Though the observed and expected case counts in this cohort are small, the results presented here nevertheless provide intriguing and potentially important information about cancer incidence and mortality among astronauts. Of the three cancers that displayed statistically significant differences in incidence rates compared to those of the general population, we believe there was one real increase (melanoma), one real decrease (lung), and one increase due, at least in part, to detection bias (prostate). Additionally, though their differences in incidence were not statistically significant, two other tumor types showed evidence of detection bias as well (colon and hematologic).
In general, detection bias refers to a change in event rates that results solely from more frequent or more intense screening in a target population. In the context of cancer, this bias will most often lead to an increase in age-specific incidence, as tumors are discovered at younger ages than they might otherwise be in the absence of regular screening. Simultaneously, detection bias will often lead to better survival (i.e. lower age-specific mortality rates), since tumors are generally caught at less advanced stages than they otherwise would be, making them more amenable to treatment. Depending on the tumor type, this increase in survival can also be reflected in lower case fatality ratios over a fixed period. In this study we saw some evidence of detection bias, as discussed below.
Prostate cancer is one cancer type that we believe should demonstrate detection bias in the astronaut cohort. Prostate cancer screening is performed by testing for levels of prostate-specific antigen in the blood. In the general population, this screening is recommended to begin at age 50 for men at average risk, but for astronauts, it begins at age 40.8,13-15 Since prostate cancer can be asymptomatic and is most often slow-growing, many such tumors are never detected for patients in the general population.16 In this analysis, we saw a nearly two-fold increase in the incidence of prostate cancer for astronauts. If this increase were indeed due to detection bias, then the SMR should be close to 100 (there should be little to no difference in the mortality rate for this cancer in astronauts and in the general population), but the case fatality rate should be lower. The SMR shows a range between 0 and 166, representing either no risk of death from this cause in the observation period or a 66% increase in risk compared to the general population, with none of the estimates statistically significant. The RCFR for prostate cancer in this cohort is 1.0, suggesting exactly as many deaths occurred for the number of astronaut cases as we would expect given the general population case fatality ratio. This would seem to argue against detection bias for prostate cancer.
Another way to gauge the possible impact of detection bias on incidence rates is to consider historical cases when screening guidelines have changed. In the early 1990’s incidence rates for prostate cancer nearly doubled in the general population, and this trend has been attributed to increases in screening with newly available prostate-specific antigen tests.17 This confirms that detection bias may be expected given the reality of early and consistent prostate cancer screening among astronauts.
Hematologic cancers are of concern to space exploration because these malignancies are known to be among the most radio-sensitive both in childhood and in adulthood.18-20 We observed 4 hematologic cancers in the astronaut cohort when fewer than 2 were expected, for an SIR of approximately 200. While the 2 observed deaths from this cancer type represented an insignificant reduction in the mortality rate, the expected number of deaths from this cancer exceeded the expected number of cases, making interpretation of the SMR difficult. The RCFR brings clarity, since the ECFR suggests that all four cases of hematologic cancers would have been expected to die over the observation period, but only 2 did.
The increased incidence of hematologic cancers among astronauts may be attributable to radiation exposure while in outer space. If so, this would be true for astronauts who have flown on the International Space Station (ISS) in the last approximately 15 years; before this time, doses of radiation exposure during space flight were below levels at which we would expect to see radiation-induced increases in cancer incidence. However, the high lethality of these tumors (as evidenced by its ECFR of 1.51) suggests that no matter the number of cases observed, all of them should have died in the observation period. The hematologic cancer SMR below 100 and the RCFR of 0.5 suggest lower mortality than expected. Unless space radiation leads to more frequent yet less lethal forms of hematologic cancers, the decrease in mortality lessens the plausibility of a true increase in incidence, including the possibility of a true increase from space radiation doses.
