Thrombocytopenia limits the feasibility of salvage lomustine chemotherapy in recurrent glioblastoma: a secondary analysis of EORTC 26101

BACKGROUND Thrombocytopenia represents the main cause of stopping alkylating chemotherapy for toxicity. Here, we explored the incidence, and the consequences for treatment exposure and survival, of thrombocytopenia induced by lomustine in recurrent glioblastoma. METHODS We performed a retrospective analysis of the associations of thrombocytopenia with treatment delivery and outcome in EORTC 26101, a randomised trial designed to define the role of lomustine versus bevacizumab versus their combination in recurrent glioblastoma. RESULTS A total of 225 patients were treated with lomustine alone (median 1 cycle) (group 1) and 283 patients were treated with lomustine plus bevacizumab (median 3 lomustine cycles) (group 2). Among cycle delays and dose reductions of lomustine for toxicity, thrombocytopenia was the leading cause. Among 129 patients (57%) of group 1 and 187 patients (66%) of group 2 experiencing at least one episode of thrombocytopenia, 36 patients (16%) in group 1 and 93 (33%) in group 2 had their treatment modified because of thrombocytopenia. Lomustine was discontinued for thrombocytopenia in 16 patients (7.1%) in group 1 and in 38 patients (13.4%) in group 2. On adjusted analysis accounting for major prognostic factors, dose modification induced by thrombocytopenia was associated with inferior progression-free survival in patients with MGMT promoter-methylated tumours in groups 1 and 2. This effect was noted for overall survival, too, but only for group 2 patients. CONCLUSION Drug-induced thrombocytopenia is a major limitation to adequate exposure to lomustine chemotherapy in recurrent glioblastoma. Mitigating thrombocytopenia to enhance lomustine exposure might improve outcome in patients with MGMT promoter-methylated tumours

Prediagnostic presentations of glioma in primary care: a case–control study

Aim: This study aimed to assess the prevalence of symptoms glioma patients may present with to the general practitioner, and whether these can be distinguished from patients with other CNS disorders or any other condition. Methods: Glioma patients were matched to CNS patients and ‘other controls’ using anonymized general practitioner registries. Prevalences were evaluated in the 5 years prior to diagnosis. Result: CNS patients reported significantly more motor symptoms in the period 60–24 months, (p = 0.039). Moreover, <6 months before diagnosis CNS patients differed significantly in mood disorders/fear compared with ‘other controls’ (p = 0.012) but not glioma patients (p = 0.816). Conclusion: Glioma patients could not be distinguished from both control groups with respect to the number or type of prediagnostic symptoms

The end-of-life phase of high-grade glioma patients: dying with dignity?

Background. In the end-of-life (EOL) phase, high-grade glioma (HGG) patients have a high symptom burden and often lose independence because of physical and cognitive dysfunction. This might affect the patient's personal dignity. We aimed to (a) assess the proportion of HGG patients dying with dignity as perceived by their relatives and (b) identify disease and care factors correlated with dying with dignity in HGG patients. Methods. We approached relatives of a cohort of 155 deceased HGG patients for the study. Participants completed a questionnaire concerning the EOL phase of the patient, covering several subthemes: (a) symptoms and signs, (b) healthrelated quality of life, (c) decision making, (d) place and quality of EOL care, and (e) dying with dignity. Results. Relatives of 81 patients participated and 75% indicated that the patient died with dignity. These patients had fewer communication deficits, experienced fewer transitions between health care settings in the EOL phase, and more frequently died at their preferred place of death. Relatives were more satisfied with the physician providing EOL care and reported that the physician adequately explained treatment options. Multivariate analysis identified satisfaction with the physician, the ability to communicate, and the absence of transitions between settings as most predictive of a dignified death. Conclusions. Physicians caring for HGG patients in the EOL phase should timely focus on explaining possible treatment options, because patients experience communication deficits toward death. Physicians should strive to allow patients to die at their preferred place and avoid transitions during the last month of life

The association between cognitive functioning and health-related quality of life in low-grade glioma patients.

BACKGROUND: Glioma patients are not only confronted with the diagnosis and treatment of a brain tumor, but also with changes in cognitive and neurological functioning that can profoundly affect their daily lives. At present, little is known about the relationship between cognitive functioning and health-related quality of life (HRQOL) during the disease trajectory. We studied this association in low-grade glioma (LGG) patients with stable disease at an average of 6 years after diagnosis. METHODS: Patients and healthy controls underwent neuropsychological testing and completed self-report measures of generic (MOS SF36) and disease-specific (EORTC BN20) HRQOL. Associations were determined with Pearson correlations, and corrections for multiple testing were made. RESULTS: We analyzed data gathered from 190 LGG patients. Performance in all cognitive domains was positively associated with physical health (SF36 Physical Component Summary). Executive functioning, processing speed, working memory, and information processing were positively associated with mental health (SF36 Mental Component Summary). We found negative associations between a wide range of cognitive domains and disease-specific HRQOL scales. CONCLUSIONS: In stable LGG patients, poorer cognitive functioning is related to lower generic and disease-specific HRQOL. This confirms that cognitive assessment of LGG patients should not be done in isolation from assessment of its impact on HRQOL, both in clinical and in research settings.status: publishe

Measuring health-related quality of life in high-grade glioma patients at the end of life using a proxy-reported retrospective questionnaire

