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This article summarises expert discussion on the management of patients with hepatocellular carcinoma (HCC), which took place during the 24th World Gastrointestinal Cancer Congress (WGICC) in Barcelona, July 2022. A multidisciplinary approach is mandatory to ensure an optimal diagnosis and staging of HCC, planning of curative and therapeutic options, including surgical, embolisation, ablative strategies, or systemic therapy. Furthermore, in many patients with HCC, underlying liver cirrhosis represents a challenge and influences the therapeutic options., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Metastatic colorectal cancer (mCRC) is a heterogenous disease caused by various genetic alterations. The BRAF V600E mutation occurs in approximately 8-12% of patients and is characterised by an aggressive clinical course and poor prognosis. Here we review the current knowledge on BRAF V600E -mutant mCRC and provide a series of consensus statements on its clinical management. The treatment landscape for BRAF V600E -mutant mCRC has changed greatly due to the emergence of molecular targeted therapies (including BRAF inhibitors) and immune checkpoint inhibitors. A scientific literature search identified available data on molecular testing, treatments, and clinical monitoring of patients with BRAF V600E -mutant mCRC. Consensus statements were discussed and developed by a European expert panel. This manuscript provides consensus management guidance for different clinical presentations of BRAF V600E -mutant mCRC and makes recommendations regarding treatment sequencing choices. To guide appropriate clinical management and treatment decisions for mCRC patients, tumour tissue analysis for DNA mismatch repair/microsatellite status and, at a minimum, KRAS, NRAS, and BRAF mutational status is mandatory at the time of diagnosis. Finally, we discuss the rapidly evolving treatment landscape for BRAF V600E -mutant mCRC and define priorities for the development of novel therapeutic strategies that are needed to improve patient outcomes., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘Andres Cervantes: Institutional research funding from Genentech, Merck Serono, Bristol Myers Squibb, Merck Sharp & Dohme, Roche, Beigene, Bayer, Servier, Lilly, Novartis, Takeda, Astellas, Takeda, and Fibrogen; and advisory board or speaker fees from Amgen, Merck Serono, Roche, Bayer, Servier, and Pierre Fabre in the last 5 years. Dirk Arnold: Participation in advisory boards and as invited speaker for AbbVie, ACE Oncology, Amgen, Aptitude Health, AstraZeneca, Boston Scientific, Bristol Myers Squibb, CRA International, Imedex, Ipsen, Ketchum, Merck, OncoLytics, Pierre Fabre, Roche, Samsung Bioepsis, Sanofi and Servier. Eric Van Cutsem: Participation to advisory boards for Abbvie, ALX, Amgen, Array, Astellas, Astrazeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, GSK, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KgaA, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Takeda, Terumo, Taiho, and Zymeworks; research grants from Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Ipsen, Lilly, Merck Sharp & Dohme, Merck KgaA, Novartis, Roche, and Servier paid to his institution. Erika Martinelli: Honoraria or consultation fees for speaker, consultancy or advisory roles, travel grant for congress participation from Amgen, AstraZeneca, Bayer, Eisai, Incyte, Merck Serono, Pierre Fabre, Roche, Servier, and ESMO. Fortunato Ciardiello: Advisory board member for Amgen, Roche, Merck KgaA, Pfizer, Bayer, Servier, MSD, Pierre Fabre, and Eisai. Harpreet Wasan: Consultant or advisory role: Servier, Pierre Fabre, Incyte, Bayer, Pfizer, Zymeworks, Merck KgaA Roche/Genentech/FM, Amgen, SIRTEX Medical, Erytech Pharma, BMS (Celgene), BTG, and UK NICE/BSI; clinical expert: Bayer, Pierre Fabre, ONCOSIL, Incyte, and Celgene; educational collaboration: Imedex/HMP, Medscape Education, and PeerView Institute for Medical Education and Physicians Education Resource (PER). Josep Tabernero: Consultant or advisory role: scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, and TheraMyc; stock ownership: Oniria Therapeutics; other: educational collaboration with Imedex/HMP, Medscape Education, MJH Life Sciences, and PeerView Institute for Medical Education and Physicians Education Resource (PER). Julien Taieb: Consultant or advisory role: scientific consultancy role for AMGEN, Astellas, AstraZeneca, BMS, F. Hoffmann-La Roche Ltd, Merck Serono, MSD, Novartis, Pfizer, Pierre Fabre, and Servier. Sebastian Stintzing: Consultant or advisory role for Amgen, Astra Zeneca, Bayer, Bayer, BMS, ESAI, Isofol, Lilly, Merck KgaA, MSD, Pierre-Fabre, Roche, Sanofi, Servier, Taiho, and Takeda; honoraria for talks from AMGEN, Astra-Zeneca, Bayer, BMS, ESAI, Isofol, Leo Pharma GmbH, Lilly, Merck KgaA, MSD, Pierre-Fabre, Roche, Sanofi, Servier, Taiho, and Takeda; institutional research funding from Merck KgaA, Pierre-Fabre, Servier, and Roche; other/educational collaborations with Medscape Foundation, COR2ED.’., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Disclosure AK reports personal fees as an invited speaker from Roche; fees paid to his institution for advisory board membership from Roche; institutional funding from Bristol Myers Squibb (BMS); non-remunerated role as a principal investigator for Roche. TB reports fees paid to his institution as a study oncologist, for expert testimony and study-related travel expenses from Roche. CP reports fees paid to her institution as an invited speaker from Roche; institutional funding as a coordinating principal investigator from Roche. GB reports personal fees for advisory board membership from Gensenta; institutional funding as a Steering Committee member from Bayer; non-remunerated roles as a principal investigator for Eli Lilly, Merck Sharp & Dohme (MSD) and Roche; member of the American Society of Clinical Oncology (ASCO). SD reports personal fees as an invited speaker from Bracco Germany; non-remunerated leadership role as President (2010-2012) and Vice-President (2012-2014) of DEGUM (German Ultrasound Society); non-remunerated role as member and chairman of the ‘Radiation Protection in Medicine’ (2017-2020) working group for the Radiation Protection Commission (SSK) at the German Federal Ministry of Environmental Protection. KH has reported no potential conflicts of interest. LM reports a non-remunerated role as co-chair of the Steering Committee for the CUPISCO trial from Roche. HM reports personal fees as an invited speaker from Amgen and Roche; personal fees for advisory board membership from AstraZeneca, Janssen and Merck; institutional funding from Roche. KO reports institutional funding from BioClavis, BioTheranostics and Leica; non-remunerated advisory role as member of Steering Group for Early Detection and Diagnosis of Cancer Roadmap for Cancer Research UK and as member of Innovation Expert Advisory Group (EAG) for NHS England Cancer Innovation Programme; co-author of the RCPath dataset on CUP and malignancy of unknown origin for the Royal College of Pathologists; Cancer Research UK affiliate at the Beatson Institute; member of the National Cancer Research Institute (UK). AP reports personal fees for a congress subscription from Amgen; personal fees for advisory board membership in urothelial cancer from Basilea; personal fees for congress expenses from Janssen. HW reports personal fees as an invited speaker and for advisory board membership from Array BioPharma, Bayer, BMS, Celgene, Erytech, Incyte, Merck KGaA, Pierre Fabre, Servier Sirtex Medical and Roche/Genentech; personal fees for consultancy from OnoSil; personal fees for an advisory role and as a Trial Steering Committee member from Zymeworks; personal fees and institutional funding for an advisory role, as a coordinating principal investigator and member of Trial Steering Committee from Sirtex Medical; non-remunerated advisory roles with Bayer, Pfizer and Pierre Fabre. GZ reports personal fees as an invited speaker from Amgen, Ipsen, Leo Pharma and Merck. GP is the Chief Medical Officer for ESMO and member of ASCO and the Hellenic Cooperative Oncology Group and the Hellenic Society of Medical Oncology (HeCOG). KF reports personal fees for advisory board membership from Curevac and Orion; fees paid to his institution as an invited speaker from Astellas, AstraZeneca, Bayer, Janssen, MSD, Novartis, Pfizer and Sanofi; fees paid to his institution for advisory board membership from AAA, Astellas, AstraZeneca, Bayer, Janssen, MSD, Novartis/AAA and Pfizer; institutional funding as trial chair from AstraZeneca, Bayer, BMS, Janssen, MSD, Orion and Pfizer; non-remunerated role as principal investigator and trial chair for Bayer, BMS, Merck, Novartis/AAA and Orion. TO has declared no conflicts of interest.

