Local control and survival after stereotactic radiosurgery for colorectal cancer brain metastases: an international multicenter analysis.

OBJECTIVE: The goal of this study was to characterize local tumor control (LC), overall survival (OS), and safety of stereotactic radiosurgery for colorectal brain metastasis (CRBM). METHODS: Ten international institutions participating in the International Radiosurgery Research Foundation provided data for this retrospective case series. This study included 187 patients with CRBM (281 tumors), with a median age of 62 years and 56.7% being male. Most patients (53.5%) had solitary tumors, although 10.7% had > 5 tumors. The median tumor volume was 2.7 cm3 (IQR 0.22-8.1 cm3), and the median margin dose was 20 Gy (IQR 18-22 Gy). RESULTS: The 3-year LC and OS rates were 72% and 20%, respectively. Symptomatic adverse radiation effects occurred in 1.6% of patients. In the multivariate analysis, age > 65 years and tumor volume > 4.0 cm3 were significant predictors of tumor progression (hazard ratio [HR] 2.6, 95% CI 1.4-4.9; p = 0.003 and HR 3.4, 95% CI 1.7-6.9; p < 0.001, respectively). Better performance status (Karnofsky Performance Scale score > 80) was associated with a reduced risk of tumor progression (HR 0.38, 95% CI 0.19-0.73; p = 0.004). Patient age > 62 years (HR 1.6, 95% CI 1.1-2.3; p = 0.03) and the presence of active extracranial disease (HR 1.7, 95% CI 1.1-2.4; p = 0.009) were significantly associated with worse OS. CONCLUSIONS: Stereotactic radiosurgery offers a high LC rate and a low rate of symptomatic adverse radiation effects for the majority of CRBMs. The OS and LC favored younger patients with high functional performance scores and inactive extracranial disease.

Local Control and Survival Outcomes After Stereotactic Radiosurgery for Brain Metastases From Gastrointestinal Primaries: An International Multicenter Analysis.

BACKGROUND: There are limited data regarding outcomes for patients with gastrointestinal (GI) primaries and brain metastases treated with stereotactic radiosurgery (SRS). OBJECTIVE: To examine clinical outcomes after SRS for patients with brain metastases from GI primaries and evaluate potential prognostic factors. METHODS: The International Radiosurgery Research Foundation centers were queried for patients with brain metastases from GI primaries managed with SRS. Primary outcomes were local control (LC) and overall survival (OS). Kaplan-Meier analysis was used for univariate analysis (UVA) of prognostic factors. Factors significant on UVA were evaluated with a Cox multivariate analysis proportional hazards model. Logistic regressions were used to examine correlations with RN. RESULTS: We identified 263 eligible patients with 543 brain metastases. Common primary sites were rectal (31.2%), colon (31.2%), and esophagus (25.5%) with a median age of 61.6 years (range: 37-91.4 years) and a median Karnofsky performance status (KPS) of 90% (range: 40%-100%). One-year and 2-year LC rates were 83.5% (95% CI: 78.9%-87.1%) and 73.0% (95% CI: 66.4%-78.5%), respectively. On UVA, age >65 years ( P = .001), dose <20 Gy ( P = .006) for single-fraction plans, KPS <90% ( P < .001), and planning target volume ≥2cc ( P = .007) were associated with inferior LC. All factors other than dose were significant on multivariate analysis ( P ≤ .002). One-year and 2-year OS rates were 68.0% (95% CI: 61.5%-73.6%) and 31.2% (95% CI: 24.6%-37.9%), respectively. Age > 65 years ( P = .006), KPS <90% ( P = .005), and extracranial metastases ( P = .05) were associated with inferior OS. CONCLUSION: SRS resulted in comparable LC with common primaries. Age and KPS were associated with both LC and OS with planning target volume and extracranial metastases correlating with LC and OS, respectively. These factors should be considered in GI cancer patient selection for SRS.

Stereotactic radiosurgery and local control of brain metastases from triple-negative breast cancer.

