What Are the Cancer Risks from Using Chest Computed Tomography to Manage Cystic Fibrosis?

Diagnostic tests may involve risks, and the benefits of the information gained from a test for patient care should sufficiently outweigh any attendant risks. In this issue of the Journal (pp. 199-203), de Jong and colleagues estimate cancer risk and loss of life expectancy from radiation received from computed tomography (CT) of the chest in caring for persons with cystic fibrosis (CF) (1). Such scans are increasingly used because they provide information on lung structure that is complementary to routine pulmonary function testing (2). Indexes derived from CT scans may also be useful intermediate markers for clinical trials (3).

In considering routine use of CT scans in persons with CF, consideration needs to be given to the radiation risk. Radiation exposure is an established cause of most cancers, and there is direct evidence from observational studies of excess risks from fractionated exposures in the dose range that would be received from repeated CT scans (50-100 mSv) (4). The most recent review of the evidence indicates that there is no threshold-that is, any ionizing radiation conveys some cancer risk (5). However, it is not feasible to quantify the risks from diagnostic exposures directly from observational studies, especially if detailed estimates according to specific patterns of age and time since exposure are required. Therefore, quantification of the risk of cancer from CT scans or other radiographic procedures usually requires extrapolation of radiation risk models from studies of populations exposed to a wider range of doses (6).

Using the methods of quantitative radiation risk assessment, de Jong and colleagues project cancer mortality and loss of life expectancy consequent to the radiation received from regular CT scans, taken either annually or biennially. The results raise concern that periodic use of CT scans for management will adversely affect survival, particularly as longevity increases for persons with CF to the fourth and fifth decades when cancer occurrence begins to rise steeply with age. The estimated risks are surprisingly high for scenarios involving annual scans and median survival of age 50 years or more and indicate a need for cautious decision analysis before implementing routine CT scanning.

The steps involved in estimating the cancer burden associated with radiation exposure are well established. An estimate of organ dose is needed that is used in combination with an organ-specific radiation risk coefficient to calculate the excess relative risk of cancer arising from the radiation dose. The radiation risk coefficients come from epidemiologic studies, primarily the long-running cohort study of atomic bomb survivors in Japan (5). The excess relative risk is then applied to the background cancer rates for the population, and life table-based projections of cancer occurrence and associated loss of life expectancy are made. These types of calculations underlie quantification of risks to workers and the general population from occupational and environmental exposures.

de Jong and colleagues do not provide the full details of their calculations and we question whether possible problems in their approach may have led to the high estimates of cancer mortality risk that they report. CT scans deliver a highly inhomogenous dose distribution and, therefore, the overall cancer risk cannot be estimated directly using risk coefficients for all solid cancers combined. Rather, the risk for each specific organ should be calculated separately by applying appropriate organ-specific doses to the age- and organ-dependent risks. For lung CT scans, the thymus, lungs, and breasts receive most of the radiation dose with some additional dose to the bone marrow (7). Consequently, increased risk for lung cancer mortality would be the primary concern and possibly also breast cancer for females with CF. Risk calculations for these sites alone give much lower estimates than those provided by de Jong and colleagues (1).

Application of the excess relative risk model for lung cancer to lung cancer rates in the general population is likely to overestimate the risks as the proportion of persons with CF who smoke is comparatively low (8). On the other hand, it is possible that the chronic lung inflammation in persons with CF would synergistically increase risk for lung cancer associated with radiation (9). In addition, the excess cancer risk would not occur immediately with the radiation dose from the CT scans but would come at a substantial lag after first exposure. There are additional uncertainties in any radiation risk assessment following this approach, including the extrapolation of excess relative risks from the Japanese atomic bomb survivors to other populations who have very different background cancer rates and the assumption of a constant excess relative risk over time. Possibly, radiation doses will drop over time with improving technology. Because of the uncertainties involved, it is important not only to calculate point estimates of the risk but also to present a range of potential estimates either from an informal or from a probabilistic uncertainty analysis.

Although de Jong and colleagues investigated several scenarios that could reduce or increase the risks (1), such as reducing radiation doses or the frequency of monitoring, another key factor that determines the cumulative risk is the age at exposure. The exposures at the youngest ages are thought to carry the greatest risks, because the organ doses are likely to be higher, as are many of the organ-specific risk coefficients (5), and also because the length of time available to cumulate excess risk is greater (10). Therefore, a monitoring strategy that reduced exposure to children would likely be most effective at reducing the subsequent cancer risk. Such a strategy may be particularly appropriate for females with CF as the breast is one of the most radiosensitive tissues, particularly at younger ages of exposure (5).

To date, the studies that have evaluated the use of CT scans for monitoring patients with CF have compared their sensitivity to other monitoring tools, such as pulmonary function tests (2). As yet there appears to be no direct evidence that such monitoring will result in prolonged survival of patients with CF (2). Studies of the potential survival benefits, preferably randomized controlled trials, therefore now need to be initiated so that any future risk of cancer will be justified by the benefits of the test.

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