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Background The optimal screening policy for lung cancer is unknown. Objective To identify efficient CT-screening scenarios where relatively more lung cancer deaths are averted for fewer CT screens. Design Comparative modeling study using 5 independent models. Data Sources The National Lung Screening Trial, the Prostate, Lung, Colorectal and Ovarian trial, the Surveillance, Epidemiology, and End Results program, and U.S. Smoking History Generator. Target Population U.S. cohort born in 1950. Time Horizon Cohort followed from ages 45 to 90. Perspective Societal. Intervention 576 scenarios with varying eligibility criteria (age, smoking pack-years, years quit) and screening intervals. Outcome Measures Benefits: lung cancer deaths averted or life-years gained; harms: CT-exams, false positives (including biopsy/surgery), overdiagnosed cases, radiation-related deaths. Results of Best-Case Annual screening from age 55 through 80 for ever-smokers with at least 30 pack-years and ex-smokers with less than 15 years since quitting was the most advantageous strategy. It would lead to 50% (45 to 54%) of cancers being detected at an early stage (I/II); 575 screens per lung cancer death averted; a 14% (8.2 to 23.5%) lung cancer mortality reduction; 497 lung cancer deaths averted; and 5,250 life-years gained per the 100,000-member cohort. Harms would include 67,550 false-positive tests, 910 biopsies or surgeries for benign lesions and 190 overdiagnosed cancers (3.7%; 1.4 to 8.3%). Results of Sensitivity Analysis The number of cancer deaths averted for the scenario varied across models between 177 and 862, and for overdiagnosed cancers between 72 and 426. Limitations Scenarios assumed 100% screening adherence. Data derived from trials with short duration were extrapolated to life-time follow-up. Conclusion Annual CT screening for lung cancer has a favorable benefit-harm ratio for individuals aged 55 through 80 years with 30 or more pack-year exposure to smoking.

IMPORTANCE The US Preventive Services Task Force (USPSTF) is updating its 2013 lung cancer screening guidelines, which recommend annual screening for adults aged 55 through 80 years who have a smoking history of at least 30 pack-years and currently smoke or have quit within the past 15 years. OBJECTIVE To inform the USPSTF guidelines by estimating the benefits and harms associated with various low-dose computed tomography (LDCT) screening strategies. DESIGN, SETTING, AND PARTICIPANTS Comparative simulation modeling with 4 lung cancer natural history models for individuals from the 1950 and 1960 US birth cohorts who were followed up from aged 45 through 90 years. EXPOSURES Screening with varying starting ages, stopping ages, and screening frequency. Eligibility criteria based on age, cumulative pack-years, and years since quitting smoking (risk factor-based) or on age and individual lung cancer risk estimation using risk prediction models with varying eligibility thresholds (risk model-based). A total of 1092 LDCT screening strategies were modeled. Full uptake and adherence were assumed for all scenarios. MAIN OUTCOMES AND MEASURES Estimated lung cancer deaths averted and life-years gained (benefits) compared with no screening. Estimated lifetime number of LDCT screenings, false-positive results, biopsies, overdiagnosed cases, and radiation-related lung cancer deaths (harms). RESULTS Efficient screening programs estimated to yield the most benefits for a given number of screenings were identified. Most of the efficient risk factor-based strategies started screening at aged 50 or 55 years and stopped at aged 80 years. The 2013 USPSTF-recommended criteria were not among the efficient strategies for the 1960 US birth cohort. Annual strategies with a minimum criterion of 20 pack-years of smoking were efficient and, compared with the 2013 USPSTF-recommended criteria, were estimated to increase screening eligibility (20.6%-23.6% vs 14.1% of the population ever eligible), lung cancer deaths averted (469-558 per 100 000 vs 381 per 100 000), and life-years gained (6018-7596 per 100 000 vs 4882 per 100 000). However, these strategies were estimated to result in more false-positive test results (1.9-2.5 per person screened vs 1.9 per person screened with the USPSTF strategy), overdiagnosed lung cancer cases (83-94 per 100 000 vs 69 per 100 000), and radiation-related lung cancer deaths (29.0-42.5 per 100 000 vs 20.6 per 100 000). Risk model-based vs risk factor-based strategies were estimated to be associated with more benefits and fewer radiation-related deaths but more overdiagnosed cases. CONCLUSIONS AND RELEVANCE Microsimulation modeling studies suggested that LDCT screening for lung cancer compared with no screening may increase lung cancer deaths averted and life-years gained when optimally targeted and implemented. Screening individuals at aged 50 or 55 years through aged 80 years with 20 pack-years or more of smoking exposure was estimated to result in more benefits than the 2013 USPSTF-recommended criteria and less ...

