Elana Farace

Effect of Radiosurgery Alone vs Radiosurgery With Whole Brain Radiation Therapy on Cognitive Function in Patients With 1 to 3 Brain Metastases: A Randomized Clinical Trial

IMPORTANCE Whole brain radiotherapy (WBRT) significantly improves tumor control in the brain after stereotactic radiosurgery (SRS), yet because of its association with cognitive decline, its role in the treatment of patients with brain metastases remains controversial. OBJECTIVE To determine whether there is less cognitive deterioration at 3 months after SRS alone vs SRS plus WBRT. DESIGN, SETTING, AND PARTICIPANTS At 34 institutions in North America, patients with 1 to 3 brain metastases were randomized to receive SRS or SRS plus WBRT between February 2002 and December 2013. INTERVENTIONS The WBRT dose schedule was 30 Gy in 12 fractions; the SRS dose was 18 to 22 Gy in the SRS plus WBRT group and 20 to 24 Gy for SRS alone. MAIN OUTCOMES AND MEASURES The primary end point was cognitive deterioration (decline >1 SD from baseline on at least 1 cognitive test at 3 months) in participants who completed the baseline and 3-month assessments. Secondary end points included time to intracranial failure, quality of life, functional independence, long-term cognitive status, and overall survival. RESULTS There were 213 randomized participants (SRS alone, n = 111; SRS plus WBRT, n = 102) with a mean age of 60.6 years (SD, 10.5 years); 103 (48%) were women. There was less cognitive deterioration at 3 months after SRS alone (40/63 patients [63.5%]) than when combined with WBRT (44/48 patients [91.7%]; difference, -28.2%; 90% CI, -41.9% to -14.4%; P < .001). Quality of life was higher at 3 months with SRS alone, including overall quality of life (mean change from baseline, -0.1 vs -12.0 points; mean difference, 11.9; 95% CI, 4.8-19.0 points; P = .001). Time to intracranial failure was significantly shorter for SRS alone compared with SRS plus WBRT (hazard ratio, 3.6; 95% CI, 2.2-5.9; P < .001). There was no significant difference in functional independence at 3 months between the treatment groups (mean change from baseline, -1.5 points for SRS alone vs -4.2 points for SRS plus WBRT; mean difference, 2.7 points; 95% CI, -2.0 to 7.4 points; P = .26). Median overall survival was 10.4 months for SRS alone and 7.4 months for SRS plus WBRT (hazard ratio, 1.02; 95% CI, 0.75-1.38; P = .92). For long-term survivors, the incidence of cognitive deterioration was less after SRS alone at 3 months (5/11 [45.5%] vs 16/17 [94.1%]; difference, -48.7%; 95% CI, -87.6% to -9.7%; P = .007) and at 12 months (6/10 [60%] vs 17/18 [94.4%]; difference, -34.4%; 95% CI, -74.4% to 5.5%; P = .04). CONCLUSIONS AND RELEVANCE Among patients with 1 to 3 brain metastases, the use of SRS alone, compared with SRS combined with WBRT, resulted in less cognitive deterioration at 3 months. In the absence of a difference in overall survival, these findings suggest that for patients with 1 to 3 brain metastases amenable to radiosurgery, SRS alone may be a preferred strategy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00377156.

Depression in patients with high-grade glioma: results of the Glioma Outcomes Project.

