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Annals of Internal Medicine
Screening for Lung Cancer With Low-Dose Computed Tomography Grand Rounds Discussion From the Beth Israel Deaconess Medical Center Gerald W. Smetana, MD; Phillip M. Boiselle, MD; and Richard M. Schwartzstein, MD
In December 2013, the U.S. Preventive Services Task Force recommended screening for lung cancer with low-dose computed tomography (LDCT) for selected current and former smokers. The Task Force based the recommendation primarily on the results of the NLST (National Lung Screening Trial). In this trial, patients randomly assigned to LDCT screening for 3 years had lower rates of both lung cancer–specific mortality and all-cause mortality (relative risk reduction, 6.7% [95% CI, 1.2% to 13.6%]; absolute risk reduction, 0.46% [CI, 0% to 0.9%]). Clinicians and health systems confront questions and challenges as they begin to implement lung cancer screening. This paper summarizes a conference during which an internist and a radiologist discuss the application of the Task Force recommendation to an individual patient. Ann Intern Med. 2015;162:577-582. doi:10.7326/M15-0055 For author affiliations, see end of text.
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s. D is a 60-year-old woman with a complex medical history that includes hypertension, chronic obstructive pulmonary disease (COPD), type 2 diabetes mellitus, hypercholesterolemia, chronic kidney disease, sciatica, peripheral vascular disease that has required both surgical and percutaneous revascularization procedures, cerebrovascular disease requiring carotid endarterectomy, coronary artery disease requiring stent placement, anxiety, and depression. She began smoking at age 13 and ever since has smoked about 1 pack of cigarettes per day for a total of approximately 47 pack-years. After several unsuccessful attempts to stop smoking using bupropion, varenicline, and nicotinereplacement therapy, she quit 2 months before presentation when faced with risk for loss of a leg due to peripheral artery disease and femoral artery thrombosis. Ms. D has Gold class II COPD with a chronic productive cough and exertional dyspnea. Peripheral artery disease limits her walking capacity to several blocks. During a recent hospitalization for COPD exacerbation, a plain chest radiograph was normal, FEV1 was 1.49 (58% predicted), FVC was 2.64 (79% predicted), and the FEV1–FVC ratio was 56%. Current medications include albuterol, fluticasone, ipratropium/albuterol, atenolol, atorvastatin, bupropion, clopidogrel, diazepam, gabapentin, glipizide, losartan, metformin, trazodone, and warfarin. She lives with her husband and son and works in a mental health facility. See the Patient Video (available at www.annals.org) to view the patient telling her story. The patient is unsure of her prognosis but hopes that it will improve now that she has quit smoking. She was unaware of the lung cancer screening guideline. Although she does
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not think having low-dose computed tomography (LDCT) would be a “big deal,” she wonders why someone who feels healthy would want to screen for lung
ABOUT BEYOND THE GUIDELINES Beyond the Guidelines is a moderator-led discussion from Grand Round Sessions from the Beth Israel Deaconess Medical Center. This manuscript is based on the Department of Medicine Grand Rounds conference held on 6 November 2014 at Beth Israel Deaconess Medical Center, Boston, Massachusetts: Moderator: Deborah Cotton, MD, MPH, Deputy Editor, Annals of Internal Medicine. For more information on Beyond the Guidelines, visit www.annals.org/GrandRounds.
AVAILABLE AT www.annals.org Patient interview video Grand Rounds video Supplement slides CME/MOC activity Questions and comments
See also: Celebrating the ACP Centennial: From the Annals Archive . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
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BEYOND THE GUIDELINES cancer. She admits that an abnormal screening CT would cause anxiety and that she would find it difficult to wait 6 months for a repeated study—she would want an immediate biopsy, even if there was only a 5% chance that the abnormality was cancer.
CONTEXT, EVIDENCE, AND GUIDELINES Lung cancer is the third most common type of cancer in the United States and the leading cause of death due to cancer; there were 158 248 lung cancer deaths in the United States in 2010 (1). Eighty-five percent of cases of lung cancer are diagnosed at a late stage; the 5-year survival rate across all stages is only 16.6% (2). Effective screening that would both increase detection rates of early-stage cancer and reduce lung cancer mortality would be an important advance, but the results of studies of screening with routine chest radiography have been disappointing (3), and this practice has been largely abandoned in the United States. In December 2013, the U.S. Preventive Services Task Force (USPSTF) recommended annual screening for lung cancer with LDCT in adults aged 55 to 80 years who have a 30 pack-year history of smoking and currently smoke or have quit within the past 15 years. These recommendations were based largely on the findings of the NLST (National Lung Screening Trial) (4). The USPSTF also recommended discontinuation of screening after 15 years of smoking cessation or if a competing medical condition limited expected survival or reduced the likelihood of surviving lung cancer surgery. Four randomized trials of LDCT screening are the focus of the evidence review on which the USPSTF based the lung cancer screening recommendations (3, 5). The largest of these trials, the NLST, was a study of 53 454 participants aged 55 to 74 years who had a smoking history (4). Forty-eight percent of participants were current smokers. Among the 52% who were former smokers, 14.8% quit smoking within 4 years of study entry, 17.3% within 4 to 10 years, and 19.5% within 10 to 15 years (6). Median exposure was 48 pack-years for both current and former smokers. Patients were randomly assigned to annual LDCT screening or posteroanterior chest radiography at baseline and annually for 2 more years. Thirty-nine percent of patients in the LDCT group had at least 1 positive screening result during the study, 96.4% of which were false positives. In contrast, 16.0% of patients in the chest radiography group had at least 1 positive result, 94.5% of which were false positives. Lung cancer–specific mortality was 247 and 309 per 100 000 personyears in the LDCT and chest radiography groups, respectively (relative risk reduction [RRR], 20.5% [95% CI, 6.8% to 26.7%]). There were 1877 deaths from any cause in the LDCT group and 2000 in the chest radiography group (RRR, 6.7% [CI, 1.2% to 13.6%]; absolute risk reduction [ARR], 0.46% [CI, 0% to 0.9%]).
