Capacity of patients with brain metastases to make treatment decisions.

OBJECTIVE: The aim of this study was to investigate medical decision-making capacity (MDC) in patients with brain metastases. METHODS: Participants were 41 adults with brain metastases with Karnofsky Performance Status scores of ≥70 who were recruited from an academic medical center and 41 demographically matched controls recruited from the community. We evaluated MDC using the Capacity to Consent to Treatment Instrument and its four clinically relevant consent standards (expressing a treatment choice, appreciation, reasoning, and understanding). Capacity impairment ratings (no impairment, mild/moderate impairment, and severe impairment) on the consent standards were also assigned to each participant with brain metastasis using cutoff scores derived statistically from the performance of the control group. RESULTS: The brain metastasis patient group performed significantly below controls on consent standards of understanding and reasoning. Capacity compromise was defined as performance ≤1.5 standard deviations below the control group mean. Using this definition, approximately 60% of the participants with brain metastases demonstrated capacity compromise on at least one MDC standard. CONCLUSION: When defining capacity compromise as performance ≤1.5 standard deviation below the control group mean, over half of patients with brain metastases have reduced capacity to make treatment decisions. This impairment is demonstrated shortly after initial diagnosis of brain metastases and highlights the importance of routine clinical assessment of MDC following diagnosis of brain metastasis. These results also indicate a need for the development and investigation of interventions to support or improve MDC in this patient population.

Cognition in patients with newly diagnosed brain metastasis: profiles and implications.

Cognitive impairment is a common symptom in patients with brain metastasis, and significant cognitive dysfunction is prevalent in a majority of patients who are still able to engage in basic self-care activities. In the current study, the neurocognitive performance of 32 patients with brain metastasis and 32 demographically-matched controls was examined using a battery of standardized neuropsychological tests, with the goal of comprehensively examining the cognitive functioning of newly diagnosed brain metastasis patients. The cognition of all patients was assessed within 1 week of beginning treatment for brain metastasis. Results indicated impairments in verbal memory, attention, executive functioning, and language in relation to healthy controls. Performance in relation to appropriate normative groups was also examined. Overall, cognitive deficits were prevalent and memory was the most common impairment. Given that cognitive dysfunction was present in this cohort of patients with largely minimal functional impairment, these results have implications for patients, caregivers and health care providers treating patients with brain metastasis.

A prospective study of cognitive function in men with non-seminomatous germ cell tumors.

OBJECTIVE: Longitudinal neuropsychological assessments were performed to determine if adjuvant chemotherapy was associated with cognitive dysfunction in men with non-seminomatous germ cell tumors (NSGCT). METHODS: Patients with NSGCT status post-orchiectomy that either received adjuvant chemotherapy (n = 55) or did not (n = 14) were recruited. Patients were tested before chemotherapy, 1 week post-chemotherapy (or 3 months later in the surveillance group) and 12 months after the baseline evaluation. RESULTS: Compared with the surveillance group, patients treated with chemotherapy had higher rates of cognitive decline at 12 months (overall cognitive decline: 0%, 52%, and 67% in the surveillance, low exposure (LE), and high exposure (HE) group, respectively), greater number of tests that declined (mean of 0.1, 1.4, and 2.0 in the surveillance, LE, and HE group, respectively), and more frequent worsening in motor dexterity (0%, 48%, and 46% in the surveillance, LE, and HE group, respectively). Compared with the surveillance group, patients receiving more cycles of chemotherapy demonstrated worse psychomotor speed and learning and memory. Younger age was associated with greater incidence of overall cognitive decline at 12-month follow-up. CONCLUSIONS: Men with NSGCT that received chemotherapy demonstrated greater rates of cognitive decline in a dose-response manner. Reductions in motor dexterity were most common. Decline in learning and memory also was evident particularly at later follow-up time points and in men receiving more chemotherapy. Men that receive chemotherapy for NSGCT are at risk for cognitive decline and may benefit from monitoring and referral for psychosocial care.

Preservation of neurocognitive function and local control of 1 to 3 brain metastases treated with surgery and carmustine wafers.

