs underwent VS-SRS followed by surgery. Four AVMs presented with rupture. The mean patient age was 25.3 years (range 13-54 years). The average initial Spetzler-Martin grade before any treatment was 4, while the average supplemented Spetzler-Martin grade (Spetzler-Martin plus Lawton-Young) was 7.1. The average AVM size in maximum dimension was 5.9 cm (range 3.3-10 cm). All AVMs were supratentorial in location and all except one were in eloquent areas of the brain, with 7 involving primary motor cortex. The mean number of VS-SRS sessions was 2.7 (range 2-5 sessions). The mean interval between first VS-SRS session and resection was 5.7 years. There were 4 hemorrhages that occurred after VS-SRS. The average Spetzler-Martin grade was reduced to 2.5 (downgrade, -1.5) and the average supplemented Spetzler-Martin grade was reduced to 5.6 (downgrade, -1.5). The maximum AVM size was reduced to an average of 3.0 cm (downsize=-2.9 cm). The mean modified Rankin Scale (mRS) scores were 1.2, 2.3, and 2.2 before VS-SRS, before surgery, and at last follow-up, respectively (mean follow-up, 6.9 years). Fifteen AVMs were cured after surgery. Ten patients had good outcomes at last follow-up (7 with mRS Score 0 or 1, and 3 with mRS Score 2). There were 2 deaths (both mRS Score 1 before treatment) and 4 patients with mRS Score 3 outcome (from mRS Scores 0, 1, and 2 [n=2])., Conclusions: Volume-staged SRS can downgrade AVMs, transforming high-grade AVMs (initially considered inoperable) into operable AVMs with acceptable surgical risks. This treatment paradigm offers an alternative to conservative observation for young patients with unruptured AVMs and long life expectancy, where the risk of hemorrhage is substantial. Difficult AVMs were cured in 15 patients. Surgical morbidity associated with downgraded AVMs is reduced to that of postradiosurgical/preoperative supplemented Spetzler-Martin grades, not their initial AVM grades.

Object: Gamma Knife radiosurgery (GKRS) is the least invasive treatment option for medically refractory, intractable trigeminal neuralgia (TN) and is especially valuable for treating elderly, infirm patients or those on anticoagulation therapy. The authors reviewed pain outcomes and complications in TN patients who required 3 radiosurgical procedures for recurrent or persistent pain., Methods: A retrospective review of all patients who underwent 3 GKRS procedures for TN at 4 participating centers of the North American Gamma Knife Consortium from 1995 to 2012 was performed. The Barrow Neurological Institute (BNI) pain score was used to evaluate pain outcomes., Results: Seventeen patients were identified; 7 were male and 10 were female. The mean age at the time of last GKRS was 79.6 years (range 51.2-95.6 years). The TN was Type I in 16 patients and Type II in 1 patient. No patient suffered from multiple sclerosis. Eight patients (47.1%) reported initial complete pain relief (BNI Score I) following their third GKRS and 8 others (47.1%) experienced at least partial relief (BNI Scores II-IIIb). The average time to initial response was 2.9 months following the third GKRS. Although 3 patients (17.6%) developed new facial sensory dysfunction following primary GKRS and 2 patients (11.8%) experienced new or worsening sensory disturbance following the second GKRS, no patient sustained additional sensory disturbances after the third procedure. At a mean follow-up of 22.9 months following the third GKRS, 6 patients (35.3%) reported continued Score I complete pain relief, while 7 others (41.2%) reported pain improvement (BNI Scores II-IIIb). Four patients (23.5%) suffered recurrent TN following the third procedure at a mean interval of 19.1 months., Conclusions: A third GKRS resulted in pain reduction with a low risk of additional complications in most patients with medically refractory and recurrent, intractable TN. In patients unsuitable for other microsurgical or percutaneous strategies, especially those receiving long-term oral anticoagulation or antiplatelet agents, GKRS repeated for a third time was a satisfactory, low risk option.

Standard treatment for Glioblastoma Multiforme (GBM) consists of a combination of chemotherapy and radiation therapy followed by adjuvant chemotherapy. While the optimal dose of radiation therapy has been established, significant variability in volume of tissue irradiated exists. In this article we review the current guidelines, patterns of care, patterns of failure, imaging advances and toxicity related to radiation therapy volumes in the treatment of GBM., (Copyright © 2014. Published by Elsevier Inc.)

A newly developed Gamma Knife relocatable eXtend frame system has enabled the delivery of multi-session Gamma Knife radiosurgery without the use of skull pin fixation frame system. In this study, we investigate and report for the first time the whole procedural radiological accuracy for administering such treatments. To quantify the radiological alignment, the commonly used Winston-Lutz test was modified and used to determine the device accuracy of the eXtend frame system. Patient setup uncertainties relative to the device were further measured for a series of treatment sessions (n = 58), and then incorporated with the Winston-Lutz test results from individual patient-specific eXtend frame systems. The whole-procedure mean 3D radiological setup uncertainty was determined to be 0.69 ± 0.73 mm (1δ) from all the cases analyzed, and the mean 90% confidence level margins were found to be 0.55, 0.78 and 0.72 mm along the x-, y-, and z-axis, respectively. Our results therefore demonstrated that sub-millimetric radiological accuracy is clinically achievable for multi-session Gamma Knife radiosurgery treatments and a 1 mm margin along the major axes is sufficient for planning multi-session Gamma Knife radiosurgery treatments.

