Background: To provide an understanding of important aspects of the participant recruitment and data collec-tion, become aware of any potential problems, and obtain necessary information in order to design a large-scale randomized controlled trial (RCT) for lung cancer and colorectal cancer (CRC) screening in China. Methods: This feasibility study was a multicentered, open-label, pilot randomized trial. A total of 2696 participants who were at high risk of lung cancer were recruited from three screening centers and randomly allocated to arm 1 ( n = 894), annual low-dose computed tomography (LDCT) plus a baseline colonoscopy; arm 2 ( n = 902), biennial LDCT plus annual fecal immunochemical test (FIT) with OC-Sensor (OC-FIT); and arm 3 ( n = 900), annual Insure -FIT plus Septin 9 blood test. Information on randomization, compliance, positivity rate, cancer case detection, and contamination with screening for lung cancer and CRC were collected. Results: Participant characteristics were similar across study arms. The compliance rate of annual LDCT screening in arm 1 was 86.4% (95% CI: 83.9%, 88.5%) at baseline (T0), and 69.0% (95% CI: 65.8%, 72.0%) and 70.7% (95% CI: 67.6%, 73.7%) at the following two rounds (T1 and T2). The compliance rates of biennial LDCT screening in arm 2 were similar to those in arm 1 in the corresponding rounds. The compliance rate was 55.5% (95% CI: 52.2%, 58.8%) for colonoscopy in arm 1, while the compliance rates of OC-FIT, Insure-FIT, and the Septin 9 test in arms 2 and 3 were all approximately 90% at T0, decreasing to 65%-80% at T1 and T2. The positivity rate, cancer case detection rate, and contamination rate of screening for lung cancer and CRC were also reported. Conclusion: In this pilot study, the feasibility of an RCT in China of lung cancer and CRC screening was demon-strated.

Cardiovascular (CV) toxicity from cancer therapy is a significant and growing concern. Conventional oncology clinical trial designs focused solely on cancer treatment efficacy have not provided sufficient information on both CV risk factors and outcomes. Similarly, traditional CV trials evaluating standard interventions typically exclude cancer patients, particularly those actively receiving cancer therapy. Neither trial type simultaneously evaluates the balance between CV toxicity and cancer outcomes; however, there is increasing collaboration among oncologists and cardiologists to design new cardio-oncology trials that address this important need. In this review, we detail 5 ongoing, oncology-based trials with integrated CV endpoints. Key design features include: 1) a careful assessment of CV risk factors and disease before, during, and after cancer therapy with standardized collection of clinical imaging, functional, and biomarker data; 2) an introduction of cardioprotective interventions at various timepoints in cancer therapy; 3) a balance of the risk of subclinical CV injury with the need for ongoing cancer treatment; and 4) an understanding of the time profile for development of clinically apparent CV toxicity. Additional critical priorities in cardio-oncology clinical research include harmonization of data collection and definitions for all physician- and patient-reported exposures and outcomes.

Cardiovascular (CV) toxicity from cancer therapy is a significant and growing concern. Conventional oncology clinical trial designs focused solely on cancer treatment efficacy have not provided sufficient information on both CV risk factors and outcomes. Similarly, traditional CV trials evaluating standard interventions typically exclude cancer patients, particularly those actively receiving cancer therapy. Neither trial type simultaneously evaluates the balance between CV toxicity and cancer outcomes; however, there is increasing collaboration among oncologists and cardiologists to design new cardio-oncology trials that address this important need. In this review, we detail 5 ongoing, oncology-based trials with integrated CV endpoints. Key design features include: 1) a careful assessment of CV risk factors and disease before, during, and after cancer therapy with standardized collection of clinical imaging, functional, and biomarker data; 2) an introduction of cardioprotective interventions at various timepoints in cancer therapy; 3) a balance of the risk of subclinical CV injury with the need for ongoing cancer treatment; and 4) an understanding of the time profile for development of clinically apparent CV toxicity. Additional critical priorities in cardio-oncology clinical research include harmonization of data collection and definitions for all physician- and patient-reported exposures and outcomes.

