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Haggstrom L, Chan WY, Nagrial A, Chantrill LA, Sim HW, Yip D, Chin V. Chemotherapy and radiotherapy for advanced pancreatic cancer. Cochrane Database Syst Rev 2024; 12:CD011044. [PMID: 39635901 PMCID: PMC11619003 DOI: 10.1002/14651858.cd011044.pub3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2024]
Abstract
BACKGROUND Pancreatic cancer (PC) is a lethal disease with few effective treatment options. Many anti-cancer therapies have been tested in the locally advanced and metastatic setting, with mixed results. This review synthesises all the randomised data available to help better inform patient and clinician decision-making. It updates the previous version of the review, published in 2018. OBJECTIVES To assess the effects of chemotherapy, radiotherapy, or both on overall survival, severe or life-threatening adverse events, and quality of life in people undergoing first-line treatment of advanced pancreatic cancer. SEARCH METHODS We searched for published and unpublished studies in CENTRAL, MEDLINE, Embase, and CANCERLIT, and handsearched various sources for additional studies. The latest search dates were in March and July 2023. SELECTION CRITERIA We included randomised controlled trials comparing chemotherapy, radiotherapy, or both with another intervention or best supportive care. Participants were required to have locally advanced, unresectable pancreatic cancer or metastatic pancreatic cancer not amenable to curative intent treatment. Histological confirmation was required. Trials were required to report overall survival. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. MAIN RESULTS We included 75 studies in the review and 51 in the meta-analysis (11,333 participants). We divided the studies into seven categories: any anti-cancer treatment versus best supportive care; various chemotherapy types versus gemcitabine; gemcitabine-based combinations versus gemcitabine alone; various chemotherapy combinations versus gemcitabine plus nab-paclitaxel; fluoropyrimidine-based studies; miscellaneous studies; and radiotherapy studies. In general, the included studies were at low risk for random sequence generation, detection bias, attrition bias, and reporting bias, at unclear risk for allocation concealment, and high risk for performance bias. Compared to best supportive care, chemotherapy likely results in little to no difference in overall survival (OS) (hazard ratio (HR) 1.08, 95% confidence interval (CI) 0.88 to 1.33; absolute risk of death at 12 months of 971 per 1000 versus 962 per 1000; 4 studies, 298 participants; moderate-certainty evidence). The adverse effects of chemotherapy and impacts on quality of life (QoL) were uncertain. Many of the chemotherapy regimens were outdated. Eight studies compared non-gemcitabine-based chemotherapy regimens to gemcitabine. These showed that 5-fluorouracil (5FU) likely reduces OS (HR 1.69, 95% CI 1.26 to 2.27; risk of death at 12 months of 914 per 1000 versus 767 per 1000; 1 study, 126 participants; moderate certainty), and grade 3/4 adverse events (QoL not reported). Fixed dose rate gemcitabine likely improves OS (HR 0.79, 95% CI 0.66 to 0.94; risk of death at 12 months of 683 per 1000 versus 767 per 1000; 2 studies, 644 participants; moderate certainty), and likely increase grade 3/4 adverse events (QoL not reported). FOLFIRINOX improves OS (HR 0.51, 95% CI 0.43 to 0.60; risk of death at 12 months of 524 per 1000 versus 767 per 1000; P < 0.001; 2 studies, 652 participants; high certainty), and delays deterioration in QoL, but increases grade 3/4 adverse events. Twenty-eight studies compared gemcitabine-based combinations to gemcitabine. Gemcitabine plus platinum may result in little to no difference in OS (HR 0.94, 95% CI 0.81 to 1.08; risk of death at 12 months of 745 per 1000 versus 767 per 1000; 6 studies, 1140 participants; low certainty), may increase grade 3/4 adverse events, and likely worsens QoL. Gemcitabine plus fluoropyrimidine improves OS (HR 0.88, 95% CI 0.81 to 0.95; risk of death at 12 months of 722 per 1000 versus 767 per 1000; 10 studies, 2718 participants; high certainty), likely increases grade 3/4 adverse events, and likely improves QoL. Gemcitabine plus topoisomerase inhibitors result in little to no difference in OS (HR 1.01, 95% CI 0.87 to 1.16; risk of death at 12 months of 770 per 1000 versus 767 per 1000; 3 studies, 839 participants; high certainty), likely increases grade 3/4 adverse events, and likely does not alter QoL. Gemcitabine plus taxane result in a large improvement in OS (HR 0.71, 95% CI 0.62 to 0.81; risk of death at 12 months of 644 per 1000 versus 767 per 1000; 2 studies, 986 participants; high certainty), and likely increases grade 3/4 adverse events and improves QoL. Nine studies compared chemotherapy combinations to gemcitabine plus nab-paclitaxel. Fluoropyrimidine-based combination regimens improve OS (HR 0.79, 95% CI 0.70 to 0.89; risk of death at 12 months of 542 per 1000 versus 628 per 1000; 6 studies, 1285 participants; high certainty). The treatment arms had distinct toxicity profiles, and there was little to no difference in QoL. Alternative schedules of gemcitabine plus nab-paclitaxel likely result in little to no difference in OS (HR 1.10, 95% CI 0.82 to 1.47; risk of death at 12 months of 663 per 1000 versus 628 per 1000; 2 studies, 367 participants; moderate certainty) or QoL, but may increase grade 3/4 adverse events. Four studies compared fluoropyrimidine-based combinations to fluoropyrimidines alone, with poor quality evidence. Fluoropyrimidine-based combinations are likely to result in little to no impact on OS (HR 0.84, 95% CI 0.61 to 1.15; risk of death at 12 months of 765 per 1000 versus 704 per 1000; P = 0.27; 4 studies, 491 participants; moderate certainty) versus fluoropyrimidines alone. The evidence suggests that there was little to no difference in grade 3/4 adverse events or QoL between the two groups. We included only one radiotherapy (iodine-125 brachytherapy) study with 165 participants. The evidence is very uncertain about the effect of radiotherapy on outcomes. AUTHORS' CONCLUSIONS Combination chemotherapy remains standard of care for metastatic pancreatic cancer. Both FOLFIRINOX and gemcitabine plus a taxane improve OS compared to gemcitabine alone. Furthermore, the evidence suggests that fluoropyrimidine-based combination chemotherapy regimens improve OS compared to gemcitabine plus nab-paclitaxel. The effects of radiotherapy were uncertain as only one low-quality trial was included. Selection of the most appropriate chemotherapy for individuals still remains unpersonalised, with clinicopathological stratification remaining elusive. Biomarker development is essential to assist in rationalising treatment selection for patients.
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Affiliation(s)
- Lucy Haggstrom
- Medical Oncology, The Kinghorn Cancer Care Centre, St Vincent's Hospital, Sydney, Australia
- Medical Oncology, Illawarra Shoalhaven Local Health District, Wollongong, Australia
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia
| | - Wei Yen Chan
- Medical Oncology, The Kinghorn Cancer Care Centre, St Vincent's Hospital, Sydney, Australia
- Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia
| | - Adnan Nagrial
- The Crown Princess Mary Cancer Centre, Westmead, Australia
- Medical School, The University of Sydney, Sydney, Australia
| | - Lorraine A Chantrill
- Medical Oncology, Illawarra Shoalhaven Local Health District, Wollongong, Australia
- University of Wollongong, Wollongong, Australia
| | - Hao-Wen Sim
- Medical Oncology, The Kinghorn Cancer Care Centre, St Vincent's Hospital, Sydney, Australia
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia
| | - Desmond Yip
- Department of Medical Oncology, The Canberra Hospital, Garran, Australia
- ANU Medical School, Australian National University, Acton, Australia
| | - Venessa Chin
- Medical Oncology, The Kinghorn Cancer Care Centre, St Vincent's Hospital, Sydney, Australia
- School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia
- Medical Oncology, Garvan Institute of Medical Research, Sydney, Australia
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Seufferlein T, Mayerle J, Boeck S, Brunner T, Ettrich TJ, Grenacher L, Gress TM, Hackert T, Heinemann V, Kestler A, Sinn M, Tannapfel A, Wedding U, Uhl W. S3-Leitlinie Exokrines Pankreaskarzinom – Version 3.1. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2024; 62:e874-e995. [PMID: 39389103 DOI: 10.1055/a-2338-3533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/12/2024]
Affiliation(s)
| | | | | | - Thomas Brunner
- Universitätsklinik für Strahlentherapie-Radioonkologie, Medizinische Universität Graz, Austria
| | | | | | - Thomas Mathias Gress
- Gastroenterologie und Endokrinologie Universitätsklinikum Gießen und Marburg, Germany
| | - Thilo Hackert
- Klinik und Poliklinik für Allgemein-, Viszeral- und Thoraxchirurgie, Universitätsklinikum Hamburg-Eppendorf, Germany
| | - Volker Heinemann
- Medizinische Klinik und Poliklinik III, Klinikum der Universität München-Campus Grosshadern, München, Germany
| | | | - Marianne Sinn
- Medizinische Klinik und Poliklinik II Onkologie und Hämatologie, Universitätsklinikum Hamburg-Eppendorf, Germany
| | | | | | - Waldemar Uhl
- Allgemein- und Viszeralchirurgie, St Josef-Hospital, Bochum, Germany
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Rehman OU, Fatima E, Nadeem ZA, Azeem A, Motwani J, Imran H, Mehboob H, Khan A, Usman O. Efficacy of Cisplatin-Containing Chemotherapy Regimens in Patients of Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-analysis. J Gastrointest Cancer 2024; 55:559-571. [PMID: 38315331 DOI: 10.1007/s12029-024-01025-7] [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] [Accepted: 01/29/2024] [Indexed: 02/07/2024]
Abstract
BACKGROUND The relative success of cisplatin-based chemotherapy regimens for PDAC in clinical trials warrants a review of the literature to assess the cumulative results. This study aims to assess the efficacy of cisplatin-containing regimens for PDAC in terms of survival and response outcomes using a systematic review and proportional meta-analysis. METHODS In this study, an electronic search was conducted on PubMed, Cochrane Library, Scopus, and Google Scholar to find relevant literature. The random effects model was used to assess pooled overall response rate, stable disease rate, progressive disease rate, 1-year overall survival rate, and their 95% CIs. Publication bias was assessed using funnel plot symmetry and the one-tailed Eggers' test. In all cases, p-value < 0.05 was indicative of significant results. The review is registered with PROSPERO: CRD42023459243. RESULTS A total of 34 studies consisting of 1599 patients were included in this review. All the included studies were of good quality. In total, 906 patients were male, and the median age of the patients was 58-69 years. Overall, 599 patients had cancer of the pancreatic head, 139 had cancer of the pancreatic body, and 102 patients had cancer of the pancreatic tail. The pooled risk ratios (RRs) revealed an overall response rate of 19.2% (95% CI, 14.6-24.2%), a stable disease rate of 42.3% (95% CI, 36.6-48.8), a 1-year overall survival rate of 40% (95% CI, 34.3-45.8), and progressive disease rate of 24.7% (95% CI, 18.8-31.2). Commonly reported adverse events were anemia, thrombocytopenia, abdominal adverse events, neutropenia, fatigue, leukopenia, alopecia, anorexia, mucositis, stomatitis, and hepatobiliary adverse events. CONCLUSION Cisplatin-containing regimens have shown moderate efficacy with significant improvement in overall survival at 1 year, stable disease rate, and progressive disease rate; however, only a small percentage of patients achieved an overall response rate.
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Affiliation(s)
- Obaid Ur Rehman
- Department of Medicine, Services Institute of Medical Sciences, Lahore, 54000, Pakistan.
| | - Eeshal Fatima
- Department of Medicine, Services Institute of Medical Sciences, Lahore, 54000, Pakistan
| | - Zain Ali Nadeem
- Department of Medicine, Allama Iqbal Medical College, Lahore, Pakistan
| | - Arish Azeem
- University of Warmia and Mazury, Olszytn, Poland
| | - Jatin Motwani
- Liaquat National Hospital and Medical College, Karachi, Pakistan
| | - Habiba Imran
- Department of Medicine, Services Institute of Medical Sciences, Lahore, 54000, Pakistan
| | - Hadia Mehboob
- Department of Medicine, Services Institute of Medical Sciences, Lahore, 54000, Pakistan
| | - Alishba Khan
- Karachi Institute of Medical Sciences, CMH Malir, Karachi, Pakistan
| | - Omer Usman
- Texas Tech University Health Sciences Center El Paso/Transmountain, El Paso, TX, USA
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Zhu Z, Tang H, Ying J, Cheng Y, Wang X, Wang Y, Bai C. Efficacy and safety of gemcitabine plus S-1 vs. gemcitabine plus nab-paclitaxel in treatment-naïve advanced pancreatic ductal adenocarcinoma. Cancer Biol Med 2023; 20:j.issn.2095-3941.2023.0189. [PMID: 37646237 PMCID: PMC10618946 DOI: 10.20892/j.issn.2095-3941.2023.0189] [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: 05/27/2023] [Accepted: 08/03/2023] [Indexed: 09/01/2023] Open
Abstract
OBJECTIVE Gemcitabine plus nab-paclitaxel (GnP) is the standard first-line therapy for advanced pancreatic ductal adenocarcinoma (PDAC). S-1, an oral fluoropyrimidine derivative, as compared with gemcitabine, is non-inferior in terms of overall survival (OS) and is associated with lower hematologic toxicity. Accordingly, S-1 is a convenient oral alternative treatment for advanced PDAC. This study was aimed at comparing the efficacy and safety of gemcitabine plus S-1 (GS) vs. GnP as first-line chemotherapy for advanced PDAC. METHODS Patients with advanced PDAC who received first-line GS or GnP at the Peking Union Medical College Hospital between March 2011 and November 2022 were evaluated. RESULTS A total of 300 patients were assessed, of whom 84 received GS and 216 received GnP. The chemotherapy completion rate was higher with GS than GnP (50.0% vs. 30.3%, P = 0.0028). The objective response rate (ORR) was slightly higher (14.3% vs. 9.7%, P = 0.35), and the median OS was significantly longer (17.9 months vs. 13.3 months, P = 0.0078), in the GS group than the GnP group. However, the median progression-free survival (PFS) did not significantly differ between groups. Leukopenia risk was significantly lower in the GS group than the GnP group (14.9% vs. 28.1%, P = 0.049). CONCLUSIONS As first-line chemotherapy for advanced PDAC, the GS regimen led to a significantly longer OS than the GnP regimen. The PFS, ORR, and incidence of severe adverse events were comparable between the GS and GnP groups.
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Affiliation(s)
- Zhou Zhu
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
- 4+4 Medical Doctor Program, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Hui Tang
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Jinrong Ying
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Yuejuan Cheng
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Xiang Wang
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Yingyi Wang
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
| | - Chunmei Bai
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100730, China
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Cui J, Jiao F, Li Q, Wang Z, Fu D, Liang J, Liang H, Xia T, Zhang T, Zhang Y, Dai G, Zhang Z, Wang J, Bai Y, Bai Y, Bi F, Chen D, Cao D, Chen J, Fang W, Gao Y, Guo J, Hao J, Hua H, Huang X, Liu W, Liu X, Li D, Li J, Li E, Li Z, Pan H, Shen L, Sun Y, Tao M, Wang C, Wang F, Xiong J, Zhang T, Zhang X, Zhan X, Zheng L, Ren G, Zhang T, Zhou J, Ma Q, Qin S, Hao C, Wang L. Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of pancreatic cancer. JOURNAL OF THE NATIONAL CANCER CENTER 2022; 2:205-215. [PMID: 39036552 PMCID: PMC11256594 DOI: 10.1016/j.jncc.2022.08.006] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 07/30/2022] [Accepted: 08/18/2022] [Indexed: 11/25/2022] Open
Abstract
Pancreatic cancer is one of the leading causes of cancer-related mortality in both developed and developing countries. The incidence of pancreatic cancer in China accounts for about a quater of the global incidence, and the epidemiological characteristics and therapeutic strategies differ due to social, economic, cultural, environmental, and public health factors. Non-domestic guidelines do not reflect the clinicopathologic characteristics and treatment patterns of Chinese patients. Thus, in 2018, the Chinese Society of Clinical Oncology (CSCO) organized a panel of senior experts from all sub-specialties within the field of pancreatic oncology to compile the Chinese guidelines for the diagnosis and treatment of pancreatic cancer. The guidelines were made based on both the Western and Eastern clinical evidence and updated every one or two years. The experts made consensus judgments and classified evidence-based recommendations into various grades according to the regional differences, the accessibility of diagnostic and treatment resources, and health economic indexes in China. Here we present the latest version of the guidelines, which covers the diagnosis, treatment, and follow-up of pancreatic cancer. The guidelines might standardize the diagnosis and treatment of pancreatic cancer in China and will encourage oncologists to design and conduct more clinical trials about pancreatic cancer.
