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Introduction: The OligoMetastatic Esophagogastric Cancer (OMEC) project aims to provide clinical practice guidelines for the definition, diagnosis, and treatment of esophagogastric oligometastatic disease (OMD)., Methods: Guidelines were developed according to AGREE II and GRADE principles. Guidelines were based on a systematic review (OMEC-1), clinical case discussions (OMEC-2), and a Delphi consensus study (OMEC-3) by 49 European expert centers for esophagogastric cancer. OMEC identified patients for whom the term OMD is considered or could be considered. Disease-free interval (DFI) was defined as the time between primary tumor treatment and detection of OMD., Results: Moderate to high quality of evidence was found (i.e. 1 randomized and 4 non-randomized phase II trials) resulting in moderate recommendations. OMD is considered in esophagogastric cancer patients with 1 organ with ≤ 3 metastases or 1 involved extra-regional lymph node station. In addition, OMD continues to be considered in patients with OMD without progression in number of metastases after systemic therapy. 18 F-FDG PET/CT imaging is recommended for baseline staging and for restaging after systemic therapy when local treatment is considered. For patients with synchronous OMD or metachronous OMD and a DFI ≤ 2 years, recommended treatment consists of systemic therapy followed by restaging to assess suitability for local treatment. For patients with metachronous OMD and DFI > 2 years, upfront local treatment is additionally recommended., Discussion: These multidisciplinary European clinical practice guidelines for the uniform definition, diagnosis and treatment of esophagogastric OMD can be used to standardize inclusion criteria in future clinical trials and to reduce variation in treatment., Competing Interests: Declaration of Competing Interest Dr. van Laarhoven reports a consultant or advisory role: Amphera, Anocca, Astellas, AstraZeneca, Beigene, Boehringer, Daiichy-Sankyo, Dragonfly, MSD, Myeloid, Servier; Research funding, medication supply, and/or other research support: Auristone, Incyte, Merck, ORCA, Servier; Speaker role: Astellas, Beigene, Benecke, BMS, Daiichy-Sankyo, JAAP, Medtalks, Novartis, Springer, Travel Congress Management B.V. Dr. Muijs reports institutional grants from: Elekta, IBA, RaySearch, Siemens, Mirada, Bergoz Instrumentation and Medical Data Works, KWF, all outside the submitted work. Dr. van Hillegersberg has a consulting and advisory role at Intuitive Surgical, Medtronic, Olympus and J&J Ethicon. Dr. de Manzoni reports personal fees from Lilly, outside the submitted work. Dr. Gani reports travel grants from Elekta and departmental research cooperation, outside the submitted work. Dr. Smyth is supported by the NIHR Biomedical Research Centre at Oxford (the views expressed in this Article are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health) and resports personal fees/grants from: Astra Zeneca, Beigene, BMS, Amal Therapeutics, Amgen, Daiichi Sankyo, Merck, Servier, Novartis, Pfizer, Roche, and Zymeworks, all outside the submitted work. Dr. Haj Mohammad reports consulation fees from: Merck, BMS, Eli Lilly, Astra Zeneca, and research funding from Servier, all outside the submitted work. Dr. Adenis reports grants and personal fees from Bayer, personal fees and non-financial support from MSD, personal fees from: BMS, Novartis, Pierre-Fabre, non-financial support from Servier, grants from Sanofi, all outside the submitted work. Dr. Lordick reports grants from: BMS and Gilead, personal fees from: Amgen, Astellas, Bayer, BMS, Daiichi Sankyo, Eli Lilly, Elsevier, Incyte, Merck, MSD, Roche, Servier, all outside the submitted work. Dr. Slingerland reports an advisory role at BMS and Lilly. Dr. van Berge Henegouwen received researcher-initiated grant from Stryker and is consultant for Alesi Surgical, Johnson and Johnson, Medtronic, BBraun and Viatris. Dr Nilsson reports advisory roles for BMS and Medtronic. Dr. Tabernero reports personal financial interest in form of scientific consultancy role for Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics and TheraMyc; and also educational collaboration with Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER). Dr. Tabernero declares institutional financial interest in form of financial support for clinical trials or contracted research for Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Janssen-Cilag SA, MedImmune, Menarini, Merck Health KGAA, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc, Spanish Association Against Cancer Scientific Foundation and Cancer Research UK. Dr. Nieuwenhuijzen reports advisory/speaker roles from Medtronic and Lilly. All remaining authors have declared no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Local treatment improves the outcomes for oligometastatic disease (OMD, i.e. an intermediate state between locoregional and widespread disseminated disease). However, consensus about the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer is lacking. The aim of this study was to develop a multidisciplinary European consensus statement on the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer., Methods: In total, 65 specialists in the multidisciplinary treatment for oesophagogastric cancer from 49 expert centres across 16 European countries were requested to participate in this Delphi study. The consensus finding process consisted of a starting meeting, 2 online Delphi questionnaire rounds and an online consensus meeting. Input for Delphi questionnaires consisted of (1) a systematic review on definitions of oligometastatic oesophagogastric cancer and (2) a discussion of real-life clinical cases by multidisciplinary teams. Experts were asked to score each statement on a 5-point Likert scale. The agreement was scored to be either absent/poor (<50%), fair (50%-75%) or consensus (≥75%)., Results: A total of 48 experts participated in the starting meeting, both Delphi rounds, and the consensus meeting (overall response rate: 71%). OMD was considered in patients with metastatic oesophagogastric cancer limited to 1 organ with ≤3 metastases or 1 extra-regional lymph node station (consensus). In addition, OMD was considered in patients without progression at restaging after systemic therapy (consensus). For patients with synchronous or metachronous OMD with a disease-free interval ≤2 years, systemic therapy followed by restaging to consider local treatment was considered as treatment (consensus). For metachronous OMD with a disease-free interval >2 years, either upfront local treatment or systemic treatment followed by restaging was considered