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Long-term outcome following neoadjuvant therapy for resectable and borderline resectable pancreatic cancer compared to upfront surgery: a meta-analysis of comparative studies by intention-to-treat analysis

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Abstract

The aim of the study was to evaluate the effect of neoadjuvant therapy on long-term survival in patients with resectable and borderline resectable pancreatic cancer. A meta-analysis was conducted using the reported randomized, controlled trials and retrospective studies using an intention-to-treat analysis to compare upfront surgery and neoadjuvant therapy in resectable or borderline resectable pancreatic cancer patients. Six comparative studies consisting of two randomized, controlled trials and four retrospective studies were included. The overall pooled hazard ratio was 0.66 (95% confidence interval: 0.50–0.87, P = 0.003), indicating that patients in the neoadjuvant group had better long-term survival than those in the upfront surgery group. However, considerable inter-study heterogeneity was observed (I2 = 62%). This meta-analysis focusing on comparative studies analyzed by intention-to-treat analysis showed that neoadjuvant therapy for resectable and borderline resectable pancreatic cancer tends to improve patients’ long-term outcomes. However, the evidence level remains too low for a firm conclusion. The well-designed, randomized, controlled trials now ongoing will provide the definite evidence needed in the future.

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References

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics for Hispanics/Latinos, 2012. CA Cancer J Clin. 2012;62:283–98.

    Article  PubMed  Google Scholar 

  2. Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med. 2014;371:1039–49.

    Article  CAS  PubMed  Google Scholar 

  3. Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, 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;389:1011–24.

    Article  CAS  PubMed  Google Scholar 

  4. Uesaka K, Boku N, Fukutomi A, Okamura Y, Konishi M, Matsumoto I, et al. Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: a phase 3, open-label, randomised, non-inferiority trial (JASPAC 01). Lancet. 2016;388:248–57.

    Article  CAS  PubMed  Google Scholar 

  5. Polistina F, Di Natale G, Bonciarelli G, Ambrosino G, Frego M. Neoadjuvant strategies for pancreatic cancer. World J Gastroenterol. 2014;20:9374–83.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Motoi F, Ishida K, Fujishima F, Ottomo S, Oikawa M, Okada T, et al. Neoadjuvant chemotherapy with gemcitabine and S-1 for resectable and borderline pancreatic ductal adenocarcinoma: results from a prospective multi-institutional phase 2 trial. Ann Surg Oncol. 2013;20:3794–801.

    Article  PubMed  Google Scholar 

  7. Christians KK, Heimler JW, George B, Ritch PS, Erickson BA, Johnston F, et al. Survival of patients with resectable pancreatic cancer who received neoadjuvant therapy. Surgery. 2016;159:893–900.

    Article  PubMed  Google Scholar 

  8. Sho M, Akahori T, Tanaka T, Kinoshita S, Tamamoto T, Nomi T, et al. Pathological and clinical impact of neoadjuvant chemoradiotherapy using full-dose gemcitabine and concurrent radiation for resectable pancreatic cancer. J Hepatobiliary Pancreat Sci. 2013;20:197–205.

    Article  PubMed  Google Scholar 

  9. Winner M, Goff SL, Chabot JA. Neoadjuvant therapy for non-metastatic pancreatic ductal adenocarcinoma. Semin Oncol. 2015;42:86–97.

    Article  PubMed  Google Scholar 

  10. Mokdad AA, Minter RM, Zhu H, Augustine MM, Porembka MR, Wang SC, et al. Neoadjuvant therapy followed by resection versus upfront resection for resectable pancreatic cancer: a propensity score matched analysis. J Clin Oncol. 2017;35:515–22.

    Article  PubMed  Google Scholar 

  11. Bergquist JR, Ivanics T, Storlie CB, Groeschl RT, Tee MC, Habermann EB, et al. Implications of CA19-9 elevation for survival, staging, and treatment sequencing in intrahepatic cholangiocarcinoma: a national cohort analysis. J Surg Oncol. 2016;114:475–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. de Geus SWL, Kasumova GG, Sachs TE, Ng SC, Kent TS, Moser AJ, et al. Neoadjuvant therapy affects margins and margins affect all: perioperative and survival outcomes in resected pancreatic adenocarcinoma. HPB (Oxford). 2018;20:573–81.

    Article  Google Scholar 

  13. Motoi F, Satoi S, Honda G, Wada K, Shinchi H, Matsumoto I, et al. A single-arm, phase II trial of neoadjuvant gemcitabine and S1 in patients with resectable and borderline resectable pancreatic adenocarcinoma: PREP-01 study. J Gastroenterol. 2018.

  14. Laurence JM, Tran PD, Morarji K, Eslick GD, Lam VW, Sandroussi C. A systematic review and meta-analysis of survival and surgical outcomes following neoadjuvant chemoradiotherapy for pancreatic cancer. J Gastrointest Surg. 2011;15:2059–69.

    Article  PubMed  Google Scholar 

  15. Liu W, Fu XL, Yang JY, Liu DJ, Li J, Zhang JF, et al. Efficacy of neo-adjuvant chemoradiotherapy for resectable pancreatic adenocarcinoma: a PRISMA-compliant meta-analysis and systematic review. Medicine (Baltimore). 2016;95:e3009.

    Article  CAS  Google Scholar 

  16. Andriulli A, Festa V, Botteri E, Valvano MR, Koch M, Bassi C, et al. Neoadjuvant/preoperative gemcitabine for patients with localized pancreatic cancer: a meta-analysis of prospective studies. Ann Surg Oncol. 2012;19:1644–62.

