An initial report from the phase III Charité Onkologie (CONKO) 001 trial of adjuvant gemcitabine vs observation in patients with completely resected pancreas cancer showed that gemcitabine treatment was associated with a significant prolongation of disease-free survival.1 As reported in JAMA by Helmut Oettle, MD, PhD, of Charité-Universitätsmedizin Berlin, and colleagues, 11-year follow-up in this trial has shown that adjuvant gemcitabine is associated with improved long-term disease-free survival and overall survival.2
In this multicenter open-label trial, 354 German and Austrian patients with macroscopically completely removed pancreatic cancer were randomly assigned to receive gemcitabine treatment at 1 g/m2 on days 1, 8, and 15 every 4 weeks for 6 months (n = 179) or observation alone (n = 175). Enrollment occurred between July 1998 and December 2004, and follow-up ended in September 2012.
Patients were stratified for tumor stage, nodal status, and resection status. The primary endpoint was disease-free survival, and secondary endpoints included overall survival, defined as the time from date of randomization to death.
The majority of patients had T3, N1 disease prior to surgery and had undergone an R0 resection. The gemcitabine and observation groups were generally well matched for age (median, 62 years in both), Karnofsky performance status (median, 80 in both), sex (59% and 56% men), primary tumor stage (T2 in 10% in both, T3 in 82% and 83%), nodal status (N0 in 29% and 27%, N1 in 70% and 71%), resection status (R0 in 81% and 85%, R1 in 19% and 15%), grade (G2 in 58% and 55%, G3 in 35% and 38%), and histology (adenocarcinoma in 98% and 96%).
Median follow-up was 136 months. As reported in the initial trial publication, median disease-free survival was 13.4 months in the gemcitabine group vs 6.7 months in the observation group (hazard ratio [HR] = 0.55, P < .001). At 5 and 10 years, disease-free survival rates were 16.6% vs 14.3% and 7.0% vs 5.8%, respectively.
On multivariate analysis including age, sex, Karnofsky performance status, primary tumor stage, nodal status, and resection status, the effect of gemcitabine treatment remained significant (HR = 0.54, P < .001). Other significant factors were T stage (HR = 1.60, P = .007, for T3-4 vs T1-2) and nodal status (HR = 1.82, P < .001, for N+ vs N0).
The effect of gemcitabine was consistent across all stratification subgroups, with heterogeneity tests showing no treatment by subgroup interaction except for a borderline significant interaction reflecting a low hazard ratio in the small subgroup of patients with microscopic residual disease. Hazard ratios were 0.50 (95% confidence interval [CI] = 0.26–0.95) for T1-2 and 0.56 (95% CI = 0.44–0.71) for T3-4 subgroups (P = .76 for heterogeneity), 0.57 (95% CI = 0.36–0.89) for N0 and 0.53 (95% CI = 0.40–0.68) for N1 subgroups (P = .77 for heterogeneity), and 0.59 (95% CI = 0.46–0.76) for R0 and 0.33 (95% CI = 0.19–0.58) for R1 subgroups (P = .06 for heterogeneity).
As noted by the investigators, since there was a high number of relapses within the first year of the study and since gemcitabine-based therapy was the standard therapy in patients with relapse after resection, the study can be seen as a comparison of immediate vs delayed postoperative therapy with gemcitabine with regard to overall survival.
Median overall survival was 22.8 months in the gemcitabine group vs 20.2 months in the observation group (HR = 0.76, P = .01). Overall survival rates at 5 and 10 years were 20.7% vs 12.2% and 10.4% vs 7.7%, respectively.
On multivariate analysis including age, sex, Karnofsky performance status, primary tumor stage, nodal status, and resection status, the effect of gemcitabine treatment remained significant (HR = 0.78, P = .03). Other significant factors were T stage (HR = 1.68, P = .003, for T3-4 vs T1-2) and nodal status (HR = 1.59, P < .001, for N+ vs N0), with age being borderline significant (HR = 1.24, P = .06, for ≥ 65 vs < 65 years).
Subgroup analysis showed consistent effects across stratification subgroups, with testing for heterogeneity showing no significant treatment by subgroup interactions. Hazard ratios were 0.58 (95% CI = 0.30–1.10) for T1-2 and 0.78 (0.61–0.99) for T3-4 subgroups (P = .39 for heterogeneity), 0.63 (95% CI = 0.40–0.97) for N0 and 0.81 (95% CI = 0.63–1.06) for N1 subgroups (P = .31 for heterogeneity), and 0.76 (95% CI = 0.60–0.98) for R0 and 0.66 (95% CI = 0.39–1.13) for R1 subgroups (P = .63 for heterogeneity).
The investigators concluded: “Among patients with macroscopic complete removal of pancreatic cancer, the use of adjuvant gemcitabine for 6 months compared with observation alone resulted in increased overall survival as well as disease-free survival. These findings provide strong support for the use of gemcitabine in this setting.” ■
Disclosure: The trial was supported by Lilly Germany, the German Cancer Society and a grant from the Charité-Universitätsmedizin Berlin. For full disclosures of the study authors, visit jama.jamanetwork.com.
1. 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 297:267-277, 2007.
2. Oettle H, Neuhaus P, Hochhaus A, et al: Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: The CONKO-001 randomized trial. JAMA 310:1473-1481, 2013.
From 12% to 15% of the approximately 45,000 patients diagnosed with pancreas adenocarcinoma undergo a potentially curative resection each year in North America, translating into roughly 5,000 to 7,000 patients who are candidates for adjuvant therapy. About 80% of these patients will relapse and...