, Volume 67, Issue 16, pp 2293–2310 | Cite as

Adjuvant Therapy in Pancreatic Cancer

A Critical Appraisal
  • Helmut Oettle
  • Peter Neuhaus
Current Opinion


Adenocarcinoma of the pancreas carries a grim prognosis. Surgery is currently the only curative option, but even the few patients undergoing complete resection of early localised disease run a high risk for relapse and death. Although numerous clinical trials have been conducted during the past 20 years to find an effective adjuvant treatment, thus far no general consensus on the most appropriate regimen has been reached. In a small randomised study performed in the 1980s by the GITSG (Gastrointestinal Tumor Study Group), encouraging results were obtained with fluorouracil (5-FU)-based split-course chemoradiotherapy, but these findings were not confirmed in a randomised study initiated some years later by the EORTC (European Organisation for Research and Treatment of Cancer). More recently, the ESPAC (European Study Group for Pancreatic Cancer)-1 trial even indicated a detrimental effect of chemoradiotherapy, while chemotherapy with 5-FU was shown to have a significant positive impact on long-term survival. However, this latter finding is in contrast to earlier studies of adjuvant chemotherapy with 5-FU combinations from Norway and Japan that did not suggest a prolonged beneficial effect of 5-FU on survival. Thus, the results for adjuvant regimens based on systemic 5-FU with or without external radiotherapy are conflicting. Clinical experience with intraoperative radiotherapy or regionally targeted chemotherapy to prevent local relapse, though encouraging, is still preliminary. More recently, gemcitabine, which is the most effective single agent in advanced pancreatic cancer, has also been evaluated in the adjuvant setting. The RTOG (Radiation Therapy Oncology Group)-9704 trial demonstrated that gemcitabine is superior to 5-FU as an addition to chemoradiotherapy, but the results did not allow conclusions about the value of radiation in the combined modality approach. The Charité Onkologie CONKO-001 is a randomised trial from Germany and Austria that compared adjuvant gemcitabine with observation alone. Gemcitabine was very well tolerated and almost doubled median disease-free survival and overall survival rate at 5 years, although the advantage in overall survival failed to reach statistical significance. In summary, the available data from randomised clinical trials of adjuvant therapy suggest that (i) chemoradiotherapy has no obvious advantage compared with chemotherapy alone; and (ii) chemotherapy with gemcitabine is effective and probably offers the best benefit-risk ratio of all currently available adjuvant treatment options.


Pancreatic Cancer Gemcitabine Advanced Pancreatic Cancer Positive Resection Margin Resected Pancreatic Cancer 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors would like to thank the many seriously ill patients for their willingness to participate in one of the clinical studies of adjuvant therapy in pancreatic cancer, and the numerous trial investigators, nurses and support staff for their enthusiasm and dedication to pursue clinical research and improve treatment for this devastating disease.

Dr Oettle received no funding for preparation of this review but received grant support for clinical research projects from the German branches of the following pharmaceutical companies: Amgen, Antisense Therapeutics, Caremark/Fresenius Cabi GmbH, GlaxoSmithKline, Lilly, Logomed, Medac, Merck KG, Novartis, Orion Clinical, Janssen Cilag/Ortho Biotech, Quintiles, Roche Pharma, Sanofi-Aventis and Ribosepharm. Dr Oettle also reports receiving compensation for providing clinical lectures for Lilly and Sanofi-Aventis between 2.5 and 5 years ago. Dr Neuhaus has no conflicts of interest that are directly relevant to the contents of this review.


