Disease-Free Survival Is Acceptable Surrogate for Overall Survival in Trials of Adjuvant Chemotherapy

Get Permission

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,” 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.”

Results of the meta-analysis “show a very tight individual-level association between [disease-free 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 and overall survival],” the researchers wrote. 

A very high trial-level association between the effects of adjuvant chemotherapy on disease-free 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.

External Validation

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.

The project was initiated and partially funded by the French Institut National du Cancer. The GASTRC Group is international and includes representation from several U.S. medical centers. The corresponding author for the study is Koji Oba, PhD, of Hokkaido University Hospital in Sapporo, Japan.

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.” ■

Oba K, et al: J Natl Cancer Inst 105:1600-1607, 2013.