The "lazarus response" in treatment-naive, poor performance status patients with non-small-cell lung cancer and epidermal growth factor receptor mutation.

In a series of more than 500 non–small-cell lung cancer (NSCLC) patients evaluated by Cella and colleagues in quality of life studies, the prevalence of poor performance status (PS; 2 to 4) among lung cancer patients was 34% when estimated by providers and 48% when determined by patients themselves; these findings strongly suggest that physicians and nurses tend to underestimate the degree of compromise in PS. Unfortunately, there is no standard therapy in advanced NSCLC patients with very poor performance status (PS 3 to 4). Median survival (MS) without therapy, which is the norm, is typically fewer than 2 to 3 months in such individuals, whether the compromise in PS is due to disease burden or comorbidity. The optimal nature of treatment for PS 2 patients with advanced NSCLC remains controversial. Data from prospective phase III trials isolating the role of platinum suggest an improvement in survival for those receiving third generation platinum-based combinations compared to the constituent, nonplatinum single agent. Lilenbaum et al, in a phase III trial, isolated the role of carboplatin in combination with paclitaxel compared to single-agent paclitaxel. They demonstrated an increase in survival for PS 2 patients receiving the combination, but the results were still dismal: 4.7 months MS for those receiving the combination compared to 2.4 months for those receiving single-agent therapy with 1-year survival rates of 19% and 10%, respectively. Virtually no PS 2 patients were alive on the single-agent arm at 2 years. More recent studies suggest that modern combination regimens may be able to generate MS times of 6 to 8 months in PS 2 individuals, but seldom higher. In Eastern Cooperative Oncology Group (ECOG) 2598, chemotherapy-naive PS 2 patients with advanced NSCLC receiving either dose-attenuated paclitaxel and carboplatin or gemcitabine and cisplatin realized MS of 6.2 and 6.9 months, respectively, with 1-year survival rates of 19% and 25%. A much larger phase III trial enrolling more than 400 patients and restricted to a PS 2 population evaluated carboplatin in combination with either paclitaxel or polyglutamated paclitaxel. The results from this trial— and, to date, the “best” results in this population—showed a MS of 7.9 months and 8.0 months, respectively, for standard versus polyglutamated paclitaxel and identical 1-year survival rates of 31%. Baseline comorbidities and anticipated toxicities are a major impediment to more aggressive therapy in poor PS patients with NSCLC. For example, work by LeChevalier et al comparing vinorelbine, either alone or in combination with cisplatin, to vindesine and cisplatin, not only failed to demonstrate a significant survival advantage in PS 2 patients receiving the cisplatin and vinorelbine combination, but also showed substantially more severe toxicity compared to the single agent. Current trials are emphasizing the role of less toxic agents in the PS 2 population; but none to date, with the exception of the work by Inoue and colleagues, highlighted in this issue of the Journal of Clinical Oncology, have assessed customized therapy based on epidermal growth factor receptor (EGFr) mutation status.