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As the global population ages, so does the number of older people being diagnosed, treated and surviving cancer. Challenges to providing appropriate healthcare management stem from the heterogeneity common in this population. Although malnutrition is highly prevalent in older people with cancer, ranging between 30 % and 80 % according to some analyses, is associated with frailty, and has been shown to be a major risk factor for poor treatment response and worse overall survival, addressing nutrition status is not always a priority among oncology healthcare providers. Evaluation of nutritional status is a two-step process: screening identifies risk factors for reduced nutritional intake and deficits that require more in-depth assessment. Screening activities can be as simple as taking weight and BMI measurements or using short nutritional questionnaires and asking the patient about unintentional weight loss to identify potential nutritional risk. Using geriatric assessment, deficits in the nutritional domain as well as in others reveal potentially reversible geriatric and medical problems to guide specific therapeutic interventions. The authors of this paper are experts in the fields of geriatric medicine, oncology, and nutrition science and believe that there is not only substantial evidence to support regularly performing screening and assessment of nutritional status in older patients with cancer, but that these measures lead to the planning and implementation of patient-centered approaches to nutrition management and thus enhanced geriatric-oncology care. This paper presents rationale for systematic nutrition screening and assessment in older adults with cancer., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: J.M.B. - Advisor to the following companies: Nutricia DANONE; Nestlé ; Fresenius; Pfizer; Novartis; Rejuvenate Biomed. Lecturer for: Nutricia DANONE; Nestlé ; Fresenius; Pfizer; Novartis. All income from the above activities goes to the institution he is working for. M.P. - Boards & Committees: BDA Prehab Sub-Group Committee. Travel grants: BDA GET Fund, RMH Charity, SIOG. Speaker fees: Fresenius Kabi, SPCC & SIOG. Research grants: Nutricia. R.B. – has participated to Advisory Boards for Nutricia Research, Eli Lilly, Novo Nordisk, Pfizer. N.M.L.B. – Advisory board: Pfizer, Abbott, Sanofi, Astellas; Travel grants: Exact Sciences, Pfizer, Lilly, Novartis; Speaker fees: Pfizer, AbbVie, Roche, Sanofi, Novartis, Servier, Gilead, AstraZeneca, Lilly. E.S-P-D-C. – Speaker fees: Amgen, Synapsis. F.S. – BMS, Sanofi, Roche, MSD, Prostrakan, Leo pharma, Janssen, Pfizer, Amgen, Pierre Fabre Oncologie, Pharmanovia, Vifor Pharma, GSK, Viatris, Helsinn. P.S. – BMS: Member of Advisory Board on cancer in the elderly (2018–2019), GSK: Conference with honoraria (2020), EISAI: Member of Advisory Board on Management of older patients with thyroid cancer (2021), AbbVie: Member of Advisory Board on Geriatric oncology in hematological malignancies (2023). The other authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Immune checkpoint inhibitor (ICI) therapies have become increasingly popular treatment options for patients with cancer, even for patients in non-metastatic settings. Survival and responses have been reported for individual tumor types, but little is known about these outcomes, collectively. We sought to provide an overview of overall survival (OS) and progression-free survival (PFS) in ICI drugs tested in registration trials., Methods: In a cross-sectional analysis of US FDA oncology ICI drug approvals (2011-2023), we searched for supporting ICI registration trials. We characterized these trials, regarding differences in median OS and PFS between patients in intervention and control arm participants in ICI registration trials; percentage of patients who receive ICI crossover; and whether there is correlation between the percentage of crossover and differences in OS or PFS., Results: Fifty-six (54.4 %) approvals had trials that reported median OS for both intervention and control arms (median difference was 2.8 months; IQR: 2.2 to 5.0 months). Sixty-five (63.1 %) approvals had trials that reported PFS data for both arms (median of 0.9 months; IQR: -0.2 to 3.0 months). Subsequent therapy was common (median=18.9 %) and was significantly correlated with a higher difference in median OS in all studies with reported differences (R2 =0.15; p = 0.001)., Conclusion: ICIs are increasingly used in the treatment of cancer, yet the median OS improvement is modest, and many ICIs have not been tested for OS benefit. OS is the outcome most meaningful for patients, and drug regulation should require better testing and reporting of these data., Competing Interests: Declaration of Competing Interest V.P. receives research funding from Arnold Ventures through a grant made to UCSF, and royalties for books and writing from Johns Hopkins Press, MedPage, and the Free Press. He declares consultancy roles with UnitedHealthcare and OptumRX; He hosts the podcasts, Plenary Session, VPZD, Sensible Medicine, writes the newsletters, Sensible Medicine, the Drug Development Letter and VP's Observations and Thoughts, and runs the YouTube channel Vinay Prasad MD MPH, which collectively earn revenue on the platforms: Patreon, YouTube and Substack. AH, MSK, and JE have no disclosures to report., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Precision oncology has a significant role to play in delivering optimal patient care. Biomarkers are critical enablers for precision oncology across the continuum of cancer diagnosis, in defining patient prognosis, and in predicting the response to treatments and their potential toxicities, as well as delineating the risk of hereditary cancer syndromes. Biomarkers also potentiate cancer drug development, accelerating patient access to safe and effective therapies. However, despite an accurate and timely diagnosis being critical to patient survival, advances in genomic testing are not being fully exploited in daily clinical practice, leading to missed opportunities to deliver the most effective treatments for patients. Biomarker testing availability and implementation often lag behind approvals of respective biomarker-informed therapies, limiting prompt patient access to these life-saving drugs. Multiple factors currently impede the routine adoption of biomarker testing including, but not limited to, cost, lack of test reimbursement, limited access, regulatory hurdles, lack of knowledge, insufficient cooperation on assay development, and the urgent need to harmonize and validate testing assays, all leading to inefficient diagnostic pathways. Clinical guidelines increasingly include genomic profiling, and recent evidence suggests that precision oncology can be delivered in a cost-effective way for financially-challenged health systems. Therefore, precision genomic testing for cancer biomarkers must be embedded into the clinical practice of oncology care delivery going forward. We articulate a series of recommendations and a call to action to underpin the mainstreaming of a biomarker-informed precision oncology approach to enhance patient outcomes and deliver cost effective 21st century cancer care., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (Copyright © 2024. Published by Elsevier Ltd.)

