Jennifer M. Croswell, MD, MPH; Stuart G. Baker, ScD; Pamela M. Marcus, PhD; Jonathan D. Clapp, BS; Barnett S. Kramer, MD, MPH
Direct-to-consumer promotion of lung cancer screening has increased, especially low-dose computed tomography (CT). However, screening exposes healthy persons to potential harms, and cumulative false-positive rates for low-dose CT have never been formally reported.
To quantify the cumulative risk that a person who participated in a 1- or 2-year lung cancer screening examination would receive at least 1 false-positive result, as well as rates of unnecessary diagnostic procedures.
Randomized, controlled trial of low-dose CT versus chest radiography. (ClinicalTrials.gov registration number: NCT00006382)
Feasibility study for the ongoing National Lung Screening Trial.
Current or former smokers, aged 55 to 74 years, with a smoking history of 30 pack-years or more and no history of lung cancer (nÂ = 3190).
Random assignment to low-dose CT or chest radiography with baseline and 1 repeated annual screening; 1-year follow-up after the final screening. Randomization was centralized and stratified by age, sex, and study center.
False-positive screenings, defined as a positive screening with a completed negative work-up or 12 months or more of follow-up with no lung cancer diagnosis.
By using a Kaplanâ€“Meier analysis, a person's cumulative probability of 1 or more false-positive low-dose CT examinations was 21% (95% CI, 19% to 23%) after 1 screening and 33% (CI, 31% to 35%) after 2. The rates for chest radiography were 9% (CI, 8% to 11%) and 15% (CI, 13% to 16%), respectively. A total of 7% of participants with a false-positive low-dose CT examination and 4% with a false-positive chest radiography had a resulting invasive procedure.
Screening was limited to 2 rounds. Follow-up after the second screening was limited to 12 months. The false-negative rate is probably an underestimate.
Risks for false-positive results on lung cancer screening tests are substantial after only 2 annual examinations, particularly for low-dose CT. Further study of resulting economic, psychosocial, and physical burdens of these methods is warranted.
National Cancer Institute.
The ongoing National Lung Screening Trial aims to define the effectiveness of screening for lung cancer. However, imaging studies to screen for lung cancer are currently marketed to patients.
These data from a pilot study for the National Lung Screening Trial show a 33% cumulative incidence of false-positive results after 2 computed tomography examinations and 15% after 2 chest radiography examinations. Substantial proportions of patients (7% for computed tomography and 4% for chest radiography) with false-positive results required invasive testing to determine that the screening-detected lesion was not cancer.
Physicians and patients should bear in mind high false-positive rates when considering screening for lung cancer with computed tomography or chest radiography.
CT = computed tomography.
* There was a lag between eligibility assessment and randomization at each center. Once the target sample size (n = 3000) was reached, persons who were eligible but had not yet consented were not randomly assigned unless they had already been invited to participate.
† “Sufficient follow-up” means that a person had a negative screening result, 12 months of documented follow-up after a positive screening result, or a completed diagnostic work-up after a positive screening examination. For the base-case analysis, persons with insufficient follow-up after a positive examination were included in the analysis but were assumed to have received a false-positive test result.
The cumulative probability is for the first false-positive result received from a number of tests done. Participants at risk for screening test 1 is the number of participants who received at least 1 screening test (at T0 if both T0 and T1 screenings were taken or at T1 if T0 screening was missed). Participants at risk for screening test 2 is the number of participants who received both tests (at T0 and T1) in whom the result of the first test received was negative. See the Appendix for more detailed information. CT = computed tomography.
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Appendix Table 9.
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H. Nancy Sokol
April 30, 2010
To the Editor:
The introduction to the report on false positive results in lung cancer screening acknowledges the increasing public attention and political advocacy for lung cancer screening in recent years. It then cites that "surveys of the U.S. community physicians...have found that two thirds of family practitioners, internists, and gynecologists, and 82% of general surgeons recommended chest radiography for lung cancer screening every 1 to 2 years (1)." I believe this statement is misleading.