Background: The BRAF inhibitor encorafenib in combination with cetuximab was recently approved for patients with BRAF V600E -mutated (BRAF V600E mut) metastatic colorectal cancer (mCRC). Approval was based on positive results from the phase 3 BEACON CRC study in BRAF V600E mut mCRC patients who had progressed after 1-2 previous regimens. This analysis provides a detailed examination of the adverse events (AEs) of interest (AEIs) with encorafenib+cetuximab in the BEACON study to aid gastrointestinal oncologists, given the limited experience with this combination., Materials and Methods: AEIs, including dermatological AEs, arthralgia/myalgia, nausea/vomiting, diarrhea, abdominal pain, fatigue/asthenia and nephrotoxicity, were examined in the doublet therapy group. Clinical characteristics associated with these AEs, AE grade, time to onset and time to resolution were also studied., Results: Safety analysis included 216/220 patients randomized to doublet therapy. The most commonly occurring AEI was dermatological toxicity (75.5%), followed by arthralgia/myalgia (56.0%) and fatigue/asthenia (56.0%). Other than nephrotoxicity (7 patients; 5/7 with Grade 3 or 4), most AEs were Grade 1 or 2. Most AEs were more common in women than men (nausea/vomiting, diarrhea, abdominal pain, dermatological AEs, and arthralgia/myalgia). Nausea/vomiting, abdominal pain and fatigue/asthenia were more common in patients aged ≥70 years. Most AEs developed early, within the first 1-2 months of treatment, and resolved within 1-2 weeks. In addition, survival outcomes were better in patients experiencing arthralgia/myalgia or dermatological toxicities., Conclusion: This analysis indicated that, except for rare cases of nephrotoxicity, encorafenib+cetuximab is well tolerated in most patients, with most AEIs being mild-to-moderate in severity, occurring early and resolving rapidly., Clinical Trial Registration: the BEACON study (ClinicalTrials.gov, NCT02928224; EudraCT, 2015-005805-35)., (Copyright © 2022. Published by Elsevier Inc.)

Background: In the BEACON CRC study (NCT02928224), encorafenib plus cetuximab with binimetinib {9.3 versus 5.9 months; hazard ratio (HR) [95% confidence interval (CI)]: 0.60 [0.47-0.75]} or without binimetinib [9.3 versus 5.9 months; HR (95% CI): 0.61 (0.48-0.77)] significantly improved overall survival (OS) compared with the previous standard of care (control) in patients with BRAF V600E metastatic colorectal cancer (mCRC). Quality of life (QoL) was a secondary endpoint, assessed using validated instruments., Patients and Methods: BEACON CRC was a randomized, open-label, phase III study comparing encorafenib plus cetuximab with or without binimetinib and the investigator's choice of irinotecan plus cetuximab or FOLFIRI plus cetuximab (chemotherapy control) in patients with previously treated BRAF V600E mCRC. Patient-reported QoL assessments included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC) and Functional Assessment of Cancer Therapy-Colorectal (FACT-C). The primary outcome for these tools was time to definitive 10% deterioration., Results: Encorafenib plus cetuximab, both with and without binimetinib, was associated with longer median times to definitive 10% deterioration versus the control group in the EORTC Global Health Status scale [HR (95% CI): 0.65 (0.52-0.80) versus 0.61 (0.49-0.75), respectively] and the FACT-C functional well-being subscale [HR (95% CI): 0.62 (0.50-0.76) versus 0.58 (0.47-0.72), respectively]. Consistent results were observed across all subscales of the EORTC and FACT-C instruments. QoL was generally maintained during treatment for the global EORTC and FACT-C scales., Conclusions: In addition to improving OS, encorafenib plus cetuximab with or without binimetinib delays QoL decline in previously treated patients with BRAF V600E-mutant mCRC., Competing Interests: Disclosure SK: Stock and other ownership interests: MolecularMatch, Navire; consulting or advisory role: Roche, Genentech, EMD Serono, Merck, Karyopharm Therapeutics, Amal Therapeutics, Navire Pharma, Symphogen, Holy Stone, Biocartis, Amgen, Novartis, Eli Lilly, Boehringer Ingelheim; research funding: Amgen (Inst), Sanofi (Inst), Biocartis (Inst), Guardant Health (Inst), Array BioPharma (Inst), Genentech (Inst), EMD Serono (Inst), MedImmune (Inst), Novartis (Inst). AG: Honoraria: Elsevier, Aptitude Health; consulting or advisory role: Genentech (Inst), Bayer (Inst), Bristol-Myers Squibb (Inst), Eli Lilly (Inst), Boston Biomedical (Inst), Amgen (Inst), Array BioPharma (Inst), Guardant Health (Inst), Daiichi Sankyo (Inst); research funding: Genentech (Inst), Bayer (Inst), Pfizer (Inst), Eisai (Inst), Eli Lilly (Inst), Boston Biomedical (Inst), Daiichi Sankyo (Inst), Array BioPharma (Inst); travel, accommodations, expenses: Genentech, Bayer, Bristol-Myers Squibb, Boston Biomedical, Amgen, Boehringer Ingelheim, Merck Sharp & Dohme. EVC: Consulting or advisory role: Array, Bayer, Biocartis, Eli Lilly, Ipsen, Roche, Servier, Bristol-Myers Squibb, Celgene, Merck Sharp & Dohme, Merck KGaA, Novartis, AstraZeneca, Sirtex, Taiho, Pierre Fabre; research funding: Amgen (Inst), Bayer (Inst), Boehringer Ingelheim (Inst), Eli Lilly (Inst), Novartis (Inst), Roche (Inst), Celgene (Inst), Ipsen (Inst), Merck (Inst), Merck KGaA (Inst), Servier (Inst), Bristol-Myers Squibb (Inst). RY: Research funding: Array BioPharma (Inst), Boehringer Ingelheim (Inst), Mirati Therapeutics (Inst); consulting: Array BioPharma, Natera, Mirati Therapeutics. HW: Honoraria: Merck KGaA, Celgene, Sirtex Medical, Servier, Array BioPharma, Shire, Genentech, ERYTECH Pharma, Amgen, Zymeworks, Pierre Fabre; consulting or advisory role: Roche Pharma AG, Sirtex Medical, ERYTECH Pharma, Shire, Incyte; speakers’ bureau: Sirtex Medical, Celgene, Merck KGaA, Servier; research funding: Sirtex Medical (Inst), Merck KGaA (Inst), Pfizer (Inst), Merck Sharp & Dohme (Inst). TY: Research funding: Chugai Pharma (Inst), Sanofi (Inst), Sumitomo Dainippon (Inst), Daiichi Sankyo (Inst), MSD (Inst), Taiho (Inst), Ono (Inst), Amgen (Inst), Parexel International (Inst). JD: Consulting or advisory role: Bionomics, Eli Lilly, Eisai, BeiGene, Ignyta (Inst); research funding: Roche (Inst), GlaxoSmithKline (Inst), Novartis (Inst), Bionomics (Inst), MedImmune (Inst), BeiGene (Inst), Eli Lilly (Inst), Bristol-Myers Squibb (Inst). FC: Consulting or advisory role: Genentech, Merck KGaA, Bayer, Amgen, Pfizer; research funding: Merck KGaA (Inst), Genentech (Inst), Servier (Inst), Symphogen (Inst), Amgen (Inst), Bayer (Inst), Merck Sharp & Dohme (Inst), Bristol-Myers Squibb (Inst), Ipsen (Inst). TKG: Honoraria: Pierre Fabre (inst). NS provided consultation