OBJECTIVE: Stereotactic radiosurgery (SRS) is an effective treatment for intracranial metastatic disease, but its role in triple-negative breast cancer requires further study. Herein, the authors report overall survival (OS) and local tumor control in a multiinstitutional cohort with triple-negative breast cancer metastases treated with SRS. METHODS: Patients treated from 2010 to 2019 at 9 institutions were included in this retrospective study if they had biopsy-proven triple-negative breast cancer with intracranial metastatic lesions treated with SRS. Patients were excluded if they had undergone prior SRS, whole-brain radiation therapy, or resection of the metastatic lesions. A retrospective chart review was conducted to determine OS, local control, and treatment efficacy. RESULTS: Sixty-eight patients with 315 treated lesions were assessed. Patients had a median Karnofsky Performance Status of 80 (IQR 70-90) and age of 57 years (IQR 48-67 years). Most treated patients had 5 or fewer intracranial lesions, with 34% of patients having a single lesion. Treated lesions were small, having a median volume owf 0.11 cm3 (IQR 0.03-0.60 cm3). Patients were treated with a median margin dose of 18 Gy (IQR 18-20 Gy) to the median 71% isodose line (IQR 50%-84%). Overall, patients had a 1-year OS of 43% and 2-year OS of 20%. Most patients (88%) were followed until death, by which time local tumor progression had occurred in only 7% of cases. Furthermore, 76% of the lesions demonstrated regression. Tumor volume was correlated with local tumor progression (p = 0.012). SRS was very well tolerated, and only 3 patients (5%) developed symptomatic radiation necrosis. CONCLUSIONS: SRS is a safe and efficacious treatment for well-selected patients with triple-negative breast cancer, especially for those with a favorable performance status and small- to moderate-volume metastatic lesions.

Reirradiation With Stereotactic Radiosurgery After Local or Marginal Recurrence of Brain Metastases From Previous Radiosurgery.

PURPOSE: Brain metastases represent a major indication for stereotactic radiosurgery (SRS), but further study is needed regarding repeat SRS (SRS2) after local or marginal recurrence after prior SRS (SRS1). We report local tumor control (LC) after SRS2 and identify predictors of radiation necrosis (RN) and symptomatic RN (SRN). METHODS AND MATERIALS: Patients had biopsy-proven non-small cell lung cancer and at least 1 brain metastasis previously treated with SRS. SRS2 was performed from 2015 to 2020 and required overlap of the prescription isodose lines with those from SRS1. Patients treated with preoperative SRS were excluded. Primary endpoints were LC by Response Assessment in Neuro-oncology criteria, RN, and SRN. RESULTS: From 8 institutions, 102 patients with 123 treated lesions were included. SRS2 was performed at a median 12 months after SRS1. SRS2 delivered a median 18 Gy (interquartile range [IQR], 16-18) margin dose to the 50% (IQR, 50%-70%) isodose line, maximum dose of 30.5 Gy (IQR, 25.0-36.0), and V12Gy of 3.38 cm3 (IQR, 0.83-7.64). One-year and 2-year LC were 79% and 72%, respectively. Local tumor control was improved with tumor volume ≤1 cm3 (P < .005). There were 25 (20%) cases of RN and 9 (7%) cases of SRN. For SRS1 and SRS2, SRN rates were higher with maximum doses ≥40 Gy or SRS2 V12Gy >9 cm3 (P < .025 for each). SRS1 and SRS2 maximum dose ≥40 Gy was also predictive of increased RN (P < .05 for each). Prior immunotherapy was not predictive of RN or SRN. CONCLUSIONS: Repeat SRS afforded a high rate of local tumor control and a low rate of SRN. At SRS2, V12Gy ≤9 cm3 and maximum dose <40 Gy may reduce the risks of RN and SRN. These results are most applicable to lesions with approximately 1 cm3 volume and 1-year interval between SRS courses.

Adverse radiation effects in volume-staged radiosurgery for large arteriovenous malformations: a multiinstitutional study.

OBJECTIVE: The optimal treatment paradigm for large arteriovenous malformations (AVMs) is controversial. One approach is volume-staged stereotactic radiosurgery (VS-SRS). The authors previously reported efficacy of VS-SRS for large AVMs in a multiinstitutional cohort; here they focus on risk of symptomatic adverse radiation effects (AREs). METHODS: This is a multicentered retrospective review of patients treated with a planned prospective volume staging approach to stereotactically treat the entire nidus of an AVM, with volume stages separated by intervals of 3-6 months. A total of 9 radiosurgical centers treated 257 patients with VS-SRS between 1991 and 2016. The authors evaluated permanent, transient, and total ARE events that were symptomatic. RESULTS: Patients received 2-4 total volume stages. The median age was 33 years at the time of the first SRS volume stage, and the median follow-up was 5.7 years after VS-SRS. The median total AVM nidus volume was 23.25 cm3 (range 7.7-94.4 cm3), with a median margin dose per stage of 17 Gy (range 12-20 Gy). A total of 64 patients (25%) experienced an ARE, of which 19 were permanent. Rather than volume, maximal linear dimension in the Z (craniocaudal) dimension was associated with toxicity; a threshold length of 3.28 cm was associated with an ARE, with a 72.5% sensitivity and a 58.3% specificity. In addition, parietal lobe involvement for superficial lesions and temporal lobe involvement for deep lesions were associated with an ARE. CONCLUSIONS: Size remains the dominant predictor of toxicity following SRS, but overall rates of AREs were lower than anticipated based on baseline features, suggesting that dose and size were relatively dissociated through volume staging. Further techniques need to be assessed to optimize outcomes.

