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Jiang P, Zong K, Peng D, Zhou B, Wu Z. Risk comparison of adverse reactions between gemcitabine monotherapy and gemcitabine combined with albumin-bound paclitaxel in pancreatic cancer: insights from the FDA Adverse Event Reporting System (FAERS) database. BMC Pharmacol Toxicol 2025; 26:65. [PMID: 40108669 PMCID: PMC11924625 DOI: 10.1186/s40360-025-00884-5] [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: 11/21/2024] [Accepted: 02/27/2025] [Indexed: 03/22/2025] Open
Abstract
BACKGROUND Pancreatic cancer (PC) is a highly aggressive malignancy with limited treatment options. Although gemcitabine monotherapy (G treatment) has long been a standard treatment, combination therapies, such as gemcitabine with albumin-bound paclitaxel (AG treatment), have shown improved outcomes and were approved by the FDA for the PC. However, the AG treatment is also associated with increased adverse events (AEs), which remain inadequately evaluated in real-world settings. METHODS We utilized the FDA Adverse Event Reporting System (FAERS) to conduct a large-scale pharmacovigilance analysis comparing the safety profiles of G and AG treatments for PC. By analyzing adverse event data from the third quarter of 2013 to the second quarter of 2024 and quantifying AE signals with reporting odds ratio (ROR) and proportional reporting ratio (PRR) methods, we compared the risk of AEs between the groups. Time to onset (TTO), subgroup and logistic regression analyses were also performed. RESULTS The study revealed a higher proportion of male (n = 2307, 54.1%) and elderly patients (age ≥ 65years, n = 2172, 50.9%) in the AG treatment group compared to the G treatment group. We found 17 preferred terms with positive signals at the top 50 common AEs, especially in gastrointestinal and blood systems. Cardiac and neurological AEs also needed to be vigilant. Biliary sepsis and infectious enterocolitis were newly identified AEs and deserve attention. Median TTO was 34 (IQR: 8-103) days (G) and 41 (IQR: 10-104) days (AG), with most AEs occurring within the first month (48.3% and 44%). Subgroup analysis revealed that male patients using the AG treatment had the highest risk of immune-mediated hepatitis (ROR = 23.51, 95% CI = 3.21-172.1), while elderly patients had elevated risks for presyncope (ROR = 24.84, 95% CI = 3.40-181.28) and falls (ROR = 18.60, 95% CI = 2.53-136.97). Logistic regression showed higher-risk fatal outcomes in males (adjusted OR = 1.42, 95% CI = 1.15-1.76, P < 0.01) and elderly patients (adjusted OR = 1.36, 95% CI = 1.10-1.69, P < 0.01). CONCLUSION This research offers critical safety insights in real-world settings, emphasizing patients at heightened AEs risk and informing clinical decision-making in PC treatment.
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Affiliation(s)
- Puen Jiang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Kezhen Zong
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Dadi Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Baoyong Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
| | - Zhongjun Wu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
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Seyedi S, Harris VK, Kapsetaki SE, Narayanan S, Saha D, Compton Z, Yousefi R, May A, Fakir E, Boddy AM, Gerlinger M, Wu C, Mina L, Huijben S, Gouge DH, Cisneros L, Ellsworth PC, Maley CC. Resistance Management for Cancer: Lessons from Farmers. Cancer Res 2024; 84:3715-3727. [PMID: 39356625 PMCID: PMC11565176 DOI: 10.1158/0008-5472.can-23-3374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 06/29/2024] [Accepted: 09/23/2024] [Indexed: 10/04/2024]
Abstract
One of the main reasons we have not been able to cure cancers is that treatments select for drug-resistant cells. Pest managers face similar challenges with pesticides selecting for pesticide-resistant insects, resulting in similar mechanisms of resistance. Pest managers have developed 10 principles that could be translated to controlling cancers: (i) prevent onset, (ii) monitor continuously, (iii) identify thresholds below which there will be no intervention, (iv) change interventions in response to burden, (v) preferentially select nonchemical control methods, (vi) use target-specific drugs, (vii) use the lowest effective dose, (viii) reduce cross-resistance, (ix) evaluate success based on long-term management, and (x) forecast growth and response. These principles are general to all cancers and cancer drugs and so could be employed broadly to improve oncology. Here, we review the parallel difficulties in controlling drug resistance in pests and cancer cells. We show how the principles of resistance management in pests might be applied to cancer. Integrated pest management inspired the development of adaptive therapy in oncology to increase progression-free survival and quality of life in patients with cancers where cures are unlikely. These pest management principles have the potential to inform clinical trial design.
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Affiliation(s)
- Sareh Seyedi
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
- School of Life Sciences, Arizona State University, Tempe, Arizona
| | - Valerie K. Harris
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
| | - Stefania E. Kapsetaki
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
| | - Shrinath Narayanan
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
- Department of Ecology and Evolution, University of Lausanne, Lausanne, Switzerland
| | - Daniel Saha
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
- School of Life Sciences, Arizona State University, Tempe, Arizona
| | - Zachary Compton
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
- School of Life Sciences, Arizona State University, Tempe, Arizona
- University of Arizona Cancer Center, University of Arizona College of Medicine, Tucson, Arizona
| | - Rezvan Yousefi
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
- The Polytechnic School, Ira A. Fulton Schools of Engineering, Arizona State University, Tempe, Arizona
| | - Alexander May
- Research Casting International, Quinte West, Ontario, Canada
| | - Efe Fakir
- Istanbul University Cerrahpasa School of Medicine, Istanbul, Turkey
| | - Amy M. Boddy
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Exotic Species Cancer Research Alliance, North Carolina State University, Raleigh, North Carolina
- Department of Anthropology, University of California Santa Barbara, Santa Barbara, California
| | - Marco Gerlinger
- Translational Oncogenomics Laboratory, Centre for Evolution and Cancer, The Institute of Cancer Research, London, United Kingdom
- Gastrointestinal Cancer Unit, The Royal Marsden Hospital, London, United Kingdom
| | - Christina Wu
- Division of Hematology and Medical Oncology, Department of Medicine, Mayo Clinic, Phoenix, Arizona
| | | | - Silvie Huijben
- School of Life Sciences, Arizona State University, Tempe, Arizona
- Center for Evolution and Medicine, Arizona State University, Tempe, Arizona
| | - Dawn H. Gouge
- Department of Entomology, University of Arizona, Tucson, Arizona
| | - Luis Cisneros
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
- School of Life Sciences, Arizona State University, Tempe, Arizona
| | | | - Carlo C. Maley
- Arizona Cancer Evolution Center, Arizona State University, Tempe, Arizona
- Center for Biocomputing, Security and Society, Biodesign Institute, Arizona State University, Tempe, Arizona
- School of Life Sciences, Arizona State University, Tempe, Arizona
- Center for Evolution and Medicine, Arizona State University, Tempe, Arizona
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Bugazia D, Al-Najjar E, Esmail A, Abdelrahim S, Abboud K, Abdelrahim A, Umoru G, Rayyan HA, Abudayyeh A, Al Moustafa AE, Abdelrahim M. Pancreatic ductal adenocarcinoma: the latest on diagnosis, molecular profiling, and systemic treatments. Front Oncol 2024; 14:1386699. [PMID: 39011469 PMCID: PMC11247645 DOI: 10.3389/fonc.2024.1386699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2024] [Accepted: 05/30/2024] [Indexed: 07/17/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of death in the United States and is expected to be ranked second in the next 10 years due to poor prognosis and a rising incidence. Distant metastatic PDAC is associated with the worst prognosis among the different phases of PDAC. The diagnostic options for PDAC are convenient and available for staging, tumor response evaluation, and management of resectable or borderline resectable PDAC. However, imaging is crucial in PDAC diagnosis, monitoring, resectability appraisal, and response evaluation. The advancement of medical technologies is evolving, hence the use of imaging in PDAC treatment options has grown as well as the utilization of ctDNA as a tumor marker. Treatment options for metastatic PDAC are minimal with the primary goal of therapy limited to symptom relief or palliation, especially in patients with low functional capacity at the point of diagnosis. Molecular profiling has shown promising potential solutions that would push the treatment boundaries for patients with PDAC. In this review, we will discuss the latest updates from evidence-based guidelines regarding diagnosis, therapy response evaluation, prognosis, and surveillance, as well as illustrating novel therapies that have been recently investigated for PDAC, in addition to discussing the molecular profiling advances in PDAC.
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Affiliation(s)
- Doaa Bugazia
- Department of Medicine, Massachusetts General Hospital, Boston, MA, United States
| | - Ebtesam Al-Najjar
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX, United States
| | - Abdullah Esmail
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX, United States
| | - Saifudeen Abdelrahim
- Challenge Early College HS, Houston Community College, Houston, TX, United States
| | - Karen Abboud
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX, United States
| | | | - Godsfavour Umoru
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX, United States
| | - Hashem A Rayyan
- Department of Medicine, Faculty of Medicine, The University of Jordan, Amman, Jordan
| | - Ala Abudayyeh
- Section of Nephrology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | | | - Maen Abdelrahim
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX, United States
- Department of Medicine, Weill Cornell Medical College, New York, NY, United States
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Elsayed M, Abdelrahim M. The Latest Advancement in Pancreatic Ductal Adenocarcinoma Therapy: A Review Article for the Latest Guidelines and Novel Therapies. Biomedicines 2021; 9:389. [PMID: 33917380 PMCID: PMC8067364 DOI: 10.3390/biomedicines9040389] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/25/2021] [Accepted: 03/27/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer deaths in the US, and it is expected to be the second leading cause of cancer deaths by 2030. The lack of effective early screening tests and alarming symptoms with early undetectable micro-metastasis at the time of presentation play a vital role in the high death rate from pancreatic cancer. In addition to this, the low mutation burden in pancreatic cancer, low immunological profile, dense tumorigenesis stroma, and decreased tumor sensitivity to cytotoxic drugs contribute to the low survival rates in PDAC patients. Despite breakthroughs in chemotherapeutic and immunotherapeutic drugs, pancreatic cancer remains one of the solid tumors that exhibit meager curative rates. Therefore, researchers must dedicate more effort to understanding the pathology and immunological behavior of PDAC, in addition to properly utilizing more advanced screening modalities and new therapeutic agents. In our review, we focus mainly on the latest updates from clinical guidelines and novel therapies that have been recently investigated or are under investigation for PDAC. We used PubMed as a search tool for finding original research articles addressing the latest developments in diagnosing and treating PDAC. Additionally, we also used the clinical trials published on clinicaltrialsgov as sources for our data.
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Affiliation(s)
- Marwa Elsayed
- School of Medicine, University of Missouri Kansas City, 2301 Holmes, St. Kansas City, MO 64018, USA;
| | - Maen Abdelrahim
- Houston Methodist Cancer Center, Houston Methodist Hospital, 6445 Main Street, Outpatient Center, 24th Floor, Houston, TX 77030, USA
- Cockrell Center of Advanced Therapeutics Phase I Program, Houston Methodist Research Institute, Houston, TX 77030, USA
- Weill Cornell Medical College, Institute of Academic Medicine, Houston, TX 77030, USA
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Dang A, Chidirala S, Veeranki P, Vallish BN. A Critical Overview of Systematic Reviews of Chemotherapy for Advanced and Locally Advanced Pancreatic Cancer using both AMSTAR2 and ROBIS as Quality Assessment Tools. Rev Recent Clin Trials 2020; 16:180-192. [PMID: 32875987 DOI: 10.2174/1574887115666200902111510] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 07/27/2020] [Accepted: 08/03/2020] [Indexed: 01/08/2023]
Abstract
BACKGROUND We performed a critical overview of published systematic reviews (SRs) of chemotherapy for advanced and locally advanced pancreatic cancer, and evaluated their quality using AMSTAR2 and ROBIS tools. MATERIALS AND METHODS PubMed and Cochrane Central Library were searched for SRs on 13th June 2020. SRs with meta-analysis which included only randomized controlled trials and that had assessed chemotherapy as one of the treatment arms were included. The outcome measures, which were looked into, were progression-free survival (PFS), overall survival (OS), and adverse events (AEs) of grade 3 or above. Two reviewers independently assessed all the SRs with both ROBIS and AMSTAR2. RESULTS Out of the 1,879 identified records, 26 SRs were included for the overview. Most SRs had concluded that gemcitabine-based combination regimes, prolonged OS and PFS, but increased the incidence of grade 3-4 toxicities when compared to gemcitabine monotherapy, but survival benefits were not consistent when gemcitabine was combined with molecular targeted agents. As per ROBIS, 24/26 SRs had 'high' risk of bias, with only 1/26 SR having 'low' risk of bias. As per AMSTAR2, 25/26 SRs had 'critically low', and 1/26 SR had 'low' confidence in the results. The study which scored 'low risk of bias' in ROBIS scored 'low confidence in results' in AMSTAR2. The inter- rater reliability for scoring the overall confidence in the SRs with AMSTAR2 and the overall domain in ROBIS was substantial; ROBIS: kappa=0.785, SEM=0.207, p<0.001; AMSTAR2: kappa= 0.649, SEM=0.323, p<0.001. CONCLUSION Gemcitabine-based combination regimens can prolong OS and PFS but also worsen AEs when compared to gemcitabine monotherapy. The included SRs have an overall low methodological quality and high risk of bias as per AMSTAR2 and ROBIS respectively.
