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Zhang T, Zhou Y, Wu Y, Shi M, Sun W, Wang R. Evaluation of the efficacy and predictive indicators of PD- 1 inhibitors combined with chemotherapy in advanced pancreatic cancer. Sci Rep 2025; 15:12175. [PMID: 40204931 PMCID: PMC11982369 DOI: 10.1038/s41598-025-97233-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 04/03/2025] [Indexed: 04/11/2025] Open
Abstract
Patients with advanced pancreatic ductal adenocarcinoma (PDAC) generally face a poor prognosis and limited therapeutic options. This study aims to evaluate the clinical efficacy of combining PD- 1 inhibitors with chemotherapy as a first-line treatment for advanced PDAC, and to explore the correlation between various clinical parameters and treatment outcomes.This retrospective study analyzed the clinical data of 57 patients with advanced PDAC treated at the First Affiliated Hospital of Bengbu Medical University from January 2022 and June 2024. Patients were allocate into the two groups: the chemotherapy-alone group (29 cases) (CT), which received either the AG regimen or the mFOLFIRINOX regimen, and the imimmunotherapy plus chemotherapy group (28 cases) (ICT), which received the AG regimen or mFOLFIRINOX regimen in combination with PD- 1 inhibitors.The study compared progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse reactions between the two groups. Additionally, it analyzed the correlation between various clinical indicators and their dynamic changes over time in relation to treatment outcomes. Kaplan-Meier curves were plotted for survival analysis, and log-rank tests assessed PFS and OS differences.Univariate and multivariate Cox regression analyses identified independent risk factors for prognosis, while logistic regression assessed the correlation between these factors and treatment response.The median PFS and OS in immunotherapy plus chemotherapy group were significantly superior to those in the chemotherapy-alone group (PFS: 7.3 vs. 5.8 months, P = 0.005; OS: 12 vs. 10.2 months, P = 0.031). The ORR in the group receive immunotherapy combined with chemotherapy was also significantly higher compared to the group treated with chemotherapy alone (42.86% vs. 17.24%, P = 0.03). No significant differences were observed in the incidence or severity of treatment-related adverse events (TRAEs) and immunotherapy-related adverse events (irAEs) between the CT and ICTgroups (any grade: 93.10% vs. 96.45%, P = 0.574; grade 3 or 4: 31.3% vs. 28.57%, P = 0.839). Patients without liver metastasis, without diabetes, or those who experience a increase in SOD levels following treatment may constitute an advantageous population for immune combination therapy. In conclusion, chemotherapy combined with PD- 1 inhibitors demonstrated favorable safety and tolerability, and significantly improved PFS, OS, and ORR compared to chemotherapy alone.
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Affiliation(s)
- Tiantian Zhang
- Departments of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, 233004, People's Republic of China
| | - Yangyang Zhou
- Departments of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, 233004, People's Republic of China
| | - Yue Wu
- Departments of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, 233004, People's Republic of China
| | - Mengting Shi
- Departments of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, 233004, People's Republic of China
| | - Weijie Sun
- Departments of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, 233004, People's Republic of China
| | - Rui Wang
- Departments of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, 233004, People's Republic of China.
- Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu Medical University 233004, Anhui, People's Republic of China.
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Hino K, Nishina T, Koizumi M, Marui K, Kokubu M, Numata Y, Imamura Y, Kanemitsu-Okada K, Otsuru T, Kuroda T, Ohno Y, Asagi A, Miyata H, Yokota T, Kumagi T, Hyodo I, Ikeda Y, Hiasa Y. A multicenter prospective observational study for health assessment questionnaires EQ-5D-5L and G8 in unresectable advanced pancreatic cancer treated with first-line gemcitabine plus nab-paclitaxel therapy. Int J Clin Oncol 2025; 30:738-748. [PMID: 40011378 DOI: 10.1007/s10147-025-02717-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 01/29/2025] [Indexed: 02/28/2025]
Abstract
BACKGROUND In chemotherapy for unresectable advanced pancreatic cancer (UPC), the clinical utility of pre-treatment health assessment questionnaires, EuroQoL 5-Dimension 5-Level (EQ-5D-5L) and G8, is unknown. This study aimed to fill this gap. METHODS This multicenter, prospective, observational study investigated the association of EQ-5D-5L and G8 with the clinical outcomes of first-line gemcitabine plus nab-paclitaxel (GnP) for UPC. Differences in survival were analyzed using the log-rank test, and multivariate analyses were performed using the Cox proportional hazards model. RESULTS Between April 2022 and September 2023, 60 patients were enrolled, and their data were analyzed. When patients were classified into two groups using the median EQ-5D-5L utility value (0.824), progression-free survival (PFS) and overall survival (OS) were significantly longer in patients with high EQ-5D-5L utility values than in those with low utility values (median PFS 7.0 vs. 4.7 months, P < 0.01; median OS 12 vs. 8.0 months, P = 0.023). Such differences were not observed in the EQ-5D-5L Visual Analog Scale or G8 scores. There was no association between the occurrence of severe adverse events and EQ-5D-5L or G8 scores. Multivariate analyses showed that high EQ-5D-5L utility value (≥ 0.824), high albumin (≥ 3.8 g/dl), and low carcinoembryonic antigen (CEA) (< 5.4 ng/mL) were preferable independent efficacy predictors for PFS and also independent prognostic factors for OS. CONCLUSION Pre-treatment EQ-5D-5L utility value, along with albumin and CEA, was an independent efficacy predictor and prognostic factor in patients with UPC treated with first-line GnP. Their usefulness should be validated in future studies.
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Affiliation(s)
- Kaori Hino
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan
- Department of Gastrointestinal Medical Oncology, NHO Shikoku Cancer Center, 160 Kou, Minami-Umemoto, Matsuyama, Ehime, 791-0280, Japan
| | - Tomohiro Nishina
- Department of Gastrointestinal Medical Oncology, NHO Shikoku Cancer Center, 160 Kou, Minami-Umemoto, Matsuyama, Ehime, 791-0280, Japan.
| | - Mitsuhito Koizumi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Kaori Marui
- Endoscopy Center, Ehime University Hospital, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Masahito Kokubu
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Yuki Numata
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Yoshiki Imamura
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Kozue Kanemitsu-Okada
- Department of Gastroenterology, Ehime Prefectural Central Hospital, 83 Kasuga-Machi, Matsuyama, Ehime, 790-0024, Japan
| | - Toru Otsuru
- Department of Gastrointestinal Medical Oncology, NHO Shikoku Cancer Center, 160 Kou, Minami-Umemoto, Matsuyama, Ehime, 791-0280, Japan
| | - Taira Kuroda
- Department of Gastroenterology, Ehime Prefectural Central Hospital, 83 Kasuga-Machi, Matsuyama, Ehime, 790-0024, Japan
| | - Yoshinori Ohno
- Department of Gastrointestinal Medical Oncology, NHO Shikoku Cancer Center, 160 Kou, Minami-Umemoto, Matsuyama, Ehime, 791-0280, Japan
| | - Akinori Asagi
- Department of Gastrointestinal Medical Oncology, NHO Shikoku Cancer Center, 160 Kou, Minami-Umemoto, Matsuyama, Ehime, 791-0280, Japan
| | - Hideki Miyata
- Department of Gastroenterology, Ehime Prefectural Central Hospital, 83 Kasuga-Machi, Matsuyama, Ehime, 790-0024, Japan
| | - Tomoyuki Yokota
- Center for Liver-Biliary-Pancreatic Diseases, Matsuyama Red Cross Hospital, 1 Bunkyo-Cho, Matsuyama, Ehime, 790-8524, Japan
| | - Teru Kumagi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Ichinosuke Hyodo
- Department of Gastrointestinal Medical Oncology, NHO Shikoku Cancer Center, 160 Kou, Minami-Umemoto, Matsuyama, Ehime, 791-0280, Japan
| | - Yoshio Ikeda
- Endoscopy Center, Ehime University Hospital, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, 454 Shitsukawa, Toon, Ehime, 791-0295, Japan
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Li Z, Fan X, Jiang D, Li Q, Liu C, Wang D, Li N, Li H, Chen Z, Tang H, Lou C, Xu H, Zhan C, Dong Y, Ma Z, Wang G, Zhang C, Lu H, Zheng T, Zhang Y. Nab-paclitaxel plus S-1 followed by gemcitabine-oxaliplatin as first-line alternating sequential treatment of pancreatic ductal adenocarcinoma. Oncologist 2024; 29:997-e1614. [PMID: 39226089 PMCID: PMC11546623 DOI: 10.1093/oncolo/oyae207] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Accepted: 07/15/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Alternating sequential administration of drugs may be a promising approach to overcome chemotherapy resistance in advanced pancreatic ductal adenocarcinoma (PDAC). METHODS This study was an open-label, single-arm, and prospective trial included patients with untreated advanced PDAC. They received 2 cycles of NS regimen (nab-paclitaxel:125 mg/m2, intravenously injected on days 1 and 8, plus S-1:40-60 mg, orally twice per day for 1-14 days) followed by 2 cycles of GemOx regimen (gemcitabine, intravenously injected on days 1 and 8, and oxaliplatin: 130 mg/m2, intravenously injected on day 1). The primary efficacy endpoint was a progression-free survival rate at 6 months (PFSR-6m). The secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). Specific mRNA transcripts were used to explore survival associated genes. RESULTS Forty-two patients received a minimum of one treatment cycle, and of these, 30 patients completed one alternating treatment consisting of 4 cycles. The PFSR-6m was 71% (95% CI = 58%-87%). The median PFS and OS were 6.53 months (95% CI = 6.03-8.43) and 11.4 months (95% CI = 9.8-14.4), respectively. Common grades 3-4 hematological AEs included neutropenia 30.9%, leukopenia 26.2%, anemia 2.4%, and thrombocytopenia in 11.9%. Patients with OS > 10 months showed high expression of HLA-DQA2 while melanoma-associated antigen genes (MAGE) were notably upregulated in patients with OS < 10 months. CONCLUSION The alternating sequential administration of the NS and GemOx regimens may be a novel approach for first-line chemotherapy in patients with advanced PDAC requiring further study (ClinicalTrials.gov Identifier: ChiCTR1900024867).
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Affiliation(s)
- Zhiwei Li
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Xiaona Fan
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Dan Jiang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Qingwei Li
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Chao Liu
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Dan Wang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Na Li
- Shenzhen Engineering Center for Translational Medicine of Precision Cancer Immunodiagnosis and Therapy, YuceBio Technology Co., Ltd, Shenzhen, People’s Republic of China
| | - Hengzhen Li
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Zhuo Chen
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Hongzhen Tang
- Shenzhen Engineering Center for Translational Medicine of Precision Cancer Immunodiagnosis and Therapy, YuceBio Technology Co., Ltd, Shenzhen, People’s Republic of China
| | - Changjie Lou
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Haitao Xu
- Department of Hepatobiliary and Pancreatic Surgery, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Chao Zhan
- Department of Hepatobiliary and Pancreatic Surgery, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Yuandi Dong
- Department of Hepatobiliary and Pancreatic Surgery, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Zhigang Ma
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Guangyu Wang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Chunhui Zhang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Haibo Lu
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Tongsen Zheng
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
| | - Yanqiao Zhang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, People’s Republic of China
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de Ortiz de Choudens S, Visotcky A, Banerjee A, Aldakkak M, Tsai S, Evans DB, Christians KK, Clarke CN, George B, Shreenivas A, Kamgar M, Chakrabarti S, Dua KS, Khan AH, Madhavan S, Erickson BA, Hall WA. Characterization of an oligometastatic state in patients with metastatic pancreatic adenocarcinoma undergoing systemic chemotherapy. Cancer Med 2024; 13:e6582. [PMID: 38140796 PMCID: PMC10807686 DOI: 10.1002/cam4.6582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 06/28/2023] [Accepted: 09/13/2023] [Indexed: 12/24/2023] Open
Abstract
PURPOSE/OBJECTIVES Most patients with pancreatic adenocarcinoma (PDAC) will present with distant metastatic disease at diagnosis. We sought to identify clinical characteristics associated with prolonged overall survival (OS) in patients presenting with metastatic PDAC. MATERIALS/METHODS Patients presenting with metastatic PDAC that received treatment at our institution with FOLFIRINOX or gemcitabine-based chemotherapies between August 1, 2011 and September 1, 2017 were included in the study. Metastatic disease burden was comprehensively characterized radiologically via individual diagnostic imaging segmentation. Landmark analysis was performed at 18 months, and survival curves were estimated using the Kaplan-Meier method and compared between groups via the log-rank test. ECOG and Charlson Comorbidity Index (CCI) were calculated for all patients. RESULTS 121 patients were included with a median age of 62 years (37-86), 40% were female, 25% had ECOG 0 at presentation. Of the 121 patients included, 33% (n = 41) were alive at 12 months and 25% (n = 31) were alive at 18 months. Landmark analysis demonstrated a significant difference between patients surviving <18 months and ≥18 months regarding the presence of lung only metastases (36% vs. 16%, p = 0.04), number of organs with metastases (≥2 vs. 1, p = 0.04), and disease volume (mean of 19.1 cc vs. 1.4 cc, p = 0.04). At Year 1, predictors for improved OS included ECOG status at diagnosis (ECOG 0 vs. ECOG 1, p = 0.04), metastatic disease volume at diagnosis (≤0.1 cc vs. >60 cc, p = 0.004), metastasis only in the liver (p = 0.04), and normalization of CA 19-9 (p < 0.001). At Year 2, the only predictor of improved OS was normalization of the CA 19-9 (p = 0.03). In those patients that normalized their CA 19-9, median overall survival was 16 months. CONCLUSIONS In this exploratory analysis normalization of CA-19-9 or volumetric metastatic disease burden less than 0.2 cc demonstrated a remarkable OS, similar to that of patients with non-metastatic disease. These metrics are useful for counseling patients and identifying cohorts that may be optimal for trials exploring metastatic and/or local tumor-directed interventions.
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Affiliation(s)
| | - Alexis Visotcky
- Division of BiostatisticsMedical College of WisconsinMilwaukeeWisconsinUSA
| | - Anjishnu Banerjee
- Division of BiostatisticsMedical College of WisconsinMilwaukeeWisconsinUSA
| | - Mohammed Aldakkak
- Department of SurgeryMedical College of WisconsinMilwaukeeWisconsinUSA
- LaBahn Pancreatic Cancer ProgramMilwaukeeWisconsinUSA
| | - Susan Tsai
- Department of SurgeryMedical College of WisconsinMilwaukeeWisconsinUSA
- LaBahn Pancreatic Cancer ProgramMilwaukeeWisconsinUSA
| | - Douglas B. Evans
- Department of SurgeryMedical College of WisconsinMilwaukeeWisconsinUSA
- LaBahn Pancreatic Cancer ProgramMilwaukeeWisconsinUSA
| | - Kathleen K. Christians
- Department of SurgeryMedical College of WisconsinMilwaukeeWisconsinUSA
- LaBahn Pancreatic Cancer ProgramMilwaukeeWisconsinUSA
| | - Callisia N. Clarke
- Department of SurgeryMedical College of WisconsinMilwaukeeWisconsinUSA
- LaBahn Pancreatic Cancer ProgramMilwaukeeWisconsinUSA
| | - Ben George
- LaBahn Pancreatic Cancer ProgramMilwaukeeWisconsinUSA
- Division of Medical OncologyMedical College of WisconsinMilwaukeeWisconsinUSA
| | - Aditya Shreenivas
- Division of Medical OncologyMedical College of WisconsinMilwaukeeWisconsinUSA
| | - Mandana Kamgar
- LaBahn Pancreatic Cancer ProgramMilwaukeeWisconsinUSA
- Division of Medical OncologyMedical College of WisconsinMilwaukeeWisconsinUSA
| | - Sakti Chakrabarti
- Division of Medical OncologyMedical College of WisconsinMilwaukeeWisconsinUSA
| | - Kulwinder S. Dua
- Division of Medical OncologyMedical College of WisconsinMilwaukeeWisconsinUSA
- Division of GastroenterologyMedical College of WisconsinMilwaukeeWisconsinUSA
| | - Abdul Haq Khan
- Division of Medical OncologyMedical College of WisconsinMilwaukeeWisconsinUSA
- Division of GastroenterologyMedical College of WisconsinMilwaukeeWisconsinUSA
| | - Srivats Madhavan
- Division of Medical OncologyMedical College of WisconsinMilwaukeeWisconsinUSA
- Division of GastroenterologyMedical College of WisconsinMilwaukeeWisconsinUSA
| | - Beth A. Erickson
- Department of Radiation OncologyMedical College of WisconsinMilwaukeeWisconsinUSA
- LaBahn Pancreatic Cancer ProgramMilwaukeeWisconsinUSA
| | - William A. Hall
- Department of Radiation OncologyMedical College of WisconsinMilwaukeeWisconsinUSA
- LaBahn Pancreatic Cancer ProgramMilwaukeeWisconsinUSA
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Wahler IL, Damanakis A, Große Hokamp N, Bruns C, Schmidt T. Therapy of Locally Advanced and Oligometastatic Pancreatic Adenocarcinoma. Cancers (Basel) 2023; 15:5881. [PMID: 38136425 PMCID: PMC10741431 DOI: 10.3390/cancers15245881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/06/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023] Open
Abstract
Pancreatic adenocarcinoma is a lethal disease, and surgical resection remains the only curative treatment option. Unfortunately, upon primary diagnosis, only 15-20% of all patients with pancreatic ductal adenocarcinoma (PDAC) have localized disease that is eligible for operation. The remainder of patients either have borderline resectable or locally advanced disease or present with distant metastasis. In this review, we present a comprehensive overview regarding the current strategies and future directions in the multimodal therapy of locally advanced and oligometastasized pancreatic adenocarcinoma and discuss the benefit of surgery following neoadjuvant therapy in these patients.
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Affiliation(s)
- Isabell Luisa Wahler
- Department of General, Visceral, Cancer and Transplant Surgery, Faculty of Medicine, University Hospital of Cologne, University of Cologne, 50937 Cologne, Germany; (I.L.W.); (A.D.)
| | - Alexander Damanakis
- Department of General, Visceral, Cancer and Transplant Surgery, Faculty of Medicine, University Hospital of Cologne, University of Cologne, 50937 Cologne, Germany; (I.L.W.); (A.D.)
| | - Nils Große Hokamp
- Department of Diagnostic and Interventional Radiology, Faculty of Medicine, University Hospital of Cologne, 50923 Cologne, Germany
| | - Christiane Bruns
- Department of General, Visceral, Cancer and Transplant Surgery, Faculty of Medicine, University Hospital of Cologne, University of Cologne, 50937 Cologne, Germany; (I.L.W.); (A.D.)
| | - Thomas Schmidt
- Department of General, Visceral, Cancer and Transplant Surgery, Faculty of Medicine, University Hospital of Cologne, University of Cologne, 50937 Cologne, Germany; (I.L.W.); (A.D.)
