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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.)

The Immunotherapy of Cancer conference (ITOC) is an European meeting providing a global platform for discussions where all those dedicated to the immunotherapy of cancer can exchange their knowledge and the latest findings about immuno-oncology. The 9th ITOC was held in Munich in September 2022. Major highlights of the 2022 edition included the key note address and life time achievement to Laurence Zitvogel on her contributions on the understanding of the role of microbiota in cancer development and therapy resistance. Her research has paved the way for therapeutic exploitation of the microbiome.

On February 24, 2022, a war began within the Ukrainian borders. At least 3.0 million Ukrainian inhabitants have already fled the country. Critical infrastructure, including hospitals, has been damaged. Children with cancer were urgently transported to foreign countries, in an effort to minimize interruption of their life-saving treatments. Most adults did not have that option. War breeds cancer-delaying diagnosis, preventing treatment, and increasing risk. We project that a modest delay in care of only 4 months for five prevalent types of cancer will lead to an excess of over 3,600 cancer deaths in the subsequent years. It is critical that we establish plans to mitigate that risk as soon as possible., Competing Interests: Christian CaglevicConsulting or Advisory Role: MSD, RocheSpeakers' Bureau: MSD, RocheResearch Funding: Merck Sharp & Dohme, Medivation, AstraZeneca, Roche, Astellas Pharma, Bristol Myers Squibb, GlaxoSmithKline, Athenex Christian RolfoConsulting or Advisory Role: Archer, Inivata, Merck Serono, Bristol Myers Squibb, Novartis, Boston Pharmaceuticals, Eisai, Mirati TherapeuticsSpeakers' Bureau: MSD, AstraZeneca, Guardant Health, Roche Molecular DiagnosticsResearch Funding: Lung Cancer Research FoundationTravel, Accommodations, Expenses: AstraZenecaUncompensated Relationships: Guardant Health Ignacio Gil-BazoConsulting or Advisory Role: MSD Oncology, Lilly, AstraZeneca Spain, Bristol Myers Squibb/CelgeneSpeakers' Bureau: MSD Oncology, AstraZeneca, Bristol Myers Squibb/Celgene, Roche, AmgenTravel, Accommodations, Expenses: MSD Oncology, Lilly Andrés CardonaHonoraria: Bristol Myers Squibb, Roche, Boehringer Ingelheim, AbbVie, Merck Sharp & Dohme, CelldexConsulting or Advisory Role: Roche, Merck Sharp & Dohme, Novartis, AstraZeneca, Bristol Myers Squibb, Foundation Medicine, Boehringer Ingelheim, Foundation for Clinical and Applied Cancer Research (FICMAC)Speakers' Bureau: Merck Sharp & Dohme, Roche, Bristol Myers Squibb, Novartis, Foundation for Clinical and Applied Cancer Research (FICMAC), Foundation MedicineTravel, Accommodations, Expenses: Merck Sharp & Dohme, Bristol Myers Squibb, Roche, Boehringer Ingelheim, Foundation Medicine Fred R. HirschConsulting or Advisory Role: AstraZeneca, Genentech, Merck, Bristol Myers Squibb, Novartis, Amgen, Oncocyte, Sanofi/Regeneron, Daiichi Sankyo/UCB Japan, Nectin Therapeutics, Novocure, Blueprint MedicinesPatents, Royalties, Other Intellectual Property: EGFR FISH and IHC for prediction of outcome in patients treated with EGFR inhibitors (Inst)Expert Testimony: Gerson Lehrman Group David R. GandaraHonoraria: Merck, AmgenConsulting or Advisory Role: AstraZeneca (Inst), Guardant Health (Inst), OncoCyte (Inst), IO Biotech (Inst), Roche/Genentech (Inst), Lilly, Novartis, Adagene (Inst), OncoHost (Inst), Ocean Genomics (Inst), Daiichi Sankyo Alliance, SanofiResearch Funding: Merck (Inst), Amgen (Inst), Genentech (Inst), AstraZeneca (Inst) Gilberto MorganConsulting or Advisory Role: Novartis Silvia NovelloConsulting or Advisory Role: SanofiSpeakers' Bureau: AstraZeneca, MSD, Bristol Myers Squibb, Roche, Pfizer, Lilly, Takeda, AbbVie, Boehringer Ingelheim, Bayer, Amgen, Beigene, Novartis, Janssen Marina-Chiara GarassinoHonoraria: MSD Oncology, AstraZeneca/MedImmune, GlaxoSmithKline, Takeda, Roche, Bristol Myers SquibbConsulting or Advisory Role: Bristol Myers Squibb, MSD, AstraZeneca, Novartis, Takeda, Roche, Tiziana Life Sciences, Sanofi, Celgene, Daiiki Sankyo, Inivata, Incyte, Pfizer, Seattle Genetics, Lilly, GlaxoSmithKline, Bayer, Blueprint Medicines, Janssen, RegeneronSpeakers' Bureau: AstraZeneca, Takeda, MSD Oncology, Celgene, Incyte, Roche, Bristol Myers Squibb, Otsuka, LillyResearch Funding: Bristol Myers Squibb (Inst), MSD (Inst), Roche/Genentech (Inst), AstraZeneca/MedImmune (Inst), Pfizer (Inst), GlaxoSmithKline (Inst), Novartis (Inst), Merck (Inst), Incyte (Inst), Takeda (Inst), Spectrum Pharmaceuticals (Inst), Blueprint Medicines (Inst), Lilly (Inst), AstraZeneca (Inst), Ipsen (Inst), Janssen (Inst), Exelixis (Inst), MedImmune (Inst), Sanofi (Inst), Amgen (Inst)Travel, Accommodations, Expenses: Pfizer, Roche, AstraZeneca Giannis MountziosHonoraria: Roche, Boehringer Ingelheim, AstraZeneca, MSD, BMS GmbH & Co KG, Novartis, Amgen, TakedaConsulting or Advisory Role: Roche, Astra Zeneca Greece, MSD, Amgen, Novartis, BMS GmbH & Co KG, TakedaSpeakers' Bureau: AstraZenecaTravel, Accommodations, Expenses: AstraZeneca, Ipsen, MSD, Roche, Novartis, BMS GmbH & Co KG Natasha B. LeighlResearch Funding: Roche Canada (Inst), Guardant Health (Inst), MSD (Inst), EMD Serono (Inst), Lilly (Inst), AstraZeneca Canada (Inst), Takeda (Inst), Amgen (Inst), Bayer (Inst), MSD Oncology (Inst)Travel, Accommodations, Expenses: Merck Sharp & Dohme Oscar ArrietaHonoraria: Pfizer, AstraZeneca, Boehringer Ingelheim, RocheConsulting or Advisory Role: AstraZeneca, Roche, Lilly, Merck, Bristol Myers SquibbResearch Funding: Roche (Inst), BMS (Inst), Merck (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: Lilly Alfredo AddeoConsulting or Advisory Role: Roche, AstraZeneca/MedImmune, Bristol Myers Squibb Foundation, MSD Oncology, Pfizer, Novartis, Astellas Pharma, Amgen, LillySpeakers' Bureau: Lilly, AstraZeneca/MedImmuneTravel, Accommodations, Expenses: Roche, Takeda Stephen V. LiuConsulting or Advisory Role: Genentech, Lilly, Bristol Myers Squibb, AstraZeneca, Takeda, Regeneron, Guardant Health, Janssen Oncology, MSD Oncology, Jazz Pharmaceuticals, Blueprint Medicines, Daiichi Sankyo/UCB Japan, BeiGene, Amgen, Turning Point Therapeutics, Elevation Oncology, Novartis, Eisai, Bayer, Gilead Sciences, SanofiResearch Funding: Genentech/Roche (Inst), Pfizer (Inst), Bayer (Inst), Merck (Inst), Blueprint Medicines (Inst), Lilly (Inst), Rain Therapeutics (Inst), Alkermes (Inst), Bristol Myers Squibb (Inst), Turning Point Therapeutics (Inst), RAPT Therapeutics (Inst), Merus (Inst), Elevation Oncology (Inst), Nuvalent, Inc (Inst), Gilead Sciences (Inst)Travel, Accommodations, Expenses: Caris Life Sciences Luis CorralesConsulting or Advisory Role: AstraZeneca, Roche, MSD Oncology, PfizerSpeakers' Bureau: Roche, AstraZeneca, MSD OncologyResearch Funding: RocheTravel, Accommodations, Expenses: Roche, AstraZeneca, MSD Oncology Vivek SubbiahConsulting or Advisory Role: MedImmune, Helsinn Therapeutics, Loxo, R-Pharm, QED TherapeuticsResearch Funding: Novartis (Inst), GlaxoSmithKline (Inst), NanoCarrier (Inst), Northwest Biotherapeutics (Inst), Genentech/Roche (Inst), Berg Pharma (Inst), Bayer (Inst), Incyte (Inst), Fujifilm (Inst), PharmaMar (Inst), D3 Oncology Solutions (Inst), Pfizer (Inst), Amgen (Inst), AbbVie (Inst), Multivir (Inst), Blueprint Medicines (Inst), LOXO (Inst), Vegenics (Inst), Takeda (Inst), Alfasigma (Inst), Agensys (Inst), Idera (Inst), Boston Biomedical (Inst), Inhibrx (Inst), Exelixis (Inst), Turning Point Therapeutics (Inst)Travel, Accommodations, Expenses: PharmaMar, Bayer, Novartis, Helsinn TherapeuticsOther Relationship: Medscape Franz Villarroel-EspindolaConsulting or Advisory Role: Ilico GeneticsResearch Funding: Gebrax-Chile Laboratory & Gebrax Cia Ltda Ricardo MoralesConsulting or Advisory Role: Pfizer Luis RaezResearch Funding: Genentech/Roche (Inst), Merck Serono (Inst), Boehringer Ingelheim (Inst), Novartis (Inst), Pfizer (Inst), Syndax (Inst), Loxo (Inst), Merck (Inst), Bristol Myers Squibb (Inst), Guardant Health (Inst), Heat Biologics (Inst), Amgen (Inst), Calithera Biosciences (Inst), Daiichi Sankyo/UCB Japan (Inst), NantHealth (Inst) Jorge AlatorreHonoraria: Bristol Myers Squibb (Mexico), AstraZeneca, Roche/GenentechConsulting or Advisory Role: MSD Oncology, AstraZeneca, Roche/Genentech, Bristol Myers Squibb, NovartisSpeakers' Bureau: Roche/Genentech, AstraZeneca, MSDTravel, Accommodations, Expenses: AstraZeneca, Roche Edgardo SantosSpeakers' Bureau: Genentech/Roche, Pfizer, Amgen, Boehringer Ingelheim, Merck, Novartis, AstraZeneca, Takeda, Genzyme, Lilly, Astellas Pharma, G1 Therapeutics, Regeneron Luis UbillosHonoraria: Tecnofarma, Fármaco UruguayoConsulting or Advisory Role: Tecnofarma, Roche, Fármaco Uruguayo, PfizerSpeakers' Bureau: Tecnofarma, RocheTravel, Accommodations, Expenses: GlaxoSmithKline, Roche, Pfizer, AstraZeneca, Tecnofarma Daniel S.W. TanHonoraria: Bristol Myers Squibb, Takeda, Novartis, Roche, PfizerConsulting or Advisory Role: Novartis, Merck, Loxo, AstraZeneca, Roche, Pfizer, C4 TherapeuticsResearch Funding: Novartis (Inst), GlaxoSmithKline (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: Pfizer, Boehringer Ingelheim, Roche Christoph ZielinskiHonoraria: Athenex, MSD, Roche, AstraZeneca, ImugeneConsulting or Advisory Role: Roche (Inst), Merck Sharp & Dohme (Inst), Imugene, Fibrogen (Inst), AstraZeneca (Inst), Servier (Inst), Athenex, Lilly (Inst), Amgen (Inst), Bristol Myers Squibb (Inst)Research Funding: Pfizer (Inst), Bristol Myers Squibb (Inst), AstraZeneca (Inst), Merck Sharp & Dohme (Inst)Patents, Royalties, Other Intellectual Property: Patent Property, ImugeneNo other potential conflicts of interest were reported.

