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Underwood PW, Leuschner T, Ejaz A, Dillhoff M, Tsai S, Pawlik TM, Manne A, Krishna SG, Miller ED, Ahmad S, Cloyd JM. Textbook Neoadjuvant Experience: Defining a Novel Composite Outcomes Measure for Patients with Pancreatic Cancer Undergoing Neoadjuvant Therapy. J Am Coll Surg 2025; 240:539-548. [PMID: 39803957 DOI: 10.1097/xcs.0000000000001277] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/22/2025]
Abstract
BACKGROUND Neoadjuvant therapy (NT) is increasingly used for patients with pancreatic ductal adenocarcinoma (PDAC). Disease progression, toxicity, and failure to undergo surgical resection are common during NT, yet little research has focused on efforts to optimize care delivery. We sought to define and validate a novel composite outcomes metric that characterizes the successful delivery of NT. STUDY DESIGN All patients with localized PDAC receiving NT in an intention-to-treat fashion between 2018 and 2023 were retrospectively evaluated. A textbook neoadjuvant experience (TNE) was defined as the absence of mortality, disease progression, or hospital admission during NT as well as the completion of all intended NT and successful surgical resection. RESULTS Among 306 patients with localized PDAC, the median age was 66 years and 58.5% were men. Overall, only 85 (28%) experienced a TNE which was more common among patients with potentially resectable (45 of 96, 47%) than borderline resectable (33 of 112, 29%) or locally advanced (7 of 98, 7%) disease. Patients with a TNE experienced greater overall survival than those individuals without a TNE (median not reached vs 16.4 months [95% CI 14.9 to 17.9 months], p < 0.001). On multivariable Cox regression analysis, a TNE was the strongest predictor of improved overall survival (hazard ratio 0.33, 95% CI 0.20 to 0.54, p < 0.001). CONCLUSIONS A TNE is infrequently achieved among patients with PDAC undergoing NT but is significantly associated with improved long-term outcomes. Future research aimed at optimizing outcomes of NT delivery should incorporate this novel composite metric that may more accurately reflect patient and provider expectations of treatment.
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Affiliation(s)
- Patrick W Underwood
- From the Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, OH (Underwood, Leuschner, Dillhoff, Tsai, Pawlik, Cloyd)
| | - Thomas Leuschner
- From the Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, OH (Underwood, Leuschner, Dillhoff, Tsai, Pawlik, Cloyd)
| | - Aslam Ejaz
- Division of Surgical Oncology Department of Surgery, University of Illinois-Chicago, Chicago, IL (Ejaz)
| | - Mary Dillhoff
- From the Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, OH (Underwood, Leuschner, Dillhoff, Tsai, Pawlik, Cloyd)
| | - Susan Tsai
- From the Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, OH (Underwood, Leuschner, Dillhoff, Tsai, Pawlik, Cloyd)
| | - Timothy M Pawlik
- From the Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, OH (Underwood, Leuschner, Dillhoff, Tsai, Pawlik, Cloyd)
| | - Ashish Manne
- Division of Medical Oncology, Department of Medicine, The Ohio State University, Columbus, OH (Manne)
| | - Somashekar G Krishna
- Division of Gastroenterology, Department of Medicine, The Ohio State University, Columbus, OH (Krishna)
| | - Eric D Miller
- Department of Radiation Oncology, The Ohio State University, Columbus, OH (Miller)
| | - Syed Ahmad
- Department of Surgery, University of Cincinnati, Cincinnati, OH (Ahmad)
| | - Jordan M Cloyd
- From the Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, OH (Underwood, Leuschner, Dillhoff, Tsai, Pawlik, Cloyd)
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Matsumoto M, Shirai Y, Tsunematsu M, Okui N, Gocho T, Onda S, Furukawa K, Haruki K, Uwagawa T, Ikegami T. Changes in Skeletal Muscle Volume During Preoperative Chemotherapy Affect the Outcome of Pancreatic Cancer. Am Surg 2025; 91:115-125. [PMID: 39180397 DOI: 10.1177/00031348241278021] [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] [Indexed: 08/26/2024]
Abstract
BACKGROUND This study aimed to investigate the effects of changes in clinicopathological factors during preoperative chemotherapy for pancreatic cancer, including skeletal muscle volume, on recurrence and prognosis after pancreatectomy. METHODS Data from 41 patients who underwent resection for pancreatic cancer after preoperative chemotherapy from 2012 to 2021 were retrospectively reviewed. Skeletal muscle volume was substituted for the psoas muscle area (PMA) at the level of the third lumbar vertebra. We investigated the relationship of clinicopathological factors during preoperative chemotherapy with disease-free survival (DFS) and overall survival (OS). The association between clinicopathological factors and a decrease in PMA was investigated. RESULTS In the multivariate analyses for DFS and OS, the factors associated with recurrence were as follows: decrease in PMA (P = 0.003) and the absence of adjuvant therapy (P = 0.03), and the factors associated with poor prognosis were as follows: decrease in PMA (P = 0.04) and the absence of adjuvant therapy (P = 0.008), and the resectability of borderline resectable and unresectable-locally advanced tumors (P = 0.033). All patients with partial response according to the Response Evaluation Criteria in Solid Tumors (version 1.1) had no decrease in PMA (P = 0.01). The proportion of patients with Evans classification ≥ II was significantly higher in the group without a decrease in PMA (P = 0.02). The proportion of patients with an average relative dose intensity of adjuvant therapy ≥0.6 was significantly higher in the group without a decrease in PMA (P = 0.02). CONCLUSION Changes in preoperative skeletal muscle volume during preoperative chemotherapy for pancreatic cancer is a potential predictor of recurrence and prognosis after pancreatectomy.
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Affiliation(s)
- Michinori Matsumoto
- Department of Surgery, The Jikei University School of Medicine, Minato-ku, Japan
| | - Yoshihiro Shirai
- Department of Surgery, The Jikei University School of Medicine, Minato-ku, Japan
| | - Masashi Tsunematsu
- Department of Surgery, The Jikei University School of Medicine, Minato-ku, Japan
| | - Norimitsu Okui
- Department of Surgery, The Jikei University School of Medicine, Minato-ku, Japan
| | - Takeshi Gocho
- Department of Surgery, The Jikei University School of Medicine, Minato-ku, Japan
| | - Shinji Onda
- Department of Surgery, The Jikei University School of Medicine, Minato-ku, Japan
| | - Kenei Furukawa
- Department of Surgery, The Jikei University School of Medicine, Minato-ku, Japan
| | - Koichiro Haruki
- Department of Surgery, The Jikei University School of Medicine, Minato-ku, Japan
| | - Tadashi Uwagawa
- Department of Surgery, The Jikei University School of Medicine, Minato-ku, Japan
| | - Toru Ikegami
- Department of Surgery, The Jikei University School of Medicine, Minato-ku, Japan
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Goetze TO, Reichart A, Bankstahl US, Pauligk C, Loose M, Kraus TW, Elshafei M, Bechstein WO, Trojan J, Behrend M, Homann N, Venerito M, Bohle W, Varvenne M, Bolling C, Behringer DM, Kratz-Albers K, Siegler GM, Hozaeel W, Al-Batran SE. Adjuvant Gemcitabine Versus Neoadjuvant/Adjuvant FOLFIRINOX in Resectable Pancreatic Cancer: The Randomized Multicenter Phase II NEPAFOX Trial. Ann Surg Oncol 2024; 31:4073-4083. [PMID: 38459418 PMCID: PMC11076394 DOI: 10.1245/s10434-024-15011-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 01/21/2024] [Indexed: 03/10/2024]
Abstract
BACKGROUND Although addition of adjuvant chemotherapy is the current standard, the prognosis of pancreatic cancers still remains poor. The NEPAFOX trial evaluated perioperative treatment with FOLFIRINOX in resectable pancreatic cancer. PATIENTS AND METHODS This multicenter phase II trial randomized patients with resectable or borderline resectable pancreatic cancer without metastases into arm (A,) upfront surgery plus adjuvant gemcitabine, or arm (B,) perioperative FOLFIRINOX. The primary endpoint was overall survival (OS). RESULTS Owing to poor accrual, recruitment was prematurely stopped after randomization of 40 of the planned 126 patients (A: 21, B: 19). Overall, approximately three-quarters were classified as primarily resectable (A: 16, B: 15), and the remaining patients were classified as borderline resectable (A: 5, B: 4). Of the 12 evaluable patients, 3 achieved partial response under neoadjuvant FOLFIRINOX. Of the 21 patients in arm A and 19 patients in arm B, 17 and 7 underwent curative surgery, and R0-resection was achieved in 77% and 71%, respectively. Perioperative morbidity occurred in 72% in arm A and 46% in arm B, whereas non-surgical toxicity was comparable in both arms. Median RFS/PFS was almost doubled in arm B (14.1 months) compared with arm A (8.4 months) in the population with surgical resection, whereas median OS was comparable between both arms. CONCLUSIONS Although the analysis was only descriptive owing to small patient numbers, no safety issues regarding surgical complications were observed in the perioperative FOLFIRINOX arm. Thus, considering the small number of patients, perioperative treatment approach appears feasible and potentially effective in well-selected cohorts of patients. In pancreatic cancer, patient selection before initiation of neoadjuvant therapy appears to be critical.
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Affiliation(s)
- Thorsten O Goetze
- Krankenhaus Nordwest, Institut für Klinisch Onkologische Forschchung IKF, University Cancer Center (UCT) Frankfurt, Frankfurt, Germany.
- University Cancer Center (UCT) Frankfurt, Goethe Universität, Frankfurt, Germany.
- Frankfurter Institut für Klinische Krebsforschung IKF am Krankenhaus Nordwest, Frankfurt, Germany.
| | - Alexander Reichart
- Krankenhaus Nordwest, Institut für Klinisch Onkologische Forschchung IKF, University Cancer Center (UCT) Frankfurt, Frankfurt, Germany
| | - Ulli S Bankstahl
- Krankenhaus Nordwest, Institut für Klinisch Onkologische Forschchung IKF, University Cancer Center (UCT) Frankfurt, Frankfurt, Germany
| | - Claudia Pauligk
- Frankfurter Institut für Klinische Krebsforschung IKF am Krankenhaus Nordwest, Frankfurt, Germany
| | - Maria Loose
- Frankfurter Institut für Klinische Krebsforschung IKF am Krankenhaus Nordwest, Frankfurt, Germany
| | - Thomas W Kraus
- Krankenhaus Nordwest, Allgemein-, Viszeral- und Minimal Invasive Chirurgie, Frankfurt, Germany
| | - Moustafa Elshafei
- Krankenhaus Nordwest, Allgemein-, Viszeral- und Minimal Invasive Chirurgie, Frankfurt, Germany
| | - Wolf O Bechstein
- Klinik für Allgemein-, Viszeral-, Transplantations- und Thoraxchirurgie, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Jörg Trojan
- Gastrointestinale Onkologie, Universitätsklinikum Frankfurt, Frankfurt, Germany
| | - Matthias Behrend
- Viszeral-, Thorax- und Gefäßchirurgie, DONAUISAR Klinikum Deggendorf, Deggendorf, Germany
| | - Nils Homann
- Medizinische Klinik II, Klinikum Wolfsburg, Wolfsburg, Germany
| | - Marino Venerito
- Klinik für Gastroenterologie, Hepatologie und Infektiologie, Universitätsklinikum Magdeburg, Magdeburg, Germany
| | - Wolfram Bohle
- Klinik für Gastroenterologie, Gastroenterologische Onkologie, Klinikum Stuttgart, Stuttgart, Germany
- Hepatologie, Infektiologie und Pneumologie, Stuttgart, Germany
| | | | - Claus Bolling
- Hämatologie/Onkologie, Agaplesion Markus Krankenhaus, Frankfurt, Germany
| | - Dirk M Behringer
- Klinik für Hämatologie, Onkologie und Palliativmedizin, Augusta-Kranken-Anstalt Bochum, Bochum, Germany
| | | | - Gabriele M Siegler
- Klinikum Nürnberg Nord/Paracelsus Medizinische Privatuniversität, Medizinische Klinik, Hämatologie/Onkologie, Nürnberg, Germany
| | - Wael Hozaeel
- Krankenhaus Nordwest, Institut für Klinisch Onkologische Forschchung IKF, University Cancer Center (UCT) Frankfurt, Frankfurt, Germany
| | - Salah-Eddin Al-Batran
- Krankenhaus Nordwest, Institut für Klinisch Onkologische Forschchung IKF, University Cancer Center (UCT) Frankfurt, Frankfurt, Germany
- University Cancer Center (UCT) Frankfurt, Goethe Universität, Frankfurt, Germany
- Frankfurter Institut für Klinische Krebsforschung IKF am Krankenhaus Nordwest, Frankfurt, Germany
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Rehman OU, Fatima E, Nadeem ZA, Azeem A, Motwani J, Imran H, Mehboob H, Khan A, Usman O. Efficacy of Cisplatin-Containing Chemotherapy Regimens in Patients of Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-analysis. J Gastrointest Cancer 2024; 55:559-571. [PMID: 38315331 DOI: 10.1007/s12029-024-01025-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/29/2024] [Indexed: 02/07/2024]
Abstract
BACKGROUND The relative success of cisplatin-based chemotherapy regimens for PDAC in clinical trials warrants a review of the literature to assess the cumulative results. This study aims to assess the efficacy of cisplatin-containing regimens for PDAC in terms of survival and response outcomes using a systematic review and proportional meta-analysis. METHODS In this study, an electronic search was conducted on PubMed, Cochrane Library, Scopus, and Google Scholar to find relevant literature. The random effects model was used to assess pooled overall response rate, stable disease rate, progressive disease rate, 1-year overall survival rate, and their 95% CIs. Publication bias was assessed using funnel plot symmetry and the one-tailed Eggers' test. In all cases, p-value < 0.05 was indicative of significant results. The review is registered with PROSPERO: CRD42023459243. RESULTS A total of 34 studies consisting of 1599 patients were included in this review. All the included studies were of good quality. In total, 906 patients were male, and the median age of the patients was 58-69 years. Overall, 599 patients had cancer of the pancreatic head, 139 had cancer of the pancreatic body, and 102 patients had cancer of the pancreatic tail. The pooled risk ratios (RRs) revealed an overall response rate of 19.2% (95% CI, 14.6-24.2%), a stable disease rate of 42.3% (95% CI, 36.6-48.8), a 1-year overall survival rate of 40% (95% CI, 34.3-45.8), and progressive disease rate of 24.7% (95% CI, 18.8-31.2). Commonly reported adverse events were anemia, thrombocytopenia, abdominal adverse events, neutropenia, fatigue, leukopenia, alopecia, anorexia, mucositis, stomatitis, and hepatobiliary adverse events. CONCLUSION Cisplatin-containing regimens have shown moderate efficacy with significant improvement in overall survival at 1 year, stable disease rate, and progressive disease rate; however, only a small percentage of patients achieved an overall response rate.