    Article  PubMed  Google Scholar 

  17. Casadei R, Di Marco M, Ricci C, Santini D, Serra C, Calculli L, et al. 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. 2015;19:1802–12.

    Article  PubMed  Google Scholar 

  18. Golcher H, Brunner TB, Witzigmann H, Marti L, Bechstein WO, Bruns C, et al. 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. 2015;191:7–16.

    Article  PubMed  Google Scholar 

  19. Jang JY, Han Y, Lee H, Kim SW, Kwon W, Lee KH, 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;268:215–22.

    Article  PubMed  Google Scholar 

  20. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med. 2009;151:W65–94.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  22. Sterne JA, Sutton AJ, Ioannidis JP, Terrin N, Jones DR, Lau J, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011;343:d4002.

    Article  PubMed  Google Scholar 

  23. Barbier L, Turrini O, Gregoire E, Viret F, Le Treut YP, Delpero JR. Pancreatic head resectable adenocarcinoma: preoperative chemoradiation improves local control but does not affect survival. HPB (Oxford). 2011;13:64–9.

    Article  Google Scholar 

  24. Fujii T, Yamada S, Murotani K, Kanda M, Sugimoto H, Nakao A, et al. Inverse probability of treatment weighting analysis of upfront surgery versus neoadjuvant chemoradiotherapy followed by surgery for pancreatic adenocarcinoma with arterial abutment. Medicine (Baltimore). 2015;94:e1647.

    Article  CAS  Google Scholar 

  25. Murakami Y, Uemura K, Sudo T, Hashimoto Y, Kondo N, Nakagawa N, et al. Survival impact of neoadjuvant gemcitabine plus S-1 chemotherapy for patients with borderline resectable pancreatic carcinoma with arterial contact. Cancer Chemother Pharmacol. 2017;79:37–47.

    Article  CAS  PubMed  Google Scholar 

  26. Shubert CR, Bergquist JR, Groeschl RT, Habermann EB, Wilson PM, Truty MJ, et al. Overall survival is increased among stage III pancreatic adenocarcinoma patients receiving neoadjuvant chemotherapy compared to surgery first and adjuvant chemotherapy: An intention to treat analysis of the National Cancer Database. Surgery. 2016;160:1080–96.

    Article  PubMed  Google Scholar 

  27. D’Angelo F, Antolino L, Farcomeni A, Sirimarco D, Kazemi Nava A, De Siena M, et al. Neoadjuvant treatment in pancreatic cancer: evidence-based medicine? A systematic review and meta-analysis. Med Oncol. 2017;34:85.

    Article  CAS  PubMed  Google Scholar 

  28. Versteijne E, Vogel JA, Besselink MG, Busch ORC, Wilmink JW, Daams JG, et al. Meta-analysis comparing upfront surgery with neoadjuvant treatment in patients with resectable or borderline resectable pancreatic cancer. Br J Surg. 2018;105:946–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ahola R, Siiki A, Vasama K, Vornanen M, Sand J, Laukkarinen J. Effect of centralization on long-term survival after resection of pancreatic ductal adenocarcinoma. Br J Surg. 2017;104:1532–8.

    Article  CAS  PubMed  Google Scholar 

  30. Lidsky ME, Sun Z, Nussbaum DP, Adam MA, Speicher PJ, Blazer DG 3rd. Going the extra mile: improved survival for pancreatic cancer patients traveling to high-volume centers. Ann Surg. 2017;266:333–8.

    Article  PubMed  Google Scholar 

  31. Heinrich S, Pestalozzi B, Lesurtel M, Berrevoet F, Laurent S, Delpero JR, et al. Adjuvant gemcitabine versus NEOadjuvant gemcitabine/oxaliplatin plus adjuvant gemcitabine in resectable pancreatic cancer: a randomized multicenter phase III study (NEOPAC study). BMC Cancer. 2011;11:346.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Tachezy M, Gebauer F, Petersen C, Arnold D, Trepel M, Wegscheider K, et al. Sequential neoadjuvant chemoradiotherapy (CRT) followed by curative surgery vs. primary surgery alone for resectable, non-metastasized pancreatic adenocarcinoma: NEOPA—a randomized multicenter phase III study (NCT01900327, DRKS00003893, ISRCTN82191749). BMC Cancer. 2014;14:411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Versteijne E, van Eijck CH, Punt CJ, Suker M, Zwinderman AH, Dohmen MA, et al. Preoperative radiochemotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC trial): study protocol for a multicentre randomized controlled trial. Trials. 2016;17:127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Unno M, Motoi F, Kosuge T, Ueno H, Yamaue H, Satoi S, et al. Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus surgery-first for resectable pancreatic carcer (Prep-02/JSAP05). J Clin Oncol. 2015;33:TPS4151-TPS.

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan

    Michiaki Unno, Tatsuo Hata & Fuyuhiko Motoi

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  1. Michiaki Unno
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  2. Tatsuo Hata
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  3. Fuyuhiko Motoi
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Correspondence to Michiaki Unno.

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Unno, M., Hata, T. & Motoi, F. Long-term outcome following neoadjuvant therapy for resectable and borderline resectable pancreatic cancer compared to upfront surgery: a meta-analysis of comparative studies by intention-to-treat analysis. Surg Today 49, 295–299 (2019). https://doi.org/10.1007/s00595-019-01786-w

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