Top

Published in:

Open Access 01-06-2020 | Pancreatectomy | Pancreatic Tumors

Impact of Neoadjuvant Therapy in Resected Pancreatic Ductal Adenocarcinoma of the Pancreatic Body or Tail on Surgical and Oncological Outcome: A Propensity-Score Matched Multicenter Study

Authors: Sanne Lof, MD, Maarten Korrel, BSc, Jony van Hilst, MD, PhD, Adnan Alseidi, MD, Gianpaolo Balzano, MD, Ugo Boggi, MD, Giovanni Butturini, MD, PhD, Riccardo Casadei, MD, PhD, Safi Dokmak, MD, Bjørn Edwin, MD, PhD, Massimo Falconi, MD, Tobias Keck, MD, Giuseppe Malleo, MD, PhD, Matteo de Pastena, MD, Ales Tomazic, MD, PhD, Hanneke Wilmink, MD, PhD, Alessandro Zerbi, MD, PhD, Marc G. Besselink, MD, PhD, Mohammed Abu Hilal, MD, PhD, for the European Consortium on Minimally Invasive Pancreatic Surgery (E-MIPS)

Published in: Annals of Surgical Oncology | Issue 6/2020

Abstract

Background

Several studies have suggested a survival benefit of neoadjuvant therapy (NAT) for pancreatic ductal adenocarcinoma (PDAC) in the pancreatic head. Data concerning NAT for PDAC located in pancreatic body or tail are lacking.

Methods

Post hoc analysis of an international multicenter retrospective cohort of distal pancreatectomy for PDAC in 34 centers from 11 countries (2007–2015). Patients who underwent resection after NAT were matched (1:1 ratio), using propensity scores based on baseline characteristics, to patients who underwent upfront resection. Median overall survival was compared using the stratified log-rank test.

Results

Among 1236 patients, 136 (11.0%) received NAT, most frequently FOLFIRINOX (25.7%). In total, 94 patients receiving NAT were matched to 94 patients undergoing upfront resection. NAT was associated with less postoperative major morbidity (Clavien–Dindo ≥ 3a, 10.6% vs. 23.4%, P = 0.020) and pancreatic fistula grade B/C (9.6% vs. 21.3%, P = 0.026). NAT did not improve overall survival [27 (95% CI 14–39) versus 31 months (95% CI 19–42), P = 0.277], as compared with upfront resection. In a sensitivity analysis of 251 patients with radiographic tumor involvement of splenic vessels, NAT (n = 37, 14.7%) was associated with prolonged overall survival [36 (95% CI 18–53) versus 20 months (95% CI 15–24), P = 0.049], as compared with upfront resection.

Conclusion

In this international multicenter cohort study, NAT for resected PDAC in pancreatic body or tail was associated with less morbidity and pancreatic fistula but similar overall survival in comparison with upfront resection. Prospective studies should confirm a survival benefit of NAT in patients with PDAC and splenic vessel involvement.

Available only for authorised users

van Erning FN, Mackay TM, van der Geest LGM, et al. Association of the location of pancreatic ductal adenocarcinoma (head, body, tail) with tumor stage, treatment, and survival: a population-based analysis. Acta Oncol (Madr). 2018;57(12):1655–1662.CrossRef

Artinyan A, Soriano PA, Prendergast C, Low T, Ellenhorn JDI, Kim J. The anatomic location of pancreatic cancer is a prognostic factor for survival. HPB. 2008;10(5):371–376. https://doi.org/10.1080/13651820802291233.CrossRefPubMedPubMedCentral

Magge D, Gooding W, Choudry H, et al. Comparative effectiveness of minimally invasive and open distal pancreatectomy for ductal adenocarcinoma. JAMA Surg. 2013;148(6):525–531. https://doi.org/10.1001/jamasurg.2013.1673.CrossRefPubMed

Ruess DA, Makowiec F, Chikhladze S, et al. The prognostic influence of intrapancreatic tumor location on survival after resection of pancreatic ductal adenocarcinoma visceral and general surgery. BMC Surg. 2015;15(1):1–8. https://doi.org/10.1186/s12893-015-0110-5.CrossRef

Winer LK, Dhar VK, Wima K, et al. The impact of tumor location on resection and survival for pancreatic ductal adenocarcinoma. J Surg Res. 2019;239:60–66. https://doi.org/10.1016/j.jss.2019.01.061.CrossRefPubMed

Gillen S, Schuster T, Büschenfelde CM Zum, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med. 2010;7(4):1–15. https://doi.org/10.1371/journal.pmed.1000267.

