Glioma.

Gliomas are primary brain tumours that are thought to develop from neural stem or progenitor cells that carry tumour-initiating genetic alterations. Based on microscopic appearance and molecular characteristics, they are classified according to the WHO classification of central nervous system (CNS) tumours and graded into CNS WHO grades 1-4 from a low to high grade of malignancy. Diffusely infiltrating gliomas in adults comprise three tumour types with distinct natural course of disease, response to treatment and outcome: isocitrate dehydrogenase (IDH)-mutant and 1p/19q-codeleted oligodendrogliomas with the best prognosis; IDH-mutant astrocytomas with intermediate outcome; and IDH-wild-type glioblastomas with poor prognosis. Pilocytic astrocytoma is the most common glioma in children and is characterized by circumscribed growth, frequent BRAF alterations and favourable prognosis. Diffuse gliomas in children are divided into clinically indolent low-grade tumours and high-grade tumours with aggressive behaviour, with histone 3 K27-altered diffuse midline glioma being the leading cause of glioma-related death in children. Ependymal tumours are subdivided into biologically and prognostically distinct types on the basis of histology, molecular biomarkers and location. Although surgery, radiotherapy and alkylating agent chemotherapy are the mainstay of glioma treatment, individually tailored strategies based on tumour-intrinsic dominant signalling pathways have improved outcome in subsets of patients.

The outcomes measured and reported in observational studies of incidental and untreated intracranial meningioma: A systematic review.

Background: The clinical management of patients with incidental intracranial meningioma varies markedly and is often based on clinician choice and observational data. Heterogeneous outcome measurement has likely hampered knowledge progress by preventing comparative analysis of similar cohorts of patients. This systematic review aimed to summarize the outcomes measured and reported in observational studies. Methods: A systematic literature search was performed to identify published full texts describing active monitoring of adult cohorts with incidental and untreated intracranial meningioma (PubMed, EMBASE, MEDLINE, and CINAHL via EBSCO, completed January 24, 2022). Reported outcomes were extracted verbatim, along with an associated definition and method of measurement if provided. Verbatim outcomes were de-duplicated and the resulting unique outcomes were grouped under standardized outcome terms. These were classified using the taxonomy proposed by the "Core Outcome Measures in Effectiveness Trials" (COMET) initiative. Results: Thirty-three published articles and 1 ongoing study were included describing 32 unique studies: study designs were retrospective n = 27 and prospective n = 5. In total, 268 verbatim outcomes were reported, of which 77 were defined. Following de-duplication, 178 unique verbatim outcomes remained and were grouped into 53 standardized outcome terms. These were classified using the COMET taxonomy into 9 outcome domains and 3 core areas. Conclusions: Outcome measurement across observational studies of incidental and untreated intracranial meningioma is heterogeneous. The standardized outcome terms identified will be prioritized through an eDelphi survey and consensus meeting of key stakeholders (including patients), in order to develop a Core Outcome Set for use in future observational studies.

The outcomes measured and reported in intracranial meningioma clinical trials: A systematic review.

Background: Meningioma clinical trials have assessed interventions including surgery, radiotherapy, and pharmacotherapy. However, agreement does not exist on what, how, and when outcomes of interest should be measured. To do so would allow comparative analysis of similar trials. This systematic review aimed to summarize the outcomes measured and reported in meningioma clinical trials. Methods: Systematic literature and trial registry searches were performed to identify published and ongoing intracranial meningioma clinical trials (PubMed, Embase, Medline, CINAHL via EBSCO, and Web of Science, completed January 22, 2022). Reported outcomes were extracted verbatim, along with an associated definition and method of measurement if provided. Verbatim outcomes were deduplicated and the resulting unique outcomes were grouped under standardized outcome terms. These were classified using the taxonomy proposed by the "Core Outcome Measures in Effectiveness Trials" (COMET) initiative. Results: Thirty published articles and 18 ongoing studies were included, describing 47 unique clinical trials: Phase 2 n = 33, phase 3 n = 14. Common interventions included: Surgery n = 13, radiotherapy n = 8, and pharmacotherapy n = 20. In total, 659 verbatim outcomes were reported, of which 84 were defined. Following de-duplication, 415 unique verbatim outcomes remained and were grouped into 115 standardized outcome terms. These were classified using the COMET taxonomy into 29 outcome domains and 5 core areas. Conclusions: Outcome measurement across meningioma clinical trials is heterogeneous. The standardized outcome terms identified will be prioritized through an eDelphi survey and consensus meeting of key stakeholders (including patients), in order to develop a core outcome set for use in future meningioma clinical trials.

