Abstract
The delivery of postoperative combined modality adjuvant therapy for completely resected pancreatic cancer was initially shown to be beneficial on the basis of a prospective, randomized trial published in 1985. Since then, oncologists have debated whether chemotherapy, chemoradiation, or both is optimal adjuvant therapy after pancreatectomy for ductal adenocarcinoma of the pancreas; no global consensus has emerged. Unfortunately, despite the completion of a number of subsequent randomized trials of adjuvant therapy since 1985, no further improvements in overall survival have materialized. This lack of progress is not simply the result of ineffective systemic therapies, but in part the result of poor trial design and calls for a more disciplined approach to the selection of patients for surgery, pathologic assessment of surgical resection margins, and postoperative (pretreatment) imaging. This is the only way to ensure that patients who receive adjuvant therapy are actually receiving therapy for radiographically occult possible microscopic disease, rather than therapy for incompletely resected locally advanced disease or early postoperative metastases. A critical analysis of completed adjuvant trials will be provided and a framework for the conduct of future trials of adjuvant therapy proposed.
Similar content being viewed by others
References
Kalser MH, Ellenberg SS. Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 1985;120:899–903
Tepper J, Nardi G, Sutt H. Carcinoma of the pancreas: review of MGH experience from 1963 to 1973. Analysis of surgical failure and implications for radiation therapy. Cancer 1976;37:1519–24
Kayahara M, Nagakawa T, Ueno K et al. An evaluation of radical resection for pancreatic cancer based on the mode of recurrence as determined by autopsy and diagnostic imaging. Cancer 1993;72:2118–23
Hishinuma S, Ogata Y, Tomikawa M et al. Patterns of recurrence after curative resection of pancreatic cancer, based on autopsy findings. J Gastrointest Surg 2006;10:511–8
Prolongation of the disease-free interval in surgically treated rectal carcinoma. Gastrointestinal Tumor Study Group. N Engl J Med 1985; 312:1465–72
O’Connell MJ, Martenson JA, Wieand HS et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994;331:502–7
Macdonald JS, Smalley SR, Benedetti J et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001;345:725–30
Krook JE, Moertel CG, Gunderson LL et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991;324:709–15
Whittington R, Bryer MP, Haller DG et al. Adjuvant therapy of resected adenocarcinoma of the pancreas. Int J Radiat Oncol Biol Phys 1991;21:1137–43
Morganti AG, Valentini V, Macchia G et al. Adjuvant radiotherapy in resectable pancreatic carcinoma. Eur J Surg Oncol 2002;28:523–30
Foo ML, Gunderson LL, Nagorney DM et al. Patterns of failure in grossly resected pancreatic ductal adenocarcinoma treated with adjuvant irradiation ± 5 fluorouracil. Int J Radiat Oncol Biol Phys 1993;26:483–9
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;15:928–37
Staley CA, Lee JE, Cleary KR et al. Preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for adenocarcinoma of the pancreatic head. Am J Surg 1996;171:118–24
Moertel CG, Childs DS Jr, Reitemeier RJ et al. Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancet 1969;2:865–7
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;230:776–82
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;350:1200–10
Sohn TA, Yeo CJ, Cameron JL et al. Resected adenocarcinoma of the pancreas-616 patients: results, outcomes, and prognostic indicators. J Gastrointest Surg 2000;4:567–79
Smeenk HG, van Eijck CH, Hop WC et al. Long-term survival and metastatic pattern of pancreatic and periampullary cancer after adjuvant chemoradiation or observation: long-term results of EORTC trial 40891. Ann Surg 2007;246:734–40
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;297:267–77
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;299:1019–26
Regine WF, Abrams RA. Adjuvant therapy for pancreatic cancer: back to the future. Int J Radiat Oncol Biol Phys 1998;42:59–63
Newman EA, Simeone DM, Mulholland MW. Adjuvant treatment strategies for pancreatic cancer. J Gastrointest Surg 2006;10:916–26
Chua YJ, Cunningham D. Adjuvant treatment for resectable pancreatic cancer. J Clin Oncol 2005;23:4532–7
Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Gastrointestinal Tumor Study Group. Cancer 1987; 59:2006–10
Evans DB, Wolff RA, Hess KR. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region. Ann Surg 2000;232:727
Garofalo MC, Regine WF, Tan MT. On statistical reanalysis, the EORTC trial is a positive trial for adjuvant chemoradiation in pancreatic cancer. Ann Surg 2006;244:332–3
Pisters PW, Wolff RA, Crane CH et al. Combined-modality treatment for operable pancreatic adenocarcinoma. Oncology (Williston Park) 2005;19:393–404, 409
Winter JM, Cameron JL, Campbell KA et al. 1423 pancreaticoduodenectomies for pancreatic cancer: a single-institution experience. J Gastrointest Surg 2006;10:1199–210
Stocken DD, Buchler MW, Dervenis C et al. Meta-analysis of randomised adjuvant therapy trials for pancreatic cancer. Br J Cancer 2005;92:1372–81
Kuhlmann KF, de Castro SM, Wesseling JG et al. Surgical treatment of pancreatic adenocarcinoma; actual survival and prognostic factors in 343 patients. Eur J Cancer 2004;40:549–58
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;234:758–68
Millikan KW, Deziel DJ, Silverstein JC et al. Prognostic factors associated with resectable adenocarcinoma of the head of the pancreas. Am Surg 1999;65:618–23
