William D. Hazelton

Biologically Based Analysis of the Data for the Colorado Uranium Miners Cohort: Age, Dose and Dose-Rate Effects

This study is a comprehensive analysis of the latest follow-up of the Colorado uranium miners cohort using the two-stage clonal expansion model with particular emphasis on effects related to age and exposure. The model provides a framework in which the hazard function for lung cancer mortality incorporates detailed information on exposure to radon and radon progeny from hard rock and uranium mining together with information on cigarette smoking. Even though the effect of smoking on lung cancer risk is explicitly modeled, a significant birth cohort effect is found which shows a linear increase in the baseline lung cancer risk with birth year of the miners in the cohort. The analysis based on the two-stage clonal expansion model suggests that exposure to radon affects both the rate of initiation of intermediate cells in the pathway to cancer and the rate of proliferation of intermediate cells. However, in contrast to the promotional effect of radon, which is highly significant, the effect of radon on the rate of initiation is found to be not significant. The model is also used to study the inverse dose-rate effect. This effect is evident for radon exposures typical for mines but is predicted to be attenuated, and for longer exposures even reversed, for the more protracted and lower radon exposures in homes. The model also predicts the drop in risk with time after exposure ceases. For residential exposures, lung cancer risks are compared with the estimates from the BEIR VI report. While the risk estimates are in agreement with those derived from residential studies, they are about two- to fourfold lower than those reported in the BEIR VI report.

Impact of Reduced Tobacco Smoking on Lung Cancer Mortality in the United States During 1975–2000

Background Considerable effort has been expended on tobacco control strategies in the United States since the mid-1950s. However, we have little quantitative information on how changes in smoking behaviors have impacted lung cancer mortality. We quantified the cumulative impact of changes in smoking behaviors that started in the mid-1950s on lung cancer mortality in the United States over the period 1975–2000. Methods A consortium of six groups of investigators used common inputs consisting of simulated cohort-wise smoking histories for the birth cohorts of 1890 through 1970 and independent models to estimate the number of US lung cancer deaths averted during 1975–2000 as a result of changes in smoking behavior that began in the mid-1950s. We also estimated the number of deaths that could have been averted had tobacco control been completely effective in eliminating smoking after the Surgeon General’s first report on Smoking and Health in 1964. Results Approximately 795 851 US lung cancer deaths were averted during the period 1975–2000: 552 574 among men and 243 277 among women. In the year 2000 alone, approximately 70 218 lung cancer deaths were averted: 44 135 among men and 26 083 among women. However, these numbers are estimated to represent approximately 32% of lung cancer deaths that could have potentially been averted during the period 1975–2000, 38% of the lung cancer deaths that could have been averted in 1991–2000, and 44% of lung cancer deaths that could have been averted in 2000. Conclusions Our results reflect the cumulative impact of changes in smoking behavior since the 1950s. Despite a large impact of changing smoking behaviors on lung cancer deaths, lung cancer remains a major public health problem. Continued efforts at tobacco control are critical to further reduce the burden of this disease.

Analysis of a Historical Cohort of Chinese Tin Miners with Arsenic, Radon, Cigarette Smoke, and Pipe Smoke Exposures Using the Biologically Based Two-Stage Clonal Expansion Model

Abstract Hazelton, W. D., Luebeck, E. G., Heidenreich, W. F. and Moolgavkar, S. H. Analysis of a Historical Cohort of Chinese Tin Miners with Arsenic, Radon, Cigarette Smoke, and Pipe Smoke Exposures Using the Biologically Based Two-Stage Clonal Expansion Model. Radiat. Res. 156, 78–94 (2001). The two-stage clonal expansion model is used to analyze lung cancer mortality in a cohort of Yunnan tin miners based on individual histories with multiple exposures to arsenic, radon, cigarette smoke, and pipe smoke. Advances in methodology include the use of nested dose–response models for the parameters of the two-stage clonal expansion model, calculation of attributable risks for all exposure combinations, use of both a fixed lag and a gamma distribution to represent the time between generation of the first malignant cell and death from lung cancer, and scaling of biological parameters allowed by parameter identifiability. The cohort consists of 12,011 males working for the Yunnan Tin Corporation, with complete exposure records, who were initially surveyed in 1976 and followed through 1988. Tobacco and arsenic dominate the attributable risk for lung cancer. Of 842 lung cancer deaths, 21.4% are attributable to tobacco alone, 19.7% to a combination of tobacco and arsenic, 15.8% to arsenic alone, 11% to a combination of arsenic and radon, 9.2% to a combination of tobacco and radon, 8.7% to combination of arsenic, tobacco and radon, 5.5% to radon alone, and 8.7% to background. The models indicate that arsenic, radon and tobacco increase cell division, death and malignant conversion of initiated cells, but with significant differences in net cell proliferation rates in response to the different exposures. Smoking a bamboo water pipe or a Chinese long-stem pipe appears to confer less risk than cigarette use, given equivalent tobacco consumption.