A possible explanation for the reduced case fatality of hematologic cancers reflected in the RCFR may have to do with the timing of cases among astronauts. The case fatality ratio for hematologic cancers may have declined over time, and if the diagnoses of hematologic cancers among astronauts were limited to only recent years, then the whole-period general population ECFR would be too high (it is 1.51 in the current analysis, Table 4). Under these circumstances, the OCFR would be lower than expected (i.e., the RCFR would be less than 1.0, which it is here, at 0.50). One way to explore this possibility is to assume that all astronaut cases and deaths occurred in a recent period, and re-compute the ECFR using general population data from the same recent period. We did this using only data from 1999 to 2017, and the ECFR was reduced to 1.15. This means that even if all the hematologic cancer cases among astronauts were diagnosed in 1999 or later, we still would have expected all 4 cases to die, and thus the RCFR would remain at 0.5.
Instead, the observed increase in incidence coupled with the decrease in mortality could, again, be suggestive of detection bias, especially since hematologic cancers as a category could be susceptible to detection bias depending on the specific cancers observed in the group. Myelodysplastic cancers are slower growing than leukemia and lymphoma and could therefore be detected via blood screening before any symptoms were apparent.21 Of the 4 cases of hematologic cancer among astronauts, 1 was a case of myelodysplastic syndrome, lending some credibility to this explanation. However, with the small case count and resulting wide confidence intervals, these results may be due to chance. No matter the explanation for this combination of incidence and mortality, we conclude that there is no strong evidence of an increase in either the incidence of, or mortality from, hematologic cancers in the astronaut cohort at this time.
Another tumor that may be susceptible to detection bias is colon cancer, where screening has historically been more frequent in the astronaut cohort than in the general population.8 However, the pattern of detection bias in colon cancer is different from that of other tumor types, since the screening technique (colonoscopy) is also a preventative intervention by way of routine removal of precancerous colon polyps during the procedure. Under these circumstances, detection bias should lower incidence and mortality, but the effect on the CFR is unclear.
Even if screening has a consistent effect on the SIR, SMR, and CFR for colon cancer, inconsistent screening practices over time could obscure or nullify these effects. In 2003, NASA reduced the frequency of colonoscopy among active-duty astronauts, leading to statistically significant increases in average time between screenings, average severity of polyps, and average age at screening – all known risk factors for colon cancer mortality.22 While the data used here are not sufficiently detailed to address the effect of the change in screening practices, a more complete data set, with diagnosis and mortality information linked to individuals, could do so. Such analyses may find differences in the SIRs, SMRs, and potentially the CFRs for colon cancer by time period, before and after this change in screening practice.
The lack of statistical significance in the reduction in incidence of colon cancer may reflect several factors. First, the expected case count for colon cancer was just under 4, making even 75% reductions in the observed number of cases insignificant. Under these conditions, only a total absence of colon cancer cases would have reached statistical significance (results not shown in Table 4). While we might indeed expect a stronger effect on incidence with intense screening, it is important to note that the average age of retirement from the Astronaut Corps is approximately 48 years of age, meaning that any colon cancer screening performed on active duty astronauts likely occurs before the period of greatest risk for colon cancer, age 50 and older.23,24 The changes in colon cancer screening in 2003 may again be a factor.
