Top

05-09-2017 | Pancreatic cancer | Article

Redefining the Positive Margin in Pancreatic Cancer: Impact on Patterns of Failure, Long-Term Survival and Adjuvant Therapy

Journal: Annals of Surgical Oncology

Authors: Arsen Osipov, MD, Nicholas Nissen, MD, Joanne Rutgers, MD, Deepti Dhall, MD, Jason Naziri, BS, Shefali Chopra, MD, Quanlin Li, MS, Andrew Eugene Hendifar, MD, MPH, Richard Tuli, MD, PhD

Publisher: Springer International Publishing

Abstract

Purpose

There is debate regarding the definition and clinical significance of margin clearance in pancreatic ductal adenocarcinoma (PDA). A comprehensive archival analysis of surgical resection margins was performed to determine the effect on locoregional recurrence and survival, and the impact of adjuvant therapy in PDA.

Methods

We identified 105 patients with resected PDA. Pancreatic, anterior, bile duct, and posterior surgical resection margins (PM; posterior surface, uncinate and vascular groove) were identified. Three pathologists reviewed all archival surgical specimens and recategorized each margin as tumor at ink/transected, <0.5, 0.5–1, >1–2, or >2 mm from the inked surface. The impact of these and other clinical variables was assessed on local control, disease-free survival (DFS), and overall survival (OS).

Results

Among all margins, PM clearance up to 2 mm was prognostic of DFS (p = 0.01) and OS (p = 0.01). Dichotomizing the PM at 2 mm revealed it to be an independent predictor of local recurrence-free survival [hazard ratio HR] 0.20, 95% confidence interval [CI] 0.048–0.881, p = 0.033), DFS (HR 0.46, 95% CI 0.22–0.96, p = 0.03), and OS (HR 0.31, 95% CI 0.14–0.74, p = 0.008). A margin status of >2 mm was also prognostic of OS in patients who received adjuvant chemotherapy (HR 0.31, 95% CI 0.11–0.89, p = 0.03), however this difference was mitigated in patients receiving adjuvant chemoradiotherapy (HR 0.40, 95% CI 0.10–1.58, p = 0.19).

Conclusion

These data highlight the clinical significance of the PM and the lack of significance of other resection margins. Clearance in excess of 2 mm should be considered to improve long-term clinical outcomes. The use of adjuvant radiotherapy should be strongly considered in patients with PMs <2 mm.

Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913–21.CrossRefPubMed

SEER Cancer Statistics Review. National Cancer Institute; 1975–2013. http://seer.cancer.gov/csr/1975_2013/. Accessed 9 Jan 2016.

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(2):118–21.CrossRefPubMedPubMedCentral

Ghaneh P, Costello E, Neoptolemos JP. Biology and management of pancreatic cancer. Postgraduate Med J. 2008;84(995):478–97.CrossRefPubMed

Oettle H, Post S, Neuhaus P, Gellert K, Langrehr J, Ridwelski K et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007;297(3):267–77.CrossRefPubMed

Stocken DD, Buchler MW, Dervenis C, Bassi C, Jeekel H, Klinkenbijl JH et al. Meta-analysis of randomised adjuvant therapy trials for pancreatic cancer. Br J Cancer. 2005;92(8):1372–81.CrossRefPubMedPubMedCentral

Yovino S, Maidment BW, Herman JM, Pandya N, Goloubeva O, Wolfgang C et al. Analysis of local control in patients receiving IMRT for resected pancreatic cancers. Int J Radiat Oncol Biol Phys. 2012;83(3):916–20.CrossRefPubMedPubMedCentral

Boyle J, Czito B, Willett C, Palta M. Adjuvant radiation therapy for pancreatic cancer: a review of the old and the new. J Gastrointest Oncol. 2015;6(4):436–44.PubMedPubMedCentral

Klinkenbijl JH, Jeekel J, Sahmoud T, van Pel R, Couvreur ML, Veenhof CH et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg. 1999;230(6):776–82; discussion 782-774.CrossRefPubMedPubMedCentral

10.

Neoptolemos JP, Stocken DD, Friess H, Bassi C, Dunn JA, Hickey H et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350(12):1200–10.CrossRefPubMed

11.

Meyer W, Jurowich C, Reichel M, Steinhauser B, Wunsch PH, Gebhardt C. Pathomorphological and histological prognostic factors in curatively resected ductal adenocarcinoma of the pancreas. Surg Today. 2000;30(7):582–87.CrossRefPubMed

12.

