Clinical, histopathological and molecular features of dedifferentiated melanomas: An EORTC Melanoma Group Retrospective Analysis

PURPOSE: Dedifferentiated melanoma (DedM) poses significant diagnostic challenges. We aimed to investigate the clinical, histopathological and molecular features of DedM. Methylation signature (MS) and copy number profiling (CNP) were carried out in a subgroup of cases. PATIENTS AND METHODS: A retrospective series of 78 DedM tissue samples from 61 patients retrieved from EORTC (European Organisation for Research and Treatment of Cancer) Melanoma Group centres were centrally reviewed. Clinical and histopathological features were retrieved. In a subgroup of patients, genotyping through Infinium Methylation microarray and CNP analysis was carried out. RESULTS: Most patients (60/61) had a metastatic DedM showing most frequently an unclassified pleomorphic, spindle cell, or small round cell morphology akin to undifferentiated soft tissue sarcoma, rarely associated with heterologous elements. Overall, among 20 successfully analysed tissue samples from 16 patients, we found retained melanoma-like MS in only 7 tissue samples while a non-melanoma-like MS was observed in 13 tissue samples. In two patients from whom multiple specimens were analysed, some of the samples had a preserved cutaneous melanoma MS while other specimens exhibited an epigenetic shift towards a mesenchymal/sarcoma-like profile, matching the histological features. In these two patients, CNP was largely identical across all analysed specimens, in line with their common clonal origin, despite significant modification of their epigenome. CONCLUSIONS: Our study further highlights that DedM represents a real diagnostic challenge. While MS and genomic CNP may help pathologists to diagnose DedM, we provide proof-of-concept that dedifferentiation in melanoma is frequently associated with epigenetic modifications

Health-related quality-of-life results from the randomised phase II TAVAREC trial on temozolomide with or without bevacizumab in 1p/19q intact first-recurrence World Health Organization grade 2 and 3 glioma (European Organization for Research and Treatment of Cancer 26091)

BACKGROUND: In an international randomised controlled phase II study of temozolomide (TMZ) versus TMZ in combination with bevacizumab (BEV) in locally diagnosed non-1p/19q co-deleted World Health Organization grade 2 or 3 gliomas with a first and contrast-enhancing recurrence after initial radiotherapy, and overall survival at 12 months was not significantly different (61% in the TMZ arm and 55% in the TMZ + BEV arm). OBJECTIVES: Health-related quality of life (HRQoL) was a key secondary end-point in this trial, and the main objective of this study was to determine the impact of the addition of BEV to TMZ on HRQoL. METHODS: HRQoL was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 (version 3) and QLQ-BN20 at baseline, and then every 12 weeks until disease progression. The pre-selected primary HRQoL end-point was the QLQ-C30 global health scale, with self-perceived cognitive functioning and pain selected as secondary HRQoL issues. Analysis was undertaken using linear mixed modelling and complemented with sensitivity analyses using summary statistics. A difference was considered clinically relevant with ≥10 points difference on a 100-point scale. RESULTS: Baseline compliance was high at 94% and remained above 60% until 72 weeks, limiting the analysis to 60 weeks. Compliance was similar in both arms. We found no statistically significant or clinically significant differences between the primary HRQoL end-point in both treatment arms (p = 0.2642). The sensitivity analyses confirmed this finding. The overall test for post-baseline differences between the two treatment arms also showed no statistically or clinically significant differences regarding the selected secondary end-point scales. INTERPRETATION: The addition of BEV to TMZ in this patient group neither improves nor negatively impacts HRQoL

Systematic review of the health-related quality of life issues facing adolescents and young adults with cancer

PURPOSE: For adolescents and young adults (AYAs), the impact of a cancer diagnosis and subsequent treatment is likely to be distinct from other age groups given the unique and complex psychosocial challenges of this developmental phase. In this review of the literature, we report the health-related quality of life (HRQoL) issues experienced by AYAs diagnosed with cancer and undergoing treatment. METHODS: MEDLINE, EMBASE, CINAHL, PsychINFO and the Cochrane Library Databases were searched for publications reporting HRQoL of AYAs. Issues generated from interviews with AYAs or from responses to patient reported outcome measures (PROMs) were extracted. RESULTS: 166 papers were reviewed in full and comprised 72 papers covering 69 primary studies, 49 measurement development or evaluation papers and 45 reviews. Of the 69 studies reviewed, 11 (16%) used interviews to elicit AYAs’ descriptions of HRQoL issues. The majority of the PROMs used in the studies represent adaptations of paediatric or adult measures. HRQoL issues were organised into the following categories: physical, cognitive, restricted activities, relationships with others, fertility, emotions, body image and spirituality/outlook on life. CONCLUSION: The HRQoL issues presented within this review are likely to be informative to health care professionals and AYAs. The extensive list of issues suggests that the impact of a cancer diagnosis and treatment during adolescence and young adulthood is widespread and reflects the complexities of this developmental phase

Association of antidepressant drug use with outcome of patients with glioblastoma

