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Published in: Annals of Surgical Oncology 3/2021

01-03-2021 | Pancreatic Tumors

Margin-Positive Pancreatic Ductal Adenocarcinoma during Pancreaticoduodenectomy: Additional Resection Does Not Improve Survival

Authors: Richard Zheng, MD, MHS, David Nauheim, BA, Jonathan Bassig, BS, Matthew Chadwick, BS, Christopher W. Schultz, PhD, Geoffrey Krampitz, MD, PhD, Harish Lavu, MD, FACS, Jordan R. Winter, MD, FACS, Charles J. Yeo, MD, FACS, Adam C. Berger, MD, FACS

Published in: Annals of Surgical Oncology | Issue 3/2021

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Abstract

Background

The impact of resecting positive margins during pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDA) remains debated. Additionally, the survival benefit of resecting multiple positive margins is unknown.

Methods

We identified patients with PDA who underwent PD from 2006 to 2015. Pancreatic neck, bile duct, and uncinate frozen section margins were assessed before and after resection of positive margins. Survival curves were compared with log-rank tests. Multivariable Cox regression assessed the effect of margin status on overall survival.

Results

Of 501 patients identified, 17.3%, 5.3%, and 19.7% had an initially positive uncinate, bile duct, or neck margin, respectively. Among initially positive bile duct and neck margins, 77.8% and 67.0% were resected, respectively. Although median survival was decreased among patients with any positive margins (15.6 vs. 20.9 months; p = 0.006), it was similar among patients with positive bile duct or neck margins with or without R1 to R0 resection (17.0 vs. 15.6 months; p = 0.20). Median survival with and without positive uncinate margins was 13.8 vs. 19.7 months (p = 0.04). Uncinate margins were never resected. Resection of additional margins when the uncinate was concurrently positive was not associated with improved survival (p = 0.37). Patients with positive margins who received adjuvant therapy had improved survival, regardless of margin resection (p = 0.03). Adjuvant therapy was independently protective against death (hazard ratio 0.6, 95% CI 0.5–0.7).