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Harada T, Uemura K, Sumiyoshi T, Shintakuya R, Okada K, Hara T, Takahashi S, Hiyama E. Increased plasma miR-370-3p expression in poor-outcome patients with pancreatic ductal adenocarcinoma. Pancreatology 2023; 23:996-1002. [PMID: 37945497 DOI: 10.1016/j.pan.2023.10.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 10/14/2023] [Accepted: 10/23/2023] [Indexed: 11/12/2023]
Abstract
OBJECTIVE To determine whether circulating microRNAs (miRNAs) can be used as prognostic biomarkers for pancreatic ductal adenocarcinoma (PDAC). METHODS Patients with PDAC (N = 120) who underwent surgical resection at Hiroshima University Hospital between November 2006 and January 2020 were enrolled in this study and grouped based on their overall survival (OS) into two groups: favorable prognosis group (F group; OS ≥ 18 months) and unfavorable prognosis group (U group; OS < 18 months). Blood plasma samples were collected prior to surgery. To identify candidate prognostic miRNAs, next-generation sequencing (NGS) analysis was used to evaluate the expression levels of miRNAs in seven of the plasma samples. Using quantitative real-time PCR (qRT-PCR), the expression levels of the selected miRNAs were determined in the remaining 113 patient plasma samples, and the relationship between miRNA expression and survival was statistically evaluated. RESULTS NGS analysis and qRT-PCR revealed significantly upregulated plasma miR-370-3p expression in the U group compared to that in the F group (p = 0.028 and p = 0.005, respectively). Moreover, miR-370-3p expression and lymph node metastasis showed a statistically significant association (p = 0.028). In a multivariate analysis of OS and recurrence-free survival (RFS), the upregulation of miR-370-3p expression in plasma was identified as an independent risk factor for poor OS (HR2.13, p = 0.004) and RFS (HR1.84, p = 0.015). CONCLUSIONS Plasma miR-370-3p expression upregulation correlates with poor prognosis in patients with PDAC.
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Affiliation(s)
- Takumi Harada
- Department of Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kenichiro Uemura
- Department of Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tatsuaki Sumiyoshi
- Department of Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Ryuta Shintakuya
- Department of Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kenjiro Okada
- Department of Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tetsuhiro Hara
- Department of Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Shinya Takahashi
- Department of Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Eiso Hiyama
- Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan.
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Ishizaki A, Okuwaki K, Kida M, Imaizumi H, Iwai T, Yamauchi H, Kaneko T, Hasegawa R, Watanabe M, Kurosu T, Ishizaki J, Kusano C. Implication of Skeletal Muscle Loss in the Prognosis of Patients with Pancreatic Ductal Adenocarcinoma Receiving Chemotherapy. Intern Med 2023; 62:2783-2793. [PMID: 36792197 PMCID: PMC10602831 DOI: 10.2169/internalmedicine.0900-22] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 12/26/2022] [Indexed: 02/16/2023] Open
Abstract
Objective The effect of sarcopenia on the prognosis of patients undergoing chemotherapy for unresectable pancreatic ductal adenocarcinoma remains largely unexplored. In this retrospective study, we investigated the relationship between sarcopenia and the prognosis of patients receiving first-line nanoparticle albumin-bound paclitaxel plus gemcitabine for unresectable pancreatic ductal adenocarcinoma. Methods We enrolled 251 patients with unresectable metastatic or locally advanced pancreatic ductal adenocarcinoma who had received chemotherapy between January 2015 and December 2020 at Kitasato University Hospital. Univariate and multivariate analyses were performed using the stratified Cox proportional hazards model to determine variables significantly associated with the progression-free and overall survival. Propensity score matching was performed to mitigate selection bias effects. Results In the propensity score-matched cohort, the progression-free and overall survival were not significantly different between the sarcopenia and non-sarcopenia groups (p=0.335, and 0.679 respectively). The skeletal muscle index decreased by 4.4% and 6.5% in the sarcopenia and non-sarcopenia groups, respectively, during the early treatment phase (p=0.084). There were no significant differences between groups with regard to major adverse events or drug toxicity occurrences. Both the progression-free and overall survival were significantly shorter in the skeletal muscle index loss group than in the non-skeletal muscle index loss group (p=0.026 and 0.045, respectively). Conclusion Skeletal muscle index loss during the initial treatment phase may be an early marker for the long-term prognosis of patients receiving nanoparticle albumin-bound paclitaxel plus gemcitabine as first-line treatment for unresectable pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Ayana Ishizaki
- Department of Gastroenterology, Kitasato University School of Medicine, Japan
| | - Kosuke Okuwaki
- Department of Gastroenterology, Kitasato University School of Medicine, Japan
| | - Mitsuhiro Kida
- Department of Gastroenterology, Kitasato University School of Medicine, Japan
| | - Hiroshi Imaizumi
- Department of Gastroenterology, Kitasato University School of Medicine, Japan
| | - Tomohisa Iwai
- Department of Gastroenterology, Kitasato University School of Medicine, Japan
| | - Hiroshi Yamauchi
- Department of Gastroenterology, Kitasato University School of Medicine, Japan
| | - Toru Kaneko
- Department of Gastroenterology, Kitasato University School of Medicine, Japan
| | - Rikiya Hasegawa
- Department of Gastroenterology, Kitasato University School of Medicine, Japan
| | - Masafumi Watanabe
- Department of Gastroenterology, Kitasato University School of Medicine, Japan
| | - Takahiro Kurosu
- Department of Gastroenterology, Kitasato University School of Medicine, Japan
| | - Junro Ishizaki
- Department of Gastroenterology, Kitasato University School of Medicine, Japan
| | - Chika Kusano
- Department of Gastroenterology, Kitasato University School of Medicine, Japan
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Li X, Huang J, Wang F, Jiang Q, Huang L, Li S, Guo G. Efficacy and safety of SOXIRI versus mFOLFIRINOX in advanced pancreatic cancer. Ther Adv Med Oncol 2023; 15:17588359231186029. [PMID: 37435561 PMCID: PMC10331348 DOI: 10.1177/17588359231186029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 06/13/2023] [Indexed: 07/13/2023] Open
Abstract
Background Modified fluorouracil/leucovorin/irinotecan/oxaliplatin (FOLFIRINOX) regimen (mFOLFIRINOX), comprised of fluorouracil, leucovorin, irinotecan and oxaliplatin, is the first-line standard chemotherapy in patients with advanced pancreatic cancer. The S-1/oxaliplatin/irinotecan (SOXIRI) regimen has also been studied recently under similar conditions. This study compared its efficacy and safety. Methods All cases of locally advanced or metastatic pancreatic cancer treated with the SOXIRI or mFOLFIRINOX regimen in Sun Yat-sen University Cancer Centre from July 2012 to June 2021 were reviewed retrospectively. The data of patients who satisfied the inclusion criteria were compared between two cohorts, including overall survival (OS), progression-free survival (PFS), objective response rate, disease control rate and safety. Results A total of 198 patients were enrolled in the study, including 102 patients treated with SOXIRI and 96 patients treated with mFOLFIRINOX. There was no significant difference in OS [12.1 months versus 11.2 months, hazard ratio (HR) = 1.04, p = 0.81] or PFS (6.5 months versus 6.8 months, HR = 0.99, p = 0.96) between patients treated with SOXIRI and mFOLFIRINOX. In the subgroup analysis, patients with slightly elevated baseline total bilirubin (TBIL) or underweight patients before chemotherapy were more likely to have a longer OS or PFS from SOXIRI than from mFOLFIRINOX. In addition, the carbohydrate antigen (CA)19-9 decline was a good predictor for the efficacy and prognosis of both chemotherapy regimens. All grade adverse events were parallel in all kinds of toxicities except that anaemia was more common in the SOXIRI group than in the mFOLFIRINOX group (41.4% versus 24%, p = 0.03). The occurrence of any grade 3 to 4 toxicity was similar in the two groups. Conclusions For locally advanced or metastatic pancreatic cancer patients, the SOXIRI regimen had similar efficacy and controllable safety compared with the mFOLFIRINOX regimen.
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Affiliation(s)
- Xujia Li
- VIP Department, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Jinsheng Huang
- VIP Department, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Fenghua Wang
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Qi Jiang
- VIP Department, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Lingli Huang
- VIP Department, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Shengping Li
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, Guangdong 510060, P.R. China
- Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Department of Pancreaticobiliary Surgery, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
| | - Guifang Guo
- VIP Department, Sun Yat-sen University Cancer Center, 651 Dongfeng Road East, Yuexiu District, Guangzhou, Guangdong 510060, P.R. China
- State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
- Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China
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9
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Dorman K, Gerckens M, Kruger S, Krueger K, Mayer Z, Rupp A, Zhang D, Weiss L, Westphalen CB, Haas M, Guenther M, Ormanns S, Klawonn F, Werner J, von Bergwelt-Baildon M, Heinemann V, Boeck S, Holdenrieder S. Serum biomarker panel diagnostics in pancreatic ductal adenocarcinoma: the clinical utility of soluble interleukins, IFN-γ, TNF-α and PD-1/PD-L1 in comparison to established serum tumor markers. J Cancer Res Clin Oncol 2023; 149:2463-2474. [PMID: 35737090 PMCID: PMC10130000 DOI: 10.1007/s00432-022-04112-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 06/03/2022] [Indexed: 11/28/2022]
Abstract
PURPOSE Novel biomarkers to better predict outcome and select the best therapeutic strategy for the individual patient are necessary for pancreatic ductal adenocarcinoma (PDAC). METHODS Using a panel assay, multiple biomarkers (IFN-γ, IL-10, IL-6, IL-8, TNF-α, CEA, CA 19-9, CYFRA 21-1, HE4, PD-1 and PD-L1 levels) were measured in serum samples of 162 patients with resected, locally advanced and metastatic PDAC in this retrospective single-center study. Optimal cut-off values to differentiate prognostic subgroups with significantly different overall survival (OS) were determined by receiver operator characteristics and Youden Index analysis. Marker levels were assessed before the start of chemotherapy and correlated with OS by univariate and multivariate Cox analysis. RESULTS Median OS for resected patients was 28.2 months, for locally advanced patients 17.9 months and for patients with metastatic disease 8.6 months. CYFRA 21-1 and IL-8 discriminated metastatic from locally advanced patients best (AUC 0.85 and AUC 0.81, respectively). In univariate analyses, multiple markers showed prognostic relevance in the various subgroups. However, multivariate Cox models comprised only CYFRA 21-1 in the resected group (HR 1.37, p = 0.015), IL-10 in locally advanced PDAC (HR 10.01, p = 0.014), as well as CYFRA 21-1 and CA 19-9 in metastatic PDAC (p = 0.008 and p = 0.010) as an independent prognostic marker for overall survival. CONCLUSION IL-10 levels may have independent prognostic value in locally advanced PDAC, whereas CYFRA 21-1 levels are prognostic after PDAC surgery. CYFRA 21-1 and IL-8 have been identified to best discriminate metastatic from locally advanced patients.
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Affiliation(s)
- Klara Dorman
- Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, 81377, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Miriam Gerckens
- Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, 81377, Munich, Germany
- Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center, Technical University of Munich, Munich, Germany
| | - Stephan Kruger
- Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Kimberly Krueger
- Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center, Technical University of Munich, Munich, Germany
| | - Zsuzsanna Mayer
- Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center, Technical University of Munich, Munich, Germany
| | - Alexander Rupp
- Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center, Technical University of Munich, Munich, Germany
| | - Danmei Zhang
- Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, 81377, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Lena Weiss
- Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - C Benedikt Westphalen
- Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Michael Haas
- Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, 81377, Munich, Germany
| | - Michael Guenther
- Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Steffen Ormanns
- Institute of Pathology, Faculty of Medicine, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Frank Klawonn
- Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center, Technical University of Munich, Munich, Germany
- Department of Computer Science, Ostfalia University, Wolfenbüttel, Germany
- Biostatistics Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Jens Werner
- Department of General, Visceral and Transplant Surgery, Ludwig-Maximilians-University of Munich, Munich, Germany
| | - Michael von Bergwelt-Baildon
- Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, 81377, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Volker Heinemann
- Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, 81377, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
| | - Stefan Boeck
- Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich, Marchioninistr. 15, 81377, Munich, Germany.
- German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany.
| | - Stefan Holdenrieder
- Munich Biomarker Research Center, Institute of Laboratory Medicine, German Heart Center, Technical University of Munich, Munich, Germany
- Center for the Evaluation of Biomarkers, CEBIO, Munich, Germany
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10
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Dayimu A, Di Lisio L, Anand S, Roca-Carreras I, Qian W, Al-Mohammad A, Basu B, Valle JW, Jodrell D, Demiris N, Corrie P. Clinical and biological markers predictive of treatment response associated with metastatic pancreatic adenocarcinoma. Br J Cancer 2023; 128:1672-1680. [PMID: 36813867 PMCID: PMC10133256 DOI: 10.1038/s41416-023-02170-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 01/05/2023] [Accepted: 01/17/2023] [Indexed: 02/24/2023] Open
Abstract
BACKGROUND Chemotherapy for metastatic pancreatic adenocarcinoma (PDAC) offers limited benefits, but survival outcomes vary. Reliable predictive response biomarkers to guide patient management are lacking. METHODS Patient performance status, tumour burden (determined by the presence or absence of liver metastases), plasma protein biomarkers (CA19-9, albumin, C-reactive protein and neutrophils) and circulating tumour DNA (ctDNA) were assessed in 146 patients with metastatic PDAC prior to starting either concomitant or sequential nab-paclitaxel + gemcitabine chemotherapy in the SIEGE randomised prospective clinical trial, as well as during the first 8 weeks of treatment. Correlations were made with objective response, death within 1 year and overall survival (OS). RESULTS Initial poor patient performance status, presence of liver metastases and detectable mutKRAS ctDNA all correlated with worse OS after adjusting for the different biomarkers of interest. Objective response at 8 weeks also correlated with OS (P = 0.026). Plasma biomarkers measured during treatment and prior to the first response assessment identified ≥10% decrease in albumin at 4 weeks predicted for worse OS (HR 4.75, 95% CI 1.43-16.94, P = 0.012), while any association of longitudinal evaluation of mutKRAS ctDNA with OS was unclear (β = 0.024, P = 0.057). CONCLUSIONS Readily measurable patient variables can aid the prediction of outcomes from combination chemotherapy used to treat metastatic PDAC. The role of mutKRAS ctDNA as a tool to guide treatment warrants further exploration. CLINICAL TRIAL REGISTRATION ISRCTN71070888; ClinialTrials.gov (NCT03529175).
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Affiliation(s)
- Alimu Dayimu
- Clinical Trials Unit, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Lorena Di Lisio
- Cancer Molecular Diagnostics Laboratory, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Shubha Anand
- Cancer Molecular Diagnostics Laboratory, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Isart Roca-Carreras
- Cancer Molecular Diagnostics Laboratory, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Wendi Qian
- Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | | | - Bristi Basu
- Department of Oncology, University of Cambridge, Cambridge, UK
| | - Juan W Valle
- University of Manchester and The Christie NHS Foundation Trust, Manchester, UK
| | - Duncan Jodrell
- Department of Oncology, University of Cambridge, Cambridge, UK
| | - Nikos Demiris
- Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- Department of Statistics, Athens University of Economics and Business, Athens, Greece
| | - Pippa Corrie
- Oncology Department, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
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11
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Robertson FP, Pandanaboyana S. Redefining resectability in pancreatic cancer after neoadjuvant therapy: are we any closer? Hepatobiliary Surg Nutr 2023; 12:131-134. [PMID: 36860247 PMCID: PMC9944546 DOI: 10.21037/hbsn-22-638] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 01/09/2023] [Indexed: 01/18/2023]
Affiliation(s)
- Francis P. Robertson
- Department of HPB and Transplant Surgery, Newcastle Upon Tyne NHS Foundation Trust, Freeman Hospital, Newcastle Upon Tyne, UK;,Division of Surgery and Interventional Science, University College London, Royal Free Campus, London, UK
| | - Sanjay Pandanaboyana
- Department of HPB and Transplant Surgery, Newcastle Upon Tyne NHS Foundation Trust, Freeman Hospital, Newcastle Upon Tyne, UK;,Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
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12
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Kawakami T, Todaka A, Oshima K, Fushiki K, Hamauchi S, Tsushima T, Yokota T, Onozawa Y, Yasui H, Yamazaki K. Biomarker analysis for patients with pancreatic cancer treated with nanoliposomal irinotecan plus 5-fluorouracil/leucovorin. BMC Cancer 2023; 23:68. [PMID: 36670426 PMCID: PMC9854093 DOI: 10.1186/s12885-023-10542-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Accepted: 01/12/2023] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Nanoliposomal irinotecan plus fluorouracil/leucovorin (5-FU/LV) is a standard second-line therapy for patients with pancreatic cancer. Identification of biomarkers is important to determine appropriate treatment strategies. We investigated the clinical practice outcomes and biomarkers associated with the nanoliposomal irinotecan plus 5-FU/LV regimen. METHODS We retrospectively reviewed the data of patients treated with nanoliposomal irinotecan plus 5-FU/LV as a second or subsequent treatment after gemcitabine-based therapy between June 2020 and March 2021 at Shizuoka Cancer Center. RESULTS We analyzed 55 consecutive patients who met the selection criteria. At a median of 9.4 months, median progression-free survival (PFS) and median overall survival (OS) were 2.3 and 6.6 months, respectively. Multivariate analysis showed that Glasgow prognostic score (GPS) was significantly associated with PFS (hazard ratio [HR] 2.16; 95% confidence interval [CI] 1.09-4.30; P = 0.028) and OS (0 vs. 1 or 2: HR 2.46; 95% CI 1.15-5.25; P = 0.029). The OS was significantly longer in patients with CA19-9 response than in those without CA19-9 response (12.6 vs. 5.6 months; HR 0.24; 95% CI 0.08-0.75; P = 0.014). CONCLUSIONS Nanoliposomal irinotecan was efficacious and tolerable in clinical practice. GPS and CA19-9 response were good candidates as predictive biomarkers, whereas GPS was a good candidate prognostic biomarker for the nanoliposomal irinotecan plus 5-FU/LV regimen.
