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Background: The European Society for Medical Oncology (ESMO)-Magnitude of Clinical Benefit Scale (MCBS) has been accepted as a robust tool to evaluate the magnitude of clinical benefit reported in trials for oncological therapies. However, the ESMO-MCBS hitherto has only been validated for solid tumours. With the rapid development of novel therapies for haematological malignancies, we aimed to develop an ESMO-MCBS version that is specifically designed and validated for haematological malignancies., Methods: ESMO and the European Hematology Association (EHA) initiated a collaboration to develop a version for haematological malignancies (ESMO-MCBS:H). The process incorporated five landmarks: field testing of the ESMO-MCBS version 1.1 (v1.1) to identify shortcomings specific to haematological diseases, drafting of the ESMO-MCBS:H forms, peer review and revision of the draft based on re-scoring (resulting in a second draft), assessment of reasonableness of the scores generated, final review and approval by ESMO and EHA including executive boards., Results: Based on the field testing results of 80 haematological trials and extensive review for feasibility and reasonableness, five amendments to ESMO-MCBS were incorporated in the ESMO-MCBS:H addressing the identified shortcomings. These concerned mainly clinical trial endpoints that differ in haematology versus solid oncology and the very indolent nature of nevertheless incurable diseases such as follicular lymphoma, which hampers presentation of mature data. In addition, general changes incorporated in the draft version of the ESMO-MCBS v2 were included, and specific forms for haematological malignancies generated. Here we present the final approved forms of the ESMO-MCBS:H, including instructions., Conclusion: The haematology-specific version ESMO-MCBS:H allows now full applicability of the scale for evaluating the magnitude of clinical benefit derived from clinical studies in haematological malignancies., (Copyright © 2023. Published by Elsevier Ltd.)

Competing Interests: CZ receives consulting fees from the UK Health Alliance on Climate Change. PY receives honoraria from Novartis, bioMérieux, and Pfizer and receives advisory board fees from Pfizer and fees for serving on a DSMB from the US National Heart, Lung, and Blood Institute all unrelated to the topic of this Comment. JM is an unpaid Board member of the International Working Group for Health systems strengthening unrelated to the topic of this Comment. DO-A receives advisory board fees from Inovio Pharmaceuticals and is a member of the Board of Directors of GLICO Healthcare all unrelated to the topic of this Comment. The other authors declare no competing interests. This Comment is being published simultaneously in multiple journals (appendix). The full list of journals and supporting journals can be found on the BMJ website.

Competing Interests: CZ receives consulting fees from the UK Health Alliance on Climate Change. PY receives honoraria from Novartis, bioMérieux, and Pfizer and receives advisory board fees from Pfizer and fees for serving on a DSMB from the US National Heart, Lung, and Blood Institute all unrelated to the topic of this Comment. JM is an unpaid Board member of the International Working Group for Health systems strengthening unrelated to the topic of this Comment. DO-A receives advisory board fees from Inovio Pharmaceuticals and is a member of the Board of Directors of GLICO Healthcare all unrelated to the topic of this Comment. The other authors declare no competing interests. This Comment is being published simultaneously in multiple journals (appendix). The full list of journals and supporting journals can be found on the BMJ website.

Competing Interests: CZ receives consulting fees from the UK Health Alliance on Climate Change. PY receives honoraria from Novartis, bioMérieux, and Pfizer and receives advisory board fees from Pfizer and fees for serving on a DSMB from the US National Heart, Lung, and Blood Institute all unrelated to the topic of this Comment. JM is an unpaid Board member of the International Working Group for Health systems strengthening unrelated to the topic of this Comment. DO-A receives advisory board fees from Inovio Pharmaceuticals and is a member of the Board of Directors of GLICO Healthcare all unrelated to the topic of this Comment. The other authors declare no competing interests. This Comment is being published simultaneously in multiple journals (appendix). The full list of journals and supporting journals can be found on the BMJ website.

