Neoadjuvant therapy versus upfront surgery for resected pancreatic adenocarcinoma: A nationwide propensity score matched analysis

Published:October 27, 2016DOI:


      Neoadjuvant therapy is an emerging paradigm in pancreatic cancer care; however, its role for resectable disease remains controversial in the absence of conclusive randomized controlled trials. The purpose of the present study is to assess the impact of neoadjuvant therapy on survival in resected pancreatic cancer patients by clinical stage.


      A retrospective cohort study using the National Cancer Data Base from 2004 to 2012 including nonmetastatic pancreatic adenocarcinoma patients who underwent pancreatectomy and initiated chemotherapy. Propensity score matching within each stage was used to account for potential selection bias between patients undergoing neoadjuvant therapy and upfront surgery. Overall survival was compared by the Kaplan-Meier method.


      In the study, 1,541 and 7,159 patients received neoadjuvant therapy followed by surgery and upfront surgery succeeded by adjuvant therapy, respectively. In clinical stage III pancreatic cancer (n = 486), neoadjuvant therapy was associated with significant survival benefit after matching (median survival 22.9 vs 17.3 months; log-rank P < .0001) compared with conventional upfront surgery followed by adjuvant therapy; however, no survival difference was found between the 2 treatment sequences in patients with clinical stage I (n = 3,149; median survival, 26.2 vs 25.7 months; P = .4418) and II (n = 5,065; median survival, 23.5 vs 23.0 months; P = .7751) disease after matching.