The reference cited is a 1994 study in which physicians were surveyed by telephone or mail between October 1989 and March 1990 (2). The survey asked participants how often they would recommend specific screening tests for breast, colon, cervical and lung cancer, offering options of "every 6 months or less, every 7 to 11 months, every 12 months..." Thus, the survey did not ascertain actual practice but what the clinicians thought the guidelines at that time would recommend; did not offer an option of "no screening recommended;" and, even if responses were consistent with practice, would reflect opinion and practice from 20 years ago.
Citing these data in the paper might suggest to readers that they are outliers by not routinely ordering lung cancer screening. The paper makes a cogent argument why such screening might lead to psychological and physical harm from false positive CT findings.
1. Croswell, JM, Baker, SG, Marcus, PM, et al. Cumulative incidence of False-positive Test Results in Lung Cancer Screening. A Randomized Trial. Ann Intern Med 2010; 152:505
2. Czaja, R, McFall, SL, Warnecke, RB, et al. Preferences of Community Physicians for Cancer Screening Guidelines. Ann Intern Med 1994; 120:602
Jennifer M. Croswell
Office of Medical Applications of Research, NIH
May 26, 2010
Dr. Sokol expresses concern over our citation of a 1994 Annals of Internal Medicine study that attempted to gain a better understanding of the cancer screening preferences of community physicians. Although the title of the article is Preferences of Community Physicians for Cancer Screening Guidelines, the survey directly queried about individual practice patterns, and not simply "what the clinicians thought the guidelines at that time would recommend" (1). The specific question posed for each screening modality was not, "What do guidelines say you should do regarding screening for this cancer?" but rather, "How often would *you* recommend screening by a physician for an individual who has no known risk factor for that cancer type?" [emphasis added] Of note, for lung cancer, no professional society at that time recommended the use of chest x-ray as a screening test in asymptomatic individuals. Despite this, there was 70% consensus across those polled that it should be performed annually or every 1 to 2 years. This represented a striking departure from guidelines and points to a clear discrepancy between national recommendations and community practices. Furthermore, although the survey did not explicitly have a "no screening recommended" option, there was an option for "other interval/specify," in which an individual could respond with "never;" as the authors point out that internists and gynecologists were less likely to "*ever recommend* chest x-ray for patients at normal risk" [emphasis added] compared to other specialties, it is clear that this did occur.
Dr. Sokol also points to the fact that the data published in 1994 may not accurately reflect current opinions or practice. This highlights the challenge we faced in attempting to find reliable estimates of the frequency of lung cancer screening in the U.S. As we noted in our article, to our knowledge it is currently not possible to accurately assess true usage patterns, a deficiency that hopefully will be rectified with future research (2). It was most certainly not our intention to suggest that those that do not routinely utilize chest x-ray or CT for lung cancer screening are "outliers" in any way, given that, as in 1994, no professional society guidelines recommend such testing. Given the known harms and currently theoretical benefits of lung cancer screening, it is essential to await the results of ongoing randomized controlled trials to better assess ultimate utility before continuing to promote such programs to the general public.
1. Czaja, R, McFall, SL, Warnecke, RB, et al. Preferences of Community Physicians for Cancer Screening Guidelines. Ann Intern Med 1994; 120:602
2. Croswell, JM, Baker, SG, Marcus, PM, et al. Cumulative incidence of False-positive Test Results in Lung Cancer Screening. A Randomized Trial. Ann Intern Med 2010; 152:505
Professor of Clinical Medicine, New York Medical College, Valhalla, New York, Medical Director, Earl
June 7, 2010
Incidence of false-positive test results in lung cancer screening
Croswell and co-authors are appreciated for providing follow-up on their 2-year lung cancer screening study (1). Their focus on "false positive" test results is important. Such a powerful term as false positive must be specifically defined. To say that "non-calcified nodules larger than 3mm at [initial scan] or 4mm at [scan one year later] were considered suspicious for lung cancer" (p. 506) does not really comport with clinical practice or, for that matter, with lung cancer screening practice over the past decade. The authors clearly state that studies have reported rates for noncalcified nodules of 25-50% depending on screening frequency and "other factors" which would include geography (histoplasmosis belt), scanner model, and the lower size limit of nodules. Since it is well-established that most of these nodules do not represent or progress to lung cancer, to refer to the entire group as "suspicious for lung cancer," is to invite excessive work-up.