  1. 1.
    Griffin JF, Smalley SR, Jewell W, et al. Patterns of failure after curative resection of pancreatic carcinoma. Cancer 1990; 66: 56–61PubMedCrossRefGoogle Scholar
  2. 2.
    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: 483–9PubMedCrossRefGoogle Scholar
  3. 3.
    National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma, v.1.2007 [online]. Available from URL: [Accessed 2007 Sep 11]
  4. 4.
    Kalser MH, Ellenberg SS. Pancreatic cancer: adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 1985; 120: 899–903PubMedCrossRefGoogle Scholar
  5. 5.
    Gastrointestinal Tumor Study Group. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Cancer 1987; 59: 2006–10CrossRefGoogle Scholar
  6. 6.
    Moertel CG, Childs Jr DS, Reitemeier RJ, et al. Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. Lancet 1969; II: 865–7CrossRefGoogle Scholar
  7. 7.
    Haslam JB, Cavanaugh PJ, Stroup SL. Radiation therapy in the treatment of irresectable adenocarcinoma of the pancreas. Cancer 1973; 32: 1341–5PubMedCrossRefGoogle Scholar
  8. 8.
    Douglass HO, Stablein DM. Ten-year follow-up of first generation surgical adjuvant studies of the Gastrointestinal Tumor Study Group. In: Salmon SE, editor. Adjuvant therapy of cancer IV. Philadelphia (PA): WB Saunders, 1990: 405–15Google Scholar
  9. 9.
    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: 776–82PubMedCrossRefGoogle Scholar
  10. 10.
    Bakkevold KE, Arnesjo B, Dahl O, et al. 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: 698–703PubMedCrossRefGoogle Scholar
  11. 11.
    Takada T, Amano H, Yasuda H, et al. Study Group of Surgical Adjuvant Therapy for Carcinomas of the Pancreas and Biliary Tract. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer 2002; 95: 1685–95Google Scholar
  12. 12.
    Neoptolemos JP, Stocken DD, Friess H, et al. European Study Group for Pancreatic Cancer. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004; 350: 1200–10Google Scholar
  13. 13.
    Regine WF, Winter KW, Abrams R, et al. RTOG 9704 a phase III study of adjuvant pre and post chemoradiation (CRT) 5-FU vs. gemcitabine (G) for resected pancreatic adenocarcinoma [oral presentation]. J Clin Oncol 2006; 24 (Pt 1): 4007Google Scholar
  14. 14.
    Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine versus observation in patients undergoing curative-intent resection of pancreatic cancer: a multicenter randomized controlled trial. JAMA 2007; 297: 267–77PubMedCrossRefGoogle Scholar
  15. 15.
    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: 332–3PubMedCrossRefGoogle Scholar
  16. 16.
    Jeekel J. Author reply to: 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 [letter]. Ann Surg 2006; 244: 333.CrossRefGoogle Scholar
  17. 17.
    Yeo CJ, Abrams RA, Grochow LB, et al. Pancreaticoduodenectomy for pancreatic adenocarcinoma: postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience. Ann Surg 1997; 225: 621–33Google Scholar
  18. 18.
    Yeo CJ, Cameron JL, Sohn TA, et al. Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes. Ann Surg 1997; 226: 248–57PubMedCrossRefGoogle Scholar
  19. 19.
    Whittington R, Bryer MP, Haller DG, et al. Adjuvant therapy of resected adenocarcinoma of the pancreas. Int J Radiat Oncol Biol Phys 1991; 21: 1137–43PubMedCrossRefGoogle Scholar
  20. 20.
    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: 928–37PubMedGoogle Scholar
  21. 21.