or attended advisory boards for AIMM Therapeutics, Boehringer Ingelheim, Ellipses Pharma and received research grants for the institute from AB Science, Abbvie, Actuate Therapeutics, Amgen, Array, AstraZeneca/MedImmune, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Cantargia, CellCentric, Cytovation, Deciphera, Genentech/Roche, GlaxoSmithKline, Incyte, Lilly, Merck Sharp & Dohme, Merus, Molecular Partners, Novartis, Pfizer, Pierre Fabre, Roche, Sanofi, Taiho, Takeda (outside the submitted work). HTA: Employment: Sarah Cannon Research Institute UK and HCAHealthcare UK; advisory boards: Roche, Servier, Biontech, Beigene, Guardant, Bayer, iOnctura, Bicycle. AB and XZ: Employment: Pfizer Inc. JT: Consulting or advisory role: Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, DaiichiSankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharmaInternational, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Scandion Oncology, Servier, Sotio Biotech, Taiho, Tessa Therapeutics and TheraMyc. And also educational collaboration with Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER). All other authors have declared no conflicts of interest. Data sharing Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer may also provide access to the related individual de-identified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information., (Copyright © 2022 The Pfizer, The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Unresectable locally advanced pancreatic cancer (LAPC) is generally managed with chemotherapy or chemoradiotherapy, but prognosis is poor with a median survival of ∼13 months (or up to 19 months in some studies). We assessed a novel brachytherapy device, using phosphorous-32 ( 32 P) microparticles, combined with standard-of-care chemotherapy., Patients and Methods: In this international, multicentre, single-arm, open-label pilot study, adult patients with histologically or cytologically proven unresectable LAPC received 32 P microparticles, via endoscopic ultrasound-guided fine-needle implantation, planned for week 4 of 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) or gemcitabine/nab-paclitaxel chemotherapy, per investigator's choice. The primary endpoint was safety and tolerability measured using Common Terminology Criteria for Adverse Events version 4.0. The lead efficacy endpoint was local disease control rate at 16 weeks., Results: Fifty patients were enrolled and received chemotherapy [intention-to-treat (ITT) population]. Forty-two patients received 32 P microparticle implantation [per protocol (PP) population]. A total of 1102 treatment-emergent adverse events (TEAEs) were reported in the ITT/safety population (956 PP), of which 167 (139 PP) were grade ≥3. In the PP population, 41 TEAEs in 16 (38.1%) patients were possibly or probably related to 32 P microparticles or implantation procedure, including 8 grade ≥3 in 3 (7.1%) patients, compared with 609 TEAEs in 42 (100%) patients attributed to chemotherapy, including 67 grade ≥3 in 28 patients (66.7%). The local disease control rate at 16 weeks was 82.0% (95% confidence interval: 68.6% to 90.9%) (ITT) and 90.5% (95% confidence interval: 77.4% to 97.3%) (PP). Tumour volume, carbohydrate antigen 19-9 levels, and metabolic tumour response at week 12 improved significantly. Ten patients (20.0% ITT; 23.8% PP) had surgical resection and median overall survival was 15.2 and 15.5 months for ITT and PP populations, respectively., Conclusions: Endoscopic ultrasound-guided 32 P microparticle implantation has an acceptable safety profile. This study also suggests clinically relevant benefits of combining 32 P microparticles with standard-of-care systemic chemotherapy for patients with unresectable LAPC., Competing Interests: Disclosure PJR: stock and other ownership interests: Perci Health Ltd. Honoraria: Sirtex Medical, Eisai, Servier, Pierre Fabre, Shire, Roche, AstraZeneca, Merck. Consulting or advisory role: Sirtex Medical, Eisai, Servier, Roche, AstraZeneca, Amgen. Speakers’ bureau: Amgen, Merck, Servier, Boston Scientific. Research funding: Sanofi, Bayer. Travel, accommodations, expenses: Roche, Ipsen. HSW: honoraria: BTG/Biocompatibles, Merck KGaA, and BMS. Consulting or advisory role: Incyte, Bayer, Roche/Genentech/ Foundation Medicine, Sirtex Medical, Celgene, OncoSil Medical, and Zymeworks. Research funding: Pfizer, Sirtex and Zymeworks. Travel, accommodations, expenses: BTG/Biocompatibles, Merck KGaA, and BMS. DC: stock and other ownership interests: MarginClear. Consulting or advisory role: Boston Scientific and OncoSil Medical. Research funding: Boston Scientific. MN: stock and other ownership interests: Pakinax Pty Ltd and Margin Clear Pty Ltd. DB: employment: SA Medical Imaging and SA Health. Research funding: Avener/Pankind and AstraZeneca. NEW: employment: OncoSil Medical Ltd. Stock and other ownership interests: OncoSil Medical Ltd. DMT: employment: OncoSil Medical Ltd. Stock and other ownership interests: OncoSil Medical Ltd. DCJ: employment: OncoSil Medical Ltd. Stock and other ownership interests: OncoSil Medical Ltd. EY: employment: Southern Star Research Pty Ltd (contractor to OncoSil Medical Ltd). All other authors have declared no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Colorectal cancer is the second leading cause of cancer deaths worldwide, with a 5-year relative survival of 14% in patients with metastatic colorectal cancer (mCRC). Patients with BRAF V600E mutations, which occur in ∼10%-15% of patients with mCRC, have a poorer prognosis compared with those with wild-type BRAF tumours. The combination of the BRAF inhibitor encorafenib with the epidermal growth factor receptor inhibitor cetuximab currently represents the only chemotherapy-free targeted therapy approved in the USA and Europe for previously treated patients with BRAF V600E-mutated mCRC. As a class, BRAF inhibitors are associated with dermatologic, gastrointestinal, and renal events, as well as pyrexia and secondary skin malignancies. Adverse event (AE) profiles of specific BRAF inhibitors vary, however, and are affected by the specific agents given in combination. In patients with mCRC, commonly reported AEs of cetuximab monotherapy include infusion reactions and dermatologic toxicities. Data from the phase III BEACON CRC study indicate that the combination of encorafenib with cetuximab has a distinct safety profile. Here we review the most frequently reported AEs that occurred with this combination in BEACON CRC and best practices for managing and mitigating AEs that require more than standard supportive care., Competing Interests: Disclosure JT declares a consulting or advisory role with Array