ORLANDO, FL—Patients who undergo serial low-dose CT screening scans for lung cancer are at high risk of false-positive results that can lead to unnecessary—and potentially harmful—follow-up tests, government researchers reported here at the ASCO Annual Meeting.
“What is surprising is how quickly the false-positive rate went up—after only two screens, CT scans falsely suggested the presence of disease in 33% of cases,” said Jennifer M. Croswell, MD, Acting Director of the NIH Office of Medical Applications of Research.
The findings come at time that many hospitals are promoting CT scans for the early detection of lung cancer, particularly in smokers and ex-smokers, she noted.
Screening Burdens Underappreciated
Dr. Croswell said she and colleagues undertook the study because the potential burdens of screening have historically been “underappreciated and under-examined.”
For the study, the researchers used data from the Lung Screening Study (LST), a randomized trial of chest x-rays and low-dose CT in lung-cancer screening. LST is a feasibility trial for the ongoing National Lung Screening Trial (NLST), which is designed to determine whether chest x-rays and/or CT scans reduce lung-cancer-related mortality.
In LST, 1,610 participants were given a baseline CT and 1,580 were given a baseline chest x-ray, with a repeat screen one year later. They were followed for one more year.
“We asked the question, what was the risk over time of getting at least one false-positive lung-cancer-screening test,” Dr. Croswell said.
A positive screen was defined as any noncalcified nodule at least 4 mm in size, or other radiographic finding deemed suspicious for cancer.
A false positive was defined as a positive screen with either a completed negative work-up or at least 12 months follow-up with no cancer diagnosis.
With Kaplan-Meier analysis, an individual's cumulative probability of having at least one false-positive CT scan was found to be 21% after one screen and 33% after two screens. For chest x-rays, the cumulative probabilities were 9% and 15% after one and two screens, respectively.
“The x-ray results were not surprising,” Dr. Croswell said. “The 15% rate of false positives after two screens was similar to what we found in the ongoing PLCO [Prostate, Lung, Colorectal, and Ovarian] cancer screening trial,” a randomized controlled trial to determine the effects of prostate, lung, colorectal, and ovarian cancer screening on disease-specific mortality (Crosswell et al: Ann Family Med 2009;7:212–222).
For CT scans, several studies have reported a high incidence of noncalcified nodules in people who were screened. This study, however, is the first to track an individual's risk of obtaining false-positive results over time, she explained.
In a multivariate analysis, the only statistically significant factor that placed an individual at higher risk of false-positive CT results was older age, with patients age 64 to 75 having a 34% increased risk of a false-positive result compared with those 55 to 64.
Being a current smoker versus a former smoker trended toward higher false-positive odds—“But these multivariate results need replication. They are not practice-changing,” Dr. Croswell stressed.
She and her colleagues then looked at diagnostic follow-up for patients with false-positive findings. Of patients getting a false-positive CT result, 6.6% had any kind of invasive diagnostic procedure and 1.6% had major surgery such as thoracotomy. This compared with 4.2% and 1.9%, respectively, for those with false-positive chest x-ray results.
The majority of patients whose CT or x-ray results later turned out to be false positives—61% and 51%, respectively—were scheduled for repeat screens.
That in itself is problematic, since “many people don't want to wait two or three months for another test. They might push for a biopsy even if the physician wants to schedule a repeat scan,” commented Peter G. Shields, MD, Deputy Director of the Lombardi Comprehensive Cancer Center at Georgetown University.
The invasive follow-up exams are particularly troubling.
“A one-in-three chance [of having a false positive] is huge, even if anxiety is the only negative effect. But the results can lead to invasive tests. That's unacceptable,” Dr. Shields said. “Many physicians recognize the high false-positive rate associated with CT scans, but nonetheless, this test is widely used in clinical practice.”
Impact on Mortality Unknown
Dr. Shields and Julie R. Gralow, MD, Director of Breast Medical Oncology at Seattle Cancer Care Alliance and Associate Professor in the Oncology Division of the University of Washington School of Medicine, agreed that one of the big problems is that no screening method for lung cancer has been shown to reduce mortality from the disease, which is detected only in its late stages.
“However, depending on the benefit, an improvement in morbidity, such as finding it earlier so that you can avoid chemotherapy, can count too. But the gold standard for any cancer-screening test should be an improvement in survival, and very few screening tests have met that standard,” Dr. Gralow said, citing mammography as one exception.
Results of the NELSON (National Lung Screening Trial and the European Nederlands-Leuvens Longkanker Screenings Onderzoek) trial, also designed to answer the question of whether lung-cancer screening reduces mortality, could be available next year, Dr. Gralow said.
In the meantime, “we have to look at the benefit [of lung cancer screening] versus the potential physical or emotional harm.”
Tobacco Use the Bigger Issue
The bigger issue is smoking, Dr. Gralow said.
Recent statistics suggest that 40 million Americans smoke, placing themselves at risk of not only lung cancer, but a host of health problems, she said.
“I would argue that we need ways not just of finding lung cancer earlier, but also of preventing disease. We should be putting efforts into prevention and cessation of smoking,” she said.