Screening for Lung Cancer With LDCT
CLINICAL QUESTIONS When the USPSTF recommendations are applied in a clinical setting, and to Ms. D in particular, several questions arise, and we present these questions to our discussants, Dr. Richard Schwartzstein, an internist, and Dr. Phillip Boiselle, a radiologist. Question 1 Do you think that LDCT screening for lung cancer adds value? If so, in which subsets of patients? Question 2 Can one generalize the results of the NLST to radiology departments outside of large academic centers and to diverse populations that may differ from that in the trial? Question 3 How can doctors help patients deal with the uncertainties associated with lung cancer screening?
DISCUSSION A Radiologist's Perspective (Dr. Phillip Boiselle) Regarding the value, LDCT screening has the potential to reduce lung cancer deaths among the estimated 9 million smokers and former smokers in the United States who meet the NLST entry criteria (4, 7). Moreover, certain subgroups of smokers are likely to gain even more value from screening than the overall NLST study population (8, 9). For example, the number of lung cancer deaths prevented per 100 000 personyears in the LDCT group of NLST was 60-fold greater in the highest-risk quintile subgroup than in the lowestrisk quintile (12.0 in quintile 5 vs. 0.2 in quintile 1; P = 0.01) (8). Moreover, the ratio of false-positive results to screening-prevented lung cancer deaths was significantly lower in the highest-risk quintile (65 in quintile 5 vs. 1648 in quintile 1; P < 0.0001). A model for lung cancer prediction (Table 1), developed by Tammema¨gi and colleagues, enables estimation of individual risk for lung cancer (9). Compared with the NLST criteria, this model has increased sensitivity (83.0% vs. 71.1%; P < 0.001) and positive predictive value (4.0% vs. 3.4%; P = 0.01) without loss of specificity (62.9% and 62.7%; P = 0.54). These data support the concept of considering an individual's personalized risk profile when considering the potential benefits and risks of LDCT screening for lung cancer. Based on an online version of the Tammema¨gi risk calculator (www.brocku.ca/lung-cancer -risk-calculator), the probability that Ms. D will develop lung cancer within the next 6 years is 2.9%; this places her in the high-risk category (2% = high) (9). As noted by Bach and Gould (10), the value of LDCT screening in an individual patient is determined primarily by comparing the risk for lung cancer with competing causes of death. In this context, it is interesting to note that more patients in the LDCT group of the NLST died from cardiovascular disease than from lung
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cancer (11), perhaps due to the shared risk factors for the competing illnesses. Although her calculated risk for lung cancer is high, Ms. D's cardiovascular disease is a substantial competing risk for death. Moreover, given her COPD, it is important to assess her candidacy for surgical resection if screening detects lung cancer. Her spirometry results alone suggest that she may be a candidate for wedge resection or potentially lobectomy, but additional tests, such as diffusion capacity, would be helpful to provide a more complete picture of lung function. In summary, although Ms. D is at high risk for lung cancer, we need to learn more about her competing medical conditions and her potential for surviving lung cancer surgery to better assess the potential value of LDCT screening. In considering whether the results of NLST can be generalized to radiology departments outside of large academic centers, it is important to recognize that nearly a quarter of participating sites in the NLST were not tertiary care academic medical centers (4, 12). Moreover, previous data from the International Early Lung Cancer Action Program showed successful application of a prescribed LDCT screening regimen across a diverse group of practice settings (13). To help ensure uniform quality of screening across practice settings, the American College of Radiology (ACR) has created LDCT screening practice parameters, a lung imaging reporting and data system (LungRADS) modeled after the BI-RADS system for mammography, and an accreditation process for ACR Lung Cancer Screening Centers (14 –16). Based on a growing awareness of the very low likelihood of lung cancer in solid nodules smaller than 6 mm, the Lung-RADS system has increased the size threshold for a positive screening result from 4 to 6 mm, which should substantially reduce false-positive results and unnecessary invasive procedures (14). With Lung-RADS, it is estimated that approximately 9 of every 10 persons screened will require no further imaging follow-up between annual LDCT scans. In a retrospective reclassification of LDCT screening results for over 2000 patients, Lung-RADS reduced the overall positive rate from 27.6% to 10.6% and increased the positive predictive value from 6.9% to 17.3% (17). The ACR and others have emphasized the importance of a multidisciplinary approach to screening that includes radiology, pulmonary medicine, pathology, thoracic surgery, medical and radiation oncology, and other related health care disciplines (16). Because surgical mortality rates directly influence the success of screening outcomes, the importance of access to highquality surgical care cannot be overemphasized (4). With regard to generalization of NLST results, it is notable that approximately 40% of participants were women and that nearly 1 in 10 participants was a member of a minority group (4). However, the NLST population differed in several respects from respondents to a 2002–2004 U.S. Census survey of individuals who met the NLST eligibility for age and smoking history (4). For example, NLST participants were younger, had a higher
Table 1. Historical Features Included in a Personalized Risk Calculator for Lung Cancer* Cumulative smoking history (pack-years) Years since quitting smoking Age Education Body mass index History of COPD, emphysema, or chronic bronchitis Personal history of cancer Family history of lung cancer Race/ethnicity
COPD = chronic obstructive pulmonary disease. * Adapted from reference 9. Risk calculator available at www .brocku.ca/lung-cancer-risk-calculator.
