Long-term Survivors Of Brain Tumors Research Articles

Diagnosis and management of complications from the treatment of primary central nervous system tumors in adults.

Central nervous system (CNS) tumor patients commonly undergo multimodality treatment in the course of their disease. Adverse effects and complications from these interventions have not been systematically studied, but pose significant challenges in clinical practice and impact function and quality of life, especially in the management of long-term brain tumor survivors. Here, the European Association of Neuro-Oncology (EANO) has developed recommendations to prevent, diagnose, and manage adverse effects and complications in the adult primary brain CNS tumor (except lymphomas) patient population with a specific focus on surgery, radiotherapy, and pharmacotherapy. Specifically, we also provide recommendations for dose adaptations, interruptions, and reexposure for pharmacotherapy that may serve as a reference for the management of standard of care in clinical trials. We also summarize which interventions are unnecessary, inactive or contraindicated. This consensus paper should serve as a reference for the conduct of standard therapy within and outside of clinical trials.

Computer-Based Cognitive Training in Children with Primary Brain Tumours: A Systematic Review.

Simple SummaryBrain tumour survivors are often burdened by late sequelae, especially neurocognitive deficits, ultimately affecting their quality of life. For many years, treatments for neurocognitive impairments have been limited to educational, pharmacological, home-based interventions, or clinic-based cognitive rehabilitation, but these treatment modalities showed several limits. More recently, cognitive rehabilitation through digital tools to increase cognitive performance through exercises and games is spreading in experimental clinical settings. However, since these are innovative interventions, there is a need to further investigate their effects on cognitive outcomes and quality of life for children with brain tumours. Therefore, in this systematic review, we analyse the current evidence and trends regarding computer-based cognitive rehabilitation in paediatric patients diagnosed with, or survivors of, brain tumours. To our knowledge, this is the first systematic review investigating these new approaches to cognitive rehabilitation in children with brain tumours.Background: Late neurocognitive sequelae are common among long-term brain tumour survivors, resulting in significantly worse quality of life. Cognitive rehabilitation through specific APP/software for PC/tablets represents an innovative intervention spreading in recent years. In this study, we aim to review the current evidence and trends regarding these innovative approaches. Methods: A systematic literature review was performed. Inclusion criteria were: (i) Studies recruiting patients diagnosed with any brain tumour before 21 years of age; (ii) studies assessing the role of digital interventions on cognitive outcomes. Case reports, case series, reviews, letters, conference proceedings, abstracts, and editorials were excluded. Results: Overall, nine studies were included; 152 patients (67.8% males) with brain tumours underwent a digital intervention. The mean age at diagnosis and the intervention enrolment ranged from 4.9 to 9.4 years and 11.1 to 13.3 years, respectively. The computer-based software interventions employed were: Cogmed, Captain’s Log, Fast ForWord, and Nintendo Wii. Most of these studies assessed the effects of cognitive training on working memory, attention, and performance in daily living activities. Conclusions: The studies suggest that this type of intervention improves cognitive functions, such as working memory, attention, and processing speed. However, some studies revealed only transient positive effects with a significant number of dropouts during follow-up. Trials with greater sample sizes are warranted. Motivating families and children to complete cognitive interventions could significantly improve cognitive outcomes and quality of life.

Late Side Effects in Normal Mouse Brain Tissue After Proton Irradiation

Radiation-induced late side effects such as cognitive decline and normal tissue complications can severely affect quality of life and outcome in long-term survivors of brain tumors. Proton therapy offers a favorable depth-dose deposition with the potential to spare tumor-surrounding normal tissue, thus potentially reducing such side effects. In this study, we describe a preclinical model to reveal underlying biological mechanisms caused by precise high-dose proton irradiation of a brain subvolume. We studied the dose- and time-dependent radiation response of mouse brain tissue, using a high-precision image-guided proton irradiation setup for small animals established at the University Proton Therapy Dresden (UPTD). The right hippocampal area of ten C57BL/6 and ten C3H/He mice was irradiated. Both strains contained four groups (nirradiated = 3, ncontrol = 1) treated with increasing doses (0 Gy, 45 Gy, 65 Gy or 85 Gy and 0 Gy, 40 Gy, 60 Gy or 80 Gy, respectively). Follow-up examinations were performed for up to six months, including longitudinal monitoring of general health status and regular contrast-enhanced magnetic resonance imaging (MRI) of mouse brains. These findings were related to comprehensive histological analysis. In all mice of the highest dose group, first symptoms of blood-brain barrier (BBB) damage appeared one week after irradiation, while a dose-dependent delay in onset was observed for lower doses. MRI contrast agent leakage occurred in the irradiated brain areas and was progressive in the higher dose groups. Mouse health status and survival corresponded to the extent of contrast agent leakage. Histological analysis revealed tissue changes such as vessel abnormalities, gliosis, and granule cell dispersion, which also partly affected the non-irradiated contralateral hippocampus in the higher dose groups. All observed effects depended strongly on the prescribed radiation dose and the outcome, i.e. survival, image changes, and tissue alterations, were very consistent within an experimental dose cohort. The derived dose–response model will determine endpoint-specific dose levels for future experiments and may support generating clinical hypotheses on brain toxicity after proton therapy.