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Affiliation(s)
- Obaid Ur Rehman
- Department of Medicine, Services Institute of Medical Sciences, Lahore, 54000, Pakistan.
| | - Eeshal Fatima
- Department of Medicine, Services Institute of Medical Sciences, Lahore, 54000, Pakistan
| | - Zain Ali Nadeem
- Department of Medicine, Allama Iqbal Medical College, Lahore, Pakistan
| | - Arish Azeem
- University of Warmia and Mazury, Olszytn, Poland
| | - Jatin Motwani
- Liaquat National Hospital and Medical College, Karachi, Pakistan
| | - Habiba Imran
- Department of Medicine, Services Institute of Medical Sciences, Lahore, 54000, Pakistan
| | - Hadia Mehboob
- Department of Medicine, Services Institute of Medical Sciences, Lahore, 54000, Pakistan
| | - Alishba Khan
- Karachi Institute of Medical Sciences, CMH Malir, Karachi, Pakistan
| | - Omer Usman
- Texas Tech University Health Sciences Center El Paso/Transmountain, El Paso, TX, USA
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Abstract
Pancreatic cancer remains among the malignancies with the worst outcomes. Survival has been improving, but at a slower rate than other cancers. Multimodal treatment, including chemotherapy, surgical resection, and radiotherapy, has been under investigation for many years. Because of the anatomical characteristics of the pancreas, more emphasis on treatment selection has been placed on local extension into major vessels. Recently, the development of more effective treatment regimens has opened up new treatment strategies, but urgent research questions have also become apparent. This review outlines the current management of pancreatic cancer, and the recent advances in its treatment. The review discusses future treatment pathways aimed at integrating novel findings of translational and clinical research.
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Affiliation(s)
- Marco Del Chiaro
- Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Aurora, CO, USA
- University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, CO, USA
| | - Toshitaka Sugawara
- Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine, Aurora, CO, USA
- Department of Hepatobiliary and Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan
| | - Sana D Karam
- University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, CO, USA
- Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO, USA
| | - Wells A Messersmith
- University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, CO, USA
- Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA
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Sugiura T, Toyama H, Fukutomi A, Asakura H, Takeda Y, Yamamoto K, Hirano S, Satoi S, Matsumoto I, Takahashi S, Morinaga S, Yoshida M, Sakuma Y, Iwamoto H, Shimizu Y, Uesaka K. Randomized phase II trial of chemoradiotherapy with S-1 versus combination chemotherapy with gemcitabine and S-1 as neoadjuvant treatment for resectable pancreatic cancer (JASPAC 04). JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2023; 30:1249-1260. [PMID: 37746781 DOI: 10.1002/jhbp.1353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 05/08/2023] [Accepted: 06/02/2023] [Indexed: 09/26/2023]
Abstract
OBJECTIVE The aim of the present study was to investigate which treatment, neoadjuvant chemoradiotherapy (NAC-RT) with S-1 or combination neoadjuvant chemotherapy with gemcitabine and S-1 (NAC-GS), is more promising as neoadjuvant treatment (NAT) for resectable pancreatic cancer in terms of effectiveness and safety. METHODS In the NAC-RT with S-1 group, the patients received a total radiation dose of 50.4 Gy in 28 fractions with oral S-1. In the NAC-GS group, the patients received intravenous gemcitabine at a dose of 1000 mg/m2 with oral S-1 for two cycles. The primary endpoint was the 2-year progression-free survival (PFS) rate. The trial was registered with the UMIN Clinical Trial Registry as UMIN000014894. RESULTS From April 2014 to April 2017, a total of 103 patients were enrolled. After exclusion of one patient because of ineligibility, 51 patients were included in the NAC-RT with S-1 group, and 51 patients were included in the NAC-GS group in the intention-to-treat analysis. The 2-year PFS rate was 45.0% (90% confidence interval [CI]: 33.3%-56.0%) in the NAC-RT with S-1 group and 54.9% (42.8%-65.5%) in the NAC-GS group (p = .350). The 2-year overall survival rate was 66.7% in the NAC-RT with S-1 group and 72.4% in the NAC-GS group (p = .300). Although leukopenia and neutropenia rates were significantly higher in the NAC-GS group than in the NAC-RT with S-1 group (p = .023 and p < .001), other adverse events of NAT and postoperative complications were comparable between the two groups. CONCLUSION Both NAC-RT with S-1 and NAC-GS are considered promising treatments for resectable pancreatic cancer.
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Affiliation(s)
- Teiichi Sugiura
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Hirochika Toyama
- Division of Hepato-Biliary-Pancreatic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Akira Fukutomi
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Hirofumi Asakura
- Radiation and Proton Therapy Center, Shizuoka Cancer Center, Shizuoka, Japan
| | - Yuriko Takeda
- Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan
| | - Kouji Yamamoto
- Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan
| | - Satoshi Hirano
- Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, Sapporo, Japan
| | - Sohei Satoi
- Department of Surgery, Kansai Medical University, Hirakata, Japan
- Division of Surgical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Ippei Matsumoto
- Department of Surgery, Kindai University, Osaka-Sayama, Japan
| | | | - Soichiro Morinaga
- Department of Hepato-Biliary-Pancreatic Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Makoto Yoshida
- Department of Medical Oncology, Sapporo Medical University, Sapporo, Japan
| | - Yasunaru Sakuma
- Department of Surgery, Jichi Medical University, Tochigi-Shimotsuke, Japan
| | - Hidetaka Iwamoto
- Division of Metabolism and Biosystemic Science, Department of Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Yasuhiro Shimizu
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Aichi, Japan
| | - Katsuhiko Uesaka
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
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Yohanathan L, Hallet J. Neoadjuvant Sequencing for Early-stage Pancreas Cancer: More Cycles, More Doses, More Chemo for More Patients? Ann Surg 2023; 278:e685-e687. [PMID: 37436870 DOI: 10.1097/sla.0000000000005987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/14/2023]
Affiliation(s)
- Lavanya Yohanathan
- Department of Surgery, Corewell East William Beaumont University Hospital, Royal Oak, MI
| | - Julie Hallet
- Department of Surgery, University of Toronto, Toronto, ON, Canada
- Division of Surgical Oncology, Odette Cancer Centre-Sunnybrook Health Sciences Centre, Toronto, ON, Canada
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Wu VS, Elshami M, Stitzel HJ, Lee JJ, Hue JJ, Kyasaram RK, Hardacre JM, Ammori JB, Winter JM, Selfridge JE, Mohamed A, Chakrabarti S, Bajor D, Mahipal A, Ocuin LM. Why the Treatment Sequence Matters: Interplay Between Chemotherapy Cycles Received, Cumulative Dose Intensity, and Survival in Resected Early-stage Pancreas Cancer. Ann Surg 2023; 278:e677-e684. [PMID: 37071769 DOI: 10.1097/sla.0000000000005830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/20/2023]
Abstract
OBJECTIVE To define the optimal threshold of perioperative chemotherapy completion and relative dose intensity (RDI) for patients with resected pancreatic ductal adenocarcinoma (PDAC). BACKGROUND Many patients who undergo pancreatectomy for PDAC fail to initiate or complete recommended perioperative chemotherapy. The association between the amount of perioperative chemotherapy received and overall survival (OS) is not well-defined. METHODS Single-institution analysis of 225 patients who underwent pancreatectomy for stage I/II PDAC (2010-2021). Associations between OS, chemotherapy cycles completed, and RDI were analyzed. RESULTS Regardless of treatment sequence, completion of ≥67% of recommended cycles was associated with improved OS compared with no chemotherapy [median OS: 34.5 vs 18.1 months; hazard ratio (HR): 0.43; 95% CI: 0.25-0.74] and <67% of cycles (median OS: 17.9 months; HR: 0.39; 95% CI: 0.24-0.64). A near-linear relationship existed between cycles completed and the RDI received (β = 0.82). A median RDI of 56% corresponded to the completion of 67% of cycles. Receipt of ≥56% RDI was associated with improved OS compared with no chemotherapy (median OS: 35.5 vs 18.1 months; HR: 0.44; 95% CI: 0.23-0.84) and <56% RDI (median OS: 27.2 months; HR: 0.44; 95% CI: 0.20-0.96). Neoadjuvant chemotherapy is associated with increased odds of receiving ≥67% of recommended cycles (odds ratio: 2.94; 95% CI: 1.45-6.26) and ≥56% RDI (odds ratio: 4.47; 95% CI: 1.72-12.50). CONCLUSIONS Patients with PDAC who received ≥67% of recommended chemotherapy cycles or ≥56% cumulative RDI had improved OS. Neoadjuvant therapy was associated with increased odds of receiving ≥67% of cycles and ≥56% cumulative RDI and should be considered in all patients with resectable PDAC.
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Affiliation(s)
- Victoria S Wu
- Case Western Reserve University School of Medicine, Cleveland, OH
| | - Mohamedraed Elshami
- Division of Surgical Oncology, Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, OH
| | - Henry J Stitzel
- Case Western Reserve University School of Medicine, Cleveland, OH
| | - Jonathan J Lee
- Case Western Reserve University School of Medicine, Cleveland, OH
| | - Jonathan J Hue
- Division of Surgical Oncology, Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, OH
| | - Ravi K Kyasaram
- Department of Cancer Informatics, University Hospitals Cleveland Medical Center/Seidman Cancer Center, Cleveland, OH
| | - Jeffrey M Hardacre
- Division of Surgical Oncology, Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, OH
| | - John B Ammori
- Division of Surgical Oncology, Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, OH
| | - Jordan M Winter
- Division of Surgical Oncology, Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, OH
| | - Jennifer Eva Selfridge
- Division of Hematology and Oncology, Department of Medicine, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH
| | - Amr Mohamed
- Division of Hematology and Oncology, Department of Medicine, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH
| | - Sakti Chakrabarti
- Division of Hematology and Oncology, Department of Medicine, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH
| | - David Bajor
- Division of Hematology and Oncology, Department of Medicine, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH
| | - Amit Mahipal
- Division of Hematology and Oncology, Department of Medicine, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH
| | - Lee M Ocuin
- Division of Surgical Oncology, Department of Surgery, University Hospitals Cleveland Medical Center, Cleveland, OH
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9
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Cassese G, Han HS, Yoon YS, Lee JS, Lee B, Cubisino A, Panaro F, Troisi RI. Role of neoadjuvant therapy for nonmetastatic pancreatic cancer: Current evidence and future perspectives. World J Gastrointest Oncol 2023; 15:911-924. [PMID: 37389109 PMCID: PMC10302990 DOI: 10.4251/wjgo.v15.i6.911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/17/2023] [Accepted: 04/24/2023] [Indexed: 06/14/2023] Open
Abstract
Pancreatic adenocarcinoma (PDAC) is one of the most common and lethal human cancers worldwide. Surgery followed by adjuvant chemotherapy offers the best chance of a long-term survival for patients with PDAC, although only approximately 20% of the patients have resectable tumors when diagnosed. Neoadjuvant chemotherapy (NACT) is recommended for borderline resectable pancreatic cancer. Several studies have investigated the role of NACT in treating resectable tumors based on the recent advances in PDAC biology, as NACT provides the potential benefit of selecting patients with favorable tumor biology and controls potential micro-metastases in high-risk patients with resectable PDAC. In such challenging cases, new potential tools, such as ct-DNA and molecular targeted therapy, are emerging as novel therapeutic options that may improve old paradigms. This review aims to summarize the current evidence regarding the role of NACT in treating non-metastatic pancreatic cancer while focusing on future perspectives in light of recent evidence.
