Cancer Epidemiology 83 (2023) 102341

Contents lists available at ScienceDirect

Cancer Epidemiology
journal homepage: www.elsevier.com/locate/canep

Effect of radiation exposure on survival after first solid cancer diagnosis in

A-bomb survivors
Richard Sposto a, *, Hiromi Sugiyama b, Tatsuaki Tsuruyama c, Alina V. Brenner b
a
Department of Statistics, Radiation Effects Research Foundation, Japan
b
Department of Epidemiology, Radiation Effects Research Foundation, Japan
c
Department of Molecular Biosciences, Radiation Effect Research Foundation, Japan

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Comparison of the estimated effect of atomic bomb radiation exposure on solid cancer incidence and
A-bomb radiation solid cancer mortality in the RERF Life Span Study (LSS) reveals a difference in the magnitude and shape of the
Cancer excess relative risk dose response. A possible contributing factor to this difference is pre-diagnosis radiation effect
Post-diagnosis survival
on post-diagnosis survival. Pre-diagnosis radiation exposure theoretically could influence post-diagnosis survival
by affecting the genetic makeup and possibly aggressiveness of cancer, or by compromising tolerance for
aggressive treatment for cancer.
Methods: We analyze the radiation effect on post-diagnosis survival in 20,463 LSS subjects diagnosed with first-
primary solid cancer between 1958 and 2009 with particular attention to whether death was caused by the first-
primary cancer, other cancer, or non-cancer diseases.
Results: From multivariable Cox regression analysis of cause-specific survival, the excess hazard at 1 Gy (EH1Gy)
for death from the first primary cancer was not significantly different from zero – p = 0.23, EH1Gy = 0.038 (95 %
CI: − 0.023, 0.104). Death from other cancer and death from non-cancer diseases both were significantly asso­
ciated with radiation dose: other cancer EH1Gy = 0.38 (95 % CI: 0.24, 0.53); non-cancer EH1Gy = 0.24 (95 % CI:
0.13, 0.36), both p < 0.001.
Conclusion: There is no detectable large effect of pre-diagnosis radiation exposure on post-diagnosis death from
the first primary cancer in A-bomb survivors.
Impact: A direct effect of pre-diagnosis radiation exposure on cancer prognosis is ruled out as an explanation for
the difference in incidence and mortality dose response in A-bomb survivors.

1. Introduction mortality models. One possible contributing factor to this difference is

The Life Span Study (LSS) of the Radiation Effects Research Foun­
dation is used to quantify the long-term effects of atomic bomb radiation
on cancer incidence and mortality [1–3]. Recently Brenner et al. [4]
updated models of solid cancer incidence and mortality using follow-up
through 2009. Since LSS follow-up for mortality begins in 1950, whereas
follow-up for incidence begins in 1958, these authors compared cancer
mortality using both follow-up from 1950 and follow-up from 1958, the
latter done to compare cancer mortality and incidence using identical
follow-up periods and identical excess-relative risk (ERR) models.
Brenner et al. [4] commented at length about the emerging evidence of
an upward curvature in all solid cancer dose response and a sex-specific
difference in dose response shape between the incidence and the
whether and how pre-diagnosis radiation exposure influences
post-cancer diagnosis survival over and above its influence on cancer
incidence.
In the LSS analyses of solid cancer incidence and mortality it is not
necessarily the case that subjects who die of solid cancers die of the same
cancer as originally diagnosed. Whereas solid cancer incidence analysis
is based on the first primary solid cancer diagnosis, subsequently diag­
nosed cancers different from the first primary may be the ultimate cause
of death.
One can conjecture about mechanisms by which pre-diagnosis ra­
diation exposure could influence mortality from an incident cancer.
Radiation-caused cancer might be genetically and therefore possibly
prognostically distinct from spontaneously occurring cancer. Evidence

* Correspondence to: Department of Statistics, Radiation Effects Research Foundation, 5–2 Hijiyama Park, Minami Ku, Hiroshima City, 732-0815, Japan.
E-mail address: rsposto@rerf.or.jp (R. Sposto).