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Affiliation(s)
- Amit Dang
- MarksMan Healthcare Communications and KYT Adhere, Hyderabad, Telangana - 500032, India
| | - Surendar Chidirala
- MarksMan Healthcare Communications and KYT Adhere, Hyderabad, Telangana - 500032, India
| | - Prashanth Veeranki
- MarksMan Healthcare Communications and KYT Adhere, Hyderabad, Telangana - 500032, India
| | - B N Vallish
- MarksMan Healthcare Communications and KYT Adhere, Hyderabad, Telangana - 500032, India
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Giovinazzo F, Soggiu F, Jang JY, Versteijne E, van Tienhoven G, van Eijck CH, Han Y, Choi SH, Kang CM, Zalupski M, Ahmad H, Yentz S, Helton S, Rose JB, Takishita C, Nagakawa Y, Abu Hilal M. Gemcitabine-Based Neoadjuvant Treatment in Borderline Resectable Pancreatic Ductal Adenocarcinoma: A Meta-Analysis of Individual Patient Data. Front Oncol 2020; 10:1112. [PMID: 32850319 PMCID: PMC7431761 DOI: 10.3389/fonc.2020.01112] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 06/03/2020] [Indexed: 12/20/2022] Open
Abstract
Background: Non-randomized studies have investigated multi-agent gemcitabine-based neo-adjuvant therapies (GEM-NAT) in borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC). Treatment sequencing and specific elements of neoadjuvant treatment are still under investigation. The present meta-analysis aims to assess the effectiveness of GEM-NAT on overall survival (OS) in BR-PDAC. Patients and Methods: A meta-analysis of individual participant data (IPD) on GEM-NAT for BR-PDAC were performed. The primary outcome was OS after treatment with GEM-based chemotherapy. In the Individual Patient Data analysis data were reappraised and confirmed as BR-PDAC on provided radiological data. Results: Six studies investigating GEM-NAT were included in the IPD metanalysis. The IPD metanalysis was conducted on 271 patients who received GEM-NAT. Pooled median patient-level OS was 22.2 months (95%CI 19.1–25.2). R0 rates ranged between 81 and 95% (I2 = 0%, p = 0.64), respectively. Median OS was 27.8 months (95%CI 23.9–31.6) in the patients who received NAT-GEM followed by resection compared to 15.4 months (95%CI 12.3–18.4) for NAT-GEM without resection and 13.0 months (95%CI 7.4–18.5) in the group of patients who received upfront surgery (p < 0.0001). R0 rates ranged between 81 and 95% (I2 = 0%, p = 0.64), respectively. Overall survival in the R0 group was 29.3 months (95% CI 24.3–34.2) vs. 16.2 months (95% CI 7·9–24.5) in the R1 group (p = 0·001). Conclusions: The present study is the first meta-analysis combining IPD from a number of international centers with BR-PDAC in a cohort that underwent multi-agent gemcitabine neoadjuvant therapy (GEM-NAT) before surgery. GEM-NAT followed by surgical resection improve survival and R0 resection in BR-PDAC. Also, GEM-NAT may result in a good palliative option in non-resected patients because of progressive disease after neoadjuvant treatment. Results from randomized controlled trials (RCTs) are awaited to validate these findings.
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Affiliation(s)
- Francesco Giovinazzo
- Department of Surgery, University Hospital of Southampton NHS Foundation Trust, Southampton, United Kingdom
| | - Fiammetta Soggiu
- Hepato-Pancreato-Biliary and Liver Transplant Unit, Royal Free Hospital, London, United Kingdom
| | - Jin-Young Jang
- Department of Surgery, Seoul National University Hospital, Seoul, South Korea
| | - Eva Versteijne
- Department of Radiation Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Geertjan van Tienhoven
- Department of Radiation Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Casper H van Eijck
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Youngmin Han
- Department of Surgery, Seoul National University Hospital, Seoul, South Korea
| | - Seong Ho Choi
- Department of Surgery, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Chang Moo Kang
- Division of HBP Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Mark Zalupski
- Department of Medicine, University of Michigan, Ann Arbor, MI, United States
| | - Hasham Ahmad
- Department of Surgery, University Hospital of Leicester NHS Trust, Leicester, United Kingdom
| | - Sarah Yentz
- Department of Medicine, University of Michigan, Ann Arbor, MI, United States
| | - Scott Helton
- Section of General, Thoracic and Vascular Surgery, Department of Surgery, Virginia Mason Medical Center, Seattle, WA, United States
| | - J Bart Rose
- Section of Surgical Oncology, University of Alabama, Birmingham, AL, United States
| | - Chie Takishita
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Yuichi Nagakawa
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Mohammad Abu Hilal
- Department of Surgery, University Hospital of Southampton NHS Foundation Trust, Southampton, United Kingdom.,Depatment of Surgery, Fondazione Poliambulanza Istituto Ospedaliero Multispecialistico, Brescia, Italy
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Attia F, Fathy S, Anani M, Hassan A, Attia F, Ibrahim G, Elazab M. Human equilibrative nucleoside transporter-1 and deoxycytidine kinase can predict gemcitabine effectiveness in Egyptian patients with Hepatocellular carcinoma. J Clin Lab Anal 2020; 34:e23457. [PMID: 32671914 PMCID: PMC7676182 DOI: 10.1002/jcla.23457] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 05/28/2020] [Accepted: 06/01/2020] [Indexed: 01/30/2023] Open
Abstract
Background Several biomarkers of gemcitabine effectiveness have been studied in cancers, but less so in hepatocellular carcinoma (HCC), which is identified as the fifth most common cancer worldwide. Investigation of human equilibrative nucleoside transporter‐1 (HENT‐1) and deoxycytidine kinase (DCK), genes involved in gemcitabine uptake and metabolism, can be beneficial in the selection of potential cancer patients who could be responding to the treatment. Aim To study HENT‐1 and DCK gene expression in HCC patients with different protocols of treatment. Methods Using real‐time PCR, we analyzed expression levels of HENT‐1 and DCK genes from peripheral blood samples of 109 patients (20 controls & 89 HCC patients) between March 2015 and March 2017. All the 89 HCC patients received the antioxidants selenium (Se) and vitamin E (Vit.E) either alone (45 patients) or in combination with gemcitabine (24 patients) or radiofrequency ablation (RFA) (20 patients). Results There was a significant increase in HENT‐1 expression levels in HCC patients treated with Se and Vit.E alone as compared to controls (P ˂ .0001), while there was no significant difference between HCC patients treated with gemcitabine or RFA as compared to controls. In contrast, expression of DCK was significantly increased in all groups of HCC patients as compared to controls (P ˂ .0001). Conclusions HENT‐1 and DCK mRNA expressions are important markers of HCC and for GEM effect and GEM sensitivity in patients with HCC. This could be beneficial in the selection of HCC patients sensitive to gemcitabine to avoid subjecting resistant patients to unnecessary chemotherapy.
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Affiliation(s)
- Fadia Attia
- Departments of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Sara Fathy
- Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt
| | - Maha Anani
- Departments of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Adel Hassan
- Infectious and Endemic Disease Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Fawzy Attia
- Internal Medicine Department, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Gehan Ibrahim
- Departments of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia, Egypt
| | - Mona Elazab
- Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt
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He C, Wang J, Zhang Y, Lin X, Li S. Irreversible electroporation after induction chemotherapy versus chemotherapy alone for patients with locally advanced pancreatic cancer: A propensity score matching analysis. Pancreatology 2020; 20:477-484. [PMID: 32131993 DOI: 10.1016/j.pan.2020.02.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 02/12/2020] [Accepted: 02/15/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Locally advanced pancreatic cancer (LAPC) is a devastating disease and irreversible electroporation (IRE) is a non-thermal ablation method that is especially suitable for the treatment of LAPC. This study aimed to compare the long-term survival of LAPC patients after induction chemotherapy followed by IRE and chemotherapy alone. METHODS From August 2015 to August 2017, a total of 132 patients with LAPC were identified. The oncological outcomes of these two treatments were analyzed by propensity score matching (PSM) analysis. RESULTS Before PSM analysis, patients with LAPC had better overall survival (OS) and progression-free survival (PFS) after induction chemotherapy followed by IRE than those who received chemotherapy alone (2-year OS rates, 57.9% vs 19.8%, P < 0.001; 2-year PFS rates, 31.4% vs 9.3%, P < 0.001). The baseline clinicopathological factors were balanced between the 2 groups through PSM analysis. Even after PSM, the OS and PFS rates of patients after induction chemotherapy followed by IRE treatment were superior to those of patients who received chemotherapy treatment alone (2-year OS rates, 57.9% vs 18.1%, P < 0.001; 2-year PFS rates, 31.4% vs 7.1%, P < 0.001). Multivariate Cox regression analysis indicated that chemotherapy plus IRE was a significant prognostic factor for both OS and PFS in patients of both the whole cohort and the matched cohort. CONCLUSIONS Induction chemotherapy followed by IRE provided better OS and PFS than chemotherapy alone for patients with LAPC. This combination method may be a more suitable treatment for patients with LAPC.
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Affiliation(s)
- Chaobin He
- Department of Pancreatobiliary Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China.
| | - Jun Wang
- Department of Pancreatobiliary Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China; Department of Ultrasonics, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China.
| | - Yu Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong, 510060, PR China.
| | - Xiaojun Lin
- Department of Pancreatobiliary Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China.
| | - Shengping Li
- Department of Pancreatobiliary Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, PR China.
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Neuzillet C, Gaujoux S, Williet N, Bachet JB, Bauguion L, Colson Durand L, Conroy T, Dahan L, Gilabert M, Huguet F, Marthey L, Meilleroux J, de Mestier L, Napoléon B, Portales F, Sa Cunha A, Schwarz L, Taieb J, Chibaudel B, Bouché O, Hammel P. Pancreatic cancer: French clinical practice guidelines for diagnosis, treatment and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, ACHBT, AFC). Dig Liver Dis 2018; 50:1257-1271. [PMID: 30219670 DOI: 10.1016/j.dld.2018.08.008] [Citation(s) in RCA: 104] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Revised: 08/06/2018] [Accepted: 08/07/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND This document is a summary of the French intergroup guidelines regarding the management of pancreatic adenocarcinoma (PA), updated in July 2018. DESIGN This collaborative work was produced under the auspices of all French medical and surgical societies involved in the management of PA. It is based on the previous guidelines, recent literature review and expert opinions. Recommendations were graded in three categories, according to the level of evidence. RESULTS Over the last seven years, significant changes in PA management have been implemented in clinical practice. Imaging/staging: diffusion magnetic resonance imaging is useful before surgery to rule out small liver metastases. SURGERY centralization of pancreatic surgery in expert centers is associated with a decreased postoperative mortality. Adjuvant chemotherapy: modified FOLFIRINOX in fit patients, or gemcitabine, or 5-FU, or gemcitabine plus capecitabine, to be discussed on a case-by-case basis. Locally advanced PA: no survival benefit of chemoradiotherapy. Metastatic PA: FOLFIRINOX and gemcitabine plus nab-paclitaxel combination are first-line standards in fit patients; second-line with 5FU/nal-IRI or 5FU/oxaliplatin combination after first-line gemcitabine. CONCLUSION Guidelines for management of PA are continuously evolving and need to be regularly updated. This constant progress is made possible through clinical and translational research. However, as each individual case is particular, they cannot substitute to multidisciplinary tumor board discussion.
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Affiliation(s)
- Cindy Neuzillet
- Department of Medical Oncology, Curie Institute, Versailles Saint-Quentin University (UVSQ), Saint-Cloud, France.
| | - Sébastien Gaujoux
- Department of Digestive, Hepato-Biliary and Pancreatic Surgery, Cochin Hospital, AP-HP, Paris Descartes Faculty of Medicine, Paris Descartes University, Sorbonne Paris Cité, Paris, France
| | - Nicolas Williet
- Hepato-Gastroenterology Department, University Hospital of Saint-Etienne, Saint Priest en Jarez, France
| | - Jean-Baptiste Bachet
- Hepato-Gastroenterology Department, Pitié Salpétrière University Hospital, AP-HP, Paris Cedex 13, France
| | - Lucile Bauguion
- Hepato-Gastroenterology Department, Departmental Hospital Center, La Roche sur Yon, France
| | - Laurianne Colson Durand
- Department of Radiotherapy, Henri Mondor Hospital, AP-HP, Université Paris Est Creteil, Créteil, France
| | - Thierry Conroy
- Department of Medical Oncology, Lorraine Institute of Oncology and Lorraine University, Vandoeuvre-lès-Nancy Cedex, France
| | - Laetitia Dahan
- Digestive Oncology Department, "DACCORD" (Digestif, Anatomie pathologique, Chirurgie, CISIH, Oncologie, Radiothérapie, Dermatologie) pole, CHU Timone, Marseille Cedex 05, France
| | - Marine Gilabert
- Paoli Calmettes Institute, Department of Medical Oncology and Cancer Research Center of Marseille (CRCM), INSERM U1068 Stress Cell, Aix-Marseille University, Marseille, France
| | - Florence Huguet
- Department of Oncology and Radiotherapy, Tenon Hospital, East Paris University Hospitals, AP-HP, Paris Sorbonne University, Paris, France
| | - Lysiane Marthey
- Gastroenterology Department, Béclère Hospital, AP-HP, Clamart, France
| | - Julie Meilleroux
- Pathology Department, Toulouse University Hospital, Toulouse, France
| | - Louis de Mestier
- Department of Gastroenterology-Pancreatology, Beaujon Hospital, APHP, Paris 7 University, Clichy, France
| | - Bertrand Napoléon
- Jean Mermoz Private Hospital, Ramsay Générale de Santé, Lyon, France
| | - Fabienne Portales
- Digestive Oncology Department, Regional Institute of Cancer, Montpellier, France
| | - Antonio Sa Cunha
- INSERM UMR 935, Paul Brousse Hospital, Hepatobiliary Center, AP-HP, Université Paris-Sud, Université Paris-Saclay, Villejuif, France
| | - Lilian Schwarz
- Department of Digestive Surgery, Hôpital Charles Nicolle, Rouen University Hospital, Rouen, France and Genomic and Personalized Medicine in Cancer and Neurological Disorders, UMR 1245 INSERM, Rouen University, France
| | - Julien Taieb
- Hepato-Gastroenterology and Digestive Oncology Department, Georges Pompidou European Hospital, AP-HP, Paris, France
| | - Benoist Chibaudel
- Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France
| | - Olivier Bouché
- Hepato-Gastroenterology and Digestive Oncology Department, Robert Debré University Hospital, Avenue Général Koenig, 51092 Reims Cedex, France
| | - Pascal Hammel
- Department of Digestive Oncology, Beaujon University Hospital (AP-HP), Paris VII Diderot University, Clichy-la-Garenne, France.
