Trends in uterine cancer incidence in the United States: The contribution of age, period and cohort effects.

OBJECTIVE: In the U.S., uterine cancer incidence is rising, with racial and ethnic minorities experiencing the largest increases. We performed age-period-cohort analyses using novel methods to examine the contribution of age at diagnosis (age), year of diagnosis (period), and birth cohort (cohort), to trends in uterine cancer incidence. METHODS: We used uterine cancer incidence data from the Surveillance, Epidemiology, and End Result (SEER) 12 database (1992-2019), and performed hysterectomy-correction. We generated hexamaps to visualize age, period, and cohort effects, and used mutual information to estimate the percent contribution of age, period, and cohort effects, individually and combined, on uterine cancer incidence, overall and by race and ethnicity and histology. RESULTS: Hexamaps showed an increase in uterine cancer in later time periods, and a cohort effect around 1933 showing a lower incidence compared with earlier and later cohorts. Age, period, and cohort effects combined contributed 86.6% (95% CI: 86.4%, 86.9%) to the incidence. Age effects had the greatest contribution (65.1%, 95% CI: 64.3%, 65.9), followed by cohort (20.7%, 95% CI: 20.1%, 21.3%) and period (14.2%, 95% CI: 13.7%, 14.8%) effects. Hexamaps showed higher incidence in recent years for non-Hispanic Blacks and non-endometrioid tumors. CONCLUSIONS: Age effects had the largest contribution to uterine cancer incidence, followed by cohort and period effects overall and across racial and ethnic groups and histologies. IMPACT: These findings can inform uterine cancer modeling studies on the effects of interventions that target risk factors which may vary across age, period, or cohort.

Risk Model-Based Lung Cancer Screening : A Cost-Effectiveness Analysis.

BACKGROUND: In their 2021 lung cancer screening recommendation update, the U.S. Preventive Services Task Force (USPSTF) evaluated strategies that select people based on their personal lung cancer risk (risk model-based strategies), highlighting the need for further research on the benefits and harms of risk model-based screening. OBJECTIVE: To evaluate and compare the cost-effectiveness of risk model-based lung cancer screening strategies versus the USPSTF recommendation and to explore optimal risk thresholds. DESIGN: Comparative modeling analysis. DATA SOURCES: National Lung Screening Trial; Surveillance, Epidemiology, and End Results program; U.S. Smoking History Generator. TARGET POPULATION: 1960 U.S. birth cohort. TIME HORIZON: 45 years. PERSPECTIVE: U.S. health care sector. INTERVENTION: Annual low-dose computed tomography in risk model-based strategies that start screening at age 50 or 55 years, stop screening at age 80 years, with 6-year risk thresholds between 0.5% and 2.2% using the PLCOm2012 model. OUTCOME MEASURES: Incremental cost-effectiveness ratio (ICER) and cost-effectiveness efficiency frontier connecting strategies with the highest health benefit at a given cost. RESULTS OF BASE-CASE ANALYSIS: Risk model-based screening strategies were more cost-effective than the USPSTF recommendation and exclusively comprised the cost-effectiveness efficiency frontier. Among the strategies on the efficiency frontier, those with a 6-year risk threshold of 1.2% or greater were cost-effective with an ICER less than $100 000 per quality-adjusted life-year (QALY). Specifically, the strategy with a 1.2% risk threshold had an ICER of $94 659 (model range, $72 639 to $156 774), yielding more QALYs for less cost than the USPSTF recommendation, while having a similar level of screening coverage (person ever-screened 21.7% vs. USPSTF's 22.6%). RESULTS OF SENSITIVITY ANALYSES: Risk model-based strategies were robustly more cost-effective than the 2021 USPSTF recommendation under varying modeling assumptions. LIMITATION: Risk models were restricted to age, sex, and smoking-related risk predictors. CONCLUSION: Risk model-based screening is more cost-effective than the USPSTF recommendation, thus warranting further consideration. PRIMARY FUNDING SOURCE: National Cancer Institute (NCI).

The Effect of Advances in Lung-Cancer Treatment on Population Mortality.