Background: Combined therapy with dabrafenib plus trametinib was approved in several countries for treatment of BRAF V600E-mutant anaplastic thyroid cancer (ATC) based on an earlier interim analysis of 23 response-assessable patients in the ATC cohort of the phase II Rare Oncology Agnostic Research (ROAR) basket study. We report an updated analysis describing the efficacy and safety of dabrafenib plus trametinib in the full ROAR ATC cohort of 36 patients with ∼4 years of additional study follow-up., Patients and Methods: ROAR (NCT02034110) is an open-label, nonrandomized, phase II basket study evaluating dabrafenib plus trametinib in BRAF V600E-mutant rare cancers. The ATC cohort comprised 36 patients with unresectable or metastatic ATC who received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily orally until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety., Results: At data cutoff (14 September 2020), median follow-up was 11.1 months (range, 0.9-76.6 months). The investigator-assessed ORR was 56% (95% confidence interval, 38.1% to 72.1%), including three complete responses; the 12-month DOR rate was 50%. Median PFS and OS were 6.7 and 14.5 months, respectively. The respective 12-month PFS and OS rates were 43.2% and 51.7%, and the 24-month OS rate was 31.5%. No new safety signals were identified with additional follow-up, and adverse events were consistent with the established tolerability of dabrafenib plus trametinib., Conclusions: These updated results confirm the substantial clinical benefit and manageable toxicity of dabrafenib plus trametinib in BRAF V600E-mutant ATC. Dabrafenib plus trametinib notably improved long-term survival and represents a meaningful treatment option for this rare, aggressive cancer., Competing Interests: Disclosure VS reports research grants from Novartis, Eli Lilly/Loxo Oncology, Roche/Genentech, Bayer, GlaxoSmithKline, NanoCarrier, VEGENICS, Celgene, Northwest Biotherapeutics, Berg Health, Incyte, Fujifilm, D3, Pfizer, MultiVir, Amgen, AbbVie, Alfasigma, Agensys, Boston Biomedical, Idera Pharmaceuticals, Inhibrx, Exelixis, Blueprint Medicines, Altum, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, National Cancer Institute–Cancer Therapy Evaluation Program, The University of Texas MD Anderson Cancer Center, Turning Point Therapeutics, Boston Pharmaceuticals, PharmaMar, and MedImmune; an advisory board/consultant position with Eli Lilly/Loxo Oncology, Helsinn, Incyte, QED Pharma, Daiichi Sankyo, Signant Health, Novartis, Relay Therapeutics, Roche, and MedImmune; travel funds from PharmaMar, Incyte, American Society of Clinical Oncology, and European Society for Medical Oncology; and other support from Medscape. ZAW reports consulting fees from Amgen, AstraZeneca, Daiichi Sankyo, Bayer, Bristol Myers Squibb, Merck, Ipsen, Five Prime, Gilead, Arcus, Astellas, Molecular Templates, and Array; support for attending meetings/travel from Daiichi Sankyo; and advisory board participation with Array and Pfizer. JHMS reports stock ownership in and employment with Modra Pharmaceuticals; consulting fees from and advisory board participation with Debiopharm; and a patent on oral taxanes. JCS reports stock in Gritstone Bio and Relay Therapeutics; and employment with Amgen. PYW reports grants from Agios, AstraZeneca/MedImmune, BeiGene, Celgene, Lilly, Roche/Genentech, Kazia, MediciNova, Merck, Nuvation Bio, Oncoceutics, Vascular Biogenics, and VBI Vaccines; and consulting fees from/advisory board participation with Agios, AstraZeneca, Bayer, Boston Pharmaceuticals, CNS Pharmaceuticals, Elevate Bio Immunomic Therapeutics, Imvax, Karyopharm, Merck, Novartis, Nuvation Bio, Vascular Biogenics, VBI Vaccines, Voyager, QED, Celularity, and Sapience. CCZ reports consulting fees from Athenex; payment or honoraria from MSD, Imugene, AstraZeneca, Servier, Lilly, Bristol Myers Squibb, Pfizer, Merck KGaA, Amgen, Takeda, Daiichi Sankyo, Roche, Boehringer Ingelheim, Celgene, and Halozyme; patents with Imugene; and a leadership or fiduciary role with the European Society for Medical Oncology and CECOG. MEC reports grants from Genentech and Merck; payment or honoraria from Exelixis and Lilly; and advisory board participation with Exelixis, Lilly, and Bayer. AB reports stock ownership in and employment with Novartis. IP and TRS report employment with Novartis. PB reports stock ownership in Novartis and GlaxoSmithKline; and employment with Novartis. BK reports research grants from MSD, AstraZeneca, and Ono Pharmaceuticals; consulting fees from AstraZeneca, MSD, ABL Bio, Genexine, Handok, CELiD, Trial Informatics, and CBS Bio; and payment or honoraria from MSD and Merck. All authors acknowledge receipt of medical writing support for this manuscript from ArticulateScience, LLC, funded by Novartis. All other authors have declared no additional conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a validated, widely used tool developed to score the clinical benefit from cancer medicines reported in clinical trials. ESMO-MCBS scores assume valid research methodologies and quality trial implementation. Studies incorporating flawed design, implementation, or data analysis may generate outcomes that exaggerate true benefit and are not generalisable. Failure to either indicate or penalise studies with bias undermines the intention and diminishes the integrity of ESMO-MCBS scores. This review aimed to evaluate the adequacy of the ESMO-MCBS to address bias generated by flawed design, implementation, or data analysis and identify shortcomings in need of amendment., Methods: As part of a refinement of the ESMO-MCBS, we reviewed trial design, implementation, and data analysis issues that could bias the results. For each issue of concern, we reviewed the ESMO-MCBS v1.1 approach against standards derived from Helsinki guidelines for ethical human research and guidelines from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use, the Food and Drugs Administration, the European Medicines Agency, and European Network for Health Technology Assessment., Results: Six design, two implementation, and two data analysis and interpretation issues were evaluated and in three, the ESMO-MCBS provided adequate protections. Seven shortcomings in the ability of the ESMO-MCBS to identify and address bias were identified. These related to (i) evaluation of the control arm, (ii) crossover issues, (iii) criteria for non-inferiority, (iv) substandard post-progression treatment, (v) post hoc subgroup findings based on biomarkers, (vi) informative censoring, and (vii) publication bias against quality-of-life data., Conclusion: Interpretation of the ESMO-MCBS scores requires critical appraisal of trials to understand caveats in trial design, implementation, and data analysis that may have biased results and conclusions. These will be addressed in future iterations of the ESMO-MCBS., Competing Interests: Disclosure TA personal fees and travel grants from Bristol-Myers Squibb (BMS), personal fees, grants and travel grants from Novartis, personal fees from Pierre Fabre, grants from Neracare, Sanofi, and SkylineDx, personal fees from CeCaVa outside the submitted work; JBa reports grants, personal fees, and nonfinancial support from Ipsen; personal fees and nonfinancial support from Pfizer, Novartis; nonfinancial support from AAA, Nanostring, Roche; grants and personal fees from Servier; and personal fees from Nutricia outside the submitted work; JBo is a statistician on the SAG-O (scientific advice committee oncology) for EMA, and scientific director of EORTC Headquarters. EORTC carries out clinical trials with many (most) pharma and some biotechs either with financial or material support, or with the company as the sponsor (intent to register new indication); he is co-responsible for the management of EORTC. AC has received honoraria/consulting fees from AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche/Genentech, Eli Lilly and Company, Takeda, Novartis, Merck Sharp & Dohme (MSD), and BMS; GC scientific advisory board for BMS, Roche, Novartis, Lilly, Pfizer, Seagen, AstraZeneca, Daichii Sankyo, and Veracyte; UD Tumour Agnostic Evidence Generation Working Group Member, Roche; BG reports receiving consulting fees from Vivio Health. CG-R BMS (institutional research and travel grants, speaker’s honoraria), Roche/Genentech (institutional research and travel grants, speaker’s honoraria), Pierre Fabre (travel and educational grants, speaker’s honoraria); MSD (travel grants); Eisai (speaker’s honoraria); Foundation Medicine (research grant, speaker’s honoraria); BK Honoraria for lectures from Ipsen, Novartis and MSD; SO research grants from Celldex and Novartis to the institution; AP received honoraria for consulting, advisory role or lectures from AstraZeneca, Agilent/Dako, Boehringer Ingelheim, BMS, Eli Lilly, Janssen, MSD, Pfizer and Roche Genentech; GP received institutional financial support for advisory board/consultancy from Roche, Amgen, Merck, MSD, BMS, and institutional support for clinical trials or contracted research from Amgen, Roche, AstraZeneca, Pfizer, Merck, BMS, MSD, Novartis, Lilly; MP consulting or advisory role: AstraZeneca, Lilly, MSD, Novartis, Pfizer, Roche, Genentech, Crescendo Biologics, Periphagen, Huya Bioscience, Debiopharm Group, Odante Therapeutics; Consulting or Advisory Role: G1 Therapeutics, Menarini, Seattle Genetics, Camel-IDS, Immunomedics, Oncolytics, Radius Health; Research Funding: AstraZeneca (Inst), Lilly (Inst), MSD (Inst), Novartis (Inst), Pfizer (Inst), Roche (Inst), Genentech (Inst), Radius Health (Inst), Synthon (Inst), Servier (Inst); Other Relationship: Radius Health; JT personal financial interest in the form of scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech, Inc., HalioDX SAS, Ikena Oncology, IQVIA, Imedex, Lilly, MSD, Menarini, Merck Serono, Mirati, Novartis, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics and TheraMyc. Institutional financial interest in the form of financial support for clinical trials or contracted research for Amgen Inc., Array Biopharma Inc., AstraZeneca Pharmaceuticals LP, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc., Janssen-Cilag SA, MSD, Novartis Farmacéutica SA, Taiho Pharma USA Inc., Pharma Mar, Spanish Association Against Cancer Scientific Foundation and Cancer Research UK; EGEdV declares: institutional financial support for advisory board/consultancy from Sanofi, Daiichi, Sankyo, NSABP, Pfizer and Merck, and institutional support for clinical trials or contracted research from Amgen, Genentech, Roche, AstraZeneca, Synthon, Nordic Nanovector, G1 Therapeutics, Bayer, Chugai Pharma, CytomX Therapeutics, Servier and Radius Health; CZ consultancies and speaker’s honoraria: Roche, Novartis, BMS, MSD, Imugene, Ariad, Pfizer, Merrimack, Merck KGaA, Fibrogen, AstraZeneca, Tesaro, Gilead, Servier, Shire, Eli Lilly, Athenex. Institution (Central European Cooperative Oncology Group): BMS, MSD, Pfizer, AstraZeneca, Servier, Eli Lilly; GZ received speaker’s honoraria from Amgen and Ipsen. All other authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Palbociclib plus endocrine therapy (ET) is the standard treatment of hormone receptor-positive and human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC). However, its efficacy has not been compared with that of chemotherapy in a phase III trial., Patients and Methods: PEARL is a multicentre, phase III randomised study in which patients with aromatase inhibitor (AI)-resistant MBC were included in two consecutive cohorts. In cohort 1, patients were randomised 1 : 1 to palbociclib plus exemestane or capecitabine. On discovering new evidence about estrogen receptor-1 (ESR1) mutations inducing resistance to AIs, the trial was amended to include cohort 2, in which patients were randomised 1 : 1 between palbociclib plus fulvestrant and capecitabine. The stratification criteria were disease site, prior sensitivity to ET, prior chemotherapy for MBC, and