Implementing Multifactorial Risk Assessment with Polygenic Risk Scores for Personalized Breast Cancer Screening in the Population Setting: Challenges and Opportunities.

Risk-stratified breast screening has been proposed as a strategy to overcome the limitations of age-based screening. A prospective cohort study was undertaken within the PERSPECTIVE I&I project, which will generate the first Canadian evidence on multifactorial breast cancer risk assessment in the population setting to inform the implementation of risk-stratified screening. Recruited females aged 40-69 unaffected by breast cancer, with a previous mammogram, underwent multifactorial breast cancer risk assessment. The adoption of multifactorial risk assessment, the effectiveness of methods for collecting risk factor information and the costs of risk assessment were examined. Associations between participant characteristics and study sites, as well as data collection methods, were assessed using logistic regression; all p-values are two-sided. Of the 4246 participants recruited, 88.4% completed a risk assessment, with 79.8%, 15.7% and 4.4% estimated at average, higher than average and high risk, respectively. The total per-participant cost for risk assessment was CAD 315. Participants who chose to provide risk factor information on paper/telephone (27.2%) vs. online were more likely to be older (p = 0.021), not born in Canada (p = 0.043), visible minorities (p = 0.01) and have a lower attained education (p < 0.0001) and perceived fair/poor health (p < 0.001). The 34.4% of participants requiring risk factor verification for missing/unusual values were more likely to be visible minorities (p = 0.009) and have a lower attained education (p ≤ 0.006). This study demonstrates the feasibility of risk assessment for risk-stratified screening at the population level. Implementation should incorporate an equity lens to ensure cancer-screening disparities are not widened.

Response Assessment in Brain Metastases Managed by Stereotactic Radiosurgery: A Reappraisal of the RANO-BM Criteria.

BACKGROUND: Brain metastases (BM) are increasingly being treated using stereotactic radiosurgery (SRS). Standardized response criteria are necessary to improve research and treatment protocols. This study's goal was to validate the RANO-BM criteria thresholds for tumor progression in a cohort of patients with brain metastases managed using SRS. METHODS: We performed a retrospective analysis of patients treated at least twice with SRS for brain metastases. Local progression, as defined by RANO-BM criteria, was compared to our multidisciplinary tumor board's treatment recommendation. A ROC curve was generated using varying diameter thresholds to assess the sensitivity and specificity of current RANO-BM criteria. RESULTS: 249 metastases in 67 patients were included in the analysis. RANO-BM criteria current progression thresholds yielded a sensitivity of 38%, a specificity of 95%, a positive predictive value of 71%, and a negative predictive value of 84% relative to our tumor board's treatment recommendation. Modified RANO-BM criteria using absolute diameter differences of 2.5 mm yielded a sensitivity of 83%, a specificity of 87%, a positive predictive value of 67% and a negative predictive value of 94%. CONCLUSIONS: Current RANO-BM criteria unreliably identifies clinically relevant tumor progression. The use of absolute diameter differences thresholds appears superior in our BM cohort.

Glycerol 3-phosphate phosphatase/PGPH-2 counters metabolic stress and promotes healthy aging via a glycogen sensing-AMPK-HLH-30-autophagy axis in C. elegans.

Metabolic stress caused by excess nutrients accelerates aging. We recently demonstrated that the newly discovered enzyme glycerol-3-phosphate phosphatase (G3PP; gene Pgp), which operates an evolutionarily conserved glycerol shunt that hydrolyzes glucose-derived glycerol-3-phosphate to glycerol, counters metabolic stress and promotes healthy aging in C. elegans. However, the mechanism whereby G3PP activation extends healthspan and lifespan, particularly under glucotoxicity, remained unknown. Here, we show that the overexpression of the C. elegans G3PP homolog, PGPH-2, decreases fat levels and mimics, in part, the beneficial effects of calorie restriction, particularly in glucotoxicity conditions, without reducing food intake. PGPH-2 overexpression depletes glycogen stores activating AMP-activate protein kinase, which leads to the HLH-30 nuclear translocation and activation of autophagy, promoting healthy aging. Transcriptomics reveal an HLH-30-dependent longevity and catabolic gene expression signature with PGPH-2 overexpression. Thus, G3PP overexpression activates three key longevity factors, AMPK, the TFEB homolog HLH-30, and autophagy, and may be an attractive target for age-related metabolic disorders linked to excess nutrients.

