Solid Cancer Incidence among the Life Span Study of Atomic Bomb Survivors: 1958-2009

Abstract

This is the third analysis of solid cancer incidence among the Life Span Study (LSS) cohort of atomic bomb survivors in Hiroshima and Nagasaki, adding eleven years of follow-up data since the previously reported analysis. For this analysis, several changes and improvements were implemented, including updated dose estimates (DS02R1) and adjustment for smoking. Here, we focus on all solid cancers in aggregate. The eligible cohort included 105,444 subjects who were alive and had no known history of cancer at the start of follow-up. A total of 80,205 subjects had individual dose estimates and 25,239 were not in either city at the time of the bombings. The follow-up period was 1958-2009, providing 3,079,484 person-years of follow-up. Cases were identified by linkage with population-based Hiroshima and Nagasaki Cancer Registries. Poisson regression methods were used to elucidate the nature of the radiation-associated risks per Gy of weighted absorbed colon dose using both excess relative risk (ERR) and excess absolute risk (EAR) models adjusted for smoking. Risk estimates were reported for a person exposed at age 30 years with attained age of 70 years. In this study, 22,538 incident first primary solid cancer cases were identified, of which 992 were associated with radiation exposure. There were 5,918 cases (26%) that occurred in the 11 years (1999-2009) since the previously reported study. For females, the dose response was consistent with linearity with an estimated ERR of 0.64 per Gy (95% CI: 0.52 to 0.77). For males, significant upward curvature over the full dose range as well as restricted dose ranges was observed and therefore, a linear-quadratic model was used, which resulted in an ERR of 0.20 (95% CI: 0.12 to 0.28) at 1 Gy and an ERR of 0.010 (95% CI: -0.0003 to 0.021) at 0.1 Gy. The shape of the ERR dose response was significantly different among males and females (P = 0.02). While there was a significant decrease in the ERR with increasing attained age, this decrease was more rapid in males compared to females. The lowest dose range that showed a statistically significant dose response using the sex-averaged, linear ERR model was 0-100 mGy (P = 0.038). In conclusion, this analysis demonstrates that solid cancer risks remain elevated more than 60 years after exposure. Sex-averaged upward curvature was observed in the dose response independent of adjustment for smoking. Findings from the current analysis regarding the dose-response shape were not fully consistent with those previously reported, raising unresolved questions. At this time, uncertainties in the shape of the dose response preclude definitive conclusions to confidently guide radiation protection policies. Upcoming results from a series of analyses focusing on the radiation risks for specific organs or organ families, as well as continued follow-up are needed to fully understand the nature of radiation-related cancer risk and its public health significance. Data and analysis scripts are available for download at: http://www.rerf.or.jp .

FIG. A1.

Proportion of deaths autopsied by year of death and colon dose categories. The autopsy program was very active primarily in the 1960s. Those dying in that decade tended to be older at the time of the bombing. More autopsies were performed on those populations exposed to higher doses, particularly in the 1960s and 1970s.

FIG. A2.

Age-at-exposure effects on radiation risk and the impact of autopsy-only cases. Sex-averaged ERR estimates at 1 Gy in linear ERR models as a function of age at exposure at attained age of 70 years. Black solid dots are nonparametric estimates when excluding autopsy-only cases (with Wald 95% confidence intervals). Open gray diamonds (offset two years to the right to avoid overlap) show nonparametric estimates when including autopsy-only cases. The dot-dash line shows a quadratic spline model fit while including autopsy-only cases. The solid black line shows a standard log-linear fit to the data when excluding autopsy-only cases. The gray dashed line represents a model where the ERR can decrease in a log-linear fashion to age at exposure = 30 years with no further changes for those exposed later in life (adopted by the BEIR VII report). After censoring the autopsy-only cases, the quadratic spline (dot-dash line) could be statistically rejected compared to the log-linear model. The BEIR VII model did not fit the data statistically better than the log-linear model. The log-linear model was used throughout this article.

FIG. 1.

Solid cancer baseline rates. Panel A: Fitted Life Span Study all-solid-cancer incidence rates for nonsmokers with no exposure (baseline rates) for the period from 1958 to 2009 versus attained age and by sex for three birth years (1895, 1915 and 1935) and averaged across cities based on a multiplicative model that included radiation and smoking. Panel B shows how the female-to-male sex ratio (F:M) varied with attained age for these three birth cohorts.

FIG. 2.

Smoking effects on solid cancer baseline rates. Panel A: Smoking ERR as a function of attained age for males (black curves) and females (gray curves). The solid curves represent lifelong smokers while the dashed curves represent past smokers from the age at which they quit (shown are male past smokers quitting at age 50 years and female past smokers quitting at age 55 years). Panel B: Total smoking risk for current smokers, past smokers and those who never smoked (thin solid curves) for males and females. The curves represent typical smoking histories. Male smokers started at age 20 years and smoked 20 cigarettes per day while female smokers started at 30 years and smoked 10 cigarettes per day (cpd).

FIG. 3.

Age-at-exposure and attained-age effects on solid cancer ERRs at 1 Gy by age at exposure and sex. Panel A shows how the radiation ERRs varied with attained age by sex (gray for females and black for males) and by age of exposure. This is a linear ERR model with multiplicative adjustment for smoking, sex-averaged age-at-exposure modification and sex-specific attained-age modification. Panel B shows how the female-to-male (F:M) ERR ratio varies with attained age at 1 Gy.

FIG. 4.

Panels A and B: Solid cancer dose-response functions for males and females (full dose range). Fitted linear (black dashed line) and linear-quadratic (black solid curve) ERRs for all solid cancers using linear and linear-quadratic dose-response functions for males and females. Also shown are ERR estimates for all 22 dose categories (points) and a nonparametric smoothed estimate (solid gray curve) with point-wise 95% confidence intervals (dashed gray curves). The ERRs are given for subjects at attained age of 70 years after exposure at age 30 years.

FIG. 5.

Panels A and B: Solid cancer dose-response functions for males and females (0–1 Gy). Fitted linear (black dashed line) and linear-quadratic (black solid curve) ERRs for all solid cancers using linear and linear-quadratic dose-response functions for males and females over the range of 0–1 Gy. Also shown are ERR estimates for 15 visible dose categories (points) and a nonparametric smoothed estimate (solid gray curve) with point-wise 95% confidence intervals (dashed gray curves). The ERRs are given for subjects at attained age of 70 years after exposure at age 30 years.

FIG. 6.

Solid cancer excess rates (EARs) at 1 Gy by attained age, sex and age at exposure. Panel A: Excess absolute rates at 1 Gy as a function of attained age for males (black curves) and females (gray curves) exposed at ages 10 years (dashed), 30 years (solid) and 50 years (dash-dot). Panel B plots the female-to-male (F:M) EAR ratio at 1 Gy as a function of attained age.

FIG. 7.

Preferred ERR and EAR models by sex. The dose-response functions in the preferred ERR (panel A) and EAR (panel B) models are shown. Panels C and D show the female-to-male (F:M) risk ratio versus dose. The dose-response curves are shown for subjects at attained age of 70 years after exposure at age 30 years.