Personalised oncology, whereby patients are given therapies based on their molecular tumour profile, is rapidly becoming an essential part of optimal clinical care, at least partly facilitated by recent advances in next-generation sequencing-based technology using liquid- and tissue-based biopsies. Consequently, clinical trials have shifted in approach, from traditional studies evaluating cytotoxic chemotherapy in largely histology-based populations to modified, biomarker-driven studies (e.g. basket, umbrella, platform) of molecularly guided therapies and cancer immunotherapies in selected patient subsets. Such modified study designs may assess, within the same trial structure, multiple cancer types and treatments, and should incorporate a multistakeholder perspective. This is key to generating complementary, fit-for-purpose and timely evidence for molecularly guided therapies that can be used as proof-of-concept to inform further study designs, lead to approval by regulatory authorities and be used as confirmation of clinical benefit for health technology assessment bodies. In general, the future of cancer clinical trials requires a framework for the application of innovative technologies and dynamic design methodologies, in order to efficiently transform scientific discoveries into clinical utility. Next-generation, modified studies that involve the joint efforts of all key stakeholders will offer individualised strategies that ultimately contribute to globalised knowledge and collective learning. In this review, we outline the background and purpose of such modified study designs and detail key aspects from a multistakeholder perspective. We also provide methodological considerations for designing the studies and highlight how insights from already-ongoing studies may address current challenges and opportunities in the era of personalised oncology., Competing Interests: Declaration of Competing Interests The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Christophe Le Tourneau has received honoraria from Novartis, Bristol Myers Squibb, MSD, Merck Serono, F. Hoffmann-La Roche Ltd, Nanobiotix, GlaxoSmithKline, Celgene, Rakuten Medical and Seattle Genetics; has had a consulting/advisory role for Amgen, MSD, Bristol Myers Squibb, Merck Serono, AstraZeneca, Nanobiotix, GlaxoSmithKline, Celgene, Rakuten, Seattle Genetics and F. Hoffmann-La Roche Ltd; has received research funding from MSD; and has received travel/accommodation expenses from MSD, Bristol Myers Squibb and AstraZeneca. Fabrice André has received institutional research funding from F. Hoffmann-La Roche, Pfizer, Eli Lilly, Novartis, AstraZeneca and Daiichi Sankyo. Åslaug Helland has received honoraria to her institution for talks and advice given to AstraZeneca, Roche, Janssen, Bayer, Novartis, Takeda, Pfizer, Eli Lilly, MSD, BMS, Eli Lilly, AbbVie, Merck and Sanofi; and has received research funding from Roche, AstraZeneca, BMS, Ultimovacs, Incyte, Eli Lilly and Novartis. Linda Mileshkin has received travel/accommodation expenses from F. Hoffmann-La Roche Ltd and BeiGene. Warnyta Minnaard is the cofounder, director and volunteer at Missie Tumor Onbekend, the CUP patient charity in the Netherlands; is also employed by Noaber Ventures; has received honoraria for various presentations at Dutch hospitals in regards to CUP and various presentations to healthcare industry companies (including pharma) on the CUP patient charity to her institution; has received meeting/travel support from F. Hoffmann-La Roche Ltd; and is a volunteer for Stichting Cancer of Unknown Primary Platform—the Netherlands (CUPP-NL). Anja Schiel is an employee of the Norwegian Medicines Agency and acted as Vice-Chair on the EUnetHTA 21 Committee for Scientific Consistency and Quality Joint Scientific Consultations. Kjetil Taskén has received honoraria to his institution for talks and advice given to Roche, Novartis, AbbVie, AstraZeneca, Bayer and Kite/Gilead. David M. Thomas is supported by an NHMRC Investigator grant (GNT1195742), as well as grants, personal fees and non-financial support from F. Hoffmann-La Roche, Pfizer and Bayer; grants and non-financial support from AstraZeneca, Seattle Genetics, Amgen, Eli Lilly and Eisai; personal fees from Omico; and non-financial support from Elevation Oncology, outside the submitted work. Maria Luisa Veronese is an employee of Incyte International Biosciences Sàrl. Gonzalo Durán-Pacheco, Lada Leyens, Kaspar Rufibach and Marlene Thomas are employees of and hold stock/shares in F. Hoffmann-La Roche Ltd. Alwin Krämer has received honoraria from F. Hoffmann-La Roche Ltd, Daiichi Sankyo and AbbVie; has received honoraria to his institution from F. Hoffmann-La Roche Ltd and Bayer; has a leadership role in F. Hoffmann-La Roche Ltd; has received institutional research funding from Merck and Bayer; has received travel/accommodation expenses from F. Hoffmann-La Roche Ltd, Celgene and Daiichi Sankyo; and has acted as an advisory consultant for Daiichi Sankyo, BMS and AbbVie. All authors received research support (medical writing support) from F. Hoffmann-La Roche Ltd., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: We sought to characterise oncology basket and umbrella trials that have been implemented, determine how many have been completed, and calculate the response rate, by tumour type and drug target., Methods: We conducted a retrospective, cross-sectional review of PubMed, Embase, and clinicaltrials.gov for all oncology basket and umbrella trials. We included all trials and publications reporting on the results of these trials, and we calculated overall response rates, stratified by tumour type and drug target., Results: Most basket and umbrella trials are phase II and non-randomised in design. Of the 180 basket trials, 99 (55.0%) had published results and 81 (45.0%) did not. Of the 73 umbrella trials, 28 (38.4%) had published results and 45 (61.6%) did not. The median response rate was 14.0 (IQR: 4.2, 31.2) for basket trials and 17.8 (IQR: 3.8, 40.4) for umbrella trials. These responses varied, depending on tumour type and drug target., Conclusions: Understanding what is known about these trials, especially given the limited but heterogenous response reported in these trials, provides context about the strengths and limitations of drugs, especially since several drugs have been approved in recent years for tumour-agnostic indications, based on the results of these types of trials., Competing Interests: Conflict of interest statement The authors declare the following financial interests/ vpersonal relationships which may be considered as potential competing interests: Vinay Prasad's Disclosures (Research funding) Arnold Ventures (Royalties) Johns Hopkins Press, Medscape, and MedPage (Honoraria) Grand Rounds/lectures from universities, medical centres, non-profits, and professional societies (Consulting) UnitedHealthcare and OptumRX (Other) Plenary Session podcast has Patreon backers, YouTube, and Substack. All other authors have no financial nor non-financial conflicts of interest to report., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Regulatory decisions on paediatric investigation plans (PIPs) aim at making effective and safe medicines timely available for children with high unmet medical need. At the same time, scientific knowledge progresses continuously leading frequently to the identification of new molecular targets in the therapeutic area of oncology. This, together with further efforts to optimise next generation medicines, results in novel innovative products in development pipelines. In the context of global regulatory development requirements for these growing pipelines of innovative products (e.g. US RACE for children Act), it is an increasing challenge to complete development efforts in paediatric oncology, a therapeutic area of rare and life-threatening diseases with high unmet needs., Objective: Regulators recognise feasibility challenges of the regulatory obligations in this context. Here, we explain the EU regulatory decision making strategy applied to paediatric oncology, which aims fostering evidence generation to support developments based on needs and robust science. Because there is a plethora of products under development within given classes of or within cancer types, priorities need to be identified and updated as evidence evolves. This also includes identifying the need for third or fourth generation products to secure focused and accelerated drug development., Conclusion: An agreed PIP, as a plan, is a living document which can be modified in light of new evidence. For this to be successful, input from the various relevant stakeholders, i.e. patients/parents, clinicians and investigators is required. To efficiently obtain this input, the EMA is co-organising with ACCELERATE oncology stakeholder engagement platform meetings., Competing Interests: Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Modern clinical cancer research increasingly relies on the visual communication of complex response and treatment sequencing data. Graphical representations used in oncology currently fail to provide adequate information on any prior treatment(s) responses, focussing on current treatment effects in isolation. We have developed a new graphical illustration, the 'iceberg plot,' to allow improved comparison of prior treatment response with current therapy. To demonstrate the potential clinical utility of this new graphical representation, we have performed an independent reanalysis of a clinical study trialling sequence-directed therapy. In this example, prior therapy responses are contrasted with current treatment response, with further validation using the 'Von Hoff' criteria to assess for exceptional response. This example demonstrates the versatility and clinical utility of the 'iceberg plot,' showing what was previously hidden and provides improved visualisation of prior and current treatment responses together., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Vinay Prasad reports research funding from Arnold