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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Fahad Hasan, M.D.[2] Sudarshana Datta, MD [3]

Overview

The pancreas was described in antiquity, but pancreatic cancer became a surgical disease only in the late 19th century. Modern care developed through three successive changes. The first was a survivable operation, pancreatoduodenectomy, developed by Kausch (1912) and popularized by Whipple (1935–1941). The second was the centralization of that operation in high-volume centers, which lowered operative mortality from roughly 25–33% in the post-Whipple decades to about 1–2% at the busiest institutions. The third was the arrival of effective multiagent, neoadjuvant, and biomarker-directed systemic therapy, culminating in the 2026 approval of the first RAS inhibitor for pancreatic adenocarcinoma.[1][2][3][4] With multimodal therapy, 5-year survival after resection is now about 20–30%. That figure contrasts with the 5–8% often quoted in older teaching, although only about 15–20% of patients have resectable disease at diagnosis.[5][6]

Historical Perspective

Early anatomic and clinical recognition

  • Herophilus of Chalcedon (~300 BC) first described the pancreas. Rufus of Ephesus (~100 AD) named it, from the Greek pan (all) and kreas (flesh). Its ductal anatomy (Wirsung, Santorini) and exocrine physiology (de Graaf; later the discovery of trypsin and lipase) were characterized between the 17th and 19th centuries.[7][8]
  • By the late 19th century, the clinical features and histology of pancreatic cancer had been described. Ductal, acinar, and islet cell cancers were distinguished as separate entities.[7]
  • A palpable, nontender gallbladder in malignant distal biliary obstruction became known as Courvoisier's sign.
  • Pancreatic surgery began in the mid-19th century with drainage procedures. Distal resections followed in the late 1800s, and resection of the pancreatic head, which was far more hazardous, developed step by step between 1898 and 1935.[8]

Development of pancreatoduodenectomy

Key milestones in pancreatic cancer surgery
Year Surgeon(s) Milestone
1882 Trendelenburg First successful excision of a solid pancreatic tumor (distal)[7][1]
1887 Kappeler Cholecystojejunostomy as palliative biliary bypass for pancreatic cancer[7]
1898 Halsted First successful local resection of an ampullary (periampullary) tumor[1]
1898 Codivilla En bloc resection of the pancreatic head and duodenum (patient did not survive long-term)[1][9]
1909/1912 Kausch First successful two-stage partial pancreatoduodenectomy, hence the eponym Kausch–Whipple procedure[1][2][9]
1935 Whipple, Parsons, Mullins Three patients presented to the American Surgical Association; two-stage procedure (biliary diversion/gastrojejunostomy, then resection)[1][9]
1940–1941 Whipple One-stage pancreatoduodenectomy with pancreaticojejunostomy[1][9][10]
1944; late 1970s Watson; Traverso and Longmire Pylorus-preserving pancreatoduodenectomy introduced and then popularized[11]
1994 Gagner and Pomp First laparoscopic pancreatoduodenectomy[12]
  • The operation became survivable only after two advances. The discovery of vitamin K allowed correction of the coagulopathy of obstructive jaundice, and blood typing and blood banking made major blood loss survivable. Before these advances, early attempts were frequently fatal.[2]
  • The classic operation removes the pancreatic head, duodenum, distal common bile duct, gallbladder, and distal stomach. Reconstruction uses pancreatico-, hepatico-, and gastrojejunostomy. Meta-analysis shows no meaningful difference in morbidity or mortality between the classic and pylorus-preserving variants.[11][10]
  • The oncologic goal has been the same since Whipple: a margin-negative (R0) resection. R0 is now increasingly defined as a tumor-free margin of at least 1 mm, although definitions vary internationally.[13][14]

From surgical nihilism to the volume–outcome era

For about 25 years after Whipple's reports, operative mortality stayed near 25–33%. This led to widespread surgical nihilism and underuse of resection.[2][9] In the 1980s and 1990s, care was concentrated in high-volume centers with better perioperative and critical care and interventional radiology. Mortality fell below 5%, and to about 1–2% at the busiest institutions.[8][3][5][9][15]