Verma V, Li J, Lin C. Neoadjuvant therapy for pancreatic cancer: systematic review of postoperative morbidity, mortality, and complications. Am J Clin Oncol Cancer Clin Trials. 2016;39(3):302–313. https://doi.org/10.1097/coc.0000000000000278.CrossRef

Mackay TM, Smits FJ, Roos D, et al. The risk of not receiving adjuvant chemotherapy after resection of pancreatic ductal adenocarcinoma: a nationwide analysis. HPB. August 2019. https://doi.org/10.1016/j.hpb.2019.06.019.CrossRefPubMed

Versteijne E, Vogel JA, Besselink MG, et al. Meta-analysis comparing upfront surgery with neoadjuvant treatment in patients with resectable or borderline resectable pancreatic cancer. Br J Surg. 2018;105(8):946–958. https://doi.org/10.1002/bjs.10870.CrossRefPubMedPubMedCentral

10.

Mokdad AA, Minter RM, Zhu H, et al. Neoadjuvant therapy followed by resection versus upfront resection for resectable pancreatic cancer: a propensity score matched analysis. J Clin Oncol. 2017;35(5):515–522. https://doi.org/10.1200/jco.2016.68.5081.CrossRefPubMed

11.

Petrelli F, Coinu A, Borgonovo K, et al. FOLFIRINOX-based neoadjuvant therapy in borderline resectable or unresectable pancreatic cancer: a meta-analytical review of published studies. Pancreas. 2015;44(4):515–521. https://doi.org/10.1097/mpa.0000000000000314.CrossRefPubMed

12.

Golcher H, Brunner TB, Witzigmann H, et al. Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer. Strahlenther Onkol. 2015;191(1):7–16. https://doi.org/10.1007/s00066-014-0737-7.CrossRefPubMed

13.

Tajima H, Ohta T, Kitagawa H, et al. Pilot study of neoadjuvant chemotherapy with gemcitabine and oral S-1 for resectable pancreatic cancer. Exp Ther Med. 2012;3(5):787–792. https://doi.org/10.3892/etm.2012.482.CrossRefPubMedPubMedCentral

14.

Denbo JW, Bruno ML, Cloyd JM, et al. Preoperative chemoradiation for pancreatic adenocarcinoma does not increase 90-day postoperative morbidity or mortality. J Gastrointest Surg. 2016;20(12):1975–1985.CrossRef

15.

Takahashi H, Ogawa H, Ohigashi H, et al. Preoperative chemoradiation reduces the risk of pancreatic fistula after distal pancreatectomy for pancreatic adenocarcinoma. Surgery. 2011;150(3):547–556. https://doi.org/10.1016/j.surg.2011.03.001.CrossRefPubMed

16.

Dreyer SB, Jamieson NB, Upstill-Goddard R, et al. Defining the molecular pathology of pancreatic body and tail adenocarcinoma. Br J Surg. 2018;105(2):e183-e191. https://doi.org/10.1002/bjs.10772.CrossRefPubMedPubMedCentral

17.

Birnbaum DJ, Bertucci F, Finetti P, Birnbaum D, Mamessier E. Head and body/tail pancreatic carcinomas are not the same tumors. Cancers (Basel). 2019;11(4):1–14. https://doi.org/10.3390/cancers11040497.CrossRef

18.

van Hilst J, de Rooij T, Klompmaker S, et al. Minimally Invasive versus Open Distal Pancreatectomy for Ductal Adenocarcinoma (DIPLOMA). Ann Surg. 2019;269(1):10–17. https://doi.org/10.1097/sla.0000000000002561.CrossRefPubMed

19.

Elm E Von, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet. 2007;370:1453–1457.CrossRef

20.

Campbell F, Cairns A, Duthie F, Feakins R. Dataset for the histopathological reporting of carcinomas of the pancreas, ampulla of Vater and common bile duct from the Royal College of Pathologists. https://www.rcpath.org/uploads/assets/34910231-c106-4629-a2de9e9ae6f87ac1/g091-pancreasdataset-mar17.pdf. Published 2017. Accessed October 3, 2018.

21.

Edge SB, Compton CC. The American Joint Committee on Cancer: The 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17(6):1471–1474. https://doi.org/10.1245/s10434-010-0985-4.CrossRefPubMed

22.