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Affiliation(s)
- Jiujie Cui
- Department of Medical Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Feng Jiao
- Department of Medical Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qi Li
- Department of Medical Oncology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zheng Wang
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Deliang Fu
- Department of Pancreatic Surgery, Huashan Hospital, Pancreatic Disease Institute, Fudan University, Shanghai, China
| | - Jun Liang
- Department of Oncology, Peking University International Hospital, Beijing, China
| | - Houjie Liang
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Tingyi Xia
- Beijing Huaxia Jingfang Cancer Radiotherapy Center, Former Air Force General Hospital and PLA General Hospital, Beijing, China
| | - Tao Zhang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Zhang
- Department of Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Guanghai Dai
- Department of Oncology, Chinese PLA General Hospital, Beijing, China
| | - Zhihong Zhang
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jian Wang
- Department of Imaging, Changzheng Hospital, Naval Military Medical University, Shanghai, China
| | - Yongrui Bai
- Department of Radiation Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yuxian Bai
- Oncology Department of Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, China
| | - Feng Bi
- Department of Medical Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Donghui Chen
- Department of Medical Oncology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Dan Cao
- Department of Medical Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Jie Chen
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Weijia Fang
- Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Yong Gao
- Department of Oncology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jianwei Guo
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jihui Hao
- Department of Pancreatic Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Haiqing Hua
- Department of Medical Oncology, Eastern Theater Command General Hospital, Qinhuai Medical District, Nanjing, China
| | - Xinyu Huang
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Wenchao Liu
- Department of Clinical Oncology, Xijing Hospital, Air Force Medical University, Xian, China
| | - Xiufeng Liu
- Department of Medical Oncology, Eastern Theater Command General Hospital, Qinhuai Medical District, Nanjing, China
| | - Da Li
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Ji Li
- Department of Pancreatic Surgery, Huashan Hospital, Pancreatic Disease Institute, Fudan University, Shanghai, China
| | - Enxiao Li
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zhiwei Li
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Hongming Pan
- Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine, Hangzhou, China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, China
| | - Yongwei Sun
- Department of Biliary-Pancreatic Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Renji Hospital, Shanghai, China
| | - Min Tao
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Chengfeng Wang
- State Key Lab of Molecular Oncology & Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fenghua Wang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jianping Xiong
- Department of Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Taiping Zhang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xuebin Zhang
- Department of Interventional Oncology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Xianbao Zhan
- Department of Medical Oncology, Changhai Hospital of Shanghai, Navy Medical University, Shanghai, China
| | - Leizhen Zheng
- Department of Oncology, Xin Hua Hospital Affiliated To Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Gang Ren
- Peking University Shougang Hospital, Beijing, China
| | - Tingting Zhang
- Oncology Department of Internal Medicine, Harbin Medical University Cancer Hospital, Harbin, China
| | - Jun Zhou
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, China
| | - Qingyong Ma
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shukui Qin
- Department of Medical Oncology, Eastern Theater Command General Hospital, Qinhuai Medical District, Nanjing, China
| | - Chunyi Hao
- Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital, Beijing, China
| | - Liwei Wang
- Department of Medical Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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Seufferlein T, Mayerle J, Böck S, Brunner T, Ettrich TJ, Grenacher L, Gress TM, Hackert T, Heinemann V, Kestler A, Sinn M, Tannapfel A, Wedding U, Uhl W. S3-Leitlinie zum exokrinen Pankreaskarzinom – Langversion 2.0 – Dezember 2021 – AWMF-Registernummer: 032/010OL. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:e812-e909. [PMID: 36368658 DOI: 10.1055/a-1856-7346] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
| | | | - Stefan Böck
- Medizinische Klinik und Poliklinik III, Universitätsklinikum München, Germany
| | - Thomas Brunner
- Universitätsklinik für Strahlentherapie-Radioonkologie, Medizinische Universität Graz, Austria
| | | | | | - Thomas Mathias Gress
- Klinik für Gastroenterologie und Endokrinologie, Universitätsklinikum Gießen und Marburg, Germany
| | - Thilo Hackert
- Klinik für Allgemein-, Viszeral- und Transplantationschirurgie Universitätsklinikum, Heidelberg, Germany
| | - Volker Heinemann
- Medizinische Klinik und Poliklinik III, Klinikum der Universität München-Campus Grosshadern, München, Germany
| | | | - Marianne Sinn
- Universitätsklinikum Hamburg-Eppendorf Medizinische Klinik und Poliklinik II Onkologie Hämatologie, Hamburg, Germany
| | | | | | - Waldemar Uhl
- Allgemein- und Viszeralchirurgie, St Josef-Hospital, Bochum, Germany
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7
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Yeh C, Bates SE. Two decades of research toward the treatment of locally advanced and metastatic pancreatic cancer: Remarkable effort and limited gain. Semin Oncol 2021; 48:34-46. [PMID: 33712267 DOI: 10.1053/j.seminoncol.2021.01.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 01/20/2021] [Indexed: 01/04/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that is diagnosed at the locally advanced or metastatic stage in approximately 80% of cases. Relative to other tumor types, progress in the treatment of this disease has been painfully slow. While agents targeting DNA repair have proven successful in a subset of patients, the majority of PDACs do not exhibit validated molecular targets. Hence, conventional chemotherapy remains at the forefront of therapy for this disease. In this review, we study two decades of efforts to improve upon the gemcitabine backbone - 67 phase II and III trials enrolling 16,446 patients - that culminated in the approvals of gemcitabine/nab-paclitaxel (Gem/NabP) and FOLFIRINOX. Today, these remain gold standards for the first-line treatment of locally advanced unresectable and metastatic PDAC, while ongoing efforts focus on improving upon the Gem/NabP backbone. Because real world data often do not reflect the data of randomized controlled trials (RCTs), we also summarize the retrospective evidence comparing the efficacy of Gem/NabP and FOLFIRINOX in the first-line setting - 29 studies reporting a median overall survival of 10.7 and 9.1 months for FOLFIRINOX and Gem/NabP, respectively. These values are surprisingly comparable to those reported by the pivotal RCTs at 11.1 and 8.5 months. Finally, there is a paucity of RCT data regarding the efficacy of second-line therapy. Hence, we conclude this review by summarizing the data that ultimately demonstrate a small but significant survival benefit of second-line therapy with Gem/NabP or FOLFIRINOX. Collectively, these studies describe the long journey, the steady effort, and the myriad lessons to be learned from 20 years of PDAC trials to inform strategies for success in clinical trials moving forward.
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Affiliation(s)
- Celine Yeh
- Department of Medicine, Columbia University Irving Medical Center, New York, NY
| | - Susan E Bates
- James J. Peters VA Medical Center, Bronx, NY; Columbia University Herbert Irving Comprehensive Cancer Center, New York, NY.
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R S P, Mal A, Valvi SK, Srivastava R, De A, Bandyopadhyaya R. Noninvasive Preclinical Evaluation of Targeted Nanoparticles for the Delivery of Curcumin in Treating Pancreatic Cancer. ACS APPLIED BIO MATERIALS 2020; 3:4643-4654. [DOI: 10.1021/acsabm.0c00515] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- Prabhuraj R S
- Centre for Research in Nanotechnology and Science, Indian Institute of Technology Bombay, Powai, Mumbai, India
| | - Arijit Mal
- Molecular Functional Imaging Lab, ACTREC, Tata Memorial Centre, Navi Mumbai, and Life Science Department, Homi Bhaba National Institute, Mumbai, India
| | - Snehal K. Valvi
- Molecular Functional Imaging Lab, ACTREC, Tata Memorial Centre, Navi Mumbai, and Life Science Department, Homi Bhaba National Institute, Mumbai, India
| | - Rohit Srivastava
- Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India
| | - Abhijit De
- Molecular Functional Imaging Lab, ACTREC, Tata Memorial Centre, Navi Mumbai, and Life Science Department, Homi Bhaba National Institute, Mumbai, India
| | - Rajdip Bandyopadhyaya
- Department of Chemical Engineering, Indian Institute of Technology Bombay, Powai, Mumbai, India
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9
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Latenstein AEJ, Mackay TM, Creemers GJ, van Eijck CHJ, de Groot JWB, Haj Mohammad N, Homs MYV, van Laarhoven HWM, Molenaar IQ, ten Tije BJ, de Vos-Geelen J, Besselink MG, van der Geest LGM, Wilmink JW. Implementation of contemporary chemotherapy for patients with metastatic pancreatic ductal adenocarcinoma: a population-based analysis. Acta Oncol 2020; 59:705-712. [PMID: 32056483 DOI: 10.1080/0284186x.2020.1725241] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Background: Positive results of randomized trials led to the introduction of FOLFIRINOX in 2012 and gemcitabine with nab-paclitaxel in 2015 for patients with metastatic pancreatic ductal adenocarcinoma. It is unknown to which extent these new chemotherapeutic regimens have been implemented in clinical practice and what the impact has been on overall survival.Material and methods: Patients diagnosed with metastatic pancreatic ductal adenocarcinoma between 2007-2016 were included from the population-based Netherlands Cancer Registry. Multilevel logistic regression and Cox regression analyses, adjusting for patient, tumor, and hospital characteristics, were used to analyze variation of chemotherapy use.Results: In total, 8726 patients were included. The use of chemotherapy increased from 31% in 2007-2011 to 37% in 2012-2016 (p < .001). Variation in the use of any chemotherapy between centers decreased (adjusted range 2007-2011: 12-67%, 2012-2016: 20-54%) whereas overall survival increased from 5.6 months to 6.4 months (p < .001) for patients treated with chemotherapy. Use of FOLFIRINOX and gemcitabine with nab-paclitaxel varied widely in 2015-2016, but both showed a more favorable overall survival compared to gemcitabine monotherapy (median 8.0 vs. 7.0 vs. 3.8 months, respectively). In the period 2015-2016, FOLFIRINOX was used in 60%, gemcitabine with nab-paclitaxel in 9.7% and gemcitabine monotherapy in 25% of patients receiving chemotherapy.Conclusion: Nationwide variation in the use of chemotherapy decreased after the implementation of FOLFIRINOX and gemcitabine with nab-paclitaxel. Still a considerable proportion of patients receives gemcitabine monotherapy. Overall survival did improve, but not clinically relevant. These results emphasize the need for a structured implementation of new chemotherapeutic regimens.
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Affiliation(s)
- Anouk E. J. Latenstein
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, The Netherlands
| | - Tara M. Mackay
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, The Netherlands
| | | | | | | | - Nadia Haj Mohammad
- Department of Medical Oncology, Regional Academic Cancer Center Utrecht, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | | | - Hanneke W. M. van Laarhoven
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, The Netherlands
| | - I. Quintus Molenaar
- Department of Surgery, Regional Academic Cancer Center Utrecht, St Antonius Hospital Nieuwegein and University Medical Center Utrecht Cancer Center, Utrecht, The Netherlands
| | - Bert-Jan ten Tije
- Department of Medical Oncology, Amphia Hospital, Breda, The Netherlands
| | - Judith de Vos-Geelen
- Department of Internal Medicine, Division of Medical Oncology, GROW – School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Marc G. Besselink
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, The Netherlands
| | - Lydia G. M. van der Geest
- Department of Research and Development, Netherlands Comprehensive Cancer Organisation (IKNL), Utrecht, the Netherlands
| | - Johanna W. Wilmink
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, The Netherlands
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10
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Network Meta-Analysis of Efficacy and Safety of Chemotherapy and Target Therapy in the First-Line Setting of Advanced Pancreatic Cancer. Cancers (Basel) 2019; 11:cancers11111746. [PMID: 31703359 PMCID: PMC6895788 DOI: 10.3390/cancers11111746] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 10/29/2019] [Accepted: 11/02/2019] [Indexed: 12/13/2022] Open
Abstract
Both gemcitabine and fluoropyrimidine are recommended backbones in the first-line treatment of pancreatic ductal adenocarcinoma (PDAC). To compare the efficacy and safety of these two therapeutic backbones, and to investigate the optimal therapies, we conducted a network meta-analysis. By retrospective analysis of randomized controlled trials (RCT), the most preferred therapeutic regimen may be predicted. The eligible RCTs of the gemcitabine-based therapies and fluoropyrimidine-based therapies were searched up to 31 August 2019. In a frequentist network meta-analysis, treatments were compared and ranked according to overall survival (OS) and progression-free survival (PFS). Thirty-two trials with 10,729 patients were included. The network meta-analyses results for overall survival and progression-free survival showed that fluoropyrimidine-based therapy seems to be the most effective treatment choice. Compared to gemcitabine combined with taxanes or immunotherapy, fluoropyrimidine-based therapy had comparable treatment effects (PFS: 0.67, p-Value = 0.11; 0.76, p-Value = 0.32; OS: 0.80, p-Value = 0.16; 0.77, p-Value = 0.21). Moreover, the combination of immunotherapy and gemcitabine had tolerable toxicities. Based on current evidence, fluoropyrimidine-based therapies and the combination of gemcitabine and taxanes were the most effective therapies in the advanced pancreatic cancer, and the combination of immunotherapy and gemcitabine can be developed into a new form of therapy.
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11
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Brunner M, Wu Z, Krautz C, Pilarsky C, Grützmann R, Weber GF. Current Clinical Strategies of Pancreatic Cancer Treatment and Open Molecular Questions. Int J Mol Sci 2019; 20:E4543. [PMID: 31540286 PMCID: PMC6770743 DOI: 10.3390/ijms20184543] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 09/11/2019] [Accepted: 09/12/2019] [Indexed: 12/24/2022] Open
Abstract
Pancreatic cancer is one of the most lethal malignancies and is associated with a poor prognosis. Surgery is considered the only potential curative treatment for pancreatic cancer, followed by adjuvant chemotherapy, but surgery is reserved for the minority of patients with non-metastatic resectable tumors. In the future, neoadjuvant treatment strategies based on molecular testing of tumor biopsies may increase the amount of patients becoming eligible for surgery. In the context of non-metastatic disease, patients with resectable or borderline resectable pancreatic carcinoma might benefit from neoadjuvant chemo- or chemoradiotherapy followed by surgeryPatients with locally advanced or (oligo-/poly-)metastatic tumors presenting significant response to (neoadjuvant) chemotherapy should undergo surgery if R0 resection seems to be achievable. New immunotherapeutic strategies to induce potent immune response to the tumors and investigation in molecular mechanisms driving tumorigenesis of pancreatic cancer may provide novel therapeutic opportunities in patients with pancreatic carcinoma and help patient selection for optimal treatment.
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Affiliation(s)
- Maximilian Brunner
- Department of General and Visceral Surgery, Friedrich Alexander University, Krankenhausstraße 12, 91054 Erlangen, Germany.
| | - Zhiyuan Wu
- Department of General and Visceral Surgery, Friedrich Alexander University, Krankenhausstraße 12, 91054 Erlangen, Germany.
| | - Christian Krautz
- Department of General and Visceral Surgery, Friedrich Alexander University, Krankenhausstraße 12, 91054 Erlangen, Germany.
| | - Christian Pilarsky
- Department of General and Visceral Surgery, Friedrich Alexander University, Krankenhausstraße 12, 91054 Erlangen, Germany.
| | - Robert Grützmann
- Department of General and Visceral Surgery, Friedrich Alexander University, Krankenhausstraße 12, 91054 Erlangen, Germany.
| | - Georg F Weber
- Department of General and Visceral Surgery, Friedrich Alexander University, Krankenhausstraße 12, 91054 Erlangen, Germany.
