Health-related quality of life after chemotherapy with or without rituximab in primary central nervous system lymphoma patients: results from a randomised phase III study.

BACKGROUND: The impact of rituximab on health-related quality of life (HRQoL) in primary central nervous system lymphoma patients is not well known. We determined the impact of rituximab added to standard high-dose methotrexate-based treatment on HRQoL in patients in a large randomised trial. PATIENTS AND METHODS: Patients from a large phase III trial (HOVON 105/ALLG NHL 24), randomly assigned to receive standard chemotherapy with or without rituximab and followed by 30 Gy whole brain radiotherapy (WBRT) in patients ≤60 years, completed the EORTC QLQ-C30 and QLQ-BN20 questionnaires before and during treatment, and up to 24 months of follow-up or progression. Differences between treatment arms over time in global health status, role functioning, social functioning, fatigue, and motor dysfunction were assessed. Differences ≥10 points were deemed clinically relevant. The effect of WBRT on HRQoL was analysed in irradiated patients. RESULTS: A total of 160/175 patients eligible for the HRQoL study completed at least one questionnaire and were included. Over time, scores improved statistically significantly and were clinically relevant in both arms. Between arms, there were no differences on any scale (range: -3.8 to +4.0). Scores on all scales were improved to a clinically relevant extent at 12 and 24 months compared with baseline in both arms, except for fatigue and motor dysfunction at 12 months (-7.4 and -8.8, respectively). In irradiated patients (n = 59), scores in all preselected scales, except motor dysfunction, remained stable up to 24 months compared with shortly after WBRT, overall mean difference ranging between 0.02 and 4.570. CONCLUSION: Compared with baseline, treatment resulted in improved HRQoL scores. The addition of rituximab to standard chemotherapy did not impact HRQoL over time. WBRT did not result in deterioration of HRQoL in the first 2 years.

Withdrawal of antiepileptic drugs in patients with low grade and anaplastic glioma after long-term seizure freedom: a prospective observational study.

BACKGROUND: When glioma patients experience long-term seizure freedom the question arises whether antiepileptic drugs (AEDs) should be continued. As no prospective studies exist on seizure recurrence in glioma patients after AED withdrawal, we evaluated the decision-making process to withdraw AEDs in glioma patients, and seizure outcome after withdrawal. METHODS: Patients with a histologically confirmed low grade or anaplastic glioma were included. Eligible patients were seizure free ≥ 1 year from the date of last antitumor treatment, or ≥ 2 years since the last seizure when seizures occurred after the end of the last antitumor treatment. Patients and neuro-oncologists made a shared decision on the preferred AED treatment (i.e. AED withdrawal or continuation). Primary outcomes were: (1) outcome of the shared decision-making process and (2) rate of seizure recurrence. RESULTS: Eighty-three patients fulfilled all eligibility criteria. However, in 12/83 (14%) patients, the neuro-oncologist had serious objections to AED withdrawal. Therefore, 71/83 (86%) patients were analyzed; In 46/71 (65%) patients it was decided to withdraw AED treatment. In the withdrawal group, 26% (12/46) had seizure recurrence during follow-up. Seven of these 12 patients (58%) had tumor progression, of which three within 3 months after seizure recurrence. In the AED continuation group, 8% (2/25) of patients had seizure recurrence of which one had tumor progression. CONCLUSION: In 65% of patients a shared decision was made to withdraw AEDs, of which 26% had seizure recurrence. AED withdrawal should only be considered in carefully selected patients with a presumed low risk of tumor progression.

Clinical applicability of and changes in perfusion MR imaging in brain metastases after stereotactic radiotherapy.

