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Background: Financial toxicity, defined as both the objective financial burden and subjective financial distress from a cancer diagnosis and its treatment, is a topic of interest in the assessment of the quality of life of patients with cancer and their families. Current evidence implicates financial toxicity in psychosocial, economic and other harms, leading to suboptimal cancer outcomes along the entire trajectory of diagnosis, treatment, supportive care, survivorship and palliation. This paper presents the results of a virtual consensus, based on the evidence base to date, on the screening and management of financial toxicity in patients with and beyond cancer organized by the European Society for Medical Oncology (ESMO) in 2022., Methods: A Delphi panel of 19 experts from 11 countries was convened taking into account multidisciplinarity, diversity in health system contexts and research relevance. The international panel of experts was divided into four working groups (WGs) to address questions relating to distinct thematic areas: patients with cancer at risk of financial toxicity; management of financial toxicity during the initial phase of treatment at the hospital/ambulatory settings; financial toxicity during the continuing phase and at end of life; and financial risk protection for survivors of cancer, and in cancer recurrence. After comprehensively reviewing the literature, statements were developed by the WGs and then presented to the entire panel for further discussion and amendment, and voting., Results and Discussion: A total of 25 evidence-informed consensus statements were developed, which answer 13 questions on financial toxicity. They cover evidence summaries, practice recommendations/guiding statements and policy recommendations relevant across health systems. These consensus statements aim to provide a more comprehensive understanding of financial toxicity and guide clinicians globally in mitigating its impact, emphasizing the importance of further research, best practices and guidelines., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Cancer is a global public health problem, requiring efficient health system investments to deliver sustainable impact on population health. Access to medicines is a critical component of health systems, having a crucial role in delivering therapeutic benefits. Since 1977, the World Health Organization (WHO) has published a Model List of Essential Medicines (EML) that includes key health interventions for the prevention and control of conditions of public health relevance. Essential medicines are selected for inclusion in the EML based on the evidence of efficacy, safety, therapeutic value, and the potential to impact population health. With the rapid changes in the therapeutic landscape of cancer treatment with new medicine approvals, there is a critical need to select and prioritise specific cancer interventions based on their intrinsic value., Materials and Methods: The European Society for Medical Oncology (ESMO) has developed a decisional methodology based on a threshold with a minimum set of technical specifications and a consensus-based procedure for decisions to select candidate cancer medicines to be submitted to the WHO for consideration for the WHO EML., Results: ESMO recognises the WHO EML as an important reference guide for medicines that all countries should include in their national EMLs. Cancer medicines on the WHO EML are used in the treatment of the majority of cancers, and are recommended in the evidence-based ESMO Clinical Practice Guidelines that medical oncologists use to treat patients. ESMO's submissions to the WHO EML in 2019 and 2021 and their respective outcomes are presented in the manuscript., Conclusion: Due to the rising costs associated with newly available therapies, structured, reproducible, and field-tested tools to evaluate the added clinical benefit from these therapies need to be implemented in pre-selecting potential candidate medicines to be included in the WHO EML. ESMO is proud to collaborate closely with WHO on this important global public health initiative., Competing Interests: Disclosure TA reports personal fees from CeCaVa, institutional grants and personal fees from Novartis, institutional grants from NeraCare, personal fees and travel grants from BMS, personal fees and travel grants from Pierre Fabre, institutional grants from Sanofi, institutional grants from SkylineDx and institutional grants from iFIT, outside the submitted work. GC has received personal fees from AstraZeneca and Daiichi Sankyo; has received grants or contracts from Merck and AstraZeneca; has received personal fees as advisory board member for AstraZeneca, BMS; Ellipsis, Merck; Lilly, Pfizer, Roche, Veracyte; has received institutional research grant from Merck; has received institutional funding for phase I studies from Astellas, AstraZeneca, BMS, Blueprint Medicine, Daiichi Sankyo, Kymab, Novartis, Philogen, Roche, Sanofi; has received consulting fees from Roche, BMS, Novartis, Lilly, Pfizer, Seagen, AstraZeneca, Ellipsis, Gilead, Merck, Celcuity, Sanofi, Exact Sciences, and Daiichi Sankyo; has received payment or honoraria for presentations, lectures, speaker bureaus, manuscript writing, or educational events from AstraZeneca, Novartis, Lilly, Pfizer, Seagen, Roche and Daiichi Sankyo; has received support for attending meetings or travel from AstraZeneca and Daiichi Sankyo; has participated on a data safety monitoring board or advisory board for Roche, BMS, Novartis, Lilly, Pfizer, Seagen, Ellipsis, Gilead, Merck, Celcuity, AstraZeneca, and Daiichi Sankyo; has an advisory role and is Member of the Scientific Council of Europa Donna, is an Officer of the Consiglio Superiore di Sanità, Italian National Health Council as Advisor for Ministry of Health, and has an advisory role in Fondazione Beretta Cancer Research Foundation. RG reports being an invited speaker from Apogen, Lilly, Mylan, Novartis, Roche, Pfizer, Medicines for Europe, Mabxience and the European Access Academy (all with no fee received); she received personal fees from AstraZeneca and travel grants form Roche; she reports an advisory role for UICC ATOM Medicines (January 2023); she reports being a full member of the Cancer Drug Development Forum (CDDF); she is co-chair and member of the European Medicines Agency (EMA) Healthcare Professional Working Party (HCPWP) and a member of the EMA Cancer Medicines Forum; she serves as expert for the evaluation of proposals submitted to Horizon Europe Health Cluster-for the Health and Digital Executive Agency (HaDEA). DT reports being a member of the EMA Healthcare Professional Working Party (HCPWP), a member of the WHO SAGE IVD and a member of the WHO EML Cancer Medicines Working Group. GB, MG, NJL and GP are full-time employees of ESMO. All the other authors have declared no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: COVID-19 has significantly affected patients with cancer and revealed unanticipated challenges in securing optimal cancer care across different disciplines. The European Society for Medical Oncology COVID-19 and CAncer REgistry (ESMO-CoCARE) is an international, real-world database, collecting data on the natural history, management, and outcomes of patients with cancer and SARS-CoV-2 infection., Methods: This is the 2nd CoCARE analysis, jointly with Belgian (Belgian Society of Medical Oncology, BSMO) and Portuguese (Portuguese Society of Medical Oncology, PSMO) registries, with data from January 2020 to December 2021. The aim is to identify significant prognostic factors for COVID-19 hospitalization and mortality (primary outcomes), as well as intensive care unit admission and overall survival (OS) (secondary outcomes). Subgroup analyses by pandemic phase and vaccination status were carried out., Results: The cohort includes 3294 patients (CoCARE: 2049; BSMO: 928, all hospitalized by eligibility criteria; PSMO: 317), diagnosed in four distinct pandemic phases (January to May 2020: 36%; June to September 2020: 9%; October 2020 to February 2021: 41%; March to December 2021: 12%). COVID-19 hospitalization rate was 54% (CoCARE/PSMO), ICU admission 14%, and COVID-19 mortality 22% (all data). At a 6-month median follow-up, 1013 deaths were recorded with 73% 3-month OS rate. No significant change was observed in COVID-19 mortality among hospitalized patients across the four pandemic phases (30%-33%). Hospitalizations and ICU admission decreased significantly (from 78% to 34% and 16% to 10%, respectively). Among 1522 patients with known vaccination status at COVID-19 diagnosis, 70% were non-vaccinated, 24% had incomplete vaccination, and 7% complete vaccination. Complete vaccination had a protective effect on hospitalization (odds ratio = 0.24; 95% confidence interval [0.14-0.38]), ICU admission (odds ratio = 0.29 [0.09-0.94]), and OS (hazard ratio = 0.39 [0.20-0.76]). In multivariable analyses, COVID-19 hospitalization was associated with patient/cancer characteristics, the first pandemic phase, the presence of COVID-19-related symptoms or inflammatory biomarkers, whereas COVID-19 mortality was significantly higher in symptomatic patients, males, older age, ethnicity other than Asian/Caucasian, Eastern Cooperative Oncology Group performance status ≥2, body mass index <25, hematological malignancy, progressive disease versus no evident disease, and advanced cancer stage., Conclusions: The updated CoCARE analysis, jointly with BSMO and PSMO, highlights factors that significantly affect COVID-19 outcomes, providing actionable clues for further reducing mortality., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) has been developed to grade clinical benefit of cancer therapies. Improvement in quality of life (QoL) is considered relevant, especially in the non-curative setting. This is reflected by an upgrade of the preliminary ESMO-MCBS score if QoL is improved compared to the control arm or a downgrade if an improvement in progression-free survival is not paralleled by an improvement in QoL or overall survival. Given the importance of QoL for the final score, a need to ensure the robustness of QoL data was recognised., Design: A checklist was created based on existing guidelines for QoL research. Field testing was carried out using clinical trials that either received an adjustment of the preliminary ESMO-MCBS score based on QoL or had QoL as the primary endpoint. Several rounds of revision and re-testing of the checklist were undertaken until a final consensus was reached., Results: The final checklist consists of four items and can be applied if three prerequisites are met: (i) QoL is at least a secondary endpoint, (ii) evidence of reliability and validity of the instrument is provided, and (iii) a statistically and clinically significant improvement in QoL is observed. The four items on the checklist pertain to the (i) hypothesis, (ii) compliance and missing data, (iii) presentation of the results, and (iv) statistical and clinical relevance. Field testing revealed that a clear QoL hypothesis and correction for multiple testing were mostly lacking, while the main statistical method was always described., Conclusions: Implementation of the ESMO-MCBS QoL checklist will facilitate objective and transparent decision making on QoL data within the ESMO-MCBS scoring process. Trials published until 1 January 2025 will have to meet the prerequisites and at least two items for crediting QoL benefit in the final ESMO-MCBS score. Trials published thereafter will have to meet all four items., Competing Interests: Disclosure SFO reports research grants from Novartis and Celldex Therapeutics and consultancy fees from BMS (paid to the institution). EGEdV reports an advisory role at Daiichi Sankyo, NSABP, and Sanofi (paid to the institution), and research funding from Amgen, AstraZeneca, Bayer, Chugai Pharma, Crescendo, CytomX Therapeutics, G1 Therapeutics, Genentech, Nordic Nanovector, Radius Health, Regeneron, Roche, Servier, and Synthon (paid to the institution). BG reports receiving consulting fees from Vivio Health. BK reports honoraria for lectures by Ipsen, Novartis, and MSD. JB reports grants, personal fees, and non-financial support from Ipsen, personal fees and non-financial support from Pfizer, non-financial support from AAA, personal fees and non-financial support from Novartis, non-financial support from Nanostring, non-financial support from Roche, grants and personal fees from Servier, and personal fees from Nutricia outside the submitted work. 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. MPi reports a Scientific Board Member at Oncolytics, consultancy fees from AstraZeneca, Camel-IDS, Immunomedics, Lilly, Menarini, MSD, Novartis, Odonate, Pfizer, Roche-Genentech, Seattle Genetics, Immutep, Seagen, NBE Therapeutics, Frame Therapeutics and research grants from AstraZeneca, Immunomedics, Lilly, Menarini, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier, Synthon (paid to the institution). All other authors have declared no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Off-label use of medicines is generally discouraged. However, several off-patent, low-cost cancer medicines remain off-label for indications in which they are commonly used in daily practice, supported by high-level evidence based on results of phase III clinical trials. This discrepancy may generate prescription and reimbursement obstacles as well as impaired access to established therapies., Methods: A list of cancer medicines that remain off-label in specific indications despite the presence of high-level evidence was generated and subjected to European Society for Medical Oncology (ESMO) expert peer review to assess for accountability of reasonableness. These medicines were then surveyed on approval procedures and workflow impact. The most illustrative examples of these medicines were reviewed by experts from the European Medicines Agency to ascertain the apparent robustness of the supporting phase III trial evidence from a regulatory perspective., Results: A total of 47 ESMO experts reviewed 17 cancer medicines commonly used off-label in six disease groups. Overall, high levels of agreement were recorded on the off-label status and the high quality of data supporting the efficacy in the off-label indications, often achieving high ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) scores. When prescribing these medicines, 51% of the reviewers had to implement a time-consuming process associated with additional workload, in the presence of litigation risks and patient anxiety. Finally, the informal regulatory expert review identified only 2 out of 18 (11%) studies with significant limitations that would be difficult to overcome in the context of a potential marketing authorisation application without additional studies., Conclusions: We highlight the common use of off-patent essential cancer medicines in indications that remain off-label despite solid supporting data as well as generate evidence on the adverse impact on patient access and clinic workflows. In the current regulatory framework, incentives to promote the extension of indications of off-patent cancer medicines are needed for all stakeholders., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: During recent years, the burden of bureaucracy in clinical research has increased dramatically, adversely impacting the activity of investigators and clinical research teams. Although compliance with the Declaration of Helsinki, the guidelines for Good Clinical Practice (GCP), and other applicable regulations remains unquestionable, their overinterpretation and substitution by the internal operating procedures of sponsors and Contract Research Organizations (CROs) have increased the administrative burden. A survey conducted by the European Society for Medical Oncology (ESMO) Clinical Research Observatory (ECRO) among 940 investigators confirmed that they considered that the administrative burden in clinical research is excessive; that administrative procedures could be reduced without affecting the safety and the rights of the patients and the quality of the data; and that bureaucracy represents an obstacle for clinical research., Methods: A panel of physicians with extensive experience in clinical research, composed by members of the ECRO and the ESMO Scientific Medical and Public Policy divisions, analyzed clinical trial procedures related to administrative workflow, pharmacovigilance, and medical care., Results: The panel identified situations that generate debate between investigators and sponsors/CROs and selected real clinical scenarios that exemplify such situations. The panel discussed and proposed specific recommendations for those situations, based on GCP., Conclusions: This initiative aspires to streamline clinical research procedures and to become a platform for discussion among all clinical trial stakeholders, with the aim of promoting the sustainability of clinical research and the care of cancer patients., Competing Interests: Disclosure JLPG has taken part in advisory boards for Bristol Myers Squibb (BMS), Merck, Merck Sharp & Dohme (MSD), Seattle Genetics, Gilead; reports speaker honorarium from BMS, MSD, Roche; reports funding from Ipsen, Roche; reports role as principal investigator (PI) for Amgen, BMS, Roche, Seattle Genetics. NP reports a research grant from Bayer. EC has taken part in advisory boards for Adcendo, Amunix, Anaveon, AstraZeneca, BMS, Chugai, Elevation Oncology, Janssen, Monta, MSD, Nanobiotix, Nouscom, Novartis, Servier, T-knife, TargImmune; reports speaker/lecturer honorarium from OncoDNA, PharmaMar, Roche/Genentech; reports full or part-time employment by HM Hospitales Group, START Madrid; reports member of board of directors of PharmaMar; reports ownership interest in Oncoart Associated, START; reports steering committee member of BeiGene, Sanofi. AA has taken part in advisory boards from Amgen, AstraZeneca, Bayer, Daiichi, Eisai, Genomic Health, Hengrui, Innate, Ipsen, Leo Pharma, Lilly, Merck, MSD, Novartis, Pfizer, Seattle Genetics. Speaker fees from Amgen, AstraZeneca, Bayer, Daiichi, Eisai, Genomic Health, Ipsen, Leo Pharma, Lilly, Merck, MSD, Novartis, Pfizer, Seattle Genetics. Research grants from BMS, Roche. HTA has taken part in advisory boards for Beigene, iOnctura; reports speaker honorarium from Guardant, Servier; reports role as PI for multiple small and large Pharma/Biotechs. TA reports speaker honorarium from BMS, Novartis, Pierre Fabre; reports writers honorarium from CeCaVa; reports research grants from iFIT, Novartis; reports funding from NeraCare, Novartis, Sanofi, SkylineDx; reports non-financial interests in ASCO, Portuguese Society of Medical Oncology; reports other from INFARMED. VG has taken part in advisory boards for APOGEPHA, BMS, Debiopharm, Eisai, EUSA Pharma, Merck Serono, MSD, Nanobiotix, Oncorena, PCI Biotech, Pfizer, Roche; reports speaker honorarium from Astellas, AstraZeneca, BMS, Eisai, Ipsen, Janssen-Cilag, Merck Serono, MSD, Novartis, Pfizer, Roche; reports stocks/shares in AstraZeneca, BMS, MSD, Seattle Genetics; reports research grants from BMS, Ipsen, MSD, Pfizer; reports steering committee member for BMS, Eisai, Ipsen, Novartis; reports trial chair for PharmaMar; reports non-financial interests in ASCO, German Cancer Society, German medical Oncology and Hematology Society, Working Group medical oncology. MFS has taken part in an advisory board for Numab; reports speaker honorarium from MSD; reports a research grant from Roche; reports non-financial interests in BMS. GB has taken part in advisory boards for Janssen, Merck, Novartis, Roche, Servier. MPL has taken part in advisory boards for Amgen, Astellas, AstraZeneca, Bayer, INCa, Janssen-Cilag BV, MSD, Novartis, Pfizer, Roche, Sanofi, Servier; reports consulting role for Julius Clinical; reports research grants from Astellas, Janssen, MSD, Sanofi. MDN reports PI roles in studies sponsored by Amgen, BMS, Mundipharma, Novartis, Roche, Sanofi, Merck, Nektar Therapeutics, Incyte, Genentech, Beigene, Hookipa. PGC reports institutional research/educational funds from: Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Bayer, Blueprint Medicines, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Glaxo, Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar. RG reports being a past core member of the European Medicines Agency (EMA) Scientific Advisory Group-Oncology (SAG-O, 2012-2021), member of the EMA Healthcare Professional Working Party and of the EMA Cancer Medicines Forum; an expert evaluator of proposal submitted to EU Commission on prevention (2020) and on artificial intelligence (2022); member of the Health Technology Assessment stakeholders group, former HTAN, and of the EUnetHTA stakeholder group; member of the steering committee of the World Health Organization (WHO) Decide Health Decision Hub; member of the Cancer Drug Development forum. She also provided consultation/lectures (no remuneration) for Novartis, Mylan, Roche, Lilly, Apogen, Pfizer and medicines for Europe and institutional financial support (clinical trials, Italy—2018) for MDS and Novartis. GP has taken part in advisory boards for Amgen, AstraZeneca, BMS, Lilly, Merck, MSD, Roche; reports role as PI for AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, BMS, Debiopharm, Ipsen, Lilly, Merck, MSD, Roche, Servier; reports grants from Amgen, AstraZeneca, Roche; reports funding from Boehringer Ingelheim, BMS, Enorasis, Genekor, Ipsen, Janssen, Merck, MSD, Pfizer, Sanofi, Servier. LCB has declared no conflicts of interest., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