https://doi.org/10.1016/j.canep.2023.102341
Received 3 August 2022; Received in revised form 28 November 2022; Accepted 16 February 2023
Available online 20 February 2023
1877-7821/© 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
R. Sposto et al. Cancer Epidemiology 83 (2023) 102341

of such genetic differences exists from murine models (e.g., [5,6]) and Table 1
recent human studies[7]. Radiation exposure could alter the immune Classification of cancer diagnoses and causes of death.
system [8,9], possibly affecting individuals’ innate ability to fight cancer Diagnostic Class Diagnosis Cancer ICD-10 Codes
and tolerance of aggressive immunosuppressive treatment for cancer
Gastrointestinal Oral C00 - C14
and therefore treatment effectiveness. Esophageal C15
Under a null hypothesis that pre-diagnosis radiation exposure does Stomach C16
not affect survival after solid cancer diagnosis, one would expect that Colon C18
post-diagnosis survival in individuals who died from the originally Rectum C19 - C20
C22.0, C22.2 - C22.4, C22.7,
diagnosed cancer would not be related to radiation dose. However, post- Liver
C22.9
diagnosis survival of individuals who died of cancers unrelated to the Intrahepatic biliary C22.1
first primary diagnosis could be associated with radiation dose in that Gall bladder C23
radiation exposure is associated with the additional incident cancer [10] Other biliary C24
Pancreatic C25
which led to the subject’s demise. Post-diagnosis survival in individuals
Other digestive C26.0, C26.8 - C26.9, C48.8
who died of non-cancer-related causes could also be associated with Respiratory Laryngeal C32
radiation dose through the effect of radiation on non-cancer mortality Lung C34
[11,12]. Other respiratory C33, C38.1 - C38.3, C38.8, C39
In this paper we investigate this null hypothesis by analyzing post- Breast/Other female Breast C50
Cervical C53
diagnosis survival and its relationship to radiation exposure in sub­ Uterine corpus C54
jects diagnosed with solid cancers in the LSS from 1958 to 2009 with Uterine not otherwise
C55
specific attention to differences in dose response for different causes of specified
death. Bockwoldt et al. [13] recently analyzed post-diagnosis survival in Ovarian C56
Other female C57 - C58
7728 LSS subjects with gastrointestinal cancer who died of this cause.
Prostate/Other
Their analysis was inconclusive as to the association between male
Prostate C61
pre-diagnosis exposure and post-diagnosis survival. In the current Other male C63
analysis, we include all first primary solid cancers in a single analysis Urinary Bladder C67
and investigate differences in the association of prior radiation exposure Kidney C64 - C65
Other urinary C68
to survival for different causes of death. This approach provides a more
Bone or connective
sensitive analysis of the association of radiation dose to post-diagnosis Other solid cancer C40 - C41
tissue
survival, especially in those who died from the originally diagnosed Melanoma C43
cancer. Non-melanoma skin
C44
cancer
C71, D33.0 - D33.2, D43.0 -
2. Methods Brain/CNS
D43.2
Thyroid C73
2.1. Study subjects and classification of incident cancers and cause of Other endocrine
C37, C74 - C75, D35.2 - D35.4,
death D44.3 - D44.5
Other solid cancer C26.1, C76 - C80, C97
Leukemia/
The LSS cohort and methods of follow-up were described in detail Leukemia/Lymphoma C81 - C96
Lymphomaa
previously [2,11]. In brief, the LSS consists of 120,321 subjects Non-cancera Non-Cancer
comprising 93,741 exposed within approximately 10 km of the atomic Alivea Alive at last contact
bomb hypocenter and 26,580 subjects who were farther away from the a
Used only for classification of cause of death
hypocenter and are considered not in city (NIC) and thus not exposed to
radiation. cancer registry and ICD classification of cause of death from the death
For this analysis subjects comprise LSS members with incident solid certificate. Hence, causes of death were classified into one of three
cancers registered in the Hiroshima and Nagasaki cancer registries be­ following failure modes:
tween 1958 and 2009 as analyzed by Grant et al. [2] and Brenner et al.
[4]. Cancers were recorded using the International Classification of (1) Death from the index solid cancer. Cause of death was an exact
Diseases for Oncology (ICD-O), Versions 1–3. [See supplement for match to the cancer diagnosis in terms of the fine categorization
further details]. Vital status of subjects was ascertained every three years in Table 1.
by the nationwide Japanese family registry system (Koseki). Causes of (2) Death from other cancer. Death was from a cancer that did not
deaths reported on death certificates were classified by RERF staff exactly match the index cancer diagnosis in Table 1.
trained in nosology using the relevant version of the International (3) Death from non-cancer. All other causes of death.
Classification of Diseases (ICD) 7th to 10th editions. The end of
follow-up for mortality was December 31, 2009. Compared to the ideal classification, some deaths from cancers that
Incident solid cancers were classified into thirty-two distinct di­ are due to the first primary cancer either through local invasion or
agnoses and then six broader diagnostic classes. Causes of death were metastasis may not be classified as due to the index cancer because they
similarly classified finely using the same diagnosis coding, with the are recorded as a different cancer on the death certificate. Hence,
addition of categories for leukemia/lymphoma (liquid cancers) and non- category (1) might be an overly pure group of deaths from the first
cancer causes of death (Table 1). primary cancer, whereas category (2) is a mixture of deaths from cancers
that are related to and not related to the first primary cancer. The same
2.2. Attribution of cause of death can be said of category (3), which may include deaths attributable, for
example, to cancer treatment side effects and which should be in cate­
In a clinical setting, one would be able in most cases to classify cause gory (1) or (2). The implications of this misclassification are discussed
of death precisely as (i) death from the first primary solid cancer, (ii) below.
death from other cancer, or (iii) death from non-cancer. In this analysis
we can only approximate this categorization, as the data available
comprise only ICD-O classification of the first primary diagnosis in the

