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Keyl J, Keyl P, Montavon G, Hosch R, Brehmer A, Mochmann L, Jurmeister P, Dernbach G, Kim M, Koitka S, Bauer S, Bechrakis N, Forsting M, Führer-Sakel D, Glas M, Grünwald V, Hadaschik B, Haubold J, Herrmann K, Kasper S, Kimmig R, Lang S, Rassaf T, Roesch A, Schadendorf D, Siveke JT, Stuschke M, Sure U, Totzeck M, Welt A, Wiesweg M, Baba HA, Nensa F, Egger J, Müller KR, Schuler M, Klauschen F, Kleesiek J. Decoding pan-cancer treatment outcomes using multimodal real-world data and explainable artificial intelligence. NATURE CANCER 2025; 6:307-322. [PMID: 39885364 PMCID: PMC11864985 DOI: 10.1038/s43018-024-00891-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 12/06/2024] [Indexed: 02/01/2025]
Abstract
Despite advances in precision oncology, clinical decision-making still relies on limited variables and expert knowledge. To address this limitation, we combined multimodal real-world data and explainable artificial intelligence (xAI) to introduce AI-derived (AID) markers for clinical decision support. We used xAI to decode the outcome of 15,726 patients across 38 solid cancer entities based on 350 markers, including clinical records, image-derived body compositions, and mutational tumor profiles. xAI determined the prognostic contribution of each clinical marker at the patient level and identified 114 key markers that accounted for 90% of the neural network's decision process. Moreover, xAI enabled us to uncover 1,373 prognostic interactions between markers. Our approach was validated in an independent cohort of 3,288 patients with lung cancer from a US nationwide electronic health record-derived database. These results show the potential of xAI to transform the assessment of clinical variables and enable personalized, data-driven cancer care.
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Affiliation(s)
- Julius Keyl
- Institute for Artificial Intelligence in Medicine, University Hospital Essen (AöR), Essen, Germany
- Institute of Pathology, University Hospital Essen (AöR), Essen, Germany
| | - Philipp Keyl
- Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany
- BIFOLD - Berlin Institute for the Foundations of Learning and Data, Berlin, Germany
| | - Grégoire Montavon
- BIFOLD - Berlin Institute for the Foundations of Learning and Data, Berlin, Germany
- Machine Learning Group, Technical University of Berlin, Berlin, Germany
- Department of Mathematics and Computer Science, Freie Universität Berlin, Berlin, Germany
| | - René Hosch
- Institute for Artificial Intelligence in Medicine, University Hospital Essen (AöR), Essen, Germany
| | - Alexander Brehmer
- Institute for Artificial Intelligence in Medicine, University Hospital Essen (AöR), Essen, Germany
| | - Liliana Mochmann
- Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Philipp Jurmeister
- Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Gabriel Dernbach
- Machine Learning Group, Technical University of Berlin, Berlin, Germany
| | - Moon Kim
- Institute for Artificial Intelligence in Medicine, University Hospital Essen (AöR), Essen, Germany
| | - Sven Koitka
- Institute for Artificial Intelligence in Medicine, University Hospital Essen (AöR), Essen, Germany
- Institute for Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen (AöR), Essen, Germany
| | - Sebastian Bauer
- Department of Medical Oncology, University Hospital Essen (AöR), Essen, Germany
- Medical Faculty, University of Duisburg-Essen, Essen, Germany
- West German Cancer Center, University Hospital Essen (AöR), Essen, Germany
- German Cancer Consortium (DKTK), Partner site University Hospital Essen (AöR), Essen, Germany
| | - Nikolaos Bechrakis
- Medical Faculty, University of Duisburg-Essen, Essen, Germany
- West German Cancer Center, University Hospital Essen (AöR), Essen, Germany
- German Cancer Consortium (DKTK), Partner site University Hospital Essen (AöR), Essen, Germany
- Department of Ophthalmology, University Hospital Essen (AöR), Essen, Germany
| | - Michael Forsting
- Institute for Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen (AöR), Essen, Germany
- Medical Faculty, University of Duisburg-Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner site University Hospital Essen (AöR), Essen, Germany
| | - Dagmar Führer-Sakel
- Medical Faculty, University of Duisburg-Essen, Essen, Germany
- West German Cancer Center, University Hospital Essen (AöR), Essen, Germany
- Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen (AöR), Essen, Germany
| | - Martin Glas
- Medical Faculty, University of Duisburg-Essen, Essen, Germany
- West German Cancer Center, University Hospital Essen (AöR), Essen, Germany
- German Cancer Consortium (DKTK), Partner site University Hospital Essen (AöR), Essen, Germany
- Division of Clinical Neurooncology, Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Medicine Essen, University Duisburg-Essen, Essen, Germany
| | - Viktor Grünwald
- Department of Medical Oncology, University Hospital Essen (AöR), Essen, Germany
- Medical Faculty, University of Duisburg-Essen, Essen, Germany
- West German Cancer Center, University Hospital Essen (AöR), Essen, Germany
- German Cancer Consortium (DKTK), Partner site University Hospital Essen (AöR), Essen, Germany
- Department of Urology, University Hospital Essen (AöR), Essen, Germany
| | - Boris Hadaschik
- Medical Faculty, University of Duisburg-Essen, Essen, Germany
- West German Cancer Center, University Hospital Essen (AöR), Essen, Germany
- German Cancer Consortium (DKTK), Partner site University Hospital Essen (AöR), Essen, Germany
- Department of Urology, University Hospital Essen (AöR), Essen, Germany
| | - Johannes Haubold
- Institute for Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen (AöR), Essen, Germany
- Medical Faculty, University of Duisburg-Essen, Essen, Germany
| | - Ken Herrmann
- Medical Faculty, University of Duisburg-Essen, Essen, Germany
- West German Cancer Center, University Hospital Essen (AöR), Essen, Germany
- German Cancer Consortium (DKTK), Partner site University Hospital Essen (AöR), Essen, Germany
- Department of Nuclear Medicine, University Hospital Essen (AöR), Essen, Germany
| | - Stefan Kasper
- Department of Medical Oncology, University Hospital Essen (AöR), Essen, Germany
- Medical Faculty, University of Duisburg-Essen, Essen, Germany
- West German Cancer Center, University Hospital Essen (AöR), Essen, Germany
- German Cancer Consortium (DKTK), Partner site University Hospital Essen (AöR), Essen, Germany
| | - Rainer Kimmig
- Medical Faculty, University of Duisburg-Essen, Essen, Germany
- West German Cancer Center, University Hospital Essen (AöR), Essen, Germany
- Department of Gynecology and Obstetrics, University Hospital Essen (AöR), Essen, Germany
| | - Stephan Lang
- Medical Faculty, University of Duisburg-Essen, Essen, Germany
- Department of Otorhinolaryngology, University Hospital Essen (AöR), Essen, Germany
| | - Tienush Rassaf
- Medical Faculty, University of Duisburg-Essen, Essen, Germany
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center Essen, University Hospital Essen (AöR), Essen, Germany
| | - Alexander Roesch
- Medical Faculty, University of Duisburg-Essen, Essen, Germany
- West German Cancer Center, University Hospital Essen (AöR), Essen, Germany
- German Cancer Consortium (DKTK), Partner site University Hospital Essen (AöR), Essen, Germany
- Department of Dermatology, University Hospital Essen (AöR), Essen, Germany
| | - Dirk Schadendorf
- Medical Faculty, University of Duisburg-Essen, Essen, Germany
- West German Cancer Center, University Hospital Essen (AöR), Essen, Germany
- German Cancer Consortium (DKTK), Partner site University Hospital Essen (AöR), Essen, Germany
- Department of Dermatology, University Hospital Essen (AöR), Essen, Germany
- Research Alliance Ruhr, Research Center One Health, University of Duisburg-Essen, Essen, Germany
| | - Jens T Siveke
- Department of Medical Oncology, University Hospital Essen (AöR), Essen, Germany
- Medical Faculty, University of Duisburg-Essen, Essen, Germany
- West German Cancer Center, University Hospital Essen (AöR), Essen, Germany
- German Cancer Consortium (DKTK), Partner site University Hospital Essen (AöR), Essen, Germany
- Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen (AöR), University of Duisburg-Essen, Essen, Germany
- Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK Partner Site Essen) and German Cancer Research Center, DKFZ, Heidelberg, Germany
| | - Martin Stuschke
- Medical Faculty, University of Duisburg-Essen, Essen, Germany
- West German Cancer Center, University Hospital Essen (AöR), Essen, Germany
- German Cancer Consortium (DKTK), Partner site University Hospital Essen (AöR), Essen, Germany
- Department of Radiotherapy, University Hospital Essen (AöR), Essen, Germany
| | - Ulrich Sure
- Medical Faculty, University of Duisburg-Essen, Essen, Germany
- West German Cancer Center, University Hospital Essen (AöR), Essen, Germany
- German Cancer Consortium (DKTK), Partner site University Hospital Essen (AöR), Essen, Germany
- Department of Neurosurgery and Spine Surgery, University Hospital Essen (AöR), Essen, Germany
| | - Matthias Totzeck
- Medical Faculty, University of Duisburg-Essen, Essen, Germany
- Department of Cardiology and Vascular Medicine, West German Heart and Vascular Center Essen, University Hospital Essen (AöR), Essen, Germany
| | - Anja Welt
- Department of Medical Oncology, University Hospital Essen (AöR), Essen, Germany
- Medical Faculty, University of Duisburg-Essen, Essen, Germany
- West German Cancer Center, University Hospital Essen (AöR), Essen, Germany
| | - Marcel Wiesweg
- Department of Medical Oncology, University Hospital Essen (AöR), Essen, Germany
- Medical Faculty, University of Duisburg-Essen, Essen, Germany
- West German Cancer Center, University Hospital Essen (AöR), Essen, Germany
- German Cancer Consortium (DKTK), Partner site University Hospital Essen (AöR), Essen, Germany
| | - Hideo A Baba
- Institute of Pathology, University Hospital Essen (AöR), Essen, Germany
- Medical Faculty, University of Duisburg-Essen, Essen, Germany
| | - Felix Nensa
- Institute for Artificial Intelligence in Medicine, University Hospital Essen (AöR), Essen, Germany
- Institute for Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen (AöR), Essen, Germany
- Medical Faculty, University of Duisburg-Essen, Essen, Germany
- German Cancer Consortium (DKTK), Partner site University Hospital Essen (AöR), Essen, Germany
| | - Jan Egger
- Institute for Artificial Intelligence in Medicine, University Hospital Essen (AöR), Essen, Germany
| | - Klaus-Robert Müller
- BIFOLD - Berlin Institute for the Foundations of Learning and Data, Berlin, Germany.
- Machine Learning Group, Technical University of Berlin, Berlin, Germany.
- Department of Artificial Intelligence, Korea University, Seoul, South Korea.
- MPI for Informatics, Saarbrücken, Germany.
| | - Martin Schuler
- Department of Medical Oncology, University Hospital Essen (AöR), Essen, Germany.
- Medical Faculty, University of Duisburg-Essen, Essen, Germany.
- West German Cancer Center, University Hospital Essen (AöR), Essen, Germany.
- German Cancer Consortium (DKTK), Partner site University Hospital Essen (AöR), Essen, Germany.
| | - Frederick Klauschen
- Institute of Pathology, Ludwig-Maximilians-University Munich, Munich, Germany.
- BIFOLD - Berlin Institute for the Foundations of Learning and Data, Berlin, Germany.
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Berlin partner site, Berlin, Germany.
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Munich partner site, Munich, Germany.
- Bavarian Cancer Research Center (BZKF), Erlangen, Germany.
| | - Jens Kleesiek
- Institute for Artificial Intelligence in Medicine, University Hospital Essen (AöR), Essen, Germany.
- Medical Faculty, University of Duisburg-Essen, Essen, Germany.
- West German Cancer Center, University Hospital Essen (AöR), Essen, Germany.
- German Cancer Consortium (DKTK), Partner site University Hospital Essen (AöR), Essen, Germany.
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Wnuk J, Hudy D, Strzelczyk JK, Michalecki Ł, Dybek K, Gisterek-Grocholska I. Serum hsa-miR-22-3p, hsa-miR-885-5p, Lipase-to-Amylase Ratio, C-Reactive Protein, CA19-9, and Neutrophil-to-Lymphocyte Ratio as Prognostic Factors in Advanced Pancreatic Ductal Adenocarcinoma. Curr Issues Mol Biol 2025; 47:27. [PMID: 39852142 PMCID: PMC11763715 DOI: 10.3390/cimb47010027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 12/28/2024] [Accepted: 01/01/2025] [Indexed: 01/26/2025] Open
Abstract
Pancreatic cancer (PC) is the seventh most common cause of cancer-related death worldwide. The low survival rate may be due to late diagnosis and asymptomatic early-stage disease. Most patients are diagnosed at an advanced stage of the disease. The search for novel prognostic factors is still needed. Two miRNAs, miR-22-3p and miR-885-5p, which show increased expression in PC, were selected for this study. The aim of this study was to evaluate the utility of these miRNAs in the prognosis of PC. Other prognostic factors such as lipase-to-amylase ratio (LAR), neutrophil-to-lymphocyte ratio (NLR), and carbohydrate antigen 19-9 (CA19-9) were also evaluated in this study. This study was conducted in 50 patients previously diagnosed with pancreatic ductal adenocarcinoma in clinical stage (CS) III and IV. All patients underwent a complete medical history, physical examination, and routine laboratory tests including a complete blood count, C-reactive protein (CRP), CA19-9, lipase, and amylase. Two additional blood samples were taken from each patient to separate plasma and serum. Isolation of miRNA was performed using TRI reagent with cel-miR-39-3p as a spike-in control. Reverse transcription of miRNA was performed using a TaqMan Advanced miRNA cDNA Synthesis Kit. The relative expression levels of miR-22-3p and miR-885-5p were measured using RT-qPCR. Serum hsa-miR-22-3p was detected in 22 cases (44%), while hsa-miR-885-5p was detected in 33 cases (66%). There were no statistically significant differences in serum or plasma miRNA expression levels between patient groups based on clinical stage, gender, or BMI. There were no statistically significant differences in LAR between patients with different CS. For NLR, CRP and CA19-9 thresholds were determined using ROC analysis (6.63, 24.7 mg/L and 4691 U/mL, respectively). Cox's F test for overall survival showed statistically significant differences between groups (p = 0.002 for NLR, p = 0.007 for CRP and p = 0.007 for CA19-9). Utility as prognostic biomarkers was confirmed in univariate and multivariate analysis for CA19-9, CRP, and NLR. The selected miRNAs and LAR were not confirmed as reliable prognostic markers in PC.
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Affiliation(s)
- Jakub Wnuk
- Department of Oncology and Radiotherapy, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 35 Ceglana St., 40-515 Katowice, Poland; (J.W.)
| | - Dorota Hudy
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 19 Jordana St., 41-808 Zabrze, Poland; (D.H.); (J.K.S.)
| | - Joanna Katarzyna Strzelczyk
- Department of Medical and Molecular Biology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 19 Jordana St., 41-808 Zabrze, Poland; (D.H.); (J.K.S.)
| | - Łukasz Michalecki
- Department of Oncology and Radiotherapy, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 35 Ceglana St., 40-515 Katowice, Poland; (J.W.)
| | - Kamil Dybek
- Central Laboratory, University Clinical Center, Medical University of Silesia in Katowice, 14 Medyków St., 40-752 Katowice, Poland
| | - Iwona Gisterek-Grocholska
- Department of Oncology and Radiotherapy, Faculty of Medical Sciences in Zabrze, Medical University of Silesia in Katowice, 35 Ceglana St., 40-515 Katowice, Poland; (J.W.)
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García-Herrera JS, Muñoz-Montaño WR, López-Basave HN, Morales-Vásquez F, Castillo-Morales C, Rivera-Mogollán LG, Hernández-Castañeda KF. Combination of neutrophil-to-lymphocyte ratio and serum CA 19-9 as a prognostic factor in pancreatic cancer. J Gastrointest Oncol 2024; 15:1805-1819. [PMID: 39279961 PMCID: PMC11399818 DOI: 10.21037/jgo-23-893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 06/14/2024] [Indexed: 09/18/2024] Open
Abstract
Background Traditionally, serum carbohydrate antigen 19-9 (CA 19-9) has been used as a key biomarker for pancreatic cancer and recently other biomarkers which reflect the systemic immune and inflammatory responses also have been explored as potential prognostic factors. The study aims to evaluate the significance of pretreatment neutrophil-to-lymphocyte ratio (NLR) and serum CA 19-9 as prognostic factor in pancreatic cancer patients. Methods A retrospective analysis was conducted in 153 consecutive patients with pancreatic cancer in Instituto Nacional de Cancerología from 2013 to 2018. Pretreatment NLR and serum CA 19-9 values were recorded as well as survivals. Results The cut-off value determined for NLR was 2.4 and for serum CA 19-9 was 553 U/mL. Survival analysis showed that the 5-year overall survival (OS) was 9% in patients with low-NLR compared with 2% for patients with high-NLR (P=0.008), and 5-year progression-free survival (PFS) was 5.7% in patients with low-NLR compared with 1.3% in patients with high-NLR (P=0.007). For patients with low-CA 19.9, 5-year OS was 8.5% compared with 0% for patients with high-CA 19-9 (P=0.002), and 5-year PFS was 4.1% in patients with low-CA 19-9 compared with 0% in patients with high-CA 19-9 (P=0.005). Classification groups created showed that 5-year OS in Group 1 (low-NLR and low-CA 19-9) was 11.8% compared with 1.9% for patients in Group 2 (either one or both high-NLR or CA 19-9) (P<0.001), and 5-year PFS was 8.6% in Group 1 and 0% in Group 2 (P=0.001). Conclusions High-NLR and high-CA 19-9 values used separately are both independently associated with worse OS and PFS in patients with pancreatic cancer. The classification groups created combining both biomarkers showed better prognostic significance than when used separately as demonstrated by survival analysis and multivariate analysis.
