Nichole T. Tanner

Lung cancer: progress in diagnosis, staging and therapy.

Lung cancer remains one of the greatest medical challenges with nearly 1.5 million new cases worldwide each year and a growing tobacco epidemic in the developing world. This review summarizes briefly the current status in growing areas of clinical research. The value of screening for early disease is not yet established and trials to see if mortality can be improved as a result are in progress. Better and more accurate staging will both streamline investigation and prove cost‐effective once ultrasound‐guided biopsy and aspiration of mediastinal nodes become universally accepted. This, allied to the new staging classification, will improve selection of cases for surgery, intensive multimodality therapy and for adjuvant treatment postoperatively. Much still needs to be done to refine staging as within a particular stage group, the outcome shows great variation. More information is needed on the genetic make‐up in some groups of tumours and not just their size; that is, more biological data on tumour growth patterns are likely to be at least as discriminating. The place of the stem cell theory of tumorigenesis is also explored in this paper. Finally, targeted therapy for advanced non‐small‐cell lung cancer is highlighted as a development with early promise, but still much clarification is required, before it can be considered as a universal approach in late disease.

An official American Thoracic Society/American College of Chest Physicians policy statement: implementation of low-dose computed tomography lung cancer screening programs in clinical practice.

RATIONALE Annual low-radiation-dose computed tomography (LDCT) screening for lung cancer has been shown to reduce lung cancer mortality among high-risk individuals and is now recommended by multiple organizations. However, LDCT screening is complex, and implementation requires careful planning to ensure benefits outweigh harms. Little guidance has been provided for sites wishing to develop and implement lung cancer screening programs. OBJECTIVES To promote successful implementation of comprehensive LDCT screening programs that are safe, effective, and sustainable. METHODS The American Thoracic Society (ATS) and American College of Chest Physicians (ACCP) convened a committee with expertise in lung cancer screening, pulmonary nodule evaluation, and implementation science. The committee reviewed the evidence from systematic reviews, clinical practice guidelines, surveys, and the experience of early-adopting LDCT screening programs and summarized potential strategies to implement LDCT screening programs successfully. MEASUREMENTS AND MAIN RESULTS We address steps that sites should consider during the main three phases of developing an LDCT screening program: planning, implementation, and maintenance. We present multiple strategies to implement the nine core elements of comprehensive lung cancer screening programs enumerated in a recent ACCP/ATS statement, which will allow sites to select the strategy that best fits with their local context and workflow patterns. Although we do not comment on cost-effectiveness of LDCT screening, we outline the necessary costs associated with starting and sustaining a high-quality LDCT screening program. CONCLUSIONS Following the strategies delineated in this policy statement may help sites to develop comprehensive LDCT screening programs that are safe and effective.

Implementation of Lung Cancer Screening in the Veterans Health Administration

Importance The US Preventive Services Task Force recommends annual lung cancer screening (LCS) with low-dose computed tomography for current and former heavy smokers aged 55 to 80 years. There is little published experience regarding implementing this recommendation in clinical practice. Objectives To describe organizational- and patient-level experiences with implementing an LCS program in selected Veterans Health Administration (VHA) hospitals and to estimate the number of VHA patients who may be candidates for LCS. Design, Setting, and Participants This clinical demonstration project was conducted at 8 academic VHA hospitals among 93 033 primary care patients who were assessed on screening criteria; 2106 patients underwent LCS between July 1, 2013, and June 30, 2015. Interventions Implementation Guide and support, full-time LCS coordinators, electronic tools, tracking database, patient education materials, and radiologic and nodule follow-up guidelines. Main Outcomes and Measures Description of implementation processes; percentages of patients who agreed to undergo LCS, had positive findings on results of low-dose computed tomographic scans (nodules to be tracked or suspicious findings), were found to have lung cancer, or had incidental findings; and estimated number of VHA patients who met the criteria for LCS. Results Of the 4246 patients who met the criteria for LCS, 2452 (57.7%) agreed to undergo screening and 2106 (2028 men and 78 women; mean [SD] age, 64.9 [5.1] years) underwent LCS. Wide variation in processes and patient experiences occurred among the 8 sites. Of the 2106 patients screened, 1257 (59.7%) had nodules; 1184 of these patients (56.2%) required tracking, 42 (2.0%) required further evaluation but the findings were not cancer, and 31 (1.5%) had lung cancer. A variety of incidental findings, such as emphysema, other pulmonary abnormalities, and coronary artery calcification, were noted on the scans of 857 patients (40.7%). Conclusions and Relevance It is estimated that nearly 900 000 of a population of 6.7 million VHA patients met the criteria for LCS. Implementation of LCS in the VHA will likely lead to large numbers of patients eligible for LCS and will require substantial clinical effort for both patients and staff.