BACKGROUND: Neurosurgical resection and whole-brain radiation therapy (WBRT) are accepted treatments for single and oligometastatic cancer to the brain. To avoid the decline in neurocognitive function (NCF) linked to WBRT, the authors conducted a prospective, multicenter, phase 2 study to determine whether surgery and carmustine wafers (CW), while deferring WBRT, could preserve NCF and achieve local control (LC). METHODS: NCF and LC were measured in 59 patients who underwent resection and received CW for a single (83%) or dominant (oligometastatic, 2 to 3 lesions) metastasis and received stereotactic radiosurgery (SRS) for tiny nodules not treated with resection plus CW. Preservation of NCF was defined as an improvement or a decline ≤ 1 standard deviation from baseline in 3 domains: memory, executive function, and fine motor skills, evaluated at 2-month intervals. RESULTS: Significant improvements in executive function and memory occurred throughout the 1-year follow-up. Preservation or improvement of NCF occurred in all 3 domains for the majority of patients at each of the 2-month intervals. NCF declined in only 1 patient. The chemowafers were well tolerated, and serious adverse events were reversible. There was local recurrence in 28% of the patients at 1-year follow-up. CONCLUSIONS: Patients with brain metastases had improvements in their cognitive trajectory, especially memory and executive function, after treatment with resection plus CW. The rate of LC (78%) was comparable to historic rates of surgery with WBRT and superior to reports of WBRT alone. For patients who undergo resection for symptomatic or large-volume metastasis or for tissue diagnosis, the addition of CW can be considered as an option.

Decline in tested and self-reported cognitive functioning after prophylactic cranial irradiation for lung cancer: pooled secondary analysis of Radiation Therapy Oncology Group randomized trials 0212 and 0214.

PURPOSE: To assess the impact of prophylactic cranial irradiation (PCI) on self-reported cognitive functioning (SRCF), a functional scale on the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30). METHODS AND MATERIALS: Radiation Therapy Oncology Group (RTOG) protocol 0214 randomized patients with locally advanced non-small cell lung cancer to PCI or observation; RTOG 0212 randomized patients with limited-disease small cell lung cancer to high- or standard-dose PCI. In both trials, Hopkins Verbal Learning Test (HVLT)-Recall and -Delayed Recall and SRCF were assessed at baseline (after locoregional therapy but before PCI or observation) and at 6 and 12 months. Patients developing brain relapse before follow-up evaluation were excluded. Decline was defined using the reliable change index method and correlated with receipt of PCI versus observation using logistic regression modeling. Fisher's exact test correlated decline in SRCF with HVLT decline. RESULTS: Of the eligible patients pooled from RTOG 0212 and RTOG 0214, 410 (93%) receiving PCI and 173 (96%) undergoing observation completed baseline HVLT or EORTC QLQ-C30 testing and were included in this analysis. Prophylactic cranial irradiation was associated with a higher risk of decline in SRCF at 6 months (odds ratio 3.60, 95% confidence interval 2.34-6.37, P<.0001) and 12 months (odds ratio 3.44, 95% confidence interval 1.84-6.44, P<.0001). Decline on HVLT-Recall at 6 and 12 months was also associated with PCI (P=.002 and P=.002, respectively) but was not closely correlated with decline in SRCF at the same time points (P=.05 and P=.86, respectively). CONCLUSIONS: In lung cancer patients who do not develop brain relapse, PCI is associated with decline in HVLT-tested and self-reported cognitive functioning. Decline in HVLT and decline in SRCF are not closely correlated, suggesting that they may represent distinct elements of the cognitive spectrum.

Phase I study of GRN1005 in recurrent malignant glioma.

PURPOSE: GRN1005 is a peptide-drug conjugate with the ability to penetrate the blood-brain barrier (BBB) and tumor cells by targeting the low-density lipoprotein receptor-related protein-1. We conducted a first-in-human phase I trial of GRN1005 in patients with recurrent glioma. METHODS: Patients received GRN1005 by intravenous infusion every 3 weeks. Doses were escalated using a modified Fibonacci scheme. Study objectives included safety, tolerability, identification of the maximum tolerated dose (MTD), pharmacokinetics, and preliminary evidence of efficacy. Tumor extracted from patients undergoing surgery following administration of GRN1005 was analyzed to determine whether therapeutic concentrations of GRN1005 were achieved. RESULTS: Sixty-three patients received GRN1005 at doses of 30 to 700 mg/m(2) every 3 weeks. Therapy was well tolerated with neutropenia, leucopenia, and fatigue as the most frequent drug-associated grade 3/4 or higher toxicities. The MTD was 650 mg/m(2) every 3 weeks. Dose-limiting toxicities were grade 3 mucositis and grade 4 neutropenia. There was no evidence of central nervous system toxicity or antibody production. Pharmacokinetic analysis showed that exposure to GRN1005 was dose proportional. We observed one complete and two partial responses. Eight of 27 patients dosed ≥ 420 mg/m(2) had stable disease, which lasted a median of 51 days. Therapeutic concentrations of GRN1005 and free paclitaxel were shown in tumor tissue of surgical patients dosed with ≥ 200 mg/m(2). CONCLUSION: GRN1005 delivers paclitaxel across the BBB and achieves therapeutic concentrations in tumor tissue. It has similar toxicity to paclitaxel and appears to have activity in recurrent glioma. The recommended phase II dose is 650 mg/m(2) every 3 weeks.

