Lung cancer is the leading cause of cancer death among women in the United States and other Western nations. The predominant cause of lung cancer in women is active cigarette smoking. Secondhand exposure to tobacco smoke is another important cause. The hypothesis that women are more susceptible than men to smoking-induced lung cancer has not been supported by the preponderance of current data, as noted by De Matteis et al. (Am J Epidemiol. 2013;177(7):601–612) in the accompanying article. However, aspects of lung cancer in men and women continue to indicate potential male-female differences in the etiology of lung cancer, based on several observations: 1) among never smokers, women have higher lung cancer incidence rates than men; 2) there is evidence that estrogen may contribute to lung cancer risk and progression; and 3) there are different clinical characteristics of lung cancer in women compared with men, such as the higher percentage of adenocarcinomas in never smokers, the greater prevalence of epidermal growth factor receptor gene (EGFR) mutations in adenocarcinomas among never smokers, and better prognosis. Considered in total, observations such as these offer enticing clues that, even amid cigarette smoking and other commonalities in the etiology of lung cancer in men and women, distinct differences may remain to be delineated that could potentially be of scientific and clinical relevance.
cigarettes; estrogen; lung cancer; men; secondhand smoke exposure; sex; smoking; women
The National Lung Screening Trial (NLST) used risk factors for lung cancer (e.g., ≥30 pack-years of smoking and <15 years since quitting) as selection criteria for lung-cancer screening. Use of an accurate model that incorporates additional risk factors to select persons for screening may identify more persons who have lung cancer or in whom lung cancer will develop.
We modified the 2011 lung-cancer risk-prediction model from our Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to ensure applicability to NLST data; risk was the probability of a diagnosis of lung cancer during the 6-year study period. We developed and validated the model (PLCOM2012) with data from the 80,375 persons in the PLCO control and intervention groups who had ever smoked. Discrimination (area under the receiver-operating-characteristic curve [AUC]) and calibration were assessed. In the validation data set, 14,144 of 37,332 persons (37.9%) met NLST criteria. For comparison, 14,144 highest-risk persons were considered positive (eligible for screening) according to PLCOM2012 criteria. We compared the accuracy of PLCOM2012 criteria with NLST criteria to detect lung cancer. Cox models were used to evaluate whether the reduction in mortality among 53,202 persons undergoing low-dose computed tomographic screening in the NLST differed according to risk.
The AUC was 0.803 in the development data set and 0.797 in the validation data set. As compared with NLST criteria, PLCOM2012 criteria had improved sensitivity (83.0% vs. 71.1%, P<0.001) and positive predictive value (4.0% vs. 3.4%, P = 0.01), without loss of specificity (62.9% and. 62.7%, respectively; P = 0.54); 41.3% fewer lung cancers were missed. The NLST screening effect did not vary according to PLCOM2012 risk (P = 0.61 for interaction).
The use of the PLCOM2012 model was more sensitive than the NLST criteria for lung-cancer detection.
In the National Lung Screening Trial (NLST), screening with low-dose computed tomography (CT) resulted in a 20% reduction in lung-cancer mortality among participants between the ages of 55 and 74 years with a minimum of 30 pack-years of smoking and no more than 15 years since quitting. It is not known whether the benefits and potential harms of such screening vary according to lung-cancer risk.
We assessed the variation in efficacy, the number of false positive results, and the number of lung-cancer deaths prevented among 26,604 participants in the NLST who underwent low-dose CT screening, as compared with the 26,554 participants who underwent chest radiography, according to the quintile of 5-year risk of lung-cancer death (ranging from 0.15 to 0.55% in the lowest-risk group [quintile 1] to more than 2.00% in the highest-risk group [quintile 5]).
The number of lung-cancer deaths per 10,000 person-years that were prevented in the CT-screening group, as compared with the radiography group, increased according to risk quintile (0.2 in quintile 1, 3.5 in quintile 2, 5.1 in quintile 3, 11.0 in quintile 4, and 12.0 in quintile 5; P = 0.01 for trend). Across risk quintiles, there were significant decreasing trends in the number of participants with false positive results per screening-prevented lung-cancer death (1648 in quintile 1, 181 in quintile 2, 147 in quintile 3, 64 in quintile 4, and 65 in quintile 5). The 60% of participants at highest risk for lung-cancer death (quintiles 3 through 5) accounted for 88% of the screening-prevented lung-cancer deaths and for 64% of participants with false positive results. The 20% of participants at lowest risk (quintile 1) accounted for only 1% of prevented lung-cancer deaths.
