Emerging Advances in the Management of Lung Cancer

Abstract

Surgery has been the accepted standard of care for early-stage non–small-cell lung cancer (NSCLC). However, the great majority of patients with lung cancer will experience disease recurrence despite the complete surgical resection of visible tumor, presumably as a result of the presence of undetectable micrometastases. The theoretical basis of adjuvant or neoadjuvant chemotherapy or radiation therapy is to provide a more complete annihilation of cancer cells than can be achieved solely with surgical removal of tumor tissue. For many years, studies of adjuvant therapy failed to show any survival benefit, as discussed by Drs. Scagliotti and Novello. Despite the skepticism expressed by the authors, recent studies using platinum/cytotoxic agent combinations have reported significant and favorable results with adjuvant therapy.1-3 Surgical resection followed by adjuvant chemotherapy is the new standard of care for patients with stages IB, II, and IIIA NSCLC. Areas for future clinical trials include randomized comparisons between neoadjuvant and adjuvant chemotherapy, establishment of optimal chemotherapy schedules and custom therapies based on patient and tumor characteristics, and further investigation of targeted molecular agents. Emerging data are demonstrating the feasibility of systemic therapy in elderly patients and those patients with a compromised performance status (PS). Conventional chemotherapy, even with newer-generation agents such as paclitaxel, can cause significant and debilitating side effects. Langer describes the advantage of a polymer–drug conjugate, CT-2103 (Xyotax™), designed to improve the therapeutic index and tolerability of paclitaxel. Conjugation of paclitaxel to a polymer results in significant passive tumor targeting by enhanced permeability and retention. The CT-2103 conjugate is associated with a lower frequency and severity of toxic events compared with paclitaxel and provides prolonged tumor drug exposure. Patients with poor PS are well suited for treatment with agents such as CT-2103. Until recently, the management of patients with poor PS in clinical practice has been empirical and inconsistent, as stated by Lilenbaum, but these patients do derive benefit from firstline chemotherapy with respect to symptom improvement and perhaps overall survival as well. The CT-2103 conjugate may extend benefits of chemotherapy to special populations such as elderly patients and those with poor PS. The results of the STELLAR™ 2, 3, and 4 trials are therefore eagerly awaited. Targeted agents, primarily the epidermal growth factor receptor (EGFR) inhibitors, have led to a new era in the treatment of patients with NSCLC. Laskin discusses the significance of bronchoalveolar carcinoma (BAC) as a useful model to explore the best use of these agents. Bronchoalveolar carcinoma is a unique subset of NSCLC, and treatment with an EGFR inhibitor may be a reasonable first-line intervention for patients with advanced BAC. Ongoing and upcoming clinical trials will attempt to answer questions that have been raised on the use and application of new agents, such as: How do EGFR inhibitors compare with chemotherapy for patients with BAC? What is the role of monoclonal antibodies against the EGFR for the treatment of BAC? Can chemotherapy be combined with EGFR inhibitors for patients with BAC? The discovery of mutations in the EGFR will facilitate selection of patients for therapy with EGFR tyrosine kinase inhibitors (TKIs). Kim focuses on the monoclonal antibody cetuximab and its incorporation into the treatment of NSCLC. The data from trials in which monoclonal antibodies are used in combination with chemotherapy for advanced NSCLC suggest that monoclonal antibodies against the EGFR may be more suited to combination with chemotherapy than with EGFR TKIs. The proteasome plays a critical role in the degradation of proteins involved in the regulation of the cell cycle, apoptosis, and angiogenesis. Bortezomib is a proteasome inhibitor approved for use in multiple myeloma. It targets pathways relevant to tumor progression and can directly modulate the expression of cyclins, p27kip1, p53, nuclear factor–κB, Bcl-2, and Bax. Bortezomib is just beginning to be explored, based on documented single-agent activity in patients with NSCLC, as described by Schenkein. This will be an excellent agent to combine with other targeted therapies. Strategies to develop patient-specific therapies using cetuximab, bortezomib, and other targeted agents include pharmacogenomics, molecular markers like gene mutations, and clinical characteristics. Ultimately, patient-specific therapies for NSCLC will achieve the goal of significantly improved patient outcomes.