Skip to main content
SpringerLink
Log in

Comparison the efficacy and safety of different neoadjuvant regimens for resectable and borderline resectable pancreatic cancer: a systematic review and network meta-analysis

  • Review
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Background

To date, the optimal recommended specific neoadjuvant regimens for resectable or borderline resectable pancreatic cancer (RPC or BRPC) remain an unanswered issue.

Methods

We systematically searched the electronic databases to identify randomized controlled trials (RCTs) comparing different neoadjuvant therapy strategies for RPC or BRPC. The primary outcome was overall survival (OS). Comprehensive analyses and evaluations were performed using the single-arm, paired, and network meta-analyses.

Results

Twelve RCTs involving 1279 patients with RPC or BRPC were enrolled. The paired meta-analysis showed that neoadjuvant therapy improved OS for both RPC (hazard ratio (HR) 0.69, 95% c.i. 0.54 to 0.87) and BRPC (HR 0.60, 0.42 to 0.86) compared with upfront surgery (UP-S). Neoadjuvant chemotherapy (NAC) also improved OS for both RPC (HR 0.63, 0.47 to 0.85) and BRPC (HR 0.44, 0.27 to 0.71), while neoadjuvant chemoradiotherapy (NACR) improved OS only for BRPC (HR 0.68, 0.52 to 0.89) and not for RPC (HR 0.79, 0.54 to 1.16). Network meta-analysis found that NAC was superior to NACR in OS for RPC/BRPC (HR 0.58, 0.37 to 0.90). Neoadjuvant chemotherapy based on modified fluorouracil/folinic acid/irinotecan/oxaliplatin (NAC-mFFX) and neoadjuvant chemotherapy based on abraxane/gemcitabine (NAC-AG) ranked first and second in OS for RPC/BRPC.

Conclusions

Both RPC and BRPC could obtain OS benefits from neoadjuvant therapy compared with UP-S, and NAC improved OS both in RPC and BRPC while NACR only improved OS in BRPC. Furthermore, NAC was superior to NACR, and NAC-mFFX and NAC-AG might be recommended sequentially as the best neoadjuvant therapy strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

References

  1. Siegel RL, Miller KD, Jemal A (2020) Cancer statistics, 2020. CA: Cancer J Clin 70(1):7–30. https://doi.org/10.3322/caac.21590

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Miller KD, Siegel RL, Lin CC, Mariotto AB, Kramer JL, Rowland JH, Stein KD, Alteri R, Jemal A (2016) Cancer treatment and survivorship statistics. CA: Cancer J Clin 66(4):271–289. https://doi.org/10.3322/caac.21349

  4. Mizrahi JD, Surana R, Valle JW, Shroff RT (2020) Pancreatic cancer. Lancet (London, England) 395(10242):2008–2020. https://doi.org/10.1016/s0140-6736(20)30974-0

    Article  CAS  PubMed  Google Scholar 

  5. Heestand GM, Murphy JD, Lowy AM (2015) Approach to patients with pancreatic cancer without detectable metastases. J Clin Oncol: J Am Soc Clin Oncol 33(16):1770–1778. https://doi.org/10.1200/jco.2014.59.7930

    Article  PubMed  Google Scholar 

  6. Oettle H, Neuhaus P, Hochhaus A, Hartmann JT, Gellert K, Ridwelski K, Niedergethmann M, Zülke C, Fahlke J, Arning MB, Sinn M, Hinke A, Riess H (2013) Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA 310(14):1473–1481. https://doi.org/10.1001/jama.2013.279201

    Article  CAS  PubMed  Google Scholar 

  7. Oettle H, Neuhaus P (2007) Adjuvant therapy in pancreatic cancer: a critical appraisal. Drugs 67(16):2293–2310. https://doi.org/10.2165/00003495-200767160-00001

    Article  CAS  PubMed  Google Scholar 

  8. Zuckerman DS, Ryan DP (2008) Adjuvant therapy for pancreatic cancer: a review. Cancer 112(2):243–249. https://doi.org/10.1002/cncr.23174

    Article  CAS  PubMed  Google Scholar 

  9. Casolino R, Braconi C, Malleo G, Paiella S, Bassi C, Milella M, Dreyer SB, Froeling FEM, Chang DK, Biankin AV, Golan T (2021) Reshaping preoperative treatment of pancreatic cancer in the era of precision medicine. Ann Oncol: J Eur Soc Med Oncol 32(2):183–196. https://doi.org/10.1016/j.annonc.2020.11.013

    Article  CAS  PubMed  Google Scholar 

  10. Heinrich S, Lang H (2017) Neoadjuvant therapy of pancreatic cancer: definitions and benefits. Int J Mole Sci 18(8). https://doi.org/10.3390/ijms18081622