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Affiliation(s)
- Juan Sebastián García-Herrera
- Gastrointestinal Tumors Division, Surgical Oncology Department, Instituto Nacional de Cancerología, Mexico City, México
| | | | - Horacio N López-Basave
- Gastrointestinal Tumors Division, Surgical Oncology Department, Instituto Nacional de Cancerología, Mexico City, México
| | | | - Carolina Castillo-Morales
- Gastrointestinal Tumors Division, Surgical Oncology Department, Instituto Nacional de Cancerología, Mexico City, México
| | - Luis G Rivera-Mogollán
- Gastrointestinal Tumors Division, Surgical Oncology Department, Instituto Nacional de Cancerología, Mexico City, México
| | - Karla F Hernández-Castañeda
- Gastrointestinal Tumors Division, Surgical Oncology Department, Instituto Nacional de Cancerología, Mexico City, México
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Javed AA, Mahmud O, Fatimi AS, Habib A, Grewal M, He J, Wolfgang CL, Besselink MG. Predictors for Long-Term Survival After Resection of Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-Analysis. Ann Surg Oncol 2024; 31:4673-4687. [PMID: 38710910 PMCID: PMC11164751 DOI: 10.1245/s10434-024-15281-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 03/26/2024] [Indexed: 05/08/2024]
Abstract
BACKGROUND Improved systemic therapy has made long term (≥ 5 years) overall survival (LTS) after resection of pancreatic ductal adenocarcinoma (PDAC) increasingly common. However, a systematic review on predictors of LTS following resection of PDAC is lacking. METHODS The PubMed, Embase, Scopus, and Cochrane CENTRAL databases were systematically searched from inception until March 2023. Studies reporting actual survival data (based on follow-up and not survival analysis estimates) on factors associated with LTS were included. Meta-analyses were conducted by using a random effects model, and study quality was gauged by using the Newcastle-Ottawa Scale (NOS). RESULTS Twenty-five studies with 27,091 patients (LTS: 2,132, non-LTS: 24,959) who underwent surgical resection for PDAC were meta-analyzed. The median proportion of LTS patients was 18.32% (IQR 12.97-21.18%) based on 20 studies. Predictors for LTS included sex, body mass index (BMI), preoperative levels of CA19-9, CEA, and albumin, neutrophil-lymphocyte ratio, tumor grade, AJCC stage, lymphovascular and perineural invasion, pathologic T-stage, nodal disease, metastatic disease, margin status, adjuvant therapy, vascular resection, operative time, operative blood loss, and perioperative blood transfusion. Most articles received a "good" NOS assessment, indicating an acceptable risk of bias. CONCLUSIONS Our meta-analysis pools all true follow up data in the literature to quantify associations between prognostic factors and LTS after resection of PDAC. While there appears to be evidence of a complex interplay between risk, tumor biology, patient characteristics, and management related factors, no single parameter can predict LTS after the resection of PDAC.
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Affiliation(s)
- Ammar A Javed
- NYU Langone Health, NYU Grossman School of Medicine, New York, USA
- Department of Surgery, Amsterdam UMC, Location University of Amsterdam, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - Omar Mahmud
- Medical College, Aga Khan University, Karachi, Pakistan
| | | | - Alyssar Habib
- NYU Langone Health, NYU Grossman School of Medicine, New York, USA
| | - Mahip Grewal
- NYU Langone Health, NYU Grossman School of Medicine, New York, USA
| | - Jin He
- Department of Surgery, Johns Hopkins School of Medicine, Baltimore, USA
| | | | - Marc G Besselink
- Department of Surgery, Amsterdam UMC, Location University of Amsterdam, Amsterdam, The Netherlands.
- Cancer Center Amsterdam, Amsterdam, The Netherlands.
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Muaddi H, Kearse L, Warner S. Multimodal Approaches to Patient Selection for Pancreas Cancer Surgery. Curr Oncol 2024; 31:2260-2273. [PMID: 38668070 PMCID: PMC11049254 DOI: 10.3390/curroncol31040167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 04/05/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
With an overall 5-year survival rate of 12%, pancreas ductal adenocarcinoma (PDAC) is an aggressive cancer that claims more than 50,000 patient lives each year in the United States alone. Even those few patients who undergo curative-intent resection with favorable pathology reports are likely to experience recurrence within the first two years after surgery and ultimately die from their cancer. We hypothesize that risk factors for these early recurrences can be identified with thorough preoperative staging, thus enabling proper patient selection for surgical resection and avoiding unnecessary harm. Herein, we review evidence supporting multidisciplinary and multimodality staging, comprehensive neoadjuvant treatment strategies, and optimal patient selection for curative-intent surgical resections. We further review data generated from our standardized approach at the Mayo Clinic and extrapolate to inform potential future investigations.
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Affiliation(s)
| | | | - Susanne Warner
- Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, MN 55902, USA; (H.M.)
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Zanin L, Sachkova A, Panciani PP, Rohde V, Fontanella MM, Schatlo B. Liquid Biopsy in Low-Grade Glioma: A Systematic Review and a Proposal for a Clinical Utility Score. Cell Mol Neurobiol 2023; 43:3833-3845. [PMID: 37704931 PMCID: PMC10661806 DOI: 10.1007/s10571-023-01406-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 08/28/2023] [Indexed: 09/15/2023]
Abstract
Liquid biopsy research on Low-Grade gliomas (LGG) has remained less conspicuous than that on other malignant brain tumors. Reliable serum markers would be precious for diagnosis, follow- up and treatment. We propose a clinical utility score (CUS) for biomarkers in LGG that mirrors their clinical usefulness. We conducted a PRISMA review. We examined each biomarker classifying them by CUS and Level of Evidence (LOE). We identified four classes of biomarkers: (1). Circulating protein-(a) vitronectin discriminates LGG from HGG (Sn:98%, Sp:91%, CUS: 3, LOE: III), (b) CTLA-4 discriminates LGG from HGG, (cutoff: 220.43 pg/ml, Sn: 82%, Sp: 78%, CUS:3, LOE:III), (c) pre-operative TGF b1 predict astrocytoma (cutoff: 2.52 ng/ml, Sn: 94.9%, Sp: 100%, CUS:3, LOE:VI). (2). micro-RNA (miR)-(a) miR-16 discriminates between WHO IV and WHO II and III groups (AUC = 0.98, CUS:3, LOE: III), (b) miR-454-3p is higher in HGG than in LGG (p = 0.013, CUS:3, LOE: III), (c) miR-210 expression is related to WHO grades (Sn 83.2%, Sp 94.3%, CUS: 3, LOE: III). (3). Circulating DNA-(a) IDH1R132H mutation detected in plasma by combined COLD and digital PCR (Sn: 60%, Sp: 100%, CUS: 3, LOE: III). 4. Exosomes-(a) SDC1 serum levels could discriminate GBM from LGG (Sn: 71%, Sp: 91%, CUS: 2C, LOE: VI). Our investigation showed that miRs appear to have the highest clinical utility. The LOE of the studies assessed is generally low. A combined approach between different biomarkers and traditional diagnostics may be considered. We identified four main classes of biomarkers produced by LGG. We examined each biomarker, classifying them by clinical utility score (CUS) and level of evidence (LOE). Micro-RNA (miRs) appears to have the highest CUS and LOE.
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Affiliation(s)
- Luca Zanin
- Unit of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Piazzale Spedali Civili 1, 25123, Brescia, Italy
| | - Alexandra Sachkova
- Institute of Clinical Pharmacology, University Medical Center Göttingen, Georg-August University, 37075, Göttingen, Germany
| | - Pier Paolo Panciani
- Unit of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Piazzale Spedali Civili 1, 25123, Brescia, Italy.
| | - Veit Rohde
- Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany
| | - Marco Maria Fontanella
- Unit of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Piazzale Spedali Civili 1, 25123, Brescia, Italy
| | - Bawarjan Schatlo
- Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany
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García-Ortiz MV, Cano-Ramírez P, Toledano-Fonseca M, Aranda E, Rodríguez-Ariza A. Diagnosing and monitoring pancreatic cancer through cell-free DNA methylation: progress and prospects. Biomark Res 2023; 11:88. [PMID: 37798621 PMCID: PMC10552233 DOI: 10.1186/s40364-023-00528-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 09/21/2023] [Indexed: 10/07/2023] Open
Abstract
Pancreatic cancer is one of the most challenging cancers due to its high mortality rates. Considering the late diagnosis and the limited survival benefit with current treatment options, it becomes imperative to optimize early detection, prognosis and prediction of treatment response. To address these challenges, significant research efforts have been undertaken in recent years to develop liquid-biopsy-based biomarkers for pancreatic cancer. In particular, an increasing number of studies point to cell-free DNA (cfDNA) methylation analysis as a promising non-invasive approach for the discovery and validation of epigenetic biomarkers with diagnostic or prognostic potential. In this review we provide an update on recent advancements in the field of cfDNA methylation analysis in pancreatic cancer. We discuss the relevance of DNA methylation in the context of pancreatic cancer, recent cfDNA methylation research, its clinical utility, and future directions for integrating cfDNA methylation analysis into routine clinical practice.
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Affiliation(s)
- María Victoria García-Ortiz
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain.
- Andalusia-Roche Network Mixed Alliance in Precision Medical Oncology, Sevilla, Spain.
- Cancer Network Biomedical Research Center (CIBERONC), Madrid, Spain.
| | - Pablo Cano-Ramírez
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
- Andalusia-Roche Network Mixed Alliance in Precision Medical Oncology, Sevilla, Spain
| | - Marta Toledano-Fonseca
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
- Andalusia-Roche Network Mixed Alliance in Precision Medical Oncology, Sevilla, Spain
- Cancer Network Biomedical Research Center (CIBERONC), Madrid, Spain
| | - Enrique Aranda
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
- Andalusia-Roche Network Mixed Alliance in Precision Medical Oncology, Sevilla, Spain
- Cancer Network Biomedical Research Center (CIBERONC), Madrid, Spain
- Medical Oncology Department, Reina Sofía University Hospital, Córdoba, Spain
- Department of Medicine, Faculty of Medicine, University of Córdoba, Córdoba, Spain
| | - Antonio Rodríguez-Ariza
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
- Andalusia-Roche Network Mixed Alliance in Precision Medical Oncology, Sevilla, Spain
- Cancer Network Biomedical Research Center (CIBERONC), Madrid, Spain
- Medical Oncology Department, Reina Sofía University Hospital, Córdoba, Spain
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Zhu Z, Cheng K, Yun Z, Zhang X, Hu X, Liu J, Wang F, Fu Z, Yue J. [ 18F] AlF-NOTA-FAPI-04 PET/CT can predict treatment response and survival in patients receiving chemotherapy for inoperable pancreatic ductal adenocarcinoma. Eur J Nucl Med Mol Imaging 2023; 50:3425-3438. [PMID: 37328622 DOI: 10.1007/s00259-023-06271-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 05/18/2023] [Indexed: 06/18/2023]
Abstract
PURPOSE We investigated whether uptake of [18F] AlF-NOTA-FAPI-04 on positron emission tomography/computed tomography (PET/CT) could predict treatment response and survival in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS We prospectively evaluated 47 patients with histopathologically confirmed primary PDAC who provided pretreatment [18F] AlF-NOTA-FAPI-04 scans to detect fibroblast activation protein (FAP) on the tumor surface by uptake of [18F] AlF-NOTA-FAPI-04. PDAC specimens were immunohistochemically stained with cancer-associated fibroblast (CAF) markers. We obtained a second PET scan after one cycle of chemotherapy to study changes in FAPI uptake variables from before to during treatment. Correlations between baseline PET variables and CAF-related immunohistochemical markers were assessed with Spearman's rank test. Cox regression and Kaplan-Meier methods were used to assess relationships between disease progression and potential predictors. Receiver operating characteristic (ROC) curve analysis was used to define the optimal cut-off points for distinguishing patients according to good response vs. poor response per RECIST v.1.1. RESULTS The FAPI PET variables maximum and mean standardized uptake values (SUVmax, SUVmean), metabolic tumor volume (MTV), and total lesion FAP expression (TLF) were positively correlated with CAF markers (FAP, α-smooth muscle actin, vimentin, S100A4, and platelet-derived growth factor receptor α/β, all P < 0.05). MTV was associated with survival in patients with inoperable PDAC (all P < 0.05). Cox multivariate regression showed that MTV was associated with overall survival (MTV hazard ratio [HR] = 1.016, P = 0.016). Greater changes from before to during chemotherapy in SUVmax, MTV, and TLF were associated with good treatment response (all P < 0.05). ΔMTV, ΔTLF, and ΔSUVmax had larger areas under the curve than ΔCA19-9 for predicting treatment response. Kaplan-Meier analysis showed that the extent of change in MTV and TLF from before to after treatment predicted progression-free survival, with cut-off values (based on medians) of - 4.95 for ΔMTV (HR = 8.09, P = 0.013) and - 77.83 for ΔTLF (HR = 4.62, P = 0.012). CONCLUSIONS A higher baseline MTV on [18F] AlF-NOTA-FAPI-04 scans was associated with poorer survival in patients with inoperable PDAC. ΔMTV was more sensitive for predicting response than ΔCA19-9. These results are clinically meaningful for identifying patients with PDAC who are at high risk of disease progression.
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Affiliation(s)
- Ziyuan Zhu
- School of Clinical Medicine, Weifang Medical University, Weifang, China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jiyan Road 440, Jinan, Shandong, China
| | - Kai Cheng
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jiyan Road 440, Jinan, Shandong, China
- PET/CT Center, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Zhang Yun
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jiyan Road 440, Jinan, Shandong, China
| | - Xiang Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jiyan Road 440, Jinan, Shandong, China
| | - Xiaoyu Hu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jiyan Road 440, Jinan, Shandong, China
| | - Jing Liu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jiyan Road 440, Jinan, Shandong, China
| | - Fuhao Wang
- School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Zheng Fu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jiyan Road 440, Jinan, Shandong, China.
- PET/CT Center, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong, China.
| | - Jinbo Yue
- School of Clinical Medicine, Weifang Medical University, Weifang, China.
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jiyan Road 440, Jinan, Shandong, China.
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9
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García-Ortiz MV, Cano-Ramírez P, Toledano-Fonseca M, Cano MT, Inga-Saavedra E, Rodríguez-Alonso RM, Guil-Luna S, Gómez-España MA, Rodríguez-Ariza A, Aranda E. Circulating NPTX2 methylation as a non-invasive biomarker for prognosis and monitoring of metastatic pancreatic cancer. Clin Epigenetics 2023; 15:118. [PMID: 37481552 PMCID: PMC10362605 DOI: 10.1186/s13148-023-01535-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 07/16/2023] [Indexed: 07/24/2023] Open
Abstract
BACKGROUND Pancreatic cancer is the most lethal cancer with a dismal prognosis mainly due to diagnosis at advanced stage and ineffective treatments. CA19-9 levels and computed tomography (CT) imaging are the main standard criteria for evaluating disease progression and treatment response. In this study we explored liquid biopsy-based epigenetic biomarkers for prognosis and monitoring disease in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). METHODS Plasma samples were collected from 44 mPDAC patients at the time of diagnosis, and in 15 of them, additional samples were obtained during follow-up of the disease. After cell-free DNA (cfDNA), isolation circulating levels of methylated NPTX2, SPARC, BMP3, SFRP1 and TFPI2 genes were measured using digital droplet PCR (ddPCR). BEAMing technique was performed for quantitation of RAS mutations in cfDNA, and CA19-9 was measured using standard techniques. RESULTS NPTX2 was the most highly and frequently methylated gene in cfDNA samples from mPDAC patients. Higher circulating NPTX2 methylation levels at diagnosis were associated with poor prognosis and efficiently stratified patients for prediction of overall survival (6.06% cut-off, p = 0.0067). Dynamics of circulating NPTX2 methylation levels correlated with disease progression and response to therapy and predicted better than CA19-9 the evolution of disease in mPDAC patients. Remarkably, in many cases the disease progression detected by CT scan was anticipated by an increase in circulating NPTX2 methylation levels. CONCLUSIONS Our study supports circulating NPTX2 methylation levels as a promising liquid biopsy-based clinical tool for non-invasive prognosis, monitoring disease evolution and response to treatment in mPDAC patients.
