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Original Investigation | Pacific Coast Surgical Association

Locally Advanced Pancreatic Cancer:  Association Between Prolonged Preoperative Treatment and Lymph-Node Negativity and Overall Survival

Brian E. Kadera, MD1; Dharma B. Sunjaya, BS1; William H. Isacoff, MD2; Luyi Li, MS1; O. Joe Hines, MD1,5; James S. Tomlinson, MD, PhD1,5; David W. Dawson, MD, PhD3,5,6; Matthew M. Rochefort, MD1; Graham W. Donald, MD1; Barbara M. Clerkin, RN, MPH1; Howard A. Reber, MD1,5; Timothy R. Donahue, MD1,4,5,6
[+] Author Affiliations
1Department of Surgery, Division of General Surgery, David Geffen School of Medicine at University of California, Los Angeles
2Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles
3Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles
4Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles
5Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles
6Institute for Molecular Medicine, David Geffen School of Medicine at University of California, Los Angeles
JAMA Surg. 2014;149(2):145-153. doi:10.1001/jamasurg.2013.2690.
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Importance  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.

Design, Setting, and Participants  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.

Main Outcomes and Measures  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 and Relevance  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.

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Figure 1.
Tumor Abutting the Superior Mesenteric Vein/Portal Vein With Significant Decrease in Size Following Downstaging Therapy

A, Pretreatment coronal-axis venous-phase computed tomographic image reveals tumor abutment of the superior mesenteric vein/portal vein. B, Posttreatment image shows a significant reduction in size, no longer impinging on the vein. This tumor was successfully removed without vascular resection.

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Figure 2.
Kaplan-Meier Analysis of Significant Prognostic Factors

Lymph node status (A), margins (B), histopathologic (HP) treatment response (C), perineural invasion (D), and SMAD4 protein expression (E) were significantly correlated with survival.

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Figure 3.
Representative Immunohistochemistry Staining of SMAD4 Protein in Tumor Cells and In Situ Hybridization for MicroRNA-21 in the Stroma

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