A phase I study to determine the safety and pharmacokinetics of intravenous administration of TAS-106 once per week for three consecutive weeks every 28 days in patients with solid tumors.

BACKGROUND: The nucleoside 3'-c-ethynylcytidine (TAS-106) was designed to inhibit RNA synthesis which occurs throughout the cell cycle except for the M phase. TAS-106 is incorporated into cells, is rapidly phosphorylated to a monophosphate form, and is preferentially distributed into malignant cells. Preclinical studies showed that TAS-106 has a wide antitumor spectrum against human cancer xenografts. This phase I study was conducted in order to determine the recommended phase II dose of TAS-106 administered once per week for three consecutive weeks, every 28 days in patients with solid tumors. PATIENTS AND METHODS: Patients were enrolled in cohorts of three, starting at 0.22 mg/m(2)/dose. Patients received at least two doses in order to be evaluable in each dose cohort. Dose escalation was stopped if two or more patients experienced dose limiting toxicity at any dose level. RESULTS: In 20 evaluable patients, TAS-106 was given at the following dose levels (mg/m(2)/dose): 0.22 (3 pts), 0.33 (3 pts), 0.66 (3 pts), 0.99 (1 pt), 1.32 (3 pts), 2.64 (3 pts) and 3.96 (1 pt). Three additional patients were evaluated at 2.64 mg/m(2)/dose for further characterization of toxicity and safety. A total of 16 patients completed courses 1 and 2. All 21 patients enrolled experienced at least one adverse event. The AE attributed to the study drug was grade 2 peripheral neuropathy characterized by peripheral sensory neuropathy, numbness, tremor, pain, and hyperesthesia involving the fingers, hands, toes, and feet. CONCLUSION: Due to neurotoxicity the MTD was the 2.64 mg/m(2)/dose for the study schedule. No suggested phase II dose was determined. However, at the 1.32 mg/m(2)/dose level, no patients experienced DLTs during course 1 or 2. This could be further studied to determine its viability as a potential phase II dosage.

Early measures of cognitive function predict survival in patients with newly diagnosed glioblastoma.

Cognitive dysfunction is a common manifestation of primary brain tumors. We evaluated the association between early cognitive dysfunction and prognosis in a cohort of patients with newly diagnosed glioblastoma. Ninety-one patients who completed neuropsychological assessment after tumor resection but before further treatment were identified in the MD Anderson Neuropsychology database. The relationship between performance on cognitive testing and survival was evaluated using not only Cox proportional hazards models that included clinical factors such as age and KPS but also the Kaplan-Meier method. Median survival time from surgery was 20.7 months. Rates of impairment on cognitive testing ranged from 7.1% for Similarities, to 60.0% for Hopkins Verbal Learning Test-Revised Total Recall. As continuous variables, the Clinical Trial Battery Composite, Trail Making Test Part B, and Controlled Oral Word Association test were associated with survival. Impairment on the Trail Making Test Part B, Controlled Oral Word Association, Similarities, and Digit Span were associated with mortality. Kaplan-Meier analysis demonstrated the survival impact of these tests on the group as a whole and in select patient subgroups defined by classification by the Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA). Cognitive impairment as measured by specific neuropsychological tests is independently associated with poor prognosis in patients with newly diagnosed glioblastoma, and this effect remains significant even within patient subgroups defined by RTOG RPA class. Executive function and attention are the cognitive domains most closely associated with prognosis in this analysis.

Refining endpoints in brain tumor clinical trials.

As targeted therapies advance treatment for brain tumors, standard clinical trial endpoints of survival, progression free survival and radiographic response have become insufficient to capture clinical benefit. Brain cancer is a malignancy with neurodegenerative features. In this setting prolongation of life and/or radiographic stability are less clinically meaningful if neurocognitive function substantially declines. Hence evaluation of new therapeutic strategies should routinely include periodic assessment of neurocognitive function.