Analysis of lung cancer incidence in the nurses' health and the health professionals' follow-up studies using a multistage carcinogenesis model

We analyzed lung cancer incidence among non-smokers, continuing smokers, and ex-smokers in the Nurses Health Study (NHS) and the Health Professionals Follow-Up Study (HPFS) using the two-stage clonal expansion (TSCE) model. Age-specific lung cancer incidence rates among non-smokers are identical in the two cohorts. Within the framework of the model, the main effect of cigarette smoke is on the promotion of partially altered cells on the pathway to cancer. Smoking-related promotion is somewhat higher among women, whereas smoking-related malignant conversion is somewhat lower. In both cohorts the relative risk for a given daily level of smoking is strongly modified by duration. Among smokers, the incidence in NHS relative to that in HPFS depends both on smoking intensity and duration. The age-adjusted risk is somewhat larger in NHS, but not significantly so. After smokers quit, the risk decreases over a period of many years and the temporal pattern of the decline is similar to that reported in other recent studies. Among ex-smokers, the incidence in NHS relative to that in HPFS depends both on previous levels of smoking and on time since quitting. The age-adjusted risk among ex-smokers is somewhat higher in NHS, possibly due to differences in the age-distribution between the two cohorts.

Multistage Models and the Incidence of Cancer in the Cohort of Atomic Bomb Survivors

Abstract Heidenreich, W. F., Luebeck, E. G., Hazelton, W. D., Paretzke, H. G. and Moolgavkar, S. H. Multistage Models and the Incidence of Cancer in the Cohort of Atomic Bomb Survivors. Radiat. Res. 158, 607–614 (2002). The analyses in this paper show that a number of biologically based models describe cancer incidence among the A-bomb survivors equally well. However, these different models can predict very different temporal patterns of risk after irradiation. No evidence was found to support the previous claim of Pierce and Mendelsohn that excess cancer risks for the solid tumors depend only upon attained age and not on age at exposure or time since exposure. Although the A-bomb survivor cohort is the largest epidemiological data set for the study of radiation and cancer, it is not large enough to discriminate among various possible carcinogenic mechanisms. Unfortunately for hypothesis generation, the data appear to be consistent with a number of different mechanistic interpretations of the role of radiation in carcinogenesis.

Impact of Tumor Progression on Cancer Incidence Curves

Cancer arises through a multistage process, but it is not fully clear how this process influences the age-specific incidence curve. Studies of colorectal and pancreatic cancer using the multistage clonal expansion (MSCE) model have identified two phases of the incidence curves. One phase is linear, beginning about age of 60 years, suggesting that at least two rare rate-limiting mutations occur before clonal expansion of premalignant cells. A second phase is exponential, seen in early-onset cancers occurring before the age of 60 years that are associated with premalignant clonal expansion. Here, we extend the MSCE model to include clonal expansion of malignant cells, an advance that permits study of the effects of tumor growth and extinction on the incidence of colorectal, gastric, pancreatic, and esophageal adenocarcinomas in the digestive tract. After adjusting the age-specific incidence for birth-cohort and calendar-year trends, we found that initiating mutations and premalignant cell kinetics can explain the primary features of the incidence curve. However, we also found that the incidence data of these cancers harbored information on the kinetics of malignant clonal expansion before clinical detection, including tumor growth rates and extinction probabilities on three characteristic time scales for tumor progression. In addition, the data harbored information on the mean sojourn times for premalignant clones until occurrence of either the first malignant cell or the first persistent (surviving) malignant clone. Finally, the data also harbored information on the mean sojourn time of persistent malignant clones to the time of diagnosis. In conclusion, cancer incidence curves can harbor significant information about hidden processes of tumor initiation, premalignant clonal expansion, and malignant transformation, and even some limited information on tumor growth before clinical detection.

Comparative analysis of 5 lung cancer natural history and screening models that reproduce outcomes of the NLST and PLCO trials.

The National Lung Screening Trial (NLST) demonstrated that low‐dose computed tomography screening is an effective way of reducing lung cancer (LC) mortality. However, optimal screening strategies have not been determined to date and it is uncertain whether lighter smokers than those examined in the NLST may also benefit from screening. To address these questions, it is necessary to first develop LC natural history models that can reproduce NLST outcomes and simulate screening programs at the population level.

