Development and psychometric evaluation of item banks for memory and attention - supplements to the EORTC CAT Core instrument.

BACKGROUND: Cancer patients may experience a decrease in cognitive functioning before, during and after cancer treatment. So far, the Quality of Life Group of the European Organisation for Research and Treatment of Cancer (EORTC QLG) developed an item bank to assess self-reported memory and attention within a single, cognitive functioning scale (CF) using computerized adaptive testing (EORTC CAT Core CF item bank). However, the distinction between different cognitive functions might be important to assess the patients' functional status appropriately and to determine treatment impact. To allow for such assessment, the aim of this study was to develop and psychometrically evaluate separate item banks for memory and attention based on the EORTC CAT Core CF item bank. METHODS: In a multistep process including an expert-based content analysis, we assigned 44 items from the EORTC CAT Core CF item bank to the memory or attention domain. Then, we conducted psychometric analyses based on a sample used within the development of the EORTC CAT Core CF item bank. The sample consisted of 1030 cancer patients from Denmark, France, Poland, and the United Kingdom. We evaluated measurement properties of the newly developed item banks using confirmatory factor analysis (CFA) and item response theory model calibration. RESULTS: Item assignment resulted in 31 memory and 13 attention items. Conducted CFAs suggested good fit to a 1-factor model for each domain and no violations of monotonicity or indications of differential item functioning. Evaluation of CATs for both memory and attention confirmed well-functioning item banks with increased power/reduced sample size requirements (for CATs ≥ 4 items and up to 40% reduction in sample size requirements in comparison to non-CAT format). CONCLUSION: Two well-functioning and psychometrically robust item banks for memory and attention were formed from the existing EORTC CAT Core CF item bank. These findings could support further research on self-reported cognitive functioning in cancer patients in clinical trials as well as for real-word-evidence. A more precise assessment of attention and memory deficits in cancer patients will strengthen the evidence on the effects of cancer treatment for different cancer entities, and therefore contribute to shared and informed clinical decision-making.

A qualitative study on the challenges health care professionals face when caring for adolescents and young adults with an uncertain and/or poor cancer prognosis.

BACKGROUND: Adolescents and young adults (AYAs, aged 18-39 years) with advanced cancer have an increased life expectancy due to improvements and refinements in cancer therapies, resulting in a growing group of AYAs living with an uncertain and/or poor cancer prognosis (UPCP). To date, no studies have examined the difficulties of health care professionals (HCPs) providing care to AYAs with a UPCP. This study aimed to understand the challenges in daily clinical practice experienced by HCPs from different disciplines who provide palliative as well as general care to AYAs with a UPCP. METHODS: HCPs from a variety of backgrounds (e.g. clinical nurse specialists, medical oncologists, neurologists psychologists) were invited for a semi-structured interview. The interviews were transcribed verbatim and analysed using reflexive thematic analysis. Two AYA patients were actively involved as research partners to increase the relevance of the study design and to optimise interpretation of results. RESULTS: Forty-nine HCPs were interviewed. Overall, we found that the threat of premature death within this young patient group increased emotional impact on HCPs and evoked a feeling of unfairness, which was an extra motivation for HCPs to provide the most optimal care possible. We generated four key themes: (i) emotional confrontation (e.g. feeling helplessness and experiencing a greater sense of empathy), (ii) questioning own professional attitude and skills, (iii) navigating uncertainty (e.g. discussing prognosis and end of life) and (iv) obstacles in the health care organisation (e.g. lack of knowledge and clarity about responsibilities). CONCLUSIONS: HCPs experienced unique emotional and practical challenges when providing care to AYAs with a UPCP. The results from this study highlight the need to develop an education module for HCPs treating AYAs with UPCP to increase their own well-being and optimise the delivery of person- and age-adjusted care.

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.

Risk of alanine transferase (ALT) elevation in patients with rheumatoid arthritis treated with methotrexate in a DAS-steered strategy.

