Lung Cancer: Evolving Concepts

David E. Midthun, M.D. Julian R. Molina, M.D., Ph.D.

Those of us in the business of diagnosing and treating lung cancer are used to thinking and writing about the devastating impact lung cancer is having on our patients daily. But when it comes to changing the gravity of that impact, we most often focus our sights on what might be possible tomorrow. There is now considerable good news for lung cancer patients today.

In 2011 there will be ~157,000 deaths from lung cancer in the United States. That is the equivalent of a fully loaded 747 crashing daily—with no survivors. Smoking rates have leveled off at ~20% of the adult population; though primary prevention remains key, early detection and more effective treatments will be the other cornerstones to saving lives from this disease.

In this issue of Seminars in Respiratory and Critical Care Medicine, Drs. Etzel and Bach discuss risk prediction models that can be used to identify individuals at highest risk who may benefit most from screening methods, and to identify those who might be the focus of further screening studies. Smoking has been identified as the greatest risk; however, up to 10 to 15% of lung cancer occurs in never smokers. Dr. Yang investigates lung cancer in never smokers and describes temporal trends and environmental risk factors. She also addresses the role of chronic lung disease and infection as risk factors as well as the effect of lifestyle as either a risk or a protective factor.

Pathology is critical to the diagnosis and directs the proper treatment of lung cancer. Drs. Travis and Rekhtman discuss the evolving issues in pathology and provide a helpful framework for the nonpathologist clinician to understanding the current stains used to identify variations in histology. Approaching lung cancer biology on a different level, Drs. Gomperts, Dubinett, and colleagues examine lung carcinogenesis from the standpoint of genetic mutations and epigenetic changes. Their review covers the latest concepts in the pathogenesis of lung cancer and highlights the roles of inflammation, field cancerization, and stem cells in the initiation of the disease. They also provide insight into the genomics, transcriptomics, epigenomics, and proteomics of lung carcinogenesis and how these advances may lead to chemoprevention strategies and therapy for lung cancer.

A recent monumental effort by the International Association for the Study of Lung Cancer (IASLC) resulted in the seventh edition of the tumor, node, and metastasis (TNM) classification for lung cancer. The multinational process was based on the analyses of a database of over 81,000 patients diagnosed with lung cancer between 1990 and 2000 that were used to validate the TNM descriptors. Drs. Rami-Porta, Bolejack, and Goldstraw review the process and results that better match prediction of stage-related prognosis for non-small-cell carcinoma, small-cell carcinoma, and carcinoid tumor. The emergence of ultrasound-guided needle aspiration of mediastinal nodes has furthered the quest for accurate staging information in a nonsurgical fashion. Dr. Arenberg provides a review of bronchioloalveolar carcinoma (BAC) and focuses on the unique epidemiological, clinical, and radiological features. He also discusses the revised nomenclature for BAC proposed by an expert panel and how this may change our view of this particular histology. Dr. Herth discusses the approach to mediastinal lymph nodes adjacent to the esophagus by transesophageal ultrasound-guided fine-needle aspiration (EUS-FNA) and the airway by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). These methods may provide complementary information, and recent studies suggest that complete and accurate mediastinal staging can be achieved by the combination of both procedures effectively eliminating the need for surgical staging.

Surgical resection remains the most effective treatment of early-stage non-small-cell lung cancer (NSCLC), and in a subset of advanced disease, chemotherapy and/or radiation therapy followed by surgical resection may be appropriate. Drs. Tomaszek and Wigle discuss the role of surgery in primary and neoadjuvant treatment as well as recent refinements in modern surgical techniques. The role of postoperative chemotherapy (adjuvant chemotherapy) in improving long-term survival appears clear for resected stage II to IIIA NSCLC. However, only one third of patients with NSCLC present with early-stage disease that is amenable to potentially curative resection. Drs. Reungwetwattana, Eadens, and Molina discuss chemotherapy in these adjuvant and neoadjuvant settings as well as for unresectable disease in stages IIIB and IV. There are several targeted agents such as inhibitors of vascular endothelial growth factor, epidermal growth factor receptor (EGFR), or tyrosine kinase that may allow an individualized treatment regimen for potential responders. Dr. Kalemkerian evaluates the approach to small-cell lung cancer (SCLC) in limited stage and discusses the issues of chemotherapy plus concurrent thoracic radiation and prophylactic cranial irradiation. Treatment of extensive-stage SCLC disease is reviewed with discussion of newer cytotoxic agents and the promise of molecularly targeted therapy. Finally Drs. Campbell and Kindler discuss malignant pleural mesothelioma. They review the unique issues that treatment of this tumor presents and highlight the role of histology in determining prognosis as well as the potential for surgical and chemotherapeutic intervention.

Exciting news has just been released from the National Lung Screening Trial (NLST). The NLST involved over 50,000 current or former smokers with 30 pack-years, ages 55 to 74. Participants were randomized between low-dose spiral computed tomography (CT) and chest x-ray at baseline, 1 year, and 2 years and then followed for 5 years. The initial results of this trial were released and revealed a reduction in lung cancer mortality with CT screening.[1] There were 354 lung cancer deaths among those in the CT arm versus 442 deaths among those in the chest x-ray arm, indicating a 20.3% reduction with CT screening. This announcement by the National Cancer Institute in November 2010 is the first indication that any test can reduce deaths from lung cancer. This is tremendously exciting news and we await publication of the data in the coming months as well as to see how CT screening is to be implemented within the care of our patients. We anticipate that many lives will be saved through screening. In addition, the identification of lung cancers carrying EGFR activating mutations and translocations of the anaplastic lymphoma kinase (ALK) gene and the development of highly active targeted agents such as erlotinib and crizotinib open the possibility of turning lung cancer from an acutely progressive process into a chronic disease.

We sincerely thank each of the authors who has contributed to this issue of Seminars in Respiratory and Critical Care Medicine dedicated to the evolving concepts in lung cancer.

REFERENCE

• 1 National Cancer Institute .National Lung Screening Trial: Questions and Answers. Available at: http://www.cancer.gov/newscenter/qa/2002/nlstqaQA/print?page=&keyword= Accessed December 4, 2010