  11. Versteijne E, van Dam JL, Suker M, Janssen QP, Groothuis K, Akkermans-Vogelaar JM, Besselink MG, Bonsing BA, Buijsen J, Busch OR, Creemers GM, van Dam RM, Eskens F, Festen S, de Groot JWB, Groot Koerkamp B, de Hingh IH, Homs MYV, van Hooft JE, Kerver ED, Luelmo SAC, Neelis KJ, Nuyttens J, Paardekooper G, Patijn GA, van der Sangen MJC, de Vos-Geelen J, Wilmink JW, Zwinderman AH, Punt CJ, van Tienhoven G, van Eijck CHJ (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: J Am Soc Clin Oncol 40(11):1220–1230. https://doi.org/10.1200/jco.21.02233

    Article  CAS  PubMed  Google Scholar 

  12. Janssen QP, Buettner S, Suker M, Beumer BR, Addeo P, Bachellier P, Bahary N, Bekaii-Saab T, Bali MA, Besselink MG, Boone BA, Chau I, Clarke S, Dillhoff M, El-Rayes BF, Frakes JM, Grose D, Hosein PJ, Jamieson NB, Javed AA, Khan K, Kim KP, Kim SC, Kim SS, Ko AH, Lacy J, Margonis GA, McCarter MD, McKay CJ, Mellon EA, Moorcraft SY, Okada KI, Paniccia A, Parikh PJ, Peters NA, Rabl H, Samra J, Tinchon C, van Tienhoven G, van Veldhuisen E, Wang-Gillam A, Weiss MJ, Wilmink JW, Yamaue H, Homs MYV, van Eijck CHJ, Katz MHG, Groot Koerkamp B (2019) Neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer: a systematic review and patient-level meta-analysis. J Natl Cancer Inst 111(8):782–794. https://doi.org/10.1093/jnci/djz073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Tempero MA, Malafa MP, Al-Hawary M, Behrman SW, Benson AB, Cardin DB, Chiorean EG, Chung V, Czito B, Del Chiaro M, Dillhoff M, Donahue TR, Dotan E, Ferrone CR, Fountzilas C, Hardacre J, Hawkins WG, Klute K, Ko AH, Kunstman JW, LoConte N, Lowy AM, Moravek C, Nakakura EK, Narang AK, Obando J, Polanco PM, Reddy S, Reyngold M, Scaife C, Shen J, Vollmer C, Wolff RA, Wolpin BM, Lynn B, George GV (2021) Pancreatic adenocarcinoma, version 2. NCCN Clinical Practice Guidelines in Oncology.  J Natl Compr Canc Netw 19(4):439–457.https://doi.org/10.6004/jnccn.2021.0017

  14. van Dam JL, Janssen QP, Besselink MG, Homs MYV, van Santvoort HC, van Tienhoven G, de Wilde RF, Wilmink JW, van Eijck CHJ, Groot Koerkamp B (2022) Neoadjuvant therapy or upfront surgery for resectableand borderline resectable pancreatic cancer: ameta-analysis of randomised controlled trials. Eur J Cancer (Oxford, England:1990) 160:140–149. https://doi.org/10.1016/j.ejca.2021.10.023

  15. Xu Y, Chen Y, Han F, Wu J, Zhang Y (2022) Neoadjuvant therapy vs. upfront surgery for resectable pancreatic cancer: an update on a systematic review and meta-analysis. Bioscience trends 15(6):365–373. https://doi.org/10.5582/bst.2021.01459

  16. Conroy T, Desseigne F, Ychou M, Bouché O, Guimbaud R, Bécouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardière C, Bennouna J, Bachet JB, Khemissa-Akouz F, Péré-Vergé D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364(19):1817–1825. https://doi.org/10.1056/NEJMoa1011923

    Article  CAS  PubMed  Google Scholar 

  17. Von Hoff DD, Ervin T, Arena FP, Chiorean EG, Infante J, Moore M, Seay T, Tjulandin SA, Ma WW, Saleh MN, Harris M, Reni M, Dowden S, Laheru D, Bahary N, Ramanathan RK, Tabernero J, Hidalgo M, Goldstein D, Van Cutsem E, Wei X, Iglesias J, Renschler MF (2013) Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369(18):1691–1703. https://doi.org/10.1056/NEJMoa1304369

    Article  CAS  Google Scholar 

  18. Hu Q, Wang D, Chen Y, Li X, Cao P, Cao D (2019) Network meta-analysis comparing neoadjuvant chemoradiation, neoadjuvant chemotherapy and upfront surgery in patients with resectable, borderline resectable, and locally advanced pancreatic ductal adenocarcinoma. Radiation oncology (London, England) 14(1):120. https://doi.org/10.1186/s13014-019-1330-0