as treatment (fair agreement)., Conclusion: The OMEC project has resulted in a multidisciplinary European consensus statement for the definition, diagnosis and treatment of oligometastatic oesophagogastric adenocarcinoma and squamous cell cancer. This can be used to standardise inclusion criteria for future clinical trials., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. van Laarhoven reports grants or advisory/speaker role from: Astellas, BMS, Dragonfly, Lilly, Merck, Novartis, Nordic Pharma, Servier; research funding or medical supply from: Bayer, BMS, Celgene, Janssen, Incyte, Lilly, Merck, Nordic Pharma, Philips, Roche, Servier; and has received unrestricted research funding (non-commercial) from: Dutch Cancer Society, NWO/ZonMw, European Research Council, MaagLeverDarm Stichting. Dr. Muijs reports institutional grants from: Elekta, IBA, RaySearch, Siemens, Mirada, Bergoz Instrumentation and Medical Data Works, KWF, all outside the submitted work. Dr. van Hillegersberg has a consulting and advisory role at Intuitive Surgical. Dr. de Manzoni reports personal fees from Lilly, outside the submitted work. Dr. Gani reports travel grants from Elekta and departmental research cooperation, outside the submitted work. Dr. Smyth reports personal fees/grants from: Astra Zeneca, Beigene, BMS, Amal Therapeutics, Amgen, Daiichi Sankyo, Merck, Servier, Novartis, Pfizer, Roche, and Zymeworks, all outside the submitted work. Dr. Haj Mohammad reports consulation fees from: Merck, BMS, Eli Lilly, Astra Zeneca, and research funding from Servier, all outside the submitted work. Dr. Adenis reports grants and personal fees from Bayer, personal fees and non-fianciel support from MSD, personal fees from: BMS, Novartis, Pierre-Fabre, non-financial support from Servier, grants from Sanofi, all outside the submitted work. Dr. Lordick reports grants from: BMS and Gilead, personal fees from: Amgen, Astellas, Bayer, BMS, Daiichi Sankyo, Eli Lilly, Elsevier, Incyte, Merck, MSD, Roche, Servier, all outside the submitted work. Dr. Slingerland reports an advisory role at BMS and Lilly. Dr. van Berge Henegouwen received researcher-initiated grant from Stryker and is consultant for Alesi Surgical, Johnson and Johnson, Medtronic, Braun and Mylan. Dr Nilsson reports advisory roles for BMS and Medtronic. All remaining authors have declared no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Epidemiologic data indicate a significant increase in the incidence of colorectal cancer in younger populations in the past three decades. Moreover, recent evidence also demonstrates a similar trend in gastric, pancreatic, and biliary tract cancers. A majority of these early-onset cases are sporadic and lack hereditary or familial background, implying a potential key role for behavioral, lifestyle, nutritional, microbial, and environmental factors. This review explores the current data on early-onset gastrointestinal cancer, exploring the etiology, unique treatment considerations for this population, future challenges, as well as implications for research and practice., Significance: The worrisome trend of an increasing incidence of early-onset gastrointestinal cancers appears to be correlated with nonhereditary etiologies in which behavioral, lifestyle, nutritional, microbial, and environmental factors, as well as host mechanisms, may play a key role. Further epidemiologic and pathogenetic research is urgently needed to better understand the underlying mechanisms and to develop preventive strategies and tailored early detection. Young patients with gastrointestinal cancer face unique challenges and unmet needs. These must be addressed in the future management of the disease to minimize treatment-related somatic morbidity and prevent psychosocial sequelae., (©2023 American Association for Cancer Research.)

The new era of immunotherapy is successfully implemented in the treatment of metastatic/locally advanced esophagogastric adenocarcinoma (EGAC), as it has been investigated in combinations with/without chemotherapy in human epidermal growth factor receptor 2 (Her2)-positive and Her2-negative tumors. Recent approvals of immune checkpoint inhibitors (ICI) enrich the therapeutic landscape in nearly every therapeutic line. Based on CHECKMATE-649, the combination of nivolumab and chemotherapy in first-line therapy of programmed cell death protein 1 (PD-L1)-positive patients with advanced gastroesophageal junction cancer (GEJC), esophageal cancer (EC), and gastric cancer (GC) was approved in Europe for PD-L1 combined positivity score (CPS) ≥ 5 patients and independently from PD-L1 score in the USA and Asia. Based on KEYNOTE-590, patients with advanced GEJC and EC qualify for the combination of pembrolizumab plus chemotherapy in Europe (CPS ≥ 10) and the USA. For Her2-positive patients, trastuzumab with first-line chemotherapy plus pembrolizumab has beneficial response rates and resulted in approval in the USA (KEYNOTE-811). In third-line therapy, superior overall survival (OS) was achieved by the administration of nivolumab (approval in Japan, ATTRACTION-02), and pembrolizumab shows a positive effect on the duration of response (KEYNOTE-059). Questions of resistance to immunotherapy or the role of gender in response to ICI need to be clarified. This review provides an overview of the current approvals of ICI in advanced EGAC and reflects results of relevant phase II/III trials with focus on possible biomarkers, including PD-L1 CPS and microsatellite-instability (MSI) status., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M.M. advisory roles for BMS, MSD, Merck, Amgen, BeiGene, Novartis, Lilly, Macrogenics, Roche, Sanofi, Servier, and Taiho. A.H. was a member of the advisory board of BMS. A.D. Wagner: Consultant or advisory role: Merck, Lilly, Pierre Fabre Pharma, Sanofi, Daichii Sankyo, Dragon-Fly Therapeutics, Servier, BMS, Astellas. I am coordinating investigator of EORTC-TRIAL 1203, which is supported by an educational grant from Roche to EORTC. R.O.: reports personal fees from BMS, Servier, Merck, Merck KGaA and a research grant from Roche (institutional). M.A.: Maria Alsina reports financial interest in form of scientific consultancy role for Amgen, BMS, MSD, Lilly and Servier. P.T-P.: Honoraria for advisory role: Astellas, BMS, Lilly, Merck, MSD, Nordic, Pfizer, Roche, Teva, Research Grants: Merck, GSK, Novartis. H.v.L: Consultant or advisory role: BMS, Dragonfly, Lilly, Merck, Nordic Pharma, Servier. Research funding and/or medication supply: Bayer, BMS, Celgene, Janssen, Incyte, Lilly, Merck, Nordic Pharma, Philips, Roche, Servier., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Recently, we have