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12
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Lichota A, Gwozdzinski K. Anticancer Activity of Natural Compounds from Plant and Marine Environment. Int J Mol Sci 2018; 19:E3533. [PMID: 30423952 PMCID: PMC6275022 DOI: 10.3390/ijms19113533] [Citation(s) in RCA: 246] [Impact Index Per Article: 35.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 11/05/2018] [Accepted: 11/06/2018] [Indexed: 02/07/2023] Open
Abstract
This paper describes the substances of plant and marine origin that have anticancer properties. The chemical structure of the molecules of these substances, their properties, mechanisms of action, their structure⁻activity relationships, along with their anticancer properties and their potential as chemotherapeutic drugs are discussed in this paper. This paper presents natural substances from plants, animals, and their aquatic environments. These substances include the vinca alkaloids, mistletoe plant extracts, podophyllotoxin derivatives, taxanes, camptothecin, combretastatin, and others including geniposide, colchicine, artesunate, homoharringtonine, salvicine, ellipticine, roscovitine, maytanasin, tapsigargin, and bruceantin. Compounds (psammaplin, didemnin, dolastin, ecteinascidin, and halichondrin) isolated from the marine plants and animals such as microalgae, cyanobacteria, heterotrophic bacteria, invertebrates (e.g., sponges, tunicates, and soft corals) as well as certain other substances that have been tested on cells and experimental animals and used in human chemotherapy.
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Affiliation(s)
- Anna Lichota
- Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-136 Lodz, Poland.
| | - Krzysztof Gwozdzinski
- Department of Molecular Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 90-136 Lodz, Poland.
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13
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Stainthorpe A, Greenhalgh J, Bagust A, Richardson M, Boland A, Beale S, Duarte R, Kotas E, Banks L, Palmer D. Paclitaxel as Albumin-Bound Nanoparticles with Gemcitabine for Untreated Metastatic Pancreatic Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. PHARMACOECONOMICS 2018; 36:1153-1163. [PMID: 29600384 PMCID: PMC6132498 DOI: 10.1007/s40273-018-0646-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
As part of the single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited Celgene Ltd to submit clinical and cost-effectiveness evidence for paclitaxel as albumin-bound nanoparticles (Nab-Pac) in combination with gemcitabine (Nab-Pac + Gem) for patients with untreated metastatic pancreatic cancer. The STA was a review of NICE's 2015 guidance (TA360) in which Nab-Pac + Gem was not recommended for patients with untreated metastatic pancreatic cancer. The review was prompted by a proposed Patient Access Scheme (PAS) discount on the price of Nab-Pac and new evidence that might lead to a change in the guidance. The Liverpool Reviews and Implementation Group at the University of Liverpool was the Evidence Review Group (ERG). This article summarises the ERG's review of the company's evidence submission for Nab-Pac + Gem, and the Appraisal Committee (AC) decision. The final scope issued by NICE listed three comparators: gemcitabine monotherapy (Gem), gemcitabine in combination with capecitabine (Gem + Cap), and a combination of oxaliplatin, irinotecan, leucovorin and fluorouracil (FOLFIRINOX). Clinical evidence for the comparison of Nab-Pac + Gem versus Gem was from the phase III CA046 randomized controlled trial. Analysis of progression-free survival (PFS) and overall survival (OS) showed statistically significant improvement for patients treated with Nab-Pac + Gem versus Gem. Clinical evidence for the comparison of Nab-Pac + Gem versus FOLFIRINOX and versus Gem + Cap was derived from a network meta-analysis (NMA). Results of the NMA did not indicate a statistically significant difference in OS or PFS for the comparison of Nab-Pac + Gem versus either Gem + Cap or FOLFIRINOX. The ERG's main concerns with the clinical effectiveness evidence were difficulties in identifying the patient population for whom treatment with Nab-Pac + Gem is most appropriate, and violation of the proportional hazards (PH) assumption in the CA046 trial. The ERG highlighted methodological issues in the cost-effectiveness analysis pertaining to the modelling of survival outcomes, estimation of drug costs and double counting of adverse-event disutilities. The AC accepted all the ERG's amendments to the company's cost-effectiveness model; however, these did not make important differences to the incremental cost-effectiveness ratios (ICERs). The company's base-case ICER was £46,932 per quality-adjusted life-year (QALY) gained for the comparison of Nab-Pac + Gem versus Gem. Treatment with Nab-Pac + Gem was dominated both by treatment with Gem + Cap and with FOLFIRINOX in the company's base case. The AC concluded that the most plausible ICER for treatment with Nab-Pac + Gem versus Gem was in the range of £41,000-£46,000 per QALY gained. The AC concluded that Nab-Pac + Gem was not cost effective compared with Gem + Cap or FOLFIRINOX, and accepted that treatment with Nab-Pac + Gem met the end-of-life criteria versus Gem but did not consider Nab-Pac + Gem to meet the end-of-life criteria compared with Gem + Cap or FOLFIRINOX. The AC also concluded that although patients who would receive Nab-Pac + Gem rather than FOLFIRINOX or Gem + Cap were difficult to distinguish, they were identifiable in clinical practice. The AC recommended treatment with Nab-Pac + Gem for patients with untreated metastatic pancreatic cancer for whom other combination chemotherapies were unsuitable and who would otherwise receive Gem.
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Affiliation(s)
- Angela Stainthorpe
- Liverpool Reviews and Implementation Group, University of Liverpool, Whelan Building, Brownlow Hill, Liverpool, L69 3GB, UK.
| | - Janette Greenhalgh
- Liverpool Reviews and Implementation Group, University of Liverpool, Whelan Building, Brownlow Hill, Liverpool, L69 3GB, UK
| | - Adrian Bagust
- Liverpool Reviews and Implementation Group, University of Liverpool, Whelan Building, Brownlow Hill, Liverpool, L69 3GB, UK
| | - Marty Richardson
- Liverpool Reviews and Implementation Group, University of Liverpool, Whelan Building, Brownlow Hill, Liverpool, L69 3GB, UK
| | - Angela Boland
- Liverpool Reviews and Implementation Group, University of Liverpool, Whelan Building, Brownlow Hill, Liverpool, L69 3GB, UK
| | - Sophie Beale
- Liverpool Reviews and Implementation Group, University of Liverpool, Whelan Building, Brownlow Hill, Liverpool, L69 3GB, UK
| | - Rui Duarte
- Liverpool Reviews and Implementation Group, University of Liverpool, Whelan Building, Brownlow Hill, Liverpool, L69 3GB, UK
| | - Eleanor Kotas
- Liverpool Reviews and Implementation Group, University of Liverpool, Whelan Building, Brownlow Hill, Liverpool, L69 3GB, UK
| | - Lindsay Banks
- North West Medicines Information Centre, Liverpool, L69 3GF, UK
| | - Daniel Palmer
- Liverpool Reviews and Implementation Group, University of Liverpool, Whelan Building, Brownlow Hill, Liverpool, L69 3GB, UK
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14
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Zhang S, Tian Y, Xie S, Zhang J, Zhao J, Chen Y, Wang C. Systemic Chemotherapy as First-line Treatment for Metastatic Pancreatic Adenocarcinoma: A Bayesian Analysis. Intern Med 2018. [PMID: 30146578 DOI: 10.2169/internalmedicine.1114-18] [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] [Indexed: 11/06/2022] Open
Abstract
Objective The preferred chemotherapy regimen for metastatic pancreatic cancer remains a matter of controversy. In the present study, we aimed to assess and rank the effectiveness and toxicity of all of the available chemotherapy regimens included in the last 15 years' randomized controlled trials (RCTs) for metastatic pancreatic adenocarcinomas objectively. Methods PubMed, Embase, Cochrane Collaboration database, and ClinicalTrials.gov were searched for RCTs comparing chemotherapy regimens as first-line treatment for metastatic pancreatic adenocarcinomas. Using a Bayesian network meta-analysis, we compared and ranked all included chemotherapy regimens in terms of the overall survival, progression-free survival, response rate, and hematological toxicity. Results We identified 2,206 articles and included in the analysis 46 eligible articles reporting 44 RCTs with a total of 9,133 patients and 48 first-line intravenous systemic chemotherapy regimens. The models showed a good fit to the data. The top-ranked chemotherapy regimen for the overall survival was FP (simplified leucovorin + fluorouracil + nab-paclitaxel), with a hazard ratio (HR) of 0.45 versus gemcitabine monotherapy (95% credible interval 0.28-0.71). The regimen ranked first for the progression-free survival was gemcitabine + erlotinib + bevacizumab (HR 0.39, 0.23-0.62). GS (gemcitabine + S-1) had the highest overall response rate [odds ratio (OR) versus gemcitabine monotherapy 7.06, 1.15-51.15]. GemCape (gemcitabine + capecitabine) + erlotinib was ranked the most hematologically toxic (OR 7.78, 0.75-95.60). Conclusion The available evidence suggests that FP ranked first for metastatic pancreatic cancer in terms of the overall survival. GemCape + erlotinib ranked the most toxic.
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Affiliation(s)
- Shuisheng Zhang
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, China
- Department of General Surgery, Peking University Third Hospital, China
| | - Yuan Tian
- Department of Radiation Oncology, Shandong Provincial Qianfoshan Hospital, China
| | - Shuanghua Xie
- Department of Cancer Epidemiology and Health Statistics, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, China
| | - Jianwei Zhang
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, China
| | - Jiuda Zhao
- Department of Medical Oncology, Affiliated Hospital of Qinghai University, China
| | - Yingtai Chen
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, China
| | - Chengfeng Wang
- Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, China
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15
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Perrier ND. From Initial Description by Wermer to Present-Day MEN1: What have We Learned? World J Surg 2018; 42:1031-1035. [PMID: 29383428 DOI: 10.1007/s00268-017-4435-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Pancreas, parathyroid, and pituitary, are referred to as the "3 Ps" of MEN1. The time has come to move beyond those Ps and begin to discuss (1) prediction, (2) pausing progression, and (3) prevention of MEN1. METHODS In preparation for the International Association of Endocrine Surgeons State of the Art address, updates and uncertainties of MEN were reviewed. This included a detailed examination of the MEN1 gene and the library of implicated mutations, exon sequencing databases and cell cycle pathways. Therapeutic options including radiofrequency ablation, systemic therapy, peptide receptor radionuclide therapy, immune checkpoint inhibitor mechanisms and preimplantation genetic testing were described. RESULTS Several key points included mutations in exon 2 are suspected of being associated with a higher rate of distant metastases, a higher rate of PNET development, and more aggressive disease. The suggestion that missense mutations involving loss of interaction with CHES1 (associated with DNA repair) correlates with more aggressive disease and is more closely associated with death related to PNET than to death from other causes was mentioned. For advanced NETs, optimism for agents under study include lanreotide, a long-acting somatostatin analog, and everolimus (Afinitor), a mammalian target of rapamycin (mTOR) inhibitor. The NETest shows the potential value of being a multidimensional tumor marker for response to therapy. Preimplantation genetic diagnosis (PGD) is applicable. CONCLUSION Adjunct modalities and determination of the effect of therapy for MEN1 is needed. Prediction through early detection of aggressive disease is an idea worth spreading. We are called us to engage with our patients about prevention, the only true cure.
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Affiliation(s)
- Nancy D Perrier
- Department of Surgical Oncology, Unit 1484, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA.
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16
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Bruera G, Massacese S, Candria S, Galvano A, Manetta R, Giordano AV, Carducci S, Di Sibio A, Ciacco E, Russo A, Ricevuto E, on behalf of Oncology Network ASL1 Abruzzo, Italy. Real life triplet FIr/FOx chemotherapy in first-line metastatic pancreatic ductal adenocarcinoma patients: recommended schedule for expected activity and safety and phase II study. Oncotarget 2018; 9:31861-31876. [PMID: 30159128 PMCID: PMC6112758 DOI: 10.18632/oncotarget.25870] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 07/18/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Gemcitabine/nab-paclitaxel and FOLFIRINOX demonstrated significantly increased survival compared with gemcitabine in metastatic pancreatic ductal adenocarcinoma (PDAC): objective response rate (ORR) 23 and 31.6%, progression-free survival (PFS) 5.5 and 6.4 months, overall survival (OS) 8.7 and 11.1 months. Present phase II study evaluated recommended first-line triplet FIr/FOx schedule. METHODS Simon two-step design: p010%, p130%, power 80%, α5%, β20%. Projected ORR: I step, 1/10; II 5/29. Schedule: 12h-timed-flat-infusion/5-fluorouracil 750-800-900 mg/m2 d1-2,8-9,15-16,22-23; irinotecan 120-140-160 mg/m2 d1,15; oxaliplatin 70-80 mg/m2 d8,22; every 4 weeks, according to clinical parameters (age, comorbidities, performance status (PS), liver function). Activity and efficacy were evaluated, and compared using log-rank; limiting toxicity syndromes (LTS), using chi-square. RESULTS Twenty-nine consecutive patients were enrolled, according to primary/intermediate/secondary Cumulative Illness Rating Scale (CIRS). Median age 62; elderly 13 (44.7%); PS2 3 (10.4%), secondary CIRS 5 (17.2%). Primary endpoint was met: ORR 53% (7/13 patients) as-treated, 50% intent-to-treat. Cumulative G3-4 toxicities: diarrhea 17%, asthenia 14%, hypertransaminasemy 7%, mucositis 7%, vomiting 3%, anemia 3%, thrombocytopenia 3%. LTS were 27.5% overall, 38.4% in elderly. At 3 months median follow-up, PFS 4 months, OS 11 months. PS2 patients showed significantly worse OS (P 0.022). CONCLUSION Intensive first-line triplet FIr/FOx is tolerable at modulated doses, and confirms high activity/efficacy in metastatic PDAC. Patients' careful selection, and exclusion of PS2, can maintain safety profile and efficient dose intensity.
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Affiliation(s)
- Gemma Bruera
- Oncology Territorial Care Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L’Aquila, L’Aquila, Italy
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
| | - Silvia Massacese
- Pharmacy Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L’Aquila, Italy
| | - Stefania Candria
- Oncology Territorial Care Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L’Aquila, L’Aquila, Italy
| | - Antonio Galvano
- Medical Oncology Unit, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
| | - Rosa Manetta
- Radiology Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L’Aquila, Italy
| | - Aldo Victor Giordano
- Radiology Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L’Aquila, Italy
| | - Sergio Carducci
- Radiology Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L’Aquila, Italy
| | - Alessandra Di Sibio
- Radiology Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L’Aquila, Italy
| | - Eugenio Ciacco
- Pharmacy Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L’Aquila, Italy
| | - Antonio Russo
- Medical Oncology Unit, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
| | - Enrico Ricevuto
- Oncology Territorial Care Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L’Aquila, L’Aquila, Italy
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
| | - on behalf of Oncology Network ASL1 Abruzzo, Italy
- Oncology Territorial Care Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, University of L’Aquila, L’Aquila, Italy
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
- Pharmacy Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L’Aquila, Italy
- Medical Oncology Unit, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
- Radiology Unit, S. Salvatore Hospital, Oncology Network ASL1 Abruzzo, L’Aquila, Italy
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Isacoff WH, Reber HA, Bedford R, Hoos W, Rahib L, Upfill-Brown A, Donahue T, Hines OJ. Low-Dose Continuous 5-Fluorouracil Combined with Leucovorin, nab-Paclitaxel, Oxaliplatin, and Bevacizumab for Patients with Advanced Pancreatic Cancer: A Retrospective Analysis. Target Oncol 2018; 13:461-468. [PMID: 29882102 PMCID: PMC6096752 DOI: 10.1007/s11523-018-0572-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Continuous-infusion 5-fluorouracil (5FU) and calcium leucovorin plus nab-paclitaxel and oxaliplatin have been shown to be active in patients with pancreatic cancer. As a protracted low-dose infusion, 5FU is antiangiogenic, and has synergy with bevacizumab. As shown in the treatment of breast cancer, bevacizumab and nab-paclitaxel are also synergetic. OBJECTIVE In this paper we retrospectively analyze the survival of 65 patients with advanced pancreatic cancer who were treated with low-dose continuous (metronomic) chemotherapy given in conjunction with conventional anti-VEGF therapy. PATIENTS AND METHODS Since July of 2008, we have treated 65 patients with 5FU (180 mg/m2/day × 14 days) via an ambulatory pump. Calcium leucovorin (20 mg/m2 IV), nab-paclitaxel (60 mg/m2) IV as a 30-min infusion, and oxaliplatin (50 mg/m2) IV as a 60-min infusion were given on days 1, 8, and 15. Bevacizumab (5 mg/kg) IV over 30 min was administered on days 1 and 15. Cycles were repeated every 28-35 days. There were 42 women and 23 men, and the median age was 59 years. Forty-six patients had stage IV disease. RESULTS The median survival was 19 months, with 82% of patients surviving 12 months or longer. The overall response rate was 49%. There were 28 patients who had received prior treatment, 15 of whom responded to therapy. Fifty-two patients had elevated CA 19-9 prior to treatment. Of these, 21 patients had 90% or greater reduction in CA 19-9 levels. This cohort had an objective response rate of 71% and a median survival of 27 months. Thirty patients stopped treatment due to disease progression, and an additional 22 stopped because of toxicity. One patient died while on therapy. CONCLUSIONS This non-gemcitabine-based regimen resulted in higher response rates and better survival than what is commonly observed with therapy given at conventional dosing schedules. Low-dose continuous (metronomic therapy) cytotoxic chemotherapy combined with antiangiogenic therapy is safe and effective.
