Past, Present, and Future of Neoadjuvant Therapy for Pancreatic Cancer
Main Article Content
Abstract
Abstract
Pancreatic cancer is a leading cause of cancer death with overall 5-year survival of 5%. For the small proportion of patients who present with localized disease, surgical resection remains a necessary treatment component to achieve lasting survival. Over the past 20-30 years, multi-modal therapy involving the addition of chemotherapy and/or radiation has emerged as an important adjunct to surgery in order to prolong survival. However, patients undergoing resection are often affected by surgical complications, early recurrences, and inability to receive the recommended adjuvant therapy. For these reasons, neoadjuvant therapy has emerged as an attractive option, and in the United States, there has been a significant trend towards neoadjuvant treatment for resectable and borderline-resectable pancreatic tumors. In this review, historical evidence leading to the emergence of neoadjuvant treatment and recent studies of neoadjuvant regimens are summarized. Finally, an overview of ongoing randomized clinical trials is presented.
Article Details
How to Cite
FISHER, Alexander V.; CHU, Brian S.; ABBOTT, Daniel E..
Past, Present, and Future of Neoadjuvant Therapy for Pancreatic Cancer.
Medical Research Archives, [S.l.], v. 5, n. Issue 9, sep. 2017.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/1484>. Date accessed: 19 apr. 2024.
Keywords
Pancreatic Cancer, Neoadjuvant Therapy, Chemotherapy, Chemoradiation
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. American Cancer Society. Cancer Facts and Figures 2016. Atlanta; 2016. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2016/cancer-facts-and-figures-2016.pdf. Accessed June 13, 2017.
2. Matrisian LM, Aizenberg R, Rosenzweig A. The alarming rise of pancreatic cancer deaths in the United states: Why we need to stem the tide today. Pancreat Cancer Action Network; Exec Summ. 2012.
3. 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):1691-1703. doi:10.1056/NEJMoa1304369.
4. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer. N Engl J Med. 2011;364(19):1817-1825. doi:10.1056/NEJMoa1011923.
5. National Comprehensive Cancer Network. NCCN Guidelines Version 2.2017 Pancreatic Adenocarcinmoa. NCCN.org. 2017. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed June 13, 2017.
6. Katz MHG, Wang H, Fleming JB, et al. Long-Term Survival After Multidisciplinary Management of Resected Pancreatic Adenocarcinoma. Ann Surg Oncol. 2009;16(4):836-847. doi:10.1245/s10434-008-0295-2.
7. Dimou F, Sineshaw H, Parmar AD, Tamirisa NP, Jemal A, Riall TS. Trends in Receipt and Timing of Multimodality Therapy in Early-Stage Pancreatic Cancer. J Gastrointest Surg. 2016;20(1):93-103; discussion 103. doi:10.1007/s11605-015-2952-7.
8. Raut CP, Tseng JF, Sun CC, et al. Impact of resection status on pattern of failure and survival after pancreaticoduodenectomy for pancreatic adenocarcinoma. Ann Surg. 2007;246(1):52-60. doi:10.1097/01.sla.0000259391.84304.2b.
9. WINTER J, CAMERON J, CAMPBELL K, et al. 1423 Pancreaticoduodenectomies for Pancreatic Cancer: A Single-Institution Experience? J Gastrointest Surg. 2006;10(9):1199-1211. doi:10.1016/j.gassur.2006.08.018.
10. 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):3496-3502. doi:10.1200/JCO.2007.15.8634.
11. 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):3487-3495. doi:10.1200/JCO.2007.15.8642.
12. Abbott DE, Tzeng C-WD, Merkow RP, et al. The Cost-Effectiveness of Neoadjuvant Chemoradiation is Superior to a Surgery-First Approach in the Treatment of Pancreatic Head Adenocarcinoma. Ann Surg Oncol. 2013;20(S3):500-508. doi:10.1245/s10434-013-2882-0.
13. Chang DK, Johns AL, Merrett ND, et al. Margin Clearance and Outcome in Resected Pancreatic Cancer. J Clin Oncol. 2009;27(17):2855-2862. doi:10.1200/JCO.2008.20.5104.
14. Neoptolemos JP, Stocken DD, Dunn JA, et al. Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial. Ann Surg. 2001;234(6):758-768. http://www.ncbi.nlm.nih.gov/pubmed/11729382. Accessed June 13, 2017.
15. Petrelli F, Coinu A, Borgonovo K, et al. FOLFIRINOX-Based Neoadjuvant Therapy in Borderline Resectable or Unresectable Pancreatic Cancer. Pancreas. 2015;44(4):515-521. doi:10.1097/MPA.0000000000000314.
16. Pingpank JF, Hoffman JP, Ross EA, et al. Effect of preoperative chemoradiotherapy on surgical margin status of resected adenocarcinoma of the head of the pancreas. J Gastrointest Surg. 5(2):121-130. http://www.ncbi.nlm.nih.gov/pubmed/11331473. Accessed July 7, 2017.
17. Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas. J Clin Oncol. 1997;15(3):928-937. doi:10.1200/JCO.1997.15.3.928.
18. Aloia TE, Lee JE, Vauthey J-N, et al. Delayed Recovery after Pancreaticoduodenectomy: A Major Factor Impairing the Delivery of Adjuvant Therapy? J Am Coll Surg. 2007;204(3):347-355. doi:10.1016/j.jamcollsurg.2006.12.011.
19. White RR, Hurwitz HI, Morse MA, et al. Neoadjuvant chemoradiation for localized adenocarcinoma of the pancreas. Ann Surg Oncol. 2001;8(10):758-765. http://www.ncbi.nlm.nih.gov/pubmed/11776488. Accessed June 30, 2017.
20. 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):2088-2096. doi:10.1245/s10434-007-9384-x.
21. Gillen S, Schuster T, Meyer Zum Büschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. Seiler C, ed. PLoS Med. 2010;7(4):e1000267. doi:10.1371/journal.pmed.1000267.
22. Wagner M, Redaelli C, Lietz M, Seiler CA, Friess H, Büchler MW. Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma. Br J Surg. 2004;91(5):586-594. doi:10.1002/bjs.4484.
23. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin. 55(1):10-30. http://www.ncbi.nlm.nih.gov/pubmed/15661684. Accessed June 22, 2017.
24. Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg. 1985;120(8):899-903. http://www.ncbi.nlm.nih.gov/pubmed/4015380. Accessed June 29, 2017.
25. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Gastrointestinal Tumor Study Group. Cancer. 1987;59(12):2006-2010. http://www.ncbi.nlm.nih.gov/pubmed/3567862. Accessed June 29, 2017.
26. Bakkevold KE, Arnesjø B, Dahl O, Kambestad B. Adjuvant combination chemotherapy (AMF) following radical resection of carcinoma of the pancreas and papilla of Vater--results of a controlled, prospective, randomised multicentre study. Eur J Cancer. 1993;29A(5):698-703. http://www.ncbi.nlm.nih.gov/pubmed/8471327. Accessed July 21, 2017.
27. Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg. 1999;230(6):776-82-4. http://www.ncbi.nlm.nih.gov/pubmed/10615932. Accessed July 21, 2017.
28. Neoptolemos JP, Stocken DD, Friess H, et al. A Randomized Trial of Chemoradiotherapy and Chemotherapy after Resection of Pancreatic Cancer. N Engl J Med. 2004;350(12):1200-1210. doi:10.1056/NEJMoa032295.
29. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007;297(3):267-277. doi:10.1001/jama.297.3.267.
30. Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant Chemotherapy With Gemcitabine and Long-term Outcomes Among Patients With Resected Pancreatic Cancer. JAMA. 2013;310(14):1473. doi:10.1001/jama.2013.279201.
31. Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008;299(9):1019-1026. doi:10.1001/jama.299.9.1019.
32. Van Laethem J-L, Hammel P, Mornex F, et al. Adjuvant gemcitabine alone versus gemcitabine-based chemoradiotherapy after curative resection for pancreatic cancer: a randomized EORTC-40013-22012/FFCD-9203/GERCOR phase II study. J Clin Oncol. 2010;28(29):4450-4456. doi:10.1200/JCO.2010.30.3446.
33. Schmidt J, Abel U, Debus J, et al. Open-label, multicenter, randomized phase III trial of adjuvant chemoradiation plus interferon Alfa-2b versus fluorouracil and folinic acid for patients with resected pancreatic adenocarcinoma. J Clin Oncol. 2012;30(33):4077-4083. doi:10.1200/JCO.2011.38.2960.
34. Pilepich M V, Miller HH. Preoperative irradiation in carcinoma of the pancreas. Cancer. 1980;46(9):1945-1949. http://www.ncbi.nlm.nih.gov/pubmed/7427900. Accessed June 22, 2017.
35. Jessup JM, Steele G, Mayer RJ, et al. Neoadjuvant therapy for unresectable pancreatic adenocarcinoma. Arch Surg. 1993;128(5):559-564. http://www.ncbi.nlm.nih.gov/pubmed/8098206. Accessed June 22, 2017.
36. Hoffman JP, Weese JL, Solin LJ, et al. A pilot study of preoperative chemoradiation for patients with localized adenocarcinoma of the pancreas. Am J Surg. 1995;169(1):71-7-8. http://www.ncbi.nlm.nih.gov/pubmed/7818001. Accessed June 22, 2017.
37. Fogelman DR, Chen J, Chabot JA, et al. The evolution of adjuvant and neoadjuvant chemotherapy and radiation for advanced pancreatic cancer: from 5-fluorouracil to GTX. Surg Oncol Clin N Am. 2004;13(4):711-35, x. doi:10.1016/j.soc.2004.06.005.
38. Treatment of locally unresectable carcinoma of the pancreas: comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. Gastrointestinal Tumor Study Group. J Natl Cancer Inst. 1988;80(10):751-755. http://www.ncbi.nlm.nih.gov/pubmed/2898536. Accessed June 22, 2017.
39. Radiation therapy combined with Adriamycin or 5-fluorouracil for the treatment of locally unresectable pancreatic carcinoma. Gastrointestinal Tumor Study Group. Cancer. 1985;56(11):2563-2568. http://www.ncbi.nlm.nih.gov/pubmed/2864997. Accessed June 22, 2017.
40. Pisters PWT, Wolff RA, Crane CH, Evans DB. Combined-modality treatment for operable pancreatic adenocarcinoma. Oncology (Williston Park). 2005;19(3):393-404, 409-10, 412-416. http://www.ncbi.nlm.nih.gov/pubmed/15828554. Accessed June 29, 2017.
41. Evans DB, Multidisciplinary Pancreatic Cancer Study Group for the MPCS. Resectable pancreatic cancer: the role for neoadjuvant/preoperative therapy. HPB (Oxford). 2006;8(5):365-368. doi:10.1080/13651820600804005.
42. White RR, Tyler DS. Neoadjuvant therapy for pancreatic cancer: the Duke experience. Surg Oncol Clin N Am. 2004;13(4):675-684. doi:10.1016/j.soc.2004.06.001.
43. Smeenk HG, de Castro SMM, Jeekel JJ, et al. Locally Advanced Pancreatic Cancer Treated with Radiation and 5-Fluorouracil: A First Step to Neoadjuvant Treatment? Dig Surg. 2005;22(3):191-197. doi:10.1159/000087973.
44. Abrams RA, Lillemoe KD, Piantadosi S. Continuing controversy over adjuvant therapy of pancreatic cancer. Lancet (London, England). 2001;358(9293):1565-1566. doi:10.1016/S0140-6736(01)06666-1.
45. Choti MA. Adjuvant Therapy for Pancreatic Cancer — The Debate Continues. N Engl J Med. 2004;350(12):1249-1251. doi:10.1056/NEJMe048002.
46. Morris SL, Beasley M, Leslie M. Chemotherapy for Pancreatic Cancer. N Engl J Med. 2004;350(26):2713-2715. doi:10.1056/NEJM200406243502617.
47. Bydder S, Spry N. Chemotherapy for pancreatic cancer. N Engl J Med. 2004;350(26):2713-5-5. http://www.ncbi.nlm.nih.gov/pubmed/15218576. Accessed June 30, 2017.
48. Crane CH, Ben-Josef E, Small W. Chemotherapy for pancreatic cancer. N Engl J Med. 2004;350(26):2713-5-5. http://www.ncbi.nlm.nih.gov/pubmed/15218575. Accessed June 30, 2017.
49. Merchant NB, Rymer J, Koehler EAS, et al. Adjuvant Chemoradiation Therapy for Pancreatic Adenocarcinoma: Who Really Benefits? J Am Coll Surg. 2009;208(5):829-838. doi:10.1016/j.jamcollsurg.2008.12.020.
50. Parikh AA, Maiga A, Bentrem D, et al. Adjuvant Therapy in Pancreas Cancer: Does It Influence Patterns of Recurrence? J Am Coll Surg. 2016;222(4):448-456. doi:10.1016/j.jamcollsurg.2015.12.031.