level of education, and were more likely to be former smokers (4). Despite these differences, the consensus is that NLST results can be generalized to patients who meet the eligibility criteria as long as they are in “reasonably good health” and are able to tolerate surgery (18). Although Ms. D meets the eligibility criteria, she differs from the general NLST population because of her competing health risks and uncertain candidacy for surgery. The cost-effectiveness of LDCT screening is another issue. A recent analysis from the NLST estimated that LDCT screening would cost $81 000 per qualityadjusted life-year gained (19). However, it is possible that screening done outside of a trial could be more expensive. Of note, widespread implementation of the Lung-RADS system has the potential to offset some costs by reducing false-positive results. To assist patients in dealing with the uncertainties of lung cancer screening requires commitment to shared decision making with careful consideration of scientific evidence and patient preferences. It is important that patients understand the risks of screening, including false-positive results that lead to subsequent tests and interventions, radiation exposure, expense, overdiagnosis, and anxiety. With respect to anxiety, a recent substudy of nearly 3000 NLST participants found no measurable increase in anxiety or decrease in quality of life at 1 month or 6 months after screening among participants with falsepositive results (20). Despite these results, Ms. D's history of anxiety, along with her apparent concerns about “watchful waiting” of screen-detected nodules, suggests that she would be at high risk for anxiety in response to false-positive results. With this in mind, a conversation about screening with Ms. D should include a detailed description of the likelihood of a positive screening result, the high percentage of positive results that prove to be false-positive, and the importance of following evidence-based nodule management recommendations. Ms. D must understand that the risk– benefit ratio of CT screening may be negatively altered if she seeks biopsy or resection of a lung nodule outside of recommended practice. If she and her primary care physician together decide to proceed with CT screening, these issues should be revisited throughout the process. For Ms. D, such
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Table 2. Applying Data From Cancer Screening Trials Population-Centered Perspective
Patient-Centered Perspective
Patient: Ms. D
Prevalence of disease in population Relative reduction in risk for death
Likelihood that disease will occur in this patient Absolute reduction in risk for death in this patient
Financial costs to society of screening and subsequent procedures arising from screening
Absolute risk for complication (physical, emotional, and financial) from interventions associated with screening
2.9% risk for lung cancer Low absolute risk reduction of 0.3% (from 1.7% to 1.4%) Moderate to high likelihood of emotional and physical illness
conversations should include annual reassessment of her risk– benefit ratio, particularly with regard to the status of competing medical conditions and the potential likelihood of surviving surgery. An Internist's Perspective (Dr. Richard Schwartzstein) When we consider recommendations for cancer screening, we must acknowledge the tension between the effects of the intervention on the population versus the effects on an individual patient (Table 2). In the first instance, RRR is important; in the second, ARR, in particular the risk for the individual for whom the recommendation is being considered, is essential. In the case of lung cancer screening, the RRR was approximately 20% (4), but the ARR was much smaller—the likelihood of dying was reduced from approximately 1.7% to 1.4%. (10). Thus, for the average person in the NLST, the risk for death from lung cancer was 1.7%. Screening reduced the chance of lung cancer death by only 0.3% and exposed the patient to possible false-positive results with subsequent unnecessary tests and interventions and anxiety during the wait for a repeated scan. Even if we accept that Ms. D has a higher risk for lung cancer than the average patient in the NLST (perhaps approximating 3%), the absolute reduction in her risk for death from lung cancer remains quite small. Although it is difficult to calculate Ms. D's risk for death in light of the information available to us, one should note that in the NLST as a whole, patients were 3 times more likely to die from causes other than lung cancer. From the perspective of public health officials, the glass is half full: Thousands of lives might be saved. However, the individual patient may interpret the net benefit of screening quite differently. How should we assess an individual's risk for lung cancer? Smoking is certainly the most substantial factor, but family history, occupational exposure, radon exposure, and history of emphysema or interstitial lung disease should also be considered (8, 21). The vast majority of cancer deaths prevented in NLST participants was in those at highest risk (8). Assessing individual risk is necessary but not sufficient to make a screening decision. The clinician and patient must also consider the risks, both physical and psychological, that accompany screening. Clinicians must take into account the patient's comorbid conditions, values, and preferences to engage in shared decision making. What makes her happy or what scares her? What are her goals? Are there any key life events in her immediate future? How does she deal with uncertainty? Does she have social support? Would pro-
ceeding with screening have financial implications for her and her family? Ms. D has an extensive smoking history and quit only recently, but we do not know about other potential risk factors. Based on age and smoking status alone, she is eligible for screening. However, her functional status is compromised because of peripheral vascular disease, lung disease, and cardiovascular disease. Comorbid conditions increase her risk for complications if she had a pulmonary nodule that warranted surgical intervention. To maximize the benefits of screening, she should be screened at a center with the expertise to assess the risks of interventions and to perform procedures in patients with multiple medical conditions. Ms. D seems to have a poor understanding of the general concept of screening and significant anxiety about her medical conditions. If a first LDCT scan is normal, she does not recognize the reason for a repeated scan a year later and is uncomfortable with the notion of sequential scans to follow a very small nodule. Only fear of an impending leg amputation motivated her to stop smoking. Her philosophy seems to be to leave well enough alone. Although I would try to educate her that lung cancer grows slowly enough to allow us to watch a small nodule for growth with repeated scans rather than immediate surgery, I suspect she would have great difficulty handling uncertainty if screening detected a small nodule. Unwillingness to adhere to the recommended screening protocol should exclude her from being a viable screening candidate. Responsibility for ordering and following scans, including those done to follow up on detected nodules, resides with the primary care physician, who must have systems in place to ensure that the studies are done and the results are noted. It is important for the patient and physician to have a shared understanding of what will happen if an abnormality is detected in order to estimate the value of a test for a particular patient. In summary, lung cancer screening is appropriate for patients with a high risk for lung cancer, low risk for complications of surgical and/or radiation oncology interventions, and values and beliefs that support following the screening protocol. Ms. D does not meet these criteria. I would not recommend lung cancer screening for her.