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Parkin A, Man J, Chou A, Nagrial AM, Samra J, Gill AJ, Timpson P, Pajic M. The Evolving Understanding of the Molecular and Therapeutic Landscape of Pancreatic Ductal Adenocarcinoma. Diseases 2018; 6:diseases6040103. [PMID: 30428574 PMCID: PMC6313363 DOI: 10.3390/diseases6040103] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 11/07/2018] [Accepted: 11/08/2018] [Indexed: 12/18/2022] Open
Abstract
Pancreatic cancer is the third leading cause of cancer-related deaths, characterised by poor survival, marked molecular heterogeneity and high intrinsic and acquired chemoresistance. Only 10⁻20% of pancreatic cancer patients present with surgically resectable disease and even then, 80% die within 5 years. Our increasing understanding of the genomic heterogeneity of cancer suggests that the failure of definitive clinical trials to demonstrate efficacy in the majority of cases is likely due to the low proportion of responsive molecular subtypes. As a consequence, novel treatment strategies to approach this disease are urgently needed. Significant developments in the field of precision oncology have led to increasing molecular stratification of cancers into subtypes, where individual cancers are selected for optimal therapy depending on their molecular or genomic fingerprint. This review provides an overview of the current status of clinically used and emerging treatment strategies, and discusses the advances in and the potential for the implementation of precision medicine in this highly lethal malignancy, for which there are currently no curative systemic therapies.
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Affiliation(s)
- Ashleigh Parkin
- The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
| | - Jennifer Man
- The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
| | - Angela Chou
- The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
- University of Sydney, Sydney, NSW 2006, Australia.
| | - Adnan M Nagrial
- The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
- Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, NSW 2145, Australia.
| | - Jaswinder Samra
- Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia.
| | - Anthony J Gill
- The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
- University of Sydney, Sydney, NSW 2006, Australia.
- Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, Sydney, NSW 2065, Australia.
- Cancer Diagnosis and Pathology Research Group, Kolling Institute of Medical Research, St Leonards, NSW 2065, Australia.
| | - Paul Timpson
- The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
- St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia.
| | - Marina Pajic
- The Kinghorn Cancer Centre, The Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, NSW 2010, Australia.
- St Vincent's Clinical School, Faculty of Medicine, University of NSW, Sydney, NSW 2010, Australia.
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11
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Van Cutsem E, Hidalgo M, Canon JL, Macarulla T, Bazin I, Poddubskaya E, Manojlovic N, Radenkovic D, Verslype C, Raymond E, Cubillo A, Schueler A, Zhao C, Hammel P. Phase I/II trial of pimasertib plus gemcitabine in patients with metastatic pancreatic cancer. Int J Cancer 2018; 143:2053-2064. [PMID: 29756206 DOI: 10.1002/ijc.31603] [Citation(s) in RCA: 74] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 03/09/2018] [Accepted: 03/13/2018] [Indexed: 08/30/2023]
Abstract
The selective MEK1/2 inhibitor pimasertib has shown anti-tumour activity in a pancreatic tumour model. This phase I/II, two-part trial was conducted in patients with metastatic pancreatic adenocarcinoma (mPaCa) (NCT01016483). In the phase I part, oral pimasertib was given once daily discontinuously (5 days on/2 days off treatment) or twice daily continuously (n = 53) combined with weekly gemcitabine (1,000 mg/m2 ) in 28-day cycles to identify the recommended phase II dose (RP2D) of pimasertib. In the phase II part, patients were randomised to pimasertib (RP2D) or placebo plus weekly gemcitabine (n = 88) to investigate progression-free survival (PFS), overall survival (OS) and safety. The RP2D was determined to be 60 mg BID. PFS and OS outcomes did not indicate any treatment benefit for pimasertib over placebo in combination with gemcitabine (median PFS 3.7 and 2.8 months, respectively, HR = 0.91, 95% CI: 0.58-1.42: median OS 7.3 vs. 7.6 months, respectively). KRAS status did not influence PFS or OS. The incidence of grade ≥3 adverse events was 91.1% and 85.7% for pimasertib/gemcitabine and placebo/gemcitabine respectively, but there was a higher incidence of ocular events with pimasertib/gemcitabine (28.9% vs. 4.8% for placebo/gemcitabine). In conclusion, no clinical benefit was observed with first-line pimasertib plus gemcitabine compared with gemcitabine alone in patients with mPaCa.
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Affiliation(s)
- Eric Van Cutsem
- Gastroenterology/Digestive Oncology, University Hospitals Gasthuisberg/Leuven & KULeuven, Leuven, Belgium
| | - Manuel Hidalgo
- Centro Nacional Investigaciones Oncologicas, Madrid, Spain and START Madrid, Madrid, Spain
| | - Jean-Luc Canon
- Service d'Oncologie-Hématologie, Grand Hopital de Charleroi, Charleroi, Belgium
| | - Teresa Macarulla
- Gastrointestinal Cancer Unit, Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology, Barcelona, Spain
| | - Igor Bazin
- Department of Clinical Pharmacology and Chemotherapy, N.N. Blokhin Russian Cancer Research Center, and I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Elena Poddubskaya
- Department of Clinical Pharmacology and Chemotherapy, N.N. Blokhin Russian Cancer Research Center, and I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Nebojsa Manojlovic
- Clinic for Gastroenterology and Hepatology, Military Medical Academy of Serbia, Belgrade, Serbia
| | - Dejan Radenkovic
- First Surgical Clinic, Clinical Center of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Chris Verslype
- Gastroenterology/Digestive Oncology, University Hospitals Gasthuisberg/Leuven & KULeuven, Leuven, Belgium
| | - Eric Raymond
- Medical Oncology Département, Saint Joseph Hospital, Paris, France
| | - Antonio Cubillo
- HM Universitario Sanchinarro, Centro Integral Oncológico Clara Campal (HM-CIOCC), and Departamento de Ciencias Médicas Clínicas, Universidad CEU San Pablo, Madrid, Spain
| | | | - Charles Zhao
- Clinical Oncology Early Development, EMD Serono, Billerica, MA
| | - Pascal Hammel
- Digestive Oncology Unit, Hôpital Beaujon, Clichy, France
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Murata S, Onozawa S, Yasui D, Ueda T, Sugihara F, Shimizu A, Suzuki K, Satake M. Evaluating the Feasibility of Isolated Pancreatic Perfusion for Chemotherapy Using Computed Tomography: An Experimental Study in Pig Models. Cardiovasc Intervent Radiol 2018; 41:1081-1088. [PMID: 29582129 DOI: 10.1007/s00270-018-1943-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Accepted: 03/18/2018] [Indexed: 01/23/2023]
Abstract
PURPOSE Percutaneous isolated pancreatic perfusion (PIPP) is performed along with interventional radiology techniques to obtain high drug concentration by occluding the arterial inlet and venous outlet of the pancreas. The experimental study aimed to evaluate the contrast distribution in PIPP under different flow rates with or without anterior mesenteric artery (AMA) occlusion. MATERIALS AND METHODS This study was approved by a local animal experiment ethics committee. Nine pigs were divided into Groups 1, 2, and 3, by infusion rates of 12, 24, and 36 mL/min. Groups 4 and 5 (3 pigs each) and Group 6 (2 pigs) underwent PIPP at the same respective infusion rates with and without AMA occlusion. Computed tomography (CT) arteriography was performed during PIPP with nonionic contrast media. The enhanced volume was calculated by adding the enhanced area in each slice using 1.25-mm axial images. The percent enhanced volume to the whole pancreas (%eV) was used to simulate drug distribution; the result was compared among groups. RESULTS Without AMA occlusion, a larger %eV was obtained with high infusion rates (P = 0.039). The median %eV in Groups 1, 2, and 3 were 57.7, 74.2, and 90.5%, respectively. With AMA occlusion, CT demonstrated duodenal enhancement at an infusion rate of 36 mL/min, and the median %eV in Groups 4, 5, and 6 were 92.8, 95.4, and 98.5%, respectively. A significantly larger %eV was obtained after AMA occlusion (P = 0.031). CONCLUSION A higher infusion rate or AMA occlusion increases the enhanced volume in PIPP in pig models. LEVEL OF EVIDENCE No level of evidence.
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Affiliation(s)
- Satoru Murata
- Radiology/Center for Interventional Radiology, Teikyo University Chiba Medical Center, 3426-3 Anesaki, Ichihara, Chiba, 299-0111, Japan.
| | - Shiro Onozawa
- Departments of Radiology, Teikyo University Mizonokuchi Hospital, 5-1-1 Futago, Takatsu-ku, Kawasaki-shi, Kanagawa, 213-8507, Japan
| | - Daisuke Yasui
- Departments of Radiology/Center for Advanced Medical Technology, Nippon Medical School, 1-1-5 Sendagi, Bunkyou-ku, Tokyo, 113-8602, Japan
| | - Tatsuo Ueda
- Departments of Radiology/Center for Advanced Medical Technology, Nippon Medical School, 1-1-5 Sendagi, Bunkyou-ku, Tokyo, 113-8602, Japan
| | - Fumie Sugihara
- Departments of Radiology/Center for Advanced Medical Technology, Nippon Medical School, 1-1-5 Sendagi, Bunkyou-ku, Tokyo, 113-8602, Japan
| | - Akira Shimizu
- Departments of Analytic Human Pathology, Nippon Medical School, 1-1-5 Sendagi, Bunkyou-ku, Tokyo, 113-8602, Japan
| | - Kenichi Suzuki
- Departments of Medical Engineering, Nippon Medical School, 1-1-5 Sendagi, Bunkyou-ku, Tokyo, 113-8602, Japan
| | - Mitsuo Satake
- Departments of Radiology/Center for Advanced Medical Technology, Nippon Medical School, 1-1-5 Sendagi, Bunkyou-ku, Tokyo, 113-8602, Japan
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Zhang XW, Ma YX, Sun Y, Cao YB, Li Q, Xu CA. Gemcitabine in Combination with a Second Cytotoxic Agent in the First-Line Treatment of Locally Advanced or Metastatic Pancreatic Cancer: a Systematic Review and Meta-Analysis. Target Oncol 2018; 12:309-321. [PMID: 28353074 DOI: 10.1007/s11523-017-0486-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND It remains controversial whether the addition of a second cytotoxic agent can further improve the therapeutic effect of gemcitabine monotherapy in advanced or metastatic pancreatic cancer (LA/MPC). OBJECTIVE The objective of the present systematic review and meta-analysis was to investigate the efficacy and safety of gemcitabine-based doublet chemotherapy regimens compared to single-agent gemcitabine in the first-line treatment of unresectable LA/MPC. METHODS We searched for randomized controlled trials (RCTs) of gemcitabine monotherapy versus gemcitabine in combination with a second cytotoxic agent in patients with LA/MPC. The last search date was December 31, 2016. RESULTS Twenty-seven RCTs were identified and included in the present systematic review and meta-analysis, involving a total of 7343 patients. The meta-analysis showed that gemcitabine-based combination therapy significantly improved overall survival (OS) (HR: 0.89; 95% confidence interval (CI): 0.85-0.94; P < 0.0001), progression-free survival (PFS) (HR: 0.80; 95% CI: 0.73-0.88; P < 0.0001), and overall response rate (ORR) (RR: 1.83; 95% CI: 1.62-2.07; P < 0.0001) in comparison to single-agent gemcitabine. Subgroup analysis suggested that the antitumor activity differed between gemcitabine-based combination regimens: doublet regimens of gemcitabine plus a taxoid, and gemcitabine plus a fluoropyrimidine, in particular an oral fluoropyrimidine, resulted in a significant OS benefit for the patients. However, the combination of gemcitabine with other cytotoxic agents, such as platinum compounds or topoisomerase inhibitors failed to reduce the mortality risk. Combination therapy caused more grade 3/4 toxicities, including neutropenia, thrombocytopenia, vomiting, diarrhea, and fatigue. CONCLUSIONS Gemcitabine-based doublet regimens demonstrated superiority over gemcitabine monotherapy in overall efficacy, but were associated with increased toxicity. Different gemcitabine-based combinations showed different antitumor activity, and doublet regimens of gemcitabine in combination with a taxoid or a fluoropyrimidine, in particular an oral fluoropyrimidine provided significant survival benefits in the first-line treatment of unresectable LA/MPC.
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Affiliation(s)
- Xiu-Wei Zhang
- Department of Pathology, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
| | - Yu-Xiang Ma
- Department of Oncologic Medicine, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Yang Sun
- Department of Oncologic Medicine, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Yu-Bo Cao
- Department of Oncologic Medicine, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China
| | - Qin Li
- Center for Translational Medicine, The Fourth Affiliated Hospital, China Medical University, Shenyang, China
| | - Chong-An Xu
- Department of Oncologic Medicine, The Fourth Affiliated Hospital, China Medical University, Shenyang, 110032, China.
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14
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Alterations in Pharmacokinetics of Gemcitabine and Erlotinib by Concurrent Administration of Hyangsayukgunja-Tang, a Gastroprotective Herbal Medicine. Molecules 2017; 22:molecules22091515. [PMID: 28891960 PMCID: PMC6151743 DOI: 10.3390/molecules22091515] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 09/01/2017] [Accepted: 09/08/2017] [Indexed: 01/17/2023] Open
Abstract
Gemcitabine and erlotinib are the chemotherapeutic agents used in the treatment of various cancers and their combination is being accepted as a first-line treatment of advanced pancreatic cancer. Hyangsayukgunja-tang (HYT) is a traditional oriental medicine used in various digestive disorders and potentially helpful to treat gastrointestinal adverse effects related to chemotherapy. The present study was aimed to evaluate the effect of HYT on the pharmacokinetics of gemcitabine and erlotinib given simultaneously in rats. Rats were pretreated with HYT at an oral dose of 1200 mg/kg/day once daily for a single day or 14 consecutive days. Immediately after pretreatment with HYT, gemcitabine and erlotinib were administered by intravenous injection (10 mg/kg) and oral administration (20 mg/kg), respectively. The effects of HYT on pharmacokinetics of the two drugs were estimated by non-compartmental analysis and pharmacokinetic modeling. The pharmacokinetics of gemcitabine and erlotinib were not altered by single dose HYT pretreatment. However, the plasma levels of OSI-420 and OSI-413, active metabolites of erlotinib, were significantly decreased in the multiple dose HYT pretreatment group. The pharmacokinetic model estimated increased systemic clearances of OSI-420 and OSI-413 by multiple doses of HYT. These data suggest that HYT may affect the elimination of OSI-420 and OSI-413.