2
R. Sposto et al. Cancer Epidemiology 83 (2023) 102341

2.3. Radiation dose
Dosimetry System 2002 Revision 1 (DS02R1) radiation dose esti­
mates were used [14]. As in [2,4] weighted absorbed colon dose (Gy)
was calculated as the sum of the gamma-ray dose plus ten times the
neutron dose to allow for the greater biological effectiveness of neu­
trons. To reduce attenuation biases due to dose errors, dose estimates
were adjusted assuming a 35 % coefficient of variation in errors for
individual doses [15].
2.4. Cox regression analysis
Cox regression analysis [16] was performed for each of the three
modes of failure separately. The time scale was years from diagnosis.
Individuals were censored at the time of last follow-up or at the time of
death from a mode of failure other than the mode of interest in the
analysis. In all analyses the model was stratified by the 32 solid cancer
diagnoses shown in Table 1, as there was demonstrable departure from
the proportional hazards assumption among the different diagnoses.
Covariables included initially in the linear predictor were sex (male,
female), age at diagnosis (continuous, centered at 69), year of birth
(continuous centered at 1919), year of diagnosis (continuous, centered
at 1988), and smoking status at diagnosis (categorical, “never”, “cur­
rent”, “past”, “unknown”) plus second order interactions among these
variables.
Radiation dose effect is reported as excess hazard at 1 Gy (EH1Gy),
where
̂
EH1Gy = e β − 1
with ̂
β the maximum partial-likelihood estimate of the log-linear slope
parameter for radiation dose in Gy. 95 % confidence intervals for EH1Gy
are based on the Wald estimates of standard errors of ̂
β.
Further details of the analysis and variable selection criteria are
provided in the supplement. Statistical computations were performed
using Stata 17 [17].

Table 2
Description of the analytic sample.
Variable Incident Solid Cancer Index Cancer Deaths Other Cancer Deaths Non-Cancer Deaths

Total 20,463 (100 %) 9301 (100 %) 2232 (100 %) 3889 (100 %)