SUMMARY Both discussants emphasized the importance of risk stratification and shared decision making. The ARR
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in both lung cancer–specific and all-cause mortality observed in the NLST was less than 1%, and screening does not benefit all patients equally. Restricting screening to the highest-risk patients as opposed to all patients who meet NLST and USPSTF eligibility criteria substantially increases the value of screening and reduces false-positive results. Tools exist to stratify risk and to help clinicians and patients decide whether to embark on a screening program. The online risk tool discussed earlier (Table 1) could be an interesting way to begin the screening discussion with patients. Screening has low value for patients whose comorbid conditions reduce their expected 5- to 10-year survival and when these conditions are sufficiently severe to preclude resection of significant lung tissue at surgery if a suspicious nodule is found during screening. In addition, the discussants agreed that screening is unsuitable for patients unable to tolerate the inherent uncertainty associated with follow-up of small screendetected nodules. Shared decision making involves a comprehensive discussion of the risks, including false-positive results, morbidity from invasive procedures that result from a positive screen, and anxiety due to indeterminate screening results, as well as the benefits, including a modest reduction in the risk for death due to cancer and in overall mortality. Clinicians should discuss the effects of LDCT screening on both RRRs and ARRs of overall and lung cancer–specific death rates. A discussion of only the effects on RRR may lead patients to overestimate benefit. Neither consultant recommended screening for all patients who would be considered eligible according to the USPSTF criteria. Our consultants disagreed somewhat about the importance and prevalence of anxiety among patients who are potentially eligible for lung cancer screening. With regard to cost-effectiveness of LDCT screening, estimates suggest that it is cost-effective at approximately $81 000 per quality-adjusted life-year (22). Finally, neither consultant considered the effects of LDCT screening on smoking behavior. With regard to Ms. D, Dr. Boiselle recommended a shared decision-making model between the patient and her primary care physician once additional data were available to evaluate competing causes of mortality and the patient's ability to tolerate surgery. Dr. Schwartzstein believed that, given Ms. D's stated values and comorbid conditions, the potential risks for screening outweighed the potential benefits. He recommended against screening. At the conclusion of the live grand rounds presentation, we asked the audience members to vote on whether they would recommend LDCT screening for Ms. D: “No” votes outweighed “yes” votes by approximately 2:1. About one third of the audience reported that they had changed their minds about screening Ms. D over the course of the discussion. A transcript of the audience question-and-answer period is available in the Appendix (available at www .annals.org). To view the entire Conference Video, including the question-and-answer session, go to www.annals.org.
AUTHOR BIOGRAPHIES Dr. Smetana is a member of the Division of General Medicine and Primary Care at Beth Israel Deaconess Medical Center and Professor of Medicine at Harvard Medical School, both in Boston, Massachusetts. Dr. Boiselle is a member of the Department of Radiology at Beth Israel Deaconess Medical Center, and Associate Dean for Academic and Clinical Affairs and a Professor of Radiology at Harvard Medical School, both in Boston, Massachusetts. Dr. Schwartzstein is a member of the Department of Medicine at Beth Israel Deaconess Medical Center, and Director of the Academy and Professor of Medicine at Harvard Medical School, both in Boston, Massachusetts.
Of note, since the grand rounds presentation, several studies on LDCT screening have been published (23–26), and readers may want to review this new information when forming an opinion on the appropriateness of screening. Acknowledgment: The authors thank the patient for sharing
her story. Grant Support: Beyond the Guidelines receives no external
support. Disclosures: Disclosures can be viewed at www.acponline.org
/authors/icmje/ConflictOfInterestForms.do?msNum=M15 -0055. Requests for Single Reprints: Gerald W. Smetana, MD, Divi-
sion of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215; e-mail, [email protected]. Current author addresses are available at www.annals.org.