Role of Gamma Knife Radiosurgery in Small Cell Lung Cancer: A Multi-Institutional Retrospective Study of the International Radiosurgery Research Foundation (IRRF).

BACKGROUND: Despite a high incidence of brain metastases in patients with small-cell lung cancer (SCLC), limited data exist on the use of stereotactic radiosurgery (SRS), specifically Gamma Knife™ radiosurgery (Elekta AB), for SCLC brain metastases. OBJECTIVE: To provide a detailed analysis of SCLC patients treated with SRS, focusing on local failure, distant brain failure, and overall survival (OS). METHODS: A multi-institutional retrospective review was performed on 293 patients undergoing SRS for SCLC brain metastases at 10 medical centers from 1991 to 2017. Data collection was performed according to individual institutional review boards, and analyses were performed using binary logistic regression, Cox-proportional hazard models, Kaplan-Meier survival analysis, and competing risks analysis. RESULTS: Two hundred thirty-two (79%) patients received SRS as salvage following prior whole-brain irradiation (WBRT) or prophylactic cranial irradiation, with a median marginal dose of 18 Gy. At median follow-up after SRS of 6.4 and 18.0 mo for surviving patients, the 1-yr local failure, distant brain failure, and OS were 31%, 49%, and 28%. The interval between WBRT and SRS was predictive of improved OS for patients receiving SRS more than 1 yr after initial treatment (21%, <1 yr vs 36%, >1 yr, P = .01). On multivariate analysis, older age was the only significant predictor for OS (hazard ratio 1.63, 95% CI 1.16-2.29, P = .005). CONCLUSION: SRS plays an important role in the management of brain metastases from SCLC, especially in salvage therapy following WBRT. Ongoing prospective trials will better assess the value of radiosurgery in the primary management of SCLC brain metastases and potentially challenge the standard application of WBRT in SCLC patients.

A Proposed Grading Scale for Predicting Outcomes After Stereotactic Radiosurgery for Dural Arteriovenous Fistulas.

BACKGROUND: There are presently no grading scales that specifically address the outcomes of cranial dural arteriovenous fistula (dAVF) after stereotactic radiosurgery (SRS). OBJECTIVE: To design a practical grading system that would predict outcomes after SRS for cranial dAVFs. METHODS: From the International Radiosurgery Research Foundation (University of Pittsburgh [41 patients], University of Pennsylvania [6 patients], University of Sherbrooke [2 patients], University of Manitoba [1 patient], West Virginia University [2 patients], University of Puerto Rico [1 patient], Beaumont Health System 1 [patient], Na Homolce Hospital [13 patients], the University of Virginia [48 patients], and Yale University [6 patients]) centers, 120 patients with dAVF treated with SRS were included in the study. The factors predicting favorable outcome (obliteration without post-SRS hemorrhage) after SRS were assessed using logistic regression analysis. These factors were pooled with the factors that were found to be predictive of obliteration from 7 studies with 736 patients after a systematic review of literature. These were entered into stepwise multiple regression and the best-fit model was identified. RESULTS: Based on the predictive model, 3 factors emerged to develop an SRS scoring system: cortical venous reflux (CVR), prior intracerebral hemorrhage (ICH), and noncavernous sinus location. Class I (score of 0-1 points) predicted the best favorable outcome of 80%. Class II patients (2 points score) had an intermediate favorable outcome of 57%, and class III (score 3 points) had the least favorable outcome at 37%. The ROC analysis showed better predictability to prevailing grading systems (AUC = 0.69; P = .04). Kaplan-Meier analysis showed statistically significant difference between the 3 subclasses of the proposed grading system for post-SRS dAVF obliteration (P = .001). CONCLUSION: The proposed dAVF grading system incorporates angiographic, anatomic, and clinical parameters and improves the prediction of the outcomes following SRS for dAVF as compared to the existing scoring systems.

Dose response and architecture in volume staged radiosurgery for large arteriovenous malformations: A multi-institutional study.