Male 9572 (47 %) 4738 (51 %) 950 (43 %) 1691 (43 %)
Sex
Female 10,891 (53 %) 4563 (49 %) 1282 (57 %) 2198 (57 %)
Hiroshima 14,747 (72 %) 6636 (71 %) 1610 (72 %) 2942 (76 %)
City
Nagasaki 5716 (28 %) 2665 (29 %) 622 (28 %) 947 (24 %)
Before 1970 3171 (15 %) 1729 (19 %) 598 (27 %) 720 (19 %)
1970–1979 3343 (16 %) 1734 (19 %) 568 (25 %) 812 (21 %)
Year of diagnosis 1980–1989 4206 (21 %) 2129 (23 %) 470 (21 %) 1010 (26 %)
1990–1999 4777 (23 %) 2135 (23 %) 413 (19 %) 933 (24 %)
2000–2009 4966 (24 %) 1574 (17 %) 183 (8 %) 414 (11 %)
Under 50 1573 (8 %) 599 (6 %) 238 (11 %) 232 (6 %)
50–59 3086 (15 %) 1397 (15 %) 396 (18 %) 483 (12 %)
Age at diagnosis 60–69 6119 (30 %) 2696 (29 %) 668 (30 %) 1024 (26 %)
70–79 6355 (31 %) 2929 (31 %) 657 (29 %) 1273 (33 %)
80+ 3330 (16 %) 1680 (18 %) 273 (12 %) 877 (23 %)
Before 1900 2463 (12 %) 1493 (16 %) 386 (17 %) 584 (15 %)
1900–1909 3693 (18 %) 2076 (22 %) 546 (24 %) 1054 (27 %)
1910–1919 3866 (19 %) 1900 (20 %) 516 (23 %) 1115 (29 %)
Year of birth
1920–1929 4647 (23 %) 1890 (20 %) 440 (20 %) 724 (19 %)
1930–1939 4114 (20 %) 1465 (16 %) 261 (12 %) 346 (9 %)
1940–1945 1680 (8 %) 477 (5 %) 83 (4 %) 66 (2 %)
0–9 2958 (14 %) 880 (9 %) 130 (6 %) 143 (4 %)
10–19 5379 (26 %) 2087 (22 %) 431 (19 %) 596 (15 %)
20–29 3756 (18 %) 1649 (18 %) 442 (20 %) 815 (21 %)
Age at exposure
30–39 3956 (19 %) 2086 (22 %) 540 (24 %) 1213 (31 %)
40–49 3069 (15 %) 1768 (19 %) 482 (22 %) 815 (21 %)
50+ 1345 (7 %) 831 (9 %) 207 (9 %) 307 (8 %)
<0.005 11,391 (56 %) 5255 (56 %) 1239 (56 %) 2127 (55 %)
0.005–0.099 5144 (25 %) 2307 (25 %) 539 (24 %) 986 (25 %)
Dose (Gy) 0.010–0.99 3220 (16 %) 1439 (15 %) 332 (15 %) 640 (16 %)
1.00–1.99 525 (3 %) 211 (2 %) 100 (4 %) 97 (2 %)
2.0+ 183 (1 %) 89 (1 %) 22 (1 %) 39 (1 %)
never smoker 6485 (32 %) 2357 (25 %) 617 (28 %) 1321 (34 %)
current smoker 5556 (27 %) 2640 (28 %) 628 (28 %) 1092 (28 %)
Smoking status at diagnosis
past smoker 1811 (9 %) 734 (8 %) 146 (7 %) 404 (10 %)
unknown 6611 (32 %) 3570 (38 %) 841 (38 %) 1072 (28 %)
Gastrointestinal 11,637 (57 %) 6189 (67 %) 1104 (49 %) 1988 (51 %)
Respiratory 2375 (12 %) 1639 (18 %) 131 (6 %) 268 (7 %)
Breast/Other female 2990 (15 %) 710 (8 %) 555 (25 %) 712 (18 %)
Cancer diagnosis categories
Prostate/Other male 868 (4 %) 166 (2 %) 63 (3 %) 195 (5 %)
Urinary 957 (5 %) 273 (3 %) 135 (6 %) 250 (6 %)
CNS/Thy/Skin/Bone/Oth 1636 (8 %) 324 (3 %) 244 (11 %) 476 (12 %)
Non cancer 3889 (19 %) 0 (0 %) 0 (0 %) 3889 (100 %)
Gastrointestinal 7230 (35 %) 6189 (67 %) 1041 (47 %) 0 (0 %)
Respiratory 1959 (10 %) 1639 (18 %) 320 (14 %) 0 (0 %)
Breast/Other female 1008 (5 %) 710 (8 %) 298 (13 %) 0 (0 %)
Cancer death categories Prostate/Other male 191 (1 %) 166 (2 %) 25 (1 %) 0 (0 %)
Urinary 350 (2 %) 273 (3 %) 77 (3 %) 0 (0 %)
CNS/Thy/Skin/Bone/Oth 708 (3 %) 324 (3 %) 384 (17 %) 0 (0 %)
Liquid 87 (0 %) 0 (0 %) 87 (4 %) 0 (0 %)
Alive 5041 (25 %) 0 (0 %) 0 (0 %) 0 (0 %)