In 2021, the Food and Drug Administration Oncology Center of Excellence announced Project Optimus focusing on dose optimization for oncology drugs. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Taskforce met to review and discuss the optimization of dosage for oncology trials and to develop a practical guide for oncology phase I trials. Defining a single recommended phase II dose based on toxicity may define doses that are neither the most effective nor the best tolerated. MDICT recommendations address the need for robust non-clinical data which are needed to inform trial design, as well as an expert team including statisticians and pharmacologists. The protocol must be flexible and adaptive, with clear definition of all endpoints. Health authorities should be consulted early and regularly. Strategies such as randomization, intrapatient dose escalation, and real-world eligibility criteria are encouraged whereas serial tumor sampling is discouraged in the absence of a strong rationale and appropriately validated assay. Endpoints should include consideration of all longitudinal toxicity. The phase I dose escalation trial should define the recommended dose range for later testing in randomized phase II trials, rather than a single recommended phase II dose, and consider scenarios where different populations may require different dosages. The adoption of these recommendations will improve dosage selection in early clinical trials of new anticancer treatments and ultimately, outcomes for patients., (Copyright © 2022 European Society for Medical Oncology. All rights reserved.)

Background: The increased number of cancer survivors and the recognition of physical and psychosocial challenges, present from cancer diagnosis through active treatment and beyond, led to the discipline of cancer survivorship., Design and Methods: Herein, we reflected on the different components of survivorship care, existing models and priorities, in order to facilitate the promotion of high-quality European survivorship care and research., Results: We identified five main components of survivorship care: (i) physical effects of cancer and chronic medical conditions; (ii) psychological effects of cancer; (iii) social, work and financial effects of cancer; (iv) surveillance for recurrences and second cancers; and (v) cancer prevention and overall health and well-being promotion. Survivorship care can be delivered by structured care models including but not limited to shared models integrating primary care and oncology services. The choice of the care model to be implemented has to be adapted to local realities. High-quality care should be expedited by the generation of: (i) focused and shared European recommendations, (ii) creation of tools to facilitate implementation of coordinated care and (iii) survivorship educational programs for health care teams and patients. The research agenda should be defined with the participation of health care providers, researchers, policy makers, patients and caregivers. The following patient-centered survivorship research areas were highlighted: (i) generation of a big data platform to collect long-term real-world data in survivors and healthy controls to (a) understand the resources, needs and preferences of patients with cancer, and (b) understand biological determinants of survivorship issues, and (ii) develop innovative effective interventions focused on the main components of survivorship care., Conclusions: The European Society for Medical Oncology (ESMO) can actively contribute in the efforts of the oncology community toward (a) promoting the development of high-quality survivorship care programs, (b) providing educational material and (c) aiding groundbreaking research by reflecting on priorities and by supporting research networking., (Copyright © 2022 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Background: As management and prevention strategies against COVID-19 evolve, it is still uncertain whether prior exposure to immune checkpoint inhibitors (ICIs) affects COVID-19 severity in patients with cancer., Methods: In a joint analysis of ICI recipients from OnCovid (NCT04393974) and European Society for Medical Oncology (ESMO) CoCARE registries, we assessed severity and mortality from SARS-CoV-2 in vaccinated and unvaccinated patients with cancer and explored whether prior immune-related adverse events (irAEs) influenced outcome from COVID-19., Findings: The study population consisted of 240 patients diagnosed with COVID-19 between January 2020 and February 2022 exposed to ICI within 3 months prior to COVID-19 diagnosis, with a 30-day case fatality rate (CFR 30 ) of 23.6% (95% CI 17.8 to 30.7%). Overall, 42 (17.5%) were fully vaccinated prior to COVID-19 and experienced decreased CFR 30 (4.8% vs 28.1%, p=0.0009), hospitalization rate (27.5% vs 63.2%, p<0.0001), requirement of oxygen therapy (15.8% vs 41.5%, p=0.0030), COVID-19 complication rate (11.9% vs 34.6%, p=0.0040), with a reduced need for COVID-19-specific therapy (26.3% vs 57.9%, p=0.0004) compared with unvaccinated patients. Inverse probability of treatment weighting (IPTW)-fitted multivariable analysis, following a clustered-robust correction for the data source (OnCovid vs ESMO CoCARE), confirmed that vaccinated patients experienced a decreased risk of death at 30 days (adjusted OR, aOR 0.08, 95% CI 0.01 to 0.69).Overall, 38 patients (15.8%) experienced at least one irAE of any grade at any time prior to COVID-19, at a median time of 3.2 months (range 0.13-48.7) from COVID-19 diagnosis. IrAEs occurred independently of baseline characteristics except for primary tumor (p=0.0373) and were associated with a significantly decreased CFR 30 (10.8% vs 26.0%, p=0.0462) additionally confirmed by the IPTW-fitted multivariable analysis (aOR 0.47, 95% CI 0.33 to 0.67). Patients who experienced irAEs also presented a higher median absolute lymphocyte count at COVID-19 (1.4 vs 0.8 10 9  cells/L, p=0.0098)., Conclusion: Anti-SARS-CoV-2 vaccination reduces morbidity and mortality from COVID-19 in ICI recipients. History of irAEs might identify patients with pre-existing protection from COVID-19, warranting further investigation of adaptive immune determinants of protection from SARS-CoV-2., Competing Interests: Competing interests: KJH declares research funding from AstraZeneca, Boehringer-Ingelheim, MSD, Replimune and advisory board fees/honoraria from Arch Oncology, AstraZeneca, BMS, Boehringer-Ingelheim, Codiak Biosciences, Inzen Therapeutics, Merck-Serono, MSD, Pfizer, Replimune. DA reports consultation/advisory role for AstraZeneca, Bristol Myers Squibb, Merck Sharp reports speaker’s engagement from AstraZeneca, Bristol Myers Squibb, Merck Sharp reports serving as local PI for Bristol Myers Squibb, Pierre Fabre Pharma and coordinating PI for OncoLytics; reports grant funding from AbbVie; reports being/been DSMB chair of Sanofi (Genzyme); reports being/been a steering committee member of Roche. Olivier Michielin reports personal fees from Bristol-Myers Squibb, MSD, Novartis, Roche, Amgen, NeraCare, outside the submitted work. JR received speaker or advisory fees from Roche, Astra Zeneca, Merck, Ferrer, Persan Farma, Teva Pharma, Leo Pharma, Fresenius kabi, MSD, BMS. Travel expenses support from BMS, MSD, RocheUrania Dafni reports honorarium as Member of the Tumor Agnostic Evidence Generation Working Group of Roche, outside the submitted work. GP reports grants from Amgen, Lilly; grants, personal fees and nonfinancial support from Merck; grants and non-financial support from AstraZeneca; grants and personal fees from Roche, Bristol Myers Squibb, MSD, Novartis, outside the submitted work. Solange Peters reports consultation/advisory role for AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Biocartis, Bio Invent, Blueprint Medicines, Boehringer Ingelheim, Bristol- Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, Elsevier, F Hoffmann-La Roche/Genentech, Foundation Medicine, Illumina, Incyte, IQVIA, Janssen, Medscape, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Novartis, Pharma Mar, Phosplatin Therapeutics, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda, Vaccibody; talk in a company’s organized public event for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, e-cancer, Eli Lilly, F. Hoffmann-La Roche/Genentech, Illumina, Medscape, Merck Sharp and Dohme, Novartis, PER, Pfizer, Prime, RTP, Sanofi, Takeda; receipt of grants/research supports from being a (sub)investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, F Hoffmann-La Roche/Genentech, GSK, Illumina, Lilly, Merck Sharp and Dohme, Merck Serono, Mirati, Novartis, and Pfizer, Phosplatin Therapeutics. Emanuela Rromano reports investigator-initiated trial (funds paid to the institution) supported by Astra-Zeneca, BMS; serves on the consultancy/advisory board for Astra-Zeneca, Merck, Roche, Pierre Fabre. ML acted as consultant for Roche, Novartis, Lilly, AstraZeneca, Exact Sciences, MSD, Pfizer, Seagen and received speaker honoraria from Roche, Novartis, Lilly, Pfizer, Takeda, Ipsen and Sandoz outside the submitted work.Alessandra Gennari has declared consulting/advisory role for Roche, MSD, Eli Lilly, Pierre Fabre, EISAI, and Daichii Sankyo; speakers bureau for Eisai, Novartis, Eli Lilly, Roche, Teva, Gentili, Pfizer, Astra Zeneca, Celgene, and Daichii Sankyo; research funds: EISAI, Eli Lilly, and Roche. CMV has received travel grants and other honoraria from BMS, MSD, Novartis and Roche. Joan Brunet has declared consulting/advisory role for MSD and Astra Zeneca. Aleix Prat has declared personal honoraria from Pfizer, Roche, MSD Oncology, Eli Lilly, and Daiichi Sankyo; travel, accommodations, and expenses paid by Daiichi Sankyo; research funding from Roche and Novartis; and consulting/advisory role for NanoString Technologies, Amgen, Roche, Novartis, Pfizer and Bristol-Myers Squibb. Mark Bower received speakers’ fee from EISAI pharma, Gilead Sciences, Merck and ViiV. JT reports consulting fees from Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F Hoffmann-La Roche, Genentech, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Scandion Oncology, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, and TheraMyc; speaker’s fees from Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education, and Physicians Education Resource; and institutional research support from Amgen, Array Biopharma, AstraZeneca Pharmaceuticals, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International, F Hoffmann-La Roche, Genentech, HalioDX, Hutchison MediPharma International, Janssen-Cilag, MedImmune, Menarini, Merck Health, Merck Sharp and has had leadership roles in the European AIDS Clinical Society, UNAIDS, WHO, and The European Hematology Association/ European Society of Medical Oncology. DJP received lecture fees from ViiV Healthcare, Bayer Healthcare, BMS, Roche, EISAI, Falk Foundation, travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, DaVolterra and Astra Zeneca; research funding (to institution) from MSD and BMS. AC received consulting fees from MSD, BMS, AstraZeneca, Roche; speakers’ fee from AstraZeneca, MSD, Novartis and Eisai. All remaining authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: ESMO COVID-19 and CAncer REgistry (ESMO-CoCARE) is an international collaborative registry-based, cohort study gathering real-world data from Europe, Asia/Oceania and Africa on the natural history, management and outcomes of patients with cancer infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)., Patients and Methods: ESMO-CoCARE captures information on patients with solid/haematological malignancies, diagnosed with coronavirus disease 2019 (COVID-19). Data collected since June 2020 include demographics, comorbidities, laboratory measurements, cancer characteristics, COVID-19 clinical features, management and outcome. Parameters influencing COVID-19 severity/recovery were investigated as well as factors associated with overall survival (OS) upon SARS-CoV-2 infection., Results: This analysis includes 1626 patients from 20 countries (87% from 24 European, 7% from 5 North African, 6% from 8 Asian/Oceanian centres), with COVID-19 diagnosis from January 2020 to May 2021. Median age was 64 years, with 52% of female, 57% of cancer stage III/IV and 65% receiving active cancer treatment. Nearly 64% patients required hospitalization due to COVID-19 diagnosis, with 11% receiving intensive care. In multivariable analysis, male sex, older age, Eastern Cooperative Oncology Group (ECOG) performance status ≥2, body mass index (BMI) <25 kg/m 2 , presence of comorbidities, symptomatic disease, as well as haematological malignancies, active/progressive cancer, neutrophil-to-lymphocyte ratio (NLR) ≥6 and OnCovid Inflammatory Score ≤40 were associated with COVID-19 severity (i.e. severe/moderate disease requiring hospitalization). About 98% of patients with mild COVID-19 recovered, as opposed to 71% with severe/moderate disease. Advanced cancer stage was an additional adverse prognostic factor for recovery. At data cut-off, and with median follow-up of 3 months, the COVID-19-related death rate was 24.5% (297/1212), with 380 deaths recorded in total. Almost all factors associated with COVID-19 severity, except for BMI and NLR, were also predictive of inferior OS, along with smoking and non-Asian ethnicity., Conclusions: Selected patient and cancer characteristics related to sex, ethnicity, poor fitness, comorbidities, inflammation and active malignancy predict for severe/moderate disease and adverse outcomes from COVID-19 in patients with cancer., Competing Interests: Disclosure MS was financed by the Ministry of Science and Higher Education of the Russian Federation within the framework of state support for the creation and development of World-Class Research Centers ‘Digital biodesign and personalized healthcare’ number 075-15-2020-926. DV reports travel, accommodations and expenses from Merk; honoraria for speakers bureau from Servier. RL reports speaker fee Astra Zeneca and institutional funding from BMS. ACr reports consulting or advisory role with Ipsen, Astellas, Pfizer, MSD Oncology Research (funding to self and hospital), Bristol-Myers Squibb, Merck (only hospital), Astellas, Amgen, Exelixis, Merck KGaA; and travel accommodations from Merck and Servier. SŠ reports honoraria and/or advisory fees from Roche, Pfizer, Novartis, Astra Zeneca and Amicus. MR received travel and personal fees from Novartis and Ipsen. TAG reports honoraria and/or advisory fees from IPSEN, Pfizer, Bayer, Sanofi, Janssen, Astellas, Adacap, Eisai, Lilly, Novartis, BMS. TKC reports institutional and personal, paid and unpaid support for research, advisory boards, consultancy and honoraria from AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers-Squibb, Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, NiKang, Nuscan, Novartis, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, Up-To-Date, CME events (PeerView, OncLive, MJH and others), outside the submitted work; institutional patents filed on molecular mutations and immunotherapy response and ctDNA; equity in Tempest, Pionyr, Osel, Nuscan; serves on committees for NCCN, GU Steering Committee and ASCO/ESMO; Medical writing and editorial assistance support may have been funded by communications companies in part; no speaker’s bureau; has mentored several non-United States citizens on research projects with potential funding (in part) from non-United States sources/Foreign components; the institution (Dana-Farber Cancer Institute) may have received additional independent funding of drug companies or/and royalties