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.)

Aims: Cancer patients suffer from impaired cardiovascular function. Elevated resting heart rate (RHR) has been identified as a marker for increased long-term mortality in cancer patients prior to the receipt of anticancer treatment. We aimed to establish whether RHR is associated with survival in treatment-naïve cancer patients., Methods and Results: This prospective study enrolled 548 unselected treatment-naïve cancer patients between 2011 and 2013. The median age of the cohort was 62 years; 40.9% were male and 32.7% had metastatic disease. Median RHR was 72 b.p.m. Most patients were in sinus rhythm (n = 507, 92.5%). Clinical heart failure was noted in 37 (6.8%) patients. RHR was not related to cancer stage (P = 0.504). Patients in the highest RHR tertile had higher levels of high-sensitivity troponin (P = 0.003) and N-terminal pro-B-type natriuretic peptide (P = 0.039). During a median follow-up of 25 months (interquartile range: 16-32 months; range: 0-40 months), 185 (33.8%) patients died from any cause [1-year-mortality: 17%, 95% confidence interval (CI) 13-20%]. In univariate survival analysis, RHR predicted all-cause mortality [crude hazard ratio (HR) for a 5 b.p.m. increase in RHR: 1.09, 95% CI 1.04-1.15; P < 0.001], and remained significantly associated with outcome after adjustment for age, gender, tumour entity, tumour stage, cardiac status and haemoglobin (adjusted HR for a 5 b.p.m. increase in RHR: 1.10, 95% CI 1.04-1.16; P < 0.001). There was no significant impact of metastatic/non-metastatic disease state on the predictive value of RHR (P = 0.433 for interaction). In subgroup analyses, the strongest associations for RHR with mortality were observed in lung (crude HR 1.14; P = 0.007) and gastrointestinal (crude HR 1.31; P < 0.001) cancer., Conclusions: Treatment-naïve cancer patients with higher RHRs display higher levels of cardiovascular biomarkers. RHR was independently associated with all-cause mortality, especially in lung and gastrointestinal cancers. Elevated RHR and cardiovascular biomarkers may represent early signs of incipient cardiac dysfunction., (© 2020 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

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.)