OBJECTIVETo study the incidence of depression among patients undergoing surgery for high-grade glioma, document factors associated with the presence of depression, and examine the relationship between depression and patient outcome. METHODSPhysician and patient reports of depression were analyzed immediately postoperatively and again 3 and 6 months after surgery for high-grade glioma. Physician-reported depression was defined according to the Diagnostic and Statistical Manual of Mental Disorders, ed 4. Patient self-assessment of depression was based on responses to questions contained in two validated functional status surveys. Concordance of physician- and patient-reported depression was examined, along with the extent of use of pharmacological treatment for depression. Additional outcomes examined included quality of life, survival, patient satisfaction, and posttreatment complications. RESULTSData from 598 patients were analyzed. In the early postoperative period, physicians reported depression in 15% of patients, whereas 93% of patients reported symptoms consistent with depression. The incidence of patient self-reported depression remained similar at 3- and 6-month follow-up, whereas physician reported depression increased from 15% in the early postoperative period to 22% at both 3- and 6-month follow-up. Concordance between physician recognition of depression and treatment of depression was low initially (33%) and increased at 3 and 6 months (51 and 60%, respectively). As compared with patients who were not depressed, survival was shorter and complications were more common among depressed patients. CONCLUSIONSymptoms of depression were common immediately after surgery for glioma, and they increased throughout the 6-month period after surgery. These findings support the hypothesis that clinically important depression is a common complication in patients with high-grade glioma. Concordance between physician recognition of depression and self-reports of depression by patients was low. Concordance between physician recognition of depression and initiation of pharmacological antidepressant therapy was fair in the early postoperative period and improved somewhat over the subsequent 6-month period; however, within the 6-month period after surgery for glioma, antidepressant therapy was provided for only 60% of patients in whom the physician recognized depressive symptoms and in only 15% of patients who self-reported symptoms of depression. Findings from this observational study suggest the need for a controlled trial that is designed to test the hypothesis that more attention to the identification of postoperative depression and aggressive treatment of depressive symptoms can improve the quality of life and survival of patients after surgery for high-grade glioma.

Caring for the brain tumor patient: Family caregiver burden and unmet needs

The rapid onset and progression of a brain tumor, cognitive and behavioral changes, and uncertainty surrounding prognosis are issues well known to health practitioners in neuro-oncology. We studied the specific challenges that family caregivers face when caring for patients experiencing the significant neurocognitive and neurobehavioral disorders associated with brain tumors. We selected 25 family caregivers of adult brain tumor patients to represent the brain tumor illness trajectory (crisis, chronic, and terminal phases). Interviews documented caregiving tasks and decision-making and information and support needs. Themes were permitted to emerge from the data in qualitative analysis. We found that the family caregivers in this study provided extraordinary uncompensated care involving significant amounts of time and energy for months or years and requiring the performance of tasks that were often physically, emotionally, socially, or financially demanding. They were constantly challenged to solve problems and make decisions as care needs changed, yet they felt untrained and unprepared as they struggled to adjust to new roles and responsibilities. Because the focus was on the patient, their own needs were neglected. Because caregiver information needs are emergent, they are not always known at the time of a clinic visit. Physicians are frequently unable to address caregiver questions, a situation compounded by time constraints and cultural barriers. We provide specific recommendations for (1) improving the delivery of information; (2) enhancing communication among patients, families, and health care providers; and (3) providing psychosocial support for family caregivers.

Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial

BACKGROUND Whole brain radiotherapy (WBRT) is the standard of care to improve intracranial control following resection of brain metastasis. However, stereotactic radiosurgery (SRS) to the surgical cavity is widely used in an attempt to reduce cognitive toxicity, despite the absence of high-level comparative data substantiating efficacy in the postoperative setting. We aimed to establish the effect of SRS on survival and cognitive outcomes compared with WBRT in patients with resected brain metastasis. METHODS In this randomised, controlled, phase 3 trial, adult patients (aged 18 years or older) from 48 institutions in the USA and Canada with one resected brain metastasis and a resection cavity less than 5·0 cm in maximal extent were randomly assigned (1:1) to either postoperative SRS (12-20 Gy single fraction with dose determined by surgical cavity volume) or WBRT (30 Gy in ten daily fractions or 37·5 Gy in 15 daily fractions of 2·5 Gy; fractionation schedule predetermined for all patients at treating centre). We randomised patients using a dynamic allocation strategy with stratification factors of age, duration of extracranial disease control, number of brain metastases, histology, maximal resection cavity diameter, and treatment centre. Patients and investigators were not masked to treatment allocation. The co-primary endpoints were cognitive-deterioration-free survival and overall survival, and analyses were done by intention to treat. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT01372774. FINDINGS Between Nov 10, 2011, and Nov 16, 2015, 194 patients were enrolled and randomly assigned to SRS (98 patients) or WBRT (96 patients). Median follow-up was 11·1 months (IQR 5·1-18·0). Cognitive-deterioration-free survival was longer in patients assigned to SRS (median 3·7 months [95% CI 3·45-5·06], 93 events) than in patients assigned to WBRT (median 3·0 months [2·86-3·25], 93 events; hazard ratio [HR] 0·47 [95% CI 0·35-0·63]; p<0·0001), and cognitive deterioration at 6 months was less frequent in patients who received SRS than those who received WBRT (28 [52%] of 54 evaluable patients assigned to SRS vs 41 [85%] of 48 evaluable patients assigned to WBRT; difference -33·6% [95% CI -45·3 to -21·8], p<0·00031). Median overall survival was 12·2 months (95% CI 9·7-16·0, 69 deaths) for SRS and 11·6 months (9·9-18·0, 67 deaths) for WBRT (HR 1·07 [95% CI 0·76-1·50]; p=0·70). The most common grade 3 or 4 adverse events reported with a relative frequency greater than 4% were hearing impairment (three [3%] of 93 patients in the SRS group vs eight [9%] of 92 patients in the WBRT group) and cognitive disturbance (three [3%] vs five [5%]). There were no treatment-related deaths. INTERPRETATION Decline in cognitive function was more frequent with WBRT than with SRS and there was no difference in overall survival between the treatment groups. After resection of a brain metastasis, SRS radiosurgery should be considered one of the standards of care as a less toxic alternative to WBRT for this patient population. FUNDING National Cancer Institute.

NCCTG N0574 (Alliance): A phase III randomized trial of whole brain radiation therapy (WBRT) in addition to radiosurgery (SRS) in patients with 1 to 3 brain metastases.

LBA4 Background: WBRT significantly improves tumor control in the brain after SRS, yet the role of adjuvant WBRT remains undefined due to concerns regarding neurocognitive risks. METHODS Patients with 1-3 brain metastases, each < 3 cm by contrast MRI, were randomized to SRS alone or SRS + WBRT and underwent cognitive testing before and after treatment. The primary endpoint was cognitive progression (CP) defined as decline > 1 SD from baseline in any of the 6 cognitive tests at 3 months. Time to CP was estimated using cumulative incidence adjusting for survival as a competing risk. RESULTS 213 patients were enrolled with 2 ineligible and 3 cancels prior to receiving treatment. Baseline characteristics were well-balanced between study arms. The median age was 60 and lung primary the most common (68%). CP at 3 months was more frequent after WBRT + SRS vs. SRS alone (88.0% vs. 61.9% respectively, p = 0.002). There was more deterioration in the WBRT + SRS arm in immediate recall (31% vs. 8%, p = 0.007), delayed recall (51% vs. 20%, p = 0.002), and verbal fluency (19% vs. 2%, p = 0.02). Intracranial tumor control at 6 and 12 months were 66.1% and 50.5% with SRS alone vs. 88.3% and 84.9% with SRS+WBRT (p < 0.001). Median OS was 10.7 for SRS alone vs. 7.5 months for SRS+WBRT respectively (HR = 1.02, p = 0.93). CONCLUSIONS Decline in cognitive function, specifically immediate recall, memory and verbal fluency, was more frequent with the addition of WBRT to SRS. Adjuvant WBRT did not improve OS despite better brain control. Initial treatment with SRS and close monitoring is recommended to better preserve cognitive function in patients with newly diagnosed brain metastases that are amenable to SRS. CLINICAL TRIAL INFORMATION NCT00377156.