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Affiliation(s)
- María Victoria García-Ortiz
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
- Andalusia-Roche Network Mixed Alliance in Precision Medical Oncology, Seville, Spain
- Cancer Network Biomedical Research Center (CIBERONC), Madrid, Spain
| | - Pablo Cano-Ramírez
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
- Andalusia-Roche Network Mixed Alliance in Precision Medical Oncology, Seville, Spain
| | - Marta Toledano-Fonseca
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
- Andalusia-Roche Network Mixed Alliance in Precision Medical Oncology, Seville, Spain
- Cancer Network Biomedical Research Center (CIBERONC), Madrid, Spain
| | - María Teresa Cano
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
- Andalusia-Roche Network Mixed Alliance in Precision Medical Oncology, Seville, Spain
- Medical Oncology Department, Reina Sofía University Hospital, Córdoba, Spain
| | - Elizabeth Inga-Saavedra
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
- Andalusia-Roche Network Mixed Alliance in Precision Medical Oncology, Seville, Spain
- Medical Oncology Department, Reina Sofía University Hospital, Córdoba, Spain
| | | | - Silvia Guil-Luna
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
- Andalusia-Roche Network Mixed Alliance in Precision Medical Oncology, Seville, Spain
- Cancer Network Biomedical Research Center (CIBERONC), Madrid, Spain
- Department of Anatomy and Comparative Pathology, University of Córdoba, Córdoba, Spain
| | - María Auxiliadora Gómez-España
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
- Andalusia-Roche Network Mixed Alliance in Precision Medical Oncology, Seville, Spain
- Cancer Network Biomedical Research Center (CIBERONC), Madrid, Spain
- Medical Oncology Department, Reina Sofía University Hospital, Córdoba, Spain
| | - Antonio Rodríguez-Ariza
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
- Andalusia-Roche Network Mixed Alliance in Precision Medical Oncology, Seville, Spain
- Cancer Network Biomedical Research Center (CIBERONC), Madrid, Spain
- Medical Oncology Department, Reina Sofía University Hospital, Córdoba, Spain
| | - Enrique Aranda
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
- Andalusia-Roche Network Mixed Alliance in Precision Medical Oncology, Seville, Spain
- Cancer Network Biomedical Research Center (CIBERONC), Madrid, Spain
- Medical Oncology Department, Reina Sofía University Hospital, Córdoba, Spain
- Department of Medicine, Faculty of Medicine, University of Córdoba, Córdoba, Spain
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10
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Varzaru B, Iacob RA, Croitoru AE, Iacob SM, Radu CE, Dumitrescu SM, Gheorghe C. Real-Life Results of Palliative Chemotherapy in Metastatic Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2023; 15:3500. [PMID: 37444612 DOI: 10.3390/cancers15133500] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 07/02/2023] [Accepted: 07/03/2023] [Indexed: 07/15/2023] Open
Abstract
PURPOSE To assess the efficacy of FOLFIRINOX(FFX), gemcitabine-based regimens (GB), and gemcitabine monotherapy (Gem) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). METHODS This is a retrospective study that included 83 patients with mPDAC treated with first-line chemotherapy (L1) with either FFX, GB or Gem between 2015 and 2017. Progression-free survival (PFS) for L1 and second-line chemotherapy (L2) (PFS-L1 and PFS-L2) and overall survival (OS) were estimated using the Kaplan-Meier method. RESULTS Median PFS-L1 for FFX, GB and Gem groups was 9 months (95% (Confidence Interval) CI 2.76-15.24), 5 months (95%CI 3.44-6.56), and 5 months (95%CI 3.76-6.24), respectively (p = 0.04). OS was 14 months (95%CI 11.16-16.85), 12 months (95%CI: 9.44-11.56), and 7 months (95%CI: 5.7-8.3) for patients treated with FFX, GB, and Gem, respectively (p = 0.0001). ECOG-PS (0/1) (Hazard Ratio (HR) 6.74, p = 0.002), age > 70 years (HR 0.25, p = 0.04), body tumors (HR 2.8, p = 0.048), CA19-9 > 39 U/mL (HR 0.26, p = 0.02), and neutrophil-to-lymphocyte ratio (NLR) > 4.15 (HR 6.76, p = 0.001) were independent prognostic factors for PFS-L1. Male gender (HR 3.02, p = 0.026), ECOG-PS (0/1) (HR 4.21, p = 0.003), L1 with FFX (HR 0.255, p = 0.007), and NLR > 4.15 (HR 2.65, p = 0.04) were independent prognostic factors of OS. PFS-L2 (HR 6.91, p = 0.013) and OS-L2 (HR 6.95, p = 0.037) were significantly higher in patients first treated with FFX. CONCLUSIONS The OS of patients who receive FFX or GB is comparable. The best PFS-L1 belongs to the FFX group. Male gender, ECOG-PS 0/1, the FFX regimen, and NLR > 4.15 were independent predictors of OS. PFS-L2 and OS-L2 were favorably impacted by L1 with FFX.
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Affiliation(s)
- Bianca Varzaru
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Gastroenterology Department, Sanador Clinical Hospital, 010991 Bucharest, Romania
| | - Razvan A Iacob
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, 022238 Bucharest, Romania
| | - Adina E Croitoru
- Oncology Department, Fundeni Clinical Institute, 022238 Bucharest, Romania
- Faculty of Medicine, Titu Maiorescu University, 040441 Bucharest, Romania
| | - Speranta M Iacob
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, 022238 Bucharest, Romania
| | | | | | - Cristian Gheorghe
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Digestive Diseases and Liver Transplantation Center, Fundeni Clinical Institute, 022238 Bucharest, Romania
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11
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Okamoto M, Shiba S, Kobayashi D, Miyasaka Y, Okazaki S, Shibuya K, Ohno T. Carbon-Ion Radiotherapy Combined with Concurrent Chemotherapy for Locally Advanced Pancreatic Cancer: A Retrospective Case Series Analysis. Cancers (Basel) 2023; 15:2857. [PMID: 37345195 DOI: 10.3390/cancers15102857] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/18/2023] [Accepted: 05/19/2023] [Indexed: 06/23/2023] Open
Abstract
Systemic chemotherapy has significantly improved in recent years. In this study. the clinical impact of carbon-ion radiotherapy (CIRT) with concurrent chemotherapy for locally advanced unresectable pancreatic cancer (URPC) was evaluated. METHODS Patients with URPC who were treated with CIRT between January 2016 and December 2020 were prospectively registered and analyzed. The major criteria for registration were (1) diagnosed as URPC on imaging; (2) pathologically diagnosed adenocarcinoma; (3) no distant metastasis; (4) Eastern Cooperative Oncology Group performance status of 0-2; (5) tumors without gastrointestinal tract invasion; and (6) available for concurrent chemotherapy. Patients who received neoadjuvant chemotherapy (NAC) for more than one year prior to CIRT were excluded. RESULTS Forty-four patients met the inclusion criteria, and thirty-seven received NAC before CIRT. The median follow-up period of living patients was 26.0 (6.0-68.6) months after CIRT. The estimated two-year overall survival, local control, and progression-free survival rates after CIRT were 56.6%, 76.1%, and 29.0%, respectively. The median survival time of all patients was 29.6 months after CIRT and 34.5 months after the initial NAC. CONCLUSION CIRT showed survival benefits for URPC even in the multiagent chemotherapy era.
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Affiliation(s)
- Masahiko Okamoto
- Heavy-Ion Medical Center, Gunma University, 3-39-22, Showa-machi, Maebashi 371-8511, Gunma, Japan
- Department of Radiation Oncology, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi 371-8511, Gunma, Japan
| | - Shintaro Shiba
- Heavy-Ion Medical Center, Gunma University, 3-39-22, Showa-machi, Maebashi 371-8511, Gunma, Japan
- Department of Radiation Oncology, Shonan Kamakura General Hospital, 1370-1, Okamoto, Kamakura 247-8533, Kanagawa, Japan
| | - Daijiro Kobayashi
- Heavy-Ion Medical Center, Gunma University, 3-39-22, Showa-machi, Maebashi 371-8511, Gunma, Japan
- Department of Radiation Oncology, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi 371-8511, Gunma, Japan
| | - Yuhei Miyasaka
- Heavy-Ion Medical Center, Gunma University, 3-39-22, Showa-machi, Maebashi 371-8511, Gunma, Japan
| | - Shohei Okazaki
- Heavy-Ion Medical Center, Gunma University, 3-39-22, Showa-machi, Maebashi 371-8511, Gunma, Japan
- Department of Radiation Oncology, Gunma Prefectural Cancer Center, 617-1, Takabayashi-nishi, Ota 373-8550, Gunma, Japan
| | - Kei Shibuya
- Heavy-Ion Medical Center, Gunma University, 3-39-22, Showa-machi, Maebashi 371-8511, Gunma, Japan
- Department of Radiation Oncology, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi 371-8511, Gunma, Japan
| | - Tatsuya Ohno
- Heavy-Ion Medical Center, Gunma University, 3-39-22, Showa-machi, Maebashi 371-8511, Gunma, Japan
- Department of Radiation Oncology, Gunma University Graduate School of Medicine, 3-39-22, Showa-machi, Maebashi 371-8511, Gunma, Japan
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12
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Le Bozec A, Brugel M, Djerada Z, Ayad M, Perrier M, Carlier C, Botsen D, Nazeyrollas P, Bouché O, Slimano F. Beta-blocker exposure and survival outcomes in patients with advanced pancreatic ductal adenocarcinoma: a retrospective cohort study (BETAPANC). Front Pharmacol 2023; 14:1137791. [PMID: 37274119 PMCID: PMC10235451 DOI: 10.3389/fphar.2023.1137791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 05/09/2023] [Indexed: 06/06/2023] Open
Abstract
Introduction: Preclinical studies have demonstrated the possible role of beta-adrenergic receptors in pancreatic ductal adenocarcinoma (PDAC) tumor invasion and migration. The current study aimed to explore the possible association between survival outcomes and beta-blocker (BB) exposure in patients with advanced PDAC. Methods: This retrospective single-center study included 182 patients with advanced PDAC. Clinical [age, sex, BMI, cardiovascular condition, presence (SBB) or absence (NSBB) of beta-1 selectivity of BB, exposure duration, and multimorbidity], oncological (stage and anticancer treatment regimen), and biological (renal and liver function) data were collected. The endpoints were overall survival (OS) and progression-free survival (PFS). Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for survival outcomes associated with BB exposure were estimated using Cox regression model and propensity score (PS) methods. Results: Forty-one patients (22.5%) were exposed to BB. A total of 104 patients progressed (57.1%) to PDAC and 139 (76.4%) patients died at the end of follow-up (median, 320 days; IQR, 438.75 days). When compared to the non-exposed group, there was no increase in survival outcomes associated with BB use (OS: HR = 1.38, 95% CI = 0.80-2.39, p = 0.25; PFS: adjusted HR = 0.95, 95% CI = 0.48-1.88, p = 0.88). Similar results were obtained using the PS method. Compared to no BB usage, SBB use was associated with a significant decrease in OS (HR = 1.80, 95% CI = 1.16-2.80, p < 10-2). Conclusion: BB exposure was not associated with improved PDAC survival outcomes. Beta-1-selectivity was not independently associated with any differences.
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Affiliation(s)
| | - Mathias Brugel
- CHU Reims, Service de Gastroentérologie et Oncologie Digestive, Reims, France
| | - Zoubir Djerada
- Université de Reims Champagne-Ardenne, HERVI, Service Pharmacologie-Toxicologie, Reims, France
| | - Marya Ayad
- CHU Reims, Oncology Day-Hospital, Reims, France
| | - Marine Perrier
- CHU Reims, Service de Gastroentérologie et Oncologie Digestive, Reims, France
| | - Claire Carlier
- CHU Reims, Oncology Day-Hospital, Reims, France
- Institut Jean Godinot, Département d’Oncologie Médicale, Reims, France
| | - Damien Botsen
- CHU Reims, Service de Gastroentérologie et Oncologie Digestive, Reims, France
- Institut Jean Godinot, Département d’Oncologie Médicale, Reims, France
| | - Pierre Nazeyrollas
- Université de Reims Champagne-Ardenne, VieFra, CHU Reims, Service Cardiologie, Reims, France
| | - Olivier Bouché
- Université de Reims Champagne-Ardenne, Biospect, CHU Reims, Service de Gastroentérologie et Oncologie Digestive, Reims, France
| | - Florian Slimano
- Université de Reims Champagne-Ardenne, Biospect, CHU Reims, Service Pharmacie, Reims, France
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13
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Keyl J, Kasper S, Wiesweg M, Götze J, Schönrock M, Sinn M, Berger A, Nasca E, Kostbade K, Schumacher B, Markus P, Albers D, Treckmann J, Schmid KW, Schildhaus HU, Siveke JT, Schuler M, Kleesiek J. Multimodal survival prediction in advanced pancreatic cancer using machine learning. ESMO Open 2022; 7:100555. [PMID: 35988455 PMCID: PMC9588888 DOI: 10.1016/j.esmoop.2022.100555] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 07/04/2022] [Accepted: 07/05/2022] [Indexed: 11/23/2022] Open
Abstract
Background Existing risk scores appear insufficient to assess the individual survival risk of patients with advanced pancreatic ductal adenocarcinoma (PDAC) and do not take advantage of the variety of parameters that are collected during clinical care. Methods In this retrospective study, we built a random survival forest model from clinical data of 203 patients with advanced PDAC. The parameters were assessed before initiation of systemic treatment and included age, CA19-9, C-reactive protein, metastatic status, neutrophil-to-lymphocyte ratio and total serum protein level. Separate models including imaging and molecular parameters were built for subgroups. Results Over the entire cohort, a model based on clinical parameters achieved a c-index of 0.71. Our approach outperformed the American Joint Committee on Cancer (AJCC) staging system and the modified Glasgow Prognostic Score (mGPS) in the identification of high- and low-risk subgroups. Inclusion of the KRAS p.G12D mutational status could further improve the prediction, whereas radiomics data of the primary tumor only showed little benefit. In an external validation cohort of PDAC patients with liver metastases, our model achieved a c-index of 0.67 (mGPS: 0.59). Conclusions The combination of multimodal data and machine-learning algorithms holds potential for personalized prognostication in advanced PDAC already at diagnosis.
We developed a machine-learning-based prediction model that outperforms the AJCC staging system and mGPS. Applying our model to an external validation cohort demonstrates generalizability. Explainable machine learning enables to understand the decision making of our model and identifies relevant parameters. Combining clinical, imaging and genetic data holds potential for personalized prognostication in advanced PDAC.
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Affiliation(s)
- J Keyl
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen (AöR), University of Duisburg-Essen, Essen, Germany; Institute for AI in Medicine (IKIM), University Hospital Essen (AöR), Essen, Germany; German Cancer Consortium (DKTK), Partner site University Hospital Essen (AöR), Essen, Germany.
| | - S Kasper
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen (AöR), University of Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner site University Hospital Essen (AöR), Essen, Germany; Medical Faculty, University of Duisburg-Essen, Essen, Germany
| | - M Wiesweg
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen (AöR), University of Duisburg-Essen, Essen, Germany; Medical Faculty, University of Duisburg-Essen, Essen, Germany
| | - J Götze
- Department of Internal Medicine II, Oncology, Hematology, BMT and Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - M Schönrock
- Department of Internal Medicine II, Oncology, Hematology, BMT and Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - M Sinn
- Department of Internal Medicine II, Oncology, Hematology, BMT and Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - A Berger
- Institute for AI in Medicine (IKIM), University Hospital Essen (AöR), Essen, Germany
| | - E Nasca
- Institute for AI in Medicine (IKIM), University Hospital Essen (AöR), Essen, Germany
| | - K Kostbade
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen (AöR), University of Duisburg-Essen, Essen, Germany; Medical Faculty, University of Duisburg-Essen, Essen, Germany
| | - B Schumacher
- Department of Gastroenterology, Elisabeth Hospital Essen, Essen, Germany
| | - P Markus
- Department of General Surgery and Traumatology, Elisabeth Hospital Essen, Essen, Germany
| | - D Albers
- Department of Gastroenterology, Elisabeth Hospital Essen, Essen, Germany
| | - J Treckmann
- Department of General, Visceral and Transplant Surgery, West German Cancer Center, University Hospital Essen (AöR), Essen, Germany
| | - K W Schmid
- Medical Faculty, University of Duisburg-Essen, Essen, Germany; Institute of Pathology, West German Cancer Center, University Hospital Essen (AöR), Essen, Germany
| | - H-U Schildhaus
- Medical Faculty, University of Duisburg-Essen, Essen, Germany; Institute of Pathology, West German Cancer Center, University Hospital Essen (AöR), Essen, Germany
| | - J T Siveke
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen (AöR), University of Duisburg-Essen, Essen, Germany; Medical Faculty, University of Duisburg-Essen, Essen, Germany; Bridge Institute of Experimental Tumor Therapy (BIT), West German Cancer Center, University Hospital Essen (AöR), Essen, Germany; Division of Solid Tumor Translational Oncology, German Cancer Consortium (DKTK) Partner site Essen, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - M Schuler
- Department of Medical Oncology, West German Cancer Center, University Hospital Essen (AöR), University of Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Partner site University Hospital Essen (AöR), Essen, Germany; Medical Faculty, University of Duisburg-Essen, Essen, Germany
| | - J Kleesiek
- Institute for AI in Medicine (IKIM), University Hospital Essen (AöR), Essen, Germany; Medical Faculty, University of Duisburg-Essen, Essen, Germany
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14
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Garajová I, Cavazzoni A, Verze M, Minari R, Pedrazzi G, Balsano R, Gelsomino F, Valle RD, Digiacomo G, Giovannetti E, Leonardi F. It Takes Two to Tango: Potential Prognostic Impact of Circulating TGF-Beta and PD-L1 in Pancreatic Cancer. Life (Basel) 2022; 12:960. [PMID: 35888050 PMCID: PMC9323895 DOI: 10.3390/life12070960] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 06/17/2022] [Accepted: 06/23/2022] [Indexed: 12/19/2022] Open
Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with rising incidence and poor prognosis. The lack of reliable prognostic biomarkers hampers the individual evaluation of the survival and recurrence potential. Methods: Here, we investigate the value of plasma levels of two potential key players in molecular mechanisms underlying PDAC aggressiveness and immune evasion, soluble TGF-beta (sTGF-beta) and sPD-L1, in both metastatic and radically-resected PDAC. To this aim we prospectively enrolled 38 PDAC patients and performed appropriate statistical analyses in order to evaluate their correlation, and role in the prediction of disease relapse/progression, and patients' outcome. Results: Metastatic patients showed lower levels of circulating sTGF-beta and higher levels of sPD-L1 compared to radically-resected patients. Moreover, a decrease in sTGF-beta levels (but not sPD-L1) was significantly associated with disease relapse in radically-resected patients. We also observed lower sTGF-beta at disease progression after first-line chemotherapy in metastatic patients, though this change was not statistically significant. We found a significant correlation between the levels of sTGF-beta and sPD-L1 before first-line chemotherapy. Conclusions: These findings support the possible interaction of TGF-beta and PD-L1 pathways and suggest that sTGF-beta and sPD-L1 might synergize and be new potential blood-based biomarkers.
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Affiliation(s)
- Ingrid Garajová
- Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy; (I.G.); (M.V.); (R.M.); (R.B.); (F.L.)
| | - Andrea Cavazzoni
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (A.C.); (G.P.); (R.D.V.)
| | - Michela Verze
- Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy; (I.G.); (M.V.); (R.M.); (R.B.); (F.L.)
| | - Roberta Minari
- Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy; (I.G.); (M.V.); (R.M.); (R.B.); (F.L.)
| | - Giuseppe Pedrazzi
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (A.C.); (G.P.); (R.D.V.)
| | - Rita Balsano
- Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy; (I.G.); (M.V.); (R.M.); (R.B.); (F.L.)
