Frequency and burden of potentially treatable symptoms in glioma patients with stable disease.

Background & aims: Glioma patients experience a multitude of symptoms that negatively affect their health-related quality of life. Symptoms vary greatly across disease phases, and the patients' stable phase might be particularly suitable for assessing and treating symptoms. Identifying symptoms and patients' needs is a first step toward improving patient care. In glioma patients with stable disease, we assessed the frequency and burden of patient-reported symptoms, examined how these symptoms co-occur, and also determined whether patients would consider treatment to ameliorate specific symptoms. Methods: In this retrospective study, patients rated the frequency and burden of seventeen symptoms on a seven-point Likert scale and stated whether they would consider treatment for these symptoms. Correlations between frequency, burden, and considering treatment were evaluated with Kendall's Tau correlation coefficients. Based on partial correlations between symptom frequencies we visualized the symptoms as a network. Results: Fifty-two glioma patients with stable disease were included (31 WHO grade II/III, 21 WHO grade IV). The top five symptoms were fatigue, memory problems, reduced physical fitness, concentration problems, and drowsiness. Fatigue had the highest median frequency (4.5, interquartile range 2.5). Over half of the patients experienced three or more symptoms simultaneously and associations between all symptoms were depicted as a network. Overall, 35% of patients would consider treatment for at least one symptom. The wish to undergo symptom treatment correlated only moderately with symptom frequency and burden (range of correlations 0.24-0.57 and 0.28-0.61, respectively). Conclusion: Glioma patients with stable disease experience multiple symptoms with a consequently high symptom burden. Despite the high prevalence of symptoms, the inclination for symptom management interventions was relatively low. The most frequent and burdensome symptoms and the way they are interrelated could serve as a roadmap for future research on symptom management in these patients.

Prospective validation of a new imaging scorecard to assess leptomeningeal metastasis: A joint EORTC BTG and RANO effort.

BACKGROUND: Validation of the 2016 RANO MRI scorecard for leptomeningeal metastasis failed for multiple reasons. Accordingly, this joint EORTC Brain Tumor Group and RANO effort sought to prospectively validate a revised MRI scorecard for response assessment in leptomeningeal metastasis. METHODS: Coded paired cerebrospinal MRI of 20 patients with leptomeningeal metastases from solid cancers at baseline and follow-up after treatment and instructions for assessment were provided via the EORTC imaging platform. The Kappa coefficient was used to evaluate the interobserver pairwise agreement. RESULTS: Thirty-five raters participated, including 9 neuroradiologists, 17 neurologists, 4 radiation oncologists, 3 neurosurgeons, and 2 medical oncologists. Among single leptomeningeal metastases-related imaging findings at baseline, the best median concordance was noted for hydrocephalus (Kappa = 0.63), and the worst median concordance for spinal linear enhancing disease (Kappa = 0.46). The median concordance of raters for the overall response assessment was moderate (Kappa = 0.44). Notably, the interobserver agreement for the presence of parenchymal brain metastases at baseline was fair (Kappa = 0.29) and virtually absent for their response to treatment. 394 of 700 ratings (20 patients x 35 raters, 56%) were fully completed. In 308 of 394 fully completed ratings (78%), the overall response assessment perfectly matched the summary interpretation of the single ratings as proposed in the scorecard instructions. CONCLUSION: This study confirms the principle utility of the new scorecard, but also indicates the need for training of MRI assessment with a dedicated reviewer panel in clinical trials. Electronic case report forms with "blocking options" may be required to enforce completeness and quality of scoring.

A multidisciplinary neuro-oncological triage panel reduces the time to referral and treatment for patients with a brain tumor.

BACKGROUND: Regional collaboration and appropriate referral management are crucial in neuro-oncological care. Lack of electronic access to medical records across health care organizations impedes interhospital consultation and may lead to incomplete and delayed referrals. To improve referral management, we have established a multidisciplinary neuro-oncological triage panel (NOTP) with digital image exchange and determined the effects on lead times, costs, and time investment. METHODS: A prospective cohort study was conducted from February 2019 to March 2020. All newly diagnosed patients referred to Brain Tumor Center Amsterdam were analyzed according to referral pathway: (1) standard referral (SR), (2) NOTP. The primary outcome was lead time, defined as time-to-referral, time-to-treatment, and total time (median days [interquartile range]). Secondary outcomes were costs and time investment. RESULTS: In total, 225 patients were included, of whom 153 had SR and 72 NOTP referral. Patients discussed in the NOTP were referred more frequently for first neurosurgical consultation (44.7% vs 28.8%) or combined neurological and neurosurgical consultation (12.8% vs 2.5%, P = .002). Time-to-referral was reduced for NOTP referral compared to SR (1 [0.25-4] vs 6 [1.5-10] days, P < .001). Total time decreased from 27 [14-48] days for the standard group to 15 [12-38.25] days for the NOTP group (P = .040). Costs and time investment were comparable for both groups. CONCLUSION: Implementation of digital referral to a multidisciplinary NOTP is feasible and leads to more swift patient-tailored referrals at comparable costs and time investment as SR. This quality improvement initiative has the potential to improve collaboration and coordination of multidisciplinary care in the field of neuro-oncology.