BackgroundLung cancer (LC) incidence in the United States (US) continues to decrease but with significant differences by histology, gender and race. Whereas squamous, large and small cell carcinoma rates have been decreasing since the mid-80s, adenocarcinoma rates remain stable in males and continue to increase in females, with large racial disparities. We analyzed LC incidence trends by histology in the US with an emphasis on gender and racial differences.MethodsLC incidence rates from 1973–2010 were obtained from the SEER cancer registry. Age-adjusted incidence trends of five major histological types by gender and race were evaluated using joinpoint regression. Trends of LC histology and stage distributions from 2005–2010 were analyzed.ResultsUS LC incidence varies by histology. Squamous, large and small cell carcinoma rates continue to decrease for all gender/race combinations, whereas adenocarcinoma rates remain relatively constant in males and increasing in females. An apparent recent increase in the incidence of squamous cell carcinoma and adenocarcinoma since 2005 can be explained by a concomitant decrease in the number of cases classified as other non-small cell carcinoma. Black males continue to be disproportionally affected by squamous LCs, and blacks continue to be diagnosed with more advanced cancers than whites.ConclusionsLC incidence by histology continues to change over time. Additional variations are expected as screening becomes disseminated. It is important to continue to monitor LC rates to evaluate the impact of screening on current trends, assess the continuing benefits of tobacco control, and focus efforts on reducing racial disparities.

The observation that the age-specific incidence curve of many carcinomas is approximately linear on a double logarithmic plot has led to much speculation regarding the number and nature of the critical events involved in carcinogenesis. By a consideration of colorectal and pancreatic cancers in the Surveillance Epidemiology and End Results (SEER) registry we show that the log-log model provides a poor description of the data, and that a much better description is provided by a multistage model that predicts two basic phases in the age-specific incidence curves, a first exponential phase until the age of ≈60 followed by a linear phase after that age. These two phases in the incidence curve reflect two phases in the process of carcinogenesis. Paradoxically, the early-exponential phase reflects events between the formation (initiation) of premalignant clones in a tissue and the clinical detection of a malignant tumor, whereas the linear phase reflects events leading to initiated cells that give rise to premalignant lesions because of abrogated growth/differentiation control. This model is consistent with Knudson's idea that renewal tissue, such as the colon, is converted into growing tissue before malignant transformation. The linear phase of the age-specific incidence curve represents this conversion, which is the result of recessive inactivation of a gatekeeper gene, such as the APC gene in the colon and the CDKN2A gene in the pancreas.colorectal | pancreatic | multistage carcinogenesis | neoplastic progression | Knudson's "two-hit" hypothesis T he precise shape of the age-specific incidence of various cancers, especially of nonembryonal solid tumors, and what information can be gleaned from their behavior, is still subject to scientific debate. A widely held view, put forward independently by Muller (1) and Nordling (2) and which reflects the basis of the Armitage-Doll model (3), conceives the stepwise progression of normal cells to cancer as a multistage process involving a number of rate-limiting (epi)genetic events. When viewed at the population level, this assumption uniquely defines the mathematical shape of the age-specific incidence of a cancer, also reflecting the assumed number of rate-limiting events. Indeed, at some level of mathematical approximation (see, e.g., ref. 4), the sequential nature of such a multistep process imposes a power-law behavior, that is, the age-specific incidence of cancers that arise as a consequence of several rate-limiting genomic alterations is predicted to increase with a power of age that is one less than the number of events necessary for malignant transformation. Although it is generally recognized that the carcinogenic process is more complicated and possibly punctuated by selection of advantageous mutations and clonal expansions (5), the qualitative power-law behavior of the age-specific cancer incidence is still considered a reasonable approximation for many cancers and continues to be invoked to argue for or against the importance of specific biological events in car...