Aim: GDF-15 is an established cardiovascular risk marker but is equally implicated in tumour biology. Elevated levels of GDF-15 have indeed been observed in distinct tumour entities. This study aimed to explore the relation of GDF-15 to other cardiac biomarkers and the general association of GDF-15 on prognosis in an unselected cohort of treatment-naïve cancer patients., Methods: We prospectively enrolled 555 consecutive patients at time of diagnosis of malignant disease prior receiving anticancer therapy. Plasma GDF-15 concentrations were determined alongside other cardiac and routine laboratory markers. All-cause mortality was defined as primary endpoint., Results: GDF-15 levels were 338 ng/L (IQR:205-534) for the total cohort, and values were comparable for different tumour entities except breast cancer. Metastatic disease was characterized by higher plasma GDF-15 [435 ng/L (IQR:279-614) vs 266 ng/L (IQR:175-427), P < .001]. GDF-15 correlated positively with inflammatory status reflected by CRP, SAA and IL-6 [r = .31, P < .001, r = .23, P < .001 and r = .14, P = .002] and cardiac biomarkers as NT-proBNP, hsTnT, MR-proADM and CT-proET-1 [r = .46; r = .46; r = .59 and r = .50; P < .001 for all]. GDF-15 was significantly associated with all-cause mortality after multivariate adjustment [adj.HR for ln(GDF-15) 1.78, 95%CI:1.47-2.16, P < .001]. There was a significant interaction between solid and haematological malignancies with loss of association of GDF-15 with outcome in myelodysplastic and myeloproliferative disease., Conclusions: Elevated plasma GDF-15 is associated with progressing disease severity and poor prognosis in solid tumours of treatment-naïve cancer patients. GDF-15 increase is accompanied by worsening systemic inflammation and a subclinical functional impairment of different organs including the heart. GDF-15 represents a promising target for our pathophysiologic understanding in cardio-oncology linking conditions of both cardiac and neoplastic disease., (© 2019 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

The transmembrane zink-metalloendopeptidase neprilysin (NEP) is implicated in cardiovascular disease but also tumor biology. The aim of the study was to investigate the relationship of circulating NEP (cNEP) levels with established cardiovascular biomarkers and its effect on overall survival in an unselected cohort of treatment-naïve cancer patients. 555 consecutive cancer patients prior anticancer therapy were enrolled prospectively. NEP levels were determined alongside routine laboratory parameters, established cardiac biomarkers, i.e. NT-proBNP, hsTnT, MR-proANP, MR-proADM, CT-proET-1 and Copeptin, and inflammatory parameters, i.e. CRP, IL-6 and SAA, in venous plasma samples. All-cause mortality was the primary endpoint. cNEP levels of 276 pg/ml (IQR: 0-5981) displayed a weak inverse correlation with age [r = -0.12, p = 0.023] and inflammatory status [r = -0.14, p = 0.007 CRP; r = -0.20, p < 0.001 IL-6 and r = -0.18, p < 0.001 SAA]. cNEP was comparable between different tumor entities and stages and not related to functional parameters of other organ systems as kidney, liver or especially the heart. Moreover, cNEP was not associated with overall survival in the total cohort [adj.HR for ln (cNEP) 1.00, 95% CI: 0.94-1.06, p = 0.887] but in myelodysplatic malignancies [adj.HR for ln (cNEP) 1.27, 95% CI: 1.01-1.61, p = 0.044]. In conclusion, cNEP lacks association with outcome but for myelodysplastic disease. cNEP shows no correlation with established cardiovascular biomarkers related to prognosis, thereby holding a limited potential as a biomarker in cardio-oncology.

Purpose: To better understand the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS v1.1) and the ASCO Value Framework Net Health Benefit score version 2 (ASCO-NHB v2), ESMO and ASCO collaborated to evaluate the concordance between the frameworks when used to assess clinical benefit attributable to new therapies., Methods: The 102 randomized controlled trials in the noncurative setting already evaluated in the field testing of ESMO-MCBS v1.1 were scored using ASCO-NHB v2 by its developers. Measures of agreement between the frameworks were calculated and receiver operating characteristic curves used to define thresholds for the ASCO-NHB v2 corresponding to ESMO-MCBS v1.1 categories. Studies with discordant scoring were identified and evaluated to understand the reasons for discordance., Results: The correlation of the 102 pairs of scores for studies in the noncurative setting is estimated to be 0.68 (Spearman's rank correlation coefficient; overall survival, 0.71; progression-free survival, 0.67). Receiver operating characteristic curves identified thresholds for ASCO-NHB v2 for facilitating comparisons with ESMO-MCBS v1.1 categories. After applying pragmatic threshold scores of 40 or less (ASCO-NHB v2) and 2 or less (ESMO-MCBS v1.1) for low benefit and 45 or greater (ASCO-NHB v2) and 4 to 5 (ESMO-MCBS v1.1) for substantial benefit, 37 discordant studies were identified. Major factors that contributed to discordance were different approaches to evaluation of relative and absolute gain for overall survival and progression-free survival, crediting tail of the curve gains, and assessing toxicity., Conclusion: The agreement between the frameworks was higher than observed in other studies that sought to compare them. The factors that contributed to discordant scores suggest potential approaches to improve convergence between the scales.

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.)

Immunotherapy by checkpoint inhibition is about to profoundly change cancer therapy. The number of indications are growing at an unprecedented speed. Clinical studies have demonstrated efficacy in a variety of solid tumors and in hematologic malignancies, although some clinical trials have produced negative results. Thus, it is fair to assume that there are obvious limitations and pitfalls in immunotherapy. Future concepts for combination treatment of immune checkpoint inhibitors have to be developed, but there is also urgent need for better and standardized biomarkers to identify those cancer patients who will benefit from treatment by checkpoint inhibition. The current overview summarizes current knowledge on immune checkpoint inhibitor treatment in malignancies, its outlook and limitations, diagnostic means and, finally, side effect management.

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.)

Venous thromboembolism (VTE) is a frequent complication of malignancy. The aim of this study was to investigate whether multi-state modelling may be a useful quantitative approach to dissect the complex epidemiological relationship between hypercoagulability, VTE, and death in cancer patients. We implemented a three-state/three-transition unidirectional illness-death model of cancer-associated VTE in data of 1,685 cancer patients included in a prospective cohort study, the Vienna Cancer and Thrombosis Study (CATS). During the two-year follow-up period, 145 (8.6 %) patients developed VTE, 79 (54.5 %) died after developing VTE, and 647 (38.4 %) died without developing VTE, respectively. VTE events during follow-up were associated with a three-fold increase in the risk of death (Transition Hazard ratio (HR)=2.98, 95 % confidence interval [CI]: 2.36-3.77, p< 0.001). This observation was independent of cancer stage. VTE events that occurred later during follow-up exerted a stronger impact on the risk of death than VTE events that occurred at earlier time points (HR for VTE occurrence one year after baseline vs at baseline=2.30, 95 % CI: 1.28-4.15, p=0.005). Elevated baseline D-dimer levels emerged as a VTE-independent risk factor for mortality (HR=1.07, 95 % CI: 1.05-1.08, p< 0.001), and also predicted mortality risk in patients who developed VTE. A higher Khorana Score predicted both the risk for VTE and death, but did not predict mortality after cancer-associated VTE. In conclusion, multi-state modeling represents a very potent approach to time-to-VTE cohort data in the cancer population, and should be used for both observational and interventional studies on cancer-associated VTE.

Background: In cancer patients, reduced serum albumin has been described as a marker for global declining health and poor prognosis. Our aim was to investigate the association of albumin concentrations with the occurrence of venous thromboembolism (VTE) and mortality in patients with cancer., Methods: This investigation was performed in the framework of the Vienna Cancer and Thrombosis Study (CATS), a prospective observational cohort study. We included 1,070 patients with active cancer and assayed serum albumin from venous blood taken at study inclusion. Risk for occurrence of VTE was calculated in a proportional subdistribution hazard regression model with respect to competing risk of death and adjusted for cancer site, leukocyte count, estimated glomerular filtration rate, and cholinesterase., Results: Patients (630 males [58.9%] and 440 females [41.1%]) were observed for a median of 723 days. During follow-up, 90 VTE events (8.4%) and 396 deaths (37.0%) occurred. The median albumin was 41.3 g/L (25th-75th percentile, 37.6-44.2). Patients with albumin levels below the 75th percentile had a 2.2-fold increased risk of VTE (95% confidence interval [CI] 1.09-4.32), as well as a 2.3-fold increased risk of death (95% CI 1.68-3.20) compared with patients with albumin above the 75th percentile., Conclusion: Decreased serum albumin levels in cancer patients were significantly associated with increased risk of VTE and mortality. Serum albumin, a marker of a cancer patient's overall prognosis, could be considered for risk assessment of important clinical outcomes such as VTE and mortality., Implications for Practice: Cancer patients are at increased risk of venous thromboembolism (VTE). In this prospective cohort study of 1,070 cancer patients, decreased serum albumin was a marker for risk of VTE and mortality, independent of kidney or liver function and inflammation markers. The study identified a group of patients with high risk of cancer-associated VTE and a reduced prognosis who may benefit from supportive therapy such as primary VTE prophylaxis., (©AlphaMed Press.)