Molality as a unit of measure for expressing 1H MRS brain metabolite concentrations in vivo

Absolute concentrations of cerebral metabolite in in vivo 1H magnetic resonance spectroscopy studies (1H-MRS) are widely reported in molar units as moles per liter of tissue, or in molal units as moles per kilogram of tissue. Such measurements require external referencing or assumptions as to local water content. To reduce the scan time, avoid assumptions that may be invalid under specific pathologies, and provide a universally accessible referencing procedure, we suggest that metabolite concentrations from 1H-MRS measurements in vivo be reported in molal units as moles per kilogram of tissue water. Using internal water referencing, a two-compartment water model, a simulated brain spectrum for peak identification, and a spectroscopic bi-exponential spin-spin relaxation segmentation technique, we measured the absolute concentrations for the four common 1H brain metabolites: choline (Cho), myo-inositol (mIno), phosphocreatine + creatine (Cr), and N-acetyl-aspartate (NAA), in the hippocampal region (n = 26) and along the Sylvian fissure (n = 61) of 35 healthy adults. A stimulated echo localization method (20 ms echo time, 10 ms mixing time, 4 s repetition time) yielded metabolite concentrations, uncorrected for metabolite relaxation or contributions from macromolecule resonances, that were expectantly higher than with molar literature values. Along the Sylvian fissure the average concentrations (coefficient of variation (CV)) in mmoles/kg of tissue water were 17.6 (12%) for NAA, 14.2 (9%) for Cr, 3.6 (13%) for Cho, and 13.2 (15%) for mIno. Respective values for the hippocampal region were 15.7 (20%), 14.7 (16%), 4.6 (19%), and 17.7 (26%). The concentrations of the two regions were significantly different (p </= 0.001) for NAA, mIno, and Cho, a trend in agreement with previous studies. All gray matter Sylvian fissure CV values, except for NAA, were also in agreement with previous 1H-MRS gray matter studies. The reduced precision of the NAA concentration was attributed to overlapping signal contributions from glutamate and glutamine (Glx), suggesting that a detailed Glx model is critical for accurate quantitation of the NAA 2.02 ppm resonance. The reduced precision of the measurements in the hippocampal region was attributed to poor spectral resolution.

Quality of life outcome is associated with cessation rather than reduction of psychogenic nonepileptic seizures

The outcome of psychogenic nonepileptic seizures (NES) is usually judged by recurrence of spells, but functional outcome or quality of life (QOL) is less well described. We tested the hypothesis that a decrease in NES recurrence yields corresponding improvement in QOL. Patients with NES were diagnosed with continuous video-EEG. We determined spell rate and QOL through a telephone interview at least six months after diagnosis. Thirty subjects consented to a follow-up interview (mean 17.4+/-1.5 months between diagnosis and interview). The rate of NES per week decreased significantly, and 10/30 (33%) had complete resolution. QOL, measured by the QOLIE-10 scale, did not improve proportionately with reduction in NES. However, subjects who reported a cessation of NES noted a significantly better total QOLIE-10 score (20.7+/-2.2) than those with continuing NES (27.4+/-1.6, P=0.02 by unpaired t test). Cessation rather than reduction of NES is associated with better QOL outcome.

A multicenter multinational registry for assessing ventriculoperitoneal shunt infections for hydrocephalus.

BACKGROUND:Reported infection rates after ventriculoperitoneal shunt surgery vary from 1 to 25%. Antibiotic-impregnated (AI) catheters may reduce shunt infection rates, but this is uncertain. OBJECTIVE:To establish a prospective shunt registry to evaluate short-term (3-month) infection rates associated with ventriculoperitoneal shunts and standard or AI catheters during surgical treatment of hydrocephalus. METHODS:A prospective, multicenter, noncontrolled, open-label registry investigated patients with de novo catheter implantation or catheter replacement of an existing ventriculoperitoneal shunt. The primary outcome was shunt infection. RESULTS:A total of 440 patients were entered into the registry at 10 sites: 3 in North America, 2 in Singapore, 4 in China and 1 in India. Seven patients were excluded. Of the 433 remaining patients, 314 had new shunts and 119 were revisions. Shunt infections occurred in 14 of 433 patients (3.2%) overall and in 2 of 37 infants (5.2%) younger than 1 year. AI catheters were used in 46 of 433 patients at 7 centers. The shunt infection rate was 0 of 46 for shunts with AI catheters and 14 of 387 (3.6%) without AI catheters. Infection rates were similar with AI catheters, adjusting for age and catheter type. CONCLUSION:The overall shunt infection rate was lower than in previous multicentered studies. The low infection rate and low rate of AI catheter use precludes any meaningful statement regarding the value of AI catheters in reducing the infection rate. Consideration should be given to performing a well designed, adequately powered, prospective randomized controlled trial to determine whether AI catheters reduce shunt infection rates.