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15
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Belfiore G, Belfiore MP, Reginelli A, Capasso R, Romano F, Ianniello GP, Cappabianca S, Brunese L. Concurrent chemotherapy alone versus irreversible electroporation followed by chemotherapy on survival in patients with locally advanced pancreatic cancer. Med Oncol 2017; 34:38. [DOI: 10.1007/s12032-017-0887-4] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Accepted: 01/11/2017] [Indexed: 01/20/2023]
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Paz-Ares L, Forster M, Boni V, Szyldergemajn S, Corral J, Turnbull S, Cubillo A, Teruel CF, Calderero IL, Siguero M, Bohan P, Calvo E. Phase I clinical and pharmacokinetic study of PM01183 (a tetrahydroisoquinoline, Lurbinectedin) in combination with gemcitabine in patients with advanced solid tumors. Invest New Drugs 2016; 35:198-206. [PMID: 27873130 DOI: 10.1007/s10637-016-0410-3] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 11/16/2016] [Indexed: 12/11/2022]
Abstract
Background To determine the recommended dose (RD) of a combination of PM01183 and gemcitabine in patients with advanced solid tumors. Methods Forty-five patients received escalating doses of PM01183/gemcitabine on Days 1 and 8 every 3 weeks (d1,8 q3wk) following a standard 3 + 3 design. Results PM01183 3.5 mg flat dose (FD)/gemcitabine 1000 mg/m2 was the highest dose level tested. Dose-limiting toxicities (DLTs) were mostly hematological and resulted in the expansion of a lower dose level (PM01183 3.5 mg FD/gemcitabine 800 mg/m2); 19 patients at this dose level were evaluable but >30% had DLT and >20% had febrile neutropenia. No DLT was observed in 11 patients treated at PM01183 3.0 mg FD/gemcitabine 800 mg/m2, which was defined as the RD. This regimen was feasible and tolerable with manageable toxicity; mainly grade 3/4 myelosuppression. Non-hematological toxicity comprised fatigue, nausea, vomiting, and transaminases increases. Fifteen (33%) patients received ≥6 cycles with no cumulative hematological toxicity. Pharmacokinetic analysis showed no evidence of drug-drug interaction. Nine of 38 patients had response as per RECIST (complete [3%] and partial [21%]), for an overall response rate (ORR) of 24% (95% Confidence Interval [CI] 12-40%). Eleven patients (29%) had disease stabilization ≥4 months. Responses were durable (median of 8.5 months): overall median progression-free survival (PFS) was 4.2 months (95% CI, 2.7-6.5 months). Conclusions The RD for this combination is PM01183 3.0 mg FD (or 1.6 mg/m2)/gemcitabine 800 mg/m2 d1,8 q3wk. This schedule is well tolerated and has antitumor activity in several advanced solid tumor types.
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Affiliation(s)
- Luis Paz-Ares
- Hospital Universitario Virgen del Rocío, Seville, Spain
- Chair of the Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
| | | | - Valentina Boni
- START Madrid, Centro Integral Oncológico Clara Campal, Hospital Universitario Madrid Sanchinarro, Madrid, Spain
| | | | - Jesús Corral
- Hospital Universitario Virgen del Rocío, Seville, Spain
| | - Samantha Turnbull
- University College of London Hospital, London, UK
- Clinical Research Fellow and SpR in Medical Oncology, Leeds Immunotherapy Team (LIT) at the Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK
| | - Antonio Cubillo
- START Madrid, Centro Integral Oncológico Clara Campal, Hospital Universitario Madrid Sanchinarro, Madrid, Spain
| | | | - Iker López Calderero
- Hospital Universitario Virgen del Rocío, Seville, Spain
- Consultant Clinical Oncologist in Can Misses Hospital, Ibiza, Spain
| | | | | | - Emiliano Calvo
- START Madrid, Centro Integral Oncológico Clara Campal, Hospital Universitario Madrid Sanchinarro, Madrid, Spain.
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17
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Shin S, Park CM, Kwon H, Lee KH. Erlotinib plus gemcitabine versus gemcitabine for pancreatic cancer: real-world analysis of Korean national database. BMC Cancer 2016; 16:443. [PMID: 27400734 PMCID: PMC4940912 DOI: 10.1186/s12885-016-2482-z] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Accepted: 07/04/2016] [Indexed: 12/18/2022] Open
Abstract
Background A randomized clinical trial has found that the addition of erlotinib to gemcitabine (GEM-E) for pancreatic cancer led to a modest increase in survival. The aim of this national population-based retrospective study was to compare the effectiveness of GEM-E to GEM alone for pancreatic cancer patients in real clinical practice. Methods Patients with pancreatic cancer (ICD-10: C25) with prescription claims of gemcitabine or erlotinib between Jan 1, 2007 and Dec 31, 2012 were retrospectively identified from the Korean Health Insurance claims database. To be included in the study population, patients were required to have had a histological or cytological diagnosis within one year before chemotherapy. Patients treated with prior radiotherapy, surgery, or chemotherapy were excluded to reduce heterogeneity. Overall survival from the initiation of therapy and the medical costs of GEM-E and GEM were compared. Results A total of 4,267 patients were included in the analysis. Overall survival was not significantly longer in patients treated with GEM-E (median 6.77 months for GEM-E vs. 6.68 months for GEM, p = 0.0977). There was also no significant difference in the respective one-year survival rates (27.0 % vs. 27.3 %; p = 0.5988). Multivariate analysis using age, gender, and comorbidities as covariates did not reveal any significant differences in survival. Based on this relative effectiveness, the incremental cost per life year gained over GEM was estimated at USD 70,843.64 for GEM-E. Conclusions GEM-E for pancreatic cancer is not more effective than GEM in a real-world setting, and it does not provide reasonable cost-effectiveness over GEM. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2482-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Sangjin Shin
- National Evidence-based healthcare Collaborating Agency, Seoul, Korea
| | - Chan Mi Park
- National Evidence-based healthcare Collaborating Agency, Seoul, Korea
| | - Hanbyeol Kwon
- National Evidence-based healthcare Collaborating Agency, Seoul, Korea
| | - Kyung-Hun Lee
- Department of Internal Medicine, Seoul National University Hospital, 101 Daehak-Ro, Jongno-Gu, Seoul, 110-744, South Korea. .,Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
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GONG JUN, TULI RICHARD, SHINDE ARVIND, HENDIFAR ANDREWE. Meta-analyses of treatment standards for pancreatic cancer. Mol Clin Oncol 2016; 4:315-325. [PMID: 26998283 PMCID: PMC4774516 DOI: 10.3892/mco.2015.716] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Accepted: 11/23/2015] [Indexed: 01/05/2023] Open
Abstract
Pancreatic cancer is the most lethal common cancer with an estimated 5-year survival rate of 6-7% (across all stages). The only potential curative therapy is surgical resection in those with localized disease. Adjuvant (postoperative) therapy confers a survival advantage over postoperative observation alone. Neoadjuvant (preoperative) therapy offers the potential to downstage initially unresectable tumors for resection, sterilize resection margins and decrease locoregional recurrence, and identify a subset of patients with aggressive disease for whom surgery will not be beneficial. Induction chemotherapy followed by consolidation chemoradiation is another recommended approach in those with locally advanced disease. For those who cannot be downstaged, cannot tolerate surgery, or were diagnosed with metastatic disease, treatment remains palliative with chemotherapy being a critical component of this approach. Recently, intensive combination chemotherapy has been shown to improve survival rates in comparison to gemcitabine alone in advanced disease. The past few decades have afforded an accumulation of high-level evidence regarding neoadjuvant, adjuvant and palliative therapies in pancreatic cancer. There are numerous reviews discussing recent retrospective studies, prospective studies and randomized controlled trials in each of these areas. However, reviews of optimal and recommended treatment strategies across all stages of pancreatic cancer that focus on the highest levels of hierarchical evidence, such as meta-analyses, are limited. The discussion of novel therapeutics is beyond the scope of this review. However, an extensive and the most current collection of meta-analyses of first-line systemic and locoregional treatment options for all stages of pancreatic cancer to date has been accumulated.
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Affiliation(s)
- JUN GONG
- Department of Internal Medicine, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - RICHARD TULI
- Department of Radiation Oncology, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - ARVIND SHINDE
- Department of Hematology and Oncology, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - ANDREW E. HENDIFAR
- Gastrointestinal and Neuroendocrine Malignancies, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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Ouyang G, Liu Z, Huang S, Li Q, Xiong L, Miao X, Wen Y. Gemcitabine plus cisplatin versus gemcitabine alone in the treatment of pancreatic cancer: a meta-analysis. World J Surg Oncol 2016; 14:59. [PMID: 26927942 PMCID: PMC4772457 DOI: 10.1186/s12957-016-0813-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 02/16/2016] [Indexed: 12/11/2022] Open
Abstract
Background Pancreatic cancer ranks as the fourth leading cause of cancer-related mortality in the USA. And gemcitabine has been the standard of care for advanced pancreatic cancer. However, a combined use of gemcitabine plus cisplatin (GemCis) has shown promising efficacies in pancreatic cancer patients. Here, system review and meta-analysis were performed to compare the efficacy and safety of GemCis versus gemcitabine (Gem) alone in the treatment of pancreatic cancer. Methods The databases of MEDLINE (PubMed), EMBASE, and Cochrane Library were systematically searched for retrieving the relevant publications prior to 31 September 2014. The primary end point was overall survival (OS) and secondary end points included 6-month survival, 1 year survival, overall response rate (ORR), clinical benefit rate (CBR), time to progression/progression-free survival (TTP/PFS), and toxicities. Results A total of nine randomized controlled trials involving 1354 patients were included for systematic evaluations. Overall, as compared with Gem alone, GemCis significantly improved the 6-month survival rate (relative risk (RR) = 1.303, 95 % confidence interval (CI) 1.090–1.558, P = 0.004), ORR (RR = 1.482, 95 % CI 1.148–1.913, P = 0.003), PFS/TTP (hazard ratio (HR) = 0.87; 95 % CI 0.78–0.93, P = 0.022), and the overall toxicities (RR = 2.164, 95 % CI 1.837–2.549, P = 0.000). However, no significance difference existed in overall survival (HR = 0.90, 95 % CI 0.80–1.42, P = 1.02), 1-year survival rate (RR = 0.956, 95 % CI 0.770–1.187, P = 0.684), and CBR (RR = 0.854, 95 % CI 0.681–1.072, P = 0.175). As for grade III/IV toxicity, seven kinds of toxicities were higher in the GemCis group. However, no significant inter-group statistical differences existed in the incidence of leukopenia, thrombocytopenia, or diarrhea. Conclusions Despite a higher incidence of three-fourths toxicity, GemCis offers better outcomes of ORR, PFS/TTP, and 6-month survival, which indicates GemCis may be a promising therapy for pancreatic cancer.
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Affiliation(s)
- Guoqing Ouyang
- Department of General Surgery, The Second Xiangya Hospital,Central South University, No.139 Renmin Road, Changsha, 410011, Hunan, People's Republic of China
| | - Zhipeng Liu
- Department of General Surgery, The Second Xiangya Hospital,Central South University, No.139 Renmin Road, Changsha, 410011, Hunan, People's Republic of China
| | - Shengfu Huang
- Department of General Surgery, The Second Xiangya Hospital,Central South University, No.139 Renmin Road, Changsha, 410011, Hunan, People's Republic of China
| | - Qianglong Li
- Department of General Surgery, The Second Xiangya Hospital,Central South University, No.139 Renmin Road, Changsha, 410011, Hunan, People's Republic of China
| | - Li Xiong
- Department of General Surgery, The Second Xiangya Hospital,Central South University, No.139 Renmin Road, Changsha, 410011, Hunan, People's Republic of China
| | - Xiongying Miao
- Department of General Surgery, The Second Xiangya Hospital,Central South University, No.139 Renmin Road, Changsha, 410011, Hunan, People's Republic of China
| | - Yu Wen
- Department of General Surgery, The Second Xiangya Hospital,Central South University, No.139 Renmin Road, Changsha, 410011, Hunan, People's Republic of China.
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Singh A, Xu J, Mattheolabakis G, Amiji M. EGFR-targeted gelatin nanoparticles for systemic administration of gemcitabine in an orthotopic pancreatic cancer model. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2015; 12:589-600. [PMID: 26656632 DOI: 10.1016/j.nano.2015.11.010] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Revised: 11/16/2015] [Accepted: 11/19/2015] [Indexed: 01/05/2023]
Abstract
UNLABELLED In this study, we have formulated redox-responsive epidermal growth factor receptor (EGFR)-targeted type B gelatin nanoparticles as a targeted vector for systemic delivery of gemcitabine therapy in pancreatic cancer. The gelatin nanoparticles were formed by ethanol-induced desolvation process to encapsulate the bound drug. The surface of the nanoparticles was decorated either with poly(ethylene glycol) (PEG) chains to impart enhanced circulation time or with EGFR targeting peptide to confer target specificity. Our in vitro studies in Panc-1 human pancreatic ductal adenocarcinoma cells confirm that gemcitabine encapsulated in EGFR-targeted gelatin nanoparticles, released through disulfide bond cleavage, had a significantly improved cytotoxic profile. Further, the in vivo anticancer activity was evaluated in an orthotopic pancreatic adenocarcinoma tumor bearing SCID beige mice, which confirmed that EGFR-targeted gelatin nanoparticles could efficiently deliver gemcitabine to the tumor leading to higher therapeutic benefit as compared to the drug in solution. FROM THE CLINICAL EDITOR The treatment of pancreatic cancer remains unsatisfactory, with an average 5-year survival of less than 5%. New treatment modalities are thus urgently needed. In this study, the authors presented their formulation of redox-responsive epidermal growth factor receptor (EGFR)-targeted type B gelatin nanoparticles as a carrier for gemcitabine. In-vitro and in-vivo experiments showed encouraging results. It is hoped that the findings would provide a novel and alternative drug delivery platform for the future.