Stereotactic frame placement for radiosurgery is assumed to be an uncomfortable experience. We developed angled anterior posts for the Leksell frame to avoid pin penetration of the temporalis muscle. This study aimed to determine the frequency of angled post requirement and quantify the patient pain experience from frame placement. We prospectively enrolled 63 patients undergoing radiosurgery. Angled posts were used when conventional post trajectory was posterior or within 3mm of the superior temporal line to avoid temporalis muscle penetration. Pain scores (0 to 10) were collected prior to frame placement, immediately after frame placement, before radiosurgery, after radiosurgery, and a day after radiosurgery. A total of 63 patients were enrolled: 33 (48%) patients required angled posts. Women were significantly more likely to require angled posts than men (60.0% versus 33.3%, respectively; p=0.034). Mean pain scores were very low, ranging from 0.33 to 2.23. There were no significant differences in pain outcomes between both groups at all time points. Stereotactic frame placement is not perceived to be a painful procedure. This information may be useful when counseling patients about the pain experience with frame application and the option of using angled anterior posts., Competing Interests: Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Unlabelled: OBJECT.: Stereotactic radiosurgery (SRS) is an established treatment modality for brain arteriovenous malformations (AVMs) in children, but the optimal treatment parameters and associated treatment-related complications are not fully understood. The authors present their single-institution experience of using SRS, at a relatively low marginal dose, to treat AVMs in children for nearly 20 years; they report angiographic outcomes, posttreatment hemorrhage rates, adverse treatment-related events, and functional outcomes., Methods: The authors conducted a retrospective review of 2 cohorts of children (18 years of age or younger) with AVMs treated from 1991 to 1998 and from 2000 to 2010., Results: A total of 80 patients with follow-up data after SRS were identified. Mean age at SRS was 12.7 years, and 56% of patients had hemorrhage at the time of presentation. Median target volume was 3.1 cm(3) (range 0.09-62.3 cm(3)), and median prescription marginal dose used was 17.5 Gy (range 12-20 Gy). Angiograms acquired 3 years after treatment were available for 47% of patients; AVM obliteration was achieved in 52% of patients who received a dose of 18-20 Gy and in 16% who received less than 18 Gy. At 5 years after SRS, the cumulative incidence of hemorrhage was 25% (95% CI 16%-37%). No permanent neurological deficits occurred in patients who did not experience posttreatment hemorrhage. Overall, good functional outcomes (modified Rankin Scale Scores 0-2) were observed for 78% of patients; for 66% of patients, functional status improved or remained the same as before treatment., Conclusions: A low marginal dose minimizes SRS-related neurological deficits but leads to low rates of obliteration and high rates of hemorrhage. To maximize AVM obliteration and minimize posttreatment hemorrhage, the authors recommend a prescription marginal dose of 18 Gy or more. In addition, SRS-related symptoms such as headache and seizures should be considered when discussing risks and benefits of SRS for treating AVMs in children.

Purpose: Arteriovenous malformations (AVMs) are a frequent cause of hemorrhagic stroke in children. Stereotactic radiosurgery (SRS) is an established treatment for these lesions, particularly those that are surgically inaccessible. Because only complete AVM obliteration is believed to protect against the future risk of hemorrhage, identifying lesion characteristics that predict response to therapy is an important objective. The goal of this study is to evaluate the influence of angiographic features of AVMs on the rate of obliteration following treatment with SRS., Methods: This is a retrospective cohort study of pediatric patients (age ≤18 years) treated with Gamma Knife SRS for cerebral AVMs between 2000 and 2012. Detailed angiographic data at the time of initial angiographic evaluation were prospectively recorded by experienced neurointerventional radiologists. The primary outcome was the rate of obliteration on a 3-year follow-up angiogram., Results: We identified 42 pediatric patients treated with SRS for cerebral AVMs. Twenty-seven patients completed 3-year angiographic follow-ups. Complete obliteration was seen in 30%, partial response in 67%, and no response in 4%. Higher SRS dose was associated with complete obliteration. Larger AVM diameter, presence of multiple draining veins, and presence of multiple draining veins reaching a sinus were associated with partial response. In this small cohort, diffuse AVM borders, presence of aneurysm, and pre-SRS embolization were not associated with obliteration., Conclusions: Our study identifies AVMs in the pediatric population with a nidus diameter of <2.5 cm and a solitary draining vein as the most likely to undergo complete obliteration after SRS treatment.

Object: Pituitary adenomas are fairly common intracranial neoplasms, and nonfunctioning ones constitute a large subgroup of these adenomas. Complete resection is often difficult and may pose undue risk to neurological and endocrine function. Stereotactic radiosurgery has come to play an important role in the management of patients with nonfunctioning pituitary adenomas. This study examines the outcomes after radiosurgery in a large, multicenter patient population., Methods: Under the auspices of the North American Gamma Knife Consortium, 9 Gamma Knife surgery (GKS) centers retrospectively combined their outcome data obtained in 512 patients with nonfunctional pituitary adenomas. Prior resection was performed in 479 patients (93.6%) and prior fractionated external-beam radiotherapy was performed in 34 patients (6.6%). The median age at the time of radiosurgery was 53 years. Fifty-eight percent of patients had some degree of hypopituitarism prior to radiosurgery. Patients received a median dose of 16 Gy to the tumor margin. The median follow-up was 36 months (range 1-223 months)., Results: Overall tumor control was achieved in 93.4% of patients at last follow-up; actuarial tumor control was 98%, 95%, 91%, and 85% at 3, 5, 8, and 10 years postradiosurgery, respectively. Smaller adenoma volume (OR 1.08 [95% CI 1.02-1.13], p = 0.006) and absence of suprasellar extension (OR 2.10 [95% CI 0.96-4.61], p = 0.064) were associated with progression-free tumor survival. New or worsened hypopituitarism after radiosurgery was noted in 21% of patients, with thyroid and cortisol deficiencies reported as the most common postradiosurgery endocrinopathies. History of prior radiation therapy and greater tumor margin doses were predictive of new or worsening endocrinopathy after GKS. New or progressive cranial nerve deficits were noted in 9% of patients; 6.6% had worsening or new onset optic nerve dysfunction. In multivariate analysis, decreasing age, increasing volume, history of prior radiation therapy, and history of prior pituitary axis deficiency were predictive of new or worsening cranial nerve dysfunction. No patient died as a result of tumor progression. Favorable outcomes of tumor control and neurological preservation were reflected in a 4-point radiosurgical pituitary score., Conclusions: Gamma Knife surgery is an effective and well-tolerated management strategy for the vast majority of patients with recurrent or residual nonfunctional pituitary adenomas. Delayed hypopituitarism is the most common complication after radiosurgery. Neurological and cranial nerve function were preserved in more than 90% of patients after radiosurgery. The radiosurgical pituitary score may predict outcomes for future patients who undergo GKS for a nonfunctioning adenoma.