Abstract Lung cancer has been the leading cause of cancer death in China since the 1990s and the disease burden likely will increase. The US National Lung Screening Trial (NLST) showed a 16-20% mortality reduction in a high-risk population that had undergone Low-Dose Computed Tomography (LDCT). China would like to confirm the main result from the US NLST in the Chinese population. The aim of this study is to obtain necessary information on performance of the organizations involved in designing, conducting, monitoring and managing the study. Another goal is to test colorectal cancer screening strategies in China. This is a first randomized trial on lung and colorectal cancer screening in China. The feasibility study will aid in the development of a practical design for the Randomized Cancer Screening Trial in China. This study has been carried out in three cites (Changsha city, Hunan province; Lanzhou city, Gansu province; and Haining city, Zhejiang province) since August, 2014. Individuals at elevated risk of lung cancer were randomized into three arms: annual low-dose helical CT exams for three years (T0, T1, T2) and baseline colonoscopy (T0); two low-dose helical CT exams (T0, T2) plus annual faecal immunochemical test (OC-faecal immunochemical tests at T0, T1, T2); and annual InSure-faecal immunochemical tests combined with Septin 9 test (T0, T1, T2). All participants will be followed for at least three years from randomization to yield data relevant to answering the study objectives. As of March 31, 2015, a total of 2696 eligible participants were enrolled at 3 cancer hospitals and randomly assigned to three study arms (894 in arm 1, 902 in arm 2, and 900 in arm 3). The gender distribution is 53% male and 47% female. Baseline characteristics of the study population by age, gender and total pack-year exposure were balanced. The rate of adherence to LDCT screening at the first round (T0) was 89.0%. 1598 participants received LDCT in the first round. The rate of abnormality was 77.4% with LDCT and 6.5% and 6.1% with suspicious for lung cancer for arm 1 and arm 2 respectively at T0. 2150 participants received colorectal cancer screening. The positivity was 34.1% with colonoscopy screening, 8.0% with OC-FIT test, 4.5% with InsureFIT test, and 5.8% with Septin9 test. Citation Format: Ping Hu, Min Dai, Jufang Shi, Jiansong Ren, Jiang Li, Xianzhen Liao, Lingbin Du, Yuqing Liu, Zhaoli Chen, Ning Wu, Qian Liu, Paul Pinsky, Philip Prorok, Richard Fagerstrom, Martina Taylor, Barnett Kramer, Jie He. The feasibility study of a randomized cancer screening trial in China. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1795.

BackgroundLung cancer has been the leading cause of cancer death in China since the 1990s, and the disease burden is predicted to increase. The US National Lung Screening Trial (NLST) showed that annual low-dose CT resulted in a 15–20% mortality reduction in high-risk populations compared with chest x-ray, and the China National Cancer Center would like to confirm this finding in the Chinese population. Additionally, China has not yet developed national guidelines for lung and colorectal cancer screening, and scientific evidence from the Chinese population is needed to inform policy making. The China Cancer Screening Trial Feasibility Study seeks to obtain information necessary to design a long-term randomised lung and colorectal cancer screening trial. The primary objectives are to develop and test all data forms and data collection procedures; to assess the feasibility of recruitment and randomisation of participants into study arms, and the success of randomisation by comparing the distribution of baseline variables across arms, contamination in each arm, and compliance with screening exams and diagnostic follow-up after positive screening in each arm; to determine the positivity rates at each screening round in each arm; to identify and collect data for cancers in each arm over the study period; to develop and test procedures that collect and store biological samples; and to assess the performance of the organisations involved in designing, conducting, monitoring, and managing the study.MethodsThe study has been set up in three cites (Changsha, Hunan province; Lanzhou, Gansu province; and Haining, Zhejiang province) since August, 2014. Individuals at elevated risk of lung cancer were randomised into three arms: annual low-dose helical CT exams for 3 years (T0, T1, T2) and baseline colonoscopy (T0); two low-dose helical CT exams (T0, T2) plus annual faecal immunochemical test (OC-faecal immunochemical tests at T0, T1, T2); and annual InSure-faecal immunochemical tests combined with Septin 9 test (T0, T1, T2). A randomly selected 6 or 9 block size was used for randomisation. Staff at screening centres and all the participants were blinded to the order of randomisation, and enrolment was done by each screening centre. All participants will be followed for at least 3 years from randomisation to yield data stated in the study objectives. This study was approved by the ethics committee of Cancer Hospital, Chinese Academy of Medical Science, in June, 2014 (14-058/848). All participants signed informed consent forms before recruitment.FindingsAs of March 31, 2015, 2700 eligible participants, 900 in each study centre, were randomised into the three arms. Participants were stratified on the basis of sex and age (50–54 years, 55–59 years, 60–64 years, 65–69 years, and 70–74 years) in each centre. Low-dose spiral CT abnormality and non-calcified nodule/mass distribution were assessed. In each arm, compliance with the screening exams, positivity rates at the baseline screening, and compliance with diagnostic follow-up after positive screening exams were also studied.InterpretationThis is the first randomised trial of lung and colorectal cancer screening in China. Results from the Feasibility Study will help to develop a practical design for the Randomised Cancer Screening Trial in China.FundingCancer Institute and Hospital, Chinese Academy of Medical Sciences, and The National Health and Family Plan Committee of China.

