|
1
|
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 SEARCH METHODS We searched for published and unpublished studies in CENTRAL, MEDLINE, Embase, and CANCERLIT, and handsearched various sources for additional studies.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.
Collapse
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
| |
Collapse
|
|
2
|
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
| |
Collapse
|
|
3
|
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.
Collapse
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
| |
Collapse
|
|
4
|
Weng W, Hong J, Owusu-Ansah KG, Chen B, Zheng S, Jiang D. Pralatrexate mediates effective killing of gemcitabine-resistant pancreatic cancer: role of mTOR/4E-BP1 signal pathway. Heliyon 2022; 8:e12064. [PMID: 36544829 PMCID: PMC9761725 DOI: 10.1016/j.heliyon.2022.e12064] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Revised: 11/07/2022] [Accepted: 11/25/2022] [Indexed: 12/12/2022] Open
Abstract
Gemcitabine is the first-line chemotherapeutic agent for pancreatic cancer. However, gemcitabine-resistance frequently leads to poor prognosis. Exploring new chemotherapeutic agents is important for patients with gemcitabine-resistant pancreatic cancer. In this study, we established a new acquired gemcitabine-resistant pancreatic cancer cell line BxPC-GEM-20 from parental BxPC-3. We found that pralatrexate significantly inhibited the growth of BxPC-GEM-20. The half-maximal inhibitory concentration of pralatrexate on BxPC-GEM-20 cell was about 3.43 ± 0.25 nM. Pralatrexate was found to effectively inhibit the clonal growth of BxPC-GEM-20 cell. Additionally, pralatrexate at 20 mg/kg had an excellent tumor inhibitory effect with an inhibitory rate of 76.92% in vivo. This pralatrexate therapy showed good safety profile that with little to no additional influence on the hepatic, renal function as well as body weight changes in nude mice. Pralatrexate was confirmed to prevent cells from entering the G2/M phase, leading to the promotion of apoptosis and autophagy. Further analysis demonstrated that the reduced phosphorylation of mTOR played a significant role in the tumor cell damage caused by pralatrexate. Pralatrexate effectively inhibited the mTOR/4E-BP1 pathway. Activation of mTOR pathway can further obstruct the repressive effect of pralatrexate on gemcitabine-resistant pancreatic cancer. In summary, pralatrexate induces effective inhibition of gemcitabine-resistant pancreatic cancer. This may lead to the expansion of pralatrexate's application and offer benefit to gemcitabine-resistant pancreatic cancer patients in the future.
Collapse
Affiliation(s)
- Wanwen Weng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China,NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China,Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China,Department of Nuclear Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jiawei Hong
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China,NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China,Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China
| | - Kwabena G. Owusu-Ansah
- Department of Internal Medicine, St. Elizabeth Youngstown Hospital, Youngstown, OH, USA,Department of Medicine, Northeastern Ohio Medical University, Rootstown, OH, USA
| | - Bingjie Chen
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China,NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China,Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China,NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China,Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China,Corresponding author.
| | - Donghai Jiang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China,NHC Key Laboratory of Combined Multi-organ Transplantation, Hangzhou 310003, China,Key Laboratory of the Diagnosis and Treatment of Organ Transplantation, Research Unit of Collaborative Diagnosis and Treatment for Hepatobiliary and Pancreatic Cancer, Chinese Academy of Medical Sciences (2019RU019), Hangzhou 310003, China,Key Laboratory of Organ Transplantation, Research Center for Diagnosis and Treatment of Hepatobiliary Diseases, Zhejiang Province, Hangzhou 310003, China,Corresponding author.
| |
Collapse
|
|
5
|
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
| |
Collapse
|
|
6
|
Alzhrani R, Alsaab HO, Vanamal K, Bhise K, Tatiparti K, Barari A, Sau S, Iyer AK. Overcoming the Tumor Microenvironmental Barriers of Pancreatic Ductal Adenocarcinomas for Achieving Better Treatment Outcomes. ADVANCED THERAPEUTICS 2021; 4:2000262. [PMID: 34212073 PMCID: PMC8240487 DOI: 10.1002/adtp.202000262] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with the lowest survival rate among all solid tumors. The lethality of PDAC arises from late detection and propensity of the tumor to metastasize and develop resistance against chemo and radiation therapy. A highly complex tumor microenvironment composed of dense stroma, immune cells, fibroblast, and disorganized blood vessels, is the main obstacle to current PDAC therapy. Despite the tremendous success of immune checkpoint inhibitors (ICIs) in cancers, PDAC remains one of the poorest responders of ICIs therapy. The immunologically "cold" phenotype of PDAC is attributed to the low mutational burden, high infiltration of myeloid-derived suppressor cells and T-regs, contributing to a significant immunotherapy resistance mechanism. Thus, the development of innovative strategies for turning immunologically "cold" tumor into "hot" ones is an unmet need to improve the outcome of PDAC ICIs therapies. Other smart strategies, such as nanomedicines, sonic Hedgehog inhibitor, or smoothened inhibitor, are discussed to enhance chemotherapeutic agents' efficiency by disrupting the PDAC stroma. This review highlights the current challenges and various preclinical and clinical strategies to overcome current PDAC therapy difficulties, thus significantly advancing PDAC research knowledge.
Collapse
Affiliation(s)
- Rami Alzhrani
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
- Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taif University, Taif 21944, Saudi Arabia
| | - Hashem O. Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taif University, Taif 21944, Saudi Arabia
| | - Kushal Vanamal
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
| | - Ketki Bhise
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
| | - Katyayani Tatiparti
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
| | - Ayatakshi Barari
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
| | - Samaresh Sau
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
| | - Arun K. Iyer
- Use-Inspired Biomaterials and Integrated Nano Delivery Systems Laboratory, Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit 48201, United States
- Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, MI, United States
| |
Collapse
|
|
7
|
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.
Collapse
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.
| |
Collapse
|
|
8
|
Lai Benjamin FL, Lu Rick X, Hu Y, Davenport HL, Dou W, Wang EY, Radulovich N, Tsao MS, Sun Y, Radisic M. Recapitulating pancreatic tumor microenvironment through synergistic use of patient organoids and organ-on-a-chip vasculature. ADVANCED FUNCTIONAL MATERIALS 2020; 30:2000545. [PMID: 33692660 PMCID: PMC7939064 DOI: 10.1002/adfm.202000545] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
Tumor progression relies heavily on the interaction between the neoplastic epithelial cells and their surrounding stromal partners. This cell cross-talk affects stromal development, and ultimately the heterogeneity impacts drug efflux and efficacy. To mimic this evolving paradigm, we have micro-engineered a three-dimensional (3D) vascularized pancreatic adenocarcinoma tissue in a tri-culture system composed of patient derived pancreatic organoids, primary human fibroblasts and endothelial cells on a perfusable InVADE platform situated in a 96-well plate. Uniquely, through synergistic engineering we combined the benefits of cellular fidelity of patient tumor derived organoids with the addressability of a plastic organ-on-a-chip platform. Validation of this platform included demonstrating the growth of pancreatic tumor organoids by monitoring the change in metabolic activity of the tissue. Investigation of tumor microenvironmental behavior highlighted the role of fibroblasts in symbiosis with patient organoid cells, resulting in a six-fold increase of collagen deposition and a corresponding increase in tissue stiffness in comparison to fibroblast free controls. The value of a perfusable vascular network was evident in drug screening, as perfusion of gemcitabine into a stiffened matrix did not show the dose-dependent effects on tumor viability as those under static conditions. These findings demonstrate the importance of studying the dynamic synergistic relationship between patient cells with stromal fibroblasts, in a 3D perfused vascular network, to accurately understand and recapitulate the tumor microenvironment.
Collapse
Affiliation(s)
- F L Lai Benjamin
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
| | - X Lu Rick
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
| | - Yangshuo Hu
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada
| | - Huyer Locke Davenport
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada
- Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Wenkun Dou
- Material Science and Engineering, University of Toronto, Toronto, Ontario, Canada
| | - Erika Y Wang
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
| | - Nikolina Radulovich
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Ming S Tsao
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Yu Sun
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
- Material Science and Engineering, University of Toronto, Toronto, Ontario, Canada
| | - Milica Radisic
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada
- Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
| |
Collapse
|
|
9
|
Chinnaiyan SK, Soloman AM, Perumal RK, Gopinath A, Balaraman M. 5 Fluorouracil-loaded biosynthesised gold nanoparticles for the in vitro treatment of human pancreatic cancer cell. IET Nanobiotechnol 2020; 13:824-828. [PMID: 31625522 DOI: 10.1049/iet-nbt.2019.0007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
In this study, green synthesis of gold nanoparticles (AuNPs) was performed by a sunlight irradiation method using the Borassus flabellifer fruit extract as a reducing agent. 5-Fluorouracil (5-FU)-loaded GG capped AuNPs (5FU-G-AuNPs) was prepared. The nanoparticles was further characterised by UV-visible spectra, particle size analysis, zeta potential, SAED, HRTEM, and XRD. The MTT assay results showed the suitability 5-FU-G-AuNPs. In this study, 5-FU-G-AuNPs exhibited potential cytotoxic and apoptotic effects on (MiaPaCa-2) cell line.
