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From JAMA
Oct 8, 2012

Evidence at the Point of Practice Change

Author Affiliations
Author Affiliations: Departments of Obstetrics, Gynecology, and Reproductive Sciences (Dr Sawaya) and Epidemiology and Biostatistics (Dr Sawaya) and Division of General Internal Medicine, Department of Medicine (Dr Tice), University of California, San Francisco.
Arch Intern Med. 2012;172(18):1415-1417. doi:10.1001/archinternmed.2012.4287
Benefits and Harms of CT Screening for Lung Cancer: A Systematic Review
Abstract

Context: Lung cancer is the leading cause of cancer death. Most patients are diagnosed with advanced disease, resulting in a very low 5-year survival. Screening may reduce the risk of death from lung cancer.

Objective: To conduct a systematic review of the evidence regarding the benefits and harms of lung cancer screening using low-dose computed tomography (LDCT). A multisociety collaborative initiative (involving the American Cancer Society, American College of Chest Physicians, American Society of Clinical Oncology, and National Comprehensive Cancer Network) was undertaken to create the foundation for development of an evidence-based clinical guideline.

Data Sources: MEDLINE (Ovid: January 1996 to April 2012), EMBASE (Ovid: January 1996 to April 2012), and the Cochrane Library (April 2012).

Study Selection: Of 591 citations identified and reviewed, 8 randomized trials and 13 cohort studies of LDCT screening met criteria for inclusion. Primary outcomes were lung cancer mortality and all-cause mortality, and secondary outcomes included nodule detection, invasive procedures, follow-up tests, and smoking cessation.

Data Extraction: Critical appraisal using predefined criteria was conducted on individual studies and the overall body of evidence. Differences in data extracted by reviewers were adjudicated by consensus.

Results: Three randomized studies provided evidence on the effect of LDCT screening on lung cancer mortality, of which the National Lung Screening Trial was the most informative, demonstrating that among 53 454 participants enrolled, screening resulted in significantly fewer lung cancer deaths (356 vs 443 deaths; lung cancer−specific mortality, 274 vs 309 events per 100 000 person-years for LDCT and control groups, respectively; relative risk, 0.80; 95% CI, 0.73-0.93; absolute risk reduction, 0.33%; P = .004). The other 2 smaller studies showed no such benefit. In terms of potential harms of LDCT screening, across all trials and cohorts, approximately 20% of individuals in each round of screening had positive results requiring some degree of follow-up, while approximately 1% had lung cancer. There was marked heterogeneity in this finding and in the frequency of follow-up investigations, biopsies, and percentage of surgical procedures performed in patients with benign lesions. Major complications in those with benign conditions were rare.

Conclusion: Low-dose computed tomography screening may benefit individuals at an increased risk for lung cancer, but uncertainty exists about the potential harms of screening and the generalizability of results.

Among the most difficult decisions made by clinicians and policymakers is determining when a new test or treatment should be integrated into routine medical practice. Attention has turned again to lung cancer screening. Bach et al1 have provided a comprehensive overview of the current evidence regarding the benefits and harms of low-dose computed tomography (LDCT) for lung cancer screening. The work is notable for its rigorous approach and its thoughtful discussion of the range of current unanswered questions. The authors conclude that LDCT may provide benefit for those at increased risk, but uncertainty exists about potential screening harms and the generalizability of results. The report formed the foundation for a clinical practice guideline by the American College of Chest Physicians and the American Society of Clinical Oncology. They jointly recommend that annual screening with LDCT be offered at select centers to smokers and former smokers aged 55 to 74 years who have smoked for 30 pack-years or more and either continued to smoke or have quit within the past 15 years. Can we reconcile a recommendation to offer screening in the face of numerous uncertainties, especially screening harms and costs?

Data from the National Lung Screening Trial (NLST) (N = 53 454)2 were weighted heavily in the meta-analysis. The NLST Data and Safety Monitoring Board stopped the trial early owing to a significant 20% reduction in lung cancer death in the LDCT group compared with the group assigned to chest radiography. In terms of harms, the NLST collected unusually detailed information about positive test results and complications subsequent to the diagnostic evaluation of positive test results. Positive test results were common: after 3 rounds of annual screening, the likelihood of having at least 1 positive test result was 391 per 1000 screened individuals, and more than 94% of the results were falsely positive.

Bach and colleagues completed the critical first steps in making a clinical guideline: performing a systematic review of the pertinent evidence and rating its quality. They have gone 1 step further by making an important judgment about whether the current state of evidence is sufficient to draw meaningful and robust conclusions about both benefits and harms. This judgment is often difficult, though essential, in providing a green light in going forward with making a positive, or a negative, recommendation. The authors believe that this goal has been met, stating that “a reasonable amount of data has been reported regarding the outcomes of LDCT screening for lung cancer and that some conclusions can be drawn regarding its risks and benefits despite many areas of uncertainty.”