Phase I and pharmacokinetic study of 3'-C-ethynylcytidine (TAS-106), an inhibitor of RNA polymerase I, II and III,in patients with advanced solid malignancies.

BACKGROUND: TAS-106 is a novel nucleoside analog that inhibits RNA polymerases I, II and II and has demonstrated robust antitumor activity in a wide range of models of human cancer in preclinical studies. This study was performed to principally evaluate the feasibility of administering TAS-106 as a bolus intravenous (IV) infusion every 3 weeks. PATIENTS AND METHODS: Patients with advanced solid malignancies were treated with escalating doses of TAS-106 as a single bolus IV infusion every 3 weeks. Plasma and urine sampling were performed during the first course to characterize the pharmacokinetic profile of TAS-106 and assess pharmacodynamic relationships. RESULTS: Thirty patients were treated with 66 courses of TAS-106 at eight dose levels ranging from 0.67-9.46 mg/m(2). A cumulative sensory peripheral neuropathy was the principal dose-limiting toxicity (DLT) of TAS-106 at the 6.31 mg/m(2) dose level, which was determined to be the maximum tolerated dose (MTD). Other mild-moderate drug-related toxicities include asthenia, anorexia, nausea, vomiting, myelosuppression, and dermatologic effects. Major objective antitumor responses were not observed. The pharmacokinetics of TAS-106 were dose-proportional. The terminal elimination half-life (t(1/2)) averaged 11.3 ± 3.3 h. Approximately 71% of TAS-106 was excreted in the urine as unchanged drug. Pharmacodynamic relationships were observed between neuropathy and: C(5min;) AUC(0-inf;) and dermatologic toxicity. CONCLUSIONS: The recommended phase II dose of TAS-106 is 4.21 mg/m(2). However, due to a cumulative drug-related peripheral sensory neuropathy that proved to be dose-limiting, further evaluation of this bolus every 21 day infusion schedule will not be pursued and instead, an alternate dosing schedule of TAS-106 administered as a continuous 24-hour infusion will be explored to decrease C(max) in efforts to minimize peripheral neuropathy and maximize antitumor activity.

Neurocognitive function before and after surgery for insular gliomas.

OBJECT: Insular gliomas can be resected with acceptable rates of neurological morbidity, but little is known with regard to impairment of higher-order neurocognitive functions. The frequency and functional impact of neurocognitive deficits in patients with gliomas has until recently been underappreciated. The authors therefore examined neurocognitive function in patients with insular gliomas and compared the findings in this group to those in a matched control group of patients with gliomas in nearby brain regions. METHODS: Thirty-three patients with WHO Grade II or III insular gliomas participated in neuropsychological evaluations before and after resection. To establish whether the pattern of neurocognitive performance was different from that of other patients with tumors in neighboring areas, patients with insular tumors were matched with control patients for age, educational level, preoperative Karnofsky Performance Scale score, tumor side, grade, and volume. The control group comprised patients in whom gliomas had been resected from frontal, temporal, and parietal areas near the insula. Baseline pre- and postoperative neurocognitive test results were compared between and within groups. RESULTS: Preoperative neurocognitive impairment was common in both insular and control groups. Patients with insular tumors had significantly worse preoperative performance on naming tests. In both groups, postoperative decline occurred in most neurocognitive domains. There were no statistically significant differences between patients in the insular and control groups with regard to rates of postoperative decline on any test. However, there were trends suggesting differential cognitive performance postoperatively, because patients with insular tumors were more likely to experience greater decline in learning and memory. Neurological morbidity was similar to prior rates reported in the literature. CONCLUSIONS: Few statistically significant differences in cognitive function were observed between patients in the insular and control groups at either the pre- or postoperative evaluation, although there was a trend for patients with insular tumors to exhibit greater postoperative decline in learning and memory. Although technically more challenging, surgery for insular region glioma appears feasible without profound neurological or cognitive morbidity for many patients.

Economic impact of stereotactic radiosurgery for malignant intracranial brain tumors.