country of origin. Co-primary endpoints were progression-free survival (PFS) in cohort 2 and in wild-type ESR1 patients (cohort 1 + cohort 2). ESR1 hotspot mutations were analysed in baseline circulating tumour DNA., Results: From March 2014 to July 2018, 296 and 305 patients were included in cohort 1 and cohort 2, respectively. Palbociclib plus ET was not superior to capecitabine in both cohort 2 [median PFS: 7.5 versus 10.0 months; adjusted hazard ratio (aHR): 1.13; 95% confidence interval (CI): 0.85-1.50] and wild-type ESR1 patients (median PFS: 8.0 versus 10.6 months; aHR: 1.11; 95% CI: 0.87-1.41). The most frequent grade 3-4 toxicities with palbociclib plus exemestane, palbociclib plus fulvestrant and capecitabine, respectively, were neutropenia (57.4%, 55.7% and 5.5%), hand/foot syndrome (0%, 0% and 23.5%), and diarrhoea (1.3%, 1.3% and 7.6%). Palbociclib plus ET offered better quality of life (aHR for time to deterioration of global health status: 0.67; 95% CI: 0.53-0.85)., Conclusions: There was no statistical superiority of palbociclib plus ET over capecitabine with respect to PFS in MBC patients resistant to AIs. Palbociclib plus ET showed a better safety profile and improved quality of life., Competing Interests: Disclosure MM has received consulting fees from AstraZeneca, Amgen, Taiho Oncology, Roche/Genentech, Novartis, PharmaMar, Eli Lilly, PUMA, Taiho Oncology, and Pfizer; speakers' honoraria from AstraZeneca, Amgen, Roche/Genentech, Novartis, Daiichi-Sankyo, and Pfizer; contracted research fees from Roche, Novartis, and PUMA. CZ has received consulting fees and speaker’s honoraria from Roche, Novartis, Bristol-Myers Squibb, Merck Sharp & Dohme, Imugene, Ariad, Pfizer, Merrimack, Merck KGaA, Fibrogen, AstraZeneca, Tesaro, Gilead, Servier, Shire, Eli Lilly, and Athenex. His institution, Central European Cancer Center, Wiener Privatklinik Hospital, has received fees from Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, AstraZeneca, and Merck KGaA. MRB has received speaker fees and advisory grants from Pfizer, Novartis, and Lilly. EC, who has a stock and other ownership interests from Lilly, has received travel and accommodation support from Roche, and her husband who has participated in consulting and advisory board activities with Bristol-Myers Squibb, Novartis, Celgene, Roche Pharma, Janssen, Amgen, Incyte, Abbvie, and Pfizer, has received travel and accommodation support from Celgene, Novartis, and Bristol-Myers Squibb. His institution has received research funding from Celgene, Janssen, Bristol-Myers Squibb, Novartis, Celgene, Roche/Genentech, Amgen, Pfizer, and Abbvie. GEICAM has received research funding from Roche/Genentech, Bristol-Myers Squibb, Novartis, Pfizer, Celgene, AstraZeneca, Merck Sharp & Dohme, Pierre Fabre, and Takeda. NT has received advisory board honoraria from AstraZeneca, Bristol-Myers Squibb, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, Bicycle Therapeutics, Taiho, Zeno Pharmaceuticals, and Repare Therapeutics and research funding from AstraZeneca, Bio-Rad, Pfizer, Roche/Genentech, Clovis, Merck Sharp & Dohme, and Guardant Health. MM has received travel and congress assistance support from Roche, Novartis, Pfizer, and Eisai. BB has received advisory board honoraria from Genentech, Novartis, Merck Sharpe and Dohme, speakers’ honoraria from Genentech, Eisai and she has received travel and congress assistance support from Pfizer. MM has received advisory board fees from Roche, Novartis, Pfizer, and Eisai. Her institution, Hospital Universitari Germans Trias i Pujol, Badalona, has received funding research from Roche, Pfizer, Novartis, Lilly, AstraZeneca, Eisai, and Kern. AA has received advisory board fees from Bayer, Spain. EA has received advisory board fees from Roche, Novartis, Pfizer, Lilly, Bristol-Myers Squibb, Genomic Health, and Nanostring. He has received travel support from Celgene. His institution, Hospitales Regional y Virgen de la Victoria, Málaga, has received funding research from Roche, Pfizer, Sysmex, Merck Sharp & Dohme, and Nanostring. EG-Y has received honoraria, travel support, and has participated in advisory boards for Pfizer, Roche, Novartis, and Eli Lilly. ÁG-Z has received investigational fees and travel support from Pfizer. JdelaH has received honoraria from AstrazZeneca, Pfizer, Novartis, Roche, and Agendia. MR has received honoraria from Novartis, Roche, and Pfizer. IÁ has received consulting or advisory board honoraria from AstraZeneca, Pfizer, Novartis, and Roche; speakers’ honoraria from AstraZeneca, Pfizer, Novartis, Roche, and Eisai; travel and congress assistance support from AstraZeneca, Pfizer, Roche, and Eisai. CH has a stock from Pfizer and AstraZeneca, she was an employee of Pfizer during the study, and is an employee of AstraZeneca currently, where she holds a stock. MK has Pfizer stock and was an employee of Pfizer during the study. MC is employed by Pfizer and has the company’s stock options. XH is employed by Pfizer and has the company’s stock options. JAG-S has consultancy/speaker fees from Novartis, Celgene, Eli Lilly, Eisai, and AstraZeneca. He received travel support from Novartis, Roche, and Pfizer. His institution, Hospital Clínico Universitario San Carlos, received research funding from AstraZeneca. MG-G has received honoraria from Pfizer and Eisai and has participated in advisory boards of Genentech and Daiichi-Sankyo. He has received travel support from Pfizer, Novartis, Daiichi-Sankyo, Roche, and Kern. All remaining authors have declared no conflicts of interest. A complete list of the PEARL trial collaborators is provided in the Supplementary Appendix., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Receptor activator of NF-kB ligand stimulates NF-kB-dependent cell signaling and acts as the primary signal for bone resorption. Retrospective analysis of a large trial comparing denosumab versus zoledronic acid in bone metastatic solid tumors suggested significant overall survival (OS) advantage for patients with lung cancer with denosumab (p = 0.01). The randomized open-label phase III SPLENDOUR trial was designed to evaluate whether the addition of denosumab to standard first-line platinum-based doublet chemotherapy improved OS in advanced NSCLC., Methods: Patients with stage IV NSCLC were randomized in a 1:1 ratio to either chemotherapy with or without denosumab (120 mg every 3-4 wks), stratified by the presence of bone metastases (at diagnosis), Eastern Cooperative Oncology Group performance status, histology, and region. To detect an OS increase from 9 to 11.25 months (hazard ratio [HR] = 0.80), 847 OS events were required. The trial closed prematurely owing to decreasing accrual rate., Results: A total of 514 patients were randomized, with 509 receiving one or more doses of the assigned treatment (chemotherapy: 252, chemotherapy-denosumab: 257). The median age was 66.1 years, 71% were men, and 59% were former smokers. Bone metastases were identified in 275 patients (53%). Median OS (95% confidence interval [CI]) was 8.7 (7.6-11.0) months in the control arm versus 8.2 (7.5-10.4) months in the chemotherapy-denosumab arm (HR = 0.96; 95% CI: 0.78-1.19; one-sided p = 0.36). For patients with bone metastasis, HR was 1.02 (95% CI: 0.77-1.35), whereas for those without, HR was 0.90 (95% CI: 0.66-1.23). Adverse events grade 3 or greater were observed in 40.9%, 5.2%, 8.7% versus 45.5%, 10.9%, 10.5% of patients. Conditional power for OS benefit was less than or equal to 10%., Conclusions: Denosumab was well-tolerated without unexpected safety concerns. There was no OS improvement for denosumab when added to chemotherapy in the intention-to-treat population and the subgroups with and without bone metastases. Our data do not provide evidence of a clinical benefit for denosumab in patients with NSCLC without bone metastases., (Copyright © 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Low-molecular-weight-heparins (LMWHs) have been established for the treatment of cancer-associated venous thromboembolism (VTE). Recently published randomized controlled trials (RCTs) have compared direct oral anticoagulants (DOACs) with LMWHs. The aim of this systematic review and meta-analysis was to evaluate efficacy and safety of DOACs versus LMWHs and update the evidence for treatment of VTE in cancer., Methods: Biomedical databases were screened for RCTs evaluating DOACs for cancer-associated VTE. Primary efficacy and safety outcomes of this meta-analysis were recurrent VTE and major bleeding at 6 months. Secondary outcomes comprised clinically relevant nonmajor bleeding (CRNMB), major gastrointestinal (GI) and genitourinary bleeding, mortality, fatal bleeding/pulmonary embolism, and treatment discontinuation rate. We performed prespecified subgroup analyses. Pooled relative risk (RR) and 95% confidence intervals (CIs) were obtained by the Mantel-Haenszel method within a random-effect model., Results: We screened 759 articles and included 4 RCTs (n = 2894). DOACs significantly reduced recurrent VTEs compared to LMWHs (5.2% vs 8.2%; RR, 0.62 [95% CI, 0.43-0.91]), but were associated with a nonsignificant increase in major bleedings (4.3% vs 3.3%; RR, 1.31 [95% CI, 0.83-2.08]) and a significant increase in CRNMB (10.4% vs 6.4%; RR, 1.65 [95% CI, 1.19-2.28]). Mortality risks were comparable between groups (RR, 0.99 [95% CI, 0.83-1.18]). Preterm treatment discontinuation was less common with DOACs (RR, 0.88 [95% CI, 0.81-0.96]). Major bleeding was more frequent in patients with GI cancer treated with DOACs (RR, 2.30 [95% CI, 1.08-4.88])., Conclusion: In patients with cancer-associated VTE, DOACs are more effective in preventing recurrent VTE compared to LMWH. However, risk of bleeding is increased with DOACs, especially in patients with GI cancer., (© 2020 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Introduction: Predatory journals harm the integrity of science as principles of 'good scientific practice' are bypassed by omitting a proper peer-review process. Therefore, we aimed to explore the awareness of predatory journals among oncologists., Methods: An online survey among oncologists working in Germany or Austria of various professional surroundings was conducted between October 2018 and April 2019., Results: One hundred and eighty-eight participants (55 women (29.2%), 128 men (68.1%)) completed the questionnaire. 41 (21.8%) participants indicated to work in a hospital, 24 (12.8%) in private practice and 112 (59.6%) in a university hospital. 98.9% of participants indicated to actively read scientific articles and consider them in clinical decision-making (96.3%). 90.4% of participants indicated to have scientific experience by publishing papers in journals with peer-review system. The open-access system was known by 170 (90.4%), predatory journals by 131 (69.7%) and Beall's list by 52 participants (27.7%). Predatory journals were more likely to be known by participants with a higher number of publications (p<0.001), with more high-impact publications (p=0.005) and with recent publications (p<0.001). Awareness of predatory journals did not correlate with gender (p=0.515) or translation of scientific literature into clinical practice (p=0.543)., Conclusions: The problematic topic of 'predatory journals' is still unknown by a considerable amount of oncologist, although the survey was taken in a cohort of oncologists with scientific experience. Dedicated educational initiatives are needed to raise awareness of this problem and to aid in the identification of predatory journals for the scientific oncology community., Competing Interests: Competing interests: ASB has research support from Daiichi Sankyo (≤ €10 000), Roche (> €10 000) and honoraria for lectures, consultation or advisory board participation from Roche Bristol-Meyers Squibb, Merck, Daiichi Sankyo (all < €5000) as well as travel support from Roche, Amgen and AbbVie., (© Author (s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