Once it is determined that evidence of benefits and harms is sufficient to move forward in making a clinical guideline, then judging the balance of benefits and harms is a next critical step.3 Methods by which this balance can be assessed explicitly include outcomes tables and single-metric analyses (eg, quality-adjusted life-years used in decision analysis and cost-effectiveness analyses). Both methods are complementary to one another.4 Outcomes tables estimate both screening benefits and harms expected to accrue in theoretical screened and unscreened cohorts followed up over a defined period. In eAppendix 4, the authors show a table of anticipated outcomes over a 7-year period among 1000 individuals screened with annual LDCT compared with 1000 individuals receiving usual care. They estimated that of 1000 high-risk smokers and former smokers undergoing usual care over a 7-year period, 16 would die of lung cancer; with LDCT screening, 13 would die. If the authors meant to estimate outcomes of annual screening for 7 years, then the benefits may be underestimated since none of the cited studies screened enrollees annually for 7 years. Perhaps more important, harms also appear to be underestimated. While several trials contribute to the estimate of false-positive test results, the cumulative risk of false-positive test results over 3 rounds of annual screening in the NLST alone was higher than the reported rate of 190 per 1000 screened individuals. Surgical procedures, nonsurgical biopsies, and follow-up imaging tests would also be greater in the LDCT group than reported if the comparison is “no screening” rather than screening with chest radiography. To avoid miscommunication, these outcomes should be reviewed, and, if more accurate estimates are available, the table should be modified. In sum, the authors conclude that the benefits are sizable enough and the harms manageable enough to offer screening to informed individuals meeting certain criteria.

Should screening be offered without knowing how it will be paid for? Screening is expensive, and legitimate questions regarding costs should be asked: Will insurers pay? Should they? In the absence of insurance coverage, should individuals opting for screening be expected to pay not only for the cost of the initial LDCT but also for the downstream costs related to the entire screening process (additional tests, biopsies)? While a recent analysis concluded that the costs per life-year saved by annual lung cancer screening among high-risk individuals aged 50 to 64 years compare favorably with those estimated for other cancers, the age range of the studied population was not that of the target population currently recommended for screening (55-74 years).5 Economic analyses of the NLST are planned by the Cancer Intervention and Surveillance Modeling Network and will provide critical information to policymakers and others.

What are next steps? To more fully inform guidelines, single-metric analyses are needed to estimate a wider range of plausible and important outcomes that have not, and often cannot, be directly measured. These outcomes include cancer deaths attributable to radiation from screening (1 per 2500 screened individuals as reported by Bach and coauthors) and effects on quality of life owing to outcomes directly related to the screening process, both beneficial and adverse (eg, anxiety). Simulation decision models will be needed to evaluate the effect of varying ages to begin and end screening. Various screening frequencies should be evaluated to determine whether, for example, biennial screening would confer similar benefits while halving the harms. Finally, various surveillance strategies for individuals with abnormal test results but no evidence of cancer should be investigated to guide clinicians regarding when they can safely end surveillance and return individuals to routine screening or end screening altogether. Models are needed because trials are unlikely to be performed to answer these important questions. Registries will be useful in ensuring that outcomes used to inform the model and ultimately to improve screening approaches are derived from real-life screening settings rather than from experimental settings.

Finally, clinicians will need to be ready, willing, and able to discuss screening and to ensure access to the most accurate probabilities of both benefits and harms in consumer-friendly formats so that decisions can be made that reflect individuals' preferences and values. The process can be complex, and unbiased presentations are important. Bach and colleagues have included helpful sample statements in eAppendix 4 to guide clinicians in such conversations.

The point at which evidence should prompt practice change is a universal and fundamental debate within medical practice. Bach and coauthors have provided a comprehensive summary of evidence related to lung cancer screening and have concluded that evidence is sufficient to offer screening to select individuals in specific settings. To some, this recommendation will represent an important medical advance in the care of patients at high risk of lung cancer, the leading cause of cancer mortality in the United States. To others, it will be a recommendation made with incomplete information on harms and insufficient attention to costs; they may choose to await more information, including the opinion of the US Preventive Services Task Force. Regardless of perspective, the process by which all of these pieces come together will provide an important road map for assessment and implementation of future health care innovations that include a delicate balance between benefits, harms, and costs.

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Article Information

Correspondence: Dr Sawaya, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, 3333 California St, Ste 335, San Francisco, CA 94143-0856 (sawayag@obgyn.ucsf.edu).

Published Online: September 10, 2012. doi:10.1001/archinternmed.2012.4287

Financial Disclosure: None reported.

References
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