The data for lung cancer suggest that astronauts have experienced a real (and marked) reduction in lung cancer incidence and mortality rates. This is likely the result of healthy lifestyle, especially resulting from low rates of smoking in contemporary astronauts.25 Consistent with this hypothesis, prior studies of cardiovascular disease among astronauts show reductions in both incidence and mortality in comparison to the general population.4-5,26 Large differences in incidence and mortality rates between a largely never-smoker population and the US population as shown in table 4 are to be expected. However, due to changing smoking patterns in the US population over time, determining whether this difference in lung cancer is entirely due to healthy behavior or whether spaceflight exposures are contributing to a cancer risk would require a more detailed analysis.27
The low SMR for lung cancer indicates a substantial reduction in mortality. However, this reduction is complicated by the low incidence since more lung cancer deaths were expected than there were actual cases of lung cancer among astronauts. Using the RCFR, which indexes mortality within the subset of observed cases, we see that astronauts had only one death when 2 would have been expected. Though the small number of lung cancer cases precludes meaningful significance testing for the RCFR, it nevertheless suggests that the observed reduction in the SMR may be more than just an artifact of the low incidence rates. As never-smokers have improved survival among lung cancer cases, this may again be due to the generally low rate of smoking among astronauts.25,28
It is possible that the relative increase in the incidence of malignant melanoma among astronauts is also due to detection bias. However, we believe that the SIR observed here represents a real increase in incidence, even if its magnitude may be overestimated to some extent. In the case of melanoma, detection bias should manifest as increased incidence and either decreased or unchanged case fatality. This effect on mortality occurs when regular screening leads not only to early detection of true cancers, but also the misdiagnosis of benign lesions as melanomas (false positives) or minor cancers that might otherwise resolve without treatment.29 Since the SMR and RCFR both show increased mortality for astronauts in comparison to the US general population, we conclude that the increase in incidence is not merely a result of detection bias.
Another factor that would tend to increase the case count is the large percentage of pilots in the Astronaut Corps. Airline pilots are known to have greater rates of melanoma, with recent meta-analyses estimating the SIR and SMR for commercial airline pilots to both be approximately 200 compared to the general populations of various nations.10-12 While exposure to galactic cosmic rays (GCR) has been suggested as a risk factor for melanoma among airline pilots, this is unlikely since melanoma is not known to be strongly radiogenic.18 The literature suggests that the more likely source of this excess risk is the amount of ultraviolet (UV) radiation pilots receive at typical flight altitudes, as well as lifestyle factors independent of profession.30 UVA radiation is of particular relevance to melanoma incidence and mortality in pilots, because the exposure at typical commercial flight altitudes can be at least twice that of ground levels.10 Table 3 shows that 70% of the astronaut cohort are licensed pilots. The RCFR also suggests that the astronaut cases may be more severe than those in the general population, which could be consistent with intense UVA exposure. In total, the evidence presented here fails to suggest any extra or unique risk of melanoma due to being an astronaut, as the results of the SIR and SMR are statistically indistinguishable from what we might expect from pilots who are not astronauts. More detailed research specifically investigating the role of hours of atmospheric flight time, time in space, and subsequent radiation exposure is forthcoming.
The HWE is a phenomenon that is composed of both a healthy worker selection effect and a healthy worker survival bias. The former is the bias created by healthy people entering the workforce and unhealthy ones being unable to, while the latter is the bias generated by only healthy people remaining in the workforce.1 As an occupational cohort of highly selected individuals with good health behaviors, access to high-quality medical care via NASA, and relative affluence, the HWE predicts that astronauts should have lower age-specific incidence rates of disease and thus, lower mortality rates in comparison to the US general population.31 While the reductions in overall mortality risk reported here are consistent with those observed in other populations, the composite results show no difference in the overall incidence of cancer among astronauts in comparison to the US general population.6 This result held true even when melanoma was removed from consideration. However, these results are difficult to interpret in light of the evidence of detection bias in several cancer types among astronauts. If we believe that, by comparison with what might be expected under rates from the general population, some cancers have artificially high incidence while others have artificially low incidence, the composite effect becomes intelligible only as the total effect of a unique blend of observed biases, rather than as the true and generalizable experience with cancer applicable to the long term health of current and future astronauts. The matter is further complicated by evidence of detection bias in 2 of the most common cancers observed in the general population, prostate and colon.
When we use a sensitivity analysis to quantify the effects of detection bias in the composite estimates, the SIRs shrink away from parity toward results that are more consistent with the HWE (see Appendix for details). However, it should be noted that the corrections made for detection bias are conservative in that they only assume that astronauts have, at best, incidence equal to that of the general population. If instead the detection bias is large enough to obscure true rates of tumor development that are actually lower than the general population, the composite SIR estimates would be even lower and may in fact reach statistical significance.