BioPharma, AstraZeneca, Bayer, BeiGene, Biocartis, Boehringer Ingelheim, Chugai Pharma, Eli Lilly, Foundation Medicine, Genentech, Genmab, HalioDX SAS, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura, Menarini, Merck Serono, Merck Sharp & Dohme, Merrimack, Merus, Molecular Partners, Novartis, Peptomyc, Pfizer, Pharmacyclics, ProteoDesign SL, Rafael Pharmaceuticals, Roche, Roche Diagnostics, Sanofi, Seattle Genetics, Servier, Symphogen, Taiho Pharmaceutical, and VCN Biosciences. TLT declares a consulting or advisory role with Pfizer and an academic advisory role for continuing medical education. AG declares honoraria from Aptitude Health and Elsevier; consulting or advisory role with Amgen (Inst), Array BioPharma (Inst), Bayer (Inst), Boston Biomedical (Inst), Bristol Myers Squibb (Inst), Daiichi Sankyo (Inst), Eli Lilly (Inst), Genentech (Inst), and Guardant Health (Inst); institutional research funding from Array BioPharma, Bayer, Boston Biomedical, Daiichi Sankyo, Eisai, Eli Lilly, Genentech, and Pfizer; travel, accommodations, and expenses from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Boston Biomedical, Genentech, and Merck Sharp & Dohme. RY declares institutional research funding from Array BioPharma and Boehringer Ingelheim; consulting fees from Array BioPharma, Mirati Therapeutics and Natera. EVC declares a consulting or advisory role with Array, AstraZeneca, Bayer, Biocartis, Bristol Myers Squibb, Celgene, Eli Lilly, Ipsen, Merck KGaA, Merck Sharp & Dohme, Novartis, Pierre Fabre, Roche, Servier, Sirtex, and Taiho; institutional research funding from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Ipsen, Merck, Merck KGaA, Novartis, Roche, and Servier. EVC declares consulting or advisory role for AstraZeneca, Bayer, Biocartis, Bristol Myers Squibb, Celgene, Eli Lilly, Ipsen, Merck Sharp & Dohme, Merck KGaA, Novartis, Pierre Fabre, Roche, Servier, Sirtex, Taiho, and Pfizer; institutional research funding from Amgen (Inst), Bayer (Inst), Boehringer Ingelheim (Inst), Eli Lilly (Inst), Novartis (Inst), Roche (Inst), Celgene (Inst), Ipsen (Inst), Merck (Inst), Merck KGaA (Inst), Servier (Inst), and Bristol Myers Squibb (Inst). HW declares honoraria from Amgen, Array BioPharma, Celgene, ERYTECH Pharma, Genentech, Merck KGaA, Pierre Fabre, Servier, Shire, Sirtex Medical, and Zymeworks; a consulting or advisory role with ERYTECH Pharma, Incyte, Roche Pharma AG, Shire, and Sirtex Medical; speakers' bureau with Celgene, Merck KGaA, Servier, and Sirtex Medical; institutional research funding from Merck KGaA, Merck Sharp & Dohme, Pfizer, and Sirtex Medical. JD declares a consulting or advisory role with BeiGene, Bionomics, Eisai, Eli Lilly, and Ignyta; institutional research funding from BeiGene, Bionomics, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, MedImmune, Novartis, and Roche. FC declares a consulting or advisory role with Amgen, Bayer, Genentech, Merck KGaA, and Pfizer; institutional research funding from Amgen, Bayer, Bristol Myers Squibb, Genentech, Ipsen, Merck KGaA, Merck Sharp & Dohme, Servier, and Symphogen. TY declares institutional research funding from Chugai Pharma, GlaxoSmithKline, Sanofi, and Sumitomo Dainippon. AG, KM, and JC-B declare employment with Pfizer Inc. SK declares stock and other ownership interests in MolecularMatch and Navire; a consulting or advisory role with Amal Therapeutics, Amgen, Biocartis, Boehringer Ingelheim, Eli Lilly, EMD Serono, Genentech, Holy Stone, Karyopharm Therapeutics, Merck, Navire Pharma, Novartis, Roche, and Symphogen; institutional research funding from Amgen, Array BioPharma, Biocartis, EMD Serono, Genentech, Guardant Health, MedImmune, Novartis, and Sanofi. LV has declared no conflicts of interest. Ethics approval The BEACON CRC study was conducted in accordance with the requirements of each country's regulatory authorities as well as the provisions of the Declaration of Helsinki and Good Clinical Practice guidelines, as defined by the International Council for Harmonisation. All patients who participated in the trial provided written informed consent. This trial was approved by the institutional review board or independent ethics committee at each centre. Data sharing The majority of data presented are from previously published sources. A small amount of unpublished data from the BEACON CRC study has been included and is not publicly available., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Intermittent systemic anti-cancer therapy in patients with advanced colorectal cancer (aCRC) may improve quality of life without compromising overall survival (OS). We aimed to use individual patient data meta-analysis (IPDMA) from multiple randomised controlled trials evaluating intermittent strategies to inform clinical practice. We also aimed to validate whether thrombocytosis as a predictive biomarker identified patients with significantly reduced OS receiving a complete treatment break., Patients and Methods: An IPDMA of intermittent strategy impact on survival was undertaken, including all relevant trials in which data were available. Intermittent strategies were classified into two groups: a planned stopping of all therapy ("treatment break strategy"; 6 trials; 2,907 patients) or to the same treatment omitting oxaliplatin ("maintenance strategy"; 3 trials; 1,271 patients). The primary analysis sample was of patients successfully completing induction therapy. Additionally, a pre-planned analysis of the predictive value of thrombocytosis on survival under a continuous versus an intermittent strategy was undertaken., Results: All trials had comparable inclusion criteria. The overall IPDMA of intermittent therapy versus continuous therapy demonstrated no detriment in OS (HR = 1.03 [95% CI 0.93-1.14]), whether from complete break (HR 1.04 [95% CI 0.87-1.26]) or maintenance strategies (HR 0.99 [95% CI 0.87-1.13]). Thrombocytosis was confirmed as a marker of poor prognosis in aCRC, but did not predict for OS detriment from treatment break strategies (interaction HR = 0.97 [95% CI 0.66-1.40] compared to continuous therapy)., Conclusion: The highest levels of evidence from this IPDMA indicate no detriment in survival for patients receiving an intermittent therapy strategy, either for maintenance or complete break strategies. Although, thrombocytosis is confirmed as a marker of poor prognosis, it is not predictive of poor outcome for patients treated with intermittent therapy. An intermittent chemotherapy strategy can therefore be applied irrespective of baseline platelet count and does not result in inferior OS compared to continuous chemotherapy., (Copyright © 2021. Published by Elsevier Ltd.)