To assess the applicability of perfusion-weighted (PWI) magnetic resonance (MR) imaging in clinical practice, as well as to evaluate the changes in PWI in brain metastases before and after stereotactic radiotherapy (SRT), and to correlate these changes to tumor status on conventional MR imaging. Serial MR images at baseline and at least 3 and 6 months after SRT were retrospectively evaluated. Size of metastases and the relative cerebral blood volume (rCBV), assessed with subjective visual inspection in the contrast enhanced area, were evaluated at each time point. Tumor behavior of metastases was categorized into four groups based on predefined changes on MRI during follow-up, or on histologically confirmed diagnosis; progressive disease (PD), pseudoprogression (PsPD), non-progressive disease (non-PD) and progression unspecified (PU). Twenty-six patients with 42 metastases were included. Fifteen percent (26/168) of all PW images could not be evaluated due to localization near large vessels or the scalp, presence of hemorrhage artefacts, and in 31% (52/168) due to unmeasurable residual metastases. The most common pattern (52%, 13/25 metastases) showed a high rCBV at baseline and low rCBV during follow-up, occurring in metastases with non-PD (23%, 3/13), PsPD (38%, 5/13) and PU (38%, 5/13). Including only metastases with a definite outcome generally showed low rCBV in PsPD or non-PD, and high rCBV in PD. Although non-PD and PsPD may be distinguished from PD after SRT using the PW images, the large proportion of images that could not be assessed due to artefacts and size severely hampers value of PWI in predicting tumor response after SRT.

Development of a questionnaire measuring instrumental activities of daily living (IADL) in patients with brain tumors: a pilot study.

Both dementia and brain tumor patients exhibit cognitive decline during the course of their disease. They might therefore experience similar problems with cognitively complex daily activities (i.e., instrumental activities of daily living (IADL)). The study's objective is to evaluate if the Amsterdam IADL Questionnaire© (A-IADL-Q), a 70-item IADL questionnaire developed for and validated in early dementia patients, is also applicable to glioma patients. The evaluation consisted of three steps. Predetermined decision rules defined which activities were retained, altered, added or excluded. In the first step, 6 neuro-oncology health care professionals (HCP) and 10 glioma patient-proxy dyads were asked to evaluate the 70 A-IADL-Q activities. In the second step, in-depth interviews were conducted with 6 HCPs and 6 other patient-proxy dyads to generate relevant activities specific to glioma patients not covered by the A-IADL-Q. In the third step, 6 new patient-proxy dyads were cognitively debriefed with the list of activities constructed in the previous steps. Results indicated that in step 1, after alterations and exclusions, 28/70 activities could be retained. Nine newly generated activities were subsequently added in step 2. In step 3, the 37 activities were presented to the patient-proxy dyads. Based on their input, several additional alterations and exclusions were made resulting in a list of 32 activities. In conclusion, this evaluation of the A-IADL-Q showed that dementia-specific IADL activities are only partly applicable to glioma patients, and that the addition of glioma specific IADL activities is necessary to capture the IADL construct. This underlines the need for a disease-specific IADL questionnaire for brain tumor patients.

Interobserver variability in the radiological assessment of magnetic resonance imaging (MRI) including perfusion MRI in glioblastoma multiforme.

BACKGROUND AND PURPOSE: Conventional magnetic resonance imaging (MRI) has limited value for differentiation of true tumor progression and pseudoprogression in treated glioblastoma multiforme (GBM). Perfusion weighted imaging (PWI) may be helpful in the differentiation of these two phenomena. Here interobserver variability in routine radiological evaluation of GBM patients is assessed using MRI, including PWI. METHODS: Three experienced neuroradiologists evaluated MR scans of 28 GBM patients during temozolomide chemoradiotherapy at three time points: preoperative (MR1) and postoperative (MR2) MR scan and the follow-up MR scan after three cycles of adjuvant temozolomide (MR3). Tumor size was measured both on T1 post-contrast and T2 weighted images according to the Response Assessment in Neuro-Oncology criteria. PW images of MR3 were evaluated by visual inspection of relative cerebral blood volume (rCBV) color maps and by quantitative rCBV measurements of enhancing areas with highest rCBV. Image interpretability of PW images was also scored. Finally, the neuroradiologists gave a conclusion on tumor status, based on the interpretation of both T1 and T2 weighted images (MR1, MR2 and MR3) in combination with PWI (MR3). RESULTS: Interobserver agreement on visual interpretation of rCBV maps was good (κ = 0.63) but poor on quantitative rCBV measurements and on interpretability of perfusion images (intraclass correlation coefficient 0.37 and κ = 0.23, respectively). Interobserver agreement on the overall conclusion of tumor status was moderate (κ = 0.48). CONCLUSIONS: Interobserver agreement on the visual interpretation of PWI color maps was good. However, overall interpretation of MR scans (using both conventional and PW images) showed considerable interobserver variability. Therefore, caution should be applied when interpreting MRI results during chemoradiation therapy.