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Affiliation(s)
- Takeshi Kawakami
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan.
| | - Akiko Todaka
- grid.415797.90000 0004 1774 9501Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Kotoe Oshima
- grid.415797.90000 0004 1774 9501Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Kunihiro Fushiki
- grid.415797.90000 0004 1774 9501Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Satoshi Hamauchi
- grid.415797.90000 0004 1774 9501Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Takahiro Tsushima
- grid.415797.90000 0004 1774 9501Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Tomoya Yokota
- grid.415797.90000 0004 1774 9501Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Yusuke Onozawa
- grid.415797.90000 0004 1774 9501Division of Clinical Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Hirofumi Yasui
- grid.415797.90000 0004 1774 9501Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Kentaro Yamazaki
- grid.415797.90000 0004 1774 9501Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
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13
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Huffman BM, Basu Mallick A, Horick NK, Wang-Gillam A, Hosein PJ, Morse MA, Beg MS, Murphy JE, Mavroukakis S, Zaki A, Schlechter BL, Sanoff H, Manz C, Wolpin BM, Arlen P, Lacy J, Cleary JM. Effect of a MUC5AC Antibody (NPC-1C) Administered With Second-Line Gemcitabine and Nab-Paclitaxel on the Survival of Patients With Advanced Pancreatic Ductal Adenocarcinoma: A Randomized Clinical Trial. JAMA Netw Open 2023; 6:e2249720. [PMID: 36602796 PMCID: PMC9856813 DOI: 10.1001/jamanetworkopen.2022.49720] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
IMPORTANCE Treatment options are limited for patients with advanced pancreatic ductal adenocarcinoma (PDAC) beyond first-line 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), with such individuals commonly being treated with gemcitabine and nab-paclitaxel. OBJECTIVE To determine whether NPC-1C, an antibody directed against MUC5AC, might increase the efficacy of second-line gemcitabine and nab-paclitaxel in patients with advanced PDAC. DESIGN, SETTING, AND PARTICIPANTS This multicenter, randomized phase II clinical trial enrolled patients with advanced PDAC between April 2014 and March 2017 whose disease had progressed on first-line FOLFIRINOX. Eligible patients had tumors with at least 20 MUC5AC staining by centralized immunohistochemistry review. Statistical analysis was performed from April to May 2022. INTERVENTIONS Patients were randomly assigned to receive gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) administered intravenously on days 1, 8, and 15 of every 4-week cycle, with or without intravenous NPC-1C 1.5 mg/kg every 2 weeks. MAIN OUTCOMES AND MEASURES The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rate (ORR), and safety. Pretreatment clinical variables were explored with Cox proportional hazards analysis. RESULTS A total of 78 patients (median [range] age, 62 [36-78] years; 32 [41%] women; 9 [12%] Black; 66 [85%] White) received second-line treatment with gemcitabine plus nab-paclitaxel (n = 40) or gemcitabine plus nab-paclitaxel and NPC-1C (n = 38). Median OS was 6.6 months (95% CI, 4.7-8.4 months) with gemcitabine plus nab-paclitaxel vs 5.0 months (95% CI, 3.3-6.5 months; P = .22) with gemcitabine plus nab-paclitaxel and NPC-1C. Median PFS was 2.7 months (95% CI, 1.9-4.1 months) with gemcitabine plus nab-paclitaxel vs 3.4 months (95% CI, 1.9-5.3 months; P = .80) with gemcitabine plus nab-paclitaxel and NPC-1C. The ORR was 3.1% (95% CI, 0.4%-19.7%) in the gemcitabine plus nab-paclitaxel and NPC-1C group and 2.9% (95% CI, 0.4%-18.7%) in the gemcitabine plus nab-paclitaxel group. No differences in toxicity were observed between groups, except that grade 3 or greater anemia occurred more frequently in patients treated with gemcitabine plus nab-paclitaxel and NPC-1C than gemcitabine plus nab-paclitaxel (39% [15 of 38] vs 10% [4 of 40]; P = .003). The frequency of chemotherapy dose reductions was similar in both groups (65% vs 74%; P = .47). Lower performance status, hypoalbuminemia, PDAC diagnosis less than or equal to 18 months before trial enrollment, lymphocyte-to-monocyte ratio less than 2.8, and CA19-9 greater than 2000 IU/mL were independently associated with poorer survival. CONCLUSIONS AND RELEVANCE In this randomized clinical trial of advanced PDAC, NPC-1C did not enhance the efficacy of gemcitabine/nab-paclitaxel. These data provide a benchmark for future trials investigating second-line treatment of PDAC. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01834235.
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Affiliation(s)
- Brandon M. Huffman
- Division of Gastrointestinal Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute/Harvard Medical School, Boston, Massachusetts
| | - Atrayee Basu Mallick
- Thomas Jefferson University/Sidney Kimmel Cancer Center, Philadelphia, Pennsylvania
| | - Nora K. Horick
- Biostatistics Center, Massachusetts General Hospital, Boston
| | - Andrea Wang-Gillam
- Washington University in St. Louis, School of Medicine, St. Louis, Missouri
| | | | | | - Muhammad Shaalan Beg
- UT Southwestern Medical Center, Dallas, Texas
- Science 37 Inc, Durham, North Carolina
| | - Janet E. Murphy
- Division of Hematology/Oncology, Massachusetts General Hospital, Boston
| | | | | | | | | | - Christopher Manz
- Division of Population Sciences, Department of Medical Oncology, Dana-Farber Cancer Institute/Harvard Medical School, Boston, Massachusetts
| | - Brian M. Wolpin
- Division of Gastrointestinal Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute/Harvard Medical School, Boston, Massachusetts
| | | | - Jill Lacy
- Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut
| | - James M. Cleary
- Division of Gastrointestinal Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute/Harvard Medical School, Boston, Massachusetts
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14
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Mie T, Ozaka M, Okamoto T, Takeda T, Ushida Y, Mori C, Furukawa T, Yamada Y, Kasuga A, Matsuyama M, Sasaki T, Inoue Y, Takahashi YU, Sasahira N. CA19-9 Reduction After 4 Months of Treatment Is a Prognostic Factor for Locally Advanced Pancreatic Cancer. In Vivo 2022; 36:2844-2851. [PMID: 36309391 PMCID: PMC9677793 DOI: 10.21873/invivo.13024] [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: 08/01/2022] [Revised: 08/22/2022] [Accepted: 08/23/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND/AIM Carbohydrate antigen 19-9 (CA19-9) levels may aid in the determination of subsequent treatment in patients with unresectable locally-advanced pancreatic cancer (LAPC) treated with chemotherapy. However, the relationship between the timing and magnitude of CA19-9 changes and clinical outcomes remains unclear. This study was conducted to identify the timing and magnitude of CA19-9 changes, which are most strongly associated with outcomes in LAPC patients. PATIENTS AND METHODS We retrospectively analyzed consecutive LAPC patients treated with gemcitabine plus nab-paclitaxel (GnP) or modified FOLFIRINOX (mFFX) as the first-line chemotherapy between March 2014 and December 2018 in our hospital. Multivariate analyses were performed to identify prognostic factors of chemotherapy in LAPC. RESULTS Ninety-four patients were included (GnP/mFFX: 72/22). The median overall survival was 20.3 months, and the median progression-free survival was 8.8 months. CA19-9 values before treatment did not affect prognosis. However, CA19-9 <100 U/ml or more than a 70% reduction in CA19-9 four months after commencing treatment was associated with a good prognosis (hazard ratio=0.17; 95% confidence interval=0.09-0.33; p<0.01). CONCLUSION CA19-9 values 4 months after commencing treatment are a significant prognostic factor in LAPC patients undergoing chemotherapy.
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Affiliation(s)
- Takafumi Mie
- Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Masato Ozaka
- Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan;
| | - Takeshi Okamoto
- Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tsuyoshi Takeda
- Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yuta Ushida
- Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Chinatsu Mori
- Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takaaki Furukawa
- Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yuto Yamada
- Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Akiyoshi Kasuga
- Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Masato Matsuyama
- Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takashi Sasaki
- Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yousuke Inoue
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Y U Takahashi
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Naoki Sasahira
- Department of Hepato-Biliary-Pancreatic Medicine, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
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Mitomycin C in Homologous Recombination Deficient Metastatic Pancreatic Cancer after Disease Progression on Platinum-Based Chemotherapy and Olaparib. Biomedicines 2022; 10:biomedicines10112705. [PMID: 36359225 PMCID: PMC9687686 DOI: 10.3390/biomedicines10112705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 10/12/2022] [Accepted: 10/21/2022] [Indexed: 12/03/2022] Open
Abstract
Recent efforts to personalize treatment with platinum-based chemotherapy and PARP inhibitors have produced promising results in homologous recombinant deficient (HRD) metastatic pancreatic cancer (MPC). However, new strategies are necessary to overcome resistance. The below case series documents patients treated at the HonorHealth Research Institute with a diagnosis of HRD MPC who received Mitomycin C (MMC) treatment from January 2013 until July 2018. Five HRD MPC patients treated with MMC were evaluated. All patients received at least one course of treatment. Mean age at MMC treatment initiation was 58 years. There were 3 females and 2 males. All patients had tumors that progressed on platinum-based chemotherapy, four patients had previous exposure to Olaparib. The median PFS was 10.1 months, and the median OS was 12.3 months. Responses were observed only in patients harboring BRCA2 mutations, no response was observed in the PALB2 mutation carrier. MMC in this heavily previously treated PC was safe, with overall manageable grade 2 gastrointestinal toxicities including nausea and vomiting, and G3 hematological toxicities including anemia and thrombocytopenia. Pancreatic cancer patients with HRD may benefit from MMC treatment. Further clinical investigation of MMC in pancreatic cancer is warranted.
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Caliez O, Pietrasz D, Ksontini F, Doat S, Simon JM, Vaillant JC, Taly V, Laurent-Puig P, Bachet JB. Circulating tumor DNA: a help to guide therapeutic strategy in patients with borderline and locally advanced pancreatic adenocarcinoma? Dig Liver Dis 2022; 54:1428-1436. [PMID: 35120842 DOI: 10.1016/j.dld.2022.01.126] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 12/16/2021] [Accepted: 01/11/2022] [Indexed: 12/29/2022]
Abstract
BACKGROUND prognostic biomarkers could be useful to better select patients with borderline resectable (BR) or locally advanced (LA) pancreatic adenocarcinoma (PA) for chemoradiotherapy (CRT) and/or secondary resection. AIMS The main objective of this work was to study characteristics, received treatments and prognostic of patients with BR or LA PA according to their baseline circulating tumor DNA status and, for secondary objective, neutrophil-to-lymphocyte Ratio (NLR). METHODS ctDNA status at baseline was determined using Next Generation Sequencing in a consecutive monocentric cohort of patients with a BR or LA PA. RESULTS 69 patients were included, 31 with BR PA and 38 with LA PA. 14 (20.3%) patients had baseline positive ctDNA. Five (7.8%) patients had NLR> 5. Patients with positive ctDNA had 3.7 months shorter progression free survival (p = 0.006). Patients with positive ctDNA had earlier progression after the beginning of CRT (4.4 vs 7.1 months; p = 0.068) and shorter relapse free survival after secondary resection (9.2 vs 22.9 months; p = 0.016). CONCLUSIONS positive ctDNA at baseline was associated with a worse prognosis in patients with BR or LA PA. These data are exploratory and must be confirmed in further prospective trials.
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Affiliation(s)
- Olivier Caliez
- Department of Gastroenterology, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; French National Institute of Health and Medical Research (INSERM), Centre de Recherche des Cordeliers, Sorbonne Université, Sorbonne Paris Cité, Université Paris Descartes, Université de Paris, Paris, France; Sorbonne Université, UPMC, Paris 6, France
| | - Daniel Pietrasz
- French National Institute of Health and Medical Research (INSERM), Centre de Recherche des Cordeliers, Sorbonne Université, Sorbonne Paris Cité, Université Paris Descartes, Université de Paris, Paris, France; Department of Digestive Surgery, Hôpital Paul Brousse, Villejuif, France
| | - Feryel Ksontini
- Department of Oncology, Institute Salah-Azaïz, Tunis, Tunisia
| | - Solène Doat
- Department of Gastroenterology, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Jean-Marc Simon
- Department of Radiation Oncology, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Jean-Christophe Vaillant
- Department of Digestive Surgery, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
| | - Valerie Taly
- French National Institute of Health and Medical Research (INSERM), Centre de Recherche des Cordeliers, Sorbonne Université, Sorbonne Paris Cité, Université Paris Descartes, Université de Paris, Paris, France
| | - Pierre Laurent-Puig
- French National Institute of Health and Medical Research (INSERM), Centre de Recherche des Cordeliers, Sorbonne Université, Sorbonne Paris Cité, Université Paris Descartes, Université de Paris, Paris, France
| | - Jean-Baptiste Bachet
- Department of Gastroenterology, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France; French National Institute of Health and Medical Research (INSERM), Centre de Recherche des Cordeliers, Sorbonne Université, Sorbonne Paris Cité, Université Paris Descartes, Université de Paris, Paris, France; Sorbonne Université, UPMC, Paris 6, France.
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Management of Pancreatic Cancer and Its Microenvironment: Potential Impact of Nano-Targeting. Cancers (Basel) 2022; 14:cancers14122879. [PMID: 35740545 PMCID: PMC9221065 DOI: 10.3390/cancers14122879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 06/01/2022] [Accepted: 06/07/2022] [Indexed: 12/10/2022] Open
Abstract
Simple Summary The poor prognosis and survival rates associated with pancreatic cancer show that there is a clear unmet need for better disease management. The heterogeneity of the tumor and its microenvironment, including stroma and fibrosis, creates a challenge for current therapy. The pathogenesis of pancreatic cancer is mediated by several factors, such as severed communication between pancreatic stellate cells and stroma and the consequences of hypoxia-inducible factors that aid in the survival of the pancreatic tumor. Given the multiple limitations of molecular targeting, multiple functional nano-targeting offers a breakthrough in pancreatic cancer treatment through its ability to overcome the physical challenges posed by the tumor microenvironment, amongst many others. Abstract Pancreatic ductal adenocarcinoma (PDAC) is rare and difficult to treat, making it a complicated diagnosis for every patient. These patients have a low survival rate along with a poor quality of life under current pancreatic cancer therapies that adversely affect healthy cells due to the lack of precise drug targeting. Additionally, chemoresistance and radioresistance are other key challenges in PDAC, which might be due in part to the lack of tumor-targeted delivery of sufficient levels of different chemotherapies because of their low therapeutic index. Thus, instead of leaving a trail of off-target damage when killing these cancer cells, it is best to find a way that targets them directly. More seriously, metastatic relapse often occurs after surgery, and therefore, achieving improved outcomes in the management of PDAC in the absence of strategies preventing metastasis is likely to be impossible. Nano-targeting of the tumor and its microenvironment has shown promise for treating various cancers, which might be a promising approach for PDAC. This review updates the advancements in treatment modalities for pancreatic cancer and highlights future directions that warrant further investigation to increase pancreatic patients’ overall survival.
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Kim SS, Lee S, Lee HS, Bang S, Han K, Park MS. Retrospective Evaluation of Treatment Response in Patients with Nonmetastatic Pancreatic Cancer Using CT and CA 19-9. Radiology 2022; 303:548-556. [PMID: 35258374 DOI: 10.1148/radiol.212236] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Background Imaging studies have limitations in evaluating pancreatic ductal adenocarcinoma (PDAC) treatment response. Purpose To investigate the effectiveness of combined CT and carbohydrate antigen 19-9 (CA 19-9) evaluation at 8 weeks after first-line treatment to predict overall survival (OS) of patients with nonmetastatic PDAC. Materials and Methods Patients with nonmetastatic PDAC who received first-line treatment with either chemotherapy or concurrent chemoradiation in a single-center PDAC cohort registry were retrospectively enrolled in the study between January 2013 and December 2016. Follow-up CT images obtained 8 weeks after treatment were evaluated according to Response Evaluation Criteria in Solid Tumors. Patients with partial response (PR) or stable disease (SD) were defined as CT responders, and those with progressive disease (PD) were defined as CT nonresponders. Patients with a normalized CA 19-9 level at 8-week follow-up were defined as CA 19-9 responders, and those with a nonnormalized or nonelevated CA 19-9 level were defined as CA 19-9 nonresponders. OS was compared using the Kaplan-Meier method with Breslow analysis. Results A total of 197 patients (mean age ± standard deviation, 65 years ± 10; 107 men) were evaluated. Patients with PD (n = 17) showed shorter OS than those with SD (n = 147; P < .001) or PR (n = 33; P = .003). OS did not differ between the patients with PR and those with SD (P = .60). When the CT and CA 19-9 responses were integrated, OS was longest in CT and CA 19-9 responders (group 1, n = 27; median OS, 26.6 months [95% CI: 9.0, 44.1]), followed by CT responders but CA 19-9 nonresponders (group 2, n = 153; median OS, 15.9 months [95% CI: 13.3, 18.5]; P = .007 vs group 1) and CT and CA 19-9 nonresponders (group 3, n = 17; median OS, 6.5 months [95% CI: 0.8, 12.2]; P < .001 vs group 2). Conclusion Integrated evaluation with CT and carbohydrate antigen 19-9 response allowed more accurate stratification of survival in patients with pancreatic ductal adenocarcinoma in the early treatment period than did evaluation according to Response Evaluation Criteria in Solid Tumors. © RSNA, 2022 Online supplemental material is available for this article.
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Affiliation(s)
- Seung-Seob Kim
- From the Department of Radiology and Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea (S.S.K., S.L., M.S.P.); Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea (H.S.L., S.B.); and Department of Radiology, Research Institute of Radiological Science, Center for Clinical Imaging Data Science (CCIDS), Yonsei University College of Medicine, Seoul, Republic of Korea (K.H.)
| | - Sunyoung Lee
- From the Department of Radiology and Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea (S.S.K., S.L., M.S.P.); Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea (H.S.L., S.B.); and Department of Radiology, Research Institute of Radiological Science, Center for Clinical Imaging Data Science (CCIDS), Yonsei University College of Medicine, Seoul, Republic of Korea (K.H.)
| | - Hee Seung Lee
- From the Department of Radiology and Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea (S.S.K., S.L., M.S.P.); Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea (H.S.L., S.B.); and Department of Radiology, Research Institute of Radiological Science, Center for Clinical Imaging Data Science (CCIDS), Yonsei University College of Medicine, Seoul, Republic of Korea (K.H.)
| | - Seungmin Bang
- From the Department of Radiology and Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea (S.S.K., S.L., M.S.P.); Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea (H.S.L., S.B.); and Department of Radiology, Research Institute of Radiological Science, Center for Clinical Imaging Data Science (CCIDS), Yonsei University College of Medicine, Seoul, Republic of Korea (K.H.)
| | - Kyunghwa Han
- From the Department of Radiology and Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea (S.S.K., S.L., M.S.P.); Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea (H.S.L., S.B.); and Department of Radiology, Research Institute of Radiological Science, Center for Clinical Imaging Data Science (CCIDS), Yonsei University College of Medicine, Seoul, Republic of Korea (K.H.)
| | - Mi-Suk Park
- From the Department of Radiology and Research Institute of Radiological Science, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea (S.S.K., S.L., M.S.P.); Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea (H.S.L., S.B.); and Department of Radiology, Research Institute of Radiological Science, Center for Clinical Imaging Data Science (CCIDS), Yonsei University College of Medicine, Seoul, Republic of Korea (K.H.)
