Skip to main content

Neoadjuvant Chemoradiation Impacts the Prognostic Effect of Surgical Margin Status in Pancreatic Adenocarcinoma



Many studies show significantly improved survival after R0 resection compared with R1 resection in pancreatic adenocarcinoma (PAC); however, the effect of neoadjuvant chemoradiation (NACRT) on this association is unknown.


The aim of this study was to evaluate the prognostic significance of positive surgical margins (SMs) after NACRT compared with upfront surgery + adjuvant therapy in PAC.


All cases of surgically resected PAC at a single institution were reviewed from 1996 to 2014; patients treated with palliative intent, metastatic disease, and biliary/ampullary tumors were excluded. The primary endpoint was overall survival (OS).


Overall, 300 patients were included; 134 patients received NACRT with concurrent 5-fluorouracil or gemcitabine followed by surgery, and 166 patients received upfront surgery (+ adjuvant chemotherapy in 72% of patients and RT in 65%); 31% of both groups had a positive SM (+SM). The median OS for patients with a +SM or negative SM (−SM) was 26.6 and 31.6 months, respectively for NACRT, and 12.0 and 24.5 months, respectively, for upfront surgery. OS was significantly improved with −SM compared with +SM in both groups (p = 0.006). When resection yielded +SM, NACRT patients had improved OS compared with upfront surgery patients (p < 0.001). On multivariable analysis, +SM in the upfront surgery group (hazard ratio [HR] 2.94, 95% confidence interval [CI] 2.04–4.24; p < 0.001) and older age (HR 1.01, 95% CI 1.00–1.03, per year; p = 0.007) predicted worse OS. +SM in the NACRT group was not associated with worse OS (HR 1.09, 95% CI 0.72–1.65; p = 0.70).


Patients with a positive margin after NACRT and surgery had longer survival compared with patients with a positive margin after upfront surgery. NACRT should be strongly considered for patients at high risk of R1 resections.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4


  1. 1.

    Pingpank JF, Hoffman JP, Ross EA, et al. Effect of preoperative chemoradiotherapy on surgical margin status of resected adenocarcinoma of the head of the pancreas. J Gastrointest Surg. 2001;5:121–30.

    CAS  Article  Google Scholar 

  2. 2.

    Ghaneh P, Kleeff J, Halloran CM, et al. the impact of positive resection margins on survival and recurrence following resection and adjuvant chemotherapy for pancreatic ductal adenocarcinoma. Ann Surg. 2019;269:520–9.

    Article  Google Scholar 

  3. 3.

    Paniccia A, Hosokawa P, Henderson W, et al. Characteristics of 10-year survivors of pancreatic ductal adenocarcinoma. JAMA Surg. 2015;150:701–10.

    Article  Google Scholar 

  4. 4.

    Brown KM, Siripurapu V, Davidson M, et al. Chemoradiation followed by chemotherapy before resection for borderline pancreatic adenocarcinoma. Am J Surg. 2008;195:318–21.

    CAS  Article  Google Scholar 

  5. 5.

    Stessin AM, Meyer JE, Sherr DL. 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;72:1128–33.

    Article  Google Scholar 

  6. 6.

    Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas. J Clin Oncol. 1997;15:928–37.

    CAS  Article  Google Scholar 

  7. 7.

    Winter JM, Cameron JL, Campbell KA, et al. 1423 pancreaticoduodenectomies for pancreatic cancer: a single-institution experience. J Gastrointest Surg. 2006;10:1199–210.

    Article  Google Scholar 

  8. 8.

    Raut CP, Tseng JF, Sun CC, et al. Impact of resection status on pattern of failure and survival after pancreaticoduodenectomy for pancreatic adenocarcinoma. Ann Surg. 2007;246:52–60.

    Article  Google Scholar 

  9. 9.

    de Geus S, Kasumova G, Eskander M, et al. Neoadjuvant therapy affects margins and margins affect all: perioperative and survival outcomes in resected pancreatic adenocarcinoma. HPB. 2017;19:S61.

    Article  Google Scholar 

  10. 10.

    Katz MHG, Ou FS, Herman JM, et al. Alliance for clinical trials in oncology (ALLIANCE) trial A021501: preoperative extended chemotherapy vs. chemotherapy plus hypofractionated radiation therapy for borderline resectable adenocarcinoma of the head of the pancreas. BMC Cancer. 2017;17:505.

    Article  Google Scholar 

  11. 11.