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

During the end of life (EOL) phase of high-grade glioma (HGG) patients, care is primarily aimed at reducing symptom burden while maintaining quality of life as long as possible. In this study, we evaluated the prevalence of symptoms and medication management in HGG patients during the EOL phase. We analyzed disease-specific symptoms, general EOL symptoms, symptom frequency, and medication use at 3 months and 1 week before death in a cohort of 178 HGG patients, based on questionnaires completed by physicians responsible for EOL care. In addition, information on patient's perceived quality of care (QOC) was derived from 87 questionnaires completed by patient's relatives. Somnolence, focal neurological deficits and cognitive disturbances were the most prevalent symptoms during the EOL phase. Overall, disease-specific symptoms occurred more often than general EOL symptoms at both 3 months and 1 week before death. Somnolence and/or dysphagia were present in 81 % of patients whose medication was withdrawn and 96 % of patients in whom antiepileptic drugs (AEDs) were withdrawn. One week before death, 65.9 % of patients with high symptom frequency experienced good QOC, compared to 87.5 % of patients with low symptom frequency (p = 0.032). Disease-specific symptoms are the main concern in EOL care for HGG patients. Somnolence and dysphagia may hamper the regular oral administration of drugs, and particularly AEDs, during the EOL phase. High symptom frequency at 1 week before death negatively affects patient's perceived QOC.

End of life care in high-grade glioma patients in three European countries: a comparative study.

Exploring cross-national differences is useful to evaluate whether different patterns of end of life (EOL) care meet patient's specific needs. This study aimed to (1) compare EOL care processes for high-grade glioma (HGG) patients in three European countries, (2) explore differences in perceived quality of care (QOC), and (3) identify aspects of good QOC in the EOL phase. We analyzed 207 questionnaires from relatives of deceased HGG patients, using a similar retrospective study design in three countries [The Netherlands (n = 83), Austria (n = 72) and the UK (n = 52)], and examined four subthemes: (1) organization of EOL care, (2) treatment preferences, (3) experiences with EOL care, (4) perceived QOC. Three months before death 75 % of patients were at home. In all countries, on average, 50 % were transferred to a hospital at least once and received effective symptom treatment during the last 3 months. In The Netherlands, Austria and UK, respectively, patients most often died at home (60 %), in a hospital (41 %) or hospice (41 %) (p < 0.001). Advance directives were present in 46 % of Dutch, 36 % of British and 6 % of Austrian patients (p < 0.001). Fifty-three percent of patients experienced good QOC, irrespective of country. Dying at the preferred place, satisfaction with information provided and effective symptom treatment were independently associated with good QOC. There are various cross-national differences in organization and experiences with EOL care for HGG, but patient's perceived QOC is similar in the three countries. As symptom treatment was considered effective in only half of HGG patients, and independently predicted good QOC, this particularly needs further improvement in all countries.

Does change in health-related quality of life score predict survival? Analysis of EORTC 08975 lung cancer trial.

