Interventions for preventing and ameliorating cognitive deficits in adults treated with cranial irradiation.
Topic: Radiation/Chemotherapy

Cognitive deficits are common in people who have received cranial irradiation and have a serious impact on daily functioning and quality of life. The benefit of pharmacological and non-pharmacological treatment of cognitive deficits in this population is unclear.

PICO
Population: Adults treated with cranial irradiation
Intervention: Interventions for preventing and ameliorating cognitive deficits
Comparison: No specific comparison mentioned in the abstract
Outcomes: Improvement in cognitive deficits, impact on daily functioning and quality of life

Included studies:
title: Phase II study of donepezil in irradiated brain tumor patients: effect on cognitive function, mood, and quality of life.
abstract: A prospective, open-label phase II study was conducted to determine whether donepezil, a US Food and Drug Administration-approved reversible acetylcholinesterase inhibitor used to treat mild to moderate Alzheimer's type dementia, improved cognitive functioning, mood, and quality of life (QOL) in irradiated brain tumor patients.
title: Memantine for the prevention of cognitive dysfunction in patients receiving whole-brain radiotherapy: a randomized, double-blind, placebo-controlled trial.
abstract: To determine the protective effects of memantine on cognitive function in patients receiving whole-brain radiotherapy (WBRT).
title: A randomized trial on the efficacy of methylphenidate and modafinil for improving cognitive functioning and symptoms in patients with a primary brain tumor.
abstract: Limited research is available regarding the efficacy of psychostimulants in treating cognitive function in primary brain tumor patients. An open-label, randomized, pilot trial examined both the general and differential efficacy of 4 weeks of methylphenidate (MPH) and modafinil (MOD) in 24 brain tumor patients. Participants completed cognitive tests and self-report measures of fatigue, sleep disturbance, mood and quality of life at baseline and after 4 weeks.Following stimulant treatment, there was evidence of a beneficial effect on test performance in speed of processing and executive function requiring divided attention. Patients with the greatest deficit in executive function at baseline appeared to derive the greatest benefit following stimulant therapy. Inconsistent, differential effects were found on a measure of attention in favor of MPH and on a measure of processing speed in favor of MOD. There was also evidence of a general beneficial effect on patient-reported measures of fatigue, mood, and quality of life, with no statistically significant differences between treatment arms in these measures over time. The results from this small pilot study should be interpreted with caution, but appear to warrant additional research, in larger study samples, targeting fatigue, processing speed and executive function, and exploring different doses of stimulants. Future studies may also wish to explore the specific patient factors that may be associated with responsiveness to psychostimulant treatment.
title: Neurocognitive training in patients with high-grade glioma: a pilot study.
abstract: Although their neurocognitive performance is one of the major concerns of patients with high-grade gliomas (HGG) and although neurocognitive deficits have been described to be associated with negative outcome, neurocognitive rehabilitation is usually not integrated into the routine care of patients with malignant gliomas. In this pilot trial, a weekly group training session for attention, verbal, and memory skills was offered to patients with HGG with pre and post-training evaluation. Eleven patients, six with glioblastoma multiforme and five with WHO grade III gliomas, median age 50 years, with a Karnofsky performance score of 80-100 participated in ten group training sessions of 90 min. For evaluation at baseline and after the training by a neuropsychologist not involved in care or training of the patients, Trail Making Tests A and B (TMTA and TMTB), Hopkins Verbal Learning Test (HVLT), and the Controlled Oral Word Association Test (COWA) were used. Comparison of mean group differences between baseline and at post-training evaluation after 12 weeks revealed improvement across all neurocognitive variables. The patients showed a great diversity in their performances, with worsening, improvement, and stabilization. However, a significant group difference was detected only for the HVLT (score 19.6 +/- 8.9 at baseline, 23.6 +/- 8.8 after 12 weeks, P = 0.04). This pilot study shows that neurocognitive training in patients with HGG is feasible as group training with weekly sessions and might be able to induce improvements in attention and memory skills.
title: The effect of modafinil on fatigue, cognitive functioning, and mood in primary brain tumor patients: a multicenter randomized controlled trial.
