Invited Review

Vol. 36 No. 2 (2025): Turkish Journal of Gastroenterology

Pancreatic Cancer: Current Concepts, Trends, and Future Directions

Main Article Content

Patrick Wenzel
Carolin Mogler
Kıvanç Görgülü
Hana Algül

Abstract

Pancreatic ductal adenocarcinoma (PC) ranks among the deadliest cancers, with a less than 15% 5-year survival rate. Epidemiological studies project that it will become the second leading cause of cancer-associated mortalities in the following decades. The hallmarks of pancreatic cancer lead to tumor aggressiveness and therapeutic resistance. For this reason, the field has been focusing on multiple dimensions to generate better therapeutic approaches, including new adjuvant, neoadjuvant, and palliative concepts to extend the survival of PC patients. Over the last 2 decades, clinical trials have significantly improved disease prognosis and patient survival. To achieve better outcomes and to deeply understand the therapeutic approaches, molecular tumor boards have become crucial for deeper exploitation of tumor genetics and tumor biology, providing better stratification markers for therapeutic regimens. Using recently developed targeted therapies, such as KRAS inhibitors, the field has gathered momentum and been tooled up with the help of new sequencing technologies. Therefore, researchers and clinicians have geared up for the battle against PC. This review will systematically discuss recent developments in adjuvant, neoadjuvant, and palliative treatment modalities. Moreover, the paradigm-shifting importance of genetic profiling on pancreatic cancer. will be explained through a showcase to frame future directions.

Cite this article as: Wenzel P, Mogler C, Görgülü K, Algül H. Pancreatic cancer: current concepts, trends, and future directions. Turk J Gastroenterol. 2025;36(2):69-81.

Article Details

References

1. Hosein AN, Brekken RA, Maitra A. Pancreatic cancer stroma: an update on therapeutic targeting strategies. Nat Rev Gastroenterol Hepatol. 2020;17(8):487-505. [CrossRef]

2. De Santis MC, Bockorny B, Hirsch E, Cappello P, Martini M. Exploiting pancreatic cancer metabolism: challenges and opportunities. Trends Mol Med. 2024;30(6):592-604. [CrossRef]

3. Görgülü K, Diakopoulos KN, Kaya-Aksoy E, et al. The role of autophagy in pancreatic cancer: from bench to the dark bedside. Cells. 2020;9(4). [CrossRef]

4. Martinez-Bosch N, Vinaixa J, Navarro P. Immune evasion in pancreatic cancer: from mechanisms to therapy. Cancers (Basel). 2018;10(1). [CrossRef]

5. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for Metastatic Pancreatic Cancer. N Engl J Med. 2011;364(19):1817-1825. [CrossRef]

6. Neoptolemos JP, Palmer DH, Ghaneh P, et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017;389(10073):1011-1024. [CrossRef]

7. Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013;310(14):1473-1481. [CrossRef]

8. Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018;379(25):2395-2406. [CrossRef]

9. Conroy T, Castan F, Lopez A, et al. Five-year outcomes of folfirinox vs gemcitabine as adjuvant therapy for pancreatic cancer: a randomized clinical trial. JAMA Oncol. 2022;8(11):1571-1578. [CrossRef]

10. Jones RP, Psarelli E-E, Jackson R, et al. Patterns of recurrence after resection of pancreatic ductal adenocarcinoma: a secondary analysis of the ESPAC-4 randomized adjuvant chemotherapy trial. JAMA Surg. 2019;154(11):1038-1048. [CrossRef]

11. Tempero MA, Pelzer U, O’Reilly EM, et al. Adjuvant nab-paclitaxel+gemcitabine in resected pancreatic ductal adenocarcinoma: results from a randomized, open-label, Phase III trial. J Clin Oncol. 2023;41(11):2007-2019. [CrossRef]

12. Liao W-C, Chien K-L, Lin Y-L, et al. Adjuvant treatments for resected pancreatic adenocarcinoma: a systematic review and network meta-analysis. Lancet Oncol. 2013;14(11):1095-1103. [CrossRef]

13. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350(12):1200-1210. [CrossRef]

14. Kunzmann V, Siveke JT, Algül H, et al. Nab-paclitaxel plus gemcitabine versus nab-paclitaxel plus gemcitabine followed by folfirinox induction chemotherapy in locally advanced pancreatic cancer (NEOLAP-AIO-PAK-0113): a multicentre, randomised, phase 2 trial. Lancet Gastroenterol Hepatol. 2021;6(2):128-138. [CrossRef]