Ventures; royalties from Johns Hopkins Press, Medscape and MedPage; consulting fees from UnitedHealthcare; speaking fees from Evicore and New Century Health; and Plenary Session Podcast has Patreon backers. All other authors have no financial nor non-financial conflicts of interest to report., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Corticosteroids are among the most prescribed drugs in oncology. The indications range from cancer-related indications for refractory symptoms, anti-cancer effects mainly in hematology, supportive measures for cancer-specific treatments and more recently immune-related adverse events induced by modern immunotherapies. In oncological emergencies, corticosteroids are common first-line treatments because of their rapid effect and wide variety of actions. In the last 5 years, with the advance of immune checkpoint inhibitors, corticosteroids are becoming routinely used to manage immune-related adverse effects. Preclinical studies suggested that corticosteroid-induced immunosuppression might dampen the activity of immunotherapies. Prospective clinical studies show that corticosteroid use is a prognostic marker for the cancer outcome in metastatic setting but does not significantly alter the patient's response to immunotherapies per se. Here, we review the state of the art on corticosteroid use in oncology, with a focus on the drugs' potential impact on immunotherapy activity. The comprehensive pharmacological characteristics of corticosteroid drugs, clinical indications, modality of administration and associated precautions for use are discussed in this article., Competing Interests: Conflict of interest statement Mihaela Aldea – nothing to disclose. Emeline Orillard – Honoraria: Astellas Janssen; Travels accommodations: Amgen Pfizer. Laura Mansi – nothing to disclose. Florian Scotte: Vifor pharma, MSD, BMS, Leo Pharma, Pierre Fabre Oncology, Bayer, Pfizer, Amgen, Helsinn, Roche, Tesaro, Mundi Pharma, Mylan, Tilray. Olivier Lambotte – BMS, MSD, Astra Zeneca, Incyte, Janssen, Gilead. Jean-Marie Michot – Principal/sub-Investigator of Clinical Trials for: Amgen, Astex, AstraZeneca, Medimmune, Roche, Sanofi, Xencor. Aurélien Marabelle – Principal/sub-Investigator of Clinical Trials for: Abbvie, Aduro biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, Astra Aeneca, Astra Zeneca Ab, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Bioalliance Pharma, Biontech Ag, Blueprint Medicines, Boehringer Ingelheim, Boston Pharmaceuticals, Inc, Bristol Myers Squibb, Bristol-Myers Squibb International Corporation, Ca, Celgene Corporation, Cephalon, Chugai Pharmaceutical Co, Clovis Oncology, Daiichi Sankyo, Debiopharm S.a, Eisai, Eli lilly, Exelixis, Forma, Gamamabs, Genentech, Inc, Gilead Sciences, Inc, Glaxosmithkline, Glenmark Pharmaceuticals, H3 Biomedicine, Inc, Hoffmann La Roche Ag, Incyte Corporation, Innate Pharma, Institut De Recherche Pierre Fabre, Iris Servier, Janssen Cilag, Janssen Research Foundation, Kura Oncology, Kyowa Kirin Pharm. Dev., Inc, Lilly France, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Kgaa, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Nanobiotix, Nektar Therapeutics, Nerviano Medical Sciences, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncomed, Oncopeptides, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Pfizer, Pharma Mar, Pierre Fabre Medicament, Plexxikon, Rigontec Gmbh, Roche, Sanofi Aventis, Sierra Oncology, Taiho Pharma, Tesaro, Tioma Therapeutics, Wyeth Pharmaceuticals France, Xencor, Y's TherapeuticsGustave Roussy Research Grants: Astrazeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi. Non-financial support (drug supplied) from Astra Zeneca, Bayer, BMS, Boehringer Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck serono, NH TherAGuiX, Pfizer, Roche. Member of Clinical Trial Scientific Committee for GSK, Astra Zeneca, Roche. Member of Data Safety and Monitoring Board for Oncovir, Inc. Scientific Advisory Boards for Innate Pharma, Merck Serono, eTheRNA, Lytix pharma, Kyowa Kirin Pharma, Bayer, Novartis, BMS, Symphogen, Genmab, Amgen, Biothera, Nektar, GSK, Oncovir, Pfizer, Seattle Genetics, Roche/Genentech, OSE immunotherapeutics, Transgene, Gritstone, Merck (MSD), Cerenis, Protagen, Partner Therapeutics, Servier, Sanofi, Pierre Fabre, Molecular Partners, IMCheck, Medicxi, Takeda, EISAI, HiFiBio, RedX, J&J, Gilead, Alkermes. Teaching/Speaker Bureau activities: Roche/Genentech, BMS, Merck (MSD), Merck Serono, Astra Zeneca/Medimmune, Amgen, Sanofi. Scientific & Medical Consulting for Roche, Pierre Fabre, Onxeo, EISAI, Bayer, Genticel, Rigontec, Daichii Sankyo, Sanofi, BioNTech, Corvus, GLG, Deerfield, Guidepoint Global, Edimark, System Analytics, imCheck, Sotio, Bioncotech, Molecular Partners, Pillar Partners, Boehringer Ingelheim, T3 Pharma, Servier, Takeda, GI Innovation. Non-Financial Support (travel expenses) from Astra Zeneca, BMS, Merck (MSD), Roche. Co-Founder & Share Holder of PEGASCY SAS (Gustave Roussy Spin Off for Drug Repositioning). Pre-Clinical and Clinical Research Grants (Institutional Funding): Merus, BMS, Boehringer Ingelheim, Transgene, Foundation MSD Avenir. Member of the following scholar societies: European Society for Medical Oncology (ESMO), American Society for Clinical Oncology (ASCO), American Association for Cancer Research (AACR), European Academy for Tumor Immunology (EATI). Founder and president of the French Society for Immunotherapy of Cancer (FITC). Member of the board of the Immuno-Oncology Group at the French Network of Comprehensive Cancer Centers (Unicancer). Member of the working group on rheumatic adverse events induced by cancer immunotherapies of the European League Against Rheumatoid Arthritis (EULAR). Supervisory Board Member of the Gustave Roussy Foundation. Member of the Steering Committee of the Immuno-Oncology Task Force at Unicancer. Member of the editorial boards of the European Journal of Cancer and ESMO IO Tech., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The fifth multistakeholder Paediatric Strategy Forum focussed on epigenetic modifier therapies for children and adolescents with cancer. As most mutations in paediatric malignancies influence chromatin-associated proteins or transcription and paediatric cancers are driven by developmental gene expression programs, targeting epigenetic mechanisms is predicted to be a very important therapeutic approach in paediatric cancer. The Research to Accelerate Cures and Equity (RACE) for Children Act FDARA amendments to section 505B of the FD&C Act was implemented in August 2020, and as there are many epigenetic targets on the FDA Paediatric Molecular Targets List, clinical evaluation of epigenetic modifiers in paediatric cancers should be considered early in drug development. Companies are also required to submit to the EMA paediatric investigation plans aiming to ensure that the necessary data to support the authorisation of a medicine for children in EU are of high quality and ethically researched. The specific aims of the forum were i) to identify epigenetic targets or mechanisms of action associated with epigenetic modification relevant to paediatric cancers and ii) to define the landscape for paediatric drug development of epigenetic modifier therapies. DNA methyltransferase inhibitors/hypomethylating agents and histone deacetylase inhibitors were largely excluded from discussion as the aim was to discuss those targets for which therapeutic agents are currently in early paediatric and adult development. Epigenetics is an evolving field and could be highly relevant to many paediatric cancers; the biology is multifaceted and new targets are frequently emerging. Targeting epigenetic mechanisms in paediatric malignancy has in most circumstances yet to reach or extend beyond clinical proof of concept, as many targets do not yet have available investigational drugs developed. Eight classes of medicinal products were discussed and prioritised based on the existing level of science to support early evaluation in children: inhibitors of menin, DOT1L, EZH2, EED, BET, PRMT5 and LSD1 and a retinoic acid receptor alpha agonist. Menin inhibitors should be moved rapidly into paediatric development, in view of their biological rationale, strong preclinical activity and ability to fulfil an unmet clinical need. A combination approach is critical for successful utilisation of any epigenetic modifiers (e.g. EZH2 and EED) and exploration of the optimum combination(s) should be supported by preclinical research and, where possible, molecular biomarker validation in advance of clinical translation. A follow-up multistakeholder meeting focussing on BET inhibitors will be held to define how to prioritise the multiple compounds in clinical development that could be evaluated in children with cancer. As epigenetic modifiers are relatively early in development in paediatrics, there is a clear opportunity to shape the landscape of therapies targeting the epigenome in order that efficient and optimum plans for their evaluation in children and adolescents are developed in a timely manner., Competing Interests: Conflicts of interest statement MLM is an employee of Syndax Pharmaceuticals Inc. PB is a scientific advisor for Novartis, Syndax and Servier. DDC and MR are consultants for Loxo Oncology and receive research support from Advanced Cell Diagnostics. PCA is an employee of Sanofi. SB is an employee of Day One Therapeutics Inc. ADD is an employee of Salarius Pharma. BG is an employee of Novartis. MH is an employee of AstraZeneca. PH is an employee of Boston Pharmaceuticals. IJ is an employee of Pfizer. MJK is an employee of Syros Pharmaceuticals. MK is an employee of Bristol Myers Squibb. ZN is an employee of Celgene. AS is an employee of Constellation Pharma. TT is an employee of Boehringer Ingelheim. ADJP has participated in advisory boards for Novartis, Takeda, Merck, Lilly and Celgene. All remaining authors have declared no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aim: The introduction of new and innovative treatment options for