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Affiliation(s)
- Gianluca Cassese
- Department of Clinical Medicine and Surgery, Division of Minimally Invasive HPB Surgery and Transplantation Service, Federico II University Hospital, Naples 80131, Italy
| | - Ho-Seong Han
- Department of Surgery, Seoul National University College of Medicine, Seongnam 13620, Gyeonggi-do, South Korea
| | - Yoo-Seok Yoon
- Department of Surgery, Seoul National University College of Medicine, Seongnam 13620, Gyeonggi-do, South Korea
| | - Jun Suh Lee
- Department of Surgery, Seoul National University College of Medicine, Seongnam 13620, Gyeonggi-do, South Korea
| | - Boram Lee
- Department of Surgery, Seoul National University College of Medicine, Seongnam 13620, Gyeonggi-do, South Korea
| | - Antonio Cubisino
- Department of HPB Surgery and Transplantation, Beaujon Hospital, Clichy 92110, France
| | - Fabrizio Panaro
- Department of Digestive Surgery and Liver Transplantation, CHU Montpellier, Montpellier 34100, France
| | - Roberto Ivan Troisi
- Department of Clinical Medicine and Surgery, Division of Minimally Invasive HPB Surgery and Transplantation Service, Federico II University Hospital, Naples 80131, Italy
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10
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Coppola A, Farolfi T, La Vaccara V, Iannone I, Giovinazzo F, Panettieri E, Tarallo M, Cammarata R, Coppola R, Caputo D. Neoadjuvant Treatments for Pancreatic Ductal Adenocarcinoma: Where We Are and Where We Are Going. J Clin Med 2023; 12:3677. [PMID: 37297872 PMCID: PMC10253643 DOI: 10.3390/jcm12113677] [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: 04/07/2023] [Revised: 05/22/2023] [Accepted: 05/24/2023] [Indexed: 06/12/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) represents a challenging disease for the surgeon, oncologist, and radiation oncologist in both diagnostic and therapeutic settings. Surgery is currently the gold standard treatment, but the role of neoadjuvant treatment (NAD) is constantly evolving and gaining importance in resectable PDACs. The aim of this narrative review is to report the state of the art and future perspectives of neoadjuvant therapy in patients with PDAC. METHODS A PubMed database search of articles published up to September 2022 was carried out. RESULTS Many studies showed that FOLFIRINOX or Gemcitabine-nab-paclitaxel in a neoadjuvant setting had a relevant impact on overall survival (OS) for patients with locally advanced and borderline resectable PDAC without increasing post-operative complications. To date, there have not been many published multicentre randomised trials comparing upfront surgery with NAD in resectable PDAC patients, but the results obtained are promising. NAD in resectable PDAC showed long-term effective benefits in terms of median OS (5-year OS rate 20.5% in NAD group vs. 6.5% in upfront surgery). NAD could play a role in the treatment of micro-metastatic disease and lymph nodal involvement. In this scenario, given the low sensitivity and specificity for lymph-node metastases of radiological investigations, CA 19-9 could be an additional tool in the decision-making process. CONCLUSIONS The future challenge could be to identify only selected patients who will really benefit from upfront surgery despite a combination of NAD and surgery.
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Affiliation(s)
- Alessandro Coppola
- Department of Surgey, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy
| | - Tommaso Farolfi
- General Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
- General Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
| | | | - Immacolata Iannone
- Department of Surgey, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy
| | - Francesco Giovinazzo
- General Surgery and Liver Transplant Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, 00168 Rome, Italy
| | - Elena Panettieri
- Hepatobiliary Surgery Unit, Fondazione Policlinico A. Gemelli IRCCS, Università del Sacro Cuore, 00168 Rome, Italy
| | - Mariarita Tarallo
- Department of Surgey, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy
| | - Roberto Cammarata
- General Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Roberto Coppola
- General Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
- General Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
| | - Damiano Caputo
- General Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy
- General Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy
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11
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Shimura M, Mizuma M, Motoi F, Kusaka A, Aoki S, Iseki M, Inoue K, Douchi D, Nakayama S, Miura T, Ishida M, Ohtsuka H, Nakagawa K, Morikawa T, Kamei T, Unno M. Negative prognostic impact of sarcopenia before and after neoadjuvant chemotherapy for pancreatic cancer. Pancreatology 2023; 23:65-72. [PMID: 36473785 DOI: 10.1016/j.pan.2022.11.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 11/12/2022] [Accepted: 11/24/2022] [Indexed: 11/29/2022]
Abstract
OBJECTIVES To elucidate the prognostic impact of sarcopenia before and after neoadjuvant chemotherapy (NAC) for pancreatic cancer (PC). METHODS We retrospectively studied 75 consecutive PC patients who underwent neoadjuvant gemcitabine plus S-1 combination therapy followed by pancreatectomy between 2008 and 2016. According to the skeletal muscle volume index (SMI), the patients were divided into the muscle attenuation group (MAG) and normal group (NG) before or after NAC. Prognostic factors for overall survival (OS) were analyzed by Cox proportional hazards models. RESULTS The MAG showed significantly poorer OS than the NG before and after NAC. Pre-NAC, median OS was 20.0 months in the MAG versus 49.0 months in the NG (p = 0.006). Post-NAC, median OS was 21.3 months in the MAG versus 48.8 months in the NG (p = 0.014). Multivariate analysis, excluding muscle attenuation after NAC because of confounding factors and lower hazard ratio (2.08, 95% confidence interval: 1.14-3.78, p = 0.016) than that before NAC (2.14, 1.23-3.70, p = 0.007) by univariate analysis, revealed the following independent prognostic factors: muscle attenuation pre-NAC (2.25, 1.26-4.05, p = 0.007); borderline resectability (1.96, 1.04-3.69, p = 0.038); operative blood loss (2.60, 1.38-4.88, p = 0.003); and distant metastasis (3.31, 1.40-7.82, p = 0.006). CONCLUSIONS Sarcopenia before and after NAC for PC is suggested to be a poor prognostic factor, with a stronger impact before than after NAC.
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Affiliation(s)
- Mitsuhiro Shimura
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan
| | - Masamichi Mizuma
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan.
| | - Fuyuhiko Motoi
- Department of Gastroenterological, General, Breast and Thyroid Surgery, Yamagata University Graduate School of Medical Science, 2-2-2 Iidanishi, Yamagata, 990-9585, Japan
| | - Akiko Kusaka
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan
| | - Shuichi Aoki
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan
| | - Masahiro Iseki
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan
| | - Koetsu Inoue
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan
| | - Daisuke Douchi
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan
| | - Shun Nakayama
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan
| | - Takayuki Miura
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan
| | - Masaharu Ishida
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan
| | - Hideo Ohtsuka
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan
| | - Kei Nakagawa
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan
| | - Takanori Morikawa
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan
| | - Takashi Kamei
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai, 980-8574, Japan
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12
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James NE, Kalakouti E, Chidambaram S, Gall TMH, Sodergren MH. Patient-Reported Quality of Life After Pancreatic and Liver Surgery. PATIENT REPORTED OUTCOMES AND QUALITY OF LIFE IN SURGERY 2023:121-145. [DOI: 10.1007/978-3-031-27597-5_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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13
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Inflammatory Cytokines and Radiotherapy in Pancreatic Ductal Adenocarcinoma. Biomedicines 2022; 10:biomedicines10123215. [PMID: 36551971 PMCID: PMC9775272 DOI: 10.3390/biomedicines10123215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/06/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a therapeutic challenge in clinical oncology. Surgery is the only potentially curative treatment. However, the majority of PDAC patients present with locally advanced/unresectable or metastatic disease, where palliative multiagent chemotherapy is the first-line treatment with the therapeutic intent to delay progression and prolong survival. For locally advanced/unresectable pancreatic cancer patients who are treated with chemotherapy, consolidative radiotherapy in the form concurrent chemoradiation or stereotactic ablative radiotherapy improves locoregional control and pain/symptom control. To improve clinical outcomes of PDAC patients, there is a dire need for discoveries that will shed more light on the pathophysiology of the disease and lead to the development of more efficacious treatment strategies. Inflammatory cytokines are known to play a role in mediating tumor progression, chemoresistance, and radioresistance in PDAC. A PubMed search on published articles related to radiotherapy, inflammatory cytokines, and pancreatic cancer patients in the English language was performed. This article primarily focuses on reviewing the clinical literature that examines the association of inflammatory cytokines with clinical outcomes and the effects of radiotherapy on inflammatory cytokines in PDAC patients.
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14
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Multiagent Chemotherapy Followed by Stereotactic Body Radiotherapy Versus Conventional Radiotherapy for Resected Pancreas Cancer. Am J Clin Oncol 2022; 45:450-457. [PMID: 36318696 DOI: 10.1097/coc.0000000000000947] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND AND PURPOSE Chemotherapy followed by margin-negative resection (R0) is the treatment of choice for patients with localized pancreatic ductal adenocarcinoma (PDAC). Neoadjuvant multiagent chemotherapy (MAC) or MAC then radiotherapy (RT) may optimize surgical candidacy. The purpose of this study was to compare pathologic outcomes of MAC followed by conventionally fractionated radiotherapy (CRT) versus stereotactic body radiotherapy (SBRT) for patients with resected PDAC. METHODS Patients diagnosed with nonmetastatic PDAC between 2012 and 2017 and who received preoperative MAC or MAC+RT were identified in the National Cancer Database. Variables associated with R0 and overall survival were identified with logistic regression and Cox analysis (P<0.05). RESULTS A total of 5273 patients were identified (MAC: 3900, MAC+CRT: 955, MAC+SBRT: 418). The median RT dose/fraction (fx) in the MAC+CRT and MAC+SBRT cohorts was 50.4 Gy/28 fx and 33 Gy/5 fx. Patients receiving MAC+CRT versus MAC+SBRT had similar rates of ypT3-T4 disease (54% vs. 58%, P=0.187), R0 (87% vs. 84%, P=0.168), and pathologic complete response (pathologic complete response; 6% vs. 4%, P=0.052), however, MAC+CRT was associated with less regional lymphatic disease (ypN+: 28% vs. 41%, P<0.001). The median overall survival of patients receiving MAC+CRT versus MAC+SBRT was 24.6 versus 29.5 months (P=0.045). CONCLUSIONS For patients with resected PDAC, MAC+CRT, and MAC+SBRT had similar rates of R0 and pathologic complete response, although MAC+CRT was associated with lower ypN+. Prospective evaluation of neoadjuvant RT regimens with attention to radiation therapy design is warranted.
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15
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Lu C, Zhu Y, Kong W, Yang J, Zhu L, Wang L, Tang M, Chen J, Li Q, He J, Li A, Qiu X, Gu Q, Chen D, Meng F, Liu B, Qiu Y, Du J. Study protocol for a prospective, open-label, single-arm, phase II study on the combination of tislelizumab, nab-paclitaxel, gemcitabine, and concurrent radiotherapy as the induction therapy for patients with locally advanced and borderline resectable pancreatic cancer. Front Oncol 2022; 12:879661. [PMID: 36059628 PMCID: PMC9434272 DOI: 10.3389/fonc.2022.879661] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Accepted: 08/01/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a fatal malignancy with a low resection rate. Chemotherapy and radiotherapy (RT) are the main treatment approaches for patients with advanced pancreatic cancer, and neoadjuvant chemoradiotherapy is considered a promising strategy to increase the resection rate. Recently, immune checkpoint inhibitor (ICI) therapy has shown remarkable efficacy in several cancers. Therefore, the combination of ICI, chemotherapy, and concurrent radiotherapy is promising for patients with potentially resectable pancreatic cancer, mainly referring to locally advanced (LAPC) and borderline resectable pancreatic cancer (BRPC), to increase the chances of conversion to surgical resectability and prolong survival. This study aims to introduce the design of a clinical trial. METHODS This is an open-label, single-arm, and single-center phase II trial. Patients with pathologically and radiographically confirmed LAPC or BRPC without prior anti-cancer treatment or severe morbidities will be enrolled. All patients will receive induction therapy and will be further evaluated by the Multiple Disciplinary Team (MDT) for the possibility of surgery. The induction therapy consists of up to four cycles of gemcitabine 1,000 mg/m2 and nab-paclitaxel 125 mg/m2 via intravenous (IV) infusion on days 1 and 8, along with tislelizumab (a PD-1 monoclonal antibody) 200 mg administered through IV infusion on day 1 every 3 weeks, concurrently with stereotactic body radiation therapy (SBRT) during the third cycle of treatment. After surgery, patients without progression will receive another two to four cycles of adjuvant therapy with gemcitabine, nab-paclitaxel, and tislelizumab. The primary objectives are objective response rate (ORR) and the R0 resection rate. The secondary objectives are median overall survival (mOS), median progression free survival (mPFS), disease control rate (DCR), pathological grade of tumor tissue after therapy, and adverse reactions. Besides, we expect to explore the value of circulating tumor DNA (ctDNA) in predicting tumor response to induction therapy and survival outcome of patients. DISCUSSION This is a protocol for a clinical trial that attempts to evaluate the safety and efficacy of the combination of anti-PD-1 antibody plus chemotherapy and radiotherapy as the induction therapy for LAPC and BRPC. The results of this phase II study will provide evidence for the clinical practice of this modality. CLINICAL TRIAL REGISTRATION http://www.chictr.org.cn/edit.aspx?pid=53720&htm=4, identifier ChiCTR2000032955.
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Affiliation(s)
- Changchang Lu
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
- Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Yahui Zhu
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Weiwei Kong
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Ju Yang
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Linxi Zhu
- Department of Hepatopancreatobiliary Surgery, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Lei Wang
- Digestive Department of Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Min Tang
- Imaging Department of Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jun Chen
- Pathology Department of Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Qi Li
- Pathology Department of Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Jian He
- Nuclear Medicine Department of Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Aimei Li
- Nuclear Medicine Department of Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Xin Qiu
- Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, China
| | - Qing Gu
- National Institute of Healthcare Data Science at Nanjing University, Nanjing, China
| | - Dongsheng Chen
- The State Key Laboratory of Translational Medicine and Innovative Drug Development, Medical Department, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing, China
| | - Fanyan Meng
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Baorui Liu
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yudong Qiu
- Department of Hepatopancreatobiliary Surgery, Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Juan Du
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
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16
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James NE, Chidambaram S, Gall TM, Sodergren MH. Quality of life after pancreatic surgery - A systematic review. HPB (Oxford) 2022; 24:1223-1237. [PMID: 35304039 DOI: 10.1016/j.hpb.2022.02.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 02/18/2022] [Accepted: 02/23/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Surgery for patients with pancreatic cancer carries a high risk of major post-operative complications and only marginally improves overall survival. This review aims to assess the impact of surgical resection on health-related quality of life (HRQOL) of pancreatic cancer patients. METHODS A systematic review of the literature was performed according to the PRISMA guidelines. All studies assessing QOL using validated questionnaires in pancreatic cancer patients undergoing surgical resection were included. RESULTS Twenty-two studies were assessed. Patients reported a decrease in physical, social and global scales within the first 3 months after surgery. These values showed improvement and were comparable to baseline values by 6 months. Recovery in emotional functioning towards baseline figures was demonstrated in the first 3 months post-operatively. Symptom scales including pain, fatigue and diarrhoea deteriorated after surgery, but reverted to baseline after 3-6 months. CONCLUSIONS Surgical resection for pancreatic cancer has short-term negative impact on QOL. In the longer term, this will improve and eventually recover to baseline values after 6 months. Knowledge on the impact of surgery on QOL of pancreatic cancer patients is necessary to facilitate decision-making and tailoring of surgical techniques to the individual patient.