      The survival impact of neoadjuvant therapy is stage-dependent. Neoadjuvant therapy does not disadvantage survival compared with conventional upfront surgery followed by adjuvant therapy in any stage, and is associated with a significant survival advantage in stage III pancreatic cancer.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Surgery
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Siegel R.
        • Ma J.
        • Zou Z.
        • Jemal A.
        Cancer statistics, 2014.
        CA Cancer J Clin. 2014; 64: 9-29
        • Aoyama T.
        • Murakawa M.
        • Katayama Y.
        • et al.
        Impact of postoperative complications on survival and recurrence in pancreatic cancer.
        Anticancer Res. 2015; 35: 2401-2409
        • Fischer R.
        • Breidert M.
        • Keck T.
        • Makowiec F.
        • Lohrmann C.
        • Harder J.
        Early recurrence of pancreatic cancer after resection and during adjuvant chemotherapy.
        Saudi J Gastroenterol. 2012; 18: 118-121
        • Valle J.W.
        • Palmer D.
        • Jackson R.
        • et al.
        Optimal duration and timing of adjuvant chemotherapy after definitive surgery for ductal adenocarcinoma of the pancreas: ongoing lessons from the ESPAC-3 study.
        J Clin Oncol. 2014; 32: 504-512
        • Neoptolemos J.P.
        • Dunn J.A.
        • Stocken D.D.
        • et al.
        Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial.
        Lancet. 2001; 358: 1576-1585
        • Oettle H.
        • Neuhaus P.
        • Hochhaus A.
        • et al.
        Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial.
        JAMA. 2013; 310: 1473-1481
        • Neoptolemos J.P.
        • Stocken D.D.
        • Friess H.
        • et al.
        A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer.
        N Engl J Med. 2004; 350: 1200-1210
        • Tempero M.A.
        • Malafa M.P.
        • Behrman S.W.
        • et al.
        Pancreatic adenocarcinoma, version 2.2014: featured updates to the NCCN guidelines.
        J Natl Compr Canc Netw. 2014; 12: 1083-1093
        • Bilimoria K.Y.
        • Bentrem D.J.
        • Ko C.Y.
        • et al.
        Multimodality therapy for pancreatic cancer in the U.S.: utilization, outcomes, and the effect of hospital volume.
        Cancer. 2007; 110: 1227-1234
        • Labori K.J.
        • Katz M.H.
        • Tzeng C.W.
        • et al.
        Impact of early disease progression and surgical complications on adjuvant chemotherapy completion rates and survival in patients undergoing the surgery first approach for resectable pancreatic ductal adenocarcinoma: a population-based cohort study.
        Acta Oncol. 2016; 55: 265-277
        • Tzeng C.W.
        • Tran Cao H.S.
        • Lee J.E.
        • et al.
        Treatment sequencing for resectable pancreatic cancer: influence of early metastases and surgical complications on multimodality therapy completion and survival.
        J Gastrointest Surg. 2014; 18 (discussion 24-15): 16-24
        • Piperdi M.
        • McDade T.P.
        • Shim J.K.
        • et al.
        A neoadjuvant strategy for pancreatic adenocarcinoma increases the likelihood of receiving all components of care: lessons from a single-institution database.
        HPB (Oxford). 2010; 12: 204-210
        • Evans D.B.
        Multidisciplinary Pancreatic Cancer Study G. Resectable pancreatic cancer: the role for neoadjuvant/preoperative therapy.
        HPB (Oxford). 2006; 8: 365-368
        • Desai N.V.
        • Sliesoraitis S.
        • Hughes S.J.
        • et al.
        Multidisciplinary neoadjuvant management for potentially curable pancreatic cancer.
        Cancer Med. 2015; 4: 1224-1239
        • Gabriel E.
        • Attwood K.
        • Du W.
        • et al.
        Association between clinically staged node-negative esophageal adenocarcinoma and overall survival benefit from neoadjuvant chemoradiation.
        JAMA Surg. 2016; 151: 234-245
        • Bilimoria K.Y.
        • Stewart A.K.
        • Winchester D.P.
        • Ko C.Y.
        The National Cancer Data Base: a powerful initiative to improve cancer care in the United States.
        Ann Surg Oncol. 2008; 15: 683-690
        • Deyo R.A.
        • Cherkin D.C.
        • Ciol M.A.
        Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases.
        J Clin Epidemiol. 1992; 45: 613-619
        • Nuttall M.
        • van der Meulen J.
        • Emberton M.
        Charlson scores based on ICD-10 administrative data were valid in assessing comorbidity in patients undergoing urological cancer surgery.
        J Clin Epidemiol. 2006; 59: 265-273
        • Rubin D.B.
        Estimating causal effects from large data sets using propensity scores.
        Ann Intern Med. 1997; 127: 757-763
        • Myers J.A.
        • Rassen J.A.
        • Gagne J.J.
        • et al.
        Effects of adjusting for instrumental variables on bias and precision of effect estimates.
        Am J Epidemiol. 2011; 174: 1213-1222
        • Austin P.C.
        An Introduction to Propensity score methods for reducing the effects of confounding in observational studies.
        Multivariate Behav Res. 2011; 46: 399-424
        • Golcher H.
        • Brunner T.B.
        • Witzigmann H.
        • et al.
        Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer: results of the first prospective randomized phase II trial.
        Strahlenther Onkol. 2015; 191: 7-16
        • Barbier L.
        • Turrini O.
        • Gregoire E.
        • Viret F.
        • Le Treut Y.P.
        • Delpero J.R.
        Pancreatic head resectable adenocarcinoma: preoperative chemoradiation improves local control but does not affect survival.
        HPB (Oxford). 2011; 13: 64-69
        • Kharofa J.
        • Tsai S.
        • Kelly T.
        • et al.
        Neoadjuvant chemoradiation with IMRT in resectable and borderline resectable pancreatic cancer.
        Radiother Oncol. 2014; 113: 41-46
        • Rose J.B.
        • Rocha F.G.
        • Alseidi A.
        • et al.
        Extended neoadjuvant chemotherapy for borderline resectable pancreatic cancer demonstrates promising postoperative outcomes and survival.
        Ann Surg Oncol. 2014; 21: 1530-1537
        • Takeda Y.
        • Nakamori S.
        • Eguchi H.
        • et al.
