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Intraoperative Radiation Mitigates the Effect of Microscopically Positive Tumor Margins on Survival Among Pancreatic Adenocarcinoma Patients Treated with Neoadjuvant FOLFIRINOX and Chemoradiation

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

Abstract

Background

Microscopically positive margins (R1) negatively impact survival in pancreatic ductal adenocarcinoma (PDAC). For patients with close/positive margins, intraoperative radiotherapy (IORT) can improve local control. The prognostic impact of an R1 resection in patients who receive total neoadjuvant therapy (TNT; FOLFIRINOX with chemoradiation) and IORT is unknown.

Methods

Clinicopathologic data were retrospectively collected for borderline/locally advanced (BR/LA) PDAC patients who received TNT and underwent resection between 2011 and 2019. Disease-free (DFS) and overall survival (OS) measured from time of diagnosis were compared between groups.

Results

Two hundred one patients received TNT and were resected, with a median DFS and OS of 24 months and 47 months, respectively. Eighty-eight patients (44%) received IORT; of these, 69 (78%) underwent an R0 and 19 (22%) an R1 resection. There was no significant difference in clinicopathologic factors between the IORT and no-IORT groups, except for resectability status (LA: IORT 69%, no-IORT 53%, p = 0.021) and surgeons’ concern for a positive/close margin. R1 resection was associated with worse DFS and OS in the no-IORT population. However, among patients who received IORT, there was no difference in DFS (R0: 29 months, IQR 14–47 vs R1: 20 months, IQR 15–28; p = 0.114) or OS (R0: 48 months, IQR 25-not reached vs R1: 37 months, IQR 30–47; p = 0.307) between patients who underwent R0 vs R1 resection. In multivariate analysis, within the IORT group, R1 resection was not associated with DFS or OS.

Conclusion

IORT may mitigate the adverse effect of an R1 resection on DFS and OS in BR/LA PDAC patients receiving TNT.

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References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30.

    Article  Google Scholar 

  2. Winter JM, Cameron JL, Campbell KA, Arnold MA, Chang DC, Coleman J, et al. 1423 pancreaticoduodenectomies for pancreatic cancer: A single-institution experience. J Gastrointest Surg. 2006;10(9):1199–210; discussion 210–1

    Article  Google Scholar 

  3. Han SS, Jang JY, Kim SW, Kim WH, Lee KU, Park YH. Analysis of long-term survivors after surgical resection for pancreatic cancer. Pancreas. 2006;32(3):271–5.

    Article  Google Scholar 

  4. Howard TJ, Krug JE, Yu J, Zyromski NJ, Schmidt CM, Jacobson LE, et al. A margin-negative R0 resection accomplished with minimal postoperative complications is the surgeon’s contribution to long-term survival in pancreatic cancer. J Gastrointest Surg. 2006;10(10):1338–45; discussion 45–6.

    Article  Google Scholar 

  5. Ferrone CR, Brennan MF, Gonen M, Coit DG, Fong Y, Chung S, et al. Pancreatic adenocarcinoma: the actual 5-year survivors. J Gastrointest Surg. 2008;12(4):701–6.

    Article  Google Scholar 

  6. Konstantinidis IT, Warshaw AL, Allen JN, Blaszkowsky LS, Castillo CF, Deshpande V, et al. Pancreatic ductal adenocarcinoma: is there a survival difference for R1 resections versus locally advanced unresectable tumors? What is a “true” R0 resection? Ann Surg. 2013;257(4):731–6.

    Article  Google Scholar 

  7. Delpero JR, Jeune F, Bachellier P, Regenet N, Le Treut YP, Paye F, et al. Prognostic value of resection margin involvement after pancreaticoduodenectomy for ductal adenocarcinoma: updates from a french prospective multicenter study. Ann Surg. 2017;266(5):787–96.

    Article  Google Scholar 

  8. Yeo CJ, Cameron JL, Lillemoe KD, Sitzmann JV, Hruban RH, Goodman SN, et al. Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients. Ann Surg. 1995;221(6):721–31; discussion 31–3.

    Article  CAS  Google Scholar 

  9. Neoptolemos JP, Stocken DD, Bassi C, Ghaneh P, Cunningham D, Goldstein D, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010;304(10):1073–81.

    Article  CAS  Google Scholar 

  10. Ghaneh P, Kleeff J, Halloran CM, Raraty M, Jackson R, Melling J, et al. The impact of positive resection margins on survival and recurrence following resection and adjuvant chemotherapy for pancreatic ductal adenocarcinoma. Ann Surg. 2019;269(3):520–9.

