Adjuvant Therapy in Pancreatic Cancer
- 101 Downloads
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.
KeywordsPancreatic Cancer Gemcitabine Advanced Pancreatic Cancer Positive Resection Margin Resected Pancreatic Cancer
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.
- 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]
- 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
- 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.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.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
- 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
- 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
- 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.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
- 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
- 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
- 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]