Collapse
Affiliation(s)
| | - Agnes Mary Soloman
- CSIR-Central Leather Research Institute, Chennai 600 020, Tamil Nadu, India
| | | | - Arun Gopinath
- CSIR-Central Leather Research Institute, Chennai 600 020, Tamil Nadu, India
| | - Madhan Balaraman
- CSIR-Central Leather Research Institute, Chennai 600 020, Tamil Nadu, India.
| |
Collapse
|
|
10
|
Abstract
OBJECTIVES We evaluated how well phase II trials in locally advanced and metastatic pancreatic cancer (LAMPC) meet current recommendations for trial design. METHODS We conducted a systematic review of phase II first-line treatment trial for LAMPC. We assessed baseline characteristics, type of comparison, and primary end point to examine adherence to the National Cancer Institute recommendations for trial design. RESULTS We identified 148 studies (180 treatment arms, 7505 participants). Forty-seven (32%) studies adhered to none of the 5 evaluated National Cancer Institute recommendations, 62 (42%) followed 1, 31 (21%) followed 2, and 8 (5%) followed 3 recommendations. Studies varied with respect to the proportion of patients with good performance status (range, 0%-80%) and locally advanced disease (range, 14%-100%). Eighty-two (55%) studies concluded that investigational agents should progress to phase III testing; of these, 24 (16%) had documented phase III trials. Three (8%) phase III trials demonstrated clinically meaningful improvements for investigational agents. One of 38 phase II trials that investigated biological investigational agents was enriched for a biomarker. CONCLUSIONS Phase II trials do not conform well to current recommendations for trial design in LAMPC.
Collapse
|
|
11
|
Tesfaye AA, Wang H, Hartley ML, He AR, Weiner L, Gabelia N, Kapanadze L, Shezad M, Brody JR, Marshall JL, Pishvaian MJ. A Pilot Trial of Molecularly Tailored Therapy for Patients with Metastatic Pancreatic Ductal Adenocarcinoma. J Pancreat Cancer 2019; 5:12-21. [PMID: 31065624 PMCID: PMC6503449 DOI: 10.1089/pancan.2019.0003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Purpose: Despite the wide adoption of tumor molecular profiling, there is a dearth of evidence linking molecular biomarkers for treatment selection to prediction of treatment outcomes in patients with metastatic pancreatic cancer. We initiated a pilot study to test the feasibility of designing a larger phase II trial of molecularly tailored treatment for metastatic pancreatic cancer. Methods: Our study aimed to assess the feasibility of following a treatment algorithm based on the expression of three published predictive markers of response to chemotherapy: ribonucleotide reductase catalytic subunit M1 (for gemcitabine); excision repair cross-complementation group 1 (for platinum agents); and thymidylate synthase (for 5-fluorouracil) in patients with untreated, metastatic pancreatic cancer. Results of the tumor biopsy analysis were used to assign patients to one of seven doublet regimens. Key secondary objectives included response rate (RR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results: Between December 2012 and March 2015, 30 patients were enrolled into the study. Ten patients failed screening primarily due to inadequate tumor tissue availability. Of the remaining 20 patients, 19 were assigned into 6 different chemotherapy doublets, and achieved an RR of 28%, with a DCR rate of 78%. The median PFS and OS were 5.78 and 8.21 months, respectively. Conclusions: The incorporation of biomarkers into a treatment algorithm is feasible and resulted in a PFS and OS similar to other doublet therapies for patients with metastatic pancreatic cancer. Based on the results from this pilot study, a larger phase II randomized trial of molecularly targeted therapy versus physicians' choice of standard of care has been initiated in the second-line setting (NCT02967770).
Collapse
Affiliation(s)
- Anteneh A Tesfaye
- Karmanos Cancer Institute, Wayne State University, Detroit, Michigan
| | - Hongkun Wang
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
| | - Marion L Hartley
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
| | - Aiwu Ruth He
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
| | - Louis Weiner
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
| | - Nina Gabelia
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
| | - Lana Kapanadze
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
| | - Muhammad Shezad
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
| | - Jonathan R Brody
- Department of Surgery, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - John L Marshall
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
| | - Michael J Pishvaian
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, District of Columbia
| |
Collapse
|
|
12
|
Chou WC, Chen YY, Hung CY, Chen JS, Lu CH, Chang PH. Evolution of the chemotherapeutic landscape and survival outcome in patients with metastatic pancreatic cancer: a four-institute cohort study in Taiwan, 2010-2016. Cancer Manag Res 2019; 11:2119-2127. [PMID: 30936744 PMCID: PMC6421872 DOI: 10.2147/cmar.s196300] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Only 5-fluorouracil (5-FU), cisplatin, and gemcitabine have been reimbursed for metastatic pancreatic cancer (mPC) treatment in Taiwan since 2003. It is uncertain whether the reimbursement of S-1 in June 2014 might change the treatment pattern and improve the survival of mPC patients in Taiwan. PATIENTS AND METHODS A total of 645 patients with newly diagnosed mPC who received palliative chemotherapy between 2010 and 2016 in Taiwan were analyzed retrospectively. Patients were stratified according to year at diagnosis of mPC for analysis of chemotherapeutic treatment pattern and survival. RESULTS Overall, the most common chemotherapeutic agents used for the treatment of mPC were gemcitabine (94.8%), followed by cisplatin (52.4%), S-1 (38.1%), and 5-FU (29.7%). The percentage of patients treated with S-1 between 2010 and 2016 increased from 2.6% to 74.0% (P<0.001), while the percentage of patients treated with 5-FU decreased from 31.6% to 21.2% (P<0.001). The percentage of patients treated with gemcitabine, cisplatin, etc. remained consistent. An increase in the number of lines of treatment was observed throughout the study period, with 27.6% of patients receiving two or more lines of treatment in 2010, compared with 50.0% of patients in 2016 (P=0.013). The 12-month survival rate increased from 11.8% in 2010 to 41.4% in 2016, corresponding to an adjusted average annual percent change of 13.6% (0.3-28.7, P<0.05). CONCLUSION Based on this multi-institute cohort study in Taiwan, the reimbursement of S-1 changed the clinical practice and is associated with an improvement in survival outcome of mPC patients.
Collapse
Affiliation(s)
- Wen-Chi Chou
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou and Chang Gung University College of Medicine, Taoyuan, Taiwan,
| | - Yen-Yang Chen
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Kaohsiung, Kaohsiung, Taiwan
| | - Chia-Yen Hung
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou and Chang Gung University College of Medicine, Taoyuan, Taiwan,
- Division of Hematology-Oncology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan
| | - Jen-Shi Chen
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou and Chang Gung University College of Medicine, Taoyuan, Taiwan,
| | - Chang-Hsien Lu
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Chiayi, Chiayi, Taiwan
| | - Pei-Hung Chang
- Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan
| |
Collapse
|
|
13
|
Zhang S, Xie W, Zou Y, Xie S, Zhang J, Yuan W, Ma J, Zhao J, Zheng C, Chen Y, Wang C. First-line chemotherapy regimens for locally advanced and metastatic pancreatic adenocarcinoma: a Bayesian analysis. Cancer Manag Res 2018; 10:5965-5978. [PMID: 30538546 PMCID: PMC6254987 DOI: 10.2147/cmar.s162980] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Background Systemic chemotherapy is the standard treatment for locally advanced and metastatic pancreatic cancer, but there is no consensus on the optimum regimen. We aimed to compare and rank the locally advanced and metastatic pancreatic adenocarcinoma chemotherapy regimens evaluated in randomized controlled trials (RCTs) in the past 15 years. Materials and methods PubMed, Embase, Cochrane Collaboration database, and ClinicalTrials.gov were searched for RCTs comparing chemotherapy regimens as first-line treatment for locally advanced and metastatic pancreatic adenocarcinomas. By using Bayesian network meta-analysis, we compared and ranked all included chemotherapy regimens in terms of overall survival, progression-free survival, response rate, and hematological toxicity. Results The analysis included 68 RCTs, with 14,908 patients and 63 treatment strategies. For overall survival, NSC-631570 (hazard ratio [HR] vs gemcitabine monotherapy 0.44, 95% credible interval: 0.24–0.76) and gemcitabine+NSC-631570 (HR 0.45, 0.24–0.86) were the two top-ranked chemotherapy regimens. For progression-free survival, PEFG (cisplatin + epirubicin + fluorouracil + gemcitabine) ranked first (HR 0.51, 0.34–0.77). PG (gemcitabine + pemetrexed) (odds ratio [OR] 4.68, 2.24–9.64) and FLEC (fluorouracil + leucovorin + epirubicin + carboplatin) (OR 4.52, 1.14–24.00) were ranked the most hematologically toxic, with gastrazole having the least toxicity (OR 0.03, 0.00–0.46). Conclusion The chemotherapy regimens NSC-631570 and gemcitabine+NSC-631570 were ranked the most efficacious for locally advanced and metastatic pancreatic adenocarcinomas in terms of overall survival, which warrants further confirmation in large-scale RCTs.
