Comparison of the estimated effect of atomic bomb radiation exposure on solid cancer incidence and solid cancer mortality in the RERF Life Span Study (LSS) reveals a difference in the magnitude and shape of the excess relative risk dose response. A possible contributing factor to this difference is pre-diagnosis radiation effect 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.
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.
From multivariable Cox regression analysis of cause-specific survival, the excess hazard at 1 Gy (EH 1Gy ) for death from the first primary cancer was not significantly different from zero – p = 0.23, EH 1Gy = 0.038 (95 % CI: −0.023, 0.104). Death from other cancer and death from non-cancer diseases both were significantly associated with radiation dose: other cancer EH 1Gy = 0.38 (95 % CI: 0.24, 0.53); non-cancer EH 1Gy = 0.24 (95 % CI: 0.13, 0.36), both p < 0.001.
There is no detectable large effect of pre-diagnosis radiation exposure on post-diagnosis death from the first primary cancer in A-bomb survivors.
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.
- • Analysis of survival of 20,000 + atomic bomb survivors diagnosed with solid cancer.
- • A-bomb radiation exposure prior to a cancer diagnosis does not influence survival from the primary diagnosed cancer.
- • A-bomb radiation exposure prior to cancer diagnosis does influence survival for non-primary cancer death causes.
- • Radiation influence on solid cancer prognosis does not contribute to the difference in mortality and incidence dose response.
The Life Span Study (LSS) of the Radiation Effects Research Foundation is used to quantify the long-term effects of atomic bomb radiation on cancer incidence and mortality . Recently Brenner et al. 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. 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 mortality models. One possible contributing factor to this difference is 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 diagnosed cancers different from the first primary may be the ultimate cause of death.
One can conjecture about mechanisms by which pre-diagnosis radiation exposure could influence mortality from an incident cancer. Radiation-caused cancer might be genetically and therefore possibly prognostically distinct from spontaneously occurring cancer. Evidence of such genetic differences exists from murine models (e.g., ) and recent human studies . Radiation exposure could alter the immune system , possibly affecting individuals’ innate ability to fight cancer and tolerance of aggressive immunosuppressive treatment for cancer and therefore treatment effectiveness.
Under a null hypothesis that pre-diagnosis radiation exposure does not affect survival after solid cancer diagnosis, one would expect that post-diagnosis survival in individuals who died from the originally diagnosed cancer would not be related to radiation dose. However, post-diagnosis survival of individuals who died of cancers unrelated to the first primary diagnosis could be associated with radiation dose in that radiation exposure is associated with the additional incident cancer which led to the subject’s demise. Post-diagnosis survival in individuals who died of non-cancer-related causes could also be associated with radiation dose through the effect of radiation on non-cancer mortality .
In this paper we investigate this null hypothesis by analyzing post-diagnosis survival and its relationship to radiation exposure in subjects diagnosed with solid cancers in the LSS from 1958 to 2009 with specific attention to differences in dose response for different causes of death. Bockwoldt et al. recently analyzed post-diagnosis survival in 7728 LSS subjects with gastrointestinal cancer who died of this cause. Their analysis was inconclusive as to the association between pre-diagnosis exposure and post-diagnosis survival. In the current analysis, we include all first primary solid cancers in a single analysis and investigate differences in the association of prior radiation exposure to survival for different causes of death. This approach provides a more sensitive analysis of the association of radiation dose to post-diagnosis survival, especially in those who died from the originally diagnosed cancer.