abstract: Fatigue, cognitive deficits, and depression are frequently reported but often undertreated symptoms that can profoundly affect daily life in patients with primary brain tumors (PBTs). To evaluate the effects of the psychostimulant modafinil on fatigue, depression, health-related quality of life (HRQOL), and cognitive functioning in PBT patients, we performed a multicenter, double-blind placebo-controlled crossover trial.
title: Initial experience with bevacizumab treatment for biopsy confirmed cerebral radiation necrosis.
abstract: Cerebral radiation necrosis is a serious complication of radiation treatment for brain tumors. Therapeutic options include corticosteroids, anticoagulation and hyperbaric oxygen with limited efficacy. Bevacizumab, an antibody against VEGF had been reported to reduce edema in patients with suspected radiation necrosis. We retrospectively reviewed 6 patients with biopsy proven cerebral radiation necrosis treated with bevacizumab between 2006 and 2008.
title: Cognitive rehabilitation in patients with gliomas: a randomized, controlled trial.
abstract: Patients with gliomas often experience cognitive deficits, including problems with attention and memory. This randomized, controlled trial evaluated the effects of a multifaceted cognitive rehabilitation program (CRP) on cognitive functioning and selected quality-of-life domains in patients with gliomas.
title: Interventions for cognitive deficits in patients with a brain tumor: an update.
abstract: Patients with brain tumors may suffer from cognitive deficits caused by the disease and/or its treatment. Here, we review recent efforts in the research on prevention or treatment of cognitive deficits in these patients. We conclude that interest in this area is growing, but that methodological difficulties persist. In addition, we describe the recently completed first randomized controlled trial on the effectiveness of cognitive rehabilitation that we conducted in patients with brain cancer. By reflecting on the methodological challenges experienced in our trial, we hope to assist others in planning and conducting future studies on both pharmacological treatments and cognitive rehabilitation programs for cognitive deficits in this patient population. We conclude with suggestions for future research directions.
title: Hyperbaric oxygen therapy for cognitive disorders after irradiation of the brain.
abstract: Analysis of the feasibility and effect of hyperbaric oxygen treatment (HBO) on cognitive functioning in patients with cognitive disorders after irradiation of the brain.
title: Phase II study of Ginkgo biloba in irradiated brain tumor patients: effect on cognitive function, quality of life, and mood.
abstract: Ginkgo biloba has been reported to improve cognitive function in older adults and patients with Alzheimer's disease and multi-infarct dementia. We conducted an open-label phase II study of this botanical product in symptomatic irradiated brain tumor survivors. Eligibility criteria included: life expectancy ≥30 weeks, partial or whole brain radiation ≥6 months before enrollment, no imaging evidence of tumor progression in previous 3 months, or stable or decreasing steroid dose, and no brain tumor treatment planned while on study. The Ginkgo biloba dose was 120 mg/day (40 mg t.i.d.) for 24 weeks followed by a 6-week washout period. Assessments performed at baseline, 12, 24 (end of treatment), and 30 weeks (end of washout) included KPS, Functional Assessment of Cancer Therapy-Brain (FACT-Br), Profile of Mood States, Mini-Mental Status Exam, Trail Making Test Parts A (TMT-A) and B (TMT-B), Digit Span Test, Modified Rey Osterrieth Complex Figure (ROCF), California Verbal Learning Test Part II, and the F-A-S Test.
title: 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.
abstract: 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).
title: Oxidative stress parameters in unmedicated and treated bipolar subjects during initial manic episode: a possible role for lithium antioxidant effects.
abstract: Studies have proposed the involvement of oxidative stress and neuronal energy dysfunctions in the pathophysiology of bipolar disorder (BD). This study evaluates plasma levels of the oxidative/energy metabolism markers, thiobarbituric acid reactive substances (TBARS), superoxide dismutase (SOD), catalase (CAT), and neuron-specific enolase (NSE) during initial episodes of mania compared to controls in 75 subjects. Two groups of manic subjects (unmedicated n=30, and lithium-treated n=15) were age/gender matched with healthy controls (n=30). TBARS and antioxidant enzymes activity (SOD and CAT) were increased in unmedicated manic patients compared to controls. Conversely, plasma NSE levels were lower during mania than in the controls. In contrast, acute treatment with lithium showed a significant reduction in both SOD/CAT ratio and TBARS levels. These results suggest that initial manic episodes are associated with both increased oxidative stress parameters and activated antioxidant defenses, which may be related to dysfunctions on energy metabolism and neuroplasticity pathways. Antioxidant effects using lithium in mania were shown, and further studies are necessary to evaluate the potential role of these effects in the pathophysiology and therapeutics of BD.