BACKGROUND: Optimal treatment paradigm for large arteriovenous malformations (AVMs) is controversial. Volume-staged stereotactic radiosurgery (VS-SRS) provides an effective option for these high-risk lesions, but optimizing treatment for these recalcitrant and rare lesions has proven difficult. METHODS: This is a multi-centered retrospective review of patients treated with a planned prospective volume staging approach to stereotactically treat the entire nidus of an AVM with volume stages separated by intervals of 3-6 months. A total of 9 radiosurgical centers treated 257 patients with VS-SRS between 1991 and 2016. We evaluated near complete response (nCR), obliteration, cure, and overall survival. RESULTS: With a median age of 33 years old at the time of first SRS volume stage, patients received 2-4 total volume stages and a median follow up of 5.7 years after VS-SRS. The median total AVM nidus volume was 23.25 cc (range: 7.7-94.4 cc) with a median margin dose per stage of 17 Gy (range: 12-20 Gy). Total AVM volume, margin dose per stage, compact nidus, lack of prior embolization, and lack of thalamic location involvement were all associated with improved outcomes. Dose >/= 17.5 Gy was strongly associated with improved rates of nCR, obliteration, and cure. With dose >/= 17.5 Gy, 5- and 10-year cure rates were 33.7% and 76.8% in evaluable patients compared to 23.7% and 34.7% of patients with 17 Gy and 6.4% and 20.6% with <17 Gy per volume-stage (p = 0.004). Obliteration rates in diffuse nidus architecture with <17 Gy were particularly poor with none achieving obliteration compared to 32.3% with doses >/= 17 Gy at 5 years (p = 0.007). Comparatively, lesions with a compact nidus architecture exhibited obliteration rates at 5 years were 10.7% vs 9.3% vs 26.6% for dose >17 Gy vs 17 Gy vs >/=17.5 Gy. CONCLUSION: VS-SRS is an option for upfront treatment of large AVMs. Higher dose was associated with improved rates of nCR, obliteration, and cure suggesting that larger volumetric responses may facilitate salvage therapy and optimize the chance for cure.

Hemorrhage risk of cerebral dural arteriovenous fistulas following Gamma Knife radiosurgery in a multicenter international consortium.

OBJECTIVE: The authors performed a study to evaluate the hemorrhagic rates of cerebral dural arteriovenous fistulas (dAVFs) and the risk factors of hemorrhage following Gamma Knife radiosurgery (GKRS). METHODS: Data from a cohort of patients undergoing GKRS for cerebral dAVFs were compiled from the International Radiosurgery Research Foundation. The annual posttreatment hemorrhage rate was calculated as the number of hemorrhages divided by the patient-years at risk. Risk factors for dAVF hemorrhage prior to GKRS and during the latency period after radiosurgery were evaluated in a multivariate analysis. RESULTS: A total of 147 patients with dAVFs were treated with GKRS. Thirty-six patients (24.5%) presented with hemorrhage. dAVFs that had any cortical venous drainage (CVD) (OR = 3.8, p = 0.003) or convexity or torcula location (OR = 3.3, p = 0.017) were more likely to present with hemorrhage in multivariate analysis. Half of the patients had prior treatment (49.7%). Post-GRKS hemorrhage occurred in 4 patients, with an overall annual risk of 0.84% during the latency period. The annual risks of post-GKRS hemorrhage for Borden type 2-3 dAVFs and Borden type 2-3 hemorrhagic dAVFs were 1.45% and 0.93%, respectively. No hemorrhage occurred after radiological confirmation of obliteration. Independent predictors of hemorrhage following GKRS included nonhemorrhagic neural deficit presentation (HR = 21.6, p = 0.027) and increasing number of past endovascular treatments (HR = 1.81, p = 0.036). CONCLUSIONS: Patients have similar rates of hemorrhage before and after radiosurgery until obliteration is achieved. dAVFs that have any CVD or are located in the convexity or torcula were more likely to present with hemorrhage. Patients presenting with nonhemorrhagic neural deficits and a history of endovascular treatments had higher risks of post-GKRS hemorrhage.

Stereotactic Radiosurgery for Trigeminal Neuralgia in Patients With Multiple Sclerosis: A Multicenter Study.