    Shaikh T, Ruth K, Scott WJ, et al. Increased time from neoadjuvant chemoradiation to surgery is associated with higher pathologic complete response rates in esophageal cancer. Ann Thorac Surg. 2015;99:270–6.

    Article  Google Scholar 

  12. 12.

    Kalady MF, de Campos-Lobato LF, Stocchi L, et al. Predictive factors of pathologic complete response after neoadjuvant chemoradiation for rectal cancer. Ann Surg. 2009;250:582–9.

    Article  Google Scholar 

  13. 13.

    Sloothaak DAM, Geijsen DE, van Leersum NJ, et al. Optimal time interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer. Br J Surg. 2013;100:933–9.

    CAS  Article  Google Scholar 

  14. 14.

    Garcia-Aguilar J, Smith DD, Avila K, et al. Optimal timing of surgery after chemoradiation for advanced rectal cancer: preliminary results of a multicenter, nonrandomized phase II prospective trial. Ann of Surg. 2011;254:97–102.

    Article  Google Scholar 

  15. 15.

    Verbeke CS. Resection margins in pancreatic cancer. Surg Clin North Am. 2013;93:647–62.

    Article  Google Scholar 

  16. 16.

    Ethun CG, Kooby DA. The importance of surgical margins in pancreatic cancer. J Surg Oncol. 2016;113:283–8.

    Article  Google Scholar 

  17. 17.

    Campbell F, Smith RA, Whelan P, et al. Classification of R1 resections for pancreatic cancer: the prognostic relevance of tumour involvement within 1 mm of a resection margin. Histopathology. 2009;55:277–83.

    Article  Google Scholar 

  18. 18.

    Osipov A, Nissen N, Rutgers J, et al. Redefining the positive margin in pancreatic cancer: impact on patterns of failure, long-term survival and adjuvant therapy. Ann Surg Oncol. 2017;24:3674–82.

    Article  Google Scholar 

  19. 19.

    Chun YS, Cooper HS, Cohen SJ, et al. Significance of pathologic response to preoperative therapy in pancreatic cancer. Ann Surg Oncol. 2011;18:3601–7.

    Article  Google Scholar 

  20. 20.

    Murphy JE, Wo JY, Ryan DP, et al. Total neoadjuvant therapy with FOLFIRINOX followed by individualized chemoradiotherapy for borderline resectable pancreatic adenocarcinoma: a phase 2 clinical trial. JAMA Oncol. 2018;4:963–9.

    Article  Google Scholar 

  21. 21.

    Tachezy M, Gebauer F, Petersen C, et al. Sequential neoadjuvant chemoradiotherapy (CRT) followed by curative surgery vs. primary surgery alone for resectable, non-metastasized pancreatic adenocarcinoma: NEOPA- a randomized multicenter phase III study. BMC Cancer. 2014;14:411 (NCT01900327, DRKS00003893, ISRCTN82191749).

    Article  Google Scholar 

  22. 22.

    Van Tienhoven G, Versteijne E, Suker M, et al. Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC-1): A randomized, controlled, multicenter phase III trial. J Clin Oncol. 2018;36:LBA4002.

    Article  Google Scholar 

  23. 23.

    Jang J-Y, Han Y, Lee H, et al. Oncological benefits of neoadjuvant chemoradiation with gemcitabine versus upfront surgery in patients with borderline resectable pancreatic cancer: a prospective, randomized, open-label, multicenter phase 2/3 trial. Ann Surg. 2018;268:215–22.

    Article  Google Scholar 

Download references


The authors would like to express their gratitude to the patients and caregivers who made this study possible.

Author information



Corresponding author

Correspondence to Joshua E. Meyer.

Ethics declarations


The Fox Chase Cancer Center institution is supported by NCI grant number P30 CA006927. Elizabeth Handorf is supported by a Pfizer grant, unrelated to the current research, and Efrat Dotan has received research support, paid to the institution and unrelated to this published work, from Pfizer, Incyte, Lilly, Merck, Boston Biomedical, GSK, AstraZeneca, Immunomedics, Oncomed, Bayer. Eddie Zhang, Lora Wang, Talha Shaikh, J. Karen Wong, John P. Hoffman, Sanjay Reddy, Harry S. Cooper, Steven J. Cohen, and Joshua E. Meyer have no disclosures to declare.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zhang, E., Wang, L., Shaikh, T. et al. Neoadjuvant Chemoradiation Impacts the Prognostic Effect of Surgical Margin Status in Pancreatic Adenocarcinoma. Ann Surg Oncol (2021).

Download citation