15. Ahmad SA, Duong M, Sohal DPS, et al. Surgical outcome results from SWOG S1505: a randomized clinical trial of mFOLFIRINOX versus gemcitabine/nab-paclitaxel for perioperative treatment of resectable pancreatic ductal adenocarcinoma. Ann Surg. 2020;272(3):481-486. [CrossRef]

16. Schwarz L, Vernerey D, Bachet J-B, et al. Resectable pancreatic adenocarcinoma neo-adjuvant FOLF(IRIN)OX-based chemotherapy - a multicenter, non-comparative, randomized, phase II trial (PANACHE01-PRODIGE48 study). BMC Cancer. 2018;18(1):762. [CrossRef]

17. Seufferlein T, Uhl W, Kornmann M, et al. Perioperative or only adjuvant gemcitabine plus nab-paclitaxel for resectable pancreatic cancer (NEONAX)—a randomized phase II trial of the AIO pancreatic cancer group. Ann Oncol. 2023;34(1):91-100. [CrossRef]

18. Versteijne E, van Dam JL, Suker M, et al. Neoadjuvant chemoradiotherapy versus upfront surgery for resectable and borderline resectable pancreatic cancer: long-term results of the Dutch randomized PREOPANC trial. J Clin Oncol. 2022;40(11):1220-1230. [CrossRef]

19. Groot Koerkamp B, Janssen QP, van Dam JL, et al. LBA83 neoadjuvant chemotherapy with folfirinox versus neoadjuvant gemcitabine-based chemoradiotherapy for borderline resectable and resectable pancreatic cancer (PREOPANC-2): a multicenter randomized controlled trial. Ann Oncol. 2023;34:S1323.

20. Katz MHG, Shi Q, Meyers J, et al. Efficacy of preoperative mFOLFIRINOX vs mFOLFIRINOX plus hypofractionated radiotherapy for borderline resectable adenocarcinoma of the pancreas: the A021501 Phase 2 randomized clinical trial. JAMA Oncol. 2022;8(9):1263-1270. [CrossRef]

21. Labori KJ, Bratlie SO, Andersson B, et al. Neoadjuvant folfirinox versus upfront surgery for resectable pancreatic head cancer (NORPACT-1): a multicentre, randomised, phase 2 trial. Lancet Gastroenterol Hepatol. 2024;9(3):205-217. [CrossRef]

22. Awais N, Satnarine T, Ahmed A, et al. A systematic review of chemotherapeutic regimens used in pancreatic cancer. Cureus. 2023;15(10):e46630. [CrossRef]

23. Yoo C, Hwang I, Song TJ, et al. FOLFIRINOX in borderline resectable and locally advanced unresectable pancreatic adenocarcinoma. Ther Adv Med Oncol. 2020;12:1758835920953294. [CrossRef]

24. Ozaka M, Nakachi K, Kobayashi S, et al. A randomised phase II study of modified folfirinox versus gemcitabine plus nab-paclitaxel for locally advanced pancreatic cancer (JCOG1407). Eur J Cancer. 2023;181:135-144. [CrossRef]

25. Fietkau R, Grützmann R, Wittel UA, et al. R0 resection following chemo (radio)therapy improves survival of primary inoperable pancreatic cancer patients. Interim results of the German randomized CONKO-007± trial. Strahlenther Onkol. 2021;197(1):8-18. [CrossRef]

26. Fietkau R, Ghadimi M, Grützmann R, et al. Randomized phase III trial of induction chemotherapy followed by chemoradiotherapy or chemotherapy alone for nonresectable locally advanced pancreatic cancer: first results of the CONKO-007 trial. J Clin Oncol. 2022;40(16_suppl):4008. [CrossRef]

27. Gourgou-Bourgade S, Bascoul-Mollevi C, Desseigne F, et al. Impact of folfirinox compared with gemcitabine on quality of life in patients with metastatic pancreatic cancer: results from the PRODIGE 4/Accord 11 randomized trial. J Clin Oncol. 2013;31(1):23-29. [CrossRef]

28. Okusaka T, Ikeda M, Fukutomi A, et al. Phase II study of folfirinox for chemotherapy-naïve Japanese patients with metastatic pancreatic cancer. Cancer Sci. 2014;105(10):1321-1326. [CrossRef]

29. Lee J-C, Kim JW, Ahn S, et al. Optimal dose reduction of folfirinox for preserving tumour response in advanced pancreatic cancer: using cumulative relative dose intensity. Eur J Cancer. 2017;76:125-133. [CrossRef]