The Central European Cooperative Oncology Group (CECOG) and 'ESMO Open-Cancer Horizons' roundtable discussion brought together stakeholders from several European Union (EU) countries involved in drug development, drug authorisation and reimbursement or otherwise affected by delayed and unequal access to innovative anticancer drugs. The approval process of drugs is well established and access delays can be caused directly or indirectly by national or regional decision-making processes on reimbursement. The two key aspects for those involved in reimbursement decisions are first the level of evidence required to decide and second pricing, which can be challenging for some innovative oncology compounds, especially in Eastern and South-Eastern European countries. Other important factors include: available healthcare budget; the structure and sophistication of healthcare authorities and health technology assessment processes; societal context and political will. From the point of view of the pharmaceutical industry, better alignment between stakeholders in the process and adaptive pathway initiatives is desirable. Key aspects for patients are improved access to clinical trials, preapproval availability and reports on real-world evidence. Restricted access limits oncologists' daily work in Eastern and South-Eastern EU countries. The roundtable discussion suggested considering the sequencing of regulatory approval and reimbursement decisions together with more flexible contracting as a possible way forward. The panel concluded that early and regular dialogue between all stakeholders including regulators, payers, patient stakeholders and industry is required to improve the situation., Competing Interests: Competing interests: The current work of AB (for MoCA and as unpaid expert for the Austrian Federal Administrative Court) informs about payers’ attitudes/concerns regarding the reimbursement of expensive medicines. However, the opinions expressed here cannot be construed as an official position of any payer organisation. LKS received relevant financial funding for activities outside the submitted work, which are speaker’s fees from Roche, Novartis, BMS and MSD. GK received relevant financial funding outside the submitted work from MSD. AL: the views expressed in this article are the personal views of the the co-author and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties. LM is a paid employee of Fight Bladder Cancer UK, and a volunteer board member of the World Bladder Cancer Patient Coalition. Fight Bladder Cancer UK has received financial support from BMS, Janssen, MSD and F. Hoffman-La Roche AG. The World Bladder Cancer Patient Coalition has received financial support from AstraZeneca, Bayer, F. Hoffman-La Roche AG, Janssen, Ipsen, MSD and Photocure. AR is an employee of MSD International and owns shares of MSD. MSD has supported this meeting together with Boehringer Ingelheim. NW received project grants and consulting and speaking fees from a large number of pharmaceutical companies, including MSD. CZ received honoraria from Roche, Novartis, BMS, MSD, Imugene, Ariad, Pfizer, Merrimack/Shire, Merck KGaA, Fibrogen, AstraZeneca, Tesaro, Gilead, Servier, Eli Lilly and Amgen., (© Author (s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