Our group has previously published the Diagnosis-Specific Graded Prognostic Assessment (GPA) showing the prognostic factors associated with survival in patients with brain metastases (BM). The purpose of this study is to investigate the relationship of breast cancer subtype to the time interval from primary diagnosis (PD) to development of BM (TPDBM), number of BM at initial BM presentation and survival. We analyzed our previously described multi-institutional retrospective database of 865 breast cancer patients treated for newly-diagnosed BM from 1993 to 2010. Several factors found to be associated with survival were incorporated into the Breast-GPA, including tumor subtype. The GPA database was further analyzed to determine if the subtype correlated with the TPDBM, number of BM, and survival from PD. After exclusions for incomplete data, 383 patients remained eligible for analysis. The subtypes were approximated as follows: Luminal B: triple positive; HER2: HER2 positive/ER/PR negative; Luminal A; ER/PR positive/HER2 negative; Basal: triple negative. Patients with Basal (90), HER2 (119), Luminal B (98) and Luminal A (76) tumor subtypes had a median TPDBM of 27.5, 35.8, 47.4 and 54.4 months (p < 0.01), median survival from PD of 39.6, 66.4, 90.3 and 72.7 months (p < 0.01) and median survival from BM of 7.3, 17.9, 22.9 and 10.0 months (p < 0.01), respectively. Tumor subtype is an important prognostic factor for survival in patients with breast cancer and BM. Although TPDBM is not an independent prognostic factor for survival (and thus not part of the Breast-GPA), the TPDBM does correlate with tumor subtype but does not correlate with the number of BM. Patients with Basal and HER2 tumor subtypes have short TPDBM. Prospective studies are needed to determine if screening brain MRIs are indicated in patients with Basal or HER2 subtypes.

Intracranial epidermoid cysts are rare benign congenital lesions for which the mainstay of treatment has been surgical resection. Due to a propensity to grow along the skull base, subtotal resection is often elected to avoid excessive surgical morbidity, but it comes with an increased risk of recurrence with its associated treatment difficulties. We here present the cases of three patients with recurrent epidermoid cyst who underwent multiple surgical resections followed by external beam radiation therapy with excellent results to date.

Object: Determining accurate target volume is critical for both prescribing and evaluating stereotactic radiosurgery (SRS) treatments. The aim of this study was to determine the reliability of contour-based volume calculations made by current major SRS platforms., Methods: Spheres ranging in diameter from 6.4 to 38.2 mm were scanned and then delineated on imaging studies. Contour data sets were subsequently exported to 6 SRS treatment-planning platforms for volume calculations and comparisons. This procedure was repeated for the case of a patient with 12 metastatic lesions distributed throughout the brain. Both the phantom and patient datasets were exported to a stand-alone workstation for an independent volume-calculation analysis using a series of 10 algorithms that included approaches such as slice stacking, surface meshing, point-cloud filling, and so forth., Results: Contour data-rendered volumes exhibited large variations across the current SRS platforms investigated for both the phantom (-3.6% to 22%) and patient case (1.0%-10.2%). The majority of the clinical SRS systems and algorithms overestimated the volumes of the spheres, compared with their known physical volumes. An independent algorithm analysis found a similar trend in variability, and large variations were typically associated with small objects whose volumes were < 0.4 cm(3) and with those objects located near the end-slice of the scan limits., Conclusions: Significant variations in volume calculation were observed based on data obtained from the SRS systems that were investigated. This observation highlights the need for strict quality assurance and benchmarking efforts when commissioning SRS systems for clinical use and, moreover, when conducting multiinstitutional cross-SRS platform clinical studies.

Object: The goal of this study was to develop a technique for performing submillimeter high-precision volume-staged Gamma Knife surgery and investigate its potential benefits in comparison with hypofractionated stereotactic radiotherapy (SRT) for treating large arteriovenous malformations (AVMs)., Methods: The authors analyzed 7 pediatric AVM cases treated with volume-staged stereotactic radiosurgery (SRS) using the Gamma Knife Perfexion at the University of California, San Francisco. The target and normal tissue contours from each case were exported for hypofractionated treatment planning based on the Gamma Knife Extend system or the CyberKnife SRT. Both the Gamma Knife Extend and CyberKnife treatment plans were matched to yield the same level of target coverage (95%-98%) and conformity indices (1.24-1.46). Finally, hypofractionated treatment plans were compared with volume-staged treatment plans for sparing normal brain by using biologically equivalent 12-Gy normal brain volumes., Results: Hypofractionated Gamma Knife Extend and CyberKnife treatment plans exhibited practically identical sparing of normal brain for the studied cases. However, when matching such values with volume-staged treatments for the biological effective dose, only conservative dose fractionation schemes, such as 27.3 Gy in 5 fractions and 25 Gy in 4 fractions, were found to be comparable to the volume-staged treatments. On average, this represents a mean 18.7% ± 7.3% reduction in the single-fraction biologically equivalent dose for hypofractionated treatments versus the reference volume-staged treatments (p < 0.001)., Conclusions: Volume staging remains advantageous over hypofractionation in delivering a higher dose to the target and for better sparing of normal brain tissue in the treatment of large AVMs. More clinical data are needed, however, to justify the clinical superiority of this increased dose when compared with a hypofractionated treatment regimen.