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Gyftopoulos A, Ziogas IA, Barbas AS, Moris D. The Synergistic Role of Irreversible Electroporation and Chemotherapy for Locally Advanced Pancreatic Cancer. Front Oncol 2022; 12:843769. [PMID: 35692753 PMCID: PMC9174659 DOI: 10.3389/fonc.2022.843769] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 04/26/2022] [Indexed: 12/11/2022] Open
Abstract
Irreversible electroporation (IRE) is a local ablative technique used in conjunction with chemotherapy to treat locally advanced pancreatic cancer (LAPC). The combination of IRE and chemotherapy has showed increased overall survival when compared to chemotherapy alone, pointing towards a possible facilitating effect of IRE on chemotherapeutic drug action and delivery. This review aims to present current chemotherapeutic regimens for LAPC and their co-implementation with IRE, with an emphasis on possible molecular augmentative mechanisms of drug delivery and action. Moreover, the potentiating mechanism of IRE on immunotherapy, M1 oncolytic virus and dendritic cell (DC)-based treatments is briefly explored. Investigating the synergistic effect of IRE on currently established treatment regimens as well as newer ones, may present exciting new possibilities for future studies seeking to improve current LAPC treatment algorithms.
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Affiliation(s)
| | - Ioannis A. Ziogas
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Andrew S. Barbas
- Department of Surgery, Duke University Medical Center, Durham, NC, United States
| | - Dimitrios Moris
- Department of Surgery, Duke University Medical Center, Durham, NC, United States
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20
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Yun WG, Kwon W, Han Y, Sohn HJ, Kim HS, Lee M, Kim H, Thomas AS, Kluger MD, Jang JY. Can Surgical Resection of Metastatic Lesions Be Beneficial to Pancreatic Ductal Adenocarcinoma Patients with Isolated Lung Metastasis? Cancers (Basel) 2022; 14:cancers14092067. [PMID: 35565195 PMCID: PMC9099489 DOI: 10.3390/cancers14092067] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/15/2022] [Accepted: 04/19/2022] [Indexed: 12/11/2022] Open
Abstract
In the era of effective chemotherapy on pancreatic ductal adenocarcinoma (PDAC) with distant metastasis, data on the effects of metastatectomy are lacking. So, we investigated the effect of metastatectomy on survival after metastasis in PDAC patients with isolated lung metastasis. This retrospective study analyzed 1342 patients who were histologically diagnosed with PDAC with distant metastasis from January 2007 to December 2018, of which 83 patients had isolated pulmonary metastasis. Additionally, 4263 patients were extracted from the National Cancer Database (NCDB) and analyzed. Log-rank test and Kaplan−Meier survival analysis were used to analyze survival after metastasis. The five-year survival rate was significantly higher in patients who underwent pulmonary metastatectomy than in those who received only chemotherapy or supportive treatment (60.6% vs. 6.2% vs. 0.0%, p < 0.001). A similar trend was observed in the NCDB (two-year survival rate, 27.4% vs. 15.8% vs. 4.7%, p < 0.001). In the multivariate analysis, lung lesion multiplicity (hazard ratio (HR) = 2.004, p = 0.017), metastatectomy (HR = 0.278, p = 0.036), chemotherapy (HR = 0.434, p = 0.024), and chemotherapy cycles (HR = 0.300, p < 0.001) had significant effects on survival. Metastatectomy with primary pancreatic lesions is recommended with effective chemotherapy in PDAC patients with isolated lung metastasis.
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Affiliation(s)
- Won-Gun Yun
- Department of Surgery and Cancer Research Institute, College of Medicine, Seoul National University, 101 Daehak-ro, Chongno-gu, Seoul 03080, Korea; (W.-G.Y.); (W.K.); (Y.H.); (H.J.S.); (H.S.K.); (M.L.); (H.K.)
| | - Wooil Kwon
- Department of Surgery and Cancer Research Institute, College of Medicine, Seoul National University, 101 Daehak-ro, Chongno-gu, Seoul 03080, Korea; (W.-G.Y.); (W.K.); (Y.H.); (H.J.S.); (H.S.K.); (M.L.); (H.K.)
| | - Youngmin Han
- Department of Surgery and Cancer Research Institute, College of Medicine, Seoul National University, 101 Daehak-ro, Chongno-gu, Seoul 03080, Korea; (W.-G.Y.); (W.K.); (Y.H.); (H.J.S.); (H.S.K.); (M.L.); (H.K.)
| | - Hee Ju Sohn
- Department of Surgery and Cancer Research Institute, College of Medicine, Seoul National University, 101 Daehak-ro, Chongno-gu, Seoul 03080, Korea; (W.-G.Y.); (W.K.); (Y.H.); (H.J.S.); (H.S.K.); (M.L.); (H.K.)
| | - Hyeong Seok Kim
- Department of Surgery and Cancer Research Institute, College of Medicine, Seoul National University, 101 Daehak-ro, Chongno-gu, Seoul 03080, Korea; (W.-G.Y.); (W.K.); (Y.H.); (H.J.S.); (H.S.K.); (M.L.); (H.K.)
| | - Mirang Lee
- Department of Surgery and Cancer Research Institute, College of Medicine, Seoul National University, 101 Daehak-ro, Chongno-gu, Seoul 03080, Korea; (W.-G.Y.); (W.K.); (Y.H.); (H.J.S.); (H.S.K.); (M.L.); (H.K.)
| | - Hongbeom Kim
- Department of Surgery and Cancer Research Institute, College of Medicine, Seoul National University, 101 Daehak-ro, Chongno-gu, Seoul 03080, Korea; (W.-G.Y.); (W.K.); (Y.H.); (H.J.S.); (H.S.K.); (M.L.); (H.K.)
| | - Alexander S. Thomas
- Division of Gastrointestinal and Endocrine Surgery, Department of Surgery, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; (A.S.T.); (M.D.K.)
| | - Michael D. Kluger
- Division of Gastrointestinal and Endocrine Surgery, Department of Surgery, Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA; (A.S.T.); (M.D.K.)
| | - Jin-Young Jang
- Department of Surgery and Cancer Research Institute, College of Medicine, Seoul National University, 101 Daehak-ro, Chongno-gu, Seoul 03080, Korea; (W.-G.Y.); (W.K.); (Y.H.); (H.J.S.); (H.S.K.); (M.L.); (H.K.)
- Correspondence:
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Deng GC, Lv Y, Yan H, Sun DC, Qu TT, Pan YT, Han QL, Dai GH. Nomogram to predict survival of patients with advanced and metastatic pancreatic Cancer. BMC Cancer 2021; 21:1227. [PMID: 34781928 PMCID: PMC8594118 DOI: 10.1186/s12885-021-08943-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 10/28/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Nomograms are rarely employed to estimate the survival of patients with advanced and metastatic pancreatic cancer (PC). Herein, we developed a comprehensive approach to using a nomogram to predict survival probability in patients with advanced and metastatic PC. METHODS A total of 323 patients with advanced and metastatic PC were identified from the Chinese People's Liberation Army (PLA) General Hospital. A baseline nomogram was constructed using baseline variables of 323 patients. Additionally, 233 patients, whose tumors showed initial responses to first-line chemotherapy, were enrolled in the chemotherapy response-based model. 128 patients and 108 patients with advanced and metastatic PC from January 2019 to April 2021 were selected for external validating baseline model and chemotherapy response-based model. The 1-year and 2-year survival probability was evaluated using multivariate COX regression models. The discrimination and calibration capacity of the nomograms were assessed using C-statistic and calibration plots. The predictive accuracy and net benefit of the nomograms were evaluated using ROC curve and DCA, respectively. RESULTS In the baseline model, six variables (gender, KPS, baseline TB, baseline N, baseline WBC and baseline CA19-9) were used in the final model. In the chemotherapy response-based model, nine variables (KPS, gender, ascites, baseline N, baseline CA 19-9, baseline CEA, change in CA 19-9 level at week, change in CEA level at week and initial response to chemotherapy) were included in the final model. The C-statistics of the baseline nomogram and the chemotherapy response-based nomogram were 0.67 (95% CI, 0.62-0.71) and 0.74 (95% CI, 0.69-0.77), respectively. CONCLUSION These nomograms were constructed to predict the survival probability of patients of advanced and metastatic PC. The baseline model and chemotherapy response-based model performed well in survival prediction.
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Affiliation(s)
- G C Deng
- School of Medicine, Nankai University, Tianjin, China
- Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Y Lv
- School of Medicine, Nankai University, Tianjin, China
| | - H Yan
- School of Medicine, Nankai University, Tianjin, China
| | - D C Sun
- School of Medicine, Nankai University, Tianjin, China
| | - T T Qu
- School of Medicine, Nankai University, Tianjin, China
- Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China
| | - Y T Pan
- School of Medicine, Nankai University, Tianjin, China
| | - Q L Han
- School of Medicine, Nankai University, Tianjin, China.
| | - G H Dai
- School of Medicine, Nankai University, Tianjin, China.
- Senior Department of Oncology, The Fifth Medical Center of PLA General Hospital, Beijing, China.
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22
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Izumo W, Higuchi R, Furukawa T, Yazawa T, Uemura S, Matsunaga Y, Shiihara M, Yamamoto M. Evaluation of Early Prognostic Factors in Patients With Pancreatic Ductal Adenocarcinoma Receiving Gemcitabine Together With Nab-paclitaxel. CANCER DIAGNOSIS & PROGNOSIS 2021; 1:399-409. [PMID: 35403152 PMCID: PMC8962866 DOI: 10.21873/cdp.10053] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 08/23/2021] [Indexed: 06/14/2023]
Abstract
BACKGROUND Gemcitabine together with nab-paclitaxel (GnP) has been shown to improve outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). However, the predictive markers for treatment effects remain unclear. This study aimed to identify early prognostic factors in patients with PDAC receiving GnP. PATIENTS AND METHODS We analyzed 113 patients who received GnP for PDAC and evaluated the relationship between clinical factors and outcomes. RESULTS The median survival time (MST) was 1.2 years. In multivariate analysis, baseline carbohydrate antigen 19-9 (CA19-9) ≥747 U/ml [hazard ratio (HR)=1.9], baseline controlling nutrition status (CONUT) score ≥5 (HR=3.7) and changing rate of CA19-9 after two GnP cycles ≥0.69 (HR=3.7) were independent risk factors for poor prognosis. When examining outcomes according to pre-chemotherapeutic measurable factors (baseline CA19-9 and CONUT), the MSTs of patients with pre-chemotherapeutic zero risk factors (pre-low-risk group, n=63) and one or more risk factors (pre-high-risk group, n=50) were 1.7 and 0.65 years (p<0.001), respectively. The MST for those with a changing rate of CA19-9 after two GnP cycles <0.69 and ≥0.69 was significantly different in both groups (2.0 and 1.2 years in the pre-low-risk group, p<0.001; 1.0 and 0.52 years in the pre-high-risk group, p<0.001). CONCLUSION These results may be useful for decision-making regarding treatment strategies in patients with PDAC receiving GnP.
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Affiliation(s)
- Wataru Izumo
- Department of Surgery, Institute of Gastroenterology, Tokyo Woman's Medical University, Tokyo, Japan
| | - Ryota Higuchi
- Department of Surgery, Institute of Gastroenterology, Tokyo Woman's Medical University, Tokyo, Japan
| | - Toru Furukawa
- Department of Investigative Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takehisa Yazawa
- Department of Surgery, Institute of Gastroenterology, Tokyo Woman's Medical University, Tokyo, Japan
| | - Shuichiro Uemura
- Department of Surgery, Institute of Gastroenterology, Tokyo Woman's Medical University, Tokyo, Japan
| | - Yutaro Matsunaga
- Department of Surgery, Institute of Gastroenterology, Tokyo Woman's Medical University, Tokyo, Japan
| | - Masahiro Shiihara
- Department of Surgery, Institute of Gastroenterology, Tokyo Woman's Medical University, Tokyo, Japan
| | - Masakazu Yamamoto
- Department of Surgery, Institute of Gastroenterology, Tokyo Woman's Medical University, Tokyo, Japan
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George B, Kent M, Surinach A, Lamarre N, Cockrum P. The Association of Real-World CA 19-9 Level Monitoring Patterns and Clinical Outcomes Among Patients With Metastatic Pancreatic Ductal Adenocarcinoma. Front Oncol 2021; 11:754687. [PMID: 34671563 PMCID: PMC8522478 DOI: 10.3389/fonc.2021.754687] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 09/14/2021] [Indexed: 12/24/2022] Open
Abstract
Background Pancreatic cancer is expected to be the third deadliest cancer in the US in 2021. Evaluation of treatment response in patients with mPDAC necessitates scheduled clinical and radiographic assessments along with monitoring serum CA 19-9 levels. Currently available single-institution data examining the importance of CA 19-9 monitoring cannot be generalized to real-world settings. We investigated the impact of serum CA 19-9 monitoring and its association with clinical outcomes in patients with mPDAC in a population-based setting. Methods Data were extracted from the Flatiron Health electronic health record (EHR)-derived de-identified database for patients diagnosed with mPDAC between January 1, 2015, and June 30, 2020. Serum CA 19-9 levels at baseline – defined as the values obtained ≤ 60 days prior to treatment initiation - and during treatment were extracted. CA 19-9 levels > 40 IU/mL were considered elevated. Survival outcomes were compared based on testing frequency, baseline CA 19-9 levels, and change in CA 19-9. Results 6,118 patients with mPDAC who received treatment were included in the analysis. The median age at diagnosis was 68 years (IQR: 61-75). Patients with normal baseline CA 19-9 experienced longer median survival than patients with elevated levels [1L: 8.8 months (95% CI: 7.9 - 10) vs. 7.2 months (6.8 – 7.5), p < 0.001; 2L: 7.2 months (6.1 – 9.2) vs. 5.2 months (4.9 – 5.6), p < 0.001; 3L: 6.1 months (5.4 – 9.1) vs. 3.9 months (3.4 – 4.3), p < 0.001]. Patients with decreasing/stable CA 19-9 during treatment experienced longer survival than patients who experienced an increase in CA 19-9 levels [1L: 10.9 months (10.5 – 11.3) vs. 5.4 months (5.1 – 5.9), p < 0.0001; 2L: 8.2 months (7.7 – 8.5) vs. 4.3 months (4.1 – 4.7), p < 0.001; 3L: 7.5 months (6.6 – 9.2) vs. 3.7 months (3.4 – 4.3), p < 0.001]. Conclusions In one of the largest, contemporary, real-world studies of patients with mPDAC, elevated CA 19-9 level at treatment initiation demonstrated a prognostic impact. Routine serial monitoring of CA 19-9 levels during treatment may be warranted, in addition to clinical and radiographic assessment, and may translate into better patient outcomes. Further validation studies are needed to understand the generalizability of these results.
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Affiliation(s)
- Ben George
- Department of Medical Oncology, Froedtert & the Medical College of Wisconsin, Milwaukee, WI, United States
| | - Matthew Kent
- Real World Data Analytics, Genesis Research, Hoboken, NJ, United States
| | - Andy Surinach
- Real World Data Analytics, Genesis Research, Hoboken, NJ, United States
| | - Neil Lamarre
- Real World Data Analytics, Genesis Research, Hoboken, NJ, United States
| | - Paul Cockrum
- Oncology HEOR, Ipsen, Cambridge, MA, United States
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Nab-paclitaxel plus S-1 with or without PD-1 inhibitor in pancreatic ductal adenocarcinoma with only hepatic metastases: a retrospective cohort study. Langenbecks Arch Surg 2021; 407:633-643. [PMID: 34518900 DOI: 10.1007/s00423-021-02321-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 08/27/2021] [Indexed: 10/20/2022]
Abstract
PURPOSE The evidence regarding programmed cell death 1 (PD-1) inhibitors on pancreatic ductal adenocarcinoma (PDAC) with metastases remains controversial. This study aimed to assess the efficacy and safety of Nab-paclitaxel plus S1 (NPS) with or without Sintilimab, a PD-1 inhibitor, in patients with PDAC with only hepatic metastases (mPDAC). METHODS Untreated mPDAC patients who received NPS with (the combination group) or without Sintilimab (the NPS group) were retrospectively studied. Surgery was considered when the pancreatic tumor became resectable or borderline resectable on radiological examinations, and with complete metabolic response of liver metastases. RESULTS Between October 2017 and February 2020, 32 patients were in the combination group and 34 patients in the NPS group. Successful salvage resection was achieved in 17 (25.8%) patients after tumor-downstaging (combination 12 vs. NPS 5, P = 0.03). The median overall survival (OS) was 16.8 months in the combination group and 10.0 months in the NPS group (P = 0.002). Remarkable OS benefit was observed in patients with decline in CA19-9 of ≥ 50% (16.0 vs. 6.5, P = 0.003), reduction in 18F-fluorodeoxyglucose uptake of primary tumor of ≥ 50% (16.5 vs. 10.0, P < 0. 001) and after salvage resection (20.1 vs. 11.0, P < 0. 001). No significant difference in Grade 3 or higher adverse events were seen between the two groups (40.6% vs. 32.4%, P = 0.49). CONCLUSIONS Despite the inherent biases of this retrospective study, the addition of Sintilimab significantly improved salvage resection rates and OS compared with the NPS regimen and had a favorable safety profile in treatment naïve mPDAC patients.