In December 2017, ESMO Open-Cancer Horizons convened a round-table discussion on the background and latest data regarding cyclin-dependent kinase (CDK)4/6 inhibitors with endocrine therapy (ET) in the treatment of endocrine-sensitive breast cancer (BC). A review on this discussion was published in summer 2018 (https://esmoopen.bmj.com/content/3/5/e000368).Endocrine-sensitive BC with non-visceral disease and limited spread of the metastases.Endocrine-sensitive BC with non-life-threatening visceral involvement. Several open questions were identified, which led to a second ESMO Open discussion on CDK4/6 inhibitors, taking place in December 2018 and covered in this article. The panel discussed two important clinical scenarios and the pro and cons of a treatment approach with CDK4/6 inhibitors for each scenario:Endocrine-sensitive BC with non-visceral disease and limited spread of the metastases.Endocrine-sensitive BC with non-life-threatening visceral involvement. Regarding scenario 1, the panel agreed that CDK4/6 inhibitors should be recommended in first-line therapy for most patients if cost and practicality allow. However, the use of single-agent ET with an aromatase inhibitor in the first-line treatment of these patients is still a possibility for a small group of patients with very limited disease, such as one or two bone lesions or limited lymph node involvement. Regarding scenario 2, chemotherapy is the first approach for patients with endocrine-sensitive metastatic BC with life-threatening visceral involvement because of the need for a faster response. The therapeutic approaches for patients with non-life-threatening visceral involvement are still under debate. Nevertheless, CDK4/6 inhibitors are currently the treatment of choice for most patients with a close follow-up of tumour response. A treatment algorithm has been suggested at the round table., Competing Interests: Competing interests: MP: honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo and Merck Sharp & Dome. JG: research support from Eisai, Genomic Health, Novartis, Pfizer and Roche; travel grants from Eisai, Genomic Health, Novartis, Pfizer and Roche; honoraria for advisory boards and speaker fees from Daiichi, Eisai, Genomic Health, Ipsen, Macrogenics, MSD, Novartis, Onxeo, Pfizer and Roche. GJ: grants, personal fees and non-financial support from Novartis and Roche; personal fees and non-financial support from Pfizer, Lilly, Amgen, BMS, Astra-Zeneca; personal fees from Celgene, Puma Technology, Daiichi Sankyo and Abbvie. AA: advisory boards, travel grants, speaker fees: Novartis, Roche, Lilly, Amgen, Eisai, BMS, MSD, LeoPharma, Genomic Health and Ipsen. CS: honoraria for lectures, consultation or advisory board participation from the following for-profit companies: Novartis, Gerson Lehrman Group, Astra-Zeneca, Lilly, Roche, Amgen, Pfitzer, Merck KGaA, and Tesaro. CCZ: honoraria from Roche, Novartis, BMS, MSD, Imugene, Ariad, Pfizer, Merrimack, Merck KGaA, Fibrogen, AstraZeneca, Tesaro, Gilead, Servier and Shire., (© Author (s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Essentials Neutrophil extracellular traps (NETs) might play a role in cancer-related coagulopathy. We determined NET biomarkers and followed cancer patients for venous thromboembolism (VTE). We found a constant association with VTE for citrullinated histone H3. Biomarkers of NET formation could reflect a novel pathomechanism of cancer-related VTE., Summary: Background Neutrophil extracellular traps (NETs) are decondensed chromatin fibers that might play a role in the prothrombotic state of cancer patients. Objectives To investigate whether the levels of citrullinated histone H3 (H3Cit), a biomarker for NET formation, cell-free DNA (cfDNA) and nucleosomes predict venous thromboembolism (VTE) in cancer patients. Patients/Methods Nine-hundred and forty-six patients with newly diagnosed cancer or progression after remission were enrolled in this prospective observational cohort study. H3Cit, cfDNA and nucleosome levels were determined at study inclusion, and patients were followed for 2 years. VTE occurred in 89 patients; the cumulative 3-month, 6-month, 12-month and 24-month incidence rates of VTE were 3.7%, 6.0%, 8.1%, and 10.0%, respectively. Results Patients with elevated H3Cit levels (> 75th percentile of its distribution, n = 236) experienced a higher cumulative incidence of VTE (2-year risk of 14.5%) than patients with levels below this cut-off (2-year risk of 8.5%, n = 710). In a competing-risk regression analysis, a 100 ng mL -1 increase in H3Cit level was associated with a 13% relative increase in VTE risk (subdistribution hazard ratio [SHR] 1.13, 95% confidence interval [CI] 1.04-1.22). This association remained after adjustment for high VTE risk and very high VTE risk tumor sites, D-dimer level, and soluble P-selectin level (SHR 1.13, 95% CI 1.04-1.22). The association of elevated nucleosome and cfDNA levels with VTE risk was time-dependent, with associations with a higher risk of VTE only during the first 3-6 months. Conclusion These data suggest that biomarkers of NET formation are associated with the occurrence of VTE in cancer patients, indicating a role of NETs in the pathogenesis of cancer-associated thrombosis., (© 2018 International Society on Thrombosis and Haemostasis.)

