Chemotherapy for Advanced Stage Non-Small Cell Lung Cancer Amir T. Fathi, MD, and Julie R. Brahmer, MD, MSc Non-small cell lung cancer (NSCLC) is a common, often fatal malignancy, and is most frequently diagnosed in the advanced stage. Systemic chemotherapy for advanced (Stage IIIB and IV), inoperable NSCLC has evolved over the course of the last few decades. Survival advantage was first noted with platinum chemotherapy, with ultimate development of platinum-containing doublet combinations, which have now become standard of care in the treatment of advanced NSCLC. Over the course of the last few years, multiple nonplatinum combinations have also been demonstrated to be efficacious, and the addition of bevacizumab to existing doublet regimens has improved outcomes in this population of patients. Maintenance regimens for advanced stage NSCLC are currently under extensive investigation. Clinical trials have also recently demonstrated increased efficacy for agents such as docetaxel and pemetrexed in the second line setting for refractory disease. Semin Thorac Cardiovasc Surg 20:210-216 © 2008 Elsevier Inc. All rights reserved. KEYWORDS non-small cell lung cancer, systemic therapy, advanced stage, combination che- motherapy T he majority of non-small cell lung cancers are diagnosed at advanced stages, either as inoperable stage III or stage IV malignancies. Stage IV non-small cell lung cancer (NSCLC), the cytotoxic treatments for which this article will attempt to outline and summarize, has a uniformly dismal prognosis and is considered incurable. 1 The mainstay of treatment for this group of patients is systemic chemother- apy. Until the 1990s, the role of chemotherapy in advanced stage NSCLC was debatable. Treatments were often quite toxic and initial attempts at using alkylating chemotherapeu- tic agents actually adversely affected survival in patients. 2 Beginning in the 1980s, platinum-based therapies were stud- ied extensively in randomized trials and though response rates were often low, these treatment regimens did seem to improve symptom control and quality of life. Meta-analyses of these trials ultimately displayed a survival advantage in patients though these were often modest, with a median sur- vival of 16 to 26 weeks and 1 year survival rates of about 15% to 25%. 2 The low response rates achieved with first generation plat- inum-based regimens prompted a search for newer, more effective agents and combinations in the treatment of ad- vanced stage NSCLC. The chemotherapeutic agents studied during this period were the taxanes, paclitaxel and docetaxel, the antimetabolite, gemcitabine, the topoisomerase I inhibi- tor, irinotecan, and a vinca alkaloid, vinorelbine. These single agents provided objective rates of 20% or higher in meta- analyses of phase II and III trials. 2 Cisplatin or carboplatin in combination with these agents have become the standard of care. No one regimen has been found to be superior. How- ever, the regimens differ in their administration schedules and toxicities. Chemotherapy for Advanced NSCLC: Combination Regimens The eventual emergence of next generation combination reg- imens significantly impacted the standard of care for patients with NSCLC. Two randomized trials compared cisplatin- based doublets versus single agent cisplatin therapy. One trial demonstrated a higher response rate with a vinorelbine/ cisplatin combination as opposed to lone cisplatin (26% ver- sus 12%) with a significant median overall survival advantage for the combination (8 months versus 6 months). 3 The other trial compared gemcitabine and cisplatin with single agent The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bal- timore, Maryland. Address reprint requests to Julie R. Brahmer, MD, MSc, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Bunting-Blaustein Cancer Research Building, Room G94, 1650 Orleans Street, Baltimore, MD 21231-1000. E-mail: brahmju@jhmi.edu 210 1043-0679/08/$-see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1053/j.semtcvs.2008.09.002