51. Burris HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15(6):2403-2413. doi:10.1200/JCO.1997.15.6.2403.
52. Andriulli A, Festa V, Botteri E, et al. Neoadjuvant/preoperative gemcitabine for patients with localized pancreatic cancer: a meta-analysis of prospective studies. Ann Surg Oncol. 2012;19(5):1644-1662. doi:10.1245/s10434-011-2110-8.
53. Katz MHG, Shi Q, Ahmad SA, 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. doi:10.1001/jamasurg.2016.1137.
54. Landry J, Catalano PJ, Staley C, et al. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J Surg Oncol. 2010;101(7):587-592. doi:10.1002/jso.21527.
55. Golcher H, Brunner TB, Witzigmann H, et al. Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer. Strahlentherapie und Onkol. 2015;191(1):7-16. doi:10.1007/s00066-014-0737-7.
56. 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):1802-1812. doi:10.1007/s11605-015-2890-4.
57. Talamonti MS, Small W, 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):150-158. doi:10.1245/ASO.2006.03.039.
58. Mornex F, Girard N, Scoazec J-Y, 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. 2006;65(5):1471-1478. doi:10.1016/j.ijrobp.2006.02.054.
59. Heinrich S, Pestalozzi BC, Schäfer 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):2526-2531. doi:10.1200/JCO.2007.15.5556.
60. Turrini O, Ychou M, Moureau-Zabotto L, et al. Neoadjuvant docetaxel-based chemoradiation for resectable adenocarcinoma of the pancreas: New neoadjuvant regimen was safe and provided an interesting pathologic response. Eur J Surg Oncol. 2010;36(10):987-992. doi:10.1016/j.ejso.2010.07.003.
61. 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):311-320. doi:10.1016/j.surg.2010.07.048.
62. Sahora K, Kuehrer I, Schindl M, Koelblinger C, Goetzinger P, Gnant M. NeoGemTax: Gemcitabine and Docetaxel as Neoadjuvant Treatment for Locally Advanced Nonmetastasized Pancreatic Cancer. World J Surg. 2011;35(7):1580-1589. doi:10.1007/s00268-011-1113-8.
63. Lee J-L, Kim SC, Kim J-H, 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):851-862. doi:10.1016/j.surg.2012.03.010.
64. Pipas JM, Zaki BI, McGowan MM, et al. Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma. Ann Oncol Off J Eur Soc Med Oncol. 2012;23(11):2820-2827. doi:10.1093/annonc/mds109.
65. 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):2692-2700. doi:10.1002/cncr.28117.
66. Shinoto M, Yamada S, Yasuda S, et al. Phase 1 trial of preoperative, short-course carbon-ion radiotherapy for patients with resectable pancreatic cancer. Cancer. 2013;119(1):45-51. doi:10.1002/cncr.27723.
67. Tinchon C, Hubmann E, Pichler A, et al. Safety and efficacy of neoadjuvant FOLFIRINOX treatment in a series of patients with borderline resectable pancreatic ductal adenocarcinoma. Acta Oncol (Madr). 2013;52(6):1231-1233. doi:10.3109/0284186X.2013.771821.
68. 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):3794-3801. doi:10.1245/s10434-013-3129-9.
69. Wo JY, Mamon HJ, Ferrone CR, et al. Phase I study of neoadjuvant accelerated short course radiation therapy with photons and capecitabine for resectable pancreatic cancer. Radiother Oncol. 2014;110(1):160-164. doi:10.1016/j.radonc.2013.10.027.
70. Sahora K, Schindl M, Kuehrer I, et al. A phase II trial of two durations of Bevacizumab added to neoadjuvant gemcitabine for borderline and locally advanced pancreatic cancer. Anticancer Res. 2014;34(5):2377-2384. http://www.ncbi.nlm.nih.gov/pubmed/24778046. Accessed July 18, 2017.
71. OʼReilly 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):142-148. doi:10.1097/SLA.0000000000000251.
72. Hong TS, Ryan DP, Borger DR, 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):830-838. doi:10.1016/j.ijrobp.2014.03.034.
73. Chan E, Arlinghaus LR, Cardin DB, et al. Phase I trial of vorinostat added to chemoradiation with capecitabine in pancreatic cancer. Radiother Oncol. 2016;119(2):312-318. doi:10.1016/j.radonc.2016.04.013.
74. Masui T, Doi R, Kawaguchi Y, et al. Concurrent gemcitabine+S-1 neoadjuvant chemotherapy contributes to the improved survival of patients with small borderline-resectable pancreatic cancer tumors. Surg Today. 2016;46(11):1282-1289. doi:10.1007/s00595-016-1310-z.
75. OKADA K-I, HIRONO S, KAWAI M, et al. Phase I Study of Nab–Paclitaxel plus Gemcitabine as Neoadjuvant Therapy for Borderline Resectable Pancreatic Cancer. Anticancer Res. 2017;37(2):853-858. doi:10.21873/anticanres.11389.
76. Nagakawa Y, Hosokawa Y, Nakayama H, et al. A phase II trial of neoadjuvant chemoradiotherapy with intensity-modulated radiotherapy combined with gemcitabine and S-1 for borderline-resectable pancreatic cancer with arterial involvement. Cancer Chemother Pharmacol. 2017;79(5):951-957. doi:10.1007/s00280-017-3288-7.
77. Joensuu TK, Kiviluoto T, Kärkkäinen P, et al. Phase I-II trial of twice-weekly gemcitabine and concomitant irradiation in patients undergoing pancreaticoduodenectomy with extended lymphadenectomy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2004;60(2):444-452. doi:10.1016/j.ijrobp.2004.03.026.
78. 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. doi:10.1097/SLA.0b013e3181ad65cc.
79. Small W, Mulcahy MF, Rademaker A, et al. Phase II Trial of Full-Dose Gemcitabine and Bevacizumab in Combination With Attenuated Three-Dimensional Conformal Radiotherapy in Patients With Localized Pancreatic Cancer. Int J Radiat Oncol. 2011;80(2):476-482. doi:10.1016/j.ijrobp.2010.02.030.
80. Laurent S, Monsaert E, Boterberg T, et al. Feasibility of radiotherapy with concomitant gemcitabine and oxaliplatin in locally advanced pancreatic cancer and distal cholangiocarcinoma: a prospective dose finding phase I-II study. Ann Oncol Off J Eur Soc Med Oncol. 2009;20(8):1369-1374. doi:10.1093/annonc/mdp005.