Conclusions

Positive PD margins at any position are associated with reduced overall survival; however, resection of additional margins may not improve survival, particularly with concurrently positive uncinate margins. Adjuvant chemotherapy improves survival with positive margins, regardless of resection.
Literature
1.
go back to reference Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011;378(9791):607–620.CrossRef Vincent A, Herman J, Schulick R, Hruban RH, Goggins M. Pancreatic cancer. Lancet. 2011;378(9791):607–620.CrossRef
2.
go back to reference 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.CrossRef 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.CrossRef
3.
go back to reference Ghaneh P, Kleeff J, Halloran CM, Raraty M, Jackson R, Melling J, 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(3):520–529.CrossRef Ghaneh P, Kleeff J, Halloran CM, Raraty M, Jackson R, Melling J, 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(3):520–529.CrossRef
4.
go back to reference Yeo CJ, Cameron JL, Lillemoe KD, Sitzmann JV, Hruban RH, Goodman SN, et al. Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients. Ann Surg. 1995;221(6):721–31; (discussion 731). Yeo CJ, Cameron JL, Lillemoe KD, Sitzmann JV, Hruban RH, Goodman SN, et al. Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients. Ann Surg. 1995;221(6):721–31; (discussion 731).
5.
go back to reference Zhang B, Lee GC, Qadan M, Fong ZV, Mino-Kenudson M, Desphande V, et al. Revision of pancreatic neck margins based on intraoperative frozen section analysis is associated with improved survival in patients undergoing pancreatectomy for ductal adenocarcinoma. Ann Surg. Epub 5 Dec 2019. https://doi.org/10.1097/sla.0000000000003503. Zhang B, Lee GC, Qadan M, Fong ZV, Mino-Kenudson M, Desphande V, et al. Revision of pancreatic neck margins based on intraoperative frozen section analysis is associated with improved survival in patients undergoing pancreatectomy for ductal adenocarcinoma. Ann Surg. Epub 5 Dec 2019. https://​doi.​org/​10.​1097/​sla.​0000000000003503​.
6.
go back to reference Nitschke P, Volk A, Welsch T, Hackl J, Reissfelder C, Rahbari M, et al. Impact of intraoperative re-resection to achieve R0 status on survival in patients with pancreatic cancer: a single-center experience with 483 patients. Ann Surg. 2017;265(6):1219–1225.CrossRef Nitschke P, Volk A, Welsch T, Hackl J, Reissfelder C, Rahbari M, et al. Impact of intraoperative re-resection to achieve R0 status on survival in patients with pancreatic cancer: a single-center experience with 483 patients. Ann Surg. 2017;265(6):1219–1225.CrossRef
7.
go back to reference Zhang X-F, Squires MH, Bagante F, Ethun CG, Salem A, Weber SM, et al. The impact of intraoperative re-resection of a positive bile duct margin on clinical outcomes for hilar cholangiocarcinoma. Ann Surg Oncol. 2018;25(5):1140–1149.CrossRef Zhang X-F, Squires MH, Bagante F, Ethun CG, Salem A, Weber SM, et al. The impact of intraoperative re-resection of a positive bile duct margin on clinical outcomes for hilar cholangiocarcinoma. Ann Surg Oncol. 2018;25(5):1140–1149.CrossRef
8.
go back to reference Park Y, Hwang DW, Kim JH, Hong S-M, Jun S-Y, Lee JH, et al. Prognostic comparison of the longitudinal margin status in distal bile duct cancer: R0 on first bile duct resection versus R0 after additional resection. J Hepatobiliary Pancreat Sci. 2019;26(5):169–178.CrossRef Park Y, Hwang DW, Kim JH, Hong S-M, Jun S-Y, Lee JH, et al. Prognostic comparison of the longitudinal margin status in distal bile duct cancer: R0 on first bile duct resection versus R0 after additional resection. J Hepatobiliary Pancreat Sci. 2019;26(5):169–178.CrossRef
9.
go back to reference Ethun CG, Kooby DA. The importance of surgical margins in pancreatic cancer. J Surg Oncol. 2016;113(3):283–288.CrossRef Ethun CG, Kooby DA. The importance of surgical margins in pancreatic cancer. J Surg Oncol. 2016;113(3):283–288.CrossRef
10.
go back to reference Barreto SG, Pandanaboyana S, Ironside N, Windsor JA. Does revision of resection margins based on frozen section improve overall survival following pancreatoduodenectomy for pancreatic ductal adenocarcinoma? A meta-analysis. HPB (Oxford). 2017;19(7):573–579.CrossRef Barreto SG, Pandanaboyana S, Ironside N, Windsor JA. Does revision of resection margins based on frozen section improve overall survival following pancreatoduodenectomy for pancreatic ductal adenocarcinoma? A meta-analysis. HPB (Oxford). 2017;19(7):573–579.CrossRef
11.
go back to reference Hermanek P, Wittekind C. Residual tumor (R) classification and prognosis. Semin Surg Oncol. 1994;10(1):12–20.CrossRef Hermanek P, Wittekind C. Residual tumor (R) classification and prognosis. Semin Surg Oncol. 1994;10(1):12–20.CrossRef
12.
