Lung Cancer Screening Insights from the NLST Benefits, Harms and Unresolved Issues

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1 Lung Cancer Screening Insights from the NLST Benefits, Harms and Unresolved Issues Christine D. Berg, MD Co-Principal Investigator NLST Adjunct Professor Department of Radiation Oncology and Molecular Radiation Sciences Johns Hopkins Medicine February 24, 2014

2 Disclosure: Consultant, Medial Cancer Screening Funding for the NLST in its entirety was provided by the National Cancer Institute, USA The FDA does not have jurisdiction over use of helical CT or CXR screening for lung cancer as it does for mammography. Takes act of Congress. 2

3 US Preventive Services Guideline Final Recommendations for Lung Cancer Screening December 31, 2013 Grade B Recommendation The USPSTF has found moderate level evidence for moderate level benefit for lung cancer screening with CT The population recommended to be screened annually is: Ages 55 79; 30 pack years; if former smoker quit within 15 years Medicare will review; the PPACA is supposed to require insurance companies to cover screening for eligible patients without a deductible

4 Lecture Objectives Information from NLST Overall results Results of baseline and subsequent two annual screens Radiation risk Cost-effectiveness analysis result Current guidelines from US groups Issues for screening implementation Who to screen; effect of occupational exposure How to evaluate positive screens

5 NLST design Prospective, randomized trial comparing low-dose helical CT screening to chest x-ray screening for three annual screens with the endpoint of lung cancer specific mortality in 53, 454 high risk participants Eligibility Age 55-74; asymptomatic current or former smoker; 30 pack year smoking history; former smokers: quit within preceding 15 years Parameters 90% power to detect 20% difference in lung cancer mortality; α = 0.05 Median follow-up for outcomes ~ 6.5 years (Maximum: 7.4) Vital status known for 97% LDCT 96% CXR

6 Cumulative Numbers of Lung Cancers and of Deaths from Lung Cancer. The National Lung Screening Trial Research Team. N Engl J Med 2011;365:

7 Table 5. Results for National Lung Screening Trial Subset. Oken, M. M. et al. JAMA 2011;306: Copyright restrictions may apply.

8 Screen positivity rate by screening round & arm Number screened Low-dose helical CT Number positive % Positive Number screened CXR Number positive % Positive Screen 1 26,309 7, ,035 2, Screen 2 24,715 6, ,089 1, Screen 3 24,102 4, ** 23,346 1, ** All screens 75,126 18, ,470 5, * Positive screen: nodule 4 mm or other findings potentially related to lung cancer. ** Abnormality stable for 3 rounds could be called negative by protocol.

9 True and false positive screens Screening Result Screen 1 N (%) Low-dose Helical CT Round 2 N (%) Round 3 N (%) Round 1 N (%) CXR Round 2 N (%) Round 3 N (%) Total Positives 7,191 (100) 6,901 (100) 4,054 (100) 2,387 (100) 1,482 (100) 1,174 (100) Lung cancer No lung cancer 270 (4) 6,911 (96) 168 (2) 6,728 (98) 211 (5) 3,838 (95) 136 (6) 2,243 (94) 65 (4) 1,416 (96) 78 (7) 1,094 (93) Data reflect the final interpretation, including benefit of historical comparison exams. Positive Screens were > 3-fold higher in the LDCT arm

10 Cancer Yield by Nodule Size T0 T1 T2 Lung Cancer Yes/No Yield Lung Cancer Yes/No Yield Lung Cancer Yes/No Yield Nodule Size 4 6 mm 18/ % 12/ % 15/ % 7 10 mm 35/ % 46/ % 58/ % / % 74/ % 86/ % mm / % 20/ % 23/ % mm > 30 mm 45/ % 8/ % 20/ %

11 Screening Result and Stage T0 T1 T2 Screen Result Positive #266 Negative #18 Positive #165 Negative #10 Positive #204 Negative #16 Stage IA 130 (48.9%) 2 (11.1%) 86 (52.1%) 1 (10.0%) 113 (55.4%) 2 (12.5%) IB 25 (9.4%) 1 (11.1%) 18 (10.9%) 1 (10.0%) 28 (13.7%) 0 IIA 7 (2.6%) 2 (11.1%) 11 (6.7%) 0 8 (3.9%) 0 IIB 11 (4.1%) 1 (5.6%) 6 (3.6%) 0 3 (1.5%) 2 (12.5%) IIIA 31 (7.9%) 2 (11.1%) 13 (7.9%) 1 (10.0%) 15 (7.4%) 0 IIIB 21 (7.9%) 7 (38.9%) 13 (7.9%) 4 (40.0%) 15 (7.4%) 4 (25.0%) IV 41 (15.4%) 3 (16.7%) 18 (10.9%) 3 (30.0%) 22 (10.8%) 8 (50.0%)