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.)

Venous thromboembolism (VTE) is a frequent complication in cancer patients. Platelet activation is thought to be involved in cancer-associated VTE. Here, we determined the association between evolving markers of platelet activation (soluble P-selectin [sP-selectin], soluble CD40 ligand [sCD40L], thrombospondin-1 [TSP-1] and platelet factor-4 [PF-4]) and the development of cancer-associated VTE. A nested matched case-control study was applied within a cohort of 1779 patients with different types of cancer that had been included in the Vienna Cancer and Thrombosis Study (CATS), a prospective, observational study on patients with newly diagnosed or progressive cancer after remission. Primary endpoint is symptomatic VTE during a maximum follow-up of 2 years. Cases (patients who developed VTE during follow-up) were matched in a 1:2 ratio to controls without VTE during follow-up with respect to tumor type, stage and time of observation in the study. In total, 131 VTE cases were compared to 262 controls. In logistic regression analysis, only sP-selectin was associated with risk of VTE. The odds ratios (OR) per double increase of sP-selectin, sCD40L, TSP-1 and PF-4 were 1.66 (95% confidence interval: 1.17-2.35, p = 0.005), 1.04 (0.89-1.21, p = 0.635), 1.09 (0.90-1.32, p = 0.360) and 1.03 (0.87-1.21, p = 0.737), respectively. In conclusion, sP-selectin, but not sCD40L, TSP-1 or PF-4 were associated with risk of VTE in cancer patients in this nested case-control study.

Purpose: Cancer patients are at an increased risk of venous thromboembolism (VTE). VEGF promotes the growth of highly thrombogenic tumor vessels. Here, we explored the utility of soluble plasma VEGF-A (sVEGF) as a biomarker for the prediction of VTE in patients with cancer., Experimental Design: Eight hundred four patients with newly diagnosed cancer or progression after remission were prospectively followed for 2 years until the occurrence of VTE or death [tumor sites: brain (n = 87), breast (n = 137), lung (n = 120), gastrointestinal (n = 143), pancreas (n = 53), prostate (n = 95), kidney (n = 22), myeloma and lymphoma (n = 99), and others (n = 48)]. Primary endpoint was symptomatic or fatal VTE. sVEGF was measured by immunoassay in baseline plasma., Results: Fifty-five patients developed VTE (6.8%) and 364 patients (45.3%) died. Five-hundred and forty-two (68.3%) participants had sVEGF levels above the detection limit of 0.5 pg/mL. The median sVEGF level (25th-75th percentile) was 8.1 pg/mL (0-17.7). The cumulative 2-year incidence of VTE was 10.2% [95% confidence interval (CI), 6.4-14.9] in patients with sVEGF greater than the 75th percentile of the sVEGF distribution (Q3, cutoff: 17.7 pg/mL), and 5.9% (95% CI, 4.2-7.9) in patients with lower levels (P = 0.03). The corresponding 2-year risk of death was 52.8% (95% CI, 46.0-60.0) and 43.9% (95% CI, 40.0-48.0), respectively (P = 0.02). In univariable time-to-VTE regression, elevated sVEGF was associated with VTE [subhazard ratio (SHR) per 10 pg/mL increase, 1.04; 95% CI,1.00-1.09; P = 0.04)]. The association between sVEGF and risk of VTE prevailed after multivariable adjustment for high-risk tumor sites, age, gender, factor VIII, thrombin generation potential, and soluble P-Selectin (adjusted SHR, 1.04; 95% CI, 1.00-1.09, P = 0.05)., Conclusions: Elevated sVEGF is associated with an increased risk of VTE in patients with cancer., (©2015 American Association for Cancer Research.)

Objective: Patients with cancer may display elevated levels of B-type natriuretic peptide (BNP) and high-sensitive troponin T (hsTnT) without clinical manifestation of cardiac disease. This study aimed to evaluate circulating cardiovascular hormones and hsTnT and their association with mortality in cancer., Methods: We prospectively enrolled 555 consecutive patients with a primary diagnosis of cancer and without prior cardiotoxic anticancer therapy. N-terminal pro BNP (NT-proBNP), mid-regional pro-atrial natriuretic peptide (MR-proANP), mid-regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), copeptin, hsTnT, proinflammatory markers interleukin 6 (IL-6) and C reactive protein (CRP), and cytokines serum amyloid A (SAA), haptoglobin and fibronectin were measured. All-cause mortality was defined as primary endpoint., Results: During a median follow-up of 25 (IQR 16-31) months, 186 (34%) patients died. All cardiovascular hormones and hsTnT levels rose with tumour stage progression. All markers were significant predictors of mortality with HRs per IQR of 1.54 (95% CI 1.24 to 1.90, p<0.001) for NT-proBNP, 1.40 (95% CI 1.10 to 1.79, p<0.01) for MR-proANP, 1.31 (95% CI 1.19 to 1.44, p<0.001) for MR-proADM, 1.21 (95% CI 1.14 to 1.30, p<0.001) for CT-proET-1, 1.22 (95% CI 1.04 to 1.42, p=0.014) for copeptin and 1.21 (95% CI 1.13 to 1.32, p<0.001) for hsTnT, independent of age, gender, tumour entity and stage, and presence of cardiac comorbidities. NT-proBNP, MR-proANP, MR-proADM and hsTnT displayed a significant correlation with IL-6 and CRP., Conclusions: Circulating levels of cardiovascular peptides like NT-proBNP, MR-proANP, MR-proADM, CT-pro-ET-1 and hsTnT were elevated in an unselected population of patients with cancer prior to induction of any cardiotoxic anticancer therapy. The aforementioned markers and copeptin were strongly related to all-cause mortality, suggesting the presence of subclinical functional and morphological myocardial damage directly linked to disease progression., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Introduction: Low-molecular-weight heparin (LMWH) and vitamin K antagonists (VKA) are current treatment options for cancer patients suffering from acute venous thromboembolism (VTE). The role of direct-acting oral anticoagulants (DOACs) for the treatment of VTE in cancer patients, particular in comparison with the current standard of care which is LMWH, remains unclear. In this network meta-analysis, we compared the relative efficacy and safety of LMWH, VKA, and DOAC for the treatment of cancer-associated VTE., Methods: A pre-specified search protocol identified 10 randomized controlled trials including 3242 cancer patients. Relative risks (RR) of recurrent VTE (efficacy) and major bleeding (safety) were analyzed using a random-effects meta-regression model., Results: LMWH emerged as significantly superior to VKA with respect to risk reduction of recurrent VTE (RR=0.60, 95%CI:0.45-0.79, p<0.001), and its safety was comparable to VKA (RR=1.08, 95%CI:0.70-1.66, p=0.74). For the DOAC vs. VKA efficacy and safety comparison, the relative risk estimates were in favor of DOAC, but had confidence intervals that still included equivalence (RR for recurrent VTE=0.65, 95%CI:0.38-1.09, p=0.10; RR for major bleeding=0.72, 95%CI:0.39-1.37, p=0.32). In the indirect network comparison between DOAC and LMWH, the results indicated comparable efficacy (RR=1.08, 95%CI:0.59-1.95, p=0.81), and a non-significant relative risk towards improved safety with DOAC (RR=0.67, 95%CI:0.31-1.46, p=0.31). The results prevailed after adjusting for different risk of recurrent VTE and major bleeding between LMWH vs. VKA and DOAC vs. VKA studies., Conclusion: The efficacy and safety of LMWH and DOACs for the treatment of VTE in cancer patients may be comparable., Funding: Austrian Science Fund (FWF-SFB-54)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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.)