3
R. Sposto et al.
2.5. Ethical considerations
This study was approved by the RERF Institutional Review Board via
approval of Research Protocols 1–75 (Study of Life-span of A-bomb
survivors, Hiroshima and Nagasaki) and 18–61 (Tumor registry study in
Hiroshima and Nagasaki). The Hiroshima and Nagasaki prefectures
approved the linkages between LSS cohort and data from the Cancer
Registries. The Hiroshima and Nagasaki Medical Associations approved
the linkages with their tumor tissue registries.
3. Results
3.1. Analysis sample description
Of 105,444 individuals in the LSS with known DS02R1 dose who
were alive and not known to have cancer before January 1, 1958 and
who were followed between 1958 and 2009, 22,538 were diagnosed
with incident solid cancer[4]. Of these, 2075 death-certification-only
cases were excluded. Of the remaining 20,463, there were 15,422
deaths, comprising 9301 (60 %) from index cancer, 2232 (15 %) from
other cancer, and 3889 (25 %) from non-cancer. Cause of death varied
by diagnostic class. For GI and respiratory cancers most deaths were due
to the index cancer (67 % and 80 %, respectively). For the other four
classes the minority of deaths were due to the index cancer (range 31–41
%). The composition of the entire analytic sample as well as individuals
who died is shown in Table 2.
3.2. Cumulative mortality of modes of failure
The 10-year cumulative mortality for each of the three modes of
failure was: Index cancer 0.463 (95 % CI: 0.456, 0.470); other cancer
0.0917 (95 % CI: 0.0876, 0.0959); non-cancer 0.134 (95 % CI: 0.129,
0.139). The 30-year cumulative mortality was: index cancer 0.484 (95 %
CI: 0.477, 0.491); other cancer 0.136 (95 % CI: 0.131, 0.142); non-
cancer 0.267 (95 % CI: 0.260, 0.275). Median time to death among
those dying of each cause is approximately 10 months for index cancer
deaths, 7 years for other cancer deaths, and 14 years for non-cancer
deaths (Fig. 1).
3.3. Cox regression analysis
The final models included the main effects of sex, smoking, age at
diagnosis, year of birth, year of diagnosis and weighted colon dose, plus:
interactions between sex and age at diagnosis, year of birth, year of
diagnosis, and diagnostic class; interactions between age at diagnosis
Fig. 1. Cumulative mortality from the index cancer, other cancer, and
non-cancer.
4
Cancer Epidemiology 83 (2023) 102341
and year of birth, year of diagnosis, and diagnostic class; and in­
teractions between years of birth and both year of diagnosis and diag­
nostic class. Parameter estimates and their standard errors are shown in
Supplemental Table 1.
For death from the index cancer there is a small and not statistically
significant (p = 0.23) excess hazard from radiation exposure (EH1Gy =
0.038; 95 % CI: − 0.023, 0.103), with the upper confidence bound
implying an upper limit of radiation effect on EH1Gy of at most about a
10 % increase.
For death from other cancer and death from non-cancer there were
statistically significant effects of radiation exposure on EH1Gy, both
p < 0.001: Other cancer EH1 Gy = 0.38 (95 % CI: 0.24, 0.53); non-cancer
EH1 Gy = 0.24 (95 % CI: 0.13, 0.36).
The interaction between dose and diagnostic class (gastrointestinal,
respiratory, breast/other female, prostate/other male, urinary, and
other) was added to the above final models and tested to investigate
whether there was evidence of differential dose effect depending on
diagnosis, but none was significant: Index cancer, p = 0.50; other can­
cer, p = 0.66; non-cancer, p = 0.79. Quadratic terms in dose were added
to investigate departure from log-linearity, but none was significant:
Index cancer, p = 0.54; other cancer, p = 0.78; non-cancer, p = 0.81.
An interaction between dose and sex was added to investigate whether
there was evidence for differential dose effect depending on sex. There
was no significant difference in the dose effect between males and fe­
males for either index cancer death or other cancer death (p = 0.31 and
p = 0.68, respectively), but there was for non-cancer death, p = 0.0075:
EH1Gy males = 0.084 (95 % CI: − 0.059, 0.25); EH1 Gy females = 0.39
(95 % CI: 0.23, 0.57). An interaction between dose and smoking was
added to investigate whether there was evidence for differential dose
effect depending on smoking history. Similar to the dose X sex interac­
tion, there was no significant difference in dose effect by smoking
category for index cancer death or other cancer death (p = 0.63 and
p = 0.68, respectively), but there was for non-cancer death
(p = 0.0044). This last manifested almost entirely as a significant dose
effect among never smokers (EH1 Gy = 0.52; 95 % CI: 0.32, 0.75), with
lesser effect among unknowns (EH1 Gy = 0.22; 95 % CI: − 0.043, 0.54),
and negligible effects among current and past smokers (EH1 Gy = 0.069;
95 % CI: − 0.085, 0.25 / EH1 Gy = − 0.008; 95 % CI: − 0.30, 0.41,
respectively). This result is confounded with the differential dose effect
for non-cancer death by sex – 89 % of never-smokers are female,