BACKGROUND: Facial pain response (PR) to various surgical interventions in patients with multiple sclerosis (MS)-related trigeminal neuralgia (TN) is much less optimal. No large patient series regarding stereotactic radiosurgery (SRS) has been published. OBJECTIVE: To evaluate the clinical outcomes of MS-related TN treated with SRS. METHODS: This is a retrospective cohort study. A total of 263 patients contributed by 9 member tertiary referral Gamma Knife centers (2 in Canada and 7 in USA) of the International Gamma Knife Research Consortium (IGKRF) constituted this study. RESULTS: The median latency period of PR after SRS was 1 mo. Reasonable pain control (Barrow Neurological Institute [BNI] Pain Scores I-IIIb) was achieved in 232 patients (88.2%). The median maintenance period from SRS was 14.1 months (range, 10 days to 10 years). The actuarial reasonable pain control maintenance rates at 1 yr, 2 yr, and 4 yr were 54%, 35%, and 24%, respectively. There was a correlation between the status of achieving BNI-I and the maintenance of facial pain recurrence-free rate. The median recurrence-free rate was 36 mo and 12.2 mo in patients achieving BNI-I and BNI > I, respectively (P = .046). Among 210 patients with known status of post-SRS complications, the new-onset of facial numbness (BNI-I or II) after SRS occurred in 21 patients (10%). CONCLUSION: In this largest series SRS offers a reasonable benefit to risk profile for patients who have exhausted medical management. More favorable initial response to SRS may predict a long-lasting pain control.

BRAF V600 Mutation and BRAF Kinase Inhibitors in Conjunction With Stereotactic Radiosurgery for Intracranial Melanoma Metastases: A Multicenter Retrospective Study.

BACKGROUND: The BRAF mutation has been identified as a potent target for the treatment of metastatic melanoma and BRAF inhibitors (BRAFi) have demonstrated promising results against melanoma brain metastases (BM). OBJECTIVE: To further investigate the effectiveness of this combined treatment regimen. METHODS: In this multicenter retrospective cohort study, 198 patients with known BRAF mutation status and treated with stereotactic radiosurgery (SRS) between 2011 and 2015 were identified. Kaplan-Meier methodology and multivariate regression analysis was then used to compare survival based on each parameter. RESULTS: The median survival after the diagnosis of BM in patients with BRAF mutation who received BRAFi was increased compared to survival in patients with wild-type BRAF (BRAF wt). In multivariate analysis, the BRAF mutation was an independent, positive prognostic factor with a hazard ratio of 0.59. BRAF mutated Patients who received BRAFi following SRS had improved survival compared to patients who received it before (P < .001) or concurrently (P = .007). PD-1 inhibitors improved survival, with more pronounced effect in patients not carrying the BRAF mutation. Among the patients who were treated with BRAFi, 10.4% developed intracerebral hematoma (ICH), in comparison to 3% of patients who were not treated with BRAFi (P = .03). CONCLUSION: In the setting of widespread use of BRAFi, the presence of a BRAF mutation is an independent predictor of better prognosis in patients with melanoma BM that underwent SRS. The effect of BRAFi is optimal when treatment is initiated at least 1 wk following SRS. BRAFi may increase the frequency of asymptomatic ICH.

Long-term Quality of Life in Survivors of Brain Metastases: A Roller Coaster of Perspective.

Longevity in cancer patients with brain metastases is increasingly being observed. This raises discussions about how best to maintain a good quality of life for these patients. Recent data suggest that post-treatment quality of life (QoL) can be maintained using new treatment options, but little data exist regarding the QoL in long-term survivors. This study of 19 patients surviving greater than two years from the initial treatment of brain metastases suggests that long-term QoL can be better than at the start of treatment and perhaps even better than normal, especially between three and five years post-treatment. This improved QoL seems mostly attributable to improved functional and social well-being and is possible as long as emotional and physical well-being are maintained within the normal range.

Post-radiosurgical edema associated with parasagittal and parafalcine meningiomas: a multicenter study.

Stereotactic radiosurgery (SRS) offers a high degree of tumor control for benign meningiomas. However, radiosurgery can occasionally incite edema or exacerbate pre-existing peri-tumoral edema. The current study investigates the incidence, timing, and extent of edema around parasagittal or parafalcine meningiomas following SRS. A retrospective multicenter review was undertaken through participating centers in the International Gamma Knife Research Foundation (previously the North American Gamma Knife Consortium or NAGKC). All included patients had a parafalcine or parasagittal meningioma and a minimum of 6 months follow up. The median follow up was 19.6 months (6-158 months). Extent of new or worsening edema was quantitatively analyzed using volumetric analysis; edema indices were longitudinally computed following radiosurgery. Analysis was performed to identify prognostic factors for new or worsening edema. A cohort of 212 patients comprised of 51.9 % (n = 110) females, 40.1 % upfront SRS and 59.9 % underwent adjuvant SRS for post-surgical residual tumor. The median tumor volume at SRS was 5.2 ml. Venous sinus compression or invasion was demonstrated in 25 % (n = 53). The median marginal dose was 14 Gy (8-20 Gy). Tumor volume control was determined in 77.4 % (n = 164 out of 212 patients). Tumor edema progressed and then regressed in 33 % (n = 70), was stable or regressed in 52.8 % (n = 112), and progressively worsened in 5.2 % (n = 11). Tumor location, tumor volume, venous sinus invasion, margin, and maximal dose were found to be significantly related to post-SRS edema in multivariate analysis. SRS affords a high degree of tumor control for patients with parasagittal or parafalcine meningiomas. Nevertheless, SRS can lead to worsening peritumoral edema in a subset of patients such as those with larger tumors (>10 cc) and venous sinus invasion/compression. Long-term follow up is required to detect and appropriately manage post-SRS edema.

