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A Prospective Phase II Trial of Neoadjuvant S-1 with Concurrent Hypofractionated Radiotherapy in Patients with Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinoma

  • Pancreatic Tumors
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Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

The ideal neoadjuvant treatment protocol for patients with pancreatic cancer (PDAC) remains unclear. We evaluated the efficacy and safety of neoadjuvant hypofractionated chemoradiotherapy with S-1 for patients with resectable (R) and borderline resectable (BR) PDAC.

Methods

Eligibility criteria included patients with R and BR PDAC, performance status 0–1, and age 20–85 years. Hypofractionated external-beam radiotherapy (30 Gy in 10 fractions) with concurrent S-1 (60 mg/m2) was delivered 5 days/week for 2 weeks prior to pancreatectomy.

Results

Fifty-seven patients were enrolled in this study, including 33 R and 24 BR [19 BR tumors with portal vein contact (BR-PV) and 5 BR tumors with arterial contact (BR-A)]. The total rates of protocol treatment completion and resection were 91% (50/57) and 96% (55/57), respectively. Seven patients failed to complete S-1 due to cholangitis (n = 5) or neutropenia (n = 2). The most common grade 3 toxicities [Common Terminology Criteria for Adverse Events (CTCAE) version 4.0] were anorexia (7%), nausea (5%), neutropenia (4%), and leukopenia (4%). No patient experienced grade 4 toxicity. Pathologically negative margins (R0) were achieved in 54 of 55 patients (98%) who underwent pancreatectomy. Pathological response was classified as Evans grade I in 8 patients (15%), IIa in 31 patients (56%), IIb in 14 patients (25%), III in 1 patient (2%), and IV in 1 patient (2%), and operative morbidity (Clavien-Dindo grade IIIb or less) was observed in 4 patients (8%). The 1- and 2-year overall survival (OS) rates were 91 and 83% in R patients, respectively, and 77 and 58% in BR patients, respectively (p = 0.03).

Conclusion

Neoadjuvant S-1 with concurrent hypofractionated radiotherapy is tolerable and appears promising for patients with R and BR PDAC.

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References

  1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012; 62(1):10–29.

    Article  PubMed  Google Scholar 

  2. Wray CJ, Ahmad SA, Matthews JB, et al. Surgery for pancreatic cancer: recent controversies and current practice. Gastroenterology 2005; 128(6):1626–41.

    Article  PubMed  Google Scholar 

  3. Vincent A, Herman J, Schulick R, et al. Pancreatic cancer. Lancet 2011; 378(9791):607–20.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Willett CG, Lewandrowski K, Warshaw AL, et al. Resection margins in carcinoma of the head of the pancreas. Implications for radiation therapy. Ann Surg 1993; 217(2):144–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Evans DB, Pisters PW, Lee JE, et al. Preoperative chemoradiation strategies for localized adenocarcinoma of the pancreas. J Hepatobiliary Pancreat Surg 1998; 5(3):242–50.

    Article  CAS  PubMed  Google Scholar 

  6. Verma V, Li J, Lin C. Neoadjuvant therapy for pancreatic cancer: systematic review of postoperative morbidity, mortality, and complications. Am J Clin Oncol 2016; 39(3):302–313.

    Article  CAS  PubMed  Google Scholar 

  7. Gillen S, Schuster T, Meyer Zum Buschenfelde C, et al. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med 2010; 7(4):e1000267.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Uesaka K, Boku N, Fukutomi A, 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(10041):248–57.

    Article  CAS  PubMed  Google Scholar 

  9. 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):1473–81.

    Article  CAS  PubMed  Google Scholar 

  10. Cloyd JM, Crane CH, Koay EJ, et al. Impact of hypofractionated and standard fractionated chemoradiation before pancreatoduodenectomy for pancreatic ductal adenocarcinoma. Cancer 2016; 122(17):2671–9.