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Shin K, Jung EK, Park SJ, Jeong S, Kim IH, Lee MA. Neutrophil-to-lymphocyte ratio and carbohydrate antigen 19-9 as prognostic markers for advanced pancreatic cancer patients receiving first-line chemotherapy. World J Gastrointest Oncol 2021; 13:915-928. [PMID: 34457195 PMCID: PMC8371515 DOI: 10.4251/wjgo.v13.i8.915] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 05/03/2021] [Accepted: 07/09/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND A decline in serum carbohydrate antigen 19-9 (CA19-9) levels during systemic chemotherapy is considered as a prognostic marker for patients with advanced pancreatic cancer. Neutrophil-to-lymphocyte ratio (NLR) has been extensively studied as a simple and useful indicator of prognosis in various cancers including pancreatic cancer. AIM To assess the prognostic significance of NLR and CA19-9 in patients with advanced pancreatic adenocarcinoma received first-line chemotherapy according to CA19-9 positivity. METHODS We retrospectively analyzed patients diagnosed with advanced pancreatic cancer who received first-line chemotherapy between January 2010 and July 2017 at the Catholic University of Seoul St. Mary's Hospital. Patients were divided according to CA19-9 positivity (CA19-9-positive vs -negative groups) and pre-and post-treatment NLR levels. To determine cut-off value of NLR and CA19-9 reduction, time-dependent receiver operating characteristic curve was applied. We evaluated overall survival (OS) and progression-free survival (PFS) for each group using Kaplan-Meier method, and we performed multivariate analyses on the entire cohort. RESULTS We included 271 patients in this study. Cut-off value of NLR and CA19-9 reduction was determined as 2.62 and 18%. Multivariate analysis showed that post-treatment NLR < 2.62 and reduction of ≥ 18% of baseline CA19-9 were significantly associated with OS and PFS. Post-treatment NLR ≥ 2.62 showed hazard ratio (HR) of 2.47 [95% confidence interval (CI): 1.84-3.32, P < 0.001] and CA19-9 decline (≥ 18%) showed HR of 0.51 (95%CI: 0.39-0.67, P < 0.001) for OS. When CA19-9-positive patients were divided into groups according to CA19-9 response (responder vs non-responder) and post-treatment NLR (< 2.62 vs ≥ 2.62), CA19-9 responder and post-treatment NLR < 2.62 group showed better survival than CA19-9 non-responder and post-treatment NLR ≥ 2.62 group (OS 11.0 mo vs 3.9 mo, P < 0.001; PFS 6.3 mo vs 2.0 mo, P < 0.001). The combination of CA19-9 decline and post-treatment NLR showed a significant correlation with clinical response in CA 19-9 positive group. Within the CA19-9-negative group, the post-treatment NLR < 2.62 group showed better survival than the post-treatment NLR ≥ 2.62 group (OS 12.7 mo vs 7.7 mo, P < 0.001; PFS 6.7 mo vs 2.1 mo, P < 0.001), and post-treatment NLR showed correlation with clinical response. CONCLUSION In advanced pancreatic cancer patients positive for CA19-9 and treated with systemic chemotherapy, the combination of post-treatment NLR < 2.62 and 18% decline of CA19-9 at the first response evaluation is a good prognostic marker. Post-treatment NLR < 2.62 alone could be used as a prognostic marker and an adjunctive tool for response evaluation in CA19-9-negative patients.
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Affiliation(s)
- Kabsoo Shin
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
- Catholic Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
| | - Eun-Kyo Jung
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
- Catholic Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
| | - Se Jun Park
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
- Catholic Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
| | - Sangwoon Jeong
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
- Catholic Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
| | - In-Ho Kim
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
- Catholic Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
| | - Myung-ah Lee
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
- Catholic Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, South Korea
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Crippa S, Belfiori G, Tamburrino D, Partelli S, Falconi M. Indications to total pancreatectomy for positive neck margin after partial pancreatectomy: a review of a slippery ground. Updates Surg 2021; 73:1219-1229. [PMID: 34331677 DOI: 10.1007/s13304-021-01141-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 07/23/2021] [Indexed: 12/23/2022]
Abstract
The extension of a partial pancreatectomy up to total pancreatectomy because of positive neck margin examined at intraoperative frozen section (IFS) analysis is an accepted procedure in modern pancreatic surgery with good accuracy. The goal of this practice is to improve the rate of radical (R0) resection in malignant tumors, mainly pancreatic ductal adenocarcinoma (PDAC), and to completely resect pre-invasive neoplasms such as intraductal papillary mucinous neoplasms (IPMNs). In the setting of IPMNs there is a consensus for pancreatic re-resection when high-grade dysplasia and invasive cancer are present at the neck margin. The presence of denudation is another indication for further resection in IPMNs. The role of IFS analysis in the management of pancreatic cancer is more debated. The presence of a positive intraoperative transection margin can be considered the surrogate of a biologically aggressive disease associated with a poorer prognosis. There are conflicting data regarding possible advantages of pancreatic re-resection up to total pancreatectomy, and the lack of randomized trials comparing different strategies does not offer a definitive answer. The goal of this review is to provide an up-to-date overview of the role IFS analysis of pancreatic margin and of pancreatic re-resection up to total pancreatectomy considering different pancreatic tumors.
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Affiliation(s)
- Stefano Crippa
- School of Medicine, Vita Salute San Raffaele University, Milan, Italy.,Division of Pancreatic Surgery, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Giulio Belfiori
- School of Medicine, Vita Salute San Raffaele University, Milan, Italy.,Division of Pancreatic Surgery, IRCCS Ospedale San Raffaele, Milan, Italy
| | | | - Stefano Partelli
- School of Medicine, Vita Salute San Raffaele University, Milan, Italy.,Division of Pancreatic Surgery, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Massimo Falconi
- School of Medicine, Vita Salute San Raffaele University, Milan, Italy. .,Division of Pancreatic Surgery, IRCCS Ospedale San Raffaele, Milan, Italy. .,Department of Surgery, Division of Pancreatic Surgery, San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy.
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Picozzi V, Alseidi A, Winter J, Pishvaian M, Mody K, Glaspy J, Larson T, Matrana M, Carney M, Porter S, Kouchakji E, Rocha F, Carrier E. Gemcitabine/nab-paclitaxel with pamrevlumab: a novel drug combination and trial design for the treatment of locally advanced pancreatic cancer. ESMO Open 2021; 5:S2059-7029(20)32637-5. [PMID: 32817130 PMCID: PMC7440698 DOI: 10.1136/esmoopen-2019-000668] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 03/16/2020] [Accepted: 04/21/2020] [Indexed: 01/06/2023] Open
Abstract
Purpose Pancreatic ductal adenocarcinomas exhibit a high degree of desmoplasia due to extensive extracellular matrix deposition. Encasement of mesenteric vessels by stroma in locally advanced pancreatic cancer (LAPC) prevents surgical resection. This study sought to determine if the addition of a monoclonal antibody to connective tissue growth factor, pamrevlumab, to neoadjuvant chemotherapy would be safe and lead to improved resectability in this surgically adverse patient population. Methods In this phase I/II trial, 37 patients with LAPC were randomised 2:1 to gemcitabine/nab-paclitaxel plus (Arm A, n=24) or minus (Arm B, n=13) pamrevlumab. Those who completed six cycles of treatment were assessed for surgical eligibility by protocol-defined criteria. Resection rates, progression-free and overall survival were evaluated. Results Eighteen (75%) patients in Arm A and seven (54%) in Arm B completed six cycles of therapy with similar toxicity patterns. In Arms A and B, carbohydrate antigen 19–9 response, as defined by ≥50% decline from baseline, occurred in 13 (65%) and 5 (42%), respectively. Sixteen (16%) per cent of patients were radiographically downstaged by National Comprehensive Cancer Network criteria (5 in Arm A (21%) and 1 (8%) in Arm B). Positron emission tomography normalised in 9 (38%) vs 3 (23%) of patients in Arm A vs Arm B, respectively, and correlated with surgical exploration. Eligibility for surgical exploration was 17 (71%) vs 2 (15%) (p=0.0019) and resection was achieved in 8 (33%) vs 1 (8%) of patients in Arm A vs Arm B (p=0.1193), respectively. Postoperative complication rates were not different between arms. Conclusions Neoadjuvant chemotherapy with pamrevlumab holds promise for enhancing resection rates in patients with LAPC without added toxicity. This combination merits evaluation in a larger patient cohort.
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Affiliation(s)
| | - Adnan Alseidi
- Virginia Mason Medical Center, Seattle, Washington, USA
| | - Jordan Winter
- Thomas Jefferson Medical Center, Philadelphia, Pennsylvania, USA
| | | | - Kabir Mody
- Mayo Clinic Jacksonville, Jacksonville, Florida, USA
| | - John Glaspy
- UCLA Medical Center, Los Angeles, California, USA
| | - Timothy Larson
- Virginia Piper Cancer Institute, Minneapolis, Minnesota, USA
| | - Marc Matrana
- Ochsner Clinic Foundation, New Orleans, Louisiana, USA
| | - Mairead Carney
- Clinical Development, FibroGen, Inc, San Francisco, California, USA
| | - Seth Porter
- Clinical Development, FibroGen, Inc, San Francisco, California, USA
| | - Elias Kouchakji
- Clinical Development, FibroGen, Inc, San Francisco, California, USA
| | - Flavio Rocha
- Virginia Mason Medical Center, Seattle, Washington, USA
| | - Ewa Carrier
- Clinical Development, FibroGen, Inc, San Francisco, California, USA
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Baron MK, Wang X, Nevala-Plagemann C, Moser JC, Haaland B, Garrido-Laguna I. Survival Outcomes Based on Sequence of Therapy Using FOLFIRINOX and Nab-Paclitaxel + Gemcitabine in Metastatic Pancreatic Ductal Adenocarcinoma. Pancreas 2021; 50:796-802. [PMID: 34347727 DOI: 10.1097/mpa.0000000000001844] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVES Optimal sequence of therapy for patients with metastatic pancreatic ductal adenocarcinoma is unknown. Combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and nab-paclitaxel + gemcitabine (nab-p/gem) are standard first-line (1L) therapies. They have never been prospectively compared. We retrospectively compared overall survival (OS) of patients treated with 1L nab-p/gem and second-line (2L) FOLFIRINOX with those treated with the reverse sequence. METHODS Patients with metastatic pancreatic ductal adenocarcinoma treated with 1L FOLFIRINOX and 2L nab-p/gem or vice versa were identified using an electronic health record-derived real-world database. Using an intent-to-treat analysis, we compared OS from initiation of 1L therapy. A Cox model, stratified by deciles of propensity score, estimated the effect of treatment sequence on OS. RESULTS The study included 3027 patients. The median OS for 1L FOLFIRINOX versus nab-p/gem was 8.6 versus 6.1 months (hazard ratio, 0.77; 95% confidence interval, 0.70-0.84). The median OS for 1L FOLFIRINOX and 2L nab-p/gem versus 1L nab-p/gem and 2L FOLFIRINOX was 11.9 versus 11.5 months (hazard ratio, 0.97; 95% confidence interval, 0.79-1.18). CONCLUSIONS In this analysis of real-world data, 1L FOLFIRINOX was associated with increased OS in propensity analysis. For patients who received both FOLFIRINOX and nab-p/gem, median OS was similar regardless of sequence.
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Affiliation(s)
| | | | | | - Justin C Moser
- Department of Oncology Clinical Trials, Honor Health Research Institute, Scottsdale, AZ
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Luo G, Jin K, Deng S, Cheng H, Fan Z, Gong Y, Qian Y, Huang Q, Ni Q, Liu C, Yu X. Roles of CA19-9 in pancreatic cancer: Biomarker, predictor and promoter. Biochim Biophys Acta Rev Cancer 2021; 1875:188409. [PMID: 32827580 DOI: 10.1016/j.bbcan.2020.188409] [Citation(s) in RCA: 187] [Impact Index Per Article: 46.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 06/29/2020] [Accepted: 07/20/2020] [Indexed: 02/07/2023]
Abstract
Carbohydrate antigen 19-9 (CA19-9) is the best validated biomarker and an indicator of aberrant glycosylation in pancreatic cancer. CA19-9 functions as a biomarker, predictor, and promoter in pancreatic cancer. As a biomarker, the sensitivity is approximately 80%, and the major challenges involve false positives in conditions of inflammation and nonpancreatic cancers and false negatives in Lewis-negative Individuals. Lewis antigen status should be determined when using CA19-9 as a biomarker. CA19-9 has screening potential when combined with symptoms and/or risk factors. As a predictor, CA19-9 could be used to assess stage, prognosis, resectability, recurrence, and therapeutic efficacy. Normal baseline levels of CA19-9 are associated with long-term survival. As a promoter, CA19-9 could be used to evaluate the biology of pancreatic cancer. CA19-9 can accelerate pancreatic cancer progression by glycosylating proteins, binding to E-selectin, strengthening angiogenesis, and mediating the immunological response. CA19-9 is an attractive therapeutic target for cancer, and strategies include therapeutic antibodies and vaccines, CA19-9-guided nanoparticles, and inhibition of CA19-9 biosynthesis.
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Affiliation(s)
- Guopei Luo
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China; Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, China
| | - Kaizhou Jin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China; Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, China
| | - Shengming Deng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China; Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, China
| | - He Cheng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China; Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, China
| | - Zhiyao Fan
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China; Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, China
| | - Yitao Gong
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China; Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, China
| | - Yunzhen Qian
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China; Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, China
| | - Qiuyi Huang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China; Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, China
| | - Quanxing Ni
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China; Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, China
| | - Chen Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China; Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, China.
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China; Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, China.
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Sigel K, Zhou M, Park YHA, Mutetwa T, Nadkarni G, Yeh C, Polak P, Sigel C, Conroy T, Juzyna B, Ychou M, Fojo T, Wisnivesky JP, Bates SE. Gemcitabine plus nab-paclitaxel versus FOLFIRINOX for unresected pancreatic cancer: Comparative effectiveness and evaluation of tumor growth in Veterans. Semin Oncol 2021; 48:69-75. [PMID: 33714591 PMCID: PMC9703645 DOI: 10.1053/j.seminoncol.2021.02.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 02/02/2021] [Indexed: 11/11/2022]
Abstract
PURPOSE Advanced, unresectable pancreatic cancer is often treated with either gemcitabine plus nab-paclitaxel (Gem/NabP) or FOLFIRINOX, although these regimens have never been compared in a head-to-head trial. In this study, we compared these two regimens using Veterans Administration (VA) data and evaluated the use of a novel tumor growth formula to predict outcomes. METHODS We identified 670 Veterans from national VA data with unresected stage II-IV pancreatic adenocarcinoma diagnosed between 2003 and 2016 who were treated with either first-line Gem/NabP or FOLFIRINOX. We compared overall survival (OS) and adverse events by treatment using propensity scores (PS) to account for allocation bias. Using longitudinal CA19-9 biomarker information we then fit the data to a novel tumor growth equation, comparing growth with OS. RESULTS We found no difference in PS-adjusted (hazard ratio [HR] 1.00; 95% confidence interval [95% CI] 0.84-1.20) or PS-matched (HR: 0.93; 95% CI: 0.76-1.13) OS between the two treatment groups. Tumor growth analysis revealed similar growth parameter values for Gem/NabP and FOLFIRINOX (P = .074 for difference). CONCLUSIONS Gem/NabP appeared noninferior to FOLFIRINOX for survival outcomes for advanced pancreatic adenocarcinoma based on national VA data. Biomarker-based growth equations may be useful for monitoring treatment response and predicting prognosis for pancreatic cancer.
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Affiliation(s)
- Keith Sigel
- The Mount Sinai School of Medicine, New York, NY.
| | - Mengxi Zhou
- The College of Physicians and Surgeons at Columbia University, New York, NY
| | | | | | - Girish Nadkarni
- The College of Physicians and Surgeons at Columbia University, New York, NY
| | - Celine Yeh
- The College of Physicians and Surgeons at Columbia University, New York, NY
| | - Paz Polak
- The Mount Sinai School of Medicine, New York, NY; The College of Physicians and Surgeons at Columbia University, New York, NY
| | - Carlie Sigel
- Memorial Sloan Kettering Cancer Center, New York, NY
| | - Thierry Conroy
- Institut de cancerologie de Lorraine, Vandouevre de Nancy, France
| | | | - Mark Ychou
- Institut de cancer de Montpellier, Montpellier, France
| | - Tito Fojo
- James J. Peters VA Medical Center, Bronx, NY; The College of Physicians and Surgeons at Columbia University, New York, NY
| | | | - Susan E Bates
- James J. Peters VA Medical Center, Bronx, NY; The College of Physicians and Surgeons at Columbia University, New York, NY
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Therapeutic response assessment in pancreatic ductal adenocarcinoma: society of abdominal radiology review paper on the role of morphological and functional imaging techniques. Abdom Radiol (NY) 2020; 45:4273-4289. [PMID: 32936417 DOI: 10.1007/s00261-020-02723-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 08/17/2020] [Accepted: 08/25/2020] [Indexed: 02/06/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related death in the United States and is projected to be the second by 2030. Systemic combination chemotherapy is considered an essential first-line treatment for the majority of patients with PDA, in both the neoadjuvant and palliative settings. In addition, a number of novel therapies are being tested in clinical trials for patients with advanced PDA. In all cases, accurate and timely assessment of treatment response is critical to guide therapy, reduce drug toxicities and cost from a failing therapy, and aid adaptive clinical trials. Conventional morphological imaging has significant limitations, especially in the context of determining primary tumor response and resectability following neoadjuvant therapies. In this article, we provide an overview of current therapy options for PDA, highlight several morphological imaging findings that may be helpful to reduce over-staging following neoadjuvant therapy, and discuss a number of emerging imaging, and non-imaging, tools that have shown promise in providing a more precise quantification of disease burden and treatment response in PDA.
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Al-Batran SE, Hofheinz RD, Reichart A, Pauligk C, Schönherr C, Schlag R, Siegler G, Dörfel S, Koenigsmann M, Zahn MO, Schubert J, Aldaoud A, Höffkes HG, Schulz H, Hahn L, Uhlig J, Blau W, Stauch M, Weniger J, Wolf M, Jacobasch L, Bildat S, Wehmeyer J, Homann N, Trojan J, Waidmann O, Fietz T, Feustel HP, Groschek M, Wierecky J, Waibel K, Mahlmann S, Schwindel U, Peters U, Schuch G, Pink D, Eschenburg H, Wörns MA, Harich HD, von Weikersthal LF, Däßler KU, Behringer DM, Messmann H, Kretzschmar A, Gallmeier E, Forstbauer H, Kunzmann V, Papke J, Büchner-Steudel P, Vehling-Kaiser U, Springfeld C, Vogel A, Ettrich TJ, Schaaf M, Hausen GZ, Götze TO. Quality of life and outcome of patients with metastatic pancreatic cancer receiving first-line chemotherapy with nab-paclitaxel and gemcitabine: Real-life results from the prospective QOLIXANE trial of the Platform for Outcome, Quality of Life and Translational Research on Pancreatic Cancer registry. Int J Cancer 2020; 148:1478-1488. [PMID: 33038277 DOI: 10.1002/ijc.33336] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/07/2020] [Accepted: 08/21/2020] [Indexed: 01/05/2023]
Abstract
Few data exist on health-related quality of life (QoL) in patients with metastatic pancreatic cancer (mPC) receiving first-line chemotherapy (Awad L ZE, Mesbah M Boston, MA. Applying survival data methodology to analyze quality of life data, in Mesbah M, Cole BF, Ting Lee M-L (eds): Statistical Methods for Quality of Life Studies: Design, Measurements and Analysis. Kluwer Academic Publishers 2002). The QOLIXANE study is a prospective, noninterventional, multicenter substudy of the Platform for Outcome, Quality of Life and Translational Research on Pancreatic Cancer (PARAGON) registry, which evaluated QoL in patients with mPC receiving first-line gemcitabine and nab-paclitaxel chemotherapy in real-life setting. QoL was prospectively measured via EORTC QLQ-C30 questionnaires at baseline and every month thereafter. Therapy and efficacy parameters were prospectively collected. Main objectives were the rate of patients without deterioration of Global Health Status/QoL (GHS/QoL) at 3 and 6 months. Six hundred patients were enrolled in 95 German study sites. Median progression-free survival was 5.9 months (95% confidence interval [CI], 5.2-6.3). Median overall survival (OS) was 8.9 months (95% CI, 7.9-10.2), while median time to deterioration of GHS/QoL was 4.7 months (95% CI, 4.0-5.6). With a baseline GHS/QoL score of 46 (SD, 22.8), baseline QoL of the patients was severely impaired, in most cases due to loss in role functioning and fatigue. In the Kaplan-Meier analysis, 61% and 41% of patients had maintained GHS/QoL after 3 and 6 months, respectively. However, in the QoL response analysis, 35% and 19% of patients had maintained (improved or stable) GHS/QoL after 3 and 6 months, respectively, while 14% and 9% had deteriorated GHS/QoL with the remaining patients being nonevaluable. In the Cox regression analysis, GHS/QoL scores strongly predicted survival with a hazard ratio of 0.86 (P < .0001). Patients with mPC have poor QoL at baseline that deteriorates within a median of 4.7 months. Treatment with gemcitabine and nab-paclitaxel is associated with maintained QoL in relevant proportions of patients. However, overall, results remain poor, reflecting the aggressive nature of the disease.