Purpose: To evaluate prognostic factors for survival after stereotactic radiosurgery (SRS) for new, progressive, or recurrent brain metastases (BM) after prior whole brain radiotherapy (WBRT)., Methods and Materials: Patients treated between 1991 and 2007 with Gamma Knife SRS for BM after prior WBRT were retrospectively reviewed. Potential prognostic factors were analyzed overall and by primary site using univariate and stepwise multivariate analyses and recursive partitioning analysis, including age, Karnofsky performance status (KPS), primary tumor control, extracranial metastases, number of BM treated, total SRS target volume, and interval from WBRT to SRS., Results: A total of 310 patients were analyzed, including 90 breast, 113 non-small-cell lung, 31 small-cell lung, 42 melanoma, and 34 miscellaneous patients. The median age was 56, KPS 80, number of BM treated 3, and interval from WBRT to SRS 8.1 months; 76% had controlled primary tumor and 60% had extracranial metastases. The median survival was 8.4 months overall and 12.0 vs. 7.9 months for single vs. multiple BM treated (p = 0.001). There was no relationship between number of BM and survival after excluding single-BM patients. On multivariate analysis, favorable prognostic factors included age <50, smaller total target volume, and longer interval from WBRT to SRS in breast cancer patients; smaller number of BM, KPS >60, and controlled primary in non-small-cell lung cancer patients; and smaller total target volume in melanoma patients., Conclusions: Among patients treated with salvage SRS for BM after prior WBRT, prognostic factors appeared to vary by primary site. Although survival time was significantly longer for patients with a single BM, the median survival time of 7.9 months for patients with multiple BM seems sufficiently long for salvage SRS to appear to be worthwhile, and no evidence was found to support the use of a cutoff for number of BM appropriate for salvage SRS., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: The diagnosis-specific Graded Prognostic Assessment (GPA) was published to clarify prognosis for patients with brain metastases. This study refines the existing Breast-GPA by analyzing a larger cohort and tumor subtype., Methods and Materials: A multi-institutional retrospective database of 400 breast cancer patients treated for newly diagnosed brain metastases was generated. Prognostic factors significant for survival were analyzed by multivariate Cox regression and recursive partitioning analysis (RPA). Factors were weighted by the magnitude of their regression coefficients to define the GPA index., Results: Significant prognostic factors by multivariate Cox regression and RPA were Karnofsky performance status (KPS), HER2, ER/PR status, and the interaction between ER/PR and HER2. RPA showed age was significant for patients with KPS 60 to 80. The median survival time (MST) overall was 13.8 months, and for GPA scores of 0 to 1.0, 1.5 to 2.0, 2.5 to 3.0, and 3.5 to 4.0 were 3.4 (n = 23), 7.7 (n = 104), 15.1 (n = 140), and 25.3 (n = 133) months, respectively (p < 0.0001). Among HER2-negative patients, being ER/PR positive improved MST from 6.4 to 9.7 months, whereas in HER2-positive patients, being ER/PR positive improved MST from 17.9 to 20.7 months. The log-rank statistic (predictive power) was 110 for the Breast-GPA vs. 55 for tumor subtype., Conclusions: The Breast-GPA documents wide variation in prognosis and shows clear separation between subgroups of patients with breast cancer and brain metastases. This tool will aid clinical decision making and stratification in clinical trials. These data confirm the effect of tumor subtype on survival and show the Breast-GPA offers significantly more predictive power than the tumor subtype alone., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Our group has previously published the Graded Prognostic Assessment (GPA), a prognostic index for patients with brain metastases. Updates have been published with refinements to create diagnosis-specific Graded Prognostic Assessment indices. The purpose of this report is to present the updated diagnosis-specific GPA indices in a single, unified, user-friendly report to allow ease of access and use by treating physicians., Methods: A multi-institutional retrospective (1985 to 2007) database of 3,940 patients with newly diagnosed brain metastases underwent univariate and multivariate analyses of prognostic factors associated with outcomes by primary site and treatment. Significant prognostic factors were used to define the diagnosis-specific GPA prognostic indices. A GPA of 4.0 correlates with the best prognosis, whereas a GPA of 0.0 corresponds with the worst prognosis., Results: Significant prognostic factors varied by diagnosis. For lung cancer, prognostic factors were Karnofsky performance score, age, presence of extracranial metastases, and number of brain metastases, confirming the original Lung-GPA. For melanoma and renal cell cancer, prognostic factors were Karnofsky performance score and the number of brain metastases. For breast cancer, prognostic factors were tumor subtype, Karnofsky performance score, and age. For GI cancer, the only prognostic factor was the Karnofsky performance score. The median survival times by GPA score and diagnosis were determined., Conclusion: Prognostic factors for patients with brain metastases vary by diagnosis, and for each diagnosis, a robust separation into different GPA scores was discerned, implying considerable heterogeneity in outcome, even within a single tumor type. In summary, these indices and related worksheet provide an accurate and facile diagnosis-specific tool to estimate survival, potentially select appropriate treatment, and stratify clinical trials for patients with brain metastases.

A technique for delivering high-precision volume-staged stereotactic radiosurgery has been developed with Leksell Gamma Knife Perfexion for treating large arteriorvenous malformations (AVMs). The technique employs a hybrid method of combining landmark registration and voxel-based 3D image registration to enable multiple staged partial-volume treatments that accommodate repeated stereotactic frame placements. The technique was clinically implemented at our institution and the results were analyzed for a series (n=14) of large AVM cases treated since 2007. Overall, an averaged 0.34±0.09 mm in matching procedural accuracy versus standard single-fraction radiosurgery was found for these treatments. Such a result is a factor of 3-4 times lower than those previously reported, and it approaches the physical accuracy of the latest Leksell Gamma Knife Perfexion system. In conclusion, volume-staged radiosurgery has been demonstrated to be deliverable with the same level of accuracy as standard single-fraction radiosurgery.

This open-label, single-arm, phase II study combined enzastaurin with temozolomide plus radiation therapy (RT) to treat glioblastoma multiforme (GBM) and gliosarcoma. Adults with newly diagnosed disease and Karnofsky performance status (KPS) ≥ 60 were enrolled. Treatment was started within 5 weeks after surgical diagnosis. RT consisted of 60 Gy over 6 weeks. Temozolomide was given at 75 mg/m(2) daily during RT and then adjuvantly at 200 mg/m(2) daily for 5 days, followed by a 23-day break. Enzastaurin was given once daily during RT and in the adjuvant period at 250 mg/day. Cycles were 28 days. The primary end point was overall survival (OS). Progression-free survival (PFS), toxicity, and correlations between efficacy and molecular markers analyzed from tumor tissue samples were also evaluated. A prospectively planned analysis compared OS and PFS of the current trial with outcomes from 3 historical phase II trials that combined novel agents with temozolomide plus RT in patients with GBM or gliosarcoma. Sixty-six patients were enrolled. The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotinib and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT. A positive correlation between O-6-methylguanine-DNA methyltransferase promoter methylation and OS was observed. Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials.