Canadian Healthcare Professionals' Views and Attitudes toward Risk-Stratified Breast Cancer Screening.

Given the controversy over the effectiveness of age-based breast cancer (BC) screening, offering risk-stratified screening to women may be a way to improve patient outcomes with detection of earlier-stage disease. While this approach seems promising, its integration requires the buy-in of many stakeholders. In this cross-sectional study, we surveyed Canadian healthcare professionals about their views and attitudes toward a risk-stratified BC screening approach. An anonymous online questionnaire was disseminated through Canadian healthcare professional associations between November 2020 and May 2021. Information collected included attitudes toward BC screening recommendations based on individual risk, comfort and perceived readiness related to the possible implementation of this approach. Close to 90% of the 593 respondents agreed with increased frequency and earlier initiation of BC screening for women at high risk. However, only 9% agreed with the idea of not offering BC screening to women at very low risk. Respondents indicated that primary care physicians and nurse practitioners should play a leading role in the risk-stratified BC screening approach. This survey identifies health services and policy enhancements that would be needed to support future implementation of a risk-stratified BC screening approach in healthcare systems in Canada and other countries.

Phase II multicenter trial combining nivolumab and radiosurgery for NSCLC and RCC brain metastases.

Background: Anti-PD-1 has activity in brain metastases (BM). This phase II open labeled non-randomized single arm trial examined the safety and efficacy of combining nivolumab with radiosurgery (SRS) in the treatment of patients with BM from non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). Methods: This was a multicenter trial (NCT02978404) in which patients diagnosed with NSCLC or RCC, having ≤ 10 cc of un-irradiated BM and no prior immunotherapy were eligible. Nivolumab (240 mg or 480 mg IV) was administered for up to 2 years until progression. SRS (15-21 Gy) to all un-irradiated BM was delivered within 14 days after the first dose of nivolumab. The primary endpoint was intracranial progression free survival (iPFS). Results: Twenty-six patients (22 NSCLC and 4 RCC) were enrolled between August 2017 and January 2020. A median of 3 (1-9) BM were treated with SRS. Median follow-up was 16.0 months (0.43-25.9 months). Two patients developed nivolumab and SRS related grade 3 fatigue. One-year iPFS and OS were 45.2% (95% CI 29.3-69.6%) and 61.3% (95% CI 45.1-83.3%), respectively. Overall response (partial or complete) of SRS treated BM was attained in 14 out of the 20 patients with ≥1 evaluable follow-up MRI. Mean FACT-Br total scores were 90.2 at baseline and improved to 146.2 within 2-4 months (P = .0007). Conclusions: The adverse event profile and FACT-Br assessments suggested that SRS during nivolumab was well tolerated. Upfront SRS with the initiation of anti-PD-1 prolonged the 1-year iPFS and achieved high intracranial control. This combined approach merits validation randomized studies.

Polygenic risk scores and risk-stratified breast cancer screening: Familiarity and perspectives of health care professionals.