Collapse
Affiliation(s)
- Shuisheng Zhang
- Department of Pancreatic and Gastric Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, ; .,Department of General Surgery, Peking University Third Hospital
| | - Weimin Xie
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital
| | - Yinghua Zou
- Department of Interventional Radiology and Vascular Surgery, Peking University First Hospital
| | - Shuanghua Xie
- Department of Cancer Epidemiology and Health Statistics
| | - Jianwei Zhang
- Department of Pancreatic and Gastric Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, ;
| | - Wei Yuan
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.,Clinical Immunology Center, Chinese Academy of Medical Science
| | - Jie Ma
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.,Clinical Immunology Center, Chinese Academy of Medical Science.,Department of Biotherapy, Beijing Hospital, National Center of Gerontology, Beijing
| | - Jiuda Zhao
- Department of Medical Oncology, Affiliated Hospital of Qinghai University, Xining
| | - Cuiling Zheng
- Department of Clinical Laboratory, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yingtai Chen
- Department of Pancreatic and Gastric Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, ;
| | - Chengfeng Wang
- Department of Pancreatic and Gastric Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, ;
| |
Collapse
|
|
14
|
Olson JL, Bold RJ. Currently available first-line drug therapies for treating pancreatic cancer. Expert Opin Pharmacother 2018; 19:1927-1940. [PMID: 30325679 DOI: 10.1080/14656566.2018.1509954] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Pancreatic adenocarcinoma is the 9th most common cancer in the United States and the 4th most common cause of cancer-related death given its poor prognosis. AREAS COVERED The authors have performed a literature search for pertinent published clinical trials, ongoing Phase 3 clinical trials, and current treatment guidelines using PubMed, Clinicaltrials.gov, and NCCN, ASCO, ESMO, and JPS websites. The review itself discusses landmark studies and ongoing research into the chemotherapy regimens recommended by each oncologic society. The authors also examine drugs that were promising but failed in Phase 3 trials and those currently being investigated. Finally, the authors provide their expert opinion on the subject and provide their future perspectives. EXPERT OPINION While advances in chemotherapy for pancreatic cancer have been limited in comparison to other cancers, there have been improvements in survival. Combination therapy and a goal of R0 resection are key elements to extend life. Novel agents directed at the unique properties of pancreatic cancer are promising.
Collapse
Affiliation(s)
- Jennifer L Olson
- a Division of Surgical Oncology , UC Davis Cancer Center , Sacramento , CA , USA
| | - Richard J Bold
- a Division of Surgical Oncology , UC Davis Cancer Center , Sacramento , CA , USA
| |
Collapse
|
|
15
|
Wang K, Baldwin GS, Nikfarjam M, He H. p21-activated kinase signalling in pancreatic cancer: New insights into tumour biology and immune modulation. World J Gastroenterol 2018; 24:3709-3723. [PMID: 30197477 PMCID: PMC6127653 DOI: 10.3748/wjg.v24.i33.3709] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 06/22/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most aggressive and lethal malignancies worldwide, with a very poor prognosis and a five-year survival rate less than 8%. This dismal outcome is largely due to delayed diagnosis, early distant dissemination and resistance to conventional chemo-therapies. Kras mutation is a well-defined hallmark of pancreatic cancer, with over 95% of cases harbouring Kras mutations that give rise to constitutively active forms of Kras. As important down-stream effectors of Kras, p21-activated kinases (PAKs) are involved in regulating cell proliferation, apoptosis, invasion/migration and chemo-resistance. Immunotherapy is now emerging as a promising treatment modality in the era of personalized anti-cancer therapeutics. In this review, basic knowledge of PAK structure and regulation is briefly summarised and the pivotal role of PAKs in Kras-driven pancreatic cancer is highlighted in terms of tumour biology and chemo-resistance. Finally, the involvement of PAKs in immune modulation in the tumour microenvironment is discussed and the potential advantages of targeting PAKs are explored.
Collapse
Affiliation(s)
- Kai Wang
- Department of Surgery, University of Melbourne, Melbourne 3084, Australia
| | - Graham S Baldwin
- Department of Surgery, University of Melbourne, Melbourne 3084, Australia
| | - Mehrdad Nikfarjam
- Department of Surgery, University of Melbourne, Melbourne 3084, Australia
| | - Hong He
- Department of Surgery, University of Melbourne, Melbourne 3084, Australia
| |
Collapse
|
|
16
|
Tiwari A, Kumar L. Pancreatic ductal adenocarcinoma: Role of chemotherapy & future perspectives. Indian J Med Res 2018; 148:254-257. [PMID: 30425214 PMCID: PMC6251265 DOI: 10.4103/ijmr.ijmr_615_18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Affiliation(s)
- Akash Tiwari
- Department of Medical Oncology, Dr BRA-Institute Rotary Cancer Hospital (IRCH), All India Institute of Medical Sciences, New Delhi 110 029, India
| | - Lalit Kumar
- Department of Medical Oncology, Dr BRA-Institute Rotary Cancer Hospital (IRCH), All India Institute of Medical Sciences, New Delhi 110 029, India
| |
Collapse
|
|
17
|
Wang XF, Huang WF, Nie J, Zhou Y, Tan DW, Jiang JH. Toxicity of chemotherapy regimens in advanced and metastatic pancreatic cancer therapy: A network meta-analysis. J Cell Biochem 2018; 119:5082-5103. [PMID: 28681936 DOI: 10.1002/jcb.26266] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Accepted: 07/05/2017] [Indexed: 02/06/2023]
Abstract
This network meta-analysis is adopted in order to compare the toxicity of different chemotherapy regimens in the treatment of advanced/metastatic pancreatic cancer (PC). Randomized controlled trials (RCTs) about different chemotherapy regimens for advanced/metastatic PC were included in this network meta-analysis using Cochrane Library and PubMed electronic databases. The network meta-analysis was performed to combine direct and indirect evidence in order to calculate the odd ratios (OR) and draw a surface under the cumulative ranking (SUCRA) curve. A total of 19 RCTs were enrolled in this network meta-analysis including 12 chemotherapy regimens (Gemcitabine, Gemcitabine + S-1 [tegafur], Gemcitabine + nab-paclitaxel, Gemcitabine + Capecitabine, Gemcitabine + Cisplatin, FOLFIRINOX [oxaliplatin + irinotecan + fluorouracil + leucovorin], Gemcitabine + oxaliplatin, Gemcitabine + irinotecan, Gemcitabine + Exatecan, Gemcitabine + pemetrexed, Gemcitabine + 5-FU, S-1). The incidence of anemia of Gemcitabine + Capecitabine regimen was higher compared with Gemcitabine regimen, Gemcitabine + pemetrexed regimen exhibited the highest incidence rates of anemia and neutropenia; while Gemcitabine + S-1, Gemcitabine + Cisplatin and FOLFIRINOX regimens exhibited the highest incidence rates of neutropenia. However, S-1 regimen exhibited lower incidence rates of leukopenia and thrombocytopenia. Moreover, the incidence rates of nausea/vomiting and rash of Gemcitabine + S-1 regimen were higher compared with Gemcitabine regimen, while Gemcitabine + Cisplatin regimen had the highest incidence rate of nausea/vomiting. This study demonstrated that the hematologic toxicity of S-1 regimen was the lowest, while Gemcitabine regimen exhibited the lowest incidence rate of non-hematologic toxicity, providing guidance for the treatment of advanced/metastatic PC.
Collapse
Affiliation(s)
- Xiao-Fang Wang
- Department of Hepatobiliary Surgery, Jiangxi Pingxiang People's Hospital, Pingxiang, P. R. China
| | - Wen-Feng Huang
- Department of Hepatobiliary Surgery, Jiangxi Pingxiang People's Hospital, Pingxiang, P. R. China
| | - Jian Nie
- Department of Hepatobiliary Surgery, Jiangxi Pingxiang People's Hospital, Pingxiang, P. R. China
| | - Yong Zhou
- Department of Hepatobiliary Surgery, Jiangxi Pingxiang People's Hospital, Pingxiang, P. R. China
| | - Ding-Wu Tan
- Department of Hepatobiliary Surgery, Jiangxi Pingxiang People's Hospital, Pingxiang, P. R. China
| | - Ji-Hao Jiang
- Department of Hepatobiliary Surgery, Jiangxi Pingxiang People's Hospital, Pingxiang, P. R. China
| |
Collapse
|
|
18
|
Zhang SH, Liu GF, Li XF, Liu L, Yu SN. Efficacy of different chemotherapy regimens in treatment of advanced or metastatic pancreatic cancer: A network meta-analysis. J Cell Physiol 2018; 233:3352-3374. [PMID: 28926090 DOI: 10.1002/jcp.26183] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Accepted: 09/12/2017] [Indexed: 12/13/2022]
Abstract
We performed a network meta-analysis (NMA) to compare the short- and long-term efficacy of Gemcitabine, Gemcitabine + S-1 (tegafur), Gemcitabine + nab-paclitaxel, Gemcitabine + Capecitabine, Gemcitabine + Cisplatin, FOLFIRINOX (oxaliplatin + irinotecan + fluorouracil + leucovorin), Gemcitabine + oxaliplatin, Gemcitabine + irinotecan, Gemcitabine + Exatecan, Gemcitabine + pemetrexed, Gemcitabine + 5-FU, and S-1 in treating advanced or metastatic pancreatic cancer (PC). The odds radios (OR) or weighted mean difference (WMD) and surface under the cumulative ranking curves (SUCRA) were evaluated by a combination of direct evidence and indirect evidence. In total twenty studies were included in this paper. For short-term efficacy, the overall response rate (ORR) was lower for patients treated with Gemcitabine compared with Gemcitabine + S-1, Gemcitabine + Cisplatin, Gemcitabine + irinotecan and S-1. The ORR for FOLFIRINOX was higher compared with Gemcitabine, Gemcitabine + Capecitabine and Gemcitabine + Cisplatin. The disease control rate (DCR) for Gemcitabine was lower compared with Gemcitabine + S-1, Gemcitabine + Cisplatin, and FOLFIRINOX. For long-term efficacy, the 12-month overall survival (OS) rate for FOLFIRINOX was higher compared with Gemcitabine, Gemcitabine + Capecitabine, Gemcitabine + Cisplatin, Gemcitabine + irinotecan, Gemcitabine + Exatecan, and Gemcitabine + pemetrexed. The SUCRA revealed that FOLFIRINOX was relatively better in both short- and long-term efficacy, while Gemcitabine was relatively poorer. In both short- and long-term efficacy, FOLFIRINOX had the best short- and long-term efficacy among the 12 chemotherapy regimens while efficacy of Gemcitabine was relatively poorer in the treatment of advanced or metastatic PC.
