title: Locally advanced pancreatic cancer: association between prolonged preoperative treatment and lymph-node negativity and overall survival.
abstract: OBJECTIVE
  Treatment of patients with locally advanced/borderline resectable (LA/BR) pancreatic ductal adenocarcinoma (PDAC) is not standardized.
  
  
  OBJECTIVE
  To (1) perform a detailed survival analysis of our institution's experience with patients with LA/BR PDAC who were downstaged and underwent surgical resection and (2) identify prognostic biomarkers that may help to guide a decision for the use of adjuvant therapy in this patient subgroup.
  
  
  METHODS
  Retrospective observational study of 49 consecutive patients from a single institution during 1992-2011 with American Joint Committee on Cancer stage III LA/BR PDAC who were initially unresectable, as determined by staging computed tomography and/or surgical exploration, and who were treated and then surgically resected.
  
  
  METHODS
  Clinicopathologic variables and prognostic biomarkers SMAD4, S100A2, and microRNA-21 were correlated with survival by univariate and multivariate Cox proportional hazard modeling.
  
  
  RESULTS
  All 49 patients were deemed initially unresectable owing to vascular involvement. After completing preoperative chemotherapy for a median of 7.1 months (range, 5.4-9.6 months), most (75.5%) underwent a pylorus-preserving Whipple operation; 3 patients (6.1%) had a vascular resection. Strikingly, 37 of 49 patients were lymph-node (LN) negative (75.5%) and 42 (85.7%) had negative margins; 45.8% of evaluable patients achieved a complete histopathologic (HP) response. The median overall survival (OS) was 40.1 months (range, 22.7-65.9 months). A univariate analysis of HP prognostic biomarkers revealed that perineural invasion (hazard ratio, 5.5; P=.007) and HP treatment response (hazard ratio, 9.0; P=.009) were most significant. Lymph-node involvement, as a marker of systemic disease, was also significant on univariate analysis (P=.05). Patients with no LN involvement had longer OS (44.4 vs 23.2 months, P=.04) than LN-positive patients. The candidate prognostic biomarkers, SMAD4 protein loss (P=.01) in tumor cells and microRNA-21 expression in the stroma (P=.05), also correlated with OS. On multivariate Cox proportional hazard modeling of HP and prognostic biomarkers, only SMAD4 protein loss was significant (hazard ratio, 9.3; P=.004).
  
  
  CONCLUSIONS
  Our approach to patients with LA/BR PDAC, which includes prolonged preoperative chemotherapy, is associated with a high incidence of LN-negative disease and excellent OS. After surgical resection, HP treatment response, perineural invasion, and SMAD4 status should help determine who should receive adjuvant therapy in this select subset of patients.
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California, Los Angeles.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Kadera
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California, Los Angeles.
authors.forename: Dharma B
authors.initials: DB
authors.lastname: Sunjaya
authors.affiliation: Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles.
authors.forename: William H
authors.initials: WH
authors.lastname: Isacoff
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California, Los Angeles.
authors.forename: Luyi
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California, Los Angeles5Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles.
authors.forename: O Joe
authors.initials: OJ
authors.lastname: Hines
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California, Los Angeles5Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles.
authors.forename: James S
authors.initials: JS
authors.lastname: Tomlinson
authors.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles5Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles6Institute for Molecular.
authors.forename: David W
authors.initials: DW
authors.lastname: Dawson
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California, Los Angeles.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Rochefort
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California, Los Angeles.
authors.forename: Graham W
authors.initials: GW
authors.lastname: Donald
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California, Los Angeles.
authors.forename: Barbara M
authors.initials: BM
authors.lastname: Clerkin
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California, Los Angeles5Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Reber
authors.affiliation: Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California, Los Angeles4Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles5Jonsson.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Donahue
mesh_terms: D000368:Aged; D001706:Biopsy; D002140:California / Q000453:epidemiology; D003131:Combined Modality Therapy / Q000379:methods; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000175:diagnosis* / Q000401:mortality / Q000628:therapy; D011300:Preoperative Care / Q000379:methods*; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate / Q000639:trends; D013997:Time Factors; D014057:Tomography, X-Ray Computed