81. Pipas JM, Barth RJ, Zaki B, et al. Docetaxel/Gemcitabine Followed by Gemcitabine and External Beam Radiotherapy in Patients With Pancreatic Adenocarcinoma. Ann Surg Oncol. 2005;12(12):995-1004. doi:10.1245/ASO.2005.04.503.
82. Alvarez R, Musteanu M, Garcia-Garcia E, et al. Stromal disrupting effects of nab-paclitaxel in pancreatic cancer. Br J Cancer. 2013;109(4):926-933. doi:10.1038/bjc.2013.415.
83. Ielpo B, Duran H, Diaz E, et al. Preoperative treatment with gemcitabine plus nab-paclitaxel is a safe and effective chemotherapy for pancreatic adenocarcinoma. Eur J Surg Oncol. 2016;42(9):1394-1400. doi:10.1016/j.ejso.2016.01.006.
84. Blazer M, Wu C, Goldberg RM, et al. Neoadjuvant Modified (m) FOLFIRINOX for Locally Advanced Unresectable (LAPC) and Borderline Resectable (BRPC) Adenocarcinoma of the Pancreas. Ann Surg Oncol. 2015;22(4):1153-1159. doi:10.1245/s10434-014-4225-1.
85. Hackert T, Sachsenmaier M, Hinz U, et al. Locally Advanced Pancreatic Cancer. Ann Surg. 2016;264(3):457-463. doi:10.1097/SLA.0000000000001850.
86. Kim SS, Nakakura EK, Wang ZJ, et al. Preoperative FOLFIRINOX for borderline resectable pancreatic cancer: Is radiation necessary in the modern era of chemotherapy? J Surg Oncol. 2016;114(5):587-596. doi:10.1002/jso.24375.
87. Roldan GE, Gunderson LL, Nagorney DM, et al. External beam versus intraoperative and external beam irradiation for locally advanced pancreatic cancer. Cancer. 1988;61(6):1110-1116. http://www.ncbi.nlm.nih.gov/pubmed/3342371. Accessed July 6, 2017.
88. Herskovic A, Martz K, Al-Sarraf M, et al. Combined Chemotherapy and Radiotherapy Compared with Radiotherapy Alone in Patients with Cancer of the Esophagus. N Engl J Med. 1992;326(24):1593-1598. doi:10.1056/NEJM199206113262403.
89. Wong RK, Malthaner R. Combined chemotherapy and radiotherapy (without surgery) compared with radiotherapy alone in localized carcinoma of the esophagus. In: Wong RK, ed. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2006:CD002092. doi:10.1002/14651858.CD002092.pub2.
90. Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA. 1999;281(17):1623-1627. http://www.ncbi.nlm.nih.gov/pubmed/10235156. Accessed July 6, 2017.
91. Bernier J, Domenge C, Ozsahin M, et al. Postoperative Irradiation with or without Concomitant Chemotherapy for Locally Advanced Head and Neck Cancer. N Engl J Med. 2004;350(19):1945-1952. doi:10.1056/NEJMoa032641.
92. Ragaz J, Jackson SM, Le N, et al. Adjuvant Radiotherapy and Chemotherapy in Node-Positive Premenopausal Women with Breast Cancer. N Engl J Med. 1997;337(14):956-962. doi:10.1056/NEJM199710023371402.
93. Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 Gene Status of the Primary Carcinoma Correlates With Patterns of Failure in Patients With Pancreatic Cancer. J Clin Oncol. 2009;27(11):1806-1813. doi:10.1200/JCO.2008.17.7188.
94. van der Geld YG, van Triest B, Verbakel WFAR, et al. Evaluation of Four-Dimensional Computed Tomography-Based Intensity-Modulated and Respiratory-Gated Radiotherapy Techniques for Pancreatic Carcinoma. Int J Radiat Oncol. 2008;72(4):1215-1220. doi:10.1016/j.ijrobp.2008.07.010.
95. Kataria T, Rawat S, Sinha SN, et al. Intensity modulated radiotherapy in abdominal malignancies: our experience in reducing the dose to normal structures as compared to the gross tumor. J Cancer Res Ther. 2(4):161-165. http://www.ncbi.nlm.nih.gov/pubmed/17998698. Accessed July 5, 2017.
96. Brown MW, Ning H, Arora B, et al. A dosimetric analysis of dose escalation using two intensity-modulated radiation therapy techniques in locally advanced pancreatic carcinoma. Int J Radiat Oncol Biol Phys. 2006;65(1):274-283. doi:10.1016/j.ijrobp.2006.01.003.
97. Yovino S, Poppe M, Jabbour S, et al. Intensity-modulated radiation therapy significantly improves acute gastrointestinal toxicity in pancreatic and ampullary cancers. Int J Radiat Oncol Biol Phys. 2011;79(1):158-162. doi:10.1016/j.ijrobp.2009.10.043.
98. Marcu LG. Altered fractionation in radiotherapy: From radiobiological rationale to therapeutic gain. Cancer Treat Rev. 2010;36(8):606-614. doi:10.1016/j.ctrv.2010.04.004.
99. Chhabra A, Kaiser A, Regine WF, Chuong MD. The expanding role of stereotactic body radiation therapy for pancreatic cancer: a review of the literature. Transl Cancer Res. 2015;4(6):659-670. doi:10.21037/5996.
100. Nichols RC, Huh S, Li Z, Rutenberg M. Proton therapy for pancreatic cancer. World J Gastrointest Oncol. 2015;7(9):141. doi:10.4251/wjgo.v7.i9.141.
101. Nichols RC, George TJ, Zaiden RA, et al. Proton therapy with concomitant capecitabine for pancreatic and ampullary cancers is associated with a low incidence of gastrointestinal toxicity. Acta Oncol. 2013;52(3):498-505. doi:10.3109/0284186X.2012.762997.
102. Chauffert B, Mornex F, Bonnetain F, et al. Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study. Ann Oncol. 2008;19(9):1592-1599. doi:10.1093/annonc/mdn281.
103. Loehrer PJ, Feng Y, Cardenes H, et al. Gemcitabine Alone Versus Gemcitabine Plus Radiotherapy in Patients With Locally Advanced Pancreatic Cancer: An Eastern Cooperative Oncology Group Trial. J Clin Oncol. 2011;29(31):4105-4112. doi:10.1200/JCO.2011.34.8904.
104. Mukherjee S, Hurt CN, Bridgewater J, et al. Gemcitabine-based or capecitabine-based chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial. Lancet Oncol. 2013;14(4):317-326. doi:10.1016/S1470-2045(13)70021-4.