Gamma Knife radiosurgery for facial nerve schwannomas: a multicenter study.

OBJECT: Facial nerve schwannomas (FNSs) are rare intracranial tumors, and the optimal management of these tumors remains unclear. Resection can be undertaken, but the tumor's intimate association with the facial nerve makes resection with neurological preservation quite challenging. Stereotactic radiosurgery (SRS) has been used to treat FNSs, and this study evaluates the outcome of this approach. METHODS: At 8 medical centers participating in the North American Gamma Knife Consortium (NAGKC), 42 patients undergoing SRS for an FNS were identified, and clinical and radiographic data were obtained for these cases. Males outnumbered females at a ratio of 1.2:1, and the patients' median age was 48 years (range 11-76 years). Prior resection was performed in 36% of cases. The mean tumor volume was 1.8 cm(3), and a mean margin dose of 12.5 Gy (range 11-15 Gy) was delivered to the tumor. RESULTS: At a median follow-up of 28 months, tumor control was achieved in 36 (90%) of the 40 patients with reliable radiographic follow-up. Actuarial tumor control was 97%, 97%, 97%, and 90% at 1, 2, 3, and 5 years postradiosurgery. Preoperative facial nerve function was preserved in 38 of 42 patients, with 60% of evaluable patients having House-Brackmann scores of 1 or 2 at last follow-up. Treated patients with a House-Brackmann score of 1 to 3 were more likely to demonstrate this level of facial nerve function at last evaluation (OR 6.09, 95% CI 1.7-22.0, p = 0.006). Avoidance of temporary or permanent neurological symptoms was more likely to be achieved in patients who received a tumor margin dose of 12.5 Gy or less (log-rank test, p = 0.024) delivered to a tumor of ≤ 1 cm(3) in volume (log-rank test, p = 0.01). CONCLUSIONS: Stereotactic radiosurgery resulted in tumor control and neurological preservation in most FNS patients. When the tumor is smaller and the patient exhibits favorable normal facial nerve function, SRS portends a better result. The authors believe that early, upfront SRS may be the treatment of choice for small FNSs, but it is an effective salvage treatment for residual/recurrent tumor that remain or progress after resection.

Gamma Knife radiosurgery for posterior fossa meningiomas: a multicenter study.

OBJECT: Posterior fossa meningiomas represent a common yet challenging clinical entity. They are often associated with neurovascular structures and adjacent to the brainstem. Resection can be undertaken for posterior fossa meningiomas, but residual or recurrent tumor is frequent. Stereotactic radiosurgery (SRS) has been used to treat meningiomas, and this study evaluates the outcome of this approach for those located in the posterior fossa. METHODS: At 7 medical centers participating in the North American Gamma Knife Consortium, 675 patients undergoing SRS for a posterior fossa meningioma were identified, and clinical and radiological data were obtained for these cases. Females outnumbered males at a ratio of 3.8 to 1, and the median patient age was 57.6 years (range 12-89 years). Prior resection was performed in 43.3% of the patient sample. The mean tumor volume was 6.5 cm(3), and a median margin dose of 13.6 Gy (range 8-40 Gy) was delivered to the tumor. RESULTS: At a mean follow-up of 60.1 months, tumor control was achieved in 91.2% of cases. Actuarial tumor control was 95%, 92%, and 81% at 3, 5, and 10 years after radiosurgery. Factors predictive of tumor progression included age greater than 65 years (hazard ratio [HR] 2.36, 95% CI 1.30-4.29, p = 0.005), prior history of radiotherapy (HR 5.19, 95% CI 1.69-15.94, p = 0.004), and increasing tumor volume (HR 1.05, 95% CI 1.01-1.08, p = 0.005). Clinical stability or improvement was achieved in 92.3% of patients. Increasing tumor volume (odds ratio [OR] 1.06, 95% CI 1.01-1.10, p = 0.009) and clival, petrous, or cerebellopontine angle location as compared with petroclival, tentorial, and foramen magnum location (OR 1.95, 95% CI 1.05-3.65, p = 0.036) were predictive of neurological decline after radiosurgery. After radiosurgery, ventriculoperitoneal shunt placement, resection, and radiation therapy were performed in 1.6%, 3.6%, and 1.5%, respectively. CONCLUSIONS: Stereotactic radiosurgery affords a high rate of tumor control and neurological preservation for patients with posterior fossa meningiomas. Those with a smaller tumor volume and no prior radiation therapy were more likely to have a favorable response after radiosurgery. Rarely, additional procedures may be required for hydrocephalus or tumor progression.