The RANO Leptomeningeal Metastasis Group proposal to assess response to treatment: lack of feasibility and clinical utility and a revised proposal.

BACKGROUND: A scorecard to evaluate magnetic resonance imaging (MRI) findings during the course of leptomeningeal metastases (LM) has been proposed by the Response Assessment in Neuro-Oncology (RANO) group. METHODS: To explore the feasibility of the Leptomeningeal Assessment in Neuro-Oncology (LANO) scorecard, cerebrospinal MRIs of 22 patients with LM from solid tumors were scored by 10 neuro-oncologists and 9 neuroradiologists at baseline and at follow-up after treatment. Raters were blinded for clinical data including treatment. Agreement between raters of single items was evaluated using a Krippendorff alpha coefficient. Agreement between numerical parameters such as scores for changes between baseline and follow-up and total scores was evaluated by determining the intraclass coefficient of correlation. RESULTS: Most raters experienced problems with the instructions of the scorecard. No acceptable alpha concordance coefficient was obtained for the rating of single items at baseline or follow-up. The most concordant ratings were obtained for spinal nodules. The concordances were worst for brain linear leptomeningeal enhancement and cranial nerve enhancement. Discordance was less prominent among neuroradiologists than among neuro-oncologists. High variability was also observed for evaluating changes between baseline and follow-up and for total scores. CONCLUSIONS: Assessing response of LM by MRI remains challenging. Central imaging review is therefore indispensable for clinical trials. Based on the present results, we propose a new, simplified scorecard that will require validation using a similar approach as pursued here. The main challenges are to define measurable versus nonmeasurable (target) lesions and measures of change that allow assessment of response.

Patients' and physicians' interpretation of chemotherapy-induced peripheral neurotoxicity.

To test if and how chemotherapy-induced peripheral neurotoxicity (CIPN) is perceived differently by patients and physicians, making assessment and interpretation challenging. We performed a secondary analysis of the CI-PeriNomS study which included 281 patients with stable CIPN. We tested: (a) the association between patients' perception of activity limitation in performing eight common tasks and neurological impairment and (b) how the responses to questions related to these daily activities are interpreted by the treating oncologist. To achieve this, we compared patients' perception of their activity limitation with neurological assessment and the oncologists' blind interpretation. Distribution of the scores attributed by oncologists to each daily life maximum limitation ("impossible") generated three groups: Group 1 included limitations oncologists attributed mainly to motor impairment; Group 2 ones mainly attributed to sensory impairment and Group 3 ones with uncertain motor and sensory impairment. Only a subset of questions showed a significant trend between severity in subjective limitation, reported by patients, and neurological impairment. In Group 1, neurological examination confirmed motor impairment in only 51%-65% of patients; 76%-78% of them also had vibration perception impairment. In Group 2, sensory impairment ranged from 84% to 100%; some degree of motor impairment occurred in 43%-56% of them. In Group 3 strength reduction was observed in 49%-50% and sensory perception was altered in up to 82%. Interpretation provided by the panel of experienced oncologists was inconsistent with the neurological impairment. These observations highlight the need of a core set of outcome measures for future CIPN trials.

Visual inspection of MR relative cerebral blood volume maps has limited value for distinguishing progression from pseudoprogression in glioblastoma multiforme patients.

AIM: We examined whether visual interpretation of relative cerebral blood volume (rCBV) color maps made with dynamic susceptibility-weighted perfusion MRI can reliably distinguish progressive disease (PD) from pseudoprogression (PsPD) in glioblastoma patients during treatment with temozolomide chemoradiation. MATERIALS & METHODS: Magnetic resonance (MR) perfusion-weighted images were evaluated based on visual inspection of rCBV maps. Sensitivity and specificity were calculated to assess if rCBV can reliably differentiate between PD and PsPD, during standard chemoradiation therapy. RESULTS: Evaluation of dynamic susceptibility-weighted contrast-enhanced perfusion MRI by visual interpretation of rCBV maps did not differentiate PD from PsPD (sensitivity = 72%; specificity = 23%). Furthermore, the interpretation of the rCBV maps had no prognostic value regarding survival. CONCLUSION: Qualitative rCBV-based dynamic susceptibility-weighted contrast-enhanced perfusion MRI does not reliably differentiate PD from PsPD, and is not prognostic for survival in glioblastoma multiforme patients during treatment with temozolomide chemoradiation.