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Affiliation(s)
- Nicole E James
- Imperial College London, Exhibition Road, South Kensington, London SWC2AZ, UK
| | - Swathikan Chidambaram
- Imperial College London, Exhibition Road, South Kensington, London SWC2AZ, UK; Department of Surgery and Cancer, Hammersmith Hospital Campus, Imperial College, London W12 0HS, UK
| | - Tamara Mh Gall
- Imperial College London, Exhibition Road, South Kensington, London SWC2AZ, UK; Department of Surgery and Cancer, Hammersmith Hospital Campus, Imperial College, London W12 0HS, UK
| | - Mikael H Sodergren
- Imperial College London, Exhibition Road, South Kensington, London SWC2AZ, UK; Department of Surgery and Cancer, Hammersmith Hospital Campus, Imperial College, London W12 0HS, UK.
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17
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Suto H, Okano K, Oshima M, Ando Y, Matsukawa H, Takahashi S, Shibata T, Kamada H, Masaki T, Suzuki Y. Prediction of local tumor control and recurrence-free survival in patients with pancreatic cancer undergoing curative resection after neoadjuvant chemoradiotherapy. J Surg Oncol 2022; 126:292-301. [PMID: 35289928 DOI: 10.1002/jso.26854] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 01/25/2022] [Accepted: 03/05/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND AND OBJECTIVES There is little data on the correlation between the reduction in fluorodeoxyglucose positron emission tomography (FDG-PET) radioactive accumulation and carbohydrate antigen 19-9 (CA19-9) levels with pathological tumor responses (PTRs) and prognosis after neoadjuvant chemoradiotherapy (NACRT) for patients with pancreatic ductal adenocarcinoma (PDAC). METHODS This study was a retrospective analysis of prospectively collected data from 102 patients with resectable (R-) and borderline resectable (BR-) PDAC who received NACRT, followed by curative resection. Data were prospectively collected and compared between the responders and nonresponders to NACRT. RESULTS Patients with 60% or more reduction in maximum standardized uptake value (SUVmax) on FDG-PET, with 75% or more reduction in CA19-9 levels, or with 50%-100% of tumor cells destroyed due to NACRT had significantly better recurrence-free survival (RFS) than each of the nonresponders (p = 0.028, <0.001, and 0.022, respectively). The reduction rates of SUVmax and CA19-9 levels were correlated with PTR. The combined evaluation of these biomarkers reflected RFS. CONCLUSIONS Reduction rates of FDG uptake and CA19-9 levels were preoperative predictors of pathological response to NACRT. These biomarkers of local response had prognostic value in R-PDAC and BR-PDAC. The combined evaluation of these biomarkers allowed for reliable prediction of RFS after surgery.
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Affiliation(s)
- Hironobu Suto
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Keiichi Okano
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Minoru Oshima
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Yasuhisa Ando
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Hiroyuki Matsukawa
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Shigeo Takahashi
- Department of Radiation Oncology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Toru Shibata
- Department of Radiation Oncology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Hideki Kamada
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Yasuyuki Suzuki
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan
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18
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Wang C, Tan G, Zhang J, Fan B, Chen Y, Chen D, Yang L, Chen X, Duan Q, Maimaiti F, Du J, Lin Z, Gu J, Luo H. Neoadjuvant Therapy for Pancreatic Ductal Adenocarcinoma: Where Do We Go? Front Oncol 2022; 12:828223. [PMID: 35785193 PMCID: PMC9245892 DOI: 10.3389/fonc.2022.828223] [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: 12/03/2021] [Accepted: 05/09/2022] [Indexed: 11/15/2022] Open
Abstract
The incidence of pancreatic ductal adenocarcinoma (PDAC) has been on the rise in recent years; however, its clinical diagnosis and treatment remain challenging. Although surgical resection remains the only chance for long-term patient survival, the likelihood of initial resectability is no higher than 20%. Neoadjuvant therapy (NAT) in PDAC aims to transform the proportion of inoperable PDACs into operable cases and reduce the likelihood of recurrence to improve overall survival. Ongoing phase 3 clinical trial aims to validate the role of NAT in PDAC therapy, including prolongation of survival, increased R0 resection, and a higher proportion of negative lymph nodes. Controversies surrounding the role of NAT in PDAC treatment include applicability to different stages of PDAC, chemotherapy regimens, radiation, duration of treatment, and assessment of effect. This review aims to summarize the current progress and controversies of NAT in PDAC.
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Affiliation(s)
- Chenqi Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Guang Tan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jie Zhang
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Bin Fan
- Department of General Surgery, The First Hospital of Northwest University (Xi’an No. 1 Hospital), Xi’an, China
| | - Yunlong Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Dan Chen
- Department of Pathology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Lili Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xiang Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Qingzhu Duan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Feiliyan Maimaiti
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jian Du
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Zhikun Lin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jiangning Gu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- *Correspondence: Haifeng Luo, ; Jiangning Gu,
| | - Haifeng Luo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- *Correspondence: Haifeng Luo, ; Jiangning Gu,
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19
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Ward EP, Zeh Iii HJ, Tsai S. Current Controversies in Neoadjuvant Therapy for Pancreatic Cancer. Surg Oncol Clin N Am 2021; 30:657-671. [PMID: 34511188 DOI: 10.1016/j.soc.2021.06.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Over the last two decades, there have been significant changes in the management of patients with localized pancreatic cancer. The rationale for an evolution toward a neoadjuvant approach and summary of relevant clinical trials is reviewed. Controversies in identifying optimal neoadjuvant therapeutic approaches are discussed.
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Affiliation(s)
- Erin P Ward
- Surgical Oncology Division, Department of Surgery, Medical College of Wisconsin, 8701 W Watertown Plank Road, Milwaukee, WI 53226, USA
| | - Herbert J Zeh Iii
- Division of Surgical Oncology, Department of Surgery, UT Southwestern (University of Texas), 5323 Harry Hines Blvd. Dallas, TX 75390, USA
| | - Susan Tsai
- Surgical Oncology Division, Department of Surgery, Medical College of Wisconsin, 8701 W Watertown Plank Road, Milwaukee, WI 53226, USA.
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20
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Mikulic D, Mrzljak A. Borderline resectable pancreatic cancer and vascular resections in the era of neoadjuvant therapy. World J Clin Cases 2021; 9:5398-5407. [PMID: 34307593 PMCID: PMC8281399 DOI: 10.12998/wjcc.v9.i20.5398] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/01/2021] [Accepted: 05/27/2021] [Indexed: 02/06/2023] Open
Abstract
While pancreatic cancer is still characterized by early systemic spread and poor outcomes, the treatment of this disease has changed significantly in recent years due to major advancements in systemic therapy and advanced surgical techniques. Broader use of effective neoadjuvant approaches combined with aggressive surgical operations within a multidisciplinary setting has improved outcomes. Borderline resectable pancreatic cancer is characterized by tumor vascular invasion, and is a setting where the combination of potent neoadjuvant chemotherapy and aggressive surgical methods, including vascular resections and reconstructions, shows its full potential. Hopefully, this will lead to improved local control and curative treatment in a number of patients with this aggressive malignancy.
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Affiliation(s)
- Danko Mikulic
- Department of Surgery, University Hospital Merkur, Zagreb 10000, Croatia
| | - Anna Mrzljak
- Department of Gastroenterology and Hepatology, University Hospital Center Zagreb, Zagreb 10000, Croatia
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21
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Mori S, Aoki T, Sakuraoka Y, Shimizu T, Yamaguchi T, Park KH, Matsumoto T, Shiraki T, Iso Y, Kubota K. Impact of adverse events of adjuvant and neoadjuvant chemotherapies on outcomes of patients with pancreatic ductal adenocarcinoma. Cancer Chemother Pharmacol 2021; 88:109-120. [PMID: 33825991 DOI: 10.1007/s00280-021-04267-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 03/22/2021] [Indexed: 10/21/2022]
Abstract
PURPOSE Recently, the number of patients with pancreatic ductal adenocarcinoma (PDAC) who have received both neoadjuvant chemotherapy (NAC) and adjuvant chemotherapy (AC) has been increasing. However, whether adverse events (AEs) during AC influence the prognosis of patients with resected PDAC who do or do not receive NAC remains uncertain. METHODS Patients with PDAC who underwent a pancreatectomy between 2011 and 2019 were divided into two groups: an upfront surgery (UFS) group (n = 72), and an NAC group (n = 77). Patients who received AC were then divided into two groups: an AE grade 0/1/2 group (AE-G-0/1/2) and an AE grade 3/4 group (AE-G-3/4). The relationship between AEs and patient outcome and predictors of AE-G-3/4 were investigated. RESULTS AC was used in 54 and 65 patients in the UFS and NAC groups, respectively. In the NAC group, the relative dose intensity (RDI) and AC completion rate as well as the overall survival rate of patients with AE-G-3/4 (n = 15) during AC were significantly worse than those of patients with AE-G-0/1/2 (n = 50). However, similar differences were not observed in the UFS group. A multivariate analysis revealed that AE-G-3/4 during NAC, AC agent (gemcitabine), an albumin level < 3.5 g/dL, and an estimated glomerular filtration rate < 90 mL/min/1.73 m2 before the initiation of AC were independent predictors of AE-G-3/4 during AC. CONCLUSIONS AE-G-3/4 during AC was associated with a lower RDI and AC completion rate and a worse outcome among patients with PDAC who had received NAC.
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Affiliation(s)
- Shozo Mori
- Department of Gastroenterological Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, Japan.
| | - Taku Aoki
- Department of Gastroenterological Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, Japan
| | - Yuhki Sakuraoka
- Department of Gastroenterological Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, Japan
| | - Takayuki Shimizu
- Department of Gastroenterological Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, Japan
| | - Takamune Yamaguchi
- Department of Gastroenterological Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, Japan
| | - Kyung-Hwa Park
- Department of Gastroenterological Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, Japan
| | - Takatsugu Matsumoto
- Department of Gastroenterological Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, Japan
| | - Takayuki Shiraki
- Department of Gastroenterological Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, Japan
| | - Yukihiro Iso
- Department of Gastroenterological Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, Japan
| | - Keiichi Kubota
- Department of Gastroenterological Surgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, Japan
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22
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Taboada AGM, Lominchar PL, Roman LM, García-Alfonso P, Martin AJM, Rodriguez JAB, Pascual JMA. Advances in neoadjuvant therapy for resectable pancreatic cancer over the past two decades. Ann Hepatobiliary Pancreat Surg 2021; 25:179-191. [PMID: 34053920 PMCID: PMC8180394 DOI: 10.14701/ahbps.2021.25.2.179] [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: 12/01/2020] [Accepted: 12/31/2020] [Indexed: 02/06/2023] Open
Abstract
In the last two decades, pancreatic cancer has been undergoing important changes in its perioperative management due to the great interest in multidisciplinary management and preoperative multimodal therapy, which in numerous studies have shown promising clinical results. Although the standard of treatment for resectable pancreatic ductal adenocarcinoma (PDAC) today is surgery followed by adjuvant therapy, as it is a biologically aggressive disease, even with complete resection, it has high rates of local and distant relapse. Several retrospective and prospective phase I/II studies have opened the window for neoadjuvant therapy with chemotherapy (CT), chemoradiotherapy (CRT), or both, as an alternative treatment for resectable pancreatic cancer, with promising results. Neoadjuvant therapy could has some advantages, including early administration of systemic treatment, in vivo assessment of response to treatment, increase resectability rate in borderline patients, increase resection rate with negative margin and survival benefit. While it seems clear that even potentially resectable disease would benefit from preoperative multimodal therapy, the optimal neoadjuvant therapeutic strategy is still controversial and currently there are only recommendations for neoadjuvant treatment, in clinical guidelines such as the NCCN and ESMO, for borderline and/or locally advanced PDAC. This review provides an overview of recent studies available and how they relate to systemic treatment of resectable PDAC in the neoadjuvant setting.
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Affiliation(s)
- Alvaro Gregorio Morales Taboada
- Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañon, Complutense University of Madrid, Madrid, Spain.,Transplant and Hepatobiliopancreatic Surgery Unit, Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Pablo Lozano Lominchar
- Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañon, Complutense University of Madrid, Madrid, Spain
| | - Lorena Martin Roman
- Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañon, Complutense University of Madrid, Madrid, Spain
| | - Pilar García-Alfonso
- Department of Medical Oncology, Department of Oncology, Hospital general Universitario Gregorio Marañon, Complutense University of Madrid, Madrid, Spain
| | - Andres Jesús Muñoz Martin
- Department of Medical Oncology, Department of Oncology, Hospital general Universitario Gregorio Marañon, Complutense University of Madrid, Madrid, Spain
| | - Jose Antonio Blanco Rodriguez
- Department of Radiation Oncology, Department of Oncology, Hospital general Universitario Gregorio Marañon, Complutense University of Madrid, Madrid, Spain
| | - Jose Manuel Asencio Pascual
- Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañon, Complutense University of Madrid, Madrid, Spain.,Transplant and Hepatobiliopancreatic Surgery Unit, Department of General and Digestive Surgery, Hospital General Universitario Gregorio Marañón, Madrid, Spain
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23
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Is Neoadjuvant Treatment Justified in Clinical T1 Pancreatic Ductal Adenocarcinoma? J Clin Med 2021; 10:jcm10040873. [PMID: 33672686 PMCID: PMC7924368 DOI: 10.3390/jcm10040873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 02/09/2021] [Accepted: 02/15/2021] [Indexed: 11/17/2022] Open
Abstract
Introduction: Studies on neoadjuvant treatment have been actively conducted in patients with resectable pancreatic cancer. However, neoadjuvant treatment effectiveness, especially in clinical T1 stage patients, still needs to be determined. We comparatively evaluated the oncologic benefit of preoperative neoadjuvant treatment in clinical T1 stage pancreatic cancer. Methods: Data from two centers were included in the comparative analysis, with overall and recurrence-free survival as primary outcomes, between January 2010 and December 2017. Results: In total, 45 patients were retrospectively reviewed in this study. Two patients in the neoadjuvant group were excluded because of distant metastasis during neoadjuvant treatment. Finally, 43 patients underwent a pancreatectomy for clinical T1 pancreatic cancer, of whom, 35 and 8 patients underwent upfront surgery and neoadjuvant treatment, respectively. Overall survival was similar in the two study groups (5-year overall survival rate: neoadjuvant group, 75%; upfront surgery group, 43.9%, p = 0.066). Conclusions: In our study on patients with clinical T1 stage pancreatic cancer, no significant differences were reported in the oncological outcome in the neoadjuvant therapy group. Large-scale prospective studies are needed to determine the survival benefits of neoadjuvant treatment for early-stage pancreatic cancer.