QOL-02. PERCEPTIONS OF LATE EFFECTS CARE NEEDS AMONG SURVIVORS OF PEDIATRIC BRAIN TUMOURS

OBJECTIVESPediatric brain tumour survivors are at risk of long-term consequences of therapy. Comprehensive late effects care may mitigate these risks, but the best care model is unclear. We sought to describe the care experience and quality of life (QOL) of pediatric brain tumour survivors at the McMaster Children’s Hospital joint adult/pediatric Neuro-Oncology clinic.METHODSCross-sectional survey data were collected. Care needs were assessed with the Cancer Care Experience Questionnaire (CCEQ), Cancer Worry Scale (CWS), and Self-Management Skills Scale (SMSS). Quality of life was measured utilizing the PedsQL Brain Tumor Module. Data were analyzed descriptively.RESULTSThirty-two childhood brain tumor survivors and/or their parents participated. Their malignancies included embryonal tumors (medulloblastoma/ATRT) (62%), ependymoma (22%), and germ cell tumours (16%). Among 77%, therapy included chemotherapy, surgery and radiation. Most respondents reported high quality cancer care, although some could not recall discussions of late effects risks and health promotion. Mean cancer worry scores were low (71.8 (± 28.4)). Survivors reported limited self-management skills (58.5 (±18.2)), with support required in clinic visits, arranging medical appointments, filling prescriptions and tasks of daily living. Overall median QOL scores were in the ‘good’ range (parental report 72.3 (±17.7), survivor 68.2 (±16.6)).CONCLUSIONIn comparison to other childhood cancer survivor cohorts, this group of long-term brain tumour survivors appear to have similar QOL, fewer cancer worries, and increased need for aid with self-management. Given this, along with the positive care experience reported, this clinic model of care appears to meet the needs of this population.

Rescue of cognitive function following fractionated brain irradiation in a novel preclinical glioma model.

More than half of long-term brain tumor survivors develop irreversible cognitive decline that severely affect their quality of life. However, there is no pre-clinical model that allows long-term assessment of cognition, and there is no treatment which ameliorates cognitive deficits in patients. Here, we report a novel glioma mouse model that offers manageable tumor growth and reliable assessment of cognitive functions in a post-treatment manner. Using this model, we found that fractionated whole-brain irradiation (fWBI), but not tumor growth, results in memory deficits. Transient inhibition of CSF-1R during fWBI prolongs survival of glioma-bearing mice and fully prevents fWBI-induced memory deficits. This result suggests that CSF-1R inhibition during radiotherapy can be explored as an approach to improve both survival and cognitive outcomes in patients who will receive fWBI. Taken together, the current study provides a proof of concept of a powerful tool to study radiation-induced cognitive deficits in glioma-bearing animals.

Mild cognitive impairment in long-term brain tumor survivors following brain irradiation.

There is no accepted classification of cognitive impairment in cancer survivors. We assess the extent of mild cognitive impairment (MCI) syndrome in brain tumor survivors using criteria adapted from the National Institute on Aging and the Alzheimer's Association (NIA-AA). We retrospectively reviewed the cognitive data of brain tumor survivors post-radiation therapy (RT) enrolled from 2008 to 2011 in a randomized trial of donepezil versus placebo for cognitive impairment. One hundred and ninety eight adult survivors with primary or metastatic brain tumors who were ≥ 6months post RT were recruited at 24 sites in the United States. Cognitive function was assessed at baseline, 12 and 24weeks post-randomization. For this analysis, we used baseline data to identify MCI and possible dementia using adapted NIA-AA criteria. Cases were subtyped into four groups: amnestic MCI-single domain (aMCI-sd), amnestic MCI-multiple domain (aMCI-md), non-amnestic MCI-single domain (naMCI-sd), and non-amnestic MCI-multiple domain (naMCI-md). One hundred and thirty one of 197 evaluable patients (66%) met criteria for MCI. Of these, 13% were classified as aMCI-sd, 58% as aMCI-md, 19% as naMCI-sd, and 10% as naMCI-md. Patients with poorer performance status, less education, lower household income and those not working outside the home were more likely to be classified as MCI. Two-thirds of post-RT brain tumor survivors met NIA-AA criteria for MCI. This taxonomy may be useful when applied to brain tumor survivors because it defines cognitive phenotypes that may be differentially associated with course, treatment response, and risk factor profiles.