BACKGROUND: Lung cancer is made up of distinct subtypes, including non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Although overall mortality from lung cancer has been declining in the United States, little is known about mortality trends according to cancer subtype at the population level because death certificates do not record subtype information. METHODS: Using data from Surveillance, Epidemiology, and End Results (SEER) areas, we assessed lung-cancer mortality and linked deaths from lung cancer to incident cases in SEER cancer registries. This allowed us to evaluate population-level mortality trends attributed to specific subtypes (incidence-based mortality). We also evaluated lung-cancer incidence and survival according to cancer subtype, sex, and calendar year. Joinpoint software was used to assess changes in incidence and trends in incidence-based mortality. RESULTS: Mortality from NSCLC decreased even faster than the incidence of this subtype, and this decrease was associated with a substantial improvement in survival over time that corresponded to the timing of approval of targeted therapy. Among men, incidence-based mortality from NSCLC decreased 6.3% annually from 2013 through 2016, whereas the incidence decreased 3.1% annually from 2008 through 2016. Corresponding lung cancer-specific survival improved from 26% among men with NSCLC that was diagnosed in 2001 to 35% among those in whom it was diagnosed in 2014. This improvement in survival was found across all races and ethnic groups. Similar patterns were found among women with NSCLC. In contrast, mortality from SCLC declined almost entirely as a result of declining incidence, with no improvement in survival. This result correlates with limited treatment advances for SCLC in the time frame we examined. CONCLUSIONS: Population-level mortality from NSCLC in the United States fell sharply from 2013 to 2016, and survival after diagnosis improved substantially. Our analysis suggests that a reduction in incidence along with treatment advances - particularly approvals for and use of targeted therapies - is likely to explain the reduction in mortality observed during this period.

Endoscopic Screening Program for Control of Esophageal Adenocarcinoma in Varied Populations: A Comparative Cost-Effectiveness Analysis.

BACKGROUND & AIMS: Guidelines suggest endoscopic screening for esophageal adenocarcinoma (EAC) among individuals with symptoms of gastroesophageal reflux disease (GERD) and additional risk factors. We aimed to determine at what age to perform screening and whether sex and race should influence the decision. METHODS: We conducted comparative cost-effectiveness analyses using 3 independent simulation models. For each combination of sex and race (White/Black, 100,000 individuals each), we considered 41 screening strategies, including one-time or repeated screening. The optimal strategy was that with the highest effectiveness and an incremental cost-effectiveness ratio <$100,000 per quality-adjusted life-year gained. RESULTS: Among White men, 536 EAC deaths were projected without screening, and screening individuals with GERD twice at ages 45 and 60 years was optimal. Screening the entire White male population once at age 55 years was optimal in 26% of probabilistic sensitivity analysis runs. Black men had fewer EAC deaths without screening (n = 84), and screening those with GERD once at age 55 years was optimal. Although White women had slightly more EAC deaths (n = 103) than Black men, the optimal strategy was no screening, although screening those with GERD once at age 55 years was optimal in 29% of probabilistic sensitivity analysis runs. Black women had a very low burden of EAC deaths (n = 29), and no screening was optimal, as benefits were very small and some strategies caused net harm. CONCLUSIONS: The optimal strategy for screening differs by race and sex. White men with GERD symptoms can potentially be screened more intensely than is recommended currently. Screening women is not cost-effective and may cause net harm for Black women.

Cost-Effectiveness of Follow-Up Ultrasound for Incidental Thyroid Nodules on CT.