Clavien PA, Barkun J, De Oliveira ML, et al. The Clavien–Dindo classification of surgical complications: five-year experience. Ann Surg. 2009;250(2):187–196. https://doi.org/10.1097/sla.0b013e3181b13ca2.CrossRefPubMed

23.

Wente MN, Bassi C, Dervenis C, et al. Delayed gastric emptying (DGE) after pancreatic surgery: a suggested definition by the International Study Group of Pancreatic Surgery (ISGPS). Surgery. 2007;142(5):761–768. https://doi.org/10.1016/j.surg.2007.05.005.CrossRefPubMed

24.

Wente MN, Veit JA, Bassi C, et al. Postpancreatectomy hemorrhage (PPH)-An International Study Group of Pancreatic Surgery (ISGPS) definition. Surgery. 2007;142(1):20–25. https://doi.org/10.1016/j.surg.2007.02.001.CrossRefPubMed

25.

Bassi C, Dervenis C, Butturini G, et al. Postoperative pancreatic fistula: an international study group (ISGPF) definition. Surgery. 2005;138(1):8–13. https://doi.org/10.1016/j.surg.2005.05.001.CrossRefPubMed

26.

Takahashi H, Akita H, Gotoh K, et al. Preoperative gemcitabine-based chemoradiation therapy for pancreatic ductal adenocarcinoma of the body and tail: Impact of splenic vessels involvement on operative outcome and pattern of recurrence. Surgery. 2015;157(3):484–495. https://doi.org/10.1016/j.surg.2014.09.022.CrossRefPubMed

27.

Hyun JJ, Rose JB, Alseidi AA, et al. Significance of radiographic splenic vessel involvement in the pancreatic ductal adenocarcinoma of the body and tail of the gland. J Surg Oncol. 2019;120(2):262–269. https://doi.org/10.1002/jso.25498.CrossRefPubMed

28.

Crippa S, Cirocchi R, Maisonneuve P, et al. Systematic review and meta-analysis of prognostic role of splenic vessels infiltration in resectable pancreatic cancer. Eur J Surg Oncol. 2018;44(1):24–30. https://doi.org/10.1016/j.ejso.2017.10.217.CrossRefPubMed

29.

de Geus SWL, Eskander MF, Bliss LA, et al. Neoadjuvant therapy versus upfront surgery for resected pancreatic adenocarcinoma: a nationwide propensity score matched analysis. Surgery. 2017;161(3):592–601.CrossRef

30.

Jang JY, 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(2):215–222. https://doi.org/10.1097/sla.0000000000002705.CrossRefPubMed

31.

Nelson DW, Chang SC, Grunkemeier G, et al. Resectable distal pancreas cancer: time to reconsider the role of upfront surgery. Ann Surg Oncol. 2018;25(13):4012–4019. https://doi.org/10.1245/s10434-018-6765-2.CrossRefPubMed

32.

Fukami Y, Kaneoka Y, Maeda A, Takayama Y, Onoe S. Prognostic impact of splenic artery invasion for pancreatic cancer of the body and tail. Int J Surg. 2016;35:64–68. https://doi.org/10.1016/j.ijsu.2016.09.076.CrossRefPubMed

33.

Partelli S, Crippa S, Barugola G, et al. Splenic artery invasion in pancreatic adenocarcinoma of the body and tail: a novel prognostic parameter for patient selection. Ann Surg Oncol. 2011;18(13):3608–3614. https://doi.org/10.1245/s10434-011-1769-1.CrossRefPubMed

34.

Mizumoto T, Toyama H, Asari S, et al. Pathological and radiological splenic vein involvement are predictors of poor prognosis and early liver metastasis after surgery in patients with pancreatic adenocarcinoma of the body and tail. Ann Surg Oncol. 2018;25(3):638–646. https://doi.org/10.1245/s10434-017-6274-8.CrossRefPubMed

35.

Kanda M, Fujii T, Sahin TT, et al. Invasion of the splenic artery is a crucial prognostic factor in carcinoma of the body and tail of the pancreas. Ann Surg. 2010;251(3):483–487.CrossRef

36.

Bissolati M, Sandri MT, Burtulo G, Zorzino L, Balzano G, Braga M. Portal vein-circulating tumor cells predict liver metastases in patients with resectable pancreatic cancer. Tumor Biol. 2015;36(2):991–996. https://doi.org/10.1007/s13277-014-2716-0.CrossRef

37.