Background: Patients with malignancies are at increased risk of serious influenza related complications with higher rates of hospitalization and mortality than healthy cohorts. Although annual vaccination against influenza infection is recommended, vaccination rates among cancer patients are apparently low. The reasons for the low compliance to influenza vaccine and the influenza vaccination rate among Austrian cancer patients have not been studied in detail yet., Patients and Methods: From July 1, 2013 to October 31, 2013, 444 patients treated in the outpatient departments of the Clinical Division of Oncology and the Clinical Division of Haematology and Haemostaseology of the General Hospital Vienna participated in a survey on different aspects of influenza vaccination., Results: In total, only 80 out of 444 patients (18%) had received influenza vaccination in the previous year. The influenza vaccination rate was higher amongst patients with haematological malignancies (22%) compared to patients with solid tumours (13%). Higher age was significantly associated with a higher probability for being vaccinated. Collecting information about influenza vaccination primarily from media or the internet was not significantly associated with influenza vaccination status. Information through a medical consultation or a recommendation by the attending physician resulted in significant higher influenza vaccination coverage rates. Only 199 out of the 444 patients (44.8%) were informed by a physician about influenza vaccination and only 18 out of 337 patients (5.3%) with a diagnosis of a malignant disease were informed by their treating oncologist. The main reasons for influenza vaccination denial were concerns about interaction with the malignant disease and potential side-effects., Conclusion: Information about influenza vaccination during a medical consultation and a clear recommendation by the attending physician are highly predictive for acceptance of influenza vaccination. Increased awareness among physicians, especially oncologists is of utmost importance to effectively improve IVR in patients with malignant disease., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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: We compared the public perception of cancer care in Poland and Austria. Both countries are members of the European Union (EU) but reflect two extremes in health-related per capita spending. Recently, the EUROCARE-5 study reported on very discrepant cancer outcomes between the two countries., Methods: A one-time survey was conducted to compare the public perception of cancer treatment in Poland and Austria. In total, 3,649 subjects, representing the general population, cancer patients, and cancer patients' family members, were surveyed., Results: In both countries, cancer was considered the most challenging problem of the health care system, and health care was indicated as the most important issue influencing political election decisions. Polish compared with Austrian cancer patients gave a significantly lower positive assessment of overall cancer treatment efficacy and detection methods. Cancer cure rates estimated by Polish and Austrian citizens were 29% and 44%, respectively. The majority of all citizens interviewed thought that cancer patients should have access to all available registered cancer drugs. However, only 18% of Poles versus 62% of Austrians agreed with the notion that the available cancer treatment in their countries is of a standard comparable to that of other EU countries. Consequently, 24% of Poles and 7% of Austrians identified financial status, age, gender, and residence as factors influencing the availability of cancer treatments., Conclusion: In both countries, cancer is considered the most challenging problem of the health care system, and health care issues may strongly influence decisions for political elections. Vast differences in the two populations' perceptions of cancer care reflect actual cancer outcomes and the national per capita spending on health-related issues., (©AlphaMed Press.)

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.)

Introduction: Patients with cancer are at risk of venous thromboembolism (VTE). Statin-use has been shown to be associated with low risk of VTE in patients without cancer, but data in cancer patients is scarce. The objective of this study was to evaluate the association of statins with risk of VTE in cancer patients in a prospective observational cohort study., Materials and Methods: Patients with newly diagnosed cancer or progression of disease after remission were included and prospectively followed for a maximum of 2 years. Study endpoint was occurrence of symptomatic VTE., Results: Patients (n=1434) were followed over a median observation period of 729 days. VTE occurred in 107 (7.5%) patients. At study inclusion, 170 (11.9%) patients took statins. Simvastatin (n=96) and atorvastatin (n=48) were the most frequently prescribed statins. VTE occurred in 6 (3.5%) patients with statins. Patients with statins had a lower risk of VTE than patients without (subhazard ratio 0.43, 95% confidence interval 0.19 to 0.98; p=0.04). In competing risk analysis, the cumulative probability of VTE in patients with statins was 2.94% after 12 months and 3.54% after 24 months, compared to 7.13% and 8.13% in the group without statins (Gray's test: p=0.04)., Conclusion: This study provides observational evidence for an association between statin use and low risk of VTE in patients with cancer. The role of statins for prevention of cancer-associated VTE needs to be confirmed in randomized, controlled trials., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Cancer patients are at high risk of developing venous thromboembolism (VTE). Red cell distribution width (RDW) has been reported to be associated with arterial and venous thrombosis and mortality in several diseases. Here, we analyzed the association between RDW and other red blood cell (RBC) parameters with risk of VTE and mortality in patients with cancer., Methods: RBC parameters were measured in 1840 patients with cancers of the brain, breast, lung, stomach, colon, pancreas, prostate, kidney; lymphoma, multiple myeloma and other tumor sites, that were included in the Vienna Cancer and Thrombosis Study (CATS), which is an ongoing prospective, observational cohort study of patients with newly diagnosed or progressive cancer after remission. Primary study outcome is occurrence of symptomatic VTE and secondary outcome is death during a maximum follow-up of 2 years., Results: During a median follow-up of 706 days, 131 (7.1%) patients developed VTE and 702 (38.2%) died. High RDW (>16%) was not associated with a higher risk of VTE in the total study cohort; in competing risk analysis accounting for death as competing variable the univariable subhazard ratio (SHR) was 1.34 (95% confidence interval [CI]: 0.80-2.23, p = 0.269). There was also no significant association between other RBC parameters and risk of VTE. High RDW was associated with an increased risk of mortality in the total study population (hazard ratio [HR, 95% CI]: 1.72 [1.39-2.12], p<0.001), and this association prevailed after adjustment for age, sex, hemoglobin, leukocyte and platelet count (HR [95% CI]: 1.34 [1.06-1.70], p = 0.016)., Conclusions: RDW and other RBC parameters were not independently associated with risk of VTE in patients with cancer and might therefore not be of added value for estimating risk of VTE in patients with cancer. We could confirm that high RDW is an independent predictor of poor overall survival in cancer.

The therapeutic potential of host-specific and tumour-specific immune responses is well recognized and, after many years, active immunotherapies directed at inducing or augmenting these responses are entering clinical practice. Antitumour immunization is a complex, multi-component task, and the optimal combinations of antigens, adjuvants, delivery vehicles and routes of administration are not yet identified. Active immunotherapy must also address the immunosuppressive and tolerogenic mechanisms deployed by tumours. This Review provides an overview of new results from clinical studies of therapeutic cancer vaccines directed against tumour-associated antigens and discusses their implications for the use of active immunotherapy.