Depressive symptoms are common among patients with glioblastoma, but patients are often not treated with antidepressants. There is only limited evidence on the association of antidepressant drug use with survival in glioblastoma. We performed a pooled analysis of patients treated within the CENTRIC, CORE, AVAglio and ACT‐IV trials to explore the relation of antidepressant drug use with progression‐free (PFS) and overall survival (OS) at baseline, at the start of maintenance therapy and at the start of maintenance cycle 4. We further assessed the association of antidepressant drugs with seizure, cognition, fatigue and a diagnosis of depression. Among more than 1700 patients, we found no significant association between the use of antidepressants at baseline or at the start of maintenance therapy and PFS or OS. However, we found OS, but not PFS, to be significantly worse in patients using antidepressants at the start of maintenance cycle 4. After adjustment for antiepileptic drug use and despite showing a trend for increased risk, seizures were not significantly associated with antidepressant drug use, nor was there a change in mini mental state examination (MMSE) scores or fatigue by antidepressant drug use at baseline. However, there was a significant positive association between antidepressant use at the start of maintenance treatment and fatigue during maintenance treatment. The association of antidepressant use at the start of maintenance cycle 4 with inferior OS of glioblastoma patients requires independent confirmation and further study. Further prospective trials should evaluate efficacy, side effects and associations with outcome of antidepressants in glioblastoma

Marizomib for patients with newly diagnosed glioblastoma: a randomized phase 3 trial

BACKGROUND: Standard treatment for patients with newly diagnosed glioblastoma includes surgery, radiotherapy (RT), and temozolomide (TMZ) chemotherapy (TMZ/RT→TMZ). The proteasome has long been considered a promising therapeutic target because of its role as a central biological hub in tumor cells. Marizomib is a novel pan-proteasome inhibitor that crosses the blood-brain barrier. METHODS: European Organisation for Research and Treatment of Cancer 1709/Canadian Cancer Trials Group CE.8 was a multicenter, randomized, controlled, open-label phase 3 superiority trial. Key eligibility criteria included newly diagnosed glioblastoma, age > 18 years and Karnofsky performance status > 70. Patients were randomized in a 1:1 ratio. The primary objective was to compare overall survival (OS) in patients receiving marizomib in addition to TMZ/RT→TMZ with patients receiving the only standard treatment in the whole population and in the subgroup of patients with MGMT promoter-unmethylated tumors. RESULTS: The trial was opened at 82 institutions in Europe, Canada, and the U.S. A total of 749 patients (99.9% of the planned 750) were randomized. OS was not different between the standard and the marizomib arm (median 17 vs. 16.5 months; HR = 1.04; P = .64). PFS was not statistically different either (median 6.0 vs. 6.3 months; HR = 0.97; P = .67). In patients with MGMT promoter-unmethylated tumors, OS was also not different between standard therapy and marizomib (median 14.5 vs. 15.1 months, HR = 1.13; P = .27). More CTCAE grade 3/4 treatment-emergent adverse events were observed in the marizomib arm than in the standard arm. CONCLUSIONS: Adding marizomib to standard temozolomide-based radiochemotherapy resulted in more toxicity, but did not improve OS or PFS in patients with newly diagnosed glioblastoma

Establishing anchor-based minimally important differences (MID) with the EORTC quality-of-life measures: a meta-analysis protocol.

INTRODUCTION: As patient assessment of health-related quality of life (HRQOL) in cancer clinical trials has increased over the years, so has the need to attach meaningful interpretations to differences in HRQOL scores between groups and changes within groups. Determining what represents a minimally important difference (MID) in HRQOL scores is useful to clinicians, patients and researchers, and can be used as a benchmark for assessing the success of a healthcare intervention. Our objective is to provide an evidence-based protocol to determine MIDs for the European Organisation for Research and Treatment for Cancer Quality of life Questionnaire core 30 (EORTC QLQ-C30). We will mainly focus on MID estimation for group-level comparisons. Responder thresholds for individual-level change will also be estimated. METHODS AND ANALYSIS: Data will be derived from published phase II and III EORTC trials that used the QLQ-C30 instrument, covering several cancer sites. We will use individual patient data to estimate MIDs for different cancer sites separately. Focus is on anchor-based methods. Anchors will be selected per disease site from available data. A disease-oriented and methodological panel will provide independent guidance on anchor selection. We aim to construct multiple clinical anchors per QLQ-C30 scale and also to compare with several anchor-based methods. The effects of covariates, for example, gender, age, disease stage and so on, will also be investigated. We will examine how our estimated MIDs compare with previously published guidelines, hence further contributing to robust MID guidelines for the EORTC QLQ-C30. ETHICS AND DISSEMINATION: All patient data originate from completed clinical trials with mandatory written informed consent, approved by local ethical committees. Our findings will be presented at scientific conferences, disseminated via peer-reviewed publications and also compiled in a MID 'blue book' which will be made available online on the EORTC Quality of Life Group website as a free guideline document