    Article  CAS  PubMed  Google Scholar 

  11. Kim EJ, Ben-Josef E, Herman JM, et al. A multi-institutional phase 2 study of neoadjuvant gemcitabine and oxaliplatin with radiation therapy in patients with pancreatic cancer. Cancer 2013; 119(15):2692–700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Varadhachary GR, Wolff RA, Crane CH, et al. Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head. J Clin Oncol 2008; 26(21):3487–95.

    Article  CAS  PubMed  Google Scholar 

  13. Evans DB, Varadhachary GR, Crane CH, et al. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol 2008; 26(21):3496–502.

    Article  CAS  PubMed  Google Scholar 

  14. Cloyd JM, Katz MH, Prakash L, et al. Preoperative therapy and pancreatoduodenectomy for pancreatic ductal adenocarcinoma: a 25-year single-institution experience. J Gastrointest Surg 2017; 21(1):164–74.

    Article  PubMed  Google Scholar 

  15. National Comprehensive Cancer Network. Pancreatic adenocarcinoma. 2016. http://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf.

  16. Ueno H, Ioka T, Ikeda M, et al. Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study. J Clin Oncol 2013; 31(13):1640–8.

    Article  CAS  PubMed  Google Scholar 

  17. Ikeda M, Okusaka T, Ito Y, et al. A phase I trial of S-1 with concurrent radiotherapy for locally advanced pancreatic cancer. Br J Cancer 2007; 96(11):1650–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Shinchi H, Maemura K, Noma H, et al. Phase-I trial of oral fluoropyrimidine anticancer agent (S-1) with concurrent radiotherapy in patients with unresectable pancreatic cancer. Br J Cancer 2007; 96(9):1353–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004; 240(2):205–13.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Bassi C, Dervenis C, Butturini G, et al. Postoperative pancreatic fistula: an international study group (ISGPF) definition. Surgery 2005; 138(1):8–13.

    Article  PubMed  Google Scholar 

  21. Wente MN, Bassi C, Dervenis C, et al. Delayed gastric emptying (DGE) after pancreatic surgery: a suggested definition by the International Study Group of Pancreatic Surgery (ISGPS). Surgery 2007; 142(5):761–8.

    Article  PubMed  Google Scholar 

  22. Evans DB, Rich TA, Byrd DR, et al. Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas. Arch Surg 1992; 127(11):1335–9.

    Article  CAS  PubMed  Google Scholar 

  23. Staley CA, Cleary KR, Abbruzzese JL, et al. The need for standardized pathologic staging of pancreaticoduodenectomy specimens. Pancreas 1996; 12(4):373–80.

    Article  CAS  PubMed  Google Scholar 

  24. O’Reilly EM, Perelshteyn A, Jarnagin WR, et al. A single-arm, nonrandomized phase II trial of neoadjuvant gemcitabine and oxaliplatin in patients with resectable pancreas adenocarcinoma. Ann Surg 2014; 260(1):142–8.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Takeda Y, Nakamori S, Eguchi H, et al. Neoadjuvant gemcitabine-based accelerated hyperfractionation chemoradiotherapy for patients with borderline resectable pancreatic adenocarcinoma. Jpn J Clin Oncol 2014; 44(12):1172–80.

    Article  PubMed  Google Scholar 

  26. Ohigashi H, Ishikawa O, Eguchi H, et al. Feasibility and efficacy of combination therapy with preoperative full-dose gemcitabine, concurrent three-dimensional conformal radiation, surgery, and postoperative liver perfusion chemotherapy for T3-pancreatic cancer. Ann Surg 2009; 250(1):88–95.

    Article  PubMed  Google Scholar 

  27. Pisters PW, Abbruzzese JL, Janjan NA, et al. Rapid-fractionation preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for resectable pancreatic adenocarcinoma. J Clin Oncol 1998; 16(12):3843–50.