Introduction: The risk for occurrence of venous thromboembolism (VTE) in cancer patients has been the aim of numerous investigations. Chronic kidney disease (CKD) is a frequent comorbidity in cancer patients and has been found to be a risk factor for VTE in the general population. We investigated the association of CKD with VTE and mortality in cancer patients., Methods: Patients were recruited into the prospective cohort study, Vienna Cancer and Thrombosis Study (CATS). CKD was estimated with equations for glomerular filtration rate (eGFR) based on serum creatinine by Modification of Diet in Renal Disease (MDRD), CKD Epidemiology collaboration (CKD-EPI) and Cockcroft-Gault equation (C-G). Patients were subsequently classified to stages of CKD according to the Kidney Diseases Outcomes Quality Initiative. Primary endpoint was occurrence of VTE and secondary endpoint was death., Results: The cohort of 1100 patients was prospectively followed over a median of 723 days. CKD with an eGFR of under 90 ml/min was common with a prevalence of 71.1%, 67.0% or 51.5% of patients calculated with MDRD, CKD-EPI and C-G equations, respectively, but severe CKD (eGFR<30 ml/min) was rare. Patients with a moderately decreased eGFR (90-60 ml/min/1.73 m(2)) based on CKD-EPI had a subdistribution hazard ratio of 0.68 (95% confidence interval 0.43-1.06). An association between CKD and occurrence of VTE or mortality could also not be shown with the other equations., Conclusions: In our investigation of a large cohort of cancer patients with a high prevalence of CKD, a reduced eGFR was not an independent risk factor for occurrence of VTE or death., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Venous thromboembolism (VTE) is a frequent complication in cancer patients. Mean platelet volume (MPV) has been associated with arterial and venous thrombosis in patients without cancer. We analysed MPV in cancer patients and investigated the association of MPV with risk of VTE and mortality. MPV was routinely determined in the Vienna Cancer and Thrombosis Study, a prospective, observational cohort study of patients with newly diagnosed or progressive cancer after remission. Study endpoints were occurrence of symptomatic VTE or death during a maximum follow-up of two years. Out of 1,544 included patients, 114 (7.4%) developed VTE and 573 (37.1%) died during a median observation time of 576 days. High MPV ≥75th percentile of the study population; ≥10.8 fL) was associated with decreased risk of VTE compared to MPV below the 75th percentile (HR [95% CI]: 0.59 [0.37-0.95], p=0.031). In multivariable analysis, including age, sex, cancer groups, newly diagnosed vs recurrent disease, platelet count and soluble P-selectin, this association remained statistically significant (0.65 [0.37-0.98], p=0.041). Mortality of patients with MPV (≥75th percentile was significantly decreased compared to those with lower MPV (0.72 [0.59-0.88], p=0.001). Two-year probability of VTE and overall survival was 5.5% and 64.7% in patients with high MPV compared to 9% and 55.7% in those with lower MPV. In conclusion, high MPV is associated with decreased VTE risk and improved survival in cancer patients. This finding is contrary to results observed in patients without cancer. Further studies are needed to confirm our results and elucidate underlying mechanisms.

The use of immunotherapy in the management of cancer is growing, and a range of new immunotherapeutic strategies is becoming available. It is important that people involved in the care of cancer understand how cancer immunotherapies differ from conventional chemotherapy and apply this knowledge to their clinical practice. Therefore, from August-September 2011 we undertook a survey of awareness, attitudes, and perceptions of cancer immunotherapy among 426 healthcare professionals (HCPs) in Europe with the aim of identifying and prioritizing educational needs. Nearly all (98%) HCPs were aware of cancer immunotherapy. While 68% of HCPs indicated a high level of interest in cancer immunotherapies, only 24% of the HCPs had direct experience with them. Overall perceptions of cancer immunotherapy among HCPs were largely positive (60%) and rarely negative (3%). The key advantages of cancer immunotherapy were perceived to be good safety and tolerability (75%), a targeted mechanism of action (61%) and good efficacy (48%). The leading barriers to use of immunotherapies were costs of treatment (58%), past clinical trial failures (45%), and access/formulary restrictions (44%). The results indicate that, among the respondents, awareness of cancer immunotherapy was high but that knowledge levels varied and direct experience with their use was limited. There appears to be a need for educational activities on cancer immunotherapy, as well as generation and communication of clinical data on long-term efficacy and safety.

Background: Cancer patients are at increased risk of venous thromboembolism (VTE)., Objective: We investigated the association of a history of VTE, superficial thrombophlebitis, or the presence of varicose veins with the occurrence of VTE during the course of cancer., Methods: Cancer patients were recruited in a prospective cohort study, the Vienna Cancer and Thrombosis Study. Patients who had VTE within 3 months before study inclusion were excluded. At study inclusion, history of VTE, history of superficial thrombophlebitis, and presence of varicose veins were recorded. Primary end point was the occurrence of symptomatic VTE. Hazard ratios were obtained using the competing risk analysis according to Fine and Gray., Results: The cohort consisted of 1270 patients followed over a median of 590 days. A history of VTE was found in 66 patients (5.2%), superficial thrombophlebitis in 79 patients (6.2%), and varicose veins in 160 patients (12.6%). Ninety-eight patients (7.7%) developed VTE during follow-up. The hazard ratios for the risk of VTE in patients with a history of VTE or superficial thrombophlebitis were 1.44 (95% confidence interval: 0.67-3.07) and 1.94 (1.04-3.61), respectively, and 2.01 (1.26-3.21) in those with varicose veins. In multivariable analysis including history of VTE, history of superficial thrombophlebitis, presence of varicose veins, and other patient-related factors, the presence of varicose veins (2.10 [1.29-3.41]) remained significantly associated with an increased risk of VTE., Conclusion: The presence of varicose veins is associated with an elevated risk of VTE in cancer patients. This clinical parameter could be useful for individual risk assessment of VTE in these patients., (© 2013 International Society on Thrombosis and Haemostasis.)

Advanced cancer is a risk factor for venous thromboembolism. However, lymph node metastases are usually not considered an established risk factor. In the framework of the prospective, observational Vienna Cancer and Thrombosis Study we investigated the association between local (N0), regional (N1-3), and distant (M1) cancer stages and the occurrence of venous thromboembolism. Furthermore, we were specifically interested in the relationship between stage and biomarkers that have been reported to be associated with venous thromboembolism. We followed 832 patients with solid tumors for a median of 527 days. The study end-point was symptomatic venous thromboembolism. At study inclusion, 241 patients had local, 138 regional, and 453 distant stage cancer. The cumulative probability of venous thromboembolism after 6 months in patients with local, regional and distant stage cancer was 2.1%, 6.5% and 6.0%, respectively (P=0.002). Compared to patients with local stage disease, patients with regional and distant stage disease had a significantly higher risk of venous thromboembolism in multivariable Cox-regression analysis including age, newly diagnosed cancer (versus progression of disease), surgery, radiotherapy, and chemotherapy (regional: HR=3.7, 95% CI: 1.5-9.6; distant: HR=5.4, 95% CI: 2.3-12.9). Furthermore, patients with regional or distant stage disease had significantly higher levels of D-dimer, factor VIII, and platelets, and lower hemoglobin levels than those with local stage disease. These results demonstrate an increased risk of venous thromboembolism in patients with regional disease. Elevated levels of predictive biomarkers in patients with regional disease underpin the results and are in line with the activation of the hemostatic system in the early phase of metastatic dissemination.