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Affiliation(s)
- William H Isacoff
- Department of Medicine, David Geffen School of Medicine at University of California Los Angeles (UCLA), 1301 20th Street, Suite 280, Santa Monica, CA, 90404, USA.
| | - Howard A Reber
- Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USA
| | - Rudolph Bedford
- Department of Medicine, David Geffen School of Medicine at University of California Los Angeles (UCLA), 1301 20th Street, Suite 280, Santa Monica, CA, 90404, USA
| | - William Hoos
- Pancreatic Action Network, Manhattan Beach, CA, USA
| | - Lola Rahib
- Pancreatic Action Network, Manhattan Beach, CA, USA
| | - Alexander Upfill-Brown
- Department of Medicine, David Geffen School of Medicine at University of California Los Angeles (UCLA), 1301 20th Street, Suite 280, Santa Monica, CA, 90404, USA
| | - Timothy Donahue
- Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USA
| | - O Joe Hines
- Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California Los Angeles (UCLA), Los Angeles, CA, USA
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O’Reilly EM, Lee JW, Lowery MA, Capanu M, Stadler ZK, Moore MJ, Dhani N, Kindler HL, Estrella H, Maynard H, Golan T, Segal A, Salo-Mullen EE, Yu KH, Epstein AS, Segal M, Brenner R, Do RK, Chen AP, Tang LH, Kelsen DP. Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: Germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma. Cancer 2018; 124:1374-1382. [PMID: 29338080 PMCID: PMC5867226 DOI: 10.1002/cncr.31218] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2017] [Revised: 11/22/2017] [Accepted: 11/28/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND A phase 1 trial was used to evaluate a combination of cisplatin, gemcitabine, and escalating doses of veliparib in patients with untreated advanced pancreatic ductal adenocarcinoma (PDAC) in 2 cohorts: a germline BRCA1/2-mutated (BRCA+) cohort and a wild-type BRCA (BRCA-) cohort. The aims were to determine the safety, dose-limiting toxicities (DLTs), maximum tolerated dose, and recommended phase 2 dose (RP2D) of veliparib combined with cisplatin and gemcitabine and to assess the antitumor efficacy (Response Evaluation Criteria in Solid Tumors, version 1.1) and overall survival. METHODS Gemcitabine and cisplatin were dosed at 600 and 25 mg/m2 , respectively, over 30 minutes on days 3 and 10 of a 21-day cycle. Four dose levels of veliparib were evaluated: 20 (dose level 0), 40 (dose level 1), and 80 mg (dose level 2) given orally twice daily on days 1 to 12 and 80 mg given twice daily on days 1 to 21 (dose level 2A [DL2A]). RESULTS Seventeen patients were enrolled: 9 BRCA+ patients, 7 BRCA- patients, and 1 patient with an unknown status. DLTs were reached at DL2A (80 mg twice daily on days 1 to 21). Two of the 5 patients in this cohort (40%) experienced grade 4 neutropenia and thrombocytopenia. Two grade 5 events occurred on protocol. The objective response rate in the BRCA+ cohort was 7 of 9 (77.8%). The median overall survival for BRCA+ patients was 23.3 months (95% confidence interval [CI], 3.8-30.2 months). The median overall survival for BRCA- patients was 11 months (95% CI, 1.5-12.1 months). CONCLUSIONS The RP2D of veliparib was 80 mg by mouth twice daily on days 1 to 12 in combination with cisplatin and gemcitabine; the DLT was myelosuppression. Substantial antitumor activity was seen in BRCA+ PDAC. A randomized phase 2 trial is currently evaluating cisplatin and gemcitabine with and without veliparib for BRCA+ PDAC (NCT01585805). Cancer 2018;124:1374-82. © 2018 American Cancer Society.
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Affiliation(s)
- Eileen M. O’Reilly
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medicine, NY, NY
| | | | | | | | - Zsofia K. Stadler
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medicine, NY, NY
| | - Malcolm J. Moore
- Princess Margaret Cancer Centre- University Health Network, Toronto, ON
| | - Neesha Dhani
- Princess Margaret Cancer Centre- University Health Network, Toronto, ON
| | | | | | | | - Talia Golan
- Sheba Medical Center, Tel Hashomer, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Amiel Segal
- Share Zedek Medical Center, Jerusalem, Israel
| | | | - Kenneth H. Yu
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medicine, NY, NY
| | - Andrew S. Epstein
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medicine, NY, NY
| | - Michal Segal
- Memorial Sloan Kettering Cancer Center, New York, NY
| | - Robin Brenner
- Memorial Sloan Kettering Cancer Center, New York, NY
| | - Richard K. Do
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medicine, NY, NY
| | | | - Laura H. Tang
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medicine, NY, NY
| | - David P. Kelsen
- Memorial Sloan Kettering Cancer Center, New York, NY
- Weill Cornell Medicine, NY, NY
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Chin V, Nagrial A, Sjoquist K, O'Connor CA, Chantrill L, Biankin AV, Scholten RJPM, Yip D, Cochrane Upper GI and Pancreatic Diseases Group. Chemotherapy and radiotherapy for advanced pancreatic cancer. Cochrane Database Syst Rev 2018; 3:CD011044. [PMID: 29557103 PMCID: PMC6494171 DOI: 10.1002/14651858.cd011044.pub2] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Pancreatic cancer (PC) is a highly lethal disease with few effective treatment options. Over the past few decades, many anti-cancer therapies have been tested in the locally advanced and metastatic setting, with mixed results. This review attempts to synthesise all the randomised data available to help better inform patient and clinician decision-making when dealing with this difficult disease. OBJECTIVES To assess the effect of chemotherapy, radiotherapy or both for first-line treatment of advanced pancreatic cancer. Our primary outcome was overall survival, while secondary outcomes include progression-free survival, grade 3/4 adverse events, therapy response and quality of life. SEARCH METHODS We searched for published and unpublished studies in CENTRAL (searched 14 June 2017), Embase (1980 to 14 June 2017), MEDLINE (1946 to 14 June 2017) and CANCERLIT (1999 to 2002) databases. We also handsearched all relevant conference abstracts published up until 14 June 2017. SELECTION CRITERIA All randomised studies assessing overall survival outcomes in patients with advanced pancreatic ductal adenocarcinoma. Chemotherapy and radiotherapy, alone or in combination, were the eligible treatments. DATA COLLECTION AND ANALYSIS Two review authors independently analysed studies, and a third settled any disputes. We extracted data on overall survival (OS), progression-free survival (PFS), response rates, adverse events (AEs) and quality of life (QoL), and we assessed risk of bias for each study. MAIN RESULTS We included 42 studies addressing chemotherapy in 9463 patients with advanced pancreatic cancer. We did not identify any eligible studies on radiotherapy.We did not find any benefit for chemotherapy over best supportive care. However, two identified studies did not have sufficient data to be included in the analysis, and many of the chemotherapy regimens studied were outdated.Compared to gemcitabine alone, participants receiving 5FU had worse OS (HR 1.69, 95% CI 1.26 to 2.27, moderate-quality evidence), PFS (HR 1.47, 95% CI 1.12 to 1.92) and QoL. On the other hand, two studies showed FOLFIRINOX was better than gemcitabine for OS (HR 0.51 95% CI 0.43 to 0.60, moderate-quality evidence), PFS (HR 0.46, 95% CI 0.38 to 0.57) and response rates (RR 3.38, 95% CI 2.01 to 5.65), but it increased the rate of side effects. The studies evaluating CO-101, ZD9331 and exatecan did not show benefit or harm when compared with gemcitabine alone.Giving gemcitabine at a fixed dose rate improved OS (HR 0.79, 95% CI 0.66 to 0.94, high-quality evidence) but increased the rate of side effects when compared with bolus dosing.When comparing gemcitabine combinations to gemcitabine alone, gemcitabine plus platinum improved PFS (HR 0.80, 95% CI 0.68 to 0.95) and response rates (RR 1.48, 95% CI 1.11 to 1.98) but not OS (HR 0.94, 95% CI 0.81 to 1.08, low-quality evidence). The rate of side effects increased. Gemcitabine plus fluoropyrimidine improved OS (HR 0.88, 95% CI 0.81 to 0.95), PFS (HR 0.79, 95% CI 0.72 to 0.87) and response rates (RR 1.78, 95% CI 1.29 to 2.47, high-quality evidence), but it also increased side effects. Gemcitabine plus topoisomerase inhibitor did not improve survival outcomes but did increase toxicity. One study demonstrated that gemcitabine plus nab-paclitaxel improved OS (HR 0.72, 95% CI 0.62 to 0.84, high-quality evidence), PFS (HR 0.69, 95% CI 0.58 to 0.82) and response rates (RR 3.29, 95% CI 2.24 to 4.84) but increased side effects. Gemcitabine-containing multi-drug combinations (GEMOXEL or cisplatin/epirubicin/5FU/gemcitabine) improved OS (HR 0.55, 95% CI 0.39 to 0.79, low-quality evidence), PFS (HR 0.43, 95% CI 0.30 to 0.62) and QOL.We did not find any survival advantages when comparing 5FU combinations to 5FU alone. AUTHORS' CONCLUSIONS Combination chemotherapy has recently overtaken the long-standing gemcitabine as the standard of care. FOLFIRINOX and gemcitabine plus nab-paclitaxel are highly efficacious, but our analysis shows that other combination regimens also offer a benefit. Selection of the most appropriate chemotherapy for individual patients still remains difficult, with clinicopathological stratification remaining elusive. Biomarker development is essential to help rationalise treatment selection for patients.
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Affiliation(s)
- Venessa Chin
- Garvan Institute of Medical ResearchThe Kinghorn Cancer Centre384 Victoria Street DarlinghurstSydneyNSWAustralia2010
- St Vincent's HospitalSydneyNSWAustralia
| | - Adnan Nagrial
- Garvan Institute of Medical ResearchThe Kinghorn Cancer Centre384 Victoria Street DarlinghurstSydneyNSWAustralia2010
- The Crown Princess Mary Cancer CentreDarcy RoadWestmeadNSWAustralia2145
| | - Katrin Sjoquist
- University of SydneyNHMRC Clinical Trials CentreK25 ‐ Medical Foundation BuildingSydneyNSWAustralia2006
- Cancer Care Centre, St George HospitalMedical OncologySt George Hospital, Gray StKogarahAustraliaNSW 2217
| | - Chelsie A O'Connor
- St Vincent's HospitalSydneyNSWAustralia
- Genesis Cancer CareSydneyNSWAustralia
- Macquarie University HospitalSydneyAustralia
| | - Lorraine Chantrill
- The Kinghorn Cancer Centre, Garvan Institute of Medical ResearchDepartment of Pancreatic Cancer382 Victoria Street DarlinghurstSydneyNSWAustralia2010
| | - Andrew V Biankin
- University of GlasgowInstitute of Cancer SciencesWolfson Wohl Cancer Research CentreGarscube Estate, Switchback RoadGlasgowUKG61 1QH
- University of New South WalesSouth Western Sydney Clinical School, Faculty of MedicineLiverpoolNSWAustralia2170
- West of Scotland Pancreatic Unit and Glasgow Royal InfirmaryGlasgowUK
| | - Rob JPM Scholten
- Julius Center for Health Sciences and Primary Care / University Medical Center UtrechtCochrane NetherlandsRoom Str. 6.126P.O. Box 85500UtrechtNetherlands3508 GA
| | - Desmond Yip
- The Canberra HospitalDepartment of Medical OncologyYamba DriveGarranACTAustralia2605
- Australian National UniversityANU Medical SchoolActonACTAustralia0200
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20
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Zhang XW, Ma YX, Sun Y, Cao YB, Li Q, Xu CA. Gemcitabine in Combination with a Second Cytotoxic Agent in the First-Line Treatment of Locally Advanced or Metastatic Pancreatic Cancer: a Systematic Review and Meta-Analysis. Target Oncol 2018; 12:309-321. [PMID: 28353074 DOI: 10.1007/s11523-017-0486-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND It remains controversial whether the addition of a second cytotoxic agent can further improve the therapeutic effect of gemcitabine monotherapy in advanced or metastatic pancreatic cancer (LA/MPC). OBJECTIVE The objective of the present systematic review and meta-analysis was to investigate the efficacy and safety of gemcitabine-based doublet chemotherapy regimens compared to single-agent gemcitabine in the first-line treatment of unresectable LA/MPC. METHODS We searched for randomized controlled trials (RCTs) of gemcitabine monotherapy versus gemcitabine in combination with a second cytotoxic agent in patients with LA/MPC. The last search date was December 31, 2016. RESULTS Twenty-seven RCTs were identified and included in the present systematic review and meta-analysis, involving a total of 7343 patients. The meta-analysis showed that gemcitabine-based combination therapy significantly improved overall survival (OS) (HR: 0.89; 95% confidence interval (CI): 0.85-0.94; P < 0.0001), progression-free survival (PFS) (HR: 0.80; 95% CI: 0.73-0.88; P < 0.0001), and overall response rate (ORR) (RR: 1.83; 95% CI: 1.62-2.07; P < 0.0001) in comparison to single-agent gemcitabine. Subgroup analysis suggested that the antitumor activity differed between gemcitabine-based combination regimens: doublet regimens of gemcitabine plus a taxoid, and gemcitabine plus a fluoropyrimidine, in particular an oral fluoropyrimidine, resulted in a significant OS benefit for the patients. However, the combination of gemcitabine with other cytotoxic agents, such as platinum compounds or topoisomerase inhibitors failed to reduce the mortality risk. Combination therapy caused more grade 3/4 toxicities, including neutropenia, thrombocytopenia, vomiting, diarrhea, and fatigue. CONCLUSIONS Gemcitabine-based doublet regimens demonstrated superiority over gemcitabine monotherapy in overall efficacy, but were associated with increased toxicity. Different gemcitabine-based combinations showed different antitumor activity, and doublet regimens of gemcitabine in combination with a taxoid or a fluoropyrimidine, in particular an oral fluoropyrimidine provided significant survival benefits in the first-line treatment of unresectable LA/MPC.
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Affiliation(s)
- Xiu-Wei Zhang
- Department of Pathology, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
| | - Yu-Xiang Ma
- Department of Oncologic Medicine, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Yang Sun
- Department of Oncologic Medicine, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Yu-Bo Cao
- Department of Oncologic Medicine, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Qin Li
- Center for Translational Medicine, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
| | - Chong-An Xu
- Department of Oncologic Medicine, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China.
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21
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Man YKS, Davies JA, Coughlan L, Pantelidou C, Blázquez-Moreno A, Marshall JF, Parker AL, Halldén G. The Novel Oncolytic Adenoviral Mutant Ad5-3Δ-A20T Retargeted to αvβ6 Integrins Efficiently Eliminates Pancreatic Cancer Cells. Mol Cancer Ther 2018; 17:575-587. [PMID: 29367266 DOI: 10.1158/1535-7163.mct-17-0671] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2017] [Revised: 09/27/2017] [Accepted: 11/30/2017] [Indexed: 12/13/2022]
Abstract
Metastatic pancreatic ductal adenocarcinomas (PDAC) are incurable due to the rapid development of resistance to all current therapeutics. Oncolytic adenoviral mutants have emerged as a promising new strategy that negates such resistance. In contrast to normal tissue, the majority of PDACs express the αvβ6 integrin receptor. To exploit this feature, we modified our previously reported oncolytic adenovirus, AdΔΔ, to selectively target αvβ6 integrins to facilitate systemic delivery. Structural modifications to AdΔΔ include the expression of the small but potent αvβ6-binding peptide, A20FMDV2, and ablation of binding to the native coxsackie and adenovirus receptor (CAR) within the fiber knob region. The resultant mutant, Ad5-3Δ-A20T, infected and killed αvβ6 integrin-expressing cells more effectively than the parental wild-type (Ad5wt) virus and AdΔΔ. Viral uptake through αvβ6 integrins rather than native viral receptors (CAR, αvβ3 and αvβ5 integrins) promoted viral propagation and spread. Superior efficacy of Ad5-3Δ-A20T compared with Ad5wt was demonstrated in 3D organotypic cocultures, and similar potency between the two viruses was observed in Suit-2 in vivo models. Importantly, Ad5-3Δ-A20T infected pancreatic stellate cells at low levels, which may further facilitate viral spread and cancer cell elimination either as a single agent or in combination with the chemotherapy drug, gemcitabine. We demonstrate that Ad5-3Δ-A20T is highly selective for αvβ6 integrin-expressing pancreatic cancer cells, and with further development, this new and exciting strategy can potentially be extended to improve the systemic delivery of adenoviruses to pancreatic cancer patients. Mol Cancer Ther; 17(2); 575-87. ©2018 AACR.