Influence of arterial transit time delays on the differentiation between tumor progression and pseudoprogression in glioblastoma by arterial spin labeling magnetic resonance imaging.

Arterial spin labeling (ASL) and dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) have shown potential for differentiating tumor progression from pseudoprogression. For pseudocontinuous ASL with a single postlabeling delay, the presence of delayed arterial transit times (ATTs) could affect the evaluation of ASL-MRI perfusion data. In this study, the influence of ATT artifacts on the perfusion assessment and differentiation between tumor progression and pseudoprogression were studied. This study comprised 66 adult patients (mean age 60 ± 13 years; 40 males) with a histologically confirmed glioblastoma who received postoperative radio (chemo)therapy. ASL-MRI and DSC-MRI scans were acquired at 3 months postradiotherapy as part of the standard clinical routine. These scans were visually scored regarding (i) the severity of ATT artifacts (%) on the ASL-MRI scans only, scored by two neuroradiologists; (ii) perfusion of the enhancing tumor lesion; and (iii) radiological evaluation of tumor progression versus pseudoprogression by one neuroradiologist. The final outcome was based on combined clinical and radiological follow-up until 9 months postradiotherapy. ATT artifacts were identified in all patients based on the mean scores of two raters. A significant difference between the radiological evaluation of ASL-MRI and DSC-MRI was observed only for ASL images with moderate ATT severity (30%-65%). The perfusion assessment showed ASL-MRI tending more towards hyperperfusion than DSC-MRI in the case of moderate ATT artifacts. In addition, there was a significant difference between the prediction of tumor progression with ASL-MRI and the final outcome in the case of severe ATT artifacts (McNemar test, p = 0.041). Despite using ASL imaging parameters close to the recommended settings, ATT artifacts frequently occur in patients with treated brain tumors. Those artifacts could hinder the radiological evaluation of ASL-MRI data and the detection of true disease progression, potentially affecting treatment decisions for patients with glioblastoma.

Clinical outcome assessment in patients with epilepsy: The value of health-related quality of life measurements.

This narrative review provides an overview of the current knowledge on health-related quality of life (HRQOL), a relevant clinical outcome in patients with epilepsy. It shows that the most important factor determining HRQOL in this patient group is seizure frequency. In particular, seizure-freedom is associated with better HRQOL scores. Many other factors may impact perceived HRQOL aspects, but their interrelation is complex and requires further research. Novel analytical approaches, such as hierarchical cluster and symptom network analyses might shed further light on this, and may result in recommendations for interventions on the most 'central' factors influencing different aspects of HRQOL in patients with epilepsy. Next, an overview of the HRQOL tools and analytical methods currently used in epilepsy care, with a focus on clinical trials, is provided. The QOLIE-31 is the most frequently applied and best validated tool. Several other questionnaires focusing on specific aspects of HRQOL (e.g., mood, social impact) are less frequently used. We show some pitfalls that should be taken into account when designing study protocols including HRQOL endpoints. This includes standardized statistical analysis approaches and predefined reporting methods for HRQOL in epilepsy populations. It has been shown in other patient groups that the lack of such standardisation negatively impacts the quality and comparability of results. We conclude with a number of recommendations for future research.

Gender balance and suitable positive actions to promote gender equality among healthcare professionals in neuro-oncology: The EANO positive action initiative.

