Korean J Gastroenterol.  2024 Sep;84(3):103-110. 10.4166/kjg.2024.079.

Neoadjuvant Therapy for Resectable or Borderline Resectable Pancreatic Cancer

• Lee SH

• KMID: 2559843
• DOI: http://doi.org/10.4166/kjg.2024.079

Abstract

Surgical resection of a primary tumor is the only effective curative treatment for patients with localized pancreatic cancer without a distant metastasis. Nevertheless, most patients eventually develop postoperative recurrence caused by micrometastases. The risk increases if a complete resection is not achieved. Three surgical stages have emerged for a preoperative assessment based on resectability: resectable, borderline resectable, and unresectable. Although controversial, considerable research has focused on the role of neoadjuvant therapy in all forms of potentially resectable pancreatic cancer. While upfront surgery with adjuvant chemotherapy remains the standard of care for patients with resectable pancreatic cancer, there is growing evidence that neoadjuvant chemotherapy improves overall survival without increasing the resection rate in patients with borderline resectable pancreatic cancer. This review describes the current treatment strategies for resectable and borderline resectable pancreatic cancer and summarizes the results of the latest clinical trials.

Keyword

Pancreatic cancer; Neoadjuvant therapy; Chemotherapy; Radiotherapy

Reference

1. Park W, Chawla A, O'Reilly EM. 2021; Pancreatic cancer: A review. JAMA. 326:851–862. DOI: 10.1001/jama.2021.13027. PMID: 34547082. PMCID: PMC9363152.

2. Groot VP, Rezaee N, Wu W, et al. 2018; Patterns, timing, and predictors of recurrence following pancreatectomy for pancreatic ductal adenocarcinoma. Ann Surg. 267:936–945. DOI: 10.1097/SLA.0000000000002234. PMID: 28338509.

3. Bilimoria KY, Talamonti MS, Sener SF, et al. 2008; Effect of hospital volume on margin status after pancreaticoduodenectomy for cancer. J Am Coll Surg. 207:510–519. DOI: 10.1016/j.jamcollsurg.2008.04.033. PMID: 18926452.

4. Varadhachary GR, Tamm EP, Abbruzzese JL, et al. 2006; Borderline resectable pancreatic cancer: definitions, management, and role of preoperative therapy. Ann Surg Oncol. 13:1035–1046. DOI: 10.1245/ASO.2006.08.011. PMID: 16865597.

5. NCCN Guidelines: Pancreatic adenocarcinoma, Version 3.2024. [Internet]. National Comprehensive Cancer Network;Available from: https://www.nccn.org/guidelines/category_1. cited 2024 Aug 1.

6. Yu XZ, Li J, Fu DL, et al. 2014; Benefit from synchronous portal-superior mesenteric vein resection during pancreaticoduodenectomy for cancer: a meta-analysis. Eur J Surg Oncol. 40:371–378. DOI: 10.1016/j.ejso.2014.01.010. PMID: 24560302.

7. Katz MH, Pisters PW, Evans DB, et al. 2008; Borderline resectable pancreatic cancer: the importance of this emerging stage of disease. J Am Coll Surg. 206:833–846. discussion 846–848. DOI: 10.1016/j.jamcollsurg.2007.12.020. PMID: 18471707. PMCID: PMC5901743.

8. Seufferlein T, Uhl W, Kornmann M, et al. 2023; 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. 34:91–100. DOI: 10.1016/j.annonc.2022.09.161. PMID: 36209981.

9. Hartwig W, Gluth A, Hinz U, et al. 2016; Outcomes after extended pancreatectomy in patients with borderline resectable and locally advanced pancreatic cancer. Br J Surg. 103:1683–1694. DOI: 10.1002/bjs.10221. PMID: 27686238.

10. Jang JY, Han Y, Lee H, et al. 2018; 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. 268:215–222. DOI: 10.1097/SLA.0000000000002705. PMID: 29462005.

11. Golcher H, Brunner TB, Witzigmann H, et al. 2015; Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer: results of the first prospective randomized phase II trial. Strahlenther Onkol. 191:7–16. DOI: 10.1007/s00066-014-0737-7. PMID: 25252602. PMCID: PMC4289008.