BACKGROUND. Thyroid nodules are common incidental findings on CT. Existing professional society recommendations, based primarily on expert opinion, advise follow-up ultrasound for nodules above size cutoffs in patients of all ages. OBJECTIVE. The purpose of this study was to use a simulation model to evaluate the cost-effectiveness of current recommendations and of other age- and size-based follow-up strategies for thyroid nodules incidentally detected on CT. METHODS. By using a simulation model with 1,000,000 adults with nodules measuring 40 mm or less that have no suspicious features, we evaluated size cutoffs from 5 to 25 mm in patients younger than an age maximum from 25 to 65 years, as well as follow-up versus no follow-up for patients above the age maximum. For each strategy, patient survival was determined by disease-specific and baseline mortality rates and surgical mortality. Costs and quality-adjusted life years (QALYs) were tabulated. A probabilistic sensitivity analysis was performed with varying model parameters. RESULTS. All cost-effective strategies recommended no follow-up for patients above the age cutoffs (which varied from 25 to 65 years). In the base-case simulation, 10 strategies were cost-effective at a willingness-to-pay threshold of $100,000/QALY. Of these, the strategy yielding the highest QALYs was follow-up for patients under 60 years old with nodules 10 mm or larger and no follow-up for patients 60 years old or older, with an incremental cost-effectiveness ratio of $50,196/QALY (95% CI, $39,233-67,479). In the probabilistic sensitivity analysis, if the 10-year disease-specific survival of patients with untreated cancer was more than 94% of patients with treated cancer, then no follow-up for any nodules was optimal. CONCLUSION. Follow-up ultrasound for thyroid nodules incidentally detected on CT is likely not cost-effective in older patients. Follow-up for most thyroid nodules in younger patients may be cost-effective. CLINICAL IMPACT. Future societal recommendations may account for the limited benefit of obtaining follow-up for incidental thyroid nodules on CT in older patients.

Cost-Effectiveness of Treatment Thresholds for Subsolid Pulmonary Nodules in CT Lung Cancer Screening.

Background Guidelines such as the Lung CT Screening Reporting and Data System (Lung-RADS) are available for determining when subsolid nodules should be treated within lung cancer screening programs, but they are based on expert opinion. Purpose To evaluate the cost-effectiveness of varying treatment thresholds for subsolid nodules within a lung cancer screening setting by using a simulation model. Materials and Methods A previously developed model simulated 10 million current and former smokers undergoing CT lung cancer screening who were assumed to have a ground-glass nodule (GGN) at baseline. Nodules were allowed to grow and to develop solid components over time according to a monthly cycle and lifetime horizon. Management strategies generated by varying treatment thresholds, including the solid component size and use of the Brock risk calculator, were tested. For each strategy, average U.S. costs and quality-adjusted life years (QALYs) gained per patient were computed, and the incremental cost-effectiveness ratios (ICERs) of those on the efficient frontier were calculated. One-way and probabilistic sensitivity analyses of results were performed by varying several relevant parameters, such as treatment costs or malignancy growth rates. Results Variants of the Lung-RADS guidelines that did not treat pure GGNs were cost-effective. Strategies based on the Brock risk calculator did not reach the efficient frontier. The strategy with the highest QALYs under a willingness-to-pay threshold of $100 000 per QALY included no treatment of GGNs and a threshold of 4-mm solid component size for treatment of subsolid nodules. This strategy yielded an ICER of $52 993 per QALY (95% CI: 44 407, 64 372). Probabilistic sensitivity analysis showed this was the optimal strategy under a range of parameter variations. Conclusion Treatment of pure ground-glass nodules was not cost-effective. Strategies that use modifications of the Lung CT Screening Reporting and Data System guidelines were cost-effective for treating part-solid nodules; an optimal threshold of 4 mm for the solid component yielded the most quality-adjusted life years. © RSNA, 2021 Online supplemental material is available for this article.

Evaluation of the Benefits and Harms of Lung Cancer Screening With Low-Dose Computed Tomography: Modeling Study for the US Preventive Services Task Force.

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 disparity in screening eligibility by sex and race/ethnicity.

Correction: Risk prediction models for selection of lung cancer screening candidates: A retrospective validation study.

[This corrects the article DOI: 10.1371/journal.pmed.1002277.].

Cost and Utilization of Lung Cancer End-of-Life Care Among Racial-Ethnic Minority Groups in the United States.