- Lab of Medical Oncology, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands
| | - Fabio Gelsomino
- Department of Oncology and Hematology, University Hospital of Modena, 41125 Modena, Italy;
| | - Raffaele Dalla Valle
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (A.C.); (G.P.); (R.D.V.)
| | - Graziana Digiacomo
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (A.C.); (G.P.); (R.D.V.)
| | - Elisa Giovannetti
- Lab of Medical Oncology, Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc), 1081 HV Amsterdam, The Netherlands
- Cancer Pharmacology Lab, AIRC Start-Up Unit, Fondazione Pisana per la Scienza, 56124 Pisa, Italy
| | - Francesco Leonardi
- Medical Oncology Unit, University Hospital of Parma, 43126 Parma, Italy; (I.G.); (M.V.); (R.M.); (R.B.); (F.L.)
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15
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Kang YM, Wang H, Li R, Pan G. Prognostic Role of Carbohydrate Antigen 19 to 9 in Predicting Survival of Patients With Pancreatic Cancer: A Meta-Analysis. Technol Cancer Res Treat 2021; 20:15330338211043030. [PMID: 34617852 PMCID: PMC8642114 DOI: 10.1177/15330338211043030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
This study evaluates the prognostic role of carbohydrate antigen 19 to 9 (CA19-9) in predicting survival of pancreatic cancer patients. Literature search was conducted in electronic databases (Google Scholar, Ovid, PubMed, and Science Direct) and study selection was based on precise eligibility criteria. Random-effects meta-analyses were performed to achieve overall estimates of median survival and hazard ratios (HRs) of survival with cutoff defined lower and higher CA19-9 levels before and after surgery or chemotherapy (CT)/radiotherapy (RT) and the changes in CA19-9 levels after any treatment. A total of 41 studies (6519 patients; 42% females; age 63.3 years [95% confidence interval [CI]: 62.2, 64.4]) were included. A pooled HR of 1.79 with a narrow 95% CI (1.58, 2.01) showed that higher CA19-9 levels or less decrease in CA19-9 levels after treatment predicted shorter survival. Median survival in patients with lower and higher preoperative CA19-9 levels was 23.2 months [95% CI: 17.2, 29.2] and 14.0 months [95% CI: 10.9, 17.2], respectively, whereas median survival with lower and higher postoperative CA19-9 levels was 25.0 months [95% CI: 21.9, 28.0] and 13.0 months [95% CI: 10.9, 15.0] respectively. Median survival with lower and higher pre-CT/RT CA19-9 levels was 11.9 months [95% CI: 10.2, 13.6] and 7.7 months [95% CI: 6.2, 9.2], respectively, whereas median survival with lower and higher post-CT/RT CA19-9 levels was 15.1 months [95% CI: 13.2, 17.0] and 10.7 months [95% CI: 7.3, 14.0] respectively. A decrease in CA19-9 levels after treatment was also associated with longer survival. Thus, both pretreatment and posttreatment CA19-9 levels or their changes after treatment have good prognostic value in determining the survival of pancreatic cancer patients.
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Affiliation(s)
- Yong-Ming Kang
- 159365Heilongjiang Provincial Hospital, Harbin, Heilongjiang, China
| | - Hao Wang
- Heilongjiang Province Land Reclamation Headquarter General Hospital, Harbin, Heilongjiang, China
| | - Ran Li
- Harbin Red Cross Central Hospital, Harbin, Heilongjiang, China
| | - Gu Pan
- 159365Heilongjiang Provincial Hospital, Harbin, Heilongjiang, China
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16
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Batra A, Tang PA, Cheung WY. Prognostic Significance of Disease Control at 12 Weeks in Patients With Advanced Pancreatic Cancer Receiving FOLFIRINOX as First-line Chemotherapy. Am J Clin Oncol 2021; 44:519-525. [PMID: 34366400 DOI: 10.1097/coc.0000000000000856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
OBJECTIVES The POLO (Pancreas Cancer Olaparib Ongoing) trial demonstrated improvement in progression-free survival (PFS) with olaparib maintenance in advanced pancreatic cancer (APC) patients with germline BRCA1/2 mutations who had disease control after 16 weeks of platinum-based first-line therapy. However, in the real-world, the first assessment is usually performed at 12 weeks. Therefore, this study aimed to identify the proportion of real-world patients with APC that have disease control at 12 weeks (DC12) after FOLFIRINOX, assess any associations of baseline variables with DC12, and to determine the effect of DC12 on PFS and overall survival (OS). METHODS APC patients treated with first-line FOLFIRINOX from 2011 to 2018 in Alberta, Canada, were identified. We conducted an analysis of baseline characteristics to identify factors associated with DC12 and to compare the PFS and OS of patients with DC12 to those with earlier disease progression. RESULTS We identified 165 APC patients treated with FOLFIRINOX with unknown BRCA1/2 status, of which 56% were men, and the median age at diagnosis was 59 years (interquartile range, 38 to 75 y). Of these, 72 (44%) had DC12. Lower serum carbohydrate antigen 19.9 and normal serum albumin were associated with a higher likelihood of DC12. The PFS and OS of patients with DC12 was significantly higher than those with earlier progression (9.3 vs. 2.5 mo; hazard ratio, 0.22; 95% confidence interval, 0.15-0.32; P<0.001; 21.6 vs. 8.9 mo; hazard ratio, 0.35; 95% confidence interval, 0.25-0.49; P<0.0001). CONCLUSION Less than half of real-world patients treated with first-line FOLFIRINOX have DC12. Patients with APC who have higher carbohydrate antigen 19.9 and low albumin are less likely to have DC12. DC12 is significantly associated with longer PFS and OS.
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Affiliation(s)
- Atul Batra
- Department of Medical Oncology, Tom Baker Cancer Center, Calgary, AB, Canada
- Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, Delhi, India
| | - Patricia A Tang
- Department of Medical Oncology, Tom Baker Cancer Center, Calgary, AB, Canada
| | - Winson Y Cheung
- Department of Medical Oncology, Tom Baker Cancer Center, Calgary, AB, Canada
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17
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Hayuka K, Okuyama H, Murakami A, Okita Y, Nishiuchi T, Okano K, Suzuki Y, Tsuji A. Gemcitabine Plus Nab-Paclitaxel as Second-Line Chemotherapy following FOLFIRINOX in Patients with Unresectable Pancreatic Cancer: A Single-Institution, Retrospective Analysis. Chemotherapy 2021; 66:58-64. [PMID: 34284397 DOI: 10.1159/000517244] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 05/09/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Patients with advanced pancreatic cancer have a poor prognosis. FOLFIRINOX (FFX) and gemcitabine plus nab-paclitaxel (GnP) have been established as first-line treatment, but they have not been confirmed as second-line treatment after FFX. The aim of this study was to evaluate the safety and efficacy of GnP as second-line therapy after FFX in patients with unresectable pancreatic cancer. METHODS Twenty-five patients with unresectable pancreatic cancer were enrolled. The patients were treated with GnP after FFX between September 2015 and September 2019. Tumor response, progression-free survival (PFS), overall survival (OS), and incidence of adverse events were evaluated. RESULTS The response rate, disease control rate, median PFS, and median OS were 12%, 96%, 5.3 months, and 15.6 months, respectively. The common grade 3 or 4 adverse events were neutropenia (76%) and anemia (16%). CONCLUSIONS GnP after FOLFIRINOX is expected to be one of the second-line recommendations for patients with unresectable pancreatic cancer.
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Affiliation(s)
- Kotone Hayuka
- Department of Clinical Oncology, Faculty of Medicine, Kagawa University, Takamatsu, Japan,
| | - Hiroyuki Okuyama
- Department of Clinical Oncology, Faculty of Medicine, Kagawa University, Takamatsu, Japan
| | - Akitsu Murakami
- Department of Clinical Oncology, Faculty of Medicine, Kagawa University, Takamatsu, Japan
| | - Yoshihiro Okita
- Department of Clinical Oncology, Faculty of Medicine, Kagawa University, Takamatsu, Japan
| | - Takamasa Nishiuchi
- Department of Clinical Oncology, Faculty of Medicine, Kagawa University, Takamatsu, Japan
| | - Keiichi Okano
- Department of Gastroenterological Surgery, Kagawa University, Takamatsu, Japan
| | - Yasuyuki Suzuki
- Department of Gastroenterological Surgery, Kagawa University, Takamatsu, Japan
| | - Akihito Tsuji
- Department of Clinical Oncology, Faculty of Medicine, Kagawa University, Takamatsu, Japan
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18
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Zeeshan MS, Ramzan Z. Current controversies and advances in the management of pancreatic adenocarcinoma. World J Gastrointest Oncol 2021; 13:472-494. [PMID: 34163568 PMCID: PMC8204360 DOI: 10.4251/wjgo.v13.i6.472] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 03/22/2021] [Accepted: 05/25/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic adenocarcinoma is a lethal disease with a mortality rate that has not significantly improved over decades. This is likely due to several challenges unique to pancreatic cancer. Most patients with pancreatic cancer are diagnosed at a late stage of disease due to the lack of specific symptoms prompting an early investigation. A small subset of patients who are diagnosed at an early stage have a better chance at survival with curative surgical resection, but most patients still succumb to the disease in a few years. The dismal overall prognosis is due to suspected micro-metastasis at an early stage. Due to this reason, there is a recent interest in treating all patients with pancreatic cancers with systemic therapy upfront (including the ones that are surgically resectable). This approach is still not the standard of care due to the lack of robust prospective data available. Recent advancements in treatment regimens of chemotherapy, radiation and immunotherapy have improved the overall short-term survival but the long-term survival still remains poor. Novel approaches in diagnosis and treatment have shown promise in clinical studies but long-term clinical data is lacking. The following manuscript presents an overview of the epidemiology, diagnosis, staging, recent advances, novel approaches and controversies in the management of pancreatic adenocarcinoma.
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Affiliation(s)
- Muhammad Shehroz Zeeshan
- Gastrointestinal Section, Department of Medicine, Texas Health Harris Methodist Hospital, Fort Worth, TX 76104, United States
| | - Zeeshan Ramzan
- Gastrointestinal Section, Department of Medicine, Texas Health Harris Methodist Hospital, Fort Worth, TX 76104, United States
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19
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Huang X, Lu Z, Zhang K, Wang G, Cai B, Wu P, Yin J, Miao Y, Jiang K. Prognostic impact of the ratio of preoperative CA19-9 to liver enzyme levels in pancreatic cancer patients with jaundice (predictability of combined CA19-9/AST and CA19-9/γ-GGT for jaundiced PDAC patients). Pancreatology 2021; 21:S1424-3903(21)00470-1. [PMID: 34090807 DOI: 10.1016/j.pan.2021.05.300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 05/02/2021] [Accepted: 05/17/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Carbohydrate antigen 19-9 (CA19-9) has been reported as the most significant survival predictor of patients with pancreatic ductal adenocarcinoma (PDAC). However, the elevation of CA19-9 could interfere with obstructive jaundice and the predictive value of CA19-9 in PDAC patients with jaundice remains to be analyzed and elucidated to find possible adjustments. OBJECTIVE To evaluate the predictability of preoperative CA19-9 and its adjustments for the overall survival (OS) of PDAC patients by analyzing the relationship between preoperative serum CA19-9 and total bilirubin (TBIL). METHODS A total of 563 consecutive patients who underwent surgery for primary pancreatic adenocarcinoma in our center between January 2015 and September 2018 were retrospectively reviewed. Clinicopathologic information was collected and preoperative parameters such as CA19-9, CEA, TBIL, γ-GGT, AST, ALT, and ALP were recorded as well as overall survival rates, which began from the date of operation to that of death or the last follow-up. Kaplan-Meier survival curves with log-rank test and Cox regression models were applied using SPSS and the survival and survminer packages in R software. RESULTS Using 39/390/1000 as the cut-off values for preoperative serum CA19-9, significant capability of OS stratification was found in the total cohort (p < 0.001, MST = 29.7/19.1/15.2/12.1 months) and patients with TBIL <102.6 μmol/L (p < 0.001, MST = 32.2/19.6/15.0/11.2 months). However, in the subgroup of TBIL≥102.6 μmol/L, this classification method was replaced by the combined scoring of CA19-9/AST and CA19-9/γ-GGT. CONCLUSIONS As an independent predictor of overall survival of PDAC patients, preoperative serum CA19-9 is defective in survival stratification when TBIL≥102.6 μmol/L but a positive survival prognosis could be achieved with the application of combined preoperative CA19-9/AST and CA19-9/γ-GGT.
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Affiliation(s)
- Xumin Huang
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Zipeng Lu
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Kai Zhang
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Guangfu Wang
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Baobao Cai
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Pengfei Wu
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Jie Yin
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China
| | - Yi Miao
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China.
| | - Kuirong Jiang
- Pancreas Center, First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Pancreas Institute, Nanjing Medical University, Nanjing, China.
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20
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Yang A, Zylberberg HM, Rustgi SD, Amin SP, Bar-Mashiah A, Boffetta P, Lucas AL. Beta-blockers have no impact on survival in pancreatic ductal adenocarcinoma prior to cancer diagnosis. Sci Rep 2021; 11:1038. [PMID: 33441781 PMCID: PMC7807087 DOI: 10.1038/s41598-020-79999-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 12/04/2020] [Indexed: 11/16/2022] Open
Abstract
Previous studies have suggested that β-adrenergic signaling may regulate the growth of various cancers. The aim of our study is to investigate the association between the incidental use of beta-blockers for various conditions on the overall survival of patients with pancreatic ductal adenocarcinoma (PDAC). Patients with histologically-confirmed PDAC between 2007 and 2011 were extracted from Surveillance, Epidemiology, and End Results registry (SEER)-Medicare linked database. Kaplan Meier and multivariable Cox Proportional-Hazard models were used to examine the association between beta-blocker usage before diagnosis and overall survival adjusting for appropriate confounders. As an additional analysis we also examined continuous beta-blocker use before and after diagnosis. From 2007 to 2011, 13,731 patients were diagnosed with PDAC. Of these, 7130 patients had Medicare Part D coverage in the 6-month period before diagnosis, with 2564 (36%) of these patients using beta-blockers in this period. Patients receiving beta-blockers had a mean survival time of 5.1 months compared to 6 months for non-users (p < 0.01). In multivariable analysis, beta-blockers usage was not associated with improved survival (Hazard Ratio (HR) 1.04, 95%, Confidence Interval (CI) 0.98–1.1, p = 0.2). When patients were stratified by conditions with indications for beta-blocker usage, such as hypertension, coronary artery disease and cardiac arrhythmia, differences in survival were insignificant compared to non-users in all groups (p > 0.05). After stratification by receptor selectivity, this lack of association with survival persisted (p > 0.05 for all). As a subgroup analysis, looking at patients with continuous Medicare Part D coverage who used beta-blockers in the 6-month period before and after cancer diagnosis, we identified 7085 patients, of which 1750 (24.7%) had continuous beta blocker use. In multivariable analysis, continuous beta-blockers usage was associated with improved survival (Hazard Ratio (HR) 0.86, 95%, Confidence Interval (CI) 0.8–0.9, p < 0.01). Beta-blocker usage before diagnosis does not confer a survival advantage in patients with PDAC, though continuous use before and after diagnosis did confer a survival advantage. Prospective studies into the mechanism for this advantage are needed.
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Affiliation(s)
- Anthony Yang
- Henry D Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1069, New York, NY, 10029, USA
| | - Haley M Zylberberg
- Henry D Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1069, New York, NY, 10029, USA
| | - Sheila D Rustgi
- Henry D Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1069, New York, NY, 10029, USA
| | - Sunil P Amin
- Division of Gastroenterology, University of Miami Leonard Miller School of Medicine, Miami, FL, USA
| | - Ariel Bar-Mashiah
- Henry D Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1069, New York, NY, 10029, USA
| | - Paolo Boffetta
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Aimee L Lucas
- Henry D Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, Box 1069, New York, NY, 10029, USA.
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21
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Real World First-Line Treatments and Outcomes of Nab-Paclitaxel Plus Gemcitabine, mFOLFIRINOX and GEMOX in Unresectable Pancreatic Cancer from a Chinese Single Institution. ACTA ACUST UNITED AC 2020; 28:209-219. [PMID: 33704188 PMCID: PMC7816170 DOI: 10.3390/curroncol28010023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/16/2020] [Accepted: 12/24/2020] [Indexed: 12/24/2022]
Abstract
Background: There have not been any head-to-head prospective studies to compare the effects of different chemotherapy regimens as first-line treatments for unresectable pancreatic cancer (UPC). We aimed to compare the effectiveness of nab-paclitaxel plus gemcitabine, mFOLFIRINOX and gemcitabine plus oxaliplatin (GEMOX) as first-line treatments by using real-world data from Chinese patients. Methods: We retrospectively included patients with UPC treated with nab-paclitaxel plus gemcitabine, mFOLFIRINOX or GEMOX as a first-line treatment at Sun Yat-sen University Cancer Center. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) were assessed. Results: A total of 117 patients were administered nab-paclitaxel plus gemcitabine (n = 62), mFOLFIRINOX (n = 30) or GEMOX (n = 25) as first-line chemotherapy. The median OS was 11.1, 10.1 and 10.2 months (p = 0.75) in the nab-paclitaxel plus gemcitabine, mFOLFIRINOX and GEMOX, respectively. The ORR was similar among the three groups (24%, 23% and 32%, p = 0.76) and the DCR was higher in the nab-paclitaxel-gemcitabine group (82%) than the other two groups (60% and 64%, p = 0.04). The most common adverse events of grade 3 or 4 were neutropenia (32%, 28% and 5%), peripheral neuropathy (13%, 16% and 0) and fatigue (9%, 16% and 5%). Febrile neutropenia occurred in 2%, 4% and 5% of the patients in the three groups. Conclusion: In the first line treatment of UPC, our results suggest that nab-paclitaxel plus gemcitabine was associated with a higher DCR than mFOLFIRINOX or GEMOX, while all groups demonstrated similar OS, PFS and ORR.
