Harms of Screening
Screening by Low-Dose Helical Computed Tomography
False-positive exams are particularly problematic in the context of lung cancer screening. Persons most likely to be screened for lung cancer, i.e., heavy smokers, have comorbidities (such as chronic obstructive pulmonary disease and heart disease) that make them poor candidates for certain diagnostic procedures.
False-positive test results must be considered when lung cancer screening with low-dose helical computed tomography (LDCT) is being evaluated. A false-positive test may lead to anxiety and invasive diagnostic procedures, such as percutaneous needle biopsy or thoracotomy. The percentage of false positives findings varies substantially among studies and is primarily attributable to differences in how a positive scan is defined (the size criteria), the thickness of the slice used between cuts (smaller slice thicknesses lead to detection of more nodules) and whether the subject resides in a geographic location where granulomatous disease is highly prevalent. A systematic review of the benefits and harms of CT screening for lung cancer reported that the follow-up of a screen-detected nodule most often included further imaging, which varied among 21 screening trials between 1% and nearly 45%. Positron emission tomography scanning was performed in 2.5% to 5% of patients. The frequency of nonsurgical biopsies or procedures in screening trials ranges from 0.7% to 4.4%. Of those biopsied, there was marked variation in the finding of a benign result (6%–79%). The rate of surgical resection for screen detected nodules in screening trials is between 0.9% and 5.6%. Of patients who underwent surgery, between 6% and 45% had a benign nodule discovered during surgery, a potential harm of lung cancer screening. In the National Lung Screening Trial (NLST), most major complications related to invasive procedures and surgeries occurred in patients diagnosed with lung cancer, with a major complication rate of 14%. Additionally, a complication rate of 4.1 deaths and 4.5 complications per 10,000 diagnostic events can be expected in patients determined to have a benign nodule. The rates of complications from the NLST may not be generalizable to a community setting; participants in the NLST were younger, better educated, and less likely to be current smokers (therefore healthier) than the population of smokers and former smokers in the general U.S. population who would be eligible for screening. Of note, 82% of the participants were enrolled at large academic medical centers and 76% of the enrollees were seen at National Cancer Institute–designated cancer centers. This may account for the extremely low complication rate and surgical mortality (1%) found in the NLST that led the multisociety position paper to strongly recommend that screening be carried out at centers with the same patient-management resources as those in the NLST.
In the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, the percentage of all positive lung cancer screens that were false-positive screens was 98%. When smoking status was considered, the percentage of false positive screens (among all positive screens) was highest in never-smokers (>99%) and lowest in current smokers (95%). After adjustment for smoking, the percentage of false-positive screens did not differ by sex.
A less familiar harm is overdiagnosis, the diagnosis of a condition that would not have become clinically significant had it not been detected by screening. Had the patient not been diagnosed with cancer, the patient would have died of other competing comorbidities. In the case of screening with LDCT, overdiagnosis could lead to unnecessary diagnosis of lung cancer requiring some combination of surgery (e.g., lobectomy, chemotherapy, and radiation therapy). Autopsy studies suggest that a significant number of individuals die with lung cancer rather than from it. In one study, about one-sixth of all lung cancers found at autopsy had not been clinically recognized before death. This may be an underestimate; depending on the extent of the autopsy, many small lung cancers that are detectable by CT may go unrecorded in an autopsy record. Studies in Japan provide additional evidence that screening with LDCT could lead to a substantial amount of overdiagnosis. Studies are needed to establish the level of overdiagnosis that might be associated with CT screening for lung cancer. However, in one study the volume-doubling times of 61 lung cancers were estimated using an exponential model and successive CT images. Lesions were classified into three of the following types:
- Type G (ground glass opacity).
- Type GS (focal glass opacity with a solid central component).
- Type S (solid nodule).
The mean-doubling times were 813 days, 457 days, and 149 days for types G, GS, and S, respectively. In this study, annual CT screening identified a large number of slowly growing adenocarcinomas that were not visible on chest x-ray suggesting overdiagnosis.
In a screening trial with more than 5,000 participants, the proportion of cancers that would be considered overdiagnoses was evaluated. Volume-doubling time was used as a surrogate for overdiagnosis. Patients with a calculated volume-doubling time of more than 400 days before surgical resection were considered as having an overdiagnosed cancer. The investigators discovered that 25% of those ultimately diagnosed with lung cancer met the criteria of an indolent screen-detected nodule, suggesting that one in four cancers in that trial were overdiagnosed. Similar rates of overdiagnosis have been documented in breast cancer. This rate is consistent with previous chest radiograph screening studies and for other solid tumors. The rate of overdiagnosis in the NLST has yet to be calculated, but the study data show a persistent gap of about 120 excess lung cancer cases in the LDCT group compared with the chest radiograph group, although long-term follow-up is needed.
About 20 years of follow-up of the Mayo Lung Project (MLP) cohort indicates that 17% of lung cancers diagnosed as the result of an intense regimen of chest x-ray and sputum cytology are overdiagnosed; 585 lung cancers had been diagnosed in the intervention arm as compared with 500 in the usual-care arm. After 13 years of follow-up of the PLCO cohort, 1,696 lung cancers had been diagnosed in the intervention arm as compared with 1,620 lung cancers in the usual-care arm. This suggests that about 6% of cancers diagnosed as the result of annual chest x-ray are overdiagnosed, although that percentage was not significantly different from 0%.
Complications of diagnostic evaluation
In the PLCO, 0.4% of participants with at least one positive screen who had a diagnostic evaluation had a complication associated with a diagnostic procedure. The most common of the 69 complications were pneumothorax (29%), atelectasis (15%), and infection (10%).
Increase in lung cancer mortality
Findings from the MLP hinted at the possibility of an increase in lung cancer mortality for persons screened with an intense regimen of chest x-ray and sputum cytology. At the end of 20 years of follow-up, the lung cancer mortality rate was 4.4 cases per 1,000 deaths in the intervention arm and 3.9 cases per 1,000 deaths in the usual-care arm. The two rates were not statistically different from one another (P = .09). No increase in risk was seen in the intervention arms of the John Hopkins University and Memorial Sloan-Kettering studies (relative risk [RR], 0.88; 95% confidence interval [CI], 0.74–1.05), and the PLCO (RR, 0.99; 95% CI, 0.87–1.22).
Another potential risk from screening with LDCT is radiation exposure. The average exposure is very low for an LDCT at 1.5 mSv. It is estimated that over a 3-year period of screening, NLST participants have been exposed to an average of 8mSv of radiation (which accounts for radiation from screens and additional imaging for screen-detected nodules). Modeling from previous work on radiation exposure and the development of cancer suggests that there could be one death per 2,500 screens in those participating in a screening program such as the NLST, although the benefit of screening (1 death avoided per 320 screens) far outweighs the risk. Younger persons and those without a significant risk of lung cancer may be more likely to suffer a radiation-induced lung cancer than may be spared a lung cancer death from screening.
Screening by Chest X-ray and/or Sputum Cytology
Unless reported above, data on harms associated with sputum cytology or a combined regimen of sputum cytology and chest x-ray have not been published.
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