Evaluation of the psychometric properties of the EORTC chemotherapy-induced peripheral neuropathy questionnaire (QLQ-CIPN20).

PURPOSE: To investigate the scale structure and psychometrics of the EORTC chemotherapy-induced peripheral neuropathy module (QLQ-CIPN20). METHODS: Using confirmatory factor analyses (CFA), we tested two hypothesized scale structure models of the QLQ-CIPN20 in 473 patients with non-small cell lung cancer, 281 patients with heterogeneous cancer diagnoses, and 500 patients with colorectal cancer. We also modeled the two hypothesized models as bi-factor models. These included a general factor, in addition to the specific domain factors. Additional models were investigated with exploratory factor analysis (EFA). Known groups validity was evaluated where justified. RESULTS: CFA could not confirm the two hypothesized models (Model 1: CFI < 0.926; TLI < 0.914; RMSEA > 0.077 and Model 2: CFI < 0.906; TLI < 0.887; RMSEA > 0.105) in any of the three samples. Including a general factor to these two hypothesized models to produce a bi-factor model also did not yield satisfactory results. Using EFA, we identified four different factor structures in the three samples that were unstable due to cross loadings of the items. When scoring the QLQ-CIPN20 as a simple, additive checklist evidence was found for known groups validity in the first two samples based on Common Toxicity Criteria (CTC-AE), and in the third sample based on exposure to CIPN-inducing chemotherapy. CONCLUSIONS: Neither CFA nor EFA yielded support for a stable subscale structure for the QLQ-CIPN20. Scoring the questionnaire as a simple additive checklist results in acceptable validity.

Seizure reduction is a prognostic marker in low-grade glioma patients treated with temozolomide.

We aimed to analyze the value of seizure reduction and radiological response as prognostic markers of survival in patients with low-grade glioma (LGG) treated with temozolomide (TMZ) chemotherapy. We retrospectively reviewed adult patients with a progressive LGG and uncontrolled epilepsy in two hospitals (VUmc Amsterdam; MCH The Hague), who received chemotherapy with TMZ between 2002 and 2014. End points were a ≥50 % seizure reduction and MRI response 6, 12 and 18 months (mo) after the start of TMZ, and their relation with progression-free survival (PFS) and overall survival (OS). We identified 53 patients who met the inclusion criteria. Seizure reduction was an independent prognostic factor for both PFS (HR 0.38; 95 % CI 0.19-0.73; p = 0.004) and OS (HR 0.39; 95 % CI 0.18-0.85; p = 0.018) after 6mo, adjusting for age and histopathological diagnosis, as well as after 12 and 18mo. Patients with an objective radiological response showed a better OS (median 87.5mo; 95 % CI 62.0-112.9) than patients without a response (median 34.4mo; 95 % CI 26.1-42.6; p = 0.046) after 12mo. However, after 6 and 18mo OS was similar in patients with and without a response on MRI. Seizure reduction is an early and consistent prognostic marker for survival after treatment with TMZ, that seems to precede the radiological response. Therefore, seizure reduction may serve as a surrogate marker for tumor response.

Antiepileptic drug treatment in the end-of-life phase of glioma patients: a feasibility study.

BACKGROUND: During the end-of-life (EOL) phase of glioma patients, a rapid deterioration in neurological functioning may interfere with the oral intake of antiepileptic drugs (AEDs). We aimed to assess the feasibility of non-oral AED treatment in an out-of-hospital setting according to an expert-based guideline. METHODS: Glioma patients with a history of epilepsy, in whom further antitumor therapy was considered to be no longer meaningful, were recruited at two Dutch hospitals. As soon as swallowing difficulties developed, the patient's caregiver administered prophylactic treatment with buccal clonazepam. Acute seizures were treated with intranasal midazolam. We evaluated the adherence to the study medication, seizure prevalence, and caregiver's satisfaction. RESULTS: Of the 34 patients who were approached, 25 gave consent to participate and 23 had died at the end of the study. Thirteen of 19 patients (68.4 %) who had developed swallowing difficulties showed adherence to the study protocol. Thirteen patients used prophylactic buccal clonazepam, of which eight patients remained seizure-free until death. Six patients received treatment with intranasal midazolam at least once. In all patients, seizure control was reached. None of the patients needed to be transferred to the hospital due to recurrent seizures. All caregivers were to some degree satisfied with the use of the study medication. CONCLUSIONS: Our results demonstrate that it is feasible to treat seizures with a combination of non-oral benzodiazepines in the EOL phase of glioma patients, as it seems to provide an important level of comfort among caregivers to be able to manage seizures at home.

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.