Gamma knife radiosurgery for cerebellopontine angle meningiomas: a multicenter study.

BACKGROUND: Resection of cerebellopontine angle (CPA) meningiomas may result in significant neurological morbidity. Radiosurgery offers a minimally invasive alternative to surgery. OBJECTIVE: To evaluate, in a multicenter cohort study, the outcomes of patients harboring CPA meningiomas who underwent Gamma Knife radiosurgery (GKRS). METHODS: From 7 institutions participating in the North American Gamma Knife Consortium, 177 patients with benign CPA meningiomas treated with GKRS and at least 6 months radiologic follow-up were included for analysis. The mean age was 59 years and 84% were female. Dizziness or imbalance (48%) and cranial nerve (CN) VIII dysfunction (45%) were the most common presenting symptoms. The median tumor volume and prescription dose were 3.6 cc and 13 Gy, respectively. The mean radiologic and clinical follow-up durations were 47 and 46 months, respectively. Multivariate regression analyses were performed to identify the predictors of tumor progression and neurological deterioration. RESULTS: The actuarial rates of progression-free survival at 5 and 10 years were 93% and 77%, respectively. Male sex (P = .014), prior fractionated radiation therapy (P = .010), and ataxia at presentation (P = .002) were independent predictors of tumor progression. Symptomatic adverse radiation effects and permanent neurological deterioration were observed in 1.1% and 9% of patients, respectively. Facial spasms at presentation (P = .007) and lower maximal dose (P = .011) were independently associated with neurological deterioration. CONCLUSION: GKRS is an effective therapy for CPA meningiomas. Depending on the patient and tumor characteristics, radiosurgery can be an adjuvant treatment to initial surgical resection or a standalone procedure that obviates the need for resection in most patients.

Stereotactic radiosurgery of petroclival meningiomas: a multicenter study.

Petroclival meningiomas are difficult to treat due to their intimate location with critical structures, and complete microsurgical resection is often associated with significant morbidity. In this study, we evaluate the outcomes of petroclival meningiomas treated with Gamma Knife radiosurgery (GKRS) as an adjunct to microsurgery or a primary treatment modality. A multicenter study of 254 patients with a benign petroclival meningioma was conducted through the North American Gamma Knife Consortium. One hundred and forty patients were treated with upfront radiosurgery, and 114 following surgery. Multivariate analysis was used to determine predictors of favorable defined as no tumor progression following radiosurgery and the absence of any new or worsening neurological function. At mean follow up of 71 months (range 6-252), tumor volumes increased in 9 % of tumors, remained stable in 52 %, and decreased in 39 %. Kaplan-Meier actuarial progression free survival rates at 3, 5, 8, 10, and 12 years were 97, 93, 87, 84, and 80 % respectively. At last clinical follow-up, 93.6 % of patients demonstrated no change or improvement in their neurological condition whereas 6.4 % of patients experienced progression of symptoms. Favorable outcome was achieved in 87 % of patients and multivariate predictors of favorable outcome included smaller tumor volume (OR = 0.92; 95 % CI 0.87-0.97, p = 0.003), female gender (OR 0.37; 95 % CI 0.15-0.89, p = 0.027), no prior radiotherapy (OR 0.03; 95 % CI 0.01-0.36, p = 0.006), and decreasing maximal dose (OR 0.92; 95 % CI 0.96-0.98, p = 0.010). GKRS of petroclival meningiomas achieves neurological preservation in most patients and with a high rate of tumor control.

A clinical model for identifying radiosensitive tumor genotypes in non-small cell lung cancer.