Collapse
Affiliation(s)
- Shu-Hua Zhang
- Department of Operating Room, China-Japan Union Hospital of Jilin University, Changchun, P. R. China
| | - Gui-Feng Liu
- Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun, P. R. China
| | - Xue-Feng Li
- Department of Anesthesiology, China-Japan Union Hospital of Jilin University, Changchun, P. R. China
| | - Lin Liu
- Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun, P. R. China
| | - Shao-Nan Yu
- Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun, P. R. China
| |
Collapse
|
|
19
|
Chin V, Nagrial A, Sjoquist K, O'Connor CA, Chantrill L, Biankin AV, Scholten RJPM, Yip D. 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: 56] [Impact Index Per Article: 8.0] [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.
Collapse
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
| | | |
Collapse
|
|
20
|
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.
Collapse
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.
| |
Collapse
|
|
21
|
Defining Eligibility of FOLFIRINOX for First-Line Metastatic Pancreatic Adenocarcinoma (MPC) in the Province of British Columbia: A Population-based Retrospective Study. Am J Clin Oncol 2017; 40:552-554. [PMID: 26165420 DOI: 10.1097/coc.0000000000000205] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND FOLFIRINOX is a first-line treatment option for patients with metastatic pancreatic cancer (MPC) and is associated with improved survival yet significantly more toxicities than standard gemcitabine. Our aim was to determine the proportion of patients with MPC who would be eligible for FOLFIRINOX based upon the pivotal ACCORD study criteria. METHODS Patients with confirmed MPC at the time of referral to the BC Cancer Agency between 2004 and 2007 were identified from the Gastrointestinal Cancers Outcomes Unit Database (GICOU). Proportion of patients that met the ACCORD study eligibility criteria was determined by chart review. Criteria for FOLFIRINOX exclusion were assessed using descriptive statistics. RESULTS A total of 100 consecutive patients with complete chart records and MPC were identified. Fifty-two (52%) were male and the median age was 68 years (range, 42 to 98 y). The most common sites of metastases were liver (63%) and peritoneum (22%). Only 26 patients fulfilled the ACCORD study eligibility criteria. The most common reasons for FOLIFIRINOX exclusion per ACCORD were poor Eastern Cooperative Oncology Group score of ≥2 (64%), age of 76 years or greater (22%), elevated bilirubin (22%), and inadequate renal function (6%). CONCLUSIONS Despite the proven survival benefit of FOLFIRINOX, only approximately one quarter of patients in the real-world setting with MPC would have been considered eligible for such therapy based upon the ACCORD eligibility criteria. Careful patient selection and more tolerable therapies are required.
Collapse
|
|
22
|
Liu GF, Li GJ, Zhao H. Efficacy and Toxicity of Different Chemotherapy Regimens in the Treatment of Advanced or Metastatic Pancreatic Cancer: A Network Meta-Analysis. J Cell Biochem 2017; 119:511-523. [PMID: 28608558 DOI: 10.1002/jcb.26210] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 06/12/2017] [Indexed: 12/29/2022]
Abstract
Objective A network meta-analysis was conducted to compare the efficacy and toxicity of different chemotherapy regimens in treating advanced or metastatic pancreatic cancer (PC). PubMed, Cochrane Library and EMBASE databases from inception to June 2016 were searched. A combination of direct and indirect evidences was referred to for calculating the weighted mean difference (WMD) or the odds ratio (OR) and to establish surface under the cumulative ranking (SUCRA) curves, so as to evaluate the efficacy and toxicity of different chemotherapy regimens in treating advanced or metastatic PC. Twenty randomized controlled trials were enrolled. Twelve chemotherapy regimens included Gemcitabine, S-1 (Tegafur), Gemcitabine + Cisplatin, Gemcitabine + Capecitabine, Gemcitabine + S-1, Gemcitabine + 5-FU (5-fluorouracil), Gemcitabine + Exatecan, Gemcitabine + Irinotecan, Gemcitabine + Nab-paclitaxel, FOLFIRINOX (Oxaliplatin + Irinotecan + Fluorouracil + Leucovorin), Gemcitabine + Oxaliplatin, and Gemcitabine + Pemetrexed. Higher overall response rate (ORR) was observed in patients treated with the gemcitabine + S-1 and FOLFIRINO regimens. Thrombocytopenia reduced in patients treated with the S-1 regimen. The Gemcitabine + S-1 and FOLFIRINO regimens had better short- and long-term efficacies than the other regimens; S-1 regimen had the lowest hematologic toxicity, while Gemcitabine + Nab-paclitaxel, FOLFIRINOX, and Gemcitabine + Pemetrexed regimens had higher incidence of non-hematologic toxicity among twelve chemotherapy regimens. The efficacy of Gemcitabine + S-1 and FOLFIRINOX regimens may be better in treating patients with advanced or metastatic pancreatic cancer, while FOLFIRINOX and Gemcitabine + Pemetrexed regimens may have relatively higher incidence of toxicity than other regimens. J. Cell. Biochem. 119: 511-523, 2018. © 2017 Wiley Periodicals, Inc.
Collapse
Affiliation(s)
- Gui-Feng Liu
- Department of Radiology, China-Japan Union Hospital of Jilin University, Changchun 130033, P.R. China
| | - Gui-Jie Li
- Department of ENT, China-Japan Union Hospital of Jilin University, Changchun 130033, P.R. China
| | - Hang Zhao
- Department of Neurosurgery, China-Japan Union Hospital of Jilin University, Changchun 130033, P.R. China
| |
Collapse
|
|
23
|
Adamska A, Domenichini A, Falasca M. Pancreatic Ductal Adenocarcinoma: Current and Evolving Therapies. Int J Mol Sci 2017; 18:E1338. [PMID: 28640192 PMCID: PMC5535831 DOI: 10.3390/ijms18071338] [Citation(s) in RCA: 412] [Impact Index Per Article: 51.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Revised: 06/01/2017] [Accepted: 06/13/2017] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), which constitutes 90% of pancreatic cancers, is the fourth leading cause of cancer-related deaths in the world. Due to the broad heterogeneity of genetic mutations and dense stromal environment, PDAC belongs to one of the most chemoresistant cancers. Most of the available treatments are palliative, with the objective of relieving disease-related symptoms and prolonging survival. Currently, available therapeutic options are surgery, radiation, chemotherapy, immunotherapy, and use of targeted drugs. However, thus far, therapies targeting cancer-associated molecular pathways have not given satisfactory results; this is due in part to the rapid upregulation of compensatory alternative pathways as well as dense desmoplastic reaction. In this review, we summarize currently available therapies and clinical trials, directed towards a plethora of pathways and components dysregulated during PDAC carcinogenesis. Emerging trends towards targeted therapies as the most promising approach will also be discussed.
Collapse
Affiliation(s)
- Aleksandra Adamska
- Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia.
| | - Alice Domenichini
- Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia.
| | - Marco Falasca
- Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia.
| |
Collapse
|
|
24
|
Vijayvergia N, Cohen SJ. Personalized medicine in sporadic pancreatic cancer without homologous recombination-deficiency: are we any closer? J Gastrointest Oncol 2016; 7:727-737. [PMID: 27747087 PMCID: PMC5056260 DOI: 10.21037/jgo.2016.08.01] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2016] [Accepted: 06/14/2016] [Indexed: 12/12/2022] Open
Abstract
Pancreatic adenocarcinoma is the fourth leading cause of cancer related death in the United States. Most patients are diagnosed at a late stage and despite recent advances in chemotherapeutic approaches, outcomes are poor. With the introduction of combination chemotherapy, novel biomarkers are clearly needed to identify subsets of patients likely to benefit from these therapies. Advances in our understanding of the molecular drivers of pancreatic cancer offer the hope of personalized therapy that may benefit our patients. In this review, we summarize the current knowledge about the biology of pancreatic cancer and its implication for treatment. We discuss recent advances in targeted therapies and the role of potential biomarkers in predicting response to established therapies. We also review novel therapeutic approaches that may be able to fulfill the promise of personalized therapy for pancreatic cancer.