Screening with low-dose CT prevented the greatest number of deaths from lung cancer among participants who were at highest risk and prevented very few deaths among those at lowest risk. These findings provide empirical support for risk-based targeting of smokers for such screening. (Funded by the National Cancer Institute.)
Clinical practice guidelines are important evidence-based resources to guide complex clinical decision making. However, it is challenging for health professionals to keep abreast available guidelines and to know how and where to access relevant guidelines. This review examines currently available guidelines for lung cancer published in the English language. Important key features are listed for each identified guideline. The methodology, approaches to dissemination and implementation, and associated resources are summarised. General challenges in the area of guideline development are highlighted. The potential to collaborate more widely across lung cancer guideline developers by sharing literature searches and assessments is discussed.
Clinical practice guidelines; clinical practice guideline development; evidence-based medicine; lung neoplasms; non-small cell lung carcinoma; small cell lung carcinoma
Tobacco use behaviors have changed significantly over the past century. Compared to 1964, smoking prevalence rates have halved from 40% to 20% and as a result there has been a slow but steady decline in the rates of tobacco-induced diseases such as heart disease and cancer. Growing awareness of the health risks of smoking were aided by the United States Surgeon Reports which were issued on a nearly annual basis starting in 1964. Concerns about the hazards of breathing in secondhand smoke pollution further contributed to the declining social acceptance of smoking, which evolved into regulatory actions restricting smoking on buses, planes, retail outlets, restaurants and bars. Today, 23 states and 493 localities have comprehensive laws restricting indoor smoking. This paper examines public policies that have made a significant impact on smoking and lung cancer rates and discusses potential future research directions to further reduce the diseases caused by smoking.
Tobacco control; Tobacco policy; Lung Cancer; Tobacco taxation; Clean Air Laws
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.
Epidermal growth factor receptor (EGFR); Kirsten rat sarcoma viral oncogene homolog (KRAS); molecular testing; personalized medicine; tyrosine kinase inhibitors; non-small cell lung cancer
Stage IIIA non-small cell lung cancer (NSCLC) is comprised of a heterogeneous group of patients with predominant ipsilateral mediastinal (N2) disease. The spectrum of lymph node presentation has lead to a host of trials involving various therapeutic combinations and optimal management has been unclear.
In 2007 and 2008, ten live research events surveyed the practice preferences of American medical oncologists using two hypothetical scenarios. The first scenario was of a stage IIIA NSCLC in the right upper lobe with a single enlarged (>1cm) 4R lymph node found to be malignant by mediastinoscopy. The second was of a bulky stage IIIA NSCLC with multi-station N2 pathologically positive nodes.
In the first secenario, 373 (92%) of the oncologists incorporated surgery into their treatment plan. Only 34 (8%) offered chemoradiotherapy alone. Neoadjuvant chemotherapy, followed by surgery, then additional chemoradiotherapy (32%) was the most commonly offered treatment strategy. In the second scenario, 209 (52%) medical oncologists chose definitive chemoradiation. 193(48%) included surgery as part of the treatment plan.
The current standard of care for IIIA N2 NSCLC recognized prior to treatment is concurrent chemoradiotherapy. This study demonstrated that a significant proportion of oncologists treating locally advanced lung cancer include surgery in as part of the treatment plan more so in single versus multi-nodal station disease. Since node positive locally advanced disease is such a common presentation for patients with lung cancer, well-designed clinical trials are needed to define the most advantageous treatment strategy for individual subsets of patients with Stage IIIA disease.
lung cancer; treatment; surgery; VATS; elderly
No high-quality study to date has shown that screening reduces lung cancer mortality, and expert groups do not recommend screening for asymptomatic individuals. Nevertheless, lung cancer screening tests are available in the U.S., and primary care physicians (PCPs) may have a role in recommending them to patients.
This study describes U.S. PCPs’ beliefs about and recommendations for lung cancer screening, and examines characteristics of PCPs who recommend screening.
A nationally representative survey of practicing PCPs was conducted in 2006–2007. Mailed questionnaires assessed PCPs’ beliefs about lung cancer screening guidelines and the effectiveness of screening tests, and whether PCPs would recommend screening for asymptomatic patients. Data were analyzed in 2009.