A better term for lung nodules below a certain diameter (10-15mm) that do not have features of malignancy such as spiculation or irregular borders is "indeterminate." Most lung nodules fall into this category and are readily identified by radiologists even if they err on the side of caution. Protocols published by the International Early Lung Cancer Action Program (2), call for repeat low dose CT scanning of indeterminate nodules, the vast majority if which do not increase in 3 to 6 months (or thereafter). If these follow-up low dose CT scans are performed within the screening program, multiple benefits accrue. Consistency of CT scan reading is assured. The needless radiation dose of a high-dose "diagnostic" CT scan can be avoided. Furthermore, most screening participants will not be subject to the variation in lung nodule work-up that personal physicians will perform and that increases the chances of invasive procedures. In our 18 month follow-up of 728 subjects with a low dose CT- detected indeterminate lung nodule, only 3 showed growth, all within 6 months, and were found to be lung cancers (3). All 3 nodules were > 5mm on initial scan and were stage I on resection. We subsequently were able to inform our participants about the small likelihood that indeterminate nodules would subsequently be found to represent lung cancers and were thereby able to avoid or allay anxiety.
In addition, separation of "suspicious" from "indeterminate" nodules and diagnosis of suspicious nodules have improved in the decade since the Croswell feasibility study (1) with advances in and greater accessibility of positron emission (PET) scans and transthoracic and bronchoscopic biopsy. Many patients who underwent thoracoscopy or thoracotomy for benign lesions a decade ago would have been spared these invasions by present-day imaging and biopsy techniques. Similarly, experience with radiation dose limitation has progressively reduced dosage screening scans to 1 to 3 mGy for non-obese subjects (4, 5).
1. Croswell JM, Baker SG, Marcus PM, Clapp JD, Kramer BS. Cumulative incidence of false-positive test results in lung cancer screening: a randomized trial. Ann Intern Med 2010;152:505-512.
2. International Early Lung Cancer Action Program Investigators. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med. 2006;355:1763-1771.
3. Markowitz SB, Miller A, Miller J, Manowitz A, Kieding S, Sider L, Morabia A. Ability of low-dose helical computed tomography to distinguish between benign and malignant non-calcified lung nodules. Chest 2007; 132:1028-1034.
4. International Early Lung Cancer Action Program website. www.ielcap.org/professionals/docs. 2/25/10
5. Xu DM, van der Zaag-Loonen HJ, Oudkerk M, Wang Y, Vliegenthart R, Scholten ET, Verschakelen J, Prokop M, de Koning HJ, van Klaveren RJ. Smooth or attached solid indeterminate nodules detected at baseline CT screening in the NELSON study: cancer risk during 1 year of follow-up. Radiology. 2009;250:264-272.
Both authors direct a federally funded lung cancer screening program and have served as medical experts in a lawsuit involving tobacco use and CT scan-based lung cancer screening.
Jennifer M. Croswell, Stuart G. Baker, Pamela M. Marcus, Jonathan D. Clapp, Barnett S. Kramer. Cumulative Incidence of False-Positive Test Results in Lung Cancer Screening: A Randomized Trial. Ann Intern Med. 2010;152:505–512. doi: 10.7326/0003-4819-152-8-201004200-00007
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Published: Ann Intern Med. 2010;152(8):505-512.
Cancer Screening/Prevention, Hematology/Oncology, Lung Cancer, Prevention/Screening, Pulmonary/Critical Care.
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