Systemic Therapy Options for Non–Small-Cell Lung Cancer in Patients with a Poor Performance Status

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Introduction

Although significant advances have been made in the systemic therapy of non–small-cell lung cancer (NSCLC) in patients with a good performance status (PS), the subgroup of patients with a poor PS has not been studied as well. Current guidelines are based primarily on extrapolation from other populations and small subgroup analyses of larger trial populations, with remarkably few direct data to shape treatment decisions. With cisplatin-based doublet chemotherapeutic regimens as a historic standard of care for patients with advanced NSCLC, those with a PS of 2 or higher on the Zubrod/ECOG (Eastern Cooperative Oncology Group) Scale (Table 1) were largely excluded from clinical trials on the basis of the presumption that they could not tolerate the toxicities of such aggressive systemic therapies.

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In recent years, however, systemic therapeutic options have become incrementally less toxic. Substitution of carboplatin for cisplatin in doublet regimens and introduction of the “third” generation of chemotherapeutic agents (vinorelbine, gemcitabine [Gemzar], paclitaxel, docetaxel [Taxotere], and pemetrexed [Alimta]) have made it possible to administer combination chemotherapy regimens in patients with advanced NSCLC and a poor PS. Finally, targeted therapies such as the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib (Iressa) and erlotinib (Tarceva) have emerged as particularly attractive options that might offer a survival benefit without the toxicities associated with conventional chemotherapy.

The study of patients with a poor PS and cancer in general, or NSCLC in particular, has been evolving rapidly over the past several years. Until just a few years ago, there were remarkably few studies dedicated to elderly and/or frail patients with NSCLC. Over the past 5 to 6 years, several trials emerged that focused initially on elderly patients (usually defined as 70 years or older), but these trials still disproportionately enrolled older patients with a favorable PS.

More recently, studies have targeted a population of patients who are either elderly or who have a PS of 2. These studies have consistently demonstrated that patients with a poor PS have a far worse overall survival (OS) than older patients with a good PS, highlighting that PS is far more predictive of outcome than chronologic age. Only in the past few years have studies that specifically focus on NSCLC patients with a PS of 2 been initiated; it is now recognized that this distinct subpopulation cannot be readily aggregated with elderly patients. Although some of our conclusions may be gleaned from subset analyses of PS2 patients from larger studies that primarily included patients with a good PS, there is the significant possibility of a selection bias that preferentially included PS2 patients capable of tolerating treatment protocols designed for patients with a favorable PS. Prospective trials designed for patients with NSCLC who have a poor PS are critically important to improve the outcomes in this population. This review will focus on the appropriate management of patients with advanced NSCLC who have a poor PS.