    Article  CAS  PubMed  Google Scholar 

  28. Pisters PW, Wolff RA, Janjan NA, et al. Preoperative paclitaxel and concurrent rapid-fractionation radiation for resectable pancreatic adenocarcinoma: toxicities, histologic response rates, and event-free outcome. J Clin Oncol 2002; 20(10):2537–44.

    Article  CAS  PubMed  Google Scholar 

  29. Talamonti MS, Small W, Jr., Mulcahy MF, et al. A multi-institutional phase II trial of preoperative full-dose gemcitabine and concurrent radiation for patients with potentially resectable pancreatic carcinoma. Ann Surg Oncol 2006; 13(2):150–8.

    Article  PubMed  Google Scholar 

  30. Chun YS, Cooper HS, Cohen SJ, et al. Significance of pathologic response to preoperative therapy in pancreatic cancer. Ann Surg Oncol 2011; 18(13):3601–7.

    Article  PubMed  Google Scholar 

  31. Wang H, Zhao Q. Pathologic complete response to neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma is associated with better prognosis. Ann Diagn Pathol 2012; 16(5):427.

    Article  PubMed  Google Scholar 

  32. Christians KK, Heimler JW, George B, et al. Survival of patients with resectable pancreatic cancer who received neoadjuvant therapy. Surgery 2016; 159(3):893–900.

    Article  PubMed  Google Scholar 

  33. Lee SM, Katz MH, Liu L, et al. Validation of a proposed tumor regression grading scheme for pancreatic ductal adenocarcinoma after neoadjuvant therapy as a prognostic indicator for survival. Am J Surg Pathol 2016; 40(12):1653–1660.

    Article  PubMed  Google Scholar 

  34. Mellon EA, Jin WH, Frakes JM, et al. Predictors and survival for pathologic tumor response grade in borderline resectable and locally advanced pancreatic cancer treated with induction chemotherapy and neoadjuvant stereotactic body radiotherapy. Acta Oncol 2016;56(3):391–397.

    Article  PubMed  Google Scholar 

  35. Katz MH, Fleming JB, Bhosale P, et al. Response of borderline resectable pancreatic cancer to neoadjuvant therapy is not reflected by radiographic indicators. Cancer 2012; 118(23):5749–56.

    Article  PubMed  Google Scholar 

  36. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011; 364(19):1817–25.

    Article  CAS  PubMed  Google Scholar 

  37. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013; 369(18):1691–703.

    Article  Google Scholar 

  38. Palmer DH, Stocken DD, Hewitt H, et al. A randomized phase 2 trial of neoadjuvant chemotherapy in resectable pancreatic cancer: gemcitabine alone versus gemcitabine combined with cisplatin. Ann Surg Oncol 2007; 14(7):2088–96.

    Article  PubMed  Google Scholar 

  39. Heinrich S, Pestalozzi BC, Schafer M, et al. Prospective phase II trial of neoadjuvant chemotherapy with gemcitabine and cisplatin for resectable adenocarcinoma of the pancreatic head. J Clin Oncol 2008; 26(15):2526–31.

    Article  CAS  PubMed  Google Scholar 

  40. Sahora K, Kuehrer I, Eisenhut A, et al. NeoGemOx: gemcitabine and oxaliplatin as neoadjuvant treatment for locally advanced, nonmetastasized pancreatic cancer. Surgery 2011; 149(3):311–20.

    Article  PubMed  Google Scholar 

  41. Lee JL, Kim SC, Kim JH, et al. Prospective efficacy and safety study of neoadjuvant gemcitabine with capecitabine combination chemotherapy for borderline-resectable or unresectable locally advanced pancreatic adenocarcinoma. Surgery 2012; 152(5):851–62.

    Article  PubMed  Google Scholar 

  42. Motoi F, Ishida K, Fujishima F, 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(12):3794–801.

    Article  PubMed  Google Scholar 

  43. Yeung RS, Weese JL, Hoffman JP, et al. Neoadjuvant chemoradiation in pancreatic and duodenal carcinoma. A phase II study. Cancer 1993; 72(7):2124–33.