Background & Aims: Whether all patients with advanced biliary tract cancer (aBTC) should be included in prospective trials, irrespective of the anatomic site of origin, is debated. Herein, we aimed to assess the survival impact of anatomic site of origin in prospective clinical trials of aBTC using landmark survival analysis., Methods: Patients enrolled into prospective first-line aBTC clinical trials (Jan 97-Dec 15) were included. Overall survival (OS) was analysed using Cox proportional hazard regression; landmark survival (LS) and 95% CIs were calculated., Results: Overall, 1,333 patients were included: median age 63 years (range 23-85); 46% male; 84% ECOG-PS0/1; 25% with locally advanced disease, 72% with metastatic, 3% not reported (NR). Patients were treated with mono-chemotherapy (23%), cisplatin/gemcitabine (36%), other combinations (39%), or NR (2%). Median OS was 10.2 months (95% CI 9.6-10.9). All sites (treatment-adjusted) had decreased risk of death vs. gallbladder cancer (GBC) (p <0.001). This reduced risk vs. GBC was maintained in those receiving cisplatin/gemcitabine for extrahepatic cholangiocarcinoma (p<0.001) and intrahepatic cholangiocarcinoma (IHC, p<0.001), but not in cholangiocarcinoma-not specified (CCA-NS, p = 0.82) or ampullary carcinoma (p = 0.96). One-year OS rates amongst patients who survived beyond 1, 2, 3 and 4 years post-trial registration were 37%, 45%, 61%, and 63%, respectively. For patients who survived 1 year, those receiving combination therapy vs. mono (p = 0.008) (acknowledging potential selection bias) and those with IHC and CCA-NS vs. GBC had better LS (both p <0.05). Metastatic disease was associated with shorter LS than locally advanced disease (p = 0.002). ECOG-PS and gender were not associated with LS (p >0.05, p = 0.08 respectively)., Conclusions: GBC is associated with worse OS than other BTC sites and should be considered as a stratification factor in clinical trials. LS rates enable adjusted prognostication for aBTC survivors., Lay Summary: Patients with gallbladder cancer have worse overall survival compared to those with biliary tract cancers of different primary origin. Thus, gallbladder cancer should be considered as a stratification factor in future clinical trials. Landmark survival rates enable adjusted prognosis prediction for patients with advanced biliary tract cancer who survive for some time., Competing Interests: Conflict of interest MMN has received honoraria from Ipsen, NuCana and Mylan, research funding from Ipsen, NuCana and Servier (previously SHIRE) and travel assistance from Ipsen, Bayer and Novartis. AL has no conflicts of interest to declare. HW has received honoraria from Lilly, Merck, Roche, and Celgene, speaker fees from Merck and Celgene, research funding from Sirtex and Pfizer, and travel assistance from Merck, Sirtex, Lilly, and Celgene. DM has honoraria and non-financial support from Amgen, Bayer, Ipsen, Merck Serono, Merck Sharp and Dohme, Roche, Sanofi, Servier; honoraria from Incyte, Shire, HalioDx and Agios. DG receives indirect research funding from Amgen, Celgene, and Pfizer and has stock ownership in Sirtex. JS has received consultancy fees from Merck and Amgen. TO receives honoraria from Chugai Pharmaceutical Co., Ltd, Pfizer Japan, Inc., Novartis Pharma K.K., Taiho Pharmaceutical Co., Ltd, Merck Serono Co., Ltd, Eli Lilly Japan K.K., Dainippon Sumitomo Pharma Co., Ltd, Eisai Co., Ltd, Bayer, Ltd, FUJI FILM Co., Ltd, and Yakult Honsha Co., Ltd. He also has a consulting or advisory role with Eli Lilly Japan K.K., Yakult Honsha Co., Ltd, Amgen, Dainippon Sumitomo Pharma Co., Ltd, Taiho Pharmaceutical Co., Ltd, OncoTherapy Science, Inc., Nobelpharma Co., Ltd, Ono Pharmaceutical Co., Ltd, Nippon Boehringer Ingelheim Co., Ltd, Nano Carrier Co., Ltd, Chugai Pharmaceutical Co., Ltd, Novartis Pharma K.K., and Zeria Pharmaceutical Co., Ltd. He receives indirect research funding from Chugai Pharmaceutical Co., Ltd, Eli Lilly Japan K.K., Eisai Co., Ltd, Novartis Pharma K.K., Shizuoka Industry, Takeda Bio Development Center Ltd, Yakult Honsha Co., Ltd, OncoTherapy Science, Inc., Otsuka Pharmaceutical Co., Ltd, Taiho Pharmaceutical Co., Ltd, Sceti Medical Labo K.K., Nippon Boehringer IngelheimCo., Ltd, Kowa Company, Ltd,KyowaHakko Kirin Co., Ltd, Merck Serono Co., Ltd, Ono Pharmaceutical Co., Ltd, Bayer, Ltd, Pfizer Japan, Inc., AstraZeneca K.K., and Dainippon Sumitomo Pharma Co., Ltd. JK receives research funding from Astra Zeneca. DW has received educational grant support from Roche, and honoraria from Bristol-Myers Squibb, Servier Suisse, Merck Sharp & Dohme, Bayer, EMD Serono, Lilly, Sanofi, Celgene, Astra Zeneca, AbbVie, Sanofi-Aventis Deutchland, SHIRE and Pfizer outside this submitted work. TA has served in a consulting/advisory role and or received honoraria from, Amgen, Bristol-Myers Squibb, Chugai, Clovis, Halliodx, MSD Oncology, Pierre Fabre, Roche/Ventana, Sanofi, Servier and has received travel, accommodation, and expenses from Roche/Ventana, MSD Oncology, and Bristol-Myers Squibb. DC receives indirect research funding from AstraZeneca, Amgen, Celgene, Merck, Serono, Sanofi, Merrimack, and Medimmune, Bayer, 4SC, Clovis, Eli Lilly and Janssen. MM receives research funding from Bayer and Lilly. LJ has received travel and accommodation funding from Amgen, Roche, and Sanofi. DK has not declared any conflicts of interest. TBS research funding (to institution): Boston Biomedical, Bayer, Amgen, Merck, Celgene, Lilly, Ipsen, Clovis, Seattle Genetics, Array Biopharma, Genentech, Abgenomics, Incyte, BMS. Consulting (to institution): Ipsen, Array Biopharma, Bayer, Genentech, Incyte and Merck. IDMC/DSMB (to self): Astra Zeneca, Exelixis, Lilly, PanCan and 1Globe. Scientific Advisory Board: Imugene, Immuneering and Sun Biopharmahas. JB has received honoraria from Merck Serono, Roche, Sanofi, and Bayer. JWV received honoraria in advisory capacity from Astra Zeneca, Agios, Taiho, Merck, Celgene, QED, PCI Biotech, Incyte, Pieris Pharmaceuticals, Genoscience Pharma, Mundipharma EDO and research funding from Lilly. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: We designed an open-label, noncomparative phase II study to assess the safety and efficacy of first-line treatment with trifluridine/tipiracil plus bevacizumab (TT-B) and capecitabine plus bevacizumab (C-B) in untreated patients with unresectable metastatic colorectal cancer (mCRC) who were not candidates for combination with cytotoxic chemotherapies., Patients and Methods: From 29 April 2016 to 29 March 2017, 153 patients were randomly assigned (1:1) to either TT-B (N = 77) or C-B (N = 76). The primary end point was progression-free survival (PFS). The primary PFS analysis was performed after 100 events (radiological progression or death) were observed. Secondary end points included overall survival (OS), quality of life (QoL; QLQ-C30 and QLQ-CR29 questionnaires), and safety., Results: Median (range) duration of treatment was 7.8 (6.0-9.7) months and 6.2 (4.1-9.1) months in the TT-B and C-B groups, respectively. Median (range) PFS was 9.2 (7.6-11.6) and 7.8 (5.5-10.1) months, respectively. Median (range) OS was 18 (15.2 to NA) and 16.2 (12.5 to NA) months, respectively. QoL questionnaires showed no relevant changes over time for either treatment. Therapies were well tolerated. Patients receiving TT-B had more grade ≥3 neutropenia (47% versus 5% with C-B). Patients receiving C-B had more grade ≥3 hand-foot syndrome (12% versus 0% with TT-B) and grade ≥3 diarrhea (8% versus 1% with TT-B), consistent with the known safety profiles of these agents., Conclusion: TT-B treatment showed promising clinical activity in untreated patients with unresectable mCRC ineligible for intensive therapy, with an acceptable safety profile and no clinically relevant changes in QoL., Clinical Trial Information: NCT02743221 (ClinicalTrials.gov)., Competing Interests: Disclosure EVC has received research funding from Amgen, Bayer, Boehringer Ingelheim, Celgene, Ipsen, Lilly, Merck, Merck KgaA, Novartis, Roche, Sanofi, and Servier; and has attended advisory board for Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Celgene, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier. ID has received research funding from AstraZeneca Pharma Poland, Bayer, Bristol-Myers Squibb, Celgene, Eli Lilly, Immutep, Janssen-Cilag, Merck, MorphoSys, Novartis, Regeneron Pharmaceuticals, Roche, Servier, Tesaro. MPS has attended advisory boards and chaired meeting for Roche, Merck, Servier, Amgen, Sanofi, and Eisai. PP has received research funding from Amgen, Celgene, Lilly, Merck KgaA, Roche, Taiho, Nordic drugs, and Servier. GA has received research funding from Servier and Bayer; has attended advisory boards for Servier, Bayer, Amgen, Sanofi, Merck Serono, Bristol-Myers Squibb, and Roche; and has received travel expense and accommodation from Servier, Bayer, Amgen, and Roche. CB has attended advisory boards for Roche, Servier, and Sanofi; and has received a research grant from Roche. RG-J has received research funding from Servier. CJAP has an advisory role for Servier. AJVdW, MF, DS, HK, and have received research funding from Servier. PG-A has attended advisory boards and chaired meeting for Roche, Merck, Amgen, Sanofi, Lilly, and Servier. HW has received honoraria, attended advisory boards, received travel grants and/or speaker for BMS, Lilly, Roche, Pfizer, Biotheranostics, Bayer, Servier, Merck-Serono KGaA, Sirtex Medical, Sanofi-Aventis, Celgene, Array; has received research funding from Sirtex Medical, Merck Serono, Pfizer, Merck; and charitable/grants from CRUK, MRC, BRC-Imperial, National Institute for Health Research (NIHR), and CUP Foundation. AF has received compensation for participation to Advisory Boards and Research Grants to his institution from Amgen, Bayer, Merck, MSD, Roche, Lilly, Servier, and Bristol Meyers Squibb. AK, AE, PA, and NA are employees of Servier. The views expressed in the submitted article are the authors' own and not an official position of the institution or funder., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In patients with metastatic colorectal cancer (mCRC) predominantly confined to the liver, whether a patient undergoes potentially curative resection of the liver lesions is a well-established principal determinant of long-term survival. There are a number of different agents, both chemotherapeutic and targeted biologic agents, which can aid in shrinking liver tumors, which would have otherwise been unresectable, allowing for potentially curative resection. The aim of this review article is to summarize the available evidence regarding optimal therapeutic strategies for converting initially unresectable metastases for potentially curative resection; we do not discuss patients who present with initially resectable disease. We have taken the approach to review trials that included R0 resection rates as one of the principal study endpoints and specifically enrolled patients with liver-limited disease. Primary tumor location has recently emerged as a putative prognostic and predictive factor in patients with mCRC; however, presently, there is a lack of resectability outcomes differentiating tumor location-defined subgroups, and several ongoing trials and retrospective analyses are anticipated to guide insights in the future. In conclusion, in patients with RAS wild-type mCRC, the data support preferential use of the anti-epidermal growth factor receptor monoclonal antibody cetuximab when combined with standard-of-care infusional doublet chemotherapy regimens (FOLFOX or FOLFIRI) for the conversion of initially unresectable metastases for potentially curative resection. Furthermore, we discuss data involving intensified chemotherapy regimens (i.e., 3-drug backbones such as FOLFOXIRI with or without a targeted biologic agent) to promote the conversion of initially unresectable metastases for potentially curative resection., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer., Methods: We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m 2 gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m 2 oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434., Findings: Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5-31·5) compared with 25·5 months (22·7-27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68-0·98], p=0·032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group., Interpretation: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma., Funding: Cancer Research UK., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND license. Published by Elsevier Ltd.. All rights reserved.)