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Affiliation(s)
- Amit Singh
- Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, USA
| | - Jing Xu
- Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, USA
| | - George Mattheolabakis
- Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, USA
| | - Mansoor Amiji
- Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA, USA.
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Colloca G, Venturino A, Guarneri D. Analysis of Response-Related and Time-to-event Endpoints in Randomized Trials of Gemcitabine-Based Treatment Versus Gemcitabine Alone as First-Line Treatment of Patients With Advanced Pancreatic Cancer. Clin Colorectal Cancer 2015; 15:264-76. [PMID: 26776098 DOI: 10.1016/j.clcc.2015.11.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Revised: 11/03/2015] [Accepted: 11/23/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND Gemcitabine-based combinations in advanced pancreatic cancer have been reported to have superior activity compared with gemcitabine alone. The results of the commonly used endpoints of clinical trials after chemotherapy or targeted therapy have been poorly reported. METHODS AND MATERIALS We performed a search of randomized trials of systemic treatment that included gemcitabine plus chemotherapy or targeted therapy versus gemcitabine alone. For selected trials, the differences between the treatment arms for every endpoint were calculated, and a correlation analysis between these differences and the differences in overall survival was performed for every intermediate endpoint. Whenever a correlation coefficient was significant, regression analysis was performed. Finally, an analysis was performed to evaluate the factors that could mediate and moderate the effect of progression-free survival on overall survival. RESULTS In addition to overall survival, progression-free survival, the overall response rate, and the disease control rate were the most frequently reported endpoints. Of the possible surrogate endpoints of overall survival, progression-free survival appears to be a reliable endpoint to assess chemotherapy (R(2) = 0.646) and chemotherapy plus targeted therapy (R(2) = 0.530) regimens and the disease control rate to assess chemotherapy (R(2) = 0.569). Of the factors that could limit the effect of progression-free survival on overall survival, the interval of radiologic evaluation could play a role. CONCLUSION In the selected trials, progression-free survival and the disease control rate were the most reliable surrogate endpoints of overall survival. Similar to the time-to-event endpoints, a standardization of response-related endpoints is strongly recommended.
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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
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Neuzillet C, Tijeras-Raballand A, Bourget P, Cros J, Couvelard A, Sauvanet A, Vullierme MP, Tournigand C, Hammel P. State of the art and future directions of pancreatic ductal adenocarcinoma therapy. Pharmacol Ther 2015; 155:80-104. [PMID: 26299994 DOI: 10.1016/j.pharmthera.2015.08.006] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Accepted: 08/17/2015] [Indexed: 12/12/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is expected to become the second cause of cancer-related death in 2030. PDAC is the poorest prognostic tumor of the digestive tract, with 80% of patients having advanced disease at diagnosis and 5-year survival rate not exceeding 7%. Until 2010, gemcitabine was the only validated therapy for advanced PDAC with a modest improvement in median overall survival as compared to best supportive care (5-6 vs 3 months). Multiple phase II-III studies have used various combinations of gemcitabine with other cytotoxics or targeted agents, most in vain, in attempt to improve this outcome. Over the past few years, the landscape of PDAC management has undergone major and rapid changes with the approval of the FOLFIRINOX and gemcitabine plus nab-paclitaxel regimens in patients with metastatic disease. These two active combination chemotherapy options yield an improved median overall survival (11.1 vs 8.5 months, respectively) thus making longer survival a reasonably achievable goal. This breakthrough raises some new clinical questions about the management of PDAC. Moreover, better knowledge of the environmental and genetic events that underpin multistep carcinogenesis and of the microenvironment surrounding cancer cells in PDAC has open new perspectives and therapeutic opportunities. In this new dynamic context of deep transformation in basic research and clinical management aspects of the disease, we gathered updated preclinical and clinical data in a multifaceted review encompassing the lessons learned from the past, the yet unanswered questions, and the most promising research priorities to be addressed for the next 5 years.
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Affiliation(s)
- Cindy Neuzillet
- INSERM UMR1149, Bichat-Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 46 rue Henri Huchard, 75018 Paris, and 100 boulevard du Général Leclerc, 92110 Clichy, France; Department of Digestive Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 100 boulevard du Général Leclerc, 92110 Clichy, France; Department of Medical Oncology, Henri Mondor University Hospital, 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France.
| | - Annemilaï Tijeras-Raballand
- Department of Translational Research, AAREC Filia Research, 1 place Paul Verlaine, 92100 Boulogne-Billancourt, France
| | - Philippe Bourget
- Department of Clinical Pharmacy, Necker-Enfants Malades University Hospital, 149 Rue de Sèvres, 75015 Paris, France
| | - Jérôme Cros
- INSERM UMR1149, Bichat-Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 46 rue Henri Huchard, 75018 Paris, and 100 boulevard du Général Leclerc, 92110 Clichy, France; Department of Pathology, Bichat-Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 46 rue Henri Huchard, 75018 Paris, and 100 boulevard du Général Leclerc, 92110 Clichy, France
| | - Anne Couvelard
- INSERM UMR1149, Bichat-Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 46 rue Henri Huchard, 75018 Paris, and 100 boulevard du Général Leclerc, 92110 Clichy, France; Department of Pathology, Bichat-Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 46 rue Henri Huchard, 75018 Paris, and 100 boulevard du Général Leclerc, 92110 Clichy, France
| | - Alain Sauvanet
- Department of Biliary and Pancreatic Surgery, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 100 boulevard du Général Leclerc, 92110 Clichy, France
| | - Marie-Pierre Vullierme
- Department of Radiology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 100 boulevard du Général Leclerc, 92110 Clichy, France
| | - Christophe Tournigand
- Department of Medical Oncology, Henri Mondor University Hospital, 51 avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France
| | - Pascal Hammel
- INSERM UMR1149, Bichat-Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 46 rue Henri Huchard, 75018 Paris, and 100 boulevard du Général Leclerc, 92110 Clichy, France; Department of Digestive Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), 100 boulevard du Général Leclerc, 92110 Clichy, France
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Vaccaro V, Sperduti I, Vari S, Bria E, Melisi D, Garufi C, Nuzzo C, Scarpa A, Tortora G, Cognetti F, Reni M, Milella M. Metastatic pancreatic cancer: Is there a light at the end of the tunnel? World J Gastroenterol 2015; 21:4788-4801. [PMID: 25944992 PMCID: PMC4408451 DOI: 10.3748/wjg.v21.i16.4788] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Revised: 02/08/2015] [Accepted: 03/31/2015] [Indexed: 02/06/2023] Open
Abstract
Due to extremely poor prognosis, pancreatic cancer (PDAC) represents the fourth leading cause of cancer-related death in Western countries. For more than a decade, gemcitabine (Gem) has been the mainstay of first-line PDAC treatment. Many efforts aimed at improving single-agent Gem efficacy by either combining it with a second cytotoxic/molecularly targeted agent or pharmacokinetic modulation provided disappointing results. Recently, the field of systemic therapy of advanced PDAC is finally moving forward. Polychemotherapy has shown promise over single-agent Gem: regimens like PEFG-PEXG-PDXG and GTX provide significant potential advantages in terms of survival and/or disease control, although sometimes at the cost of poor tolerability. The PRODIGE 4/ACCORD 11 was the first phase III trial to provide unequivocal benefit using the polychemotherapy regimen FOLFIRINOX; however the less favorable safety profile and the characteristics of the enrolled population, restrict the use of FOLFIRINOX to young and fit PDAC patients. The nanoparticle albumin-bound paclitaxel (nab-Paclitaxel) formulation was developed to overcome resistance due to the desmoplastic stroma surrounding pancreatic cancer cells. Regardless of whether or not this is its main mechanisms of action, the combination of nab-Paclitaxel plus Gem showed a statistically and clinically significant survival advantage over single agent Gem and significantly improved all the secondary endpoints. Furthermore, recent findings on maintenance therapy are opening up potential new avenues in the treatment of advanced PDAC, particularly in a new era in which highly effective first-line regimens allow patients to experience prolonged disease control. Here, we provide an overview of recent advances in the systemic treatment of advanced PDAC, mostly focusing on recent findings that have set new standards in metastatic disease. Potential avenues for further development in the metastatic setting and current efforts to integrate new effective chemotherapy regimens in earlier stages of disease (neoadjuvant, adjuvant, and multimodal approaches in both resectable and unresectable patients) are also briefly discussed.
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Girelli R, Prejanò S, Cataldo I, Corbo V, Martini L, Scarpa A, Claudio B. Feasibility and safety of electrochemotherapy (ECT) in the pancreas: a pre-clinical investigation. Radiol Oncol 2015; 49:147-54. [PMID: 26029026 PMCID: PMC4387991 DOI: 10.1515/raon-2015-0013] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2014] [Accepted: 02/12/2015] [Indexed: 12/13/2022] Open
Abstract
Background. Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease generally refractory to standard chemotherapeutic agents; therefore improvements in anticancer therapies are mandatory. A major determinant of therapeutic resistance in PDAC is the poor drug delivery to neoplastic cells, mainly due to an extensive fibrotic reaction. Electroporation can be used in vivo to increase cancer cells’ local uptake of chemotherapeutics (electrochemotherapy, ECT), thus leading to an enhanced tumour response rate. In the present study, we evaluated the in vivo effects of reversible electroporation in normal pancreas in a rabbit experimental model. We also tested the effect of electroporation on pancreatic cancer cell lines in order to evaluate their increased sensitivity to chemotherapeutic agents. Materials and methods. The application in vivo of the European Standard Operating Procedure of Electrochemotherapy (ESOPE) pulse protocol (1000 V/cm, 8 pulses, 100 μs, 5 KHz) was tested on the pancreas of normal New Zealand White Rabbits and short and long-term toxicity were assessed. PANC1 and MiaPaCa2 cell lines were tested for in vitro electrochemotherapy experiments with and without electroporation. Levels of cell permeabilization were determined by flow cytometry, whereas cell viability and drug (cisplatin and bleomycin) sensitivity of pulsed cells were measured by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Results. In healthy rabbits, neither systemic nor local toxic effects due to the electroporation procedure were observed, demonstrating the safety of the optimized electric parameters in the treatment of the pancreas in vivo. In parallel, we established an optimized protocol for ECT in vitro that determined an enhanced anti-cancer effect of bleomycin and cisplatin with respect to treatment without electroporation. Conclusions. Our data suggest that electroporation is a safe procedure in the treatment of PDAC because it does not affect normal pancreatic parenchyma, but has a potentiating effect on cytotoxicity of bleomycin in pancreatic tumour cell lines. Therefore, ECT could be considered as a valid alternative for the local control of non-resectable pancreatic cancer.
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Affiliation(s)
- Roberto Girelli
- Pancreatic Unit - Casa di Cura Pederzoli, Peschiera del Garda (VR), Italy
| | - Simona Prejanò
- ARC-NET Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy
| | - Ivana Cataldo
- ARC-NET Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy
| | - Vincenzo Corbo
- ARC-NET Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy
| | - Lucia Martini
- Laboratory of Preclinical and Surgical Studies and Laboratory of Biocompatibility, Innovative Technologies and Advanced Therapies, Rizzoli Orthopedic Institute Bologna, Italy
| | - Aldo Scarpa
- ARC-NET Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy
| | - Bassi Claudio
- Department of Surgery and Oncology, Pancreas Institute, University and Hospital Trust of Verona, Verona, Italy
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Murata S, Onozawa S, Mine T, Ueda T, Sugihara F, Yasui D, Kumita SI, Shimizu A, Satake M. Minimizing Systemic Leakage of Cisplatin during Percutaneous Isolated Pancreas Perfusion Chemotherapy: A Pilot Study. Radiology 2015; 276:102-9. [PMID: 25734552 DOI: 10.1148/radiol.15141596] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
PURPOSE To evaluate the feasibility of percutaneous isolated pancreas perfusion (PIPP) by using a pig model. MATERIALS AND METHODS All experiments were approved by the institutional Animal Experiment Ethics Committee. Fifteen pigs were assigned to five groups, and PIPP was performed. Angiographic and dye injection studies were performed to confirm the patency of the PIPP system (group 1). Blood that contained cisplatin (1.5 mg per kilogram of body weight) in an extracorporeal circuit was circulated through the pancreas at three infusion rates (40, 60, and 80 mL/min) to determine the optimal infusion rate in terms of safety and pharmacologic effectiveness (groups 2, 3, and 4, respectively). Chronological laboratory data and histologic findings were assessed in group 5, which received the optimal infusion rate. Maximum platinum concentration (Cmax) and area under the platinum concentration-time curve were compared by using the Kruskal-Wallis and Mann-Whitney U tests. RESULTS Angiography and dye injection confirmed the patency of the PIPP system. Histopathologic examinations showed no abnormalities in the pancreas or other organs at a 40 mL/min infusion rate of cisplatin. However, edematous changes in the pancreas were observed at higher infusion rates. The pharmacologic effectiveness did not differ significantly among groups; therefore, the optimal infusion rate of 40 mL/min was selected. The median pancreatic-to-systemic exposure ratios were 71.8 for Cmax and 54.8 for the area under the curve. All laboratory data remained normal or returned to pretreatment levels within 1 week. CONCLUSION PIPP at a 40 mL/min infusion rate appears to be safe and feasible for perfusion of the pancreas.