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Affiliation(s)
- Y K Stella Man
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, United Kingdom
| | - James A Davies
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Lynda Coughlan
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York
| | | | - Alfonso Blázquez-Moreno
- Department of Immunology and Oncology, Centro Nacional de Biotecnología-Consejo Superior de Investigaciones Científicas, Madrid, Spain
| | - John F Marshall
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, United Kingdom
| | - Alan L Parker
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Gunnel Halldén
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, United Kingdom.
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22
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The E1B19K-deleted oncolytic adenovirus mutant AdΔ19K sensitizes pancreatic cancer cells to drug-induced DNA-damage by down-regulating Claspin and Mre11. Oncotarget 2017; 7:15703-24. [PMID: 26872382 PMCID: PMC4941271 DOI: 10.18632/oncotarget.7310] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 01/27/2016] [Indexed: 11/25/2022] Open
Abstract
Adenovirus-mediated sensitization of cancer cells to cytotoxic drugs depends on simultaneous interactions of early viral genes with cell death and survival pathways. It is unclear what cellular factors mediate these interactions in the presence of DNA-damaging drugs. We found that adenovirus prevents Chk1-mediated checkpoint activation through inactivation of Mre11 and downregulation of the pChk1 adaptor-protein, Claspin, in cells with high levels of DNA-damage induced by the cytotoxic drugs gemcitabine and irinotecan. The mechanisms for Claspin downregulation involve decreased transcription and increased degradation, further attenuating pChk1-mediated signalling. Live cell imaging demonstrated that low doses of gemcitabine caused multiple mitotic aberrations including multipolar spindles, micro- and multi-nucleation and cytokinesis failure. A mutant virus with the anti-apoptotic E1B19K-gene deleted (AdΔ19K) further enhanced cell killing, Claspin downregulation, and potentiated drug-induced DNA damage and mitotic aberrations. Decreased Claspin expression and inactivation of Mre11 contributed to the enhanced cell killing in combination with DNA-damaging drugs. These results reveal novel mechanisms that are utilised by adenovirus to ensure completion of its life cycle in the presence of cellular DNA damage. Taken together, our findings reveal novel cellular targets that may be exploited when developing improved anti-cancer therapeutics.
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23
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Yoshino K, Kamiura S, Yokoi T, Nakae R, Fujita M, Takemura M, Adachi K, Wakimoto A, Nishizaki T, Shiki Y, Tsutsui T, Kanda Y, Kobayashi E, Hashimoto K, Mabuchi S, Ueda Y, Sawada K, Tomimatsu T, Kimura T. Combination chemotherapy with irinotecan and gemcitabine for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancer: a multicenter phase I/II trial (GOGO-Ov 6). Cancer Chemother Pharmacol 2017; 80:1239-1247. [PMID: 29080971 DOI: 10.1007/s00280-017-3468-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Accepted: 10/16/2017] [Indexed: 01/22/2023]
Abstract
PURPOSE To develop a new therapeutic strategy for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancers, we evaluated the feasibility and efficacy of irinotecan and gemcitabine combination chemotherapy. METHODS Patients with taxane/platinum-resistant/refractory cancer received escalating doses of irinotecan and gemcitabine (level 1: 80 and 800 mg/m2, respectively; level 2: 100 and 1000 mg/m2) on days 1 and 8 on a 21-day cycle. Genotyping for UGT1A1*6 and *28 polymorphisms was performed for possible adverse irinotecan sensitivity. RESULTS A total of 35 patients were enrolled. The recommended dose was defined as 100 mg/m2 irinotecan and 1000 mg/m2 gemcitabine (level 2). The observed common grade 3/4 toxicities were neutropenia (60%), anemia (17.1%), diarrhea (8.6%), thrombocytopenia (5.7%) and nausea (5.7%). Groups homozygous for UGT1A1*6 or *28 were associated with grade 3/4 neutropenia and diarrhea. Objective responses were 20%, including one complete response and six partial responses. In 29 patients treated with the recommended dose, the median progression-free survival and overall survival were 3.8 months (95% CI 2.1-6.0 months) and 17.4 months (95% CI 9.9-21.9 months), respectively, while the 1-year survival rate was 58.6%. CONCLUSIONS Combination chemotherapy with irinotecan and gemcitabine represents a safe and effective treatment combination for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancers.
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Affiliation(s)
- Kiyoshi Yoshino
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 5650871, Japan.
| | - Shoji Kamiura
- Department of Gynecologic Oncology, Osaka International Cancer Institute, 3-1-69 Otemae, Chuo-ku, Osaka, Osaka, 5418567, Japan
| | - Takeshi Yokoi
- Department of Obstetrics and Gynecology, Kaizuka City Hospital, 3-10-20 Hori, Kaizuka, Osaka, 5970015, Japan
| | - Ruriko Nakae
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Masami Fujita
- Department of Obstetrics and Gynecology, Nissay Hospital, 6-3-8 Nishi-ku Itachibori, Osaka, Osaka, 5500012, Japan
| | - Masahiko Takemura
- Department of Obstetrics and Gynecology, Osaka General Medical Center, 3-1-56 Sumiyoshi-ku Manndai-higashi, Osaka, Osaka, 5588558, Japan
| | - Kazushige Adachi
- Department of Obstetrics and Gynecology, Minoh City Hospital, 5-7-1 Kayano, Minoh, Osaka, 5620014, Japan
| | - Akinori Wakimoto
- Department of Obstetrics and Gynecology, Toyonaka Municipal Hospital, 4-14-1 Shibahara, Toyonaka, Osaka, 5608565, Japan
| | - Takamichi Nishizaki
- Department of Obstetrics and Gynecology, Suita Municipal Hospital, 2-13-20 Katayama-cho, Suita, Osaka, 5640082, Japan
| | - Yasuhiko Shiki
- Department of Obstetrics and Gynecology, Osaka Rosai Hospital, 1179-3 Kita-ku, Nagasone-cho, Sakai, Osaka, 5918025, Japan
| | - Tateki Tsutsui
- Department of Obstetrics and Gynecology, Japan Community Healthcare Organization (JCHO) Osaka Hospital, Fukusima-ku, Fukushima, Osaka, Osaka, 5530003, Japan
| | - Yuki Kanda
- Department of Gynecology, Otemae Hospital, 1-5-34 Chuo-ku Otemae, Osaka, Osaka, 5400008, Japan
| | - Eiji Kobayashi
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Kae Hashimoto
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Seiji Mabuchi
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Yutaka Ueda
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Kenjiro Sawada
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Takuji Tomimatsu
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 5650871, Japan
| | - Tadashi Kimura
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 5650871, Japan
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Survival outcome and prognostic factors after pancreatoduodenectomy for distal bile duct carcinoma: a retrospective multicenter study. Langenbecks Arch Surg 2017; 402:831-840. [PMID: 28612115 DOI: 10.1007/s00423-017-1590-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 05/09/2017] [Indexed: 12/15/2022]
Abstract
PURPOSE Pancreatoduodenectomy is the most common operative procedure performed for distal bile duct carcinoma. Data on outcome after surgery for this rare malignancy is scarce, especially from western countries. The purpose of this study is to explore the prognostic factors and outcome after pancreatoduodenectomy for distal bile duct carcinoma. METHODS Patients receiving pancreatoduodenectomy for distal bile duct carcinoma were identified from institutional databases of five German and one Russian academic centers for pancreatic surgery. Univariable and multivariable general linear model, Kaplan-Meier method, and Cox regression were used to identify prognostic factors for postoperative mortality and overall survival. RESULTS N = 228 patients operated from 1994 to 2015 were included. Reoperation (OR 5.38, 95%CI 1.51-19.22, p = 0.010), grade B/C postpancreatectomy hemorrhage (OR 3.73, 95%CI 1.13-12.35, p = 0.031), grade B/C postoperative pancreatic fistula (OR 4.29, 95%CI 1.25-14.72, p = 0.038), and advanced age (OR 4.00, 95%CI 1.12-14.03, p = 0.033) were independent risk factors for in-hospital mortality in multivariable analysis. Median survival was 29 months, 5-year survival 27%. Positive resection margin (HR 2.07, 95%CI 1.29-3.33, p = 0.003), high tumor grade (HR 1.71, 95%CI 1.13-2.58, p = 0.010), lymph node (HR 1.68, 95%CI 1.13-2.51, p = 0.011), and distant metastases (HR 2.70, 95%CI 1.21-5.58, p = 0.014), as well as severe non-fatal postoperative complications (HR 1.64, 95%CI 1.04-2.58, p = 0.033) were independent negative prognostic factors for survival in multivariable analysis. CONCLUSION Distant metastases and positive resection margin are the strongest negative prognostic factors for survival after pancreatoduodenectomy for distal bile duct carcinoma; thus, surgery with curative intent is only warranted in patients with local disease, where R0 resection is feasible.
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Hamada T, Nakai Y, Isayama H, Yasunaga H, Matsui H, Takahara N, Mizuno S, Kogure H, Matsubara S, Yamamoto N, Tada M, Koike K. Progression-free survival as a surrogate for overall survival in first-line chemotherapy for advanced pancreatic cancer. Eur J Cancer 2016; 65:11-20. [PMID: 27451020 DOI: 10.1016/j.ejca.2016.05.016] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Revised: 04/24/2016] [Accepted: 05/15/2016] [Indexed: 02/09/2023]
Abstract
BACKGROUND Overall survival (OS), as the primary end-point in first-line chemotherapy trials, requires a prolonged follow-up time and may be confounded by subsequent regimens. This study aimed to evaluate the correlation between OS and surrogate end-points (progression-free survival [PFS], response rate and disease control rate), and to identify a potential surrogate for OS in advanced pancreatic cancer. METHODS Based on an electronic search, we identified randomized controlled phase II and III trials of first-line chemotherapy for advanced pancreatic cancer. Correlation analyses were performed between surrogate end-points and OS, and between improvements in surrogates and those in OS. RESULTS Fifty trials (II/II-III/III, 17/2/31) with 111 treatment arms were identified, and 15,906 patients were analysed. PFS was most strongly correlated with OS (correlation coefficient, 0.76). Weighted linear regression models revealed the greatest determinant coefficient of 0.84 between the hazard ratio (HR) of the experimental arms compared with the control arms of PFS and that of OS. The approximate equation was log HROS = 0.01 + 0.77 × log HRPFS, indicating that risk reduction of OS via chemotherapy would translate into a 77% risk reduction of PFS. The surrogacy of PFS for OS was robust throughout our subgroup analyses: e.g., biologic versus non-biologic regimens, locally advanced versus metastatic disease. CONCLUSIONS The surrogacy of PFS for OS in pancreatic cancer was validated. Therefore, the use of PFS as the primary end-point in clinical trials could facilitate the early introduction of new effective chemotherapy regimens into clinical practice.
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Affiliation(s)
- Tsuyoshi Hamada
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
| | - Yousuke Nakai
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Hiroyuki Isayama
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Hideo Yasunaga
- Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Tokyo, Japan.
| | - Hiroki Matsui
- Department of Clinical Epidemiology and Health Economics, School of Public Health, The University of Tokyo, Tokyo, Japan.
| | - Naminatsu Takahara
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Suguru Mizuno
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Hirofumi Kogure
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Saburo Matsubara
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Natsuyo Yamamoto
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Minoru Tada
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
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Hafeez Bhatti AB, Dar FS, Sahaab E, Khan NY, Zia H, Rana A, Salih M, Shah NH. Survival advantage with para aortic lymphadenectomy in peri-ampullary cancer: A retrospective cohort study. Int J Surg 2016; 31:58-62. [PMID: 27262530 DOI: 10.1016/j.ijsu.2016.05.069] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 05/15/2016] [Accepted: 05/28/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND Metastatic para aortic lymph nodes (PALN) in patients with peri ampullary cancer entail poor prognosis. Role of curative surgery in these patients remains debatable. The objective of the current study was to evaluate outcome after extended pancreaticoduodenectomy (PD) in patients with and without positive PALN. METHODS We reviewed 65 patients who underwent extended PD with PALN removal between 2011 and 2014. Patients were divided into two groups; those with positive PALN and those without. Patients were sub classified for pancreatic and non-pancreatic cancer. Outcome was determined based on median and estimated 3 year overall survival. RESULTS Median age was 57 (32-85) years. PALN were involved in 15 (23%) patients. Overall 3 year survival for patients with and without positive PALN was 60% and 54% (P = 0.7). Significant difference in survival was present between patients with pancreatic cancer and positive PALN [9 (3-12) months] versus non-pancreatic cancers with positive PALN [17.5 (13-38) months] (P = 0.02). Four out of five patients with pancreatic cancer and positive PALN had survival >6 months and 3 out of these 5 patients were alive at the last follow up. CONCLUSION Curative surgery may benefit some patients with pancreatic cancer and positive PALN and should be considered selectively.
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Affiliation(s)
- Abu Bakar Hafeez Bhatti
- Department of HPB and Liver Transplantation, Shifa International Hospital, Islamabad, Pakistan.
| | - Faisal Saud Dar
- Department of HPB and Liver Transplantation, Shifa International Hospital, Islamabad, Pakistan
| | - Eraj Sahaab
- Department of HPB and Liver Transplantation, Shifa International Hospital, Islamabad, Pakistan
| | - Nusrat Yar Khan
- Department of HPB and Liver Transplantation, Shifa International Hospital, Islamabad, Pakistan
| | - Haseeb Zia
- Department of HPB and Liver Transplantation, Shifa International Hospital, Islamabad, Pakistan
| | - Atif Rana
- Department of Radiology, Shifa International Hospital, Islamabad, Pakistan
| | - Muhammad Salih
- Department of Gastroenterology and Hepatology, Shifa International Hospital, Pakistan
| | - Najmul Hassan Shah
- Department of Gastroenterology and Hepatology, Shifa International Hospital, Pakistan
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Deshpande V, Konstantinidis IT, Castillo CFD, Hezel AF, Haigis KM, Ting DT, Bardeesy N, Goyal L, Zhu AX, Warshaw AL, Lillemoe KD, Ferrone CR. Intra-pancreatic Distal Bile Duct Carcinoma is Morphologically, Genetically, and Clinically Distinct from Pancreatic Ductal Adenocarcinoma. J Gastrointest Surg 2016; 20:953-9. [PMID: 26956004 DOI: 10.1007/s11605-016-3108-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 02/15/2016] [Indexed: 01/31/2023]
Abstract
PURPOSE Differentiating intra-pancreatic distal bile duct carcinoma invading the pancreas from pancreatic ductal adenocarcinomas (PDAC) surrounding the distal common bile duct (CBD) can be challenging. Our aim is to identify clinical, morphological, and genetic features characteristic of intra-pancreatic distal bile duct carcinoma. METHODS Clinicopathologic data of 550 patients undergoing a pancreaticoduodenectomy between September 1990 and May 2008 were reviewed. KRAS status was assessed with mass-spectrometric genotyping. RESULTS Ninety-seven patients with intra-pancreatic adenocarcinomas surrounding the CBD were identified; slides were available for 80. Two relationships with the CBD were recognized as follows: type I (n = 42): cancer grew concentrically around the CBD and type II (n = 38): cancer grew asymmetrically around the CBD. Type I adenocarcinomas were associated with high-grade biliary dysplasia (45 vs. 13 %; p = 0.003); type II were associated with high-grade pancreatic intra-epithelial neoplasia (PanIN-2 or -3) (39 vs. 9 %; p = 0.003). Type I tumors had a better median survival (46 months) compared to type II (23 months) or other PDAC (20 months) (p < 0.001). Mutated KRAS was identified in 3/26 (11 %) type I and 20/21 (95 %) type II cancers (p < 0.001). There may be poorer survival in the presence of a KRAS mutation than wild-type KRAS (22.9 vs. 41.6 months; p = 0.3). CONCLUSIONS Distal periductal adenocarcinomas fall into two distinct groups with biologic, morphologic and genetic differences. Those growing symmetrically around the CBD are more likely to be intra-pancreatic distal bile duct carcinomas and are associated with improved survival whereas cancers with asymmetric growth are more likely to have KRAS mutations and to be PDACs. These findings facilitate a more accurate histopathological diagnosis, which could improve patient selection for therapeutic trials.