Bilimoria KY, Bentrem DJ, Ko CY, Ritchey J, Stewart AK, Winchester DP et al. Validation of the 6th edition AJCC pancreatic cancer staging system: report from the National cancer database. Cancer. 2007;110(4):738–44.CrossRefPubMed

13.

Hartwig W, Hackert T, Hinz U, Gluth A, Bergmann F, Strobel O et al. Pancreatic cancer surgery in the new millennium: better prediction of outcome. Ann Surg. 2011;254(2):311–19.CrossRefPubMed

14.

Butturini G, Stocken DD, Wente MN, Jeekel H, Klinkenbijl JH, Bakkevold KE et al. Influence of resection margins and treatment on survival in patients with pancreatic cancer: meta-analysis of randomized controlled trials. Arch Surg. 2008;143(1):75–83, discussion 83.CrossRefPubMed

15.

Chang DK, Johns AL, Merrett ND, Gill AJ, Colvin EK, Scarlett CJ et al. Margin clearance and outcome in resected pancreatic cancer. J Clin Oncol. 2009;27(17):2855–62.CrossRefPubMed

16.

Paniccia A, Hosokawa P, Henderson W, Schulick RD, Edil BH, McCarter MD et al. Characteristics of 10-Year Survivors of Pancreatic Ductal Adenocarcinoma. JAMA Surg. 2015;150(8):701–10.CrossRefPubMed

17.

Verbeke CS. Resection margins in pancreatic cancer. Pathologe. 2013;34 (Suppl 2):241–47.CrossRefPubMed

18.

Ethun CG, Kooby DA. The importance of surgical margins in pancreatic cancer. J Surg Oncol. 2016;113(3):283–88.CrossRefPubMed

19.

Campbell F, Smith RA, Whelan P, Sutton R, Raraty M, Neoptolemos JP 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(3):277–83.CrossRefPubMed

20.

Gill AJ, Johns AL, Eckstein R, Samra JS, Kaufman A, Chang DK et al. Synoptic reporting improves histopathological assessment of pancreatic resection specimens. Pathology. 2009;41(2):161–67.CrossRefPubMed

21.

Katz MH, Merchant NB, Brower S, Branda M, Posner MC, Traverso LW et al. Standardization of surgical and pathologic variables is needed in multicenter trials of adjuvant therapy for pancreatic cancer: results from the ACOSOG Z5031 trial. Ann Surg Oncol. 2011;18(2):337–44.CrossRefPubMed

22.

College of American Pathologists. Protocol for the Examination of Specimens From Patients With Carcinoma of the Exocrine Pancreas. 2013; http://www.cap.org/apps/docs/committees/cancer/cancer_protocols/2013/PancreasExo_13protocol_3201.pdf. Accessed December 11, 2016.

23.

Osipov A, Naziri J, Hendifar A, Dhall D, Rutgers JK, Chopra S et al. Impact of margin status and lymphadenectomy on clinical outcomes in resected pancreatic adenocarcinoma: implications for adjuvant radiotherapy. J Gastrointest Oncol. 2016;7(2):239–47.PubMedPubMedCentral

24.

Nitta T, Nakamura T, Mitsuhashi T, Asano T, Okamura K, Tsuchikawa T et al. The impact of margin status determined by the one-millimeter rule on tumor recurrence and survival following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma. Surg Today. 2016;47(4): 490-497.CrossRefPubMed

25.

Pathologists TRCo. The Royal College of Pathologists. Standards and Minimum Datasets for Reporting Cancers. Dataset for the histopathological reporting of carcinomas of the pancreas, ampulla of Vater and common bile duct. London 2002.

26.

Esposito I, Kleeff J, Bergmann F, Reiser C, Herpel E, Friess H et al. Most pancreatic cancer resections are R1 resections. Ann Surg Oncol. 2008;15(6):1651–60.CrossRefPubMed

27.

Sobin LH GM, Wittekind C (2009) International Union Against Cancer TNM classification of malignant tumours. 7th edWiley-Blackwell, Oxford.

28.

Griffin JF, Smalley SR, Jewell W, Paradelo JC, Reymond RD, Hassanein RE et al. Patterns of failure after curative resection of pancreatic carcinoma. Cancer. 1990;66(1):56–61.CrossRefPubMed

29.

Gnerlich JL, Luka SR, Deshpande AD, Dubray BJ, Weir JS, Carpenter DH et al. Microscopic margins and patterns of treatment failure in resected pancreatic adenocarcinoma. Arch Surg. 2012;147(8):753–60.CrossRefPubMed

30.