BACKGROUND: Little is known about whether changes in health-related quality of life (HRQoL) scores from baseline during treatment also predict survival, which we aim to investigate in this study. METHODS: We analysed data from 391 advanced non-small-cell lung cancer (NSCLC) patients enrolled in the EORTC 08975 study, which compared palliative chemotherapy regimens. HRQoL was assessed at baseline and after each chemotherapy cycle using the EORTC QLQ-C30 and QLQ-LC13. The prognostic significance of HRQoL scores at baseline and their changes over time was assessed with Cox regression, after adjusting for clinical and socio-demographic variables. RESULTS: After controlling for covariates, every 10-point increase in baseline pain and dysphagia was associated with 11% and 12% increased risk of death with hazard ratios (HRs) of 1.11 and 1.12, respectively. Every 10-point improvement of physical function at baseline (HR=0.93) was associated with 7% lower risk of death. Every 10-point increase in pain (HR=1.08) was associated with 8% increased risk of death at cycle 1. Every 10-point increase in social function (HR=0.91) at cycle 2 was associated with 9% lower risk of death. CONCLUSIONS: Our findings suggest that changes in HRQoL scores from baseline during treatment, as measured on subscales of the EORTC QLQ-C30 and QLQ-LC13, are significant prognostic factors for survival.

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

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.

Minimal clinically meaningful differences for the EORTC QLQ-C30 and EORTC QLQ-BN20 scales in brain cancer patients.

BACKGROUND: We aimed to determine the smallest changes in health-related quality of life (HRQoL) scores in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core 30 and the Brain Cancer Module (QLQ-BN20), which could be considered as clinically meaningful in brain cancer patients. MATERIALS AND METHODS: World Health Organisation performance status (PS) and mini-mental state examination (MMSE) were used as clinical anchors appropriate to related subscales to determine the minimal clinically important differences (MCIDs) in HRQoL change scores (range 0-100) in the QLQ-C30 and QLQ-BN20. A threshold of 0.2 standard deviation (SD) (small effect) was used to exclude anchor-based MCID estimates considered too small to inform interpretation. RESULTS: Based on PS, our findings support the following integer estimates of the MCID for improvement and deterioration, respectively: physical (6, 9), role (14, 12), and cognitive functioning (8, 8); global health status (7, 4*), fatigue (12, 9), and motor dysfunction (4*, 5). Anchoring with MMSE, cognitive functioning MCID estimates for improvement and deterioration were (11, 2*) and for communication deficit were (9, 7). Estimates with asterisks were <0.2 SD and were excluded from our MCID range of 5-14. CONCLUSION: These estimates can help clinicians evaluate changes in HRQoL over time, assess the value of a health care intervention and can be useful in determining sample sizes in designing future clinical trials.

Efficacy of anti-epileptic drugs in patients with gliomas and seizures.

Although seizures in brain tumor patients are common, the knowledge on optimal anti-seizure therapy in this patient group is limited. An observational study was carried out using a database of all patients from the neuro-oncology service during the period 2000-2005, with data on seizure characteristics, therapy with AEDs, the underlying brain tumor and its treatment. A total of 140 brain tumor patients were studied of whom 23.6% had a low-grade glioma, 53.6% a high-grade glioma, and 22.8% belonged to a mixed group existing of ependymoma, meningioma, and brain metastasis. Epilepsy as the presenting sign was more frequent in low-grade vs. high-grade gliomas (69.7 vs. 52%, P = 0.087), and a total of 75.8% of patients developed seizures with low-grade and of 80.0% with high-grade gliomas. Of all 99 patients with seizures, 80.1% received valproic acid (VPA) as first choice, and either levetiracetam (LEV), carbamazepine (CBZ) or lamotrigine (LMT) as the most frequent next choice. Patients treated with a combination of VPA and LEV showed the highest percentage of responders (81.5%), with a decline in seizure frequency of more than two categories in 55.6% and seizure freedom in 59%. No correlation was found between the use of VPA and survival. A combination of VPA and LEV seems effective, if seizure control cannot be achieved by VPA alone. This indicates that adding levetiracetam may be preferable over sequential trials of AED monotherapy in treatment-resistant seizures in patients with brain tumors.

[Three patients with tuberculous meningitis: treatment started at tentative diagnosis]. / Drie patiënten met tuberculeuze meningitis; behandeling al starten bij waarschijnlijkheidsdiagnose.

