Disease-Free Survival Is Acceptable Surrogate for Overall Survival in Trials of Adjuvant Chemotherapy for Gastric Cancers
Disease-free survival is an acceptable surrogate for overall survival in trials of cytotoxic agents for gastric cancer in the adjuvant setting, the GASTRIC group concluded after conducting a meta-analysis of data from 3,288 individual patients enrolled in 14 randomized clinical trials. The trials compared adjuvant chemotherapy vs surgery alone for patients with curatively resected gastric cancer.
“Surrogacy of [disease-free survival] was assessed through the correlation between the endpoints as well as through the correlation between the treatment effects on the endpoints,” the authors explained in an article in the Journal of the National Cancer Institute.
While overall survival “is considered the gold standard endpoint” in investigations of the effectiveness of surgery and adjuvant chemotherapy for gastric cancers, using overall survival as the endpoint “requires an extended follow-up period,” the authors noted. In addition, “its measurement is potentially diluted by nonmalignant causes of death and therapies for recurrent/advanced disease.”
Association Between Disease-Free and Overall Survival
Results of the meta-analysis “show a very tight individual-level association between [disease-free survival] and [overall survival] (Spearman rank correlation coefficient = 0.974; 95% confidence interval = 0.971–0.976), indicating that in individual patients, [disease-free survival] is highly predictive of [overall survival]. The strong correlation between [the two endpoints] can be partly attributed to the short time from relapse to death in gastric cancer (median of < 12 months across all the included trials). Further, 16% of all the analyzed patients died without documented relapse and, therefore, had the same [disease-free survival and overall survival],” the researchers wrote.
A very high trial-level association between the effects of adjuvant chemotherapy on disease-free survival and overall survival “indicates that almost all of the variability in the treatment effects on [overall survival] can be explained by the treatment effects on [disease-free survival],” the authors added.
An external validation using data from six trials found that the “hazard ratios for [overall survival] predicted according to [disease-free survival] were in very good agreement with those actually observed for [overall survival],” the researchers reported.
Could Reduce Trial Duration and Costs
Depending on follow-up, using disease-free rather than overall survival as the primary endpoint in future clinical trials of adjuvant chemotherapies could reduce the duration of trials by 15% to 30%, as well as costs, according to the authors. They pointed out that since they only investigated cytotoxic agents, “future trials investigating agents with different mechanisms of actions, such as [targeted] therapy, will require separate validation of the surrogacy relation before it is applied routinely.”
Koji Oba, PhD, of Hokkaido University Hospital, Japan, is corresponding author of the Journal of the National Cancer Institute article.
The study was partially supported by the French Institut National du Cancer, the Clinical Research Support Unit, and the Epidemiological and Clinical Research Information Network. A meeting was supported financially by unrestricted grants from GlaxoSmithKline, but the funders were not involved in the analysis of the data and did not comment on the present paper. Dr. Oba was supported by the Banyu Fellowship Program, sponsored by the Banyu Life Science Foundation International.
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