Purpose: Patients with cancer are at risk of venous thromboembolism (VTE). Tumor-related factors could help estimate patients' individual risk for VTE. Currently, only scarce information on the association between tumor grade and VTE is available. We thus evaluated the role of tumor grade and its association with VTE., Patients and Methods: The Vienna Cancer and Thrombosis Study is a prospective, observational cohort study including patients with newly diagnosed cancer or progression of disease after remission. Study end point is the occurrence of symptomatic VTE., Results: Seven hundred forty-seven patients with solid tumors received follow-up for a median of 526 days. VTE occurred in 52 patients (7.0%). At study inclusion, 468 patients had low-grade tumors (G1 and G2) and 279 had high-grade tumors (G3 and G4). In multivariable Cox regression analysis including tumor grade, tumor histology, tumor sites, stage, sex, and age, patients with high-grade tumors had a significantly higher risk of VTE compared with those with low-grade tumors (hazard ratio, 2.0; 95% CI, 1.1 to 3.5; P = .015). The cumulative probability of developing VTE after 6 months was higher in patients with high-grade tumors than in those with low-grade tumors (8.2% v 4.0%; log-rank test P = .037). Patients with high-grade tumors had higher D-dimer levels (P = .008) and leukocyte counts (P < .001), and lower hemoglobin levels (P = .008)., Conclusion: The tumor grade may help identify patients with cancer who are at high risk of VTE. The association of tumor grade with recently identified biomarkers indicates a link between tumor differentiation and pathogenesis of cancer-associated VTE.

Background: Systemic activation of hemostasis is frequently observed in cancer patients, even in the absence of thrombosis. Moreover, this activation has been implicated in tumor progression, angiogenesis and metastatic spread. Increased levels of D-dimer, which is a degradation product of cross-linked fibrin, indicate a global activation of hemostasis and fibrinolysis., Design and Methods: In a prospective and observational cohort study, we assessed the prognostic value of D-dimer levels for overall survival and mortality risk in 1178 cancer patients included in the Vienna Cancer and Thrombosis Study (CATS). Patients were followed over 2 years at regular intervals until occurrence of symptomatic venous thromboembolism or death. D-dimer levels were measured with a quantitative D-dimer latex agglutination assay, Results: The main solid tumors were malignancies of the lung (n=182), breast (n=157), lower gastrointestinal tract (n=133), pancreas (n=74), stomach (n=50), kidney (n=37), prostate (n=133), and brain (n=148); 201 of the patients had hematologic malignancies; 63 had other tumors. During a median follow-up of 731 days, 460 (39.0%) patients died. The overall survival probabilities for patients with D-dimer levels categorized into four groups based on the 1(st), 2(nd) and 3(rd) quartiles of the D-dimer distribution in the total study population were 88%, 82%, 66% and 53% after 1 year, and 78%, 66%, 50% and 30% after 2 years, respectively (P<0.001). The univariate hazard ratio of D-dimer (per double increase) for mortality was 1.5 (95% confidence interval: 1.4-1.6, P<0.001) and remained increased in multivariable analysis including tumor subgroups, age, sex and venous thromboembolism., Conclusions: High D-dimer levels were associated with poor overall survival and increased mortality risk in cancer patients.

Venous thromboembolism (VTE) is a life-threatening complication in cancer patients. Identification of risk factors has been in focus in the past years. Functional single nucleotide polymorphisms (SNP) of coagulation factors known to influence the concentration or function may be considered to influence the risk of VTE in cancer patients. We evaluated the influence of fibrinogen plasma levels, the -455G>A SNP in the fibrinogen beta gene and the Val34Leu (163G>T) SNP in the factor XIII A-subunit (FXIII-A) gene on the risk of VTE. In 1,079 tumour patients recruited for the prospective Vienna Cancer and Thrombosis Study (CATS) fibrinogen levels were determined by the Clauss method. The FXIII-A Val34Leu and the fibrinogen -455G>A SNPs were tested by allele-specific PCR. The median follow-up time was 604 days, 83 thrombotic events occurred. The median fibrinogen level was 381 mg/dl (25th-75th percentile: 312 to 467). In a multivariable Cox model adjusted to chemotherapy, surgery, radiotherapy, age and sex, neither the fibrinogen concentration (hazard ratio [HR] =1.05, confidence interval [CI] 0.839-1.310 p=0.68), nor the -455G>A SNP (HR=0.77, 95%CI 0.491-1.197; p=0.24), nor the Val34Leu SNP (HR=0.99, 95%CI 0.646-1.542 p=0.99) were associated with occurrence of VTE. The fibrinogen concentration was not significantly different among the fibrinogen -455G or A genotype carriers (p = 0.33). Disseminated intravascular coagulation was observed in only five patients, none of these developed VTE. In conclusion, fibrinogen plasma levels, the fibrinogen -455G>A and the FXIII-A Val34Leu polymorphisms were not associated with VTE in our study.

Accumulating evidence indicates that microparticles (MPs) are important mediators of the interaction between cancer and the hemostatic system. We conducted a large prospective cohort study to determine whether the number of circulating procoagulant MPs is elevated in cancer patients and whether the elevated MP levels are predictive of occurrence of venous thrombembolism (VTE). We analyzed plasma samples of 728 cancer patients from the ongoing prospective observational Vienna Cancer and Thrombosis Study. Study endpoint was the occurrence of symptomatic VTE. Sixty-five age- and sex-matched healthy controls were recruited for defining the cut-off point for elevated MPs (4.62 nanomolar phosphatidylserine [nM PS]), which was set at the 95th percentile of MP levels in healthy controls. The measurement of MPs was performed after capture onto immobilized annexin V, and determination of their procoagulant activity was quantified with a prothrombinase assay. During a median observation period of 710 days, 53 patients developed VTE. MP levels (nM PS) were significantly higher in cancer patients than in healthy controls (median [25th-75th percentile], 3.95 [1.74-7.96] vs. 1.19 [0.81-1.67], p<0.001). Multivariate analysis including age, sex, surgery, chemo- and radiotherapy showed no statistically significant association of the hazard ratio of elevated MPs with VTE (0.95 [95% CI, 0.55-1.64], p=0.856). In conclusion, MP levels were elevated in cancer patients compared to healthy individuals in this study. However, elevated MP levels were not predictive of VTE.

Background: The incidence of venous thromboembolism (VTE) is increased among cancer patients., Objective: We assessed serum levels of C-reactive protein (CRP) in order to study their prognostic significance for VTE and survival in the prospective observational Cancer and Thrombosis Study (CATS)., Patients and Methods: This study includes patients with recently diagnosed cancer or progression of disease after remission. Occurrence of VTE and information on the patients' anti-cancer-treatment are recorded. Observation ends with occurrence of objectively confirmed VTE, death or after 2 years. CRP levels were determined by an immunonephelometric method., Results: We included 705 consecutive patients with solid tumors. During the observation period, VTE occurred in 43 (6.1%) patients and 413 (58.6%) died. The cumulative probability of VTE was 6.6% after 1 year. In univariate analysis, CRP (as metric variable, per double increase) was associated with VTE [hazard ratio (HR) 1.2, 95% confidence interval (CI) 1.1-1.3 P = 0.048]. However, in multivariable analysis including chemotherapy, surgery and radiotherapy, metastasis, cancer-site and sP-selectin the association with VTE (HR 1.0, 95% CI 0.9-1.2 P = 0.932) was no longer observed. CRP was clearly associated with worse survival probability with a HR of 1.3 (95% CI 1.2-1.3, P < 0.0001) in multivariable analysis. The cumulative survival after 12 months was 43% in patients with CRP above the 75th percentile (1.8 mg dL(-1) ) and 82% in those below the 75th percentile., Conclusions: In cancer patients elevated CRP was not independently associated with VTE. CRP was significantly associated with worse survival., (© 2010 International Society on Thrombosis and Haemostasis.)