Planning robotic radiosurgery treatments for multiple (n > 3) metastatic brain lesions is challenging due to the need of satisfying a large number of dose-volume constraints and the requirement of prescribing different dose levels to individual targets. In this study, we developed a sequential two-step optimization technique to improve the planning quality of such treatments. In contrast to the conventional approach of where all targets are simultaneously planned, we have developed a two-step optimization method. In this method, the first step was to create treatment plans for individual targets. In the second step, the 3D dose matrices associated with each plan were exported to Dicom-RT digital files and subsequently optimized. For the optimization, a singular-value-decomposition (SVD) algorithm was implemented to minimize the dose interferences among different targets. Finally, we compared the optimized treatment plans with the treatment plans created using the conventional method to determine the effectiveness of the new method. Large improvements in target dose distributions as well as normal brain sparing were found for the two-step optimization treatment plans as compared with the conventional treatment plans. The two-step optimization significantly lowered the volume of normal brain receiving relatively low doses. For example, the normal brain volume receiving 12-Gy was reduced by averaged 42% (range 34%-47%) with the two-step optimization. Such improvements generally enlarged with increasing number of targets being treated regardless of target sizes. Of note, normal brain dose was found to increase non-linearly with increasing number of targets. In summary, a two-step optimization technique is demonstrated to significantly improve the treatment plan quality as well as reduce the planning effort for multi-target robotic radiosurgery.

Background: Although considered slow-growing, low-grade malignancies, chordomas are locally aggressive and destructive tumors with high recurrence rates., Objective: To assess patient survival, tumor control, complications, and selected variables that predict outcome in patients who underwent Gamma Knife stereotactic radiosurgery (SRS) as primary, adjuvant, or salvage management for chordomas of the skull base., Methods: Six participating centers of the North American Gamma Knife Consortium identified 71 patients who underwent SRS for chordoma. The median patient age was 45 years (range, 7-80 years). The median SRS target volume was 7.1 cm³ (range, 0.9-109 cm³), and median margin dose was 15.0 Gy (range, 9-25 Gy)., Results: At a median follow-up of 5 years (range, 0.6-14 years) after SRS, 23 patients died of tumor progression. The 5-year actuarial overall survival after SRS was 80% for the entire group, 93% for the no prior fractionated radiation therapy (RT) group (n = 50), and 43% for the prior RT group (n = 21). Younger age, longer interval between initial diagnosis and SRS, no prior RT, < 2 cranial nerve deficits, and smaller total tumor volume were significantly associated with longer patient survival. The 5-year treated tumor control rate after SRS was 66% for the entire group, 69% for the no prior RT group, and 62% for the prior RT group. Older age, recurrent group, prior RT, and larger tumor volume were significantly associated with worse tumor control., Conclusion: Stereotactic radiosurgery is a potent treatment option for small sized chordomas, especially in younger patients and as part of a multipronged attack that includes surgical resection when possible.

Object: The Leksell Gamma Knife and the Accuray CyberKnife systems have been used in the radio surgical treatment of trigeminal neuralgia. The 2 techniques use different delivery methods and different treatment parameters. In the past, CyberKnife treatments have been associated with an increased incidence of treatment-related complications, such as facial numbness. The goal of this study was to develop a method for planning a CyberKnife treatment for trigeminal neuralgia that would reproduce the dosimetric characteristics of a Gamma Knife plan. A comparison between Gamma Knife and CyberKnife treatment plans obtained with this method is presented., Methods: Five patients treated using the Gamma Knife Perfexion Unit were selected for this study. All patients underwent CT cisternography to accurately identify the position of the trigeminal nerve. The Gamma Knife plans used either one 4-mm-diameter collimator or two coincident 4-mm collimators (one open and one with sector blocking) placed at identical isocenter coordinates. A maximum local dose of 80 Gy was prescribed. Critical structures and representative isodose lines were outlined in GammaPlan and exported to the CyberKnife treatment planning platform. CyberKnife treatments were developed using the 5-mm-diameter cone and the trigeminal node set, which provides an effective collimation diameter of 4 mm at the isocenter. The 60-Gy isodose volume imported from GammaPlan was used as the target in the CyberKnife plans. The CyberKnife treatments were optimized to achieve target dose and critical structure sparing similar to the Gamma Knife plans. Isocentric and nonisocentric delivery techniques were investigated. Treatment plans were compared in terms of dosimetric characteristics, delivery, and planning efficiency., Results: CyberKnife treatments using the 5-mm cone and the trigeminal node set can closely reproduce the dose distribution of Gamma Knife plans. CyberKnife isocentric and nonisocentric plans provide comparable results. The average length of the trigeminal nerve receiving a dose of 60 Gy was 4.5, 4.5, and 4.4 mm for Gamma Knife, nonisocentric CyberKnife, and isocentric CyberKnife, respectively. However, minimizing the dose to the critical structures was more difficult with the CyberKnife and required the use of tuning structures. In addition, the dose fall off away from the target was steeper in Gamma Knife plans, probably due to the larger number of beams (192 beams for perfexion vs ~ 100 beams for cyberknife). While the treatment time with the cyberknife is generally shorter, the planning time is significantly longer., Conclusions: CyberKnife radiosurgical parameters can be optimized to mimic the dose distribution of Gamma Knife plans. However, Gamma Knife plans result in superior sparing of critical structures (brainstem, temporal lobe,and cranial nerves VII and VIII) and in steeper dose fall off away from the target. The clinical significance of these effects is unknown. (DOI: 10.3171/2010.8.GKS101002)

Purpose: Controversy endures regarding the optimal treatment of patients with brain metastases (BMs). Debate persists, despite many randomized trials, perhaps because BM patients are a heterogeneous population. The purpose of the present study was to identify significant diagnosis-specific prognostic factors and indexes (Diagnosis-Specific Graded Prognostic Assessment [DS-GPA])., Methods and Materials: A retrospective database of 5,067 patients treated for BMs between 1985 and 2007 was generated from 11 institutions. After exclusion of the patients with recurrent BMs or incomplete data, 4,259 patients with newly diagnosed BMs remained eligible for analysis. Univariate and multivariate analyses of the prognostic factors and outcomes by primary site and treatment were performed. The significant prognostic factors were determined and used to define the DS-GPA prognostic indexes. The DS-GPA scores were calculated and correlated with the outcomes, stratified by diagnosis and treatment., Results: The significant prognostic factors varied by diagnosis. For non-small-cell lung cancer and small-cell lung cancer, the significant prognostic factors were Karnofsky performance status, age, presence of extracranial metastases, and number of BMs, confirming the original GPA for these diagnoses. For melanoma and renal cell cancer, the significant prognostic factors were Karnofsky performance status and the number of BMs. For breast and gastrointestinal cancer, the only significant prognostic factor was the Karnofsky performance status. Two new DS-GPA indexes were thus designed for breast/gastrointestinal cancer and melanoma/renal cell carcinoma. The median survival by GPA score, diagnosis, and treatment were determined., Conclusion: The prognostic factors for BM patients varied by diagnosis. The original GPA was confirmed for non-small-cell lung cancer and small-cell lung cancer. New DS-GPA indexes were determined for other histologic types and correlated with the outcome, and statistical separation between the groups was confirmed. These data should be considered in the design of future randomized trials and in clinical decision-making., ((c) 2010 Elsevier Inc. All rights reserved.)