OBJECTIVE: To determine incidence of increased levels of alanine transferase (ALT) >2× upper limit of normal (ULN) in patients receiving methotrexate (MTX), treated according to a dynamic strategy, and to identify predictors of ALT of >2× ULN. METHODS: Data of 508 recent-onset rheumatoid arthritis (RA) patients from the BeSt study, randomized to initial monotherapy or combination therapy, were used. Treatment was dynamic, aiming at a disease activity score = ≤ 2.4. ALT was measured every three months. With logistic regression analyses, baseline variables predictive of first ALT of >2× ULN were identified and the association between use of concomitant antirheumatic drugs, the actual and cumulative dose of MTX and ALT of >2× ULN was determined. RESULTS: In total, 498 patients ever initiated MTX, with a total duration on MTX of 1,416 patient-years. In 89 patients, a first incidence of ALT of >2× ULN occurred. Incidence rate was 6.3 per 100 patient-years and cumulative incidence 18 %. ACPA positivity and baseline ALT of >1× ULN were independent predictors of later ALT of >2× ULN (OR 1.8 (95 % CI, 1.1-3.1) and OR 3.1 (95 % CI, 1.6-6.2), respectively). Smoking showed a trend (OR 1.6 (95 % CI, 0.98-2.7)). Mean MTX dosage over time was higher in patients with an ALT of >2× ULN. Patients who did not have an ALT of >2× ULN used more concomitant disease-modifying antirheumatic drugs and longer. CONCLUSIONS: In RA patients treated with MTX according to a dynamic strategy resembling daily clinical practice, incidence of increased ALT of >2× ULN was lower than previously reported, and also without treatment adjustments, persistence was rare. The recommendations for ALT monitoring may be reevaluated.

Risk factors for reported influenza and influenza-like symptoms in patients with rheumatoid arthritis.

OBJECTIVES: To determine the prevalence and predictors of influenza and influenza-like symptoms in patients with rheumatoid arthritis (RA). METHOD: Questionnaires were sent to patients registered as having RA and they were asked to fill in per month any period and details of influenza-like symptoms and vaccination. An experienced rheumatologist assessed the level of disease activity and use of anti-rheumatic medication. The prevalence of reported influenza (fever > 38°C, headache, muscle soreness, and coughing and/or dyspnoea) and influenza-like symptoms was determined and risk factors were identified by logistic regression analysis. RESULTS: Of the 1692 patients approached, 783 (46%) patients were eligible for follow-up. Fifty per cent of the patients reported influenza-like symptoms, 5.9% had symptoms suggesting influenza, and 74% reported vaccination. The prevalence of influenza and influenza-like symptoms per month ranged from 0.0% to 2.3% and from 10.4% to 19.7%, respectively. Anti-tumour necrosis factors (anti-TNFs) [odds ratio (OR) 2.4, 95% confidence interval (CI) 1.2-4.8] and body mass index (BMI) (OR 1.06, 95% CI 1.0-1.1) were independently associated with symptoms of influenza. A trend was found for patients not in remission, patients using leflunomide, and patients with previous lung conditions. Independent risk factors of influenza-like symptoms were age (OR 0.98, 95% CI 0.97-0.99), female gender (OR 1.8, 95% CI 1.3-2.5), influenza vaccination (OR 1.6, 95% CI 1.1-2.4), and previous lung condition (OR 1.7, 95% CI 1.2-2.4). CONCLUSIONS: In 2009-2010, the prevalence of reported influenza in patients with RA was 5.9%. Patients using anti-TNFs and with higher BMI seemed to be more at risk for influenza symptoms. Milder upper respiratory tract infections were reported more often by females, younger patients, and those vaccinated against influenza or with previous lung conditions.

Discontinuation of infliximab and potential predictors of persistent low disease activity in patients with early rheumatoid arthritis and disease activity score-steered therapy: subanalysis of the BeSt study.

OBJECTIVE: To describe the disease course after the cessation of infliximab in early rheumatoid arthritis patients with disease activity score (DAS)-steered treatment and to identify predictors of persistent low disease activity. METHODS: In a post-hoc analysis of the BeSt study, disease activity and joint damage progression were observed in patients treated with methotrexate plus infliximab, who discontinued infliximab after achieving low disease activity (DAS ≤2.4) for 6 months. Predictors were identified using Cox regression analysis. RESULTS: 104 patients discontinued infliximab, of whom 77 had received infliximab plus methotrexate as initial treatment. Mean DAS at the time of infliximab cessation was 1.3, median symptom duration was 23 months and median Sharp/van derHeijde score was 5.5. The median follow-up was 7.2 years. Infliximab was re-introduced after loss of low disease activity in 48%, after a median of 17 months. The joint damage progression rate did not increase in the year after cessation, regardless of flare. After re-introduction of infliximab, 84% of these patients again achieved a DAS ≤2.4. In the multivariable model, smoking, infliximab treatment duration ≥18 months and shared epitope (SE) were independently associated with the re-introduction of infliximab: 6% of the non-smoking, SE-negative patients treated <18 months needed infliximab re-introduction. CONCLUSION: Cessation of infliximab was successful in 52%, with numerically higher success rates in patients initially treated with infliximab. Of the 48% who flared, 84% regained low disease activity. The joint damage progression rate did not increase in the year after cessation. Smoking, long infliximab treatment duration and SE were independently associated with re-introduction of infliximab.