Collapse
Affiliation(s)
- Namrata Vijayvergia
- Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| | - Steven J Cohen
- Department of Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA
| |
Collapse
|
|
25
|
Sohn BS, Yuh YJ, Song HS, Kim BS, Lee KH, Jang JS, Kim SR. Triplet cytotoxic chemotherapy with gemcitabine, 5-fluorouracil and cisplatin for advanced pancreatic cancer. Oncol Lett 2015; 10:1204-1210. [PMID: 26622653 DOI: 10.3892/ol.2015.3347] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Accepted: 05/20/2015] [Indexed: 01/05/2023] Open
Abstract
In advanced or relapsed pancreatic cancer, mono- or duo-therapy has shown modest efficacy at best. The present study evaluated the efficacy of a triplet combination in relapsed or advanced pancreatic cancer. A total of 37 patients with adenocarcinoma of the pancreas in stage III/IV or with relapsed disease were treated with a gemcitabine, 5-fluorouracil and cisplatin (GFP) regimen every 3 weeks. Only 29 out of 37 patients were evaluable for response due to early treatment interruption in 8 patients. The overall response rate was 24.1% and the disease control rate was 68.9%. The progression-free survival (PFS) rate was 61.5, 30.9 and 17.6% at 3, 6 and 9 months, respectively, and the overall survival (OS) rate was 46.5 and 30.6% at 6 and 12 months, respectively. Grade 3/4 leukopenia, neutropenia and thrombocytopenia occurred in 18.4, 29.9 and 24.5% of 147 cycles, respectively. Old age and a poor performance status (PS) were associated with the early discontinuation of chemotherapy (P=0.038 and P=0.036, respectively). In patients <65 years old and with a PS of <2, the median PFS and OS times were 5.3 months and 10.3 months, respectively. Overall, although GFP resulted in acceptable response and survival rates, it does not appear to have marked superiority to gemcitabine-based single or duplet chemotherapy.
Collapse
Affiliation(s)
- Byeong Seok Sohn
- Department of Internal Medicine, College of Medicine, Inje University Sanggye Paik Hospital, Seoul 139-707, Republic of Korea
| | - Young Jin Yuh
- Department of Internal Medicine, College of Medicine, Inje University Sanggye Paik Hospital, Seoul 139-707, Republic of Korea
| | - Hong Suk Song
- Department of Hematooncology, Dongsan Medical Center, Keimyung University School of Medicine, Daegu 700-712, Republic of Korea
| | - Bong-Seog Kim
- Department of Internal Medicine, Veterans Health Service Medical Center, Seoul 139-707, Republic of Korea
| | - Kyung Hee Lee
- Division of Oncology, Department of Internal Medicine, Yeungnam University College of Medicine, Daegu 702-701, Republic of Korea
| | - Joung-Soon Jang
- Division of Hematology/Oncology, Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul 139-707, Republic of Korea
| | - Sung Rok Kim
- Department of Internal Medicine, College of Medicine, Inje University Sanggye Paik Hospital, Seoul 139-707, Republic of Korea
| |
Collapse
|
|
26
|
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.
Collapse
|
|
27
|
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.
Collapse
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
| |
Collapse
|
|
28
|
Tu C, Zheng F, Wang JY, Li YY, Qian KQ. An Updated Meta-analysis and System Review:is Gemcitabine+Fluoropyrimidine in Combination a Better Therapy Versus Gemcitabine Alone for Advanced and Unresectable Pancreatic Cancer? Asian Pac J Cancer Prev 2015; 16:5681-6. [DOI: 10.7314/apjcp.2015.16.14.5681] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
|
|
29
|
Liu Y, Huang QK, Hong WD, Wu JM, Sun XC. The addition of S-1 to gemcitabine-based chemotherapy improves survival with increased toxicity for patients with advanced pancreatic cancer: combined meta-analysis of efficacy and safety profile. Clin Res Hepatol Gastroenterol 2015; 39:254-60. [PMID: 25304193 DOI: 10.1016/j.clinre.2014.08.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2014] [Revised: 07/08/2014] [Accepted: 08/28/2014] [Indexed: 02/08/2023]
Abstract
PURPOSE To investigate the efficiency and safety profile of the addition of S-1 to gemcitabine (GEM)-based chemotherapy for advanced pancreatic cancer (APC). METHODS Computerized search was undertaken to identify randomized controlled trials of S-1 plus GEM versus GEM monotherapy in APC patients. The outcomes included overall survival (OS), progression-free survival (PFS), response rate, and toxicities. RESULTS Five studies with 917 patients were included. Overall, there was a significant difference between the two regimens in terms of OS (HR=0.83, 95%CI=0.72-0.96, P=0.01), PFS (HR=0.64, 95%CI=0.56-0.74, P<0.0001), and overall response rate (ORR; RR=2.36, 95%CI=1.73-3.22, P<0.00001). Occurrence of grade 3/4 hematological toxicities (neutropenia, thrombocytopenia) and non-hematological toxicities (diarrhea, nausea/vomit, rush, stomatitis/mucositis) were significantly higher with GEM/S-1 treatment. CONCLUSIONS This meta-analysis indicated a significant survival benefit with increased toxicity when S-1 was combined with GEM. GEM/S-1 might be an option of first-line chemotherapy for APC patients, at least in Asia.
Collapse
Affiliation(s)
- Yang Liu
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, No. 2, Fuxue Road, Wenzhou 325000, Zhejiang Province, PR China
| | - Qing-ke Huang
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, No. 2, Fuxue Road, Wenzhou 325000, Zhejiang Province, PR China
| | - Wan-dong Hong
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, No. 2, Fuxue Road, Wenzhou 325000, Zhejiang Province, PR China
| | - Jin-ming Wu
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, No. 2, Fuxue Road, Wenzhou 325000, Zhejiang Province, PR China
| | - Xue-cheng Sun
- Department of Gastroenterology and Hepatology, the First Affiliated Hospital of Wenzhou Medical University, No. 2, Fuxue Road, Wenzhou 325000, Zhejiang Province, PR China.
| |
Collapse
|
|
30
|
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.
Collapse
Affiliation(s)
- Fausto Petrelli
- Medical Oncology Unit, Oncology Department, Azienda Ospedaliera Treviglio, Piazzale Ospedale 1, 24047 Treviglio (BG), Italy.
| | | | | | | | | |
Collapse
|
|
31
|
Collins DC, Morris PG. Systemic therapy for advanced pancreatic cancer: individualising cytotoxic therapy. Expert Opin Pharmacother 2015; 16:851-61. [DOI: 10.1517/14656566.2015.1024654] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
|
|
32
|
Sherman WH, Chu K, Chabot J, Allendorf J, Schrope BA, Hecht E, Jin B, Leung D, Remotti H, Addeo G, Postolov I, Tsai W, Fine RL. Neoadjuvant gemcitabine, docetaxel, and capecitabine followed by gemcitabine and capecitabine/radiation therapy and surgery in locally advanced, unresectable pancreatic adenocarcinoma. Cancer 2015; 121:673-80. [PMID: 25492104 DOI: 10.1002/cncr.29112] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Revised: 09/07/2014] [Accepted: 09/08/2014] [Indexed: 01/11/2023]
Abstract
BACKGROUND This prospective study was undertaken to assess toxicity, resectability, and survival in pancreatic adenocarcinoma patients presenting with locally advanced, unresectable disease treated with neoadjuvant gemcitabine, docetaxel, and capecitabine (GTX) and gemcitabine and capecitabine (GX)/radiation therapy (RT). METHODS All patients presenting to the Pancreas Center were evaluated for eligibility. Forty-five patients (mean age, 64 years; range, 44-83 years)-34 patients deemed unresectable because of arterial involvement and 11 patients deemed unresectable because of extensive venous involvement-were treated with 6 cycles of GTX. Those with arterial involvement were treated with GX/RT after chemotherapy. RESULTS The GTX and GX/RT treatments were tolerated with the expected drug-related toxicities. There were no bowel perforations, cases of pancreatitis, or delayed strictures. Among those with arterial involvement, 29 underwent subsequent resection, with 20 (69%) achieving R0 resections. All 11 patients with venous-only involvement underwent resection, with 8 achieving R0 resections and 3 achieving complete pathologic responses. For the arterial arm, the 1-year survival rate was 71% (24 of 34 patients), and the median survival was 29 months (95% confidence interval, 21-38 months). Thirteen patients (38%) have not relapsed (range, 5-49+ months). For the venous arm, the median survival has not been reached at more than 42 months. Six patients (55%) in the venous arm did not experience recurrence (range, 6.2-42+ months). CONCLUSIONS GTX plus GX/RT is an effective neoadjuvant regimen that can be safely administered to patients up to at least the age of 83 years. It is associated with a high response rate, a high rate of R0 resections, and prolonged overall survival.