Long-term Survivors of Childhood Brain Tumors: Impact on General Health and Quality of Life.

We review and summarize the key issues affecting general health and quality of life (QOL) of pediatric long-term survivors of brain tumors. Long-term survivors of brain tumors are at risk of considerable late morbidity and mortality. Lengthening survival in brain tumors has highlighted the deep impact of tumor and its treatment on the physical, psychological, functional, and social health and QOL of these survivors. Evolution in tumor therapy including surgery, radiotherapy, and systemic therapies, etc., has the potential to mitigate this impact to some extent. Sensitization of health staff, policy makers, and the primary designers of clinical trials towards integration of QOL end points while measuring survival in brain tumor patients is the need of the hour. New developments in tumor therapeutics must not only provide quantitative gain but also improve the quality of survival in these long-term survivors. While majority of the issues presented pertain to survivorship in pediatric brain tumor population, similar challenges are likely to exist in young adults surviving brain tumors as well.

Exploration of Morbidity in a Serial Study of Long-Term Brain Tumor Survivors: A Focus on Pain.

Children surviving brain tumors are frequently identified as having substantially decreased health-related quality of life (HRQL) in cross-sectional studies. This study explored the HRQL of a cohort of such survivors, who were recruited as adolescents and followed for a decade, in order to determine the trajectory of their morbidities. Children diagnosed between January 1, 1985, and December 31, 1998, more than 2 years from diagnosis (N = 40), were recruited in 2000/2001 (T1) aged 16.74 ± 4.23 years. Health Utilities Index questionnaires (HUI2/3) were completed in 2000/2001 and again at 5 years (T2) and 10 years (T3), with 37 and 25 participants then aged 21.54 ± 4.29 and 27.97 ± 4.07 years, respectively. In addition to study subjects, parental proxies completed questionnaires at T1 and T2, while study subjects selected proxies at T3. Single attributes (domains/dimensions) of HRQL and details of pain were analyzed. Cognition was the attribute compromised most often (T1 = 66.7% of participants, T2 = 62.2%, T3 = 60.0%). Pain was also reported frequently (T1 = 35%, T2 = 25%, T3 = 52%), and at T3 correlated moderately with HUI2 sensation (0.77) and HUI3 vision (0.44), speech (0.51), and ambulation (0.50). The lower median utility score for pain at T3 than at T1/T2 was a clinically important difference. Severe pain was identified in the lower extremities, back, upper extremities, and abdomen. Morbidity was observed also in emotion (worry HUI2 and unhappiness HUI3), sensation, and vision. Decreased HRQL in survivors of brain tumors in childhood is multifaceted. Pain is a prominent burden, along with morbidity in cognition, emotion, sensation, and vision. Further studies should explore pain and neurologic deficits, and potential opportunities for therapeutic intervention.

Health-related Quality of Life in Long-term Survivors of Brain Tumors in Childhood and Adolescence

Survivors of brain tumors in childhood experience adverse sequelae that are greater in prevalence and severity than those encountered by survivors of all other forms of cancer in early life, reflected in a burden of morbidity by instruments measuring health-related quality of life (HRQL). However, there are few studies of the change in HRQL over time in such populations. Patients who were above 5 years of age, at least 2 years from completion of therapy, and able to communicate in English were eligible for study of HRQL by the Health Utilities Index HUI2 and HUI3 at study entry, and again 5 and 10 years later. An initial cohort of 40 patients was reduced to 37 and 25 at the second and third time points, respectively, although only 1 death occurred during the study. HRQL showed a progressive decline over the decade, reaching conventional levels of clinical significance for the sizes of the changes. Median scores for HUI2 were 0.93, 0.90, and 0.88; and for HUI3 were 0.88, 0.85, and 0.77 at baseline, 5, and 10 years, respectively. The serial decline in HRQL demands further examination and an exploration of potential targets for therapeutic intervention.

Phase III randomized, double-blind, placebo-controlled trial of donepezil in irradiated brain tumor survivors.

