Cognitive impairment and associations with structural brain networks, endocrine status, and risk genotypes in patients with newly diagnosed prostate cancer referred to androgen-deprivation therapy.

BACKGROUND: Evidence suggests that patients with prostate cancer (PCPs) receiving androgen-deprivation therapy (ADT) are at risk for cognitive impairment. Research with other populations with cancer indicates that cognitive impairment may also occur before systemic treatment. The authors assessed cognitive impairment in untreated PCPs referred to ADT and explored associations with structural brain networks, endocrine status, and selected genotypes. METHODS: Forty untreated PCPs and 27 healthy controls (HCs) who completed a questionnaire package underwent neuropsychological testing, magnetic resonance imaging, and blood sampling. Cognitive impairment was defined as a z score ≤-2 on 1 neuropsychological test or ≤-1.5 on 2 neuropsychological tests. Structural brain networks were investigated using diffusion-weighted imaging and graph theory. Associations of cognitive performance with patient-reported outcome measures (PROMs), brain networks, testosterone levels, and genotypes (apolipoprotein ε [APOE], catechol-O-methyltransferase [COMT], and brain-derived neurotrophic factor [BDNF]) were explored. RESULTS: PCPs performed poorer than HCs on 7 of 15 neuropsychological tests and exhibited a higher frequency of cognitive impairment (57.5% vs 22.2%; P ≤ .01 to .03). All neuropsychological outcomes were associated with ≥1 PROM (P ≤ .01 to .04). Compared with the HC group, the PCP group exhibited altered global network organization as well as disrupted regional network characteristics in frontal and temporal regions (P < .01). PCPs had lower testosterone levels (P < .01) than HCs, which correlated with better visuospatial performance (r = -0.33; P = .04). No effects were found of APOE, COMT, or BDNF. CONCLUSIONS: The current results suggest that untreated PCPs may demonstrate cognitive impairment and that psychological and behavioral symptoms (PROMs), as well as impairment in structural brain networks, might be the underlying mechanisms.

A national study on the inter-observer variability in the delineation of organs at risk in the brain.

BACKGROUND: The Danish Neuro Oncology Group (DNOG) has established national consensus guidelines for the delineation of organs at risk (OAR) structures based on published literature. This study was conducted to finalise these guidelines and evaluate the inter-observer variability of the delineated OAR structures by expert observers. MATERIAL AND METHODS: The DNOG delineation guidelines were formed by participants from all Danish centres that treat brain tumours with radiotherapy. In a two-day workshop, guidelines were discussed and finalised based on a pilot study. Following this, the ten participants contoured the following OARs on T1-weighted gadolinium enhanced MRI from 13 patients with brain tumours: optic tracts, optic nerves, chiasm, spinal cord, brainstem, pituitary gland and hippocampus. The metrics used for comparison were the Dice similarity coefficient (Dice), mean surface distance (MSD) and others. RESULTS: A total of 968 contours were delineated across the 13 patients. On average eight (range six to nine) individual contour sets were made per patient. Good agreement was found across all structures with a median MSD below 1 mm for most structures, with the chiasm performing the best with a median MSD of 0.45 mm. The Dice was as expected highly volume dependent, the brainstem (the largest structure) had the highest Dice value with a median of 0.89 whereas smaller volumes such as the chiasm had a Dice of 0.71. CONCLUSION: Except for the caudal definition of the spinal cord, the variances observed in the contours of OARs in the brain were generally low and consistent. Surface mapping revealed sub-regions of higher variance for some organs. The data set is being prepared as a validation data set for auto-segmentation algorithms for use within the Danish Comprehensive Cancer Centre - Radiotherapy and potential collaborators.

Long-term cognitive dysfunction after radiation therapy for primary brain tumors.

Background: The extent of radiation therapy (RT)-induced changes in cognitive function is unknown. RT with protons instead of photons spares the healthy brain tissue more and is believed to reduce the risk of cognitive dysfunction. There is modest knowledge on which parts of the brain we need to spare, to prevent cognitive dysfunction. To uncover which cognitive domains is most affected, we compared cognitive functioning in brain tumor patients treated with neurosurgery and RT with brain tumor patients treated with neurosurgery alone. Methods: A cross-sectional study assessing cognitive function in 110 patients with a primary brain tumor grades I-III or medulloblastoma (grade IV) treated at Aarhus University Hospital (AUH), Denmark between 2006 and 2016. Two cohorts were established: a cohort of 81 brain tumor patients who had received neurosurgery followed by RT (RT+), and a cohort of 29 brain tumor patients who had only received neurosurgery (RT-). The patients underwent questionnaires and neuropsychological assessment with standardized tests. Results: Mean age was 53.5 years with an average time since diagnosis of 7.3 years. Compared with normative data, lower average scores were observed for the entire group on domains concerning of verbal learning and memory (p < .001), attention and working memory (p < .001), processing speed (p < .001), and executive functioning (p < .001). Compared to RT- patients, RT + patients scored lower on domains concerning processing speed (p = .04) and executive function (p = .05) and had higher impairment frequency on verbal fluency (p = .02) with 16% of patients exceeding 1.5 SD below normative data. Conclusions: Our results indicate that treatment, including RT, for a primary brain tumor may have negative long-term impact on cognitive function, especially on processing speed and executive function.