potentially involved in research around the subject matter. TKC is supported in part by the Dana-Farber/Harvard Cancer Center Kidney SPORE (2P50CA101942-16) and Program 5P30CA006516-56, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham and Loker Pinard Funds for Kidney Cancer Research at DFCI. s provided upon request for scope of clinical practice and research. DA reports consultation/advisory role for AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Sanofi (Genzyme), Bayer, Terumo, Roche, Hexal, Samsung Bioepis, Pierre Fabre Pharma, CRA International, Ketchum, IQVIA; reports speaker’s engagement from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Sanofi (Genzyme), Bayer, Eli Lilly, Terumo, Boston Scientific, Amgen, Roche, Ipsen, Merck (Serono), Samsung Bioepis, Pierre Fabre Pharma, Servier, PharmaCept, PRMA Consulting, Tactics MD LLC, WebMD Health Corp, From Research to Practice, Aptitude Health, art tempi media, ACE Oncology, Imedex, streamitup Germany, MedAhead (Austria), Clinical Care Options (CCO); reports serving as local PI for Bristol Myers Squibb, Pierre Fabre Pharma and coordinating PI for OncoLytics; reports grant funding from AbbVie; reports being/been DSMB chair of Sanofi (Genzyme); reports being/been a steering committee member of Roche. KH declares research funding from AstraZeneca, Boehringer-Ingelheim, MSD, Replimune and advisory board fees/honoraria from Arch Oncology, AstraZeneca, BMS, Boehringer-Ingelheim, Codiak Biosciences, Inzen Therapeutics, Merck-Serono, MSD, Pfizer, Replimune. OM reports personal fees from Bristol-Myers Squibb, MSD, Novartis, Roche, Amgen, NeraCare GmbH, outside the submitted work. UD reports honorarium as Member of the Tumor Agnostic Evidence Generation Working Group of Roche, outside the submitted work. GP reports grants from Amgen, Lilly; grants, personal fees and nonfinancial support from Merck; grants and non-financial support from AstraZeneca; grants and personal fees from Roche, Bristol Myers Squibb, MSD, Novartis, outside the submitted work. SPe reports consultation/advisory role for AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Biocartis, Bio Invent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, Elsevier, F. Hoffmann-La Roche/Genentech, Foundation Medicine, Illumina, Incyte, IQVIA, Janssen, Medscape, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Novartis, Pharma Mar, Phosplatin Therapeutics, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda, Vaccibody; talk in a company’s organized public event for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, e-cancer, Eli Lilly, F. Hoffmann-La Roche/Genentech, Illumina, Medscape, Merck Sharp and Dohme, Novartis, PER, Pfizer, Prime, RTP, Sanofi, Takeda; receipt of grants/research supports from being a (sub)investigator in trials (institutional financial support for clinical trials) sponsored by Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, F. Hoffmann-La Roche/Genentech, GSK, Illumina, Lilly, Merck Sharp and Dohme, Merck Serono, Mirati, Novartis, and Pfizer, Phosplatin Therapeutics. ER reports investigator-initiated trial (funds paid to the institution) supported by Astra-Zeneca, BMS; serves on the consultancy/advisory board for Astra-Zeneca, Merck, Roche, Pierre Fabre. All other authors have declared no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Patients with cancer are at increased risk of severe COVID-19 disease, but have heterogeneous presentations and outcomes. Decision-making tools for hospital admission, severity prediction, and increased monitoring for early intervention are critical. We sought to identify features of COVID-19 disease in patients with cancer predicting severe disease and build a decision support online tool, COVID-19 Risk in Oncology Evaluation Tool (CORONET)., Methods: Patients with active cancer (stage I-IV) and laboratory-confirmed COVID-19 disease presenting to hospitals worldwide were included. Discharge (within 24 hours), admission (≥ 24 hours inpatient), oxygen (O 2 ) requirement, and death were combined in a 0-3 point severity scale. Association of features with outcomes were investigated using Lasso regression and Random Forest combined with Shapley Additive Explanations. The CORONET model was then examined in the entire cohort to build an online CORONET decision support tool. Admission and severe disease thresholds were established through pragmatically defined cost functions. Finally, the CORONET model was validated on an external cohort., Results: The model development data set comprised 920 patients, with median age 70 (range 5-99) years, 56% males, 44% females, and 81% solid versus 19% hematologic cancers. In derivation, Random Forest demonstrated superior performance over Lasso with lower mean squared error (0.801 v 0.807) and was selected for development. During validation (n = 282 patients), the performance of CORONET varied depending on the country cohort. CORONET cutoffs for admission and mortality of 1.0 and 2.3 were established. The CORONET decision support tool recommended admission for 95% of patients eventually requiring oxygen and 97% of those who died (94% and 98% in validation, respectively). The specificity for mortality prediction was 92% and 83% in derivation and validation, respectively. Shapley Additive Explanations revealed that National Early Warning Score 2, C-reactive protein, and albumin were the most important features contributing to COVID-19 severity prediction in patients with cancer at time of hospital presentation., Conclusion: CORONET, a decision support tool validated in health care systems worldwide, can aid admission decisions and predict COVID-19 severity in patients with cancer., Competing Interests: Rebecca J. LeeSpeakers' Bureau: AstraZenecaResearch Funding: Bristol Myers Squibb (Inst), AstraZeneca/MedImmune (Inst) Rohan ShottonHonoraria: ServierTravel, Accommodations, Expenses: Servier Laurence AlbigesConsulting or Advisory Role: Bristol Myers Squibb (Inst), Ipsen (Inst), Roche (Inst), Novartis (Inst), Pfizer (Inst), Astellas Pharma (Inst), Merck (Inst), MSD (Inst), AstraZeneca (Inst), Janssen (Inst), Eisai (Inst), Corvus Pharmaceuticals (Inst), Bellerophon Therapeutics (Inst)Research Funding: Bristol Myers Squibb (Inst)Travel, Accommodations, Expenses: BMS, MSD Dirk ArnoldEmployment: Asklepios KlinikenHonoraria: Bayer, Merck Serono, Roche/Genentech, Servier, Bristol Myers Squibb, Merck Sharp and Dome, AstraZeneca, Amgen, Boston Scientific, Pierre Fabre, IpsenConsulting or Advisory Role: Bayer, Merck Serono, Biocompatibles, Terumo, Bristol Myers Squibb, MSD Oncology, AstraZenecaResearch Funding: Roche/Genentech (Inst), Sanofi (Inst), Oncolytics (Inst)Travel, Accommodations, Expenses: Boston ScientificUncompensated Relationships: ESMO Council, ESMO Journals (Ann Oncol, ESMO Open), German Society for Hematology and Medical Oncology, German Cancer Society, European Organisation for Research and Treatment of Cancer (EORTC) Kathryn BanfillStock and Other Ownership Interests: Roche (I)Honoraria: AstraZeneca Mark BaxterHonoraria: IpsenTravel, Accommodations, Expenses: Ipsen Fabrice BarlesiHonoraria: Genentech/Roche, Pfizer, Pierre Fabre, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Lilly, Novartis, Merck Serono, MSD Oncology, Takeda, Bayer, Seattle Genetics, Mirati TherapeuticsConsulting or Advisory Role: Roche/Genentech, Pfizer, Novartis, Pierre Fabre, Bristol Myers Squibb, AstraZeneca/MedImmune, Boehringer Ingelheim, Lilly, Merck Serono, MSD Oncology, Takeda, Bayer, Mirati TherapeuticsResearch Funding: Roche/Genentech (Inst), AstraZeneca/MedImmune (Inst), Bristol Myers Squibb (Inst), Pierre Fabre (Inst), AbbVie (Inst), Amgen (Inst), Bayer (Inst), Boehringer Ingelheim (Inst), Eisai (Inst), Lilly (Inst), Ipsen (Inst), Innate Pharma (Inst), Novartis (Inst), Merck Serono (Inst), MSD Oncology (Inst), Pfizer (Inst), Sanofi/Aventis (Inst), Takeda (Inst)Travel, Accommodations, Expenses: Roche/Genentech, Bristol Myers Squibb, AstraZeneca/MedImmune, MSD Oncology Benjamin BesseResearch Funding: AstraZeneca (Inst), Pfizer (Inst), Lilly (Inst), Onxeo (Inst), Inivata (Inst), AbbVie (Inst), Amgen (Inst), Blueprint Medicines (Inst), Celgene (Inst), GlaxoSmithKline (Inst), Sanofi (Inst), Takeda (Inst), Cristal Therapeutics (Inst), Daiichi Sankyo (Inst), Janssen Oncology (Inst), OSE Immunotherapeutics (Inst), BeiGene (Inst), Boehringer Ingelheim (Inst), Roche/Genentech (Inst), Tolero Pharmaceuticals (Inst), 4D Pharma (Inst), Aptitude Health (Inst), Cergentis (Inst), Chugai Pharma (Inst), Genzyme (Inst), Ipsen (Inst), Turning Point Therapeutics (Inst), Eisai (Inst) Antonio CallesHonoraria: AstraZeneca, Boehringer Ingelheim, Pfizer, Roche/Genentech, Lilly, Novartis, Merck Sharp & Dohme, Bristol Myers Squibb, Amgen, Bayer, Takeda, Sanofi/RegeneronConsulting or Advisory Role: Boehringer Ingelheim, Roche/Genentech, Lilly, Merck Sharp & Dohme, Novartis, Pfizer, Bristol Myers Squibb, Takeda, Igen Biotech, Sanofi/RegeneronResearch Funding: MSD Oncology Ellen CopsonHonoraria: Roche, Pfizer, AstraZeneca, Lilly, NovartisConsulting or Advisory Role: Lilly, NanoString Technologies, Pfizer, Sanofi/Aventis, RocheSpeakers' Bureau: Roche, Pfizer, AstraZeneca, Sanofi/AventisResearch Funding: SECA, AstraZeneca (Inst)Travel, Accommodations, Expenses: Roche, AstraZeneca Adina E. CroitoruConsulting or Advisory Role: Ipsen, Pfizer, MSD OncologyResearch Funding: Bristol Myers Squibb (Inst), Amgen (Inst), Astellas Pharma (Inst), Exelixis (Inst), Merck (Inst), Merck KGaA (Inst)Travel, Accommodations, Expenses: Merck, ServierUncompensated Relationships: Lilly, Roche, Bayer, Pfizer, Sanofi Leonie EastlakeTravel, Accommodations, Expenses: Servier Paul FitzpatrickStock and Other Ownership Interests: AstraZeneca/MedImmuneResearch Funding: AstraZeneca/MedImmune (Inst)Other Relationship: Pistoia Alliance, EHDEN IMI project Henrik FrederiksenResearch Funding: AbbVie (Inst), Gilead Sciences (Inst), Sanofi (Inst) Hannah FrostResearch Funding: AstraZeneca (Inst) Sarju GanatraExpert Testimony: Haymarket Medical EducationTravel, Accommodations, Expenses: Haymarket Medical Education Andreas GlenthøjHonoraria: Novo NordiskConsulting or Advisory Role: Novartis, Celgene/Bristol Myers Squibb, Bluebird Bio, Sanofi, Novo Nordisk, AgiosResearch Funding: Sanofi, Saniona A/STravel, Accommodations, Expenses: Agios Fabio GomesHonoraria: AstraZeneca, Merck Serono, Roche Donna M. GrahamConsulting or Advisory Role: Clinigen GroupSpeakers' Bureau: Cancer Drug Development ForumResearch Funding: Pfizer (Inst) Kevin HarringtonHonoraria: Arch Oncology (Inst), AstraZeneca (Inst), BMS (Inst), Boehringer Ingelheim (Inst), Merck Serono (Inst), MSD (Inst), Oncolys BioPharma (Inst), Pfizer (Inst), Replimune (Inst), Inzen Therapeutics (Inst), Codiak Biosciences (Inst)Consulting or Advisory Role: Arch Oncology (Inst), AstraZeneca (Inst), BMS (Inst), Boehringer Ingelheim (Inst), Merck Serono (Inst), MSD (Inst), Oncolys BioPharma (Inst), Replimune (Inst), Inzen Therapeutics (Inst)Speakers' Bureau: BMS (Inst), Merck Serono (Inst), MSD (Inst)Research Funding: AstraZeneca (Inst), Merck Sharp & Dohme (Inst), Replimune (Inst), Boehringer Ingelheim (Inst) Lasse H. JakobsenHonoraria: Takeda, Roche Khurum KhanHonoraria: ServierConsulting or Advisory Role: Bayer Health Christophe MassardConsulting or Advisory Role: Amgen, Astellas Pharma, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm Group, Genentech/Roche, Ipsen, Janssen, Lilly, MSD, Novartis, Pfizer, Sanofi, ORION, Taiho Pharmaceutical, Blueprint Medicines, Innate Pharma, PharmaMar, Faron Pharmaceuticals Olivier MichielinConsulting or Advisory Role: Bristol Myers Squibb, MSD, Novartis, Roche, Amgen, Pierre FabreResearch Funding: MSD, Bristol Myers Squibb, NeraCare GmbHExpert Testimony: Bristol Myers SquibbTravel, Accommodations, Expenses: Bristol Myers Squibb, MSD Anne C. MosenthalHonoraria: Springer Nature Berta ObispoHonoraria: Sanofi, Lilly, Angelini, LEO Pharma, RoviConsulting or Advisory Role: Rovi George PentheroudakisHonoraria: Roche, Amgen, Bristol Myers Squibb, MSD, MerckConsulting or Advisory Role: Roche, AmgenResearch Funding: Roche (Inst), Amgen (Inst), Bristol Myers Squibb (Inst), Merck (Inst), AstraZeneca (Inst), Novartis (Inst), Pfizer (Inst)Travel, Accommodations, Expenses: Sanofi, MSD, Roche, Amgen, BMS Solange PetersHonoraria: Roche (Inst), Bristol Myers Squibb (Inst), Novartis (Inst), Pfizer (Inst), MSD (Inst), AstraZeneca (Inst), Takeda (Inst), Illumina (Inst), Medscape (Inst), Prime Oncology (Inst), RMEI Medical Education (Inst), Research to Practice (Inst), PER (Inst), Imedex (Inst), ecancer (Inst)Consulting or Advisory Role: Roche/Genentech (Inst), Novartis (Inst), Bristol Myers Squibb (Inst), Pfizer (Inst), MSD (Inst), Amgen (Inst), AstraZeneca (Inst), Janssen (Inst), Regeneron (Inst), Merck Serono (Inst), Boehringer Ingelheim (Inst), Takeda (Inst), Lilly (Inst), AbbVie (Inst), Bayer (Inst), Biocartis (Inst), Debiopharm Group (Inst), Illumina (Inst), PharmaMar (Inst), Sanofi (Inst), Seattle Genetics (Inst), Blueprint Medicines (Inst), Daiichi Sankyo (Inst), Incyte (Inst), Bioinvent (Inst), Clovis Oncology (Inst), Vaccibody (Inst), Phosplatin Therapeutics (Inst), Foundation Medicine (Inst)Research Funding: Roche (Inst), BMS (Inst), MSD (Inst), Amgen (Inst), Lilly (Inst), AstraZeneca (Inst), Pfizer (Inst), Illumina (Inst), Merck Serono (Inst), Novartis (Inst), Biodesix (Inst), Boehringer Ingelheim (Inst), Iovance Biotherapeutics (Inst), Phosplatin Therapeutics (Inst)Travel, Accommodations, Expenses: Roche, Bristol Myers Squibb, MSD, Sanofi, IncyteUncompensated Relationships: Journal of Thoracic Oncology, ESMO, European Thoracic Oncology Platform (ETOP), Annals of Oncology (I) Kimberly Rieger-ChristResearch Funding: Veracyte, Ravel, Grail, Exact Sciences, Nucleix Timothy RobinsonTravel, Accommodations, Expenses: Daiichi Sankyo/Lilly Emanuela RomanoConsulting or Advisory Role: AstraZeneca/MedImmune (Inst), Bristol Myers Squibb (Inst), Roche/Genentech (Inst)Research Funding: Bristol Myers Squibb, AmgenTravel, Accommodations, Expenses: AstraZeneca/MedImmune, Bristol Myers Squibb, Roche Michael RoweHonoraria: MSDSpeakers' Bureau: ServierTravel, Accommodations, Expenses: Astellas Pharma Anne ThomasConsulting or Advisory Role: BMSSpeakers' Bureau: Bristol Myers SquibbExpert Testimony: BMS Lance TurtleSpeakers' Bureau: Eisai (Inst) David ViñalSpeakers' Bureau: ServierTravel, Accommodations, Expenses: Merck Caroline WilsonConsulting or Advisory Role: Roche, Pfizer Carlo PalmieriHonoraria: PfizerConsulting or Advisory Role: Pfizer, Daiichi-Sankyo, Lilly, Novartis, Seattle GeneticsResearch Funding: Pfizer, Daiichi-SankyoTravel, Accommodations, Expenses: Roche Donal LandersEmployment: AstraZeneca, AthenexLeadership: DeLondra OncologyStock and Other Ownership Interests: DeLondra OncologyResearch Funding: AstraZeneca (Inst) Timothy CooksleyHonoraria: Bristol Myers Squibb Foundation Caroline DiveConsulting or Advisory Role: Biocartis, Merck, AstraZeneca, GRAIL, Boehringer IngelheimResearch Funding: AstraZeneca, Astex Pharmaceuticals, Bioven, Amgen, Carrick Therapeutics, Merck, Taiho Oncology, GlaxoSmithKline, Bayer, Boehringer Ingelheim, Roche, BMS, Novartis, Celgene, Epigene Therapeutics, Angle, Menarini, Clearbridge Biomedics, Thermo Fisher Scientific, NeoMed André FreitasResearch Funding: AstraZeneca (Inst) Anne C. ArmstrongStock and Other Ownership Interests: AstraZeneca (I)Consulting or Advisory Role: Gilead Sciences, MSDResearch Funding: AstraZeneca/MedImmune (Inst)Travel, Accommodations, Expenses: Gilead Sciences, MSD OncologyNo other potential conflicts of interest were reported.