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Affiliation(s)
- Satoru Murata
- From the Departments of Radiology and Center for Advanced Medical Technology (S.M., S.O., T.M., T.U., F.S., D.Y., S.K.) and Analytic Human Pathology (A.S.), Nippon Medical School, 1-1-5 Sendagi, Bunkyou-ku, Tokyo 113-8602, Japan; and Department of Diagnostic Radiology, National Cancer Center East, Kashiwa, Chiba, Japan (M.S.)
| | - Shiro Onozawa
- From the Departments of Radiology and Center for Advanced Medical Technology (S.M., S.O., T.M., T.U., F.S., D.Y., S.K.) and Analytic Human Pathology (A.S.), Nippon Medical School, 1-1-5 Sendagi, Bunkyou-ku, Tokyo 113-8602, Japan; and Department of Diagnostic Radiology, National Cancer Center East, Kashiwa, Chiba, Japan (M.S.)
| | - Takahiko Mine
- From the Departments of Radiology and Center for Advanced Medical Technology (S.M., S.O., T.M., T.U., F.S., D.Y., S.K.) and Analytic Human Pathology (A.S.), Nippon Medical School, 1-1-5 Sendagi, Bunkyou-ku, Tokyo 113-8602, Japan; and Department of Diagnostic Radiology, National Cancer Center East, Kashiwa, Chiba, Japan (M.S.)
| | - Tatsuo Ueda
- From the Departments of Radiology and Center for Advanced Medical Technology (S.M., S.O., T.M., T.U., F.S., D.Y., S.K.) and Analytic Human Pathology (A.S.), Nippon Medical School, 1-1-5 Sendagi, Bunkyou-ku, Tokyo 113-8602, Japan; and Department of Diagnostic Radiology, National Cancer Center East, Kashiwa, Chiba, Japan (M.S.)
| | - Fumie Sugihara
- From the Departments of Radiology and Center for Advanced Medical Technology (S.M., S.O., T.M., T.U., F.S., D.Y., S.K.) and Analytic Human Pathology (A.S.), Nippon Medical School, 1-1-5 Sendagi, Bunkyou-ku, Tokyo 113-8602, Japan; and Department of Diagnostic Radiology, National Cancer Center East, Kashiwa, Chiba, Japan (M.S.)
| | - Daisuke Yasui
- From the Departments of Radiology and Center for Advanced Medical Technology (S.M., S.O., T.M., T.U., F.S., D.Y., S.K.) and Analytic Human Pathology (A.S.), Nippon Medical School, 1-1-5 Sendagi, Bunkyou-ku, Tokyo 113-8602, Japan; and Department of Diagnostic Radiology, National Cancer Center East, Kashiwa, Chiba, Japan (M.S.)
| | - Shin-ichiro Kumita
- From the Departments of Radiology and Center for Advanced Medical Technology (S.M., S.O., T.M., T.U., F.S., D.Y., S.K.) and Analytic Human Pathology (A.S.), Nippon Medical School, 1-1-5 Sendagi, Bunkyou-ku, Tokyo 113-8602, Japan; and Department of Diagnostic Radiology, National Cancer Center East, Kashiwa, Chiba, Japan (M.S.)
| | - Akira Shimizu
- From the Departments of Radiology and Center for Advanced Medical Technology (S.M., S.O., T.M., T.U., F.S., D.Y., S.K.) and Analytic Human Pathology (A.S.), Nippon Medical School, 1-1-5 Sendagi, Bunkyou-ku, Tokyo 113-8602, Japan; and Department of Diagnostic Radiology, National Cancer Center East, Kashiwa, Chiba, Japan (M.S.)
| | - Mitsuo Satake
- From the Departments of Radiology and Center for Advanced Medical Technology (S.M., S.O., T.M., T.U., F.S., D.Y., S.K.) and Analytic Human Pathology (A.S.), Nippon Medical School, 1-1-5 Sendagi, Bunkyou-ku, Tokyo 113-8602, Japan; and Department of Diagnostic Radiology, National Cancer Center East, Kashiwa, Chiba, Japan (M.S.)
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Chao YJ, Sy ED, Hsu HP, Shan YS. Predictors for resectability and survival in locally advanced pancreatic cancer after gemcitabine-based neoadjuvant therapy. BMC Surg 2014; 14:72. [PMID: 25258022 PMCID: PMC4182443 DOI: 10.1186/1471-2482-14-72] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Accepted: 09/10/2014] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND To evaluate the predictors for resectability and survival of patients with locally advanced pancreatic cancer (LAPC) treated with gemcitabine-based neoadjuvant therapy (GBNAT). METHODS Between May 2003 and Dec 2009, 41 tissue-proved LAPC were treated with GBNAT. The location of pancreatic cancer in the head, body and tail was 17, 18 and 6 patients respectively. The treatment response was evaluated by RECIST criteria. Surgical exploration was based on the response and the clear plan between tumor and celiac artery/superior mesentery artery. Kaplan-Meier analysis and Cox Model were used to calculate the resectability and survival rates. RESULTS Finally, 25 patients received chemotherapy (CT) and 16 patients received concurrent chemoradiation therapy (CRT). The response rate was 51% (21 patients), 2 CR (1 in CT and 1 in CRT) and 19 PR (10 in CT and 9 in CRT). 20 patients (48.8%) were assessed as surgically resectable, in which 17 (41.5%) underwent successful resection with a 17.6% positive-margin rate and 3 failed explorations were pancreatic head cancer for dense adhesion. Two pancreatic neck cancer turned fibrosis only. Patients with surgical intervention had significant actuarial overall survival. Tumor location and post-GBNAT CA199 < 152 were predictors for resectability. Post-GBNAT CA-199 < 152 and post-GBNAT CA-125 < 32.8 were predictors for longer disease progression-free survival. Pre-GBNAT CA-199 < 294, post-GBNAT CA-125 < 32.8, and post-op CEA < 6 were predictors for longer overall survival. CONCLUSION Tumor location and post-GBNAT CA199 < 152 are predictors for resectability while pre-GBNAT CA-199 < 294, post-GBNAT CA-125 < 32.8, post-GBNAT CA-199 < 152 and post-op CEA < 6 are survival predictors in LAPC patients with GBNAT.
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Affiliation(s)
| | | | | | - Yan-Shen Shan
- Division of General Surgery, Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan.
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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.
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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:
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Gresham GK, Wells GA, Gill S, Cameron C, Jonker DJ. Chemotherapy regimens for advanced pancreatic cancer: a systematic review and network meta-analysis. BMC Cancer 2014; 14:471. [PMID: 24972449 PMCID: PMC4097092 DOI: 10.1186/1471-2407-14-471] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Accepted: 06/16/2014] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Advanced pancreatic cancer confers poor prognosis and treatment advancement has been slow. Recent randomized clinical trials (RCTs) have demonstrated survival benefits for combination therapy compared to gemcitabine alone. However, the comparative benefits and harms of available combination chemotherapy treatments are not clear. We therefore conducted a systematic review and Bayesian network meta-analysis to assess the comparative safety and efficacy of chemotherapy regimens for the treatment of advanced pancreatic cancer. METHODS MEDLINE, PubMed, EMBASE, Cochrane Central Registry of Clinical trials and abstracts from major scientific meetings were searched for RCTs published from 2002 to 2013. Key outcomes were overall survival (OS), progression free survival (PFS), and safety including grade 3-4 febrile neutropenia, neutropenia, vomiting, diarrhea, fatigue and sensory neuropathy. Bayesian network meta-analyses were conducted to calculate survival and safety outcomes using gemcitabine (GEM) as the reference comparator. Effect estimates and 95% credible intervals were calculated for each comparison. Mean ranks and the probability of being best were obtained for each treatment analyzed in the network meta-analysis. RESULTS The search identified 23 studies involving 19 different treatment regimens and 9,989 patients. FOLFIRINOX, GEM/cisplatin/epirubicin/5FU (PEFG), GEM/NAB-paclitaxel (NAB-P), GEM/erlotinib+/-bevacizumab, GEM/capecitabine, and GEM/oxaliplatin were associated with statistically significant improvements in OS and PFS relative to gemcitabine alone and several other treatments. They were amongst the top ranked for survival outcomes amongst other treatments included. No significant differences were found for other combination chemotherapy treatments. Effect estimates from indirect comparisons matched closely to estimates derived from pairwise comparisons. Overall, combination therapies had greater risk for evaluated grade 3-4 toxicities over gemcitabine alone. CONCLUSIONS In the absence of head-to-head comparisons, we performed a mixed-treatment analysis to achieve high-quality information on the effectiveness and safety of each treatment. This study suggests that some combination therapies may offer greater benefits in the treatment of advanced pancreatic cancer than others. To more fully elucidate the comparative benefits and harms of different combination chemotherapy regimens, rigorously conducted comparative studies, or network meta-analysis of patient-level data are required.
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Affiliation(s)
- Gillian K Gresham
- Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - George A Wells
- Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Sharlene Gill
- British Columbia Cancer Agency, Vancouver, British Columbia, Canada
| | - Christopher Cameron
- Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Derek J Jonker
- The Ottawa Hospital Cancer Centre, Ottawa, Ontario, Canada
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Li Q, Yuan Z, Yan H, Wen Z, Zhang R, Cao B. Comparison of gemcitabine combined with targeted agent therapy versus gemcitabine monotherapy in the management of advanced pancreatic cancer. Clin Ther 2014; 36:1054-63. [PMID: 24986485 DOI: 10.1016/j.clinthera.2014.05.066] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Revised: 05/06/2014] [Accepted: 05/30/2014] [Indexed: 01/28/2023]
Abstract
PURPOSE Targeted therapy has brought great clinical benefits for patients with multiple solid tumors, but its effects in patients with locally advanced/metastatic pancreatic cancer (LA/MPC) are disputed. This systematic evaluation compared the efficacy and safety profiles of gemcitabine combined with targeted agents (GEM + TA) versus gemcitabine administered as monotherapy or combined with placebo (GEM ± PLC) in LA/MPC patients. METHODS PubMed and EMBASE were searched for relevant randomized controlled trials published on or before April 30, 2013. The primary end points were overall survival (OS) and progression-free survival (PFS); the secondary end points were 1-year survival rate, objective response rate (ORR), and toxicity rates (TRs), defined as the prevalence of grade 3/4 adverse events. The systematic evaluation was performed by using Review Manager version 5.1.7. FINDINGS A total of 10 randomized controlled trials involving 3899 patients (2195 males; mean age, 63.6 years) were included in the systematic evaluation. The results reported that there was no significant difference in OS (hazard ratio [HR] = 0.97 [P = 0.85]), PFS (HR = 0.95 [P = 0.14]), or ORR (odds ratio [OR] = 0.95 [P = 0.69]) between GEM + TA and GEM ± PLC. However, a marginal difference in 1-year survival rate (OR = 0.80 [P = 0.05]) between the 2 groups was observed. The grade 3/4 TRs of anemia, diarrhea, nausea, neutropenia, thrombocytopenia, and vomiting were not significantly different between the 2 groups. However, the prevalence of grade 3/4 rash was significantly greater in the GEM + TA group (OR = 8.31 [P < 0.01]). IMPLICATIONS Based on the results from this analysis, the addition of targeted agents to a regimen of gemcitabine treatment does not bring survival benefits except 1-year survival rate to patients with LA/MPC.
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Affiliation(s)
- Qin Li
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, People׳s Republic of China
| | - Zhenyan Yuan
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, People׳s Republic of China
| | - Han Yan
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, People׳s Republic of China
| | - Zhaoyang Wen
- Experimental Center for Basic Medical Teaching, Capital Medical University, Beijing, People׳s Republic of China
| | - Ruixue Zhang
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, People׳s Republic of China
| | - Bangwei Cao
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, People׳s Republic of China; Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, People׳s Republic of China; Beijing Digestive Diseases Center, Beijing Friendship Hospital, Capital Medical University, Beijing, People׳s Republic of China.
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Frontline treatment with gemcitabine, oxaliplatin and erlotinib for the treatment of advanced or metastatic pancreatic cancer: a multicenter phase II study of the Hellenic Oncology Research Group (HORG). Cancer Chemother Pharmacol 2014; 74:333-40. [PMID: 24930058 DOI: 10.1007/s00280-014-2509-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Accepted: 06/02/2014] [Indexed: 02/08/2023]
Abstract
PURPOSE Intravenous gemcitabine is the standard of care for patients with metastatic cancer of the pancreas. Gemcitabine-based chemotherapy combinations, either doublets or triplets, have been tested in the past but have offered a small advantage (Brodoefel et al. in Eur J Radiol 73:594-600, 2010). In the present study, we present the results of the triplet gemcitabine-oxaliplatin-erlotinib combination as firstline treatment in this setting. PATIENTS AND METHODS Seventy-one eligible patients were included in this study. All patients received chemotherapy with gemcitabine (1,100 mg/m(2) on days 1 and 8) plus oxaliplatin (130 mg/m(2) on day 8) and erlotinib (100 mg p.o./day for 21 days). The treatment cycle was 21 days. RESULTS Partial response was achieved in 15 patients (21%; 95% CI 11.63-30.62) and stable disease in 15 patients (21%). Forty-one patients (57.8%) experienced disease progression. Median progression-free survival was 5.2 months (range 0.6-34.7; 95% CI 3.71-6.76). The median overall survival was 10.5 months (95% CI 7.39-13.61) and the 1-year survival estimate 47.3%. The main adverse events were grade 3/4 anemia occurring in three (4.2%) patients and grade 3 and 4 thrombocytopenia occurring in eight (11.3%) and three (4.2%) patients, respectively. Grade 4 neutropenia was rare (1.4%), and one patient presented febrile neutropenia. CONCLUSION This study demonstrated that the combination of gemcitabine, oxaliplatin and erlotinib is active, well tolerated and safe for patients with metastatic adenocarcinoma of the pancreas. However, the results do not seem to be better than those reported with chemotherapy alone.