However, the possible positive influence of the HWE on astronauts’ risk of cancer over their lifetimes may be counterbalanced by unique occupational exposures such as increased exposure to UVA radiation and space radiation. Given this, levels of risk for cancers may be no different for astronauts and the general population. The best course of action for interpretation then may be to carefully scrutinize individual cancer types rather than relying on composite estimates. In addition, advances in molecular analysis of tumors may provide ability to decipher contribution of these various environmental hazards based on their unique mutational signatures.32
The study conducted here uses aggregate counts of observed tumors and deaths against aggregated person-years of follow-up, stratified by calendar year, age, sex, and race. While this allows us to compute the overall trends in incidence and mortality, it does not allow for more detailed analysis of which demographic groups may be more or less likely to develop or die from each cancer type. However, given that even in aggregate form the numbers of tumors and deaths in most categories is quite small, the value of a more detailed analysis of incidence and mortality may be limited for all but the most frequently diagnosed tumors. In addition, some tumors are already demographically specific to some extent (female breast cancer and prostate cancer). Nevertheless, the ability analyze the data in terms of years or decades and the ability to test the association between time in space and flight time in aircraft may prove enlightening. Future research will examine incidence and mortality in these ways, with data that link tumors and deaths to individuals.
The use of 1999 incidence rates for all years prior to 1999 will likely bias the SIRs upwards, since the incidence of many cancers have declined in the general population for many years. This means that the expected counts generated for follow-up time before 1999 are likely too low, as higher rates in earlier periods would have led to greater expected cancer counts. This would in turn somewhat elevate all the SIRs presented in Table 4 but would not change the overall pattern of results. Even if we were to increase the expected case counts in Table 4 by 25%, no currently insignificant individual tumor result would become significant and no significant results would lose significance. The change resulting from applying higher historical incidence rates would almost certainly be less than a 25% increase in tumor counts, since the person-years affected would be from comparatively early periods when the Astronaut Corps was smaller, and the members were on average younger and thus at lower risk of developing cancers. This suggests that the impact of using these rates on our conclusions is minimal. This reasoning holds for SMRs as well, since the period where rates were unavailable (1958 to 1967) is smaller, and the astronaut person-years from this time are even fewer and younger than average.
The statistical power of the study is low, as highlighted also by the power analysis conducted by Elgart et al. (2018) in a subset of this cohort. Thus, the usefulness of SIR and SMR analysis in a small and highly selected occupational cohort is limited. However, the fact that some cancers appear to be in excess suggests that these increases are more likely to be real, as discussed above. This paper calculates the difference between the astronaut and general US population as an initial step in trying to determine potential risks from space flight exposures. While the low statistical power makes it unlikely to establish increased risk in terms of conventional thresholds for statistical significance in the near future, such information can still be useful in constraining possible risks. Future work extending this initial effort will look specifically at the upper bounds of risk estimates from the astronaut cohort in order to place such constraints on current NASA models that calculate space radiation risks.
The work presented here is useful in understanding the trends in cancer incidence and mortality among US astronauts. The results are constrained primarily by the limited pool of observation time and events (cancer diagnoses and deaths) that have accumulated to date. However, the framework presented here can easily be revised to include additional data as they are collected and will provide greater insights as such data accumulates. More detailed research looking at occupational exposures is needed to determine if aircraft flight time or time in space have contributed to the risk of developing and/or dying from various cancers. Such efforts will need to be repeated over time, as more data accrue and newer classes of astronauts prepare to spend greater amounts of time outside of low Earth orbit, where space radiation dose-rates are more intense and spaceflight exposures may be prolonged.
As humans continue to master the immediate dangers of living and working in space, the post-mission, long-term health risks become more important; cancers are but one of many such dangers. Through continued occupational surveillance, targeted cohort studies, and ongoing basic and translational research, we can gain a better understanding of these long-term health risks for astronauts. This understanding will be key to continued space exploration as humans return to the Moon and expand out to Mars and beyond.