PURPOSE: Health care professionals are expected to take on an active role in the implementation of risk-based cancer prevention strategies. This study aimed to explore health care professionals' (1) self-reported familiarity with the concept of polygenic risk score (PRS), (2) perceived level of knowledge regarding risk-stratified breast cancer (BC) screening, and (3) preferences for continuing professional development. METHODS: A cross-sectional survey was conducted using a bilingual-English/French-online questionnaire disseminated by health care professional associations across Canada between November 2020 and May 2021. RESULTS: A total of 593 professionals completed more than 2 items and 453 responded to all questions. A total of 432 (94%) participants were female, 103 (22%) were physicians, and 323 (70%) were nurses. Participants reported to be unfamiliar with (20%), very unfamiliar (32%) with, or did not know (41%) the concept of PRS. Most participants reported not having enough knowledge about risk-stratified BC screening (61%) and that they would require more training (77%). Online courses and webinar conferences were the preferred continuing professional development modalities. CONCLUSION: The study indicates that health care professionals are currently not familiar with the concept of PRS or a risk-stratified approach for BC screening. Online information and training seem to be an essential knowledge transfer modality.

Traduction franco-canadienne de l'Assessment of Systematic Reviews Revised (AMSTAR 2) : validation transculturelle et fidélité interjuges.

Objective: Produce a French-Canadian translation of AMSTAR 2, affirm its content validity, and examine interrater reliability. Methods: Based on Vallerand's methodological approach, we conducted forward and parallel inverse-translations. Subsequently, an expert panel evaluated the translations to create a preliminary experimental French-Canadian version. A second expert panel examined this version and proposed additional modifications. Twenty future health professionals then rated the second experimental version for ambiguity on a scale (from 1 to 7). The principal co-investigators then reviewed the problematic elements and proposed a pre-official version. To ascertain content validity, a final back-translation was conducted resulting in the official version. Four judges evaluated 13 systematic reviews using the official French-Canadian version of AMSTAR 2. The Kappa coefficient was used to evaluate interrater reliability. Results: This rigorous adaptation enabled the development of a Franco-Canadian version of AMSTAR 2. Its application demonstrated low ambiguity (mean 1.15; SD 0.26) as well as good overall interrater reliability (total κ > 0.64) across all items. Conclusion: The French-Canadian version of AMSTAR 2 can now support francophone clinicians, educators, and managers in Canada as they undertake evidence-based practice.

Phosphoglycolate phosphatase homologs act as glycerol-3-phosphate phosphatase to control stress and healthspan in C. elegans.

Metabolic stress due to nutrient excess and lipid accumulation is at the root of many age-associated disorders and the identification of therapeutic targets that mimic the beneficial effects of calorie restriction has clinical importance. Here, using C. elegans as a model organism, we study the roles of a recently discovered enzyme at the heart of metabolism in mammalian cells, glycerol-3-phosphate phosphatase (G3PP) (gene name Pgp) that hydrolyzes glucose-derived glycerol-3-phosphate to glycerol. We identify three Pgp homologues in C. elegans (pgph) and demonstrate in vivo that their protein products have G3PP activity, essential for glycerol synthesis. We demonstrate that PGPH/G3PP regulates the adaptation to various stresses, in particular hyperosmolarity and glucotoxicity. Enhanced G3PP activity reduces fat accumulation, promotes healthy aging and acts as a calorie restriction mimetic at normal food intake without altering fertility. Thus, PGP/G3PP can be considered as a target for age-related metabolic disorders.

Risk-Stratified Approach to Breast Cancer Screening in Canada: Women's Knowledge of the Legislative Context and Concerns about Discrimination from Genetic and Other Predictive Health Data.

The success of risk-stratified approaches in improving population-based breast cancer screening programs depends in no small part on women's buy-in. Fear of genetic discrimination (GD) could be a potential barrier to genetic testing uptake as part of risk assessment. Thus, the objective of this study was twofold. First, to evaluate Canadian women's knowledge of the legislative context governing GD. Second, to assess their concerns about the possible use of breast cancer risk levels by insurance companies or employers. We use a cross-sectional survey of 4293 (age: 30-69) women, conducted in four Canadian provinces (Alberta, British Colombia, Ontario and Québec). Canadian women's knowledge of the regulatory framework for GD is relatively limited, with some gaps and misconceptions noted. About a third (34.7%) of the participants had a lot of concerns about the use of their health information by employers or insurers; another third had some concerns (31.9%), while 20% had no concerns. There is a need to further educate and inform the Canadian public about GD and the legal protections that exist to prevent it. Enhanced knowledge could facilitate the implementation and uptake of risk prediction informed by genetic factors, such as the risk-stratified approach to breast cancer screening that includes risk levels.