Current management of limited-stage SCLC and CONVERT trial impact:Results of the EORTC Lung Cancer Group survey

Objectives: The CONVERT trial showed that twice-daily (BD) concurrent chemoradiotherapy should continue tobe considered the standard of care in localised LS-SCLC. A survey was conducted to assess the impact of theCONVERT trial in clinical practice and to identify any relevant research questions for future trials in this setting.Methods and materials: An EORTC Group online survey of LS-SCLC practice was distributed to the EORTC LCGand to members of several European thoracic oncology societies between April and December 2018.Results: 198 responses were analysed. The majority of respondents (88%, n=174) were aware of the CONVERTtrial. Radiation oncologists comprised 56% of all respondents. Once-daily (OD) radiotherapy is still the mostcommonly used regimen, however the use of concurrent BD radiotherapy increased after the publication ofCONVERT (n=59/186, 32% prior to and n=78/187, 42% after the publication, p=0.053). The main reasonsfor not implementing BD after the CONVERT publication were logistical issues (n=88, 44%), inconvenience forpatients (n=56, 28%), and the absence of a statistical survival difference between the two arms in CONVERT(n=38, 19%). Brain MRI was used by 28% during staging but more than half (60%) of the respondents did notroutinely image the brain during follow-up. The main research questions of interest in LS-SCLC were 1) integratingnovel targeted therapies-immunotherapies (n=160, 81%), 2) PCI (+/- hippocampal sparing) vs. MRIsurveillance (n=140, 71%) and, 3) biomarker driven trials (n=92, 46%).Conclusion: Once daily radiotherapy (60–66 Gy in 30–33 fractions) remains the most prescribed radiotherapyfractionation, despite the findings suggested by the CONVERT trial.info:eu-repo/semantics/publishe

General population normative data for the EORTC QLQ-C30 health-related quality of life questionnaire based on 15,386 persons across 13 European countries, Canada and the Unites States

OBJECTIVE: The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 health-related quality of life questionnaire is one of the most widely used cancer-specific health-related quality of life questionnaires worldwide. General population norm data can facilitate the interpretation of QLQ-C30 data obtained from cancer patients. This study aimed at systematically collecting norm data from the general population to develop European QLQ-C30 norm scores and to generate comparable norm data for individual countries in Europe and North America. METHODS: We collected QLQ-C30 data from the general population across 11 European Union (EU) countries, Russia, Turkey, Canada and United States (n \u3e /= 1000/country). Representative samples were stratified by sex and age groups (18-39, 40-49, 50-59, 60-69 and \u3e /= 70 years). After applying weights based on the United Nations population distribution statistics, we calculated QLQ-C30 domain scores to generate a \u27European QLQ-C30 Norm\u27 based on the EU countries. Further, we calculated QLQ-C30 norm scores for all 15 individual countries. RESULTS: A total of 15,386 respondents completed the online survey. For the EU sample, most QLQ-C30 domains showed differences by sex/age, with men scoring somewhat better health than women, while age effects varied across domains. Substantially larger differences were seen in inter-country comparisons, with Austrian and Dutch respondents reporting consistently better health compared with British and Polish respondents. CONCLUSIONS: This study is the first to systematically collect EORTC QLQ-C30 general population norm data across Europe and North America applying a consistent data collection method across 15 countries. These new norm data facilitate valid intra-country as well as inter-country comparisons and QLQ-C30 score interpretation

The role of pharmacology in anticancer drug development

Drug development consists of many sequential and parallel steps; failure in one of the steps can lead to discontinuation of the process. The process is time-consuming and very expensive, especially the clinical phase. In order to enhance cancer drug development in the 1980s, the National Cancer Institute (NCI) adopted a new screening system using 60 different tumour cell lines from various histologies. All standard drugs were tested in this panel and it is still open for testing of new chemical entities (NCE) of potential interest. The European NCI compounds initiative, a collaborative programme of the NCI, the Cancer Research Campaign (CRC; now CRUK) and the Pharmacology and Molecular Mechanism Group (PAMM) of the EORTC (European Organization on Research and Treatment of Cancer), was initiated in 1993. The programme aimed to help the NCI reducing its backlog of in vivo testing by further evaluation of interesting European compounds using a pharmacologically directed approach. Considerable multidisciplinary expertise in drug development was combined by the CRC and EORTC-PAMM: chemists, pharmacists, biologists, pharmacologists, oncologists. Selection criteria for European NCI compounds included novelty of the NCE, in vitro activity, if available in vivo and hollow fibre activity, and COMPARE negativity. Over a period of more than 20 years 95 out of approximately 2,000 reviewed compounds were selected. These compounds were put through a series of stepwise pharmacological tests comprising solubility (suitable formulation to administer the NCE to mice), feasibility to develop a simple analytical assay (usually HPLC), limited toxicology and angiogenic properties. This paper provides examples to illustrate the rigorousness of the elimination process of the compounds and discusses the way to improve the process by inclusion of more physico-chemical parameters