Background: The proportion of women among healthcare and biomedical research professionals in neuro-oncology is growing. With changes in cultural expectations and work-life balance considerations, more men aspire to nonfull-time jobs, yet, leadership positions remain dominated by men. Methods: The European Association of Neuro-Oncology (EANO) disparity committee carried out a digital survey to explore gender balance and actions suitable to promote gender equality. The survey was distributed among EANO members in 2021, with responses analyzed descriptively. Results: In total, 262 participants completed the survey (141 women, 53.8%; median age 43). Respondents were neurosurgeons (68, 26.0%); neurologists (67, 25.6%), medical oncologists (43, 16.4%), or other healthcare or research professionals; 208 participants (79.4%) worked full-time. Positive action to enforce the role of women in neuro-oncology was deemed necessary by 180 participants (68.7%), but only 28 participants (10.7%) agreed that women only should be promoted until gender balance is reached. A majority of respondents (162, 61.8%) felt that women with an equivalent CV should be prioritized over men to reach gender balance. If in the future the balance favored women at higher positions, 112 respondents (42.7%) agreed to apply positive action for men. The top indicators considered relevant to measure gender balance were: salary for similar positions (183/228, 80.3%), paid overtime (176/228, 77.2%), number of permanent positions (164/228, 71.9%), protected time for research (161/227, 70.9%), and training opportunities (157/227, 69.2%). Conclusions: Specific indicators may help to measure and promote gender balance and should be considered for implementation among healthcare professionals in neuro-oncology.

Survival, neurocognitive function, and health-related quality of life outcomes after rituximab-methotrexate, BCNU, teniposide, and prednisolone for primary CNS lymphoma: Final results of the HOVON 105/ALLG NHL 24 study.

BACKGROUND: Studies on the efficacy of rituximab in primary CNS lymphoma (PCNSL) reported conflicting results. Our international randomized phase 3 study showed that the addition of rituximab to high-dose methotrexate, BCNU, teniposide, and prednisolone (MBVP) in PCNSL was not efficacious in the short term. Here we present long-term results after a median follow-up of 82.3 months. METHODS: One hundred and ninety-nine eligible newly diagnosed, nonimmunocompromised patients with PCNSL aged 18-70 years with WHO performance status 0-3 was randomized between treatment with MBVP chemotherapy with or without rituximab, followed by high-dose cytarabine consolidation in responding patients, and reduced-dose WBRT in patients aged ≤ 60 years. Event-free survival was the primary endpoint. Overall survival rate, neurocognitive functioning (NCF), and health-related quality of life (HRQoL) were additionally assessed, with the IPCG test battery, EORTC QLQ-C30 and QLQ-BN20 questionnaires, respectively. RESULTS: For event-free survival, the hazard ratio was 0.85, 95% CI 0.61-1.18, P = .33. Overall survival rate at 5 years for MBVP and R-MBVP was 49% (39-59) and 53% (43-63) respectively. In total, 64 patients died in the MBVP arm and 55 in the R-MBVP arm, of which 69% were due to PCNSL. At the group level, all domains of NCF and HRQoL improved to a clinically relevant extent after treatment initiation, and remained stable thereafter up to 60 months of follow-up, except for motor speed which deteriorated between 24 and 60 months. Although fatigue improved initially, high levels persisted in the long term. CONCLUSIONS: Long-term follow-up confirms the lack of added value of rituximab in addition to MBVP and HD-cytarabine for PCNSL.

MRI phenotypes of glioblastomas early after treatment are suggestive of overall patient survival.

Background: Distinguishing true tumor progression (TP) from treatment-induced abnormalities (eg, pseudo-progression (PP) after radiotherapy) on conventional MRI scans remains challenging in patients with a glioblastoma. We aimed to establish brain MRI phenotypes of glioblastomas early after treatment by combined analysis of structural and perfusion tumor characteristics and assessed the relation with recurrence rate and overall survival time. Methods: Structural and perfusion MR images of 67 patients at 3 months post-radiotherapy were visually scored by a neuroradiologist. In total 23 parameters were predefined and used for hierarchical clustering analysis. Progression status was assessed based on the clinical course of each patient 9 months after radiotherapy (or latest available). Multivariable Cox regression models were used to determine the association between the phenotypes, recurrence rate, and overall survival. Results: We established 4 subgroups with significantly different tumor MRI characteristics, representing distinct MRI phenotypes of glioblastomas: TP and PP rates did not differ significantly between subgroups. Regression analysis showed that patients in subgroup 1 (characterized by having mostly small and ellipsoid nodular enhancing lesions with some hyper-perfusion) had a significant association with increased mortality at 9 months (HR: 2.6 (CI: 1.1-6.3); P = .03) with a median survival time of 13 months (compared to 22 months of subgroup 2). Conclusions: Our study suggests that distinct MRI phenotypes of glioblastomas at 3 months post-radiotherapy can be indicative of overall survival, but does not aid in differentiating TP from PP. The early prognostic information our method provides might in the future be informative for prognostication of glioblastoma patients.