Women's Views on Multifactorial Breast Cancer Risk Assessment and Risk-Stratified Screening: A Population-Based Survey from Four Provinces in Canada.

Risk-stratified screening for breast cancer (BC) is increasingly considered as a promising approach. However, its implementation is challenging and needs to be acceptable to women. We examined Canadian women's attitudes towards, comfort level about, and willingness to take part in BC risk-stratified screening. We conducted an online survey in women aged 30 to 69 years in four Canadian provinces. In total, 4293 women completed the questionnaire (response rate of 63%). The majority of women (63.5% to 72.8%) expressed favorable attitudes towards BC risk-stratified screening. Most women reported that they would be comfortable providing personal and genetic information for BC risk assessment (61.5% to 67.4%) and showed a willingness to have their BC risk assessed if offered (74.8%). Most women (85.9%) would also accept an increase in screening frequency if they were at higher risk, but fewer (49.3%) would accept a reduction in screening frequency if they were at lower risk. There were few differences by province; however, outcomes varied by age, education level, marital status, income, perceived risk, history of BC, prior mammography, and history of genetic test for BC (all p ≤ 0.01). Risk-based BC screening using multifactorial risk assessment appears to be acceptable to most women. This suggests that the implementation of this approach is likely to be well-supported by Canadian women.

Brain irradiation leads to persistent neuroinflammation and long-term neurocognitive dysfunction in a region-specific manner.

Long-term cognitive deficits are observed after treatment of brain tumors or metastases by radiotherapy. Treatment optimization thus requires a better understanding of the effects of radiotherapy on specific brain regions, according to their sensitivity and interconnectivity. In the present study, behavioral tests supported by immunohistology and magnetic resonance imaging provided a consistent picture of the persistent neurocognitive decline and neuroinflammation after the onset of irradiation-induced necrosis in the right primary somatosensory cortex of Fischer rats. Necrosis surrounded by neovascularization was first detected 54 days after irradiation and then spread to 110 days in the primary motor cortex, primary somatosensory region, striatum and right ventricle, resulting in fiber bundle disruption and demyelination in the corpus callosum of the right hemisphere. These structural damages translated into selective behavioral changes including spatial memory loss, disinhibition of anxiety-like behaviors, hyperactivity and pain hypersensitivity, but no significant alteration in motor coordination and grip strength abilities. Concomitantly, activated microglia and reactive astrocytes, accompanied by infiltration of leukocytes (CD45+) and T-cells (CD3+) cooperated to shape the neuroinflammation response. Overall, our study suggests that the slow and gradual onset of cellular damage would allow adaptation in brain regions that are susceptible to neuronal plasticity; while other cerebral structures that do not have this capacity would be more affected. The planning of radiotherapy, adjusted to the sensitivity and adaptability of brain structures, could therefore preserve certain neurocognitive functions; while higher doses of radiation could be delivered to brain areas that can better adapt to this treatment. In addition, strategies to block early post-radiation events need to be explored to prevent the development of long-term cognitive dysfunction.

Adherence trajectories of adjuvant endocrine therapy in the five years after its initiation among women with non-metastatic breast cancer: a cohort study using administrative databases.