Using Endobronchial Ultrasound Features to Predict Lymph Node Metastasis in Patients With Lung Cancer

PURPOSES Reliable staging of the mediastinum determines TNM classification and directs therapy for non-small cell lung cancer (NSCLC). Our aim was to evaluate predictors of mediastinal lymph node metastasis in patients undergoing endobronchial ultrasound (EBUS). METHODS Patients with known or suspected lung cancer undergoing EBUS for staging were included. Lymph node radiographic characteristics on chest CT/PET scan and ultrasound characteristics of size, shape, border, echogenicity, and number were correlated with rapid on-site evaluation (ROSE) and final pathology. Logistic regression (estimated with generalized estimating equations to account for correlation across nodes within patients) was used with cancer (vs normal pathology) as the outcome. ORs compare risks across groups, and testing was performed with two-sided α of 0.05. RESULTS Two hundred twenty-seven distinct lymph nodes (22.5% positive for malignancy) were evaluated in 100 patients. Lymph node size, by CT scan and EBUS measurements, and round and oval shape were predictive of mediastinal metastasis. Increasing size of lymph nodes on EBUS was associated with increasing malignancy risk (P = .0002). When adjusted for CT scan size, hypermetabolic lymph nodes on PET scan did not predict malignancy. Echogenicity and border contour on EBUS and site of biopsy were not significantly associated with cancer. In 94.8% of lymph nodes with a clear diagnosis, the ROSE of the first pass correlated with subsequent passes. CONCLUSIONS Lymph node size on CT scan and EBUS and round or oval shape by EBUS are predictors of malignancy, but no single characteristic can exclude a visualized lymph node from biopsy. Further, increasing the number of samples taken is unlikely to significantly improve sensitivity.

Management of Pulmonary Nodules by Community Pulmonologists: A Multicenter Observational Study

BACKGROUND: Pulmonary nodules (PNs) are a common reason for referral to pulmonologists. The majority of data for the evaluation and management of PNs is derived from studies performed in academic medical centers. Little is known about the prevalence and diagnosis of PNs, the use of diagnostic testing, or the management of PNs by community pulmonologists. METHODS: This multicenter observational record review evaluated 377 patients aged 40 to 89 years referred to 18 geographically diverse community pulmonary practices for intermediate PNs (8-20 mm). Study measures included the prevalence of malignancy, procedure/test use, and nodule pretest probability of malignancy as calculated by two previously validated models. The relationship between calculated pretest probability and management decisions was evaluated. RESULTS: The prevalence of malignancy was 25% (n = 94). Nearly one-half of the patients (46%, n = 175) had surveillance alone. Biopsy was performed on 125 patients (33.2%). A total of 77 patients (20.4%) underwent surgery, of whom 35% (n = 27) had benign disease. PET scan was used in 141 patients (37%). The false-positive rate for PET scan was 39% (95% CI, 27.1%-52.1%). Pretest probability of malignancy calculations showed that 9.5% (n = 36) were at a low risk, 79.6% (n = 300) were at a moderate risk, and 10.8% (n = 41) were at a high risk of malignancy. The rate of surgical resection was similar among the three groups (17%, 21%, 17%, respectively; P = .69). CONCLUSIONS: A substantial fraction of intermediate-sized nodules referred to pulmonologists ultimately prove to be lung cancer. Despite advances in imaging and nonsurgical biopsy techniques, invasive sampling of low-risk nodules and surgical resection of benign nodules remain common, suggesting a lack of adherence to guidelines for the management of PNs.

Lung Cancer Screening

The United States Preventive Services Task Force recommends lung cancer screening with low-dose computed tomography (LDCT) in adults of age 55 to 80 years who have a 30 pack-year smoking history and are currently smoking or have quit within the past 15 years. This recommendation is largely based on the findings of the National Lung Screening Trial. Both policy-level and clinical decision-making about LDCT screening must consider the potential benefits of screening (reduced mortality from lung cancer) and possible harms. Effective screening requires an appreciation that screening should be limited to individuals at high risk of death from lung cancer, and that the risk of harm related to false positive findings, overdiagnosis, and unnecessary invasive testing is real. A comprehensive understanding of these aspects of screening will inform appropriate implementation, with the objective that an evidence-based and systematic approach to screening will help to reduce the enormous mortality burden of lung cancer.

The Utility of Nodule Volume in the Context of Malignancy Prediction for Small Pulmonary Nodules

BACKGROUND An estimated 150,000 pulmonary nodules are identified each year, and the number is likely to increase given the results of the National Lung Screening Trial. Decision tools are needed to help with the management of such pulmonary nodules. We examined whether adding any of three novel functions of nodule volume improves the accuracy of an existing malignancy prediction model of CT scan-detected nodules. METHODS Swensens 1997 prediction model was used to estimate the probability of malignancy in CT scan-detected nodules identified from a sample of 221 patients at the Medical University of South Carolina between 2006 and 2010. Three multivariate logistic models that included a novel function of nodule volume were used to investigate the added predictive value. Several measures were used to evaluate model classification performance. RESULTS With use of a 0.5 cutoff associated with predicted probability, the Swensen model correctly classified 67% of nodules. The three novel models suggested that the addition of nodule volume enhances the ability to correctly predict malignancy; 83%, 88%, and 88% of subjects were correctly classified as having malignant or benign nodules, with significant net improved reclassification for each (P<.0001). All three models also performed well based on Nagelkerke R2, discrimination slope, area under the receiver operating characteristic curve, and Hosmer-Lemeshow calibration test. CONCLUSIONS The findings demonstrate that the addition of nodule volume to existing malignancy prediction models increases the proportion of nodules correctly classified. This enhanced tool will help clinicians to risk stratify pulmonary nodules more effectively.