Colorectal cancer (CRC) is one of the most common malignancies in Western countries. Over the last 20 years, and the last decade in particular, the clinical outcome for patients with metastatic CRC (mCRC) has improved greatly due not only to an increase in the number of patients being referred for and undergoing surgical resection of their localised metastatic disease but also to a more strategic approach to the delivery of systemic therapy and an expansion in the use of ablative techniques. This reflects the increase in the number of patients that are being managed within a multidisciplinary team environment and specialist cancer centres, and the emergence over the same time period not only of improved imaging techniques but also prognostic and predictive molecular markers. Treatment decisions for patients with mCRC must be evidence-based. Thus, these ESMO consensus guidelines have been developed based on the current available evidence to provide a series of evidence-based recommendations to assist in the treatment and management of patients with mCRC in this rapidly evolving treatment setting., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Biliary tract cancer is an uncommon cancer with a poor outcome. We assembled data from the National Cancer Research Institute (UK) ABC-02 study and 10 international studies to determine prognostic outcome characteristics for patients with advanced disease., Methods: Multivariable analyses of the final dataset from the ABC-02 study were carried out. All variables were simultaneously included in a Cox proportional hazards model, and backward elimination was used to produce the final model (using a significance level of 10%), in which the selected variables were associated independently with outcome. This score was validated externally by receiver operating curve (ROC) analysis using the independent international dataset., Results: A total of 410 patients were included from the ABC-02 study and 753 from the international dataset. An overall survival (OS) and progression-free survival (PFS) Cox model was derived from the ABC-02 study. White blood cells, haemoglobin, disease status, bilirubin, neutrophils, gender, and performance status were considered prognostic for survival (all with P < 0.10). Patients with metastatic disease {hazard ratio (HR) 1.56 [95% confidence interval (CI) 1.20-2.02]} and Eastern Cooperative Oncology Group performance status (ECOG PS) 2 had worse survival [HR 2.24 (95% CI 1.53-3.28)]. In a dataset restricted to patients who received cisplatin and gemcitabine with ECOG PS 0 and 1, only haemoglobin, disease status, bilirubin, and neutrophils were associated with PFS and OS. ROC analysis suggested the models generated from the ABC-02 study had a limited prognostic value [6-month PFS: area under the curve (AUC) 62% (95% CI 57-68); 1-year OS: AUC 64% (95% CI 58-69)]., Conclusion: These data propose a set of prognostic criteria for outcome in advanced biliary tract cancer derived from the ABC-02 study that are validated in an international dataset. Although these findings establish the benchmark for the prognostic evaluation of patients with ABC and confirm the value of longheld clinical observations, the ability of the model to correctly predict prognosis is limited and needs to be improved through identification of additional clinical and molecular markers., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The superiority of cisplatin and gemcitabine (CisGem) chemotherapy over gemcitabine (Gem) alone in patients with advanced biliary tract cancer (ABC) has been demonstrated in two randomised trials; ABC02 and the Biliary Tract (BT) 22 study. We used a combined dataset from these two trials to investigate the derived neutrophil-to-lymphocyte ratio (dNLR), which is thought to be a prognostic factor associated with clinical outcomes in several solid tumours, including ABC., Methods: White blood cell (WBC) and absolute neutrophil count (ANC) were available for 379 of 410 patients from ABC-02 and all 83 patients in BT-22. The dNLR was calculated as ANC/(WBC-ANC), as previously specified. We examined the association between dNLR and overall survival (OS) and progression-free survival (PFS), as well as comparing the treatment effect in two patient groups defined by their dNLR level. A high dNLR was defined as ≥3.0, which was approximately the upper tertile value., Results: A total of 462 individual patient records were analysed, 328 with baseline dNLR <3 and 134 with dNLR ≥3. There were 443 deaths in the cohort, and all surviving patients had a dNLR <3. There was strong evidence that dNLR was closely associated with both OS [hazard ratio (HR), 1.62; 95% confidence interval (CI) 1.32-2.01] and PFS (HR, 1.40; 95% CI 1.13-1.72). There was limited evidence (P = 0.10) of a differential effect of CisGem on OS between the two dNLR groups, but this was clearest in the ABC-02 dataset (P = 0.06). There was good evidence (P = 0.008) of an association between low baseline dNLR and long-term survival on a CisGem regimen. There was also good evidence of an association between ECOG performance status (split at 0 and 1 versus 2) on both OS (P < 0.001) and PFS (P = 0.01), but no evidence of a differential treatment effect, with both groups receiving benefit from the addition of cisplatin., Conclusions: These data confirm that high dNLR is associated with worse OS and PFS, and suggests it may also be predictive of benefit for the addition of cisplatin to gemcitabine in European patients with ABC. Incorporating dNLR into the clinical context may better inform prognosis and chemotherapy decisions in ABC patients., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Two recent studies (ABC-02 [UK] and BT22 [Japan]) have demonstrated the superiority of cisplatin and gemcitabine (CisGem) chemotherapy over gemcitabine (Gem) alone for patients with pathologically proven advanced biliary tract cancer (BTC: cholangiocarcinoma, gallbladder and ampullary cancers). This pre-planned analysis evaluates the efficacy of CisGem with increased statistical power., Patients and Methods: We carried out a meta-analysis of individual patient-level data of these studies to establish the effect of CisGem versus Gem on progression-free survival (PFS), overall survival (OS) and carried out exploratory subgroup analyses., Results: CisGem demonstrates a significant improvement in PFS [hazard ratio (HR)=0.64, 95% confidence interval (CI) 0.53-0.76, P<0.001] and OS (HR=0.65, 95% CI 0.54-0.78, P<0.001) over Gem. This effect is most marked among patients with good performance status (PS 0-1): HR for PFS is 0.61 (95% CI 0.51-0.74), P<0.001 and OS HR=0.64 (95% CI 0.53-0.77), P<0.001. CisGem resulted in improved PFS and OS for intra- and extra-hepatic cholangiocarcinomas and gallbladder cancer. The treatment effect between UK and Japanese patients was consistent with respect to OS (HR=0.65, 95% CI 0.53-0.79 and 0.65, 95% CI 0.42-1.03, respectively); with similar OS in the combination arms (median 11.7 and 11.1 months, respectively). Subgroups least likely to benefit included patients with ampullary tumours and poor performance status (PS2)., Conclusions: CisGem is the standard of care for the first-line treatment of good-PS patients with advanced BTC regardless of ethnicity. Future studies should aim to enhance the effectiveness of this regimen in the first-line setting, establish the role of subsequent (second-line) therapy and assess the role of rationally developed molecular-targeted therapies.

This paper explores the enigma of cancer of unknown primary (CUP) in relation to rapidly improving molecular diagnostic approaches. It is based on the first global collaboration meeting on improving research and clinical outcomes in CUP organized by the CUP Foundation. We review the difficulties of classifying this widely heterogeneous disease and the available diagnostic and pathological evaluative techniques, focusing on molecular profiling. Retrospective studies in CUP patients are shown to provide indirect validation of the accuracy of several platforms of gene expression profiling assays that may identify CUP subsets that respond favorably to active chemotherapy regimens. This review concludes that the recent major improvements in pathologic and molecular diagnostics, coupled with new improved therapies for several specific advanced solid tumors, need to be harmonized with more evidence from clinical-translational trials. All patients with CUP could thus be appropriately managed without the constant uncertainty that has previously severely hampered patient care and optimal outcomes. The longer-term objective is to understand the biology of highly metastatic disease, leading to the development of future global therapeutic programs. Current clinical studies, such as CUP-ONE, will address some of these issues.