BACKGROUND: The end-of-life period is a crucial time in lung cancer care. To have a better understanding of the racial-ethnic disparities in health care expenditures, access, and quality, we evaluated these disparities specifically in the end-of-life period for patients with lung cancer in the U.S. MATERIALS AND METHODS: We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database to analyze characteristics of lung cancer care among those diagnosed between the years 2000 and 2011. Linear and logistic regression models were constructed to measure racial-ethnic disparities in end-of-life care cost and utilization among non-Hispanic (NH) Asian, NH black, Hispanic, and NH white patients while controlling for other risk factors such as age, sex, and SEER geographic region. RESULTS: Total costs and hospital utilization were, on average, greater among racial-ethnic minorities compared with NH white patients in the last month of life. Among patients with NSCLC, the relative total costs were 1.27 (95% confidence interval [CI], 1.21-1.33) for NH black patients, 1.36 (95% CI, 1.25-1.49) for NH Asian patients, and 1.21 (95% CI, 1.07-1.38) for Hispanic patients. Additionally, the odds of being admitted to a hospital for NH black, NH Asian, and Hispanic patients were 1.22 (95% CI, 1.15-1.30), 1.47 (95% CI, 1.32-1.63), and 1.18 (95% CI, 1.01-1.38) times that of NH white patients, respectively. Similar results were found for patients with SCLC. CONCLUSION: Minority patients with lung cancer have significantly higher end-of-life medical expenditures than NH white patients, which may be explained by a greater intensity of care in the end-of-life period. IMPLICATIONS FOR PRACTICE: This study investigated racial-ethnic disparities in the cost and utilization of medical care among lung cancer patients during the end-of-life period. Compared with non-Hispanic white patients, racial-ethnic minority patients were more likely to receive intensive care in their final month of life and had statistically significantly higher end-of-life care costs. The findings of this study may lead to a better understanding of the racial-ethnic disparities in end-of-life care, which can better inform future end-of-life interventions and help health care providers develop less intensive and more equitable care, such as culturally competent advanced care planning programs, for all patients.

Effect and cost-effectiveness of national gastric cancer screening in Japan: a microsimulation modeling study.

BACKGROUND: A national endoscopic screening program for gastric cancer was rolled out in Japan in 2015. We used a microsimulation model to estimate the cost-effectiveness of current screening guidelines and alternative screening strategies in Japan. METHODS: We developed a microsimulation model that simulated a virtual population corresponding to the Japanese population in risk factor profile and life expectancy. We evaluated 15 endoscopic screening scenarios with various starting ages, stopping ages, and screening intervals. The primary outcomes were quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratio. Cost-effective screening strategies were determined using a willingness-to-pay threshold of $50,000 per QALY gained. One-way sensitivity and probabilistic sensitivity analyses were done to explore model uncertainty. RESULTS: Using the threshold of $50,000 per QALY, a triennial screening program for individuals aged 50 to 75 years was the cost-effective strategy, with an incremental cost-effectiveness ratio of $45,665. Compared with no endoscopic screening, this strategy is predicted to prevent 63% of gastric cancer mortality and confer 27.2 QALYs gained per 1000 individuals over a lifetime period. Current screening guidelines were not on the cost-effectiveness efficient frontier. The results were robust on one-way sensitivity analyses and probabilistic sensitivity analysis. CONCLUSIONS: This modeling study suggests that the endoscopic screening program in Japan would be cost-effective when implemented between age 50 and 75 years, with the screening repeated every 3 years. These findings underscore the need for further evaluation of the current gastric cancer screening recommendations.

Cost-Effectiveness Analysis of Lung Cancer Screening in the United States: A Comparative Modeling Study.

Background: Recommendations vary regarding the maximum age at which to stop lung cancer screening: 80 years according to the U.S. Preventive Services Task Force (USPSTF), 77 years according to the Centers for Medicare & Medicaid Services (CMS), and 74 years according to the National Lung Screening Trial (NLST). Objective: To compare the cost-effectiveness of different stopping ages for lung cancer screening. Design: By using shared inputs for smoking behavior, costs, and quality of life, 4 independently developed microsimulation models evaluated the health and cost outcomes of annual lung cancer screening with low-dose computed tomography (LDCT). Data Sources: The NLST; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; SEER (Surveillance, Epidemiology, and End Results) program; Nurses' Health Study and Health Professionals Follow-up Study; and U.S. Smoking History Generator. Target Population: Current, former, and never-smokers aged 45 years from the 1960 U.S. birth cohort. Time Horizon: 45 years. Perspective: Health care sector. Intervention: Annual LDCT according to NLST, CMS, and USPSTF criteria. Outcome Measures: Incremental cost-effectiveness ratios (ICERs) with a willingness-to-pay threshold of $100 000 per quality-adjusted life-year (QALY). Results of Base-Case Analysis: The 4 models showed that the NLST, CMS, and USPSTF screening strategies were cost-effective, with ICERs averaging $49 200, $68 600, and $96 700 per QALY, respectively. Increasing the age at which to stop screening resulted in a greater reduction in mortality but also led to higher costs and overdiagnosis rates. Results of Sensitivity Analysis: Probabilistic sensitivity analysis showed that the NLST and CMS strategies had higher probabilities of being cost-effective (98% and 77%, respectively) than the USPSTF strategy (52%). Limitation: Scenarios assumed 100% screening adherence, and models extrapolated beyond clinical trial data. Conclusion: All 3 sets of lung cancer screening criteria represent cost-effective programs. Despite underlying uncertainty, the NLST and CMS screening strategies have high probabilities of being cost-effective. Primary Funding Source: CISNET (Cancer Intervention and Surveillance Modeling Network) Lung Group, National Cancer Institute.

