Newer Cytotoxic and Targeted Agents Are Advancing the Treatment of Lung Cancer

Abstract

Non–small-cell lung cancer (NSCLC) accounts for about 80% of all cases of lung cancer diagnosed in the United States.1 Approximately one third of the patients with NSCLC have advanced disease at the time of diagnosis.2 Such patients are not candidates for surgical resection or definitive combined modality therapy. The treatment of advanced NSCLC has continued to evolve over recent years. We have moved from an era of therapeutic nihilism to optimism, largely due to the advent of the newer cytotoxic agents such as the gemcitabine, taxanes, vinorelbine, and irinotecan developed in the 1990s, which have complemented the platinum compounds for the treatment of advanced NSCLC.3-8 Doublet chemotherapy combinations have become the current standard of care for patients with advanced NSCLC who have a good performance status. Noncytotoxic, molecularly targeted agents that are currently under various phases of development for the treatment of lung cancer will serve as the cornerstones for further innovations in the treatment of NSCLC. In this supplement, the role of gemcitabine, pemetrexed (Alimta®), and LY900003 (formerly ISIS 3521) in the management of lung cancer has been reviewed in detail. Martin J. Edelman, MD, discusses the development of the gemcitabine/carboplatin regimen for first-line treatment of patients with advanced NSCLC. Gemcitabine in combination with carboplatin has a better therapeutic index when compared to its combination with cisplatin. It is a suitable regimen for adding selective/targeted therapies. Surgery and radiation have shown more curative potential than chemotherapy, but these therapies are successful primarily during early disease stages. Gemcitabine is a potent radiosensitizer. Corey J. Langer, MD, concludes after an extensive review that gemcitabine at doses of 180-300 mg/m 2 /week or 35 mg/m 2 twice weekly concurrently with thoracic radiotherapy can be administered without significant esophagitis/pneumonitis. There is minimal potential for radiation recall when gemcitabine regimens are administered after the acute effects of radiation have resolved. Socinski et al outline the incorporation of gemcitabine-based doublets in the management of early-stage resectable NSCLC. The activity as measured by response rate in early-stage NSCLC is high (53%-70%). As we increase our understanding of NSCLC, systemic therapy along with local modalities of treatment may provide a benefit with increased potential for cure. Alex A. Adjei, MD, PhD, provides an in-depth review of the data with pemetrexed in this supplement. Pemetrexed is a novel multitargeted antifolate, which, in combination with cisplatin, has shown provocative activity in mesothelioma and thus will soon be approved by the US Food and Drug Administration for the management of this disease. It has also shown evidence of activity in NSCLC as a single agent and with either gemcitabine or cisplatin. Davies and colleagues discuss the current status of development of antisense oligonucleotides with emphasis on the role of LY900003 for lung cancer. LY900003 is directed against protein kinase C–α and, in combination with chemotherapy, has shown considerable efficacy against advanced NSCLC.9 The development of other antisense molecules for lung cancer, eg, ISIS 3521, oblimersen, GTI-321, GTI-2040, and GTI-2501 is still in its infancy, and there is a continued search for new antisense targets. Chiappori and Rocha-Lima have reviewed the data with gemcitabine in small-cell lung cancer (SCLC). Gemcitabine combinations demonstrate comparable results to those of standard therapies in patients with extensive-stage SCLC. The gemcitabine/paclitaxel and gemcitabine/topoisomerase I inhibitor combinations have generated some enthusiasm but await future testing in randomized phase III trials. These are fairly well tolerated, and the efficacy requires further confirmation. The development and implementation of chemotherapeutic cancer therapy facilitated unprecedented therapeutic accomplishments during the 20th century. It is becoming increasingly evident that the current methods of chemotherapy are nearing their maximum levels of efficacy and that it may be time for a fundamental change in the approach to cancer therapy: a shift toward more specific, targeted therapeutic techniques. Novel targeted therapies are currently under evaluation and hold the hope for the future.