go back to reference Bassi C, Dervenis C, Butturini G, Fingerhut A, Yeo C, Izbicki J, et al. Postoperative pancreatic fistula: an international study group (ISGPF) definition. Surgery. 2005;138(1):8–13.CrossRef Bassi C, Dervenis C, Butturini G, Fingerhut A, Yeo C, Izbicki J, et al. Postoperative pancreatic fistula: an international study group (ISGPF) definition. Surgery. 2005;138(1):8–13.CrossRef
14.
go back to reference Allen PJ, Kuk D, Fernandez-Del Castillo C, et al. Multi-institutional validation study of the american joint commission on cancer (8th Edition) Changes for T and N staging in patients with pancreatic adenocarcinoma. Ann Surg. 2017;265:185–191. Allen PJ, Kuk D, Fernandez-Del Castillo C, et al. Multi-institutional validation study of the american joint commission on cancer (8th Edition) Changes for T and N staging in patients with pancreatic adenocarcinoma. Ann Surg. 2017;265:185–191.
15.
go back to reference Sohal DPS, Walsh RM, Ramanathan RK, Khorana AA. Pancreatic adenocarcinoma: treating a systemic disease with systemic therapy. J Natl Cancer Inst. 2014;106(3):dju011. Sohal DPS, Walsh RM, Ramanathan RK, Khorana AA. Pancreatic adenocarcinoma: treating a systemic disease with systemic therapy. J Natl Cancer Inst. 2014;106(3):dju011.
16.
go back to reference Yamamoto T, Yagi S, Kinoshita H, Sakamoto Y, Okada K, Uryuhara K, et al. Long-term survival after resection of pancreatic cancer: a single-center retrospective analysis. World J Gastroenterol. 2015;21(1):262–268.CrossRef Yamamoto T, Yagi S, Kinoshita H, Sakamoto Y, Okada K, Uryuhara K, et al. Long-term survival after resection of pancreatic cancer: a single-center retrospective analysis. World J Gastroenterol. 2015;21(1):262–268.CrossRef
17.
go back to reference Jamieson NB, Foulis AK, Oien KA, Going JJ, Glen P, Dickson EJ, et al. Positive mobilization margins alone do not influence survival following pancreatico-duodenectomy for pancreatic ductal adenocarcinoma. Ann Surg. 2010;251(6):1003–1010.CrossRef Jamieson NB, Foulis AK, Oien KA, Going JJ, Glen P, Dickson EJ, et al. Positive mobilization margins alone do not influence survival following pancreatico-duodenectomy for pancreatic ductal adenocarcinoma. Ann Surg. 2010;251(6):1003–1010.CrossRef
18.
go back to reference Petrucciani N, Nigri G, Debs T, Giannini G, Sborlini E, Antolino L, et al. Frozen section analysis of the pancreatic margin during pancreaticoduodenectomy for cancer: does extending the resection to obtain a secondary R0 provide a survival benefit? Results of a systematic review. Pancreatology. 2016;16(6):1037–1043.PubMed Petrucciani N, Nigri G, Debs T, Giannini G, Sborlini E, Antolino L, et al. Frozen section analysis of the pancreatic margin during pancreaticoduodenectomy for cancer: does extending the resection to obtain a secondary R0 provide a survival benefit? Results of a systematic review. Pancreatology. 2016;16(6):1037–1043.PubMed
19.
go back to reference Kooby DA, Lad NL, Squires MH, Maithel SK, Sarmiento JM, Staley CA, et al. Value of intraoperative neck margin analysis during Whipple for pancreatic adenocarcinoma: a multicenter analysis of 1399 patients. Ann Surg. 2014;260(3):494–501; (discussion 501). Kooby DA, Lad NL, Squires MH, Maithel SK, Sarmiento JM, Staley CA, et al. Value of intraoperative neck margin analysis during Whipple for pancreatic adenocarcinoma: a multicenter analysis of 1399 patients. Ann Surg. 2014;260(3):494–501; (discussion 501).
20.
go back to reference Lad NL, Squires MH, Maithel SK, Fisher SB, Mehta VV, Cardona K, et al. Is it time to stop checking frozen section neck margins during pancreaticoduodenectomy? Ann Surg Oncol. 2013;20(11):3626–3633.CrossRef Lad NL, Squires MH, Maithel SK, Fisher SB, Mehta VV, Cardona K, et al. Is it time to stop checking frozen section neck margins during pancreaticoduodenectomy? Ann Surg Oncol. 2013;20(11):3626–3633.CrossRef
21.
go back to reference Fatima J, Schnelldorfer T, Barton J, Wood CM, Wiste HJ, Smyrk TC, et al. Pancreatoduodenectomy for ductal adenocarcinoma: implications of positive margin on survival. Arch Surg. 2010;145(2):167–172.CrossRef Fatima J, Schnelldorfer T, Barton J, Wood CM, Wiste HJ, Smyrk TC, et al. Pancreatoduodenectomy for ductal adenocarcinoma: implications of positive margin on survival. Arch Surg. 2010;145(2):167–172.CrossRef
22.
go back to reference Pang TCY, Wilson O, Argueta MA, Hugh TJ, Chou A, Samra JS, et al. Frozen section of the pancreatic neck margin in pancreatoduodenectomy for pancreatic adenocarcinoma is of limited utility. Pathology. 2014;46(3):188–192.CrossRef Pang TCY, Wilson O, Argueta MA, Hugh TJ, Chou A, Samra JS, et al. Frozen section of the pancreatic neck margin in pancreatoduodenectomy for pancreatic adenocarcinoma is of limited utility. Pathology. 2014;46(3):188–192.CrossRef
23.
go back to reference Mathur A, Ross SB, Luberice K, Kurian T, Vice M, Toomey P, et al. Margin status impacts survival after pancreaticoduodenectomy but negative margins should not be pursued. Am Surg. 2014;80(4):353–360.CrossRef Mathur A, Ross SB, Luberice K, Kurian T, Vice M, Toomey P, et al. Margin status impacts survival after pancreaticoduodenectomy but negative margins should not be pursued. Am Surg. 2014;80(4):353–360.CrossRef