whereas 81 % of current smokers and 79 % of past smokers are male.
Unknown smokers are roughly equally divided by sex.
The estimated EH1 Gy is shown in Fig. 2 for the three modes of failure,
separated by sex for non-cancer cause.
Forty-one percent of subjects exposed to < 0.005 Gy were not in the
Fig. 2. Excess hazard of death at 1 Gy weighted colon dose exposure for each of
the three modes of death. (Point estimates and 95 % confidence intervals).
R. Sposto et al.
city (NIC) at the times of the bombings. When added to the above
baseline models, NIC status was significant for index cancer death,
p < 0.006, hazard ratio (HR) = 0.93 (95 % CI: 0.89, 0.98) and for non-
cancer death, p < 0.001, HR = 0.87 (95 % CI: 0.80, 0.94), meaning that
NIC subjects had slightly better post-diagnosis survival compared to in-
city subjects exposed to < 0.005 Gy. Twenty-eight percent of subjects
resided in Nagasaki at the time of the bombings. When added to the
above models, city was significant only for index cancer deaths,
p < 0.002, HR = 1.08 (95 % CI: 1.03, 1.13), meaning that Nagasaki
subjects had a slightly worse post-diagnosis survival than Hiroshima
subjects. The addition of either NIC or city to the baseline model resulted
in small changes in the estimated EH1 Gy but did not change the result
that dose effect was not significant for index cancer but was significant
for other cancers and non-cancer.
A separate analysis, described in the supplement, which stratified for
the baseline variables yielded comparable results.
When the model (without dose X sex interaction) was used to analyze
all deaths from solid cancer, all deaths from any cancer, or all deaths
from any cause, the corresponding excess hazard estimates were: Solid
cancer EH1Gy = 0.098 (95 % CI: 0.041, 0.16); any cancer EH1Gy = 0.11
(95 % CI: 0.048, 0.16); any cause EH1 Gy = 0.13 (95 % CI: 0.084, 0.19);
all p ≤ 0.001.
4. Discussion
One question that arises is why the estimated dose response and the
shape of the dose response differs between cancer incidence and mor­
tality analysis in the RERF LSS. Complexities in the relationship between
cancer incidence and mortality contribute to such differences. When
analyzing morphologically and topographically different cancers
together as a group, such as is done in the LSS, different cancers will
have different radiation sensitivities for incidence while also having
different post-diagnosis prognosis, even when the latter is not influenced
by pre-diagnosis radiation exposure. An illustrative hypothetical
example would be where, in a collection of cancers, incidence dose
response in all cancers combined is driven solely by one essentially non-
fatal cancer, resulting in no dose response detectable for mortality in all
cancers combined. Another potential contributor to the incidence/
mortality difference in dose response is that, even when focus is on a
cohort followed over identical time periods, individuals who die from a
solid cancer may not have been diagnosed with the solid cancer during
that time period but rather were diagnosed before the beginning of
mortality follow-up, meaning that mortality from less fatal cancers
could be overrepresented in the early periods of follow-up. Also, it can
be shown mathematically that even in the simple case of a single type of
cancer where the excess relative risk for cancer incidence is linear in
dose and there is no dose effect on post-diagnosis survival, there
nevertheless is non-linearity in the mortality ERR dose effect which also
differs in magnitude by age at follow-up. Two other potential contrib­
utors, which are the subject of this paper, are that there could be an
influence of pre-diagnosis radiation exposure on post-diagnosis survival,
and that individuals may die from a subsequent solid cancer different
from their first primary cancer diagnosis.
We have shown that among subjects with incident solid cancer in the
LSS who die of the same cancer (by our definition of index cancer), there
is no evidence of a large effect of pre-diagnosis radiation exposure on the
probability of death due to the original cancer. There is evidence of an
effect of pre-diagnosis radiation exposure on the probability of death
from cancer different from the first primary diagnosis. This observation
is consistent with the idea that some deaths arise from radiation-related
second or higher order primary cancers that developed independently
from the first primary cancer [10]. Although deaths from unrelated solid
cancer make up only 19 % of total solid cancer deaths, their inclusion in
analysis of post-diagnosis survival results in a significant pre-diagnosis
radiation dose effect.
Bockwoldt et al.[13] reported post-diagnosis mortality excess hazard
5
Cancer Epidemiology 83 (2023) 102341
rate of 0.38 (95 % CI: − 0.10, 1.12) in their analysis of 7728 gastroin­
testinal cancers from the LSS and concluded that this was inconclusive
about a relationship between pre-diagnosis radiation exposure and