Some researchers in other regions have recommended human papillomavirus (HPV) vaccination to reduce risk of ovarian cancer, but not in North America, where evidence has previously suggested no role for HPV in ovarian cancer. Here we use a large sample of ovarian cancer transcriptomes (RNA-Seq) from The Cancer Genome Atlas (TCGA) database to address whether HPV is involved with ovarian cancer in North America. We estimate that a known high-risk type of HPV (type 18) is present and active in 1.5% of cases of ovarian epithelial cancers in the US and Canada. Our detection methods were verified by negative and positive controls, and our sequence matches indicated high validity, leading to strong confidence in our conclusions. Our results indicate that previous reports of zero prevalence of HPV in North American cases of ovarian cancer should not be considered conclusive. This is important because currently used vaccines protect against the HPV-18 that is active in ovarian tumors and, therefore, may reduce risk in North America of cancers of the ovaries as well as of the cervix and several other organ sites.

Abstract Background: The predictive value of chemopreventive agent efficacy in morphologic (in vitro/in vivo) assays for efficacy in animal (mouse and rat) in vivo tumor assays is not well characterized. Over a 25-year period, the Chemopreventive Agent Development Research Group in the U.S. NCI’s Division of Cancer Prevention has tested approximately 800 agents for potential chemopreventive activity. The current project focuses on a subset of 146 that were tested in both morphologic and mammary gland tumor assays in order to gain a deeper understanding of the relevant predictive value. Materials and Methods: The early stages of the testing pathway involve two critical steps: (1) in vitro/in vivo morphologic assays and, for agents successful in these, (2) testing for tumor prevention (measured in terms of tumor incidence and multiplicity reduction) in animal tumor assays. The ultimate goal is to test agents that successfully decrease tumor incidence and multiplicity in animal tumor assays in humans. In the current project we evaluated the predictive values of the earlier-stage (morphologic) assays for efficacy in the later-stage (animal tumor, specifically mammary tumor) assays. Statistical modeling to determine how well the six most commonly used morphologic assays predicted efficacy of the 146 tested agents in mouse and rat mammary gland tumor assays was carried out by multimodel inference applied to ordinal logistic regression. Results: The ability of these six morphologic assays to predict tumor outcomes was evaluated in the mouse and rat mammary gland cancer assays. Based on this statistical modeling, each morphologic assay was assigned a value describing how strongly it predicted outcomes in the mammary gland tumor assays. Selected morphologic assays (the mouse mammary organ culture (MMOC) and human foreskin epithelial cell (HFE) morphologic assays) in combination give a predictive value that meaningfully forecasts results for chemopreventive efficacy in the mouse and rat mammary gland tumor assays. Conclusions: These predictive models can be used to guide our future decision-making with respect to agent selection as well as morphologic and animal tumor assay use. Our future work is focused on deepening our understanding of our Predictive Value approach by: (1) identifying the mammary gland tumor assays that best reflect anti-tumor efficacy in animals; (2) teasing apart those classes of agents that exhibit the highest predictive values overall; and (3) examining which agent classes show the highest efficacy in specific mammary gland tumor assays. Citation Format: Barbara K Dunn, Vernon E Steele, Carol F Topp, Richard M Fagerstrom, Barnett S Kramer. Understanding predictive values of short-term morphologic assays of cancer chemoprevention for efficacy in animal mammary gland tumor assays [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-11-06.