Chemotherapy-induced neutropenia is a major risk factor for infection-related morbidity and mortality and also a significant dose-limiting toxicity in cancer treatment. Patients developing severe (grade 3/4) or febrile neutropenia (FN) during chemotherapy frequently receive dose reductions and/or delays to their chemotherapy. This may impact the success of treatment, particularly when treatment intent is either curative or to prolong survival. In Europe, prophylactic treatment with granulocyte-colony stimulating factors (G-CSFs), such as filgrastim (including approved biosimilars), lenograstim or pegfilgrastim is available to reduce the risk of chemotherapy-induced neutropenia. However, the use of G-CSF prophylactic treatment varies widely in clinical practice, both in the timing of therapy and in the patients to whom it is offered. The need for generally applicable, European-focused guidelines led to the formation of a European Guidelines Working Party by the European Organisation for Research and Treatment of Cancer (EORTC) and the publication in 2006 of guidelines for the use of G-CSF in adult cancer patients at risk of chemotherapy-induced FN. A new systematic literature review has been undertaken to ensure that recommendations are current and provide guidance on clinical practice in Europe. We recommend that patient-related adverse risk factors, such as elderly age (≥65 years) and neutrophil count be evaluated in the overall assessment of FN risk before administering each cycle of chemotherapy. It is important that after a previous episode of FN, patients receive prophylactic administration of G-CSF in subsequent cycles. We provide an expanded list of common chemotherapy regimens considered to have a high (≥20%) or intermediate (10-20%) risk of FN. Prophylactic G-CSF continues to be recommended in patients receiving a chemotherapy regimen with high risk of FN. When using a chemotherapy regimen associated with FN in 10-20% of patients, particular attention should be given to patient-related risk factors that may increase the overall risk of FN. In situations where dose-dense or dose-intense chemotherapy strategies have survival benefits, prophylactic G-CSF support is recommended. Similarly, if reductions in chemotherapy dose intensity or density are known to be associated with a poor prognosis, primary G-CSF prophylaxis may be used to maintain chemotherapy. Clinical evidence shows that filgrastim, lenograstim and pegfilgrastim have clinical efficacy and we recommend the use of any of these agents to prevent FN and FN-related complications where indicated. Filgrastim biosimilars are also approved for use in Europe. While other forms of G-CSF, including biosimilars, are administered by a course of daily injections, pegfilgrastim allows once-per-cycle administration. Choice of formulation remains a matter for individual clinical judgement. Evidence from multiple low level studies derived from audit data and clinical practice suggests that some patients receive suboptimal daily G-CSFs; the use of pegfilgrastim may avoid this problem., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

The risk of venous thromboembolism (VTE) is increased in cancer patients. To improve prediction of VTE in cancer patients, we performed a prospective and observational cohort study of patients with newly diagnosed cancer or progression of disease after remission. A previously developed risk scoring model for prediction of VTE that included clinical (tumor entity and body mass index) and laboratory (hemoglobin level and thrombocyte and leukocyte count) parameters was expanded by incorporating 2 biomarkers, soluble P-selectin, and D-Dimer. Of 819 patients 61 (7.4%) experienced VTE during a median follow-up of 656 days. The cumulative VTE probability in the original risk model after 6 months was 17.7% in patients with the highest risk score (≥ 3, n = 93), 9.6% in those with score 2 (n = 221), 3.8% in those with score 1 (n = 229), and 1.5% in those with score 0 (n = 276). In the expanded risk model, the cumulative VTE probability after 6 months in patients with the highest score (≥ 5, n = 30) was 35.0% and 10.3% in those with an intermediate score (score 3, n = 130) as opposed to only 1.0% in patients with score 0 (n = 200); the hazard ratio of patients with the highest compared with those with the lowest score was 25.9 (8.0-84.6). Clinical and standard laboratory parameters with addition of biomarkers enable prediction of VTE and allow identification of cancer patients at high or low risk of VTE.

Biological features of tumor cells relevant to progression, metastasis, and prognosis in cancer patients have been investigated for many years. During the past few years, the concept of tumor stem cells has gained widespread acceptance. The cancer stem cell (CSC) model is based on the observation that continuous growth of tumors depends on a small population of immature neoplastic cells with unlimited proliferative potential. In contrast to these CSC, more mature clonal cells in the same neoplasm undergo apoptosis and die after a variable number of cell divisions. The self-renewal capacity of CSC plays a central role in this scenario and enables permanent tumor cell repopulation in vivo in patients as well as in experimental animals, e.g., immunodeficient mice. Based on the stem cell concept, it is clear that the success of an anti-neoplastic approach depends on efficient targeting and elimination of CSC. An important aspect of CSC is their intrinsic resistance against conventional drugs. Therefore, a major focus in current research is molecular targets and their expression in CSC, with the goal to use targeted drugs for CSC elimination. It is the hope for the future that therapeutic approaches involving CSC-targeting concepts will lead to sustained remission and thus improvement of prognosis in leukemia and cancer patients.

Background: In cancer patients, laboratory parameters that predict venous thromboembolism (VTE) are scarce. Increased platelet count has been found to be a risk factor for VTE in cancer patients receiving chemotherapy (CHT). We have assessed high platelet count as a risk predictor for VTE in patients with cancer undergoing discriminative anti-cancer treatments and investigated whether platelet count correlates with thrombopoietin (TPO) levels., Design and Methods: The Cancer and Thrombosis Study (CATS) is an ongoing prospective observational study of patients with newly diagnosed cancer or progression of disease, which started in October 2003. Occurrence of VTE and information on the patients' anti-cancer treatment during follow-up were recorded., Results: Between October 2003 and February 2008, 665 patients with solid tumors were included (314 female/351 male, mean age 62 years). VTE occurred in 44 patients (18 female/26 male, mean age 62 years). The cumulative probability of VTE after 1 year was 34.3% in patients with a platelet count (PC) above the 95th percentile representing 443 x 10(9)/L compared with 5.9% in those below 443 x 10(9)/L. High platelet count [hazard ratio (HR): 3.50, 95% confidence interval (CI): 1.52-8.06, P = 0.0032], soluble P-selectin [HR: 2.66, 95% CI: 1.42-4.96, P = 0.0021] and surgery [HR: 4.05, 95% CI: 1.74-9.46, P = 0.0012] were statistically significant risk factors for VTE in multivariable analysis along with leucocyte count, age, gender, radio- and CHT. We found no correlation between platelet count and TPO levels., Conclusions: High PC is a clinically important, independent risk predictor for VTE in cancer patients. PC was not found to be associated with TPO levels.

Objective: Patients with cancer are at an increased risk for venous thromboembolism (VTE). Clotting factor VIII activity (FVIII) has been established as risk factor of primary and recurrent VTE. We investigated FVIII as predictive parameter of VTE in cancer patients., Methods and Results: The prospective observational Cancer and Thrombosis Study (CATS) includes patients with newly diagnosed cancer or disease progression, study end point is symptomatic VTE. FVIII was measured on a Sysmex CA 7000 analyzer. Data on 840 patients (median age: 62 years, 25th to 75th percentile 53 to 68, 378 women) were available for analyses, of these 111 patients had hematologic malignancies and 729 solid cancer. During a median observation time of 495 days 62 events occurred. Cumulative probability of VTE after 6 months was 14% in patients with elevated FVIII-levels and 4% in those with normal levels (P=0.001). The association was strongest in younger patients: whereas in 40-year-old patients a 2-fold VTE risk per factor VIII increase of 20% was observed (HR=2.0 [95% CI: 1.5 to 2.7], P<0.0001), this association was still present but attenuated in older patients., Conclusions: FVIII is independently associated with an increased risk of VTE in cancer patients. The association between FVIII and VTE risk declines with increasing age.