These estimates suggest that before age 50 the mortality reduction required to outweigh the radiation risk from lung CT screening may be substantial, or in some cases unattainable (>100%). For smokers aged about 50 the required mortality reduction is considerably lower, but until results from the randomized screening trials are available it is uncertain what the net benefit could be. The trials are powered to detect about a 20% reduction in lung cancer mortality due to screening. Estimates of the mortality reduction from observational studies depend upon the use of models to generate a theoretical control group of unscreened individuals. In an analysis of this type of the Mayo study McMahon et al estimated that five annual screens with low-dose CT reduced lung cancer mortality by 28% at six years. No confidence bounds were provided, but given the small number of deaths in the study they are likely to be wide.21
A pooled analysis of three observational studies (which included the Mayo study), found no evidence overall for a reduction in lung cancer mortality (RR=1.0) but with a wide confidence interval (0.7-1.3).22
Our calculations involve a number of assumptions. One of the most important in the radiation risk estimate is the assumed form of the joint effect of smoking and radiation. A recent analysis of the data from the Japanese atomic bomb survivors found that the joint effect of radiation and smoking appeared to be closer to additive than to multiplicative.8
Several previous studies of cancer patients treated with radiotherapy, however, found that the joint effect of the two exposures was consistent with a multiplicative model.23-25
It is possible that the two exposures interact differently at low and at high doses of radiation exposure and further work is currently ongoing to try to understand these differences. We took account of this uncertainty by using a weighted average approach and allowed these weights to vary in the calculation of the credibility intervals.3
This source of uncertainty was one of the key determinants of the width of the credibility intervals. However, in general the conclusions would not be altered materially even at the extremes of the credibility intervals. This suggests that the difference in the results for current and never smokers is due to factors other than the assumed joint effect of radiation exposure and smoking. In particular the fact that lung cancer rates appear to increase more rapidly with increasing age in current than in never smokers ().
Concern has been raised about the appropriateness of transferring risk estimates from the Japanese atomic bomb survivors to other populations exposed to fractionated low-dose exposures.3
These concerns are particularly relevant for lung cancer because the rates have been very low in Japan in comparison with the US. If the excess relative risk model were not the correct biological model for radiation-induced lung cancer then using it to transfer risk estimates from the Japanese to the US could result in over-estimation of the risk. This is an additional reason that the BEIR VII committee recommended that a weighted average of the excess relative and excess absolute risk models be used for estimating risks for the US population rather than using only the excess relative risk.3
The use of this weighted average risk model is one of the explanations for why our risk estimates of the radiation-induced lung cancer mortality for a single lung CT screen at age 50 are approximately three times lower than estimates from an earlier publication.2
Brenner used only the excess relative risk component of the risk model from the Japanese atomic bomb survivors for his calculations.26
Another reason that our risk estimates are lower is because our estimated absorbed lung dose was lower (3.9 compared to 5.2 mGy per screen) presumably due to the use of a more recent, optimised screening protocol.13
In the current paper we assumed a linear no-threshold dose-response relationship for estimating radiation risk estimates at low doses. The BEIR VII committee recommended that these risk estimates be reduced by a dose and dose reduction effectiveness factor (DDREF) of 1.5 for exposures of 0.1 Gy or lower.3
There are considerable uncertainties surrounding the application of a DDREF though, and because there is also radiobiological evidence that supports downturning dose-response curves at low doses we have not applied a DDREF to the current risk estimates.27
Preston et al concluded that there was no evidence of departure from linearity at low doses for radiation-induced breast cancer, and so did not recommend that a DDREF should be applied to estimate breast cancer risk from fractionated radiation exposures.17
The evidence for the effects of dose fractionation on radiation-induced lung cancer risk is limited to the studies of patients with tuberculosis who received multiple fluoroscopies.28,29
The risk per unit dose was lower in these studies than in the Japanese atomic bomb survivors. This could be due to the effect of dose fractionation, but could also be due to confounding with the underlying disease or smoking. If we had applied a DDREF to our calculations then it would have reduced our risk estimates for radiation-induced lung cancer by about 33%, but this would not have had a material impact upon our conclusions.