This article is the result of a round table discussion held at the European Lung Cancer Conference (ELCC) in Geneva in May 2017. Its purpose is to explore and discuss the advances in the knowledge about the biology and treatment of brain metastases originating from non -small cell lung cancer. The authors propose a series of recommendations for research and treatment within the discussed context., Competing Interests: Competing interests: MP: Research support from Boehringer-Ingelheim, GlaxoSmithKline, Merck Sharp and Dohme and Roche and honoraria for lectures, consultation or advisory board participation from Bristol-Myers Squibb, Novartis, Gerson Lehrman Group (GLG), CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, AstraZeneca and AbbVie. FW: Research support from Boehringer Ingelheim, Genentech and Roche. Honoraria for lectures, consultation and advisory board participation from UCB, Roche and Boehringer Ingelheim. CM: Honoraria from Lilly and Boehringer Ingelheim. EM: Research support from AstraZeneca, Merck KGaA, advisory board participation from Merck KGaA. CZ: Honoraria from Ariad, Novartis, Boehringer Ingelheim, Roche and AstraZeneca.

T H 17 cells are major drivers of inflammation and involved in several autoimmune diseases. Tissue inflammation is a beneficial host response to infection, but it can also contribute to autoimmunity. The crosstalk between a tissue and the immune system during an inflammatory response is key for preserving tissue integrity and restoring physiological processes. However, how the inflamed tissue regulates the magnitude of an immune response by controlling pro-inflammatory T cells is not well characterized so far. Here we show that T H 17 cells accumulating in the small intestine upon inflammation express the IL-33 receptor (ST2) and intestinal epithelial cells (IEC) are the main source of the alarmin interleukin-33 (IL-33). We show that pro-inflammatory T H 17 cells acquire a regulatory phenotype with immunosuppressive properties in response to IL-33. Absence of ST2 signaling promotes the secretion of pro-inflammatory cytokines by T H 17 cells and dampens the secretion of IL-10. Our results provide new insights into the mechanisms by which IEC, via IL-33/ST2 axis, may control pro-inflammatory T H 17 cells in the small intestine to sustain homeostasis.

Background: The ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) version 1.0 (v1.0) was published in May 2015 and was the first version of a validated and reproducible tool to assess the magnitude of clinical benefit from new cancer therapies. The ESMO-MCBS was designed to be a dynamic tool with planned revisions and updates based upon recognition of expanding needs and shortcomings identified since the last review., Methods: The revision process for the ESMO-MCBS incorporates a nine-step process: Careful review of critiques and suggestions, and identification of problems in the application of v1.0; Identification of shortcomings for revision in the upcoming version; Proposal and evaluation of solutions to address identified shortcomings; Field testing of solutions; Preparation of a near-final revised version for peer review for reasonableness by members of the ESMO Faculty and Guidelines Committee; Amendments based on peer review for reasonableness; Near-final review by members of the ESMO-MCBS Working Group and the ESMO Executive Board; Final amendments; Final review and approval by members of the ESMO-MCBS Working Group and the ESMO Executive Board., Results: Twelve issues for revision or amendment were proposed for consideration; proposed amendments were formulated for eight identified shortcomings. The proposed amendments are classified as either structural, technical, immunotherapy triggered or nuanced. All amendments were field tested in a wide range of studies comparing scores generated with ESMO-MCBS v1.0 and version 1.1 (v1.1)., Conclusions: ESMO-MCBS v1.1 incorporates 10 revisions and will allow for scoring of single-arm studies. Scoring remains very stable; revisions in v1.1 alter the scores of only 12 out of 118 comparative studies and facilitate scoring for single-arm studies., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The blood-brain barrier (BBB) protects the central nervous system (CNS) from potentially harmful substances and molecules by limiting their influx from the blood stream into the brain parenchyma. Understanding the structure and functioning of the BBB is of major importance for the development of effective medical treatments for primary and secondary brain tumours. Therefore, we provide here a concise and illustrated educational description of the anatomy and physiology of the BBB and current concepts on its role for targeted cancer therapies and immuno-oncology., Competing Interests: Competing interests: None declared.