Inflammation is an established driver of severe SARS-CoV-2 infection and a mechanism linked to the increased susceptibility to fatal COVID-19 demonstrated by patients with cancer. As patients with cancer exhibit a higher level of inflammation compared with the general patient population, patients with cancer and COVID-19 may uniquely benefit from strategies targeted at overcoming the unrestrained pro-inflammatory response. Targeted and non-targeted anti-inflammatory therapies may prevent end-organ damage in SARS-CoV-2-infected patients with cancer and decrease mortality. Here, we review the clinical role of selective inhibition of pro-inflammatory interleukins, tyrosine kinase modulation, anti-tumor necrosis factor agents, and other non-targeted approaches including corticosteroids in their roles as disease-modulating agents in patients with COVID-19 and cancer. Investigation of these therapeutics in this highly vulnerable patient group is posited to facilitate the development of tailored therapeutics for this patient population, aiding the transition of systemic inflammation from a prognostic domain to a source of therapeutic targets., Competing Interests: Disclosure DJP has received lecture fees from ViiV Healthcare and Bayer Healthcare; travel expenses from Bristol-Myers Squibb (BMS) and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, and AstraZeneca; and received research funding (to institution) from Merck Sharp & Dohme (MSD) and BMS. AC has received lecture fees from AstraZeneca, MSD, Novartis, and Astellas and consulting fees/advisory board grants from AstraZeneca, MSD, Roche, and BMS. AG has declared consulting/advisory roles for Roche, MSD, Eli Lilly, Pierre Fabre, EISAI, and Daichii Sankyo; speakers bureau for Eisai, Novartis, Eli Lilly, Roche, Teva, Gentili, Pfizer, AstraZeneca, Celgene, and Daichii Sankyo; research funds from EISAI, Eli Lilly, and Roche. GP has received advisory board fees from Amgen, AstraZeneca, BMS, Lilly, Merck, MSD, Roche and research funding (to institution) from Amgen, Abbvie, Boehringer, AstraZeneca, BMS, Lilly, Merck, MSD, Roche, Debiopharm, Ipsen, Pfizer, Servier. ER received research funding from Amgen, AstraZeneca, and BMS; travel expenses from Astra Zeneca, BMS, Merck, and Roche. All other authors have declared no conflicts of interest., (Copyright © 2021 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.)