Transsphenoidal surgery for pituitary adenoma in elderly patients

SummaryBackground. As the population continues to age, the number of elderly patients with symptomatic pituitary tumours will continue to increase. Little information exists as to the safety of pituitary surgery in this patient population. The current study was undertaken to evaluate the presentation and perioperative risk associated with transsphenoidal surgery in patients over the age of 70. Methods. A retrospective chart review was undertaken for patients over the age of 70 undergoing transsphenoidal surgery at the Penn State Hershey Medical Center between 1995 and 2005. Findings. Sixty-four patients over the age of 70 were identified with an average age of 73.4 years (range 70–84). The average follow-up period was 44 months (range 14–104). Symptoms of mass effect were the presenting complaint in 72% of patients while 9% had documentation of growth on imaging studies. Twelve percent presented with a history consistent with apoplexy. Three patients (5%) presented with acromegaly. Post-operative hospital stay averaged 2.6 days (range 2–7). Eight patients had new hormonal deficits post-operatively (1 ACTH, 3 TSH, 2 ACTH/TSH, 2 vasopressin). There were no cardiopulmonary complications and no deaths within 90 days of surgery. Conclusions. Transsphenoidal surgery can be performed in patients over the age of 70 without undo significant risks. Surgical removal of pituitary adenomas should be considered the mainstay of treatment in elderly patients in whom treatment is necessary. Patients who are medically suitable candidates should be offered surgical resection as would their younger counterparts.

A reanalysis of gender differences in IQ scores following unilateral brain lesions

Meta-analyses of gender differences in the consequences of unilateral brain lesions have reported a positive correlation between the percentage of men in studies and the magnitude of the difference between Verbal and Performance IQ. Such findings are limited by both the indirectness of the methodology and the focus on V-P differences rather than on the separate effects of brain lesions on VIQ and PIQ. We conducted a repeated-measures analysis of studies that reported separate VIQ and PIQ means for men and women with unilateral lesions. Women showed lower IQ scores following lesions to the hemisphere thought to be nondominant for each function. Gender differences in the effects of unilateral brain lesions on intellectual performance have been observed for more than 25 years (Lansdell, 1962). Male patients appear to experience greater lateralized intellectual deficits following unilateral lesions, as measured by greater discrepancies between Verbal and Performance IQ scores. Such a gender difference is potentially important because of its implications for fundamental questions of functional brain organization in men and women, and because differences between VIQ and PIQ have been used as psychometric signs of lateralized brain damage (e.g., Lawson & Inglis, 1983). This gender difference has received renewed attention since Inglis and Lawson (1981,1982) reported a correlation of 0.48 between Verbal-Performance (V-P) discrepancy and the percentage of men included in 18 samples from 16 different studies. Inglis and Lawsons meta-analysis was replicated, using additional samples, by Bornstein and Matarazzo (1982), Bornstein (1984), and Snow, Freedman, and Ford (1986). The unusual meta-analytic methodology of correlating V-P discrepancies with the percentage of male subjects in each study was necessitated by the paucity of studies reporting Verbal and Performance IQs separately for male and female subjects. More recently, Kaufman (1990) identified a sample of eight studies that reported V-P discrepancies separately for male and female subjects. In patients with right hemisphere lesions, V-P differences were twice as large in male as in female subjects. In male patients with left hemisphere lesions, mean PIQ was higher than the mean VIQ, whereas in female patients with left hemisphere lesions the mean PIQ was slightly higher. We believe another brief examination of this literature is warranted. There are now 12 studies that have reported eight separate means for Verbal and Performance IQ in male and female patients with left and right hemisphere lesions. Analysis of these studies will allow gender differences to be studied with greater precision than was possible with the useful but indirect