1. Lung Cancer Screening in 2013 Cheryl Czerlanis, MD Loyola University Medical Center March 02, 2013

2. The scope of the problem  An estimated 29% of the global population older than 15 years smokes tobacco.  75% of patients with lung cancer present with symptoms due to locally advanced or metastatic disease.  Overall five-year survival for lung cancer is 16%. Fry WA. Cancer 1999;86:1867-76.

3. Ten Leading Cancer Types for the Estimated New Cancer Cases and Deaths by Sex, 2013 From Seigel,R et al. CA Cancer J Clin 2013; 63(1): 14.

4. Five-year overall survival by stage (percent) Goldstraw, P, et al. J Thorac Oncol 2007; 2:706.

5. Screening Test Principles 1. The disease must be prevalent 2. There must be an advantage to early detection 3. Screening must be safe, sensitive, and have an acceptable rate of false positives 4. Cost to society must be acceptable Henschke CI. Radiol Clinic No Amer 2000;38(3):287-95. Reduce mortality, improve quality of life, or both.

6. Screening Rationale: Early diagnosis 5–year Survival Stage Distribution Wagner H. Cancer Screening 1996;118-49. Mountain CF. Chest 1997;111:1710-17. Inoue K. Thorac Cardiovasc Surg 1998;116:407-11.

7. Outcomes to be assessed in lung cancer screening trials  Cancer detection rates  Stage at detection  Disease–specific mortality  Overall survival Mortality rate is the number of persons who die of a certain cause in a time period per population. Survival rates calculate the percentage of persons with a disease who are still alive a set amount of time after diagnosis.

8. Methodological biases  Bias related to apparent effects of early diagnosis and treatment that may inflate the benefit seen by screening  Measured in terms of how screen-detected cases compare to cases detected by signs and symptoms Lead time bias Length time bias Overdiagnosis bias Volunteer bias

9. Prior Attempts  Four nonrandomized uncontrolled studies  Philadelphia Pulmonary Neoplasm Research Project  VA Trial  Tokyo Metropolitan Government Study  South London Lung Cancer Study  Two nonrandomized but controlled studies  North London Cancer Study  Erfurt County Study Patz, EF Jr. NEJM 2000;343(22):1627-33. 1950’s

10. Four randomized trials of CXR and Sputum Cytology (SC) Mayo Lung Project (MLP) Czechoslovakian Study Memorial Sloan-Kettering Lung Project Johns Hopkins Study 1970’s

11. Results  Increased  Number of early stage cancers  Number of resectable cancers  NO Reduction in Lung Cancer Mortality  Why?  Screened patients had a higher likelihood of being diagnosed and living longer from the time of diagnosis.  But equal numbers of patients in both groups ultimately died of cancer. Patz, EF Jr. NEJM 2000;343(22):1627-33.

12. Low-dose screening CT  No Contrast  Low Radiation Dose  Average effective dose varies between 0.6 mSv and 1.5 mSv  Equivalent to 2 to 5 chest x-rays or a transatlantic flight  Less than a minute  $150-400

13. Rationale for CT screening Onset of tumor Detectable by CT Onset of symptoms Detectable by CXR Increased window of opportunity

14. Early Lung Cancer Action Program (ELCAP)  Cornell and NYU  1000 patients  Entry Criteria  Age > 60  ≥ 10 pack year smoking history  Actual Mean Patient  Age = 67  45 pack years  Plain film and CT imaging Henschke CI. Lancet 1999;354(173):99-105.

15. ELCAP Protocol  If Negative  Recommend annual repeat CT  If Diffuse disease  Recommend Pulmonary Evaluation  If Positive  <5mm – Follow-up CT scan at 3, 6, 12, 24 months  6 – 10 mm – Investigator discretion  > 10 mm – Biopsy or Surgery Henschke CI. Lancet 1999;354(173):99-105.

16. ELCAP Data  233 “Positive” Scans (23.3%)  33 also seen on CXR  Conversely, less than half of the “nodules” seen on CXR were confirmed on CT  27 Malignant NCN (2.7%)  CXR missed 20 of these  Mainly adenocarcinoma  (Plus 4 other malignancies: 2 endobronchial lesions and 2 mediastinal adenopathy) Henschke CI. Lancet 1999;354(173):99-105.