Brain metastases occur frequently in cancer patients and can lead to neurological complications that result in decreased quantity and quality of life. Treatment alternatives include whole-brain radiation therapy, neurosurgery and the newest modality, stereotactic radiosurgery (SRS). This article reviews economic evaluations of SRS in the metastatic setting compared with other treatment options. Studies were included if they were published in peer-reviewed journals, primarily focused on patients with malignant brain metastasis and included a cost analysis between interventions. Uncertainty surrounding the cost-effectiveness of SRS is due to a lack of efficacy information between treatment alternatives, methodological limitations and design differences between the available studies. When cost-effectiveness ratios are available, SRS appears to be a reasonable option in resource-limited settings, with incremental cost-effectiveness ratios just below the US$50,000 range. However, better-designed economic analysis in the setting of randomized clinical trials or observational studies needs to be conducted to fully understand the economic value of SRS.

Cognitive impairment in men with testicular cancer prior to adjuvant therapy.

BACKGROUND: Cognitive dysfunction experienced by individuals with cancer represents an important survivorship issue because of its potential to affect occupational, scholastic, and social activities. Whereas early efforts to characterize cognitive dysfunction primarily focused on the effects of chemotherapy, more recent evidence indicates that impairment may exist before systemic treatment. This study characterized cognitive dysfunction before adjuvant chemotherapy in a sample of men diagnosed with nonseminomatous germ cell tumors (NSGCT) of the testis. METHODS: Men with newly diagnosed NSGCT were recruited after orchiectomy but before adjuvant chemotherapy. Patients completed neuropsychological tests to assess attention, learning, language, executive function, and motor function. Self-report measures of depression and anxiety were also administered. An overall cognitive function index was computed for participants. Cognitive impairment was defined as a z-score of less than or equal to -1.5 on 2 or more tests, or a z-score of less than or equal to -2.0 on a single test. RESULTS: Approximately 46% of patients exhibited cognitive impairment at the time of assessment, which is significantly greater than would be expected considering healthy population norms (binomial test: P < .0001). Patients exhibited impairments in motor function, verbal learning, and executive function much more frequently relative to normative expectations (binomial test: P < .0001). CONCLUSIONS: The prevalence of cognitive impairment in men with newly diagnosed NSGCT is unexpectedly high before the receipt of adjuvant chemotherapy. Efforts to track cognitive function over time and to develop effective interventions are warranted.

Phase III trial of prophylactic cranial irradiation compared with observation in patients with locally advanced non-small-cell lung cancer: neurocognitive and quality-of-life analysis.

PURPOSE: There are scant data regarding the effects of prophylactic cranial irradiation (PCI) on neurocognitive function (NCF) and quality of life (QOL). Radiation Therapy Oncology Group trial 0214 showed no overall survival (OS) benefit for PCI in stage III non-small-cell lung cancer (NSCLC) at 1 year. However, there was a significant decrease in brain metastases (BM). This analysis focuses on the impact of PCI on NCF and QOL. PATIENTS AND METHODS: Patients with stage III NSCLC who completed definitive therapy without progression were randomly assigned to PCI or observation. NCF was assessed with Mini-Mental Status Examination (MMSE), Activities of Daily Living Scale (ADLS), and Hopkins Verbal Learning Test (HVLT). QOL was assessed with the European Organisation for Research and Treatment of Cancer (EORTC) core tool (QOL Questionnaire-QLQC30) and brain module (QLQBN20). RESULTS: There were no statistically significant differences at 1 year between the two arms in any component of the EORTC-QLQC30 or QLQBN20 (P > .05), although a trend for greater decline in patient-reported cognitive functioning with PCI was noted. There were no significant differences in MMSE (P = .60) or ADLS (P = .88). However, for HVLT, there was greater decline in immediate recall (P = .03) and delayed recall (P = .008) in the PCI arm at 1 year. CONCLUSION: PCI in stage III NSCLC significantly decreases the risk of BM without improving 1-year OS. There were no significant differences in global cognitive function (MMSE) or QOL after PCI, but there was a significant decline in memory (HVLT) at 1 year. This study provides prospective data regarding the relative risks and benefits of PCI in this setting and the need to use sensitive cognitive assessments.

Neurocognitive and quality of life measures in patients with metastatic brain disease.

The assessment of neurocognitive function and quality of life (QOL) in patients with brain metastases has become increasingly recognized as an important addition to traditional outcome measures such as length of survival and time to disease progression. Although objective assessment of neurocognitive function using standardized neuropsychological tests is well established, QOL represents a more subjective concept for which no gold standard assessment tool has been identified. Assessment of both neurocognitive function and QOL should involve reliable and valid measures that are sensitive to the cognitive domains and aspects of patient well-being that are most affected by brain metastases and associated treatments. Thorough evaluation of these factors is critical to understanding baseline (ie, pretreatment) cognitive functioning and QOL, monitoring the effects of necessary treatments and allowing comparison of available treatments, informing future treatment decisions, and facilitating the development and implementation of tailored behavioral and pharmacologic interventions that minimize the effect of symptoms on functional well-being.