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22
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Vargas CVF, Ceolin L, Scheffel RS, Benini AF, Graudenz MS, Maia AL. The tissue expression pattern of CA 19.9 is associated with oncological features in medullary thyroid carcinoma. Endocrine 2020; 70:544-551. [PMID: 32535684 DOI: 10.1007/s12020-020-02377-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 06/01/2020] [Indexed: 02/07/2023]
Abstract
PURPOSE Elevated serum levels of carbohydrate antigen 19.9 (CA19.9), a well-established tumor marker in pancreatic neoplasms, has been proposed as a prognostic marker of tumor aggressiveness in medullary thyroid carcinoma (MTC). A hypothesis of C-cell dedifferentiation has been raised. Here, we evaluated the expression of CA19.9 and CD133, a stem cell marker, in MTC tissues. METHODS MTC samples from patients attending a university-based hospital were evaluated for CA19.9 and CD133 expression by immunohistochemistry. Clinical data were retrieved from medical records. RESULTS Tumor specimens from 70 MTC patients (57.1% hereditary) were evaluated. The age at diagnosis was 36.1 ± 16.3 years, and 58.6% were female; 53% of patients had cervical and 20% distant metastases. CA19.9 staining was detected in 87% of the samples, but no association was observed with biochemical markers, tumor size, local or distant metastases (All P > 0.05). Remarkable, CA19.9 expression was higher in the metastasis than in primary tumor samples (P = 0.0002). CD133 was expressed in 90.5% samples, but no correlation was found with CA19.9. Interestingly, we identified three distinct expression patterns to CA19.9: individual, focal, and diffuse cells. Sporadic MTC was associated with the individual cell pattern (70.6%), while the hereditary form with the focal expression pattern (63.9%; P = 0.04). Remarkably, the diffuse pattern was associated with larger tumor size and distant metastases (P = 0.032). CONCLUSIONS The majority of samples stained for CA19.9, suggesting it is an MTC cell-intrinsic feature. Three distinct expression patterns were identified, which were associated with the hereditary or sporadic form, larger tumor size, and presence of metastases.
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Affiliation(s)
- Carla Vaz Ferreira Vargas
- Thyroid Unit, Hospital de Clínicas de Porto Alegre, Medical School, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Lucieli Ceolin
- Thyroid Unit, Hospital de Clínicas de Porto Alegre, Medical School, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Rafael Selbach Scheffel
- Thyroid Unit, Hospital de Clínicas de Porto Alegre, Medical School, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
- Department of Pharmacology, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Antônio Felippe Benini
- Thyroid Unit, Hospital de Clínicas de Porto Alegre, Medical School, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Márcia Silveira Graudenz
- Thyroid Unit, Hospital de Clínicas de Porto Alegre, Medical School, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
- Pathology Division, Hospital de Clínicas de Porto Alegre, Medical School, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
| | - Ana Luiza Maia
- Thyroid Unit, Hospital de Clínicas de Porto Alegre, Medical School, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
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23
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Yu S, Zhang C, Xie KP. Therapeutic resistance of pancreatic cancer: Roadmap to its reversal. Biochim Biophys Acta Rev Cancer 2020; 1875:188461. [PMID: 33157162 DOI: 10.1016/j.bbcan.2020.188461] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/20/2020] [Accepted: 10/24/2020] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer is a lethal disease with limited opportunity for resectable surgery as the first choice for cure due to its late diagnosis and early metastasis. The desmoplastic stroma and cellular genetic or epigenetic alterations of pancreatic cancer impose physical and biological barriers to effective therapies, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy. Here, we review the current therapeutic options for pancreatic cancer, and underlying mechanisms and potential reversal of therapeutic resistance, a hallmark of this deadly disease.
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Affiliation(s)
- Sen Yu
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital Affiliated to the South China University of Technology, School of Medicine, Guangzhou, Guangdong, People's Republic of China
| | - Chunyu Zhang
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital Affiliated to the South China University of Technology, School of Medicine, Guangzhou, Guangdong, People's Republic of China
| | - Ke-Ping Xie
- Department of Gastroenterology and Hepatology, Guangzhou First People's Hospital Affiliated to the South China University of Technology, School of Medicine, Guangzhou, Guangdong, People's Republic of China.
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24
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Grossberg AJ, Chu LC, Deig CR, Fishman EK, Hwang WL, Maitra A, Marks DL, Mehta A, Nabavizadeh N, Simeone DM, Weekes CD, Thomas CR. Multidisciplinary standards of care and recent progress in pancreatic ductal adenocarcinoma. CA Cancer J Clin 2020; 70:375-403. [PMID: 32683683 PMCID: PMC7722002 DOI: 10.3322/caac.21626] [Citation(s) in RCA: 294] [Impact Index Per Article: 58.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 05/21/2020] [Accepted: 05/26/2020] [Indexed: 12/12/2022] Open
Abstract
Despite tremendous gains in the molecular understanding of exocrine pancreatic cancer, the prognosis for this disease remains very poor, largely because of delayed disease detection and limited effectiveness of systemic therapies. Both incidence rates and mortality rates for pancreatic cancer have increased during the past decade, in contrast to most other solid tumor types. Recent improvements in multimodality care have substantially improved overall survival, local control, and metastasis-free survival for patients who have localized tumors that are amenable to surgical resection. The widening gap in prognosis between patients with resectable and unresectable or metastatic disease reinforces the importance of detecting pancreatic cancer sooner to improve outcomes. Furthermore, the developing use of therapies that target tumor-specific molecular vulnerabilities may offer improved disease control for patients with advanced disease. Finally, the substantial morbidity associated with pancreatic cancer, including wasting, fatigue, and pain, remains an under-addressed component of this disease, which powerfully affects quality of life and limits tolerance to aggressive therapies. In this article, the authors review the current multidisciplinary standards of care in pancreatic cancer with a focus on emerging concepts in pancreatic cancer detection, precision therapy, and survivorship.
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Affiliation(s)
- Aaron J. Grossberg
- Department of Radiation Medicine, Oregon Health & Science University, Portland, OR
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR
- Cancer Early Detection Advanced Research Center, Oregon Health & Science University, Portland, OR
| | - Linda C. Chu
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Christopher R. Deig
- Department of Radiation Medicine, Oregon Health & Science University, Portland, OR
| | - Eliot K. Fishman
- The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD
| | - William L. Hwang
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA
- Broad Institute of Harvard and MIT, Cambridge, MA
| | - Anirban Maitra
- Departments of Pathology and Translational Molecular Pathology, Sheikh Ahmed Pancreatic Cancer Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Daniel L. Marks
- Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, OR
- Department of Pediatrics and Pape Family Pediatric Research Institute, Oregon Health & Science University, Portland, OR
| | - Arnav Mehta
- Broad Institute of Harvard and MIT, Cambridge, MA
- Dana Farber Cancer Institute, Boston, MA
| | - Nima Nabavizadeh
- Department of Radiation Medicine, Oregon Health & Science University, Portland, OR
| | - Diane M. Simeone
- Departments of Surgery and Pathology, Perlmutter Cancer Center, NYU Langone Health, New York, NY
| | - Colin D. Weekes
- Division of Hematology/Oncology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA
| | - Charles R. Thomas
- Department of Radiation Medicine, Oregon Health & Science University, Portland, OR
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25
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Toledano-Fonseca M, Cano MT, Inga E, Rodríguez-Alonso R, Gómez-España MA, Guil-Luna S, Mena-Osuna R, de la Haba-Rodríguez JR, Rodríguez-Ariza A, Aranda E. Circulating Cell-Free DNA-Based Liquid Biopsy Markers for the Non-Invasive Prognosis and Monitoring of Metastatic Pancreatic Cancer. Cancers (Basel) 2020; 12:cancers12071754. [PMID: 32630266 PMCID: PMC7409337 DOI: 10.3390/cancers12071754] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/26/2020] [Accepted: 06/29/2020] [Indexed: 12/20/2022] Open
Abstract
Liquid biopsy may assist in the management of cancer patients, which can be particularly applicable in pancreatic ductal adenocarcinoma (PDAC). In this study, we investigated the utility of circulating cell-free DNA (cfDNA)-based markers as prognostic tools in metastatic PDAC. Plasma was obtained from 61 metastatic PDAC patients, and cfDNA levels and fragmentation were determined. BEAMing technique was used for quantitative determination of RAS mutation allele fraction (MAF) in cfDNA. We found that the prognosis was more accurately predicted by RAS mutation detection in plasma than in tissue. RAS mutation status in plasma was a strong independent prognostic factor for both overall survival (OS) and progression-free survival (PFS). Moreover, RAS MAF in cfDNA was also an independent risk factor for poor OS, and was strongly associated with primary tumours in the body/tail of the pancreas and liver metastases. Higher cfDNA levels and fragmentation were also associated with poorer OS and shorter PFS, body/tail tumors, and hepatic metastases, whereas cfDNA fragmentation positively correlated with RAS MAF. Remarkably, the combination of CA19-9 with MAF, cfDNA levels and fragmentation improved the prognostic stratification of patients. Furthermore, dynamics of RAS MAF better correlated with patients’ outcome than standard CA19-9 marker. In conclusion, our study supports the use of cfDNA-based liquid biopsy markers as clinical tools for the non-invasive prognosis and monitoring of metastatic PDAC patients.
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Affiliation(s)
- Marta Toledano-Fonseca
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), E14004 Córdoba, Spain; (M.T.-F.); (S.G.-L.); (R.M.-O.); (J.R.d.l.H.-R.); (E.A.)
- Cancer Network Biomedical Research Center (CIBERONC), E28029 Madrid, Spain;
| | - M. Teresa Cano
- Medical Oncology Department, Reina Sofía University Hospital, E14004 Córdoba, Spain; (M.T.C.); (E.I.); (R.R.-A.)
| | - Elizabeth Inga
- Medical Oncology Department, Reina Sofía University Hospital, E14004 Córdoba, Spain; (M.T.C.); (E.I.); (R.R.-A.)
| | - Rosa Rodríguez-Alonso
- Medical Oncology Department, Reina Sofía University Hospital, E14004 Córdoba, Spain; (M.T.C.); (E.I.); (R.R.-A.)
| | - M. Auxiliadora Gómez-España
- Cancer Network Biomedical Research Center (CIBERONC), E28029 Madrid, Spain;
- Medical Oncology Department, Reina Sofía University Hospital, E14004 Córdoba, Spain; (M.T.C.); (E.I.); (R.R.-A.)
| | - Silvia Guil-Luna
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), E14004 Córdoba, Spain; (M.T.-F.); (S.G.-L.); (R.M.-O.); (J.R.d.l.H.-R.); (E.A.)
- Cancer Network Biomedical Research Center (CIBERONC), E28029 Madrid, Spain;
| | - Rafael Mena-Osuna
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), E14004 Córdoba, Spain; (M.T.-F.); (S.G.-L.); (R.M.-O.); (J.R.d.l.H.-R.); (E.A.)
| | - Juan R. de la Haba-Rodríguez
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), E14004 Córdoba, Spain; (M.T.-F.); (S.G.-L.); (R.M.-O.); (J.R.d.l.H.-R.); (E.A.)
- Cancer Network Biomedical Research Center (CIBERONC), E28029 Madrid, Spain;
- Medical Oncology Department, Reina Sofía University Hospital, E14004 Córdoba, Spain; (M.T.C.); (E.I.); (R.R.-A.)
| | - Antonio Rodríguez-Ariza
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), E14004 Córdoba, Spain; (M.T.-F.); (S.G.-L.); (R.M.-O.); (J.R.d.l.H.-R.); (E.A.)
- Cancer Network Biomedical Research Center (CIBERONC), E28029 Madrid, Spain;
- Medical Oncology Department, Reina Sofía University Hospital, E14004 Córdoba, Spain; (M.T.C.); (E.I.); (R.R.-A.)
- Correspondence:
| | - Enrique Aranda
- Maimónides Biomedical Research Institute of Córdoba (IMIBIC), E14004 Córdoba, Spain; (M.T.-F.); (S.G.-L.); (R.M.-O.); (J.R.d.l.H.-R.); (E.A.)
- Cancer Network Biomedical Research Center (CIBERONC), E28029 Madrid, Spain;
- Medical Oncology Department, Reina Sofía University Hospital, E14004 Córdoba, Spain; (M.T.C.); (E.I.); (R.R.-A.)
- Department of Medicine, Faculty of Medicine, University of Córdoba, E14004 Córdoba, Spain
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26
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Mizrahi JD, Surana R, Valle JW, Shroff RT. Pancreatic cancer. Lancet 2020; 395:2008-2020. [PMID: 32593337 DOI: 10.1016/s0140-6736(20)30974-0] [Citation(s) in RCA: 1614] [Impact Index Per Article: 322.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Revised: 04/06/2020] [Accepted: 04/17/2020] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer is a highly fatal disease with a 5-year survival rate of approximately 10% in the USA, and it is becoming an increasingly common cause of cancer mortality. Risk factors for developing pancreatic cancer include family history, obesity, type 2 diabetes, and tobacco use. Patients typically present with advanced disease due to lack of or vague symptoms when the cancer is still localised. High quality computed tomography with intravenous contrast using a dual phase pancreatic protocol is typically the best method to detect a pancreatic tumour and to determine surgical resectability. Endoscopic ultrasound is an increasingly used complementary staging modality which also allows for diagnostic confirmation when combined with fine needle aspiration. Patients with pancreatic cancer are often divided into one of four categories based on extent of disease: resectable, borderline resectable, locally advanced, and metastatic; patient condition is also an important consideration. Surgical resection represents the only chance for cure, and advancements in adjuvant chemotherapy have improved long-term outcomes in these patients. Systemic chemotherapy combinations including FOLFIRINOX (5-fluorouracil, folinic acid [leucovorin], irinotecan, and oxaliplatin) and gemcitabine plus nab-paclitaxel remain the mainstay of treatment for patients with advanced disease. Data on the benefit of PARP inhibition as maintenance therapy in patients with germline BRCA1 or BRACA2 mutations might prove to be a harbinger of advancement in targeted therapy. Additional research efforts are focusing on modulating the pancreatic tumour microenvironment to enhance the efficacy of the immunotherapeutic strategies.
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Affiliation(s)
- Jonathan D Mizrahi
- Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Rishi Surana
- Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Juan W Valle
- Division of Cancer Sciences, University of Manchester, Department of Medical Oncology, Christie NHS Foundation Trust, Manchester, UK
| | - Rachna T Shroff
- Division of Hematology and Oncology, Department of Medicine, University of Arizona Cancer Center, Tucson, AZ, USA.
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27
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Sun KD, Zhang YJ, Zhu LP, Yang B, Wang SY, Yu ZH, Zhang HC, Chen X. Abnormal serum carbohydrate antigen 19-9 levels in a patient with splenic retiform haemangioendothelioma concomitant with hepatic amyloidosis: A case report. World J Clin Cases 2020; 8:1108-1115. [PMID: 32258081 PMCID: PMC7103981 DOI: 10.12998/wjcc.v8.i6.1108] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/21/2020] [Accepted: 03/14/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Carbohydrate antigen 19-9 (CA 19-9) is a glycoprotein that is used as a reliable tool for monitoring pancreatic cancer. Serum CA 19-9 levels are increased in patients suffering from liver, lung, and other non-malignant diseases. Haemangioendothelioma is a vascular neoplasm with a borderline biological behaviour. However, no case of haemangioendothelioma has yet been reported to be associated with CA 19-9.
CASE SUMMARY A 54-year-old Chinese man was referred to our hospital for discontinuous fatigue and unintentional weight loss for over one year. Laboratory investigations revealed an elevated serum CA 19-9 concentration of 39 IU/mL (reference interval, 0–37 IU/mL) over one year before admission. Afterwards, coagulopathy appeared, and the patient’s serum CA 19-9 concentration increased continuously. At the time of admission, abdominal pain and haemorrhagic shock burst occurred, and emergency medical operation was performed. Laboratory investigations conducted upon admission showed a serum CA19-9 concentration of 392.56 IU/mL. Surgical resection of the spleen was undertaken, and pathological examination showed retiform haemangioendothelioma. The patient developed jaundice ten days after surgical excision of the spleen. Pathological examination of needle biopsy samples of the liver yielded a diagnosis of hepatic amyloidosis.
CONCLUSION We describe a rare case of splenic retiform haemangioenthelioma concomitant with hepatic amyloidosis. Physicians should note abnormal serum CA 19-9 levels with early symptoms of fatigue and unintentional weight loss.
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Affiliation(s)
- Kai-Di Sun
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Yu-Jie Zhang
- Department of Pathology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Lan-Ping Zhu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Bo Yang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Sai-Yu Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Zi-Han Yu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Hai-Cheng Zhang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Xin Chen
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin 300052, China
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28
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Kato T, Ban D, Tateishi U, Ogura T, Ogawa K, Ono H, Mitsunori Y, Kudo A, Tanaka S, Tanabe M. Reticular pattern around superior mesenteric artery in computed tomography imaging predicting poor prognosis of pancreatic head cancer. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2020; 27:114-123. [PMID: 31702106 DOI: 10.1002/jhbp.700] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Some patients with pancreatic ductal adenocarcinoma (PDAC) demonstrate a reticular pattern around the superior mesenteric artery (SMA) in computed tomography scans. This study aimed to clarify the clinical significance of the reticular pattern in pancreatic head cancer. METHODS A total of 91 patients with pancreatic head cancer, who underwent upfront pancreaticoduodenectomy between 2004 and 2017, were included. Patients without reticular pattern (Non-group, n = 39); with reticular pattern around SMA (Ret-group, n = 39); and with soft tissue contact (Soft-group, n = 13) were compared. RESULTS Median overall survival (OS) of patients in the Ret-group was significantly worse than that in the Non-group (21.3 vs. 57.0 months; P < 0.001) and equivalent to that in the Soft-group. In the multivariate analysis, reticular pattern and high CA19-9 levels were identified as independent predictors of OS. Microscopically, only fibrotic thickenings were identified corresponding to the reticular pattern areas, and no difference in the frequency of early local recurrence was noted between the Non and Ret-groups. Lymphovascular invasion was significantly different between the two groups; furthermore, early distant recurrence was more frequent in the Ret-group. CONCLUSIONS The reticular pattern around SMA is an important prognostic factor related to frequent distant recurrence in patients with pancreatic cancer.