        Neoadjuvant gemcitabine-based accelerated hyperfractionation chemoradiotherapy for patients with borderline resectable pancreatic adenocarcinoma.
        Jpn J Clin Oncol. 2014; 44: 1172-1180
        • Talamonti M.S.
        • Small Jr., W.
        • Mulcahy M.F.
        • et al.
        A multi-institutional phase II trial of preoperative full-dose gemcitabine and concurrent radiation for patients with potentially resectable pancreatic carcinoma.
        Ann Surg Oncol. 2006; 13: 150-158
        • Kim E.J.
        • Ben-Josef E.
        • Herman J.M.
        • et al.
        A multi-institutional phase 2 study of neoadjuvant gemcitabine and oxaliplatin with radiation therapy in patients with pancreatic cancer.
        Cancer. 2013; 119: 2692-2700
        • Landry J.
        • Catalano P.J.
        • Staley C.
        • et al.
        Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma.
        J Surg Oncol. 2010; 101: 587-592
        • White R.R.
        • Hurwitz H.I.
        • Morse M.A.
        • et al.
        Neoadjuvant chemoradiation for localized adenocarcinoma of the pancreas.
        Ann Surg Oncol. 2001; 8: 758-765
        • Motoi F.
        • Ishida K.
        • Fujishima F.
        • et al.
        Neoadjuvant chemotherapy with gemcitabine and S-1 for resectable and borderline pancreatic ductal adenocarcinoma: results from a prospective multi-institutional phase 2 trial.
        Ann Surg Oncol. 2013; 20: 3794-3801
        • Sho M.
        • Akahori T.
        • Tanaka T.
        • et al.
        Pathological and clinical impact of neoadjuvant chemoradiotherapy using full-dose gemcitabine and concurrent radiation for resectable pancreatic cancer.
        J Hepatobiliary Pancreat Sci. 2013; 20: 197-205
        • Takahashi H.
        • Ogawa H.
        • Ohigashi H.
        • et al.
        Preoperative chemoradiation reduces the risk of pancreatic fistula after distal pancreatectomy for pancreatic adenocarcinoma.
        Surgery. 2011; 150: 547-556
        • Turrini O.
        • Ychou M.
        • Moureau-Zabotto L.
        • et al.
        Neoadjuvant docetaxel-based chemoradiation for resectable adenocarcinoma of the pancreas: new neoadjuvant regimen was safe and provided an interesting pathologic response.
        Eur J Surg Oncol. 2010; 36: 987-992
        • Christians K.K.
        • Heimler J.W.
        • George B.
        • et al.
        Survival of patients with resectable pancreatic cancer who received neoadjuvant therapy.
        Surgery. 2016; 159: 893-900
        • Kalser M.H.
        • Ellenberg S.S.
        Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection.
        Arch Surg. 1985; 120: 899-903
        • Artinyan A.
        • Anaya D.A.
        • McKenzie S.
        • Ellenhorn J.D.
        • Kim J.
        Neoadjuvant therapy is associated with improved survival in resectable pancreatic adenocarcinoma.
        Cancer. 2011; 117: 2044-2049
        • Dimou F.
        • Sineshaw H.
        • Parmar A.D.
        • Tamirisa N.P.
        • Jemal A.
        • Riall T.S.
        Trends in receipt and timing of multimodality therapy in early-stage pancreatic cancer.
        J Gastrointest Surg. 2016; 20 (discussion 103): 93-103
        • Stessin A.M.
        • Meyer J.E.
        • Sherr D.L.
        Neoadjuvant radiation is associated with improved survival in patients with resectable pancreatic cancer: an analysis of data from the surveillance, epidemiology, and end results (SEER) registry.
        Int J Radiat Oncol Biol Phys. 2008; 72: 1128-1133
        • Franko J.
        • Puri D.R.
        • Goldman C.D.
        Impact of radiation therapy sequence on survival among patients with resected pancreatic head ductal carcinoma.
        Ann Surg Oncol. 2012; 19: 26-30
        • Parmar A.D.
        • Vargas G.M.
        • Tamirisa N.P.
        • Sheffield K.M.
        • Riall T.S.
        Trajectory of care and use of multimodality therapy in older patients with pancreatic adenocarcinoma.
        Surgery. 2014; 156: 280-289
        • Petrelli F.
        • Coinu A.
        • Borgonovo K.
        • et al.
        FOLFIRINOX-based neoadjuvant therapy in borderline resectable or unresectable pancreatic cancer: a meta-analytical review of published studies.
        Pancreas. 2015; 44: 515-521
        • Ferrone C.R.
        • Marchegiani G.
        • Hong T.S.
        • et al.
        Radiological and surgical implications of neoadjuvant treatment with FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer.
        Ann Surg. 2015; 261: 12-17
        • Mellon E.A.
        • Hoffe S.E.
        • Springett G.M.
        • et al.
        Long-term outcomes of induction chemotherapy and neoadjuvant stereotactic body radiotherapy for borderline resectable and locally advanced pancreatic adenocarcinoma.
        Acta Oncol. 2015; 54: 979-985
        • Bergquist J.R.
        • Puig C.A.
        • Shubert C.R.
        • et al.
        Carbohydrate antigen 19-9 elevation in anatomically resectable, early stage pancreatic cancer is independently associated with decreased overall survival and an indication for neoadjuvant therapy: a national cancer database study.
        J Am Coll Surg. 2016; 223: 52-65
        • Saka B.
        • Balci S.
        • Basturk O.
        • et al.
        Pancreatic ductal adenocarcinoma is spread to the peripancreatic soft tissue in the majority of resected cases, rendering the AJCC T-Stage Protocol (7th Edition) inapplicable and insignificant: a size-based staging system (pT1: </=2, pT2: >2-</=4, pT3: >4 cm) is more valid and clinically relevant.
        Ann Surg Oncol. 2016; 23: 2010-2018
        • Edge S.
        • Byrd D.R.
        • Compton C.C.
        • Fritz A.G.
        • Greene F.L.
        • Trotti A.
        AJCC cancer staging manual.
        7th ed. Springer, New York (NY)2010
        • Bickenbach K.A.
        • Gonen M.
        • Tang L.H.
        • et al.
        Downstaging in pancreatic cancer: a matched analysis of patients resected following systemic treatment of initially locally unresectable disease.
        Ann Surg Oncol. 2012; 19: 1663-1669
        • Colbert L.E.
        • Hall W.A.
        • Nickleach D.
        • et al.
        Chemoradiation therapy sequencing for resected pancreatic adenocarcinoma in the National Cancer Data Base.
        Cancer. 2014; 120: 499-506