NCI9s Division of Cancer Prevention has over 25 years entered some 800 agents into a program designed to test cancer preventive efficacy. Early in the testing pathway are 2 sequential critical steps: (1) in vitro/in vivo morphologic assays and, (2) for agents successful in step 1, cancer-preventive testing (measured in terms of tumor incidence and multiplicity reduction) in animal tumor assays. The ultimate intention is to follow successful testing in animals with entry into clinical trial testing in humans. To facilitate the optimal selection of appropriate morphologic tests for specific disease-site animal tumor models, we undertook the current project. We evaluated the success of our strategy by determining how accurately the earlier stage (morphologic) assays predict efficacy in the later-stage (animal tumor) assays. Focusing on 210 agents that were tested in both morphologic and animal tumor assays, we carried out statistical modeling of how well the 6 most commonly used morphologic assays predicted drug efficacy in animal tumor models. Using multimodel inference, three statistical models were generated to evaluate the ability of these 6 morphologic assays to predict tumor outcomes in 3 different sets of animal tumor assays: (1) all tumor types, (2) breast cancer only, and (3) colon cancer only. Using this statistical modeling approach, each morphologic assay was assigned a value reflecting how strongly it predicted outcomes in each of the 3 different sets of animal tumor assays. The goal is to use predictive models such as these to guide our future decision-making with respect to selection of preventive agents as well as morphologic and animal tumor assays. In this manner, we hope to improve the efficiency of our overall approach to chemoprevention agent development. Citation Format: Barbara K. Dunn, Vernon E. Steele, Richard M. Fagerstrom, Carol F. Topp, David Ransohoff, Leslie G. Ford, Barnett S. Kramer. Predicting efficacy of chemopreventive agents in animal tumor assays by statistical modeling. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B53.

Abstract Background: Understanding the ability of chemopreventive agent efficacy in morphologic (in vitro/in vivo) assays to predict efficacy in animal (mouse and rat) in vivo tumor assays has not been well studied. The Chemopreventive Agent Development Research Group (CADRG) in the U.S. NCI's Division of Cancer Prevention has, over 25 years, tested approximately 800 agents for potential chemopreventive activity. Of these agents, a subset of 146 that were tested in both morphologic and mammary gland tumor assays constitutes the focus of our current project. Our goal is to gain deeper insight into the relevant predictive values. Materials and Methods: Two critical steps are involved in the early stages of the CADRG testing pathway: (1) in vitro/in vivo morphologic assays and, for agents successful in these, (2) testing for tumor prevention (measured in terms of tumor incidence and multiplicity reduction) in animal tumor assays. Ultimately, our goal is to test agents that successfully decrease tumor incidence and multiplicity in animal tumor assays in humans. In the project presented here, we evaluated the predictive values of earlier-stage (morphologic) assays for efficacy in later-stage (animal tumor, specifically mammary tumor) assays. We used statistical modeling to determine how well the six most commonly used morphologic assays predicted efficacy of the 146 tested agents in mouse and rat mammary gland tumor assays. For this purpose multimodel inference was applied to ordinal logistic regression. Results: We evaluated the ability of the six morphologic assays to predict tumor outcomes in the mouse and rat mammary gland cancer assays. In our statistical modeling approach, each morphologic assay was assigned a value describing how strongly it predicted outcomes in the mammary gland tumor assays. Specific morphologic assays (mouse mammary organ culture/MMOC and human foreskin epithelial cell/HFE morphologic assays) in combination yielded predictive values that are reasonably suggestive of the efficacy demonstrated by chemopreventive agents in the mouse and rat mammary gland tumor assays. Conclusions: Predictive models such as these should prove useful in guiding future decision-making regarding agent selection and morphologic and animal tumor assay use. Our current strategy is to gain insight into the Predictive Value approach by: (1) identifying the mammary gland tumor assays that best reflect anti-tumor efficacy in animals; (2) teasing apart those classes of agents that exhibit the highest predictive values overall; and (3) examining those classes of agents that exhibit the highest efficacy in specific mammary gland tumor assays. Citation Format: Barbara K. Dunn, Vernon E. Steele, Richard M. Fagerstrom, Carol F. Topp, Barnett S. Kramer. Chemoprevention of mammary cancer: Modeling predictive values of short-term morphologic assays for efficacy in animal tumor assays. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2813. doi:10.1158/1538-7445.AM2015-2813