witnessed impressive diagnostic and therapeutic changes for gastrointestinal cancer patients. New challenges brought by the COVID-19 pandemic have led us to re-evaluate our work priorities. Thanks to the commendable resilience of both investigators and patients, however, clinical research never stopped. In addition to conducting cutting-edge research and serving patients' needs, as EORTC Gastrointestinal Tract Cancer Group, we are committed to pursuing educational initiatives beneficial to the entire European oncology community and beyond. In this regard, we have been providing critical discussions of new data from major international meetings. In this article, we discuss results of important selected studies presented at the 2022 ASCO Gastrointestinal Cancer Symposium, putting them in perspectives and highlighting potential implications for routine practice. With the number of in-person attendees and practice-changing/informing trials presented, this meeting represented a milestone in the return to normality as well as in the fight against cancer., Competing Interests: Declaration of Competing Interest Francesco Sclafani. Consultancy/advisory role and honoraria: AMAL Therapeutics, Bayer, Bristol-Myers Squibb, Dragonfly Therapeutics, Nordic Pharma, Roche. Grants/Research funding: Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Roche, Sanofi. Travel grants: Bayer, Lilly. Supported by: La Fondation Contre le Cancer. Elisa Fontana. Employee of Hospital Corporation of America (HCA) International. Anna Dorothea Wagner. Consultancy/advisory role and honoraria: Astellas Pharma, Bristol-Myers Squibb, Daiichi Sankyo, Dragonfly Therapeutics, Merck, Hoffmann-La Roche, Lilly, Pierre Fabre Pharma, Sanofi, Servier. Grants/Research funding: Roche. Juan Valle. Consultancy/advisory role and honoraria: Agios, AstraZeneca, Baxter, Genoscience Pharma, Hutchison Medipharma, Imaging Equipment Ltd (AAA), Incyte, Ipsen, Mundipharma EDO, Mylan, NuCana, QED, Servier, Sirtex, Zymeworks. Grants: NuCana. Elizabeth Smyth. Consultancy/advisory role and honoraria: AMAL Therapeutics, AstraZeneca, Astellas, Beigene, Bristol-Myers Squibb, Celgene, Elsevier, Five Prime Therapeutics, Gritstone Oncology, Merck, Novartis, Pfizer, Roche, Servier, Zymeworks. Grants/Research funding: Bristol-Myers Squibb. Radka Obermannova. Consultancy/advisory role and honoraria: Bristol-Myers Squibb, Merck, MSD, Servier. Grants/Research funding: Roche. Cindy Neuzillet. Consultancy/advisory role and honoraria: Amgen, AstraZeneca, Baxter, Bristol-Myers Squibb, Fresenius Kabi, Incyte Biosciences, Merck, MSD, Mylan, Novartis, Nutricia, Pierre Fabre, Roche, Sanofi, Servier D. Grants/Research funding: AstraZeneca, Fresenius Kabi, Nutricia, OSE Immunotherapeutics, Roche, Servier. Manfred P Lutz. Consultancy/advisory role and honoraria: Servier. Thibaud Koessler. Consultancy/advisory role and honoraria: AMAL Therapeutics, Bayer, Boehringer Ingelheim, Lilly, Merck, MSD, Roche, Vifor. Dirk Arnold. Consultancy/advisory role and honoraria: ACE Oncology, Amgen, Art Tempi Media, Astra Zeneca, Bayer, Boston Scientific, Bristol-Myers Squibb, Personal Aptitude Health, Clinical Care Options (CCO), CRA International, Eli Lilly, Hexal, Imedex, Ipsen, IQVIA, Ketchum, MedAhead, Merck Serono, Merck, Sharp and Dome, PharmaCept, Pierre Fabre Pharma, PRMA Consulting, Roche, Samsung Bioepsis, Sanofi Genzyme, Servier, Streamitup Germany, Tactics MD LLC, Terumo, WebMD Health Corp, Elsevier. Leadership positions: OncoLytics (Project Lead). Maria Alsina. Consultancy/advisory role and honoraria: Amgen, Bristol-Myers Squibb, MSD, Lilly, Servier. Markus Moehler. Consultancy/advisory role and honoraria: Amgen, Bristol-Myers Squibb, Lilly, MCI Group, Merck Serono, MSD, Pfizer, Roche, Taiho. Grants/Research funding: AIO, Amgen, BMBF or HORIZON Europe, Bristol-Myers Squibb, EORTC, German Cancer Aid, Merck Serono, MSD, Pfizer. All conflicts of interest declared by the authors are outside the submitted work. All other authors have declared no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Gastric carcinoma and gastro-oesophageal junction (GC/GEJ) carcinoma remain a significant global problem, with patients presenting with symptoms often found to have advanced or metastatic disease. Treatment options for these patients have broadened in recent years with new chemotherapy agents, agents targeting angiogenic pathways and the development of immune checkpoint inhibitors (ICIs). Most initial advances have occurred in the refractory setting, where it is important to balance treatment benefits versus toxicity and patient quality of life. In the first-line treatment of advanced/metastatic GC/GEJ, platinum- and fluoropyrimidine-based chemotherapy protocols remain the backbone of therapy (with or without HER2- targeted therapy), with the FOLFIRI regimen offering an alternative in patients deemed unsuitable for a platinum agent. Microsatellite instability-high or mismatch repair-deficient cancers have been shown to benefit most from ICIs. In unselected patients previously treated with doublet or triplet platinum- and fluoropyrimidine-based chemotherapy and second-line chemotherapy with irinotecan or taxanes have formed the backbone of therapy with or without the addition of the vascular endothelial growth factor receptor-2 inhibitor ramucirumab in addition to paclitaxel. Beyond this, efficacy has been demonstrated with oral trifluridine/tipiracil and with single-agent nivolumab, in selected refractory patients. In this review, we highlight the positive evidence from key trials that have led to our current practice algorithm, with particular focus on the refractory advanced disease setting, discussing the areas of active research and highlighting the factors, including biomarkers and the influence of ethnicity, that contribute to therapeutic decision-making., Competing Interests: Competing Interests: All authors have no COI directly related to this work. BUT COI Statements from authors with industry unrelated to this work are as follows: Nick Pavlakis: Advisory Boards MSD, Merck, BMS, Takeda, Beigene, Astra Zeneca, Roche, Amgen, Novartis Speaking Honoraria Roche, Pierre-Faber Research Funding – to institution Bayer, Roche Christos Karapetis: Advisory Board Amgen, Astra Zeneca, Beigene, BMS, Eli Lilly, Eisai, Ipsen, Merck, MSD, Pierre Fabre, Roche, Takeda Timothy Price: Advisory Board MSD, Merck Serono, Pierre Fabre, BMS, Servier Radka Obermannova: Personal fee BMS, Merck, MSD, Servie Research support (to institution): Roche Florian Lordick: Honorari BMS, MSD, Roche, Astra Zeneca Lorraine Chantrill: Advisory Board Pierre Fabre, AstraZeneca, BMS, Merck, (© The Author(s), 2022.)