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BEYOND THE GUIDELINES 5. de Koning HJ, Meza R, Plevritis SK, ten Haaf K, Munshi VN, Jeon J, et al. Benefits and harms of computed tomography lung cancer screening strategies: a comparative modeling study for the U.S. Preventive Services Task Force. Ann Intern Med. 2014;160:311-20. [PMID: 24379002] doi:10.7326/M13-2316 6. Aberle DR, Adams AM, Berg CD, Clapp JD, Clingan KL, Gareen IF, et al; National Lung Screening Trial Research Team. Baseline characteristics of participants in the randomized national lung screening trial. J Natl Cancer Inst. 2010;102:1771-9. [PMID: 21119104] doi:10.1093/jnci/djq434 7. Moyer VA; U.S. Preventive Services Task Force. Screening for lung cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014;160:330-8. [PMID: 24378917] doi: 10.7326/M13-2771 8. Kovalchik SA, Tammemagi M, Berg CD, Caporaso NE, Riley TL, Korch M, et al. Targeting of low-dose CT screening according to the risk of lung-cancer death. N Engl J Med. 2013;369:245-54. [PMID: 23863051] doi:10.1056/NEJMoa1301851 9. Tammema¨gi MC, Katki HA, Hocking WG, Church TR, Caporaso N, Kvale PA, et al. Selection criteria for lung-cancer screening. N Engl J Med. 2013;368:728-36. [PMID: 23425165] doi:10.1056/NEJMoa 1211776 10. Bach PB, Gould MK. When the average applies to no one: personalized decision making about potential benefits of lung cancer screening. Ann Intern Med. 2012;157:571-3. [PMID: 22893040] 11. Chiles C, Paul NS. Beyond lung cancer: a strategic approach to interpreting screening computed tomography scans on the basis of mortality data from the National Lung Screening Trial. J Thorac Imaging. 2013;28:347-54. [PMID: 24071622] doi:10.1097/RTI .0000000000000052 12. Parker MS, Groves RC, Fowler AA 3rd, Shepherd RW, Cassano AD, Cafaro PL, et al. Lung cancer screening with low-dose computed tomography: an analysis of the MEDCAC decision. J Thorac Imaging. 2015;30:15-23. [PMID: 25286290] doi:10.1097/RTI .0000000000000119 13. Henschke CI, Yankelevitz DF, Libby DM, Pasmantier MW, Smith JP, Miettinen OS; International Early Lung Cancer Action Program Investigators. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med. 2006;355:1763-71. [PMID: 17065637] 14. American College of Radiology. Lung CT Screening Reporting and Data System (Lung-RADS). Accessed at www.acr.org/Quality -Safety/Resources/LungRADS on 27 October 2014. 15. Boiselle PM. Lung cancer screening: narrowing the gaps [Editorial]. J Thorac Imaging. 2014;29:259. [PMID: 25100143] doi: 10.1097/RTI.0000000000000104
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Annals of Internal Medicine
Screening for Lung Cancer With Low-Dose Computed Tomography Grand Rounds Discussion From the Beth Israel Deaconess Medical Center Gerald W. Smetana, MD; Phillip M. Boiselle, MD; and Richard M. Schwartzstein, MD
In December 2013, the U.S. Preventive Services Task Force recommended screening for lung cancer with low-dose computed tomography (LDCT) for selected current and former smokers. The Task Force based the recommendation primarily on the results of the NLST (National Lung Screening Trial). In this trial, patients randomly assigned to LDCT screening for 3 years had lower rates of both lung cancer–specific mortality and all-cause mortality (relative risk reduction, 6.7% [95% CI, 1.2% to 13.6%]; absolute risk reduction, 0.46% [CI, 0% to 0.9%]). Clinicians and health systems confront questions and challenges as they begin to implement lung cancer screening. This paper summarizes a conference during which an internist and a radiologist discuss the application of the Task Force recommendation to an individual patient. Ann Intern Med. 2015;162:577-582. doi:10.7326/M15-0055 For author affiliations, see end of text.
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s. D is a 60-year-old woman with a complex medical history that includes hypertension, chronic obstructive pulmonary disease (COPD), type 2 diabetes mellitus, hypercholesterolemia, chronic kidney disease, sciatica, peripheral vascular disease that has required both surgical and percutaneous revascularization procedures, cerebrovascular disease requiring carotid endarterectomy, coronary artery disease requiring stent placement, anxiety, and depression. She began smoking at age 13 and ever since has smoked about 1 pack of cigarettes per day for a total of approximately 47 pack-years. After several unsuccessful attempts to stop smoking using bupropion, varenicline, and nicotinereplacement therapy, she quit 2 months before presentation when faced with risk for loss of a leg due to peripheral artery disease and femoral artery thrombosis. Ms. D has Gold class II COPD with a chronic productive cough and exertional dyspnea. Peripheral artery disease limits her walking capacity to several blocks. During a recent hospitalization for COPD exacerbation, a plain chest radiograph was normal, FEV1 was 1.49 (58% predicted), FVC was 2.64 (79% predicted), and the FEV1–FVC ratio was 56%. Current medications include albuterol, fluticasone, ipratropium/albuterol, atenolol, atorvastatin, bupropion, clopidogrel, diazepam, gabapentin, glipizide, losartan, metformin, trazodone, and warfarin. She lives with her husband and son and works in a mental health facility. See the Patient Video (available at www.annals.org) to view the patient telling her story. The patient is unsure of her prognosis but hopes that it will improve now that she has quit smoking. She was unaware of the lung cancer screening guideline. Although she does
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not think having low-dose computed tomography (LDCT) would be a “big deal,” she wonders why someone who feels healthy would want to screen for lung
ABOUT BEYOND THE GUIDELINES Beyond the Guidelines is a moderator-led discussion from Grand Round Sessions from the Beth Israel Deaconess Medical Center. This manuscript is based on the Department of Medicine Grand Rounds conference held on 6 November 2014 at Beth Israel Deaconess Medical Center, Boston, Massachusetts: Moderator: Deborah Cotton, MD, MPH, Deputy Editor, Annals of Internal Medicine. For more information on Beyond the Guidelines, visit www.annals.org/GrandRounds.
AVAILABLE AT www.annals.org Patient interview video Grand Rounds video Supplement slides CME/MOC activity Questions and comments
See also: Celebrating the ACP Centennial: From the Annals Archive . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 577
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BEYOND THE GUIDELINES cancer. She admits that an abnormal screening CT would cause anxiety and that she would find it difficult to wait 6 months for a repeated study—she would want an immediate biopsy, even if there was only a 5% chance that the abnormality was cancer.