    Article  Google Scholar 

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

    Article  Google Scholar 

  12. Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817–25.

    Article  CAS  Google Scholar 

  13. Murphy JE, Wo JY, Ryan DP, Jiang W, Yeap BY, Drapek LC, et al. Total neoadjuvant therapy with FOLFIRINOX followed by individualized chemoradiotherapy for borderline resectable pancreatic adenocarcinoma: a phase 2 clinical trial. JAMA Oncol. 2018;4(7):963–9.

    Article  Google Scholar 

  14. Murphy JE, Wo JY, Ryan DP, Clark JW, Jiang W, Yeap BY, et al. Total neoadjuvant therapy with FOLFIRINOX in combination with Losartan followed by chemoradiotherapy for locally advanced pancreatic cancer: a phase 2 clinical trial. JAMA Oncol. 2019;5(7):1020–7.

    Article  Google Scholar 

  15. Ferrone CR, Marchegiani G, Hong TS, Ryan DP, Deshpande V, McDonnell EI, et al. Radiological and surgical implications of neoadjuvant treatment with FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer. Ann Surg. 2015;261(1):12–7.

    Article  Google Scholar 

  16. Sindelar WF, Kinsella TJ. Studies of intraoperative radiotherapy in carcinoma of the pancreas. Ann Oncol. 1999;10 Suppl 4:226–30.

    Article  Google Scholar 

  17. Palta M, Willett C, Czito B. The role of intraoperative radiation therapy in patients with pancreatic cancer. Semin Radiat Oncol. 2014;24(2):126–31.

    Article  Google Scholar 

  18. Harrison JM, Wo JY, Ferrone CR, Horick NK, Keane FK, Qadan M, et al. Intraoperative radiation therapy (IORT) for borderline resectable and locally advanced pancreatic ductal adenocarcinoma (BR/LA PDAC) in the era of modern neoadjuvant treatment: short-term and long-term outcomes. Ann Surg Oncol. 2020;27(5):1400–6.

    Article  Google Scholar 

  19. Cai S, Hong TS, Goldberg SI, Fernandez-del Castillo C, Thayer SP, Ferrone CR, et al. Updated long-term outcomes and prognostic factors for patients with unresectable locally advanced pancreatic cancer treated with intraoperative radiotherapy at the Massachusetts General Hospital, 1978 to 2010. Cancer. 2013;119(23):4196–204.

    Article  Google Scholar 

  20. Callery MP, Chang KJ, Fishman EK, Talamonti MS, William Traverso L, Linehan DC. Pretreatment assessment of resectable and borderline resectable pancreatic cancer: expert consensus statement. Ann Surg Oncol. 2009;16(7):1727–33.

    Article  Google Scholar 

  21. Faris JE, Blaszkowsky LS, McDermott S, Guimaraes AR, Szymonifka J, Huynh MA, et al. FOLFIRINOX in locally advanced pancreatic cancer: the Massachusetts General Hospital Cancer Center experience. Oncologist. 2013;18(5):543–8.

    Article  CAS  Google Scholar 

  22. Hong TS, Ryan DP, Borger DR, Blaszkowsky LS, Yeap BY, Ancukiewicz M, et al. A phase 1/2 and biomarker study of preoperative short course chemoradiation with proton beam therapy and capecitabine followed by early surgery for resectable pancreatic ductal adenocarcinoma. Int J Radiat Oncol Biol Phys. 2014;89(4):830–8.

    Article  CAS  Google Scholar 

  23. Katz MH, Shi Q, Ahmad SA, Herman JM, Marsh Rde W, Collisson E, et al. Preoperative modified FOLFIRINOX treatment followed by capecitabine-based chemoradiation for borderline resectable pancreatic cancer: alliance for clinical trials in oncology trial A021101. JAMA Surg. 2016;151(8):e161137.

    Article  Google Scholar 

  24. Willett CG, Czito BG, Tyler DS. Intraoperative radiation therapy. J Clin Oncol. 2007;25(8):971–7.

    Article  Google Scholar 

  25. Zerbi A, Fossati V, Parolini D, Carlucci M, Balzano G, Bordogna G, et al. Intraoperative radiation therapy adjuvant to resection in the treatment of pancreatic cancer. Cancer. 1994;73(12):2930–5.