Secular trends in short-term mortality after pancreatoduodenectomy
Era / dataset Mortality Source
1940s–1970s (post-Whipple) ~25–33% [2][9]
Sweden, 1960s → 2010–2016 17.2% → 1.6% [6]
US NCDB (pancreatic adenocarcinoma), 2004 → 2020 (90-day) 8.0% → 5.3% [16]
ACS-NSQIP, 2006 → 2016 (30-day) 2.9% → 1.5% [17]
Contemporary high-volume centers ~1–2% or lower [3][18]
  • Recent mortality reductions have come mainly from better rescue of patients once complications occur (less "failure to rescue"), through timely ICU escalation and interventional management. The incidence of major complications has stayed relatively stable.[17][19]
  • The volume–outcome benefit appears to plateau at roughly 40–50 procedures per year. It is much stronger for pancreatoduodenectomy than for distal pancreatectomy.[20][21][22]
  • Access to high-volume centers still differs by race, socioeconomic status, and geography.[23]

Minimally invasive surgery

Minimally invasive pancreatoduodenectomy, now mostly robotic, has expanded substantially. Its rate in ACS-NSQIP roughly doubled over the past decade. Compared with laparoscopy, the robotic approach has lower conversion and positive-margin rates. Thirty-day mortality and complication rates have remained stable, and no approach has been shown to be superior to open surgery.[12][24][25]

From palliation to multimodal and precision therapy

For most of the 20th century, systemic options were negligible and advanced disease was managed palliatively. Effective systemic therapy is a development of the past three decades.

Landmark developments in systemic therapy
Year Development Key finding
1997 Gemcitabine monotherapy Became the first-line standard after showing clinical benefit and a modest survival advantage over fluorouracil[26][14]
2000s Erlotinib + gemcitabine First targeted (EGFR) combination; only marginal benefit over gemcitabine alone[27][28]
2000s–2010s Adjuvant trials (CONKO-001, ESPAC-3, ESPAC-4) Adjuvant gemcitabine beat observation; 5-FU/leucovorin was roughly equivalent to gemcitabine; gemcitabine–capecitabine was superior[13][29]
2011 FOLFIRINOX (PRODIGE 4/ACCORD 11) Metastatic disease: median OS 11.1 vs 6.8 months vs gemcitabine (HR 0.57)[26][30][27]
2013 Gemcitabine + nab-paclitaxel (MPACT) Metastatic disease: median OS 8.5 vs 6.7 months vs gemcitabine (HR 0.72)[28][31]
2018 Adjuvant modified FOLFIRINOX (PRODIGE 24/CCTG PA.6) Median OS ~54 vs ~35 months vs adjuvant gemcitabine; current adjuvant standard for fit patients[13][29]
2019 Olaparib maintenance (POLO) Germline BRCA1/BRCA2 became the first predictive biomarker in pancreatic cancer; maintenance therapy after platinum-based chemotherapy[32][33]
2020s Neoadjuvant therapy (PREOPANC series) Practice shifted toward upfront systemic therapy for borderline resectable and selected resectable disease[34][35]
2023 NALIRIFOX (NAPOLI-3) Metastatic disease: median OS 11.1 vs 9.2 months vs gemcitabine–nab-paclitaxel; no clear advantage over FOLFIRINOX on cross-trial comparison[26][14][13]
2010s–2020s Tumor-agnostic targeted agents Pembrolizumab (MSI-H/dMMR, TMB-H), dabrafenib–trametinib (BRAF V600E), NTRK fusion inhibitors (larotrectinib, entrectinib), selpercatinib (RET fusion)[4][13]
2026 Daraxonrasib (RASolute 302) FDA-approved August 26, 2026 as the first RAS-targeted therapy for metastatic pancreatic adenocarcinoma, for patients after at least one prior systemic therapy or who cannot receive multiagent therapy[36][31]
  • Because of this progression, germline and somatic profiling (BRCA1/BRCA2, PALB2, MSI/MMR, KRAS, BRAF, NTRK/RET fusions) is now standard practice.[4][13]
  • Resectability, once defined only by anatomic vessel involvement, is increasingly defined by tumor biology as well, including CA 19-9 levels and response to neoadjuvant therapy.[14]
  • Whether neoadjuvant therapy benefits clearly resectable disease is still debated. Randomized evidence is stronger for borderline resectable and locally advanced disease.[35][37]

