Lung Cancer: Advances and Controversies

Over the last several years we have witnessed significant changes in the way we view and treat lung cancer, driven by results of innovative and highly important studies. Malignancies of the lung are responsible for the majority of cancer-related deaths in the United States and worldwide, given their high prevalence and low cure rate. Therefore, any improvement in our understanding of this disease and in the therapies we are able to offer can result in substantial medical and social benefits.

Of paramount importance is understanding lung cancer etiology. We are all aware that factors in addition to tobacco exposure are responsible for the development of lung cancer, especially in cases of younger patients and life-time non-smokers. Based on studies performed at the Harvard School of Public Health, Drs. Geoffrey Liu, Wei Zhou, and David Christiani review the role of polymorphisms in genes: including the CYP and glutathione s-transferase superfamilies; genes that deal with DNA repair, such as XPD, XRCC1, and MGMT; and tumor suppressor genes, such as p53, in the individual's risk of developing lung cancer.

Therapy for lung cancer is an area that has witnessed great strides over the past decade. Dr. Renato Martins reviews the optimal therapy for locally advanced or stage III non-small cell lung cancer, which currently comprises 30% of all new diagnoses. This is an area of many controversies, but well-designed studies have shed light on several issues. We are all in agreement that combined modality therapy with the use of doublet chemotherapy and state-of-the-art radiation therapy is the standard of care, but the best way to deliver such therapy and the sequencing of these treatments remain unclear. The role of hyperfractionated radiation and treatment of the less common group of stage III patients on the basis of T4 tumors is also detailed. Drs. Majid Mohiuddin and Noah Choi, from the Radiation Oncology Department of the Massachusetts General Hospital, expand on the many different indications for radiation therapy in non-small cell lung cancer. They also discuss the toxicities of therapy: primarily esophagitis and pneumonitis, which clearly relate to the volume of lung-radiated, and also the addition of highly radio-sensitizing, modern chemotherapy.

Lung cancer is increasingly becoming a disease of the elderly. As thoracic oncologists, we have seen the median age of diagnosis increase from 65 to 70 years of age during the last decade. Drs. Lecia Sequist and Panos Fidias review in detail the available data on therapy for older patients with advanced lung cancer and also the tools that might help us better define the expected tolerance of these patients to our aggressive, standard of care regimens.

Platinum-based chemotherapy has been evaluated not only in late stages, but also in early lung cancer. A topic of significant controversy in the oncology community, adjuvant therapy was usually associated with negative trials and pessimism. However, we now have five positive randomized trials in patients with stages I (primarily IB), II, and resectable IIIa, the latest one presented at the 2005 meeting of the American Society of Clinical Oncology. The expected absolute survival benefit in 3-5 years post resection ranges from 5 to more than 10%, similar to breast and colon cancer adjuvant regimens. These studies are reviewed by Drs. Sarada Gurubhagavatula and Tom Lynch.

Studies on advanced lung cancer are detailed in the article by Dr. Tracey Evans of the University of Pennsylvania. The feeling of most oncologists, however, is that current chemotherapy has reached a therapeutic plateau, and emphasis is given on novel agents. Two such agents, both small molecule tyrosine-kinase inhibitors of the epidermal growth factor receptor (EGFR TKIs), have gained FDA approval for second- and third-line therapy. Gefitinib and erlotinib have also captured the attention of oncologists and patients alike because of the identification by groups in the Massachusetts General Hospital, Memorial Sloan Kettering, and Dana Farber Cancer Institute of activating mutations in the EGFR gene that predict for significant responses with the use of these agents. The timely topic of the factors predicting for responses to gefitinib and erlotinib is addressed by Drs. Jeff Engelman and Pasi Jänne.

Drs. Khanh Morrow and Edward Kim give us information on novel agents beyond the EGFR TKIs. The addition of the monoclonal antibody bevacizumab, which targets the vascular endothelial growth factor (VEGF), has shown a survival advantage over chemotherapy alone in the treatment of advanced NSCLC and has become the new standard of care according to investigators of the Eastern Oncology Cooperative Group. While non-small cell lung cancer is gaining more attention, progress has been slow for the 15% of patients presenting with small cell lung cancer. Drs. Christos Christodoulou and Dimosthenis Skarlos provide insight into the studies that established the current standard of care (combined early chemotherapy and radiation in limited stage disease, and combination platinum-topoisomerase chemotherapy in extensive stage disease). Finally, Drs. David Jackman, Lucian Chirieac, and Pasi Jänne discuss the unique characteristics and treatment of bronchioloalveolar carcinoma.

This issue of Seminars in Respiratory and Critical Care Medicine deals with the most important aspects of the new knowledge gathered over the last five years in lung cancer research and the questions that this knowledge raises for future directions. We hope that the readers find these reviews helpful in their daily practice.