Latest clinical research in leptomeningeal disease (LMD)-a narrative review.

BACKGROUND AND OBJECTIVE: Leptomeningeal disease (LMD) is associated with poor survival and health-related quality of life (HRQoL). There is an urgent need for clinical research in this area to improve the outcomes. The purpose of this study is to summarize the areas of active clinical research in LMD, identify the knowledge gap, and suggest future research directions. METHODS: A narrative review of clinical trials in LMD was conducted based on a search in clinicatrials.gov using the search term "leptomeningeal" under "condition or disease". Clinical trials in patients with LMD arising from solid malignancy that were labelled as "not yet recruiting", "recruiting", "enrolling by invitation" or "active, not recruiting" were included. Studies which were deemed to have significant impact on future research direction in LMD were selected for discussion. KEY CONTENT AND FINDINGS: A total of 38 clinical trials were included. Of these 38 trials, 19 are discussed in this review, with focus on their research questions and impact on future research directions. Most of the studies that were not selected for discussion focused on biomarker-driven interventions. Four key areas of research were identified, namely the (I) diagnosis, response assessment or molecular profiling of LMD (n=2); (II) advances in radiotherapy (n=3); (III) intrathecal treatment (n=13); (IV) novel drug carrier for systemic treatment (n=1). The research questions in the 19 discussed clinical trials included the tumour microenvironment of LMD, the role of novel molecular techniques in LMD, combination of radiotherapy with drugs, and cell-based immunotherapy. Among these 19 studies, 11 were phase 1 trials, 3 were phase 2 or phase 1/2 trials, 2 were phase 3 or phase 2/3 trials and the study phase was not reported in the remaining 3 studies. The existing knowledge gaps are discussed, including the lack of primary site-specific prognostic tools, cost-effectiveness studies, dedicated HRQoL assessment tools for LMD and sequencing of treatment. CONCLUSIONS: The current clinical trials in LMD offer the promise to improve the diagnosis and treatment outcomes of patients with LMD. More research is needed to overcome the potential hurdles in the current treatment and bridge the knowledge gaps as identified in this review, to improve patients' quantity and quality of survival.

RNA-sequencing to discover genes and signaling pathways associated with venous thromboembolism in glioblastoma patients: A case-control study.

BACKGROUND: Glioblastoma patients are at high risk of developing venous thromboembolism (VTE). Tumor-intrinsic features are considered to play a role, but the underlying pathophysiological mechanisms remain incompletely understood. OBJECTIVES: To identify tumor-expressed genes and signaling pathways that associate with glioblastoma-related VTE by using next generation RNA-sequencing (RNA-Seq). METHODS: The tumor gene expression profile of 23 glioblastoma patients with VTE and 23 glioblastoma patients without VTE was compared using an unpaired analysis. Ingenuity Pathway Analysis (IPA) core analysis was performed on the top 50 differentially expressed genes to explore associated functions and pathways. Based on full RNA-Seq data, molecular glioblastoma subtypes were determined by performing cluster analysis. RESULTS: Of the 19,327 genes, 1246 (6.4 %) were differentially expressed between glioblastoma patients with and without VTE (unadjusted P < 0.05). The most highly overexpressed gene was GLI1, a classical target gene in the Sonic Hedgehog (Shh) signaling pathway (log2 fold change: 3.7; unadjusted P < 0.0001, adjusted P = 0.219). In line, Shh signaling was among the top canonical pathways and processes associated with VTE. The proportion of patients with the proneural/neural glioblastoma subtype was higher among those with VTE than controls. CONCLUSION: Shh signaling may be involved in the development of glioblastoma-related VTE.

Impact of timing of antiseizure medication withdrawal on seizure recurrence in glioma patients: a retrospective observational study.