CONTEXT, EVIDENCE, AND GUIDELINES Lung cancer is the third most common type of cancer in the United States and the leading cause of death due to cancer; there were 158 248 lung cancer deaths in the United States in 2010 (1). Eighty-five percent of cases of lung cancer are diagnosed at a late stage; the 5-year survival rate across all stages is only 16.6% (2). Effective screening that would both increase detection rates of early-stage cancer and reduce lung cancer mortality would be an important advance, but the results of studies of screening with routine chest radiography have been disappointing (3), and this practice has been largely abandoned in the United States. In December 2013, the U.S. Preventive Services Task Force (USPSTF) recommended annual screening for lung cancer with LDCT in adults aged 55 to 80 years who have a 30 pack-year history of smoking and currently smoke or have quit within the past 15 years. These recommendations were based largely on the findings of the NLST (National Lung Screening Trial) (4). The USPSTF also recommended discontinuation of screening after 15 years of smoking cessation or if a competing medical condition limited expected survival or reduced the likelihood of surviving lung cancer surgery. Four randomized trials of LDCT screening are the focus of the evidence review on which the USPSTF based the lung cancer screening recommendations (3, 5). The largest of these trials, the NLST, was a study of 53 454 participants aged 55 to 74 years who had a smoking history (4). Forty-eight percent of participants were current smokers. Among the 52% who were former smokers, 14.8% quit smoking within 4 years of study entry, 17.3% within 4 to 10 years, and 19.5% within 10 to 15 years (6). Median exposure was 48 pack-years for both current and former smokers. Patients were randomly assigned to annual LDCT screening or posteroanterior chest radiography at baseline and annually for 2 more years. Thirty-nine percent of patients in the LDCT group had at least 1 positive screening result during the study, 96.4% of which were false positives. In contrast, 16.0% of patients in the chest radiography group had at least 1 positive result, 94.5% of which were false positives. Lung cancer–specific mortality was 247 and 309 per 100 000 personyears in the LDCT and chest radiography groups, respectively (relative risk reduction [RRR], 20.5% [95% CI, 6.8% to 26.7%]). There were 1877 deaths from any cause in the LDCT group and 2000 in the chest radiography group (RRR, 6.7% [CI, 1.2% to 13.6%]; absolute risk reduction [ARR], 0.46% [CI, 0% to 0.9%]).
Screening for Lung Cancer With LDCT
CLINICAL QUESTIONS When the USPSTF recommendations are applied in a clinical setting, and to Ms. D in particular, several questions arise, and we present these questions to our discussants, Dr. Richard Schwartzstein, an internist, and Dr. Phillip Boiselle, a radiologist. Question 1 Do you think that LDCT screening for lung cancer adds value? If so, in which subsets of patients? Question 2 Can one generalize the results of the NLST to radiology departments outside of large academic centers and to diverse populations that may differ from that in the trial? Question 3 How can doctors help patients deal with the uncertainties associated with lung cancer screening?
DISCUSSION A Radiologist's Perspective (Dr. Phillip Boiselle) Regarding the value, LDCT screening has the potential to reduce lung cancer deaths among the estimated 9 million smokers and former smokers in the United States who meet the NLST entry criteria (4, 7). Moreover, certain subgroups of smokers are likely to gain even more value from screening than the overall NLST study population (8, 9). For example, the number of lung cancer deaths prevented per 100 000 personyears in the LDCT group of NLST was 60-fold greater in the highest-risk quintile subgroup than in the lowestrisk quintile (12.0 in quintile 5 vs. 0.2 in quintile 1; P = 0.01) (8). Moreover, the ratio of false-positive results to screening-prevented lung cancer deaths was significantly lower in the highest-risk quintile (65 in quintile 5 vs. 1648 in quintile 1; P < 0.0001). A model for lung cancer prediction (Table 1), developed by Tammema¨gi and colleagues, enables estimation of individual risk for lung cancer (9). Compared with the NLST criteria, this model has increased sensitivity (83.0% vs. 71.1%; P < 0.001) and positive predictive value (4.0% vs. 3.4%; P = 0.01) without loss of specificity (62.9% and 62.7%; P = 0.54). These data support the concept of considering an individual's personalized risk profile when considering the potential benefits and risks of LDCT screening for lung cancer. Based on an online version of the Tammema¨gi risk calculator (www.brocku.ca/lung-cancer -risk-calculator), the probability that Ms. D will develop lung cancer within the next 6 years is 2.9%; this places her in the high-risk category (2% = high) (9). As noted by Bach and Gould (10), the value of LDCT screening in an individual patient is determined primarily by comparing the risk for lung cancer with competing causes of death. In this context, it is interesting to note that more patients in the LDCT group of the NLST died from cardiovascular disease than from lung
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cancer (11), perhaps due to the shared risk factors for the competing illnesses. Although her calculated risk for lung cancer is high, Ms. D's cardiovascular disease is a substantial competing risk for death. Moreover, given her COPD, it is important to assess her candidacy for surgical resection if screening detects lung cancer. Her spirometry results alone suggest that she may be a candidate for wedge resection or potentially lobectomy, but additional tests, such as diffusion capacity, would be helpful to provide a more complete picture of lung function. In summary, although Ms. D is at high risk for lung cancer, we need to learn more about her competing medical conditions and her potential for surviving lung cancer surgery to better assess the potential value of LDCT screening. In considering whether the results of NLST can be generalized to radiology departments outside of large academic centers, it is important to recognize that nearly a quarter of participating sites in the NLST were not tertiary care academic medical centers (4, 12). Moreover, previous data from the International Early Lung Cancer Action Program showed successful application of a prescribed LDCT screening regimen across a diverse group of practice settings (13). To help ensure uniform quality of screening across practice settings, the American College of Radiology (ACR) has created LDCT screening practice parameters, a lung imaging reporting and data system (LungRADS) modeled after the BI-RADS system for mammography, and an accreditation process for ACR Lung Cancer Screening Centers (14 –16). Based on a growing awareness of the very low likelihood of lung cancer in solid nodules smaller than 6 mm, the Lung-RADS system has increased the size threshold for a positive screening result from 4 to 6 mm, which should substantially reduce false-positive results and unnecessary invasive procedures (14). With Lung-RADS, it is estimated that approximately 9 of every 10 persons screened will require no further imaging follow-up between annual LDCT scans. In a retrospective reclassification of LDCT screening results for over 2000 patients, Lung-RADS reduced the overall positive rate from 27.6% to 10.6% and increased the positive predictive value from 6.9% to 17.3% (17). The ACR and others have emphasized the importance of a multidisciplinary approach to screening that includes radiology, pulmonary medicine, pathology, thoracic surgery, medical and radiation oncology, and other related health care disciplines (16). Because surgical mortality rates directly influence the success of screening outcomes, the importance of access to highquality surgical care cannot be overemphasized (4). With regard to generalization of NLST results, it is notable that approximately 40% of participants were women and that nearly 1 in 10 participants was a member of a minority group (4). However, the NLST population differed in several respects from respondents to a 2002–2004 U.S. Census survey of individuals who met the NLST eligibility for age and smoking history (4). For example, NLST participants were younger, had a higher
Table 1. Historical Features Included in a Personalized Risk Calculator for Lung Cancer* Cumulative smoking history (pack-years) Years since quitting smoking Age Education Body mass index History of COPD, emphysema, or chronic bronchitis Personal history of cancer Family history of lung cancer Race/ethnicity
COPD = chronic obstructive pulmonary disease. * Adapted from reference 9. Risk calculator available at www .brocku.ca/lung-cancer-risk-calculator.