cancer patients is accompanied by a tremendous increase in healthcare costs. Consequently, new financing approaches are strongly needed to reduce the burden on the healthcare system. The introduction of biosimilars - biological drugs containing the active substance of an already approved reference biological drug - can potentially relieve the burden on healthcare systems. Calculating the costs for three frequently used biosimilars, we simulated the health-economic impact of biosimilars in the real world for the German healthcare system., Methods: Based on available health-economic analyses, the actual prescription and cost containment potential of biosimilars compared to the originator were calculated exemplarily for the cost-intensive therapies trastuzumab in breast cancer, rituximab in follicular lymphoma and G-CSF in supportive care. Incidence calculations were based e.g. on data from the Robert-Koch-Institution, Munich Cancer Registry, and quality indicators of certified centres. Cost calculation was based on Lauer-Taxe® (official reference for pharmaceutical price information)., Results: The application of biosimilars would generate potential annual savings for the chosen examples of up to 4.9 Mio EUR for rituximab in follicular lymphoma, 40.5 Mio EUR for filgrastim, 56.4 Mio EUR for pegfilgrastim, and between 95.9 and 120.5 Mio EUR for trastuzumab., Conclusions: The consequent use of biosimilars allows a considerable reduction of overall treatment costs, especially for cost-intensive long-term maintenance treatments and therapies with high incidences. If the option of biosimilar usage is fully exploited, enormous resources could be released within the healthcare system in order to offset financing new innovative therapies., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The advancement of therapeutic strategies in oncology such as precision oncology has generated significant interest in better estimating the response of modern phase I cancer clinical trials. These estimates have varied widely. In this commentary, we provide an umbrella review of phase I response rates and discuss methodological reasons for variation in prior estimates which include limited use of unpublished data, the inclusion of expansion cohorts that artificially raise response rates of cumulative response rates, varying enrolment of haematologic malignancies, and increased next in class drugs., Competing Interests: Conflict of interest statement V.P. reports receiving research funding from Arnold Ventures royalties from Johns Hopkins Press, Medscape; honoraria for Grand Rounds/lectures from universities, medical centres and non-profit and professional societies consulting fees from United Healthcare speaking fees from Evicorereports being a member of Plenary Session podcast, which has Patreon backers., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Only one class of targeted agents (anti-GD2 antibodies) has been incorporated into front-line therapy for neuroblastoma since the 1980s. The Neuroblastoma New Drug Development Strategy (NDDS) initiative commenced in 2012 to accelerate the development of new drugs for neuroblastoma. Advances have occurred, with eight of nine high-priority targets being evaluated in paediatric trials including anaplastic lymphoma kinase inhibitors being investigated in front-line, but significant challenges remain. This article reports the conclusions of the second NDDS forum, which expanded across the Atlantic to further develop the initiative. Pre-clinical and clinical data for 40 genetic targets and mechanisms of action were prioritised and drugs were identified for early-phase trials. Strategies to develop drugs targeting TERT, telomere maintenance, ATRX, alternative lengthening of telomeres (ALT), BRIP1 and RRM2 as well as direct targeting of MYCN are high priority and should be championed for drug discovery. Promising pre-clinical data suggest that targeting of ALT by ATM or PARP inhibition may be potential strategies. Drugs targeting CDK2/9, CDK7, ATR and telomere maintenance should enter paediatric clinical development rapidly. Optimising the response to anti-GD2 by combinations with chemotherapy, targeted agents and other immunological targets are crucial. Delivering this strategy in the face of small patient cohorts, genomically defined subpopulations and a large number of permutations of combination trials, demands even greater international collaboration. In conclusion, the NDDS provides an internationally agreed, biologically driven selection of prioritised genetic targets and drugs. Improvements in the strategy for conducting trials in neuroblastoma will accelerate bringing these new drugs more rapidly to front-line therapy., Competing Interests: Conflict of interest statement LM has participated in advisory boards for Novartis, AstraZeneca, Roche/Genentech, Mundipharma, Bayer and Amgen, has received honoraria from Celgene and Novartis for educational events and travel grants from Mundipharma, Celgene and Amgen, and is a member of the Executive Committee of SIOPEN, a non-profit organisation that receives royalties for the sales of dinutuximab beta. SGD has received travel expenses from Loxo Oncology, Roche, and Salarius and consulting fee from Loxo Oncology. BG has participated in advisory boards for Roche/Genentech, Bayer, BMS, Celgene, Merck KG, Tesaro and Boehringer Ingelheim. MI provides advice to Bayer Canada. SB is an employee of, and owns shares in, Pfizer Ltd. HC is an employee of, and owns shares in, Hoffman La Roche. SD is an employee of Cyclacel Limited. MM and PM are employees of Astrazeneca. JS is 6-THIO-DG Scientific Founder and MAIA Scientific Advisor. GV provides advice to Roche, BMS, Celgene, Takeda, Aceta Pharma, Merck, Bayer, Servier and Novartis. ADJP provides advice to Novartis, Takeda, Merck, Lilly and Celgene., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: On February 23rd, the 1st case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was diagnosed at the University Hospital Trust of Verona, Italy. On March 13th, the Oncology Section was converted into a 22-inpatient bed coronavirus disease (COVID) Unit, and we reshaped our organisation to face the SARS-CoV-2 epidemic, while maintaining oncological activities., Methods: We tracked down (i) volumes of oncological activities (January 1st - March 31st, 2020 versus the same period of 2019), (ii) patients' and caregivers' perception and (iii) SARS-CoV-2 infection rate in oncology health professionals and SARS-CoV-2 infection-related hospital admissions of "active"' oncological patients., Results: As compared with the same trimester in 2019, the overall reduction in total numbers of inpatient admissions, chemotherapy administrations and specialist visits in January-March 2020 was 8%, 6% and 3%, respectively; based on the weekly average of daily accesses, reduction in some of the oncological activities became statistically significant from week 11. The overall acceptance of adopted measures, as measured by targeted questionnaires administered to a sample of 241 outpatients, was high (>70%). Overall, 8 of 85 oncology health professionals tested positive for SARS-CoV-2 infection (all but one employed in the COVID Unit, no hospital admissions and no treatment required); among 471 patients admitted for SARS-CoV-2 infection, 7 had an "active"' oncological disease (2 died of infection-related complications)., Conclusions: A slight, but statistically significant reduction in oncology activity was registered during the SARS-CoV-2 epidemic peak in Verona, Italy. Organisational and protective measures adopted appear to have contributed to keep infections in both oncological patients and health professionals to a minimum., Competing Interests: Conflict of interest statement M.M. reports receiving personal fees from Pfizer, EUSA Pharma and Astra Zeneca, outside the submitted manuscript. S.P. reports receiving honoraria or speakers' fee from Astra Zeneca, Eli-Lilly, BMS, Boehringer Ingelheim, MSD and Roche, outside the submitted manuscript. All remaining authors have declared no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

It has recently been suggested that precision oncology studies should be reanalysed using the intention-to-treat (ITT) methodology developed for randomized controlled clinical trials. This reanalysis dramatically decreases response rates in precision medicine studies. We contend that the ITT analysis of precision oncology trials is invalid. The ITT methodology was developed three decades ago to mitigate the problems of randomized trials, which try to ensure that both arms have an unselected patient population free from confounders. In contrast, precision oncology trials specifically select patients for confounders (that is biomarkers) that predict response. To demonstrate the issues inherent in an ITT reanalysis for precision cancer medicine studies, we take as an example the drug larotrectinib (TRK inhibitor) approved because of remarkable responses in malignancies harbouring NTRK fusions. Based on large-scale studies, NTRK fusions are found in ~0.31% of tumours. In a non-randomized pivotal study of larotrectinib, 75% of the 55 treated patients responded. Based upon the prevalence of NTRK fusions, ~18,000 patients would need to be screened to enrol the 55 treated patients. Utilizing the ITT methodology, the revised response rate to larotrectinib would be 0.23%. This is, of course, a dramatic underestimation of the efficacy of this now Food and Drug Administration (FDA)-approved drug. Similar issues can be shown for virtually any biomarker-based precision clinical trial. Therefore, retrofitting the ITT analysis developed for unselected patient populations in randomized trials yields misleading conclusions in precision medicine studies., Competing Interests: Conflict of interest statement J.S. receives research funds from Foundation Medicine Inc., Novartis Pharmaceuticals, Blueprint Medicines, and Amgen, as well as consultant fees from Loxo, Biotheranostics, and Grand Rounds. R.K. has research funding from