survival. The current analysis of 20,463 combined incident solid can­
cers, stratified by cancer type, resulted in greater precision and thus
greater certainty in the ability to rule out a general pre-diagnosis radi­
ation effect on subsequent survival.
An ancillary observation in the current study is the significant dose
effect in females for non-cancer death which was not evident in males,
which is confounded by observation of a significant dose effect in never
smokers, which comprise primarily females, but no dose effect in current
or former smokers, which are predominantly males. Whether this result
is due to sex, smoking, or unknown confounding variables will require
further investigation.
A weakness in the current analysis is that the criteria by which we
have classified underlying causes of death as related to or unrelated to
the first primary cancer diagnosis is based on information available from
death certificates, whereas a rigorous analysis would require review of
medical records, something that is not feasible in the context of the LSS.
This can result in misclassification bias in the post-diagnosis survival
analysis for different causes of death. The death rate from the first pri­
mary cancer is underestimated in our analysis based on index cancers
due to the possible omission of deaths from metastatic or invasive pre­
sentations at death. It seems unlikely that this misclassification would
induce bias that could mask a true dose effect on post-cancer diagnosis
survival. The misclassification would have to be dose dependent in a
way where deaths from the primary cancer were more likely in higher
dose exposed individuals to be classified as due to unrelated cancer.
Therefore we believe that our finding of a non-significant dose response
and upper confidence bound of 0.10 on the excess hazard at 1 Gy reli­
ably provides no evidence that exposure to radiation prior to diagnosis
affects post-diagnosis survival in any important way. For death from
other cancer, there will potentially be bias in both the overall death rate
and dose response, as this group is contaminated by cancer deaths that
should be attributed to the index cancer. In the current analysis, since
there was not a detectable dose response for index cancer deaths, the
bias in estimation for other cancer deaths will be positive for the base­
line and negative for the dose response. Despite this possible negative
bias, we nevertheless observed a significant dose response for other
cancer deaths.
Another potential weakness of the analysis is that we have assumed a
common radiation effects across all diagnostic strata. Although there
was no evidence of effect modification by broad diagnostic class, we are
unable to conclude anything about possible dose effects for individual
cancer types. Also, staging, detailed treatment, and other clinical in­
formation that is typically important for modelling survival from cancer
was not sufficiently available and was not included in these models.
Such information, if available, would help refine the baseline hazard,
but it seems unlikely that its inclusion could affect the conclusion about
the effect of pre-diagnosis radiation exposure on post-diagnosis survival,
especially for death from the first primary cancer.
It is unlikely that bias in the relationship between radiation dose and
survival could have resulted from dose dependence on the cancer
treatment received for particular types and stages of primary cancer, as
the precise radiation doses received are not known to survivors or their
physicians and would not likely factor into treatment decisions. How­
ever, there is theoretically bias resulting from increased screening for
cancer among subjects exposed at higher radiation dose. Residents of
Hiroshima and Nagasaki could apply for an Atomic Bomb Survivor’s
Health Handbook and be entitled to enhanced access to medical eval­
uation and treatment. It is possible that distal (lower exposure dose)
survivors were less likely to apply for these handbooks than proximal
(higher exposure dose) survivors. To the extent that this would result in
earlier cancer detection and better prognosis, this would bias against
observing higher post-incidence mortality from index cancer among
higher dose exposed subjects. We think that such screening bias is
R. Sposto et al.
negligible, but there are no data available to assess the rate at which
survivors applied for and received these handbooks or utilized them in
order to assess the magnitude of such bias if it exists.
CRediT authorship contribution statement
Richard Sposto: Conceptualization, Methodology, Software, Formal
analysis, Writing-original draft, Writing-review and editing, Hiromi
Sugiyama: Conceptualization, Data curation, Writing-review and edit­
ing, Tatsuaki Tsuruyama: Writing-review and editing, Alina V.
Brenner: Conceptualization, Data curation, Writing-review and editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgements
The Radiation Effects Research Foundation (RERF), Hiroshima and
Nagasaki, Japan is a public interest foundation funded by the Japanese
Ministry of Health, Labour and Welfare (MHLW) and the US Department
of Energy (DOE). The research was also funded in part through DOE
award DE-HS0000031 to the National Academy of Sciences. This pub­
lication was supported by RERF Research Protocols 1–75 and 18–61.
The views of the authors do not necessarily reflect those of the two
governments.
Appendix A. Supporting information
Supplementary data associated with this article can be found in the
online version at doi:10.1016/j.canep.2023.102341.
References
[1] A.V. Brenner, D.L. Preston, R. Sakata, H. Sugiyama, A.B. de Gonzalez, B. French,
M. Utada, E.K. Cahoon, A. Sadakane, K. Ozasa, E.J. Grant, K. Mabuchi, Incidence of
breast cancer in the life span study of atomic bomb survivors: 1958-2009, Radiat.
Res (2018).
[2] E.J. Grant, A. Brenner, H. Sugiyama, R. Sakata, A. Sadakane, M. Utada, E.
K. Cahoon, C.M. Milder, M. Soda, H.M. Cullings, D.L. Preston, K. Mabuchi,
K. Ozasa, Solid cancer incidence among the life span study of atomic bomb
survivors: 1958-2009, Radiat. Res 187 (5) (2017) 513–537.
Cancer Epidemiology 83 (2023) 102341
[3] D.L. Preston, E. Ron, S. Tokuoka, S. Funamoto, N. Nishi, M. Soda, K. Mabuchi,
K. Kodama, Solid cancer incidence in atomic bomb survivors: 1958-1998, Radiat.
Res. 168 (1) (2007) 1–64.
[4] A.V. Brenner, D.L. Preston, R. Sakata, J. Cologne, H. Sugiyama, M. Utada, E.
K. Cahoon, E. Grant, K. Mabuchi, K. Ozasa, Comparison of all solid cancer mortality
and incidence dose-response in the life span study of atomic bomb survivors, 1958-
2009, Radiat. Res (2022).
[5] T. Imaoka, S. Yamashita, M. Nishimura, S. Kakinuma, T. Ushijima, Y. Shimada,
Gene expression profiling distinguishes between spontaneous and radiation-
induced rat mammary carcinomas, J. Radiat. Res. 49 (4) (2008) 349–360.
[6] K. Daino, N. Ugolin, S. Altmeyer-Morel, M.N. Guilly, S. Chevillard, Gene expression
profiling of alpha-radiation-induced rat osteosarcomas: identification of
dysregulated genes involved in radiation-induced tumorigenesis of bone, Int. J.
Cancer 125 (3) (2009) 612–620.
[7] L.M. Morton, D.M. Karyadi, C. Stewart, T.I. Bogdanova, E.T. Dawson, M.
K. Steinberg, J. Dai, S.W. Hartley, S.J. Schonfeld, J.N. Sampson, Y.E. Maruvka,
V. Kapoor, D.A. Ramsden, J. Carvajal-Garcia, C.M. Perou, J.S. Parker, M. Krznaric,
M. Yeager, J.F. Boland, A. Hutchinson, B.D. Hicks, C.L. Dagnall, J.M. Gastier-
Foster, J. Bowen, O. Lee, M.J. Machiela, E.K. Cahoon, A.V. Brenner, K. Mabuchi,
V. Drozdovitch, S. Masiuk, M. Chepurny, L.Y. Zurnadzhy, M. Hatch, A. Berrington
de Gonzalez, G.A. Thomas, M.D. Tronko, G. Getz, S.J. Chanock, Radiation-related
genomic profile of papillary thyroid carcinoma after the Chernobyl accident,
Science 372 (6543) (2021).
[8] D.S. Gridley, M.J. Pecaut, G.A. Nelson, Total-body irradiation with high-LET
particles: acute and chronic effects on the immune system, Am. J. Physiol. Regul.
Integr. Comp. Physiol. 282 (3) (2002) R677–R688.
[9] K. Lumniczky, N. Impens, G. Armengol, S. Candeias, A.G. Georgakilas,
S. Hornhardt, O.A. Martin, F. Rodel, D. Schaue, Low dose ionizing radiation effects
on the immune system, Environ. Int 149 (2021), 106212.
[10] C.I. Li, N. Nishi, J.A. McDougall, E.O. Semmens, H. Sugiyama, M. Soda, R. Sakata,
M. Hayashi, F. Kasagi, A. Suyama, K. Mabuchi, S. Davis, K. Kodama, K.J. Kopecky,
Relationship between radiation exposure and risk of second primary cancers
among atomic bomb survivors, Cancer Res. 70 (18) (2010) 7187–7198.
[11] K. Ozasa, Y. Shimizu, A. Suyama, F. Kasagi, M. Soda, E.J. Grant, R. Sakata,
H. Sugiyama, K. Kodama, Studies of the mortality of atomic bomb survivors,
Report 14, 1950-2003: an overview of cancer and noncancer diseases, Radiat. Res.
177 (3) (2012) 229–243.
[12] K. Ozasa, I. Takahashi, E.J. Grant, Radiation-related risks of non-cancer outcomes
in the atomic bomb survivors, Ann. ICRP 45 (1 Suppl) (2016) 253–261.
[13] B. Bockwoldt, H. Sugiyama, K. Tsai, P. Bhatti, A.V. Brenner, A. Hu, K.F. Kerr,
E. Morenz, B. French, A.I. Phipps, Gastrointestinal cancer survival and radiation
exposure among atomic bomb survivors: the life span study, Cancer Epidemiol.
Biomark. Prev. (2020).
[14] H.M. Cullings, E.J. Grant, S.D. Egbert, T. Watanabe, T. Oda, F. Nakamura,
T. Yamashita, H. Fuchi, S. Funamoto, K. Marumo, R. Sakata, Y. Kodama, K. Ozasa,
K. Kodama, DS02R1: improvements to atomic bomb survivors’ input data and
implementation of dosimetry system 2002 (DS02) and resulting changes in
estimated doses, Health Phys. 112 (1) (2017) 56–97.
[15] D.A. Pierce, D.L. Preston, D.O. Stram, M. Vaeth, Allowing for dose-estimation
errors for the A-bomb survivor data, J. Radiat. Res. 32 (Suppl: p) (1991) 108–121.
[16] D.R. Cox, D. Oakes, Analysis of Survival Data, Chapman and Hall, New York, 1984.
[17] StataCorp, Stata Statistical Software: Release 17, StataCorp LLC, College Station,
TX, 2021.