Comparison of survival outcomes among cancer patients treated in and out of clinical trials

Abstract

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.

Figures

Figure 1.

Study identification flow diagram. One hundred two phase III SWOG studies were examined over the 25-year period from 1987 to 2011. Among these, 64 were excluded from further consideration, 33 because of early closure (of which 30 were closed early because of poor accrual, two were closed early because of changed relationship with the drug manufacturer, and one was a positive study based on progression-free survival), 12 were still active or recently closed, seven did not have upfront randomization, six had nonsurvival endpoints, and six were studies for recurrent disease. Of the 38 considered for comparison with Surveillance, Epidemiology, and End Results (SEER) registry data, 17 were excluded because SEER did not have essential staging criteria to replicate the SWOG study. In the end, 21 of 38 studies (55% of those considered for stage comparison) were identified.

Figure 2.

Horizontal barplots of the difference between Surveillance, Epidemiology, and End Results (SEER) and SWOG patients for each demographic and stage factor, in descending order of the absolute difference in percentages between SWOG and SEER cohorts. The SWOG percentage is also shown in each figure. Bars to the right of center indicate a higher proportion in SEER, and bars to the left of center indicate a higher proportion in SWOG.

Figure 3.

Forest plot of univariate and multivariable hazard ratios (HRs) for overall survival, by study, ordered in descending order of average 2-year overall survival. In univariate analyses, two of 11 (18%) good-prognosis studies and nine of 10 (90%) poor-prognosis studies showed evidence of a survival benefit for trial patients (P = .002 by Fisher exact test). In multivariable analyses, zero of 11 good-prognosis studies and nine of 10 poor-prognosis studies showed evidence of a survival benefit for trial patients (P < .001). AML = acute myeloid leukemia; NSCLC = non–small cell lung cancer; SCLC = small cell lung cancer.

Figure 4.

Overall survival and corresponding hazard functions for aggregate (equally weighted) study data by prognosis.

Figure 5.

Total, cancer-specific, and non-cancer-specific deaths by year of follow-up by prognosis. For each of the first 5 years, the proportion of patients experiencing death of any kind, cancer-specific death, and non-cancer-specific death relative to the number of patients at risk in each year is plotted for both SWOG and Surveillance, Epidemiology, and End Results (SEER) patients. Consistent with the Kaplan–Meier survival plots in Figure 4, the total event rate is notably lower in SWOG patients in the first year. In years 2 to 5, in contrast, the proportions of total events in SWOG and SEER patients are more similar and are decreasing as the risk of death decreases. For both good- and poor-prognosis patients, the pattern of a relatively lower event rate for SWOG patients in year 1 is mostly reflective of a diminished rate of cancer-related deaths in year 1; although non-cancer-related deaths are also lower in SWOG patients, this difference was small and relatively stable across all 5 years of follow-up. Indeed, in good-prognosis patients, the unweighted ratio of the rate of SEER cancer deaths to SWOG cancer deaths was 1.60 in year 1 but was less than one (only 0.78) in years 2 to 5. For non-cancer-specific deaths, the ratios are very similar whether in year 1 (1.57) or years 2 to 5 (1.52), indicating the pattern change over time occurs in cancer-related deaths only. A similar pattern held for poor-prognosis cancers. In summary, the difference in the patterns of death for trial vs nontrial patients between year 1 vs. years 2 to 5 is largely attributable to different patterns of cancer deaths.