Background: Perioperative chemotherapy is a recommended treatment approach for localised oesophago-gastric junction adenocarcinoma, but not all patients respond to neoadjuvant chemotherapy. Early identification of non-responders and treatment adaptation in the preoperative period could improve outcomes. GastroPET is a national, multicentre phase II trial evaluating a 18 FDG-PET/CT-guided preoperative treatment strategy with the R0 resection rate as a primary endpoint. Here, we report on the accuracy of the methodology, the feasibility of the study design and patient safety data after enrolment of the first 63 patients., Methods: Patients with locally advanced oesophago-gastric junction adenocarcinoma (Siewert I - III) stage Ib-IIIc underwent baseline 18FDG-PET/CT scanning and re-evaluation after 14 days of oxaliplatinum-5FU-(docetaxel) chemotherapy. Responders were defined by a ⩾ 35% decrease in tumour FDG standardised uptake value (SUV) average from baseline. Responders continued with the same chemotherapy for 2 to 3 months prior to surgery. PET-non-responders switched to preoperative chemoradiotherapy [weekly carboplatin and paclitaxel with concurrent radiotherapy (45 Gy in 25 fractions)]. Here, we aim to confirm the feasibility of FDG-PET-based response assessment in a multicenter setting and to compare local versus central reading. In addition, we report on the feasibility of the study conduct and patient safety data., Results: A total of 64 patients received baseline and sequential 14-day 18FDG-PET/CT scanning. And, 63 were allocated to the respective treatment arm according to PET-response [35 (56%) responders and 28 (44%) non-responders]. The concordance of local versus central reading of SUV changes was 100%. Until the date of this analysis, 47 patients (28 responders and 19 non-responders) completed surgery. Postoperative complications of grade ⩾ 3 (Common Terminology Criteria for Adverse Events, CTCAE Version 5.0) were reported in five responders (18%; 95% CI: 7.9-36%) and two non-responders (11%; 95% CI: 2.9-31%), with no statistical difference ( p  = 0.685). One patient in each arm died after surgery, leading to a postoperative in-hospital mortality rate of 4.3% (2/47 patients; 95% CI: 1.2-14%)., Conclusion: Local and central FDG-SUV quantification and PET-response assessment showed high concordance. This confirms the accuracy of a PET-response-guided treatment algorithm for locally advanced oesophago-gastric junction cancer in a multicenter setting. Preoperative treatment adaptation revealed feasible and safe for patients., Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article., (© The Author(s), 2021.)

Background and Objectives : The treatment of gastroesophageal junction (GEJ) adenocarcinoma consists of either perioperative chemotherapy or preoperative chemoradiotherapy. Radiotherapy (RT) in the neoadjuvant setting is associated with a higher probability of resections with negative margins (R0) and better tumor regression rate, which might be enhanced by incrementing RT dose with potential impact on treatment results. This virtual planning study demonstrates the feasibility of increasing the dose to GEJ tumor and involved nodes using PET/CT imaging. Materials and Methods : 16 patients from the chemoradiotherapy arm of the phase II GastroPET study were treated by a prescribed dose of 45.0 Gray (Gy) in 25 fractions. PET/CT was performed before treatment. The prescribed dose was virtually boosted on PET/CT-positive areas to 54.0 Gy by 9 Gy in 5 fractions. Dose-volume histograms (DVH) were compared, and normal tissue complication (NTCP) modeling was performed for both dose schedules. Results : DVHs were exceeded in mean heart dose in one case for 45.0 Gy and two cases for 54.0 Gy, peritoneal space volume criterion V 45Gy < 195 ccm in three cases for 54.0 Gy and V 15Gy < 825 ccm in one case for both dose schedules. The left lung volume of 25 Gy isodose exceeded 10% in most cases for both schedules. The NTCP values for the heart, spine, liver, kidneys and intestines were zero for both schemes. An increase in NTCP value was for lungs (median 3.15% vs. 4.05% for 25 × 1.8 Gy and 25 + 5 × 1.8 Gy, respectively, p = 0.013) and peritoneal space (median values for 25 × 1.8 Gy and 25 + 5 × 1.8 Gy were 3.3% and 14.25%, respectively, p < 0.001). Conclusion: Boosting PET/CT-positive areas in RT of GEJ tumors is feasible, but prospective trials are needed.

Background LY3022855 is a recombinant, immunoglobulin, human monoclonal antibody targeting the colony-stimulating factor-1 receptor. This phase 1 trial determined the safety, pharmacokinetics, and antitumor activity of LY3022855 in combination with durvalumab or tremelimumab in patients with advanced solid cancers who had received standard anti-cancer treatments. Methods In Part A (dose-escalation), patients received intravenous (IV) LY3022855 25/50/75/100 mg once weekly (QW) combined with durvalumab 750 mg once every two weeks (Q2W) IV or LY3022855 50 or 100 mg QW IV with tremelimumab 75/225/750 mg once every four weeks. In Part B (dose-expansion), patients with non-small cell lung cancer (NSCLC) or ovarian cancer (OC) received recommended phase 2 dose (RP2D) of LY3022855 from Part A and durvalumab 750 mg Q2W. Results Seventy-two patients were enrolled (median age 61 years): Part A = 33, Part B = 39. In Part A, maximum tolerated dose was not reached, and LY3022855 100 mg QW and durvalumab 750 mg Q2W was the RP2D. Four dose-limiting equivalent toxicities occurred in two patients from OC cohort. In Part A, maximum concentration, area under the concentration-time curve, and serum concentration showed dose-dependent increase over two cycles of therapy. Overall rates of complete response, partial response, and disease control were 1.4%, 2.8%, and 33.3%. Treatment-emergent anti-drug antibodies were observed in 21.2% of patients. Conclusions LY3022855 combined with durvalumab or tremelimumab in patients with advanced NSCLC or OC had limited clinical activity, was well tolerated. The RP2D was LY3022855 100 mg QW with durvalumab 750 mg Q2W. ClinicalTrials.gov ID: NCT02718911 (Registration Date: May 3, 2011)., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Biliary tract cancers are aggressive, rare, gastrointestinal malignancies with a poor prognosis; approximately half of patients with these cancers survive for less than 1 year after diagnosis with advanced disease. We aimed to evaluate the efficacy and safety of ramucirumab or merestinib in addition to first-line cisplatin-gemcitabine in patients with locally advanced or metastatic biliary tract cancer., Methods: We did a randomised, double-blind, phase 2 study at 81 hospitals across 18 countries. We enrolled patients with histologically or cytologically confirmed, non-resectable, recurrent, or metastatic biliary tract adenocarcinoma, who were treatment-naive, aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0 or 1, estimated life expectancy of 3 months or more, and measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1. Eligible