Presenter: Amy Berrington de Gonzalez Presenter's Affiliation: Johns Hopkins University Type of Session: Scientific
Diagnostic X-rays provide a great medical benefit to patients with only a small risk of secondary cancers.
This increase in risk of secondary malignancy has been shown in prior studies:
Example: The increased risk of breast cancer seen in patients who underwent frequent fluoroscopic examinations for tuberculosis.
However, in these studies the doses that the patients received were fairly large ranging from 0.1 to 0.8 Gy.
What is the effect of lower doses of radiation on the risk of developing secondary malignancies?
It is difficult to estimate this risk directly due to the low incidence of secondary malignancies related to lower dose diagnostic radiology studies.
Therefore an indirect assessment of the risk of secondary malignancy is used based on the data from prior studies, such as those of the atomic bomb survivors.
The dose from diagnostic radiology studies is small, but a large number of people are exposed.
It is estimated that up to 1% of malignancies are related to diagnostic imaging (Berrington de Gonzalez, Lancet 2004).
The present study examined the risk benefit ratio of two screening tests.
Screening diagnostic mammograms in high risk pre-menopausal women.
Screening chest CT for lung cancer in smokers and non-smokers.
Breast cancer screening in high risk pre-menopausal women.
Recent guidelines by the National Comprehensive Cancer Network (NCCN) suggest that in women with BRCA mutations annual screening MRI and mammograms should start at the age of 25.
Recent guidelines by the American Cancer Society (ACS) suggest that in women with BRCA mutations annual screening MRI and mammograms should start at the age of 30.
The benefit from screening mammography in pre-menopausal women is smaller.
There is a lower incidence of breast cancer in younger patients.
Due to higher breast density, mammograms are less likely to detect breast cancer in younger patients.
Younger patients will be exposed to more radiation with earlier screening which may increase the risk of developing secondary malignancies.
At what age do the benefits of screening mammograms start to outweigh the risk of secondary malignancy in patients with BRCA mutations?
The life table method was used to analyze risk versus benefit.
Prior studies of screening mammography have suggested that the benefits outweigh the risks, even in young patients. However, this estimate assumed that the risk of developing a secondary malignancy from radiation exposure was the same for patients with a BRCA mutation as those without.
However, if one uses the assumption that the risk of developing a secondary malignancy from radiation exposure in patients with a BRCA mutation is proportional to the baseline risk seen in these patients, the age at which the benefit outweighs risk is 40.
Additionally, the increase in risk in patients with a BRCA mutation who are treated with radiation may be additive or multiplicative. There have been studies which have supported both models. However, from the current data, the multiplicative model appears most appropriate.
Further studies have suggested that cells with BRCA mutations are hypersensitive to radiation and a supra-multiplicative interaction between the BRCA mutation and radiation may occur, though this has not been confirmed.
Data for the benefit of screening mammography was taken from prior studies. Screening mammograms reduced mortality by approximately 15%.
Data for the risk of developing a secondary malignancy was taken from previous studies as well.
In women with BRCA1 mutations it was estimated that there would be six deaths per 1000 women related to screening in women who started screening mammograms at the age of 25-34. Three deaths could be prevented with screening in this same age group. The benefit was found to increase with age and the risk decreased with age. No net benefit was seen until the age group of 30-39 (women were analyzed in 10 year intervals which overlapped by 5 years).
Women with BRCA2 mutations, who are at lower risk for developing breast cancer compared with BRCA1 patients, were also studied. The study found a smaller risk but also a smaller benefit. No net benefit was seen until the age of 35-44.
Women with two relatives with breast cancer were also studied. These women have an approximately 30% lifetime risk of developing breast cancer, lower than patients with a BRCA2 mutation. They had even smaller risks and benefits. There was no net benefit until patients were 35-44.
Chest CT screening for lung cancer in smokers and non-smokers.
Prior studies have suggested that a mortality benefit of at least 5% is necessary to balance the risk of secondary malignancy related to annual scanning (this risk was estimated to be 5.5%) (Brenner, Radiology 2004).
Currently there is a National Lung Screening Trial (NLST) underway that is powered to detect a 20% mortality benefit with three annual CT scans.
The benefit used in the present analysis was based on the 20% benefit being used in the NLST, which may be generous.
The risk for secondary cancer related to scans was based on prior studies such as those of the atomic bomb survivors.
There was a question as to whether smoking had an additive or multiplicative interaction with radiation. There was data to support both interactions. It was therefore decided to weight the combined risk such that it was between the additive and multiplicative risks.
Exposure per CT was estimated to be 4 mGy.
The background lung cancer rate was estimated using prior epidemiologic studies.
Using the above defined parameters the benefits in mortality of screening CT was compared with the increase in incidence or breast and lung cancer (note: they compared mortality with increased incidence).
There was no net benefit for screening CT in female smokers until the age of 50.
There was no net benefit for screening CT in female non-smokers even at the age of 60.
There was no net benefit for screening CT in male smokers until the age of 50; however the risk for lung cancer rose rapidly after 50, with a larger benefit for screening.
In non-smoking men, the benefit was similar to non-smoking women.
The decrease in mortality from annual CT screening may be between 10-20%, pending results from NLST, however smoking cessation is estimated to decrease the risk of death by 50-60%.
Screening studies of young patients provides a small benefit, even in women at high risk.
MRI alone may be a more appropriate screening test in women younger than 35.
Screening CT for lung cancer may not be appropriate in smokers less than 50 and may never be appropriate in non-smokers.
It is critical to perform further studies to improve the models used to evaluate the risk and benefit of these screening studies. Whether an additive, multiplicative, or supra-multiplicative interaction is used between a susceptibility factor, such as smoking, and radiation will have a profound effect on the risk benefit ratio.
The use of CT screening in lung cancer requires further study. The benefit of 20% was based on the assumption that the NLST trial will be positive. However, given that there is a 5.5% risk of secondary malignancy with annual screening and the increased risk of mortality from invasive procedures in patients with false positives, it is important to study this further.