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Affiliation(s)
- Tomotaka Kato
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Daisuke Ban
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Ukihide Tateishi
- Department of Diagnostic Radiology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Toshiro Ogura
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Kosuke Ogawa
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroaki Ono
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Yusuke Mitsunori
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Atsushi Kudo
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Shinji Tanaka
- Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Minoru Tanabe
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
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29
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Laurent L, Sefrioui D, Bignon AL, Parzy A, Sidali S, Hassine M, Gangloff A, Galais MP, Bouhier-Leporrier K, Michel P, Di Fiore F. CA19.9 decrease >15% is a predictor of favourable outcome in patients treated for advanced pancreatic carcinoma: analysis of two independent cohorts. HPB (Oxford) 2019; 21:582-588. [PMID: 30466797 DOI: 10.1016/j.hpb.2018.09.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2018] [Revised: 08/19/2018] [Accepted: 09/06/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Although carbohydrate antigen 19.9 (CA19.9) is widely used in pancreatic adenocarcinoma (PA), no consensual cut-off value of CA19.9 decrease has been established for treatment monitoring. METHODS This was a retrospective study including patients with a baseline CA19.9 ≥ 37 UI/ml and with locally advanced or metastatic PA from two French centers. CA19.9 measurements were performed at baseline and first CT-scan evaluation. The aim was to use a training set to determine the best cut-off of CA19.9 decrease for predicting progressive disease (PD) and to analyze its performance in an independent validation cohort. RESULTS A total of 95 and 93 patients were included in the training and validation sets, respectively. A ≤15% CA19.9 decrease was the best cut-off for predicting PD with a sensitivity (Se) = 68% and a specificity (Sp) = 90%. In the validation set, this threshold was associated with Se = 76% and Sp = 83%. A >15% CA19.9 decrease was significantly associated with improved PFS (median 8.3 versus 3.1 months, p < 0.0001) and OS (median 14 versus 7.2 months, p < 0.0001). A >15% CA19.9 decrease was also identified as a factor independently associated with OS (HRa = 0.25, 95% CI:0.14-0.44). CONCLUSIONS A CA 19.9 decrease >15% is a favourable predictor of outcome in patients treated for advanced PA.
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Affiliation(s)
- Lucie Laurent
- Rouen University Hospital, Department of Hepato-Gastroenterology, Digestive Oncology Unit, F 76000, Rouen, France
| | - David Sefrioui
- Normandie Univ, UNIROUEN, Inserm U1245, IRON Group, Rouen University Hospital, Department of Hepato-Gastroenterology, Digestive Oncology Unit, F 76000, Rouen, France
| | - Anne-Laure Bignon
- Caen University Hospital, Department of Hepato-Gastroenterology and Nutrition, F 14000, Caen, France
| | - Aurélie Parzy
- Centre Régional François Baclesse, Digestive Oncology Unit, F 14000, Caen, France
| | - Sabrina Sidali
- Rouen University Hospital, Department of Hepato-Gastroenterology, Digestive Oncology Unit, F 76000, Rouen, France
| | - Mélanie Hassine
- Rouen University Hospital, Department of Hepato-Gastroenterology, Digestive Oncology Unit, F 76000, Rouen, France
| | - Alice Gangloff
- Rouen University Hospital, Department of Hepato-Gastroenterology, Digestive Oncology Unit, F 76000, Rouen, France
| | - Marie-Pierre Galais
- Centre Régional François Baclesse, Digestive Oncology Unit, F 14000, Caen, France
| | - Karine Bouhier-Leporrier
- Caen University Hospital, Department of Hepato-Gastroenterology and Nutrition, F 14000, Caen, France
| | - Pierre Michel
- Normandie Univ, UNIROUEN, Inserm U1245, IRON Group, Rouen University Hospital, Department of Hepato-Gastroenterology, Digestive Oncology Unit, F 76000, Rouen, France
| | - Frédéric Di Fiore
- Normandie Univ, UNIROUEN, Inserm U1245, IRON Group, Rouen University Hospital, Digestive Oncology Unit and Department of Medical Oncology, Henri Becquerel Centre, Rouen, F 76000, Rouen, France.
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30
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Rieser CJ, Zenati M, Hamad A, Al Abbas AI, Bahary N, Zureikat AH, Zeh HJ, Hogg ME. CA19-9 on Postoperative Surveillance in Pancreatic Ductal Adenocarcinoma: Predicting Recurrence and Changing Prognosis over Time. Ann Surg Oncol 2018; 25:3483-3491. [PMID: 29786131 DOI: 10.1245/s10434-018-6521-7] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Serum carbohydrate antigen 19-9 (CA19-9) correlates with response to therapy and overall survival (OS) for patients with pancreatic ductal adenocarcinoma (PDAC). This study aimed to define the chronologic relationship between CA19-9 elevation and radiographic recurrence to develop a model that can predict the risk of recurrence (RFS) and prognosis during interval surveillance for patients with resected PDAC. METHODS A retrospective review examined patients undergoing surgery for pancreatic adenocarcinoma from January 2010 to May 2016. Their CA19-9 levels were classified at diagnosis, after surgery, and at 6-month surveillance intervals. Recurrence was defined by radiographic evidence. The CA19-9 levels were correlated with RFS and OS at every time point using multivariate analysis. RESULTS The study examined 525 patients. Five patterns of CA19-9 were identified: normal ("nonsecretors," 18.5%), always elevated, and high at diagnosis but normal after resection involving three patterns with varied behavior during surveillance. These five patterns had implications for RFS and OS. When elevation of CA19-9, as assessed at 6-month intervals, was analyzed relative to detection of radiographic disease, CA19-9 had poor positive predictive value (average, 35%) but high negative predictive value (average, 92%) for radiographic recurrence. Conditional RFS showed that CA19-9 elevation did not equal radiographic recurrence but predicted subsequent RFS. Additionally, conditional OS showed that CA19-9 elevation alone was predictive at each time point. CONCLUSION This study showed that CA19-9 patterns beyond the post-resection period predict RFS and OS. High CA19-9 frequently is discordant with recurrence on imaging and may precede it by more than 6 months. At each surveillance interval, CA19-9 is predictive of prognosis, which may help in counseling patients and could be used to direct protocols of salvage chemotherapy.
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Affiliation(s)
- Caroline J Rieser
- Department of Surgical Oncology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Mazen Zenati
- Department of Surgical Oncology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Ahmad Hamad
- Department of Surgical Oncology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Amr I Al Abbas
- Department of Surgical Oncology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Nathan Bahary
- Department of Medical Oncology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Amer H Zureikat
- Department of Surgical Oncology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Herbert J Zeh
- Department of Surgical Oncology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Melissa E Hogg
- Department of Surgical Oncology, University of Pittsburgh, Pittsburgh, PA, USA.
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31
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Hsu CP, Lee LY, Hsu JT, Hsu YP, Wu YT, Wang SY, Yeh CN, Chen TC, Hwang TL. CD44 Predicts Early Recurrence in Pancreatic Cancer Patients Undergoing Radical Surgery. In Vivo 2018; 32:1533-1540. [PMID: 30348713 PMCID: PMC6365743 DOI: 10.21873/invivo.11411] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 08/09/2018] [Accepted: 08/10/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND/AIM Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of digestive cancer. Recurrence within one year after surgery is inevitable in most PDAC patients. Recently, cluster of differentiation 44 (CD44) has been shown to be associated with tumor initiation, metastasis and prognosis. This study aimed to explore the correlation of CD44 expression with clinicopathological factors and the role of CD44 in predicting early recurrence (ER) in PDAC patients after radical surgery. MATERIALS AND METHODS PDAC patients who underwent radical resection between January 1999 and March 2015 were enrolled in this study. Tumor recurrence within 6 months after surgery was defined as ER. Immunohistochemical staining was performed with anti-CD44 antibodies. The association between clinicopathological parameters and CD44 expression was analyzed. Predictors for ER were also assessed with univariate and multivariate analyses. RESULTS Overall, 155 patients were included in this study. Univariate analysis revealed CA19-9 levels (p=0.014), CD44 histoscores (H-scores; p=0.002), differentiation (p=0.010), nodal status (p=0.005), stage (p=0.003), vascular invasion (p=0.007), lymphatic invasion (p<0.001) and perineural invasion (p=0.042) as risk factors for ER. In multivariate analysis, high CA19-9 levels and CD44 H-scores and poor differentiation independently predicted ER. CONCLUSION High CA19-9 levels, CD44 H-scores and poor differentiation are independent predictors for ER in PDAC patients undergoing radical resection. Therefore, the determination of CD44 expression might help in identifying patients at a high risk of ER for more aggressive treatment after radical surgery.
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MESH Headings
- Aged
- Antigens, Tumor-Associated, Carbohydrate/genetics
- Biomarkers, Tumor/genetics
- Carcinoma, Pancreatic Ductal/epidemiology
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/pathology
- Carcinoma, Pancreatic Ductal/surgery
- Female
- Humans
- Hyaluronan Receptors/genetics
- Kaplan-Meier Estimate
- Lymphatic Metastasis
- Male
- Middle Aged
- Neoplasm Recurrence, Local/epidemiology
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/surgery
- Prognosis
- Risk Factors
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Affiliation(s)
- Chih-Po Hsu
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan, R.O.C
| | - Li-Yu Lee
- Department of Pathology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan, R.O.C
| | - Jun-Te Hsu
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan, R.O.C.
| | - Yu-Pao Hsu
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan, R.O.C
| | - Yu-Tung Wu
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan, R.O.C
| | - Shang-Yu Wang
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan, R.O.C
| | - Chun-Nan Yeh
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan, R.O.C
| | - Tse-Ching Chen
- Department of Pathology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan, R.O.C
| | - Tsann-Long Hwang
- Department of General Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan, R.O.C.
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Mahipal A, Tella SH, Kommalapati A, Goyal G, Soares H, Neuger A, Copolla D, Kim J, Kim R. Phase 1 trial of enzalutamide in combination with gemcitabine and nab-paclitaxel for the treatment of advanced pancreatic cancer. Invest New Drugs 2018; 37:473-481. [PMID: 30298303 DOI: 10.1007/s10637-018-0676-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 10/02/2018] [Indexed: 01/05/2023]
Abstract
Background Androgens were shown to play a key role in the growth and progression of pancreatic cancer. We evaluated the safety and tolerability of the combination of enzalutamide, a novel androgen receptor (AR) antagonist with gemcitabine and nab-paclitaxel as a first-line treatment in advanced pancreatic cancer. Methods We used the standard 3 + 3 dose escalation design with cohort expansion to evaluate 2 dose levels of enzalutamide: 80 mg and 160 mg/day orally (phase 1a) in combination with gemcitabine and nab-paclitaxel in metastatic pancreatic cancer patients. In the expansion phase (phase 1b), AR+ was a pre-requisite criterion. We also evaluated the full pharmacokinetic (PK) profile for nab-paclitaxel and enzalutamide. Results We enrolled 24 patients, 12 patients in phase 1a and 12 patients in phase 1b. The median age was 68 (range, 32-84) years. No DLTs were observed. Grade 3/4 treatment related adverse events included neutropenia (44%), anemia (40%), leukopenia (24%), nausea and vomiting (20%), diarrhea (16%), infections (12%), thrombocytopenia (8%), thromboembolic event (8%), hypertension (8%), hypokalemia (8%), hyponatremia (8%), and ALT elevation (8%). Median overall survival and progression-free survival was 9.73 [95%CI:9.73-13.5] and 7.53 (95%CI:6.05-12.8) months, respectively. PK analysis suggests that the combination therapy does not impact the kinetics of either drug evaluated. Enzalutamide reached steady-state levels between day 22 and 29 and the mean half-life of nab-paclitaxel was 19.6 ± 4.7 h. Conclusions Enzalutamide 160 mg daily in combination with gemcitabine and nab-paclitaxel can be safely administered with no unexpected toxicities. We also noticed preliminary signals of efficacy with this combination.
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Affiliation(s)
- Amit Mahipal
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.
- Department of Oncology, Mayo Clinic, 200 1st street SW, Rochester, MN, 55906, USA.
| | - Sri Harsha Tella
- Department of Internal Medicine, University of South Carolina School of Medicine, Columbia, SC, USA
| | - Anuhya Kommalapati
- Department of Internal Medicine, University of South Carolina School of Medicine, Columbia, SC, USA
| | - Gaurav Goyal
- Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
| | - Heloisa Soares
- Department of Oncology, University of New Mexico, Albuquerque, NM, USA
| | - Anthony Neuger
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Domenico Copolla
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Jongphil Kim
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL, USA
| | - Richard Kim
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA
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33
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Tingle SJ, Severs GR, Goodfellow M, Moir JA, White SA. NARCA: A novel prognostic scoring system using neutrophil-albumin ratio and Ca19-9 to predict overall survival in palliative pancreatic cancer. J Surg Oncol 2018; 118:680-686. [PMID: 30196571 DOI: 10.1002/jso.25209] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 07/26/2018] [Indexed: 01/05/2023]
Abstract
BACKGROUND AND OBJECTIVES Several serum based-markers and ratios have been investigated for their prognostic value in pancreatic ductal adenocarcinoma (PDAC). This cohort study aimed to combine these into a novel prognostic scoring system. METHODS A retrospective cohort study was performed on 145 patients with unresectable histologically-confirmed PDAC. Based on the existing literature the following markers were investigated: neutrophil-lymphocyte ratio (NLR), neutrophil-albumin ratio (NAR), platelet-lymphocyte ratio (PLR), fibrinogen, and Ca19-9. These values were dichotomized about their medians for Kaplan-Meier and Cox regression analysis. RESULTS Univariate Cox regression revealed statistically significant prognostic value for: NLR, NAR, PLR, fibrinogen, and Ca19-9. When combining these using Cox regression analysis adjusting for other prognostic indicators, only NAR (hazard ratios [HR] = 3.174, P = 0.022) and Ca19-9 (HR = 2.697, P = 0.031) were independent predictors of survival. Combining NAR and Ca19-9 we split the cohort into three "NARCA" groups: NARCA0 = NAR ≤ 0.13 and Ca19-9 ≤ 770, NARCA1 = either NAR > 0.13 or Ca19-9 >770, NARCA2 = NAR > 0.13 and Ca19-9 > 770. Median survival was 20.5, 9.7 and 4.1 months in NARCA0, 1, and 2 respectively ( P < 0.0005, log-rank test). A separate validation cohort confirmed the prognostic significance of the score ( P = 0.048). CONCLUSIONS Combining NAR and Ca19-9 into a prognostic score allows stratification of unresectable PDAC patients into groups with significantly different overall survival.
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Affiliation(s)
- Samuel J Tingle
- Department of HPB Surgery, Freeman Hospital, Newcastle Upon Tyne, United Kingdom
| | - George R Severs
- Department of HPB Surgery, Freeman Hospital, Newcastle Upon Tyne, United Kingdom
| | - Michael Goodfellow
- Department of HPB Surgery, Freeman Hospital, Newcastle Upon Tyne, United Kingdom
| | - John A Moir
- Department of HPB Surgery, Freeman Hospital, Newcastle Upon Tyne, United Kingdom
| | - Steven A White
- Department of HPB Surgery, Freeman Hospital, Newcastle Upon Tyne, United Kingdom
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34
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Okano K, Suto H, Oshima M, Ando Y, Nagao M, Kamada H, Kobara H, Masaki T, Okuyama H, Okita Y, Tsuji A, Suzuki Y. 18F-fluorodeoxyglucose positron emission tomography to indicate conversion surgery in patients with initially unresectable locally advanced pancreatic cancer. Jpn J Clin Oncol 2018; 48:434-441. [PMID: 29590448 DOI: 10.1093/jjco/hyy033] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 03/05/2018] [Indexed: 12/16/2022] Open
Abstract
Objective Advances in chemotherapy and chemoradiotherapy have enabled conversion of initially unresectable locally advanced (UR-LA) pancreatic adenocarcinoma (PDAC) to a resectable disease. However, definitive criteria for conversion surgery have not been established. We evaluated the potential of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) to indicate conversion surgery in patients with primary UR-LA PDAC. Methods Twenty consecutive patients with UR-LA PDAC underwent chemoradiation or chemotherapy followed by assessment with FDG-PET. We defined PET responders (standardized uptake value <3.0) with marked reduction (>80%) of carbohydrate antigen 19-9 as potential candidates for conversion surgery. Outcomes were compared with those of the patients with resectable (R; n = 94) and borderline resectable (BR; n = 37) PDAC. Results Eight of the 20 patients (40%) were considered PET responders with marked reduction of CA19-9 and received conversion surgery (UR-LAR) 3-9 months (median, 5 months) after the initiation of therapy. Complete resection (R0) was achieved in 7 of 8 patients (87.5%) with UR-LAR. There was no significant difference in R0 rates, morbidity, or mortality among the UR-LAR, R and BR groups. The overall survival (OS) curve was better in the UR-LAR group than in the group that did not receive surgery. There was no significant difference in OS between the UR-LAR and the R or BR groups. Conclusions FDG-PET could be a potential indicator for conversion surgery in patients with primary UR-LA PDAC and may help in selecting patients who qualify for complete surgical resection and have a promising prognosis.