level of education, and were more likely to be former smokers (4). Despite these differences, the consensus is that NLST results can be generalized to patients who meet the eligibility criteria as long as they are in “reasonably good health” and are able to tolerate surgery (18). Although Ms. D meets the eligibility criteria, she differs from the general NLST population because of her competing health risks and uncertain candidacy for surgery. The cost-effectiveness of LDCT screening is another issue. A recent analysis from the NLST estimated that LDCT screening would cost $81 000 per qualityadjusted life-year gained (19). However, it is possible that screening done outside of a trial could be more expensive. Of note, widespread implementation of the Lung-RADS system has the potential to offset some costs by reducing false-positive results. To assist patients in dealing with the uncertainties of lung cancer screening requires commitment to shared decision making with careful consideration of scientific evidence and patient preferences. It is important that patients understand the risks of screening, including false-positive results that lead to subsequent tests and interventions, radiation exposure, expense, overdiagnosis, and anxiety. With respect to anxiety, a recent substudy of nearly 3000 NLST participants found no measurable increase in anxiety or decrease in quality of life at 1 month or 6 months after screening among participants with falsepositive results (20). Despite these results, Ms. D's history of anxiety, along with her apparent concerns about “watchful waiting” of screen-detected nodules, suggests that she would be at high risk for anxiety in response to false-positive results. With this in mind, a conversation about screening with Ms. D should include a detailed description of the likelihood of a positive screening result, the high percentage of positive results that prove to be false-positive, and the importance of following evidence-based nodule management recommendations. Ms. D must understand that the risk– benefit ratio of CT screening may be negatively altered if she seeks biopsy or resection of a lung nodule outside of recommended practice. If she and her primary care physician together decide to proceed with CT screening, these issues should be revisited throughout the process. For Ms. D, such
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Table 2. Applying Data From Cancer Screening Trials Population-Centered Perspective
Patient-Centered Perspective
Patient: Ms. D
Prevalence of disease in population Relative reduction in risk for death
Likelihood that disease will occur in this patient Absolute reduction in risk for death in this patient
Financial costs to society of screening and subsequent procedures arising from screening
Absolute risk for complication (physical, emotional, and financial) from interventions associated with screening
2.9% risk for lung cancer Low absolute risk reduction of 0.3% (from 1.7% to 1.4%) Moderate to high likelihood of emotional and physical illness
conversations should include annual reassessment of her risk– benefit ratio, particularly with regard to the status of competing medical conditions and the potential likelihood of surviving surgery. An Internist's Perspective (Dr. Richard Schwartzstein) When we consider recommendations for cancer screening, we must acknowledge the tension between the effects of the intervention on the population versus the effects on an individual patient (Table 2). In the first instance, RRR is important; in the second, ARR, in particular the risk for the individual for whom the recommendation is being considered, is essential. In the case of lung cancer screening, the RRR was approximately 20% (4), but the ARR was much smaller—the likelihood of dying was reduced from approximately 1.7% to 1.4%. (10). Thus, for the average person in the NLST, the risk for death from lung cancer was 1.7%. Screening reduced the chance of lung cancer death by only 0.3% and exposed the patient to possible false-positive results with subsequent unnecessary tests and interventions and anxiety during the wait for a repeated scan. Even if we accept that Ms. D has a higher risk for lung cancer than the average patient in the NLST (perhaps approximating 3%), the absolute reduction in her risk for death from lung cancer remains quite small. Although it is difficult to calculate Ms. D's risk for death in light of the information available to us, one should note that in the NLST as a whole, patients were 3 times more likely to die from causes other than lung cancer. From the perspective of public health officials, the glass is half full: Thousands of lives might be saved. However, the individual patient may interpret the net benefit of screening quite differently. How should we assess an individual's risk for lung cancer? Smoking is certainly the most substantial factor, but family history, occupational exposure, radon exposure, and history of emphysema or interstitial lung disease should also be considered (8, 21). The vast majority of cancer deaths prevented in NLST participants was in those at highest risk (8). Assessing individual risk is necessary but not sufficient to make a screening decision. The clinician and patient must also consider the risks, both physical and psychological, that accompany screening. Clinicians must take into account the patient's comorbid conditions, values, and preferences to engage in shared decision making. What makes her happy or what scares her? What are her goals? Are there any key life events in her immediate future? How does she deal with uncertainty? Does she have social support? Would pro-