We established an international consortium to review and discuss relevant clinical evidence in order to develop expert consensus statements related to cancer management during the severe acute respiratory syndrome coronavirus 2-related disease (COVID-19) pandemic. The steering committee prepared 10 working packages addressing significant clinical questions from diagnosis to surgery. During a virtual consensus meeting of 62 global experts and one patient advocate, led by the European Society for Medical Oncology, statements were discussed, amended and voted upon. When consensus could not be reached, the panel revised statements until a consensus was reached. Overall, the expert panel agreed on 28 consensus statements that can be used to overcome many of the clinical and technical areas of uncertainty ranging from diagnosis to therapeutic planning and treatment during the COVID-19 pandemic., Competing Interests: Disclosures AA reports personal fees from BMS, AstraZeneca, MSD, Pfizer, Roche, Takeda and Boehringer outside the submitted work. LA reports other from BMS, MSD, Novartis, Amgen, Ipsen, Roche, Pfizer, Merck, AstraZeneca, Exelixis, Peloton Therapeutics and Corvus Pharmaceuticals outside the submitted work. PAA reports grants and personal fees from BMS, Roche Genentech and Array outside the submitted work; personal fees from MSD, Novartis, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Syndax, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, and Eisai outside the submitted work; advisory role with Boehringer Ingelheim outside the submitted work. SB reports grants and personal fees from AstraZeneca/MedImmune and GSK/Tesaro outside the submitted work; personal fees from Amgen, Clovis, Mersana, Seattle Genetics, Genmabs, Merck Serono, Roche and Immunogen outside the submitted work. FB reports personal fees from AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd., Novartis, Merck, MSD, Pierre Fabre, Pfizer and Takeda outside the submitted work. CCa is a member of AstraZeneca's IMED External Science Panel, a member of Illumina's Scientific Advisory Board and a recipient of research grants (administered by the University of Cambridge) from Genentech, Roche, AstraZeneca and Servier. FC reports personal fees from Amgen, Astellas/Medivation, AstraZeneca, Celgene, Daiichi Sankyo, Eisai, GE Oncology, Genentech, GSK, MacroGenics, Medscape, MSD, Merus BV, Mylan, Mundipharma, Novartis, Pfizer, Pierre Fabre, prIME Oncology, Roche, Samsung Bioepis, Sanofi, Seattle Genetics and Teva outside the submitted work. AC reports grants, personal fees and other from Merck Serono, Servier, Roche, Lilly, Novartis, Takeda, Astellas and Bayer outside the submitted work; personal fees and other from Pierre Fabre, Amgen and Foundation Medicine outside the submitted work; grants from Genentech, FibroGen, Amcure, Sierra Oncology, AstraZeneca, MedImmune, BMS, MSD, AbbVie, Theradex, Array, Tesaro and Johnson & Johnson outside the submitted work. TKC reports grants, personal fees, non-financial support and other from BMS, Exelixis, Pfizer, (during the conduct of the study), Merck, BMS, Exelixis, AstraZeneca, Lilly, Eisai, Novartis, GSK, Lilly, Pfizer and EMD Serono outside the submitted work; has a patent null pending and stock ownership in Pionyr and Tempest; has received travel, accommodations and expenses in relation to consulting, advisory roles and clinical trials; medical writing and editorial assistance support may have been provided by communications companies funded by pharmaceutical companies; the institution (Dana Farber Cancer Institute) may have received additional independent funding from drug companies and/or royalties potentially involved in research around the subject matter; is a member of the NCCN kidney panel. MLKC reports personal fees from Janssen, Astellas, MSD Oncology, Bayer and Illumina outside the submitted work; personal fees and non-financial support from AstraZeneca and Varian outside the submitted work; non-financial support from PV Med and Decipher Biosciences outside the submitted work. CC reports personal fees from Pfizer, Novartis, Eli Lilly and Roche outside the submitted work. GC reports grants from Roche and Pfizer outside the submitted work; personal fees from Daiichi Sankyo, MSD and AstraZeneca outside the submitted work. EdA reports personal fees from Roche/Genentech, Novartis, Seattle Genetics and Zodiac; other from Roche/Genentech and GSK/Novartis; grants from AstraZeneca, GSK/Novartis, Roche/Genentech and Servier outside the submitted work. DDR reports advisory boards and grants from BMS, AstraZeneca, Boehringer Ingelheim, Celgene, Seattle Genetics, Roche/Genentech and Merck/Pfizer outside the submitted work; other from Philips and Olink outside the submitted work. EDV reports institutional financial support for her advisory role from Daiichi Sankyo, Merck, NSABP, Pfizer, Sanofi and Synthon outside the submitted work; institutional financial support for clinical trials or contracted research from Amgen, AstraZeneca, Bayer, Chugai Pharma, CytomX Therapeutics, G1 Therapeutics, Genentech, Nordic Nanovector, Radius Health, Regeneron, Roche and Synthon outside the submitted work. RDe reports personal fees from AstraZeneca, Roche, MSD, Eisai, Pfizer and Novartis outside the submitted work. RDz reports personal fees and non-financial support from Roche and AstraZeneca outside the submitted work; personal fees from Novartis, Pfizer, Takeda, Seattle Genetics, Foundation Medicine and MSD outside the submitted work. CF-F reports grants and other from AstraZeneca and Elekta outside the submitted work. EF reports personal fees from AbbVie, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, BMS, Eli Lilly, Guardant Health, Janssen, Medscape, Merck KGaA, MSD, Novartis, Pfizer, prIME Oncology, Roche, Samsung, Takeda, TouchIME, GSK and Bayer outside the submitted work; grants from Grant For Oncology Innovation (GOI) and Fundación Merck Salud outside the submitted work; is an independent board member of Grifols. MG reports grants and personal fees from Eli Lilly, Otsuka Pharma, AstraZeneca, Novartis, BMS, Roche, Pfizer, Celgene, Incyte, Bayer, MSD, GSK, Spectrum Pharmaceuticals, Blueprint Medicine and Boehringer Ingelheim outside the submitted work; personal fees from Seattle Genetics, Daiichi Sankyo, Janssen, Inivata, Takeda and Sanofi Aventis outside the submitted work; grants from United Therapeutics Corporation, Merck KGaA, Turning Point, Ipsen, MedImmune, Exelisis, Tiziana Sciences, Clovis and Merck Serono outside the submitted work; non-financial support from MSD, Pfizer and Eli Lilly outside the submitted work. PG reports personal fees from Roche, from MSD, BMS, Boehringer Ingelheim, Pfizer, AbbVie, Novartis, Lilly, AstraZeneca, Janssen, Blueprint Medicines, Takeda, Gilead and ROVI outside the submitted work. JH reports grants and other from BMS, MSD, Novartis, BioNTech and Amgen outside the submitted work; other from Achilles Therapeutics, GSK, Immunocore, Ipsen, Merck Serono, Molecular Partners, Pfizer, Roche/Genentech, Sanofi, Seattle Genetics, Third Rock Ventures and Vaximm outside the submitted work; personal fees from Neogene Therapeutics outside the submitted work. EH reports grants, non-financial support and other from Lilly, Roche/Genentech, Daiichi Sankyo, AstraZeneca, Eisai and Novartis outside the submitted work; grants and non-financial support from Tesaro, Radius Health, Clovis, Medivation and EMD Serono outside the submitted work; grants and other from Puma Biotechnology, Pfizer, Mersana, Boehringer Ingelheim, Cascadian Therapeutics, Silverback and Black Diamond outside the submitted work; grants from Hutchinson MediPharma, OncoMed, MedImmune, Stem CentRx, Curis, Verastem, Zymeworks, Syndax, Lycera, Rgenix, Millenium, TapImmune, BerGenBio, H3 Biomedicine, Acerta Pharma, Takeda, MacroGenics, AbbVie, Immunomedics, Fujifilm, eFFECTOR Therapeutics, Merus, NuCana, Regeneron, Leap Therapeutics, Taiho Pharmaceutical, EMD Serono, Syros, Clovis, CytomX, InventisBio, Deciphera, ArQule, Sermonix Pharmaceuticals, Sutro Biopharma, Zenith Epigenetics, Arvinas, Torque Therapeutics, Harpoon Therapeutics, Fochon Pharmaceuticals, Orinove, Molecular Templates, Unum Therapeutics, Aravive, Compugen, Dana Farber Cancer Institute, G1 Therapeutics, Karyopharm Therapeutics and Torque Therapeutics outside the submitted work; other from Nanostring; non-financial support from Amgen, Bayer, BMS, Genzyme, Helsinn Therapeutics, HERON, Lexicon, Merck, Roche, Sysmex, Guardant Heallth and Foundation Medicine outside the submitted work. PAJ reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Daiichi Sankyo and Takeda Oncology outside the submitted work; personal fees from Pfizer, Roche/Genentech, Merrimack Pharmaceuticals, Chugai Pharmaceuticals, Araxes Pharma, Ignyta, Mirati Therapeutics, Novartis, Voronoi, SFJ Pharmaceuticals, Biocartis and LOXO Oncology outside the submitted work; grants from Puma and Astellas Pharmaceuticals outside the submitted work; receives post-marketing royalties from DFCI owned intellectual property on EGFR mutations licensed to Lab Corp. KJ reports personal fees from MSD, Merck (USA), Amgen, Helsinn, Riemser, Tesaro, Kreussler, Voluntis, Pfizer, Pomme-med, PharmaMar, ClinSol Research, Hexal, G1 Therapeutics, Shire, prIME Oncology, medupdate, art tempi and UpToDate outside the submitted work. RK reports grants and personal fees from MSD, Janssen, Astellas, Bayer and Pfizer outside the submitted work. SBK has received research funding from Novartis, Sanofi-Aventis, Kyowa-Kirin Inc and DongKook Pharm Co.; has participated as a consultant in advisory boards for Novartis, AstraZeneca, Lilly, Enzychem, Dae Hwa Pharmaceutical Co. Ltd., ISU Abxis and Daiichi-Sankyo. FL reports personal fees from Amgen, Astellas, AstraZeneca, BioNTech, Eli Lilly, Elsevier, Excerpta Medica, Imedex, Infomedica, medupdate, Merck Serono, MSD, Corvus, proMedicis, Springer Nature, streamedup!, Zymeworks, Bayer and Roche outside the submitted work; grants and personal fees from Iomedico and BMS outside the submitted work. JPM reports personal fees from Roche, AstraZeneca, Bayer, Innate, Merck Serono, Boehringer Ingelheim, Novartis, Janssen, Incyte, Cue Biopharma, ALX Oncology and Pfizer outside the submitted work; grants and personal fees from BMS outside the submitted work; other from Amgen, MSD, PsiOxus, Debio and Nanobiotix outside the submitted work. TSKM reports grants, personal fees and other from AstraZeneca outside the submitted work; grants and personal fees from Roche/Genentech, Pfizer, MSD, Novartis, SFJ Pharmaceutical and BMS outside the submitted work; grants from Clovis Oncology, XCovery and G1 Therapeutics Inc. outside the submitted work; non-financial support from GeneDecode outside the submitted work; personal fees from Boehringer Ingelheim, Lilly, Merck Serono, Vertex Pharmaceuticals, Oncogenex, Celgene, Ignyta, Cirina, Fishawack Facilitate, Takeda Oncology, Janssen, OrigiMed, Hengrui Therapeutics, Sanofi-Aventis R&D, Yuhan Corporation, PrIME Oncology, Amoy Diagnostics, Loxo-Oncology, ACEA Pharma, Alpha Biopharma Co. Ltd., CStone Pharmaceuticals, IQVIA, MoreHealth, InMed Medical Communication, Virtus Medical Group, Biolidics Ltd., Bayer, Daiichi Sankyo, Incyte Corporation, Lunit Inc., Mirati Therapeutics Inc. and Gritstone Oncology Inc. outside the submitted work; other from Hutchison ChiMed, Sanomics, ASCO and CSCO outside the submitted work. AP reports honoraria for consulting, advisory role or lectures from AstraZeneca, Agilent/Dako, BMS, Eli Lilly, MSD and Roche Genentech. GP reports grants, personal fees and non-financial support from Merck outside the submitted work; grants and non-financial support from AstraZeneca outside the submitted work; grants and personal fees from Roche, BMS, MSD and Novartis outside the submitted work; grants from Amgen and Lilly outside the submitted work. SP has received educational grants, provided consultation, attended advisory boards and/or provided lectures for AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, BioInvent, Blueprint Medicines, Boehringer Ingelheim, BMS, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, MSD, Merck Serono, Merrimack, Novartis, PharmaMar, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda and Vaccibody, from whom she has received honoraria (all fees to institution). MR reports personal fees from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, GSK, Lilly, Merck, MSD, Novartis, Pfizer, Roche and Samsung Bioepis outside the submitted work. RSS reports attending advisory boards for VCN-BCN, Agendia, Guardant Health, Roche Diagnostics, Ferrer, Pfizer, Novartis, Ipsen, Amgen, Merck, Roche Pharma, Lilly and MSD; speaker's fees from Pfizer, Amgen, Novartis, Merck, MSD, AstraZeneca and Celgene; leadership role and stocks or ownership interest with Sace Medhealth. FS reports financial interests, honoraria for speaker, consultancy or advisory role, royalties and/or direct research funding from Tesaro, Helsinn, Vifor, MSD, Roche, Amgen, Pierre Fabre Oncology, Pfizer, Leo Pharma, Arrow BMS, Mylan and Mundi-Pharma outside of the submitted work. SS reports grants and personal fees from AstraZeneca outside the submitted work; grants from Varian Medical Systems and ViewRay Inc. outside the submitted work; personal fees from MSD and Celgene, outside the submitted work. ES reports personal fees from Astellas, AstraZeneca, BMS, Celgene, Five Prime Therapeutics, Gritstone Oncology, Merck, Servier and Zymeworks outside the submitted work. RS reports grants and personal fees from AstraZeneca and Boehringer Ingelheim outside the submitted work; personal fees from BMS, Eli Lilly, MSD, Novartis, Pfizer, Taiho Pharmaceutical, Takeda, Yuhan and Amgen outside the submitted work. JCS reports personal fees from Abbvie, AstraZeneca, Bayer, Blend Therapeutics, Boeringher Ingelheim, Cytomix, Daiichi Sankyo, Eli Lilly, Genmab, Guardiant Health, Inivata, Merck, Netcancer, Roche, Servier, PharmaMar and Tarveda outside the submitted work; was a full time employee of AstraZeneca from September 2017 to December 2019. FS reports unrestricted research grants from Celgene, Fresenius and Helsinn; participation in company-led clinical trials with Novartis; advisory boards for Helsinn, Mundipharma, Novartis, Fresenius and Kaiku Health. JT reports personal fees from Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael Pharmaceuticals, F. Hoffmann-La Roche Ltd., Sanofi, SeaGen, Seattle Genetics, Servier, Symphogen, Taiho, VCN Biosciences, Biocartis, Foundation Medicine, HalioDX SAS and Roche Diagnostics outside the submitted work. EVC reports grants from Amgen, Bayer, Boehringer Ingelheim, BMS, Celgene, Ipsen, Lilly, MSD, Merck KGaA, Novartis, Roche and Servier; advisory boards for Array, AstraZeneca, Bayer, Biocartis, BMS, Celgene, Daiichi, Halozyme, GSK, Pierre Fabre, Incyte, Ipsen, Lilly, MSD, Merck KGaA, Novartis, Pierre Fabre, Roche, Servier, Sirtex and Taiho outside the submitted work. PEvS reports IASLC board member; treasurer BACTS; external expert for AstraZeneca, MSD and Institut National du Cancer, France (institutional fees). GV reports grants from Associazione Italiana per la Ricerca sul Cancro (AIRC), Ministry of Health and Istituto Nazionale Assicurazione Infortuni sul Lavoro outside the submitted work; honoraria from Ab Medica SpA, Medtronic and Verb Medical. JY reports personal fees from Boehringer Ingelheim, Eli Lilly, Bayer, Roche/Genentech, Chugai Pharmaceutical, MSD, Pfizer, Novartis, BMS, Ono Pharmaceuticals, AstraZeneca, Merck Serono, Celgene, Yuhan Pharmaceuticals, Daiichi Sankyo, Hansoh Pharmaceuticals, Takeda Oncology, Blueprint Medicines and Amgen outside the submitted work. IFC, NIC, JYD, DDU, NG, RGJ, VG, UG, OAM, GM, RO, KP, CS, DSW, JS, DT and HvH have declared no significant conflict of interest., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