Nine hundred and sixty-two PCPs completed the survey (absolute response rate=70.6%; cooperation rate=76.8%). One quarter said that major guidelines support lung cancer screening. Two thirds said that low–radiation dose spiral CT (LDCT) is very or somewhat effective in reducing lung cancer mortality in current smokers; LDCT was perceived as more effective than chest × ray or sputum cytology. Responding to vignettes describing asymptomatic patients of varying smoking exposure, 67% of PCPs recommended lung cancer screening for at least one of the vignettes. Most PCPs recommending screening said they would use chest × ray; up to 26% would use LDCT. In adjusted analyses, PCPs’ beliefs and practice style were strongly associated with their lung cancer screening recommendations.
Many PCPs’ lung cancer screening beliefs and recommendations are inconsistent with current evidence and guidelines. Provider education regarding lung cancer screening’s evidence base and guideline content is indicated.
With advances in technology, detection of small pulmonary nodules is increasing. Nodule detection software (NDS) has been developed to assist radiologists with pulmonary nodule diagnosis. Although it may increase sensitivity for small nodules, often there is an accompanying increase in false-positive findings. We designed a study to examine the extent to which computed tomography (CT) NDS influences the confidence of radiologists in identifying small pulmonary nodules.
Materials and Methods
Eight radiologists (readers) with different levels of experience examined thoracic CT scans of 131 cases and identified all the clinically relevant pulmonary nodules. The reference standard was established by an expert, dedicated thoracic radiologist. For each nodule, the readers recorded nodule size, density, location, and confidence level. Two weeks (or more) later, the readers reinterpreted the same scans; however, this time they were provided marks, when present, as indicated by NDS and asked to reassess their level of confidence. The effect of NDS on changes in reader confidence was assessed using multivariable generalized linear regression models.
A total of 327 unique nodules were identified. Declines in confidence were significantly (P<0.05) associated with the absence of an NDS mark and smaller nodules (odds ratio=71.0, 95% confidence interval =14.8–339.7). Among nodules with pre-NDS confidence less than 100%, increases in confidence were significantly (P<0.05) associated with the presence of an NDS mark (odds ratio=6.0, 95% confidence interval =2.7–13.6) and larger nodules. Secondary findings showed that NDS did not improve reader diagnostic accuracy.
Although in this study NDS does not seem to enhance reader accuracy, the confidence of the radiologists in identifying small pulmonary nodules with CT is greatly influenced by NDS.
clinical decision making; computed tomography scan; diagnostic imaging; lung neoplasm; diagnostic errors
Fospropofol disodium is a water-soluble prodrug of propofol. A subset analysis was undertaken of elderly patients (≥65 y) undergoing flexible bronchoscopy, who were part of a larger multicenter, randomized, double-blind study.
Patients received fentanyl citrate (50 mcg) followed by fospropofol at initial (4.88mg/kg) and supplemental (1.63mg/kg) doses. The primary end point was sedation success (3 consecutive Modified Observer's Assessment of Alertness/Sedation scores of ≤4 and procedure completion without alternative sedative or assisted ventilation). Treatment success, time to fully alert, patient and physician satisfaction, and safety/tolerability were also evaluated.
In the elderly patients subset (n=61), sedation success was 92%, the mean time to fully alert was 8.0±10.9 min, and memory retention was 72% during recovery, and these were comparable with the younger patients subgroup (age, <65 y). Sedation-related adverse events occurred in 23% of the elderly and 18% of the younger patients (age, <65 y) group. Hypoxemia occurred in 26% of the elderly and 18% of the younger patients group, but no escalation of care was required.
Fospropofol provided safe and effective sedation, rapid time to fully alert, and high satisfaction in this elderly subset undergoing flexible bronchoscopy, which was comparable with outcomes in younger patients.
bronchoscopy; elderly; fospropofol; sedation
This study was designed to identify nurses' perspectives on nursing skills that are important yet under-utilized in end-of-life care.
A 45-item survey was administered to nurses (n = 717) in four U.S. states with a response rate of 79%. We identified skills that were endorsed by more than 60% of nurses as extremely important and also endorsed as not currently practiced by more than 25% of nurses. We used Chi square statistics to examine professional characteristics associated with ratings of end-of-life care skills including practice settings, years of experience, and end-of-life care education. Content analysis was used to examine nurses' responses to open-ended questions.
Nineteen items were endorsed as extremely important and also ranked as under-utilized. These end-of-life care skills included communication skills, symptom management competencies especially those concerning anxiety and depression, and issues related to patient-centered care systems. Four complementary themes emerged from qualitative analysis of nurses' comments, which supported the quantitative findings.