Neoadjuvant FOLFIRINOX for Patients with Borderline Resectable or Locally Advanced Pancreatic Cancer: Results of a Decision Analysis.

BACKGROUND: The effectiveness and cost-effectiveness of using neoadjuvant FOLFIRINOX (nFOLFIRINOX) for patients with borderline resectable or locally advanced pancreatic ductal adenocarcinoma (BR/LA PDAC) are unknown. Our objective was to determine whether nFOLFIRINOX is more effective or cost-effective for patients with BR/LA PDAC compared with upfront resection surgery and adjuvant gemcitabine plus capecitabine (GEM/CAPE) or gemcitabine monotherapy (GEM). MATERIALS AND METHODS: We performed a decision-analysis to assess the value of nFOLFIRINOX versus GEM/CAPE or GEM using a mathematical simulation model. Model transition probabilities were estimated using published and institutional clinical data. Model outcomes included overall and disease-free survival, quality-adjusted life-years (QALYs), cost in U.S. dollars, and cost-effectiveness expressed as an incremental cost-effectiveness ratio. Deterministic and probabilistic sensitivity analyses explored the uncertainty of model assumptions. RESULTS: Model results found median overall survival (34.5/28.0/22.0 months) and disease-free survival (15.0/14.0/13.0 months) were better for nFOLFIRINOX compared with GEM/CAPE and GEM. nFOLFIRINOX was the optimal strategy on an efficiency frontier, resulting in an additional 0.35 life-years, or 0.30 QALYs, at a cost of $46,200/QALY gained compared with GEM/CAPE. Sensitivity analysis found that cancer recurrence and complete resection rates most affected model results, but were otherwise robust. Probabilistic sensitivity analyses found that nFOLFIRINOX was cost-effective 92.4% of the time at a willingness-to-pay threshold of $100,000/QALY. CONCLUSION: Our modeling analysis suggests that nFOLFIRINOX is preferable to upfront surgery for patients with BR/LA PDAC from both an effectiveness and cost-effectiveness standpoint. Additional clinical data that further define the long-term effectiveness of nFOLFIRINOX are needed to confirm our results. IMPLICATIONS FOR PRACTICE: Increasingly, neoadjuvant FOLFIRINOX has been used for borderline resectable and locally advanced pancreatic cancer with the goal of rendering them resectable and decreasing risk of recurrence. Despite many efforts to show the benefits of neoadjuvant over adjuvant therapies, clinical evidence to guide this decision is largely lacking. Decision-analytic modeling can provide a methodologic platform that integrates the best available data to quantitatively explore clinical decisions by simulating a hypothetical clinical trial. This modeling analysis suggests that neoadjuvant FOLFIRINOX is preferable to upfront surgery and adjuvant therapies by various outcome metrics including quality-adjusted life years, overall survival, and incremental cost-effectiveness ratio.

The effect of radiographic emphysema in assessing lung cancer risk.