PURPOSE: Non-small cell lung cancer (NSCLC) includes a spectrum of radiosensitive and radioresistant tumors. However, little is known about the molecular determinants of cellular radiation responses. We examined clinical outcomes after gamma knife radiotherapy for NSCLC intracranial metastases to evaluate the use of this model for determining radiosensitive tumor genotypes. EXPERIMENTAL DESIGN: Between 2005 and 2012, 239 patients with NSCLC were enrolled in a prospective gamma knife data repository. Molecular pathology regarding EGF receptor (EGFR), ALK, and KRAS mutation status was available for 81 patients. Local and distant brain control was determined for 79 patients with 469 brain metastases. Modified Cox proportional hazards models were established to evaluate local control for treated lesions after serial gamma knife treatments. RESULTS: In total, 11% of patients developed in-field recurrence. No patients with metastases from tumors with EGFR mutations (0/164 lesions) or EML4-ALK translocations (0/61 lesions) recurred in-field. In contrast, 19% of patients without these mutations and 18% of patients with KRAS mutations recurred in-field (10/139 and 3/105 lesions, respectively). Rates of distant brain recurrence did not significantly differ across tumor genotypes. The predicted median in-field local control was significantly longer for EGFR-mutant and ALK-translocated tumors compared with other patients with NSCLC (P < 0.001), whereas distant brain recurrence time was equivalent (P = 0.97). On multivariate analysis, EGFR mutation, ALK translocation, and metastasis size were independent predictors for superior local control after gamma knife treatment. CONCLUSIONS: This study suggests that EGFR kinase domain mutations and EML4-ALK translocations are radiosensitive NSCLC genotypes, and proposes a novel model to identify radiosensitive subtypes of NSCLC.

Molecular genetics of addiction and related heritable phenotypes: genome-wide association approaches identify "connectivity constellation" and drug target genes with pleiotropic effects.

Genome-wide association (GWA) can elucidate molecular genetic bases for human individual differences in complex phenotypes that include vulnerability to addiction. Here, we review (a) evidence that supports polygenic models with (at least) modest heterogeneity for the genetic architectures of addiction and several related phenotypes; (b) technical and ethical aspects of importance for understanding GWA data, including genotyping in individual samples versus DNA pools, analytic approaches, power estimation, and ethical issues in genotyping individuals with illegal behaviors; (c) the samples and the data that shape our current understanding of the molecular genetics of individual differences in vulnerability to substance dependence and related phenotypes; (d) overlaps between GWA data sets for dependence on different substances; and (e) overlaps between GWA data for addictions versus other heritable, brain-based phenotypes that include bipolar disorder, cognitive ability, frontal lobe brain volume, the ability to successfully quit smoking, neuroticism, and Alzheimer's disease. These convergent results identify potential targets for drugs that might modify addictions and play roles in these other phenotypes. They add to evidence that individual differences in the quality and quantity of brain connections make pleiotropic contributions to individual differences in vulnerability to addictions and to related brain disorders and phenotypes. A "connectivity constellation" of brain phenotypes and disorders appears to receive substantial pathogenic contributions from individual differences in a constellation of genes whose variants provide individual differences in the specification of brain connectivities during development and in adulthood. Heritable brain differences that underlie addiction vulnerability thus lie squarely in the midst of the repertoire of heritable brain differences that underlie vulnerability to other common brain disorders and phenotypes.

Calorie restriction increases cigarette use in adult smokers.

RATIONALE: Cigarette smokers weigh less than nonsmokers, and smokers often gain weight when they quit. This is a major barrier to smoking cessation, especially among women. However, strict dieting is not recommended during smoking cessation out of concern that it might promote relapse. This concern derives, in part, from the observation that calorie restriction increases self-administration of drugs of abuse in animals. This relationship has never been experimentally demonstrated in humans. OBJECTIVES: To evaluate whether calorie restriction increases cigarette smoking in humans. METHODS: Seventeen (nine males, eight females) healthy, normal-weight smokers not attempting to quit were cycled in partially counterbalanced order, double-blind, through four diets-normal calorie (2,000-2,800 kcal/day), low calorie (700 kcal/day deficit), low-carbohydrate (CHO)/normal-calorie, and low-CHO/low-calorie-for 6 days per diet in an inpatient research ward. Smoking was assessed by cigarette counts, breath carbon monoxide (CO) levels, and cigarette craving. RESULTS: Compared with the normal-calorie diet, while on the low-calorie diet, subjects smoked 8% more cigarettes (P<0.02) and had 11% higher breath CO levels (P<0.01). The low-CHO/normal-calorie diet showed no significant effect on either variable, but there was a 15% increase in breath CO levels (P<0.05) on the low-CHO/low-calorie diet. There were no changes in self-reported cigarette craving or mood. CONCLUSIONS: Consistent with animal studies, moderate calorie restriction was associated with a small but statistically significant increase in cigarette smoking, with no independent effect of CHO deprivation. These findings suggest that dieting may increase smoking behavior and could impede smoking-cessation attempts.