2006 Background: This RCT assessed the effect of 24 weeks of 5-10 mg per day of donepezil, an acetyl cholinesterase inhibitor, on cognitive functioning (primary endpoint) and fatigue, mood and QOL in long-term brain tumor survivors following partial or whole-brain irradiation. Cognitive results are reported herein. Methods: From 2/08-12/11,198 adult primary and metastatic brain tumor survivors > 6 months post radiation treatment (>30 Gray) recruited at 24 sites affiliated with the Wake Forest Community Clinical Oncology Program Research Base, 3 CTSU sites and M.D. Anderson Cancer Center were randomly assigned to receive donepezil (n=99) or placebo (n=99). Cognitive function was assessed at baseline, 12 and 24 weeks with Hopkins Verbal Learning Test-Revised, Rey-Osterreith Complex Figure, Trail Making Test, Digit Span, Controlled Oral Word Association, and Grooved Pegboard. A Cognitive Composite (CC) score was the primary outcome. Results: The sample was 91% White, 54% female, and median age was 55 yrs. 66% had primary tumors, 27% brain metastases and 8% PCI. Median time since diagnosis: 38 mos. 95% had 0-1 ECOG performance status scores. 74% completed the study. CC score improved significantly by 24 weeks in both arms (p < .01); however, there was not a statistically significant difference between groups (p = .57). Donepezil group performed better than placebo on HVLT Recognition (p = .03) and Discrimination (p = .01) and GP-Dominant Hand (p = 0.02). Significant interactions were found between treatment arm and baseline cognitive scores for: CC (p = .01), HVLT Immed. Recall (p = .03), HVLT %Savings (p < .01), Digit Span Forward (p = .01), ROCF Copy (p = .03), TMT-B (p = .05) and GP-Dominant (p < .01). In all cases, the benefit of donepezil, relative to placebo, was greater for those with worse baseline scores. Conclusions: Long-term brain tumor survivors treated with brain irradiation who have cognitive impairment can benefit from 5-10mg of donepezil for 24 weeks. Improvements in verbal memory, working memory, visuo- and psychomotor performance and executive functioning were observed in this group. (Study supported by NIH/NINR grant 5R01NR009675-04, NIH/NCI grant 2 U10 CA 81851-09-13 and Eisai, Inc.) Clinical trial information: NCT00369785.

Medical Management of Patients With Brain Tumors

Patients with brain tumors require meticulous attention to medical issues resulting from their disease or its therapy. The following specific issues are the ones most frequently arising in the purview of neurologists: (1) Vasogenic edema: Corticosteroids should be used in divided doses in the minimum amount required to control symptoms and should be tapered as quickly as possible. Some patients may require long-term steroid supplementation, and symptoms of adrenal insufficiency should be investigated with 8 AM: cortisol measurement and treated with appropriate repletion. (2) Seizures: Patients with brain tumors should receive antiepileptic drugs only if they have had seizures, and the drugs should be chosen to minimize cognitive effects and interactions with concurrently administered chemotherapy. Levetiracetam is an excellent choice for patients with partial seizures and is available both orally and parenterally. Lamotrigine is another reasonable choice but requires slow titration. (3) Venous thromboembolism: All brain tumor patients should receive perioperative venous thrombosis prophylaxis with compression boots and enoxaparin or dalteparin. Lifelong treatment with low molecular weight heparinoids or warfarin is required for those developing venous thromboembolism. (4) Other problems: Long-term survivors of brain tumors should be monitored indefinitely for cognitive problems, endocrine dysfunction, and development of secondary neoplasms. Modafinil can improve mood and attention impairments.

Hyperbaric oxygen treatment improved neurophysiologic performance in brain tumor patients after neurosurgery and radiotherapy

Cognitive performance often is impaired permanently in long-term brain tumor survivors after neurosurgery and radiotherapy. Hyperbaric oxygen treatment (HBOT) stimulates neovascularization of hypoperfused tissue and may result in improved functionality of damaged tissue. In this pilot study, clinical neurophysiologic tests were used to assess the effect of HBOT on brain performance. Ten long-term brain tumor survivors received HBOT for severe cognitive deficits after neurosurgery and radiosurgery. Patients were tested before HBOT and at 6 weeks and 4 months after HBOT. The tests comprised a quantitative electroencephalographic (EEG) examination, the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) for memory performance, and 2 cognitive tests, the number connection test (NCT) and the continuous reaction time test (CRTT). Late event-related components (LERCs) of averaged evoked EEG responses to a visual odd-ball stimulus were analyzed from whole-head activity maps. For comparison, a control group of healthy individuals (no HBOT) also were investigated. After HBOT, the amplitude of the LERC with the longest latency, P3b (involved in object interpretation) was improved significantly (P = .02). The amplitudes of the N200 (occipital, negative) and the intermediate P3a (centroparietal, positive), LERCs with shorter latencies, and of a small, positive, occipital visual component did not change. Neither latencies nor reaction times changed after HBOT. However, P3a and P3b (parietal, positive) latencies were longer in survivors than in healthy individuals. The NCT produced inconclusive results, but the IQCODE revealed an improvement. When outcomes of the NCT, CRTT, IQCODE, and P3b amplitudes were evaluated in common tests, HBOT appeared to provide substantial improvement (P<.006). On the basis of the current results, the authors concluded tentatively that HBOT improves neurophysiologic performance in long-term brain tumor survivors.