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Affiliation(s)
- Vikram Deshpande
- Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA.
| | | | | | - Aram F Hezel
- Department of Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Kevin M Haigis
- Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA, 02114, USA
| | - David T Ting
- Department of Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Nabeel Bardeesy
- Department of Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Lipika Goyal
- Department of Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Andrew X Zhu
- Department of Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Andrew L Warshaw
- Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
| | - Keith D Lillemoe
- Department of Surgery, Massachusetts General Hospital, Boston, MA, USA
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Colloca G, Venturino A, Guarneri D. Analysis of Response-Related and Time-to-event Endpoints in Randomized Trials of Gemcitabine-Based Treatment Versus Gemcitabine Alone as First-Line Treatment of Patients With Advanced Pancreatic Cancer. Clin Colorectal Cancer 2015; 15:264-76. [PMID: 26776098 DOI: 10.1016/j.clcc.2015.11.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Revised: 11/03/2015] [Accepted: 11/23/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND Gemcitabine-based combinations in advanced pancreatic cancer have been reported to have superior activity compared with gemcitabine alone. The results of the commonly used endpoints of clinical trials after chemotherapy or targeted therapy have been poorly reported. METHODS AND MATERIALS We performed a search of randomized trials of systemic treatment that included gemcitabine plus chemotherapy or targeted therapy versus gemcitabine alone. For selected trials, the differences between the treatment arms for every endpoint were calculated, and a correlation analysis between these differences and the differences in overall survival was performed for every intermediate endpoint. Whenever a correlation coefficient was significant, regression analysis was performed. Finally, an analysis was performed to evaluate the factors that could mediate and moderate the effect of progression-free survival on overall survival. RESULTS In addition to overall survival, progression-free survival, the overall response rate, and the disease control rate were the most frequently reported endpoints. Of the possible surrogate endpoints of overall survival, progression-free survival appears to be a reliable endpoint to assess chemotherapy (R(2) = 0.646) and chemotherapy plus targeted therapy (R(2) = 0.530) regimens and the disease control rate to assess chemotherapy (R(2) = 0.569). Of the factors that could limit the effect of progression-free survival on overall survival, the interval of radiologic evaluation could play a role. CONCLUSION In the selected trials, progression-free survival and the disease control rate were the most reliable surrogate endpoints of overall survival. Similar to the time-to-event endpoints, a standardization of response-related endpoints is strongly recommended.
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Cao C, Kuang M, Xu W, Zhang X, Chen J, Tang C. Gemcitabine plus S-1: a hopeful frontline treatment for Asian patients with unresectable advanced pancreatic cancer. Jpn J Clin Oncol 2015; 45:1122-30. [PMID: 26518328 DOI: 10.1093/jjco/hyv141] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 08/24/2015] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE Gemcitabine-based chemotherapy is widely used for unresectable advanced pancreatic cancer which contains locally advanced and metastatic pancreatic cancer. We performed meta-analysis to examine whether gemcitabine plus S-1 could improve treatment efficacy as first-line chemotherapy for those patients when compared with gemcitabine alone. METHODS STATA was used to estimate the summary hazard ratios or odds ratios and their 95% confidence intervals. Heterogeneity among trials was examined by Cochran's χ(2) test. Publication bias was evaluated by Begg's and Egger's tests. Subgroup analysis based on the extent of disease was performed. RESULTS Four randomized controlled trials including 878 Asian patients were analyzed. In total meta-analysis, gemcitabine plus S-1 significantly improved overall survival (hazard ratio, 0.82; 95% confidence interval, 0.70-0.96; P = 0.015), progression-free survival (hazard ratio, 0.64; 95% confidence interval, 0.55-0.74; P < 0.001), overall response rate (odds ratio, 3.00; 95% confidence interval, 2.04-4.41; P < 0.001) and disease control rate (odds ratio, 1.78; 95% confidence interval, 1.32 to 2.39; P < 0.001), and was associated with more but manageable hematologic (leukocytopenia, neutropenia, thrombocytopenia) and non-hematologic (diarrhea, stomatitis, nausea, rash) adverse events. In subgroup analysis, gemcitabine plus S-1, comparing with gemcitabine, significantly improved overall survival in locally advanced patients (hazard ratio, 0.69; 95% confidence interval, 0.48 to 0.99; P = 0.022) but not in metastatic patients (hazard ratio, 0.75; 95% confidence interval, 0.46-1.23; P = 0.256). CONCLUSION This meta-analysis confirmed the survival benefits of gemcitabine plus S-1 as first-line treatment for unresectable advanced pancreatic cancer at least in Asia, while good Eastern Cooperative Oncology group performance status was warranted. Importantly, we highlighted the significant overall survival benefit of gemcitabine plus S-1 in locally advanced patients but not in metastatic patients.
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Affiliation(s)
- Chunxiang Cao
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing Department of Radiation Oncology, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou
| | - Meng Kuang
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing
| | - Wei Xu
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing
| | - Xunlei Zhang
- Department of Oncology, Nantong Tumor Hospital, Nantong
| | - Jinfei Chen
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing
| | - Cuiju Tang
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing
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Cho M, Wang-Gillam A, Myerson R, Gao F, Strasberg S, Picus J, Sorscher S, Fournier C, Nagaraj G, Parikh P, Suresh R, Linehan D, Tan BR. A phase II study of adjuvant gemcitabine plus docetaxel followed by concurrent chemoradation in resected pancreaticobiliary carcinoma. HPB (Oxford) 2015; 17:587-93. [PMID: 25800066 PMCID: PMC4474505 DOI: 10.1111/hpb.12413] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 02/17/2015] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Adjuvant gemcitabine with or without chemoradiation is a standard therapeutic option for patients with resected pancreatic cancer. The feasibility and toxicity of gemcitabine with docetaxel before and after 5-fluorouracil (5FU)-based chemoradiation in the adjuvant pancreatic and biliary cancer setting were investigated. METHODS After a curative-intent resection, eligible patients with pancreaticobiliary cancers were treated with two cycles of gemcitabine and docetaxel followed by 5FU-based chemoradiation. Four weeks after completing chemoradiation, two cycles of gemcitabine and docetaxel were administered. The primary endpoint was the incidence of severe toxicities. Secondary endpoints included disease-free survival (DFS) and overall survival (OS). RESULTS Fifty patients with pancreaticobiliary cancers were enrolled. Twenty-nine patients had pancreatic cancer whereas 21 patients had biliary tract or ampullary cancers. There was one death as a result of pneumonia, and 15% of patients experienced grade 3 or greater non-haematological toxicities. The median DFS and OS for patients with pancreatic cancer were 9.6 and 17 months, respectively, and for those with resected biliary tract cancer were 12 and 23 months, respectively. CONCLUSIONS This combination of gemcitabine and docetaxel with chemoradiation is feasible and tolerable in the adjuvant setting. Future studies utilizing a different gemcitabine/taxane combination and schedule may be appropriate in the adjuvant treatment of both pancreatic cancer and biliary tumours.
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Affiliation(s)
- May Cho
- Department of Medicine, Washington University School of MedicineSt. Louis, MO, USA
| | - Andrea Wang-Gillam
- Department of Medicine, Washington University School of MedicineSt. Louis, MO, USA
| | - Robert Myerson
- Department of Radiation Oncology, Washington University School of MedicineSt. Louis, MO, USA
| | - Feng Gao
- Division of Biostatistics, Washington University School of MedicineSt. Louis, MO, USA
| | - Steven Strasberg
- Department of Surgery, Washington University School of MedicineSt. Louis, MO, USA
| | - Joel Picus
- Department of Medicine, Washington University School of MedicineSt. Louis, MO, USA
| | - Steven Sorscher
- Department of Medicine, Washington University School of MedicineSt. Louis, MO, USA
| | - Chloe Fournier
- Department of Medicine, Washington University School of MedicineSt. Louis, MO, USA
| | - Gayathri Nagaraj
- Division of Medical Oncology and Hematology, Loma Linda UniversityLoma Linda, CA, USA
| | - Parag Parikh
- Department of Radiation Oncology, Washington University School of MedicineSt. Louis, MO, USA
| | - Rama Suresh
- Department of Medicine, Washington University School of MedicineSt. Louis, MO, USA
| | - David Linehan
- Department of Surgery, Washington University School of MedicineSt. Louis, MO, USA
| | - Benjamin R Tan
- Department of Medicine, Washington University School of MedicineSt. Louis, MO, USA
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Kim EJ, Semrad TJ, Bold RJ. Phase II clinical trials on investigational drugs for the treatment of pancreatic cancers. Expert Opin Investig Drugs 2015; 24:781-94. [PMID: 25809274 PMCID: PMC4684166 DOI: 10.1517/13543784.2015.1026963] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
INTRODUCTION Despite some recent advances in treatment options, pancreatic cancer remains a devastating disease with poor outcomes. In a trend contrary to most malignancies, both incidence and mortality continue to rise due to pancreatic cancer. The majority of patients present with advanced disease and there are no treatment options for this stage that have demonstrated a median survival > 1 year. As the penultimate step prior to Phase III studies involving hundreds of patients, Phase II clinical trials provide an early opportunity to evaluate the efficacy of new treatments that are desperately needed for this disease. AREAS COVERED This review covers the results of published Phase II clinical trials in advanced pancreatic adenocarcinoma published within the past 5 years. The treatment results are framed in the context of the current standards of care and the historic challenge of predicting Phase III success from Phase II trial results. EXPERT OPINION Promising therapies remain elusive in pancreatic cancer based on recent Phase II clinical trial results. Optimization and standardization of clinical trial design in the Phase II setting, with consistent incorporation of biomarkers, is needed to more accurately identify promising therapies that warrant Phase III evaluation.
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Affiliation(s)
- Edward J. Kim
- Division of Hematology and Oncology, UC Davis Cancer Center, Sacramento, CA 95817, USA
| | - Thomas J. Semrad
- Division of Hematology and Oncology, UC Davis Cancer Center, Sacramento, CA 95817, USA
| | - Richard J. Bold
- Division of Surgical Oncology, UC Davis Cancer Center, Sacramento, CA 95817, USA
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Petrelli F, Coinu A, Borgonovo K, Cabiddu M, Barni S. Progression-free survival as surrogate endpoint in advanced pancreatic cancer: meta-analysis of 30 randomized first-line trials. Hepatobiliary Pancreat Dis Int 2015; 14:124-31. [PMID: 25865683 DOI: 10.1016/s1499-3872(15)60344-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Progression-free survival (PFS) has not been extensively investigated as a surrogate for survival in the first-line treatments of pancreatic cancer. The aim of this review was to evaluate PFS as a potential surrogate endpoint for overall survival (OS) in advanced pancreatic cancer in trials comparing poly-chemotherapy to gemcitabine alone. DATA SOURCES A systematic literature search in PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials was conducted. The key words included randomized trial, first-line chemotherapy, pancreatic cancer, gemcitabine and poly-chemotherapy. Adjusted weighted linear regression was used to calculate RS (Spearman's rank-order correlation coefficient) between PFS and post-progression survival (PPS) with OS (RS) and between treatment effects on PFS and OS (RHR). RESULTS A total of 30 trials including 8467 patients met the inclusion criteria. Correlation between the treatment effects on PFS and OS (RHR=0.78) and between the endpoint PFS and OS was high across all studies (RS=0.75). The slope of the regression line was 0.76+/-0.26, indicating that an agent producing a 10% risk reduction for PFS will provide a 7.6%+/-2.6% risk reduction for OS. Correlation between PPS and OS was very strong (RS=0.71) and accounted for more than 50% of the whole OS variability (R2=0.57). CONCLUSION Because of the robust correlation with OS and the potential influence of PPS caused by the second line therapies, it may be justified to consider PFS as a surrogate endpoint in trials evaluating new cytotoxic agents when gemcitabine is the control arm.
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Affiliation(s)
- Fausto Petrelli
- Medical Oncology Unit, Oncology Department, Azienda Ospedaliera Treviglio, Piazzale Ospedale 1, 24047 Treviglio (BG), Italy.
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Xie J, Yuan J, Lu L. Gemcitabine fixed-dose rate infusion for the treatment of pancreatic carcinoma: a meta-analysis of randomized controlled trials. Diagn Pathol 2014; 9:214. [PMID: 25421173 PMCID: PMC4251942 DOI: 10.1186/s13000-014-0214-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2014] [Accepted: 10/26/2014] [Indexed: 02/08/2023] Open
Abstract
Background Pre-clinical evidence shows that fixed dose rate (FDR) infusion of gemcitabine could optimize plasma concentration of gemcitabine, while the clinical efficacy and toxicity of FDR infusion of gemcitabine in advanced pancreatic carcinoma has not been systematically investigated. Thus, this meta-analysis was designed to ascertain this issue. Methods Databases of EMBASE, PubMed, and Cochrane Library were searched for eligible randomized controlled trials (RCTs). RCTs comparing FDR and standard 30-min infusion of gemcitabine in advanced pancreatic carcinoma were included. The primary endpoints were treatment efficacy (overall response rate, 1-year survival rate, median survival, and time to treatment failure) and toxicities were secondary endpoints (neutropenia, thrombocytopenia, anemia, and vomiting). Relative risks or mean differences and corresponding 95% confidence intervals (CIs) were calculated. Result After careful and rigorous selection, 3 eligible RCTs including 764 patients of advanced pancreatic adenocarcinoma were included in this meta-analysis. For treatment efficacy, FDR gemcitabine provided significantly longer median survival over standard gemcitabine (Mean Difference = 1.24 months, 95% CI: 0.39-2.09), while there was no statistical difference in other endpoints of treatment efficacy. For toxicities, patients with FDR gemcitabine experienced significantly more grade 3/4 hematological toxicities than those received standard gemcitabine (neutropenia, thrombocytopenia, and anemia), while there was no difference for vomiting. Conclusion Compared with standard 30-min infusion, FDR gemcitabine provide longer median survival, but increased the risk of hematological toxicities for patients with advanced pancreatic adenocarcinoma. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_214 Electronic supplementary material The online version of this article (doi:10.1186/s13000-014-0214-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jiqing Xie
- Department of Pharmacy, General Hospital of Jinan Military Command, Jinan, 250031, China.
| | - Jing Yuan
- Department of Medical Information, General Hospital of Jinan Military Command, Jinan, 250031, China.
| | - Laichun Lu
- Department of Pharmacy, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Changjiang Road 10, Chongqing, 400042, China.
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Buc E, Orry D, Antomarchi O, Gagnière J, Da Ines D, Pezet D. Resection of pancreatic ductal adenocarcinoma with synchronous distant metastasis: is it worthwhile? World J Surg Oncol 2014; 12:347. [PMID: 25407113 PMCID: PMC4289271 DOI: 10.1186/1477-7819-12-347] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2014] [Accepted: 07/04/2014] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The purpose of this study is to report prolonged survival in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) managed by chemotherapy and surgery. METHODS Between January 2009 and August 2013, 284 patients with metastatic PDAC were managed in our oncologic department. Among them, three (1%) with a single metastasis (liver in two cases and interaorticaval in one case) underwent one- or two-stage surgical resection of the metastasis and the main tumor. Perioperative data were recorded retrospectively, including disease-free and overall survival. RESULTS The three patients had chemotherapy (FOLFOX or FOLFIRINOX regimen) with objective response or stable disease prior to surgery. Median time between chemotherapy and surgery was 9 (8 to 15) months. Resection consisted in pancreaticoduodenectomy in the three cases. None of the patients had grade III/IV postoperative complications, and median hospital stay was 12 (12 to 22) days. All the patients had postoperative chemotherapy. Only one patient experienced recurrence 11 months after surgery and died after 32.5 months. The two other patients were alive with no recurrence 26.3 and 24.7 months after initial treatment. CONCLUSION Radical resection of PDAC with single distant metastases can offer prolonged survival with low morbidity after accurate selection by neoadjuvant chemotherapy.