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Affiliation(s)
- Salah-Eddin Al-Batran
- Krankenhaus Nordwest, UCT-University Cancer Center, Frankfurt, Germany.,Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest, Frankfurt, Germany
| | | | - Alexander Reichart
- Krankenhaus Nordwest, UCT-University Cancer Center, Frankfurt, Germany.,Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest, Frankfurt, Germany
| | - Claudia Pauligk
- Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest, Frankfurt, Germany
| | - Caroline Schönherr
- Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest, Frankfurt, Germany
| | - Rudolf Schlag
- Gemeinschaftspraxis Schlag/Schöttker, Würzburg, Germany
| | | | | | | | | | | | - Ali Aldaoud
- HELIOS Park-Klinikum, Pankreaszentrum Leipzig, Leipzig, Germany
| | - Heinz-Gert Höffkes
- Universitätsmedizin Marburg, Klinikum Fulda, Fulda, Germany.,MVZ Osthessen GmbH, Fulda, Germany
| | - Holger Schulz
- Pioh Frechen-Köln Praxis Internistischer Onkologie und Hämatologie, Frechen, Germany
| | - Lars Hahn
- Dokusan Gesellschaft für med. Studien GmbH und Co. KG, Herne, Germany
| | - Jens Uhlig
- Hämatologisch-Onkologische Schwerpunktpraxis, Naunhof, Germany
| | - Wolfgang Blau
- Medizinische Klinik IV/V des Universitätsklinikums Gießen und Marburg, Gießen, Germany
| | - Martina Stauch
- Schwerpunktpraxis für Hämatologie/Onkologie, Kronach, Germany
| | - Jörg Weniger
- Gemeinschaftspraxis für Hämatologie und Onkologie Dres. Weniger/Bittrich/Schütze, Erfurt, Germany
| | - Martin Wolf
- Klinikum Kassel GmbH, Klinik für Hämatologie und Onkologie, Kassel, Germany
| | - Lutz Jacobasch
- Onkologische Gemeinschaftspraxis Dr. med. Lutz Jacobasch, Dresden, Germany
| | - Stephan Bildat
- Klinikum Herford, Medizinische Klinik II & MVZ für Onkologie, Onkologisches Zentrum, Herford, Germany
| | - Jürgen Wehmeyer
- Gemeinschaftspraxis für Hämatologie und Onkologie, Münster, Germany
| | - Nils Homann
- Med. Klinik II Klinikum Wolfsburg, Wolfsburg, Germany
| | - Jörg Trojan
- Klinikum der J. W. Goethe-Universität Frankfurt, Frankfurt, Germany
| | - Oliver Waidmann
- Klinikum der J. W. Goethe-Universität Frankfurt, Frankfurt, Germany
| | - Thomas Fietz
- Schwerpunktpraxis für Hämatologie, Onkologie und Gastroenterologie Dres Banhardt/Fietz/Hertkorn, Singen, Germany
| | | | | | - Jan Wierecky
- Überörtliche Gemeinschaftspraxis, Schwerpunkt Hämatologie, Onkologie und Palliativmedizin, Hamburg, Germany
| | - Karin Waibel
- medius Kliniken gGmbH, medius Klinik Ostfildern-Ruit, Ostfildern-Ruit, Germany
| | | | - Uwe Schwindel
- GPR Gesundheits- und Pflegezentrum gGmbH, I. Medizinische Klinik, Rüsselsheim, Germany
| | - Uwe Peters
- Ambulantes Tumorzentrum Spandau Dres. Peters und Saeuberlich-Knigge, Berlin, Germany
| | - Gunter Schuch
- Hämatologisch-Onkologische Praxis Altona (HOPA), Hamburg, Germany
| | - Daniel Pink
- Klinik und Poliklinik für Innere Medizin C, Hämatologie und Onkologie, Transplantationszentrum, Palliativmedizin, Universität Greifswald, Greifswald, Germany.,Klinik für Hämatologie, Onkologie und Palliativmedizin, Sarkomzentrum Berlin-Brandenburg, HELIOS Klinikum Bad-Saarow, Brandenburg, Germany
| | | | - Marcus-A Wörns
- I. Med. Klinik und Poliklinik, Universitätsmedizin Mainz, Germany
| | | | | | | | | | - Helmut Messmann
- Universitätsklinikum Augsburg, III. Medizinische Klinik, Augsburg, Germany
| | | | - Eike Gallmeier
- Universitätsklinikum Gießen und Marburg GmbH, Klinik für Innere Medizin, Marburg, Germany
| | | | - Volker Kunzmann
- Universitätsklinik Würzburg, Zentrum Innere Medizin, Medizinische Klinik und Poliklinik II, Würzburg, Germany
| | - Jens Papke
- Praxis Prof. Dr. med. Jens Papke, Neustadt/Sa, Germany
| | - Petra Büchner-Steudel
- Universitätsklinikum Halle (Saale), Klinik und Poliklinik für Innere Medizin I, Halle, Germany
| | | | - Christoph Springfeld
- Nationales Centrum für Tumorerkrankungen (NCT), Abt. Medizinische Onkologie Universitätsklinikum Heidelberg, Heidelberg, Germany
| | - Arndt Vogel
- Medizinische Hochschule Hannover, Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Hannover, Germany
| | - Thomas J Ettrich
- Universitätsklinikum Ulm, Klinik für Innere Medizin I, Ulm, Germany
| | - Marina Schaaf
- Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest, Frankfurt, Germany
| | - Gerrit Zur Hausen
- Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest, Frankfurt, Germany
| | - Thorsten Oliver Götze
- Krankenhaus Nordwest, UCT-University Cancer Center, Frankfurt, Germany.,Institut für Klinische Krebsforschung IKF GmbH am Krankenhaus Nordwest, Frankfurt, Germany
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Iede K, Yamada T, Kato R, Ueda M, Tsuda Y, Nakashima S, Ohta K, Matsuyama J, Ikenaga M, Tominaga S. Predictive implications of decreased CA19-9 at 8 weeks during nab-paclitaxel plus gemcitabine for the induction of second-line chemotherapy for patients with advanced pancreatic cancer. Cancer Rep (Hoboken) 2020; 3:e1289. [PMID: 32969199 PMCID: PMC7941508 DOI: 10.1002/cnr2.1289] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 08/03/2020] [Accepted: 08/06/2020] [Indexed: 12/27/2022] Open
Abstract
Background Second‐line (2L) chemotherapy after nab‐paclitaxel plus gemcitabine (AG) is important for improving the survival of patients with advanced pancreatic cancer (APC). However, many patients fail to receive 2L chemotherapy because of rapid disease progression. Therefore, early recognition of any ineffectiveness during AG might lead to an increased induction rate of 2L chemotherapy. Aim We investigated the significance of treatment response at 8 weeks as a predictive factor for the induction of 2L chemotherapy after AG. Methods and results From January 2015 to January 2019, 41 patients with APC underwent AG as first‐line chemotherapy at our institute. Thirty‐three patients were evaluated at 8 weeks. Sixteen patients (48%) underwent 2L chemotherapy and 17 (52%) underwent no 2L chemotherapy. Clinical features and treatment response at 8 weeks were, retrospectively, compared among patients. Predictive factors for the induction of 2L chemotherapy were analyzed. Patients with an objective response by 8 weeks received 2L chemotherapy more frequently (P = .026). Decreased CA19‐9 (<50%) at 8 weeks was identified as an independent negative predictive factor for the induction of 2L chemotherapy. Conclusions Decreased CA19‐9 (<50%) at 8 weeks may indicate the ineffectiveness of AG and signify that a move to 2L chemotherapy may be required without delay.
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Affiliation(s)
- Kiyotsugu Iede
- Department of Clinical Oncology, Higashiosaka City Medical Center, Higashiosaka, Japan
| | - Terumasa Yamada
- Department of Gastroenterological Surgery, Higashiosaka City Medical Center, Higashiosaka, Japan
| | - Ryo Kato
- Department of Gastroenterological Surgery, Higashiosaka City Medical Center, Higashiosaka, Japan
| | - Masami Ueda
- Department of Gastroenterological Surgery, Higashiosaka City Medical Center, Higashiosaka, Japan
| | - Yujiro Tsuda
- Department of Gastroenterological Surgery, Higashiosaka City Medical Center, Higashiosaka, Japan
| | - Shinsuke Nakashima
- Department of Gastroenterological Surgery, Higashiosaka City Medical Center, Higashiosaka, Japan
| | - Katsuya Ohta
- Department of Gastroenterological Surgery, Higashiosaka City Medical Center, Higashiosaka, Japan
| | - Jin Matsuyama
- Department of Gastroenterological Surgery, Higashiosaka City Medical Center, Higashiosaka, Japan
| | - Masakazu Ikenaga
- Department of Gastroenterological Surgery, Higashiosaka City Medical Center, Higashiosaka, Japan
| | - Shusei Tominaga
- Department of Clinical Oncology, Higashiosaka City Medical Center, Higashiosaka, Japan
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Kocher HM, Basu B, Froeling FEM, Sarker D, Slater S, Carlin D, deSouza NM, De Paepe KN, Goulart MR, Hughes C, Imrali A, Roberts R, Pawula M, Houghton R, Lawrence C, Yogeswaran Y, Mousa K, Coetzee C, Sasieni P, Prendergast A, Propper DJ. Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer. Nat Commun 2020; 11:4841. [PMID: 32973176 PMCID: PMC7518421 DOI: 10.1038/s41467-020-18636-w] [Citation(s) in RCA: 144] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Accepted: 09/02/2020] [Indexed: 12/20/2022] Open
Abstract
Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress pancreatic ductal adenocarcinoma (PDAC) growth. Here, in a phase Ib, dose escalation and expansion, trial for patients with advanced, unresectable PDAC (n = 27), ATRA is re-purposed as a stromal-targeting agent in combination with gemcitabine-nab-paclitaxel chemotherapy using a two-step adaptive continual re-assessment method trial design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D, primary outcome) is the FDA/EMEA approved dose of gemcitabine-nab-paclitaxel along-with ATRA (45 mg/m2 orally, days 1-15/cycle). Dose limiting toxicity (DLT) is grade 4 thrombocytopenia (n = 2). Secondary outcomes show no detriment to ATRA pharmacokinetics.. Median overall survival for RP2D treated evaluable population, is 11.7 months (95%CI 8.6-15.7 m, n = 15, locally advanced (2) and metastatic (13)). Exploratory pharmacodynamics studies including changes in diffusion-weighted (DW)-MRI measured apparent diffusion coefficient after one cycle, and, modulation of cycle-specific serum pentraxin 3 levels over various cycles indicate stromal modulation. Baseline stromal-specific retinoid transport protein (FABP5, CRABP2) expression may be predicitve of response. Re-purposing ATRA as a stromal-targeting agent with gemcitabine-nab-paclitaxel is safe and tolerable. This combination will be evaluated in a phase II randomized controlled trial for locally advanced PDAC. Clinical trial numbers: EudraCT: 2015-002662-23; NCT03307148. Trial acronym: STARPAC.
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Affiliation(s)
- Hemant M Kocher
- Centre for Tumour Biology, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University London, London, EC1M 6BQ, UK.
- Centre for Experimental Cancer Medicine, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University of London, London, EC1M 6BQ, UK.
- Barts and the London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, Whitechapel, London, E1 1FR, UK.
- Barts Pancreas Tissue Bank, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University London, London, EC1M 6BQ, UK.
| | - Bristi Basu
- Department of Oncology, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust-Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK
| | - Fieke E M Froeling
- Department of Surgery and Cancer, Imperial College London-Hammersmith Hospital, London, W12 0HS, UK
- Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY, 11724, USA
| | - Debashis Sarker
- School of Cancer and Pharmaceutical Sciences, King's College London, Guy's Hospital Campus, London, SE1 9RT, UK
| | - Sarah Slater
- Barts and the London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, Whitechapel, London, E1 1FR, UK
| | - Dominic Carlin
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Nandita M deSouza
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Katja N De Paepe
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Michelle R Goulart
- Centre for Tumour Biology, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University London, London, EC1M 6BQ, UK
| | - Christine Hughes
- Centre for Tumour Biology, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University London, London, EC1M 6BQ, UK
| | - Ahmet Imrali
- Barts Pancreas Tissue Bank, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University London, London, EC1M 6BQ, UK
| | - Rhiannon Roberts
- Barts Pancreas Tissue Bank, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University London, London, EC1M 6BQ, UK
| | - Maria Pawula
- PK/Bioanalytics Core Facility, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK
| | - Richard Houghton
- PK/Bioanalytics Core Facility, Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK
| | - Cheryl Lawrence
- Centre for Experimental Cancer Medicine, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Yathushan Yogeswaran
- Centre for Experimental Cancer Medicine, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Kelly Mousa
- Centre for Experimental Cancer Medicine, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Carike Coetzee
- Centre for Experimental Cancer Medicine, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University of London, London, EC1M 6BQ, UK
| | - Peter Sasieni
- Cancer Prevention Trials Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, EC1M 6BQ, UK
- School of Cancer & Pharmaceutical Sciences, and King's Clinical Trials Unit, King's College London, London, SE1 9RT, UK
| | - Aaron Prendergast
- Centre for Experimental Cancer Medicine, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University of London, London, EC1M 6BQ, UK
| | - David J Propper
- Centre for Experimental Cancer Medicine, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University of London, London, EC1M 6BQ, UK
- Barts and the London HPB Centre, The Royal London Hospital, Barts Health NHS Trust, Whitechapel, London, E1 1FR, UK
- Centre for Cancer and Inflammation, Barts Cancer Institute-A CRUK Centre of Excellence, Queen Mary University London, London, EC1M 6BQ, UK
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Salleh S, Thyagarajan A, Sahu RP. Exploiting the relevance of CA 19-9 in pancreatic cancer. JOURNAL OF CANCER METASTASIS AND TREATMENT 2020; 6:31. [PMID: 37822969 PMCID: PMC10566512 DOI: 10.20517/2394-4722.2020.70] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/13/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth most common cause of cancer-related deaths in the United States. It has a poor prognosis and remains a difficulty to treat malignancy. Over the past several decades, significant efforts have been directed towards developing new approaches to enhance the efficacy of therapeutic regimens for PDAC treatment. In recent years, the measurement of serum carbohydrate antigen 19-9 (CA 19-9) has become one of the most validated and extensively used tumour biomarkers for PDAC. In particular, serum CA 19-9 levels have been explored as a validated tool to predict either the signs of disease progression or the response to treatment. However, despite its clinical relevance, the implications on diagnosis or accurately predicting tumour resectability, and monitoring disease symptoms in PDAC patients remains limited. This current review highlights the recent updates on the applicability of CA 19-9, its exploitation, and challenges in predicting the treatment efficacy and responses in PDAC patients.
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Affiliation(s)
- Syaza Salleh
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine Wright State University, Dayton, OH 45435, USA
| | - Anita Thyagarajan
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine Wright State University, Dayton, OH 45435, USA
| | - Ravi P Sahu
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine Wright State University, Dayton, OH 45435, USA
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36
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Colloca GA, Venturino A, Guarneri D. Tumor growth kinetics by CA 19-9 in patients with unresectable pancreatic cancer receiving chemotherapy: A retrospective analysis. Pancreatology 2020; 20:1189-1194. [PMID: 32747196 DOI: 10.1016/j.pan.2020.07.397] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 07/19/2020] [Accepted: 07/21/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Recently, measures of tumor growth kinetics calculated by carbohydrate antigen 19-9 (CA 19-9) determinations after cytotoxic chemotherapy (CHT) have been reported as effective prognostic indicators in locally-advanced unresectable and metastatic pancreatic adenocarcinoma (mPDAC). The study aims to evaluate the prognostic role of tumor kinetics measured by CA 19-9 in patients with mPDAC, measuring it by three different ways. METHODS Patients with mPDAC receiving a first-line CHT between 2009 and 2017 were identified, and those for whom CA 19-9 data were available were enrolled. Three CA 19-9-related variables were calculated: CA 19-9 related reduction rate (RR) and tumor growth rate (G), after 8 weeks of CHT, tumor growth and inflammation index (TGII), after 90 days of CHT. The relationships with the outcome were analysed, and a Cox model has been build with each of the three variables. RESULTS Of 118 patients only 48 were eligible for the analysis. RR, G, or TGII appear as significant prognostic factors, and, after multivariate analysis, a reduction rate of 20% the baseline or more was associated with good survival (HR 0.321; CIs 0.156-0.661) as well as a G > -0.4%/day (HR 2.114; CIs 1.034-4.321), whereas TGII >190 was not correlated with the outcome (HR 1.788; CIs 0.789-4.055). CONCLUSIONS In patients with mPDAC, after 8 weeks of first-line CHT, CA 19-9-related tumor reduction or growth rate appear as valuable prognostic factors.