Distress persists in long-term brain tumor survivors with glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor. The prognosis for GBM patients is extremely poor with an estimated median survival of 12 months. Despite this statistic, a number of GBM patients are living longer than in the past as new detection and treatment approaches are used. However, little is known about the psychological correlates of this disease. To address this issue we investigated distress and its sources in long-term survivors (LTS) of this disease. Participants were asked to complete the National Comprehensive Cancer Network's (NCCN) Distress Thermometer, a single-item rapid screening tool for distress. Participants were also asked to designate sources of distress from a 34-item list developed by the NCCN. Distress scores and sources of distress for long-term GBM survivors (>18 months) were compared to patients diagnosed within the last 18 months (<18 months). Eight-three brain tumor patients participated in this study. Fifty-nine percent of LTS met the > or = 4 cut-off score for distress (M = 4.61, SD 3.12) as compared to 49% of patients diagnosed less than 18 months (M = 3.93, SD = 2.21; x(2) = 0.406, NS), LTS reported fewer items of concern while more LTS reported being distressed. This study indicates that LTS of GBM report experiencing distress at similar levels to other brain tumor patients. Level of distress for LTS is directly related to the total number of concerns in both emotional and physical domains. Regardless of LTS status, distress continues to be a part of the disease trajectory for many GBM patients. As such, attention to distress in these survivors of a major life threatening disease is warranted in follow up surveillance visits.

The effect of tianeptine in the prevention of radiation-induced neurocognitive impairment

Radiation-induced neurocognitive impairment is an undesirable radiation-induced toxicity and a common health problem in patients with primary or metastatic brain tumor. It greatly impairs quality of life for long-term brain tumor survivors. Hippocampus is the most important brain structure for neurocognitive functions. It has been shown that radiation affects the hippocampal neurogenesis due to either induce the apoptosis or reduce the precursor cell proliferation in the hippocampus. Radiation-induced microglial inflammatory response is also negative regulator of neurogenesis. Tianeptine is a clinically effective antidepressant that induces neurogenesis. It has also been shown that tianeptine is able to reduce apoptosis and cytoprotective against the effects of proinflammatory cytokines in the hippocampus. Given the putative role of impaired hippocampal neurogenesis in radiation-induced neurocognitive impairment we think that tianeptine can be effective for preventing radiation-induced neurocognitive impairment by increasing hippocampal neurogenesis.

Radiological and clinical assessment of long-term brain tumour survivors after radiotherapy

Background and purpose: Late adverse effects of therapeutic brain radiotherapy (RT) may develop after long latency periods and our objective was to assess long-term brain tumour survivors following RT to large partial brain volumes. Materials and methods: Assessment of MRI, SOMA/LENT score, quality of life and neuroendocrine function was performed in 33 adult brain tumour patients 6–25 years following RT. Fraction dose was 1.8 Gy to a median total dose of 54 Gy (range: 45.0–59.4 Gy). Ten patients had been given two opposing portals including one whole hemisphere, while 23 patients had in addition received an ipsilateral field. In 25 patients the hypothalamic and pituitary area had been included in the RT field. Results were compared within the study group and towards the general population matched for age and gender. Results: All patients had white matter changes with increased signal intensity on T2 and FLAIR images. Discrete lesions (grade 1), beginning confluence of lesions (grade 2), and large confluent areas (grade 3) were present in 8, 8 and 17 patients, respectively. Patients treated with intra-arterial chemotherapy and patients at higher age at follow-up had significantly more grade 3 changes. Atrophy, lacunar lesions and contrast enhancement was found in 17, 18 and 23 patients, respectively. Significantly worse clinical status and quality of life was found in patients with white matter changes grade 3 or atrophy. Patients given full-dose RT to less volume did not have significantly less toxicity. Two cases of meningioma were found at 16 and 22 years after RT. Nineteen neuroendocrine abnormalities were observed in 16/25 patients. Conclusions: External radiotherapy to the brain at a standard fractionation regime will cause varying degrees of late neurotoxicity and/or neuroendocrine disturbances in most patients. Life-long follow-up is recommended.