Tjeerd J. Postma

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

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.

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

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.

Cognitive Rehabilitation in Patients With Gliomas: A Randomized, Controlled Trial

PURPOSE 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. PATIENTS AND METHODS One hundred forty adult patients with low-grade and anaplastic gliomas, favorable prognostic factors, and both subjective cognitive symptoms and objective cognitive deficits were recruited from 11 hospitals in the Netherlands. Patients were randomly assigned to an intervention group or to a waiting-list control group. The intervention incorporated both computer-based attention retraining and compensatory skills training of attention, memory, and executive functioning. Participants completed a battery of neuropsychological (NP) tests and self-report questionnaires on cognitive functioning, fatigue, mental health-related quality of life, and community integration at baseline, after completion of the CRP, and at 6-month follow-up. RESULTS At the immediate post-treatment evaluation, statistically significant intervention effects were observed for measures of subjective cognitive functioning and its perceived burden but not for the objective NP outcomes or for any of the other self-report measures. At the 6-month follow-up, the CRP group performed significantly better than the control group on NP tests of attention and verbal memory and reported less mental fatigue. Group differences in other subjective outcomes were not significant at 6 months. CONCLUSION The CRP has a salutary effect on short-term cognitive complaints and on longer-term cognitive performance and mental fatigue. Additional research is needed to identify which elements of the intervention are most effective.

Symptoms and problems in the end-of-life phase of high-grade glioma patients.

Despite multimodal treatment, it is not possible to cure high-grade glioma (HGG) patients. Therefore, the aim of treatment is not only to prolong life, but also to prevent deterioration of health-related quality of life as much as possible. When the patients condition declines and no further tumor treatment seems realistic, patients in the Netherlands are often referred to a primary care physician for end-of-life care. This end-of-life phase has not been studied adequately yet. The purpose of this study was to explore specific problems and needs experienced in the end-of-life phase of patients with HGG. We retrospectively examined the files of 55 patients who received treatment in our outpatient clinic and died between January 2005 and August 2008. The clinical nurse specialist in neuro-oncology maintained contact on a regular basis with (relatives of) HGG patients once tumor treatment for recurrence was no longer given. She systematically asked for signs and symptoms. The majority of the patients experienced loss of consciousness and difficulty with swallowing, often arising in the week before death. Seizures occurred in nearly half of the patients in the end-of-life phase and more specifically in one-third of the patients in the week before dying. Other common symptoms reported in the end-of-life phase are progressive neurological deficits, incontinence, progressive cognitive deficits, and headache. Our study demonstrates that HGG patients, unlike the general cancer population, have specific symptoms in the end-of-life phase. Further research is needed in order to develop specific palliative care guidelines for these patients.

PCV chemotherapy for recurrent glioblastoma multiforme

The authors evaluated response, time to progression (TTP), survival, prognostic factors, and toxicity in 63 patients with a recurrent glioblastoma multiforme treated with procarbazine, lomustine, and vincristine (PCV) chemotherapy. Complete and partial response was observed in two (3%) and five patients (8%). In 16 patients (25%), stable disease was observed. Median TTP and survival were 13 and 33 weeks. Age < 40 years and Karnofsky Performance Status ≥ 90 were associated with longer TTP and survival. PCV treatment was generally well tolerated.

The course of neurocognitive functioning in high-grade glioma patients

We evaluated the course of neurocognitive functioning in newly diagnosed high-grade glioma patients and specifically the effect of tumor recurrence. Following baseline assessment (after surgery and before radiotherapy), neurocognitive functioning was evaluated at 8 and 16 months. Neurocognitive summary measures were calculated to detect possible deficits in the domains of (1) information processing, (2) psychomotor function, (3) attention, (4) verbal memory, (5) working memory, and (6) executive functioning. Repeated-measures analyses of covariance were used to evaluate changes over time. Thirty-six patients were tested at baseline only. Follow-up data were obtained for 32 patients: 14 had a follow-up at 8 months, and 18 had an additional follow-up at 16 months. Between baseline and eight months, patients deteriorated in information-processing capacity, psychomotor speed, and attentional functioning. Further deterioration was observed between 8 and 16 months. Of 32 patients, 15 suffered from tumor recurrence before the eight-month follow-up. Compared with recurrence-free patients, not only did patients with recurrence have lower information-processing capacity, psychomotor speed, and executive functioning, but they also exhibited a more pronounced deterioration between baseline and eight-month follow-up. This difference could be attributed to the use of antiepileptic drugs in the patient group with recurrence. This study showed a marked decline in neurocognitive functioning in HGG patients in the course of their disease. Patients with tumor progression performed worse on neurocognitive tests than did patients without progression, which could be attributed to the use of antiepileptic drugs. The possibility of deleterious effects is important to consider when prescribing antiepileptic drug treatment.

Compromised Health-Related Quality of Life in Patients With Low-Grade Glioma

PURPOSE To investigate the generic and condition-specific health-related quality of life (HRQL) of patients with low-grade glioma (LGG). PATIENTS AND METHODS A total of 195 patients with LGG, which was diagnosed, on average, 5.6 years before the study, were compared with 100 patients with hematologic (non-Hodgkins) lymphoma and chronic lymphatic leukemia cancer (NHL/CLL) and 205 general population controls who were comparable with patients with LGG at the group level for age, sex, and education (healthy controls). Generic HRQL was assessed with the Short Form-36 (SF-36) Health Survey, and condition-specific HRQL was assessed with the Medical Outcomes Study cognitive function questionnaire and the European Organisation for Research and Treatment of Cancer brain cancer module. Objective neurocognitive functioning was assessed with a standardized battery of neuropsychological tests. RESULTS No statistically significant differences were observed between patients with LGG and patients with NHL/CLL in SF-36 scores. Patients with LGG scored significantly lower than healthy controls on six of eight scales and on the mental health component score of the SF-36. Approximately one quarter of patients with LGG reported serious neurocognitive symptoms. Female sex, epilepsy burden, and number of objectively assessed neurocognitive deficits were associated significantly with both generic and condition-specific HRQL. Clinical variables, including the time since diagnosis, tumor lateralization, extent of surgery, and radiotherapy, did not show a consistent relationship with HRQL. CONCLUSION Patients with LGG experienced significant problems across a broad range of HRQL domains, many of which were not condition-specific. However, the neurocognitive deficits and epilepsy that were relatively prevalent among patients with LGG were associated with negative HRQL outcomes and, thus, contributed additionally to the vulnerability of this population of patients with cancer.