30. Cho IR, Kang H, Jo JH, et al. FOLFIRINOX vs gemcitabine/nab-paclitaxel for treatment of metastatic pancreatic cancer: single-center cohort study. World J Gastrointest Oncol. 2020;12(2):182-194. [CrossRef]

31. Yamao K, Takenaka M, Yoshikawa T, et al. Clinical safety and efficacy of secondary prophylactic pegylated G-CSF in advanced pancreatic cancer patients treated with mFOLFIRINOX: a single-center retrospective study. Intern Med. 2019;58(14):1993-2002. [CrossRef]

32. Usón Junior PLS, Rother ET, Maluf FC, Bugano DDG. Meta-analysis of modified folfirinox regimens for patients with metastatic pancreatic cancer. Clin Colorectal Cancer. 2018;17(3):187-197. [CrossRef]

33. Von Hoff DDV, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369(18):1691-1703. [CrossRef]

34. Pusceddu S, Ghidini M, Torchio M, et al. Comparative effectiveness of gemcitabine plus nab-paclitaxel and folfirinox in the first-line setting of metastatic pancreatic cancer: a systematic review and meta-analysis. Cancers (Basel). 2019;11(4). [CrossRef]

35. Wainberg ZA, Melisi D, Macarulla T, et al. NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial. Lancet. 2023;402(10409):1272-1281. [CrossRef]

36. Wang-Gillam A, Hubner RA, Siveke JT, et al. NAPOLI-1 phase 3 study of liposomal irinotecan in metastatic pancreatic cancer: final overall survival analysis and characteristics of long-term survivors. Eur J Cancer. 2019;108:78-87. [CrossRef]

37. Wang-Gillam A, Li CP, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545-557. [CrossRef]

38. Ohba A, Ozaka M, Ogawa G, et al. 1616O Nab-paclitaxel plus gemcitabine versus modified folfirinox or S-IROX in metastatic or recurrent pancreatic cancer (JCOG1611, GENERATE): a multicentred, randomized, open-label, three-arm, phase II/III trial. Ann Oncol. 2023;34:S894. [CrossRef]

39. Dayyani F, Macarulla T, Johnson A, Wainberg ZA. Second-line treatment options for patients with metastatic pancreatic ductal adenocarcinoma: a systematic literature review. Cancer Treat Rev. 2023;113:102502. [CrossRef]

40. Oettle H, Riess H, Stieler JM, et al. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 trial. J Clin Oncol. 2014;32(23):2423-2429. [CrossRef]

41. Gill S, Ko Y-J, Cripps C, et al. PANCREOX: a randomized Phase III study of fluorouracil/leucovorin with or without oxaliplatin for second-line advanced pancreatic cancer in patients who have received gemcitabine-based chemotherapy. J Clin Oncol. 2016;34(32):3914-3920. [CrossRef]

42. Wang S, Zheng Y, Yang F, et al. The molecular biology of pancreatic adenocarcinoma: translational challenges and clinical perspectives. Signal Transduct Target Ther. 2021;6(1):249. [CrossRef]

43. Pishvaian MJ, Blais EM, Brody JR, et al. Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial. Lancet Oncol. 2020;21(4):508-518. [CrossRef]

44. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503(7477):548-551. [CrossRef]

45. Strickler JH, Satake H, George TJ, et al. Sotorasib in KRAS p.G12C-Mutated Advanced Pancreatic Cancer. N Engl J Med. 2023;388(1):33-43. [CrossRef]

46. Awad MM, Liu S, Rybkin II, et al. Acquired resistance to KRASG12C inhibition in cancer. N Engl J Med. 2021;384(25):2382-2393. [CrossRef]

47. Frank KJ, Mulero-Sánchez A, Berninger A, et al. Extensive preclinical validation of combined RMC-4550 and LY3214996 supports clinical investigation for KRAS mutant pancreatic cancer. Cell Rep Med. 2022;3(11):100815. [CrossRef]

48. Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381(4):317-327. [CrossRef]

49. Kindler HL, Hammel P, Reni M, et al. Overall survival results from the POLO trial: A Phase III study of active maintenance olaparib versus placebo for germline BRCA-mutated metastatic pancreatic cancer. J Clin Oncol. 2022;40(34):3929-3939. [CrossRef]

50. Javle M, Shacham-Shmueli E, Xiao L, et al. Olaparib monotherapy for previously treated pancreatic cancer with DNA damage repair genetic alterations other than germline BRCA variants: findings from 2 Phase 2 nonrandomized clinical trials. JAMA Oncol. 2021;7(5):693-699. [CrossRef]

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