Gebauer F, Tachezy M, Vashist YK, Marx AH, Yekebas E, Izbicki JR et al. Resection margin clearance in pancreatic cancer after implementation of the Leeds pathology protocol (LEEPP): clinically relevant or just academic? World J Surg. 2015;39(2):493–99.CrossRefPubMed

31.

John BJ, Naik P, Ironside A, Davidson BR, Fusai G, Gillmore R et al. Redefining the R1 resection for pancreatic ductal adenocarcinoma: tumour lymph nodal burden and lymph node ratio are the only prognostic factors associated with survival. HPB (Oxford). 2013;15(9):674–80.CrossRefPubMedPubMedCentral

32.

Chandrasegaram MD, Goldstein D, Simes J, Gebski V, Kench JG, Gill AJ et al. Meta-analysis of radical resection rates and margin assessment in pancreatic cancer. Br J Surg. 2015;102(12):1459–72.CrossRefPubMed

33.

Van den Broeck A, Sergeant G, Ectors N, Van Steenbergen W, Aerts R, Topal B. Patterns of recurrence after curative resection of pancreatic ductal adenocarcinoma. Eur J Surg Oncol. 2009;35(6):600–04.CrossRefPubMed

34.

Sperti C, Pasquali C, Piccoli A, Pedrazzoli S. Recurrence after resection for ductal adenocarcinoma of the pancreas. World J Surg. 1997;21(2):195–200.CrossRefPubMed

35.

Konstantinidis IT, Warshaw AL, Allen JN, Blaszkowsky LS, Fernandez-del Castillo C, Deshpande V et al. Pancreatic ductal adenocarcinoma: is there a survival difference for R1 resections versus locally advanced unresectable tumors? What is a “true” R0 resection? Ann Surg. 2013;257(4):731–36.CrossRefPubMed

36.

Walker EJ, Ko AH. Beyond first-line chemotherapy for advanced pancreatic cancer: an expanding array of therapeutic options? World J Gastroenterol. 2014;20(9):2224–36.CrossRefPubMedPubMedCentral

37.

Gill S, Sargent D. End points for adjuvant therapy trials: has the time come to accept disease-free survival as a surrogate end point for overall survival? Oncologist. 2006;11(6):624–29.CrossRefPubMed

38.

Verbeke CS, Menon KV. Redefining resection margin status in pancreatic cancer. HPB (Oxford). 2009;11(4):282–89.CrossRefPubMedPubMedCentral

39.

Liu C, Tian X, Xie X, Gao H, Zhuang Y, Yang Y. Comparison of uncinate process cancer and non-uncinate process pancreatic head cancer. J Cancer. 2016;7(10):1242–49.CrossRefPubMedPubMedCentral

40.

Jin G, Sugiyama M, Tuo H, Oki A, Abe N, Mori T et al. Distribution of lymphatic vessels in the neural plexuses surrounding the superior mesenteric artery. Pancreas. 2006;32(1):62–66.CrossRefPubMed

41.

Jang JY, Kang MJ, Heo JS, Choi SH, Choi DW, Park SJ et al. A prospective randomized controlled study comparing outcomes of standard resection and extended resection, including dissection of the nerve plexus and various lymph nodes, in patients with pancreatic head cancer. Ann Surg. 2014;259(4):656–64.CrossRefPubMed

42.

Hernandez J, Mullinax J, Clark W, Toomey P, Villadolid D, Morton C et al. Survival after pancreaticoduodenectomy is not improved by extending resections to achieve negative margins. Ann Surg. 2009;250(1):76–80.CrossRefPubMed

43.

Neoptolemos JP, Stocken DD, Dunn JA, Almond J, Beger HG, Pederzoli P et al. Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial. Ann Surg. 2001;234(6):758–68.CrossRefPubMedPubMedCentral

44.

Herman JM, Swartz MJ, Hsu CC, Winter J, Pawlik TM, Sugar E et al. Analysis of fluorouracil-based adjuvant chemotherapy and radiation after pancreaticoduodenectomy for ductal adenocarcinoma of the pancreas: results of a large, prospectively collected database at the Johns Hopkins Hospital. J Clin Oncol. 2008;26(21):3503–10.CrossRefPubMedPubMedCentral

45.

Rwigema JC, Heron DE, Parikh SD, Zeh HJ, Moser JA, Bahary N et al. Adjuvant stereotactic body radiotherapy for resected pancreatic adenocarcinoma with close or positive margins. J Gastrointest Cancer. 2012;43(1):70–76.CrossRefPubMed