24.
go back to reference Keane FK, Wo JY, Ferrone CR, Clark JW, Blaszkowsky LS, Allen JN, et al. Intraoperative radiotherapy in the era of intensive neoadjuvant chemotherapy and chemoradiotherapy for pancreatic adenocarcinoma. Am J Clin Oncol. 2018;41(6):607–612.CrossRef Keane FK, Wo JY, Ferrone CR, Clark JW, Blaszkowsky LS, Allen JN, et al. Intraoperative radiotherapy in the era of intensive neoadjuvant chemotherapy and chemoradiotherapy for pancreatic adenocarcinoma. Am J Clin Oncol. 2018;41(6):607–612.CrossRef
25.
go back to reference Otsuka S, Ebata T, Yokoyama Y, Mizuno T, Tsukahara T, Shimoyama Y, et al. Clinical value of additional resection of a margin-positive distal bile duct in perihilar cholangiocarcinoma. Br J Surg. 2019;106(6):774–782.CrossRef Otsuka S, Ebata T, Yokoyama Y, Mizuno T, Tsukahara T, Shimoyama Y, et al. Clinical value of additional resection of a margin-positive distal bile duct in perihilar cholangiocarcinoma. Br J Surg. 2019;106(6):774–782.CrossRef
26.
go back to reference Osipov A, Nissen N, Rutgers J, Dhall D, Naziri J, Chopra S, 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(12):3674–3682.CrossRef Osipov A, Nissen N, Rutgers J, Dhall D, Naziri J, Chopra S, 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(12):3674–3682.CrossRef
28.
go back to reference Campbell F, Foulis AK, Verbeke CC. Dataset for the Histopathological Reporting of Carcinomas of the Pancreas, Ampulla of Vater and Common Bile Duct. London: The Royal College of Pathologists; 2010. Campbell F, Foulis AK, Verbeke CC. Dataset for the Histopathological Reporting of Carcinomas of the Pancreas, Ampulla of Vater and Common Bile Duct. London: The Royal College of Pathologists; 2010.
29.
go back to reference 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. 2017;47(4):490–497.CrossRef 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. 2017;47(4):490–497.CrossRef
30.
go back to reference Delpero JR, Jeune F, Bachellier P, Regenet N, Le Treut YP, Paye F, et al. Prognostic value of resection margin involvement after pancreaticoduodenectomy for ductal adenocarcinoma: updates from a french prospective multicenter study. Ann Surg. 2017;266(5):787–796.CrossRef Delpero JR, Jeune F, Bachellier P, Regenet N, Le Treut YP, Paye F, et al. Prognostic value of resection margin involvement after pancreaticoduodenectomy for ductal adenocarcinoma: updates from a french prospective multicenter study. Ann Surg. 2017;266(5):787–796.CrossRef
31.
go back to reference van Roessel S, Kasumova GG, Tabatabaie O, Ng SC, van Rijssen LB, Verheij J, et al. Pathological margin clearance and survival after pancreaticoduodenectomy in a US and European pancreatic center. Ann Surg Oncol. 2018;25(6):1760–1767.CrossRef van Roessel S, Kasumova GG, Tabatabaie O, Ng SC, van Rijssen LB, Verheij J, et al. Pathological margin clearance and survival after pancreaticoduodenectomy in a US and European pancreatic center. Ann Surg Oncol. 2018;25(6):1760–1767.CrossRef
32.
go back to reference Pine JK, Haugk B, Robinson SM, Darne A, Wilson C, Sen G, et al. Prospective assessment of resection margin status following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma after standardisation of margin definitions. Pancreatology. 2020;20(3):537–544.CrossRef Pine JK, Haugk B, Robinson SM, Darne A, Wilson C, Sen G, et al. Prospective assessment of resection margin status following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma after standardisation of margin definitions. Pancreatology. 2020;20(3):537–544.CrossRef
36.
go back to reference Schmidt CM, Glant J, Winter JM, Kennard J, Dixon J, Zhao Q, et al. Total pancreatectomy (R0 resection) improves survival over subtotal pancreatectomy in isolated neck margin positive pancreatic adenocarcinoma. Surgery. 2007;142(4):572–578; (discussion 578). Schmidt CM, Glant J, Winter JM, Kennard J, Dixon J, Zhao Q, et al. Total pancreatectomy (R0 resection) improves survival over subtotal pancreatectomy in isolated neck margin positive pancreatic adenocarcinoma. Surgery. 2007;142(4):572–578; (discussion 578).
Metadata
Title
Margin-Positive Pancreatic Ductal Adenocarcinoma during Pancreaticoduodenectomy: Additional Resection Does Not Improve Survival
Authors
Richard Zheng, MD, MHS
David Nauheim, BA
Jonathan Bassig, BS
Matthew Chadwick, BS
Christopher W. Schultz, PhD
Geoffrey Krampitz, MD, PhD
Harish Lavu, MD, FACS
Jordan R. Winter, MD, FACS
Charles J. Yeo, MD, FACS
Adam C. Berger, MD, FACS
Publication date
01-03-2021
Publisher
Springer International Publishing
Published in
Annals of Surgical Oncology / Issue 3/2021
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-020-09000-9

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