BACKGROUND:Over 25 years, the National Cancer Institute's Division of Cancer Prevention has entered some 800 agents into a chemopreventive agent testing program. Two critical steps involve: 1) in vitro/in vivo morphologic assays and 2) animal tumor assays (incidence/multiplicity reduction). We sought to determine how accurately the earlier-stage (morphologic) assays predict efficacy in the later-stage (animal tumor) assays.METHODS:Focusing on 210 agents tested in both morphologic and animal tumor assays, we carried out statistical modeling of how well the six most commonly used morphologic assays predicted drug efficacy in animal tumor assays. Using multimodel inference, three statistical models were generated to evaluate the ability of these six morphologic assays to predict tumor outcomes in three different sets of animal tumor assays: 1) all tumor types, 2) mammary cancer only, and 3) colon cancer only. Using this statistical modeling approach, each morphologic assay was assigned a value reflecting how strongly it predicted outcomes in each of the three different sets of animal tumor assays.RESULTS:We demonstrated differences in the predictive value of specific morphologic assays for positive animal tumor assay results. Some of the morphologic assays were strongly predictive of meaningful positive efficacy outcomes in animal tumor assays representing specific cancer types, particularly the aberrant crypt focus (ACF) assay for colon cancer. Moreover, less strongly predictive assays can be combined and sequenced, resulting in enhanced composite predictive ability.CONCLUSIONS:Predictive models such as these could be used to guide selection of preventive agents as well as morphologic and animal tumor assays, thereby improving the efficiency of our approach to chemopreventive agent development.

Unsatisfactory progress in cancer medicine and prevention calls for new research approaches. Research can broaden its view of cancer to include not only specific molecular elements, but also the process that explains their origin and dynamics. This process is Darwinian evolution of somatic cells. Applicable modeling techniques are available from process-oriented systems biology. We review relevant concepts and techniques, and their application to four key open questions in cancer prevention research. Helpful concepts are transferable from classical evolutionary biology and ecology, while useful techniques include computational agent-based modeling. The research questions we review include (1) why do benign neoplasms often progress to malignancy? (2) what is the chronological sequence of molecular events in cancer progression? (3) how can we find reliable molecular biomarkers for cancer? and (4) will evolved drug resistance stymie efforts at a long-term cancer chemoprevention? We conclude that molecular analysis can be usefully augmented with process-oriented systems biology to guide empirical research into the most productive directions.