A Japan Society of Clinical Oncology (JSCO)-hosted expert meeting was held in Japan on 27 October 2019, which comprised experts from the JSCO, the Japanese Society of Medical Oncology (JSMO), the European Society for Medical Oncology (ESMO), the American Society of Clinical Oncology (ASCO), and the Taiwan Oncology Society (TOS). The purpose of the meeting was to focus on what we have learnt from both microsatellite instability (MSI)/deficient mismatch repair (dMMR) biomarkers in predicting the efficacy of anti-programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) immunotherapy, and the neurotrophic tyrosine receptor kinase (NTRK) gene fusions in predicting the efficacy of inhibitors of the tropomyosin receptor kinase (TRK) proteins across a range of solid tumour types. The recent regulatory approvals of the anti-PD-1 antibody pembrolizumab and the TRK inhibitors larotrectinib and entrectinib, based on specific tumour biomarkers rather than specific tumour type, have heralded a paradigm shift in cancer treatment approaches. The purpose of the meeting was to develop international expert consensus recommendations on the use of such tumour-agnostic treatments in patients with solid tumours. The aim was to generate a reference document for clinical practice, for pharmaceutical companies in the design of clinical trials, for ethics committees in the approval of clinical trial protocols and for regulatory authorities in relation to drug approvals, with a particular emphasis on diagnostic testing and patient selection., Competing Interests: Disclosure EB has received research funding from Taiho, Chugai, Astellas, Merck biopharma, Daiichi Sankyo, Ono, Kyowa-Kirin and Takeda; HB has received fees for consultancy/advisory roles paid to his institution from Mersana, AstraZeneca, FORMA therapeutics, Janssen, Novartis, Roche/Genentech, MedImmune, BMS, Celgene, Incyte, Boehringer Ingelheim, Eisai and Tolero Pharmaceuticals, and research funding paid to his institution from AstraZeneca, Novartis, MedImmune, BMS, Celgene, Incyte, Janssen, Roche/Genentech, MacroGenics, Boehringer Ingelheim, Lilly, Seattle Genetics, Merck, Agios, Jounce Therapeutics, Moderna Therapeutics, CytomX Therapeutics, GlaxoSmithKline, Verastem, Tesaro, Immunocore, Takeda, Millennium, Biomed Valley Discoveries, TG therapeutics, eFFECTOR Therapeutics, Gilead Sciences, BioAtla, CicloMed, Loxo, Vertex, Harpoon Therapeutics, Jiangsu Hengrui Medicine, Arch, Kyocera, Arvinas and Revolution Medicines; AC has received fees for consultancy/advisory roles from Merck Serono, Roche, BeiGene, Bayer, Servier, Eli Lilly, Novartis, Takeda, Astellas and Pierre Fabre and research funding from Genentech, Merck Serono, Roche, BeiGene, Bayer, Servier, Eli Lilly, Novartis, Takeda, Astellas, FibroGen, Amcure, Sierra Oncology, AstraZeneca, Medimmune, BMS and MSD; FC has received fees for consultancy/advisory roles from Phillips; L-TC has received research funding from Novartis, Merck Serono, TTY, Polaris, SyncorePharm, Pfizer, and BMS, honoraria from ONO, Eli Lilly, MSD, Pharma Engine, TTY, SyncorePharm, Novartis, AstraZeneca and Ipsen, patents and royalties for ENO-1 mAb from HuniLife, and is a Scientific Advisory Board member at Pharma Engine and a board member at Sinopharm Taiwan, Ltd; YK has received fees for consultancy/advisory roles from Ono Asahi Kasei and BMS research funding from Taiho, Chugai, Yakult, Daiichi-Sankyo, Merck Serono, Asahi Kasei, EA Pharma, Otsuka Pharmaceutical Co., Ltd, Otsuka Pharmaceutical Factory Inc., Takeda, Shionogi, Kaken Pharmaceuticals, Kowa Pharmaceuticals, Astellas, Medicon, Dainippon Sumitomo Pharmaceuticals, Taisho Toyama Pharmaceuticals, Kyowa Kirin, Pfizer Japan, Ono, NIHON, Japan Blood Products Organization, Medtronic Japan, Sanofi K.K., and grants from Eisai, Tsumura, KCI Licensing, Inc, Abbott Japan, Fuji Film and Toyama Chemical Co.; YKo has receive research funding from Taiho, Chugai, Takeda, MSD, Nihon Kayaku, Yakult, Lilly Japan, Ono, EA Pharma, Novartis, Daiichi-Sankyo, BMS and Sanofi; YN has received fees for consultancy/advisory roles from Eli Lilly, AstraZeneca, Chugai, Pfizer, Novartis, Eisai, Bayer, Fuji Film Toyama Chemistry, Shionogi, Taiho, Ono, Guardent Health, Kyowa Kirin and Mundipharma; MJO has received fees for consultancy/advisory roles from Janssen Research and Development LLC, AgilVax, Takeda Pharmaceuticals (Japan), Acrotech Biopharma, Promega, Genentech Inc., and Novartis Pharmaceuticals and research funding from Roche, BMS, Merck, AstraZeneca and Nouscom; GP has received fees for consultancy/advisory roles from Roche, Merck and Amgen and research funding from: Roche, Amgen, Novartis, MSD, BMS, Pfizer, Boehringer and Astra Zeneca; AS has received fees for consultancy from Genentech, AstraZeneca and Medtronic and for advisory boards from AstraZeneca and Takeda; JT has received fees for consultancy/advisory roles from Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Eli Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael Pharmaceuticals, F. Hoffmann-La Roche Ltd, Sanofi, SeaGen, Seattle Genetics, Servier, Symphogen, Taiho, VCN Biosciences, Biocartis, Foundation Medicine, HalioDx SAS and Roche Diagnostics; MT has received fees for consultancy/advisory roles from Chugai; HT has received research funding from Sysmex, Takeda and Daiichi-Sankyo; KHY has received fees for consultancy/advisory roles from Amgen, Boehringer Ingelheim, Bayer, BMS, MSD, Merck Serono, Eli Lilly, Ono and Takeda; KY has received fees for consultancy/advisory roles from Abbott, AbbVie, Asa hi Kasei Pharma, Astellas, Biogen Japan, Celgene, Chugai, Covidien Japan, Daiichi Sankyo, Eisai, Eli Lilly Japan, GlaxoSmithKline, Johnson & Johnson, KCI, Kyowa Kirin, Meiji Seika Pharma, Merck Serono, MSD, Nippon Kayaku, Novartis, Ono Pharm., Otsuka Pharm., Sanofi, Taiho Pharm., Toray Medical, Tsumura and Yakult Honsha; TY has received research funding from Novartis Pharma K.K., MSD K.K., Sumitomo Dainippon Pharma Co., Ltd, Chugai, Sanofi K.K., Daiichi Sankyo, Parexel International Inc., Ono, GlaxoSmithKline K.K. and Boehringer Ingelheim Japan. JYD and SM declare no conflicts of interests., (Copyright © 2020 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Treatment of oncologic patients has progressed greatly the last few years with the development of immune checkpoint inhibitors (ICPIs). These drugs are associated with the immune system and, thus, may cause side effects of immune origin, the so called immune related adverse events (irAEs). Immune related AEs may actually affect all organs and systems and frequently resemble clinical entities commonly encountered in clinical practice. As ICPIs have improved both quality of life and life expectancy, clinicians of various specialties may need to deal with irAEs in their everyday practice. Therefore, they should be able to recognize them timely and treat them accordingly. Herein, we review the pathophysiology, clinical manifestations and treatment of irAEs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Cancer-associated thrombosis (CAT), the second leading cause of death in patients with cancer can be treated with low molecular weight heparin (LMWH) according to guidelines., Patients and Methods: A multicenter prospective observational study was carried out to record anti-thrombotic treatment practice, assess thrombosis recurrence and bleeding, and identify potential risk factors. Adult patients from 18 Oncology Departments throughout Greece were followed-up for 12 months., Results: A total of 120 patients with CAT receiving anticoagulant treatment were enrolled (35% incidental); 85% were treated for more than 6 months, 95.8% were treated with tinzaparin and smaller percentages with other agents. Thrombosis recurred in three patients and there was minor bleeding in four patients. Bleeding was associated with high body mass index (>35 kg/m 2 ), trauma history, renal insufficiency and bevacizumab use., Conclusion: Incidental thrombosis contributes significantly to CAT burden. Long-term use of LMWH seems to be effective and safe. Several risk factors associated with bleeding should be considered during anti-coagulation therapy planning., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Internet fake information, parapharmacy and counterfeit drugs are a market of hundreds of billion dollars. Misleading internet data decrease patients' compliance to medical care, promote use of questionable and detrimental practices, and jeopardize patient outcome. This is particularly harmful among cancer patients, especially when pain and nutritional aspects are considered. Provision of Web recommendations for the general audience (patients, relatives, general population) from official medical-providers might be useful to outweigh the detrimental internet information produced by non-medical providers., Methods: 370 oncology and anesthesiology related societies were analyzed. Our objective was to evaluate the magnitude of web-recommendation for cancer cachexia and cancer pain for the general audience provided by official medical organizations' web sites at global level., Results: Magnitude of web-recommendations at global level was surprisingly scant both for coverage and consistency. Seven official medical societies provided updated web-recommendation for cancer cachexia to their patients/family members, and 15 for cancer pain. Scantiness was unrelated by continent, developmental index, oncology tradition, economic-geographic area and society type scrutinized., Conclusions: Patients need expert advice when exposed to fake internet information largely dominated by paramedical market profits. In this era of "new media" the patients' net-education represents a new major educational challenge for medical societies.