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Abstract
OBJECTIVES This analysis investigated nomogram use to evaluate metastatic pancreatic cancer prognosis. METHODS Thirty-four baseline factors were examined in the Metastatic Pancreatic Adenocarcinoma Clinical Trial (MPACT) (nab-paclitaxel plus gemcitabine vs gemcitabine) data set. Factors significantly (P < 0.1) associated with overall survival (OS) in a univariable model or with known clinical relevance were tested further. In a multivariable model, factors associated with OS (P < 0.1) were selected to generate the primary nomogram, which was internally validated using bootstrapping, a concordance index, and calibration plots. RESULTS Using data from 861 patients, 6 factors were retained (multivariable analysis): neutrophil-lymphocyte ratio, albumin level, Karnofsky performance status, sum of longest diameter of target lesions, presence of liver metastases, and previous Whipple procedure. The nomogram distinguished low-, medium-, and high-risk groups (concordance index, 0.67; 95% confidence interval, 0.65-0.69; median OS, 11.7, 8.0, and 3.3 months, respectively). CONCLUSIONS This nomogram may guide estimates of the range of OS outcomes and contribute to patient stratification in future prospective metastatic pancreatic cancer trials; however, external validation is required to improve estimate reliability and applicability to a general patient population. Caution should be exercised in interpreting these results for treatment decisions: patient characteristics could differ from those included in the nomogram development.
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38
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Meijer LL, Garajová I, Caparello C, Le Large TYS, Frampton AE, Vasile E, Funel N, Kazemier G, Giovannetti E. Plasma miR-181a-5p Downregulation Predicts Response and Improved Survival After FOLFIRINOX in Pancreatic Ductal Adenocarcinoma. Ann Surg 2020; 271:1137-1147. [PMID: 30394883 DOI: 10.1097/sla.0000000000003084] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE The aim of the study was to identify plasma microRNA (miRNA) biomarkers for stratifying and monitoring patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) treated with FOLFIRINOX, and to investigate their functional roles. SUMMARY BACKGROUND DATA FOLFIRINOX has become a standard therapy for patients with advanced PDAC and can be used to potentially downstage disease. However, only a subset of patients respond, and biomarkers to guide decision-making are urgently needed. METHODS We used microarray-based profiling to discover deregulated miRNAs in pre- and postchemotherapy plasma samples from patients based on their progression-free survival (PFS) after FOLFIRINOX. Nine candidate plasma miRNAs were validated in an independent cohort (n = 43). The most discriminative plasma miRNA was correlated with clinicopathological factors and survival, and also investigated in an additional cohort treated with gemcitabine plus nab-paclitaxel. Expression patterns were further evaluated in matched tumor tissues. In vitro studies explored its function, key downstream gene-targets, and interaction with 5-fluorouracil, irinotecan, and oxaliplatin. RESULTS Plasma miR-181a-5p was significantly downregulated in non-progressive patients after FOLFIRINOX. In multivariate analysis, this decline correlated with improved PFS and overall survival, especially when combined with CA19-9 decline [hazard ratio (HR) = 0.153, 95% confidence interval (CI), 0.067-0.347 and HR = 0.201, 95% CI, 0.070-0.576, respectively]. This combination did not correlate with survival in patients treated with gemcitabine plus nab-paclitaxel. Tissue expression of miR-181a-5p reflected plasma levels. Inhibition of miR-181a-5p coupled with oxaliplatin exposure in pancreatic cell lines decreased cell viability. CONCLUSIONS Plasma miR-181a-5p is a specific biomarker for monitoring FOLFIRINOX response. Decline in plasma miR-181a-5p and CA19-9 levels is associated with better prognosis after FOLFIRINOX and may be useful for guiding therapeutic choices and surgical exploration.
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Affiliation(s)
- Laura L Meijer
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, VU University Amsterdam, the Netherlands
| | - Ingrid Garajová
- Department of Medical Oncology, Cancer Center Amsterdam, VU University Amsterdam, The Netherlands
- Department of Medical Oncology, University Hospital S. Orsola-Malpighi, Bologna, Italy
| | - Chiara Caparello
- Department of Medical Oncology, University Hospital of Pisa, Pisa, Italy
| | - Tessa Y S Le Large
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, VU University Amsterdam, the Netherlands
- Department of Medical Oncology, Cancer Center Amsterdam, VU University Amsterdam, The Netherlands
- Laboratory of Experimental Oncology & Radiobiology, Academic Medical Center, Amsterdam, The Netherlands
| | - Adam E Frampton
- HPB Surgical Unit, Department of Surgery & Cancer, Imperial College, London, United Kingdom
| | - Enrico Vasile
- Department of Medical Oncology, University Hospital of Pisa, Pisa, Italy
| | - Niccola Funel
- Cancer Pharmacology Lab, AIRC-Start-Up Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University Hospital of Pisa, Pisa, Italy
| | - Geert Kazemier
- Department of Surgery, Cancer Center Amsterdam, Amsterdam UMC, VU University Amsterdam, the Netherlands
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, VU University Amsterdam, The Netherlands
- Cancer Pharmacology Lab, AIRC-Start-Up Unit, Department of Translational Research and New Technologies in Medicine and Surgery, University Hospital of Pisa, Pisa, Italy
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39
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Rose JB, Edwards AM, Rocha FG, Clark C, Alseidi AA, Biehl TR, Lin BS, Picozzi VJ, Helton WS. Sustained Carbohydrate Antigen 19-9 Response to Neoadjuvant Chemotherapy in Borderline Resectable Pancreatic Cancer Predicts Progression and Survival. Oncologist 2020; 25:859-866. [PMID: 32277842 DOI: 10.1634/theoncologist.2019-0878] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 03/26/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND As neoadjuvant therapy of borderline resectable pancreatic cancer (BRPC) is becoming more widely used, better indicators of progression are needed to help guide therapeutic decisions. MATERIALS AND METHODS A retrospective review was performed on all patients with BRPC who received 24 weeks of neoadjuvant chemotherapy. Patients with chemotoxicity or medical comorbidities limiting treatment completion and nonexpressors of carbohydrate antigen 19-9 (CA19-9) were excluded. Serum CA19-9 response was analyzed as a predictor of disease progression, recurrence, and survival. RESULTS One hundred four patients were included; 39 (37%) progressed on treatment (18 local and 21 distant) and 65 (63%) were resected (68% R0). Multivariate logistic regression analysis determined that the percent decrease in CA19-9 from baseline to minimum value (odds ratio [OR] 0.947, p ≤ .0001) and the percent increase from minimum value to final restaging CA19-9 (OR 1.030, p ≤ .0001) were predictive of progression. A receiver operating characteristics curve analysis determined cutoff values predictive of progression, which were used to create four prognostic groups. CA19-9 responses were categorized as follows: (1) always normal (n = 6); (2) poor response (n = 31); (3) unsustained response (n = 19); and (4) sustained response (n = 48). Median overall survival for Groups 1-4 was 58, 16, 20, and 38 months, respectively (p ≤ .0001). CONCLUSION Patients with initially elevated CA19-9 levels who do not have a decline to a sustained low level are at risk for progression, recurrence, and poor survival. Alternative treatment strategies prior to an attempt at curative resection should be considered in this cohort. IMPLICATIONS FOR PRACTICE This study identified percent changes in carbohydrate antigen 19-9 blood levels while on chemotherapy that predict tumor growth in patients with advanced pancreas cancer. These changes could be used to better select patients who would benefit from surgical removal of their tumors and improve survival.
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Affiliation(s)
- J Bart Rose
- Division of Surgical Oncology, University of Alabama, Birmingham, Alabama, USA
| | - Alicia M Edwards
- Section of General, Thoracic and Vascular Surgery, Seattle, Washington, USA
| | - Flavio G Rocha
- Section of General, Thoracic and Vascular Surgery, Seattle, Washington, USA
| | - Carolyn Clark
- Section of General, Thoracic and Vascular Surgery, Seattle, Washington, USA
| | - Adnan A Alseidi
- Section of General, Thoracic and Vascular Surgery, Seattle, Washington, USA
| | - Thomas R Biehl
- Section of General, Thoracic and Vascular Surgery, Seattle, Washington, USA
| | - Bruce S Lin
- Section of Hematology and Oncology, Virginia Mason Medical Center, Seattle, Washington, USA
| | - Vincent J Picozzi
- Section of Hematology and Oncology, Virginia Mason Medical Center, Seattle, Washington, USA
| | - W Scott Helton
- Section of General, Thoracic and Vascular Surgery, Seattle, Washington, USA
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40
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Perri G, Prakash LR, Katz MHG. Response to Preoperative Therapy in Localized Pancreatic Cancer. Front Oncol 2020; 10:516. [PMID: 32351893 PMCID: PMC7174698 DOI: 10.3389/fonc.2020.00516] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 03/23/2020] [Indexed: 12/22/2022] Open
Abstract
Evaluation of response to preoperative therapy for patients with pancreatic adenocarcinoma has been historically difficult. Therefore, preoperative regimens have generally been selected on the basis of baseline data such as radiographic stage and serum CA 19-9 level and then typically administered for a pre-specified duration as long as 6 months or more. The decision to proceed with resection following preoperative therapy likewise has rested upon the absence of disease progression rather than evidence for tumor response. This article reviews the basis for the evaluation of therapeutic response after preoperative therapy for pancreatic cancer in the existing scientific literature, and providing updates and new perspectives.
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Affiliation(s)
- Giampaolo Perri
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Laura R Prakash
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Matthew H G Katz
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
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Reni M, Peretti U, Zanon S, Macchini M, Balzano G, Mazza E, Tamburrino D, Orsi G, Arcidiacono PG, Falconi M, Gianni L. Time to CA19-9 nadir: a clue for defining optimal treatment duration in patients with resectable pancreatic ductal adenocarcinoma. Cancer Chemother Pharmacol 2020; 85:641-650. [PMID: 32157412 DOI: 10.1007/s00280-020-04047-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 02/19/2020] [Indexed: 10/24/2022]
Abstract
BACKGROUND Defining optimal treatment duration in patients with resectable pancreatic ductal adenocarcinoma (PDAC) receiving primary chemotherapy is an unmet need. The role of time to CA19-9 nadir and of nadir magnitude was explored in this study. PATIENTS AND METHODS The databases of our institution's prospective trials were queried to speculate on the time to maximum chemotherapy response. Patients with pathologically proven, metastatic (N = 356) or non-metastatic non-resected (N = 163) PDAC and elevated baseline (> 34 UI/mL) CA19-9 were analyzed. Survival curves were estimated using the Kaplan-Meier method and compared by means of the log-rank test for analyses including at least 45 patients. Multivariable Cox proportional hazards model was used to estimate clinical features for their association with OS. All probability values were from two-sided tests. RESULTS Time to CA19-9 nadir was ≥ 4 months in 184 of 346 (53%) metastatic and 121 of 163 (74%) non-metastatic patients (p = 0.002). The likelihood of a later nadir was higher with taxane-based chemotherapy as compared to taxane-free combinations (73% versus 56%; p = 0.02). Both metastatic and non-metastatic patients had significantly longer survival when nadir occurred later. Patients with a larger CA19-9 nadir magnitude had significantly longer survival. Metastatic patients with CA19-9 reduced by < 50%, 50-89%, or > 89% and had a median survival of 7.4, 9.8, and 14.7 months, respectively (p ≤ 0.001 for all comparisons). The corresponding figures for non-metastatic patients were 10.6; 17.0; and 18.7 months, respectively (p ≤ 0.02 for < 50% versus 50-89% or > 89%; p = 0.14 for 50-89% versus > 89%). Multivariable analyses showed that time to CA19-9 nadir but not CA19-9 nadir magnitude was independently predictive of survival. CONCLUSION The present study suggests that a 4-6 months program might be a more suitable candidate for prospective assessment in comparison to shorter pre-defined period in patients who are candidates to surgery after primary chemotherapy.
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Affiliation(s)
- Michele Reni
- Department of Medical Oncology, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132, Milan, Italy.
| | - Umberto Peretti
- Department of Medical Oncology, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132, Milan, Italy
| | - Silvia Zanon
- Department of Medical Oncology, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132, Milan, Italy
| | - Marina Macchini
- Department of Medical Oncology, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132, Milan, Italy
| | - Gianpaolo Balzano
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132, Milan, Italy
| | - Elena Mazza
- Department of Medical Oncology, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132, Milan, Italy
| | - Domenico Tamburrino
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132, Milan, Italy
| | - Giulia Orsi
- Department of Medical Oncology, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132, Milan, Italy
| | - Paolo Giorgio Arcidiacono
- Pancreato-Biliary Endoscopy and Endosonography Division, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132, Milan, Italy
| | - Massimo Falconi
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Center IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132, Milan, Italy
- Università "Vita E Salute", Via Olgettina 58, 20132, Milan, Italy
| | - Luca Gianni
- Department of Medical Oncology, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132, Milan, Italy
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Zeh HJ, Bahary N, Boone BA, Singhi AD, Miller-Ocuin JL, Normolle DP, Zureikat AH, Hogg ME, Bartlett DL, Lee KK, Tsung A, Marsh JW, Murthy P, Tang D, Seiser N, Amaravadi RK, Espina V, Liotta L, Lotze MT. A Randomized Phase II Preoperative Study of Autophagy Inhibition with High-Dose Hydroxychloroquine and Gemcitabine/Nab-Paclitaxel in Pancreatic Cancer Patients. Clin Cancer Res 2020; 26:3126-3134. [PMID: 32156749 DOI: 10.1158/1078-0432.ccr-19-4042] [Citation(s) in RCA: 155] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 02/05/2020] [Accepted: 03/06/2020] [Indexed: 12/19/2022]
Abstract
PURPOSE We hypothesized that autophagy inhibition would increase response to chemotherapy in the preoperative setting for patients with pancreatic adenocarcinoma. We performed a randomized controlled trial to assess the autophagy inhibitor hydroxychloroquine in combination with gemcitabine and nab-paclitaxel. PATIENTS AND METHODS Participants with potentially resectable tumors were randomized to two cycles of nab-paclitaxel and gemcitabine (PG) alone or with hydroxychloroquine (PGH), followed by resection. The primary endpoint was histopathologic response in the resected specimen. Secondary clinical endpoints included serum CA 19-9 biomarker response and margin negative R0 resection. Exploratory endpoints included markers of autophagy, immune infiltrate, and serum cytokines. RESULTS Thirty-four patients in the PGH arm and 30 in the PG arm were evaluable for the primary endpoint. The PGH arm demonstrated statistically improved Evans grade histopathologic responses (P = 0.00016), compared with control. In patients with elevated CA 19-9, a return to normal was associated with improved overall and recurrence-free survival (P < 0.0001). There were no differences in serious adverse events between arms and chemotherapy dose number was equivalent. The PGH arm had greater evidence of autophagy inhibition in their resected specimens (increased SQSTM1, P = 0.027, as well as increased immune cell tumor infiltration, P = 0.033). Overall survival (P = 0.59) and relapse-free survival (P = 0.55) did not differ between the two arms. CONCLUSIONS The addition of hydroxychloroquine to preoperative gemcitabine and nab-paclitaxel chemotherapy in patients with resectable pancreatic adenocarcinoma resulted in greater pathologic tumor response, improved serum biomarker response, and evidence of autophagy inhibition and immune activity.
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Affiliation(s)
- Herbert J Zeh
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Nathan Bahary
- Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
| | - Brian A Boone
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Aatur D Singhi
- Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | | | - Daniel P Normolle
- Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Amer H Zureikat
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Melissa E Hogg
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - David L Bartlett
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Kenneth K Lee
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Allan Tsung
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - J Wallis Marsh
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Pranav Murthy
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Daolin Tang
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Natalie Seiser
- HPB and Transplant Institute at St. Vincent's Medical Center, Los Angeles, California
| | - Ravi K Amaravadi
- Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Virginia Espina
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia
| | - Lance Liotta
- Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia
| | - Michael T Lotze
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.,Department of Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania.,Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania
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Motoi F, Unno M. Neoadjuvant treatment for resectable pancreatic adenocarcinoma: What is the best protocol? Ann Gastroenterol Surg 2020; 4:100-108. [PMID: 32258974 PMCID: PMC7105839 DOI: 10.1002/ags3.12311] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 11/27/2019] [Accepted: 12/16/2019] [Indexed: 12/13/2022] Open
Abstract
Although upfront surgery has been the gold standard for pancreatic adenocarcinoma that is planned for resection, it should be compared with the alternative strategy of neoadjuvant therapy. Despite the many reports of the efficacy of neoadjuvant therapy, most of them were not comparative. Recently Prep-02/JSAP05 study clearly demonstrated the significant survival benefit of neoadjuvant chemotherapy over upfront surgery for pancreatic adenocarcinoma that is planned for resection. These findings opened a new chapter of neoadjuvant therapy. Ongoing trials are expected to confirm the evidence. This review summarizes the past, present, and future perspectives of neoadjuvant therapy and its optimization.
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Affiliation(s)
- Fuyuhiko Motoi
- Department of SurgeryTohoku University Graduate School of MedicineAoba‐kuJapan
| | - Michiaki Unno
- Department of SurgeryTohoku University Graduate School of MedicineAoba‐kuJapan
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44
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Oba A, Ho F, Bao QR, Al-Musawi MH, Schulick RD, Del Chiaro M. Neoadjuvant Treatment in Pancreatic Cancer. Front Oncol 2020; 10:245. [PMID: 32185128 PMCID: PMC7058791 DOI: 10.3389/fonc.2020.00245] [Citation(s) in RCA: 152] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 02/13/2020] [Indexed: 12/13/2022] Open
Abstract
Thanks to the development of modern chemotherapeutic regimens, survival after surgery for pancreatic ductal adenocarcinoma (PDAC) has improved and pancreatologists worldwide agree that the treatment of PDAC demands a multidisciplinary approach. Neoadjuvant treatment (NAT) plays a major role in the treatment of PDAC since only about 20% of patients are considered resectable at the time of diagnosis. Moreover, increasing data demonstrating the benefits of NAT for borderline resectable/locally advanced PDAC are driving a shift from up-front surgery to NAT in the multidisciplinary treatment of even resectable PDAC. Our understanding of the role of NAT in PDAC has evolved from tumor shrinkage to controlling potential micrometastases and selecting patients who may benefit from radical resection. The present review gives an overview on the current literature of NAT concepts for BR/LA PDAC and resectable PDAC.