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Chan SL, Chan ST, Chan EH, He ZX. Systemic treatment for inoperable pancreatic adenocarcinoma: review and update. CHINESE JOURNAL OF CANCER 2014; 33:267-76. [PMID: 24472302 PMCID: PMC4059864 DOI: 10.5732/cjc.013.10134] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Revised: 10/08/2013] [Accepted: 10/30/2013] [Indexed: 12/17/2022]
Abstract
There have been many clinical trials conducted to evaluate novel systemic regimens for unresectable pancreatic cancer. However, most of the trial results were negative, and gemcitabine monotherapy has remained the standard systemic treatment for years. A number of molecular targeted agents, including those against epidermal growth factor receptor and vascular endothelial growth factor receptors, have also been tested. In recent years, there have been some breakthroughs in the deadlock: three regimens, namely gemcitabine-erlotinib, FOLFIRINOX, and gemcitabine-nab-paclitaxel, have been shown to prolong the overall survival of patients when compared with gemcitabine monotherapy. In addition, emerging data suggested that the membrane protein human equilibrative nucleotide transporter 1 is a potential biomarker with which to predict the efficacy of gemcitabine. Here we review the literature on the development of systemic agents for pancreatic cancer, discuss the current choices of treatment, and provide future directions on the development of novel agents.
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Affiliation(s)
- Stephen L Chan
- State Key Laboratory in Oncology in South China, Sir YK Pao Center for Cancer, Department of Clinical Oncology and Hong Kong Cancer Institute and Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
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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.
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Li J, Podoltsev N, Saif MW. Management of advanced pancreatic cancer. Expert Rev Clin Pharmacol 2014; 2:527-41. [DOI: 10.1586/ecp.09.30] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Olszewski AJ, Grossbard ML, Chung MS, Chalasani SB, Malamud S, Mirzoyev T, Kozuch PS. Phase I study of oxaliplatin in combination with gemcitabine, irinotecan, and 5-fluorouracil/leucovorin (G-FLIE) in patients with metastatic solid tumors including adenocarcinoma of the pancreas. J Gastrointest Cancer 2013. [PMID: 23208490 DOI: 10.1007/s12029-012-9466-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
PURPOSE The aims of this study were to establish the maximum tolerated dose (MTD) of oxaliplatin in combination with fixed doses of gemcitabine, irinotecan, and 5-fluorouracil/leucovorin (G-FLIE) in solid tumors, including advanced pancreatic cancer, and to evaluate the toxicity of the regimen. METHODS Patients with metastatic solid tumors were treated with a regimen consisting of gemcitabine (500 mg/m(2) by fixed-dose-rate infusion), irinotecan (120 mg/m(2)), leucovorin 300 mg, bolus/infusion 5-fluorouracil (400 and 1,500 mg/m2, respectively), and oxaliplatin at doses from 50 to 85 mg/m(2) according to the escalation schema. Treatment was repeated every 14 days. RESULTS The study enrolled 25 patients with a median age of 64 years and median Karnofsky performance score of 80. Patients had metastatic adenocarcinomas of pancreas (n = 9), as well as gastroesointestinal, hepatobiliary, or unknown primary tumors. With only one dose limiting toxicity (neutropenia and constipation), the MTD of oxaliplatin was not reached up to the pre-specified maximum level of 85 mg/m(2). Other toxicities predictably included cytopenias, fatigue, sensory neuropathy, nausea/vomiting, diarrhea, and constipation. Four partial responses and ten disease stabilizations were observed. The overall median time to disease progression was 17 weeks (2-110 weeks) with median overall survival of 31.5 weeks (7-139 weeks). CONCLUSIONS G-FLIE is a tolerable multi-agent chemotherapy regimen with the oxaliplatin dose up to 85 mg/m(2). The combination of full-dose oxaliplatin with gemcitabine, irinotecan, and 5-fluorouracil is feasible with attenuated doses of the drugs, but further optimization is necessary before assessment of efficacy.
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Affiliation(s)
- Adam J Olszewski
- St Luke's-Roosevelt Hospital Center, Continuum Cancer Centers of New York, 10th Ave and 59th St, New York, NY 10019, USA
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Kruse M, Parthan A, Coombs J, Sasane M, Taylor D. Comparison of different adjuvant therapies for 9 resectable cancer types. Postgrad Med 2013; 125:83-91. [PMID: 23816774 DOI: 10.3810/pgm.2013.03.2643] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
PURPOSE The objective of this study was to compare the clinical benefit across adjuvant therapies for cancer treatment, including adjuvant imatinib, and to quantify the results using the number-needed-to-treat (NNT) approach. METHOD We reviewed studies meeting the following criteria: 1) US and European randomized clinical trial populations consisting of patients with cancer who underwent surgical resection of the primary tumor and were considered cancer free; 2) comparators were either placebo or no treatment; and 3) recurrence-free survival (RFS) and overall survival (OS) rates were reported and showed benefit with the experimental treatment. The NNT was calculated as the inverse of the difference in event rate between the study groups in each trial. RESULTS We identified 26 adjuvant treatment trials in 9 cancer types. With longer follow-up (3 years vs 1 year), 62.5% of treatments compared with placebo showed a decreased RFS NNT, including imatinib (7 vs 4). The largest relative decrease in RFS NNT over time was 91% (with trastuzumab or cyclophosphamide therapy). Approximately 25% of the treatments resulted in an increase in RFS NNT over time. The RFS NNT for imatinib was lower than that for all other treatments at 3 years of follow-up and lower than that for all but 2 treatments at 1 year. At both year 1 and year 3, the NNT for OS ranged from 6 to 100. Imatinib had an OS NNT of 31 at 3 years. CONCLUSION With longer follow-up duration, most adjuvant cancer treatments showed a decreased NNT. Imatinib had one of the lowest NNTs among the adjuvant treatments at 1 and 3 years of follow-up using the RFS data.
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Vaccaro V, Bria E, Sperduti I, Gelibter A, Moscetti L, Mansueto G, Ruggeri EM, Gamucci T, Cognetti F, Milella M. First-line erlotinib and fixed dose-rate gemcitabine for advanced pancreatic cancer. World J Gastroenterol 2013; 19:4511-4519. [PMID: 23901226 PMCID: PMC3725375 DOI: 10.3748/wjg.v19.i28.4511] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2013] [Revised: 04/03/2013] [Accepted: 05/10/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate activity, toxicity, and prognostic factors for survival of erlotinib and fixed dose-rate gemcitabine (FDR-Gem) in advanced pancreatic cancer.
METHODS: We designed a single-arm prospective, multicentre, open-label phase II study to evaluate the combination of erlotinib (100 mg/d, orally) and weekly FDR-Gem (1000 mg/m2, infused at 10 mg/m2 per minute) in a population of previously untreated patients with locally advanced, inoperable, or metastatic pancreatic cancer. Primary endpoint was the rate of progression-free survival at 6 mo (PFS-6); secondary endpoints were overall response rate (ORR), response duration, tolerability, overall survival (OS), and clinical benefit. Treatment was not considered to be of further interest if the PFS-6 was < 20% (p0 = 20%), while a PFS-6 > 40% would be of considerable interest (p1 = 40%); with a 5% rejection error (α = 5%) and a power of 80%, 35 fully evaluable patients with metastatic disease were required to be enrolled in order to complete the study. Analysis of prognostic factors for survival was also carried out.
RESULTS: From May 2007 to September 2009, 46 patients were enrolled (male/female: 25/21; median age: 64 years; median baseline carbohydrate antigen 19-9 (CA 19-9): 897 U/mL; locally advanced/metastatic disease: 5/41). PFS-6 and median PFS were 30.4% and 14 wk (95%CI: 10-19), respectively; 1-year and median OS were 20.2% and 26 wk (95%CI: 8-43). Five patients achieved an objective response (ORR: 10.9%, 95%CI: 1.9-19.9); disease control rate was 56.5% (95%CI: 42.2-70.8); clinical benefit rate was 43.5% (95%CI: 29.1-57.8). CA 19-9 serum levels were decreased by > 25% as compared to baseline in 14/23 evaluable patients (63.6%). Treatment was well-tolerated, with skin rash being the most powerful predictor of both longer PFS (P < 0.0001) and OS (P = 0.01) at multivariate analysis (median OS for patients with or without rash: 42 wk vs 15 wk, respectively, Log-rank P = 0.03). Additional predictors of better outcome were: CA 19-9 reduction, female sex (for PFS), and good performance status (for OS).
CONCLUSION: Primary study endpoint was not met. However, skin rash strongly predicted erlotinib efficacy, suggesting that a pharmacodynamic-based strategy for patient selection deserves further investigation.
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Wang BH, Cao WM, Yu J, Wang XL. Gemcitabine-based concurrent chemoradiotherapy versus chemotherapy alone in patients with locally advanced pancreatic cancer. Asian Pac J Cancer Prev 2013; 13:2129-32. [PMID: 22901181 DOI: 10.7314/apjcp.2012.13.5.2129] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE To explore improved treatment by retrospectively comparing survival time of gemcitabine-based concurrent chemoradiotherapy (GemRT) versus chemotherapy (Gem) alone in patients with locally advanced pancreatic cancer (LAPC). METHODS From January 2005 to June 2010, 56 patients with LAPC from Subei People's Hospital were treated either with Gem (n=21) or GemRT (n=35). Gem consisted of 4-6 cycles gemcitabine alone (1000 mg/m2 on Days 1, 8, 15, 28-day a cycle). GemRT consisted of 50.4Gy/28F radiotherapy with concurrent 2 cycles of gemcitabine (1000 mg/m2 on days of radiation 1, 8, 15, 21-day a cycle). Radiation was delivered to the gross tumor volume plus 1-1.5 cm by use of a three-dimensional conformal technique. The follow-up time was calculated from the time of diagnosis to the date of death or last contact. Kaplan-Meier methodology wes used to evaluate survival. RESULTS Patient characteristics were not significantly different between treatment groups. The disease control rate and the objective response rate of GemRT versus Gem was 97.1% vs 71.4%, 74.3% vs 38.1%. The overall survival (OS) was significantly better for GemRT compared to Gem (median 13 months versus 8 months; 51.4% versus 14.3% at 1 year, respectively). CONCLUSION Radiation therapy at 50.4Gy with 2 concurrent cycles of gemcitabine results in favorable rates of OS. Concurrent chemoradiotherapy should be the first choice for patients with LAPC.
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Affiliation(s)
- Bu-Hai Wang
- Department of Oncology of Subei People's Hospital, Yangzhou University, Yangzhou, China.
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Danielsson K, Ansari D, Andersson R. Personalizing pancreatic cancer medicine: what are the challenges? Per Med 2013; 10:45-59. [DOI: 10.2217/pme.12.111] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The P4 paradigm for future medicine promises changes in cancer management with improved Prediction of treatment response, Prevention of disease, Personalization of therapy, and Participation by patients. Significant challenges remain for the implementation of the P4 principles for pancreatic cancer, but many strides have been made in the past several years that should facilitate a future in which the disease can be detected at earlier stages and treatments can be customized to target features of a particular patient’s disease. This article summarizes the basic molecular biology of pancreatic tumors and the current state of pancreatic cancer treatment, as well as targeted treatments in the pipeline that might enable future personalized pancreatic cancer treatment and prediction of response to treatment. It also discusses possible directions for screening patients at high risk of developing the disease, detecting tumors at earlier stages, and increasing patient involvement in designing treatment.
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Affiliation(s)
- Krissi Danielsson
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, SE-221 85, Lund, Sweden
| | - Daniel Ansari
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, SE-221 85, Lund, Sweden
| | - Roland Andersson
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, SE-221 85, Lund, Sweden
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Corbo V, Tortora G, Scarpa A. Molecular pathology of pancreatic cancer: from bench-to-bedside translation. Curr Drug Targets 2012; 13:744-52. [PMID: 22458520 PMCID: PMC3419918 DOI: 10.2174/138945012800564103] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2010] [Revised: 03/20/2012] [Accepted: 03/27/2012] [Indexed: 02/08/2023]
Abstract
Pancreatic ductal adenocarcinoma (referred here as pancreatic cancer) is a lethal disease with the worst prognosis among all solid tumors. Surgical resection represents the only hope for cure but it is possible only in patients that present with local disease (about 20% of cases). Whether dismal prognosis of pancreatic cancer is a result of late diagnosis or early dissemination to distant organ is still a debate. Moreover, this disease shows an intrinsic chemotherapeutic resistance that has been mainly ascribed to the presence of a dense stromal reaction that significantly impairs drugs delivery. Clinical management of pancreatic cancer patients relies on few molecular markers (e.g., the diagnostic marker CA19-9) that, however, present several limitations to their use. The clinical usefulness of somatic alterations in well-characterized genes (such as KRAS and TP53), whose detection is technically feasible in different biological samples, has been extensively investigated leading to inconsistent results. Furthermore, none of the candidate molecular markers identified in recent years has shown an appropriate clinical performance and therefore none is routinely used. This depicts a scenario where the identification of novel and effective clinical biomarkers is mandatory. Very recent genome-wide comprehensive studies have shed light on the high degree of genetic complexity and heterogeneity of the pancreatic cancers. Although far from being introduced into the clinical settings, results from those studies are expected to change definitively the perspective through which we look at the clinical management of pancreatic cancer patients towards a personalized cancer medicine.
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Affiliation(s)
- Vincenzo Corbo
- ARC-NET Research Centre, University Hospital of Verona, Verona, Italy
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Sun C, Ansari D, Andersson R, Wu DQ. Does gemcitabine-based combination therapy improve the prognosis of unresectable pancreatic cancer? World J Gastroenterol 2012; 18:4944-58. [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.
