Locally advanced non-small cell lung cancer: do we know the questions? A survey of randomized trials from 1966-1993.

Background: Substantial lack of consensus exists regarding the appropriate management of patients with locally advanced non-small cell lung cancer (NSCLC). The purpose of the present study was to investigate why published clinical trials have not resolved this uncertainty, and to examine the potential of current randomized studies to resolve the major controversies regarding the treatment of locally advanced NSCLC.
Methods: A literature search identified papers addressing the therapy of locally advanced NSCLC published in the English language from January 1966 through May 1993. The treatment modalities studied in these trials were recorded. The CD-ROM Physician Data Query database was used to identify ongoing studies in NSCLC. For phase III trials in stage III NSCLC, the treatment modalities, eligibility criteria, outcome measures, and statistical considerations were recorded.
Results: A total of 164 reports of phase III trials were identified, representing 11% of the 1516 publications meeting search criteria. A wide range of comparisons have been reported; the number of study arms, the number of different modalities employed as control arms, and the number of modalities employed as investigational arms increased over time. Eighteen active phase III protocols open to patients with stage III NSCLC were identified. In trials which enrolled patients with stage IIIB disease, therapy in control arms employed six different strategies of surgery, radiation, or chemotherapy, alone or in combination, and investigational arms were equally heterogeneous. Variation was also present in the spectrum of disease stages studied, in patient eligibility criteria, and in the clinical outcome measures investigated. The magnitude of improvement in survival sought was varied in its absolute magnitude, in the selection of survival probability for the control arm, and in the time point of its evaluation.
Implications: We demonstrated diversity in research practice reflected in five major types of variation: (i) selection of control arms, (ii) selection of study investigational arms, (iii) choice of eligibility criteria, (iv) outcome measures selected for study, and (v) type and magnitude of benefit sought in the primary outcome measure. This variation has important implications regarding the inability of these studies to address some fundamental management controversies, and the ability to generalize the results of these trials to the general population of NSCLC patients. This diversity reflects a poorly defined process for setting the goals of clinical research. The generation of future trials may be improved by strategies that identify the most important controversies, identify important outcome measures, improve consensus among physicians, and provide the opportunity to incorporate patients' preferences in this clinical situation.