PURPOSE: Lung cancer risk models optimise screening by identifying subjects at highest risk, but none of them consider emphysema, a risk factor identifiable on baseline screen. Subjects with a negative baseline low-dose CT (LDCT) screen are at lower risk for subsequent diagnosis and may benefit from risk stratification prior to additional screening, thus we investigated the role of radiographic emphysema as an additional predictor of lung cancer diagnosis in participants with negative baseline LDCT screens of the National Lung Screening Trial. METHODS: Our cohorts consist of participants with a negative baseline (T0) LDCT screen (n=16 624) and participants who subsequently had a negative 1-year follow-up (T1) screen (n=14 530). Lung cancer risk scores were calculated using the Bach, PLCOm2012 and Liverpool Lung Project models. Risk of incident lung cancer diagnosis at the end of the study and number screened per incident lung cancer were compared between participants with and without radiographic emphysema. RESULTS: Radiographic emphysema was independently associated with nearly double the hazard of lung cancer diagnosis at both the second (T1) and third (T2) annual LDCT in all three risk models (HR range 1.9-2.0, p<0.001 for all comparisons). The number screened per incident lung cancer was considerably lower in participants with radiographic emphysema (62 vs 28 at T1 and 91 vs 40 at T2). CONCLUSION: Radiographic emphysema is an independent predictor of lung cancer diagnosis and may help guide decisions surrounding further screening for eligible patients.

Cancer Risk in Subsolid Nodules in the National Lung Screening Trial.

Background Subsolid pulmonary nodules, comprising pure ground-glass nodules (GGNs) and part-solid nodules (PSNs), have a high risk of indolent malignancy. Lung Imaging Reporting and Data System (Lung-RADS) nodule management guidelines are based on expert opinion and lack independent validation. Purpose To evaluate Lung-RADS estimates of the malignancy rates of subsolid nodules, using nodules from the National Lung Screening Trial (NLST), and to compare Lung-RADS to the NELSON trial classification as well as the Brock University calculator. Materials and Methods Subsets of GGNs and PSNs were selected from the NLST for this retrospective study. A thoracic radiologist reviewed the baseline and follow-up CT images, confirmed that they were true subsolid nodules, and measured the nodules. The primary outcome for each nodule was the development of malignancy within the follow-up period (median, 6.5 years). Nodules were stratified according to Lung-RADS, NELSON trial criteria, and the Brock model. For analyses, nodule subsets were weighted on the basis of frequency in the NLST data set. Nodule stratification models were tested by using receiver operating characteristic curves. Results A total of 622 nodules were evaluated, of which 434 nodules were subsolid. At baseline, 304 nodules were classified as Lung-RADS category 2, with a malignancy rate of 3%, which is greater than the 1% in Lung-RADS (P = .004). The malignancy rate for GGNs smaller than 10 mm (two of 129, 1.3%) was smaller than that for GGNs measuring 10-19 mm (11 of 153, 6%) (P = .01). The malignancy rate for Lung-RADS category 3 was 14% (13 of 67), which is greater than the reported 2% in Lung-RADS (P < .001). The Brock model predicted malignancy better than Lung-RADS and the NELSON trial scheme (area under the receiver operating characteristic curve = 0.78, 0.70, and 0.67, respectively; P = .02 for Brock model vs NELSON trial scheme). Conclusion Subsolid nodules classified as Lung Imaging Reporting and Data System (Lung-RADS) categories 2 and 3 have a higher risk of malignancy than reported. The Brock risk calculator performed better than measurement-based classification schemes such as Lung-RADS. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Kauczor and von Stackelberg in this issue.

A Decision Analysis of Follow-up and Treatment Algorithms for Nonsolid Pulmonary Nodules.