The radiation-induced lung cancer risks were about three times higher for females than for males because the radiation risk parameters in the Japanese atomic bomb survivors are estimated to be higher for females.3
This is also true for several other cancer sites, but the difference is larger for lung cancer, and does not seem to be explained by differences in smoking patterns.8
It is uncertain whether these differences reflect real biological variability in radiation sensitivity. Further research into this question is warranted as it has important implications for radiation protection.
Smoking specific lung cancer rates are also uncertain. However, the estimated rates used here were broadly similar to those available from other populations.9,10,30,31
Furthermore, because the lung cancer rates were used in both the calculation of the radiation risk and the estimation of the mortality rate in the absence of screening, increases or decreases in the rates would impact both estimates in a similar direction and hence the mortality reduction required to outweigh the risk (which is the ratio of these two estimates) should not be materially altered by this source of uncertainty.
The relatively short screening period of three years used in our calculations was chosen so that the strong age-dependence of the risk-benefit comparison would be evident. Also the results from lung CT screening trials such as the National Lung Screening Trial will provide estimates of the relative and absolute reduction in lung cancer mortality from similar periods of lung CT screening (3 screens) for smokers aged about 50 and older. Indirect methods will still have to be used though to estimate the absolute reduction in lung cancer mortality for never or younger smokers. We used the method of incidence-based mortality rates previously to estimate the absolute reduction in breast cancer mortality from mammographic screening before age 50 in the UK. Assuming a 17% mortality reduction from screening our estimate of 0.6 deaths prevented per 1000 women screened from age 40-49 was similar to the observed reduction of 0.4 deaths per 1000 women screened from age 40-47 in the UK Age trial.32,33
Although we developed risk estimates for the general category of never-smokers our results should be broadly applicable to never-smokers who have been exposed to other risk factors such as second-hand tobacco and asbestos. Typically these factors are associated with about a two-fold higher risk of lung cancer than for a never smoker,34
and this would double the potential absolute benefit from screening but would also slightly increase the radiation risk. Similarly, although we conducted our calculations for current smokers of 40 cigarettes per day the balance of the risks and benefits would be similar for current smokers with different smoking histories.
As far as we are aware this is the first paper to estimate and highlight the risk of radiation-induced breast cancer incidence from lung CT screening. The radiation dose to the breast from a lung CT screen is similar in magnitude to the average dose from a two-view mammogram.35
The risk of radiation-induced breast cancer is higher for pre-menopausal women and increases with decreasing age at exposure and so becomes comparatively more important for screening of younger women. Even if not fatal, a radiation-induced breast cancer is an important detrimental effect of radiation exposure and so these potential risks should also be take into account in the decision making process.
Our calculations are based on the radiation exposure received from the screening scans. Studies suggest that up to 20% of lung CT screens for current older smokers will reveal abnormalities suspicious for cancer, and these subjects are usually referred to receive additional follow-up CT scans.36
The additional radiation dose will be highly dependent on the type and number of follow-up scans, in particular whether they are further low-dose or full diagnostic CT scans. Inclusion of these additional scans in the current estimates would have further increased radiation risks and therefore further increased the mortality reduction required to outweigh the risks. We are currently conducting additional research to evaluate the patterns of follow-up CT scans after lung CT screening and this will be the topic of a future publication.
Although the calculations depend on a number of uncertain assumptions we have based the assumptions on the best data that are currently available. We also calculated credibility intervals to quantify the effect of the uncertainties in the parameters and the assumptions; even when the extremes of these intervals are considered the conclusions are generally unaltered. The results suggest that before age 50 the mortality reduction from lung CT screening required to outweigh the radiation risk may be substantial, and in some cases unattainable (i.e.>100%). In the absence of direct data these indirect approaches for comparing the risks and the benefits of screening provide valuable evidence to help inform those making screening decisions.