Incyte, Genentech, Merck Serono, Pfizer, Sequenom, Grifols, Omniseq, Foundation Medicine Inc., Guardant Health, and Konica Minolta, as well as consultant fees from Loxo, Actuate Therapeutics, Roche, Xbiotech and NeoMed. She serves as an advisor to Soluventis. She receives speaker fees from Roche, and has an equity interest in IDbyDNA, Curematch, Inc., and Soluventis. All other authors have no relationships to disclose., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Children with cancer often undergo long treatment trajectories involving repeated needle procedures that potentially cause pain and distress. As part of a comprehensive effort to develop clinical practice guidelines (CPGs) to address pain prevention and management in children with cancer, we aimed to provide recommendations on the pharmacological and psychological management of procedure-related pain and distress., Methods: Of the international inter-disciplinary CPG development panel (44 individuals), two working groups including 13 healthcare professionals focused on procedural pain and distress. Grading of Recommendations Assessment, Development and Evaluation methodology was used, including the use of systematic literature reviews to inform recommendations and the use of evidence to decision frameworks. At an in-person meeting in February 2018, the guideline panel discussed these frameworks and formulated recommendations which were then discussed with a patient-parent panel consisting of 4 survivors and 5 parents., Results: The systematic reviews led to the inclusion of 48 randomised controlled trials (total number of participants = 2271). Quality of evidence supporting the recommendations ranged from very low to moderate. Strong recommendations were made for the use of topical anesthetics in all needle procedures, for offering deep sedation (DS)/general anesthesia (GA) to all children undergoing lumbar puncture, for the use of DS/ GA in major procedures in children of all ages, for the use of hypnosis in all needle procedures and for the use of active distraction in all needle procedures., Conclusion: In this CPG, an evidence-based approach to manage procedure-related pain and distress in children with cancer is presented. As children with cancer often undergo repeated needle procedures during treatment, prevention and alleviation of procedure-related pain and distress is of the utmost importance to increase quality of life in these children and their families., Competing Interests: Conflict of interest statement The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: For optimal oncological care, it is recommended to discuss every patient with cancer in a multidisciplinary team meeting (MDTM). This is a time consuming and expensive practice, leading to a growing demand to change the current workflow. We aimed to investigate the number of patients discussed in MDTMs and to identify characteristics associated with not being discussed., Methods: Data of patients with a newly diagnosed solid malignant tumour in 2015 and 2016 were analysed through the nationwide population-based Netherlands Cancer Registry (NCR). We clustered tumour types in groups that were frequently discussed within a tumour-specific MDTM. Tumour types without information about MDTMs in the NCR were excluded. Multivariable logistic regression analyses were used to analyse factors associated with not being discussed., Results: Out of 105.305 patients with cancer, 91% were discussed in a MDTM, varying from 74% to 99% between the different tumour groups. Significantly less frequently discussed were patients aged ≥75 years (odds ratio [OR] = 0.7, 95% confidence interval [CI] = 0.6-0.7), patients diagnosed with disease stage I (OR = 0.5, 95% CI = 0.5-0.6), IV (OR = 0.4, 95% CI = 0.4-0.4) or unknown (OR = 0.2, 95% CI = 0.2-0.2) and patients who received no treatment (OR = 0.3, 95% CI = 0.3-0.3). Patients who received a multidisciplinary treatment were more likely to be discussed in contrary to a monodisciplinary treatment (OR = 4.6, 95% CI = 4.2-5.1)., Conclusion: In general, most patients with cancer were actually discussed in a MDTM, although differences were observed between tumour groups. Factors associated with not being discussed may, at least partially, reflect the absence of a multidisciplinary question. These results form a starting point for debate on a more durable and efficient new MDTM strategy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Academic, industry, regulatory leaders and patient advocates in cancer clinical research met in November 2018 at the Innovation and Biomarkers in Cancer Drug Development meeting in Brussels to address the existing dichotomy between increasing calls for personalised oncology approaches based on individual molecular profiles and the need to make resource and regulatory decisions at the societal level in differing health-care delivery systems around the globe. Novel clinical trial designs, the utility and limitations of real-world evidence (RWE) and emerging technologies for profiling patient tumours and tumour-derived DNA in plasma were discussed. While randomised clinical trials remain the gold standard approach to defining clinical utility of local and systemic therapeutic interventions, the broader adoption of comprehensive tumour profiling and novel trial designs coupled with RWE may allow patient and physician autonomy to be appropriately balanced with broader assessments of safety and overall societal benefit., (Copyright © 2019. Published by Elsevier Ltd.)

Introduction: Cancer in the elderly is a major public issue. However, older patients have long been debarred from clinical trials. There is a high unmet medical need for specific trials addressing oncology strategies adapted to older patients' conditions. While randomised phase III trials remain the gold standard, they usually require large numbers of patients. In this perspective, late single-arm phase II trials assessing treatment feasibility might prove a good alternative. However, it is essential to take into account the heterogeneity in an ageing population characterised by frailty. Standard parallel phase II studies in defined frail and non-frail populations also require a high number of patients. Used in molecular subtyping and treatment effect heterogeneity, stratified adaptive designs can improve statistical performance, but they have never been used in geriatric oncology. This report describes their potential benefits and useful applications as compared with standard designs., Methods: In a heterogeneous population, stratified adaptive designs allowed us to select subgroups of interest in two stages. Operational characteristics were evaluated through simulations of clinical trials under different scenarios., Results: Simulations showed that the use of stratified adaptive designs can efficiently minimise both the number of patients to be included and accrual duration with competitive statistical power and high heterogeneity detection rate at interim analysis., Conclusion: Compared with classical phase II designs, stratified adaptive phase II trial methodology offers a promising approach to improve clinical research in geriatric oncology. These designs may also be efficient in other populations such as children or adolescents and young adults., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Neuro-oncology has evolved as a growing, but still small, highly specialised and multidisciplinary field at the interface of several diagnostic and therapeutic disciplines. The major challenge in the field of primary tumours is to translate the almost unique progress in deciphering the highly complex molecular genetic nature of many primary brain tumours, notably glioblastoma, into advances that allow for clinical benefit for affected patients. Furthermore, metastases to the central nervous system are an increasingly prevalent complication in many systemic cancers. Their diagnosis and management require major expertise, notably with consideration of several new systemic therapy options, such as targeted therapy and immuno-oncology approaches. These new treatments contribute to challenges within the third major domain of neuro-oncology, the diagnosis, treatment and prevention of nervous system toxicity of old and new anti-cancer treatments. All these considerations strongly argue for the development of specialised centres of excellence to improve care for patients with brain tumour across Europe., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Clinical trials investigating immuno-oncology (IO) drug combinations are largely based on empiricism or limited non-clinical evaluations. This study identified the current combination IO drug clinical trials and investigated how tumour molecular profiling can help rationalise IO drug combinations., Methods: IO targets were identified via PubMed search and expert opinion. IO drugs were compiled by searching the National Cancer Institute Drug Dictionary and pharmaceutical pipelines, August 2016. Combination IO trials were obtained by searching doublet IO drug combinations in www.clinicaltrials.gov from September to November 2016. IO target gene expressions were extracted from The Cancer Genome Atlas (TCGA) data set and compared with normal tissues from the Genotype-Tissue Expression database. Differentially expressed genes for each cancer were determined using the Wilcoxon rank-sum test, and p-values were corrected for multiple testing., Results: In total, 178 IO targets were identified; 90 targets have either regulatory approved or investigational therapeutics. In total, 410 combination trials involving ≥2 IO drugs were identified: skin (n = 102) and genitourinary (n = 41) malignancies have the largest number of combination IO trials; 109 trials involved >2 disease sites. Summative patient accrual estimates among all trials are 71,345. Trials combining cytotoxic T lymphocyte antigen 4 (CTLA4) with programmed cell death protein 1 (n = 79) and CTLA4 with programmed cell death ligand 1 (n = 44) are the most common. Gene expression data