12 Radiation Risks vs Benefits 3 screens Smokers Age Whole body effective dose (weighted average dose to each organ) Low dose helical CT: 1.5mSv Radiation risk from screens 1-3 lung cancer deaths per 10,000 screened 0.3 breast cancers per 10,000 females screened Radiation risk from follow-up CT scans Low-dose or thin-section chest CT + 25% Diagnostic chest CT + 100% Cumulative mortality reduction NLST 30 lung cancer deaths per 10,000 screened

13 NLST Cost Effectiveness Analysis Comparison: LDCT, CXR, No Screen Health effects: LYs and QALYs Costs: $US (reference 2009) Perspective: Societal Time horizon: Within-trial and lifetime Discount rate: 3%

14 SUMMARY CEA Black et al NLST LDCT ICER $67,000 per QALY life gained Some uncertainty within NLST Highly sensitive to lung ca risk Full report to follow

15 What next and for whom?

16 Organization ACCP/ ASCO/ ATS endorsed Type of Statement NLST Like Subjects? Existing Guidelines Evidence based guideline Suggest it be offered Others? No ACS Guideline May be considered No ALA Guidance Recommended No NCCN Consensus guidelines Recommended Yes, for some individuals AATS Guideline Recommended Age 50-79; 20 pack years and five year cumulative risk of 5% or more; lung cancer survivors USPSTF Guideline Recommended Ages 50 to 79 with annual screening until age 79 or more than 15 years post smoking cessation

17 American Academy of Family Practitioners Clinical Recommendation Lung Cancer Screening January 13, 2104 I Recommendation: Insufficient evidence Comments: Paucity of high-quality evidence; only one study at major medical centers and with strict follow-up of nodules Favorable results of NLST not replicated in a community setting

18 Challenges for Successful Lung Cancer Screening Programs Effective smoking cessation Selection of high-risked individuals most likely to benefit from lung cancer screening Effective and efficient evaluation of abnormal lowdose helical CT examinations Monitoring of quality standards in ongoing program

19 NLST LSS Study of Factors Associated with Smoking Behavior Screening Result Odds Ratios (95% CI; p-values) Normal no abnormalities (Referent group) 1.00 Negative for lung cancer, minor other abnormalities 0.85 ( ; p = 0.037) Negative for lung cancer, significant other abnormalities Odds ratios from multivariable* longitudinal logistic analysis for being a current smoker given the previous screening result ( ; p = 0.004) Positive for lung cancer 0.46 ( ; p < 0.001) Positive for lung cancer, stable, no significant change from previous screen 0.67 ( ; p = 0.003) Conclusion: The probability of subsequent smoking is inversely associated with the abnormality of screening result in a dose-response fashion. Tammemagi, M and Taylor K

20 Optimizing screening avertable deaths Within the NLST, some subgroups may have little benefit from LDCT screening Use of risk might allow us to extend LDCT screening to smokers at high risk but who did not qualify under NLST criteria Organizations may wish to consider review of risk stratification options and consider revision of guidelines; what data needs to be collected for this to occur?

21 Several Risk Prediction Models Bach, Spitz, LLP, COSMOS NCCN: Back of the envelope risk but does consider occupational exposure Two models from NLST data in NEJM 2013 Tammemagi et al Incidence based Kovalchik et al Lung cancer mortality based

22 Effective and efficient evaluation of abnormal lowdose helical CT examinations NLST had positivity rate of 24.2% overall ; average false-positive rate of 97%; Sens/Spec : 93.7%/76.6%; PPV 3.8% High cost; higher radiation exposure for follow-up testing One approach to consider is prediction model for probability of lung cancer in a nodule PanCan approach NEJM 369(10): Model variables include patient characteristics and image characteristics Age, gender, family history of lung cancer, emphysema Nodule size, nodule type (nonsolid or with ground-glass opacity; part-solid; solid); nodule location, (upper vs. middle or lower lobe); nodule count per scan,, spiculation

23 Classification accuracy for predicting nodule malignancy Parsimonious model with spiculation Risk Score Threshold Sensitivity (%) Specificity (%) PPV (%) NPV (%) Accuracy (%) Proportion Nodules Positive (%) 2% % % Abbreviations: PPV, positive predictive value; N, number; NPV, negative predictive value.

24 NLST Data, Image and Specimen Access Website Access to entire research community Data transfer agreement required Name, , summary of research proposal on website Return of research papers requested for tracking and posting Biospecimens OREPOSITORY.aspx

25 Summary Opportunity to significantly improve outcome of patients with lung cancer Selection of high-risk group to screen critical Current recommendations from all major groups may benefit from revision with new information from risk models Continued research to minimize burden of false-positives also critical International collaboration to better define the screening process and most cost-effective diagnostic and treatment pathways Screening is NOT a substitute for effective tobacco control policies

26 Acknowledgements Full list of all collaborators FNEJMoa &viewType=Popup&viewClass=Suppl Special thanks to Martin Tammemägi

27 With appreciation 53,454 trial participants without whom these studies would not have been possible