In this implementation phase of the European Cancer Patient's Bill of Rights (BoR), we confirm the following three patient-centred principles that underpin this initiative:The right of every European citizen to receive the most accurate information and to be proactively involved in his/her care.The right of every European citizen to optimal and timely access to a diagnosis and to appropriate specialised care, underpinned by research and innovation.The right of every European citizen to receive care in health systems that ensure the best possible cancer prevention, the earliest possible diagnosis of their cancer, improved outcomes, patient rehabilitation, best quality of life and affordable health care. The key aspects of working towards implementing the BoR are:Agree our high-level goal. The vision of 70% long-term survival for patients with cancer in 2035, promoting cancer prevention and cancer control and the associated progress in ensuring good patient experience and quality of life.Establish the major mechanisms to underpin its delivery. (1) The systematic and rigorous sharing of best practice between and across European cancer healthcare systems and (2) the active promotion of Research and Innovation focused on improving outcomes; (3) Improving access to new and established cancer care by sharing best practice in the development, approval, procurement and reimbursement of cancer diagnostic tests and treatments.Work with other organisations to bring into being a Europe based centre that will (1) systematically identify, evaluate and validate and disseminate best practice in cancer management for the different countries and regions and (2) promote Research and Innovation and its translation to maximise its impact to improve outcomes., Competing Interests: Competing interests: None declared.

Background: The randomised phase III TANIA trial demonstrated that continuing bevacizumab with second-line chemotherapy for locally recurrent/metastatic breast cancer (LR/mBC) after progression on first-line bevacizumab-containing therapy significantly improved progression-free survival (PFS) compared with chemotherapy alone [hazard ratio (HR) = 0.75, 95% confidence interval (CI) 0.61-0.93]. We report final results from the TANIA trial, including overall survival (OS) and health-related quality of life (HRQoL)., Patients and Methods: Patients with HER2-negative LR/mBC that had progressed on or after first-line bevacizumab plus chemotherapy were randomised to receive standard second-line chemotherapy either alone or with bevacizumab. At second progression, patients initially randomised to bevacizumab continued bevacizumab with their third-line chemotherapy, but those randomised to chemotherapy alone were not allowed to cross over to receive third-line bevacizumab. The primary end point was second-line PFS; secondary end points included third-line PFS, combined second- and third-line PFS, OS, HRQoL and safety., Results: Of the 494 patients randomised, 483 received second-line therapy; 234 patients (47% of the randomised population) continued to third-line study treatment. The median duration of follow-up at the final analysis was 32.1 months in the chemotherapy-alone arm and 30.9 months in the bevacizumab plus chemotherapy arm. There was no statistically significant difference between treatment arms in third-line PFS (HR = 0.79, 95% CI 0.59-1.06), combined second- and third-line PFS (HR = 0.85, 95% CI 0.68-1.05) or OS (HR = 0.96, 95% CI 0.76-1.21). Third-line safety results showed increased incidences of proteinuria and hypertension with bevacizumab, consistent with safety results for the second-line treatment phase. No differences in HRQoL were detected., Conclusions: In this trial, continuing bevacizumab beyond first and second progression of LR/mBC improved second-line PFS, but no improvement in longer term efficacy was observed. The second-line PFS benefit appears to be achieved without detrimentally affecting quality of life., Clinicaltrialsgov: NCT01250379., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS) is a standardised, generic, validated tool to stratify the magnitude of clinical benefit that can be anticipated from anticancer therapies. The ESMO-MCBS is intended to both assist oncologists in explaining the likely benefits of a particular treatment to their patients as well as to aid public health decision makers' prioritise therapies for reimbursement. From its inception the ESMO-MCBS Working Group has invited questions and critiques to promote understanding and to address misunderstandings regarding the nuanced use of the scale, and to identify shortcomings in the scale to be addressed in future planned revisions and updates. The ESMO-MCBS V.1.0 has attracted many questions regarding its development, structure and potential applications. These questions, together with responses from the ESMO-MCBS Working Group, have been edited and collated, and are herein presented as a supplementary resource., Competing Interests: Conflicts of Interest: None declared.

Latin America and the Caribbean have not yet developed strong clinical cancer research programmes. In order to improve this situation two international cancer organisations, the Latin American Society of Clinical Oncology (SLACOM) and the European Society of Medical Oncology (ESMO) worked closely with the Peruvian Cooperative Oncology Group (GECOPERU) and organised a clinical cancer research workshop held in Lima, Peru, in October 2015. Many oncologists from different Latin American countries participated in this gathering. The opportunities for and strengths of clinical oncology research in Latin American and Caribbean countries were identified as the widespread use of the Spanish language, the high cancer burden, growing access to information, improving patient education, access to new drugs for research centres, regional networks and human resources. However, there are still many weaknesses and problems including the long timeline for regulatory approval, lack of economic investment, lack of training and lack of personnel participating in clinical research, lack of cancer registries, insufficient technology and insufficient supplies for the diagnosis and treatment of cancer, few cancer specialists, low general levels of education and the negative attitude of government authorities towards clinical research., Competing Interests: Conflicts of Interest: None declared.

Biologically distinct subtypes of metastatic breast cancer (MBC) have been defined by multiple efforts in recent years, showing broad heterogeneity at the molecular level of disease. Throughout this endeavour, oncogenic drivers within MBC were identified as potential therapeutic targets. With recent results from clinical trials targeting these well-known cancer-promoting pathways, this review is trying to elucidate as well as summarise current new therapeutic aspects in MBC and shed light on translational aspects within this entity., Competing Interests: Conflicts of Interest: None declared.

Unlabelled: ESSENTIALS: Hemostasis biomarkers impact thrombosis occurrence and survival in cancer patients. We performed a longitudinal analysis of hemostatic parameters in 112 cancer patients. Hemostatic parameters are associated with disease state, patients' prognosis, and the risk of VTE. The procoagulant state exists not only at diagnosis, but also during the course of disease., Background: Hemostasis biomarkers are known to have an impact on venous thromboembolism (VTE) occurrence and survival in cancer patients., Objectives: As there are almost no data on longitudinal changes, we aimed to evaluate those in the present prospective observational study during chemotherapy and the course of disease., Patients/methods: Patients with cancer of the brain (n = 39), lung (n = 41), colon (n = 15) or pancreas (n = 17) were included before initiation of antitumor therapy. Blood samples for determination of factor VIII, thrombin peak height, D-dimer, F1 + 2 , fibrinogen and soluble P-selectin (sP-selectin) were drawn on a monthly basis. The study endpoints were death, VTE occurrence, or completion of the study period., Results: Overall, 546 blood samples of 112 patients were analyzed. D-dimer and sP-selectin levels were significantly higher in patients with distant metastasis than in those without. Patients with complete remission had significantly lower levels of F1 + 2 , D-dimer and fibrinogen. Peak height thrombin levels showed a decrease over time in all tumor types. Levels of biomarkers behaved differently in the various tumor types. Patients who developed VTE (n = 14) showed increasing levels of FVIII, sP-selectin, and D-dimer. At the last blood sampling time-point before VTE occurrence, in 13 patients the D-dimer level was above the median, and in seven of these patients it was even above the 75th percentile; however, the individual course was highly variable. Regarding survival, steadily increased FVIII, sP-selectin and D-dimer levels were associated with higher mortality., Conclusions: Hemostatic parameters show an association with disease state, prognosis, and the risk of VTE, not only at diagnosis, but also during the course of antineoplastic treatment., (© 2015 International Society on Thrombosis and Haemostasis.)

