Updated analysis of disease-free survival (DFS) in the NO16968 trial confirms a survival benefit with the addition of oxaliplatin in adjuvant treatment of stage III colorectal cancer. The study compared XELOX (capecitabine plus oxaliplatin) versus bolus 5-fluorouracil/leucovorin (5-FU/LV) in 1886 patients with resected stage III colon cancer, and the updated analysis was based on a median follow-up of 7 years. “After this study and overall experience with more than 5000 patients, oxaliplatin should now be considered standard treatment for stage III colon cancer,” stated lead author Hans-Joachim Schmoll, MD, University Clinic Halle in Germany, who presented these findings at the American Society of Clinical Oncology Gastrointestinal Symposium held in San Francisco, California.
An earlier analysis of the study with median follow-up of 4.75 years demonstrated a significant DFS advantage for XELOX over 5-FU/LV (hazard ratio [HR], 0.80; P = .0045), but no significant difference was seen between the 2 arms for overall survival (OS). The updated analysis, with median follow-up of 7 years (minimum follow-up of 6.6 years), showed that OS was significantly better for the XELOX arm: 73% versus 67%, respectively (HR, 0.83, P = .0367). DFS, the primary end point, also significantly favored XELOX with longer follow-up: 63% versus 56%, respectively (HR, 0.80; P = .0038). Patients were randomized to adjuvant treatment with XELOX versus bolus 5- FU/LV for a total of 6 months. Both arms were well balanced at baseline for sex, age, ECOG performance status, carcinoembryonic antigen level, and lymph node classification.
Commenting on the DFS and OS curves for both arms, Schmoll said that the curves remain separated after 7 years. The death rate was 26% in the XELOX arm compared with 30% in the 5-FU/LV arm. This difference was mainly driven by excess deaths from colon cancer in the control arm: 20% for XELOX and 26% for 5-FU/LV. The number of deaths due to other cancers, treatment, or unrelated deaths was similar in the 2 arms. Schmoll commented that chemotherapy in the current era is more effective, prolonging the time until curves start to separate compared with earlier trials; it takes longer to demonstrate the true benefit of oxaliplatin with modern chemotherapy. He said that in future trials, longer follow-up is needed for DFS and OS.
A multivariate analysis for prognositic factors confirmed the treatment effect of XELOX (HR, 0.84; P = .047). Subgroup analysis showed no major difference in DFS and OS, with all subgroups favoring XELOX, with 2 exceptions: black American ethnicity and laparoscopic surgery favored the control arm. “These are very small numbers of patients, and the confidence intervals are wide. This is a chance finding,” Schmoll stated. Now 3 randomized stage III trials (MOSAIC, NSABP CO-7, and NO16968) with about 5000 patients and a median follow-up of 6 to 8 years demonstrate a clear benefit for oxaliplatin, Schmoll said. About 22% of patients in the NO16968 trial were aged 70 and older, and in these patients the magnitude of the survival benefit of oxaliplatin was somewhat less than in younger patients.
A translational research program for this trial is under way. “This is the most important part of the program,” Schmoll stated. Formal discussant of this trial, Gail Eckhardt, MD, University of Colorado at Denver, said, “Many trials show that the addition of oxaliplatin demonstrates improvement in DFS in stage III patients. Toxicity is an important determinant going forward. Diarrhea and hand-foot syndrome are concerning toxicities with oxaliplatin-containing regimens. We can assume the regimens [studied in this trial] are equivalent, and we need to move forward with integration of new agents. In stage III patients we need better predictive markers for response to oxaliplatin and ways to minimize toxicity.” She also said that the optimal duration of oxaliplatin therapy remains to be defined.