105. Hammel P, Huguet F, van Laethem J-L, et al. Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib. JAMA. 2016;315(17):1844. doi:10.1001/jama.2016.4324.
2. Matrisian LM, Aizenberg R, Rosenzweig A. The alarming rise of pancreatic cancer deaths in the United states: Why we need to stem the tide today. Pancreat Cancer Action Network; Exec Summ. 2012.
3. 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):1691-1703. doi:10.1056/NEJMoa1304369.
4. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer. N Engl J Med. 2011;364(19):1817-1825. doi:10.1056/NEJMoa1011923.
5. National Comprehensive Cancer Network. NCCN Guidelines Version 2.2017 Pancreatic Adenocarcinmoa. NCCN.org. 2017. https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Accessed June 13, 2017.
6. Katz MHG, Wang H, Fleming JB, et al. Long-Term Survival After Multidisciplinary Management of Resected Pancreatic Adenocarcinoma. Ann Surg Oncol. 2009;16(4):836-847. doi:10.1245/s10434-008-0295-2.
7. Dimou F, Sineshaw H, Parmar AD, Tamirisa NP, Jemal A, Riall TS. Trends in Receipt and Timing of Multimodality Therapy in Early-Stage Pancreatic Cancer. J Gastrointest Surg. 2016;20(1):93-103; discussion 103. doi:10.1007/s11605-015-2952-7.
8. Raut CP, Tseng JF, Sun CC, et al. Impact of resection status on pattern of failure and survival after pancreaticoduodenectomy for pancreatic adenocarcinoma. Ann Surg. 2007;246(1):52-60. doi:10.1097/01.sla.0000259391.84304.2b.
9. WINTER J, CAMERON J, CAMPBELL K, et al. 1423 Pancreaticoduodenectomies for Pancreatic Cancer: A Single-Institution Experience? J Gastrointest Surg. 2006;10(9):1199-1211. doi:10.1016/j.gassur.2006.08.018.
10. 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):3496-3502. doi:10.1200/JCO.2007.15.8634.
11. 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):3487-3495. doi:10.1200/JCO.2007.15.8642.
12. Abbott DE, Tzeng C-WD, Merkow RP, et al. The Cost-Effectiveness of Neoadjuvant Chemoradiation is Superior to a Surgery-First Approach in the Treatment of Pancreatic Head Adenocarcinoma. Ann Surg Oncol. 2013;20(S3):500-508. doi:10.1245/s10434-013-2882-0.
13. Chang DK, Johns AL, Merrett ND, et al. Margin Clearance and Outcome in Resected Pancreatic Cancer. J Clin Oncol. 2009;27(17):2855-2862. doi:10.1200/JCO.2008.20.5104.
14. Neoptolemos JP, Stocken DD, Dunn JA, et al. Influence of resection margins on survival for patients with pancreatic cancer treated by adjuvant chemoradiation and/or chemotherapy in the ESPAC-1 randomized controlled trial. Ann Surg. 2001;234(6):758-768. http://www.ncbi.nlm.nih.gov/pubmed/11729382. Accessed June 13, 2017.
15. Petrelli F, Coinu A, Borgonovo K, et al. FOLFIRINOX-Based Neoadjuvant Therapy in Borderline Resectable or Unresectable Pancreatic Cancer. Pancreas. 2015;44(4):515-521. doi:10.1097/MPA.0000000000000314.
16. Pingpank JF, Hoffman JP, Ross EA, et al. Effect of preoperative chemoradiotherapy on surgical margin status of resected adenocarcinoma of the head of the pancreas. J Gastrointest Surg. 5(2):121-130. http://www.ncbi.nlm.nih.gov/pubmed/11331473. Accessed July 7, 2017.
17. Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas. J Clin Oncol. 1997;15(3):928-937. doi:10.1200/JCO.1997.15.3.928.
18. Aloia TE, Lee JE, Vauthey J-N, et al. Delayed Recovery after Pancreaticoduodenectomy: A Major Factor Impairing the Delivery of Adjuvant Therapy? J Am Coll Surg. 2007;204(3):347-355. doi:10.1016/j.jamcollsurg.2006.12.011.
19. White RR, Hurwitz HI, Morse MA, et al. Neoadjuvant chemoradiation for localized adenocarcinoma of the pancreas. Ann Surg Oncol. 2001;8(10):758-765. http://www.ncbi.nlm.nih.gov/pubmed/11776488. Accessed June 30, 2017.
20. 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):2088-2096. doi:10.1245/s10434-007-9384-x.
21. Gillen S, Schuster T, Meyer Zum Büschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. Seiler C, ed. PLoS Med. 2010;7(4):e1000267. doi:10.1371/journal.pmed.1000267.
22. Wagner M, Redaelli C, Lietz M, Seiler CA, Friess H, Büchler MW. Curative resection is the single most important factor determining outcome in patients with pancreatic adenocarcinoma. Br J Surg. 2004;91(5):586-594. doi:10.1002/bjs.4484.
23. Jemal A, Murray T, Ward E, et al. Cancer statistics, 2005. CA Cancer J Clin. 55(1):10-30. http://www.ncbi.nlm.nih.gov/pubmed/15661684. Accessed June 22, 2017.
24. Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg. 1985;120(8):899-903. http://www.ncbi.nlm.nih.gov/pubmed/4015380. Accessed June 29, 2017.
25. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Gastrointestinal Tumor Study Group. Cancer. 1987;59(12):2006-2010. http://www.ncbi.nlm.nih.gov/pubmed/3567862. Accessed June 29, 2017.
26. Bakkevold KE, Arnesjø B, Dahl O, Kambestad B. Adjuvant combination chemotherapy (AMF) following radical resection of carcinoma of the pancreas and papilla of Vater--results of a controlled, prospective, randomised multicentre study. Eur J Cancer. 1993;29A(5):698-703. http://www.ncbi.nlm.nih.gov/pubmed/8471327. Accessed July 21, 2017.
27. Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg. 1999;230(6):776-82-4. http://www.ncbi.nlm.nih.gov/pubmed/10615932. Accessed July 21, 2017.
28. Neoptolemos JP, Stocken DD, Friess H, et al. A Randomized Trial of Chemoradiotherapy and Chemotherapy after Resection of Pancreatic Cancer. N Engl J Med. 2004;350(12):1200-1210. doi:10.1056/NEJMoa032295.
29. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial. JAMA. 2007;297(3):267-277. doi:10.1001/jama.297.3.267.
30. Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant Chemotherapy With Gemcitabine and Long-term Outcomes Among Patients With Resected Pancreatic Cancer. JAMA. 2013;310(14):1473. doi:10.1001/jama.2013.279201.
31. Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008;299(9):1019-1026. doi:10.1001/jama.299.9.1019.
32. Van Laethem J-L, Hammel P, Mornex F, et al. Adjuvant gemcitabine alone versus gemcitabine-based chemoradiotherapy after curative resection for pancreatic cancer: a randomized EORTC-40013-22012/FFCD-9203/GERCOR phase II study. J Clin Oncol. 2010;28(29):4450-4456. doi:10.1200/JCO.2010.30.3446.
33. Schmidt J, Abel U, Debus J, et al. Open-label, multicenter, randomized phase III trial of adjuvant chemoradiation plus interferon Alfa-2b versus fluorouracil and folinic acid for patients with resected pancreatic adenocarcinoma. J Clin Oncol. 2012;30(33):4077-4083. doi:10.1200/JCO.2011.38.2960.
34. Pilepich M V, Miller HH. Preoperative irradiation in carcinoma of the pancreas. Cancer. 1980;46(9):1945-1949. http://www.ncbi.nlm.nih.gov/pubmed/7427900. Accessed June 22, 2017.
35. Jessup JM, Steele G, Mayer RJ, et al. Neoadjuvant therapy for unresectable pancreatic adenocarcinoma. Arch Surg. 1993;128(5):559-564. http://www.ncbi.nlm.nih.gov/pubmed/8098206. Accessed June 22, 2017.
36. Hoffman JP, Weese JL, Solin LJ, et al. A pilot study of preoperative chemoradiation for patients with localized adenocarcinoma of the pancreas. Am J Surg. 1995;169(1):71-7-8. http://www.ncbi.nlm.nih.gov/pubmed/7818001. Accessed June 22, 2017.
37. Fogelman DR, Chen J, Chabot JA, et al. The evolution of adjuvant and neoadjuvant chemotherapy and radiation for advanced pancreatic cancer: from 5-fluorouracil to GTX. Surg Oncol Clin N Am. 2004;13(4):711-35, x. doi:10.1016/j.soc.2004.06.005.
38. Treatment of locally unresectable carcinoma of the pancreas: comparison of combined-modality therapy (chemotherapy plus radiotherapy) to chemotherapy alone. Gastrointestinal Tumor Study Group. J Natl Cancer Inst. 1988;80(10):751-755. http://www.ncbi.nlm.nih.gov/pubmed/2898536. Accessed June 22, 2017.
39. Radiation therapy combined with Adriamycin or 5-fluorouracil for the treatment of locally unresectable pancreatic carcinoma. Gastrointestinal Tumor Study Group. Cancer. 1985;56(11):2563-2568. http://www.ncbi.nlm.nih.gov/pubmed/2864997. Accessed June 22, 2017.
40. Pisters PWT, Wolff RA, Crane CH, Evans DB. Combined-modality treatment for operable pancreatic adenocarcinoma. Oncology (Williston Park). 2005;19(3):393-404, 409-10, 412-416. http://www.ncbi.nlm.nih.gov/pubmed/15828554. Accessed June 29, 2017.
41. Evans DB, Multidisciplinary Pancreatic Cancer Study Group for the MPCS. Resectable pancreatic cancer: the role for neoadjuvant/preoperative therapy. HPB (Oxford). 2006;8(5):365-368. doi:10.1080/13651820600804005.
42. White RR, Tyler DS. Neoadjuvant therapy for pancreatic cancer: the Duke experience. Surg Oncol Clin N Am. 2004;13(4):675-684. doi:10.1016/j.soc.2004.06.001.
43. Smeenk HG, de Castro SMM, Jeekel JJ, et al. Locally Advanced Pancreatic Cancer Treated with Radiation and 5-Fluorouracil: A First Step to Neoadjuvant Treatment? Dig Surg. 2005;22(3):191-197. doi:10.1159/000087973.
44. Abrams RA, Lillemoe KD, Piantadosi S. Continuing controversy over adjuvant therapy of pancreatic cancer. Lancet (London, England). 2001;358(9293):1565-1566. doi:10.1016/S0140-6736(01)06666-1.
45. Choti MA. Adjuvant Therapy for Pancreatic Cancer — The Debate Continues. N Engl J Med. 2004;350(12):1249-1251. doi:10.1056/NEJMe048002.
46. Morris SL, Beasley M, Leslie M. Chemotherapy for Pancreatic Cancer. N Engl J Med. 2004;350(26):2713-2715. doi:10.1056/NEJM200406243502617.
47. Bydder S, Spry N. Chemotherapy for pancreatic cancer. N Engl J Med. 2004;350(26):2713-5-5. http://www.ncbi.nlm.nih.gov/pubmed/15218576. Accessed June 30, 2017.
48. Crane CH, Ben-Josef E, Small W. Chemotherapy for pancreatic cancer. N Engl J Med. 2004;350(26):2713-5-5. http://www.ncbi.nlm.nih.gov/pubmed/15218575. Accessed June 30, 2017.
49. Merchant NB, Rymer J, Koehler EAS, et al. Adjuvant Chemoradiation Therapy for Pancreatic Adenocarcinoma: Who Really Benefits? J Am Coll Surg. 2009;208(5):829-838. doi:10.1016/j.jamcollsurg.2008.12.020.
50. Parikh AA, Maiga A, Bentrem D, et al. Adjuvant Therapy in Pancreas Cancer: Does It Influence Patterns of Recurrence? J Am Coll Surg. 2016;222(4):448-456. doi:10.1016/j.jamcollsurg.2015.12.031.
51. Burris HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997;15(6):2403-2413. doi:10.1200/JCO.1997.15.6.2403.
52. Andriulli A, Festa V, Botteri E, et al. Neoadjuvant/preoperative gemcitabine for patients with localized pancreatic cancer: a meta-analysis of prospective studies. Ann Surg Oncol. 2012;19(5):1644-1662. doi:10.1245/s10434-011-2110-8.
53. Katz MHG, Shi Q, Ahmad SA, 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. doi:10.1001/jamasurg.2016.1137.
54. Landry J, Catalano PJ, Staley C, et al. Randomized phase II study of gemcitabine plus radiotherapy versus gemcitabine, 5-fluorouracil, and cisplatin followed by radiotherapy and 5-fluorouracil for patients with locally advanced, potentially resectable pancreatic adenocarcinoma. J Surg Oncol. 2010;101(7):587-592. doi:10.1002/jso.21527.