Acute and late onset cognitive dysfunction associated with chemotherapy in women with breast cancer.

BACKGROUND: Growing evidence supports cognitive dysfunction associated with standard dose chemotherapy in breast cancer survivors. We determined the incidence, nature, and chronicity of cognitive dysfunction in a prospective longitudinal randomized phase 3 treatment trial for patients with T1-3, N0-1, M0 breast cancer receiving 5-fluorouracil, doxorubicin, and cyclophosphamide with or without paclitaxel. METHODS: Forty-two patients underwent a neuropsychological evaluation including measures of cognition, mood, and quality of life. Patients were scheduled to be assessed before chemotherapy, during and shortly after chemotherapy, and 1 year after completion of chemotherapy. RESULTS: Before chemotherapy, 21% (9 of 42) evidenced cognitive dysfunction. In the acute interval, 65% (24 of 37) demonstrated cognitive decline. At the long-term evaluation, 61% (17 of 28) evidenced cognitive decline after cessation of treatment. Within this group of patients, 71% (12 of 17) evidenced continuous decline from the acute interval, and, notably, 29% (5 of 17) evidenced new delayed cognitive decline. Cognitive decline was most common in the domains of learning and memory, executive function, and processing speed. Cognitive decline was not associated with mood or other measured clinical or demographic characteristics, but late decline may be associated with baseline level of performance. CONCLUSIONS: Standard dose systemic chemotherapy is associated with decline in cognitive function during and shortly after completion of chemotherapy. In addition, delayed cognitive dysfunction occurred in a large proportion of patients. These findings are consistent with a developing body of translational animal research demonstrating both acute and delayed structural brain changes as well as functional changes associated with common chemotherapeutic agents such as 5-fluorouracil.

Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial.

BACKGROUND: It is unclear whether the benefit of adding whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) for the control of brain-tumours outweighs the potential neurocognitive risks. We proposed that the learning and memory functions of patients who undergo SRS plus WBRT are worse than those of patients who undergo SRS alone. We did a randomised controlled trial to test our prediction. METHODS: Patients with one to three newly diagnosed brain metastases were randomly assigned using a standard permutated block algorithm with random block sizes to SRS plus WBRT or SRS alone from Jan 2, 2001, to Sept 14, 2007. Patients were stratified by recursive partitioning analysis class, number of brain metastases, and radioresistant histology. The randomisation sequence was masked until assignation, at which point both clinicians and patients were made aware of the treatment allocation. The primary endpoint was neurocognitive function: objectively measured as a significant deterioration (5-point drop compared with baseline) in Hopkins Verbal Learning Test-Revised (HVLT-R) total recall at 4 months. An independent data monitoring committee monitored the trial using Bayesian statistical methods. Analysis was by intention-to-treat. This trial is registered at www.ClinicalTrials.gov, number NCT00548756. FINDINGS: After 58 patients were recruited (n=30 in the SRS alone group, n=28 in the SRS plus WBRT group), the trial was stopped by the data monitoring committee according to early stopping rules on the basis that there was a high probability (96%) that patients randomly assigned to receive SRS plus WBRT were significantly more likely to show a decline in learning and memory function (mean posterior probability of decline 52%) at 4 months than patients assigned to receive SRS alone (mean posterior probability of decline 24%). At 4 months there were four deaths (13%) in the group that received SRS alone, and eight deaths (29%) in the group that received SRS plus WBRT. 73% of patients in the SRS plus WBRT group were free from CNS recurrence at 1 year, compared with 27% of patients who received SRS alone (p=0.0003). In the SRS plus WBRT group, one case of grade 3 toxicity (seizures, motor neuropathy, depressed level of consciousness) was attributed to radiation treatment. In the group that received SRS, one case of grade 3 toxicity (aphasia) was attributed to radiation treatment. Two cases of grade 4 toxicity in the group that received SRS alone were diagnosed as radiation necrosis. INTERPRETATION: Patients treated with SRS plus WBRT were at a greater risk of a significant decline in learning and memory function by 4 months compared with the group that received SRS alone. Initial treatment with a combination of SRS and close clinical monitoring is recommended as the preferred treatment strategy to better preserve learning and memory in patients with newly diagnosed brain metastases.