Calibrating disease progression models using population data: a critical precursor to policy development in cancer control

There are many more strategies for early detection of cancer than can be evaluated with randomized trials. Consequently, model-projected outcomes under different strategies can be useful for developing cancer control policy provided that the projections are representative of the population. To project population-representative disease progression outcomes and to demonstrate their value in assessing competing early detection strategies, we implement a model linking prostate-specific antigen (PSA) levels and prostate cancer progression and calibrate it to disease incidence in the US population. PSA growth is linear on the logarithmic scale with a higher slope after disease onset and with random effects on intercepts and slopes; parameters are estimated using data from the Prostate Cancer Prevention Trial. Disease onset, metastatic spread, and clinical detection are governed by hazard functions that depend on age or PSA levels; parameters are estimated by comparing projected incidence under observed screening and biopsy patterns with incidence observed in the Surveillance, Epidemiology, and End Results registries. We demonstrate implications of the model for policy development by projecting early detections, overdiagnosis, and mean lead times for PSA cutoffs 4.0 and 2.5 ng/mL and for screening ages 50-74 or 50-84. The calibrated model validates well, quantifies the tradeoffs involved across policies, and indicates that PSA screening with cutoff 4.0 ng/mL and screening ages 50-74 performs best in terms of overdiagnosis per early detection. The model produces representative outcomes for selected PSA screening policies and is shown to be useful for informing the development of sound cancer control policy.

Exploring the Recent Trend in Esophageal Adenocarcinoma Incidence and Mortality Using Comparative Simulation Modeling

Background: The incidence of esophageal adenocarcinoma (EAC) has increased five-fold in the United States since 1975. The aim of our study was to estimate future U.S. EAC incidence and mortality and to shed light on the potential drivers in the disease process that are conduits for the dramatic increase in EAC incidence. Methods: A consortium of three research groups calibrated independent mathematical models to clinical and epidemiologic data including EAC incidence from the Surveillance, Epidemiology, and End Results (SEER 9) registry from 1975 to 2010. We then used a comparative modeling approach to project EAC incidence and mortality to year 2030. Results: Importantly, all three models identified birth cohort trends affecting cancer progression as a major driver of the observed increases in EAC incidence and mortality. All models predict that incidence and mortality rates will continue to increase until 2030 but with a plateauing trend for recent male cohorts. The predicted ranges of incidence and mortality rates (cases per 100,000 person years) in 2030 are 8.4 to 10.1 and 5.4 to 7.4, respectively, for males, and 1.3 to 1.8 and 0.9 to 1.2 for females. Estimates of cumulative cause-specific EAC deaths between both sexes for years 2011 to 2030 range between 142,300 and 186,298, almost double the number of deaths in the past 20 years. Conclusions: Through comparative modeling, the projected increases in EAC cases and deaths represent a critical public health concern that warrants attention from cancer control planners to prepare potential interventions. Impact: Quantifying this burden of disease will aid health policy makers to plan appropriate cancer control measures. Cancer Epidemiol Biomarkers Prev; 23(6); 997–1006. ©2014 AACR.

Biologically Based Analysis of Lung Cancer Incidence in a Large Canadian Occupational Cohort with Low-Dose Ionizing Radiation Exposure, and Comparison with Japanese Atomic Bomb Survivors

Lung cancer incidence is analyzed in a large Canadian National Dose Registry (CNDR) cohort with individual annual dosimetry for low-dose occupational exposure to gamma and tritium radiation using the two-stage clonal expansion model (TSCE) and extensions of the model with up to 10 initiation steps. Models with clonal expansion turned off provide very poor fits and are rejected. Characteristic and distinct temporal patterns of excess relative risk (ERR) are found for dose response affecting early, middle, or late stages of carcinogenesis, that is, initiation with one or more stages, clonal expansion, or malignant conversion. Both fixed lag and lag distributions are used to model time from first malignant cell to incidence. Background rates are adjusted for gender and birth cohort. Lacking individual smoking data, surrogate annual smoking doses based on U.S. annual per capita cigarette consumption appear to account for much of the birth cohort effect, leaving radiation dose response relatively unchanged. The mean cumulative exposure for males receiving nonzero cumulative doses of gamma and tritium radiation was 18.2 mSv. The males have a significant dose response with 33 out of a total of 322 lung cancer cases attributable to radiation. There were 78 incident lung cancer among females, (with mean cumulative exposure of 3.8 mSv among females with nonzero exposure). The dose response for females appears smaller than for males but does not differ significantly from zero or from the male dose response. Findings for males include significant dose-response relationships for promotion and malignant conversion, but not initiation, and a protraction effect (sometimes called an inverse-dose-rate effect, where risk increases with protraction of a given dose). The dose response predicted by our analysis appears consistent with the risk for lung cancer incidence in the Japanese atomic bomb survivors cohort, provided that proper adjustments are made for duration of exposure and differences in background rate parameters. We acknowledge support from the Department of Energy (DOE) under grant DE-FG02-03ER63675, and from the Center for Disease Control (CDC) under grant R01 0H07864. This report makes use of data obtained from the Radiation Effects Research Foundation (RERF) in Hiroshima, Japan. RERF is a private foundation funded equally by the Japanese Ministry of Health and Welfare and the U.S. Department of Energy through the U.S. National Academy of Sciences. The conclusions in this report are those of the authors and do not necessarily reflect the scientific judgment of RERF or its funding agencies.