55. Golcher H, Brunner TB, Witzigmann H, et al. Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer. Strahlentherapie und Onkol. 2015;191(1):7-16. doi:10.1007/s00066-014-0737-7.
56. 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):1802-1812. doi:10.1007/s11605-015-2890-4.
57. Talamonti MS, Small W, 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):150-158. doi:10.1245/ASO.2006.03.039.
58. Mornex F, Girard N, Scoazec J-Y, 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. 2006;65(5):1471-1478. doi:10.1016/j.ijrobp.2006.02.054.
59. Heinrich S, Pestalozzi BC, Schäfer 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):2526-2531. doi:10.1200/JCO.2007.15.5556.
60. Turrini O, Ychou M, Moureau-Zabotto L, et al. Neoadjuvant docetaxel-based chemoradiation for resectable adenocarcinoma of the pancreas: New neoadjuvant regimen was safe and provided an interesting pathologic response. Eur J Surg Oncol. 2010;36(10):987-992. doi:10.1016/j.ejso.2010.07.003.
61. 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):311-320. doi:10.1016/j.surg.2010.07.048.
62. Sahora K, Kuehrer I, Schindl M, Koelblinger C, Goetzinger P, Gnant M. NeoGemTax: Gemcitabine and Docetaxel as Neoadjuvant Treatment for Locally Advanced Nonmetastasized Pancreatic Cancer. World J Surg. 2011;35(7):1580-1589. doi:10.1007/s00268-011-1113-8.
63. Lee J-L, Kim SC, Kim J-H, 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):851-862. doi:10.1016/j.surg.2012.03.010.
64. Pipas JM, Zaki BI, McGowan MM, et al. Neoadjuvant cetuximab, twice-weekly gemcitabine, and intensity-modulated radiotherapy (IMRT) in patients with pancreatic adenocarcinoma. Ann Oncol Off J Eur Soc Med Oncol. 2012;23(11):2820-2827. doi:10.1093/annonc/mds109.
65. 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):2692-2700. doi:10.1002/cncr.28117.
66. Shinoto M, Yamada S, Yasuda S, et al. Phase 1 trial of preoperative, short-course carbon-ion radiotherapy for patients with resectable pancreatic cancer. Cancer. 2013;119(1):45-51. doi:10.1002/cncr.27723.
67. Tinchon C, Hubmann E, Pichler A, et al. Safety and efficacy of neoadjuvant FOLFIRINOX treatment in a series of patients with borderline resectable pancreatic ductal adenocarcinoma. Acta Oncol (Madr). 2013;52(6):1231-1233. doi:10.3109/0284186X.2013.771821.
68. 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):3794-3801. doi:10.1245/s10434-013-3129-9.
69. Wo JY, Mamon HJ, Ferrone CR, et al. Phase I study of neoadjuvant accelerated short course radiation therapy with photons and capecitabine for resectable pancreatic cancer. Radiother Oncol. 2014;110(1):160-164. doi:10.1016/j.radonc.2013.10.027.
70. Sahora K, Schindl M, Kuehrer I, et al. A phase II trial of two durations of Bevacizumab added to neoadjuvant gemcitabine for borderline and locally advanced pancreatic cancer. Anticancer Res. 2014;34(5):2377-2384. http://www.ncbi.nlm.nih.gov/pubmed/24778046. Accessed July 18, 2017.
71. OʼReilly 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):142-148. doi:10.1097/SLA.0000000000000251.
72. Hong TS, Ryan DP, Borger DR, 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):830-838. doi:10.1016/j.ijrobp.2014.03.034.
73. Chan E, Arlinghaus LR, Cardin DB, et al. Phase I trial of vorinostat added to chemoradiation with capecitabine in pancreatic cancer. Radiother Oncol. 2016;119(2):312-318. doi:10.1016/j.radonc.2016.04.013.
74. Masui T, Doi R, Kawaguchi Y, et al. Concurrent gemcitabine+S-1 neoadjuvant chemotherapy contributes to the improved survival of patients with small borderline-resectable pancreatic cancer tumors. Surg Today. 2016;46(11):1282-1289. doi:10.1007/s00595-016-1310-z.
75. OKADA K-I, HIRONO S, KAWAI M, et al. Phase I Study of Nab–Paclitaxel plus Gemcitabine as Neoadjuvant Therapy for Borderline Resectable Pancreatic Cancer. Anticancer Res. 2017;37(2):853-858. doi:10.21873/anticanres.11389.
76. Nagakawa Y, Hosokawa Y, Nakayama H, et al. A phase II trial of neoadjuvant chemoradiotherapy with intensity-modulated radiotherapy combined with gemcitabine and S-1 for borderline-resectable pancreatic cancer with arterial involvement. Cancer Chemother Pharmacol. 2017;79(5):951-957. doi:10.1007/s00280-017-3288-7.
77. Joensuu TK, Kiviluoto T, Kärkkäinen P, et al. Phase I-II trial of twice-weekly gemcitabine and concomitant irradiation in patients undergoing pancreaticoduodenectomy with extended lymphadenectomy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys. 2004;60(2):444-452. doi:10.1016/j.ijrobp.2004.03.026.
78. 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. doi:10.1097/SLA.0b013e3181ad65cc.
79. Small W, Mulcahy MF, Rademaker A, et al. Phase II Trial of Full-Dose Gemcitabine and Bevacizumab in Combination With Attenuated Three-Dimensional Conformal Radiotherapy in Patients With Localized Pancreatic Cancer. Int J Radiat Oncol. 2011;80(2):476-482. doi:10.1016/j.ijrobp.2010.02.030.
80. Laurent S, Monsaert E, Boterberg T, et al. Feasibility of radiotherapy with concomitant gemcitabine and oxaliplatin in locally advanced pancreatic cancer and distal cholangiocarcinoma: a prospective dose finding phase I-II study. Ann Oncol Off J Eur Soc Med Oncol. 2009;20(8):1369-1374. doi:10.1093/annonc/mdp005.
81. Pipas JM, Barth RJ, Zaki B, et al. Docetaxel/Gemcitabine Followed by Gemcitabine and External Beam Radiotherapy in Patients With Pancreatic Adenocarcinoma. Ann Surg Oncol. 2005;12(12):995-1004. doi:10.1245/ASO.2005.04.503.