PURPOSE: Despite the benefits of adjuvant endocrine therapy (AET) for reducing recurrence and mortality risks after hormone-sensitive breast cancer, AET adherence is sub-optimal for a high proportion of women. However, little is known about long-term patterns of AET adherence over the minimally recommended 5 years. Our objectives were to: (1) identify 5-year AET adherence trajectory groups; (2) describe trajectory groups according to adherence measures traditionally used (i.e., Proportion of Days Covered); and (3) explore factors associated with trajectories. METHODS: We conducted a 5-year cohort study using data from a French national study that included AET dispensing data. Women diagnosed with first non-metastatic breast cancer and having at least 1 AET dispensing in the 12 months after diagnosis were included. Group-based trajectory modeling was used to identify adherence trajectory groups by clustering similar patterns of monthly AET dispensing. Multinomial logistic regressions were used to identify factors associated with trajectories. RESULTS: Among 674 women, five AET adherence trajectory groups were identified: (1) quick decline and stop (5.2% of women); (2) moderate decline and stop (6.4%); (3) slow decline (17.2%); (4) high adherence (30.0%); and (5) maintenance of very high adherence (41.2%). Mean 5-year Proportion of Days Covered varied from 10 to 97% according to trajectories. Women who did not receive chemotherapy or a personalized care plan were more likely to belong to trajectories where AET adherence declined and stopped. CONCLUSION: Our results provide information on the diversity of longitudinal AET adherence patterns, the timing of decline and discontinuation and associated factors that could inform healthcare professionals.

Repeat stereotactic radiosurgery for the management of locally recurrent brain metastases.

PURPOSE: Stereotactic radiosurgery (SRS) is a well-established treatment option for brain metastases (BM). Repeat SRS for progressive BM is an increasingly used paradigm, although little data is available to support this practice. The goal of this study was to assess the safety and efficacy of a second SRS procedure on a previously treated BM. METHODS: We performed a retrospective metastasis-level analysis of patients who underwent two SRS procedures on the same lesion and for whom at least 6 months of radiological follow-up was available. The data collected included patient characteristics, clinical symptoms at time of treatment, SRS parameters, radiological response per RANO-BM criteria, clinical evolution and survival. RESULTS: Seventy-five BM in 56 patients were included in the analysis. Most frequent primary histologies were non-small-cell lung cancer (59%) and breast cancer (19%). At the second SRS, median treatment volume was 1.19 cc (range 0.07-20.6) treated with a median margin dose of 18 Gy (range 12-20) at the 50% isodose line (range 30-80%). Median follow-up was 11 months. Progression per RANO-BM criteria occurred in 31%, yielding actuarial local control at 1, 2, and 5 years of 68%, 54% and 54% respectively. At last follow-up, 10 patients (18%) had improved relative to the initial presentation, while 21 (38%) were stable and 25 (44%) were deteriorated. Radiation-induced edema and radionecrosis occurred in 8.3% and 5% respectively. The median survival from the diagnosis of BM was 30 months. CONCLUSION: Repeat SRS is a safe and effective novel therapeutic approach to consider in carefully selected patients.

Diffusion MRI monitoring of specific structures in the irradiated rat brain.

PURPOSE: The analysis of biological and mesoscopic structures properties by diffusion MRI (dMRI) in brain after radiation therapy remains challenging. In our study, we described the consequences associated with an unwanted dose to healthy tissue, assessing radiation-induced brain alterations of living rats with dMRI compared to histopathology and behavioral assays. METHODS: The right primary motor cortex M1 of the rat brain was targeted by stereotactic radiosurgery with a mean radiation dose of 41 Gy. Multidirectional single b-value dMRI data of the whole brain were acquired with a 7T small-animal scanner before irradiation until 110 days post-irradiation. Diffusion tensor imaging metrics, such as fractional anisotropy (FA), mean diffusivity (MD), axial (AD), and radial diffusivity (RD) were compared to brain alterations detected by immunohistochemistry and motor performances measured by a behavioral test. RESULTS: Between days 90 and 110, radiation necrosis was observed into the white matter spreading into M1 . Results showed a reduction of FA in the corpus callosum and in the striatum, which was driven by an increase in RD from 90 to 110 days post-irradiation, whereas only RD increased in M1 . Values of RD and AD increased in the irradiated hippocampus, while FA remained constant. Moreover, an increased MD, AD and RD was observed in the hippocampus that was probably related to inflammation as well as reactive astrogliosis after 110 days post-irradiation. Finally, rats did not exhibit locomotor deficits. CONCLUSIONS: dMRI metrics can assess brain damage; the sensitivity of dMRI metrics depends on the brain region.