from TCGA were mined to extract the 178 IO targets in 9089 tumours originating from 19 cancer types. IO target expression-clustered heatmap analysis identified several promising drug combinations., Conclusion: Our review highlights the great interest in combination IO clinical trials. Our analysis can enrich IO combination therapy selection., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Due to the complexity of diagnosis and treatment, care for children and young adolescents with cancer preferably occurs in specialised paediatric oncology centres with potentially better cure rates and minimal late effects. This study assessed where children with cancer in the Netherlands were treated since 2004., Methods: All patients aged under 18 diagnosed with cancer between 2004 and 2013 were selected from the Netherlands Cancer Registry (NCR) and linked with the Dutch Childhood Oncology Group (DCOG) database. Associations between patient and tumour characteristics and site of care were tested statistically with logistic regression analyses., Results: This population-based study of 6021 children diagnosed with cancer showed that 82% of them were treated in a paediatric oncology centre. Ninety-four percent of the patients under 10 years of age, 85% of the patients aged 10-14 and 48% of the patients aged 15-17 were treated in a paediatric oncology centre. All International Classification of Childhood Cancers (ICCC), 3rd edition, ICCC-3 categories, except embryonal tumours, were associated with a higher risk of treatment outside a paediatric oncology centre compared to leukaemia. Multivariable analyses by ICCC-3 category revealed that specific tumour types such as chronic myelogenous leukaemia (CML), embryonal carcinomas, bone tumours other type than osteosarcoma, non-rhabdomyosarcomas, thyroid carcinomas, melanomas and skin carcinomas as well as lower-staged tumours were associated with treatment outside a paediatric oncology centre., Conclusion: The site of childhood cancer care in the Netherlands depends on the age of the cancer patient, type of tumour and stage at diagnosis. Collaboration between paediatric oncology centre(s), other academic units is needed to ensure most up-to-date paediatric cancer care for childhood cancer patients at the short and long term., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Randomised clinical trials (RCTs) are considered the basis of evidence-based medicine. It is recognised more and more that application of RCT results in daily practice of clinical decision-making is limited because the RCT world does not correspond with the clinical real world. Recent strategies aiming at substitution of RCT databases by improved population-based registries (PBRs) or by improved electronic health record (EHR) systems to provide significant data for clinical science are discussed. A novel approach exemplified by the HemoBase haemato-oncology project is presented. In this approach, a PBR is combined with an advanced EHR, providing high-quality data for observational studies and support of best practice development. This PBR + EHR approach opens a perspective on randomised registry trials., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Dose-escalation trials aim to identify the maximum tolerated dose and, importantly, the recommended phase II dose (RP2D) and rely on the occurrence of dose-limiting toxicities (DLTs) during the first treatment cycle. Molecularly targeted agents (MTAs) often follow continuous and prolonged administrations, displaying a distinct toxicity profile compared to conventional chemotherapeutics, and classical DLT criteria might not be appropriate to evaluate MTAs' toxicity. We investigated this issue in children., Methods: The Innovative Therapies for Children with Cancer Consortium (ITCC) phase I trials of novel anticancer agents between 2004 and 2015 were analysed. Data from investigational product, trial design, items defining DLT/RP2D were extracted. A survey on dose-escalation process, DLTs and RP2D definition was conducted among the ITCC clinical trials committee members., Results: Thirteen phase I trials with 15 dose-escalation cohorts were analysed. They explored 11 MTAs and 2 novel cytotoxics; 12 evaluated DLT during cycle 1. Definition of DLT was heterogeneous: Grade III-IV haematologic toxicities that were transient or asymptomatic and grade III-IV non-haematological toxicities manageable with adequate supportive care were often excluded, whereas some included dose intensity or grade II toxicities into DLT. None of the studies considered delayed toxicity into the RP2D definition., Conclusion: DLTs should be homogeneously defined across trials, limiting the number of exceptions due to specific toxicities. Dose escalation should still be based on safety data from cycle 1, but delayed and overall toxicities, pharmacokinetic parameters and pharmacodynamic data should be considered to refine the final RP2D. The evaluation of long-term toxicity in the developing child cannot be adequately addressed in early trials., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The concept of 'personalised medicine' aims at allocating patients to different treatment options based on individual characteristics to optimise treatment benefit and side effects. In oncology, personalised treatments coupled to biomarkers have led to the approval of targeted agents with high anti-tumour activity. However, these therapies are often limited to narrow, molecularly defined subsets of patients with a specific morphomolecular tumour profile. Recently, it became obvious that the same molecular alteration might drive oncogenesis in many different tumours, and it might be beneficial to target the alteration in a histology informed but entity-overarching way. Consequently, Universal Genomic Testing (UGT) of tumours encompassing panel sequencing to whole-exome and transcriptome sequencing is propagated to revolutionise oncology. This article will describe the developments leading to identification and application of potential biomarkers using UGT. On this basis, it will review the clinical evidence of this approach and summarise recommendations for the ongoing evaluation of UGT as the next step in oncological decision-making., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

An urgent need remains for new paediatric oncology drugs to cure children who die from cancer and to reduce drug-related sequelae in survivors. In 2007, the European Paediatric Regulation came into law requiring industry to create paediatric drug (all types of medicinal products) development programmes alongside those for adults. Unfortunately, paediatric drug development is still largely centred on adult conditions and not a mechanism of action (MoA)-based model, even though this would be more logical for childhood tumours as these have much fewer non-synonymous coding mutations than adult malignancies. Recent large-scale sequencing by International Genome Consortium and Paediatric Cancer Genome Project has further shown that the genetic and epigenetic repertoire of driver mutations in specific childhood malignancies differs from more common adult-type malignancies. To bring about much needed change, a Paediatric Platform, ACCELERATE, was proposed in 2013 by the Cancer Drug Development Forum, Innovative Therapies for Children with Cancer, the European Network for Cancer Research in Children and Adolescents and the European Society for Paediatric Oncology. The Platform, comprising multiple stakeholders in paediatric oncology, has three working groups, one with responsibility for promoting and developing high-quality MoA-informed paediatric drug development programmes, including specific measures for adolescents. Key is the establishment of a freely accessible aggregated database of paediatric biological tumour drug targets to be aligned with an aggregated pipeline of drugs. This will enable prioritisation and conduct of early phase clinical paediatric trials to evaluate these drugs against promising therapeutic targets and to generate clinical paediatric efficacy and safety data in an accelerated time frame. Through this work, the Platform seeks to ensure that potentially effective drugs, where the MoA is known and thought to be relevant to paediatric malignancies, are evaluated in early phase clinical trials, and that this approach to generate pre-clinical and clinical data is systematically pursued by academia, sponsors, industry, and regulatory bodies to bring new paediatric oncology drugs to front-line therapy more rapidly., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Randomised controlled trials (RCTs) represent a major source of information on treatment-related adverse events (AEs). In this study, we reviewed the use and the reporting methods of aggregated-AEs (A-AEs) outcomes in RCTs reports published in oncology and compared that to the expectations of European Organisation for Research and Treatment of Cancer (EORTC) membership., Methods: RCTs reports published between 2007 and 2011 were reviewed regarding the reporting of A-AEs-outcomes. A-AEs were defined as summary outcome combining several related AEs, usually grouped by organ system e.g. cardiac-AEs, dermatologic-AEs. Trial characteristics associated with the use of A-AEs outcomes were investigated. The expectation of EORTC members concerning A-AEs utilisation was queried through a survey., Results: Among 325 RCTs published between 2007 and 2011, 94 (29%) included one or more A-AE outcomes. A clear description of the nature of AEs included in such aggregations was provided in 19 articles (20%). No description of A-AEs was conversely provided in the other 75 articles (80%). The most commonly used A-AEs-outcomes were dermatologic-AEs (45%) and cardiac-AEs (33%). In multivariate analysis, the use of A-AEs outcomes was more frequent when trials were conducted in Europe (p = 0.038) and in trials performed on colon/rectal cancers (p = 0.016). Finally, there is no consensus of EORTC members regarding the utilisation of A-AEs but a majority of them (88%) felt