17. 233 Patients with non-calcified nodules % mm Size of Largest NCN Number of NCN’s/Scan number % Henschke CI. Lancet 1999;354(173):99-105.

18. Chance of Malignancy % mm Size of Largest NCNNumber of NCN’s/Scan number % 12% 10% 14% 1% 24% 33% 80% Henschke CI. Lancet 1999;354(173):99-105.

19. Characteristics of the 27 lung cancers  85% were stage I  83% missed by CXR  96% were resectable Stage distribution Results Henschke CI. Lancet 1999;354(173):99-105.

20. CT scan versus CXR  More sensitive  Non-calcified nodules (23 versus 7 percent)  Malignancy (2.7 versus 0.7 percent)  Benign nodules (20.6 versus 6.1 percent)  BUT no stage shift  3.0/1000 versus 2.1to 3.8/1000 with advanced disease Patz, EF Jr. NEJM 2000;343(22):1627-33.

21. Other results  The rate of biopsy for benign disease was 1.7%  4 of 233 patients  No patient underwent a thoracotomy for a benign lesion in the ELCAP study  ELCAP had no control group  Mortality inferences are subject to bias

22. Meta-analysis of baseline findings of randomized, controlled trials Name Screening Duration Control Arm Age Garg/Colorado University 200150-80 DANISH2004-200649-74 NELSON2004-50-75 ITALUNG2004-200655-69 LSS2000-2004CXR55-77 DEPISCAN2002-2004CXR50-75 DANTE2001-2006CXR60-74

23. CT Screening for lung cancer Odds Ratio95% CI Higher number of stage 1 cancers 3.92.0 – 7.4 Higher total lung cancers 4.12.4 – 7.1 Detection of false- positive nodules 3.12.6 – 3.7 Thoracotomies for benign lesions Event rate 3.7 per 1000 3.5 – 3.8 Gopal M. J Thorac Oncol. 2010;5:1233-1239.

24. National lung cancer screening trial  More than 53,000 current or former smokers were enrolled in NLST at more than 30 study sites across the country (2002–2004)  Examined the risks and benefits of spiral CT scans compared to chest X-rays.  Repeated at one and two years after the first scan.  Powered to detect a 20% reduction in mortality due to screening.

25. NLST design Prospective, randomized trial comparing low-dose helical CT screening to chest x-ray screening with the endpoint of lung cancer specific mortality in high risk participants Eligibility  Age 55-74  Asymptomatic current or former smoker; 30 pack year smoking history  Former smokers: quit within preceding 15 years  No prior lung cancer diagnosis  No evidence of other cancer within preceding 5 years http://radiology.rsna.org/content/early/2010/10/28/radiol.10091808.fullhttp://radiology.rsna.org/content/early/2010/10/28/radiol.10091808.fullSlides courtesy of Christine Berg, MD (NIH)

26. NLST primary endpoint http://radiology.rsna.org/content/early/2010/10/28/radiol.10091808.full Helical CT vs. CXR Lung cancer-specific mortality 20% difference α5% Power90% Compliance85% CT | 80% CXR Contamination 5% CT | 10% CXR Size25,000 / arm

27.  Secondary endpoints  All cause mortality  Lung cancer: prevalence | incidence | interval cancers  Stage distribution  Screening test performance  Medical resource utilization for [+] screen NLST secondary endpoints http://radiology.rsna.org/content/early/2010/10/28/radiol.10091808.fullhttp://radiology.rsna.org/content/early/2010/10/28/radiol.10091808.fullSlides courtesy of Christine Berg, MD (NIH)

28. 53,454 participantsNLST US Census Male (%)59.058.5 Age 55-59 (%)42.835.2 60-64 (%)30.629.3 65-69 (%)17.820.8 70-74 (%) 8.814.7 Race | Ethnicity Black (%)4.45.5 Hispanic (%)1.72.4 Comparing NLST with eligible US census population Aberle DR, et al. Natl Cancer Inst (2010) 102 (23): 1771-1779.

