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Background: Temozolomide chemotherapy versus radiotherapy in patients with a high-risk low-grade glioma has been shown to have no significant effect on progression-free survival. If these treatments have a different effect on health-related quality of life (HRQOL), it might affect the choice of therapy. We postulated that temozolomide compromises HRQOL and global cognitive functioning to a lesser extent than does radiotherapy.Methods: We did a prospective, phase 3, randomised controlled trial at 78 medical centres and large hospitals in 19 countries. We enrolled adult patients (aged ≥18 years) with histologically confirmed diffuse (WHO grade II) astrocytoma, oligodendroglioma, or mixed oligoastrocytoma, with a WHO performance status of 2 or lower, without previous chemotherapy or radiotherapy, who needed active treatment other than surgery. We randomly assigned eligible patients (1:1) using a minimisation technique, stratified by WHO performance status (0-1 vs 2), age (<40 years vs ≥40 years), presence of contrast enhancement on MRI, chromosome 1p status (deleted vs non-deleted vs indeterminate), and the treating medical centre, to receive either radiotherapy (50·4 Gy in 28 fractions of 1·8 Gy for 5 days per week up to 6·5 weeks) or temozolomide chemotherapy (75 mg/m2 daily, for 21 of 28 days [one cycle] for 12 cycles). The primary endpoint was progression-free survival (results published separately); here, we report the results for two key secondary endpoints: HRQOL (assessed using the European Organisation for Research and Treatment of Cancer's [EORTC] QLQ-C30 [version 3] and the EORTC Brain Cancer Module [QLQ-BN20]) and global cognitive functioning (assessed using the Mini-Mental State Examination [MMSE]). We did analyses on the intention-to-treat population. This study is closed and is registered at EudraCT, number 2004-002714-11, and at ClinicalTrials.gov, number NCT00182819.Findings: Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 eligible patients to either radiotherapy (n=240) or temozolomide chemotherapy (n=237). The difference in HRQOL between the two treatment groups was not significant during the 36 months' follow-up (mean between group difference [averaged over all timepoints] 0·06, 95% CI -4·64 to 4·75, p=0·98). At baseline, 32 (13%) of 239 patients who received radiotherapy and 32 (14%) of 236 patients who received temozolomide chemotherapy had impaired cognitive function, according to the MMSE scores. After randomisation, five (8%) of 63 patients who received radiotherapy and three (6%) of 54 patients who received temozolomide chemotherapy and who could be followed up for 36 months had impaired cognitive function, according to the MMSE scores. No significant difference was recorded between the groups for the change in MMSE scores during the 36 months of follow-up.Interpretation: The effect of temozolomide chemotherapy or radiotherapy on HRQOL or global cognitive functioning did not differ in patients with low-grade glioma. These results do not support the choice of temozolomide alone over radiotherapy alone in patients with high-risk low-grade glioma.Funding: Merck Sharp & Dohme-Merck & Co, National Cancer Institute, Swiss Cancer League, National Institute for Health Research, Cancer Research UK, Canadian Cancer Society Research Institute, National Health and Medical Research Council, European Organisation for Research and Treatment of Cancer Cancer Research Fund. [ABSTRACT FROM AUTHOR]

Patient-reported outcomes (PROs) are increasingly used in single-arm cancer studies. We reviewed 60 papers published between 2018 and 2021 of single-arm studies of cancer treatment with PRO data for current practice on design, analysis, reporting, and interpretation. We further examined the studies' handling of potential bias and how they informed decision making. Most studies (58; 97%) analysed PROs without stating a predefined research hypothesis. 13 (22%) of the 60 studies used a PRO as a primary or co-primary endpoint. Definitions of PRO objectives, study population, endpoints, and missing data strategies varied widely. 23 studies (38%) compared the PRO data with external information, most often by using a clinically important difference value; one study used a historical control group. Appropriateness of methods to handle missing data and intercurrent events (including death) were seldom discussed. Most studies (51; 85%) concluded that PRO results supported treatment. Conducting and reporting of PROs in cancer single-arm studies need standards and a critical discussion of statistical methods and possible biases. These findings will guide the Setting International Standards in Analysing Patient-Reported Outcomes and Quality of Life Data in Cancer Clinical Trials–Innovative Medicines Initiative (SISAQOL-IMI) in developing recommendations for the use of PRO-measures in single-arm studies. [ABSTRACT FROM AUTHOR]

The use of item libraries for patient-reported outcome (PRO) measurement in oncology allows for the customisation of PRO assessment to measure key health-related quality of life concepts of relevance to the target population and intervention. However, no high-level recommendations exist to guide users on the design and implementation of these customised PRO measures (item lists) across different PRO measurement systems. To address this issue, a working group was set up, including international stakeholders (academic, independent, industry, health technology assessment, regulatory, and patient advocacy), with the goal of creating recommendations for the use of item libraries in oncology trials. A scoping review was carried out to identify relevant publications and highlight any gaps. Stakeholders commented on the available guidance for each research question, proposed recommendations on how to address gaps in the literature, and came to an agreement using discussion-based methods. Nine primary research questions were identified that formed the scope and structure of the recommendations on how to select items and implement item lists created from item libraries. These recommendations address methods to drive item selection, plan the structure and analysis of item lists, and facilitate their use in conjunction with other measures. The findings resulted in high-level, instrument-agnostic recommendations on the use of item-library-derived item lists in oncology trials. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The Response Assessment in Neuro-Oncology-Patient-Reported Outcome (RANO-PRO) working group is an international multidisciplinary collaboration that provides guidance on the use of patient-reported outcome (PRO) measures in clinical trials and practice for adult patients with brain tumours. Findings from both PROs and traditional outcome measures, such as survival, and clinical or radiological response, are essential to inform the research community, policy makers, physicians, and patients in the treatment decision-making process. Previous initiatives in oncology have focused on guidelines concerning the collection, analysis, interpretation, and reporting of PRO data. However, we recommend the application of appropriate PRO instruments, with respect to its content and measurement properties (ie, research question, content validity, and other measurement properties), in brain tumour research. PROs should be well defined and reliable to generate high-quality evidence, and our recommendations on the use of specific PRO measures could help to improve the quality of PRO evidence derived from neuro-oncological studies, and might add a new dimension in how the value of therapeutics is assessed in patients with brain tumours. In this Policy Review, we present the RANO-PRO working plan for the use of PROs in adults with brain tumours. [ABSTRACT FROM AUTHOR]

The European Association for Neuro-Oncology guideline provides recommendations for the clinical care of adult patients with astrocytic and oligodendroglial gliomas, including glioblastomas. The guideline is based on the 2016 WHO classification of tumours of the central nervous system and on scientific developments since the 2014 guideline. The recommendations focus on pathological and radiological diagnostics, and the main treatment modalities of surgery, radiotherapy, and pharmacotherapy. In this guideline we have also integrated the results from contemporary clinical trials that have changed clinical practice. The guideline aims to provide guidance for diagnostic and management decisions, while limiting unnecessary treatments and costs. The recommendations are a resource for professionals involved in the management of patients with glioma, for patients and caregivers, and for health-care providers in Europe. The implementation of this guideline requires multidisciplinary structures of care, and defined processes of diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Patient-reported outcomes (PROs), such as symptoms, function, and other health-related quality-of-life aspects, are increasingly evaluated in cancer randomised controlled trials (RCTs) to provide information about treatment risks, benefits, and tolerability. However, expert opinion and critical review of the literature showed no consensus on optimal methods of PRO analysis in cancer RCTs, hindering interpretation of results. The Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data Consortium was formed to establish PRO analysis recommendations. Four issues were prioritised: developing a taxonomy of research objectives that can be matched with appropriate statistical methods, identifying appropriate statistical methods for PRO analysis, standardising statistical terminology related to missing data, and determining appropriate ways to manage missing data. This Policy Review presents recommendations for PRO analysis developed through critical literature reviews and a structured collaborative process with diverse international stakeholders, which provides a foundation for endorsement; ongoing developments of these recommendations are also discussed., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Although patient-reported outcomes (PROs), such as health-related quality of life, are important endpoints in randomised controlled trials (RCTs), there is little consensus about the analysis, interpretation, and reporting of these data. We did a systematic review to assess the variability, quality, and standards of PRO data analyses in advanced breast cancer RCTs. We searched PubMed for English language articles published in peer-reviewed journals between Jan 1, 2001, and Oct 30, 2017. Eligible articles were those that reported PRO results from RCTs of adult patients with advanced breast cancer receiving anti-cancer treatments with reported sample sizes of at least 50 patients-66 RCTs met the selection criteria. Only eight (12%) RCTs reported a specific PRO research hypothesis. Heterogeneity in the statistical methods used to assess PRO data was observed, with a mixture of longitudinal and cross-sectional techniques. Not all articles addressed the problem of multiple testing. Fewer than half of RCTs (28 [42%]) reported the clinical significance of their findings. 