Adding Oxaliplatin to Leucovorin/Fluorouracil Increases Survival in Second-Line Treatment of Gemcitabine-Refractory Pancreatic Cancer


Key Points

  • The addition of oxaliplatin to leucovorin/fluorouracil significantly improved overall survival in patients progressing on gemcitabine monotherapy.
  • The combination regimen was generally well-tolerated.

In the German phase III CONKO-003 trial reported in the Journal of Clinical Oncology, Oettle et al found that second-line oxaliplatin, leucovorin, and fluorouracil (5-FU) significantly increased overall survival and time to progression vs leucovorin/5-FU in patients with advanced pancreatic cancer progressing on gemcitabine monotherapy.

Study Details

In this open-label trial, 160 patients from 16 German centers were randomly assigned between January 2004 and May 2007 to receive oxaliplatin, leucovorin, and 5-FU (n = 76) or leucovorin/5-FU (n = 84). The leucovorin/5-FU regimen consisted of leucovorin at 200 mg/m2 followed by continuous infusion 5-FU at 2,000 mg/m2 over 24 hours on days 1, 8, 15, and 22. The oxaliplatin, leucovorin, and 5-FU regimen consisted of leucovorin/5-FU plus oxaliplatin at 85 mg/m2 given before leucovorin/5-FU on days 8 and 22; after a 3-week rest period from day 23 to 42, the second course was started on day 43 (day 1 of second cycle).

Treatment was continued until disease progression or unacceptable toxicity. Patients were stratified according to presence of metastases, duration of first-line therapy, and Karnofsky performance status. The primary endpoint was overall survival. 

The oxaliplatin, leucovorin, and 5-FU and leucovorin/5-FU groups were generally balanced for age (median, 62 and 61 years), sex (53% and 57% male), primary surgery (45% and 32%, P = .14), time from randomization to treatment (mean, 5.5 and 4.1 days), Karnofsky performance status (70–80 in 46% and 52%, 90–100 in 54% and 48%), duration of first-line gemcitabine (< 3 months in 28% and 25%, 3–6 months in 33% and 38%, > 6 months in 40% and 37%), M stage (0 in 12% and 1 in 88% in both), and progression-free survival with first-line treatment (median, 4.6 and 5.3 months).

Improved Overall Survival

Median follow-up was 54.1 months. Median overall survival was 5.9 months in the oxaliplatin, leucovorin, and 5-FU group vs 3.3 months in the leucovorin/5-FU group (hazard ratio [HR] = 0.66, P = .010). Hazard ratios for overall survival favored oxaliplatin, leucovorin, and 5-FU in all stratification subgroups, with hazard ratios being significant in patients who received > 6 months of gemcitabine (HR = 0.58, 95% confidence interval [CI] = 0.35–0.98) and in those with M0 status (HR = 0.56, 95% CI = 0.47–0.92). Time to progression was 2.9 vs 2.0 months (HR = 0.68, P = .019).

Overall, 29% of oxaliplatin, leucovorin, and 5-FU patients and 21% of leucovorin/5-FU patients received third-line therapy; of these, 32% in the oxaliplatin, leucovorin, and 5-FU group received taxane therapy and 72% in the leucovorin/5-FU group received oxaliplatin-based therapy.


Most hematologic and nonhematologic adverse events were grade 1 or 2. Rates of adverse events of any grade were similar in the treatment groups except for grade 1 or 2 neurotoxicity, which occurred in 38.2% of the oxaliplatin, leucovorin, and 5-FU group vs 7.1% of the leucovorin/5-FU group (P < .001); grade 3 neuropathy occurred in 3.9% of oxaliplatin, leucovorin, and 5-FU patients. Grade 3 thrombocytopenia occurred in 1.3% of patents in the oxaliplatin, leucovorin, and 5-FU group, and grade 3 anemia occurred in 3.9% vs 2.4%. In addition to neuropathy, the most common adverse events of any grade were nausea/emesis and diarrhea, which occurred with similar frequency in the two groups. A dose reduction to 75% was required in 10% of oxaliplatin doses, and 9% of planned oxaliplatin doses were not given.

The investigators concluded, “[T]his phase III trial demonstrates the superiority of [oxaliplatin, leucovorin, and 5-FU] in extending overall survival compared with [leucovorin/5-FU] in outpatients with advanced gemcitabine-refractory pancreatic cancer who qualified for subsequent second-line therapy. Furthermore, addition of oxaliplatin to [leucovorin/5-FU] did not result in clinically relevant increased toxicity. Therefore, we recommend this phase III-confirmed [oxaliplatin, leucovorin, and 5-FU] regimen as standard of care for the second-line treatment of patients with advanced pancreatic cancer who have experienced progression during first-line treatment with gemcitabine.”

Helmut Oettle, MD, of Charité Universitätsmedizin, Berlin, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by Charité Forschungsförderung, Arbeitsgemeinschaft Internistische Onkologie, Deutsche Krebsgesellschaft, sanofi-aventis, and Amgen.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.