Clinical resistance to chemotherapy is a frequent event in cancer treatment and is closely linked to poor outcome. High-grade serous (HGS) ovarian cancer is characterized by p53 mutation and high levels of genomic instability. Treatment includes platinum-based chemotherapy and initial response rates are high; however, resistance is frequently acquired, at which point treatment options are largely palliative. Recent data indicate that platinum-resistant clones exist within the sensitive primary tumor at presentation, implying resistant cell selection after treatment with platinum chemotherapy. The AKT pathway is central to cell survival and has been implicated in platinum resistance. Here, we show that platinum exposure induces an AKT-dependent, prosurvival, DNA damage response in clinically platinum-resistant but not platinum-sensitive cells. AKT relocates to the nucleus of resistant cells where it is phosphorylated specifically on S473 by DNA-dependent protein kinase (DNA-PK), and this activation inhibits cisplatin-mediated apoptosis. Inhibition of DNA-PK or AKT, but not mTORC2, restores platinum sensitivity in a panel of clinically resistant HGS ovarian cancer cell lines: we also demonstrate these effects in other tumor types. Resensitization is associated with prevention of AKT-mediated BAD phosphorylation. Strikingly, in patient-matched sensitive cells, we do not see enhanced apoptosis on combining cisplatin with AKT or DNA-PK inhibition. Insulin-mediated activation of AKT is unaffected by DNA-PK inhibitor treatment, suggesting that this effect is restricted to DNA damage-mediated activation of AKT and that, clinically, DNA-PK inhibition might prevent platinum-induced AKT activation without interfering with normal glucose homeostasis, an unwanted toxicity of direct AKT inhibitors.

Background: Oxaliplatin, 5-fluorouracil (5-FU), and leucovorin (LV) are standard first-line treatments for patients with metastatic colorectal cancer (mCRC). The aim of this multicentre, open-label, phase IIIb study was to assess the addition of oxaliplatin to two different 5-FU regimens., Patients and Methods: Patients with previously untreated mCRC were randomised to arm A [two-weekly oxaliplatin 85 mg/m(2) + either continuous intravenous infusion (CIV) of 5-FU without LV or two-weekly bolus and CIV 5-FU + LV (LV5FU2)] or arm B (5-FU CIV or LV5FU2 alone). Irinotecan monotherapy was planned on progression., Results: A total of 725 patients were enrolled. After a fixed follow-up of 2 years for each patient, 2-year survival rates were 27.3% and 24.8% in arms A and B, respectively (hazard ratio 0.93; 95% confidence interval 0.78-1.10). The addition of oxaliplatin significantly improved response rates (54.1 versus 29.8%; P < 0.0001) and median progression-free survival (7.9 versus 5.9 months; P < 0.0001). The most common grade 3-4 toxic effects were neutropenia (arm A, 33%; arm B, 5%), diarrhoea (arm A, 14%; arm B, 8%), and fatigue (arm A, 9%; arm B, 8%)., Conclusions: Despite improved rates of tumour control, these results failed to demonstrate a survival benefit from the addition of oxaliplatin to infused 5-FU and lend further support to the use of sequential monotherapy in some patients with mCRC.

Background: Axitinib (AG-013736) is a potent and selective oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, which have an important role in pancreatic cancer. The aim of this study was to assess the safety and efficacy of gemcitabine plus axitinib versus gemcitabine alone., Methods: Between January and August, 2006, 103 patients with unresectable, locally advanced, or metastatic pancreatic cancer were randomly assigned in a two to one ratio to receive gemcitabine (1000 mg/m(2)) plus axitinib 5 mg twice daily (n=69) or gemcitabine (1000 mg/m(2)) alone (n=34) by a centralised registration system. The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00219557., Findings: All randomised patients were included in the efficacy analyses. Median overall survival was longer with gemcitabine plus axitinib than with gemcitabine alone (6.9 [95% CI 5.3-10.1] months vs 5.6 [3.9-8.8] months). The hazard ratio for survival with gemcitabine plus axitinib versus with gemcitabine alone, adjusted for stratification factors, was 0.71 (95% CI 0.44-1.13). The most common grade 3 or worse adverse events were fatigue (15 [22%] patients in the gemcitabine plus axitinib group vs one [3%] in the gemcitabine alone group), abdominal pain (eight [12%] vs five [16%]), and asthenia (eight [12%] vs one [3%])., Interpretation: Gemcitabine plus axitinib showed a similar safety profile to gemcitabine alone; the small, non-statistically significant gain in overall survival needs to be assessed in a randomised phase III trial.

Introduction: Selective internal radiation therapy (SIRT) is emerging as a new therapeutic modality in recent years for management of non-resectable hepatic malignancies. Our experience in clinical application of this treatment is reported here., Material and Methods: From June 2004, patients whose liver tumours were no longer amenable for any conventional treatment with either chemotherapy or surgery were considered for yttrium-90 microspheres treatment after discussion at our multidisciplinary meeting. A pre-treatment planning was carried out with visceral angiography and technetium-99m macroaggregated albumin (MAA) for assessment of both tumour volume and extrahepatic shunting in addition to a baseline PET and CT scans, respectively. Two weeks later, a second visceral angiogram was performed to deliver the calculated dosage of microspheres into the arterial system supplying the tumour. Patients were then followed up with tumour markers, repeat PET and CT scans of abdomen at 6 weeks and 3 monthly thereafter., Result: Twenty-one patients (F=11, M=10; age range 40-75 years, mean=58 years) received yttrium-90 microspheres consisting of liver metastases from colorectal primary (n=10) and non-colorectal primaries (n=8), and primary liver tumours (n=3). One patient received 2 treatments. The mean administered activity of microspheres delivered was 1.9 GBq (range 1.2-2.5 GBq). Injection of microspheres had no immediate effect on either clinical haematology or liver function tests. At follow-up, 86% of patients showed decreased activity on PET scan at 6 weeks (p=0.01). The mean pre-treatment SUV was 12.2+/-3.7 and the mean post-treatment SUV was 9.3+/-3.7, indicating a significant improvement measured with PET activity. Only 13% showed a reduction in the size of tumour on CT scan. For patients with colorectal liver metastases, there was no significant reduction in CEA level (127+/-115 vs 75+/-72 micro/l, p=0.39). Complications were seen in 4 patients (19%) including radiation hepatitis (n=2), cholecystitis (n=1) and duodenal ulceration (n=1). All resolved without surgical intervention. Seven patients died at follow-up from progressive extrahepatic disease (33%)., Conclusion: SIRT should be considered for patients with advanced liver cancer. It has a significant effect on liver disease in the absence of extrahepatic disease. PET imaging has an integral role in the assessment of patients treated with yttrium-90 SIR-Spheres.