title: Cognitive rehabilitation for early post-surgery inpatients affected by primary brain tumor: a randomized, controlled trial.
abstract: Cognitive impairment is one of the most common neurological disorders in neuro-oncological patients and exerts a deep negative impact on quality of life interfering with familiar, social and career-related activities. To test the effectiveness of early cognitive rehabilitation treatment for inpatients affected by primary brain tumors. Out of 109 consecutive patients enrolled in the study, 58 patients were randomly assigned to a rehabilitation group or to a control group. The rehabilitation consisted of 16 one-hour individual sessions of therapist-guided cognitive training, spread over 4 weeks, combining computer exercises and metacognitive training. Patients in the control group received usual care without cognitive training. All patients were evaluated by means of a comprehensive neuropsychological battery at the admission (T0) and after 4 weeks (T1). Patients in the rehabilitation group showed a significant improvement of cognitive functions. In particular, the domains that benefited most from the training were visual attention and verbal memory. The control group exhibited only a slightly, not statistically relevant, enhancement of cognitive performances. Cognitive rehabilitation for neuro-oncological inpatients resulted in a significant enhancement of cognitive performances after the training, also providing a foundation for early administration. Future research should be aimed to clarify the patients' characteristics that predict neuropsychological improvement, to identify the most effective elements in rehabilitative programs and to study the effects of treatment extension to everyday life.
title: A prospective study of cognitive functions following conventional radiotherapy for supratentorial gliomas in young adults: 4-year results.
abstract: To evaluate the effects of limited field conventional cerebral radiotherapy (RT) on cognitive functions of adults.
title: Donepezil and vitamin E for preventing cognitive dysfunction in small cell lung cancer patients: preliminary results and suggestions for future study designs.
abstract: Up to 90% of small cell lung cancer (SCLC) patients suffer cognitive dysfunction. Since donepezil and vitamin E have been somewhat successful in treating other dementias, this study tested the hypothesis that these agents can prevent cognitive decline in SCLC patients. Because accrual was poor, this trial also offered opportunities for suggesting other study designs for future clinical trials on cognitive dysfunction in this group of patients.
title: Phase II study of alpha-tocopherol in improving the cognitive function of patients with temporal lobe radionecrosis.
abstract: Radiotherapy is an important treatment modality for brain tumors and is the standard radical treatment for nasopharyngeal carcinoma (NPC). However, the treatment is not free of side effects, and one possible neurologic sequela is the occurrence of temporal lobe radionecrosis (TLN) associated with cognitive dysfunction. Currently, there is no effective intervention to improve patients' cognitive performance.
title: Factors impacting volumetric white matter changes following whole brain radiation therapy.
abstract: Whole brain radiation therapy (WBRT) is one of the most effective modalities for treatment of brain metastases. With increasing cancer control there is growing concern regarding the long-term effects of treatment. These effects are seen as white matter change (WMC) on brain MRI. Severity of WMC is implicated in cognitive and functional decline in many patient groups. Our objective was to identify clinical factors associated with greater accumulation of WMC following WBRT. Through retrospective review of serial MRIs obtained from 30 patients surviving greater than 1 year after WBRT, treated at a single institution between 2002 and 2007, we calculated volumetric WMC over time using segmentation software. Changes related to tumor, secondary effects, surgery or radiosurgery were excluded. Factors that influenced the rate of WMC accumulation were identified through multivariate analysis. Following WBRT, patients accumulated WMC at an average rate of 0.07% of total brain volume per month. In multivariate analyses, greater rates of accumulation were independently associated with older age (β = 0.004, p < .0001), poor levels of glycemic control (β = 0.048, p < .0001) and hypertension diagnosis (β = 0.084, p < .0001). Long-term survivors of cancer allow assessment of late effects of treatment modalities. Radiation injury appears to be related to a steady rate of white matter damage over time, as indicated by progressive accumulation of WMC. Our results suggest that rate of WMC accumulation is enhanced by parameters such as hyperglycemia and hypertension. This has significant clinical impact by clearly identifying hyperglycemia, steroid-induced hyperglycemia, and other vascular risk factors as targets for intervention to decrease WMC in patients receiving WBRT.