Collapse
|
|
33
|
Hidalgo M, Cascinu S, Kleeff J, Labianca R, Löhr JM, Neoptolemos J, Real FX, Van Laethem JL, Heinemann V. Addressing the challenges of pancreatic cancer: future directions for improving outcomes. Pancreatology 2015; 15:8-18. [PMID: 25547205 DOI: 10.1016/j.pan.2014.10.001] [Citation(s) in RCA: 365] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 10/01/2014] [Accepted: 10/03/2014] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC), which accounts for more than 90% of all pancreatic tumours, is a devastating malignancy with an extremely poor prognosis, as shown by a 1-year survival rate of around 18% for all stages of the disease. The low survival rates associated with PDAC primarily reflect the fact that tumours progress rapidly with few specific symptoms and are thus at an advanced stage at diagnosis in most patients. As a result, there is an urgent need to develop accurate markers of pre-invasive pancreatic neoplasms in order to facilitate prediction of cancer risk and to help diagnose the disease at an earlier stage. However, screening for early diagnosis of prostate cancer remains challenging and identifying a highly accurate, low-cost screening test for early PDAC for use in clinical practice remains an important unmet need. More effective therapies are also crucial in PDAC, since progress in identifying novel therapies has been hampered by the genetic complexity of the disease and treatment remains a major challenge. Presently, the greatest step towards improved treatment efficacy has been made in the field of palliative chemotherapy by introducing FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan and oxaliplatin) and gemcitabine/nab-paclitaxel. Strategies designed to raise the profile of PDAC in research and clinical practice are a further requirement in order to ensure the best treatment for patients. This article proposes a number of approaches that may help to accelerate progress in treating patients with PDAC, which, in turn, may be expected to improve the quality of life and survival for those suffering from this devastating disease.
Collapse
Affiliation(s)
- Manuel Hidalgo
- Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain.
| | - Stefano Cascinu
- Department of Medical Oncology, University of Ancona, Ancona, Italy
| | - Jörg Kleeff
- Department of General Surgery, Technische Universität München, Munich, Germany
| | | | - J-Matthias Löhr
- Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm, Sweden
| | - John Neoptolemos
- National Institutes of Health Research Liverpool Pancreas Biomedical Research Unit and Cancer Research UK Liverpool Clinical Trials Unit Director, University of Liverpool and Royal Liverpool University Hospital, Liverpool, UK
| | - Francisco X Real
- Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid and Universitat Pompeu Fabra, Barcelona, Spain
| | - Jean-Luc Van Laethem
- Department of Gastroenterology-GI Cancer Unit, Erasme University Hospital, Brussels, Belgium
| | - Volker Heinemann
- Comprehensive Cancer Centre Munich, Klinikum der Universität München, Munich, Germany
| |
Collapse
|
|
34
|
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.
Collapse
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
| |
Collapse
|
|
35
|
Li Q, Yan H, Liu W, Zhen H, Yang Y, Cao B. Efficacy and safety of gemcitabine-fluorouracil combination therapy in the management of advanced pancreatic cancer: a meta-analysis of randomized controlled trials. PLoS One 2014; 9:e104346. [PMID: 25093849 PMCID: PMC4122434 DOI: 10.1371/journal.pone.0104346] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Accepted: 07/07/2014] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Gemcitabine (GEM) is the standard first-line chemotherapy that provides limited clinical benefits for patients with locally advanced/metastatic pancreatic adenocarcinoma (LA/MPC). However, the fluorouracil derivatives (CAP and S-1) show promising efficacy in these patients. This study compared the efficacy and safety of GEM with GEM plus fluorouracil drugs in the treatment of LA/MPC. METHODS Pubmed, EMBASE and Cochrane Library databases were searched for relevant randomized controlled trials published on or before January 2014. The Cochrane Collaboration's tool was used to assess the risk of bias in randomized trials. The primary end point was overall survival (OS); the secondary end points were one-year survival rate, objective response rate (ORR) and toxicity rates (TRs). RESULTS A total of 8 randomized controlled trials involving 2,126 patients were included in the systematic evaluation. The results showed that OS was significantly improved (HR 0.83, P<0.01; HR 0.87, P = 0.03; HR 0.80, P = 0.01; respectively) and ORR was significantly increased (OR 0.51, P<0.01; OR 0.66, P = 0.03; OR 0.35, P<0.01; respectively) in the GEM+5-FU/CAP/S-1, GEM+CAP and GEM+S-1 groups compared to the GEM alone group. In addition, the one-year survival rate was significantly increased (OR 0.78 P = 0.01; OR 0.47, P = 0.04; respectively) in the GEM+5-FU/CAP/S-1 and GEM+S-1 groups compared to the GEM alone group. The frequency of grade 3/4 TRs were higher in GEM+5-FU/CAP/S-1 group, the significant increase of grade 3/4 neutropenia, thrombocytopenia and diarrhea were observed. CONCLUSIONS GEM combined with fluorouracil drugs significantly improved OS and increased one-year survival rate and ORR compared to GEM alone in LA/MPC patients. GEM combined with fluorouracil drugs may be considered as an acceptable alternative treatment for LA/MPC patients.
Collapse
Affiliation(s)
- Qin Li
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Han Yan
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Wenting Liu
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Digestive Diseases Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Hongchao Zhen
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Digestive Diseases Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yifan Yang
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Digestive Diseases Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Bangwei Cao
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- Beijing Digestive Diseases Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
- * E-mail:
| |
Collapse
|
|
36
|
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.
Collapse
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
| |
Collapse
|
|
37
|
FOLFIRI in patients with locally advanced or metastatic pancreatic or biliary tract carcinoma: a monoinstitutional experience. Anticancer Drugs 2014; 24:980-5. [PMID: 23928570 DOI: 10.1097/cad.0b013e328364e66b] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Pancreatic and biliary tract carcinomas are very chemoresistant. After a first-line treatment with a gemcitabine-based regimen, no second-line scheme is consolidated in clinical practice. The aim of this study was to evaluate the toxicity and the activity of the FOLFIRI regimen as first-line or second-line chemotherapy in patients with pancreatic or biliary tract tumors. Fifty-four patients (30 with pancreatic tumor, nine with gallbladder tumor, and 15 with biliary tract tumor) were treated with FOLFIRI (irinotecan 180 mg/m², day 1; leucovorin 100 mg/m² intravenously, days 1 and 2; 5-fluorouracil 400 mg/m² intravenous bolus, days 1 and 2; and 600 mg/m² in 22 h intravenously, continuous infusion days 1 and 2; every 14 days). Toxicity was recorded at each cycle according to the NCI-CTC V3.0 criteria, the response rate was verified each four cycles according to the RECIST criteria, and the progression-free survival rates as well as the overall survival rates were calculated according to the Kaplan-Meier method. Overall, the toxicity was mild. Grade 3-4 neutropenia occurred in 42.6% of patients. Grade 3-4 gastrointestinal toxicity was rare. FOLFIRI as a first-line treatment produced a response rate of 25%. In the second-line group, 9/21 patients (42.9%) obtained a stable disease as best response. In the entire population, the median progression-free survival rates were 3.1 months [95% confidence interval (CI), 1.9-4.4] and 3.5 months (95% CI, 2.6-4.4), respectively, in the first-line and the second-line cohort of patients. The median overall survival rates were 14.5 months (95% CI, 7.0-22.1) and 6.2 months (95% CI, 5.4-7.0), respectively, in the first-line and the second-line cohort of patients. FOLFIRI is feasible and well tolerated in patients with pancreatic or biliary tract tumors; it has a good activity in first line and mostly in patients with pancreatic cancer.
Collapse
|
|
38
|
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.
Collapse
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.
| |
Collapse
|
|
39
|
Cleistanthane diterpenes from the seed of Caesalpinia sappan and their antiausterity activity against PANC-1 human pancreatic cancer cell line. Fitoterapia 2013; 91:148-153. [DOI: 10.1016/j.fitote.2013.08.018] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 08/24/2013] [Accepted: 08/26/2013] [Indexed: 11/22/2022]
|
|
40
|
Lee JJ, Huang J, England CG, McNally LR, Frieboes HB. Predictive modeling of in vivo response to gemcitabine in pancreatic cancer. PLoS Comput Biol 2013; 9:e1003231. [PMID: 24068909 PMCID: PMC3777914 DOI: 10.1371/journal.pcbi.1003231] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Accepted: 08/03/2013] [Indexed: 01/03/2023] Open
Abstract
A clear contradiction exists between cytotoxic in-vitro studies demonstrating effectiveness of Gemcitabine to curtail pancreatic cancer and in-vivo studies failing to show Gemcitabine as an effective treatment. The outcome of chemotherapy in metastatic stages, where surgery is no longer viable, shows a 5-year survival <5%. It is apparent that in-vitro experiments, no matter how well designed, may fail to adequately represent the complex in-vivo microenvironmental and phenotypic characteristics of the cancer, including cell proliferation and apoptosis. We evaluate in-vitro cytotoxic data as an indicator of in-vivo treatment success using a mathematical model of tumor growth based on a dimensionless formulation describing tumor biology. Inputs to the model are obtained under optimal drug exposure conditions in-vitro. The model incorporates heterogeneous cell proliferation and death caused by spatial diffusion gradients of oxygen/nutrients due to inefficient vascularization and abundant stroma, and thus is able to simulate the effect of the microenvironment as a barrier to effective nutrient and drug delivery. Analysis of the mathematical model indicates the pancreatic tumors to be mostly resistant to Gemcitabine treatment in-vivo. The model results are confirmed with experiments in live mice, which indicate uninhibited tumor proliferation and metastasis with Gemcitabine treatment. By extracting mathematical model parameter values for proliferation and death from monolayer in-vitro cytotoxicity experiments with pancreatic cancer cells, and simulating the effects of spatial diffusion, we use the model to predict the drug response in-vivo, beyond what would have been expected from sole consideration of the cancer intrinsic resistance. We conclude that this integrated experimental/computational approach may enhance understanding of pancreatic cancer behavior and its response to various chemotherapies, and, further, that such an approach could predict resistance based on pharmacokinetic measurements with the goal to maximize effective treatment strategies.
