Twenty-seven years of phase III trials for patients with extensive disease small-cell lung cancer: disappointing results

Abstract

Background: Few studies have formally assessed whether treatment outcomes have improved substantially over the years for patients with extensive disease small-cell lung cancer (ED-SCLC) enrolled in phase III trials. The objective of the current investigation was to determine the time trends in outcomes for the patients in those trials.

Methods and findings: We searched for trials that were reported between January 1981 and August 2008. Phase III randomized controlled trials were eligible if they compared first-line, systemic chemotherapy for ED-SCLC. Data were evaluated by using a linear regression analysis.

Results: In total, 52 trials were identified that had been initiated between 1980 and 2006; these studies involved 10,262 patients with 110 chemotherapy arms. The number of randomized patients and the proportion of patients with good performance status (PS) increased over time. Cisplatin-based regimens, especially cisplatin and etoposide (PE) regimen, have increasingly been studied, whereas cyclophosphamide, doxorubicin, and vincristine-based regimens have been less investigated. Multiple regression analysis showed no significant improvement in survival over the years. Additionally, the use of a PE regimen did not affect survival, whereas the proportion of patients with good PS and the trial design of assigning prophylactic cranial irradiation were significantly associated with favorable outcome.

Conclusions and significance: The survival of patients with ED-SCLC enrolled in phase III trials did not improve significantly over the years, suggesting the need for further development of novel targets, newer agents, and comprehensive patient care.

Figure 1. Flow chart showing the progress of trials through the review.

Figure 2. Trends in trial characteristics.

These charts show the associations between year of trial initiation and number of randomized patients (A), proportion of patients with good PS (B), and proportion of male patients (C) in each trial. The size of solid circles represents data weighted on the basis of the number of randomized patients. Abbreviations: PS, performance status.

Figure 3. Relationship between year of trial initiation and median survival time.

Analysis was weighted by the number of randomized patients. Each trial is represented by a circle; the size of each circle is proportional to the sample size of randomized patients in the given trial.