participants were randomly assigned (2:1:2:1) to receive either intravenous ramucirumab 8 mg/kg or placebo (on days 1 and 8 in 21-day cycles) or oral merestinib 80 mg or placebo (once daily) until disease progression, unacceptable toxicity, death, or patient or investigator request for discontinuation. All participants received intravenous cisplatin 25 mg/m 2 and gemcitabine 1000 mg/m 2 (on days 1 and 8 in 21-day cycles), for a maximum of eight cycles. Randomisation was done by an interactive web response system using a permuted block method (blocks of six) and was stratified by primary tumour site, geographical region, and presence of metastatic disease. Participants, investigators, and the study funder were masked to treatment assignment within the intravenous and oral groups. The primary endpoint was investigator-assessed progression-free survival (in the intention-to-treat population). The safety analysis was done in all patients who received at least one dose of their assigned treatment. This trial is registered with ClinicalTrials.gov, NCT02711553, and long-term follow-up is ongoing., Findings: Between May 25, 2016, and Aug 8, 2017, 450 patients were assessed for eligibility and 309 (69%) were enrolled and randomly assigned to ramucirumab (n=106), merestinib (n=102), or pooled placebo (n=101); 306 received at least one dose of study treatment. The median follow-up time for progression-free survival at data cutoff (Feb 16, 2018) was 10·9 months (IQR 8·1-14·1). Median progression-free survival was 6·5 months (80% CI 5·7-7·1) in the ramucirumab group, 7·0 months (6·2-7·1) in the merestinib group, and 6·6 months (5·6-6·8) in the pooled placebo group (ramucirumab vs placebo hazard ratio 1·12 [80% CI 0·90-1·40], two-sided stratified p=0·48; merestinib vs placebo 0·92 [0·73-1·15], two-sided stratified p=0·64). The most common grade 3 or worse adverse events were neutropenia (51 [49%] of 104 patients in the ramucirumab group; 48 [47%] of 102 in the merestinib group; and 33 [33%] of 100 in the pooled placebo group), thrombocytopenia (36 [35%]; 19 [19%]; and 17 [17%]), and anaemia (28 [27%]; 16 [16%]; and 19 [19%]). Serious adverse events occurred in 53 (51%) patients in the ramucirumab group, 56 (55%) in the merestinib group, and 48 (48%) in the pooled placebo group. Treatment-related deaths (deemed related by the investigator) occurred in one (1%) of 104 patients in the ramucirumab group (cardiac arrest) and two (2%) of 102 patients in the merestinib group (pulmonary embolism [n=1] and sepsis [n=1])., Interpretation: Adding ramucirumab or merestinib to first-line cisplatin-gemcitabine was well tolerated, with no new safety signals, but neither improved progression-free survival in patients with molecularly unselected, locally advanced or metastatic biliary tract cancer. The role of these targeted inhibitors remains investigational, highlighting the need for further understanding of biliary tract malignancies and the contribution of molecular selection., Funding: Eli Lilly and Company., Competing Interests: Declaration of interests JWV reports personal fees from Agios, AstraZeneca, Debiopharm, Delcath Systems, Genoscience Pharma, Imaging Equipment, Incyte, Ipsen, Keocyt, Merck, Mundipharma EDO, Novartis, PCI Biotech, Pieris Pharmaceuticals, QED, and Wren Laboratories; personal fees and non-financial support from Pfizer; grants and personal fees from Servier; and grants, personal fees, and non-financial support from NuCana, outside of the submitted work. AV reports personal fees from Eli Lilly and Company, during the conduct of the study; and personal fees from Roche, AstraZeneca, EISAI, Bayer, Merck, Bristol Myers Squibb, Merck Sharp & Dohme, Incyte, PierreFabre, Ipsen, and Sanofi, outside of the submitted work. CSD reports honoraria from Bristol Myers Squibb, Merck Zymeworks, BeiGene, Taiho Onoclogy, Exelixis, Eli Lilly and Company, Astellas, and Bayer; grants and personal fees from Bristol Myers Squibb, Zymeworks, Beigene, and Exelixis; personal fees from Merck, Taiho Oncology, Eli Lilly and Company, Astellas, and Bayer; grants and non-financial support from AstraZeneca; and grants from Amgen, Agios Pharmaceuticals, Array BioPharma, Genmab, Macrogenics, and Merrimack Pharmaceuticals, outside of the submitted work. J-SC reports grants from Eli Lilly and Company, Ono Pharmaceutical, Janssen, AstraZeneca, Merck KGaA, Astellas Pharma, Senhwa Biosciences, and Syncore, outside of the submitted work. EVC reports consulting fees from Array, Astellas, AstraZeneca, Bayer, Biocartis, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Daiichi, Halozyme, GlaxoSmithKline, Incyte, Ipsen, Eli Lilly and Company, Merck Sharp & Dohme, Merck KGaA, Novartis, Pierre Fabre, Roche, Servier, Sirtex, and Taiho; and grants from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Ipsen, Eli Lilly and Company, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, and Servier paid to the institution, outside of the submitted work. L-TC reports grants from Ministry of Science and Technology, Taiwan, Ministry of Health and Welfare, Taiwan, Pfizer, GlaxoSmithKline, Merck Serono, OBI, and Polaris; personal fees from Eli Lilly and Company, PharamEngine, Shire, Merck Sharp & Dohme, Bristol Myers Squibb, ONO, and Five Prime; grants and non-financial support from Celgene; and grants, personal fees, and non-financial support from Novartis, TTY, and Syncore, outside of the submitted work. HW reports personal fees and non-financial support from CELGENE; non-financial support from AstraZeneca; personal fees and honoraria from Incyte; grants, personal fees, and consulting from SIRTEX medical; personal fees from and advisory board for Zymeworks; and personal fees from BTG, outside of the submitted work. L-YB reports funding related to the JSBF clinical trial from Eli Lilly and Company, during the conduct of the study. RC was employed by Eli Lilly and Company, during the conduct of the study; and is a shareholder of Eli Lilly and Company, outside of the submitted work. RAW reports employment with and stock ownership in Eli Lilly and Company, during the conduct of the study; and has patents pending related to clinical use of merestinib and ramucirumab. ACG, WZ, JL, CT, PJE, AA, SCM, and BAM were employees and shareholders of Eli Lilly and Company, during the conduct of the study. JMO was an employee of Eli Lilly and Company, during the conduct of the study. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Last year the field of immunotherapy was finally introduced to GI oncology, with several changes in clinical practice such as advanced hepatocellular carcinoma or metastatic colorectal MSI-H. At the virtual ASCO-GI symposium 2021, several large trial results have been reported, some leading to a change of practice. Furthermore, during ASCO-GI 2021, results from early phase trials have been presented, some with potential important implications for future treatments. We provide here an overview of these important results and their integration into routine clinical practice., (© 2021. The Author(s).)