To develop, validate, and report on the use of a retrospective proxy-reported questionnaire measuring health-related quality of life (HRQoL) in the end-of-life (EOL) phase of high-grade glioma (HGG) patients. Items relevant for the defined construct were selected using existing questionnaires, topics identified as important in literature, and expert opinion (experienced neuro-oncologists and EOL experts). Psychometric properties, content validity and internal consistency, were determined and the questionnaire was subsequently adapted. Proxy-reported HRQoL data of HGG patients in the EOL, including changes over time, were analyzed. Twenty-nine items were selected covering seven domains; physical comfort, physical and cognitive functioning, psychological, social and spiritual well-being, and overall quality of life. Relatives of 83 deceased HGG patients completed the questionnaire. Content validity was assessed to be adequate. Internal consistency in the domains varied from reasonable to good. Two items were excluded due to poor psychometric properties. Symptom burden increased (p 50). Overall quality of life was rated as poor, mean (SD) of 29 (26). Measuring HRQoL at the EOL of HGG patients with a retrospective, proxy-reported questionnaire was feasible, yielding a validated instrument. HRQoL was reported as poor and deteriorated as death approached

The end-of-life phase of high-grade glioma patients: a systematic review

High-grade gliomas (HGG) are rare and incurable; yet, these neoplasms result in a disproportionate share of cancer morbidity and mortality. Treatment of HGG patients is directed not merely towards prolonging life but also towards quality of life, which becomes the major goal in the end of life (EOL). The latter has received increasing attention over the last decade. We reviewed the literature related to the EOL phase of HGG patients from 1966 up to April 2012. Articles were retrieved from PubMed, Embase, Cinahl, PsycINFO and Cochrane database. We then selected papers for analysis using pre-determined inclusion criteria and subtracted information on the topics of interest. The search yielded 695 articles, of which 17 were classified eligible for analysis according to pre-defined inclusion criteria. Reviewed topics were symptoms and signs, quality of life and quality of dying, caregiver burden, organization and location of palliative care, supportive treatment, and EOL decision making. Nearly all identified studies were observational, with only two non-randomized intervention studies. Symptom burden is high in the EOL phase and affects the quality of life of both patient and carer. Palliative care services are more intensively used compared to other cancer patients. Cognitive deficits increase as the disease progresses, hampering communication and decision making. The EOL phase of HGG is substantially different from other patient groups, and more clinical studies in HGG on supportive medication, advance care planning and decision making are required. The organization of care, development of guidelines and interventions to decrease caregiver burden in the EOL phase are critical as well

Bevacizumab and temozolomide in patients with first recurrence of WHO grade II and III glioma, without 1p/19q co-deletion (TAVAREC): a randomised controlled phase 2 EORTC trial

BACKGROUND: Bevacizumab is frequently used in the treatment of recurrent WHO grade II and III glioma, but without supporting evidence from randomised trials. Therefore, we assessed the use of bevacizumab in patients with first recurrence of grade II or III glioma who did not have 1p/19q co-deletion. METHODS: The TAVAREC trial was a randomised, open-label phase 2 trial done at 32 centres across Europe in patients with locally diagnosed grade II or III glioma without 1p/19q co-deletion, with a first and contrast-enhancing recurrence after initial radiotherapy or chemotherapy, or both. Previous chemotherapy must have been stopped at least 6 months before enrolment and radiotherapy must have been stopped at least 3 months before enrolment. Random group assignment was done electronically through the European Organisation for Research and Treatment of Cancer web-based system, stratified by a minimisation procedure using institution, initial histology (WHO grade II vs III), WHO performance status (0 or 1 vs 2), and previous treatment (radiotherapy, chemotherapy, or both). Patients were assigned to receive either temozolomide (150-200 mg/m2, orally) monotherapy on days 1-5 every 4 weeks for a maximum of 12 cycles, or the same temozolomide regimen in combination with bevacizumab (10 mg/kg, intravenously) every 2 weeks until progression. The primary endpoint was overall survival at 12 months in the per-protocol population. Safety analyses were done in all patients who started their allocated treatment. The study is registered at EudraCT (2009-017422-39) and ClinicalTrials.gov (NCT01164189), and is complete. FINDINGS: Between Feb 8, 2011, and July 31, 2015, 155 patients were enrolled and randomly assigned to receive either monotherapy (n=77) or combination therapy (n=78). Overall survival in the per-protocol population at 12 months was achieved by 44 (61% [80% CI 53-69]) of 72 patients in the temozolomide group and 38 (55% [47-69]) of 69 in the combination group. The most frequent toxicity was haematological: 17 (23%) of 75 patients in the monotherapy group and 25 (33%) of 76 in the combination group developed grade 3 or 4 haematological toxicity. Other than haematological toxicities, the most common adverse events were nervous system disorders (59 [79%] of 75 patients in the monotherapy group vs 65 [86%] of 76 in the combination group), fatigue (53 [70%] vs 61 [80%]), and nausea (39 [52%] vs 43 [56%]). Infections were more frequently reported in the combination group (29 [38%] of 76 patients) than in the monotherapy group (17 [23%] of 75). One treatment-related death was reported in the combination group (infection after intratumoral haemorrhage during a treatment-related grade 4 thrombocytopenia). INTERPRETATION: We found no evidence of improved overall survival with bevacizumab and temozolomide combination treatment versus temozolomide monotherapy. The findings from this study provide no support for further phase 3 studies on the role of bevacizumab in this disease. FUNDING: Roche Pharmaceuticals.status: publishe