Evolution of neuroendocrine neoplasm classification

Nineteenth-century "islet cell" terminology gave way to a series of WHO classifications (2010, 2017, 2019, and the 2022 endocrine classification). These incorporated the Ki-67 proliferation index and established the current separation of well-differentiated neuroendocrine tumors (NET G1–G3) from poorly differentiated neuroendocrine carcinomas (NEC) and mixed neoplasms (MiNEN).[38][39][40] Pancreatic NETs behave more indolently than ductal adenocarcinoma, which led the AJCC 8th edition to adopt a separate staging system for them.[39]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Are C, Dhir M, Ravipati L (2011). "History of pancreaticoduodenectomy: early misconceptions, initial milestones and the pioneers". HPB (Oxford). 13 (6): 377–84. doi:10.1111/j.1477-2574.2011.00305.x. PMID 21609369.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 Howard JM (1999). "Development and progress in resective surgery for pancreatic cancer". World J Surg. 23 (9): 901–6. doi:10.1007/s002689900597.
  3. ↑ 3.0 3.1 3.2 Hackert T, Klaiber U, Pausch T, Mihaljevic AL, Büchler MW (2020). "Fifty years of surgery for pancreatic cancer". Pancreas. 49 (8): 1005–1013. doi:10.1097/MPA.0000000000001634.
  4. ↑ 4.0 4.1 4.2 Mannucci A, Goel A (2025). "Advances in pancreatic cancer early diagnosis, prevention, and treatment: the past, the present, and the future". CA Cancer J Clin. doi:10.3322/caac.70035.
  5. ↑ 5.0 5.1 Kleeff J, Korc M, Apte M, La Vecchia C, Johnson CD, Biankin AV, et al. (2016). "Pancreatic cancer". Nat Rev Dis Primers. 2: 16022. doi:10.1038/nrdp.2016.22.
  6. ↑ 6.0 6.1 Xu H, Bretthauer M, Fang F, et al. (2024). "Dramatic improvements in outcome following pancreatoduodenectomy for pancreatic and periampullary cancers". Br J Cancer. 131 (4): 747–754. doi:10.1038/s41416-024-02757-w.
  7. ↑ 7.0 7.1 7.2 7.3 Busnardo AC, DiDio LJ, Tidrick RT, Thomford NR (1983). "History of the pancreas". Am J Surg. 146 (5): 539–50. doi:10.1016/0002-9610(83)90286-6. PMID 6356946.
  8. ↑ 8.0 8.1 8.2 Belghiti J, Sauvanet A (2025). "Ancient and modern history of pancreatic surgery". Pancreas. doi:10.1097/MPA.0000000000002537.
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 Wray CJ, Ahmad SA, Matthews JB, Lowy AM (2005). "Surgery for pancreatic cancer: recent controversies and current practice". Gastroenterology. 128 (6): 1626–41. doi:10.1053/j.gastro.2005.03.035.
  10. ↑ 10.0 10.1 Fernández-del Castillo C, Morales-Oyarvide V, McGrath D, Wargo JA, Ferrone CR, Thayer SP, Lillemoe KD, Warshaw AL (2012). "Evolution of the Whipple procedure at the Massachusetts General Hospital". Surgery. 152 (3 Suppl 1): S56–63. doi:10.1016/j.surg.2012.05.022. PMID 22770961.
  11. ↑ 11.0 11.1 Hüttner FJ, Fitzmaurice C, Schwarzer G, et al. (2016). "Pylorus-preserving pancreaticoduodenectomy (pp Whipple) versus pancreaticoduodenectomy (classic Whipple) for surgical treatment of periampullary and pancreatic carcinoma". Cochrane Database Syst Rev. doi:10.1002/14651858.CD006053.pub6.