Purpose: The relative roles of stereotactic radiosurgery (SRS) vs. whole brain radiotherapy (WBRT) in the treatment of patients with brain metastases from breast cancer remain undefined. In this study, we reviewed our experience with these patients., Materials and Methods: We retrospectively reviewed all patients treated between 1991 and 2005 with Gamma Knife SRS for brain metastases from breast cancer. The actuarial survival and freedom from progression endpoints were calculated using the Kaplan-Meier method., Results: Between 1991 and 2005, 176 patients underwent SRS for brain metastases from breast cancer. The median survival time was 16.0 months for 95 newly diagnosed patients and 11.7 months for 81 patients with recurrent brain metastases. In the newly diagnosed patients, omission of upfront WBRT did not significantly affect the MST (p = .20), brain freedom from progression (p = .75), or freedom from new brain metastases (p = .83). Longer survival was associated with age <50 years, Karnofsky performance score >or=70, primary tumor control, estrogen receptor positivity, and Her2/neu overexpression. No association was found between the number of treated brain metastases and the survival time., Conclusion: We have described prognostic factors for breast cancer patients treated with SRS for newly diagnosed or recurrent brain metastases. Most patient subsets had a median survival time of >or=11 months. Unexpectedly, upfront WBRT did not appear to improve brain freedom from progression, and a larger number of brain metastases was not associated with a shorter survival time. Breast cancer might be distinct from other primary sites in terms of prognostic factors and the roles of WBRT and SRS for brain metastases.

Background and Purpose: MR image-guided gamma knife radiosurgery is often used to treat intra-axial metastatic neoplasms. Following treatment, it is often difficult to determine whether a progressively enhancing lesion is due to metastatic tumor recurrence or radiation necrosis. The purpose of our study was to determine whether relative cerebral blood volume (rCBV), relative peak height (rPH), and percentage of signal-intensity recovery (PSR) derived from dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging can distinguish recurrent metastatic tumor from radiation necrosis., Materials and Methods: Twenty-seven patients with systemic cancer underwent gamma knife radiosurgery for metastatic lesions of the brain and subsequently developed enlarging regions of enhancement within the radiation field. Subsequent surgical resection or clinicoradiologic follow-up established a diagnosis of recurrent metastatic tumor or radiation necrosis. Perfusion MR imaging datasets were retrospectively reprocessed, and regions of interest were drawn around the entire contrast-enhancing region. The resulting T2* signal-intensity time curves produced rCBV, rPH, and PSR values for each examination. A Welch t test was used to compare imaging values between groups., Results: The mean, minimum, and maximum PSR values were significantly lower (P < .01) in cases of recurrent metastatic tumor. The mean and maximum rCBV and rPH values were significantly higher (P < .02) in the recurrent metastatic tumor group., Conclusions: The findings of our study suggest that perfusion MR imaging may be used to differentiate recurrent intra-axial metastatic tumor from gamma knife-induced radiation necrosis.

Purpose: To evaluate the efficacy and toxicity of surgical resection and permanent iodine-125 brachytherapy without adjuvant whole brain radiation therapy (WBRT) for brain metastases., Methods and Materials: Forty patients were treated with permanent iodine-125 brachytherapy at the time of resection of brain metastases from 1997 to 2003. Actuarial freedom from progression (FFP) and survival were measured from the date of surgery and estimated using the Kaplan-Meier method, with censoring at last imaging for FFP endpoints., Results: The median survival was 11.3 months overall, 12.0 months in 19 patients with newly diagnosed brain metastases and 7.3 months in 21 patients with recurrent brain metastases. Twenty-two patients (55%) remained free of progression of brain metastases, three failed at the resection cavity (including one with leptomeningeal dissemination), two failed with leptomeningeal spread only, and 13 failed elsewhere in the brain including two who also had leptomeningeal disease. The 1-year resection cavity FFP probabilities were 92%, 86% and 88%; and brain FFP probabilities were 29%, 43% and 37% for the newly diagnosed, recurrent and all patients, respectively. Symptomatic necrosis developed 7.4-40.0 months (median, 19.5 months) after brachytherapy in 9 patients (23%), confirmed by resection in 6 patients., Conclusions: Excellent local control was achieved using permanent iodine-125 brachytherapy for brain metastasis resection cavities, although there is a high risk of radiation necrosis over time. These data support consideration of permanent brachytherapy without adjuvant WBRT as a treatment option in patients with symptomatic or large newly diagnosed or recurrent brain metastases.