    Mehta VK, Fisher GA, Ford JM, et al. Adjuvant radiotherapy and concomitant 5-fluorouracil by protracted venous infusion for resected pancreatic cancer. Int J Radiat Oncol Biol Phys 2000; 48: 1483–7PubMedCrossRefGoogle Scholar
  22. 22.
    Reni M, Passoni P, Bonetto E, et al. Final results of a prospective trial of a PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) regimen followed by radiotherapy after curative surgery for pancreatic adenocarcinoma. Oncology 2005; 68: 239–45PubMedCrossRefGoogle Scholar
  23. 23.
    Penberthy DR, Rich TA, Shelton 3rd CH, et al. A pilot study of chronomodulated infusional 5-fluorouracil chemoradiation for pancreatic cancer. Ann Oncol 2001; 12: 681–4PubMedCrossRefGoogle Scholar
  24. 24.
    Al-Sukhun S, Zalupski MM, Ben-Josef E, et al. Chemoradiotherapy in the treatment of regional pancreatic carcinoma: a phase II study. Am J Clin Oncol 2003; 26: 543–9PubMedCrossRefGoogle Scholar
  25. 25.
    Picozzi VJ, Kozarek RA, Traverso LW. Interferon-based adjuvant chemoradiation therapy after pancreaticoduodenectomy for pancreatic adenocarcinoma. Am J Surg 2003; 185: 476–80PubMedCrossRefGoogle Scholar
  26. 26.
    Picozzi VJ, Traverso LW. The Virginia Mason approach to localized pancreatic cancer. Surg Oncol Clin N Am 2004; 13: 663–74PubMedCrossRefGoogle Scholar
  27. 27.
    Sindelar WF, Kinsella T, Tepper J, et al. Experimental and clinical studies with intraoperative radiotherapy. Surg Gynecol Obstet 1983; 157: 205–19PubMedGoogle Scholar
  28. 28.
    Glaser K, Bodner E, Kingler A. Adjuvant intraoperative radiation therapy during pancreatectomy. In: Büchler M, Malfertheiner P, editors. Standards in pancreatic surgery. Berlin, Heidelberg, New York: Springer Verlag, 1993Google Scholar
  29. 29.
    Zerbi A, Fossati V, Parolini D, et al. Intraoperative radiation therapy adjuvant to resection in the treatment of pancreatic cancer. Cancer 1994; 73: 2930–5PubMedCrossRefGoogle Scholar
  30. 30.
    Fossati V, Cattaneo GM, Zerbi A, et al. The role of intraoperative therapy by electron beam and combination of adjuvant chemotherapy and external radiotherapy in carcinoma of the pancreas. Tumori 1995; 81: 23–31PubMedGoogle Scholar
  31. 31.
    Di Carlo V, Zerbi A, Balzano G, et al. Intraoperative and postoperative radiotherapy in pancreatic cancer. Int J Pancreatol 1997; 21: 53–8PubMedGoogle Scholar
  32. 32.
    Hosotani R, Kogire M, Arii S, et al. Results of pancreatectomy with radiation therapy for pancreatic cancer. Hepatogastroenterology 1997; 44: 1528–35PubMedGoogle Scholar
  33. 33.
    Sunamura M, Kobari M, Lozonschi L, et al. Intraoperative radiotherapy for pancreatic adenocarcinoma. J Hepatobiliary Pancreat Surg 1998; 5: 151–6PubMedCrossRefGoogle Scholar
  34. 34.
    Kokubo M, Nishimura Y, Shibamoto Y, 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: 1081–7PubMedCrossRefGoogle Scholar
  35. 35.
    Alfieri S, Morganti AG, Di Giorgio A, 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: 343–7PubMedCrossRefGoogle Scholar
  36. 36.
    Reni M, Panucci MG, Ferreri AJ, 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: 651–8PubMedCrossRefGoogle Scholar
  37. 37.
    Sindelar WF, Kinsella TJ. Randomized trial of intraoperative radiotherapy in resected carcinoma of the pancreas. Int J Radiat Oncol Biol Phys 1986; 12 Suppl. 1: 148CrossRefGoogle Scholar
  38. 38.
    Lygidakis NJ, Sgourakis G, Georgia D, et al. Regional targeting chemoimmunotherapy in patients undergoing pancreatic resection in an advanced stage of their disease: a prospective randomized study. Ann Surg 2002; 236: 806–13PubMedCrossRefGoogle Scholar