Platinum-Induced Neurotoxicity and Preventive Strategies: Past, Present, and Future

Neurotoxicity is a burdensome side effect of platinum-based chemotherapy that prevents administration of the full efficacious dosage and often leads to treatment withdrawal. Peripheral sensory neurotoxicity varies from paresthesia in fingers to ataxic gait, which might be transient or irreversible. Because the number of patients being treated with these neurotoxic agents is still increasing, the need for understanding the pathogenesis of this dramatic side effect is critical. Platinum derivatives, such as cisplatin and carboplatin, harm mainly peripheral nerves and dorsal root ganglia neurons, possibly because of progressive DNA-adduct accumulation and inhibition of DNA repair pathways (e.g., extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase/stress-activated protein kinase, and p38 mitogen-activated protein kinass), which finally mediate apoptosis. Oxaliplatin, with a completely different pharmacokinetic profile, may also alter calcium-sensitive voltage-gated sodium channel kinetics through a calcium ion immobilization by oxalate residue as a calcium chelator and cause acute neurotoxicity. Polymorphisms in several genes, such as voltage-gated sodium channel genes or genes affecting the activity of pivotal metal transporters (e.g., organic cation transporters, organic cation/carnitine transporters, and some metal transporters, such as the copper transporters, and multidrug resistance-associated proteins), can also influence drug neurotoxicity and treatment response. However, most pharmacogenetics studies need to be elucidated by robust evidence. There are supportive reports about the effectiveness of several neuroprotective agents (e.g., vitamin E, glutathione, amifostine, xaliproden, and venlafaxine), but dose adjustment and/or drug withdrawal seem to be the most frequently used methods in the management of platinum-induced peripheral neurotoxicity. To develop alternative options in the treatment of platinum-induced neuropathy, studies on in vitro models and appropriate trials planning should be integrated into the future design of neuroprotective strategies to find the best patient-oriented solution.

Interobserver variability in the radiological assessment of response to chemotherapy in glioma

Objective: To assess the interobserver variability in the radiologic assessment of response to chemotherapy in patients with recurrent glioma. Methods: Five clinicians with experience in the treatment and follow-up of patients with glioma measured tumor size in 20 pairs of CT and 20 pairs of MRI scans of 35 patients who had been treated with chemotherapy for recurrent glioma. Tumor size was defined as the product of the two largest perpendicular enhancing tumor diameters on the postcontrast images. To assess the interobserver variability in the measurements of tumor size, and in the classification according to the widely used Macdonald response criteria, intraclass correlation coefficients (ICC) and weighted kappa values were calculated. Results: Substantial interobserver agreement was noted in the manual, two-dimensional measurements of tumor size on CT and MRI in patients treated with chemotherapy for recurrent glioma (overall ICC 0.64). Classification of response to chemotherapy according to the Macdonald criteria resulted in moderate interobserver agreement (overall weighted kappa 0.51). In 65% of evaluated CT and in 55% of evaluated MRI studies, no complete consensus was found for the categorical tumor response measurement. Conclusion: The radiologic assessment of response to chemotherapy in patients with recurrent glioma is susceptible to considerable interobserver variability. This underlines the difficulties that arise in scoring response to chemotherapy by conventional radiologic techniques.

Gemcitabine uptake in glioblastoma multiforme: potential as a radiosensitizer

Glioblastoma multiforme (GBM), the most frequent malignant brain tumor, has a poor prognosis, but is relatively sensitive to radiation. Both gemcitabine and its metabolite difluorodeoxyuridine (dFdU) are potent radiosensitizers. The aim of this phase 0 study was to investigate whether gemcitabine passes the blood-tumor barrier, and is phosphorylated in the tumor by deoxycytidine kinase (dCK) to gemcitabine nucleotides in order to enable radiosensitization, and whether it is deaminated by deoxycytidine deaminase (dCDA) to dFdU. Gemcitabine was administered at 500 or 1000 mg/m(2) just before surgery to 10 GBM patients, who were biopsied after 1-4 h. Plasma gemcitabine and dFdU levels varied between 0.9 and 9.2 microM and 24.9 and 72.6 microM, respectively. Tumor gemcitabine and dFdU levels varied from 60 to 3580 pmol/g tissue and from 29 to 72 nmol/g tissue, respectively. The gene expression of dCK (beta-actin ratio) varied between 0.44 and 2.56. The dCK and dCDA activities varied from 1.06 to 2.32 nmol/h/mg protein and from 1.51 to 5.50 nmol/h/mg protein, respectively. These enzyme levels were sufficient to enable gemcitabine phosphorylation, leading to 130-3083 pmol gemcitabine nucleotides/g tissue. These data demonstrate for the first time that gemcitabine passes the blood-tumor barrier in GBM patients. In tumor samples, both gemcitabine and dFdU concentrations are high enough to enable radiosensitization, which warrants clinical studies using gemcitabine in combination with radiation.