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Ciliberto D, Botta C, Correale P, Rossi M, Caraglia M, Tassone P, Tagliaferri P. Role of gemcitabine-based combination therapy in the management of advanced pancreatic cancer: a meta-analysis of randomised trials. Eur J Cancer 2012; 49:593-603. [PMID: 22989511 DOI: 10.1016/j.ejca.2012.08.019] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2012] [Revised: 07/20/2012] [Accepted: 08/19/2012] [Indexed: 01/26/2023]
Abstract
BACKGROUND Pancreatic cancer is the fourth leading cause of cancer-related death worldwide. Gemcitabine is the mainstay treatment for advanced disease. However, almost all up-to-date trials, that evaluated the benefit of gemcitabine-combination schedules, failed to demonstrate an improvement in overall survival (OS). In this study, we performed a systematic review and a meta-analysis of randomised clinical trials (RCTs) to investigate the efficacy and safety of gemcitabine-based combination regimens as compared to gemcitabine alone in the management of pancreatic cancer. METHODS Clinical trials were collected by searching different databases (PubMed, Embase and the Central Registry of Controlled Trials of the Cochrane Library) and abstracts from major cancer meetings. We considered period ranging from January 1997 to January 2012. Primary end-point was OS, secondary end-points were response rate (RR), disease control rate (DCR) and safety. Hazard ratios (HRs) of OS, odds-ratios (ORs) of RR, DCR and risk ratios of grade 3-4 toxicity rates (TRs), were extracted as presented in retrieved studies and used for statistical analysis. Meta-analytic estimates were derived using random-effects model. FINDINGS Thirty-four trials for a total of 10,660 patients were selected and included in the final analysis. The analysis showed that combination chemotherapy confers benefit in terms of OS (HR: 0.93; 95% confidence interval (CI): 0.89-0.97; p=0.001). ORs for both RR and DCR demonstrated a significant advantage for combination therapy (OR for RR: 0.60, 95%CI: 0.47-0.76, p<0.001; OR for DCR: 0.79; 95%CI: 0.66-0.93; p=0.006). Toxicities were more frequent with the combination treatment and significance in terms of risk ratio was reached for diarrhoea (0.53, 95%CI: 0.36-0.79), nausea (0.74, 95%CI: 0.56-0.96), neutropenia (0.71, 95%CI: 0.59-0.85) and thrombocytopenia (0.57, 95%CI: 0.43-0.75). INTERPRETATION The combination chemotherapy as compared to gemcitabine alone significantly improves OS in advanced pancreatic cancer (APC). However, this advantage is marginal whereas the treatment-related toxicity is increased, suggesting the use of gemcitabine-based combination regimens only in selected patient populations. New prospective trials, based on translational approaches and innovative validated biomarkers, are eagerly awaited on this topic.
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Affiliation(s)
- Domenico Ciliberto
- Medical Oncology Unit, Campus Salvatore Venuta, Department of Experimental and Clinical Medicine, ''Magna Graecia'' University and ''Tommaso Campanella'' Cancer Center, Catanzaro, Italy
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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]
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Löhr JM, Haas SL, Bechstein WO, Bodoky G, Cwiertka K, Fischbach W, Fölsch UR, Jäger D, Osinsky D, Prausova J, Schmidt WE, Lutz MP. Cationic liposomal paclitaxel plus gemcitabine or gemcitabine alone in patients with advanced pancreatic cancer: a randomized controlled phase II trial. Ann Oncol 2012; 23:1214-1222. [PMID: 21896540 DOI: 10.1093/annonc/mdr379] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Paclitaxel embedded in cationic liposomes (EndoTAG™-1; ET) is an innovative agent targeting tumor endothelial cells. This randomized controlled phase II trial evaluated the safety and efficacy of ET in combination with gemcitabine (GEM) in advanced pancreatic cancer (PDAC). PATIENTS AND METHODS Chemotherapy-naive patients with locally advanced or metastatic disease were randomly assigned to receive weekly GEM 1000 mg/m(2) or GEM plus twice-weekly ET 11, 22 or 44 mg/m(2) for 7 weeks. After a safety run-in of 100 patients, a second cohort continued treatment. End points included overall survival (OS), progression-free survival (PFS), tumor response and safety. RESULTS Two hundred and twelve patients were randomly allocated to the study and 200 were treated (80% metastatic, 20% locally advanced). Adverse events were manageable and reversible. Transient thrombocytopenia and infusion reactions with chills and pyrexia mostly grade 1 or 2 occurred in the ET groups. Disease control rate after the first treatment cycle was 43% with GEM and 60%, 65% and 52% in the GEM + ET cohorts. Median PFS reached 2.7 compared with 4.1, 4.6 and 4.4 months, respectively. Median OS was 6.8 compared with 8.1, 8.7 and 9.3 months, respectively. CONCLUSIONS Treatment of advanced PDAC with GEM + ET was generally well tolerated. GEM + ET showed beneficial survival and efficacy. A randomized phase III trial should confirm this positive trend.
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Affiliation(s)
- J M Löhr
- Department of Medicine II, University Hospital Mannheim, Mannheim, Germany; Department of Surgical Gastroenterology, Karolinska Institutet, Stockholm, Sweden.
| | - S L Haas
- Department of Medicine II, University Hospital Mannheim, Mannheim, Germany; Department of Surgical Gastroenterology, Karolinska Institutet, Stockholm, Sweden
| | - W-O Bechstein
- Department of General and Visceral Surgery, University Hospital Frankfurt, Frankfurt/Main, Germany
| | - G Bodoky
- Department of Oncology, Szent Laszlo Hospital, Budapest, Hungary
| | - K Cwiertka
- Department of Oncology, University Hospital Olomouc, Olomouc, Czech Republic
| | - W Fischbach
- Department of Medicine II, Klinikum Aschaffenburg, Aschaffenburg
| | - U R Fölsch
- Department of General Internal Medicine, University Hospital Schleswig-Holstein, Kiel
| | - D Jäger
- Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany
| | - D Osinsky
- Institute of Oncology AMS of Ukraine, Kiev, Ukraine
| | - J Prausova
- Department of Oncological Radiotherapy, University Hospital Prague, Prague, Czech Republic
| | - W E Schmidt
- Department of Medicine I, St. Josef-Hospital, Ruhr-University, Bochum
| | - M P Lutz
- Department of Medicine, Caritasklinik St. Theresia, Saarbrücken, Germany
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Ying JE, Zhu LM, Liu BX. Developments in metastatic pancreatic cancer: is gemcitabine still the standard? World J Gastroenterol 2012; 18:736-45. [PMID: 22371633 PMCID: PMC3286136 DOI: 10.3748/wjg.v18.i8.736] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2011] [Revised: 08/26/2011] [Accepted: 09/03/2011] [Indexed: 02/06/2023] Open
Abstract
In the past 15 years, we have seen few therapeutic advances for patients with pancreatic cancer, which is the fourth leading cause of cancer-related death in the United States. Currently, only about 6% of patients with advanced disease respond to standard gemcitabine therapy, and median survival is only about 6 mo. Moreover, phase III trials have shown that adding various cytotoxic and targeted chemotherapeutic agents to gemcitabine has failed to improve overall survival, except in cases in which gemcitabine combined with erlotinib show minimal survival benefit. Several meta-analyses have shown that the combination of gemcitabine with either a platinum analog or capecitabine may lead to clinically relevant survival prolongation, especially for patients with good performance status. Meanwhile, many studies have focused on the pharmacokinetic modulation of gemcitabine by fixed-dose administration, and metabolic or transport enzymes related to the response and toxicity of gemcitabine. Strikingly, a phase III trial in 2010 showed that, in comparison to gemcitabine alone, the FOLFIRINOX regimen in patients with advanced disease and good performance status, produced better median overall survival, median progression-free survival, and objective response rates. This regimen also resulted in greater, albeit manageable toxicity.
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Zhang DEX, Dai YDI, Yuan SX, Tao L. Prognostic factors in patients with pancreatic cancer. Exp Ther Med 2011; 3:423-432. [PMID: 22969906 DOI: 10.3892/etm.2011.412] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2011] [Accepted: 11/18/2011] [Indexed: 12/30/2022] Open
Abstract
The identification of prognostic factors for pancreatic cancer patients could provide insightful information for their management in the clinic. A total of 302 pancreatic cancer patients were enrolled in this study. The clinicopathological characteristics, treatment selection and laboratory test data were retrospectively retrieved from the medical records and follow-up data were obtained via telephone interview. Cox survival analysis was used to assess the potential prognostic factors, and survival curves were obtained by Kaplan-Meier analyses. The mortality rate of the patients was 83.4% (252/302) and the median survival of these patients was 6.1 months, with 1-, 2- and 3-year survival rates of 30.1 (91/302), 10.6 (32/302) and 2.6% (8/302), respectively. The most influential factors for the survival of these patients were the site of primary cancer, tumor stage, treatment selection, serum levels of glutamic-pyruvic transaminase, albumin, lactate dehydrogenase and hemoglobin, and white blood cell counts (P<0.05). The median survival of patients who did not receive any treatment or just received supportive treatment was 1.3 months, while the median overall survival of patients who underwent surgery, chemotherapy, biliary drainage therapy, arterial interventional chemotherapy and comprehensive treatment was 11.0, 7.3, 3.5, 9.0 and 11.0 months, respectively (P<0.05). Furthermore, single-drug chemotherapy was not statistically associated with patient survival in those who received the multi-drug regimen (P>0.05). However, the mortality risk of patients who received platinum chemotherapy was decreased [hazard ratio (HR)=0.56, 95% CI 0.35-0.88, P=0.011] compared to the patients who did not receive this treatment (P<0.05). Tumor stage, treatment selection, serum albumin levels, urea nitrogen, CA19-9, white blood cell and platelet counts were independent prognostic factors for the prediction of survival in pancreatic cancer. Future studies are required in order to verify these data. Chemotherapy with platinum regimens could improve overall survival in patients with pancreatic cancer.
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Affiliation(s)
- DE-Xiang Zhang
- Department of General Surgery, Jinshan Hospital Affiliated to Fudan University, Shanghai 200540
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Vaccaro V, Sperduti I, Milella M. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011; 365:768-9; author reply 769. [PMID: 21864184 DOI: 10.1056/nejmc1107627] [Citation(s) in RCA: 122] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Vaccaro V, Melisi D, Bria E, Cuppone F, Ciuffreda L, Pino MS, Gelibter A, Tortora G, Cognetti F, Milella M. Emerging pathways and future targets for the molecular therapy of pancreatic cancer. Expert Opin Ther Targets 2011; 15:1183-96. [PMID: 21819318 DOI: 10.1517/14728222.2011.607438] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Pancreatic cancer treatment remains a challenge for clinicians and researchers. Despite undisputable advances in the comprehension of the molecular mechanisms underlying cancer development and progression, early disease detection and clinical management of patients has made little, if any, progress in the past 20 years. Clinical development of targeted agents directed against validated pathways, such as the EGF/EGF receptor axis, the mutant KRAS protein, MMPs, and VEGF-mediated angiogenesis, alone or in combination with gemcitabine-based standard chemotherapy, has been disappointing. AREAS COVERED This review explores the preclinical rationale for clinical approaches aimed at targeting the TGF-β, IGF, Hedgehog, Notch and NF-κB signaling pathways, to develop innovative therapeutic strategies for pancreatic cancer. EXPERT OPINION Although some of the already clinically explored approaches (particularly EGFR and KRAS targeting) deserve further clinical consideration, by employing more innovative and creative clinical trial designs than the gemcitabine-targeted agent paradigm that has thus far invariably failed, the targeting of emerging and relatively unexplored signaling pathways holds great promise to increase our understanding of the complex molecular biology and to advance the clinical management of pancreatic cancer.
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Affiliation(s)
- Vanja Vaccaro
- Medical Oncology A, Regina Elena National Cancer Institute, Rome, Italy
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Gómez-Martín C, Hidalgo M, Tabernero J, Isla D. SEOM clinical guidelines for the treatment of pancreatic cancer. Clin Transl Oncol 2011; 13:528-35. [PMID: 21821486 DOI: 10.1007/s12094-011-0693-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Pancreatic cancer (PC) is one of the main causes of cancer-related death in the United States and Europe. Due to its poor long-term survival, all patients with PC should undergo a comprehensive evaluation by a Multidisciplinary Tumor Committee to establish the best therapeutic strategy. Pathologic PC diagnosis should be made according to the latest WHO classification of malignant tumours and an accurate staging is crucial to assess resectability, determine the extension and, in some cases, reestablish biliary flow. For patients with localised resectable disease the standard treatment option is radical pancreatic resection. The aim of resection is to obtain microscopically negative margins (R0) and also to resect the drainage lymph nodes. In those cases diagnosed with locally advanced unresectable or metastatic PC, palliative bypass of intestinal or biliary obstruction followed by chemotherapy or chemoradiation remains the main palliative treatment option. Since 1997, gemcitabine monotherapy has been considered the standard of care for advanced PC. In recent years new chemotherapy combinations and targeted agents have demonstrated significant antitumoral activity, increasing the armamentarium that can be used against this lethal disease.
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Affiliation(s)
- Carlos Gómez-Martín
- Servicio de Oncología Médica, Hospital Universitario 12 de Octubre, Madrid, Spain.
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Effects and mechanisms of the combination of suberoylanilide hydroxamic acid and bortezomib on the anticancer property of gemcitabine in pancreatic cancer. Pancreas 2011; 40:966-73. [PMID: 21487323 DOI: 10.1097/mpa.0b013e3182156d5a] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OBJECTIVES Earlier studies that dealt with the combination therapy of gemcitabine and histone deacetylation inhibitors for pancreatic cancer revealed unsatisfactory results. The activation of nuclear factor κB (NF-κB) was referred as one of the attributable causes, and we attempted to overcome this resistance by the addition of a proteasome inhibitor. METHODS The influences of suberoylanilide hydroxamic acid (vorinostat, SAHA), a histone deacetylase inhibitor, and bortezomib, a novel selective antagonist of 26S proteasome, with or without gemcitabine on cell growth and apoptosis and the expressions of related proteins were observed in pancreatic cancer cell lines (MiaPaCa-2 and ASPC-1). The xenograft model of pancreatic cancer was used to notice effects in vivo. RESULTS Vorinostat and bortezomib had independent inhibitory effects and potentiated the antitumor property of gemcitabine in vitro. In the xenograft model, more augmented effects were achieved when bortezomib was combined with gemcitabine than gemcitabine alone. The down-regulation of pAkt and suppression of NF-κB activity was induced by the triple combination. CONCLUSIONS The triple combination of vorinostat, bortezomib, and gemcitabine resulted in the strongest antitumor effects both in vitro and in vivo and pAkt and NF-κB seems to be involved in this process.
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