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.

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.)

Background: With the development of modern therapies and better care of patients with autoimmune rheumatic diseases (ARDs) increased survival has been achieved. However, ARDs may share an association with risk of lymphomas and solid tumors. The increased cancer risk in these patients is mainly due to high inflammatory activity and severity of disease, rather than the immunosuppressive therapy., Patients and Methods: We studied the coexistence or later development of cancer with ARDs in a retrospective audit of a reference university hospital and critically reviewed published literature. Fourteen out of 1,730 patients with rheumatoid arthritis (RA) and Sjogren's syndrome (SS) followed-up at the University Hospital of Ioannina over the last 33 years developed secondary malignancies, both solid tumors and lymphomas., Results and Conclusion: The most frequent cancer associated with ARDs is diffuse large B-cell lymphoma (DLBCL). The average risk of lymphoma in RA may be composed of a markedly increased risk in patients with most severe disease. Solid tumors were presented mainly in RA patients and renal cell carcinoma was the most frequently found., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

The use of bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), in combination with standard therapeutic approaches, has offered clinical benefit for patients with advanced colorectal, breast, ovarian, renal, non small-cell lung cancer and glioblastoma. However, the strategy of administering bevacizumab until disease progression has been challenged by certain preclinical evidence, suggesting that prolonged exposure to anti-VEGF treatment may elicit an adaptive-evasive response, resulting in a more aggressive tumor phenotype. Moreover, the use of bevacizumab in adjuvant chemotherapeutic regimens has led to less promising results than expected. Despite our poor understanding of how bevacizumab acts in micrometastatic disease, numerous clinical trials (involving >20,000 cancer patients) are ongoing or are planned to test the therapeutic benefit in the adjuvant setting. The discrepancy of bevacizumab's efficiency in the two settings calls into question the validity of current strategies that use similar treatment regimens for early and advanced diseases. Herein, we review the mechanisms of bevacizumab activity in the macro- as compared to the micrometastatic environment and discuss possible alternative strategies in the adjuvant setting that might spur attention for future clinical trials. Rather than providing an encyclopedic survey of the literature, we highlight exemplary principles., (© 2013.)

