Summary Cognitive function, with survival and response on brain imaging, is increasingly regarded as an important outcome measure in patients with brain tumours. This measure provides us with information on a patient's clinical situation and adverse treatment effects. Radiotherapy has been regarded as the main cause of cognitive decline in these patients, because children with brain tumours can develop intellectual deterioration caused by radiotherapy. In long-term surviving patients, radiotherapy may indeed lead to cognitive deficits, or even dementia. Recent studies, however, have made clear that focal radiotherapy in patients with glioma is not the main reason for cognitive deficits. The tumour itself and other medical treatments contribute largely to the cognitive deficits. Cognitive function is now also recognised as an independent prognostic factor in the survival of glioma patients. Additionally, cognitive deterioration can be the first indicator of progressive disease after treatment.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(04)00680-5.pdf

Cognitive deficits in adult patients with brain tumours.

Summary Background Our previous study on cognitive functioning among 195 patients with low-grade glioma (LGG) a mean of 6 years after diagnosis suggested that the tumour itself, rather than the radiotherapy used to treat it, has the most deleterious effect on cognitive functioning; only high fraction dose radiotherapy (>2 Gy) resulted in significant added cognitive deterioration. The present study assesses the radiological and cognitive abnormalities in survivors of LGG at a mean of 12 years after first diagnosis. Methods Patients who have had stable disease since the first assessment were invited for follow-up cognitive assessment (letter–digit substitution test, concept shifting test, Stroop colour–word test, visual verbal learning test, memory comparison test, and categoric word fluency). Compound scores in six cognitive domains (attention, executive functioning, verbal memory, working memory, psychomotor functioning, and information processing speed) were calculated to detect differences between patients who had radiotherapy and patients who did not have radiotherapy. White-matter hyperintensities and global cortical atrophy were rated on MRI scans. Findings 65 patients completed neuropsychological follow-up at a mean of 12 years (range 6–28 years). 32 (49%) patients had received radiotherapy (three had fraction doses >2 Gy). The patients who had radiotherapy had more deficits that affected attentional functioning at the second follow-up, regardless of fraction dose, than those who did not have radiotherapy (−1·6 [SD 2·4] vs −0·1 [1·3], p=0·003; mean difference 1·4, 95% CI 0·5–2·4). The patients who had radiotherapy also did worse in measures of executive functioning (−2·0 [3·7] vs −0·5 [1·2], p=0·03; mean difference 1·5, 0·2–2·9) and information processing speed (−2·0 [3·7] vs −0·6 [1·5], p=0·05; mean difference 0·8, 0·009–1·6]) between the two assessments. Furthermore, attentional functioning deteriorated significantly between the first and second assessments in patients who had radiotherapy (p=0·25). In total, 17 (53%) patients who had radiotherapy developed cognitive disabilities deficits in at least five of 18 neuropsychological test parameters compared with four (27%) patients who were radiotherapy naive. White-matter hyperintensities and global cortical atrophy were associated with worse cognitive functioning in several domains. Interpretation Long-term survivors of LGG who did not have radiotherapy had stable radiological and cognitive status. By contrast, patients with low-grade glioma who received radiotherapy showed a progressive decline in attentional functioning, even those who received fraction doses that are regarded as safe (≤2 Gy). These cognitive deficits are associated with radiological abnormalities. Our results suggest that the risk of long-term cognitive and radiological compromise that is associated with radiotherapy should be considered when treatment is planned. Funding Kaptein Fonds; Schering Plough.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(09)70204-2.pdf

Cognitive and radiological effects of radiotherapy in patients with low-grade glioma: long-term follow-up

The application of graph theoretical analysis to complex networks in the brain

Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(11)70057-2.pdf

Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas

Object Seizures play an important role in the clinical presentation and postoperative quality of life of patients who undergo surgical resection of low-grade gliomas (LGGs). The aim of this study was to identify factors that influenced perioperative seizure characteristics and postoperative seizure control. Methods The authors performed a retrospective chart review of all cases involving adult patients who underwent initial surgery for LGGs at the University of California, San Francisco between 1997 and 2003. Results Three hundred and thirty-two cases were included for analysis; 269 (81%) of the 332 patients presented with ≥ 1 seizures (generalized alone, 33%; complex partial alone, 16%; simple partial alone, 22%; and combination, 29%). Cortical location and oligodendroglioma and oligoastrocytoma subtypes were significantly more likely to be associated with seizures compared with deeper midline locations and astrocytoma, respectively (p = 0.017 and 0.001, respectively; multivariate analysis). Of the 269 p...

Seizure characteristics and control following resection in 332 patients with low-grade gliomas

Low-grade gliomas frequently are associated with epilepsy. The purpose of this study is to determine the impact of epilepsy and antiepileptic drug (AED) treatment on cognitive functioning and health-related quality of life (HRQOL) in these patients. One hundred fifty-six patients without clinical or radiological signs of tumor recurrence for at least 1 year after histological diagnosis and with an epilepsy burden (based on seizure frequency and AED use) ranging from none to severe were compared with healthy controls. The association between epilepsy burden and cognition/HRQOL was also investigated. Eighty-six percent of the patients had epilepsy and 50% of those using AEDs actually were seizure-free. Compared with healthy controls, glioma patients had significant reductions in information processing speed, psychomotor function, attentional functioning, verbal and working memory, executive functioning, and HRQOL. The increase in epilepsy burden that was associated with significant reductions in all cognitive domains except for attentional and memory functioning could primarily be attributed to the use of AEDs, whereas the decline in HRQOL could be ascribed to the lack of complete seizure control. In conclusion, low-grade glioma patients suffer from a number of neuropsychological and psychological problems that are aggravated by the severity of epilepsy and by the intensity of the treatment.

Hans Baaijen

Papers

Epilepsy in low-grade gliomas: the impact on cognitive function and quality of life.