This study provides a summary of skills nurses feel are important and under-utilized in their care of patients with life-limiting illnesses. The findings support the need to target both nursing education and healthcare system interventions to improve the use of practical end-of-life care skills by nurses with a focus on communication and symptom management skills.
Lung cancer is the leading cause of cancer-related death worldwide. At the time of initial presentation, most patients are at an advance stage of disease and have a poor associated prognosis. Those diagnosed and treated at earlier stages have a significantly better outcome with 5-year survival for stage I disease approaching 75%. Ideally a screening strategy for lung cancer would detect disease at an earlier stage and allow for potential surgical cure. The purpose of this review is to examine past and current evidence as it relates to lung cancer screening.
lung cancer; screening; national lung cancer screening trial; chest radiograph; computed tomography
Little is known about the natural history of malignant solitary pulmonary nodules (SPN). Experts’ beliefs may help fill these knowledge gaps and explain variation in clinical practices.
Using a modified Delphi process, we surveyed a group of lung cancer experts about tumor growth, disease progression and prognosis in patients with malignant SPN. After completing the first survey, experts were given the opportunity during a second survey to revise their responses in light of their peers’ beliefs.
The response rate was 100% (14/14) for both surveys. There was consensus that disease progression depends on the tumor growth rate, that survival for patients with untreated lung cancer is approximated by a declining exponential function, and that treatment is delayed by approximately 1 tumor volume doubling time (TVDT) in patients who undergo a period of “watchful waiting”. Just over half of experts (8/14) agreed that lung cancer progresses in 3steps (from local to regional to distant disease), while 43% (6/14) preferred a 2-step model (from local to systemic disease). Likewise, 64% of experts (9/14) believed that malignant nodules grow exponentially, while 36% (5/14) believed that growth is slower than exponential. Experts’ estimates of the risk of disease progression during a period of observation lasting 1 TVDT varied from 1% to 50%. Estimates of 5-year survival for patients in whom diagnosis and treatment were delayed by 1 TVDT varied between 40% and 80%.
There is substantial variability in experts’ beliefs about the natural history of untreated, malignant SPN. Different beliefs may be partly responsible for variation in management practices.
Lung Neoplasms; Coin lesion; pulmonary; Delphi technique; survival; disease progression; tumor growth
Effective strategies for managing patients with solitary pulmonary nodules (SPN) depend critically on the pre-test probability of malignancy.
To validate two previously developed models that estimate the probability that an indeterminate solitary pulmonary nodule (SPN) is malignant, based on clinical characteristics and radiographic findings.
We retrospectively collected data on age, smoking and cancer history, nodule size, location, and spiculation from the medical records of 151 veterans (145 men, 6 women; range 39 to 87 years) with an SPN measuring 7 to 30 mm (inclusive) and a final diagnosis established by histopathology or 2-year follow-up. We compared each patient's final diagnosis to the probability of malignancy predicted by two models: one developed by investigators at the Mayo Clinic and another that we developed from patients enrolled in a VA Cooperative Study. We assessed model accuracy by calculating areas under the receiver operating characteristic (ROC) curve and model calibration by comparing predicted and observed rates of malignancy.
The area under the ROC curve for the Mayo Clinic model (0.80; 95% CI 0.72-0.88) was higher than that of the VA model (0.73; 95% CI 0.64-0.82), but this difference was not statistically significant (P=0.10). Calibration curves showed that the probability of malignancy was underestimated by the Mayo Clinic model and overestimated by the VA model.
Two existing prediction models are sufficiently accurate to guide decisions about the selection and interpretation of subsequent diagnostic tests in patients with SPNs, although clinicians should also consider the prevalence of malignancy in their practice setting when choosing a model.
Lung Neoplasms; Coin Lesion; pulmonary; Diagnosis; Models; statistical; Receiver Operating Characteristic (ROC) curve
In recent years, there has been a rapid growth in diagnostic and therapeutic procedures performed by respirologists.
To assess the number and type of procedures performed in Canadian respirology training programs, for comparison with the American College of Chest Physicians minimum competency guidelines, and to assess fellow satisfaction with procedural training during their fellowships.
Internet-based surveys of Canadian respirology fellows and respirology fellowship program directors were conducted.