  12. ↑ 12.0 12.1 Kornaropoulos M, Moris D, Beal EW, et al. (2017). "Total robotic pancreaticoduodenectomy: a systematic review of the literature". Surg Endosc. 31 (11): 4382–4392. doi:10.1007/s00464-017-5523-z.
  13. ↑ 13.0 13.1 13.2 13.3 13.4 13.5 National Comprehensive Cancer Network (September 11, 2026). "NCCN Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma". NCCN.
  14. ↑ 14.0 14.1 14.2 14.3 Roth S, Apte M, Balachandran VP, et al. (2026). "Pancreatic cancer". Nat Rev Dis Primers. 12 (1): 23. doi:10.1038/s41572-026-00699-6.
  15. ↑ Cameron JL, Riall TS, Coleman J, Belcher KA (2006). "One thousand consecutive pancreaticoduodenectomies". Ann Surg. 244 (1): 10–5. doi:10.1097/01.sla.0000217673.04165.ea. PMID 16794383.
  16. ↑ Steinl G, Mayhew MM, Shen C, et al. (2026). "Mortality after pancreatoduodenectomy for pancreatic malignancy: improving patient selection and safety of the operative technique". Surg Oncol. 65: 102390. doi:10.1016/j.suronc.2026.102390.
  17. ↑ 17.0 17.1 Pastrana Del Valle J, Mahvi DA, Fairweather M, et al. (2021). "The improvement in post-operative mortality following pancreaticoduodenectomy between 2006 and 2016 is associated with an improvement in the ability to rescue patients after major morbidity, not in the rate of major morbidity". HPB (Oxford). 23 (3): 434–443. doi:10.1016/j.hpb.2020.07.013.
  18. ↑ Bassi C, Marchegiani G, Giuliani T, et al. (2022). "Pancreatoduodenectomy at the Verona Pancreas Institute: the evolution of indications, surgical techniques, and outcomes: a retrospective analysis of 3000 consecutive cases". Ann Surg. 276 (6): 1029–1038. doi:10.1097/SLA.0000000000004753.
  19. ↑ Kinny-Köster B, Halm D, Tran D, et al. (2026). "Who do we fail to rescue after pancreatoduodenectomy? Outcomes among >4000 procedures expose windows of opportunity". Ann Surg. 283 (2): 277–285. doi:10.1097/SLA.0000000000006429.
  20. ↑ Rompen IF, Menso JE, Ingwersen E, et al. (2025). "Impact of merging two high-volume centers on patient outcome: 1000 consecutive pancreatoduodenectomies". Ann Surg. doi:10.1097/SLA.0000000000006953.
  21. ↑ Shindo Y, Endo H, Yamamoto H, et al. (2026). "Hospital volume and operative mortality in pancreaticoduodenectomy and hepatectomy: analysis of the National Clinical Database in Japan". J Hepatobiliary Pancreat Sci. doi:10.1002/jhbp.70168.
  22. ↑ Kuemmerli C, Schneider MA, Joliat GR, et al. (2022). "Trends in pancreatic surgery in Switzerland: a survey and nationwide analysis over two decades". Langenbecks Arch Surg. 407 (8): 3423–3435. doi:10.1007/s00423-022-02679-2.
  23. ↑ Brown NS, Horns J, Scaife CL (2025). "Disparity in access to high-volume facilities for pancreatic surgery: intersection of race, socioeconomics, and geography". J Am Coll Surg. doi:10.1097/XCS.0000000000001673.
  24. ↑ Lee FG, Bews KA, Bisht R, et al. (2026). "A decade of pancreatoduodenectomy outcomes for pancreatic adenocarcinoma: 2014–2023 analysis of the NSQIP Pancreatectomy PUF database". HPB (Oxford). 28 (5): 709–720. doi:10.1016/j.hpb.2026.01.016.
  25. ↑ Nießen A, Hackert T (2022). "State-of-the-art surgery for pancreatic cancer". Langenbecks Arch Surg. 407 (2): 443–450. doi:10.1007/s00423-021-02362-y.