Object: The authors conducted a study to determine whether prognostic factors and the applicability of prognostic systems vary by primary tumor site in patients treated with radiosurgery for brain metastases., Methods: The authors evaluated data obtained in patients who underwent radiosurgery with or without whole-brain radiotherapy (WBRT) from 1991 to 2005 for newly diagnosed brain metastases. Four groups were analyzed: 1) all primary sites combined, 2) breast, 3) lung, and 4) melanoma primary sites. Kaplan-Meier, log-rank, Cox proportional hazard uni- and multivariate analysis, and recursive partitioning analysis (RPA) were used to assess prognostic factors and 4 prognostic systems: Radiation Therapy Oncology Group (RTOG) RPA, Graded Prognostic Assessment (GPA), basic score for brain metastases (BSBM), and the newly proposed Golden grading system (GGS). The GGS divides patients into 4 prognostic groups by age >or= 65 years, Karnofsky Performance Scale (KPS) score < 70, and known presence of extracranial metastases., Results: Data acquired in 479 newly diagnosed patients with 1664 lesions were analyzed. The median survival time from diagnosis of brain metastases was 12.1 months; the median follow-up was 25.4 months in 73 patients who were censored. Survival and prognostic factors were equivalent for 369 patients treated with radiosurgery compared with 110 patients treated with radiosurgery and WBRT, so these subsets were combined. Multivariate analysis of all primary sites combined demonstrated age < 65 years, KPS score >or= 70, no known extracranial metastases, and or= 70 years, primary tumor control, and 3 metastases was 15.6 and 16.9 months, respectively, for breast, 16.5 and 11.3 months for lung, and 9.0 and 5.7 months for melanoma. Analysis of the 4 prognostic systems (RTOG RPA, BSBM, GPA, and GGS) showed that each prognostic system's clinical applicability varied depending on primary tumor site. The RPA confirmed that GGS and primary tumor site are significant variables for prognosis., Conclusions: Favorable prognostic factors for patients with newly diagnosed brain metastases treated with radiosurgery vary by primary site. The 4 prognostic grading systems analyzed were applicable to different primary sites depending on which prognostic factors each individual system incorporated. Therefore, the authors recommend further development and use of primary-specific prognostic systems.

Background: As breast cancer patients live longer with control of systemic disease, survival after the diagnosis of brain metastases (BM) also appears to be improving., Methods: The authors conducted a retrospective review of 112 breast cancer patients diagnosed with BM from 1997 to 2007 and correlated clinical and pathologic characteristics including hormone receptor (HR) and Her2/neu status with outcomes., Findings: Median time to BM diagnosis (TTBM) was 38 months (range, 0-204 months). TTBM was shorter for patients with HR- versus HR+ disease (median 28.8 vs. 61.2 months, P < 0.001, Wilcoxon test). No difference in TTBM was observed for patients with HER2- versus HER2+ disease (median 37.4 vs. 34.9 months, P = 0.81). Median survival after the diagnosis of BM was 14.4 months. There was no significant difference in median survival after BM diagnosis for patients with HR+ versus HR- cancers (19.9 vs. 11.0 months, P = 0.18, log rank) or for patients with HER2+ versus HER2- disease (23.1 vs. 13.3 months, P = 0.11, log rank). Survival was significantly longer in patients with stable or responding systemic disease at BM diagnosis compared to patients with progressing systemic disease (31 vs. 6.3 months, P < 0.001). Multivariate analysis revealed that HR positivity, age <50, Karnofsky Performance Score (KPS) > or =80, and stable or responding systemic disease at BM diagnosis were associated with improved survival., Interpretation: Subsets of patients with breast cancer BM are surviving longer. Control of systemic disease was most strongly associated with improved outcomes, and HER2/neu overexpression did not shorten survival after the diagnosis of BM.

Purpose: To assess clinical and imaging outcomes in patients treated with Gamma Knife stereotactic radiosurgery (SRS) for brainstem metastases., Materials and Methods: We reviewed all patients with brain metastases treated with SRS at the University of California, San Francisco from 1991-2005 to identify patients who had SRS to a brainstem metastasis. Survival time and freedom from progression (FFP) were calculated from date of SRS using the Kaplan-Meier method. Prognostic factors were evaluated using the log-rank test and Cox proportional hazards model., Results: From 1991 through 2005, 42 consecutive patients with brainstem metastases had SRS to 44 lesions (seven midbrain, 31 pontine, and six medullary) in 42 sessions. Primary diagnoses included 14 cases of lung cancer (one small-cell), 10 melanoma, 12 breast cancer, five renal cell, and one unknown. The median age was 55 years (range, 25-79). The median survival time was 9 months after SRS. Longer survival time was associated with single metastasis, non-melanoma histology, and extracranial disease control. The median target volume was 0.26 ml (0.015-2.8 ml) and the median prescribed dose was 16.0 Gy (10.0-19.8 Gy). Brainstem lesion FFP was 90% at 6 months and 77% at 1 year. Four patients had brainstem complications following treatment. Poor brainstem outcome was associated with melanoma and renal cell histology as well as brainstem lesion volume > or =1 ml., Conclusions: In this series, SRS using a median dose of 16 Gy provided excellent local control with relatively low morbidity in patients with brainstem metastases less than 1 ml or non-melanoma, non-renal cell histology.

Purpose: To evaluate the feasibility of gross total resection and permanent I-125 brachytherapy followed by hyperfractionated radiotherapy for patients with newly diagnosed glioblastoma., Methods and Materials: From April 1999 to May 2002, 21 patients with glioblastoma multiforme were enrolled on a Phase I protocol investigating planned gross total resection and immediate placement of permanent I-125 seeds, followed by postoperative hyperfractionated radiotherapy to a dose of 60 Gy at 100 cGy b.i.d., 5 days per week. Median age and Karnofsky performance status were 50 years (range, 32-65 years) and 90 (range, 70-100), respectively. Toxicity was assessed according to Radiation Therapy Oncology Group criteria., Results: Eighteen patients completed treatment according to protocol. The median preoperative tumor volume on magnetic resonance imaging was 18.6 cm(3) (range, 4.4-41.2 cm(3)). The median brachytherapy dose measured 5 mm radially outward from the resection cavity was 400 Gy (range, 200-600 Gy). Ten patients underwent 12 reoperations, with 11 of 12 reoperations demonstrating necrosis without evidence of tumor. Because of high toxicity, the study was terminated early. Median progression-free survival and overall survival were 57 and 114 weeks, respectively, but not significantly improved compared with historical patients treated at University of California, San Francisco, with gross total resection and radiotherapy without brachytherapy., Conclusions: Treatment with gross total resection and permanent I-125 brachytherapy followed by hyperfractionated radiotherapy as performed in this study results in high toxicity and reoperation rates, without demonstrated improvement in survival.