    CAS  PubMed  Google Scholar 

  44. Hoffman JP, Lipsitz S, Pisansky T, et al. Phase II trial of preoperative radiation therapy and chemotherapy for patients with localized, resectable adenocarcinoma of the pancreas: an Eastern Cooperative Oncology Group Study. J Clin Oncol 1998; 16(1):317–23.

    Article  CAS  PubMed  Google Scholar 

  45. Moutardier V, Giovannini M, Lelong B, et al. A phase II single institutional experience with preoperative radiochemotherapy in pancreatic adenocarcinoma. Eur J Surg Oncol 2002; 28(5):531–9.

    Article  CAS  PubMed  Google Scholar 

  46. Magnin V, Moutardier V, Giovannini MH, et al. Neoadjuvant preoperative chemoradiation in patients with pancreatic cancer. Int J Radiat Oncol Biol Phys 2003; 55(5):1300–4.

    Article  PubMed  Google Scholar 

  47. Mornex F, Girard N, Scoazec JY, et al. Feasibility of preoperative combined radiation therapy and chemotherapy with 5-fluorouracil and cisplatin in potentially resectable pancreatic adenocarcinoma: the French SFRO-FFCD 97-04 phase II trial. Int J Radiat Oncol Biol Phys 2006; 65(5):1471–8.

    Article  CAS  PubMed  Google Scholar 

  48. Turrini O, Viret F, Moureau-Zabotto L, et al. Neoadjuvant 5 fluorouracil-cisplatin chemoradiation effect on survival in patients with resectable pancreatic head adenocarcinoma: a ten-year single institution experience. Oncology 2009; 76(6):413–9.

    Article  CAS  PubMed  Google Scholar 

  49. Chakraborty S, Morris MM, Bauer TW, et al. Accelerated fraction radiotherapy with capecitabine as neoadjuvant therapy for borderline resectable pancreatic cancer. Gastrointest Cancer Res 2014; 7(1):15–22.

    PubMed  PubMed Central  Google Scholar 

  50. Casadei R, Di Marco M, Ricci C, 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(10):1802–12.

    Article  PubMed  Google Scholar 

  51. Golcher H, Brunner TB, Witzigmann H, 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(1):7–16.

    Article  PubMed  Google Scholar 

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Disclosure

Keiichi Okano, Hironobu Suto, Minoru Oshima, Eri Maeda, Naoki Yamamoto, Keitaro Kakinoki, Hideki Kamada, Tsutomu Masaki, Shigeo Takahashi, Toru Shibata, and Yasuyuki Suzuki have no conflicts of interest to disclose.

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Authors and Affiliations

  1. Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa, Japan

    Keiichi Okano MD, PhD, FACS, Hironobu Suto MD, Minoru Oshima MD, PhD, Eri Maeda MD, Naoki Yamamoto MD, PhD, Keitaro Kakinoki MD, PhD & Yasuyuki Suzuki MD, PhD

  2. Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa, Japan

    Hideki Kamada MD, PhD & Tsutomu Masaki MD, PhD

  3. Department of Radiation Oncology, Faculty of Medicine, Kagawa University, Miki-cho, Kagawa, Japan

    Shigeo Takahashi MD & Toru Shibata MD, PhD

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  1. Keiichi Okano MD, PhD, FACS
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Correspondence to Keiichi Okano MD, PhD, FACS.

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Okano, K., Suto, H., Oshima, M. et al. A Prospective Phase II Trial of Neoadjuvant S-1 with Concurrent Hypofractionated Radiotherapy in Patients with Resectable and Borderline Resectable Pancreatic Ductal Adenocarcinoma. Ann Surg Oncol 24, 2777–2784 (2017). https://doi.org/10.1245/s10434-017-5921-4

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  • DOI: https://doi.org/10.1245/s10434-017-5921-4

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