Collapse
Affiliation(s)
- James J. Lee
- School of Medicine, University of Louisville, Louisville, Kentucky, United States of America
| | - Justin Huang
- School of Medicine, University of Louisville, Louisville, Kentucky, United States of America
| | - Christopher G. England
- Department of Pharmacology/Toxicology, University of Louisville, Louisville, Kentucky, United States of America
| | - Lacey R. McNally
- School of Medicine, University of Louisville, Louisville, Kentucky, United States of America
- James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, United States of America
- * E-mail: (LRM); (HBF)
| | - Hermann B. Frieboes
- James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky, United States of America
- Department of Bioengineering, University of Louisville, Louisville, Kentucky, United States of America
- * E-mail: (LRM); (HBF)
| |
Collapse
|
|
41
|
Huang P, Zhong XY, Xu Y, Cui YF. Role of neoadjuvant therapy and adjuvant therapy in treatment of pancreatic cancer. Shijie Huaren Xiaohua Zazhi 2013; 21:1292-1296. [DOI: 10.11569/wcjd.v21.i14.1292] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is a highly malignant tumor that has a low resection rate. In Western countries, pancreatic cancer is the fourth cause of death in malignant tumors. Combined therapy is particularly important for the treatment of pancreatic cancer. Preoperative neoadjuvant therapy and postoperative adjuvant therapy are important parts of combined treatment for pancreatic cancer. Adjuvant therapy can improve survival and quality of life of patients with pancreatic cancer, and neoadjuvant therapy can reduce the primary lesion and lymph node metastasis, provide patients with the possibility of surgery to improve radical resection, decrease intraoperative bleeding and postoperative complications, and improve postoperative survival and life quality of patients. This article reviews the role of adjuvant therapy and neoadjuvant therapy in the management of pancreatic cancer.
Collapse
|
|
42
|
Gonçalves A, Gilabert M, François E, Dahan L, Perrier H, Lamy R, Re D, Largillier R, Gasmi M, Tchiknavorian X, Esterni B, Genre D, Moureau-Zabotto L, Giovannini M, Seitz JF, Delpero JR, Turrini O, Viens P, Raoul JL. BAYPAN study: a double-blind phase III randomized trial comparing gemcitabine plus sorafenib and gemcitabine plus placebo in patients with advanced pancreatic cancer. Ann Oncol 2012; 23:2799-2805. [PMID: 22771827 DOI: 10.1093/annonc/mds135] [Citation(s) in RCA: 169] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Sorafenib is an oral anticancer agent targeting Ras-dependent signaling and angiogenic pathways. A phase I trial demonstrated that the combination of gemcitabine and sorafenib was well tolerated and had activity in advanced pancreatic cancer (APC) patients. The BAYPAN study was a multicentric, placebo-controlled, double-blind, randomized phase III trial comparing gemcitabine/sorafenib and gemcitabine/placebo in the treatment of APC. PATIENTS AND METHODS The patient eligibility criteria were locally advanced or metastatic pancreatic adenocarcinoma, no prior therapy for advanced disease and a performance status of zero to two. The primary end point was progression-free survival (PFS). The patients received gemcitabine 1000 mg/m(2) i.v., weekly seven times followed by 1 rest week, then weekly three times every 4 weeks plus sorafenib 200 mg or placebo, two tablets p.o., twice daily continuously. RESULTS Between December 2006 and September 2009, 104 patients were enrolled on the study (52 pts in each arm) and 102 patients were treated. The median and the 6-month PFS were 5.7 months and 48% for gemcitabine/placebo and 3.8 months and 33% for gemcitabine/sorafenib (P = 0.902, stratified log-rank test), respectively. The median overall survivals were 9.2 and 8 months, respectively (P = 0.231, log-rank test). The overall response rates were similar (19 and 23%, respectively). CONCLUSION The addition of sorafenib to gemcitabine does not improve PFS in APC patients.
Collapse
Affiliation(s)
- A Gonçalves
- Department of Medical Oncology, Institut Paoli-Calmettes, Marseille; Cancer Research Center of Marseille, U1068 INSERM, CNRS UMR7258; Aix-Marseille University, Marseille; Clinical Investigation Center 9502, Marseille.
| | - M Gilabert
- Department of Medical Oncology, Institut Paoli-Calmettes, Marseille
| | - E François
- Department of Medical Oncology, Centre Antoine Lacassagne, Nice
| | - L Dahan
- Aix-Marseille University, Marseille; Clinical Investigation Center 9502, Marseille; Department of Digestive Oncology, Hôpital de le Timone, Assistance Publique-Hôpitaux de Marseille, Marseille
| | - H Perrier
- Digestive Oncology Unit, Hôpital Saint-Joseph, Marseille
| | - R Lamy
- Department of Oncology, Centre Hospitalier Bretagne Sud (Lorient), Lorient
| | - D Re
- Medicine Unit, Centre Hospitalier Antibes Juan-les-Pins, Antibes
| | - R Largillier
- Department of Oncology, Centre azuréen de cancérologie, Mougins
| | - M Gasmi
- Department of Gastro-enterology, Hôpital Nord APHM, Marseille
| | - X Tchiknavorian
- Department of Medical Oncology, Centre Hospitalier Toulon, Toulon, France
| | - B Esterni
- Department of Medical Oncology, Institut Paoli-Calmettes, Marseille; Clinical Investigation Center 9502, Marseille
| | - D Genre
- Department of Medical Oncology, Institut Paoli-Calmettes, Marseille; Clinical Investigation Center 9502, Marseille
| | | | - M Giovannini
- Department of Medical Oncology, Institut Paoli-Calmettes, Marseille
| | - J-F Seitz
- Aix-Marseille University, Marseille; Clinical Investigation Center 9502, Marseille; Department of Digestive Oncology, Hôpital de le Timone, Assistance Publique-Hôpitaux de Marseille, Marseille
| | - J-R Delpero
- Department of Medical Oncology, Institut Paoli-Calmettes, Marseille; Cancer Research Center of Marseille, U1068 INSERM, CNRS UMR7258; Aix-Marseille University, Marseille; Clinical Investigation Center 9502, Marseille
| | - O Turrini
- Department of Medical Oncology, Institut Paoli-Calmettes, Marseille; Cancer Research Center of Marseille, U1068 INSERM, CNRS UMR7258; Aix-Marseille University, Marseille
| | - P Viens
- Department of Medical Oncology, Institut Paoli-Calmettes, Marseille; Cancer Research Center of Marseille, U1068 INSERM, CNRS UMR7258; Aix-Marseille University, Marseille; Clinical Investigation Center 9502, Marseille
| | - J-L Raoul
- Department of Medical Oncology, Institut Paoli-Calmettes, Marseille; Cancer Research Center of Marseille, U1068 INSERM, CNRS UMR7258
| |
Collapse
|
|
43
|
Sun C, Ansari D, Andersson R, Wu DQ. Does gemcitabine-based combination therapy improve the prognosis of unresectable pancreatic cancer? World J Gastroenterol 2012; 18:4944-58. [PMID: 23002368 PMCID: PMC3447278 DOI: 10.3748/wjg.v18.i35.4944] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [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.
Collapse
|
|
44
|
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.
Collapse
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
| | | | | | | | | | | | | |
Collapse
|
|
45
|
Unresectable Pancreatic Cancer: Arterial Embolization to Achieve a Single Blood Supply for Intraarterial Infusion of 5-Fluorouracil and Full-Dose IV Gemcitabine. AJR Am J Roentgenol 2012; 198:1445-52. [DOI: 10.2214/ajr.11.8008] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
|
|
46
|
Herreros-Villanueva M, Hijona E, Cosme A, Bujanda L. Adjuvant and neoadjuvant treatment in pancreatic cancer. World J Gastroenterol 2012; 18:1565-72. [PMID: 22529684 PMCID: PMC3325521 DOI: 10.3748/wjg.v18.i14.1565] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2011] [Revised: 10/23/2011] [Accepted: 01/22/2012] [Indexed: 02/06/2023] Open
Abstract
Pancreatic adenocarcinoma is one of the most aggressive human malignancies, ranking 4th among causes for cancer-related death in the Western world including the United States. Surgical resection offers the only chance of cure, but only 15 to 20 percent of cases are potentially resectable at presentation. Different studies demonstrate and confirm that advanced pancreatic cancer is among the most complex cancers to treat and that these tumors are relatively resistant to chemotherapy and radiotherapy. Currently there is no consensus around the world on what constitutes “standard” adjuvant therapy for pancreatic cancer. This controversy derives from several studies, each fraught with its own limitations. Standards of care also vary somewhat with regard to geography and economy, for instance chemo-radiotherapy followed by chemotherapy or vice versa is considered the optimal therapy in North America while chemotherapy alone is the current standard in Europe. Regardless of the efforts in adjuvant and neoadjuvant improved therapy, the major goal to combat pancreatic cancer is to find diagnostic markers, identifying the disease in a pre-metastatic stage and making a curative treatment accessible to more patients. In this review, authors examined the different therapy options for advanced pancreatic patients in recent years and the future directions in adjuvant and neoadjuvant treatments for these patients.