Pathological complete response (pCR) achievement is undoubtedly the essential goal of neoadjuvant therapy for breast cancer, directly affecting survival endpoints. This retrospective study of 237 triple-negative breast cancer (TNBC) patients with a median follow-up of 36 months evaluated the role of adding platinum salts into standard neoadjuvant chemotherapy (NACT). After the initial four standard NACT cycles, early clinical response (ECR) was assessed and used to identify tumors and patients generally sensitive to NACT. BRCA1/2 mutation, smaller unifocal tumors, and Ki-67 ≥ 65% were independent predictors of ECR. The total pCR rate was 41%, the achievement of pCR was strongly associated with ECR (OR = 15.1, p < 0.001). According to multivariable analysis, the significant benefit of platinum NACT was observed in early responders ≥45 years, Ki-67 ≥ 65% and persisted lymph node involvement regardless of BRCA1/2 status. Early responders with pCR had a longer time to death (HR = 0.28, p < 0.001) and relapse (HR = 0.26, p < 0.001). The pCR was achieved in only 7% of non-responders. However, platinum salts favored non-responders' survival outcomes without statistical significance. Toxicity was significantly often observed in patients with platinum NACT ( p = 0.003) but not for grade 3/4 ( p = 0.155). These results based on real-world evidence point to the usability of ECR in NACT management, especially focusing on the benefit of platinum salts.

Background: In a prospective study with long-term follow-up, we analyzed circulating T cell subsets in patients with metastatic colorectal cancer (mCRC) in the context of primary tumor sidedness, KRAS status, and clinical outcome. Our primary goal was to investigate whether baseline levels of circulating T cell subsets serve as a potential biomarker of clinical outcome of mCRC patients treated with an anti-VEGF-based regimen., Methods: The study group consisted of 36 patients with colorectal adenocarcinoma who started first-line chemotherapy with bevacizumab for metastatic disease. We quantified T cell subsets including Tregs and CD8 + T cells in the peripheral blood prior to therapy initiation. Clinical outcome was evaluated as progression-free survival (PFS), overall survival (OS), and objective response rate (ORR)., Results: 1) mCRC patients with KRAS wt tumors had higher proportions of circulating CD8 + cytotoxic T cells among all T cells but also higher measures of T regulatory (Treg) cells such as absolute count and a higher proportion of Tregs in the CD4 + subset. 2) A low proportion of circulating Tregs among CD4 + cells, and a high CD8:Treg ratio at initiation of VEGF-targeting therapy, were associated with favorable clinical outcome. 3) In a subset of patients with primarily right-sided mCRC, superior PFS and OS were observed when the CD8:Treg ratio was high., Conclusions: The baseline level of circulating immune cells predicts clinical outcome of 1st-line treatment with the anti-VEGF angio/immunomodulatory agent bevacizumab. Circulating immune biomarkers, namely the CD8:Treg ratio, identified patients in the right-sided mCRC subgroup with favorable outcome following treatment with 1st-line anti-VEGF treatment.

Gastrointestinal (GI) cancers are common in all parts of the world. Effective prevention and early detection of GI cancers are not universally implemented. Therefore, it must be anticipated that the incidence and the mortality of GI cancers will remain high within the next decades. The European Society for Medical Oncology (ESMO) Gastrointestinal Cancer Faculty aims to increase the skills of medical oncologists and other disciplines involved in treating GI malignancies. We aimed to increase the survival chances for patients with GI cancers, augment their quality of life and enable successful return to normal social and professional life during the period of survivorship. ESMO also aims to decrease the economic burden of GI cancer in our societies and national healthcare systems. Therefore, the ESMO Gastrointestinal Cancer Faculty initiated a consensus process based on the Delphi method to identify the most important educational needs of physicians who are concerned with GI malignancies. This paper summarises the process and its results and outlines the mission of ESMO in education., Competing Interests: Competing interests: FL reports receiving grants, personal fees and non-financial support from BMS; and personal fees from Astellas, Astra Zeneca, Biontech, Eli Lilly, Elsevier, Infomedica, Merck, MSD, Roche, Servier and Amgen outside the submitted work. EVC reports participation in advisory boards for Astrazeneca, Bayer, Bristol-Myers Squibb, Celgene, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche and Servier, and receiving research grants from Amgen, Bayer, Boehringer Ingelheim, Celgene, Ipsen, Lilly, Roche, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche and Servier paid to the institution outside the submitted work. JT reports personal fees and others from Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, 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. FC reports receiving personal fees from Roche/Genentech, Merck Serono, Pfizer, Amgen, Servier, Lilly, Bayer, Bristol-Myers Squibb and Celgene; and grants from Bayer, Amgen, and Merck Serono outside the submitted work. AC reports having a consultant or advisory role at Merck Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astelas and Pierre Fabre; receiving research funding from Genentech, Merck Serono, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astelas, Fibrogen, Amcure, Sierra Oncology, Astra Zeneca, Medimmune, BMS, MSD and Pierre Fabre; receiving speaker honoraria from Merck Serono, Roche, Angem, Bayer, Servier and Foundation Medicine; and receiving grant support from Merck Serono and Roche. RO, DV, JYD and KMG have no conflict of interest to declare.