that a clear description of A-AEs should systematically be reported., Conclusions: The use of A-AEs is infrequent in oncology RCT manuscripts although their use is accepted by most clinicians. However, a clear definition of A-AEs is strongly recommended if they are to be used in order to avoid a loss of important details about drug toxicities that is useful to clinicians., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Purpose: Correct interpretation of subgroup analyses (SGA) is important as it influences selection of therapeutic interventions for patient subsets. The primary aim of our study was to compare reporting of SGA between industry and non-industry sponsored trials., Methods: We performed a systematic literature review and extracted data from journal articles (JA) and conference abstracts (CA) published over a decade reporting SGA results of phase III randomised controlled gastrointestinal (GI) oncology trials with patient participants of ≥150., Results: In JA, SGA was reported in 100/145 (69%) trials: 41/54 industry sponsored (76%; 95% confidence interval [CI]: 63-86%) and 59/91 non-industry sponsored (65%; 95% CI: 55-74%) trials (p = 0.16). In CA, SGA was reported in 86/204 (42%) trials: 43/83 industry sponsored (52%; 95% CI: 41-62%) and 43/121 non-industry sponsored (36%; 95% CI: 28-44%) trials (p = 0.02). Number of SGA performed per trial was significantly larger for industry compared to non-industry sponsored trials in both JA (median 6 versus 2, p = 0.003) and CA (median 1 versus 0, p = 0.023). Claims of subgroup effect were made in 52% of trials in JA and 50% in CA, with significant test of interaction evident in only 25% of JA and 16% of CA, with no difference between industry and non-industry trials. Industry sponsored trials with a significant primary end-point reported more SGA (p < 0.001 JA; p = 0.046 CA)., Conclusions: Industry sponsored trials reported more SGA. Claimed subgroup effects were often not accompanied by significant interaction test; thus circumspection should be adopted when using SGA to deviate from standard therapeutic decision-making in GI oncology., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Dermatofibrosarcoma protuberans (DFSP) is a skin fibroblastic tumour that is locally aggressive, with a tendency for local recurrence, but rarely metastasizes. A unique collaboration of multi-disciplinary experts from the European Dermatology Forum (EDF), the European Association of Dermato-Oncology (EADO) and the European Organization of Research and Treatment of Cancer (EORTC) was formed to make recommendations on DFSP diagnosis and treatment, based on systematic literature reviews and the experts' experience. Diagnosis is suspected clinically and confirmed by pathology. Analysis by fluorescence in situ hybridisation (FISH) or multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) to detect specific chromosomal translocations and fusion gene transcripts is useful to confirm a difficult DFSP diagnosis. Treatment is mainly surgical, with the aim to achieve complete resection of the tumour. In order to reduce the recurrence rate, the treatment of choice of DFSP seems to be Mohs' micrographic surgery (MMS) and related variants. In hospitals where only standard histopathological procedures are available, standard excision with lateral safety margin of 3cm is advisable. Imatinib (Glivec®) is approved in Europe for the treatment of inoperable primary tumours, locally inoperable recurrent disease, and metastatic DFSP. Imatinib has also been given to patients with extensive, difficult-to-operate tumours for preoperative reduction of tumour size, but the usefulness of this attitude should be confirmed by clinical trials. Therapeutic decisions for patients with fibrosarcomatous DFSP should be primarily made by an interdisciplinary oncology team ('tumour board')., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objective: The aim of this study is to assess age-specific compliance to quality indicators (QIs) regarding the treatment of breast cancer as defined by European Society of Breast Cancer Specialists (EUSOMA) for patients across Europe., Methods: All patients entered into this study were affected by in situ or invasive breast cancer, diagnosed and treated between 2003 and 2012 at 27 Breast Units across Europe, who were entered into the EUSOMA database. Patients were categorised according to age; compliance to thirteen QIs was assessed for each age group and per time period (2003-2007 and 2008-2012). Compliance to QIs was tested by multivariable logistic regression models adjusted for breast unit, incidence year and tumour characteristics., Results: Overall, 41,871 patients with a mean age of 59.6years were available for analysis. The highest compliance was reached for patients aged 55-64years and in the time period 2008-2012, whilst the lowest compliance was observed for women aged over 74 or under 40years and in the earlier time period. In multivariable logistic regression models, a significant difference between age categories was shown for 12 out of 13 QIs (P<0.001). Compliance to the QIs for patients aged ⩾75years was significantly lower when compared to patients aged 55-64years for ten QIs, whilst for patients in the youngest age group this was true for seven QIs., Conclusion: In conclusion, we found that among the 27 included breast units across Europe, compliance to QIs for breast cancer treatment is often lower in the youngest and oldest breast cancer patients, with a tendency to overtreatment in the youngest patients, and to under-treatment in the elderly., (Copyright © 2015. Published by Elsevier Ltd.)

Seven years after the launch of the European Paediatric Medicine Regulation, limited progress in paediatric oncology drug development remains a major concern amongst stakeholders - academics, industry, regulatory authorities, parents, patients and caregivers. Restricted increases in early phase paediatric oncology trials, legal requirements and regulatory pressure to propose early Paediatric Investigation Plans (PIPs), missed opportunities to explore new drugs potentially relevant for paediatric malignancies, lack of innovative trial designs and no new incentives to develop drugs against specific paediatric targets are some unmet needs. Better access to new anti-cancer drugs for paediatric clinical studies and improved collaboration between stakeholders are essential. The Cancer Drug Development Forum (CDDF), previously Biotherapy Development Association (BDA), with Innovative Therapy for Children with Cancer Consortium (ITCC), European Society for Paediatric Oncology (SIOPE) and European Network for Cancer Research in Children and Adolescents (ENCCA) has created a unique Paediatric Oncology Platform, involving multiple stakeholders and the European Union (EU) Commission, with an urgent remit to improve paediatric oncology drug development. The Paediatric Oncology Platform proposes to recommend immediate changes in the implementation of the Regulation and set the framework for its 2017 revision; initiatives to incentivise drug development against specific paediatric oncology targets, and repositioning of drugs not developed in adults. Underpinning these changes is a strategy for mechanism of action and biology driven selection and prioritisation of potential paediatric indications rather than the current process based on adult cancer indications. Pre-competitive research and drug prioritisation, early portfolio evaluation, cross-industry cooperation and multi-compound/sponsor trials are being explored, from which guidance for innovative trial designs will be provided., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The Methodology for the Development of Innovative Cancer Therapies (MDICT) task force discussed incorporation of genomic profiling into early (Phase I and II) clinical trials in oncology. The task force reviewed the challenges of standardising genomics data in a manner conducive to conducting clinical trials. Current barriers to successful and efficient implementation were identified and discussed, as well as the methods of genomic analysis, the proper setting for study and strategies to facilitate timely completion of genomics-based studies. The importance of properly capturing and cataloguing outcomes was also discussed. Several recommendations regarding the use of genomics in these trials are provided., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Clinical decision-making in patients with early stage breast cancer requires adequate risk estimation by medical oncologists. This survey evaluates the agreement among oncologists on risk estimations and adjuvant systemic treatment (AST) decisions and the impact of adding the 70-gene signature to known clinico-pathological factors., Methods: Twelve medical oncologists assessed 37 breast cancer cases (cT1-3N0M0) and estimated their risk of recurrence (high or low) and gave a recommendation for AST. Cases were presented in two written questionnaires sent 4 weeks apart. Only the second questionnaire included the 70-gene signature result., Results: The level of agreement among oncologists in risk estimation (κ=0.57) and AST recommendation (κ=0.57) was 'moderate' in the first questionnaire. Adding the 70-gene signature result significantly increased the agreement in risk estimation to 'substantial' (κ=0.61), while agreement in AST recommendations remained 'moderate' (κ=0.56). Overall, the proportion of high risk was reduced with 7.4% (range: 6.9-22.9%; p<0.001) and the proportion of chemotherapy that was recommended was reduced with 12.2% (range: 5.4-29.5%; p<0.001)., Conclusion: Oncologists' risk estimations and AST recommendations vary greatly. Even though the number of participating oncologists is low, our results underline the need for a better standardisation tool in clinical decision-making, in which integration of the 70-gene signature may be helpful in certain subgroups to provide patients with individualised, but standardised treatment., (Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.)

