Six randomized trials34–39,52–55 that have compared various treatment regimens for patients with advanced disease have included an analysis of HRQOL measurements and treatment outcomes Two of these trials52–53 used the FACT-L questionnaire, and both confirmed the prognostic significance of the baseline FACT-L for overall survival. In the ECOG 5592 trial,53 high baseline scores on the physical well-being and trial outcome index subscales of the FACT-L questionnaire were also significant predictors of both response to treatment and time to disease progression and overall survival. Likewise, in the SWOG 9509 trial,52 patients with a total FACT-L score of ≤ 98 (median FACT-L score) had a significantly worse survival compared with those with higher scores (p = 0.003), and the baseline total FACT-L score remained a significant prognostic factor in the multivariate model even when treatment arm, PS, weight loss (< 5%/≥ 5%), stage (IIIB/IV), and lactate dehydrogenase were considered. Of the three trials35,39,52 that used the EORTC QLQ-C30 questionnaire, two trials35,52 confirmed the prognostic significance of the baseline QOL for survival in multivariate models. In the Multicenter Italian Lung Cancer in the Elderly Study,52 overall QOL was the most significant prognostic factor for survival in the multivariate analysis (p = 0.0003), followed by PS (p = 0.006), number of disease sites (p = 0.02), and instrumental activities of daily living (p = 0.04). Similarly, in the Big Lung Trial,35 global QOL was a significant prognostic factor in the multivariate model (p = 0.009), but other subscales and symptoms were also identified, including role functioning (p = 0.026), fatigue (p = 0.013), appetite loss (p = 0.023), and constipation (p = 0.0003). In the third trial56 that used the EORTC QLQ-C30 questionnaire, QOL subscales including pain (p < 0.0001), appetite loss (p = 0.048), fatigue (p = 0.020), lung cancer symptoms (p = 0.049), level of physical functioning (p = 0.051), and overall QOL (p = 0.026) were significant predictors of survival in the univariate analysis. However, in the multivariate model, only the European Organization for Research and Cancer Treatment pain subscale (p = 0.020) added any prognostic information to the clinical factors that were identified (nonadenocarcinoma histology, albumin < 3.5 mg/dL).