  26. ↑ 26.0 26.1 26.2 Mastrantoni L, Chiaravalli M, Spring A, et al. (2024). "Comparison of first-line chemotherapy regimens in unresectable locally advanced or metastatic pancreatic cancer: a systematic review and Bayesian network meta-analysis". Lancet Oncol. 25 (12): 1655–1665. doi:10.1016/S1470-2045(24)00511-4.
  27. ↑ 27.0 27.1 Yu IS, Cheung WY (2018). "A contemporary review of the treatment landscape and the role of predictive and prognostic biomarkers in pancreatic adenocarcinoma". Can J Gastroenterol Hepatol. 2018: 1863535. doi:10.1155/2018/1863535.
  28. ↑ 28.0 28.1 Park W, Chawla A, O'Reilly EM (2021). "Pancreatic cancer: a review". JAMA. 326 (9): 851–862. doi:10.1001/jama.2021.13027.
  29. ↑ 29.0 29.1 Chawla A (2021). "Contemporary trials evaluating neoadjuvant therapy for resectable pancreatic cancer". J Surg Oncol. 123 (6): 1423–1431. doi:10.1002/jso.26393.
  30. ↑ Sohal D, Kennedy EB, Cinar P, et al. (2020). "Metastatic pancreatic cancer: ASCO guideline update". J Clin Oncol. 38 (27): 3217–3230. doi:10.1200/JCO.20.01364. Vancouver style error: initials (help)
  31. ↑ 31.0 31.1 May MS, Park W, O'Reilly EM (2026). "Treating pancreatic ductal adenocarcinoma: the targeted revolution is here". Drugs. 86 (4): 507–532. doi:10.1007/s40265-026-02295-0.
  32. ↑ Mizrahi JD, Surana R, Valle JW, Shroff RT (2020). "Pancreatic cancer". Lancet. 395 (10242): 2008–2020. doi:10.1016/S0140-6736(20)30974-0.
  33. ↑ Stoop TF, Javed AA, Oba A, et al. (2025). "Pancreatic cancer". Lancet. 405 (10485): 1182–1202. doi:10.1016/S0140-6736(25)00261-2.
  34. ↑ Janssen QP, van Dam JL, van Bekkum ML, et al. (2025). "Neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy in resectable and borderline resectable pancreatic cancer (PREOPANC-2): a multicentre, open-label, phase 3 randomised trial". Lancet Oncol. 26 (10): 1346–1356. doi:10.1016/S1470-2045(25)00363-8.
  35. ↑ 35.0 35.1 Dreyer SB, Beer P, Hingorani SR, Biankin AV (2025). "Improving outcomes of patients with pancreatic cancer". Nat Rev Clin Oncol. 22 (6): 439–456. doi:10.1038/s41571-025-01019-9.
  36. ↑ AGA News (August 2026). "FDA approves first RAS-targeted therapy for metastatic pancreatic cancer". American Gastroenterological Association.
  37. ↑ Wood LD, Canto MI, Jaffee EM, Simeone DM (2022). "Pancreatic cancer: pathogenesis, screening, diagnosis, and treatment". Gastroenterology. 163 (2): 386–402.e1. doi:10.1053/j.gastro.2022.03.056.
  38. ↑ Klimstra DS, Modlin IR, Coppola D, Lloyd RV, Suster S (2010). "The pathologic classification of neuroendocrine tumors: a review of nomenclature, grading, and staging systems". Pancreas. 39 (6): 707–12. doi:10.1097/MPA.0b013e3181ec124e. PMID 20664470.
  39. ↑ 39.0 39.1 Lam AK, Ishida H (2021). "Pancreatic neuroendocrine neoplasms: clinicopathological features and pathological staging". Histol Histopathol. 36 (4): 367–382. doi:10.14670/HH-18-288.
  40. ↑ Kasajima A, Perren A, Klöppel G (2026). "Concept of neuroendocrine neoplasms of all organs with a focus on grading, subtyping". Virchows Arch. 488 (1): 3–20. doi:10.1007/s00428-025-04296-y.
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