Gamma Knife Stereotactic Radiosurgery for Nonvestibular Cranial Nerve Schwannomas.

BACKGROUND: Nonvestibular cranial schwannomas represent a rare type of benign intracranial tumor. Few studies have evaluated the use of stereotactic radiosurgery (SRS) as a primary management option for these lesions. We performed a retrospective review of our institution's experience focusing on efficacy with regard to tumor control and clinical symptom stabilization as well as treatment safety. METHODS: Patients were included if they underwent at least 1 SRS procedure for a nonvestibular schwannoma and had at least 6 months of available imaging follow-up. Demographic, SRS dose planning, clinical, and imaging data were collected from chart reviews of treated patients. χ2 and Kaplan-Meier analyses were performed. RESULTS: Between 2004 and 2016, 35 schwannomas were treated in 34 patients. Median follow-up was 48 months. Median age at time of treatment was 51 years. Three patients had neurofibromatosis 2. Schwannoma location was trigeminal (57%), facial (20%), jugular foramen (14%), abducens (6%), and trochlear (3%). Median margin dose delivered was 13 Gy. The 5-year and 10-year tumor control rates were 94.4% and 88.5%, respectively. Presenting clinical symptoms stabilized or improved in 79% of cases after radiosurgery, and new or worsening symptoms were seen in 21%. CONCLUSIONS: SRS is a safe and effective modality for treatment of nonvestibular cranial nerve schwannomas.

Understanding the continuum of radionecrosis and vascular disorders in the brain following gamma knife irradiation: An MRI study.

PURPOSE: The radiation dose delivered to brain tumors is limited by the possibility to induce vascular damage and necrosis in surrounding healthy tissue. In the present study, we assessed the ability of MRI to monitor the cascade of events occurring in the healthy rat brain after stereotactic radiosurgery, which could be used to optimize the radiation treatment planning. METHODS: The primary somatosensory forelimb area (S1FL) and the primary motor cortex in the right hemisphere of Fischer rats (n = 6) were irradiated with a single dose of Gamma Knife radiation (Leksell Perfexion, Elekta AG, Stockholm, Sweden). Rats were scanned with a small-animal 7 Tesla MRI scanner before treatment and 16, 21, 54, 82, and 110 days following irradiation. At every imaging session, T2 -weighted (T2 w), Gd-DTPA dynamic contrast-enhanced MRI (DCE-MRI), and T2*-weighted ( T2* w) images were acquired to measure changes in fluid content, blood vessel permeability, and structure, respectively. At days 10, 110, and 140, histopathology was performed on brain sections. Locomotion and spatial memory ability were assessed longitudinally by behavioral tests. RESULTS: No vascular changes were initially observed. After 54 days, a small necrotic volume in the white matter below the S1FL, surrounded by an area presenting significant vascular permeability, was revealed. Between 54 and 110 days, the necrotic volume increased and was accompanied by the formation of a ring-like region, where a mixture of necrosis and permeable blood vessels were observed, as confirmed by histology. Behavioral changes were only observed after day 82. CONCLUSION: Together, DCE-MRI and T2* w images supported by histology provided a coherent picture of the phenomena involved in the formation of new, leaky blood vessels, which was followed by the detection of radionecrosis in a preclinical model of brain irradiation. Magn Reson Med 78:1420-1431, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Gamma Knife irradiation method based on dosimetric controls to target small areas in rat brains.