    Article  CAS  Google Scholar 

  26. Alfieri S, Morganti AG, Di Giorgio A, Valentini V, Bossola M, Trodella L, et al. Improved survival and local control after intraoperative radiation therapy and postoperative radiotherapy: a multivariate analysis of 46 patients undergoing surgery for pancreatic head cancer. Arch Surg. 2001;136(3):343–7.

    Article  CAS  Google Scholar 

  27. Reni M, Panucci MG, Ferreri AJ, Balzano G, Passoni P, Cattaneo GM, et al. Effect on local control and survival of electron beam intraoperative irradiation for resectable pancreatic adenocarcinoma. Int J Radiat Oncol Biol Phys. 2001;50(3):651–8.

    Article  CAS  Google Scholar 

  28. Ogawa K, Karasawa K, Ito Y, Ogawa Y, Jingu K, Onishi H, et al. Intraoperative radiotherapy for resected pancreatic cancer: a multi-institutional retrospective analysis of 210 patients. Int J Radiat Oncol Biol Phys. 2010;77(3):734–42.

    Article  Google Scholar 

  29. Valentini V, Calvo F, Reni M, Krempien R, Sedlmayer F, Buchler MW, et al. Intra-operative radiotherapy (IORT) in pancreatic cancer: joint analysis of the ISIORT-Europe experience. Radiother Oncol. 2009;91(1):54–9.

    Article  Google Scholar 

  30. Kokubo M, Nishimura Y, Shibamoto Y, Sasai K, Kanamori S, Hosotani R, et al. Analysis of the clinical benefit of intraoperative radiotherapy in patients undergoing macroscopically curative resection for pancreatic cancer. Int J Radiat Oncol Biol Phys. 2000;48(4):1081–7.

    Article  CAS  Google Scholar 

  31. Okamoto A, Matsumoto G, Tsuruta K, Baba H, Karasawa K, Kamisawa T, et al. Intraoperative radiation therapy for pancreatic adenocarcinoma: the Komagome hospital experience. Pancreas. 2004;28(3):296–300.

    Article  Google Scholar 

  32. Willett CG, Del Castillo CF, Shih HA, Goldberg S, Biggs P, Clark JW, et al. Long-term results of intraoperative electron beam irradiation (IOERT) for patients with unresectable pancreatic cancer. Ann Surg. 2005;241(2):295–9.

    Article  Google Scholar 

  33. Michelakos T, Pergolini I, Castillo CF, Honselmann KC, Cai L, Deshpande V, et al. Predictors of resectability and survival in patients with borderline and locally advanced pancreatic cancer who underwent neoadjuvant treatment with FOLFIRINOX. Ann Surg. 2019;269(4):733–40.

    Article  Google Scholar 

  34. Keane FK, Wo JY, Ferrone CR, Clark JW, Blaszkowsky LS, Allen JN, et al. Intraoperative radiotherapy in the era of intensive neoadjuvant chemotherapy and chemoradiotherapy for pancreatic adenocarcinoma. Am J Clin Oncol. 2018;41(6):607–12.

    Article  Google Scholar 

  35. Jin L, Shi N, Ruan S, Hou B, Zou Y, Zou X, et al. The role of intraoperative radiation therapy in resectable pancreatic cancer: a systematic review and meta-analysis. Radiat Oncol. 2020;15(1):76.

    Article  Google Scholar 

Download references

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Author notes

  1. Yurie Sekigami and Theodoros Michelakos have contributed equally to this work.

Authors and Affiliations

  1. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Wang 460, 15 Parkman Street, Boston, MA, 02114, USA

    Yurie Sekigami MD, Theodoros Michelakos MD, Carlos Fernandez-del Castillo MD, Filippos Kontos MD, Motaz Qadan MD, PhD, Jon Harrison MD, Onofrio Catalano MD, Keith D. Lillemoe MD & Cristina R. Ferrone MD

  2. Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Jennifer Y. Wo MD, Onofrio Catalano MD & Theodore S. Hong MD

  3. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Vikram Deshpande MBBS & Onofrio Catalano MD

  4. Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Onofrio Catalano MD

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  1. Yurie Sekigami MD
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Correspondence to Cristina R. Ferrone MD.

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Sekigami, Y., Michelakos, T., Fernandez-del Castillo, C. et al. Intraoperative Radiation Mitigates the Effect of Microscopically Positive Tumor Margins on Survival Among Pancreatic Adenocarcinoma Patients Treated with Neoadjuvant FOLFIRINOX and Chemoradiation. Ann Surg Oncol 28, 4592–4601 (2021). https://doi.org/10.1245/s10434-020-09444-z

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