    Article  CAS  PubMed  Google Scholar 

  19. Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, Ioannidis JP, Straus S, Thorlund K, Jansen JP, Mulrow C, Catalá-López F, Gøtzsche PC, Dickersin K, Boutron I, Altman DG, Moher D (2015) The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med 162(11):777–784. https://doi.org/10.7326/m14-2385

    Article  PubMed  Google Scholar 

  20. Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (2019) Cochrane handbook for systematic reviews of interventions. John Wiley & Sons

    Book  Google Scholar 

  21. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR (2007) Practical methods for incorporating summary time-to-event data into meta-analysis. Trials 8(1):1–16

    Article  Google Scholar 

  22. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses Bmj 327(7414):557–560

    PubMed  Google Scholar 

  23. Shim SR, Kim SJ, Lee J, Rücker G (2019) Network meta-analysis: application and practice using R software. Epidemiol Health 41

  24. Lu G, Ades A (2006) Assessing evidence inconsistency in mixed treatment comparisons. J Am Stat Assoc 101(474):447–459

    Article  CAS  Google Scholar 

  25. van Valkenhoef G, Dias S, Ades A, Welton NJ (2016) Automated generation of node-splitting models for assessment of inconsistency in network meta-analysis. Research Synth Methods 7(1):80–93

    Article  Google Scholar 

  26. Khera R, Murad MH, Chandar AK, Dulai PS, Wang Z, Prokop LJ, Loomba R, Camilleri M, Singh S (2016) Association of pharmacological treatments for obesity with weight loss and adverse events: a systematic review and meta-analysis. JAMA 315(22):2424–2434. https://doi.org/10.1001/jama.2016.7602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Versteijne E, Suker M, Groothuis K, Akkermans-Vogelaar JM, Besselink MG, Bonsing BA, Buijsen J, Busch OR, Creemers G-JM, van Dam RM (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(16):1763

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Al-Batran S-E, Reichart A, Bankstahl US, Pauligk C, Kraus TW, Bechstein WO, Trojan J, Behrend M, Potenberg J, Homann N (2021) Randomized multicenter phase II/III study with adjuvant gemcitabine versus neoadjuvant/adjuvant FOLFIRINOX in resectable pancreatic cancer: the NEPAFOX trial. In: ed. Am Soc Clin Oncol

  29. Casadei R, Di Marco M, Ricci C, Santini D, Serra C, Calculli L, D’Ambra M, Guido A, Morselli-Labate AM, Minni F (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(10):1802–1812

    Article  PubMed  Google Scholar 

  30. Ghaneh P, Palmer DH, Cicconi S, Halloran C, Psarelli EE, Rawcliffe CL, Sripadam R, Mukherjee S, Wadsley J, Al-Mukhtar A (2020) ESPAC-5F: four-arm, prospective, multicenter, international randomized phase II trial of immediate surgery compared with neoadjuvant gemcitabine plus capecitabine (GEMCAP) or FOLFIRINOX or chemoradiotherapy (CRT) in patients with borderline resectable pancreatic cancer. J Clin Oncol: J Am Soc Clin Oncol 38(15_suppl):4505

  31. Jang J-Y, Han Y, Lee H, Kim S-W, Kwon W, Lee K-H, Oh D-Y, Chie EK, Lee JM, Heo JS (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(2):215–222

    Article  PubMed  Google Scholar 

  32. Katz MH, Shi Q, Meyers JP, Herman JM, Choung M, Wolpin BM, Ahmad S, Marsh RdW, Schwartz LH, Behr S (2021) Alliance A021501: preoperative mFOLFIRINOX or mFOLFIRINOX plus hypofractionated radiation therapy (RT) for borderline resectable (BR) adenocarcinoma of the pancreas. In: ed. Am Soc Clin Oncol

  33. Motoi F, Kosuge T, Ueno H, Yamaue H, Satoi S, Sho M, Honda G, Matsumoto I, Wada K, Furuse J (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(2):190–194

    Article  PubMed  Google Scholar 

  34. Reni M, Balzano G, Zanon S, Zerbi A, Rimassa L, Castoldi R, Pinelli D, Mosconi S, Doglioni C, Chiaravalli M (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(6):413–423

    Article  PubMed  Google Scholar 

  35. Sohal DP, Duong M, Ahmad SA, Gandhi NS, Beg MS, Wang-Gillam A, Wade JL, Chiorean EG, Guthrie KA, Lowy AM (2021) Efficacy of perioperative chemotherapy for resectable pancreatic adenocarcinoma: a phase 2 randomized clinical trial. JAMA Oncol 7(3):421–427

    Article  PubMed  Google Scholar 

  36. Yamaguchi J, Yokoyama Y, Fujii T, Yamada S, Takami H, Kawashima H, Ohno E, Ishikawa T, Maeda O, Ogawa H (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(6):1043–1049