The Association between Smoking Abstinence and Mortality in the National Lung Screening Trial

RATIONALE Smoking is the largest contributor to lung cancer risk, and those who continue to smoke after diagnosis have a worse survival. Screening for lung cancer with low-dose computed tomography (LDCT) reduces mortality in high-risk individuals. Smoking cessation is an essential component of a high-quality screening program. OBJECTIVES To quantify the effects of smoking history and abstinence on mortality in high-risk individuals who participated in the NLST (National Lung Screening Trial). METHODS This is a secondary analysis of a randomized controlled trial (NLST). MEASUREMENTS AND MAIN RESULTS Measurements included self-reported demographics, medical and smoking history, and lung cancer-specific and all-cause mortality. Cox regression was used to study the association of mortality with smoking status and pack-years. Kaplan-Meier survival curves were examined for differences in survival based on trial arm and smoking status. Current smokers had an increased lung cancer-specific (hazard ratio [HR], 2.14-2.29) and all-cause mortality (HR, 1.79-1.85) compared with former smokers irrespective of screening arm. Former smokers in the control arm abstinent for 7 years had a 20% mortality reduction comparable with the benefit reported with LDCT screening in the NLST. The maximum benefit was seen with the combination of smoking abstinence at 15 years and LDCT screening, which resulted in a 38% reduction in lung cancer-specific mortality (HR, 0.62; 95% confidence interval, 0.51-0.76). CONCLUSIONS Seven years of smoking abstinence reduced lung cancer-specific mortality at a magnitude comparable with LDCT screening. This reduction was greater when abstinence was combined with screening, highlighting the importance of smoking cessation efforts in screening programs.

The role of molecular analyses in the era of personalized therapy for advanced NSCLC

Platinum-based doublet chemotherapy is the traditional treatment of choice for advanced non-small cell lung cancer (NSCLC); however, the efficacy of these regimens has reached a plateau. Increasing evidence demonstrates that patients with sensitizing mutations in the epidermal growth factor receptor (EGFR) experience improved progression-free survival and response rates with first-line gefitinib or erlotinib therapy relative to traditional platinum-based chemotherapy, while patients with EGFR-mutation negative tumors gain greater benefit from platinum-based chemotherapy. These results highlight the importance of molecular testing prior to the initiation of first-line therapy for advanced NSCLC. Routine molecular testing of tumor samples represents an important paradigm shift in NSCLC therapy and would allow for individualized therapy in specific subsets of patients. As these and other advances in personalized treatment are integrated into everyday clinical practice, pulmonologists will play a vital role in ensuring that tumor samples of adequate quality and quantity are collected in order to perform appropriate molecular analyses to guide treatment decisions. This article provides an overview of clinical trial data supporting molecular analysis of NSCLC, describes specimen acquisition and testing methods currently in use, and discusses future directions of personalized therapy for patients with NSCLC.

Racial Differences in Outcomes within the National Lung Screening Trial. Implications for Widespread Implementation

RATIONALE Black individuals with lung cancer (LC) experience higher mortality because they present with more advanced disease and are less likely to undergo curative resection for early-stage disease. The National Lung Screening Trial (NLST) demonstrated improved LC mortality by screening high-risk patients with low-dose computed tomography (LDCT). The benefit of LDCT screening in black individuals is unknown. OBJECTIVES Examine results of the NLST by race. METHODS This was a secondary analysis of a randomized trial (NCT00047385) performed in 33 U.S. centers. MEASUREMENTS AND MAIN RESULTS Overall and lung cancer-specific mortality were measured. Screening with LDCT reduced LC mortality in all racial groups but more so in black individuals (hazard ratio [HR], 0.61 vs. 0.86). Smoking increased the likelihood of death from LC, and when stratified by race black smokers were twice as likely to die as white smokers (HR, 4.10 vs. 2.25). Adjusting for sociodemographic and behavioral characteristics, black individuals experienced higher all-cause mortality than white individuals (HR, 1.35; 95% confidence interval, 1.22-1.49); however, black individuals screened with LDCT had a reduction in all-cause mortality. Black individuals were younger, were more likely to be current smokers, had more comorbidities, and had fewer years of formal education than white individuals (P < 0.05). CONCLUSIONS Black individuals screened with LDCT had decreased mortality from lung cancer. However, the demographics associated with improved LC survival were less commonly found in black individuals. The overall mortality in the NLST was higher for black individuals than white individuals, but improved in black individuals screened, suggesting that this subgroup may have had improved access to care. To realize the reductions in mortality from LC screening, dissemination efforts need to be tailored to meet the needs of this community.