BACKGROUND The National Lung Screening Trial was conducted to determine whether three annual screenings (rounds T0, T1, and T2) with low-dose helical computed tomography (CT), as compared with chest radiography, could reduce mortality from lung cancer. We present detailed findings from the first two incidence screenings (rounds T1 and T2). METHODS We evaluated the rate of adherence of the participants to the screening protocol, the results of screening and downstream diagnostic tests, features of the lung-cancer cases, and first-line treatments, and we estimated the performance characteristics of both screening methods. RESULTS At the T1 and T2 rounds, positive screening results were observed in 27.9% and 16.8% of participants in the low-dose CT group and in 6.2% and 5.0% of participants in the radiography group, respectively. In the low-dose CT group, the sensitivity was 94.4%, the specificity was 72.6%, the positive predictive value was 2.4%, and the negative predictive value was 99.9% at T1; at T2, the positive predictive value increased to 5.2%. In the radiography group, the sensitivity was 59.6%, the specificity was 94.1%, the positive predictive value was 4.4%, and the negative predictive value was 99.8% at T1; both the sensitivity and the positive predictive value increased at T2. Among lung cancers of known stage, 87 (47.5%) were stage IA and 57 (31.1%) were stage III or IV in the low-dose CT group at T1; in the radiography group, 31 (23.5%) were stage IA and 78 (59.1%) were stage III or IV at T1. These differences in stage distribution between groups persisted at T2. CONCLUSIONS Low-dose CT was more sensitive in detecting early-stage lung cancers, but its measured positive predictive value was lower than that of radiography. As compared with radiography, the two annual incidence screenings with low-dose CT resulted in a decrease in the number of advanced-stage cancers diagnosed and an increase in the number of early-stage lung cancers diagnosed. (Funded by the National Cancer Institute; NLST ClinicalTrials.gov number, NCT00047385.).

BACKGROUND:Lung cancer is the largest contributor to mortality from cancer. The National Lung Screening Trial (NLST) showed that screening with low-dose helical computed tomography (CT) rather than with chest radiography reduced mortality from lung cancer. We describe the screening, diagnosis, and limited treatment results from the initial round of screening in the NLST to inform and improve lung-cancer-screening programs. METHODS:At 33 U.S. centers, from August 2002 through April 2004, we enrolled asymptomatic participants, 55 to 74 years of age, with a history of at least 30 pack-years of smoking. The participants were randomly assigned to undergo annual screening, with the use of either low-dose CT or chest radiography, for 3 years. Nodules or other suspicious findings were classified as positive results. This article reports findings from the initial screening examination. RESULTS:A total of 53,439 eligible participants were randomly assigned to a study group (26,715 to low-dose CT and 26,724 to chest radiography); 26,309 participants (98.5%) and 26,035 (97.4%), respectively, underwent screening. A total of 7191 participants (27.3%) in the low-dose CT group and 2387 (9.2%) in the radiography group had a positive screening result; in the respective groups, 6369 participants (90.4%) and 2176 (92.7%) had at least one follow-up diagnostic procedure, including imaging in 5717 (81.1%) and 2010 (85.6%) and surgery in 297 (4.2%) and 121 (5.2%). Lung cancer was diagnosed in 292 participants (1.1%) in the low-dose CT group versus 190 (0.7%) in the radiography group (stage 1 in 158 vs. 70 participants and stage IIB to IV in 120 vs. 112). Sensitivity and specificity were 93.8% and 73.4% for low-dose CT and 73.5% and 91.3% for chest radiography, respectively. CONCLUSIONS:The NLST initial screening results are consistent with the existing literature on screening by means of low-dose CT and chest radiography, suggesting that a reduction in mortality from lung cancer is achievable at U.S. screening centers that have staff experienced in chest CT. (Funded by the National Cancer Institute; NLST ClinicalTrials.gov number, NCT00047385.).

Photograph shows two male technicians wearing white lab coats, one wearing shorts, in a large room with multiple sequencing machines. Each genomic sequencer has two beige, cube-shaped parts, one the size of a small refrigerator; the other, lesser-sized portion is the size of a large computer printer. A computer screen sits atop each of the smaller cubes.