PURPOSE: Targeted and whole-brain irradiation in humans can result in significant side effects causing decreased patient quality of life. To adequately investigate structural and functional alterations after stereotactic radiosurgery, preclinical studies are needed. The purpose of this work is to establish a robust standardized method of targeted irradiation on small regions of the rat brain. METHODS: Euthanized male Fischer rats were imaged in a stereotactic bed, by computed tomography (CT), to estimate positioning variations relative to the bregma skull reference point. Using a rat brain atlas and the stereotactic bregma coordinates obtained from CT images, different regions of the brain were delimited and a treatment plan was generated. A single isocenter treatment plan delivering ≥ 100 Gy in 100% of the target volume was produced by Leksell GammaPlan using the 4 mm diameter collimator of sectors 4, 5, 7, and 8 of the Gamma Knife unit. Impact of positioning deviations of the rat brain on dose deposition was simulated by GammaPlan and validated with dosimetric measurements. RESULTS: The authors' results showed that 90% of the target volume received 100 ± 8 Gy and the maximum of deposited dose was 125 ± 0.7 Gy, which corresponds to an excellent relative standard deviation of 0.6%. This dose deposition calculated with GammaPlan was validated with dosimetric films resulting in a dose-profile agreement within 5%, both in X- and Z-axes. CONCLUSIONS: The authors' results demonstrate the feasibility of standardizing the irradiation procedure of a small volume in the rat brain using a Gamma Knife.

Comparison Between Surgical Resection and Stereotactic Radiosurgery in Patients with a Single Brain Metastasis from Non-Small Cell Lung Cancer.

BACKGROUND: The management of patients with single brain metastasis (BM) from non-small cell lung cancer (NSCLC) is controversial. Surgical resection (SR) with adjuvant irradiation and stereotactic radiosurgery (SRS) are performed in the treatment of such lesions. This study compared both modalities in terms of tumor control and survival. METHODS: During the period 2004-2011, 115 patients with single BM from NSCLC were treated with SR or SRS at our institution. Median patient age was 61 years. SR was performed in 43 patients, and SRS was performed in 72 patients. Most patients who underwent SR had adjuvant irradiation. Of patients, 63% in the SR group and 56% in the SRS group had synchronous presentation of BM and lung primary tumor. Thoracic disease was managed with curative intent in 60% of patients in the SR group compared with 50% of patients in the SRS group. RESULTS: Median follow-up was 10.2 months. Local control was 72% in patients in the SR group and 79% in patients in the SRS group (P = 0.992). Median survival for patients in the SR group was 13.3 months, and median survival for patients in the SRS group was 7.8 months (P = 0.047). Multivariate analyses revealed aggressive treatment of the primary NSCLC as an independent factor associated with prolonged survival in patients undergoing SR. In the SRS group, patients with metachronous metastasis showed a better prognosis. Metachronous presentation was associated with more aggressive management of the primary tumor. CONCLUSIONS: In this study, patients with single BM undergoing SR had a survival advantage. However, because SR and SRS achieved comparable local control of BM, patients receiving SRS should benefit from an equally aggressive treatment of the primary NSCLC, as thoracic management was the most important predictor of survival.

Image-guided, intensity-modulated radiation therapy (IG-IMRT) for skull base chordoma and chondrosarcoma: preliminary outcomes.