82. Alvarez R, Musteanu M, Garcia-Garcia E, et al. Stromal disrupting effects of nab-paclitaxel in pancreatic cancer. Br J Cancer. 2013;109(4):926-933. doi:10.1038/bjc.2013.415.
83. Ielpo B, Duran H, Diaz E, et al. Preoperative treatment with gemcitabine plus nab-paclitaxel is a safe and effective chemotherapy for pancreatic adenocarcinoma. Eur J Surg Oncol. 2016;42(9):1394-1400. doi:10.1016/j.ejso.2016.01.006.
84. Blazer M, Wu C, Goldberg RM, et al. Neoadjuvant Modified (m) FOLFIRINOX for Locally Advanced Unresectable (LAPC) and Borderline Resectable (BRPC) Adenocarcinoma of the Pancreas. Ann Surg Oncol. 2015;22(4):1153-1159. doi:10.1245/s10434-014-4225-1.
85. Hackert T, Sachsenmaier M, Hinz U, et al. Locally Advanced Pancreatic Cancer. Ann Surg. 2016;264(3):457-463. doi:10.1097/SLA.0000000000001850.
86. Kim SS, Nakakura EK, Wang ZJ, et al. Preoperative FOLFIRINOX for borderline resectable pancreatic cancer: Is radiation necessary in the modern era of chemotherapy? J Surg Oncol. 2016;114(5):587-596. doi:10.1002/jso.24375.
87. Roldan GE, Gunderson LL, Nagorney DM, et al. External beam versus intraoperative and external beam irradiation for locally advanced pancreatic cancer. Cancer. 1988;61(6):1110-1116. http://www.ncbi.nlm.nih.gov/pubmed/3342371. Accessed July 6, 2017.
88. Herskovic A, Martz K, Al-Sarraf M, et al. Combined Chemotherapy and Radiotherapy Compared with Radiotherapy Alone in Patients with Cancer of the Esophagus. N Engl J Med. 1992;326(24):1593-1598. doi:10.1056/NEJM199206113262403.
89. Wong RK, Malthaner R. Combined chemotherapy and radiotherapy (without surgery) compared with radiotherapy alone in localized carcinoma of the esophagus. In: Wong RK, ed. Cochrane Database of Systematic Reviews. Chichester, UK: John Wiley & Sons, Ltd; 2006:CD002092. doi:10.1002/14651858.CD002092.pub2.
90. Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA. 1999;281(17):1623-1627. http://www.ncbi.nlm.nih.gov/pubmed/10235156. Accessed July 6, 2017.
91. Bernier J, Domenge C, Ozsahin M, et al. Postoperative Irradiation with or without Concomitant Chemotherapy for Locally Advanced Head and Neck Cancer. N Engl J Med. 2004;350(19):1945-1952. doi:10.1056/NEJMoa032641.
92. Ragaz J, Jackson SM, Le N, et al. Adjuvant Radiotherapy and Chemotherapy in Node-Positive Premenopausal Women with Breast Cancer. N Engl J Med. 1997;337(14):956-962. doi:10.1056/NEJM199710023371402.
93. Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 Gene Status of the Primary Carcinoma Correlates With Patterns of Failure in Patients With Pancreatic Cancer. J Clin Oncol. 2009;27(11):1806-1813. doi:10.1200/JCO.2008.17.7188.
94. van der Geld YG, van Triest B, Verbakel WFAR, et al. Evaluation of Four-Dimensional Computed Tomography-Based Intensity-Modulated and Respiratory-Gated Radiotherapy Techniques for Pancreatic Carcinoma. Int J Radiat Oncol. 2008;72(4):1215-1220. doi:10.1016/j.ijrobp.2008.07.010.
95. Kataria T, Rawat S, Sinha SN, et al. Intensity modulated radiotherapy in abdominal malignancies: our experience in reducing the dose to normal structures as compared to the gross tumor. J Cancer Res Ther. 2(4):161-165. http://www.ncbi.nlm.nih.gov/pubmed/17998698. Accessed July 5, 2017.
96. Brown MW, Ning H, Arora B, et al. A dosimetric analysis of dose escalation using two intensity-modulated radiation therapy techniques in locally advanced pancreatic carcinoma. Int J Radiat Oncol Biol Phys. 2006;65(1):274-283. doi:10.1016/j.ijrobp.2006.01.003.
97. Yovino S, Poppe M, Jabbour S, et al. Intensity-modulated radiation therapy significantly improves acute gastrointestinal toxicity in pancreatic and ampullary cancers. Int J Radiat Oncol Biol Phys. 2011;79(1):158-162. doi:10.1016/j.ijrobp.2009.10.043.
98. Marcu LG. Altered fractionation in radiotherapy: From radiobiological rationale to therapeutic gain. Cancer Treat Rev. 2010;36(8):606-614. doi:10.1016/j.ctrv.2010.04.004.
99. Chhabra A, Kaiser A, Regine WF, Chuong MD. The expanding role of stereotactic body radiation therapy for pancreatic cancer: a review of the literature. Transl Cancer Res. 2015;4(6):659-670. doi:10.21037/5996.
100. Nichols RC, Huh S, Li Z, Rutenberg M. Proton therapy for pancreatic cancer. World J Gastrointest Oncol. 2015;7(9):141. doi:10.4251/wjgo.v7.i9.141.
101. Nichols RC, George TJ, Zaiden RA, et al. Proton therapy with concomitant capecitabine for pancreatic and ampullary cancers is associated with a low incidence of gastrointestinal toxicity. Acta Oncol. 2013;52(3):498-505. doi:10.3109/0284186X.2012.762997.
102. Chauffert B, Mornex F, Bonnetain F, et al. Phase III trial comparing intensive induction chemoradiotherapy (60 Gy, infusional 5-FU and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study. Ann Oncol. 2008;19(9):1592-1599. doi:10.1093/annonc/mdn281.
103. Loehrer PJ, Feng Y, Cardenes H, et al. Gemcitabine Alone Versus Gemcitabine Plus Radiotherapy in Patients With Locally Advanced Pancreatic Cancer: An Eastern Cooperative Oncology Group Trial. J Clin Oncol. 2011;29(31):4105-4112. doi:10.1200/JCO.2011.34.8904.
104. Mukherjee S, Hurt CN, Bridgewater J, et al. Gemcitabine-based or capecitabine-based chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial. Lancet Oncol. 2013;14(4):317-326. doi:10.1016/S1470-2045(13)70021-4.
105. Hammel P, Huguet F, van Laethem J-L, et al. Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients With Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib. JAMA. 2016;315(17):1844. doi:10.1001/jama.2016.4324.