Purpose: The goal of our analysis was to study pretherapeutic circulating 25-OHD plasma levels in patients with previously untreated advanced gastric cancer treated in the randomised controlled phase III Erbitux (cetuximab) in combination with Xeloda (capecitabine) and cisplatin in advanced esophago-gastric cancer (EXPAND) trial (NCT00678535) and to explore whether low 25-OHD plasma levels are associated with worse prognosis and may compromise the clinical efficacy of cetuximab., Methods: Six hundred thirty patients with available pretherapeutic 25-OHD plasma levels and treated with chemotherapy based on capecitabine and cisplatin, or chemotherapy and cetuximab, were included. The Cox proportional hazard regression model was used to analyse the association between low 25-OHD and survival in both treatment arms., Results: Majority of study patients were found to have severe vitamin D deficiency. No prognostic impact of 25-OHD plasma levels could be found in our patient cohort, and there was no indication of an interference of 25-OHD plasma levels and the efficacy of treatment with the anti-epidermal growth factor receptor monoclonal antibody cetuximab., Conclusions: Although majority of patients with advanced gastric cancer show hypovitaminosis D deficiency, there is no proof for a negative impact on survival or reduced treatment response. A prospective study is needed to investigate the potential benefit of vitamin D supplementation in this patient cohort during first-line chemotherapy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Multimodal primary treatment of localised adenocarcinoma of the stomach, the oesophagus and the oesophagogastric junction (AEG) was reviewed by a multidisciplinary expert panel in a moderated consensus session. Here, we report the key points of the discussion and the resulting recommendations. The exact definition of the tumour location and extent by white light endoscopy in conjunction with computed tomography scans is the backbone for any treatment decision. Their value is limited with respect to the infiltration depth, lymph node involvement and peritoneal involvement. Additional endoscopic ultrasound was recommended mainly for tumours of the lower oesophagogastric junction (i.e. AEG type II and III according to Siewert) and in early cancers before endoscopic resection. Laparoscopy to diagnose peritoneal involvement was thought to be necessary before the start of neoadjuvant treatment in all gastric cancers and in AEG type II and III. In general, perioperative multimodal treatment was suggested for all locally advanced oesophageal tumours and for gastric cancers with a clinical stage above T1N0. There was consensus that the combination of fluorouracil, folinic acid, oxaliplatin and docetaxel is now a new standard chemotherapy (CTx) regimen for fit patients. In contrast, the optimal choice of perioperative CTx versus neoadjuvant radiochemotherapy (neoRCTx), especially for AEG, was identified as an open question. Expert treatment recommendations depend on the tumour location, biology, the risk of incomplete (R1) resection, response to treatment, local or systemic recurrence risks, the predicted perioperative morbidity and patients' comorbidities. In summary, any treatment decision requires an interdisciplinary discussion in a comprehensive multidisciplinary setting., (Copyright © 2019. Published by Elsevier Ltd.)

Background/aim: In Western countries, most patients with gastric cancer (GC) present in advanced stages. Therefore, there is imminent clinical need for novel diagnostic and prognostic biomarkers. Deregulation of microRNAs has been reported as a frequent event in GC development in a number of studies. Our study validated the potential of microRNAs to serve as diagnostic and prognostic biomarkers in patients with GC from the Central European population., Materials and Methods: Using quantitative real-time polymerase chain reaction, expression levels of six microRNAs (miR-10b, -21, -93, -107, - 143, and -145) were examined in 67 tumor tissues and 67 paired adjacent gastric tissues, and correlated with clinicopathological features of GC patients., Results: Expression levels of miR-10b, miR-21, miR-93, and miR-107 were significantly higher in GC samples compared to non-tumor tissue. Furthermore, the expression levels of miR-10b, miR-143, and miR-145 positively correlated with advanced stages, and increased expression of miR-10b, miR-21 and miR-145 was significantly associated with worse prognosis of gastric cancer patients., Conclusion: Our results indicate that selected tissue microRNAs have the potential to serve as relevant diagnostic and prognostic biomarkers of GC in a central European population., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Despite recent progress, the outlook for most patients with pancreatic cancer remains poor. There is variation in how patients are managed globally due to differing interpretations of the evidence, partly because studies in this disease are challenging to undertake. This article collates the evidence upon which current best practice is based and offers an expert opinion from an international faculty on how latest developments should influence current treatment paradigms. Areas covered: Optimal chemotherapy for first and subsequent lines of therapy; optimal management of locally advanced, non-metastatic cancer including the role of neoadjuvant chemo(radio)therapy, current evidence for adjuvant chemotherapy, major advances in pancreatic cancer genomics and challenges in supportive care particularly relevant to patients with pancreatic cancer. For each section, literature was reviewed by comprehensive search techniques, including clinical trial websites and abstracts from international cancer meetings. Expert commentary: For each section, a commentary is provided. Overall the challenges identified were: difficulties in diagnosing pancreatic cancer early, challenges for performing randomised clinical trials in all stages of the disease, some progress in systemic therapy with new agents and in identifying molecular subtypes that may be clinically relevant and move towards personalized therapy, but still, pancreatic cancer remains a very poor prognosis cancer with significant palliative care needs.

Purpose: To characterize ramucirumab exposure-response relationships for efficacy and safety in patients with metastatic colorectal cancer (mCRC) using data from the RAISE study., Methods: Sparse pharmacokinetic samples were collected; a population pharmacokinetic analysis was conducted. Univariate and multivariate Cox proportional hazards models analyzed the relationship between predicted ramucirumab minimum trough concentration at steady state (C min,ss ) and survival. Kaplan-Meier analysis was used to evaluate survival from patients in the ramucirumab plus folinic acid, 5-fluorouracil, and irinotecan (FOLFIRI) treatment arm stratified by C min,ss quartiles (Q). An ordered categorical model analyzed the relationship between C min,ss and safety outcomes., Results: Pharmacokinetic samples from 906 patients were included in exposure-efficacy analyses; samples from 905 patients were included in exposure-safety analyses. A significant association was identified between C min,ss and overall survival (OS) and progression-free survival (PFS) (p < 0.0001 for both). This association remained significant after adjusting for baseline factors associated with OS or PFS (p < 0.0001 for both). Median OS was 11.5, 12.9, 16.4, and 16.7, and 12.4 months for ramucirumab C min,ss Q1, Q2, Q3, Q4, and placebo group, respectively. Median PFS was 5.4, 4.6, 6.8, 8.5, and 5.2 months for ramucirumab C min,ss Q1, Q2, Q3, Q4, and placebo group, respectively. The risk of Grade ≥3 neutropenia was associated with an increase in ramucirumab exposure., Conclusions: Exploratory exposure-response analyses suggested a positive relationship between efficacy and ramucirumab exposure with manageable toxicities in patients from the RAISE study with mCRC over the ranges of exposures achieved by a dose of 8 mg/kg every 2 weeks in combination with FOLFIRI.

