The thoughtful paper by Weiss and colleagues highlights many of the important clinical and translational science advances of the past 2 decades that have shaped our knowledge and management approaches to non-small-cell lung cancer (NSCLC). The authors have chosen their topics of discussion carefully and have been cautious not to "overreach" in their assessment of realized gains vs persisting challenges. The acknowledgement that a trimodality approach in stage IIIA disease "cannot be recommended as standard" and the assessment that "the best [multimodality therapy approaches] in [stage IIIB disease] ... continue to be explored" are fair presentations of the current state of the art.
Several other issues might have been chosen for greater emphasis, but space is always the enemy of the engaged author. As a commentator, I will briefly discuss a few additional topics that may add modestly to the scope of the Weiss manuscript.
Lung Cancer in Women
As the authors note early in their paper, the American epidemic of lung cancer is driven in larger measure than ever before by new diagnoses in women. While the overwhelming etiologic agent in both women and men remains the self-administered, inhaled carcinogens of tobacco smoke, the resulting disease in women is different in many ways. The histology is more often adenocarcinoma, the age of onset is earlier, the frequency of "never smokers" (though not necessarily smoke-unexposed given the prevalence of secondhand smoke) is higher, and EGFR mutation frequency is increased.
Moreover, emerging evidence suggests that sensitivity to carcinogens is different in women than in men. The CYP1A1 gene product is associated with activation of inhaled procarcinogens. CYP1A1 gene expression in lung tissue is greater in female than in male smokers. At the same time, the absence of carcinogen-detoxifying enzymes such as GSTM1 may have greater effects in lung tissue in women.
As noted by Patel, "It is incumbent upon us to have a better understanding of the genetic, metabolic, and hormonal factors that affect the way women react to carcinogens and lung cancer. This information could affect the way patients who smoke are screened and evaluated as well as the way smoking cessation and lung cancer prevention programs are directed."
Endoesophageal/Endobronchial Ultrasound-Guided Staging
In their discussion of staging, the authors focus on the role of imaging and mediastinoscopy in the determination of operability. They also allude to the potential of video-assisted thoracic surgery (VATS) to reach additional lymph node stations. However, they fail to discuss two effective nonsurgical staging strategies—endoscopic (endoesophageal) ultrasound (EUS) with guided fine-needle aspiration (FNA) and endobronchial ultrasound (EBUS) with guided transbronchial FNA. These techniques have clear efficacy in assessing the extent of intrathoracic spread of lung cancer. Endoscopic ultrasound has been available for nearly 2 decades and is a staple of evaluation for esophageal, gastric, and pancreatic disease. For a variety of reasons, it is less widely applied to the evaluation of patients with lung cancer. EBUS has a substantially shorter track record but is increasingly practiced by interventional pulmonologists.
Both EUS and EBUS can be done in the outpatient setting using conscious sedation and offer increased accuracy over computed tomography (CT) and positron-emission tomography (PET). They each substantially increase the number of potentially sampled lymph node stations compared to cervical mediastinoscopy alone (ie, EUS enables sampling of nodal stations 5, 7, 8, 9; EBUS facilitates sampling of both right- and left-sided nodal stations 2, 4, 10, and 11, as well as level 7). In experienced hands, EUS can also be used to biopsy suspicious left adrenal masses, pericardial and left-sided pleural fluid, and even selected accessible liver lesions (B. Hoffman, personal communication).