Purpose To evaluate management strategies and treatment options for patients with ground-glass nodules (GGNs) by using decision-analysis models. Materials and Methods A simulation was developed for 1 000 000 hypothetical patients with GGNs undergoing follow-up per the Lung Imaging Reporting and Data System (Lung-RADS) recommendations. The initial age range was 55-75 years (mean, 64 years). Nodules could grow and develop solid components over time. Clinically significant malignancy rates were calibrated to data from the National Lung Screening Trial. Annual versus 3-year-interval follow-up of Lung-RADS category 2 nodules was compared, and different treatment strategies were tested (stereotactic body radiation therapy, surgery, and no therapy). Results Overall, 2.3% (22 584 of 1 000 000) of nodules were clinically significant malignancies; 6.3% (62 559 of 1 000 000) of nodules were treated. Only 30% (18 668 of 62 559) of Lung-RADS category 4B or 4X nodules were clinically significant malignancies. The risk of clinically significant malignancy for persistent nonsolid nodules after baseline was higher than Lung-RADS estimates for categories 2 and 3 (3% vs <1% and 1%-2%, respectively). Overall survival (OS) at 10 years was 72% (527 827 of 737 306; 95% confidence interval [CI]: 71%, 72%) with annual follow-up and 71% (526 507 of 737 306; 95% CI: 71%, 72%) with 3-year-interval follow-up (P < .01). At 10 years, OS among patients whose nodules progressed to Lung-RADS category 4B or 4X was 80% after radiation therapy (49 945 of 62 559; 95% CI: 80%, 80%), 79% after surgery (49 139 of 62 559; 95% CI: 78%, 79%), and 74% after no therapy (46 512 of 62 559; 95% CI: 74%, 75%) (P < .01). Conclusion Simulation modeling suggests that the follow-up interval for evaluating ground-glass nodules can be increased from 1 year to 3 years with minimal change in outcomes. Stereotactic body radiation therapy demonstrated the best outcomes compared with lobectomy and with no therapy for nonsolid nodules. © RSNA, 2018 Online supplemental material is available for this article.

Development and validation of a model to predict outcomes of colon cancer surveillance.

PURPOSE: Clinical trials suggest that intensive surveillance of colon cancer (CC) survivors to detect recurrence increases curative-intent treatment, although any survival benefit of surveillance as currently practiced appears modest. Realizing the potential of surveillance will require tools for identifying patients likely to benefit and for optimizing testing regimens. We describe and validate a model for predicting outcomes for any schedule of surveillance in CC survivors with specified age and cancer stage. METHODS: A Markov process parameterized based on individual-level clinical trial data generates natural history events for simulated patients. A utilization submodel simulates surveillance and diagnostic testing. We validate the model against outcomes from the follow-up after colorectal surgery (FACS) trial. RESULTS: Prevalidation sensitivity analysis showed no parameter influencing curative-intent treatment by > 5.0% or overall five-year survival (OS5) by > 1.5%. In validation, the proportion of recurring subjects predicted to receive curative-intent treatment fell within FACS 95% CI for carcinoembryonic antigen (CEA)-intensive, computed tomography (CT)-intensive, and combined CEA+CT regimens, but not for a minimum surveillance regimen, where the model overestimated recurrence and curative treatment. The observed OS5 fell within 95% prediction intervals for all regimens. CONCLUSION: The model performed well in predicting curative surgery for three of four FACS arms. It performed well in predicting OS5 for all arms.

Testing for Verification Bias in Reported Malignancy Risks for Side-Branch Intraductal Papillary Mucinous Neoplasms: A Simulation Modeling Approach.

OBJECTIVE: The objective of our study was to test for the possibility that published malignancy risks for side-branch intraductal papillary mucinous neoplasms (IPMNs) are overestimates, likely due to verification bias. MATERIALS AND METHODS: We tested for possible verification bias using simulation modeling techniques. First, in age-defined hypothetical cohorts of 10 million persons, we projected the frequency of pancreatic ductal adenocarcinoma (PDAC) arising from side-branch IPMNs over 5 years using published estimates of their prevalence (4.4%) and rate of malignant transformation (1.9%). Second, we projected the total number of PDAC cases in corresponding cohorts over the same time horizon using national cancer registry data. For each cohort, we determined whether the percentage of all PDAC cases that arose from side-branch IPMNs (i.e., side-branch IPMN-associated PDAC cases) was clinically plausible using an upper limit of 10% to define plausibility, as estimated from the literature. Model assumptions and parameter uncertainty were evaluated in sensitivity analysis. RESULTS: Across all cohorts, percentages of side-branch IPMN-associated PDACs greatly exceeded 10%. In the base case (mean age = 55.7 years), 80% of PDAC cases arose from side-branch IPMNs (7877/9786). In the oldest cohort evaluated (mean age = 75 years), this estimate was 76% (14,227/18,714). In a secondary analysis, we found that if an upper limit threshold of 10% for side-branch IPMN-associated PDAC was imposed, the model-predicted rate of malignancy for side-branch IPMNs would be less than 0.24% over a 5-year time horizon, substantially lower than most literature-based estimates. CONCLUSION: Our results suggest that reported malignancy risks associated with side-branch IPMNs are likely to be overestimates and imply the presence of verification bias.