A 30-year-old man and a 37-year-old woman with no history of tuberculosis developed symptoms of headache, vomiting and subsequent aggressive behaviour. After several lumbar punctures, the PCR test for tuberculosis in the cerebrospinal fluid was positive, and a definitive diagnosis of tuberculous meningitis was made. Treatment with antimycobacterial agents was not started until a few days after hospital admission. The man recovered, but was treated for brainstem tuberculoma 12 months later; the woman died on day 11 of hospitalisation. A third patient, a 31-year-old man, was admitted to the hospital for miliary tuberculosis. He had signs of progressive apathy and meningismus. Mycobacterium tuberculosis was found in his cerebrospinal fluid. Each of these patients underwent cerebrospinal fluid drainage due to communicating hydrocephalus and each had hyponatraemia. Tuberculous meningitis is a lethal complication of tuberculosis that is often diagnosed late due to the insidious nature of its symptoms. Early treatment with antituberculous drugs and dexamethasone--even before a definitive microbiological diagnosis is made--may prevent severe neurological damage and death.

The prognostic value of health-related quality-of-life data in predicting survival in glioblastoma cancer patients: results from an international randomised phase III EORTC Brain Tumour and Radiation Oncology Groups, and NCIC Clinical Trials Group study.

This is one of the few studies that have explored the value of baseline symptoms and health-related quality of life (HRQOL) in predicting survival in brain cancer patients. Baseline HRQOL scores (from the EORTC QLQ-C30 and the Brain Cancer Module (BN 20)) were examined in 490 newly diagnosed glioblastoma cancer patients for the relationship with overall survival by using Cox proportional hazards regression models. Refined techniques as the bootstrap re-sampling procedure and the computation of C-indexes and R(2)-coefficients were used to try and validate the model. Classical analysis controlled for major clinical prognostic factors selected cognitive functioning (P=0.0001), global health status (P=0.0055) and social functioning (P<0.0001) as statistically significant prognostic factors of survival. However, several issues question the validity of these findings. C-indexes and R(2)-coefficients, which are measures of the predictive ability of the models, did not exhibit major improvements when adding selected or all HRQOL scores to clinical factors. While classical techniques lead to positive results, more refined analyses suggest that baseline HRQOL scores add relatively little to clinical factors to predict survival. These results may have implications for future use of HRQOL as a prognostic factor in cancer patients.

Neuronavigation and surgery of intracerebral tumours.

Approximately four decades after the successful clinical introduction of framebased stereotactic neurosurgery by Spiegel and Wycis, frameless stereotaxy emerged to enable more elaborate image guidance in open neurosurgical procedures. Frameless stereotaxy, or neuronavigation, relies on one of several different localizing techniques to determine the position of an operative instrument relative to the surgical field, without the need for a coordinate frame rigidly fixed to the patients' skull. Currently, most systems are based on the optical triangulation of infrared light sources fixed to the surgical instrument. In its essence, a navigation system is a three-dimensional digitiser that correlates its measurements to a reference data set, i.e. a preoperatively acquired CT or MRI image stack. This correlation is achieved through a patient-to-image registration procedure resulting in a mathematical transformation matrix mapping each position in 'world space' onto 'image space'. Thus, throughout the remainder of the surgical procedure, the position of the surgical instrument can be demonstrated on a computer screen, relative to the CT or MRI images. Though neuronavigation has become a routinely used addition to the neurosurgical armamentarium, its impact on surgical results has not yet been examined sufficiently. Therefore, the surgeon is left to decide on a case-by-case basis whether to perform surgery with or without neuronavigation. Future challenges lie in improvement of the interface between the surgeon and the neuronavigator and in reducing the brainshift error, i.e. inaccuracy introduced by changes in tissue positions after image acquisition.

Interleukin-8 CSF levels predict survival in patients with leptomeningeal metastases.