Response rates for program director and respirology fellow surveys were 71% (10 of 14) and 62% (41 of 66), respectively. Thirty-eight per cent of respirology fellows reported the presence of an interventional pulmonologist at their institution. Flexible bronchoscopy was the only procedure reported by a large majority of respirology fellows (79.5%) to meet American College of Chest Physicians recommendations (100 procedures). As reported by respirology fellows, recommended numbers of procedures were met by 59.5% of fellows for tube thoracostomy, 21% for transbronchial needle aspiration and 5.4% for closed pleural biopsy. Respirology fellows in programs with an interventional pulmonologist were more likely to have completed some form of additional interventional bronchoscopy training (80% versus 32%; P=0.003), had increased exposure to and expressed improved satisfaction with training in advanced diagnostic and therapeutic procedures, but did not increase their likelihood of achieving recommended numbers for any procedures.
Canadian respirology fellows perform lower numbers of basic respiratory procedures, other than flexible bronchoscopy, than that suggested by the American College of Chest Physicians guidelines. Exposure and training in advanced diagnostic and therapeutic procedures is minimal. A concerted effort to improve procedural training is required to improve these results.
Bronchoscopy; Education; Needle biopsy; Pulmonary training; Respirology
There has been resurgence of interest in lung cancer screening using low‐dose computed tomography. The implications of directing a screening programme at smokers has been little explored.
A nationwide telephone survey was conducted. Demographics, certain clinical characteristics and attitudes about screening for lung cancer were ascertained. Responses of current, former and never smokers were compared.
2001 people from the US were interviewed. Smokers were significantly (p<0.05) more likely than never smokers to be male, non‐white, less educated, and to report poor health status or having had cancer, and less likely to be able to identify a usual source of healthcare. Compared with never smokers, current smokers were less likely to believe that early detection would result in a good chance of survival (p<0.05). Smokers were less likely to be willing to consider computed tomography screening for lung cancer (71.2% (current smokers) v 87.6% (never smokers) odds ratio (OR) 0.48; 95% confidence interval (CI) 0.32 to 0.71). More never smokers as opposed to current smokers believed that the risk of disease (88% v 56%) and the accuracy of the test (92% v 71%) were important determinants in deciding whether to be screened (p<0.05). Only half of the current smokers would opt for surgery for a screen‐diagnosed cancer.
The findings suggest that there may be substantial obstacles to the successful implementation of a mass‐screening programme for lung cancer that will target cigarette smokers.
Objective: To determine how patients with lung cancer value the trade off between the survival benefit of chemotherapy and its toxicities.
Design: Scripted interviews that included three hypothetical scenarios. Each scenario described the same patient with metastatic non-small cell lung cancer with an expected survival of 4 months without treatment. Subjects were asked to indicate the minimum survival benefit required to accept the side effects of chemotherapy in the first two scenarios (mild toxicity and severe toxicity). In the third scenario, subjects were asked to choose between chemotherapy and supportive care when the benefit of chemotherapy was either to prolong life by 3 months or to palliate symptoms.
Subjects: 81 patients previously treated with cis-platinum based chemotherapy for advanced non-small cell lung cancer.
Main outcome measure: Survival threshold for accepting chemotherapy.
Results: The minimum survival threshold for accepting the toxicity of chemotherapy varied widely in patients. Several patients would accept chemotherapy for a survival benefit of 1 week, while others would not choose chemotherapy even for a survival benefit of 24 months. The median survival threshold for accepting chemotherapy was 4.5 months for mild toxicity and 9 months for severe toxicity. When given the choice between supportive care and chemotherapy only 18 (22%) patients chose chemotherapy for a survival benefit of 3 months; 55 (68%) patients chose chemotherapy if it substantially reduced symptoms without prolonging life.
Conclusions: Patients’ willingness to accept chemotherapy for the treatment of metastatic lung cancer varies widely. Many would not choose chemotherapy for its likely survival benefit of 3 months but would if it improved quality of life. The conflict between these patients’ preferences and the care they previously received has several explanations, one being that some patients had not received the treatment they would have chosen had they been fully informed.
Key messagesThe median survival of patients with metastatic non-small cell lung cancer is improved by about 3 months with the addition of chemotherapyLung cancer patients who had had chemotherapy were interviewed in this study to learn about their treatment preferences with a range of survival benefitsSeveral patients would choose chemotherapy for a survival benefit of as little as 1 week, while others would not choose chemotherapy even when offered a survival benefit of 24 monthsMost patients would not choose chemotherapy for its likely survival benefit of 3 months, but would if it improved quality of lifeSome patients with lung cancer may not be getting the treatment they would choose were they fully informed