Nishimura Y, Hosotani R, Shibamoto Y et al. External and intraoperative radiotherapy for resectable and unresectable pancreatic cancer: analysis of survival rates and complications. Int J Radiat Oncol Biol Phys 1997;39:39–49
Takai S, Satoi S, Toyokawa H et al. Clinicopathologic evaluation after resection for ductal adenocarcinoma of the pancreas: a retrospective, single-institution experience. Pancreas 2003;26:243–9
Richter A, Niedergethmann M, Sturm JW et al. Long-term results of partial pancreaticoduodenectomy for ductal adenocarcinoma of the pancreatic head: 25-year experience. World J Surg 2003;27:324–9
Lu DS, Reber HA, Krasny RM et al. Local staging of pancreatic cancer: criteria for unresectability of major vessels as revealed by pancreatic-phase, thin-section helical CT. AJR Am J Roentgenol 1997;168:1439–43
Tamm E, Charnsangavej C, Szklaruk J. Advanced 3-D imaging for the evaluation of pancreatic cancer with multidetector CT. Int J Gastrointest Cancer 2001;30:65–71
Fuhrman GM, Charnsangavej C, Abbruzzese JL et al. Thin-section contrast-enhanced computed tomography accurately predicts the resectability of malignant pancreatic neoplasms. Am J Surg 1994;167:104–11
Zhong L, Li L, Yao QY. Preoperative evaluation of pancreaticobiliary tumor using MR multi-imaging techniques. World J Gastroenterol 2005;11:3756–61
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;246:52–60
Greene FL, Page DL, Fleming ID et al. AJCC cancer staging manual, 6th edition. New York: Springer, 2002
Evans DB, Rich TA, Byrd DR et al. Preoperative chemoradiation and pancreaticoduodenectomy for adenocarcinoma of the pancreas. Arch Surg 1992;127:1335–9
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;16:3843–50
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;16:317–23
White RR, Tyler DS. Neoadjuvant therapy for pancreatic cancer: the Duke experience. Surg Oncol Clin N Am 2004;13:675–84
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;20:2537–44
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; (in press)
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 (in press)
Blackstock AW, Mornex F, Partensky C et al. Adjuvant gemcitabine and concurrent radiation for patients with resected pancreatic cancer: a phase II study. Br J Cancer 2006;95:260–5
Nukui Y, Picozzi VJ, Traverso LW. Interferon-based adjuvant chemoradiation therapy improves survival after pancreaticoduodenectomy for pancreatic adenocarcinoma. Am J Surg 2000;179:367–71
Picozzi VJ, Abrams RA, Traverso LW, et al. ACOSOG Z05031: report on a multicenter, phase II trial for adjuvant therapy of resected pancreatic cancer using cisplatin, 5-FU, and alpha-interferon (abstract 4505). J Clin Oncol 2008; 26:214s.
Jaffee EM, Hruban RH, Biedrzycki B et al. Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: a phase I trial of safety and immune activation. J Clin Oncol 2001;19:145–56
Laheru D, Yeo C, Biedrzycki B et al. A safety and efficacy trial of lethally irradiated allogeneic pancreatic tumor cells transfected with the GM-CSF gene in combination with adjuvant chemoradiotherapy for the treatment of adenocarcinoma of the pancreasPost operative vaccination for patients with resected pancreatic cancer. J Clin Oncol 2007;25(Suppl 18S):3010
Tseng JF, Raut CP, Lee JE et al. Pancreaticoduodenectomy with vascular resection: margin status and survival duration. J Gastrointest Surg 2004;8:935–49
Varadhachary GR, Tamm EP, Abbruzzese JL et al. Borderline resectable pancreatic cancer: definitions, management, and role of preoperative therapy. Ann Surg Oncol 2006;13:1035–46
Varadhachary GR, Tamm EP, Crane C et al. Borderline resectable pancreatic cancer. Curr Treat Options Gastroenterol 2005;8:377–84
Katz MHG, Pisters PWT, Evans DB, et al. Borderline resectable pancreatic cancer: the importance of this emerging stage of disease. J Am Coll Surg 2008; 206:833–46
Brown KM, Siripurapu V, Davidson M et al. Chemoradiation followed by chemotherapy before resection for borderline pancreatic adenocarcinoma. Am J Surg 2008;195:318–21
Bosset JF, Collette L, Calais G et al. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 2006;355:1114–23
Sauer R, Becker H, Hohenberger W et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004;351:1731–40
Cunningham D, Allum WH, Stenning SP et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med 2006;355:11–20
Walsh TN, Noonan N, Hollywood D et al. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 1996;335:462–7
Breslin TM, Hess KR, Harbison DB et al. Neoadjuvant chemoradiotherapy for adenocarcinoma of the pancreas: treatment variables and survival duration. Ann Surg Oncol 2001;8:123–32
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;13:150–8
Greer SE, Pipas JM, Sutton JE et al. Effect of neoadjuvant therapy on local recurrence after resection of pancreatic adenocarcinoma. J Am Coll Surg 2008;206:451–7
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 2001;5:121–30
Ferrone CR, Finkelstein DM, Thayer SP et al. Perioperative CA19-9 levels can predict stage and survival in patients with resectable pancreatic adenocarcinoma. J Clin Oncol 2006;24:2897–902
Acknowledgments
Supported by the Hamill Foundation and the Various Donor Account for Pancreatic Cancer Research, University of Texas M. D. Anderson Cancer Center.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wolff, R.A., Varadhachary, G.R. & Evans, D.B. Adjuvant Therapy for Adenocarcinoma of the Pancreas: Analysis of Reported Trials and Recommendations for Future Progress. Ann Surg Oncol 15, 2773–2786 (2008). https://doi.org/10.1245/s10434-008-0002-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1245/s10434-008-0002-3