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24
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Factors Predicting Response, Perioperative Outcomes, and Survival Following Total Neoadjuvant Therapy for Borderline/Locally Advanced Pancreatic Cancer. Ann Surg 2021; 273:341-349. [PMID: 30946090 DOI: 10.1097/sla.0000000000003284] [Citation(s) in RCA: 276] [Impact Index Per Article: 69.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE To identify predictive factors associated with operative morbidity, mortality, and survival outcomes in patients with borderline resectable (BR) or locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) undergoing total neoadjuvant therapy (TNT). BACKGROUND The optimal preoperative treatment sequencing for BR/LA PDA is unknown. TNT, or systemic chemotherapy followed by chemoradiation (CRT), addresses both occult metastases and positive margin risks and thus is a potentially optimal strategy; however, factors predictive of perioperative and survival outcomes are currently undefined. METHODS We reviewed our experience in BR/LA patients undergoing resection from 2010 to 2017 following TNT assessing operative morbidity, mortality, and survival in order to define outcome predictors and response endpoints. RESULTS One hundred ninety-four patients underwent resection after TNT, including 123 (63%) BR and 71 (37%) LA PDAC. FOLFIRINOX or gemcitabine along with nab-paclitaxel were used in 165 (85%) and 65 (34%) patients, with 36 (19%) requiring chemotherapeutic switch before long-course CRT and subsequent resection. Radiologic anatomical downstaging was uncommon (28%). En bloc venous and/or arterial resection was required in 125 (65%) patients with 94% of patients achieving R0 margins. The 90-day major morbidity and mortality was 36% and 6.7%, respectively. Excluding operative mortalities, the median, 1-year, 2-year, and 3-year recurrence-free survival (RFS) [overall survival (OS)] rates were 23.5 (58.8) months, 65 (96)%, 48 (78)%, and 32 (62)%, respectively. Radiologic downstaging, vascular resection, and chemotherapy regimen/switch were not associated with survival. Only 3 factors independently associated with prolonged survival, including extended duration (≥6 cycles) chemotherapy, optimal post-chemotherapy CA19-9 response, and major pathologic response. Patients achieving all 3 factors had superior survival outcomes with a survival detriment for each failing factor. In a subset of patients with interval metabolic (PET) imaging after initial chemotherapy, complete metabolic response highly correlated with major pathologic response. CONCLUSION Our TNT experience in resected BR/LA PDAC revealed high negative margin rates despite low radiologic downstaging. Extended duration chemotherapy with associated biochemical and pathologic responses highly predicted postoperative survival. Potential modifications of initial chemotherapy treatment include extending cycle duration to normalize CA19-9 or achieve complete metabolic response, or consideration of chemotherapeutic switch in order to achieve these factors may improve survival before moving forward with CRT and subsequent resection.
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25
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Olecki EJ, Stahl KA, Torres MB, Peng JS, Dixon M, Shen C, Gusani NJ. Adjuvant Chemotherapy After Neoadjuvant Chemotherapy for Pancreatic Cancer is Associated with Improved Survival for Patients with Low-Risk Pathology. Ann Surg Oncol 2021; 28:3111-3122. [PMID: 33521899 DOI: 10.1245/s10434-020-09546-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 12/14/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND With limited evidence, the benefit of adjuvant chemotherapy (AT) after completion of neoadjuvant chemotherapy (NT) and surgical resection for patients with pancreatic adenocarcinoma is debated. Guidelines recommend 6 months of AT for patients receiving NT. However, the patient-derived benefit from additional AT remains unknown. METHODS The National Cancer Database from 2006 to 2015 was used to identify patients undergoing NT. The chi-square test and multivariable logistic regression were used to identify differences between those receiving only NT and those receiving NT and AT. Survival analysis using the Kaplan-Meier method and the Cox proportional hazard ratio model was applied to the entire cohort and to subgroups with differing lymph node ratios (LNRs), tumor sizes, grades, and surgical margin statuses. RESULTS Of the 3897 patients who received NT, 36.7 % received additional AT. Analysis of the entire cohort showed that associated survival was significantly improved with NT and AT compared with NT alone (hazard ratio [HR], 0.83; p < 0.001). In the subgroup analysis, the survival benefit of additional AT remained significant for those with negative nodal disease, an LNR lower than 0.15, low-grade histology, and negative margin status. Overall survival did not differ between those receiving NT only and those receiving NT and AT in the group with an LNR of 0.15 or higher, high-grade histology, and positive margins. CONCLUSION This study identified an increasing trend in the use of AT after NT and showed an associated survival benefit for subgroups with low-risk pathologic features. These results suggest that the addition of AT after NT likely beneficial for these subgroups.
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Affiliation(s)
- Elizabeth J Olecki
- Department of Surgery, College of Medicine, The Pennsylvania State University, Hershey, PA, USA
| | - Kelly A Stahl
- Department of Surgery, College of Medicine, The Pennsylvania State University, Hershey, PA, USA
| | - Madeline B Torres
- Department of Surgery, College of Medicine, The Pennsylvania State University, Hershey, PA, USA
| | - June S Peng
- Program for Liver, Pancreas, and Foregut Tumors, Department of Surgery, College of Medicine, The Pennsylvania State University, Hershey, PA, USA
| | - Matthew Dixon
- Program for Liver, Pancreas, and Foregut Tumors, Department of Surgery, College of Medicine, The Pennsylvania State University, Hershey, PA, USA
| | - Chan Shen
- Department of Surgery, College of Medicine, The Pennsylvania State University, Hershey, PA, USA.,Department of Public Health Sciences, College of Medicine, The Pennsylvania State University, Hershey, PA, USA
| | - Niraj J Gusani
- Section of Surgical Oncology, Baptist MD Anderson Cancer Center, 1301 Palm Avenue, Jacksonville, FL, 32207, USA.
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26
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Miccio JA, Talcott WJ, Patel T, Park HS, Cecchini M, Salem RR, Khan SA, Stein S, Kortmansky JS, Lacy J, Narang A, Herman J, Jabbour SK, Hallemeier CL, Johung K, Jethwa KR. Margin negative resection and pathologic downstaging with multiagent chemotherapy with or without radiotherapy in patients with localized pancreas cancer: A national cancer database analysis. Clin Transl Radiat Oncol 2020; 27:15-23. [PMID: 33392398 PMCID: PMC7772693 DOI: 10.1016/j.ctro.2020.12.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 12/11/2020] [Accepted: 12/12/2020] [Indexed: 01/02/2023] Open
Abstract
Purpose Margin-negative (R0) resection is the only potentially curative treatment for patients with pancreatic ductal adenocarcinoma (PDAC). Pre-operative multi-agent chemotherapy alone (MAC) or MAC followed by pre-operative radiotherapy (MAC + RT) may be used to improve resectability and potentially survival. However, the optimal pre-operative regimen is unknown. Methods Patients with non-metastatic PDAC from 2006 to 2016 who received pre-operative MAC or MAC + RT before oncologic resection were identified in the National Cancer Database. Univariable and multivariable (MVA) associates with R0 resection were identified with logistic regression, and survival was analyzed secondarily with the Kaplan Meier method and Cox regression analysis. Results 4,599 patients were identified (MAC: 3,109, MAC + RT: 1,490). Compared to those receiving MAC, patients receiving MAC + RT were more likely to have cT3-4 disease (76% vs 64%, p < 0.001) and cN + disease (33% vs 29%, p = 0.010), but were less likely to have ypT3-4 disease (59% vs 74%, p < 0.001) and ypN + disease (32% vs 55%, p < 0.001) and more likely to have a pathologic complete response (5% vs 2%, p < 0.001) and R0 resection (86% vs 80%, p < 0.001). On MVA, MAC + RT (OR 1.58, 95% CI 1.33-1.89, p < 0.001), evaluation at an academic center (OR 1.33, 95% CI 1.14-1.56, p < 0.001), and female sex (OR 1.43, 95% CI 1.23-1.67, p < 0.001) were associated with higher odds of R0 resection, while cT3-4 disease (OR 0.81, 95% CI 0.68-0.96, p = 0.013) was associated with lower odds of R0 resection. Conclusion For patients with localized PDAC who receive pre-operative MAC, the addition of pre-operative RT was associated with improved rates of R0 resection and pathologic response.
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Key Words
- AJCC, American Joint Committee on Cancer
- Chemotherapy
- IQR, interquartile range
- LR, logistic regression
- LVI, lymphovascular invasion
- MAC, multiagent chemotherapy
- MVA, multivariable analysis
- NCDB, National Cancer Database
- Neoadjuvant therapy
- OS, overall survival
- PDAC, pancreatic ductal adenocarcinoma
- Pancreatic cancer
- R0, margin negative
- RT, radiotherapy
- Radiotherapy
- Surgery
- UVA, univariable analysis
- pCR, pathologic complete response
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Affiliation(s)
- Joseph A Miccio
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Wesley J Talcott
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Timil Patel
- Department of Medical Oncology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Henry S Park
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Michael Cecchini
- Department of Medical Oncology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Ronald R Salem
- Department of Surgery, Yale School of Medicine, New Haven, CT 06520, USA
| | - Sajid A Khan
- Department of Surgery, Yale School of Medicine, New Haven, CT 06520, USA
| | - Stacey Stein
- Department of Medical Oncology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Jeremy S Kortmansky
- Department of Medical Oncology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Jill Lacy
- Department of Medical Oncology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Amol Narang
- Department of Radiation Oncology & Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Joseph Herman
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA
| | - Salma K Jabbour
- Department of Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
| | | | - Kimberly Johung
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA
| | - Krishan R Jethwa
- Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT 06520, USA
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27
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Jaworski JJ, Morgan RD, Sivakumar S. Circulating Cell-Free Tumour DNA for Early Detection of Pancreatic Cancer. Cancers (Basel) 2020; 12:E3704. [PMID: 33317202 PMCID: PMC7763954 DOI: 10.3390/cancers12123704] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 12/04/2020] [Indexed: 01/11/2023] Open
Abstract
Pancreatic cancer is a lethal disease, with mortality rates negatively associated with the stage at which the disease is detected. Early detection is therefore critical to improving survival outcomes. A recent focus of research for early detection is the use of circulating cell-free tumour DNA (ctDNA). The detection of ctDNA offers potential as a relatively non-invasive method of diagnosing pancreatic cancer by using genetic sequencing technology to detect tumour-specific mutational signatures in blood samples before symptoms manifest. These technologies are limited by a number of factors that lower sensitivity and specificity, including low levels of detectable ctDNA in early stage disease and contamination with non-cancer circulating cell-free DNA. However, genetic and epigenetic analysis of ctDNA in combination with other standard diagnostic tests may improve early detection rates. In this review, we evaluate the genetic and epigenetic methods under investigation in diagnosing pancreatic cancer and provide a perspective for future developments.
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Affiliation(s)
- Jedrzej J. Jaworski
- MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK;
| | - Robert D. Morgan
- Department of Medical Oncology, Christie NHS Foundation Trust, Manchester M20 4BX, UK;
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9PL, UK
| | - Shivan Sivakumar
- Department of Oncology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK
- Department of Medical Oncology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, UK
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28
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Patient experience and quality of life during neoadjuvant therapy for pancreatic cancer: a systematic review and study protocol. Support Care Cancer 2020; 29:3009-3016. [PMID: 33030596 DOI: 10.1007/s00520-020-05813-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 10/02/2020] [Indexed: 12/15/2022]
Abstract
PURPOSE Neoadjuvant therapy (NT) is increasingly being offered to patients with pancreatic ductal adenocarcinoma (PDAC) prior to surgical resection. However, the experience and quality of life (QOL) of patients undergoing NT are poorly understood. METHODS A systematic review of the Cinahl, Embase, Medline, Pubmed, Scopus, and Web of Science databases was conducted to evaluate the available literature pertaining to the experience and QOL of patient's undergoing NT for PDAC. RESULTS Among 6041 articles screened, only six met criteria for full-text review including three prospective clinical trials of NT with QOL secondary endpoints. Overall, global QOL during or following NT did not significantly change from baseline. Pain scores seemed to improve during NT while the impact of NT on physical functioning varied across studies. No studies were identified evaluating other aspects of the patient experience. CONCLUSION Although NT appears to have a minor impact on the QOL of patients with PDAC, this systematic review identified significant evidence gaps in the literature. A protocol of a prospective observational cohort study utilizing a digital smartphone app that aims to evaluate the patient experience and longitudinal QOL of patients with PDAC undergoing NT is presented.