Introduction: A comprehensive evaluation of breast reconstruction (BRR) surgery includes measurement of patient reported outcomes (PROs). There is, however, a lack of validated BRR-specific PRO measures (PROMs) that adequately assess relevant issues. This study is developing a European Organisation for Research and Treatment of Cancer (EORTC) questionnaire/module specific for PROs in BRR to supplement the cancer-core and breast cancer EORTC questionnaires, respectively: the QLQ-C30 and QLQ-BR23., Methods: Phases I and II of questionnaire development followed EORTC guidelines including a systematic literature review to identify all potential 'issues' (concepts relevant to PROs) and semi-structured interviews with 89 patients and 9 European multi-disciplinary health care professionals (HCPs) (Sweden, Italy and the United Kingdom [UK]). Interviewers asked participants the 'relevance' of outcomes identified in the literature and captured additional 'issues' of importance., Results: The literature search and interviews of patients and HCPs yielded 69 issues relating to BRR operationalised into 31 provisional items (single questions) for the module, which was conceptualised to contain five scales: treatment/surgery related symptoms (affecting the shoulder, arm and reconstructed breast), body image, sexuality, cosmetic outcomes (pertaining to three areas: breast, donor site and nipple) and overall satisfaction., Discussion: The provisional development of the EORTC BRR module has 31 items addressing issues of importance to patients as well as HCPs. Further international testing is underway as a UK National Cancer Research Network trial to ensure that this PROM will be psychometrically and clinically robust and applicable for use in clinical trials, cohort studies, national audit and clinical practice., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Gastro-oesophageal reflux disease (GORD) is assessed by two reflux symptom items in the oesophageal-specific module (QLQ-OES18) of the health-related quality of life (HRQL) questionnaire developed by EORTC. This study validated such assessment of GORD., Methods: This validation study included a random sample of the Swedish population, aged 40-79years, who completed the QLQ-OES18 ('test questionnaire') and a more comprehensive reflux questionnaire ('standard questionnaire') in 2008. In the 'test questionnaire', GORD was defined using two cut-offs for reflux symptoms experienced during the last week. 'Definition 1' represented responses 'quite a bit' or more reflux symptoms and 'definition 2' represented 'a little' or more reflux symptoms. The 'standard questionnaire' assessed GORD during the last 3months., Results: Among 6969 invited individuals, 4910 (70.5%) responded to both questionnaires. There were generally good correlations between the responses to the individual reflux items in the comparison questionnaires. Compared to the 'standard questionnaire', 'definition 1' of GORD in the 'test questionnaire' showed high positive predictive value (0.81), high negative predictive value (0.93) and high specificity (0.99), but low sensitivity (0.32); while 'definition 2' of GORD rendered low positive predictive value (0.39), high negative predictive value (0.98), moderate specificity (0.85) and moderate sensitivity (0.83)., Conclusions: The assessment of GORD in the QLQ-OES18 questionnaire would benefit from adding items and assessing a longer period of history of reflux symptoms and its treatment. As it stands, the choice of cut-off for the response alternatives strongly influences the specificity and sensitivity of the GORD assessment., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background and Aims: Little is known about the epidemiology of rare epithelial digestive cancers. The aim of this study was to report on their incidence, prevalence and survival across Europe., Methods: The analysis was carried out on 50,646 cases diagnosed from 1995 to 2002 within a population of 162,000,000 in 21 European countries. Age-standardised incidence rates were computed using the European standard population. Prevalence rates, relative survival and period survival indicators for the years 2000-2002 were calculated. The expected number of new cases per year and of prevalent cases in Europe was estimated., Results: There were large variations in gallbladder epithelial cancer incidence rates: the incidence in Eastern Europe was 7 times higher than in the UK & Ireland. Differences between incidence rates were smaller for the other sites. The estimated number of new epithelial cancers arising in the EU each year was estimated to be 11,050 for extrahepatic bile duct cancer, 10,713 for gallbladder cancer, 5427 for anal cancer and 3595 for small intestine cancer. The corresponding estimated number of total prevalent cases was 18,483, 15,620, 40,589 and 13,276. There was also a large variation in the 5-year relative survival rate. For epithelial cancer of the anal canal, this varied between 66% (Central Europe) and 44% (Eastern Europe). The corresponding rates for small intestine cancers were 33% and 20%, for extrahepatic bile duct cancers, 17% and 12% and for gallbladder cancer 13% and 10%., Conclusion: There are large variations within Europe in the incidence and survival of rare digestive cancers according to geographic area., (Copyright © 2011. Published by Elsevier Ltd.)

A survey was conducted among European Cancer Organisations by the European CanCer Organisation (ECCO) to evaluate initiatives on cancer guideline development. An electronic questionnaire based on the 'Appraisal of Guidelines Research and Evaluation' (AGREE) instrument was sent to different ECCO members and other Scientific European Organisations involved in cancer care. Between April 2010 and July 2010, 30 European Cancer Organisations (ECOs) were contacted and 21 responded to the questionnaire. Of these, 13 were involved in the production of clinical practice guidelines. The majority of the cancer guidelines were treatment or disease-management related (84.6%). The objectives were appropriate clinical care (76.9%), cost containment (7.7%) or both (23.1%). Almost all organisations developed guidelines for their members but more than half were also aimed at policy makers (53.9%). In 69% of cases, the guidelines were developed according to specific instructions by searches in an electronic data base while in 46.2% there was a manual evaluation of the original articles. Disciplines almost always involved in guideline development groups were the medical and nursing specialities, while in some groups, communication specialists were always involved. Patients, as key stakeholders of the guidelines were involved by eight organisations in their development. The median costs for the development of a cancer guideline were between 25000 and 50,000 euro. This survey shows that many European cancer organisations are producing cancer guidelines. Since their development is both costly and time consuming, a coordinated approach should be encouraged., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Although many imaging biomarkers have been described for cancer research, few are sufficiently robust, reliable and well-characterised to be used as routine tools in clinical cancer research. In particular, biomarkers which show that investigational therapies have reduced tumour cell proliferation, or induced necrotic or apoptotic cell death are not commonly used to support decision-making in drug development, even though such pharmacodynamic effects are common goals of many classes of investigational drugs. Moreover we lack well-qualified biomarkers of propensity to metastasise. The qualification and technical validation of imaging biomarkers poses unique challenges not always encountered when validating biospecimen biomarkers. These include standardisation of acquisition and analysis, imaging-pathology correlation, cross-sectional clinical-biomarker correlations and correlation with outcome. Such work is ideally suited to precompetitive research and public-private partnerships, and this has been recognised within the Innovative Medicines Initiative (IMI), a Joint Undertaking between the European Union and the European Federation of Pharmaceutical Industries and Associations, which has initiated projects in the areas of drug safety, drug efficacy, knowledge management and training., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Magnetic resonance imaging (MRI) can be made sensitive to diffusion of water molecules in biological tissues: this phenomenon can be quantitated to provide a biomarker, the apparent diffusion coefficient (ADC). Over the past decade, evidence has accumulated from numerous clinical and animal studies that ADC is abnormal in tumours; that elevated ADC reflects an elevated non-cellular fraction; and that acute increases in ADC following therapy can indicate that tumour cells have been killed. However there remain substantial challenges in ensuring robust and valid ADC measurements, particularly in multicentre studies in common sites of metastasis such as lung and liver. Moreover, there is uncertainty about how best to select the timing of observation post-therapy to avoid false-negatives, and how to minimise the confounding factors which could decouple drug-induced ADC increase from drug-induced cell kill. In this review we summarise the physical basis of the biomarker, the evidence that it reflects non-viable fraction, particularly in extracranial tumours, and suggest a roadmap for validation and qualification., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Aim of the Study: Clinical practice guidelines (CPG) are an appropriate method to optimise routine clinical care. Numerous CPGs for the diagnosis and treatment of breast cancer have been developed by national health institutions or medical societies. While a comparison of methodological criteria has been undertaken before, it is unknown whether these CPGs differ in their actual treatment recommendations., Methods: We included national breast cancer CPGs from the USA, Canada, Australia, the UK, and Germany that satisfy internationally recognised methodological criteria and are in widespread use in daily clinical care. Treatment recommendations for adjuvant invasive breast cancer including surgery, radiation, endocrine therapy, chemotherapy and anti-HER2-therapy were compared., Results: Recommendations for endocrine therapy show discordances regarding optimal usage of ovarian function suppression for premenopausal patients and aromatase inhibitors for postmenopausal patients. However, most other treatment recommendations exhibit a large degree of congruency. This reflects the fact that they rest on the same evidence base, and that many national guidelines are adopted from other guidelines so that well accepted guidelines are cited within other guidelines., Concluding Statement: Considering that the development of guidelines is a very expensive and resource-intensive task the question arises whether the development of national guidelines in numerous countries is worth the effort since the recommendations differ only marginally., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The incidence of cancer during pregnancy is a rare phenomenon and is estimated to occur in 1:1000 pregnancies. This co-existence is likely to rise since the delay of childbearing to the later reproductive age is nowadays more common in families. The most frequent malignancies diagnosed during pregnancy are breast cancer, cervical cancer, haematological malignancies (lymphomas and acute leukaemias) and melanoma. Less common tumours are gastrointestinal, urological and lung cancers [1]., (Copyright © 2011 Elsevier Ltd. All rights reserved.)