Object: This study was designed to assess the presentation, management, and outcome of cases involving patients who had a supratentorial glioma that subsequently progressed in the posterior fossa (PF)., Methods: The authors performed a retrospective chart review of adult patients treated between 1997 and 2005 for supratentorial gliomas that progressed in the PF. The 29 patients with PF progression in this study were relatively young (median age of 34 years at original presentation). Twenty of these patients presented with symptoms. The symptoms were typically nonspecific to this population, at times leading to delays in diagnosis. Overall, these symptoms resolved in eight patients (40%) and progressed or remained unchanged in 12 (60%). Patients treated with more than 5000 cGy of radiation administered to the PF were more likely to have symptom resolution than those who received any other form of treatment, including reduced doses of radiation (p = 0.004). The patients treated with higher doses also survived significantly longer after PF progression (univariate analysis, p = 0.01, and after adjusting for tumor grade, p = 0.04)., Conclusions: Patients with PF progression of supratentorial infiltrative gliomas may benefit from treatment, and the authors recommend more than 5000 cGy of radiation to the PF if prior radiotherapy ports and doses allow.

Object: Whole-brain radiotherapy (WBRT) after resection of a single brain metastasis can cause long-term radiation toxicity. The authors evaluated the efficacy of resection and placement of 125I seeds (without concomitant WBRT) for newly diagnosed single brain metastases., Methods: In a retrospective review from two institutions (1997-2003), 15 women and 11 men (mean age 55 years) with single brain metastasis underwent gross-total resection and placement of permanent low-activity 125I seeds. Primary systemic cancer sites varied. Patients were monitored clinically and radiographically. With neuroimaging evidence of local recurrence or new distant metastasis, further treatment was administered at the physician's discretion. By the median follow-up evaluation (12 months), the local tumor control rate was 96%. Distant metastases occurred in three patients within 3 months, suggesting synchronous metastasis, and in six patients more than 3 months after treatment, indicating metachronous metastasis. Treatment in these cases included radiosurgery in seven patients, WBRT in two, and resection together with 125I seed placement in one. Two patients who suffered radiation necrosis required operative intervention (lesion diameter > 3 cm, total activity > 40 mCi). All 26 patients who had been treated using resection and placement of 125I seeds had a stable or an improved Karnofsky Performance Scale score. At the last review, nine of 16 living patients showed no evidence of treatment failure. The median actuarial survival rate was 17.8 months (Kaplan-Meier method)., Conclusions: Permanent 125I brachytherapy applied at the initial operation without WBRT provided excellent local tumor control. Local control and patient survival rates were at least as good as those reported for resection combined with WBRT. Although the authors noted a higher incidence of distant metastases compared with that reported in other studies of initial WBRT, these metastases were generally well controlled with a combination of surgery, stereotactic radiosurgery, and, less often, WBRT. Twenty-four patients (92%) never required WBRT, thus avoiding potential long-term radiation-induced neurotoxicity.

Glioblastoma multiforme (GBM) tumors almost invariably recur despite initial treatments. Correct diagnosis using a variety of imaging techniques and the involvement of a multidisciplinary tumor board are critical for evaluating each stage of a patient's progression and determining optimal management. Standard therapies for recurrence generally include repeated resection, radiation therapy, chemotherapy, and supportive care; however, salvage therapy must be highly individualized, and not all patients are eligible for every type of standard therapy. Factors such as the size and location of the tumor, previous treatment, and general health of the patient must be taken into consideration. Although standard therapies can prolong a patient's duration of survival, the median survival time for patients with recurrent GBM is usually less than 1 year. Experimental targeted drug therapies have been developed to inhibit aberrant cell-signaling pathways involved in tumorigenesis, and enrolling patients in clinical trials using these therapies is another option for treatment of recurrent GBM. The use of these novel therapies is often confined to large research institutions, but the severe limitations of standard treatment options make it important to highlight the potential of experimental therapies. In this paper the authors outline standard therapies and review the emerging role of targeted drug therapy in the treatment of recurrent GBM.

High-grade gliomas represent a significant source of cancer-related death, and usually recur despite treatment. In this analysis of current brain tumor medicine, we review diagnosis, standard treatment, and emerging therapies for recurrent astrocytomas. Difficulties in interpreting radiographic evidence, especially with regard to differentiating between tumor and necrosis, present a formidable challenge. The most accurate diagnoses come from tissue confirmation of recurrent tumor, but a combination of imaging techniques, such as magnetic resonance spectroscopy imaging, may also be relevant for diagnosis. Repeat resection can prolong life, but repeat irradiation of the brain poses serious risks and results in necrosis of healthy brain tissue; therefore, reirradiation is usually not offered to patients with recurrent tumors. We describe the use of conventional radiotherapy, intensity-modulated radiotherapy, brachytherapy, radiosurgery, and photodynamic therapy for recurrent high-grade glioma. The use of chemotherapy is limited by drug distribution and toxicity, but the development of new drug-delivery techniques such as convection-enhanced delivery, which delivers therapeutic molecules at an effective concentration directly to the brain, may provide a way to reduce systemic exposure to cytotoxic agents. We also discuss targeted therapies designed to inhibit aberrant cell-signaling pathways, as well as new experimental therapies such as immunotherapy. The treatment of this devastating disease has so far been met with limited success, but emerging knowledge of neuroscience and the development of novel therapeutic agents will likely give patients new options and require the neuro-oncology community to redefine clinical trial design and strategy continually.

The prognostic significance of the histologic type and grade of gliomas at initial surgery is well established, but the value of histologic findings in resections after radiotherapy is unclear. Despite this uncertainty, pathologic interpretation of specimens after radiotherapy influences immediate treatment decisions. It is important to determine if, and to what extent, treatment decisions should be based on this information. We aimed to determine the prognostic value of pathologic evaluation in postradiation specimens from 54 patients with similar clinical features who underwent a second surgery for the treatment of radiologic worsening after external beam radiotherapy. We categorized the specimens from the second surgery as either recurrent tumor (category 1) or radionecrosis (category 2). Patients in category 1 had actively proliferating neoplasms with classical features of glioblastoma, whereas patients in category 2 had no evidence of tumor in their surgical specimens. Cases in which a clear-cut definition could not be made were labeled indeterminate (category 3). Despite the morphological evidence of tumor, there were no significant differences between categories 1 and 2 in any of the survival parameters tested. The only difference between groups was higher frequency of iodine 125 (125I) placement at second surgery in category 1 patients (P <.028). Patients in category 1 with or without 125I treatment had similar survival characteristics. We conclude that histopathologic evaluation of postradiotherapy specimens was not helpful in predicting outcome or dictating further management. A comprehensive prospective study with advanced radiologic, pathologic, and molecular analyses may be more useful to determine prognostically valuable parameters.