BACKGROUND: Withdrawal of antiseizure medication treatment (ASM) can be considered after completion of antitumour treatment in glioma patients who no longer suffer from seizures. We compared the risk for recurrent seizures after ASM withdrawal between patients with short-term, medium-term versus long-term seizure freedom after antitumour treatment. METHODS: In this retrospective observational study, the primary outcome was time to recurrent seizure, from the starting date of no ASM treatment up to 36 months follow-up. Cox proportional hazards models were used to study the effect of risk factors on time to recurrent seizure. Stratification was done with information known at baseline. Short-term seizure freedom was defined as ≥ 3 months, but < 12 months; medium-term as 12-24 months; and long-term as ≥ 24 months seizure freedom from the date of last antitumour treatment. RESULTS: This study comprised of 109 patients; 31% (34/109) were in the short-term, 29% (32/109) in the medium-term, and 39% (43/109) in the long-term group. A recurrent seizure was experienced by 47% (16/34) of the patients in the short-term, 31% (10/32) in the medium-term, and 44% (19/43) in the long-term group. Seizure recurrence risk was similar between patients in the short-term group as compared to the medium-term (cause-specific adjusted hazard ratio [aHR] = 0.65 [95%CI = 0.29-1.46]) and long-term group (cause-specific aHR = 1.04 [95%CI = 0.52-2.09]). CONCLUSIONS: Seizure recurrence risk is relatively similar between patients with short-term, medium-term, and long-term seizure freedom after completion of antitumour treatment.

Development of a core outcome set for use in adult primary glioma phase III interventional trials: A mixed methods study.

Background: Glioma interventional studies should collect data aligned with patient priorities, enabling treatment benefit assessment and informed decision-making. This requires effective data synthesis and meta-analyses, underpinned by consistent trial outcome measurement, analysis, and reporting. Development of a core outcome set (COS) may contribute to a solution. Methods: A 5-stage process was used to develop a COS for glioma trials from the UK perspective. Outcome lists were generated in stages 1: a trial registry review and systematic review of qualitative studies and 2: interviews with glioma patients and caregivers. In stage 3, the outcome lists were de-duplicated with accessible terminology, in stage 4 outcomes were rated via a 2-round Delphi process, and stage 5 comprised a consensus meeting to finalize the COS. Patient-reportable COS outcomes were identified. Results: In Delphi round 1, 96 participants rated 35 outcomes identified in stages 1 and 2, to which a further 10 were added. Participants (77/96) rated the resulting 45 outcomes in round 2. Of these, 22 outcomes met a priori threshold for inclusion in the COS. After further review, a COS consisting of 19 outcomes grouped into 7 outcome domains (survival, adverse events, activities of daily living, health-related quality of life, seizure activity, cognitive function, and physical function) was finalized by 13 participants at the consensus meeting. Conclusions: A COS for glioma trials was developed, comprising 7 outcome domains. Additional research will identify appropriate measurement tools and further validate this COS.

Depression and anxiety in glioma patients.

AbstractGlioma patients carry the burden of having both a progressive neurological disease and cancer, and may face a variety of symptoms, including depression and anxiety. These symptoms are highly prevalent in glioma patients (median point prevalence ranging from 16-41% for depression and 24-48% for anxiety when assessed by self-report questionnaires) and have a major impact on health-related quality of life and even overall survival time. A worse overall survival time for glioma patients with depressive symptoms might be due to tumor progression and/or its supportive treatment causing depressive symptoms, an increased risk of suicide or other (unknown) factors. Much is still unclear about the etiology of depressive and anxiety symptoms in glioma. These psychiatric symptoms often find their cause in a combination of neurophysiological and psychological factors, such as the tumor and/or its treatment. Although these patients have a particular idiosyncrasy, standard treatment guidelines for depressive and anxiety disorders apply, generally recommending psychological and pharmacological treatment. Only a few nonpharmacological trials have been conducted evaluating the efficacy of psychological treatments (eg, a reminiscence therapy-based care program) in this population, which significantly reduced depressive and anxiety symptoms. No pharmacological trials have been conducted in glioma patients specifically. More well-designed trials evaluating the efficacy of nonpharmacological treatments for depressive and anxiety disorders in glioma are urgently needed to successfully treat psychiatric symptoms in brain tumor patients and to improve (health-related) quality of life.