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Affiliation(s)
- Atsushi Oba
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Denver, CO, United States.,Department of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Felix Ho
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Denver, CO, United States
| | - Quoc Riccardo Bao
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Denver, CO, United States.,Department of Surgery, Oncology, and Gastroenterology, University of Padua, Padua, Italy
| | - Mohammed H Al-Musawi
- Clinical Trials Office, Department of Surgery, University of Colorado, Anschutz Medical Campus, Denver, CO, United States
| | - Richard D Schulick
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Denver, CO, United States
| | - Marco Del Chiaro
- Division of Surgical Oncology, Department of Surgery, University of Colorado, Anschutz Medical Campus, Denver, CO, United States
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45
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Wu D, Li X, Zhang X, Han F, Lu X, Liu L, Zhang J, Dong M, Yang H, Li H. Pharmacometabolomics Identifies 3-Hydroxyadipic Acid, d-Galactose, Lysophosphatidylcholine (P-16:0), and Tetradecenoyl-l-Carnitine as Potential Predictive Indicators of Gemcitabine Efficacy in Pancreatic Cancer Patients. Front Oncol 2020; 9:1524. [PMID: 32064236 PMCID: PMC7000527 DOI: 10.3389/fonc.2019.01524] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 12/18/2019] [Indexed: 12/28/2022] Open
Abstract
Gemcitabine (GEM)-based chemotherapy is the standard regimen for the treatment of pancreatic cancer (PC). However, chemoresistance is a major challenge in PC treatment. Reliable biomarkers are urgently needed to predict the response to GEM-based therapies. GEM-sensitive (GEM-S) and GEM-resistant (GEM-R) pancreatic carcinoma xenograft models were established, and GEM monotherapy and GEM plus nanoparticle albumin-bound paclitaxel (nab-PTX) doublet therapy were administered to GEM-S/R tumor-bearing mice. Metabolomic mass spectrometry (MS) analysis of serum, liver, and tumor samples was performed using an ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometer. The results showed that both GEM monotherapy and combination therapy significantly inhibited the tumor growth in GEM-S subgroup. However, in the GEM-R subgroup, tumor growth was not significantly inhibited by GEM monotherapy, but was significantly suppressed by GEM combination therapy. Metabolic profiling analysis by hierarchical cluster analysis and partial least squares discriminant analysis showed that the differences in metabolites were most significant in serum of three types of samples in the GEM-S/R subgroups, regardless of the administration of GEM monotherapy or combination therapy. The differential metabolite analysis of serum samples revealed 38 and 26 differential metabolites between the GEM-R and GEM-S subgroups treated with GEM monotherapy or combination therapy, and four common discriminating metabolites were investigated: 3-hydroxyadipic acid, d-galactose, lysophosphatidylcholine (LysoPC) (P-16:0), and tetradecenoyl-l-carnitine. The relative amounts of the four metabolites changed significantly and consistently after GEM monotherapy or combination therapy. The levels of these four metabolites were significantly different in the GEM-S and GEM-R pancreatic carcinoma xenograft models; thus, these metabolites could be effective predictive indicators of the efficacy of chemotherapy in PC patients, regardless of the administration of GEM alone or GEM plus nab-PTX.
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Affiliation(s)
- Dongyuan Wu
- Department of Biochemistry and Molecular Biology, Basic Medical Science College, Harbin Medical University, Harbin, China.,Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Xinyuan Li
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Xiaohan Zhang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Fang Han
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Xin Lu
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Lei Liu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Junsheng Zhang
- College of Basic Medicine, Harbin Medical University, Harbin, China
| | - Mei Dong
- Department of Pharmacy, Harbin Medical University Cancer Hospital, Harbin, China
| | - Huanjie Yang
- School of Life Science and Technology, Harbin Institute of Technology, Harbin, China
| | - Hui Li
- Department of Biochemistry and Molecular Biology, Basic Medical Science College, Harbin Medical University, Harbin, China
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Jameson GS, Borazanci E, Babiker HM, Poplin E, Niewiarowska AA, Gordon MS, Barrett MT, Rosenthal A, Stoll-D’Astice A, Crowley J, Shemanski L, Korn RL, Ansaldo K, Lebron L, Ramanathan RK, Von Hoff DD. Response Rate Following Albumin-Bound Paclitaxel Plus Gemcitabine Plus Cisplatin Treatment Among Patients With Advanced Pancreatic Cancer: A Phase 1b/2 Pilot Clinical Trial. JAMA Oncol 2020; 6:125-132. [PMID: 31580386 PMCID: PMC6777241 DOI: 10.1001/jamaoncol.2019.3394] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2019] [Accepted: 06/20/2019] [Indexed: 01/05/2023]
Abstract
Importance Genomes of metastatic pancreatic cancers frequently contain intrachromosomal aberrations, indicating a DNA repair deficiency associated with sensitivity to DNA damaging agents, such as platinum. Objective To determine response rate following treatment with nab-paclitaxel plus gemcitabine plus platinum-based cisplatin for patients with metastatic pancreatic ductal adenocarcinoma (PDA). Design, Setting, and Participants This was a single-arm, open-label, phase 1b/2 clinical trial of nab-paclitaxel plus gemcitabine plus cisplatin treatment in which 25 patients with previously untreated metastatic PDA were enrolled. The trial was conducted from December 2013 to July 2016 at 3 US sites, with the last patient receiving study treatment at the end of October 2016, and the study closing January 2018. Interventions Patients were treated with nab-paclitaxel plus gemcitabine plus various doses of cisplatin, 25 mg/m2, 37.5 mg/m2, and 50 mg/m2, on days 1 and 8 of a 21-day cycle. Main Outcomes and Measures Primary end point was complete response rate as assessed by Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST), and levels of carbohydrate antigen 19-9 (or in nonexpressers, carbohydrate antigen 125 or carcinoembryonic antigen). Efficacy analysis included evaluable patients (those who received at least 1 dose of study treatment and had at least 1 postbaseline tumor assessment). Results Of 25 patients enrolled in the study, the median (range) age was 65.0 (47.0-79.0) years, 14 (56%) were men, and most (24) were white (96%). The maximum tolerable dose of cisplatin was 25 mg/m2. The most common treatment-related adverse events grade 3 or higher were thrombocytopenia (17 patients [68%]), anemia (8 patients [32%]), and neutropenia (6 patients [24%]). Fatal events occurred for 3 patients (12%); 2 were related to study participation. A median (range) of 8 (1-15) cycles was completed. The RECIST responses in 24 evaluable patients included 2 complete responses (8%), which was below the primary end point of 25%, 15 partial responses (62%), 4 stable disease (17%), and 3 progressive disease (12%), with median overall survival of 16.4 (95% CI, 10.2-25.3) months; 16 patients (64%) were alive at 1 year, 10 (40%) at 2 years, 4 (16%) at 3 years, and 1 (4%) at 4 plus years. Overall survival ranged from 36 to 59 months. Median progression-free survival was 10.1 (95% CI, 6.0-12.5) months. Thus, the overall response rate was 71%, and the disease control rate was 88%. Conclusions and Relevance This triple drug regimen showed substantial clinical activity in this small study. Although the primary end point was not reached, the high overall response rate, disease control rate, and median survival time among patients with advanced PDA treated with this combination are encouraging. The regimen is being studied in patients with PDA in the neoadjuvant setting and in patients with advanced biliary cancers. Trial Registration ClinicalTrials.gov identifier: NCT01893801.
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Affiliation(s)
- Gayle S. Jameson
- HonorHealth Research Institute, Scottsdale, Arizona
- Translational Genomics Research Institute, an Affiliate of City of Hope, Phoenix, Arizona
| | - Erkut Borazanci
- HonorHealth Research Institute, Scottsdale, Arizona
- Translational Genomics Research Institute, an Affiliate of City of Hope, Phoenix, Arizona
| | - Hani M. Babiker
- Translational Genomics Research Institute, an Affiliate of City of Hope, Phoenix, Arizona
- Comprehensive Cancer Center, The University of Arizona, Tucson
| | | | | | | | | | | | | | - John Crowley
- Cancer Research And Biostatistics, Seattle, Washington
| | | | | | | | | | | | - Daniel D. Von Hoff
- HonorHealth Research Institute, Scottsdale, Arizona
- Translational Genomics Research Institute, an Affiliate of City of Hope, Phoenix, Arizona
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47
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Damanakis AI, Ostertag L, Waldschmidt D, Kütting F, Quaas A, Plum P, Bruns CJ, Gebauer F, Popp F. Proposal for a definition of "Oligometastatic disease in pancreatic cancer". BMC Cancer 2019; 19:1261. [PMID: 31888547 PMCID: PMC6937989 DOI: 10.1186/s12885-019-6448-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Accepted: 12/11/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND To date, patients with metastasized pancreatic ductal adenocarcinoma (PDAC M1) are regarded as a uniform collective. We hypothesize the existence of oligometastatic disease (OMD): a state of PDAC M1 disease with better tumor biology, limited metastasis, and increased survival. METHODS Data of 128 PDAC M1 patients treated at the University of Cologne between 2008 and 2018 was reviewed. Interdependence between clinical parameter was calculated using the Mann-Whitney U-Test. Survival curves were generated using the Kaplan-Meier method and analyzed using the log-rank test. RESULTS Eighty-one (63%) patients had metastases confined to one organ (single organ metastasis, SOG) whereas the remaining 47 (37%) showed multiple metastatic sites (multi-organ metastasis, MOG). Survival analysis revealed a median overall survival (OS) of 12.2 months for SOG vs 4.5 months for MOG (95% CI 5.7-9.8; p < 0.001). We defined limited disease by the presence of ≤4 metastases in liver or lung. Limited disease together with CA 19-9 baseline < 1000 U/ml and response or stable disease after first-line chemotherapy defined OMD. We identified 8 patients with hepatic metastases and 2 with pulmonary metastases matching all OMD criteria. This group of 10 (7.8%) had a median overall survival of 19.4 vs 7.2 months compared to the remaining patients (95% CI 5.7-9.8; p = 0.009). CONCLUSION We propose a definition of oligometastatic disease in PDAC including anatomical criteria and biological criteria reflecting better tumor biology. The 10 OMD patients (7.8%) survived significantly longer and might even benefit from surgical resection in the future.
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Affiliation(s)
- Alexander I Damanakis
- Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany.
| | - Luisa Ostertag
- Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany
| | - Dirk Waldschmidt
- Department of Gastroenterology, University Hospital of Cologne, Cologne, Germany
| | - Fabian Kütting
- Department of Gastroenterology, University Hospital of Cologne, Cologne, Germany
| | - Alexander Quaas
- Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - Patrick Plum
- Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany
| | - Christiane J Bruns
- Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany
| | - Florian Gebauer
- Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany
| | - Felix Popp
- Department of General, Visceral, Cancer and Transplantation Surgery, University Hospital of Cologne, Cologne, Germany
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Chan KKW, Guo H, Cheng S, Beca JM, Redmond-Misner R, Isaranuwatchai W, Qiao L, Earle C, Berry SR, Biagi JJ, Welch S, Meyers BM, Mittmann N, Coburn N, Arias J, Schwartz D, Dai WF, Gavura S, McLeod R, Kennedy ED. Real-world outcomes of FOLFIRINOX vs gemcitabine and nab-paclitaxel in advanced pancreatic cancer: A population-based propensity score-weighted analysis. Cancer Med 2019; 9:160-169. [PMID: 31724340 PMCID: PMC6943167 DOI: 10.1002/cam4.2705] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Revised: 10/27/2019] [Accepted: 10/29/2019] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND In Ontario, FOLFIRINOX (FFX) and gemcitabine + nab-paclitaxel (GnP) have been publicly funded for first-line unresectable locally advanced pancreatic cancer (uLAPC) or metastatic pancreatic cancer (mPC) since April 2015. We examined the real-world effectiveness and safety of FFX vs GnP for advanced pancreatic cancer, and in uLAPC and mPC. METHODS Patients receiving first-line FFX or GnP from April 2015 to March 2017 were identified in the New Drug Funding Program database. Baseline characteristics and outcomes were obtained through the Ontario Cancer Registry and other population-based databases. Overall survival (OS) was assessed using Kaplan-Meier and weighted Cox proportional hazard models, weighted by the inverse propensity score adjusting for baseline characteristics. Weighted odds ratio (OR) for hospitalization and emergency department visits (EDV) were estimated from weighted logistic regression models. RESULTS For 1130 patients (632 FFX, 498 GnP), crude median OS was 9.6 and 6.1 months for FFX and GnP, respectively. Weighted OS was improved for FFX vs GnP (HR = 0.77, 0.70-0.85). Less frequent EDV and hospitalization were observed in FFX (EDV: 67.8%; Hospitalization: 49.2%) than GnP (EDV: 77.7%; Hospitalization: 59.3%). More frequent febrile neutropenia-related hospitalization was observed in FFX (5.8%) than GnP (3.3%). Risk of EDV and hospitalization were significantly lower for FFX vs GnP (EDV: OR = 0.68, P = .0001; Hospitalization: OR = 0.76, P = .002), whereas the risk of febrile neutropenia-related hospitalization was significantly higher (OR = 2.12, P = .001). Outcomes for uLAPC and mPC were similar. CONCLUSION In the real world, FFX had longer OS, less frequent all-cause EDV and all-cause hospitalization, but more febrile neutropenia-related hospitalization compared to GnP.
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Affiliation(s)
- Kelvin K W Chan
- Cancer Care Ontario, Toronto, ON, Canada.,Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada.,Canadian Centre for Applied Research in Cancer Control, Toronto, ON, Canada
| | - Helen Guo
- Cancer Care Ontario, Toronto, ON, Canada
| | - Sierra Cheng
- Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Jaclyn M Beca
- Canadian Centre for Applied Research in Cancer Control, Toronto, ON, Canada.,Pharmacoeconomics Research Unit, Cancer Care Ontario, Toronto, ON, Canada
| | | | - Wanrudee Isaranuwatchai
- Canadian Centre for Applied Research in Cancer Control, Toronto, ON, Canada.,Pharmacoeconomics Research Unit, Cancer Care Ontario, Toronto, ON, Canada
| | - Lucy Qiao
- Cancer Care Ontario, Toronto, ON, Canada
| | - Craig Earle
- Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada.,Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Scott R Berry
- Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - James J Biagi
- Cancer Centre of Southeastern Ontario, Kingston, ON, Canada
| | | | | | | | - Natalie Coburn
- Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada
| | | | | | - Wei F Dai
- Cancer Care Ontario, Toronto, ON, Canada
| | | | | | - Erin D Kennedy
- Cancer Care Ontario, Toronto, ON, Canada.,Mount Sinai Hospital, Toronto, ON, Canada
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49
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Population pharmacokinetics and exposure-overall survival analysis of the transforming growth factor-β inhibitor galunisertib in patients with pancreatic cancer. Cancer Chemother Pharmacol 2019; 84:1003-1015. [PMID: 31482224 DOI: 10.1007/s00280-019-03931-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 08/16/2019] [Indexed: 12/21/2022]
Abstract
PURPOSE To evaluate the exposure-overall survival (OS) relationship in patients with advanced pancreatic cancer treated with galunisertib plus gemcitabine (GG) or gemcitabine plus placebo (GP). METHODS Galunisertib 300 mg/day was given orally as intermittent dosing and gemcitabine as per label. Galunisertib exposure metrics for each patient in the GG arm (n = 99) of a phase 2 study of pancreatic cancer were calculated. Parametric survival models were used to identify influential baseline and response covariates on OS. RESULTS The population pharmacokinetics dataset included data from 297 patients/healthy subjects (age: 22-84 years, weight: 39-126 kg) across multiple studies, including this pancreatic cancer study. Galunisertib was rapidly absorbed with peak concentrations attained within 0.5-2 h and had an elimination half-life of 8 h. Between-subject variance on apparent clearance was estimated to be 47%. Age was the only characteristic to have a statistically significant effect on apparent clearance. A parametric Weibull survival model with treatment effect (dose) estimated a hazard ratio of 0.796, after adjusting for patient baseline factors that were significantly associated with OS. There was also a flat daily exposure-OS relationship within the observed exposure range, once all significant baseline covariates were included. Response covariates, such as reduction in CA19-9, time on treatment, and cumulative exposure over treatment cycles were also identified as significant factors for OS for patients with pancreatic cancer. CONCLUSIONS This analysis suggests that 300 mg/day galunisertib administered as 150 mg twice daily for 14 days on/14 days off treatment is an appropriate dosing regimen for patients with pancreatic cancer.
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50
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Chen Y, Wang YR, Deng GC, Dai GH. CA19-9 decrease and survival according to platelet level in patients with advanced pancreatic cancer. BMC Cancer 2019; 19:860. [PMID: 31470818 PMCID: PMC6716806 DOI: 10.1186/s12885-019-6078-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Accepted: 08/22/2019] [Indexed: 12/16/2022] Open
Abstract
Background CA19–9 decrease during treatment has been associated with superior survival of pancreatic cancer in several studies. The evidence to show the correlation of high platelet level with inferior survival is insufficient in pancreatic cancer. It also remains unclear whether the association between CA19–9 decrease and survival was corresponded to different levels of platelet in metastatic pancreatic cancer. Methods We measured CA19–9 serum concentration and platelet level at baseline and after the second cycle of chemotherapy for 200 advanced pancreatic cancer patients. A Cox proportional hazards model was used to compute mortality hazard ratios (HRs) for CA19–9 decrease, adjusting for potential confounders, including age, sex, KPS, prediagnosis body mass index, Diabetes Mellitus, tumor location, first-line chemotherapy regimen, and radiotherapy. Results We found that the association of CA19–9 decrease with superior overall survival was stronger in advanced pancreatic cancer with a low level of platelet (Pinteraction < 0.001) compared with intermediate and high level of platelet. Multivariable-adjusted hazard ratios per unit decrease of CA19–9 change was 0.45 [95% confidence interval (CI), 0.33 to 0.62] in cases with low platelet level, 0.74 (95% CI, 0.50 to 1.09) in cases with intermediate platelet level, and 0.94 (95% CI, 0.74 to 1.10) in cases with high platelet level. A similar differential association was found between CA19–9 decrease and progression-free survival in strata of platelet level (Pinteraction = 0.034). Conclusion The association of CA19–9 decrease with superior pancreatic cancer survival appeared to be pronounced in patients with a low platelet level. This finding could provide supports for the underlying mechanisms of CA19–9 involved in platelet / tumor cell interaction. Electronic supplementary material The online version of this article (10.1186/s12885-019-6078-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Y Chen
- Department of Medical Oncology, Chinese People's Liberation Army (PLA) General Hospital and Chinese PLA Medical School, Beijing, 100853, China.,Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, 52 Fucheng Road, Haidian District, Beijing, 100142, China
| | - Y R Wang
- Department of Medical Oncology, Chinese People's Liberation Army (PLA) General Hospital and Chinese PLA Medical School, Beijing, 100853, China
| | - G C Deng
- Department of Medical Oncology, Chinese People's Liberation Army (PLA) General Hospital and Chinese PLA Medical School, Beijing, 100853, China
| | - G H Dai
- Department of Medical Oncology, Chinese People's Liberation Army (PLA) General Hospital and Chinese PLA Medical School, Beijing, 100853, China.
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