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Affiliation(s)
- Keiichi Okano
- Departments of Gastroenterological Surgery, Kagawa University
| | - Hironobu Suto
- Departments of Gastroenterological Surgery, Kagawa University
| | - Minoru Oshima
- Departments of Gastroenterological Surgery, Kagawa University
| | - Yasuhisa Ando
- Departments of Gastroenterological Surgery, Kagawa University
| | - Mina Nagao
- Departments of Gastroenterological Surgery, Kagawa University
| | | | | | | | - Hiroyuki Okuyama
- Clinical Oncology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Yoshihiro Okita
- Clinical Oncology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Akihito Tsuji
- Clinical Oncology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Yasuyuki Suzuki
- Departments of Gastroenterological Surgery, Kagawa University
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35
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Nab-paclitaxel plus gemcitabine versus FOLFIRINOX as the first-line chemotherapy for patients with metastatic pancreatic cancer: retrospective analysis. Invest New Drugs 2018; 36:732-741. [PMID: 29616439 DOI: 10.1007/s10637-018-0598-5] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Accepted: 03/26/2018] [Indexed: 12/29/2022]
Abstract
Purpose nab-paclitaxel plus gemcitabine (AG) and FOLFIRINOX have been established as standard first-line treatment in metastatic pancreatic cancer (mPC). We performed retrospective analysis comparing the efficacies of AG and FOLFIRINOX in daily practice setting. Materials and Methods We analyzed 308 patients who presented initially as mPC and received AG (n = 149) or FOLFIRINOX (n = 159) as first-line treatment between 2013 and 2016. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Result There were no significant differences between the two groups in terms of baseline characteristics, except older age and higher Charlson Comorbidity Index (CCI) score in AG group. The response rates (34% vs 34%) and median PFS (6.8 vs 5.1 months) were comparable between two groups (p = 0.88 and p = 0.19, respectively), while median OS was significantly better with AG than FOLFIRINOX (11.4 vs 9.6 months; p = 0.002). Elevated baseline CA19-9 level and liver metastasis were independent adverse prognostic factors for PFS and OS. In subgroup analyses, PFS with AG was better in patients with age ≥ 65 years, peritoneal metastasis, and higher CCI than that with FOLFIRINOX. Conclusion Both AG and FOLFIRINOX showed comparable efficacy outcomes in daily practice setting. AG might be preferentially considered in patients with peritoneal metastasis, comorbid medical conditions or old age.
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36
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Chen Y, Shao Z, Chen W, Xie H, Wu Z, Qin G, Zhao N. A varying-coefficient cox model for the effect of CA19-9 kinetics on overall survival in patients with advanced pancreatic cancer. Oncotarget 2018; 8:29925-29934. [PMID: 28404893 PMCID: PMC5444714 DOI: 10.18632/oncotarget.15557] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 01/23/2017] [Indexed: 12/12/2022] Open
Abstract
Purpose To evaluate the relationship between serum CA19-9 and overall survival in patients with advanced pancreatic cancer. Methods 109 advanced pancreatic cancer patients with gemcitabine based first-line chemotherapy were included. The effect of pretreatment CA19-9 level on overall survival was modeled by Cox proportional hazard regression. The effect of CA19-9 kinetics on overall survival was modeled by an extended Cox regression with a time varying coefficient and a time varying covariate. Results Univariate analysis indicated that baseline CA19-9 correlated with OS (HR = 1.66, p < 0.01) and this association remained significant within multivariate analysis (HR = 1.56, P < 0.01). For the analysis of CA19-9 kinetics, the extended Cox model showed that the effect of CA19-9 on overall survival changed with time: increased in the first two months and reached the top at a HR of about 2, then decreased for the next two months to a HR of about 1.56 and finally tended to be stable. The combination of pretreatment CA19-9 and CA19-9 at 2 month may better evaluate the patients’ prognosis compared to pretreatment CA19-9 alone. Conclusion Pretreatment CA19-9 and CA19-9 kinetics may serve as a useful serum biomarker in advanced pancreatic cancer.
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Affiliation(s)
- Yuntao Chen
- Department of Biostatistics, School of Public Health and Key Laboratory of Public Health Safety, Fudan University, Shanghai 200032, China.,Collaborative Innovation Center of Social Risks Governance in Health, Fudan University, Shanghai 200032, China
| | - Zhenyi Shao
- Collaborative Innovation Center of Social Risks Governance in Health, Fudan University, Shanghai 200032, China
| | - Wen Chen
- Collaborative Innovation Center of Social Risks Governance in Health, Fudan University, Shanghai 200032, China
| | - Hua Xie
- Collaborative Innovation Center of Social Risks Governance in Health, Fudan University, Shanghai 200032, China
| | - Zhenyu Wu
- Department of Biostatistics, School of Public Health and Key Laboratory of Public Health Safety, Fudan University, Shanghai 200032, China.,Collaborative Innovation Center of Social Risks Governance in Health, Fudan University, Shanghai 200032, China
| | - Guoyou Qin
- Department of Biostatistics, School of Public Health and Key Laboratory of Public Health Safety, Fudan University, Shanghai 200032, China.,Collaborative Innovation Center of Social Risks Governance in Health, Fudan University, Shanghai 200032, China
| | - Naiqing Zhao
- Department of Biostatistics, School of Public Health and Key Laboratory of Public Health Safety, Fudan University, Shanghai 200032, China.,Collaborative Innovation Center of Social Risks Governance in Health, Fudan University, Shanghai 200032, China
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37
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Song JY, Chen MQ, Guo JH, Lian SF, Xu BH. Combined pretreatment serum CA19-9 and neutrophil-to-lymphocyte ratio as a potential prognostic factor in metastatic pancreatic cancer patients. Medicine (Baltimore) 2018; 97:e9707. [PMID: 29369199 PMCID: PMC5794383 DOI: 10.1097/md.0000000000009707] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The aim of this study was to explore the role of combined pretreatment serum carbohydrate antigen 19-9 (CA19-9) and neutrophil-to-lymphocyte ratio (NLR) as potential prognostic factors in metastatic pancreatic cancer patients.We investigated pretreatment serum CA19-9 and NLR in 59 metastatic pancreatic cancer patients, determined the patients' thresholds by receiver operating characteristic curve analysis, and assessed their prognostic values by Kaplan-Meier curve and Cox regression models.Results of multivariate analysis showed high CA19-9, high NLR, and high score (the scoring system of CA19-9 and NLR) were significantly correlated with overall survival. Area under the curve of the scoring system was higher than that of CA19-9 or NLR.Combined pretreatment serum CA19-9 and NLR is a better prognostic biomarker of metastatic pancreatic cancer patients than CA19-9 or NLR alone.
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38
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Mirkin KA, Hollenbeak CS, Wong J. Prognostic impact of carbohydrate antigen 19-9 level at diagnosis in resected stage I-III pancreatic adenocarcinoma: a U.S. population study. J Gastrointest Oncol 2017; 8:778-788. [PMID: 29184681 PMCID: PMC5674264 DOI: 10.21037/jgo.2017.07.04] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
BACKGROUND Pancreatic adenocarcinoma is a highly aggressive cancer, with surgical resection and systemic therapy offering the only hope for long-term survival. Carbohydrate antigen 19-9 (CA 19-9) has been used as a prognostic marker after resection; however, the relationship between survival and pre-treatment CA 19-9 level remains unclear. This study evaluates pre-treatment serum CA 19-9 level as a predictor for long-term survival. METHODS The U.S. National Cancer Data Base [2004-2012] was reviewed for patients with clinical stages I-III resected pancreatic adenocarcinoma with recorded pre-treatment CA 19-9 levels (U/mL). Kaplan Meier and Weibull survival analyses were performed. RESULTS Four thousand seven hundred and one patients were included: 12.6% received neoadjuvant therapy (NAT), 27.4% underwent surgery, and 60.1% underwent surgery and adjuvant therapy. Amongst those who underwent initial surgery, there was no association between CA 19-9 levels ≤800 (≤100, 101-300, 301-500, 501-800) with survival (stage I P=0.7592, stage II P=0.5088, stage III P=0.9037). Levels >800 were associated with significantly worse survival in all stages (P≤0.0001, all). Amongst those who received NAT, levels >800 were associated with worse survival in early (stage I P=0.0001), but not advanced stage disease (stage II P=0.1891, stage III P=0.9316). In multivariable analyses, levels >800 demonstrated a 3.29 greater hazard of mortality with respect to patients with levels ≤100 (P<0.0001). CONCLUSIONS Pre-treatment CA 19-9 levels >800 appear to be associated with advanced disease, and are negatively associated with long-term survival. However, levels ≤800 had no significant association with survival. Although this study suggests an association, further study is needed to evaluate whether patients with CA 19-9 levels >800 benefit from NAT.
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Affiliation(s)
- Katelin A. Mirkin
- Department of Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA, USA
| | - Christopher S. Hollenbeak
- Department of Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA, USA
- Department of Public Health Sciences, The Pennsylvania State University, College of Medicine, Hershey, PA, USA
| | - Joyce Wong
- Department of Surgery, The Pennsylvania State University, College of Medicine, Hershey, PA, USA
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Ueno M, Li CP, Ikeda M, Ishii H, Mizuno N, Yamaguchi T, Ioka T, Oh DY, Ichikawa W, Okusaka T, Matsuyama Y, Arai D, Chen LT, Park YS, Furuse J. A randomized phase II study of gemcitabine plus Z-360, a CCK2 receptor-selective antagonist, in patients with metastatic pancreatic cancer as compared with gemcitabine plus placebo. Cancer Chemother Pharmacol 2017. [PMID: 28634650 PMCID: PMC5532401 DOI: 10.1007/s00280-017-3351-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Background We investigated the efficacy and safety of 60, 120, or 240 mg of Z-360, which is a highly potent cholecystokinin2-receptor-selective antagonist, combined with gemcitabine in patients with metastatic pancreatic cancer. Methods Patients were randomly assigned in a 1:1:1:1 ratio to one of four treatment groups. Patients received 1000 mg/m2 gemcitabine for each cycle and Z-360 tablets of 60 mg (GZ 60 mg group), 120, 240 mg or placebo tablets (Gem group) orally twice daily. The primary endpoint was overall survival (OS). Results The median OS was 1.3 months longer in the GZ 60 mg group compared with the Gem group (8.5 vs. 7.2 months) and the risk of death was reduced by 19% compared with the Gem group, although there were no statistically significant differences. The study treatments were well tolerated. Conclusions In this Phase II study, no statistically significant differences between the GZ groups and Gem group were detected in any analysis. However, Z-360 in dose of 60 mg tends to improve OS in patients with metastatic pancreatic cancer with low toxic effect. Further exploratory trials with other agents such as gemcitabine plus nab-paclitaxel might be beneficial. Electronic supplementary material The online version of this article (doi:10.1007/s00280-017-3351-4) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Makoto Ueno
- Division of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, 2-3-2, Nakao, Asahi-ku, Yokohama-shi, Kanagawa, 241-8515, Japan.
| | - Chung Pin Li
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, 201, Section 2, Shin-Pai Road, Taipei, 11217, Taiwan.,School of Medicine, National Yang-Ming University, 155, Section 2, Linong Street, Taipei, 112, Taiwan
| | - Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa-shi, Chiba, 277-8577, Japan
| | - Hiroshi Ishii
- Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31, Ariake, Koto-ku, Tokyo, 135-8550, Japan.,Department of Gastroenterology, Clinical Research Center, National Hospital Organization Shikoku Cancer Center, 160, Kou, Minamiumemoto-machi, Matsuyama-shi, Ehime, 791-0280, Japan
| | - Nobumasa Mizuno
- Department of Gastroenterology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, 464-8681, Japan
| | - Taketo Yamaguchi
- Department of Gastroenterology, Chiba Cancer Center, 666-2 Nitona-cho, Chuo-ku, Chiba-shi, Chiba, 260-8717, Japan
| | - Tatsuya Ioka
- Department of Gastrointestinal Cancer Screening and Surveillance, Osaka Medical Center for Cancer and Cardiovascular Disease, 3-3 Nakamichi 1-Chome, Higashinari-ku, Osaka, 537-8511, Japan.,Department of Gastrointestinal Cancer Screening and Surveillance, Osaka International Cancer Institute, 3-1-69, Otemae, Chuo-ku, Osaka, 541-8567, Japan
| | - Do Youn Oh
- Division of Medical Oncology, Department of Internal Medicine, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea
| | - Wataru Ichikawa
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, 1-30 Fujigaoka, Aoba-ku, Yokohama, Kanagawa, 227-8501, Japan
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan
| | - Yutaka Matsuyama
- Department of Biostatistics, School of Public Health, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan
| | - Daichi Arai
- Division of Clinical Research 3, ZERIA Pharmaceutical Co., Ltd., 10-11, Nihonbashi Kobuna-cho, Chuo-ku, Tokyo, 103-8351, Japan
| | - Li Tzong Chen
- National Institute of Cancer Research, National Health Research Institutes, 367, Sheng-Li Rd., North District, 70456, Tainan, Taiwan
| | - Young Suk Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Irwon-Dong, Gangnam-Gu, Seoul, 06351, South Korea
| | - Junji Furuse
- Department of Internal Medicine, Medical Oncology, Kyorin University School of Medicine, 6-20-2, Shinkawa, Mitaka-shi, Tokyo, 181-8611, Japan
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Nguyen KT, Kalyan A, Beasley HS, Singhi AD, Sun W, Zeh HJ, Normolle D, Bahary N. Gemcitabine/nab-paclitaxel as second-line therapy following FOLFIRINOX in metastatic/advanced pancreatic cancer-retrospective analysis of response. J Gastrointest Oncol 2017; 8:556-565. [PMID: 28736642 DOI: 10.21037/jgo.2017.01.23] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Given the tolerability of nPG in first-line therapy, we desired to evaluate the response and toxicity profiles of second-line gemcitabine with nab-paclitaxel (nPG) following FOLFIRINOX. Methods: We retrospectively identified 30 patients who received first-line FOLFIRINOX for unresectable or metastatic pancreatic adenocarcinoma followed by second-line nPG. Response was evaluated by RECIST criteria and carbohydrate antigen 19-9 (CA19-9) change. RESULTS Median age was 63 years with 77% percent having metastatic disease. Nineteen patients (63%) achieved PR based on CA19-9. Median overall survival (OS) with nPG was 12.4 months (mo) and median progression-free survival (PFS) was 3.7 mo. Median PFS and OS for patients with at least stable CA19-9 were 4.7 and 13.9 mo since initiation of nPG. Patients with an increased CA19-9 level during nPG had a shorter median PFS (1.4 mo) and OS (5.3 mo). A significant PFS difference was demonstrated in patients with at least stable disease as the best RECIST response versus in those with progressive disease (5.4 vs. 1.9 mo, P<0.001). Grade 3/4 adverse events include thrombocytopenia (33%), anemia (23%), nausea (17%), lymphopenia (7%), infectious complications (6%), diarrhea (3%), and neuropathy (3%). CONCLUSIONS This study demonstrates a clinical benefit of second-line nPG. The study also suggests a possible use of CA19-9 to predict response to therapy.
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Affiliation(s)
- Khanh T Nguyen
- Department of Hematology and Oncology, University of Pittsburgh, Pennsylvania, USA
| | - Aparna Kalyan
- Developmental Therapeutics Program of Department of Hematology and Oncology, Northwestern University, Illinois, USA
| | - H Scott Beasley
- Department of Radiology, University of Pittsburgh, Pennsylvania, USA
| | - Aatur D Singhi
- Department of Pathology, University of Pittsburgh, Pennsylvania, USA
| | - Weijing Sun
- Department of Hematology and Oncology, University of Pittsburgh, Pennsylvania, USA
| | - Herbert J Zeh
- Division of Gastrointestinal Surgical Oncology, University of Pittsburgh, Pennsylvania, USA
| | - Daniel Normolle
- Department of Biostatistics, University of Pittsburgh, Pennsylvania, USA
| | - Nathan Bahary
- Department of Hematology and Oncology, University of Pittsburgh, Pennsylvania, USA
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Du R, Sun W, Lin L, Sun J, Peng K, Xu Y, Xu M, Chen Y, Bi Y, Wang W, Li D, Lu J. Serum CA 19-9 and risk of incident diabetes in middle-aged and elderly Chinese: a prospective cohort study. Acta Diabetol 2017; 54:201-208. [PMID: 27804035 DOI: 10.1007/s00592-016-0937-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 10/19/2016] [Indexed: 01/06/2023]
Abstract
AIMS Carbohydrate antigen (CA) 19-9 is a tumor marker for gastrointestinal and pancreatic cancers. Previous studies found that CA 19-9 was elevated in patients with diabetes, but little is known about its relationship with diabetes risk in prospective studies. Our objective was to evaluate the association between serum CA 19-9 and the risk of incident diabetes in Chinese population. METHODS Data were obtained from a prospective cohort study among 2391 middle-aged and elderly Chinese with a median follow-up of 3.8 years. The measurement for the study outcome was incident diabetes. RESULTS Compared with individuals in the lowest quartile, those in the highest quartile of CA 19-9 had significantly higher incidence of diabetes (12.54 vs. 8.86%, P = 0.04). In the fully adjusted logistic regression model, compared with the lowest quartile, the highest quartile of CA 19-9 was significantly associated with 58% increased risk of incident diabetes [odds ratio (OR), 95% confidence interval (CI) 1.58, 1.02-2.44]. Stratified analysis suggested that the increased risk was seen only in women (OR, 95% CI 1.96, 1.10-3.48), or participants aged ≥65 (OR, 95% CI 2.32, 1.03-5.19), or those with body mass index ≥24 (OR, 95% CI 2.09, 1.20-3.63), or current nondrinkers (OR, 95% CI 1.79, 1.09-2.92), or those with impaired glucose regulation (IGR) (OR, 95% CI 2.49, 1.33-4.67). Significant interaction was detected between IGR and serum CA 19-9 (P for interaction <0.0001). CONCLUSIONS Serum CA 19-9 is associated with a significantly increased risk of diabetes among the middle-aged and elderly Chinese population. Further investigations are needed to confirm this association and disclose potential mechanisms.