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29
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Le VH, O'Connor VV, Li D, Melstrom LG, Fong Y, DiFronzo AL. Outcomes of neoadjuvant therapy for cholangiocarcinoma: A review of existing evidence assessing treatment response and R0 resection rate. J Surg Oncol 2020; 123:164-171. [PMID: 32974932 DOI: 10.1002/jso.26230] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 09/03/2020] [Accepted: 09/05/2020] [Indexed: 12/15/2022]
Abstract
Adjuvant chemotherapy for cholangiocarcinoma (CCA) has not been shown to gain significant improvements in survival. Factors contributing to suboptimal treatment response include aggressive disease biology and late clinical presentation. When feasible, surgical resection is the first line of treatment. Yet, recurrence remains high and long-term survival is rare. Neoadjuvant therapy is an appealing approach, with oncologic advantages in allowing the treatment of occult systemic disease and selection of patients most likely to benefit from radical surgery. However, given the surgery-first treatment paradigm for CCA, there is a paucity of data supporting neoadjuvant therapy. This review summarizes the current evidence on treatment response and margin-negative (R0) resection rate associated with neoadjuvant therapy for CCA.
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Affiliation(s)
- Viet H Le
- Department of Surgery, City of Hope National Medical Center, Duarte, California, USA
| | - Victoria V O'Connor
- Department of Surgery, Kaiser Permanente - Los Angeles Medical Center, Los Angeles, California, USA
| | - Daneng Li
- Department of Medical Oncology and Therapeutic Research, City of Hope National Medical Center, Duarte, California, USA
| | - Laleh G Melstrom
- Department of Surgery, City of Hope National Medical Center, Duarte, California, USA
| | - Yuman Fong
- Department of Surgery, City of Hope National Medical Center, Duarte, California, USA
| | - Andrew L DiFronzo
- Department of Surgery, Kaiser Permanente - Los Angeles Medical Center, Los Angeles, California, USA
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30
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Müller PC, Frey MC, Ruzza CM, Nickel F, Jost C, Gwerder C, Hackert T, Z'graggen K, Kessler U. Neoadjuvant Chemotherapy in Pancreatic Cancer: An Appraisal of the Current High-Level Evidence. Pharmacology 2020; 106:143-153. [PMID: 32966993 DOI: 10.1159/000510343] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 07/20/2020] [Indexed: 01/11/2023]
Abstract
At the time of diagnosis, only about 20% of patients with pancreatic ductal adenocarcinoma (PDAC) have resectable disease. PDAC treatment necessitates a multidisciplinary approach, and adjuvant chemotherapy after upfront resection is an established means of preventing recurrence. Neoadjuvant chemotherapy (NAT), originally introduced to downstage tumor size, is nowadays more frequently used for selection of patients with favorable tumor biology and to control potential micrometastases. While NAT is routinely applied in locally advanced (LA) PDAC, there is increasing evidence demonstrating benefits of NAT in borderline resectable (BR) PDAC. The concept of NAT has recently been tested in resectable PDAC, but to date NAT has been restricted to clinical trials, as the data are limited and no clear benefits have yet been shown in this patient group. This review summarizes the current evidence for NAT in resectable, BR, and LA PDAC, with a focus on high-level evidence and randomized controlled trials.
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Affiliation(s)
- Philip C Müller
- Department of Surgery, Hirslanden Klinik Beau-Site, Bern, Switzerland.,Swiss Pancreas Center, Hirslanden Klinik Beau-Site, Bern, Switzerland
| | - Michael C Frey
- Swiss Pancreas Center, Hirslanden Klinik Beau-Site, Bern, Switzerland.,Department of Pediatric Surgery, University Hospital Bern, University of Bern, Bern, Switzerland
| | - Claudio M Ruzza
- Department of Surgery, Hirslanden Klinik Beau-Site, Bern, Switzerland.,Swiss Pancreas Center, Hirslanden Klinik Beau-Site, Bern, Switzerland
| | - Felix Nickel
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Christian Jost
- Swiss Pancreas Center, Hirslanden Klinik Beau-Site, Bern, Switzerland.,Department of Gastroenterology, Hirslanden Klinik Beau-Site, Bern, Switzerland
| | - Christoph Gwerder
- Swiss Pancreas Center, Hirslanden Klinik Beau-Site, Bern, Switzerland.,Department of Oncology, Hirslanden Klinik Beau-Site, Bern, Switzerland
| | - Thilo Hackert
- Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Kaspar Z'graggen
- Department of Surgery, Hirslanden Klinik Beau-Site, Bern, Switzerland, .,Swiss Pancreas Center, Hirslanden Klinik Beau-Site, Bern, Switzerland,
| | - Ulf Kessler
- Department of Surgery, Hirslanden Klinik Beau-Site, Bern, Switzerland.,Swiss Pancreas Center, Hirslanden Klinik Beau-Site, Bern, Switzerland.,Department of Pediatric Surgery, University Hospital Bern, University of Bern, Bern, Switzerland
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31
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Giovinazzo F, Soggiu F, Jang JY, Versteijne E, van Tienhoven G, van Eijck CH, Han Y, Choi SH, Kang CM, Zalupski M, Ahmad H, Yentz S, Helton S, Rose JB, Takishita C, Nagakawa Y, Abu Hilal M. Gemcitabine-Based Neoadjuvant Treatment in Borderline Resectable Pancreatic Ductal Adenocarcinoma: A Meta-Analysis of Individual Patient Data. Front Oncol 2020; 10:1112. [PMID: 32850319 PMCID: PMC7431761 DOI: 10.3389/fonc.2020.01112] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 06/03/2020] [Indexed: 12/20/2022] Open
Abstract
Background: Non-randomized studies have investigated multi-agent gemcitabine-based neo-adjuvant therapies (GEM-NAT) in borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC). Treatment sequencing and specific elements of neoadjuvant treatment are still under investigation. The present meta-analysis aims to assess the effectiveness of GEM-NAT on overall survival (OS) in BR-PDAC. Patients and Methods: A meta-analysis of individual participant data (IPD) on GEM-NAT for BR-PDAC were performed. The primary outcome was OS after treatment with GEM-based chemotherapy. In the Individual Patient Data analysis data were reappraised and confirmed as BR-PDAC on provided radiological data. Results: Six studies investigating GEM-NAT were included in the IPD metanalysis. The IPD metanalysis was conducted on 271 patients who received GEM-NAT. Pooled median patient-level OS was 22.2 months (95%CI 19.1–25.2). R0 rates ranged between 81 and 95% (I2 = 0%, p = 0.64), respectively. Median OS was 27.8 months (95%CI 23.9–31.6) in the patients who received NAT-GEM followed by resection compared to 15.4 months (95%CI 12.3–18.4) for NAT-GEM without resection and 13.0 months (95%CI 7.4–18.5) in the group of patients who received upfront surgery (p < 0.0001). R0 rates ranged between 81 and 95% (I2 = 0%, p = 0.64), respectively. Overall survival in the R0 group was 29.3 months (95% CI 24.3–34.2) vs. 16.2 months (95% CI 7·9–24.5) in the R1 group (p = 0·001). Conclusions: The present study is the first meta-analysis combining IPD from a number of international centers with BR-PDAC in a cohort that underwent multi-agent gemcitabine neoadjuvant therapy (GEM-NAT) before surgery. GEM-NAT followed by surgical resection improve survival and R0 resection in BR-PDAC. Also, GEM-NAT may result in a good palliative option in non-resected patients because of progressive disease after neoadjuvant treatment. Results from randomized controlled trials (RCTs) are awaited to validate these findings.
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Affiliation(s)
- Francesco Giovinazzo
- Department of Surgery, University Hospital of Southampton NHS Foundation Trust, Southampton, United Kingdom
| | - Fiammetta Soggiu
- Hepato-Pancreato-Biliary and Liver Transplant Unit, Royal Free Hospital, London, United Kingdom
| | - Jin-Young Jang
- Department of Surgery, Seoul National University Hospital, Seoul, South Korea
| | - Eva Versteijne
- Department of Radiation Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Geertjan van Tienhoven
- Department of Radiation Oncology, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Casper H van Eijck
- Department of Surgery, Erasmus MC Cancer Institute, Rotterdam, Netherlands
| | - Youngmin Han
- Department of Surgery, Seoul National University Hospital, Seoul, South Korea
| | - Seong Ho Choi
- Department of Surgery, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Chang Moo Kang
- Division of HBP Surgery, Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Mark Zalupski
- Department of Medicine, University of Michigan, Ann Arbor, MI, United States
| | - Hasham Ahmad
- Department of Surgery, University Hospital of Leicester NHS Trust, Leicester, United Kingdom
| | - Sarah Yentz
- Department of Medicine, University of Michigan, Ann Arbor, MI, United States
| | - Scott Helton
- Section of General, Thoracic and Vascular Surgery, Department of Surgery, Virginia Mason Medical Center, Seattle, WA, United States
| | - J Bart Rose
- Section of Surgical Oncology, University of Alabama, Birmingham, AL, United States
| | - Chie Takishita
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Yuichi Nagakawa
- Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan
| | - Mohammad Abu Hilal
- Department of Surgery, University Hospital of Southampton NHS Foundation Trust, Southampton, United Kingdom.,Depatment of Surgery, Fondazione Poliambulanza Istituto Ospedaliero Multispecialistico, Brescia, Italy
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32
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Motoi F, Unno M. Adjuvant and neoadjuvant treatment for pancreatic adenocarcinoma. Jpn J Clin Oncol 2020; 50:483-489. [PMID: 32083290 DOI: 10.1093/jjco/hyaa018] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 01/21/2020] [Accepted: 01/28/2020] [Indexed: 02/06/2023] Open
Abstract
The prognosis of pancreatic adenocarcinoma is dismal. Hence, advances in multidisciplinary treatment strategies, including surgery, are urgently needed. Early recurrence of distant organ metastases suggests that there are occult metastases even in cases with resectable disease. Several randomized controlled trials on adjuvant chemotherapy have been conducted to prolong survival after resection. CONKO-001 study was the first to demonstrate significant improvement in disease-free survival after surgery with gemcitabine administration. The JASPAC-01 study showed the superiority of adjuvant S1 over gemcitabine in survival after resection. Based on the results, adjuvant S1 therapy is the prescribed standard of care in Japan. Recently, the PRODIGE 24/CCTG PA.6 study showed that survival of patients treated with a modified FOLFIRINOX regimen as adjuvant therapy was significantly longer than those treated with adjuvant gemcitabine therapy. Although the evidence from these trials on adjuvant chemotherapy have been the gold-standard treatment for curatively resected and fully recovered patients, resectable disease at diagnosis is not the status, resected disease after curative resection. Currently, neoadjuvant therapy is considered to be a promising alternative to surgery for pancreatic cancer. Although there are many reports regarding neoadjuvant chemoradiotherapy, so far there has been no solid evidence proving the advantage of this strategy versus standard up-front surgery. Newly obtained results from the Prep-02/JSAP05 randomized phase II/III study, comparing neoadjuvant therapy with up-front surgery, revealed significant improvement in overall survival with neoadjuvant chemotherapy by intention-to-treat analysis. Thus, neoadjuvant intervention might become a new standard strategy in cases undergoing planned resection for pancreatic cancer.
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Affiliation(s)
- Fuyuhiko Motoi
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Michiaki Unno
- Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
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33
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Pathanki AM, Attard JA, Bradley E, Powell-Brett S, Dasari BVM, Isaac JR, Roberts KJ, Chatzizacharias NA. Pancreatic exocrine insufficiency after pancreaticoduodenectomy: Current evidence and management. World J Gastrointest Pathophysiol 2020; 11:20-31. [PMID: 32318312 PMCID: PMC7156847 DOI: 10.4291/wjgp.v11.i2.20] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2019] [Revised: 03/13/2020] [Accepted: 03/22/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreaticoduodenectomy (PD) is the commonest procedure performed for pancreatic cancer. Pancreatic exocrine insufficiency (PEI) may be caused or exacerbated by surgery and remains underdiagnosed and undertreated. The aim of this review was to ascertain the incidence of PEI, its consequences and management in the setting of PD for indications other than chronic pancreatitis. A literature search of databases (MEDLINE, EMBASE, Cochrane and Scopus) was carried out with the MeSH terms "pancreatic exocrine insufficiency" and "Pancreaticoduodenectomy". Studies that analysed PEI and its complications in the setting of PD for malignant and benign disease were included. Studies reporting PEI in the setting of PD for chronic pancreatitis, conference abstracts and reviews were excluded. The incidence of PEI approached 100% following PD in some series. The pre-operative incidence varied depending on the characteristics of the patient cohort and it was higher (46%-93%) in series where pancreatic cancer was the predominant indication for surgery. Variability was also recorded with regards to the method used for the diagnosis and evaluation of pancreatic function and malabsorption. Pancreatic enzyme replacement therapy is the mainstay of the management. PEI is common and remains undertreated after PD. Future studies are required for the identification of a well-tolerated, reliable and reproducible diagnostic test in this setting.