Background Characterizing the smoking patterns for different birth cohorts is essential for evaluating the impact of tobacco control interventions and predicting smoking-related mortality, but the process of estimating birth cohort smoking histories has received limited attention. Purpose Smoking history summaries were estimated beginning with the 1890 birth cohort in order to provide fundamental parameters that can be used in studies of cigarette smoking intervention strategies Methods U.S. National Health Interview Surveys conducted from 1965 to 2009 were used to obtain cross-sectional information on current smoking behavior. Surveys that provided additional detail on history for smokers including age at initiation and cessation, and smoking intensity were used to construct smoking histories for participants up to the date of survey. After incorporating survival differences by smoking status, age-period cohort models with constrained natural splines were used to estimate the prevalence of current, former and never smokers in cohorts beginning in 1890. This approach was then used to obtain yearly estimates of initiation, cessation and smoking intensity for the age-specific distribution for each birth cohort. These rates were projected forward through 2050 based on recent trends. Results This summary of smoking history shows clear trends by gender, cohort and age over time. If current patterns persist, a slow decline in smoking prevalence is projected from 2010 through 2040. Conclusions A novel method of generating smoking histories has been applied to develop smoking histories that can be used in micro-simulation models, and has been incorporated in the National Cancer Institute’s Smoking History Generator. These aggregate estimates developed by age, gender and cohort will provide a complete source of smoking data over time.

BackgroundSelection of candidates for lung cancer screening based on individual risk has been proposed as an alternative to criteria based on age and cumulative smoking exposure (pack-years). Nine previously established risk models were assessed for their ability to identify those most likely to develop or die from lung cancer. All models considered age and various aspects of smoking exposure (smoking status, smoking duration, cigarettes per day, pack-years smoked, time since smoking cessation) as risk predictors. In addition, some models considered factors such as gender, race, ethnicity, education, body mass index, chronic obstructive pulmonary disease, emphysema, personal history of cancer, personal history of pneumonia, and family history of lung cancer.Methods and findingsRetrospective analyses were performed on 53,452 National Lung Screening Trial (NLST) participants (1,925 lung cancer cases and 884 lung cancer deaths) and 80,672 Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) ever-smoking participants (1,463 lung cancer cases and 915 lung cancer deaths). Six-year lung cancer incidence and mortality risk predictions were assessed for (1) calibration (graphically) by comparing the agreement between the predicted and the observed risks, (2) discrimination (area under the receiver operating characteristic curve [AUC]) between individuals with and without lung cancer (death), and (3) clinical usefulness (net benefit in decision curve analysis) by identifying risk thresholds at which applying risk-based eligibility would improve lung cancer screening efficacy. To further assess performance, risk model sensitivities and specificities in the PLCO were compared to those based on the NLST eligibility criteria. Calibration was satisfactory, but discrimination ranged widely (AUCs from 0.61 to 0.81). The models outperformed the NLST eligibility criteria over a substantial range of risk thresholds in decision curve analysis, with a higher sensitivity for all models and a slightly higher specificity for some models. The PLCOm2012, Bach, and Two-Stage Clonal Expansion incidence models had the best overall performance, with AUCs >0.68 in the NLST and >0.77 in the PLCO. These three models had the highest sensitivity and specificity for predicting 6-y lung cancer incidence in the PLCO chest radiography arm, with sensitivities >79.8% and specificities >62.3%. In contrast, the NLST eligibility criteria yielded a sensitivity of 71.4% and a specificity of 62.2%. Limitations of this study include the lack of identification of optimal risk thresholds, as this requires additional information on the long-term benefits (e.g., life-years gained and mortality reduction) and harms (e.g., overdiagnosis) of risk-based screening strategies using these models. In addition, information on some predictor variables included in the risk prediction models was not available.ConclusionsSelection of individuals for lung cancer screening using individual risk is superior to selection criteria based on age and pack-years alone. T...

We analyzed mesothelioma incidence in the Surveillance, Epidemiology, and End Results (SEER) database over the period 1973-2005 using extensions of the age-period-cohort (APC) models. In these analyses, the usual non-specific age effects of the conventional APC models were replaced by hazard functions derived from two multistage models of carcinogenesis, the Armitage-Doll model and the two-stage clonal expansion (TSCE) model. The extended APC models described the incidence data on pleural and peritoneal mesotheliomas well. After adjustment for temporal trends, the data suggest that the age-specific incidence rates of both pleural and peritoneal mesotheliomas are identical in men and women. Driven largely by birth cohort effects, age-adjusted rates of pleural mesothelioma among men rose from about 7.5 per million person-years in 1973 to about 20 per million person-years in the early 1990s and appear to be stable or declining thereafter. Age-adjusted rates of pleural mesothelioma among women have remained more or less constant at about 2.5 per million person-years over the period 1973-2005. Age-adjusted rates for peritoneal mesothelioma in both men (1.2 per million person-years) and women (0.8 per million person-years) exhibit no temporal trends over the period of the study. We estimate that approximately 94,000 cases of pleural and 15,000 cases of peritoneal mesothelioma will occur in the US over the period 2005-2050.