Skip to main content
SpringerLink
Log in

Adjuvant Therapy in Pancreatic Cancer

A Critical Appraisal

  • Current Opinion
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Table I
Fig. 1

Similar content being viewed by others

References

  1. Griffin JF, Smalley SR, Jewell W, et al. Patterns of failure after curative resection of pancreatic carcinoma. Cancer 1990; 66: 56–61

    Article  PubMed  CAS  Google Scholar 

  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: 483–9

    Article  PubMed  CAS  Google Scholar 

  3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Pancreatic adenocarcinoma, v.1.2007 [online]. Available from URL: http://www.nccn.org/professionals/physician_gls/PDF/pancreatic.pdf [Accessed 2007 Sep 11]

  4. Kalser MH, Ellenberg SS. Pancreatic cancer: adjuvant combined radiation and chemotherapy following curative resection. Arch Surg 1985; 120: 899–903

    Article  PubMed  CAS  Google Scholar 

  5. Gastrointestinal Tumor Study Group. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Cancer 1987; 59: 2006–10

    Article  Google Scholar 

  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: 865–7

    Article  Google Scholar 

  7. Haslam JB, Cavanaugh PJ, Stroup SL. Radiation therapy in the treatment of irresectable adenocarcinoma of the pancreas. Cancer 1973; 32: 1341–5

    Article  PubMed  CAS  Google Scholar 

  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: 405–15

    Google Scholar 

  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: 776–82

    Article  PubMed  CAS  Google Scholar 

  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: 698–703

    Article  PubMed  CAS  Google Scholar 

  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: 1685–95

    Google Scholar 

  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: 1200–10

    CAS  Google Scholar 

  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): 4007

    Google Scholar 

  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: 267–77

    Article  PubMed  CAS  Google Scholar 

  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: 332–3

    Article  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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: 621–33

    CAS  Google Scholar 

  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: 248–57

    Article  PubMed  CAS  Google Scholar 

  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: 1137–43

    Article  PubMed  CAS  Google Scholar 

  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: 928–37

    PubMed  CAS  Google Scholar 

  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: 1483–7

    Article  PubMed  CAS  Google Scholar 

  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: 239–45

    Article  PubMed  CAS  Google Scholar 

  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: 681–4

    Article  PubMed  CAS  Google Scholar 

  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: 543–9

    Article  PubMed  CAS  Google Scholar 

  25. Picozzi VJ, Kozarek RA, Traverso LW. Interferon-based adjuvant chemoradiation therapy after pancreaticoduodenectomy for pancreatic adenocarcinoma. Am J Surg 2003; 185: 476–80

    Article  PubMed  Google Scholar 

  26. Picozzi VJ, Traverso LW. The Virginia Mason approach to localized pancreatic cancer. Surg Oncol Clin N Am 2004; 13: 663–74

    Article  PubMed  Google Scholar 

  27. Sindelar WF, Kinsella T, Tepper J, et al. Experimental and clinical studies with intraoperative radiotherapy. Surg Gynecol Obstet 1983; 157: 205–19

    PubMed  CAS  Google Scholar 

  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, 1993

    Google Scholar 

  29. Zerbi A, Fossati V, Parolini D, et al. Intraoperative radiation therapy adjuvant to resection in the treatment of pancreatic cancer. Cancer 1994; 73: 2930–5

    Article  PubMed  CAS  Google Scholar 

  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: 23–31

    PubMed  CAS  Google Scholar 

  31. Di Carlo V, Zerbi A, Balzano G, et al. Intraoperative and postoperative radiotherapy in pancreatic cancer. Int J Pancreatol 1997; 21: 53–8

    PubMed  Google Scholar 

  32. Hosotani R, Kogire M, Arii S, et al. Results of pancreatectomy with radiation therapy for pancreatic cancer. Hepatogastroenterology 1997; 44: 1528–35

    PubMed  CAS  Google Scholar 

  33. Sunamura M, Kobari M, Lozonschi L, et al. Intraoperative radiotherapy for pancreatic adenocarcinoma. J Hepatobiliary Pancreat Surg 1998; 5: 151–6

    Article  PubMed  CAS  Google Scholar 

  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: 1081–7

    Article  PubMed  CAS  Google Scholar 

  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: 343–7

    Article  PubMed  CAS  Google Scholar 

  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: 651–8

    Article  PubMed  CAS  Google Scholar 

  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: 148

    Article  Google Scholar 

  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: 806–13

    Article  PubMed  Google Scholar 

  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: 504–8

    Article  PubMed  CAS  Google Scholar 

  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: 946–9

    Article  PubMed  CAS  Google Scholar 

  41. Ishikawa O, Ohigashi H, Sasaki Y, et al. Adjuvant therapies in extended pancreatectomy for ductal adenocarcinoma of the pancreas. Hepatogastroenterology 1998; 45: 644–50

    PubMed  CAS  Google Scholar 

  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: 1576–85

    CAS  Google Scholar 

  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: 758–68

    PubMed  CAS  Google Scholar 

  44. Morris SL, Beasley M, Leslie M. Chemotherapy for pancreatic cancer. N Engl J Med 2004; 350: 2713–5

    Article  PubMed  CAS  Google Scholar 

  45. Bydder S, Spry N. Chemotherapy for pancreatic cancer. N Engl J Med 2004; 350: 2713–5

    Article  PubMed  Google Scholar 

  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: 965–6

    Article  PubMed  Google Scholar 

  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: 235–44

    Article  Google Scholar 

  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: 2403–13

    PubMed  CAS  Google Scholar 

  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: 1185–91

    CAS  Google Scholar 

  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: 771–86

    Article  PubMed  CAS  Google Scholar 

  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: 1372–81

    CAS  Google Scholar 

  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: 689–97

    Article  PubMed  Google Scholar 

  53. ClinicalTrials.gov. Gemcitabine and radiation therapy compared with gemcitabine alone in treating patients who have undergone surgery for pancreatic cancer [online]. Available from URL: http://www.clinicaltrials.gov/ct/show/NCT00064207/ [Accessed 2007 Aug 30]

Download references

Acknowledgements

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.

Author information

Authors and Affiliations

  1. Department of Medical Hematology and Oncology, Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Med. Klinik m. S. Hämatologie und Onkologie, Augustenburger Platz 1, Berlin, 13353, Germany

    Helmut Oettle MD, PhD

  2. Department of General, Visceral and Transplantation Surgery, Charité-Berlin University School of Medicine, Campus Virchow-Klinikum, Berlin, Germany

    Peter Neuhaus

Authors
  1. Helmut Oettle MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter Neuhaus
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Oettle, H., Neuhaus, P. Adjuvant Therapy in Pancreatic Cancer. Drugs 67, 2293–2310 (2007). https://doi.org/10.2165/00003495-200767160-00001

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-200767160-00001

Keywords

Search

Navigation