Collapse
|
|
47
|
Stokes JB, Adair SJ, Slack-Davis JK, Walters DM, Tilghman RW, Hershey ED, Lowrey B, Thomas KS, Bouton AH, Hwang RF, Stelow EB, Parsons JT, Bauer TW. Inhibition of focal adhesion kinase by PF-562,271 inhibits the growth and metastasis of pancreatic cancer concomitant with altering the tumor microenvironment. Mol Cancer Ther 2011; 10:2135-45. [PMID: 21903606 DOI: 10.1158/1535-7163.mct-11-0261] [Citation(s) in RCA: 177] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Current therapies for pancreatic ductal adenocarcinoma (PDA) target individual tumor cells. Focal adhesion kinase (FAK) is activated in PDA, and levels are inversely associated with survival. We investigated the effects of PF-562,271 (a small-molecule inhibitor of FAK/PYK2) on (i) in vitro migration, invasion, and proliferation; (ii) tumor proliferation, invasion, and metastasis in a murine model; and (iii) stromal cell composition in the PDA microenvironment. Migration assays were conducted to assess tumor and stromal cell migration in response to cellular factors, collagen, and the effects of PF-562,271. An orthotopic murine model was used to assess the effects of PF-562,271 on tumor growth, invasion, and metastasis. Proliferation assays measured PF-562,271 effects on in vitro growth. Immunohistochemistry was used to examine the effects of FAK inhibition on the cellular composition of the tumor microenvironment. FAK and PYK2 were activated and expressed in patient-derived PDA tumors, stromal components, and human PDA cell lines. PF-562,271 blocked phosphorylation of FAK (phospho-FAK or Y397) in a dose-dependent manner. PF-562,271 inhibited migration of tumor cells, cancer-associated fibroblasts, and macrophages. Treatment of mice with PF-562,271 resulted in reduced tumor growth, invasion, and metastases. PF-562,271 had no effect on tumor necrosis, angiogenesis, or apoptosis, but it did decrease tumor cell proliferation and resulted in fewer tumor-associated macrophages and fibroblasts than control or gemcitabine. These data support a role for FAK in PDA and suggest that inhibitors of FAK may contribute to efficacious treatment of patients with PDA.
Collapse
Affiliation(s)
- Jayme B Stokes
- Department of Surgery, University of Virginia, Charlottesville, Virginia, USA
| | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Open-label trial on efficacy and security of treatment with gemcitabine and oral modulation with tegafur and levofolinic acid (GEMTG) in patients with advanced pancreatic cancer. Clin Transl Oncol 2011; 13:61-6. [PMID: 21239357 DOI: 10.1007/s12094-011-0618-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
AIM Advanced pancreatic cancer has a bad prognosis, with a median overall survival (OS) no longer than 4-6 months. Since the end of last century, monotherapy with gemcitabine has remained the elective therapy, but new schedules are needed in order to improve these results. We aim to evaluate the efficacy of tegafur and levofolinic acid (LV) associated with gemcitabine, as well as its toxicity, progression-free survival and OS in advanced pancreatic cancer. PATIENTS AND METHODS An open-label, multicentric, prospective, non-controlled trial was carried out on patients with advanced or disseminated pancreatic cancer. Gemcitabine 1250 mg/m² was administered on the 1st and 8th days of the cycle, tegafur 750 mg/m²/day for 21 consecutive days and LV 25 mg/day continuously, every 28 days, with a maximum of six cycles. The primary variable was tumour overall response rate (ORR). Secondarily, time to progression (TTP), OS and scheme toxicity were determined. RESULTS Forty patients were recruited; the male/female ratio was 30:10, with a mean age of 61 years. Forty percent had a Karnofsky index of 90% or 100%. Only 11 patients (27%) completed the six cycles of treatment, but more than 50% received three or more cycles. Dose intensity was 89.56% for gemcitabine and 87.36% for tegafur. Efficacy ORR was 22.5% (CI 95%, 6-37%). TTP was 3.87 months (CI 95%, 2.1-5.6), time to treatment failure was 2.97 months (CI 95%, 2.43-4.67) and OS 6.3 months (CI 95%, 4-7). The chemotherapeutic combination was well accepted; most haematologic and non-haematologic toxicities were grade 1 or 2. The most prevalent grade 3/4 toxicities were asthenia (30%), liver biochemistry disorders (25%), diarrhoea (15%) and stomatitis (12%). CONCLUSIONS The administration of gemcitabine, associated with oral tegafur and leucovorin, has activity against advanced pancreatic cancer, with an adequate toxicity profile.
Collapse
|
|
49
|
Trouilloud I, Dubreuil O, Boussaha T, Lepère C, Landi B, Zaanan A, Bachet JB, Taieb J. Medical treatment of pancreatic cancer: new hopes after 10 years of gemcitabine. Clin Res Hepatol Gastroenterol 2011; 35:364-74. [PMID: 21435966 DOI: 10.1016/j.clinre.2011.02.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2010] [Revised: 02/07/2011] [Accepted: 02/09/2011] [Indexed: 02/04/2023]
Abstract
Exocrine pancreatic cancer has a very poor prognosis. R0 resection of the tumor is to date the only potentially curative approach, but less than 20% of patients are eligible for a curative surgery at diagnosis. Until recently, gemcitabine was the standard treatment for advanced and metastatic pancreatic cancer patients, since it was shown more than a decade ago to induce clinical benefit and to improve survival when compared to weekly bolus 5-fluorouracil. In order to improve patients' outcome many trials have, during the last 10 years, explored the pharmacokinetic modulation of gemcitabine and combination therapies with gemcitabine and other anti-cancer agents with consistent negative results. It is finally a trial assessing the efficacy of a combination chemotherapy without gemcitabine: the FOLFIRINOX regimen, reported this year, that has shown for the first time a significant improvement in progression free and overall survivals. In parallel, many trials testing new targeted agents in these patients are currently ongoing. After 10 years without significant progress in the treatment of pancreatic cancer patients, the hope that a significant improvement in the outcome of these patients can be achieved has been raised.
Collapse
Affiliation(s)
- Isabelle Trouilloud
- Service d'oncologie digestive, hôpital européen Georges-Pompidou, AP-HP, université Paris V, 20, rue Leblanc, 75015 Paris, France.
| | | | | | | | | | | | | | | |
Collapse
|
|
50
|
Hu J, Zhao G, Wang HX, Tang L, Xu YC, Ma Y, Zhang FC. A meta-analysis of gemcitabine containing chemotherapy for locally advanced and metastatic pancreatic adenocarcinoma. J Hematol Oncol 2011; 4:11. [PMID: 21439076 PMCID: PMC3079694 DOI: 10.1186/1756-8722-4-11] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2010] [Accepted: 03/26/2011] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The objectives of the present study are to investigate the efficacy and safety profile of gemcitabine-based combinations in the treatment of locally advanced and metastatic pancreatic adenocarcinoma (LA/MPC). METHODS We performed a computerized search using combinations of the following keywords: "chemotherapy", "gemcitabine", "trial", and "pancreatic cancer". RESULTS Thirty-five trials were included in the present analysis, with a total of 9,979 patients accrued. The analysis showed that the gemcitabine-based combination therapy was associated with significantly better overall survival (OS) (ORs, 1.15; p = 0.011), progression-free survival (PFS) (ORs, 1.27; p < 0.001), and overall response rate (ORR) (ORs, 1.58; p < 0.001) than gemcitabine monotherapy. Similar results were obtained when the gemcitabine-fluoropyrimidine combination was compared with gemcitabine, with the OS (ORs, 1.33; p = 0.007), PFS (ORs, 1.53; p < 0.001), and ORR (ORs 1.47, p = 0.03) being better in the case of the former. The OS (ORs, 1.33; p = 0.019), PFS (ORs, 1.38; p = 0.011), and one-year survival (ORs, 1.40; p = 0.04) achieved with the gemcitabine-oxaliplatin combination were significantly greater than those achieved with gemcitabine alone. However, no survival benefit (OS: ORs, 1.01, p = 0.93; PFS: ORs, 1.19, p = 0.17) was noted when the gemcitabine-cisplatin combination was compared to gemcitabine monotherapy. The combinations of gemcitabine and other cytotoxic agents also afforded disappointing results. Our analysis indicated that the ORR improved when patients were treated with the gemcitabine-camptothecin combination rather than gemcitabine alone (ORs, 2.03; p = 0.003); however, there were no differences in the OS (ORs, 1.03; p = 0.82) and PFS (ORs, 0.97; p = 0.78) in this case. CONCLUSIONS Gemcitabine in combination with capecitabine or oxaliplatin was associated with enhanced OS and ORR as compared with gemcitabine in monotherapy, which are likely to become the preferred standard first-line treatment of LA/MPC.
Collapse
Affiliation(s)
- Jing Hu
- Department of Oncology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Gang Zhao
- Department of Surgery, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Hong-Xia Wang
- Department of Oncology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Lei Tang
- Department of Oncology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Ying-Chun Xu
- Department of Oncology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Yue Ma
- Department of Oncology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Feng-Chun Zhang
- Department of Oncology, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou 215021, China
| |
Collapse
|