    Article  PubMed  Google Scholar 

  37. Ettrich TJ, Uhl W, Kornmann M, Algül H, Friess H, Koenig A, Gallmeier E, Lutz MP, Wille K, Schimanski CC (2022) Perioperative or adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer: updated final results of the randomized phase II AIO-NEONAX trial. In: ed. Am Soc Clin Oncol

  38. Golcher H, Brunner TB, Witzigmann H, Marti L, Bechstein W-O, Bruns C, Jungnickel H, Schreiber S, Grabenbauer GG, Meyer T (2015) Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer. Strahlenther Onkol 191(1):7–16

    Article  PubMed  Google Scholar 

  39. Satoi S, Unno M, Motoi F, Matsuyama Y, Matsumoto I, Aosasa S, Shirakawa H, Wada K, Fujii T, Yoshitomi H (2019) The effect of neoadjuvant chemotherapy with gemcitabine and S-1 for resectable pancreatic cancer (randomized phase II/III trial; Prep-02/JSAP-05). In: ed. Am Soc Clin Oncol

  40. Versteijne E, Vogel JA, Besselink MG, Busch ORC, Wilmink JW, Daams JG, van Eijck CHJ, Groot Koerkamp B, Rasch CRN, van Tienhoven G (2018) Meta-analysis comparing upfront surgery with neoadjuvant treatment in patients with resectable or borderline resectable pancreatic cancer. Br J Surg 105(8):946–958. https://doi.org/10.1002/bjs.10870

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ghanem I, Lora D, Herradón N, de Velasco G, Carretero-González A, Jiménez-Varas M, Vázquez de Parga P, Feliu J (2022) Neoadjuvant chemotherapy with or without radiotherapy versus upfront surgery for resectable pancreatic adenocarcinoma: a meta-analysis of randomized clinical trials. ESMO open 7(3). https://doi.org/10.1016/j.esmoop.2022.100485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yamada M, Sugiura T, Okamura Y, Ito T, Yamamoto Y, Ashida R, Ohgi K, Aramaki T, Endo M, Uesaka K (2021) Clinical implication of node-negative resectable pancreatic cancer. Ann Surg Oncol 28(4):2257–2264. https://doi.org/10.1245/s10434-020-09543-x

    Article  PubMed  Google Scholar 

  43. Lambert A, Schwarz L, Ducreux M, Conroy T (2021) Neoadjuvant treatment strategies in resectable pancreatic cancer. Cancers 13(18). https://doi.org/10.3390/cancers13184724

  44. Damm M, Efremov L, Birnbach B, Terrero G, Kleeff J, Mikolajczyk R, Rosendahl J, Michl P, Krug S (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 13(17). https://doi.org/10.3390/cancers13174326

Download references

Funding

This study was funded by the Guangdong Provincial Natural Science Foundation (grant no. 2021A1515012368).

Author information

Author notes

  1. Xujia Li and Jinsheng Huang equally contributed to this work.

Authors and Affiliations

  1. VIP Department, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People’s Republic of China

    Xujia Li, Jinsheng Huang, Chang Jiang, Ping Chen, Qi Quan, Qi Jiang & Guifang Guo

  2. State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People’s Republic of China

    Xujia Li, Jinsheng Huang, Chang Jiang, Ping Chen, Qi Quan, Qi Jiang, Shengping Li & Guifang Guo

  3. Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People’s Republic of China

    Xujia Li, Jinsheng Huang, Chang Jiang, Ping Chen, Qi Quan, Qi Jiang, Shengping Li & Guifang Guo

  4. Department of Pancreaticobiliary Surgery, Sun Yat-Sen University Cancer Center, 651 Dongfeng Road East, Guangzhou, 510060, People’s Republic of China

    Shengping Li

Authors
  1. Xujia Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jinsheng Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chang Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ping Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qi Quan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qi Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shengping Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Guifang Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Xujia Li and Jinsheng Huang contributed to the conception and design of the study, administrative support, data interpretation, and manuscript writing. Chang Jiang and Ping Chen participated in data acquisition, statistical analysis, and data interpretation, as well as manuscript writing. Qi Quan and Qi Jiang were in charge of statistical analysis, data interpretation, and manuscript writing. Shengping Li and Guifang Guo were responsible for data interpretation and manuscript writing.

Corresponding authors

Correspondence to Shengping Li or Guifang Guo.

Ethics declarations

Ethical approval

An ethics statement is not applicable because this study is based exclusively on published literature.

Consent for publication

All authors declare their consent for publication. The manuscript does not contain any material that could be overtly or indirectly linked to any individual.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 1302 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, X., Huang, J., Jiang, C. et al. Comparison the efficacy and safety of different neoadjuvant regimens for resectable and borderline resectable pancreatic cancer: a systematic review and network meta-analysis. Eur J Clin Pharmacol 79, 323–340 (2023). https://doi.org/10.1007/s00228-022-03441-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-022-03441-9

Keywords

Search

Navigation