Smoking and Lung Cancer Mortality in the United States From 2015 to 2065: A Comparative Modeling Approach.

Background: Tobacco control efforts implemented in the United States since the 1960s have led to considerable reductions in smoking and smoking-related diseases, including lung cancer. Objective: To project reductions in tobacco use and lung cancer mortality from 2015 to 2065 due to existing tobacco control efforts. Design: Comparative modeling approach using 4 simulation models of the natural history of lung cancer that explicitly relate temporal smoking patterns to lung cancer rates. Setting: U.S. population, 1964 to 2065. Participants: Adults aged 30 to 84 years. Measurements: Models were developed using U.S. data on smoking (1964 to 2015) and lung cancer mortality (1969 to 2010). Each model projected lung cancer mortality by smoking status under the assumption that current decreases in smoking would continue into the future (status quo trends). Sensitivity analyses examined optimistic and pessimistic scenarios. Results: Under the assumption of continued decreases in smoking, age-adjusted lung cancer mortality was projected to decrease by 79% between 2015 and 2065. Concomitantly, and despite the expected growth, aging, and longer life expectancy of the U.S. population, the annual number of lung cancer deaths was projected to decrease from 135 000 to 50 000 (63% reduction). However, 4.4 million deaths from lung cancer are still projected to occur in the United States from 2015 to 2065, with about 20 million adults aged 30 to 84 years continuing to smoke in 2065. Limitation: Projections assumed no changes to tobacco control efforts in the future and did not explicitly consider the potential effect of lung cancer screening. Conclusion: Tobacco control efforts implemented since the 1960s will continue to reduce lung cancer rates well into the next half-century. Additional prevention and cessation efforts will be required to sustain and expand these gains to further reduce the lung cancer burden in the United States. Primary Funding Source: National Cancer Institute.

Population impact of lung cancer screening in the United States: Projections from a microsimulation model.

BACKGROUND: Previous simulation studies estimating the impacts of lung cancer screening have ignored the changes in smoking prevalence over time in the United States. Our primary rationale was to perform, to our knowledge, the first simulation study that estimates the health outcomes of lung cancer screening with explicit modeling of smoking trends for the whole US population. METHODS/FINDINGS: Utilizing a well-validated microsimulation model, we estimated the benefits and harms of an annual low-dose computed tomography screening scenario with a realistic screening adherence rate versus a no-screening scenario for the US population from 2016-2030. The Centers for Medicare and Medicaid Services (CMS) eligibility criteria were applied: age 55-77 years at time of screening, history of at least 30 pack-years of smoking, and current smoker or former smoker with fewer than 15 years since quitting. In the screened population, cumulative mortality reduction was projected to reach 16.98% (95% CI 16.90%-17.07%). Cumulative mortality reduction was estimated to be 3.52% (95% CI 3.50%-3.53%) for the overall study population, with annual mortality reduction peaking at 4.38% (95% CI 4.36%-4.41%) in 2021 and falling to 3.53% (95% CI 3.50%-3.56%) by 2030. Lung cancer screening would save a projected 148,484 life-years (95% CI 147,429-149,540) across the total population through 2030. There were estimated to be 9,054 (95% CI 9,011-9,098) overdiagnosed cases among the 252,429 (95% CI 251,208-253,649) screen-detected lung cancer diagnoses, yielding an overdiagnosis rate of 3.59%. The limitations of our study are that we do not explicitly model race or socioeconomic status and our model was calibrated to data from studies performed in academic centers, both of which may impact the generalizability of our results. We also exclusively model the effects of the CMS guidelines for lung cancer screening and not any other screening strategies. CONCLUSIONS: The mortality reduction and life-years gained estimated by this study are lower than those of single birth cohort studies. Single cohort studies neglect the changing dynamics of smoking behavior across generations, whereas this study reflects the trend of decreasing smoking prevalence since the 1960s. Maximum benefit could be derived from lung cancer screening through 2021; in later years, mortality reduction due to screening will decline. If a comprehensive screening program is not implemented in the near future, the opportunity to achieve these benefits will have passed.