Liu X, Li C, Li J, et al. Detection of CTCs in portal vein was associated with intrahepatic metastases and prognosis in patients with advanced pancreatic cancer. J Cancer. 2018;9(11):2038–2045. https://doi.org/10.7150/jca.23989.CrossRefPubMedPubMedCentral

38.

Gemenetzis G, Groot VP, Yu J, et al. Circulating tumor cells dynamics in pancreatic adenocarcinoma correlate with disease status. Ann Surg. 2018;268(3):408–420. https://doi.org/10.1097/sla.0000000000002925.CrossRefPubMed

39.

Heinrich S, Besselink M, Moehler M, et al. Opinions and use of neoadjuvant therapy for resectable, borderline resectable, and locally advanced pancreatic cancer: international survey and case-vignette study. BMC Cancer. 2019;19(1):1–9.CrossRef

40.

Zettervall SL, Ju T, Holzmacher JL, Rivas L, Lin PP, Vaziri K. Neoadjuvant radiation is associated with fistula formation following pancreaticoduodenectomy. J Gastrointest Surg. 2018;22(6):1026–1033. https://doi.org/10.1007/s11605-018-3725-x.CrossRefPubMed

41.

Chatterjee D, M.H. K, Rashid A, et al. Pancreatic intraepithelial neoplasia and histologic changes in non-neoplastic pancreas associated with neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma. Histopathology. 2013;63(6):841–851. doi:https://doi.org/10.1111/his.12234.

42.

Cools KS, Sanoff HK, Kim HJ, Yeh JJ, Stitzenberg KB. Impact of neoadjuvant therapy on postoperative outcomes after pancreaticoduodenectomy. J Surg Oncol. 2018;118(3):455–462. https://doi.org/10.1002/jso.25183.CrossRefPubMedPubMedCentral

43.

Suker M, Beumer BR, Sadot E, et al. A patient-level meta-analysis of FOLFIRINOX for locally advanced pancreatic cancer. Lancet. 2016;17(6):801–810.CrossRef

Title: Impact of Neoadjuvant Therapy in Resected Pancreatic Ductal Adenocarcinoma of the Pancreatic Body or Tail on Surgical and Oncological Outcome: A Propensity-Score Matched Multicenter Study
Authors: Sanne Lof, MD
Maarten Korrel, BSc
Jony van Hilst, MD, PhD
Adnan Alseidi, MD
Gianpaolo Balzano, MD
Ugo Boggi, MD
Giovanni Butturini, MD, PhD
Riccardo Casadei, MD, PhD
Safi Dokmak, MD
Bjørn Edwin, MD, PhD
Massimo Falconi, MD
Tobias Keck, MD
Giuseppe Malleo, MD, PhD
Matteo de Pastena, MD
Ales Tomazic, MD, PhD
Hanneke Wilmink, MD, PhD
Alessandro Zerbi, MD, PhD
Marc G. Besselink, MD, PhD
Mohammed Abu Hilal, MD, PhD
for the European Consortium on Minimally Invasive Pancreatic Surgery (E-MIPS)
Publication date: 01-06-2020
Publisher: Springer International Publishing
Keyword: Pancreatectomy
Published in: Annals of Surgical Oncology / Issue 6/2020
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-019-08137-6

At a glance: The STEP trials

Springer Medicine

Impact of Neoadjuvant Therapy in Resected Pancreatic Ductal Adenocarcinoma of the Pancreatic Body or Tail on Surgical and Oncological Outcome: A Propensity-Score Matched Multicenter Study

Abstract

Background

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 6/2020

ASO Author Reflections: Characteristics of Papillary Thyroid Cancer of Thyroid Isthmus and Clinical Implications of Its Extrathyroidal Extension

Novel Prognostic Implications of DUPAN-2 in the Era of Initial Systemic Therapy for Pancreatic Cancer

Surgical Management of the Axilla in Patients with Occult Breast Cancer (cT0 N+) After Neoadjuvant Chemotherapy

Model of Patient-Specific Immune-Enhanced Organoids for Immunotherapy Screening: Feasibility Study

Regional Node Basin Recurrence in Melanoma Patients: More Common After Node Dissection for Macroscopic Rather than Clinically Occult Nodal Disease

Management of Cancer Surgery Cases During the COVID-19 Pandemic: Considerations