Comparison of Survival Outcomes Among Cancer Patients Treated in and out of Clinical Trials

Joseph M. Unger; William E. Barlow; Diane P. Martin; Scott D. Ramsey; Michael LeBlanc; Ruth Etzioni; Dawn L. Hershman


J Natl Cancer Inst. 2014;106(3) 

In This Article

Abstract and Introduction


Background. Clinical trials test the efficacy of a treatment in a select patient population. We examined whether cancer clinical trial patients were similar to nontrial, "real-world" patients with respect to presenting characteristics and survival.

Methods. We reviewed the SWOG national clinical trials consortium database to identify candidate trials. Demographic factors, stage, and overall survival for patients in the standard arms were compared with nontrial control subjects selected from the Surveillance, Epidemiology, and End Results program. Multivariable survival analyses using Cox regression were conducted. The survival functions from aggregate data across all studies were compared separately by prognosis (≥50% vs <50% average 2-year survival). All statistical tests were two-sided.

Results. We analyzed 21 SWOG studies (11 good prognosis and 10 poor prognosis) comprising 5190 patients enrolled from 1987 to 2007. Trial patients were younger than nontrial patients (P < .001). In multivariable analysis, trial participation was not associated with improved overall survival for all 11 good-prognosis studies but was associated with better survival for nine of 10 poor-prognosis studies (P < .001). The impact of trial participation on overall survival endured for only 1 year.

Conclusions. Trial participation was associated with better survival in the first year after diagnosis, likely because of eligibility criteria that excluded higher comorbidity patients from trials. Similar survival patterns between trial and nontrial patients after the first year suggest that trial standard arm outcomes are generalizable over the long term and may improve confidence that trial treatment effects will translate to the real-world setting. Reducing eligibility criteria would improve access to clinical trials.


Randomized cancer clinical trials represent a final step in evaluating the efficacy of new treatments. However, few adult cancer patients participate in trials (<3%) in the United States.[1,2] Reasons for low rates of clinical trial participation are numerous.[3–5] Trials may not be available for patients willing to participate, or when they are available, patients are often excluded because they do not meet trial eligibility criteria.[6–9]

Trial eligibility criteria must satisfy two opposing factors.[10] They must be sufficiently narrow to establish a homogeneous sample, so the effect of treatment is roughly consistent across the cohort. Eligibility criteria that are too broad risk including patients for which the treatment is not optimal, which could mask the overall treatment effect. Eligibility should also be sufficiently broad that the results are generalizable. One possible difference between trial and nontrial patients is that trial eligibility criteria rule out poor-prognosis patients with prior comorbid conditions. Yet if the trial cohort is otherwise representative of the general cancer population with respect to cancer histology and stage, any differences in survival induced by ruling out poor-prognosis patients may not endure over time.

Despite attempts by clinical trialists to establish equipoise between homogeneity and generalizability, clinical trials are sometimes criticized for sacrificing generalizability.[11] To assess generalizability in a systematic fashion, we evaluated whether presenting characteristics and survival outcomes for patients on the standard arms of a series of randomized phase III cancer clinical trials were representative of outcomes in patients receiving non–clinical trial treatment.