Abstract Over the past 25 years the Chemoprevention Agent Development Research Group of the Division of Cancer Prevention in the NCI has entered approximately 800 agents into a program designed to test for cancer preventive efficacy. The first 2 key steps in the testing pathway are in vitro/in vitro morphologic assays and, for agents successful in these, anti-tumor testing (tumor incidence and multiplicity reduction) in animal tumor models. Ultimately, agents that successfully decrease tumor incidence and multiplicity in animal models could progress to testing in humans. The goal of the current project is to evaluate the success of our program by determining how accurately the earlier stage assays (morphologic assays) predict efficacy in the later-stage assays (animal tumor assays). In our approach the 208 agents that were tested in both morphologic and animal tumor assays in this program were included in our analysis. Statistical modeling of the input from the 6 most commonly used morphologic assays into predicting the efficacy of agents in animal tumor models was carried out by multimodel inference. The statistical models that were generated predicted the ability of these 6 morphologic assays to predict tumor outcomes in animal models representing (1) all tumor types, (2) breast cancer only, and (3) colon cancer only. The statistical models assigned each morphologic assay a value describing how strongly it predicted outcomes in each of the 3 animal tumor assay settings. The development of these predictive models will guide our future decision-making with respect to agent selection as well as morphologic and animal tumor assay use. Our goal is to improve the efficiency of the overall process of chemoprevention agent development. Citation Format: Barbara K. Dunn, Vernon E. Steele, Richard M. Fagerstrom, Carol F. Topp, David Ransohoff, Christopher Cunningham, Ronald A. Lubet, Leslie G. Ford, Barnett S. Kramer. Predictive value tools as an aid in chemopreventive agent development. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2595. doi:10.1158/1538-7445.AM2013-2595

BACKGROUND The aggressive and heterogeneous nature of lung cancer has thwarted efforts to reduce mortality from this cancer through the use of screening. The advent of low-dose helical computed tomography (CT) altered the landscape of lung-cancer screening, with studies indicating that low-dose CT detects many tumors at early stages. The National Lung Screening Trial (NLST) was conducted to determine whether screening with low-dose CT could reduce mortality from lung cancer. METHODS From August 2002 through April 2004, we enrolled 53,454 persons at high risk for lung cancer at 33 U.S. medical centers. Participants were randomly assigned to undergo three annual screenings with either low-dose CT (26,722 participants) or single-view posteroanterior chest radiography (26,732). Data were collected on cases of lung cancer and deaths from lung cancer that occurred through December 31, 2009. RESULTS The rate of adherence to screening was more than 90%. The rate of positive screening tests was 24.2% with low-dose CT and 6.9% with radiography over all three rounds. A total of 96.4% of the positive screening results in the low-dose CT group and 94.5% in the radiography group were false positive results. The incidence of lung cancer was 645 cases per 100,000 person-years (1060 cancers) in the low-dose CT group, as compared with 572 cases per 100,000 person-years (941 cancers) in the radiography group (rate ratio, 1.13; 95% confidence interval [CI], 1.03 to 1.23). There were 247 deaths from lung cancer per 100,000 person-years in the low-dose CT group and 309 deaths per 100,000 person-years in the radiography group, representing a relative reduction in mortality from lung cancer with low-dose CT screening of 20.0% (95% CI, 6.8 to 26.7; P=0.004). The rate of death from any cause was reduced in the low-dose CT group, as compared with the radiography group, by 6.7% (95% CI, 1.2 to 13.6; P=0.02). CONCLUSIONS Screening with the use of low-dose CT reduces mortality from lung cancer. (Funded by the National Cancer Institute; National Lung Screening Trial ClinicalTrials.gov number, NCT00047385.).