Health-Related Quality of Life in Intracranial Meningioma: Current Evidence and Future Directions.

Historically, largely due to the good prognosis for survival, there has been little attention paid to the possible impact of meningiomas and their treatment on health-related quality of life (HRQoL). However, in the last decade there has been increasing evidence that patients with intracranial meningiomas suffer from long-term decreases in their HRQoL. Compared with controls and normative data, meningioma patients have worse HRQoL scores both before and after intervention and continuing long term (even after >4 years of follow-up). Overall, surgery results in improvements in many aspects of HRQoL. The limited available studies investigating the impact of radiotherapy suggest that this type of treatment decreases HRQoL scores, especially in the long term. There is however only limited evidence on additional determinants of HRQoL. Patients with anatomically complex skull base meningiomas and severe comorbidities, including epilepsy, report the lowest HRQoL scores. Other tumor and sociodemographic characteristics have shown weak associations with HRQoL. Furthermore, about one-third of caregivers of meningioma patients report caregiver burden, warranting interventions to improve caregiver HRQoL. As antitumor interventions may not improve HRQoL scores to be comparable to those of the general population, more attention should be paid to the development of integrative rehabilitation and supportive care programs for meningioma patients.

Information about missing patient-reported outcome data in breast cancer trials is frequently not documented: a scoping review.

OBJECTIVES: This review addresses the common problem of missing patient-reported outcome (PRO) data in clinical trials by assessing the current practice of their statistical handling as reported in publications of randomized controlled trials (RCTs) in patients with breast cancer. STUDY DESIGN AND SETTING: We searched PubMed to identify RCTs evaluating biomedical treatments in breast cancer patients with at least one PRO endpoint published between January 2019 and February 2022. Two reviewers independently assessed the eligibility of the publications for this scoping review and extracted prespecified information on missing PRO data and related statistical practices. RESULTS: Of 1,598 publications identified, 118 trials met the inclusion criteria. Eighty-eight (74.6%) trials reported the extent of missing data, with 11 (9.3%) not containing any missing PRO data. Twenty-one (19.6%) trials explicitly stated the statistical approach for handling missing data, with a preference for single imputation over multiple imputation approaches (57.2%/19.0%). Only six (5.6%) trials reported a sensitivity analysis to examine the extent to the results being affected by changes in assumptions made about missing PRO data. CONCLUSION: International efforts to raise awareness of the importance of accurately reporting state-of-the-art handling of missing PRO data are not yet fully reflected in the current literature of breast cancer RCTs.

The prevalence and severity of fatigue in meningioma patients and its association with patient-, tumor- and treatment-related factors.

Background: Fatigue is a commonly reported and severe symptom in primary brain tumor patients, but the exact occurrence in meningioma patients is unknown. This study aimed to determine the frequency and severity of fatigue in meningioma patients as well as associations between the level of fatigue and patient-, tumor-, and treatment-related factors. Methods: In this multicenter cross-sectional study, meningioma patients completed questionnaires on fatigue (MFI-20), sleep (PSQI), anxiety and depression (HADS), tumor-related symptoms (MDASI-BT), and cognitive functioning (MOS-CFS). Multivariable regression models were used to evaluate the independent association between fatigue and each patient-, tumor-, and treatment-related factor separately, corrected for relevant confounders. Results: Based on predetermined in- and exclusion criteria, 275 patients, on average 5.3 (SD = 2.0) year since diagnosis, were recruited. Most patients had undergone resection (92%). Meningioma patients reported higher scores on all fatigue subscales compared to normative data and 26% were classified as fatigued. Having experienced a complication due to resection (OR 3.6, 95% CI: 1.8-7.0), having received radiotherapy (OR 2.4, 95% CI: 1.2-4.8), a higher number of comorbidities (OR 1.6, 95% CI: 1.3-1.9) and lower educational level (low level as reference; high level OR 0.3, 95% CI: 0.2-0.7) were independently associated with more fatigue. Conclusions: Fatigue is a frequent problem in meningioma patients even many years after treatment. Both patient- and treatment-related factors were determinants of fatigue, with the treatment-related factors being the most likely target for intervention in this patient population.

Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints in Cancer Clinical Trials-Innovative Medicines Initiative (SISAQOL-IMI): stakeholder views, objectives, and procedures.

Patient-reported outcomes (PROs), such as symptoms, functioning, and other health-related quality-of-life concepts are gaining a more prominent role in the benefit-risk assessment of cancer therapies. However, varying ways of analysing, presenting, and interpreting PRO data could lead to erroneous and inconsistent decisions on the part of stakeholders, adversely affecting patient care and outcomes. The Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints in Cancer Clinical Trials-Innovative Medicines Initiative (SISAQOL-IMI) Consortium builds on the existing SISAQOL work to establish recommendations on design, analysis, presentation, and interpretation for PRO data in cancer clinical trials, with an expanded set of topics, including more in-depth recommendations for randomised controlled trials and single-arm studies, and for defining clinically meaningful change. This Policy Review presents international stakeholder views on the need for SISAQOL-IMI, the agreed on and prioritised set of PRO objectives, and a roadmap to ensure that international consensus recommendations are achieved.

Minimally important differences for interpreting EORTC QLQ-C30 change scores over time: A synthesis across 21 clinical trials involving nine different cancer types.

INTRODUCTION: Early guidelines for minimally important differences (MIDs) for the EORTC QLQ-C30 proposed ≥10 points change as clinically meaningful for all scales. Increasing evidence that MIDs can vary by scale, direction of change, cancer type and estimation method has raised doubt about a single global standard. This paper identifies MID patterns for interpreting group-level change in EORTC QLQ-C30 scores across nine cancer types. METHODS: Data were obtained from 21 published EORTC Phase III trials that enroled 13,015 patients across nine cancer types (brain, colorectal, advanced breast, head/neck, lung, mesothelioma, melanoma, ovarian, and prostate). Anchor-based MIDs for within-group change and between-group differences in change over time were obtained via mean change method and linear regression, respectively. Separate MIDs were estimated for improvements and deteriorations. Distribution-based estimates were derived and compared with anchor-based MIDs. RESULTS: Anchor-based MIDs mostly ranged from 5 to 10 points. Differences in MIDs for improvement vs deterioration, for both within-group and between-group, were mostly within a 2-points range. Larger differences between within-group and between-group MIDs were observed for several scales in ovarian, lung and head/neck cancer. Most anchor-based MIDs ranged between 0.3 SD and 0.5 SD distribution-based estimates. CONCLUSIONS: Our results reinforce recent claims that no single MID can be applied to all EORTC QLQ-C30 scales and disease settings. MIDs varied by scale, improvement/deterioration, within/between comparisons and by cancer type. Researchers applying commonly used rules of thumb must be aware of the risk of dismissing changes that are clinically meaningful or underpowering analyses when smaller MIDs apply.

Repair of joint damage in patients with rheumatoid arthritis does not relate to previous suppression of inflammation: a subanalysis after 8 years treat-to-target in the BeSt-trial.

OBJECTIVES: To investigate whether repair of erosions and joint space narrowing (JSN) in rheumatoid arthritis (RA) occurs and whether clinical variables predict this. METHODS: Eight-year follow-up data of the BeSt-study were used. Patients with recent onset RA (1987 criteria) were randomised to four treatment strategies and treated-to-target (Disease Activity Score (DAS)≤2.4). Yearly radiographs of hands and feet were scored in non-chronological order by four independent readers, using the Sharp/van der Heijde score (SHS). Damage repair was defined as a negative ΔSHS in an individual joint, seen by ≥3 out of 4 readers and persisting ≥2 consecutive years. Associations between repair and DAS, prednisone use, infliximab use, anticitrullinated protein antibody, gender, age, body mass index, symptom duration and randomisation arm were investigated with logistic regression analyses, corrected for mean SHS. RESULTS: Repair was seen in 17 patients (5.3%); 10 had regression of JSN, 7 of erosions, none had both. There were no significant associations in any of the regression analyses. CONCLUSION: After 8 years of treatment to target DAS≤2.4 in 508 patients with recent onset RA, repair of JSN and erosions was seen in 17/320 patients (5.3%). Probably due to the rarity of repair, we found no associations with suppression of disease activity or other predictors and repair.