Background: Angiogenesis is an important therapeutic target in colorectal carcinoma. Ramucirumab is a human IgG-1 monoclonal antibody that targets the extracellular domain of VEGF receptor 2. We assessed the efficacy and safety of ramucirumab versus placebo in combination with second-line FOLFIRI (leucovorin, fluorouracil, and irinotecan) for metastatic colorectal cancer in patients with disease progression during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine., Methods: Between Dec 14, 2010, and Aug 23, 2013, we enrolled patients into the multicentre, randomised, double-blind, phase 3 RAISE trial. Eligible patients had disease progression during or within 6 months of the last dose of first-line therapy. Patients were randomised (1:1) via a centralised, interactive voice-response system to receive 8 mg/kg intravenous ramucirumab plus FOLFIRI or matching placebo plus FOLFIRI every 2 weeks until disease progression, unacceptable toxic effects, or death. Randomisation was stratified by region, KRAS mutation status, and time to disease progression after starting first-line treatment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01183780.ld, Findings: We enrolled 1072 patients (536 in each group). Median overall survival was 13·3 months (95% CI 12·4-14·5) for patients in the ramucirumab group versus 11·7 months (10·8-12·7) for the placebo group (hazard ratio 0·844 95% CI 0·730-0·976; log-rank p=0·0219). Survival benefit was consistent across subgroups of patients who received ramucirumab plus FOLFIRI. Grade 3 or worse adverse events seen in more than 5% of patients were neutropenia (203 [38%] of 529 patients in the ramucirumab group vs 123 [23%] of 528 in the placebo group, with febrile neutropenia incidence of 18 [3%] vs 13 [2%]), hypertension (59 [11%] vs 15 [3%]), diarrhoea (57 [11%] vs 51 [10%]), and fatigue (61 [12%] vs 41 [8%])., Interpretation: Ramucirumab plus FOLFIRI significantly improved overall survival compared with placebo plus FOLFIRI as second-line treatment for patients with metastatic colorectal carcinoma. No unexpected adverse events were identified and toxic effects were manageable., Funding: Eli Lilly., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Alisertib is an investigational, oral, selective inhibitor of aurora kinase A. We aimed to investigate the safety and activity of single-agent alisertib in patients with predefined types of advanced solid tumours., Methods: We did a multicentre phase 1/2 study at 40 centres in four countries (Czech Republic, France, Poland, and the USA). Here, we report results from phase 2; enrolment for the study began on Feb 16, 2010, and ended on May 3, 2013. Adult patients were eligible for the study if they had either breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, or gastro-oesophageal adenocarcinoma that had relapsed or was refractory to chemotherapy. Patients had to have undergone two or fewer previous cytotoxic regimens (four or fewer for breast cancer patients), not including adjuvant or neoadjuvant treatments. Enrolment followed a two-stage design: to proceed to the second stage, two or more objective responses were needed in the first 20 response-assessable patients in each of the five tumour cohorts. Alisertib was administered orally in 21-day cycles at the recommended phase 2 dose of 50 mg twice daily for 7 days followed by a break of 14 days. The protocol-specified primary endpoint was the proportion of patients with an objective response, assessed by Response Evaluation Criteria In Solid Tumors version 1.1 in the response-assessable population (ie, patients with measurable disease who received at least one dose of alisertib and had undergone at least one post-baseline tumour assessment). This completed trial is registered with ClinicalTrials.gov, NCT01045421., Findings: By May 31, 2013, 249 patients had been treated, 53 with breast cancer, 60 with small-cell lung cancer, 26 with non-small-cell lung cancer, 55 with head and neck squamous-cell carcinoma, and 55 with gastro-oesophageal adenocarcinoma. Among response-assessable patients, an objective response was noted in nine (18%, 95% CI 9-32) of 49 women with breast cancer, ten (21%, 10-35) of 48 participants with small-cell lung cancer, one (4%, 0-22) of 23 patients with non-small-cell lung cancer, four (9%, 2-21) of 45 people with head and neck squamous-cell carcinoma, and four (9%, 2-20) of 47 individuals with gastro-oesophageal adenocarcinoma; all were partial responses. Adverse events were similar across tumour types. The most frequent drug-related grade 3-4 adverse events included neutropenia (n=107 [43%]), leukopenia (53 [21%]), and anaemia (26 [10%]). Serious drug-related adverse events were reported in 108 (43%) patients., Interpretation: These data support further clinical assessment of alisertib in patients with solid tumours, particularly those with breast cancer and small-cell lung cancer., Funding: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Data from the Czech national registry were analysed retrospectively to describe treatment outcomes for capecitabine and oxaliplatin (XELOX) regimen with bevacizumab versus 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) regimen with bevacizumab in the first-line therapy for metastatic colorectal cancer (mCRC)., Methods: A national registry containing anonymised individual data on patients treated with targeted therapies was used as a data source. In total, 2,191 mCRC patients who received a first-line therapy with bevacizumab combined with either FOLFOX regimen (n = 1,218, 55.6%) or XELOX regimen (n = 973, 44.4%) were included in the present analysis., Results: No statistically significant difference in survival was observed between the two groups, with median overall survival (OS) of 27.0 months (95% confidence interval [CI] 24.6-29.5 months) and 30.6 months (95% CI 27.8-33.4 months) for FOLFOX/bevacizumab and XELOX/bevacizumab, respectively (p = 0.281). Median progression-free survival (PFS) was 11.4 months (95% CI 10.7-12.1 months) for FOLFOX/bevacizumab and 11.5 months (95% CI 10.8-12.3 months) for XELOX/bevacizumab (p = 0.337). The number of metastatic sites was identified as the most significant predictor of PFS and, together with the presence/absence of metastatic disease at diagnosis, also for OS., Conclusions: According to this large registry-based analysis, XELOX and FOLFOX regimens have similar effectiveness for use in combination with bevacizumab in the first-line treatment of mCRC. Multiple metastatic sites and the presence of metastatic disease at diagnosis were the strongest negative predictors of OS regardless of backbone chemotherapy regimen.

Vitamin D is the third steroid hormone playing important bio-logical roles in the development of breast cancer. Decreased plasma levels of its 25- hydroxyderivative, 25OHD, display robust associations with higher incidence of breast cancer and shorter overall survival. Although no consensus exists, most authors agree that optimal plasma levels shall be within 75- 150 nmol/ l whereas levels higher than 375 nmol/ l can be potentially toxic with higher risk of hypercalcemia. To date, no data are available on the optimal levels of vitamin D related to the risk of breast cancer development, its phenotype features and the course of the disease. Published studies mostly describe associations among higher levels of 25OHD and lower bio-logically aggressiveness of the tumor. The polymorphism of VDR gene coding for the steroid receptor for vitamin Dmay be associated with higher disease incidence and also be of negative prognostic significance in breast cancer. This review presents an overall summary of the current knowledge and publications on vitamin D and breast cancer.

Phase I trials in oncology usually enrolling patients with advanced disease who have failed standard treatment options. The primary endpoint of these studies is to establish the recommended dose and/or schedule of new drugs or drug combinations for phase II trials. The guiding principle for dose escalation in phase I trials is to avoid unnecessary exposure of patients to sub-therapeutic doses of an agent. The mission of phase I clinical trials is to accelerate the development of new anticancer drugs with the purpose of improving quality of life and survival for patients with cancer.