12. Casadei R, Di Marco M, Ricci C, et al. 2015; Neoadjuvant chemoradiotherapy and surgery versus surgery alone in resectable pancreatic cancer: A single-center prospective, randomized, controlled trial which failed to achieve accrual targets. J Gastrointest Surg. 19:1802–1812. DOI: 10.1007/s11605-015-2890-4. PMID: 26224039.

13. Reni M, Balzano G, Zanon S, et al. 2018; Safety and efficacy of preoperative or postoperative chemotherapy for resectable pancreatic adenocarcinoma (PACT-15): a randomised, open-label, phase 2-3 trial. Lancet Gastroenterol Hepatol. 3:413–423. DOI: 10.1016/S2468-1253(18)30081-5. PMID: 29625841.

14. Versteijne E, Suker M, Groothuis K, et al. 2020; Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer: Results of the dutch randomized phase III PREOPANC trial. J Clin Oncol. 38:1763–1773. DOI: 10.1200/JCO.19.02274. PMID: 32105518. PMCID: PMC8265386.

15. Versteijne E, van Dam JL, Suker M, et al. 2022; Neoadjuvant chemoradiotherapy versus upfront surgery for resectable and borderline resectable pancreatic cancer: Long-term results of the dutch randomized PREOPANC trial. J Clin Oncol. 40:1220–1230. DOI: 10.1200/JCO.21.02233. PMID: 35084987.

16. van Dam JL, Janssen QP, Besselink MG, et al. 2022; Neoadjuvant therapy or upfront surgery for resectable and borderline resectable pancreatic cancer: A meta-analysis of randomised controlled trials. Eur J Cancer. 160:140–149. DOI: 10.1016/j.ejca.2021.10.023. PMID: 34838371.

17. Committee of the Korean clinical practice guideline for pancreatic cancer and National Cancer Center, Korea. Korean clinical practice guideline for pancreatic cancer 2021: A summary of evidence-based, multi-disciplinary diagnostic and therapeutic approaches. Pancreatology. 2021; 21:1326–1341. DOI: 10.1016/j.pan.2021.05.004. PMID: 34148794.

18. Conroy T, Desseigne F, Ychou M, et al. 2011; FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 364:1817–1825. DOI: 10.1056/NEJMoa1011923. PMID: 21561347.

19. Von Hoff DD, Ervin T, Arena FP, et al. 2013; Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 369:1691–1703. DOI: 10.1056/NEJMoa1304369. PMID: 24131140. PMCID: PMC4631139.

20. Conroy T, Hammel P, Hebbar M, et al. 2018; FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 379:2395–2406. DOI: 10.1056/NEJMoa1809775. PMID: 30575490.

21. Schwarz L, Bachet JB, Meurisse A, et al. 2022; Resectable pancreatic adenocarcinoma neo-adjuvant FOLF(IRIN)OX-based chemotherapy: A multicenter, non-comparative, randomized, phase II trial (PANACHE01-PRODIGE48 study). J Clin Oncol. 40:4134. DOI: 10.1200/JCO.2022.40.16_suppl.4134. PMID: 30041614. PMCID: PMC6057099.

22. Labori KJ, Bratlie SO, Andersson B, et al. 2024; Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1): a multicentre, randomised, phase 2 trial. Lancet Gastroenterol Hepatol. 9:205–217. DOI: 10.1016/S2468-1253(23)00405-3. PMID: 38237621.

23. Ghaneh P, Palmer D, Cicconi S, et al. 2023; Immediate surgery compared with short-course neoadjuvant gemcitabine plus capecitabine, FOLFIRINOX, or chemoradiotherapy in patients with borderline resectable pancreatic cancer (ESPAC5): a four-arm, multicentre, randomised, phase 2 trial. Lancet Gastroenterol Hepatol. 8:157–168. DOI: 10.1016/S2468-1253(22)00348-X. PMID: 36521500.

24. Motoi F, Kosuge T, Ueno H, et al. 2019; Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer (Prep-02/JSAP05). Jpn J Clin Oncol. 49:190–194. DOI: 10.1093/jjco/hyy190. PMID: 30608598.

25. Sohal DPS, Duong M, Ahmad SA, et al. 2021; Efficacy of perioperative chemotherapy for resectable pancreatic adenocarcinoma: A phase 2 randomized clinical trial. JAMA Oncol. 7:421–427. DOI: 10.1001/jamaoncol.2020.7328. PMID: 33475684. PMCID: PMC7821078.