The value of any new therapeutic strategy or treatment is determined by the magnitude of its clinical benefit balanced against its cost. Evidence for clinical benefit from new treatment options is derived from clinical research, in particular phase III randomised trials, which generate unbiased data regarding the efficacy, benefit and safety of new therapeutic approaches. To date, there is no standard tool for grading the magnitude of clinical benefit of cancer therapies, which may range from trivial (median progression-free survival advantage of only a few weeks) to substantial (improved long-term survival). Indeed, in the absence of a standardised approach for grading the magnitude of clinical benefit, conclusions and recommendations derived from studies are often hotly disputed and very modest incremental advances have often been presented, discussed and promoted as major advances or 'breakthroughs'. Recognising the importance of presenting clear and unbiased statements regarding the magnitude of the clinical benefit from new therapeutic approaches derived from high-quality clinical trials, the European Society for Medical Oncology (ESMO) has developed a validated and reproducible tool to assess the magnitude of clinical benefit for cancer medicines, the ESMO Magnitude of Clinical Benefit Scale (ESMO-MCBS). This tool uses a rational, structured and consistent approach to derive a relative ranking of the magnitude of clinically meaningful benefit that can be expected from a new anti-cancer treatment. The ESMO-MCBS is an important first step to the critical public policy issue of value in cancer care, helping to frame the appropriate use of limited public and personal resources to deliver cost-effective and affordable cancer care. The ESMO-MCBS will be a dynamic tool and its criteria will be revised on a regular basis., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

As the leading cause of cancer death worldwide, lung cancer continues to impose a major burden on healthcare systems and cause significant challenges for clinicians and patients. Most patients present with advanced disease at the time of diagnosis and have a poor prognosis, with the vast majority surviving less than 5 years. Although new therapies have been introduced in recent years that target molecular disease drivers present in a subset of patients, there is a significant need for treatments able to improve response and extend survival while minimizing effects on quality of life. Recent evidence of clinical efficacy for immunotherapeutic approaches for lung cancer suggests that they will become the next major therapeutic advance for this disease. Non-small-cell lung cancer, which accounts for approximately 85% of lung cancer cases, has historically been considered a nonimmunogenic disease; however, as with several other malignancies, recent data show that much of this lack of immune responsiveness is functional rather than structural (i.e., possible to overcome therapeutically). This review explores the key elements of the immune system involved in non-small-cell lung cancer and briefly examines immunotherapeutic strategies in development to shift the balance of immune activity away from a tumor-induced immune-suppressive state toward an active antitumor immune response.

Background: In studies on cancer-associated venous thromboembolism (VTE), patients not only are at risk for VTE but also may die from their underlying malignancy., Objectives: In this competing-risk (CR) scenario, we systematically compared the performance of standard (Kaplan-Meier estimator [1-KM]), log-rank test, and Cox model) and specific CR methods for time-to-VTE analysis., Patients and Methods: Cancer patients (1542) were prospectively followed for a median of 24 months. VTE occurred in 112 (7.3%) patients, and 572 (37.1%) patients died., Results: In comparison with the CR method, 1-KM slightly overestimated the cumulative incidence of VTE (cumulative VTE incidence at 12 and 24 months [1-KM vs. CR]: 7.22% vs. 6.74%, and 8.40% vs. 7.54%, respectively). Greater bias was revealed in tumor entities with high early mortality (e.g., pancreatic cancer, n = 99, 24-month cumulative VTE incidence: 28.37% vs. 19.30%). Comparing the (subdistribution) hazard of VTE between patients with low and high baseline D-dimer, the Cox model yielded a higher estimate than the corresponding CR model (hazard vs. subdistribution hazard ratio [95% CI] 2.85 [1.92-4.21] vs. 2.47 [1.67-3.65]). For this comparison, the log-rank test yielded a higher test statistic and smaller P-value than Gray's test (χ(2) on 1 degree of freedom: 29.88 vs. 21.34)., Conclusion: In patients with cancer who are at risk for VTE and death, standard and CR methods for time-to-VTE analysis can generate differing results. For 1-KM, the magnitude of bias is a direct function of competing mortality. Consequently, bias tends to be negligible in cancer patient populations with low mortality but can be considerable in populations at high risk of death., (© 2014 International Society on Thrombosis and Haemostasis.)

Background: Patients with cancer are at an increased risk for venous thromboembolism (VTE). The risk varies markedly in different patient populations. Factor V (FV) Leiden is the most common genetic risk factor for VTE, and the impact of FV Leiden on cancer-associated thrombosis is not yet fully elucidated., Objective: To study the impact of FV Leiden on the risk of thrombosis in cancer patients., Methods: In the prospective observational Vienna Cancer And Thrombosis Study (CATS), 982 patients were included and were followed until occurrence of VTE or death, for a maximum period of 2 years. FV Leiden was determined by genotyping at inclusion. Main outcome measures were symptomatic or lethal objectively confirmed VTE., Results: Of the 982 patients, FV Leiden was diagnosed in 72 (7.3%, 70 were heterozygous and 2 were homozygous). Ten of 72 (13.9%) patients with FV Leiden developed VTE, whereas this was the case in 69 of 910 (7.6%) patients without FV Leiden. In multivariate analysis that included age, sex, different tumor types, tumor stage, newly diagnosed vs. recurrence of disease, and the treatment modalities, the hazard ratio was 2.0 (95% confidence interval 1.0-4.0). In Kaplan-Meier analysis, the probability for development of VTE was 13% in those with and 5.7% in those without FV Leiden after 6 months; after 1 year, the corresponding risks were 15% and 7.3%., Conclusions: FV Leiden is a genetically determined and thus disease-independent parameter, which is associated with VTE in cancer patients and could therefore be used for individual risk assignment., (© 2014 International Society on Thrombosis and Haemostasis.)