PURPOSE Multiple cancer screening tests have been advocated for the general population; however, clinicians and patients are not always well-informed of screening burdens.We sought to determine the cumulative risk of a false-positive screening result and the resulting risk of a diagnostic procedure for an individual participating in a multimodal cancer screening program.METHODS Data were analyzed from the intervention arm of the ongoing Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, a randomized controlled trial to determine the effects of prostate, lung, colorectal, and ovarian cancer screening on disease-specifi c mortality.The 68,436 participants, aged 55 to 74 years, were randomized to screening or usual care.Women received serial serum tests to detect cancer antigen 125 (CA-125), transvaginal sonograms, posteroanterior-view chest radiographs, and fl exible sigmoidoscopies.Men received serial chest radiographs, fl exible sigmoidoscopies, digital rectal examinations, and serum prostate-specifi c antigen tests.Fourteen screening examinations for each sex were possible during the 3-year screening period. RESULTSAfter 14 tests, the cumulative risk of having at least 1 false-positive screening test is 60.4% (95% CI, 59.8%-61.0%)for men, and 48.8% (95% CI, 48.1%-49.4%)for women.The cumulative risk after 14 tests of undergoing an invasive diagnostic procedure prompted by a false-positive test is 28.5% (CI, 27.8%-29.3%)for men and 22.1% (95% CI, 21.4%-22.7%)for women.CONCLUSIONS For an individual in a multimodal cancer screening trial, the risk of a false-positive fi nding is about 50% or greater by the 14th test.Physicians should educate patients about the likelihood of false positives and resulting diagnostic interventions when counseling about cancer scree ning.

OBJECTIVE. The purpose of this study was to describe the effect of implementing an imaging quality assurance program on CT image quality in the Lung Screening Study component of the National Lung Screening Trial.MATERIALS AND METHODS. The National Lung Screening Trial is a multicenter study in which 53,457 subjects at increased risk of lung cancer were randomized to undergo three annual chest CT or radiographic screenings for lung cancer to determine the relative effect of use of the two screening tests on lung cancer mortality. Of the 26,724 subjects randomized to the CT screening arm of the National Lung Screening Trial, the Lung Screening Study randomized 17,309 through 10 screening centers. The others were randomized through the American College of Radiology Imaging Network. Quality assurance procedures were implemented that included centralized review of a random sample of 1,504 Lung Screening Study CT examinations. Quality defect rates were tabulated.RESULTS. Quality defect rates ranged from 0% (section reconstruction interval) to 7.1% (reconstructed field of view), and most errors were sporadic. However, a recurrently high effective tube current-time product setting at one center, excessive streak artifact at one center, and excessive section thickness at one center were detected and corrected through the quality assurance process. Field-of-view and scan length errors were less frequent over the second half of the screening period (p < 0.01 for both parameters, two-tailed, paired Student's t test). Error rates varied among the screening centers and reviewers for most parameters evaluated.CONCLUSION. Our experience suggested that centralized monitoring of image quality is helpful for reducing quality defects in multicenter trials.

PURPOSE:To evaluate agreement among radiologists on the interpretation of pulmonary findings at low-dose computed tomographic (CT) screening examinations for lung cancer.MATERIALS AND METHODS:Institutional review board approval and informed consent were obtained. HIPAA guidelines were followed. Sixteen radiologists from the 10 National Lung Screening Trial screening centers of the National Cancer Institute's Lung Screening Study network reviewed image subsets from 135 baseline low-dose screening CT examinations in 135 trial participants (89 men, 46 women; mean age, 62.7 years +/- 5.4 [standard deviation]). Interpretations were classified into one of four of the following categories: noncalcified nodule 4 mm or larger in greatest transverse dimension (positive screening result); noncalcified nodule smaller than 4 mm in greatest transverse dimension (negative screening result); calcified, benign nodule (negative screening result); or no nodule (negative screening result). A recommendation for follow-up evaluation was obtained for each case. Interobserver agreement was evaluated by using the multirater kappa statistic and by using response frequencies and descriptive statistics.RESULTS:Multirater kappa values ranged from 0.58 (for agreement among all four classifications; 95% confidence interval: 0.55, 0.61) to 0.64 (for agreement on classification as a positive or negative screening result; 95% confidence interval: 0.62, 0.65). The average percentage of reader pairs in agreement on the screening result per case (percentage agreement) was 82%. There was wide variation in the total number of abnormalities detected and classified as pulmonary nodules, with differences of up to more than twofold among radiologists. For cases classified as positive, multirater kappa for follow-up recommendations was 0.35.CONCLUSION:Interobserver agreement was moderate to substantial; potential for considerable improvement exists. Clinical trial registration no. NCT00047385.