Median survival of patients with leptomeningeal metastases (LM) is 4 to 6 months, with a few long-term survivors. Current prognostic factors for survival have limited value. The authors measured the CSF levels of nine inflammatory proteins in 57 patients with LM and determined their prognostic value. High interleukin (IL)-8 CSF levels predicted short-term survival independently. The data indicate that IL-8 CSF levels may serve as a prognosticator in patients with LM, but prospective validation is needed.

CSF levels of angiogenesis-related proteins in patients with leptomeningeal metastases.

The authors determined the levels of vascular endothelial growth factor (VEGF) and urokinase-type plasminogen activator (uPA) in the CSF of patients with leptomeningeal metastases (LM; n = 53), cancer patients without LM (n = 18), and subjects without malignancy (n = 25). Median levels of uPA and VEGF were significantly higher in patients with LM, supporting the hypothesis that angiogenesis contributes to LM. VEGF was negatively correlated with survival in patients with LM, suggesting its use as a prognostic factor.

Proton MRS imaging in the follow-up of patients with suspected low-grade gliomas.

We compared the value of changes in proton magnetic resonance spectroscopic imaging ((1)H-MRSI) with changes in clinical status and/or contrast-enhanced magnetic resonance imaging (MRI) in the monitoring of patients with suspected low-grade glioma (LGG). From June 1, 1999 till May 31, 2002, we included consecutive, neurologically intact adult patients suspected of having an LGG, demonstrating non-enhancing supratentorial lesions without edema or mass effect on MRI, and in whom all treatment (including a diagnostic biopsy) was deferred. Till January 1, 2003, patients were surveyed clinically and radiologically (contrast-enhanced MRI and (1)H-MRSI). Patients who showed progression on clinical examination and/or MRI were denoted as progressive disease. Other patients were denoted as stable disease. A decrease in NAA/CHO ratio of > or =20% compared to the baseline value was considered as indicative for progression on (1)H-MRSI. We included 14 patients with suspected LGG. Seven patients demonstrated progressive disease during the follow-up period, preceded or accompanied by concomitant (1)H-MRSI changes in five patients. Four of these five patients were operated on within the follow-up interval. The histological diagnosis demonstrated high-grade glioma in three and LGG in one patient. In the other two patients with progressive disease, no progression was found on (1)H-MRSI. The other seven patients demonstrated stable disease, but four of them showed progression on (1)H-MRSI. Our data do not show convincing evidence that (1)H-MRSI contributes to adequate monitoring and follow-up of patients with suspected LGG. Future research should preferably include pathological data at the time of (1)H-MRSI changes.

[Impaired cognitive functioning in low-grade glioma patients: relationship to tumor localisation, radiotherapy and the use of anticonvulsants]. / Verminderd cognitief functioneren van patiënten met een laaggradig glioom: samenhang met de tumorlokalisatie, de bestraling en het gebruik van anti-epileptica.

OBJECTIVE: To determine the effects of radiotherapy and other medical interventions on cognitive functioning in patients with a low-grade glioma (LGG). DESIGN: Cross-sectional study. METHOD: A total of 195 LGG patients, of whom 104 had received radiotherapy 1-22 years previously, were compared to 100 patients with a low-grade haematological malignancy and 195 healthy controls. The analysis was aimed at differentiating between the effects of the tumour (disease duration, lateralisation) and treatment effects (neurosurgery, radiotherapy, use of anticonvulsants) on cognitive function and the relative risk of cognitive disability. RESULTS: LGG patients had lower performance levels in all cognitive domains than haematological patients and performed even worse when they were compared to healthy controls. Radiotherapy was associated with poorer cognitive functioning; however, cognitive disability was found only in patients receiving fractional doses exceeding 2 Gy. The use of anticonvulsants was strongly associated with disorders in the area of attention and planning functions. CONCLUSION: In this study, the tumour itself was the most damaging factor with respect to cognitive function and radiotherapy was associated with cognitive disability only if elevated fractional doses were used. Epilepsy or the use of anticonvulsants was also associated with diminished cognitive functioning.