26. Murphy JE, Wo JY, Ryan DP, et al. 2018; Total neoadjuvant therapy with FOLFIRINOX followed by individualized chemoradiotherapy for borderline resectable pancreatic adenocarcinoma: A phase 2 clinical trial. JAMA Oncol. 4:963–969. DOI: 10.1001/jamaoncol.2018.0329. PMID: 29800971. PMCID: PMC6145728.

27. Katz MHG, Shi Q, Meyers J, et al. 2022; 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. 8:1263–1270. DOI: 10.1001/jamaoncol.2022.2319. PMID: 35834226. PMCID: PMC9284408.

28. Janssen QP, Buettner S, Suker M, et al. 2019; Neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer: A systematic review and patient-level meta-analysis. J Natl Cancer Inst. 111:782–794. DOI: 10.1093/jnci/djz073. PMID: 31086963. PMCID: PMC6695305.

29. Janssen QP, van Dam JL, Doppenberg D, et al. 2022; FOLFIRINOX as initial treatment for localized pancreatic adenocarcinoma: A retrospective analysis by the trans-atlantic pancreatic surgery consortium. J Natl Cancer Inst. 114:695–703. DOI: 10.1093/jnci/djac018. PMID: 35157075. PMCID: PMC9086789.

30. Koerkamp BG, Janssen QP, van Dam JL, et al. 2023; 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. 34(Suppl 2):S1323. DOI: 10.1016/j.annonc.2023.10.084.

31. Damm M, Efremov L, Birnbach B, et al. 2021; Efficacy and safety of neoadjuvant gemcitabine plus nab-paclitaxel in borderline resectable and locally advanced pancreatic cancer-a systematic review and meta-analysis. Cancers (Basel). 13:4326. DOI: 10.3390/cancers13174326. PMID: 34503138. PMCID: PMC8430874.

32. Yamaguchi J, Yokoyama Y, Fujii T, et al. 2022; Results of a phase II study on the use of neoadjuvant chemotherapy (FOLFIRINOX or GEM/nab-PTX) for borderline-resectable pancreatic cancer (NUPAT-01). Ann Surg. 275:1043–1049. DOI: 10.1097/SLA.0000000000005430. PMID: 35258510.

33. O'Shea AE, Bohan PMK, Carpenter EL, et al. 2022; Downstaging of pancreatic adenocarcinoma with either neoadjuvant chemotherapy or chemoradiotherapy improves survival. Ann Surg Oncol. 29:6015–6028. DOI: 10.1245/s10434-022-11800-0. PMID: 35583691.

34. Janssen QP, van Dam JL, Kivits IG, et al. 2021; Added value of radiotherapy following neoadjuvant FOLFIRINOX for resectable and borderline resectable pancreatic cancer: A systematic review and meta-analysis. Ann Surg Oncol. 28:8297–8308. DOI: 10.1245/s10434-021-10276-8. PMID: 34142290. PMCID: PMC8591030.

35. Springfeld C, Ferrone CR, Katz MHG, et al. 2023; Neoadjuvant therapy for pancreatic cancer. Nat Rev Clin Oncol. 20:318–337. DOI: 10.1038/s41571-023-00746-1. PMID: 36932224.

36. Olecki EJ, Stahl KA, Torres MB, et al. 2021; Adjuvant chemotherapy after neoadjuvant chemotherapy for pancreatic cancer is associated with improved survival for patients with low-risk pathology. Ann Surg Oncol. 28:3111–3122. DOI: 10.1245/s10434-020-09546-8. PMID: 33521899.

37. Kamarajah SK, White SA, Naffouje SA, Salti GI, Dahdaleh F. 2021; Adjuvant chemotherapy associated with survival benefit following neoadjuvant chemotherapy and pancreatectomy for pancreatic ductal adenocarcinoma: A population-based cohort study. Ann Surg Oncol. 28:6790–6802. DOI: 10.1245/s10434-021-09823-0. PMID: 33786676. PMCID: PMC8460503.

38. van Roessel S, van Veldhuisen E, Klompmaker S, et al. 2020; Evaluation of adjuvant chemotherapy in patients with resected pancreatic cancer after neoadjuvant FOLFIRINOX treatment. JAMA Oncol. 6:1733–1740. DOI: 10.1001/jamaoncol.2020.3537. PMID: 32910170. PMCID: PMC7489392.