Cognitive impairment and associations with structural brain networks, endocrine status, and risk genotypes in newly orchiectomized testicular cancer patients.

A higher incidence of cognitive impairment (CI) has previously been reported among orchiectomized testicular cancer patients (TCPs), but little is known about the underlying pathophysiology. The present study assessed CI in newly orchiectomized TCPs and explored the structural brain networks, endocrine status, and selected genotypes. Forty TCPs and 22 healthy controls (HCs) underwent neuropsychological testing and magnetic resonance imaging, and provided a blood sample. CI was defined as a z-score ≤ -2 on one neuropsychological test or ≤ -1.5 on two neuropsychological tests, and structural brain networks were investigated using graph theory. Associations of cognitive performance with brain networks, endocrine status (including testosterone levels and androgen receptor CAG repeat length), and genotypes (APOE, BDNF, COMT) were explored. Compared with HCs, TCPs performed poorer on 6 out of 15 neuropsychological tests, of which three tests remained statistically significant when adjusted for relevant between-group differences (p < 0.05). TCPs also demonstrated more CI than HCs (65% vs. 36%; p = 0.04). While global brain network analysis revealed no between-group differences, regional analysis indicated differences in node degree and betweenness centrality in several regions (p < 0.05), which was inconsistently associated with cognitive performance. In TCPs, CAG repeat length was positively correlated with delayed memory performance (r = 0.36; p = 0.02). A COMT group × genotype interaction effect was found for overall cognitive performance in TCPs, with risk carriers performing worse (p = 0.01). No effects were found for APOE, BDNF, or testosterone levels. In conclusion, our results support previous findings of a high incidence of CI in newly orchiectomized TCPs and provide novel insights into possible mechanisms.

Treatment plan comparison of proton vs photon radiotherapy for lower-grade gliomas.

BACKGROUND AND PURPOSE: Patients with lower-grade gliomas are long-term survivors after radiotherapy and may benefit from the reduced dose to normal tissue achievable with proton therapy. Here, we aimed to quantify differences in dose to the uninvolved brain and contralateral hippocampus and compare the risk of radiation-induced secondary cancer for photon and proton plans for lower-grade glioma patients. MATERIALS AND METHODS: Twenty-three patients were included in this in-silico planning comparative study and had photon and proton plans calculated (50.4 Gy(RBE = 1.1), 28 Fx) applying similar dose constraints to the target and organs at risk. Automatically calculated photon plans were generated with a 3 mm margin from clinical target volume (CTV) to planning target volume. Manual proton plans were generated using robust optimisation on the CTV. Dose metrics of organs at risk were compared using population mean dose-volume histograms and Wilcoxon signed-rank test. Secondary cancer risk per 10,000 persons per year (PPY) was estimated using dose-volume data and a risk model for secondary cancer induction. RESULTS: CTV coverage (V95%>98%) was similar for the two treatment modalities. Mean dose (Dmean) to the uninvolved brain was significantly reduced from 21.5 Gy (median, IQR 17.1-24.4 Gy) with photons compared to 10.3 Gy(RBE) (8.1-13.9 Gy(RBE)) with protons. Dmean to the contralateral hippocampus was significantly reduced from 6.5 Gy (5.4-11.7 Gy) with photons to 1.5 Gy(RBE) (0.4-6.8 Gy(RBE)) with protons. The estimated secondary cancer risk was reduced from 6.7 PPY (median, range 3.3-10.4 PPY) with photons to 3.0 PPY (1.3-7.5 PPY) with protons. CONCLUSION: A significant reduction in mean dose to uninvolved brain and contralateral hippocampus was found with proton planning. The estimated secondary cancer risk was reduced with proton therapy.

Cognitive impairment following radiation to hippocampus and other brain structures in adults with primary brain tumours.

BACKGROUND: Radiation therapy (RT) to the brain may result in cognitive impairment. The primary objective of the present study was to examine the relationship between RT dose to the hippocampus and learning and memory functions. Secondary objective was to examine relationships between doses to other brain structures and specific cognitive functions. METHODS: A cross-sectional analysis was undertaken in 78 primary brain tumour patients after RT. Cognitive function was assessed by neuropsychological tests. Test scores were standardized using normative data adjusted for age and level of education. Test-specific cognitive impairment was determined as a z-score ≤-1.5. Radiation dose to brain structures and test-specific cognitive impairment outcomes were fitted to a logistic regression model. RESULTS: High RT dose to the left hippocampus was associated with impaired verbal learning and memory (p = 0.04). RT dose to the left hippocampus, left temporal lobe, left frontal lobe and total frontal lobe were associated with verbal fluency impairment (p < 0.05) and doses to the thalamus and the left frontal lobe with impaired executive functioning (p ≤ 0.03). Finally, RT dose to the brain and thalamus were associated with impaired processing speed (p ≤ 0.05). CONCLUSION: The present study indicates that the hippocampus may be vulnerable to radiation and that high radiation doses to the left hippocampus may lead to significant verbal learning and memory impairment. High RT doses to the left hippocampus and other left side structures may result in impairments in verbal fluency, executive function, and processing speed. Validation of these findings are being undertaken in a prospective study.