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Adjuvant Chemotherapy With Gemcitabine vs Observation in Patients Undergoing Curative-Intent Resection of Pancreatic Cancer
A Randomized Controlled Trial
Helmut Oettle, MD, PhD;
Stefan Post, MD, PhD;
Peter Neuhaus, MD, PhD;
Klaus Gellert, MD, PhD;
Jan Langrehr, MD, PhD;
Karsten Ridwelski, MD, PhD;
Harald Schramm, MD, PhD;
Joerg Fahlke, MD, PhD;
Carl Zuelke, MD;
Christof Burkart, MD;
Klaus Gutberlet, MD;
Erika Kettner, MD;
Harald Schmalenberg, MD;
Karin Weigang-Koehler, PhD;
Wolf-Otto Bechstein, MD, PhD;
Marco Niedergethmann, MD, PhD;
Ingo Schmidt-Wolf, MD, PhD;
Lars Roll;
Bernd Doerken, MD, PhD;
Hanno Riess, MD, PhD
JAMA. 2007;297:267-277.
Context The role of adjuvant therapy in resectable pancreatic cancer is still uncertain, and no recommended standard exists.
Objective To test the hypothesis that adjuvant chemotherapy with gemcitabine administered after complete resection of pancreatic cancer improves disease-free survival by 6 months or more.
Design, Setting, and Patients Open, multicenter, randomized controlled phase 3 trial with stratification for resection, tumor, and node status. Conducted from July 1998 to December 2004 in the outpatient setting at 88 academic and community-based oncology centers in Germany and Austria. A total of 368 patients with gross complete (R0 or R1) resection of pancreatic cancer and no prior radiation or chemotherapy were enrolled into 2 groups.
Intervention Patients received adjuvant chemotherapy with 6 cycles of gemcitabine on days 1, 8, and 15 every 4 weeks (n = 179), or observation ([control] n = 175).
Main Outcome Measures Primary end point was disease-free survival, and secondary end points were overall survival, toxicity, and quality of life. Survival analysis was based on all eligible patients (intention-to-treat).
Results More than 80% of patients had R0 resection. The median number of chemotherapy cycles in the gemcitabine group was 6 (range, 0-6). Grade 3 or 4 toxicities rarely occurred with no difference in quality of life (by Spitzer index) between groups. During median follow-up of 53 months, 133 patients (74%) in the gemcitabine group and 161 patients (92%) in the control group developed recurrent disease. Median disease-free survival was 13.4 months in the gemcitabine group (95% confidence interval, 11.4-15.3) and 6.9 months in the control group (95% confidence interval, 6.1-7.8; P<.001, log-rank). Estimated disease-free survival at 3 and 5 years was 23.5% and 16.5% in the gemcitabine group, and 7.5% and 5.5% in the control group, respectively. Subgroup analyses showed that the effect of gemcitabine on disease-free survival was significant in patients with either R0 or R1 resection. There was no difference in overall survival between the gemcitabine group (median, 22.1 months; 95% confidence interval, 18.4-25.8; estimated survival, 34% at 3 years and 22.5% at 5 years) and the control group (median, 20.2 months; 95% confidence interval, 17-23.4; estimated survival, 20.5% at 3 years and 11.5% at 5 years; P = .06, log-rank).
Conclusions Postoperative gemcitabine significantly delayed the development of recurrent disease after complete resection of pancreatic cancer compared with observation alone. These results support the use of gemcitabine as adjuvant chemotherapy in resectable carcinoma of the pancreas.
Trial Registration isrctn.org Identifier: ISRCTN34802808
Author Affiliations: Department of Medical Oncology and Hematology, Charité School of Medicine, Campus Virchow-Klinikum, Berlin, Germany (Drs Oettle, Doerken, and Riess and Mr Roll); Department of Surgery, University Hospital, Mannheim, Germany (Drs Post and Niedergethmann); Department of General, Visceral and Transplantation Surgery, Charité School of Medicine, Campus Virchow-Klinikum (Drs Neuhaus and Langrehr); Department of General and Visceral Surgery, Sana Hospital Lichtenberg, Berlin, Germany (Dr Gellert); Department of General and Visceral Surgery (Dr Ridwelski), and Altstadt Hospital, City Hospital, Magdeburg, Germany (Dr Kettner); Department of General, Visceral and Pediatric Surgery, Waldklinikum, Gera, Germany (Dr Schramm); Department of Surgery, University Hospital, Magdeburg, Germany (Dr Fahlke); University Hospital, Regensburg, Germany (Dr Zuelke); Medical Department II, University Hospital, Tuebingen, Germany (Dr Burkart); Bremen Mitte Hospital, Bremen, Germany (Dr Gutberlet); Medical Department II, University Hospital, Jena, Germany (Dr Schmalenberg); Nord Hospital, Nuremberg, Germany (Dr Weigang-Koehler); Department of Visceral and Vascular Surgery, University Hospital, Frankfurt am Main, Germany (Dr Bechstein); and Medical Department and Outpatient Clinic I, University Hospital, Bonn, Germany (Dr Schmidt-Wolf).
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