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Affiliation(s)
- Adithya M Pathanki
- Department of HPB and Liver Transplantation, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2TH, United Kingdom
| | - Joseph A Attard
- Department of HPB and Liver Transplantation, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2TH, United Kingdom
| | - Elizabeth Bradley
- Department of Nutrition and Dietetics, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2TH, United Kingdom
| | - Sarah Powell-Brett
- Department of HPB and Liver Transplantation, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2TH, United Kingdom
| | - Bobby V M Dasari
- Department of HPB and Liver Transplantation, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2TH, United Kingdom
| | - John R Isaac
- Department of HPB and Liver Transplantation, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2TH, United Kingdom
| | - Keith J Roberts
- Department of HPB and Liver Transplantation, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2TH, United Kingdom
| | - Nikolaos A Chatzizacharias
- Department of HPB and Liver Transplantation, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2TH, United Kingdom
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34
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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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35
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A contemporary evidence basis for neoadjuvant chemotherapy in upfront resectable pancreatic adenocarcinoma: a systematic review of the literature. JOURNAL OF PANCREATOLOGY 2020. [DOI: 10.1097/jp9.0000000000000037] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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36
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Kim KH, Hwang HK, Kang IC, Lee WJ, Kang CM. Oncologic impact of preoperative prognostic nutritional index change in resected pancreatic cancer following neoadjuvant chemotherapy. Pancreatology 2020; 20:247-253. [PMID: 31889624 DOI: 10.1016/j.pan.2019.12.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 10/26/2019] [Accepted: 12/11/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Although several studies have focused on the oncologic impact of the preoperative prognostic nutritional index (PNI), there is no study correlating the preoperative PNI changes with the oncologic outcome of resected pancreatic cancer following neoadjuvant chemotherapy (NAC). METHODS We retrospectively analyzed 107 pancreatic ductal adenocarcinoma patients who underwent NAC followed by surgical resection. ΔPNI was defined as post-NAC PNI subtracted from pre-NAC PNI. Patients were divided into high (≥-1.94, n = 54) and low ΔPNI groups (<-1.94, n = 53). Long-term oncologic outcomes, such as overall survival (OS) and disease-free survival (DFS), were compared. Univariate and multivariate analysis were used to identify independent prognostic factors. RESULTS The high ΔPNI group correlated with lower pre-NAC PNI (46.96 ± 4.68 vs. 51.77 ± 5.63, p < 0.001) and higher post-NAC PNI (50.05 ± 4.80 vs. 42.56 ± 7.44, p < 0.001) more than the low ΔPNI group. The high ΔPNI group was also associated with longer OS compared with the low ΔPNI group (mean OS: 63.97 months [95% CI: 49.95-77.99] vs. 41.16 months [95% CI: 27.66-54.66], p = 0.003); there was no significant difference in DFS (p > 0.05). Multivariate analysis revealed that low ΔPNI was an independent risk factor for OS (HR, 3.516; 95% CI, 1.885-6.558; p < 0.001), but not for DFS (p > 0.05). CONCLUSIONS Low ΔPNI (<-1.94) was an independent risk factor for the overall survival of resected pancreatic cancer patients following NAC. In the preoperative setting, improving the PNI can better the long-term oncologic outcome of this condition.
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Affiliation(s)
| | - Ho Kyoung Hwang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, South Korea; Pancreatobiliary Cancer Clinic, Yonsei Cancer Center, Severance Hospital, Seoul, South Korea
| | - In Cheon Kang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, South Korea; Pancreatobiliary Cancer Clinic, Yonsei Cancer Center, Severance Hospital, Seoul, South Korea
| | - Woo Jung Lee
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, South Korea; Pancreatobiliary Cancer Clinic, Yonsei Cancer Center, Severance Hospital, Seoul, South Korea
| | - Chang Moo Kang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Yonsei University College of Medicine, South Korea; Pancreatobiliary Cancer Clinic, Yonsei Cancer Center, Severance Hospital, Seoul, South Korea.
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37
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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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38
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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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39
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Barbour AP, Samra JS, Haghighi KS, Donoghoe MW, Burge M, Harris MT, Chua YJ, Mitchell J, O'Rourke N, Chan H, Gebski VJ, Gananadha S, Croagh DG, Kench JG, Goldstein D. The AGITG GAP Study: A Phase II Study of Perioperative Gemcitabine and Nab-Paclitaxel for Resectable Pancreas Cancer. Ann Surg Oncol 2020; 27:2506-2515. [PMID: 31997125 DOI: 10.1245/s10434-020-08205-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND While combination therapy with nab-paclitaxel/gemcitabine (nab-gem) is effective in pancreatic ductal adenocarcinoma (PDAC), its efficacy as perioperative chemotherapy is unknown. The primary objective of this multicenter, prospective, single-arm, phase II study was to determine whether neoadjuvant therapy with nab-gem was associated with higher complete resection rates (R0) in resectable PDAC, while the secondary objectives were to determine the utility of radiological assessment of response to preoperative chemotherapy and the safety and efficacy of nab-gem as perioperative therapy. METHODS Patients were recruited from eight Australian sites, and 42 patients with radiologically defined resectable PDAC and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled. Participants received two cycles of preoperative nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 on days 1, 8, and 15 (28-day cycle) presurgery, and four cycles postoperatively. Early response to chemotherapy was measured with fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scans on day 15. RESULTS Preoperative nab-gem was completed by 93% of participants, but only 63% postoperatively. Thirty-six patients had surgery: 6 (17%) were unresectable, 15 (52%) had R0 (≥ 1 mm) resections, 14 (48%) had R1 (< 1 mm) resections, and 1 patient did not have PDAC. Median progression-free survival was 12.3 months and median overall survival (OS) was 23.5 months: R0 patients had an OS of 35 months versus 25.6 months for R1 patients after surgery. Seven patients had not progressed after 43 months. CONCLUSIONS The GAP trial demonstrated that perioperative nab-gem was tolerable. Although the primary endpoint of an 85% R0 rate was not met, the R0 rate was similar to trials using a > 1 mm R0 resection definition, and survival rates were comparable with recent adjuvant studies.
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Affiliation(s)
- Andrew P Barbour
- Princess Alexandra Hospital, Brisbane, QLD, Australia. .,The University of Queensland, Brisbane, QLD, Australia.
| | | | | | - Mark W Donoghoe
- National Health and Medical Research Council Clinical Trials Centre, Sydney, NSW, Australia.,Stats Central, University of NSW, Sydney, NSW, Australia
| | - Matthew Burge
- The University of Queensland, Brisbane, QLD, Australia.,Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
| | | | - Yu Jo Chua
- The Canberra Hospital, Woden, ACT, Australia
| | - Jenna Mitchell
- National Health and Medical Research Council Clinical Trials Centre, Sydney, NSW, Australia
| | - Nick O'Rourke
- Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
| | | | - Val J Gebski
- National Health and Medical Research Council Clinical Trials Centre, Sydney, NSW, Australia
| | - Sivakumar Gananadha
- The Canberra Hospital, Woden, ACT, Australia.,Australian National University, Canberra, ACT, Australia
| | - Daniel G Croagh
- Monash Medical Centre, Melbourne, VIC, Australia.,Monash University, Melbourne, VIC, Australia
| | - James G Kench
- Royal Prince Alfred Hospital, Sydney, NSW, Australia.,Central Clinical School, University of Sydney, Sydney, NSW, Australia
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40
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Abstract
The aim of this study was to evaluate outcomes of patients with resectable pancreatic adenocarcinoma (PDAC) who underwent neoadjuvant chemotherapy. The MEDLINE and PubMed databases were searched to identify relevant original articles investigating neoadjuvant therapy in resectable PDAC. Qualitative analyses were performed to investigate patient selection, disease stage, impact on perioperative outcomes, and cost-effectiveness. Forty-three studies met inclusion criteria for this review. Neoadjuvant chemotherapy for upfront resectable PDAC is cost-effective, safe, may result in lower stage disease and has potential survival advantages. With proper patient selection, neoadjuvant chemotherapy is an appropriate approach for upfront resectable PDAC. Nevertheless, the risk for disease progression and losing a curative surgical window highlights the need for appropriate patient identification, further discovery of superior biomarkers or molecular profiles representative of positive treatment response, and additional prospective comparative study.
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41
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Mehtsun WT, Hashimoto DA, Ferrone CR. Status of 5-Year Survivors of the Whipple Procedure for Pancreatic Adenocarcinoma. Adv Surg 2019; 53:253-269. [PMID: 31327451 DOI: 10.1016/j.yasu.2019.04.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Affiliation(s)
- Winta T Mehtsun
- Department of Surgery, Massachusetts General Hospital, 15 Parkman Street, WAC 460, Boston, MA 02114, USA
| | - Daniel A Hashimoto
- Department of Surgery, Massachusetts General Hospital, 15 Parkman Street, WAC 460, Boston, MA 02114, USA
| | - Cristina R Ferrone
- Department of Surgery, Massachusetts General Hospital, 15 Parkman Street, WAC 460, Boston, MA 02114, USA.
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42
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Pathological tumor response to neoadjuvant therapy in borderline resectable pancreatic cancer. Hepatobiliary Pancreat Dis Int 2019; 18:305-306. [PMID: 31262654 DOI: 10.1016/j.hbpd.2019.06.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 06/13/2019] [Indexed: 02/05/2023]
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43
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Swords DS, Francis SR, Lloyd S, Garrido-Laguna I, Mulvihill SJ, Gruhl JD, Christensen MC, Stoddard GJ, Firpo MA, Scaife CL. Lymph Node Ratio in Pancreatic Adenocarcinoma After Preoperative Chemotherapy vs. Preoperative Chemoradiation and Its Utility in Decisions About Postoperative Chemotherapy. J Gastrointest Surg 2019; 23:1401-1413. [PMID: 30187332 DOI: 10.1007/s11605-018-3953-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Accepted: 08/24/2018] [Indexed: 01/31/2023]
Abstract
BACKGROUND Single-center studies in pancreatic adenocarcinoma have suggested that preoperative chemotherapy (PCT) is associated with higher lymph node ratio (LNR) than preoperative chemoradiation (PCRT). The association of postoperative chemotherapy with overall survival (OS) in patients treated with PCT and PCRT remains unclear. Our objectives were to investigate whether (1) PCT is associated with higher LNR than PCRT and (2) postoperative chemotherapy is associated with longer OS after PCT and PCRT in LNR-stratified cohorts. METHODS A retrospective cohort study was performed of patients with pancreatic adenocarcinoma treated with PCT or PCRT followed by resection between 2006 and 2014 in the National Cancer Database. Temporal trends were evaluated with Cuzick's test. OS was evaluated with multivariable Cox regression and inverse probability weighted (IPW) Cox regression. RESULTS Of 4187 patients, 1993 (47.6%) received PCT. PCT rates were stable at approximately 30% in 2006-2010 (p = 0.33) but increased to 64.9% by 2014 (p < 0.001). Node positivity rates were higher after PCT than PCRT (62.7 vs. 41.8%, P < 0.001) and mean LNR was higher (0.10 [95% CI 0.096, 0.11] vs. 0.058 [95% CI 0.052, 0.063], P < 0.001). Postoperative chemotherapy was associated with longer OS in patients with LNR 0.01-0.149 after PCT by univariate analysis (median OS 34.5 vs. 26.5 months, P = 0.002), multivariable Cox regression (HR 0.64, 95% CI 0.48, 0.84), and IPW Cox regression (HR 0.72, 95% CI 0.55, 0.94). Postoperative chemotherapy was not associated with longer OS for patients who were node-negative or who had LNR ≥ 0.15 after PCT or for any patient subgroups after PCRT. CONCLUSIONS PCT is associated with a higher LNR and higher rates of node positivity than PCRT. Postoperative chemotherapy is associated with longer OS than observation in patients with a LNR of 0.01-0.149 after PCT.
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Affiliation(s)
- Douglas S Swords
- Division of General Surgery, Department of Surgery, University of Utah, 30 North 1900 East, Salt Lake City, UT, 84132, USA.
| | - Samual R Francis
- Department of Radiation Oncology, University of Utah, Salt Lake City, UT, USA
| | - Shane Lloyd
- Department of Radiation Oncology, University of Utah, Salt Lake City, UT, USA
| | - Ignacio Garrido-Laguna
- Division of Medical Oncology, Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA
| | - Sean J Mulvihill
- Division of General Surgery, Department of Surgery, University of Utah, 30 North 1900 East, Salt Lake City, UT, 84132, USA
| | - Joshua D Gruhl
- Department of Radiation Oncology, University of Utah, Salt Lake City, UT, USA
| | - Miles C Christensen
- Department of Radiation Oncology, University of Utah, Salt Lake City, UT, USA
| | - Gregory J Stoddard
- Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA
| | - Matthew A Firpo
- Division of General Surgery, Department of Surgery, University of Utah, 30 North 1900 East, Salt Lake City, UT, 84132, USA
| | - Courtney L Scaife
- Division of General Surgery, Department of Surgery, University of Utah, 30 North 1900 East, Salt Lake City, UT, 84132, USA
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Use of Machine-Learning Algorithms in Intensified Preoperative Therapy of Pancreatic Cancer to Predict Individual Risk of Relapse. Cancers (Basel) 2019; 11:cancers11050606. [PMID: 31052270 PMCID: PMC6562932 DOI: 10.3390/cancers11050606] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 04/24/2019] [Accepted: 04/26/2019] [Indexed: 12/12/2022] Open
Abstract
Background: Although surgical resection is the only potentially curative treatment for pancreatic cancer (PC), long-term outcomes of this treatment remain poor. The aim of this study is to describe the feasibility of a neoadjuvant treatment with induction polychemotherapy (IPCT) followed by chemoradiation (CRT) in resectable PC, and to develop a machine-learning algorithm to predict risk of relapse. Methods: Forty patients with resectable PC treated in our institution with IPCT (based on mFOLFOXIRI, GEMOX or GEMOXEL) followed by CRT (50 Gy and concurrent Capecitabine) were retrospectively analyzed. Additionally, clinical, pathological and analytical data were collected in order to perform a 2-year relapse-risk predictive population model using machine-learning techniques. Results: A R0 resection was achieved in 90% of the patients. After a median follow-up of 33.5 months, median progression-free survival (PFS) was 18 months and median overall survival (OS) was 39 months. The 3 and 5-year actuarial PFS were 43.8% and 32.3%, respectively. The 3 and 5-year actuarial OS were 51.5% and 34.8%, respectively. Forty-percent of grade 3-4 IPCT toxicity, and 29.7% of grade 3 CRT toxicity were reported. Considering the use of granulocyte colony-stimulating factors, the number of resected lymph nodes, the presence of perineural invasion and the surgical margin status, a logistic regression algorithm predicted the individual 2-year relapse-risk with an accuracy of 0.71 (95% confidence interval [CI] 0.56–0.84, p = 0.005). The model-predicted outcome matched 64% of the observed outcomes in an external dataset. Conclusion: An intensified multimodal neoadjuvant approach (IPCT + CRT) in resectable PC is feasible, with an encouraging long-term outcome. Machine-learning algorithms might be a useful tool to predict individual risk of relapse. A small sample size and therapy heterogeneity remain as potential limitations.