48 (73%) did not report how missing data were handled. Our systematic review shows a need to improve standards in the analysis, interpretation, and reporting of PRO data in cancer RCTs. Lack of standardisation makes it difficult to draw robust conclusions and compare findings across trials. The Setting International Standards in the Analyzing Patient-Reported Outcomes and Quality of Life Data Consortium was set up to address this need and develop recommendations on the analysis of PRO data in RCTs., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Measures of health-related quality of life (HRQOL) and other patient-reported outcomes generate important data in cancer randomised trials to assist in assessing the risks and benefits of cancer therapies and fostering patient-centred cancer care. However, the various ways these measures are analysed and interpreted make it difficult to compare results across trials, and hinders the application of research findings to inform publications, product labelling, clinical guidelines, and health policy. To address these problems, the Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data (SISAQOL) initiative has been established. This consortium, directed by the European Organisation for Research and Treatment of Cancer (EORTC), was convened to provide recommendations on how to standardise the analysis of HRQOL and other patient-reported outcomes data in cancer randomised trials. This Personal View discusses the reasons why this project was initiated, the rationale for the planned work, and the expected benefits to cancer research, patient and provider decision making, care delivery, and policy making., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Outcome of low-grade glioma (WHO grade II) is highly variable, reflecting molecular heterogeneity of the disease. We compared two different, single-modality treatment strategies of standard radiotherapy versus primary temozolomide chemotherapy in patients with low-grade glioma, and assessed progression-free survival outcomes and identified predictive molecular factors., Methods: For this randomised, open-label, phase 3 intergroup study (EORTC 22033-26033), undertaken in 78 clinical centres in 19 countries, we included patients aged 18 years or older who had a low-grade (WHO grade II) glioma (astrocytoma, oligoastrocytoma, or oligodendroglioma) with at least one high-risk feature (aged >40 years, progressive disease, tumour size >5 cm, tumour crossing the midline, or neurological symptoms), and without known HIV infection, chronic hepatitis B or C virus infection, or any condition that could interfere with oral drug administration. Eligible patients were randomly assigned (1:1) to receive either conformal radiotherapy (up to 50·4 Gy; 28 doses of 1·8 Gy once daily, 5 days per week for up to 6·5 weeks) or dose-dense oral temozolomide (75 mg/m 2 once daily for 21 days, repeated every 28 days [one cycle], for a maximum of 12 cycles). Random treatment allocation was done online by a minimisation technique with prospective stratification by institution, 1p deletion (absent vs present vs undetermined), contrast enhancement (yes vs no), age (<40 vs ≥40 years), and WHO performance status (0 vs ≥1). Patients, treating physicians, and researchers were aware of the assigned intervention. A planned analysis was done after 216 progression events occurred. Our primary clinical endpoint was progression-free survival, analysed by intention-to-treat; secondary outcomes were overall survival, adverse events, neurocognitive function (will be reported separately), health-related quality of life and neurological function (reported separately), and correlative analyses of progression-free survival by molecular markers (1p/19q co-deletion, MGMT promoter methylation status, and IDH1/IDH2 mutations). This trial is closed to accrual but continuing for follow-up, and is registered at the European Trials Registry, EudraCT 2004-002714-11, and at ClinicalTrials.gov, NCT00182819., Findings: Between Sept 23, 2005, and March 26, 2010, 707 patients were registered for the study. Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 patients to receive either radiotherapy (n=240) or temozolomide chemotherapy (n=237). At a median follow-up of 48 months (IQR 31-56), median progression-free survival was 39 months (95% CI 35-44) in the temozolomide group and 46 months (40-56) in the radiotherapy group (unadjusted hazard ratio [HR] 1·16, 95% CI 0·9-1·5, p=0·22). Median overall survival has not been reached. Exploratory analyses in 318 molecularly-defined patients confirmed the significantly different prognosis for progression-free survival in the three recently defined molecular low-grade glioma subgroups (IDHmt, with or without 1p/19q co-deletion [IDHmt/codel], or IDH wild type [IDHwt]; p=0·013). Patients with IDHmt/non-codel tumours treated with radiotherapy had a longer progression-free survival than those treated with temozolomide (HR 1·86 [95% CI 1·21-2·87], log-rank p=0·0043), whereas there were no significant treatment-dependent differences in progression-free survival for patients with IDHmt/codel and IDHwt tumours. Grade 3-4 haematological adverse events occurred in 32 (14%) of 236 patients treated with temozolomide and in one (<1%) of 228 patients treated with radiotherapy, and grade 3-4 infections occurred in eight (3%) of 236 patients treated with temozolomide and in two (1%) of 228 patients treated with radiotherapy. Moderate to severe fatigue was recorded in eight (3%) patients in the radiotherapy group (grade 2) and 16 (7%) in the temozolomide group. 119 (25%) of all 477 patients had died at database lock. Four patients died due to treatment-related causes: two in the temozolomide group and two in the radiotherapy group., Interpretation: Overall, there was no significant difference in progression-free survival in patients with low-grade glioma when treated with either radiotherapy alone or temozolomide chemotherapy alone. Further data maturation is needed for overall survival analyses and evaluation of the full predictive effects of different molecular subtypes for future individualised treatment choices., Funding: Merck Sharpe & Dohme-Merck & Co, Canadian Cancer Society, Swiss Cancer League, UK National Institutes of Health, Australian National Health and Medical Research Council, US National Cancer Institute, European Organisation for Research and Treatment of Cancer Cancer Research Fund., (Copyright © 2016 Elsevier Ltd. All rights reserved.)