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Affiliation(s)
- Emmanuel Buc
- />Department of Digestive and HPB Surgery, CHU Estaing - 1, Place Lucie et Raymond Aubrac, 63003 Clermont-Ferrand, France
| | - David Orry
- />Department of Oncologic Surgery, Centre Georges François Leclerc, Dijon, France
| | - Olivier Antomarchi
- />Department of Digestive and HPB Surgery, CHU Estaing - 1, Place Lucie et Raymond Aubrac, 63003 Clermont-Ferrand, France
| | - Johan Gagnière
- />Department of Digestive and HPB Surgery, CHU Estaing - 1, Place Lucie et Raymond Aubrac, 63003 Clermont-Ferrand, France
| | - David Da Ines
- />Department of Radiology, CHU Estaing, Clermont-Ferrand, France
| | - Denis Pezet
- />Department of Digestive and HPB Surgery, CHU Estaing - 1, Place Lucie et Raymond Aubrac, 63003 Clermont-Ferrand, France
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Chan K, Shah K, Lien K, Coyle D, Lam H, Ko YJ. A Bayesian meta-analysis of multiple treatment comparisons of systemic regimens for advanced pancreatic cancer. PLoS One 2014; 9:e108749. [PMID: 25286060 PMCID: PMC4186762 DOI: 10.1371/journal.pone.0108749] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Accepted: 08/25/2014] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND For advanced pancreatic cancer, many regimens have been compared with gemcitabine (G) as the standard arm in randomized controlled trials. Few regimens have been directly compared with each other in randomized controlled trials and the relative efficacy and safety among them remains unclear. METHODS A systematic review was performed through MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ASCO meeting abstracts up to May 2013 to identify randomized controlled trials that included advanced pancreatic cancer comparing the following regimens: G, G+5-fluorouracil, G+ capecitabine, G+S1, G+ cisplatin, G+ oxaliplatin, G+ erlotinib, G+ nab-paclitaxel, and FOLFIRINOX. Overall survival and progression-free survival with 95% credible regions were extracted using the Parmar method. A Bayesian multiple treatment comparisons was performed to compare all regimens simultaneously. RESULTS Twenty-two studies were identified and 16 were included in the meta-analysis. Median overall survival, progression free survival, and response rates for G arms from all trials were similar, suggesting no significant clinical heterogeneity. For overall survival, the mixed treatment comparisons found that the probability that FOLFIRINOX was the best regimen was 83%, while it was 11% for G+ nab-paclitaxel and 3% for G+ S1 and G+ erlotinib, respectively. The overall survival hazard ratio for FOLFIRINOX versus G+ nab-paclitaxel was 0.79 [0.50-1.24], with no obvious difference in toxicities. The hazard ratios from direct pairwise comparisons were consistent with the mixed treatment comparisons results. CONCLUSIONS FOLFIRINOX appeared to be the best regimen for advanced pancreatic cancer probabilistically, with a trend towards improvement in survival when compared with other regimens by indirect comparisons.
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Affiliation(s)
- Kelvin Chan
- Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada
- Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
| | - Keya Shah
- Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Kelly Lien
- Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Doug Coyle
- University of Ottawa, Ottawa, ON, Canada
| | - Henry Lam
- Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Yoo-Joung Ko
- Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada
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Xu K, Niu L, Yang D. Cryosurgery for pancreatic cancer. Gland Surg 2014; 2:30-9. [PMID: 25083453 DOI: 10.3978/j.issn.2227-684x.2013.02.02] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Accepted: 02/18/2013] [Indexed: 01/11/2023]
Abstract
The procedure of pancreatic cryosurgery is performed with intraoperative or percutaneous approaches. Based on current data and our initial experience, cryoablation appears to be a feasible, potentially safe and promising option in patients with locally advanced and unresectable pancreatic cancer. It is suggested that there are almost no known contraindications to the use of cryosurgery for pancreatic cancer. For most patients with pancreatic cancer, cryosurgery can substitute conventional surgery.
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Affiliation(s)
- Kecheng Xu
- 1 Department of Oncology, Affiliated Fuda Hospital, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, No. 91-93 Judezhong Road, Haizhu District, Guangzhou 510305, China ; 2 Guangzhou Fuda Cancer Hospital, Jinan University School of Medicine, No. 2 Tangdexi Road, Tianhe District, Guangzhou 510305, China
| | - Lizhi Niu
- 1 Department of Oncology, Affiliated Fuda Hospital, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, No. 91-93 Judezhong Road, Haizhu District, Guangzhou 510305, China ; 2 Guangzhou Fuda Cancer Hospital, Jinan University School of Medicine, No. 2 Tangdexi Road, Tianhe District, Guangzhou 510305, China
| | - Daming Yang
- 1 Department of Oncology, Affiliated Fuda Hospital, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Science, No. 91-93 Judezhong Road, Haizhu District, Guangzhou 510305, China ; 2 Guangzhou Fuda Cancer Hospital, Jinan University School of Medicine, No. 2 Tangdexi Road, Tianhe District, Guangzhou 510305, China
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Petrelli F, Coinu A, Borgonovo K, Cabiddu M, Ghilardi M, Barni S. Polychemotherapy or gemcitabine in advanced pancreatic cancer: a meta-analysis. Dig Liver Dis 2014; 46:452-9. [PMID: 24565950 DOI: 10.1016/j.dld.2014.01.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Revised: 12/10/2013] [Accepted: 01/01/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Gemcitabine monotherapy is the cornerstone of treatment for advanced pancreatic cancer. To date, no clear survival benefit has been found when combination chemotherapy has been compared with gemcitabine alone, except in a few studies. This meta-analysis compared the efficacy of polychemotherapy with gemcitabine alone in advanced pancreatic cancer. METHODS Randomised trials comparing combination chemotherapy with gemcitabine alone were identified through electronic searches of PubMed, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials. Overall survival, reported as the hazard ratio at the 95% confidence interval, was the primary outcome measure. RESULTS 29 trials (19 phase III and 10 small randomised trials) that included 8421 patients were identified. Overall, polychemotherapy significantly improved overall survival (hazard ratio=0.87; 95% CI, 0.81-0.93; P<0.0001), progression-free survival (hazard ratio=0.77; 95% CI, 0.70-0.84; P<0.00001), and response rate (risk ratio=1.71; 95% CI, 1.42-2.07; P<0.00001) compared with gemcitabine alone. CONCLUSIONS Compared with gemcitabine monotherapy, combinations of two or more drugs (particularly those with novel agents or associated with >20% response rates and triplets) improved outcomes and response rate in advanced pancreatic cancer, and they could be considered a new standard of care in advanced settings.
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Affiliation(s)
- Fausto Petrelli
- Medical Oncology Unit, Oncology Department, Azienda Ospedaliera Treviglio, Treviglio (BG), Italy.
| | - Andrea Coinu
- Medical Oncology Unit, Oncology Department, Azienda Ospedaliera Treviglio, Treviglio (BG), Italy
| | - Karen Borgonovo
- Medical Oncology Unit, Oncology Department, Azienda Ospedaliera Treviglio, Treviglio (BG), Italy
| | - Mary Cabiddu
- Medical Oncology Unit, Oncology Department, Azienda Ospedaliera Treviglio, Treviglio (BG), Italy
| | - Mara Ghilardi
- Medical Oncology Unit, Oncology Department, Azienda Ospedaliera Treviglio, Treviglio (BG), Italy
| | - Sandro Barni
- Medical Oncology Unit, Oncology Department, Azienda Ospedaliera Treviglio, Treviglio (BG), Italy
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Feng W, Zhang B, Cai D, Zou X. Therapeutic potential of histone deacetylase inhibitors in pancreatic cancer. Cancer Lett 2014; 347:183-90. [PMID: 24534202 DOI: 10.1016/j.canlet.2014.02.012] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Revised: 01/22/2014] [Accepted: 02/10/2014] [Indexed: 02/06/2023]
Abstract
Pancreatic cancer is a devastating disease with a dismal prognosis. Surgical resection is the only curative option but is heavily hampered by delayed diagnosis. Due to few therapeutic treatments available, novel and efficacious therapy is urgently needed. Histone deacetylase inhibitors (HDACIs) are emerging as a prominent class of therapeutic agents for pancreatic cancer and have exhibited significant anticancer potential with negligible toxicity in preclinical studies. Clinical evaluations of HDACIs are currently underway. HDACIs as monotherapy in solid tumors have proven less effective than hematological malignancies, the combination of HDACIs with other anticancer agents have been assessed for advanced pancreatic cancer. In this review, we describe the molecular mechanism underpin the anticancer effect of HDACIs in pancreatic cancer and summarize the recent advances in the rationale for the combination strategies incorporating HDACIs. In addition, we discuss the importance of identifying predictors of response to HDACI-based therapy.
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Affiliation(s)
- Wan Feng
- Department of Gastroenterology, The Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing 210008, PR China; Medical School of Nanjing University, Nanjing, PR China
| | - Bin Zhang
- Department of Gastroenterology, The Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing 210008, PR China
| | - Dawei Cai
- Medical School of Nanjing University, Nanjing, PR China
| | - Xiaoping Zou
- Department of Gastroenterology, The Drum Tower Hospital Affiliated to Medical School of Nanjing University, Nanjing 210008, PR China.
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Wolfgang CL, Herman JM, Laheru DA, Klein AP, Erdek MA, Fishman EK, Hruban RH. Recent progress in pancreatic cancer. CA Cancer J Clin 2013; 63:318-48. [PMID: 23856911 PMCID: PMC3769458 DOI: 10.3322/caac.21190] [Citation(s) in RCA: 676] [Impact Index Per Article: 56.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Revised: 03/22/2013] [Accepted: 03/22/2013] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is currently one of the deadliest of the solid malignancies. However, surgery to resect neoplasms of the pancreas is safer and less invasive than ever, novel drug combinations have been shown to improve survival, advances in radiation therapy have resulted in less toxicity, and enormous strides have been made in the understanding of the fundamental genetics of pancreatic cancer. These advances provide hope but they also increase the complexity of caring for patients. It is clear that multidisciplinary care that provides comprehensive and coordinated evaluation and treatment is the most effective way to manage patients with pancreatic cancer.
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Affiliation(s)
- Christopher L. Wolfgang
- Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
| | - Joseph M. Herman
- Department of Radiation Oncology & Molecular Radiation Sciences, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
| | - Daniel A. Laheru
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
| | - Alison P. Klein
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
- Department of Epidemiology, the Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | - Michael A. Erdek
- Department of Anesthesiology and Critical Care Medicine, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
| | - Elliot K. Fishman
- Department of Radiology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
| | - Ralph H. Hruban
- Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
- Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine
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40
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Ma WW, Hidalgo M. The winning formulation: the development of paclitaxel in pancreatic cancer. Clin Cancer Res 2013; 19:5572-9. [PMID: 23918602 DOI: 10.1158/1078-0432.ccr-13-1356] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Paclitaxel has wide application in anticancer therapy but was never considered an efficacious agent in pancreatic cancer. A review of the experience with the Cremaphor formulation hinted at paclitaxel's activity in pancreatic cancer, but the early development was hampered by significant toxicities such as neutropenia and infection at clinically tolerable doses. However, such efficacy was confirmed in the recently completed phase III Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT), in which the addition of nab-paclitaxel to gemcitabine significantly improved the survival of patients with metastatic pancreatic cancer. Several other Cremaphor-free formulations of paclitaxel had also been evaluated in pancreatic cancer, and the reasons for the success of the albumin nanoparticulate are examined here. In the era of biologic and molecularly targeted agents, the success of nab-paclitaxel in recalcitrant pancreatic cancer is a timely reminder of the importance and relevance of pharmacology and novel drug delivery technology in the development of anticancer drugs.
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Affiliation(s)
- Wen Wee Ma
- Authors' Affiliations: Roswell Park Cancer Institute, Buffalo, New York; and Centro Nacional de Investigaciones Oncologicas and Hospital de Madrid, Madrid, Spain
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41
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Wolfgang CL, Herman JM, Laheru DA, Klein AP, Erdek MA, Fishman EK, Hruban RH. Recent progress in pancreatic cancer. CA Cancer J Clin 2013. [PMID: 23856911 DOI: 10.1002/caac.21190] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer is currently one of the deadliest of the solid malignancies. However, surgery to resect neoplasms of the pancreas is safer and less invasive than ever, novel drug combinations have been shown to improve survival, advances in radiation therapy have resulted in less toxicity, and enormous strides have been made in the understanding of the fundamental genetics of pancreatic cancer. These advances provide hope but they also increase the complexity of caring for patients. It is clear that multidisciplinary care that provides comprehensive and coordinated evaluation and treatment is the most effective way to manage patients with pancreatic cancer.
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Affiliation(s)
- Christopher L Wolfgang
- Associate Professor, Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD; Associate Professor, Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD; Associate Professor, Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD
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42
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Tumour-stroma interactions in pancreatic ductal adenocarcinoma: rationale and current evidence for new therapeutic strategies. Cancer Treat Rev 2013; 40:118-28. [PMID: 23849556 DOI: 10.1016/j.ctrv.2013.04.004] [Citation(s) in RCA: 90] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2012] [Revised: 04/16/2013] [Accepted: 04/18/2013] [Indexed: 12/16/2022]
Abstract
Most patients with pancreatic cancer present with advanced/metastatic disease and have a dismal prognosis. Despite the proven albeit modest benefits of gemcitabine demonstrated over a decade ago, subsequent advances have been slow, suggesting it may be time to take a different approach. It is thought that some key characteristics of pancreatic cancer, such as the desmoplasia, restricted vasculature and hypoxic environment, may prevent the delivery of chemotherapy to the tumour thereby explaining the limited benefits observed to-date. Moreover, there is evidence to suggest that the stroma is not only a mechanical barrier but also constitutes a dynamic compartment of pancreatic tumours that is critically involved in tumour formation, progression and metastasis. Thus, targeting the stroma and the tumour represents a promising therapeutic strategy. Currently, several stroma-targeting agents are entering clinical development. Among these, nab-paclitaxel appears promising since it combines cytotoxic therapy with targeted delivery via its proposed ability to bind SPARC on tumour and stromal cells. Preclinical data indicate that co-treatment with nab-paclitaxel and gemcitabine results in stromal depletion, increased tumour vascularization and intratumoural gemcitabine concentration, and increased tumour regression compared with either agent alone. Phase I/II study data also suggest that a high level of antitumor activity can be achieved with this combination in pancreatic cancer. This was recently confirmed in a Phase III study which showed that nab-paclitaxel plus gemcitabine significantly improved overall survival (HR 0.72) and progression-free survival (HR 0.69) versus gemcitabine alone for the first-line treatment of patients with metastatic pancreatic cancer.
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43
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Seng S, Liu Z, Chiu SK, Proverbs-Singh T, Sonpavde G, Choueiri TK, Tsao CK, Yu M, Hahn NM, Oh WK, Galsky MD. Risk of venous thromboembolism in patients with cancer treated with Cisplatin: a systematic review and meta-analysis. J Clin Oncol 2012; 30:4416-26. [PMID: 23150697 DOI: 10.1200/jco.2012.42.4358] [Citation(s) in RCA: 168] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
PURPOSE Several reports suggest that cisplatin is associated with an increased risk of thromboembolism. However, because the excess risk of venous thromboembolic events (VTEs) with cisplatin-based chemotherapy has not been well described, we conducted a systemic review and meta-analysis of randomized controlled trials evaluating the incidence and risk of VTEs associated with cisplatin-based chemotherapy. METHODS PubMed was searched for articles published from January 1, 1990, to December 31, 2010. Eligible studies included prospective randomized phase II and III trials evaluating cisplatin-based versus non-cisplatin-based chemotherapy in patients with solid tumors. Data on all-grade VTEs were extracted. Study quality was calculated using Jadad scores. Incidence rates, relative risks (RRs), and 95% CIs were calculated using a random effects model. RESULTS A total of 8,216 patients with various advanced solid tumors from 38 randomized controlled trials were included. The incidence of VTEs was 1.92% (95% CI, 1.07 to 2.76) in patients treated with cisplatin-based chemotherapy and 0.79% (95% CI, 0.45 to 1.13) in patients treated with non-cisplatin-based regimens. Patients receiving cisplatin-based chemotherapy had a significantly increased risk of VTEs (RR, 1.67; 95% CI, 1.25 to 2.23; P = .01). Exploratory subgroup analysis revealed the highest RR of VTEs in patients receiving a weekly equivalent cisplatin dose > 30 mg/m(2) (2.71; 95% CI, 1.17 to 6.30; P = .02) and in trials reported during 2000 to 2010 (1.72; 95% CI, 1.27 to 2.34; P = .01). CONCLUSION Cisplatin is associated with a significant increase in the risk of VTEs in patients with advanced solid tumors when compared with non-cisplatin-based chemotherapy.