BACKGROUND: We report our preliminary outcomes following high-dose image-guided intensity modulated radiotherapy (IG-IMRT) for skull base chordoma and chondrosarcoma. METHODS: Forty-two consecutive IG-IMRT patients, with either skull base chordoma (n = 24) or chondrosarcoma (n = 18) treated between August 2001 and December 2012 were reviewed. The median follow-up was 36 months (range, 3-90 mo) in the chordoma cohort, and 67 months (range, 15-125) in the chondrosarcoma cohort. Initial surgery included biopsy (7% of patients), subtotal resection (57% of patients), and gross total resection (36% of patients). The median IG-IMRT total doses in the chondrosarcoma and chordoma cohorts were 70 Gy and 76 Gy, respectively, delivered with 2 Gy/fraction. RESULTS: For the chordoma and chondrosarcoma cohorts, the 5-year overall survival and local control rates were 85.6% and 65.3%, and 87.8% and 88.1%, respectively. In total, 10 patients progressed locally: 8 were chordoma patients and 2 chondrosarcoma patients. Both chondrosarcoma failures were in higher-grade tumors (grades 2 and 3). None of the 8 patients with grade 1 chondrosarcoma failed, with a median follow-up of 77 months (range, 34-125). There were 8 radiation-induced late effects-the most significant was a radiation-induced secondary malignancy occurring 6.7 years following IG-IMRT. Gross total resection and age were predictors of local control in the chordoma and chondrosarcoma patients, respectively. CONCLUSIONS: We report favorable survival, local control and adverse event rates following high dose IG-IMRT. Further follow-up is needed to confirm long-term efficacy.

Early Gamma Knife stereotactic radiosurgery to the tumor bed of resected brain metastasis for improved local control.

OBJECT: Optimal case management after surgical removal of brain metastasis remains controversial. Although postoperative whole-brain radiation therapy (WBRT) has been shown to prevent local recurrence and decrease deaths, this modality can substantially decrease neurocognitive function and quality of life. Stereotactic radiosurgery (SRS) can theoretically achieve the same level of local control with fewer side effects, although studies conclusively demonstrating such outcomes are lacking. To assess the effectiveness and safety profile of tumor bed SRS after resection of brain metastasis, the authors performed a retrospective analysis of 110 patients who had received such treatment at the Centre Hospitalier Universitaire de Sherbrooke. They designed the study to identify risk factors for local recurrence and placed special emphasis on factors that could potentially be addressed. METHODS: Patients who had received treatment from 2004 through 2013 were included if they had undergone surgical removal of 1 or more brain metastases and if the tumor bed was treated by SRS regardless of the extent of resection or prior WBRT. All cases were retrospectively analyzed for patient and tumor-specific factors, treatment protocol, adverse outcomes, cavity outcomes, and survival for as long as follow-up was available. Univariate and multivariate Cox regression analyses were performed to identify risk factors for local recurrence and predictors of increased survival times. RESULTS: Median patient age at first SRS treatment was 58 years (range 37-84 years). The most frequently diagnosed primary tumor was non-small cell lung cancer. The rate of gross-total resection was 81%. The median Karnofsky Performance Scale score was 90%. Tumor bed SRS was performed at a median of 3 weeks after surgery. Median follow-up and survival times were 10 and 11 months, respectively. Actuarial local control of the cavity at 12 months was 73%; median time to recurrence was 6 months. According to multivariate analysis, risk factors for recurrence were a longer surgery-to-SRS delay (HR 1.625, p = 0.003) and a lower maximum radiation dose delivered to the cavity (HR 0.817, p = 0.006). Factors not associated with increased recurrence were subtotal or piecemeal resections, prior WBRT, histology of the primary tumor, and larger cavity volume. No factors predictive of survival were identified. Symptomatic radiation-induced enhancement occurred in 6% of patients and leptomeningeal dissemination in 11%. Pathologically confirmed radiation-induced necrosis occurred in 1 (0.9%) patient. CONCLUSIONS: Adjuvant tumor bed SRS after the resection of brain metastasis is a valuable alternative to adjuvant WBRT. Risk factors for local recurrence are lower maximum radiation dose and a surgery-to-SRS delay longer than 3 weeks. Outcomes were not worse for patients who had undergone prior WBRT and subtotal or piecemeal resections. Pending the results of prospective randomized controlled trials, the authors' study supports the safety and efficacy of adjuvant SRS after resection of brain metastasis. SRS should be performed as early as possible, ideally within 3 weeks of the surgery.