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Affiliation(s)
- Rui Du
- National Clinical Research Center for Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin 2nd Road, Shanghai, 200025, China
| | - Wanwan Sun
- National Clinical Research Center for Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin 2nd Road, Shanghai, 200025, China
| | - Lin Lin
- National Clinical Research Center for Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin 2nd Road, Shanghai, 200025, China
| | - Jichao Sun
- National Clinical Research Center for Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin 2nd Road, Shanghai, 200025, China
| | - Kui Peng
- National Clinical Research Center for Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin 2nd Road, Shanghai, 200025, China
| | - Yu Xu
- National Clinical Research Center for Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin 2nd Road, Shanghai, 200025, China
| | - Min Xu
- National Clinical Research Center for Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin 2nd Road, Shanghai, 200025, China
| | - Yuhong Chen
- National Clinical Research Center for Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin 2nd Road, Shanghai, 200025, China
| | - Yufang Bi
- National Clinical Research Center for Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin 2nd Road, Shanghai, 200025, China
| | - Weiqing Wang
- National Clinical Research Center for Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin 2nd Road, Shanghai, 200025, China
| | - Donghui Li
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jieli Lu
- National Clinical Research Center for Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Rui Jin 2nd Road, Shanghai, 200025, China.
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Sato Y, Fujimoto D, Uehara K, Shimizu R, Ito J, Kogo M, Teraoka S, Kato R, Nagata K, Nakagawa A, Otsuka K, Hamakawa H, Takahashi Y, Imai Y, Tomii K. The prognostic value of serum CA 19-9 for patients with advanced lung adenocarcinoma. BMC Cancer 2016; 16:890. [PMID: 27842505 PMCID: PMC5109711 DOI: 10.1186/s12885-016-2897-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2015] [Accepted: 10/30/2016] [Indexed: 12/13/2022] Open
Abstract
Background This study aimed to assess the prognostic accuracy of serum CA 19-9 in patients with advanced lung adenocarcinoma. Methods We retrospectively reviewed data of 246 patients who were diagnosed at our institute with advanced (stage IIIB or IV) lung adenocarcinoma between March 2006 and December 2012. We excluded patients who received no chemotherapy, or for whom we had no data on pre-treatment tumor markers. We also evaluated 116 consecutive resected specimens from patients with clinical stage I lung adenocarcinoma pathologically. Results The 76 (31 %) patients who were CA 19-9+ had shorter overall survival (OS) than CA 19-9− group (12.5 vs 26.2 months, P = 0.005). Cox’s multivariate regression analysis identified Eastern Cooperative Oncology Group Performance Status 0 or 1 (P < 0.001), mutated epidermal growth factor receptor (EGFR) status (P < 0.001), stage IIIB (P < 0.001), CYFRA 21-1− (P < 0.001), CA 19-9− (P = 0.005) and use of platinum doublet therapy (P = 0.034) as independent predictors of longer OS. We stratified patients by CA 19-9 and CYFRA 21-1 as double positive (CA 19-9+/CYFRA 21-1+, n = 59), single positive (either CA19-9+ or CYFRA 21-1+, n = 113), or double negative (CA 19-9−/CYFRA 21-1−, n = 74). Their respective OS were 10.0, 23.3 and 31.8 months (P < 0.001). Pathological analysis also correlated CA 19-9 expression with malignant features such as vessel invasion, pleural invasion, cancer invasive factors and mucin production. Conclusions CA 19-9 and CYFRA 21-1 are independent prognostic markers in patients with advanced lung adenocarcinoma. Combined use of CA 19-9 and CYFRA 21-1 provides further prognostic information in patients with advanced lung adenocarcinoma. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2897-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yuki Sato
- Department of Respiratory Medicine, Kobe City Medical Center, General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Daichi Fujimoto
- Department of Respiratory Medicine, Kobe City Medical Center, General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan.
| | - Keiichiro Uehara
- Department of Pathology, Kobe City Medical Center, General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Ryoko Shimizu
- Department of Respiratory Medicine, Kobe City Medical Center, General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Jiro Ito
- Department of Respiratory Medicine, Kobe City Medical Center, General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Mariko Kogo
- Department of Respiratory Medicine, Kobe City Medical Center, General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Shunsuke Teraoka
- Department of Respiratory Medicine, Kobe City Medical Center, General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Ryoji Kato
- Department of Respiratory Medicine, Kobe City Medical Center, General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Kazuma Nagata
- Department of Respiratory Medicine, Kobe City Medical Center, General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Atsushi Nakagawa
- Department of Respiratory Medicine, Kobe City Medical Center, General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Kojiro Otsuka
- Department of Respiratory Medicine, Kobe City Medical Center, General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Hiroshi Hamakawa
- Department of Thoracic Surgery, Kobe City Medical Center, General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Yutaka Takahashi
- Department of Thoracic Surgery, Kobe City Medical Center, General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Yukihiro Imai
- Department of Pathology, Kobe City Medical Center, General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
| | - Keisuke Tomii
- Department of Respiratory Medicine, Kobe City Medical Center, General Hospital, 2-1-1 Minatojima-minamimachi, Chuo-ku, Kobe, 650-0047, Japan
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CA19-9-related tumor kinetics after first-line chemotherapy of patients with advanced pancreatic cancer: a monoinstitutional experience. Med Oncol 2016; 33:103. [PMID: 27522503 DOI: 10.1007/s12032-016-0817-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2016] [Accepted: 08/05/2016] [Indexed: 01/04/2023]
Abstract
The absolute value of carbohydrate antigen 19-9 (CA19-9) pretreatment and its reduction after chemotherapy are established prognostic variables for patients with advanced pancreatic cancer. The present study is a retrospective monoinstitutional evaluation of the prognostic role of the CA19-9 reduction and some CA19-9-related tumor kinetics parameters, such as tumor growth rate constant (G), kinetic tumor response and log ratio. Forty-one cases met the selection criteria. After 8 weeks only G reported an inverse relationship with OS (r = -0.494) that was confirmed by regression analysis (R (2) = 0.192). G after 8 weeks of chemotherapy appears as a possible surrogate end point of overall survival.
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Al-Shamsi HO, Alzahrani M, Wolff RA. The clinical utility of normal range carbohydrate antigen 19-9 level as a surrogate marker in evaluating response to treatment in pancreatic cancer-a report of two cases. J Gastrointest Oncol 2016; 7:E45-51. [PMID: 27284488 PMCID: PMC4880787 DOI: 10.21037/jgo.2016.01.05] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Carbohydrate antigen 19-9 (CA 19-9) is a tumor marker that is has been has been intensely studied and investigated as a surrogate marker in pancreatic cancer (PC). It is also commonly utilized in the clinical management of PC. We report two cases where normal range CA 19-9 level has been shown to be useful as a surrogate marker for following PC progression and response to treatment. Initially in our cases, both patients had a resectable tumor and their tumor markers were within normal range. In both cases the normal range CA 19-9 increase from the baseline was associated with corresponding progressive disease on imaging studies and CA 19-9 decline was in keeping with response to systemic and local therapy despite being within the normal range. To our knowledge, this is the first case report where we report the utility of serial normal values of CA 19-9 as a useful tool in following PC disease activity and in response to treatment. Clinicians should consider measuring serial normal values of CA 19-9 in patients with PC and normal range CA 19-9 which may help in assessing response to treatment in subset of this population.
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Yildirim BA, Özdemir Y, Colakoglu T, Topkan E. Impact of presence and degree of pretreatment weight loss in locally-advanced pancreatic cancer patients treated with definitive concurrent chemoradiotherapy. Pancreatology 2016; 16:599-604. [PMID: 27029854 DOI: 10.1016/j.pan.2016.03.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2015] [Revised: 02/03/2016] [Accepted: 03/06/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND To assess the impact of the presence and degree of pretreatment weight loss (WL) on the survival of locally-advanced pancreas cancer (LAPC) patients treated with concurrent chemoradiotherapy (C-CRT). METHODS Seventy-three patients who received 50.4 Gy C-CRT were analyzed. All patients underwent laparoscopy (n = 18) or laparotomy (n = 55), and biopsies were obtained for histologic examination of the primary tumor and enlarged/metabolically active regional lymph nodes. Pretreatment WL and percentage WL (PWL) were calculated by utilizing data obtained 6 months prior to and during hospital admission. The primary objective was to assess the influence WL status on overall survival (OS), and the secondary objective was the identification of a PWL cut-off value, if available. RESULTS Forty-five (61.6%) patients had WL. Median OS was 14.4 months for the entire study population which was significantly longer in the non-WL than the WL cohort (21.4 vs. 11.3 months; p < 0.003). On further analysis a cut-off value of 3.1% was identified for WL. Accordingly, patients with WL < 3.1% had significantly longer OS than those with WL ≥ 3.1% (25.8 vs. 10.1 months; p < 0.001). In multivariate analysis, both the WL status (p < 0.001) and PWL (p = 0.002) retained their independent significance. CONCLUSION Both the presence and degree of WL prior to C-CRT had strong adverse effects on the survival of LAPC patients, even if they presented with a BMI > 20 kg/m(2). Additionally, a WL of ≥3.1% in the last 6 months appeared to be a strong cut-off for the stratification of such patients into distinctive survival groups.
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Affiliation(s)
- Berna Akkus Yildirim
- Baskent University Adana Medical Faculty, Department of Radiation Oncology, Adana, Turkey.
| | - Yurday Özdemir
- Baskent University Adana Medical Faculty, Department of Radiation Oncology, Adana, Turkey
| | - Tamer Colakoglu
- Baskent University Adana Medical Faculty, Department of General Surgery, Adana, Turkey
| | - Erkan Topkan
- Baskent University Adana Medical Faculty, Department of Radiation Oncology, Adana, Turkey
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Abstract
CA19-9 (carbohydrate antigen 19-9, also called cancer antigen 19-9 or sialylated Lewis a antigen) is the most commonly used and best validated serum tumor marker for pancreatic cancer diagnosis in symptomatic patients and for monitoring therapy in patients with pancreatic adenocarcinoma. Normally synthesized by normal human pancreatic and biliary ductal cells and by gastric, colon, endometrial and salivary epithelia, CA 19-9 is present in small amounts in serum, and can be over expressed in several benign gastrointestinal disorders. Importantly, it exhibits a dramatic increase in its plasmatic levels during neoplastic disease. However, several critical aspects for its clinical use, such as false negative results in subjects with Lewis (a-b-) genotype and false positive elevation, occasional and transient, in patients with benign diseases, together with its poor positive predictive value (72.3 %), do not make it a good cancer-specific marker and renders it impotent as a screening tool. In the last years a large number of putative biomarkers for pancreatic cancer have been proposed, most of which is lacking of large scale validation. In addition, none of these has showed to possess the requisite sensitivity/specificity to be introduced in clinical use. Therefore, although with important limitations we well-know, CA 19-9 continues being the only pancreatic cancer marker actually in clinical use.
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Eskander MF, Bliss LA, Tseng JF. Pancreatic adenocarcinoma. Curr Probl Surg 2016; 53:107-54. [DOI: 10.1067/j.cpsurg.2016.01.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Accepted: 01/04/2016] [Indexed: 12/17/2022]
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48
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Chung KH, Ryu JK, Lee BS, Jang DK, Lee SH, Kim YT. Early decrement of serum carbohydrate antigen 19-9 predicts favorable outcome in advanced pancreatic cancer. J Gastroenterol Hepatol 2016; 31:506-12. [PMID: 26250642 DOI: 10.1111/jgh.13075] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2015] [Revised: 07/14/2015] [Accepted: 07/23/2015] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIM The role of carbohydrate antigen 19-9 (CA 19-9) for predicting treatment outcome in pancreatic ductal adenocarcinoma (PDAC) remains to be elucidated. This study was aimed to determine the correlation between early decrement in CA 19-9 concentration and prognosis of advanced PDAC after chemotherapy. METHODS All patients confirmed with locally advanced or metastatic PDAC who received initial systemic chemotherapy for at least two cycles in our institution between January 2012 and December 2013 were included. Serum CA 19-9 concentrations at baseline and 8 weeks after the initiation of chemotherapy were obtained. Correlation between CA 19-9 decrement and survival outcomes (time to progression [TTP] and overall survival [OS]) were evaluated. RESULTS A total of 183 patients with initially elevated CA 19-9 were included. OS and TTP was significantly longer for patients whose serum CA 19-9 concentration decreased more than 10% from baseline (n = 103), than that for patients whose serum CA 19-9 was not decreased (n = 80) (423 vs 155 days, P < 0.001 for OS and 222 vs 75 days, P < 0.001 for TTP). In multivariate analysis, CA 19-9 decrement more than 10% from baseline was still a significant factor for longer OS (hazard ratio for progression 0.275 [0.184-0.412], P < 0.001) and TTP (0.322 [0.219-0.473], P < 0.001) in both stage III and IV. CONCLUSIONS The early decrement of CA 19-9 after the initiation of chemotherapy was an independent factor related with better survival outcomes in unresectable PDAC.
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Affiliation(s)
- Kwang Hyun Chung
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ji Kon Ryu
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ban Seok Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Dong Kee Jang
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sang Hyub Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yong-Tae Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
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Aldakkak M, Christians KK, Krepline AN, George B, Ritch PS, Erickson BA, Johnston FM, Evans DB, Tsai S. Pre-treatment carbohydrate antigen 19-9 does not predict the response to neoadjuvant therapy in patients with localized pancreatic cancer. HPB (Oxford) 2015; 17:942-52. [PMID: 26255895 PMCID: PMC4571763 DOI: 10.1111/hpb.12448] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Accepted: 04/28/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND The prognostic value of CA19-9 in patients with pancreatic cancer (PC) treated with neoadjuvant therapy has not been well described. METHODS Pre-treatment CA19-9 levels (with concomitant normal bilirubin level) in patients with localized PC were categorized as normal (≤35), low (36-200), moderate (201-1000), or high (>1000). Post-treatment CA19-9 was measured after neoadjuvant therapy, prior to surgery. RESULTS Pre-treatment CA19-9 levels were evaluable in 235 patients, levels were normal in 60 (25%) patients, low in 78 (33%) patients, moderate in 69 (29%) and high in 28 (12%). After neoadjuvant therapy, post-treatment CA19-9 normalized (≤ 35) in 40 (51%) of the patients in the low group, 14 (21%) of the moderate and 5 (19%) of the high group (P < 0.001). Of the 235 patients, 168 (71%) completed all intended therapy including a pancreatectomy; 44 (73%), 62 (79%), 46 (67%) and 16 (57%) of the normal, low, moderate and high groups (P = 0.10). Among these 168 patients, the median overall survival was 38.4, 43.6, 44.7, 27.2 and 26.4 months for normal, low, moderate and high CA19-9 groups (log rank P = 0.72). Among resected patients, an elevated pre-treatment CA19-9 was of little prognostic value; instead, it was the CA19-9 response to neoadjuvant therapy that was prognostic [hazard ratio (HR): 1.80, P = 0.02]. CONCLUSIONS Among patients who completed neoadjuvant therapy and surgery, pre-treatment CA19-9 obtained at the time of diagnosis was not predictive of overall survival, but normalization of post-treatment CA19-9 in response to neoadjuvant therapy was highly prognostic.
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Affiliation(s)
- Mohammed Aldakkak
- Departments of Surgery, Pancreatic Cancer Program, The Medical College of WisconsinMilwaukee, WI, USA
| | - Kathleen K Christians
- Departments of Surgery, Pancreatic Cancer Program, The Medical College of WisconsinMilwaukee, WI, USA
| | - Ashley N Krepline
- Departments of Surgery, Pancreatic Cancer Program, The Medical College of WisconsinMilwaukee, WI, USA
| | - Ben George
- Departments of Medicine, Pancreatic Cancer Program, The Medical College of WisconsinMilwaukee, WI, USA
| | - Paul S Ritch
- Departments of Medicine, Pancreatic Cancer Program, The Medical College of WisconsinMilwaukee, WI, USA
| | - Beth A Erickson
- Departments of Radiation Oncology, Pancreatic Cancer Program, The Medical College of WisconsinMilwaukee, WI, USA
| | - Fabian M Johnston
- Departments of Surgery, Pancreatic Cancer Program, The Medical College of WisconsinMilwaukee, WI, USA
| | - Douglas B Evans
- Departments of Surgery, Pancreatic Cancer Program, The Medical College of WisconsinMilwaukee, WI, USA
| | - Susan Tsai
- Departments of Surgery, Pancreatic Cancer Program, The Medical College of WisconsinMilwaukee, WI, USA
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Usón Junior PLS, França MS, Rodrigues HV, Macedo ALDV, Goldenberg A, Smaletz O, Armentano DPD, Simon SD, Gansl RC. Higher overall survival in metastatic pancreatic cancer: the impact of where and how treatment is delivered. ACTA ACUST UNITED AC 2015; 13:347-51. [PMID: 26313433 PMCID: PMC4943777 DOI: 10.1590/s1679-45082015ao3303] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Accepted: 06/08/2015] [Indexed: 01/05/2023]
Abstract
Objective To determine the overall survival of patients with advanced pancreatic cancer and evaluate factors that impact prognosis in a private cancer center. Methods Data from the Hospital Cancer Registry at Hospital Israelita Albert Einstein were retrospectively collected. The patients enrolled had metastatic cancer at diagnosis or earlier staging and subsequent recurrence. Cases of neuroendocrine tumors were excluded. Results A total of 65 patients were evaluated, including 63 with adenocarcinoma. The median overall survival for patients in all stages was 20.7 months (95%CI: 15.6-25.7), while the overall survival of metastatic disease was 13.3 months. Among the 33 cases with stage IV cancer, there was no evidence of a statistically significant association between median survival and CA19-9 dosage (p=0.212), tumor location (p=0.482), first treatment performed (p=0.337), lymphovascular invasion (p=0.286), and age (p=0.152). However, the number of lines of chemotherapy was significantly associated with survival (log-rank p=0.013), with an estimated median survival of 10.2 months for patients who received up to two lines of treatment and 23.5 months for those receiving more than two lines of chemotherapy. Conclusion The survival of patients treated was longer than that reported in the literature. The only statistically significant factor related to increased survival was higher number of lines of chemotherapy received. We believe that the higher socioeconomic status of patients surveyed in this study, as well as their greater access to treatment options, may have influenced their overall survival.
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Affiliation(s)
| | | | | | | | | | - Oren Smaletz
- Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
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