title: A phase III, double-blind, placebo-controlled prospective randomized clinical trial of d-threo-methylphenidate HCl in brain tumor patients receiving radiation therapy.
abstract: The quality of life (QOL) and neurocognitive function of patients with brain tumors are negatively affected by the symptoms of their disease and brain radiation therapy (RT). We assessed the effect of prophylactic d-threo-methylphenidate HCl (d-MPH), a central nervous system (CNS) stimulant on QOL and cognitive function in patients undergoing RT.
title: Effect of bevacizumab on radiation necrosis of the brain.
abstract: Because blocking vascular endothelial growth factor (VEGF) from reaching leaky capillaries is a logical strategy for the treatment of radiation necrosis, we reasoned that bevacizumab might be an effective treatment of radiation necrosis.
title: Cognitive function as a predictor of survival in patients with recurrent malignant glioma.
abstract: To determine the contribution of cognitive function in predicting the survival of patients with recurrent malignant brain tumors.
title: Cognitive rehabilitation and problem-solving to improve quality of life of patients with primary brain tumors: a pilot study.
abstract: Caregivers of patients with brain tumors frequently identify cognitive impairment in their loved ones as their greatest burden, but only one published study has examined a cognitive-rehabilitation intervention for adults with brain tumors. Emotional distress and poor quality of life (QOL) also have been identified as important issues, yet they have been excluded from most intervention studies that target coping and mood. The primary aim of this pilot study was to determine the feasibility and tolerability of a combined cognitive-rehabilitation and problem-solving-therapy intervention for patients with brain tumors and their caregivers. In all, 19 patient/caregiver pairs were enrolled and randomized, and 13 pairs completed the 2-week trial. After receiving the intervention, 88% of patients used the study-specific strategies, and 88% indicated that they would recommend the intervention to other patients diagnosed with a brain tumor. The study intervention was described as "very helpful" or "somewhat helpful" by 88% of study participants. Caregivers were similarly enthusiastic about the intervention. The results showed that patients with brain tumors who have cognitive impairment can participate meaningfully in a structured intervention, and they supported further research into the potential effectiveness of formal rehabilitation targeting cognitive and QOL symptoms for patients with brain tumors and their caregivers.
title: Methylphenidate therapy improves cognition, mood, and function of brain tumor patients.
abstract: Patients with malignant glioma develop progressive neurobehavioral deficits over the course of their illness. These are caused both by the effects of the disease and the effects of radiation and chemotherapy. We sought to determine whether methylphenidate treatment would improve these patients' neurobehavioral functioning despite their expected neurologic deterioration.
title: Predictors of neuropsychological improvement following cognitive rehabilitation in patients with gliomas.
abstract: This study investigated the specific patient factors that predict responsiveness to a cognitive rehabilitation program. The program has previously been demonstrated to be successful at the group level in patients with gliomas, but it is unclear which patient characteristics optimized the effect of the intervention at the individual level. Four categories of possible predictors of improvement were selected for evaluation: sociodemographic and clinical variables, self-reported cognitive symptoms, and objective neuropsychological test performance. Hierarchical logistic regression analyses were conducted, beginning with the most accessible (sociodemographic) variables and ending with the most difficult (baseline neuropsychological) to identify in clinical practice. Nearly 60% of the participants of the intervention were classified as reliably improved. Reliable improvement was predicted by age (p = .003) and education (p = .011). Additional results suggested that younger patients were more likely to benefit specifically from the cognitive rehabilitation program (p = .001), and that higher education was also associated with improvement in the control group (p = .024). The findings are discussed in light of brain reserve theory. A practical implication is that cognitive rehabilitation programs should take the patients' age into account and, if possible, adapt programs to increase the likelihood of improvement among older participants.
title: Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system.
abstract: To conduct a controlled trial of bevacizumab for the treatment of symptomatic radiation necrosis of the brain.