29. NLST US Census Married66.660.9 Education < HS6.121.3 ≥ College31.514.4 Current smoker48.257.1 Median pack yrs48.047.0 Comparing NLST with US census population Aberle DR, et al. Natl Cancer Inst (2010) 102 (23): 1771-1779.

30.  Compared with similar US population, NLST cohort has similar gender distribution and smoking exposure  However, NLST participants  Younger  Better educated  Less likely to be current smokers Comparing NLST with US census population Aberle DR, et al. Natl Cancer Inst (2010) 102 (23): 1771-1779.

31. Screening exam compliance Study Year Helical CT Chest X-ray Total Expected Screened ScreenedExpectedScreenedExpected T0 26,71398.5%26,72297.5%53,43598.0% T1 26,28294.0%26,39891.3%52,68092.6% T2 25,93592.9%26,09789.5%52,03291.2%

32. Screen positivity rate by screening round & arm Low dose helical CT CXR Number screened Number positive % Positive Positive Number screened Number positive % Positive Screen 126,3147,19327.326,0492,3879.2 Screen 224,7186,90227.924,0971,4826.2 Screen 324,1044,054 16.8**23,3531,175 5.0** All screens75,13618,14924.273,4995,0446.9 Positive screen: nodule ≥ 4 mm or other findings potentially related to lung cancer. * Positive screen: nodule ≥ 4 mm or other findings potentially related to lung cancer. **Abnormality stable for 3 rounds could be called negative by protocol.

33. True and false positive screens Screening Result Low Dose Helical CT CXR Screen 1 N (%) Round 2 N (%) Round 3 N (%) Round 1 N (%) Round 2 N (%) Round 3 N (%) Total Positives Lung cancer No lung cancer 7,193 (100) 270 (4) 6,923 (96) 6,902 (100) 168 (2) 6,734 (98) 4,054 (100) 211 (5) 3,843 (95) 2,387 (100) 136 (6) 2,251 (94) 1,482 (100) 65 (4) 1,417 (96) 1,175 (100) 78 (7) 1,097 (93) Data reflect the final interpretation, including benefit of historical comparison exams.

34. Interim analysis: lung cancer mortality 10-20-2010Arm Person Years (py) Lung cancer deaths Lung cancer mortality per 100,000 py Reduction in lung cancer mortality (%) Value of test statistic Efficacy boundary CT144,097.635424520.3–3.21–2.02 CXR143,363.5442308 Deficit of lung cancer deaths in CT arm exceeds that expected by chance, even allowing for multiple looks at the data. p = 0.0041

35. Interim analysis: all-cause mortality 10-20-2010  Lung cancer: 25% of all deaths in NLST  Lung cancer: 56% of 126 excess deaths in CXR arm p = 0.023 Arm Person Years (py) Deaths All-cause mortality per 100,000 py Reduction in all cause mortality (%) Value of test statistic Value for significance CT167,389.9187011176.9–2.27–1.96 CXR166,328.219961200

36. Kaplan-Meier curves for lung cancer mortality 1.00 0.99 0.98 0.97 0.96 0.95 0.94 0.93 0.92 0.91 0.90 01234567012345670123456701234567 Probability of survival: ALL participants CT arm CXR arm Years from randomization

37. Kaplan-Meier curves for all-cause mortality 1.00 0.99 0.98 0.97 0.96 0.95 0.94 0.93 0.92 0.91 0.90 012345678012345678012345678012345678 Years from randomization Probability of survival: ALL participants CT arm CXR arm

38. Results  At the time the DSMB held its final meeting on October 20, 2010:  356 deaths from lung cancer had occurred among participants in the CT arm of the study  443 lung cancer deaths had occurred among those in the chest X-ray group  The DSMB concluded that this 20.3 percent reduction in lung cancer mortality met the standard for statistical significance and recommended ending the study.

39. Conclusions  The vast majority of lung nodules detected by either CT or CXR are benign.  Most CT-detected nodules require some form of additional follow-up.  CT detects more lung cancers than does CXR.  Most of these excess cancers are early stage cancers.  Screening programs still uncover late-stage cancers on initial and interval scans.