Solid tumours initiate angiogenesis to support their growth by producing growth factors such as VEGF. Depriving the tumour of the excessive vessels that support its growth became the target for developing anti-angiogenic agents that could provide, in combination with chemotherapy, improved anti-cancer treatment. Naturally most agents targeted VEGF and its signalling cascades. Almost 10 years have lapsed since the first anti-angiogenic drug approved by the FDA in 2004 (a humanized antibody inhibiting VEGF-A) and several other agents followed afterwards. There is sufficient accumulated experience to conclude that the clinical results of anti-angiogenic therapy are very modest resulting in moderate improvement in overall survival. Moreover, the clinical outcome is associated with the development of resistance to the anti-angiogenic agent and the increased risk of invasion and metastasis. The initial expectations are, as yet, unfilled, and the entire concept and strategy of the anti-angiogenic intervention in cancer requires re-evaluation. In the present Mini Review we discuss these issues emphasising the underlying molecular mechanisms., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Pregnancy complicated by cancer is relatively rare but, as women in western societies tend to delay childbearing to the third and fourth decade of life, this phenomenon is going to be encountered more often in the future., Material and Methods: Review of the literature and description of the different diagnostic and therapeutic approaches which are required to diagnose and treat pregnant mothers with cancer., Results: As in non-pregnant patients, every effort should be made to provide the maximal benefit and best prognosis to the pregnant patient. In most cases, in order to avoid any harm to the fetus, different diagnostic approach should be incorporated and treatment should be tailored to each pregnant woman. Cooperation of multidisciplinary teams, incorporating medical and radiation oncologists, surgeons, obstetricians, neonatologists and experienced nursing staff, is required to provide optimal care for the patient. The benefits from use of surgery, chemotherapy and/or radiotherapy as well as the mother's wishes and beliefs need to be factored into recommendations and treatment planning., Conclusions: With the experience gained, the developments in clinical and radiation oncology and the cooperation of multidisciplinary teams, treatment of cancer during pregnancy with normal fetal outcome is feasible., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Heterogeneity in aspects of development, structure and context of oncology guidelines was not evaluated. We analysed and critically examined its implications., Materials and Methods: Nine cancer clinical practice guidelines were selected on the basis of popularity among oncologists. The relevant Web sites and publications on three tumours were examined and characteristics grouped in the data domains: producing organisation, methodology, guideline structure and content, implementation and evaluation and scientific agreement., Results: ASCO, ESMO, NICE, SIGN, START, NHMRC, NCI, NCCN and CCO guidelines were examined. Development was initiated by stakeholders or authorised bodies, run by task forces with varying degrees of multidisciplinarity, with rare endorsement of external guidelines. Recommendation formulation was on the basis of evidence, shaped via interactive processes of expert review and public consultation-based modifications. Guidelines varied in comprehensiveness per tumour type, number, size, format, grading of evidence, update and legal issues. Orientation for clinic use or as reference document, end-users and binding or elective nature also varied. Standard dissemination strategies were used, though evaluation of adoption and of impact on health outcomes was implemented with considerable heterogeneity., Conclusions: Heterogeneity in development, structure, user and end points of guidelines is evident, though necessary in order to meet divergent demands. Crucial for their effectiveness are adherence to methodological standards, a clear definition of what the guideline intends to do for whom and a systematic evaluation of their impact on health care.

Nowadays three quarters of adolescents with cancer are cured but half of them experience a late toxic effect of antineoplastic therapy that interferes with their physical and psychosocial health. This review recapitulates late effects associated with radiation therapy, chemotherapy and surgery, reviews risk factors and prognosis and suggests follow-up and management strategies, excluding fertility issues. Adolescents with cancer should be the focus of active clinical research for the optimisation of antineoplastic treatment as well as for breakthroughs in the follow-up, prevention and management of toxic effects.

Background: Although protracted intravenous 5-fluorouracil is superior to bolus regimens in terms of tumour exposure to the drug during DNA synthesis as well as activity and safety, the oral fluoropyrimidine capecitabine is administered intermittently. In this phase I study, we investigated an alternative, dose-intense continuous regimen., Materials and Methods: Oral capecitabine was administered twice daily continuously with weekend breaks, in patients with advanced solid tumours refractory to standard therapy. Dose escalation proceeded from 1,331 to 2,510 mg/m(2) daily. Dose limiting toxicity (DLT) consisted of any grade-3 or 4 adverse event except for alopecia and skin toxicity resolving within 7 days., Results: Twenty-five heavily pretreated patients participated in the study. No DLT occurred in the first four cohorts. Two out of four patients developed grade III diarrhoea in the fourth week of capecitabine at 2,510 mg/m(2) (DLT). The most common toxic episodes during all cycles of treatment were grade 1-2 fatigue, skin erythema, abdominal cramps, nausea, constipation and neutropenia. Disease regression was seen in three and stabilisation with clinical benefit in ten patients (clinical benefit response 54%). Pharmacokinetic studies of capecitabine and metabolites in four patients at 2,250 mg/m(2 )daily showed rapid absorption, short plasma half-lives with the exception of FBAL and absence of accumulation or conversion saturation during the course of therapy. At this dose, administered dose intensity in eight patients was 99.3% of the planned one., Conclusions: Weekday on-weekend off capecitabine maximizes cytotoxic impact on tumour cells during S-phase by safely simulating protracted fluoropyrimidine therapy at a recommended dose (2,250 mg/m(2)) close to that of the intermittent schedule and clearly higher than the continuous one of 1,331 mg/m(2).

Introduction: Despite unique tumor epidemiology and a higher cancer incidence compared to pediatric patients, adolescents and young adults have not been receiving specialized, multidisciplinary, centralized care. In an effort to emphasize this need, we present outcome and toxicity data from a reference centre., Methods: Cohort of 150 patients aged 15-30 treated for malignant tumors of lymphoid and solid organs from 1986 to 2002., Results: Patients aged 15-19 commonly had lymphomas, germ cell tumors and pediatric sarcomas, whereas those aged 20-30 experienced germ cell tumors, lymphomas, melanomas and epithelial tumors more often. Overall 5- and 10-year survival was 80%, whereas 5-year and 10-year time to treatment failure was 68% and 43.5% respectively. 24% of patients experienced persistent, late treatment-related toxicities that interfered with their normal lifestyle., Conclusion: Despite the need for specialized care, psychosocial support and enrollment in clinical trials, youngsters have not been recognized as a patient group with distinct needs. Development of "Juvenile" oncology is required.

Purpose: We performed a phase I study of two fixed dosing schemes of cisplatin, a DNA cross-linker, with intravenous escalating topotecan, a DNA-topoisomerase I inhibitor., Experimental Design: 40 patients with advanced solid tumors received intravenous cisplatin at a fixed dose of either 25 mg/m2 (schedule A) or 20 mg/m2 (schedule B) daily for 3 days with standard hydration. Topotecan escalation proceeded in 0.75, 0.90, 1.0, 1.15 mg/m2 cohorts in schedule A and 1.0, 1.1, 1.2, 1.3 mg/m2 cohorts in schedule B, administered intravenously at the end of cisplatin infusion daily for 3 days, repeated every 3 weeks. Dose-limiting toxicity (DLT) consisted of protracted grade IV neutropenia, febrile neutropenia, grade IV thrombocytopenia and any grade III/IV non-hematological toxicity. Epoetin and granulocyte colony-stimulating factor support was allowed on severe myeloablation. Endpoints were the identification of maximal tolerated dose (MTD), DLT and other toxicity., Results: The MTD was reached in cohort 25/1.15 mg/m2 in schedule A and 20/1.2 mg/m2 in schedule B. All DLT seen consisted of three episodes of febrile neutropenia and two of grade IV thrombocytopenia in schedule A, with three episodes of febrile neutropenia and one of protracted neutropenia in schedule B. Myelosuppression was substantial in all cohorts despite granulocyte colony-stimulating factor and epoetin support, peaked on the third week of treatment and resulted in administration of chemotherapy at a median of every 4 weeks. Non-hematologic toxicity was mild. The response rate was 51% with seven complete responses occurring in patients with ovarian cancer, small cell and non-small cell lung cancer and cancer of unknown primary. The recommended dose was 20/ 1.1 mg/m2 for cisplatin and topotecan on schedule B, as the number of responses and administered topotecan dose were higher in schedule B recommended dose with lower cisplatin dose, minimizing problems of nephrotoxicity and vomiting., Conclusions: The schedule B daily cisplatin-topotecan x 3 combination with secondary cytokine support is associated with promising activity and schedule convenience. However, substantial myelosuppression undermines its applicability in the palliative setting, stressing the need for less toxic regimens., (Copyright (c) 2005 S. Karger AG, Basel)

Despite unique tumour epidemiology, a higher cancer incidence and modest survival improvement compared to paediatric patients, adolescents and young adults aged 15-30 have not been considered as a separate, "special" group of patients in the frame of medical oncology. In an effort to emphasise this need, we review the particular characteristics of diagnosed tumours, a aetiologic associations, nosologic classification, management, outcome and late toxic effects. Adolescents and young adults are in need of specialised care for intensive treatment of curable malignancies, skilled nursing care, interaction with peers, family and physicians as well as continuous psychosocial support. Enrollment in clinical research trials and close follow-up via the development of a cooperative infrastructure are imperative for the optimisation of management and avoidance of late effects. Similar to geriatric and paediatric oncology, we call for the intensification of treatment, support and research multidisciplinary efforts in order to better fulfil the pressing demands of this patient group.

Background: We aimed to define the maximum tolerated dose (MTD) and characterize the toxicity of the combination of pegylated liposomal doxorubicin (PLD; Caelyx trade mark ) and weekly paclitaxel (wPTX), and to investigate pharmacokinetics of PLD in this combination., Methods: A phase I study was performed with an initial dose of 50 mg/m(2) wPTX and 30 mg/m(2) PLD. The paclitaxel dose was escalated in increments of 10 mg/m(2) and PLD in increments of 5 mg/m(2) until the MTD was reached. The pharmacokinetics of PLD were studied at the highest achieved dose levels., Results: Forty-four cancer patients were enrolled. The MTD was 30/90 and 35/80 mg/m(2) for PLD/wPTX. Dose-limiting toxicities included treatment delay for neutropenia grade 3, febrile neutropenia, palmar-plantar erythrodysesthesia and deep venous thrombosis. Toxicity below the MTD was mild: skin toxicity grade 1-2 developed at high cumulative doses and vascular thrombotic events occurred in two patients with predisposing factors. No cardiotoxicity or clinically relevant peripheral neuropathy was seen. Nausea/vomiting and alopecia were negligible. Three complete responses and nine partial responses were documented among 34 evaluable cases. PLD plasma concentrations were evaluated in seven patients treated at subMTD. Paclitaxel produced a median 53.5% increase of PLD area under the concentration curve (range 4.4%-219%)., Conclusions: The combination of PLD/wPTX constitutes an active chemotherapy regimen with mild toxicity that merits investigation in phase II at 30/80 or 35/70 mg/m(2). Patients should be monitored for a potentially increased risk of thromboembolic events.

Purpose: Diflomotecan (BN80915) is an E-ring modified camptothecin analogue that possesses greater lactone stability in plasma compared with other topoisomerase I inhibitors, a potential advantage for antitumor activity. As with other camptothecins, oral administration has pharmacological and clinical advantages. This Phase I study was performed to assess the feasibility of the administration of oral diflomotecan, to determine the maximum-tolerated, dose its bioavailability, and to explore the pharmacokinetics., Experimental Design: An initial i.v. bolus was administered to assess the bioavailability of diflomotecan. Fourteen days later, diflomotecan was administered p.o. once daily for 5 days to adult patients with solid malignant tumors and repeated every 3 weeks. BN80915 and its open lactone form BN80942 were measured., Results: Twenty-two patients entered the study and received a total of 57 cycles of oral diflomotecan at flat dose levels of 0.10, 0.20, 0.27, and 0.35 mg. The main toxicity was hematological, but some patients experienced alopecia, mild gastrointestinal toxicity, and fatigue. At the 0.35-mg dose level, 2 of 4 patients experienced dose-limiting toxicity comprising grade 3 thrombocytopenia with epistaxis and febrile neutropenia in 1 patient and uncomplicated grade 4 neutropenia lasting for >7 days in another. Toxicity was acceptable at the 0.27-mg dose level at which dose-limiting toxicities were observed in 3 of 12 patients (grade 4 neutropenia > 7 days, complicated by fever in 1 patient but without other signs of infection). After two cycles of diflomotecan, 6 patients had disease stabilization, which was maintained in 2 patients for 9 months and >1 year, respectively. Diflomotecan pharmacokinetics were linear over the dose range studied. Systemic exposure correlated with the fall in WBC counts. The mean oral bioavailability (+/-SD) was 72.24 +/- 59.2% across all dose levels. Urinary excretion of BN80915 was very low., Conclusions: The recommended oral diflomotecan dose for Phase II studies is 0.27 mg/day x 5 every 3 weeks. This regimen is convenient and generally well tolerated with a favorable pharmacokinetic profile and high but variable bioavailability.