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Advances of pathological complete response after neoadjuvant therapy for pancreatic cancer. JOURNAL OF PANCREATOLOGY 2019. [DOI: 10.1097/jp9.0000000000000009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
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Piątek M, Kuśnierz K, Bieńkowski M, Pęksa R, Kowalczyk M, Nawrocki S. Primarily resectable pancreatic adenocarcinoma - to operate or to refer the patient to an oncologist? Crit Rev Oncol Hematol 2019; 135:95-102. [PMID: 30819452 DOI: 10.1016/j.critrevonc.2019.01.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2018] [Revised: 01/12/2019] [Accepted: 01/21/2019] [Indexed: 12/13/2022] Open
Abstract
The aim of this work is to investigate the optimal therapeutic sequence of resectable pancreatic cancer - primary surgery with adjuvant therapy or neoadjuvant followed by resection. Application of the neoadjuvant approach in routine treatment of pancreatic cancer is rapidly growing every year, despite the lack of final results from randomized trials. Recent advancements in the adjuvant therapy, due to the more effective chemotherapy regimens, favor the upfront surgery strategy. On the other hand, theoretical background and metaanalyses favor the neoadjuvant strategy. Currently, primary resection with adjuvant chemotherapy remains the standard approach in resectable pancreatic cancer, but the first recommendations considering the neoadjuvant approach as an option seem to arise among the scientific societies with a global impact. Preliminary results of Prodige 24 study and PREOPANC-1 trial demonstrates that both options are worth further evaluation in clinical trials. Their results should soon provide more answers to this important clinical questions.
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Affiliation(s)
- Michał Piątek
- Department of Oncology, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Katarzyna Kuśnierz
- Department of Gastrointestinal Surgery, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | | | - Rafał Pęksa
- Department of Patomorphology, Medical University of Gdańsk, Poland
| | - Marek Kowalczyk
- Department of Radiotherapy, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Sergiusz Nawrocki
- Department of Radiotherapy, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Katowice, Poland
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Bradley A, Van Der Meer R. Neoadjuvant therapy versus upfront surgery for potentially resectable pancreatic cancer: A Markov decision analysis. PLoS One 2019; 14:e0212805. [PMID: 30817807 PMCID: PMC6394923 DOI: 10.1371/journal.pone.0212805] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 02/09/2019] [Indexed: 12/16/2022] Open
Abstract
Background Neoadjuvant therapy has emerged as an alternative treatment strategy for potentially resectable pancreatic cancer. In the absence of large randomized controlled trials offering a direct comparison, this study aims to use Markov decision analysis to compare efficacy of traditional surgery first (SF) and neoadjuvant treatment (NAT) pathways for potentially resectable pancreatic cancer. Methods An advanced Markov decision analysis model was constructed to compare SF and NAT pathways for potentially resectable pancreatic cancer. Transition probabilities were calculated from randomized control and Phase II/III trials after comprehensive literature search. Utility outcomes were measured in overall and quality-adjusted life months (QALMs) on an intention-to-treat basis as the primary outcome. Markov cohort analysis of treatment received was the secondary outcome. Model uncertainties were tested with one and two-way deterministic and probabilistic Monte Carlo sensitivity analysis. Results SF gave 23.72 months (18.51 QALMs) versus 20.22 months (16.26 QALMs). Markov Cohort Analysis showed that where all treatment modalities were received NAT gave 35.05 months (29.87 QALMs) versus 30.96 months (24.86QALMs) for R0 resection and 34.08 months (29.87 QALMs) versus 25.85 months (20.72 QALMs) for R1 resection. One-way deterministic sensitivity analysis showed that NAT was superior if the resection rate was greater than 51.04% or below 75.68% in SF pathway. Two-way sensitivity analysis showed that pathway superiority depended on obtaining multimodal treatment in either pathway. Conclusion Whilst NAT is a viable alternative to traditional SF approach, superior pathway selection depends on the individual patient’s likelihood of receiving multimodal treatment in either pathway.
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Affiliation(s)
- Alison Bradley
- Department of Management Science, Strathclyde Business School, University of Strathclyde, Glasgow, Scotland, United Kingdom
- West of Scotland Pancreatic Cancer Unit, Glasgow Royal Infirmary, Glasgow, Scotland, United Kingdom
- * E-mail:
| | - Robert Van Der Meer
- Department of Management Science, Strathclyde Business School, University of Strathclyde, Glasgow, Scotland, United Kingdom
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Raufi AG, Manji GA, Chabot JA, Bates SE. Neoadjuvant Treatment for Pancreatic Cancer. Semin Oncol 2019; 46:19-27. [DOI: 10.1053/j.seminoncol.2018.12.002] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 12/11/2018] [Indexed: 02/06/2023]
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49
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Ren X, Wei X, Ding Y, Qi F, Zhang Y, Hu X, Qin C, Li X. Comparison of neoadjuvant therapy and upfront surgery in resectable pancreatic cancer: a meta-analysis and systematic review. Onco Targets Ther 2019; 12:733-744. [PMID: 30774360 PMCID: PMC6348975 DOI: 10.2147/ott.s190810] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Objective The role of neoadjuvant therapy (NAT) in resectable pancreatic cancer (RPC) remains controversial. Therefore, this meta-analysis was performed to compare the clinical differences between NAT and upfront surgery in RPC. Materials and methods A systematic literature search was performed in PubMed, Embase, Web of Science, and the Cochrane Register of Controlled Trials databases. Only patients with RPC who underwent tumor resection and received adjuvant or neoadjuvant treatment were enrolled. The OR or HR and 95% CIs were calculated employing fixed-effects or random-effects models. The HR and its 95% CI were extracted from each article that provided survival curve. Publication bias was estimated using funnel plots and Egger’s regression test. Results In total, eleven studies were included with 9,386 patients. Of these patients, 2,508 (26.7%) received NAT. For patients with RPC, NAT resulted in an increased R0 resection rate (OR=1.89; 95% CI=1.26–2.83) and a reduced positive lymph node rate (OR=0.34; 95% CI=0.31–0.37) compared with upfront surgery. Nevertheless, patients receiving NAT did not exhibit a significantly increased overall survival (OS) time (HR=0.91; 95% CI=0.79–1.05). Conclusion In patients with RPC, R0 resection rate and positive lymph node rate after NAT were superior to those of patients with upfront surgery. The NAT group exhibited no significant effect on OS time when compared with the upfront surgery group. However, this conclusion requires more clinical evidence to improve its credibility.
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Affiliation(s)
- Xiaohan Ren
- Department of First Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu 210009, China
| | - Xiyi Wei
- Department of First Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu 210009, China
| | - Yichao Ding
- Department of First Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu 210009, China
| | - Feng Qi
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, China,
| | - Yundi Zhang
- Department of First Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu 210009, China
| | - Xin Hu
- Department of First Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu 210009, China
| | - Chao Qin
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, China,
| | - Xiao Li
- Department of Urology, Jiangsu Institute of Cancer Research, Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu 210009, China,
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Gianotti L, Besselink MG, Sandini M, Hackert T, Conlon K, Gerritsen A, Griffin O, Fingerhut A, Probst P, Abu Hilal M, Marchegiani G, Nappo G, Zerbi A, Amodio A, Perinel J, Adham M, Raimondo M, Asbun HJ, Sato A, Takaori K, Shrikhande SV, Del Chiaro M, Bockhorn M, Izbicki JR, Dervenis C, Charnley RM, Martignoni ME, Friess H, de Pretis N, Radenkovic D, Montorsi M, Sarr MG, Vollmer CM, Frulloni L, Büchler MW, Bassi C. Nutritional support and therapy in pancreatic surgery: A position paper of the International Study Group on Pancreatic Surgery (ISGPS). Surgery 2018; 164:1035-1048. [PMID: 30029989 DOI: 10.1016/j.surg.2018.05.040] [Citation(s) in RCA: 145] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Revised: 05/28/2018] [Accepted: 05/29/2018] [Indexed: 02/06/2023]
Abstract
BACKGROUND The optimal nutritional therapy in the field of pancreatic surgery is still debated. METHODS An international panel of recognized pancreatic surgeons and pancreatologists decided that the topic of nutritional support was of importance in pancreatic surgery. Thus, they reviewed the best contemporary literature and worked to develop a position paper to provide evidence supporting the integration of appropriate nutritional support into the overall management of patients undergoing pancreatic resection. Strength of recommendation and quality of evidence were based on the approach of the grading of recommendations assessment, development and evaluation Working Group. RESULTS The measurement of nutritional status should be part of routine preoperative assessment because malnutrition is a recognized risk factor for surgery-related complications. In addition to patient's weight loss and body mass index, measurement of sarcopenia and sarcopenic obesity should be considered in the preoperative evaluation because they are strong predictors of poor short-term and long-term outcomes. The available data do not show any definitive nutritional advantages for one specific type of gastrointestinal reconstruction technique after pancreatoduodenectomy over the others. Postoperative early resumption of oral intake is safe and should be encouraged within enhanced recovery protocols, but in the case of severe postoperative complications or poor tolerance of oral food after the operation, supplementary artificial nutrition should be started at once. At present, there is not enough evidence to show the benefit of avoiding oral intake in clinically stable patients who are complicated by a clinically irrelevant postoperative pancreatic fistula (a so-called biochemical leak), while special caution should be given to feeding patients with clinically relevant postoperative pancreatic fistula orally. When an artificial nutritional support is needed, enteral nutrition is preferred whenever possible over parenteral nutrition. After the operation, regardless of the type of pancreatic resection or technique of reconstruction, patients should be monitored carefully to assess for the presence of endocrine and exocrine pancreatic insufficiency. Although fecal elastase-1 is the most readily available clinical test for detection of pancreatic exocrine insufficiency, its sensitivity and specificity are low. Pancreatic enzyme replacement therapy should be initiated routinely after pancreatoduodenectomy and in patients with locally advanced disease and continued for at least 6 months after surgery, because untreated pancreatic exocrine insufficiency may result in severe nutritional derangement. CONCLUSION The importance of this position paper is the consensus reached on the topic. Concentrating on nutritional support and therapy is of utmost value in pancreatic surgery for both short- and long-term outcomes.
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Affiliation(s)
- Luca Gianotti
- School of Medicine and Surgery, University of Milan-Bicocca, and Department of Surgery, San Gerardo Hospital, Monza, Italy.
| | - Marc G Besselink
- Department of Surgery, Cancer Center Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Marta Sandini
- School of Medicine and Surgery, University of Milan-Bicocca, and Department of Surgery, San Gerardo Hospital, Monza, Italy
| | - Thilo Hackert
- Department of Surgery, University of Heidelberg, Heidelberg, Germany
| | - Kevin Conlon
- Department of Surgery, Trinity College Dublin, Tallaght Hospital, Dublin, Ireland
| | - Arja Gerritsen
- Department of Surgery, Cancer Center Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Oonagh Griffin
- Department of Surgery, Trinity College Dublin, Tallaght Hospital, Dublin, Ireland
| | - Abe Fingerhut
- University of Graz Hospital, Surgical Research Unit, Graz, Austria
| | - Pascal Probst
- Department of Surgery, University of Heidelberg, Heidelberg, Germany
| | | | - Giovanni Marchegiani
- Department of General and Pancreatic Surgery, The Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
| | - Gennaro Nappo
- Pancreatic Surgery Unit, Humanitas University, Humanitas Research Hospital, Milan, Italy
| | - Alessandro Zerbi
- Pancreatic Surgery Unit, Humanitas University, Humanitas Research Hospital, Milan, Italy
| | - Antonio Amodio
- Unit of Gastroenterology, University of Verona Hospital Trust, Verona, Italy
| | - Julie Perinel
- Department of Digestive Surgery, E. Herriot Hospital, Hospices Civils de Lyon, Lyon-Sud Faculty of Medicine, Lyon, France
| | - Mustapha Adham
- Department of Digestive Surgery, E. Herriot Hospital, Hospices Civils de Lyon, Lyon-Sud Faculty of Medicine, Lyon, France
| | - Massimo Raimondo
- Division of General Surgery, Department of Surgery, Mayo Clinic, Jacksonville, FL
| | - Horacio J Asbun
- Division of General Surgery, Department of Surgery, Mayo Clinic, Jacksonville, FL
| | - Asahi Sato
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Kyoichi Takaori
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | | | - Marco Del Chiaro
- Pancreatic Surgery Unit - Division of Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC) - Karolinska Institutet at Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Maximilian Bockhorn
- Department of General, Visceral and Thoracic-Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Jakob R Izbicki
- Department of General, Visceral and Thoracic-Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Christos Dervenis
- University of Cyprus and Department of Surgical Oncology and HPB Surgery Metropolitan Hospital, Athens, Greece
| | - Richard M Charnley
- Department of HPB & Transplant Surgery, Freeman Hospital, Newcastle upon Tyne, UK
| | - Marc E Martignoni
- Department of Surgery, Klinikum rechts der Isar, Technische Universität, München, Germany
| | - Helmut Friess
- Department of Surgery, Klinikum rechts der Isar, Technische Universität, München, Germany
| | | | - Dejan Radenkovic
- Clinic for Digestive Surgery, Clinical Center of Serbia and School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Marco Montorsi
- Department of Surgery, Humanitas University, Humanitas Research Hospital, Milan, Italy
| | - Michael G Sarr
- Department of Gastroenterologic and General Surgery, Mayo Clinic, Rochester, MN
| | - Charles M Vollmer
- Department of Surgery, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA
| | - Luca Frulloni
- Department of Medicine, University of Verona, Verona, Italy
| | - Markus W Büchler
- Department of Surgery, University of Heidelberg, Heidelberg, Germany
| | - Claudio Bassi
- Department of General and Pancreatic Surgery, The Pancreas Institute, University of Verona Hospital Trust, Verona, Italy
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