  39. 39.
    Cantore M, Serio G, Pederzoli P, et al. Adjuvant intra-arterial 5-fluoruracil, leucovorin, epirubicin and carboplatin with or without systemic gemcitabine after curative resection for pancreatic adenocarcinoma. Cancer Chemother Pharmacol 2006; 58: 504–8PubMedCrossRefGoogle Scholar
  40. 40.
    Beger HG, Gansauge F, Büchler MW, et al. Intraarterial adjuvant chemotherapy after pancreaticoduodenectomy for pancreatic cancer: significant reduction in occurrence of liver metastasis. World J Surg 1999; 23: 946–9PubMedCrossRefGoogle Scholar
  41. 41.
    Ishikawa O, Ohigashi H, Sasaki Y, et al. Adjuvant therapies in extended pancreatectomy for ductal adenocarcinoma of the pancreas. Hepatogastroenterology 1998; 45: 644–50PubMedGoogle Scholar
  42. 42.
    Neoptolemos JP, Dunn JA, Stocken DD, et al. European Study Group for Pancreatic Cancer. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet 2001; 358: 1576–85Google Scholar
  43. 43.
    Neoptolemos JP, Stocken DD, Dunn JA, et al. European Study Group for Pancreatic Cancer. 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: 758–68PubMedGoogle Scholar
  44. 44.
    Morris SL, Beasley M, Leslie M. Chemotherapy for pancreatic cancer. N Engl J Med 2004; 350: 2713–5PubMedCrossRefGoogle Scholar
  45. 45.
    Bydder S, Spry N. Chemotherapy for pancreatic cancer. N Engl J Med 2004; 350: 2713–5PubMedCrossRefGoogle Scholar
  46. 46.
    Koshy MC, Landry JC, Cavanaugh SX, et al. A challenge to the therapeutic nihilism of ESPAC-1. Int J Radiat Oncol Biol Phys 2005; 61: 965–6PubMedCrossRefGoogle Scholar
  47. 47.
    Dickler A, Abrams RA. Radiochemotherapy in the management of pancreatic cancer. Part II: use in adjuvant and locally unresectable settings. Semin Radiat Oncol 2005; 15: 235–44CrossRefGoogle Scholar
  48. 48.
    Burris 3rd 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: 2403–13PubMedGoogle Scholar
  49. 49.
    Ducreux M, Rougier P, Pignon JP, et al. Groupe Digestif of the Federation Nationale des Centres de Lutte Contre le Cancer Digestif. A randomised trial comparing 5-FU with 5-FU plus cisplatin in advanced pancreatic carcinoma. Ann Oncol 2002; 13: 1185–91Google Scholar
  50. 50.
    Oettle H, Arnold D, Hempel C, et al. The role of gemcitabine alone and in combination in the treatment of pancreatic cancer. Anticancer Drugs 2000; 11: 771–86PubMedCrossRefGoogle Scholar
  51. 51.
    Stocken DD, Buchler MW, Dervenis C, et al. Pancreatic Cancer Meta-analysis Group. Meta-analysis of randomised adjuvant therapy trials for pancreatic cancer. Br J Cancer 2005; 92: 1372–81Google Scholar
  52. 52.
    Khanna A, Walker GR, Livingstone AS, et al. Is adjuvant 5-FU-based chemoradiotherapy for resectable pancreatic adenocarcinoma beneficial? A meta-analysis of an unanswered question. J Gastrointest Surg 2006; 10: 689–97PubMedCrossRefGoogle Scholar
  53. 53. Gemcitabine and radiation therapy compared with gemcitabine alone in treating patients who have undergone surgery for pancreatic cancer [online]. Available from URL: [Accessed 2007 Aug 30]

Copyright information

© Adis Data Information 2007

Authors and Affiliations

  • Helmut Oettle
    • 1
  • Peter Neuhaus
    • 2
  1. 1.Department of Medical Hematology and OncologyCharité-Universitätsmedizin BerlinBerlinGermany
  2. 2.Department of General, Visceral and Transplantation SurgeryCharité-Berlin University School of Medicine, Campus Virchow-KlinikumBerlinGermany

Personalised recommendations