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Affiliation(s)
- Sonia Seng
- Southcoast Centers for Cancer Care, Fairhaven, MA, USA
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Fixed-dose rate infusion and standard rate infusion of gemcitabine in patients with advanced non-small-cell lung cancer: a meta-analysis of six trials. Cancer Chemother Pharmacol 2012; 70:861-73. [PMID: 23053260 DOI: 10.1007/s00280-012-1974-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2012] [Accepted: 09/11/2012] [Indexed: 01/22/2023]
Abstract
PURPOSE To compare the response, survival, hematological and non-hematological toxicities of gemcitabine administrated at fixed-dose rate infusion (10 mg/m(2)/min, FDR) and standard 30 min infusion in patients with advanced non-small-cell lung cancer (NSCLC). METHODS Electronic databases of MEDLINE, EMBASE and Cochrane Library were searched using key words of "gemcitabine," "fixed-dose rate," "non-small-cell lung cancer" and their alternative spellings. An expanded search of references of relative articles was also performed. The last search was performed on September 10, 2012. Primary endpoints were overall survival rate (ORR) and 1-year survival rate (1-year SR); hematological and non-hematological toxicities were secondary endpoints. RESULTS Six randomized controlled trials, involving 867 patients, met our inclusion criteria and were analyzed. Pooled results showed that FDR infusion of gemcitabine had an equal ORR (RR = 0.91, 95 % CI: 0.74-1.13; heterogeneity p = 0.39) and 1-year SR (RR = 1.09, 95 % CI: 0.93-1.29; heterogeneity p = 0.75) compared with standard infusion. Subgroup analysis found that chemotherapy drug combinations do not affect the results of ORR or 1-year SR. Patients received FDR infusion, however, experienced more grade 3/4 hematological (neutropenia, leukopenia and anemia) and non-hematological (diarrhea and fatigue) toxicities. CONCLUSION This meta-analysis found that FDR infusion of gemcitabine had equal ORR and 1-year SR with standard infusion in patients with advanced NSCLC, while FDR infusion was associated with more grade 3/4 hematological and non-hematological toxicities.
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45
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Sun C, Ansari D, Andersson R, Wu DQ. Does gemcitabine-based combination therapy improve the prognosis of unresectable pancreatic cancer? World J Gastroenterol 2012; 18:4944-4958. [PMID: 23002368 PMCID: PMC3447278 DOI: 10.3748/wjg.v18.i35.4944] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2011] [Revised: 02/01/2012] [Accepted: 04/12/2012] [Indexed: 02/06/2023] Open
Abstract
AIM To assess whether gemcitabine-based combination therapy improves the prognosis of unresectable pancreatic cancer compared with gemcitabine treatment alone. METHODS A quantitative up-to-date meta-analysis was undertaken to investigate the efficacy of gemcitabine-based combination treatment compared with gemcitabine monotherapy in locally advanced or metastatic pancreatic cancer. Inclusion was limited to high-quality randomized clinical trials. RESULTS Twenty-six studies were included in the present analysis, with a total of 8808 patients recruited. The studies were divided into four subgroups based on the different kinds of cytotoxic agents, including platinum, fluoropyrimidine, camptothecin and targeted agents. Patients treated with gemcitabine monotherapy had significantly lower objective response rate [risk ratio (RR), 0.72; 95% confidence interval (CI): 0.63-0.83; P < 0.001], and lower 1-year overall survival (RR, 0.90; 95%CI: 0.82-0.99; P = 0.04). Gemcitabine monotherapy caused fewer complications, including fewer grade 3-4 toxicities: including vomiting (RR, 0.75; 95%CI: 0.62-0.89; P = 0.001), diarrhea (RR, 0.66; 95%CI: 0.49-0.89; P = 0.006), neutropenia (RR, 0.88; 95%CI: 0.72-1.06; P = 0.18), anemia (RR, 0.96; 95%CI: 0.82-1.12; P = 0.60), and thrombocytopenia (RR, 0.76; 95%CI: 0.60-0.97; P = 0.03) compared with gemcitabine combination therapies. CONCLUSION Gemcitabine combination therapy provides a modest improvement of survival, but is associated with more toxicity compared with gemcitabine monotherapy.
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Ciliberto D, Botta C, Correale P, Rossi M, Caraglia M, Tassone P, Tagliaferri P. Role of gemcitabine-based combination therapy in the management of advanced pancreatic cancer: a meta-analysis of randomised trials. Eur J Cancer 2012; 49:593-603. [PMID: 22989511 DOI: 10.1016/j.ejca.2012.08.019] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2012] [Revised: 07/20/2012] [Accepted: 08/19/2012] [Indexed: 01/26/2023]
Abstract
BACKGROUND Pancreatic cancer is the fourth leading cause of cancer-related death worldwide. Gemcitabine is the mainstay treatment for advanced disease. However, almost all up-to-date trials, that evaluated the benefit of gemcitabine-combination schedules, failed to demonstrate an improvement in overall survival (OS). In this study, we performed a systematic review and a meta-analysis of randomised clinical trials (RCTs) to investigate the efficacy and safety of gemcitabine-based combination regimens as compared to gemcitabine alone in the management of pancreatic cancer. METHODS Clinical trials were collected by searching different databases (PubMed, Embase and the Central Registry of Controlled Trials of the Cochrane Library) and abstracts from major cancer meetings. We considered period ranging from January 1997 to January 2012. Primary end-point was OS, secondary end-points were response rate (RR), disease control rate (DCR) and safety. Hazard ratios (HRs) of OS, odds-ratios (ORs) of RR, DCR and risk ratios of grade 3-4 toxicity rates (TRs), were extracted as presented in retrieved studies and used for statistical analysis. Meta-analytic estimates were derived using random-effects model. FINDINGS Thirty-four trials for a total of 10,660 patients were selected and included in the final analysis. The analysis showed that combination chemotherapy confers benefit in terms of OS (HR: 0.93; 95% confidence interval (CI): 0.89-0.97; p=0.001). ORs for both RR and DCR demonstrated a significant advantage for combination therapy (OR for RR: 0.60, 95%CI: 0.47-0.76, p<0.001; OR for DCR: 0.79; 95%CI: 0.66-0.93; p=0.006). Toxicities were more frequent with the combination treatment and significance in terms of risk ratio was reached for diarrhoea (0.53, 95%CI: 0.36-0.79), nausea (0.74, 95%CI: 0.56-0.96), neutropenia (0.71, 95%CI: 0.59-0.85) and thrombocytopenia (0.57, 95%CI: 0.43-0.75). INTERPRETATION The combination chemotherapy as compared to gemcitabine alone significantly improves OS in advanced pancreatic cancer (APC). However, this advantage is marginal whereas the treatment-related toxicity is increased, suggesting the use of gemcitabine-based combination regimens only in selected patient populations. New prospective trials, based on translational approaches and innovative validated biomarkers, are eagerly awaited on this topic.
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Affiliation(s)
- Domenico Ciliberto
- Medical Oncology Unit, Campus Salvatore Venuta, Department of Experimental and Clinical Medicine, ''Magna Graecia'' University and ''Tommaso Campanella'' Cancer Center, Catanzaro, Italy
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Neuzillet C, Hentic O, Rousseau B, Rebours V, Bengrine-Lefèvre L, Bonnetain F, Lévy P, Raymond E, Ruszniewski P, Louvet C, Hammel P. FOLFIRI regimen in metastatic pancreatic adenocarcinoma resistant to gemcitabine and platinum-salts. World J Gastroenterol 2012; 18:4533-41. [PMID: 22969226 PMCID: PMC3435778 DOI: 10.3748/wjg.v18.i33.4533] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2012] [Revised: 03/16/2012] [Accepted: 04/13/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the efficacy and safety of the FOLFIRI regimen in patients with metastatic pancreatic adenocarcinoma (PAC) after the failure of gemcitabine and platinum salts.
METHODS: All consecutive patients with histologically confirmed, metastatic PAC and World Health Organization performance status (PS) ≤ 2 received FOLFIRI-1 [irinotecan 180 mg/m2 on day 1 and leucovorin 400 mg/m2 followed by 5-fluorouracil (5-FU) 400 mg/m2 bolus, then 5-FU 2400 mg/m2 as a 46-h infusion, biweekly] or FOLFIRI-3 (irinotecan 100 mg/m2 on day 1 and leucovorin 400 mg/m2, then 5-FU 2400 mg/m2 as a 46-h infusion and irinotecan 100 mg/m2 repeated on day 3, biweekly) after failure of gemcitabine and platinum-based chemotherapies as a systematic policy in two institutions between January 2005 and May 2010. Tumor response, time to progression (TTP), overall survival rate (OS) and grade 3-4 toxicities were retrospectively studied. Subgroup analyses were performed to search for prognostic factors.
RESULTS: Sixty-three patients (52.4% male, median age 59 years) were analyzed. Among them, 42.9% were PS 0, 38.1% were PS 1 and 19.0% were PS 2. Fifty one patients (81.0%) had liver metastases. Before the FOLFIRI regimen, patients had received 1 line (n = 19), 2 lines (n = 39) or 3 lines (n = 5) of chemotherapy. Median TTP obtained with the line before FOLFIRI was 3.9 mo (95% CI: 3.4-5.3 mo). A total of 480 cycles was completed (median: 6 cycles, range: 1-51 cycles). The main reason for discontinuing FOLFIRI was tumor progression (90.3%). Tumor control was achieved in 25 patients (39.7%) (partial response: n = 5, stable disease: n = 20) with FOLFIRI. Median TTP was 3.0 mo (95% CI: 2.1-3.9 mo) and median OS was 6.6 mo (95% CI: 5.3-8.1 mo). Dose adaptation was required in 36 patients (57.1%). Fifteen patients (23.8%) had grade 3-4 toxicities, mainly hematological (n = 11) or digestive (n = 4). Febrile neutropenia occurred in 3 patients. There was no toxic death. PS 2 was significantly associated with poor TTP [hazard ratio (HR): 16.036, P < 0.0001] and OS (HR: 4.003, P = 0.004).
CONCLUSION: The FOLFIRI regimen had an acceptable toxicity and an interesting efficacy in our study, limited to patients in good condition (PS 0-1).
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Belli C, Cereda S, Reni M. Role of taxanes in pancreatic cancer. World J Gastroenterol 2012; 18:4457-65. [PMID: 22969215 PMCID: PMC3435767 DOI: 10.3748/wjg.v18.i33.4457] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2012] [Revised: 04/09/2012] [Accepted: 04/12/2012] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most deadly cancers and is characterized by a poor prognosis. Single agent gemcitabine, despite its limited activity and modest impact on disease outcome, is considered as the standard therapy in pancreatic cancer. Most of the combination regimens used in the treatment of this disease, also including the targeted agents, did not improve the outcome of patients. Also, taxanes have been tested as single agent and in combination chemotherapy, both in first line and as salvage chemotherapy, as another possible option for treating pancreatic cancer. The inclusion of taxanes in combination with gemcitabine as upfront therapy obtained promising results. Accordingly, taxanes, and above all, new generation taxanes, appear to be suitable candidates for further testing to assess their role against pancreatic cancer in various clinical settings.
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Löhr JM, Haas SL, Bechstein WO, Bodoky G, Cwiertka K, Fischbach W, Fölsch UR, Jäger D, Osinsky D, Prausova J, Schmidt WE, Lutz MP. Cationic liposomal paclitaxel plus gemcitabine or gemcitabine alone in patients with advanced pancreatic cancer: a randomized controlled phase II trial. Ann Oncol 2012; 23:1214-1222. [PMID: 21896540 DOI: 10.1093/annonc/mdr379] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Paclitaxel embedded in cationic liposomes (EndoTAG™-1; ET) is an innovative agent targeting tumor endothelial cells. This randomized controlled phase II trial evaluated the safety and efficacy of ET in combination with gemcitabine (GEM) in advanced pancreatic cancer (PDAC). PATIENTS AND METHODS Chemotherapy-naive patients with locally advanced or metastatic disease were randomly assigned to receive weekly GEM 1000 mg/m(2) or GEM plus twice-weekly ET 11, 22 or 44 mg/m(2) for 7 weeks. After a safety run-in of 100 patients, a second cohort continued treatment. End points included overall survival (OS), progression-free survival (PFS), tumor response and safety. RESULTS Two hundred and twelve patients were randomly allocated to the study and 200 were treated (80% metastatic, 20% locally advanced). Adverse events were manageable and reversible. Transient thrombocytopenia and infusion reactions with chills and pyrexia mostly grade 1 or 2 occurred in the ET groups. Disease control rate after the first treatment cycle was 43% with GEM and 60%, 65% and 52% in the GEM + ET cohorts. Median PFS reached 2.7 compared with 4.1, 4.6 and 4.4 months, respectively. Median OS was 6.8 compared with 8.1, 8.7 and 9.3 months, respectively. CONCLUSIONS Treatment of advanced PDAC with GEM + ET was generally well tolerated. GEM + ET showed beneficial survival and efficacy. A randomized phase III trial should confirm this positive trend.
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Affiliation(s)
- J M Löhr
- Department of Medicine II, University Hospital Mannheim, Mannheim, Germany; Department of Surgical Gastroenterology, Karolinska Institutet, Stockholm, Sweden.
| | - S L Haas
- Department of Medicine II, University Hospital Mannheim, Mannheim, Germany; Department of Surgical Gastroenterology, Karolinska Institutet, Stockholm, Sweden
| | - W-O Bechstein
- Department of General and Visceral Surgery, University Hospital Frankfurt, Frankfurt/Main, Germany
| | - G Bodoky
- Department of Oncology, Szent Laszlo Hospital, Budapest, Hungary
| | - K Cwiertka
- Department of Oncology, University Hospital Olomouc, Olomouc, Czech Republic
| | - W Fischbach
- Department of Medicine II, Klinikum Aschaffenburg, Aschaffenburg
| | - U R Fölsch
- Department of General Internal Medicine, University Hospital Schleswig-Holstein, Kiel
| | - D Jäger
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - D Osinsky
- Institute of Oncology AMS of Ukraine, Kiev, Ukraine
| | - J Prausova
- Department of Oncological Radiotherapy, University Hospital Prague, Prague, Czech Republic
| | - W E Schmidt
- Department of Medicine I, St. Josef-Hospital, Ruhr-University, Bochum
| | - M P Lutz
- Department of Medicine, Caritasklinik St. Theresia, Saarbrücken, Germany
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Páez D, Labonte MJ, Lenz HJ. Pancreatic cancer: medical management (novel chemotherapeutics). Gastroenterol Clin North Am 2012; 41:189-209. [PMID: 22341258 DOI: 10.1016/j.gtc.2011.12.004] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Pancreatic adenocarcinoma is the fourth leading cause of cancer death and has an extremely poor prognosis: The 5-year survival probability is less than 5% for all stages. The only chance for cure or longer survival is surgical resection; however, only 10% to 20% of patients have resectable disease. Although surgical techniques have improved, most who undergo complete resection experience a recurrence. Adjuvant systemic therapy reduces the recurrence rate and improves outcomes. There is a potential role for radiation therapy as part of treatment for locally advanced disease, although its use in both the adjuvant and neoadjuvant settings remains controversial. Palliative systemic treatment is the only option for patients with metastatic disease. To date, however, only the gemcitabine plus erlotinib combination, and recently the FOLFIRINOX regimen, have been associated with relatively small but statistically significant improvements in OS when compared directly with gemcitabine alone. Although several meta-analyses have suggested a benefit associated with combination chemotherapy, whether this benefit is clinically meaningful remains unclear, particularly in light of the enhanced toxicity associated with combination regimens. There is growing evidence that the exceptionally poor prognosis in PC is caused by the tumor's characteristic abundant desmoplastic stroma that plays a critical role in tumor cell growth, invasion, metastasis, and chemoresistance. Carefully designed clinical trials that include translational analysis will provide a better understanding of the tumor biology and its relation to the host stromal cells. Future directions will involve testing of new targeted agents, understanding the pharmacodynamics of our current targeted agents, searching for predictive and prognostic biomarkers, and exploring the efficacy of different combinations strategies.
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Affiliation(s)
- David Páez
- Division of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Keck School of Medicine, Los Angeles, CA 90033, USA
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