ceeding with screening have financial implications for her and her family? Ms. D has an extensive smoking history and quit only recently, but we do not know about other potential risk factors. Based on age and smoking status alone, she is eligible for screening. However, her functional status is compromised because of peripheral vascular disease, lung disease, and cardiovascular disease. Comorbid conditions increase her risk for complications if she had a pulmonary nodule that warranted surgical intervention. To maximize the benefits of screening, she should be screened at a center with the expertise to assess the risks of interventions and to perform procedures in patients with multiple medical conditions. Ms. D seems to have a poor understanding of the general concept of screening and significant anxiety about her medical conditions. If a first LDCT scan is normal, she does not recognize the reason for a repeated scan a year later and is uncomfortable with the notion of sequential scans to follow a very small nodule. Only fear of an impending leg amputation motivated her to stop smoking. Her philosophy seems to be to leave well enough alone. Although I would try to educate her that lung cancer grows slowly enough to allow us to watch a small nodule for growth with repeated scans rather than immediate surgery, I suspect she would have great difficulty handling uncertainty if screening detected a small nodule. Unwillingness to adhere to the recommended screening protocol should exclude her from being a viable screening candidate. Responsibility for ordering and following scans, including those done to follow up on detected nodules, resides with the primary care physician, who must have systems in place to ensure that the studies are done and the results are noted. It is important for the patient and physician to have a shared understanding of what will happen if an abnormality is detected in order to estimate the value of a test for a particular patient. In summary, lung cancer screening is appropriate for patients with a high risk for lung cancer, low risk for complications of surgical and/or radiation oncology interventions, and values and beliefs that support following the screening protocol. Ms. D does not meet these criteria. I would not recommend lung cancer screening for her.
SUMMARY Both discussants emphasized the importance of risk stratification and shared decision making. The ARR
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in both lung cancer–specific and all-cause mortality observed in the NLST was less than 1%, and screening does not benefit all patients equally. Restricting screening to the highest-risk patients as opposed to all patients who meet NLST and USPSTF eligibility criteria substantially increases the value of screening and reduces false-positive results. Tools exist to stratify risk and to help clinicians and patients decide whether to embark on a screening program. The online risk tool discussed earlier (Table 1) could be an interesting way to begin the screening discussion with patients. Screening has low value for patients whose comorbid conditions reduce their expected 5- to 10-year survival and when these conditions are sufficiently severe to preclude resection of significant lung tissue at surgery if a suspicious nodule is found during screening. In addition, the discussants agreed that screening is unsuitable for patients unable to tolerate the inherent uncertainty associated with follow-up of small screendetected nodules. Shared decision making involves a comprehensive discussion of the risks, including false-positive results, morbidity from invasive procedures that result from a positive screen, and anxiety due to indeterminate screening results, as well as the benefits, including a modest reduction in the risk for death due to cancer and in overall mortality. Clinicians should discuss the effects of LDCT screening on both RRRs and ARRs of overall and lung cancer–specific death rates. A discussion of only the effects on RRR may lead patients to overestimate benefit. Neither consultant recommended screening for all patients who would be considered eligible according to the USPSTF criteria. Our consultants disagreed somewhat about the importance and prevalence of anxiety among patients who are potentially eligible for lung cancer screening. With regard to cost-effectiveness of LDCT screening, estimates suggest that it is cost-effective at approximately $81 000 per quality-adjusted life-year (22). Finally, neither consultant considered the effects of LDCT screening on smoking behavior. With regard to Ms. D, Dr. Boiselle recommended a shared decision-making model between the patient and her primary care physician once additional data were available to evaluate competing causes of mortality and the patient's ability to tolerate surgery. Dr. Schwartzstein believed that, given Ms. D's stated values and comorbid conditions, the potential risks for screening outweighed the potential benefits. He recommended against screening. At the conclusion of the live grand rounds presentation, we asked the audience members to vote on whether they would recommend LDCT screening for Ms. D: “No” votes outweighed “yes” votes by approximately 2:1. About one third of the audience reported that they had changed their minds about screening Ms. D over the course of the discussion. A transcript of the audience question-and-answer period is available in the Appendix (available at www .annals.org). To view the entire Conference Video, including the question-and-answer session, go to www.annals.org.
AUTHOR BIOGRAPHIES Dr. Smetana is a member of the Division of General Medicine and Primary Care at Beth Israel Deaconess Medical Center and Professor of Medicine at Harvard Medical School, both in Boston, Massachusetts. Dr. Boiselle is a member of the Department of Radiology at Beth Israel Deaconess Medical Center, and Associate Dean for Academic and Clinical Affairs and a Professor of Radiology at Harvard Medical School, both in Boston, Massachusetts. Dr. Schwartzstein is a member of the Department of Medicine at Beth Israel Deaconess Medical Center, and Director of the Academy and Professor of Medicine at Harvard Medical School, both in Boston, Massachusetts.
Of note, since the grand rounds presentation, several studies on LDCT screening have been published (23–26), and readers may want to review this new information when forming an opinion on the appropriateness of screening. Acknowledgment: The authors thank the patient for sharing
her story. Grant Support: Beyond the Guidelines receives no external
support. Disclosures: Disclosures can be viewed at www.acponline.org
/authors/icmje/ConflictOfInterestForms.do?msNum=M15 -0055. Requests for Single Reprints: Gerald W. Smetana, MD, Divi-
sion of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215; e-mail, [email protected]. Current author addresses are available at www.annals.org.
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