40. Conclusions  Prior to the NLST trial, there had been no evidence of a mortality benefit for lung cancer-related mortality with CT screening.  The NLST trial showed a 20% relative risk reduction in lung-cancer specific mortality.

41. Cost-effectiveness ratio  Modeling algorithm  Analysis based on a model designed prior to completion of NSLT modeled cost-effectiveness of CT scan screening for six patient cohorts Different ages and smoking histories  CT screening may decrease lung cancer at 10 years by 18 to 25% at a cost ranging from $126,000 to $269,000 per quality adjusted life year (QALY) Cost-effective ratio for other screened cancers Colorectal cancer was $47,700 per QALY Breast cancer was $13,300 to $32,000 per QALY McMahon PM, et al. J Thorac Oncol 2011; 6:1841.

42. Number needed to screen  NNS represents the number of patients who must screened over a given period of time to prevent one death from the disease in question.  Reflects both the prevalence of the disease and the effectiveness of therapy.  Does not specifically account for the risks or the costs of screening.  Reciprocal of the frequency of the reduction in absolute risk.

43. Other screening modalities SCREENING MODALITYNUMBER NEEDED TO SCREEN Annual screening mammography of women ages 40-84 1 84 Biennial screening mammography of women ages 50-74 1 144 Guaiac-based FOBT screening 2 1,173 to prevent 1 death over 10 years Colonoscopy 3 200 men with regular screening Papanicolaou smear screening for cervical cancer 4 1,140 women with regular screening to prevent 1 death over 10 years Low-dose CT screening for lung cancer 5 256 persons screened annually for three years to prevent 1 death over 6 years 1 Hendrick RE, et al. Am J Roentgenol. 2012 Mar;198(3):723-8. 2 Hewitson P, et al. Cochrane Database Syst Rev. 2007;(1):CD001216. 3 Barrett B et al. Fam Med 2011;43(4):248-53. 4 Benedet JL, et al. Am J Obstet Gynecol. 1992;166:1254–9. 5 Berg CD, et al. N Eng J Med. 2011;365(5):395-409.

44. Recommendations for screening by expert groups  In 2012, a systematic review was commissioned by American Cancer Society (ACS), American College of Chest Physicians (ACCP), American Society of Clinical Oncology (ASCO), and the National Comprehensive Cancer Network (NCCN)  Screening guidelines supporting low-dose CT scans for high-risk groups were issued by the NCCN and ACCP/ASCO Bach, PB, et al. JAMA. 2012: 307(22): 2418-2429.

45. Guidelines for lung cancer screening American Cancer Society Recommends that clinicians with access to high-volume, high-quality lung cancer screening and treatment centers should initiate a discussion about screening with apparently healthy patients aged 55 years to 74 years who have at least a 30 pack-year smoking history and who currently smoke or have quit within the past 15 years. 2013 ACCP/ASCORecommends annual low-dose CT screening for high-risk individuals (ages 55 to 74 years with 30 pack-year history of smoking and current smoker or quit within past 15 years). 2012 National Comprehensive Cancer Network (NCCN) Recommends annual low-dose CT screening for high-risk individuals (ages 55 to 74 years with 30 pack-year history of smoking or 20 pack- year history with an additional risk factor). 2011 US Preventive Services Task Force Evidence is insufficient to recommend for or against screening asymptomatic persons for lung cancer with CXR, low-dose CT, or a combination. 2004; undergoing review Canadian Task Force on the Periodic Health Examination Recommends against the use of chest x-ray in asymptomatic persons. Evidence is insufficient to recommend for or against screening with spiral CT in asymptomatic persons. 2003; undergoing review

46. Issues to be addressed  Optimal population for screening  Cost-effectiveness of screening  Optimal management of screen-detected nodules  Optimal screening interval and number of screening rounds  Reimbursement issues  Importance of implementing screening programs only in the setting of multidisciplinary programs with experience in evaluation and management of early lung cancers

47. A proven intervention