Lung Cancer Screening in 2013

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 Clin2013; 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 • The disease must be prevalent • There must be an advantage to early detection • Screening must be safe, sensitive, and have an acceptable rate of false positives • Cost to society must be acceptable Reduce mortality, improve quality of life, or both. Henschke CI. Radiol Clinic No Amer 2000;38(3):287-95.

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 1950’s • 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.

10. Four randomized trials of CXR and Sputum Cytology (SC) 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 Detectable by CXR Onset of symptoms 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 Size of Largest NCN Number of NCN’s/Scan % % number mm Henschke CI. Lancet 1999;354(173):99-105.

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

19. Characteristics of the 27 lung cancers Stage distribution Results • 85% were stage I • 83% missed by CXR • 96% were resectable 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 diseasewas 1.7% • 4 of 233 patients • No patient underwent a thoracotomyfor 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

23. CT Screening for lung cancer 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.full Slides courtesy of Christine Berg, MD (NIH)

26. NLST primary endpoint http://radiology.rsna.org/content/early/2010/10/28/radiol.10091808.full

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

28. Comparing NLST with eligible US census population Aberle DR, et al. Natl Cancer Inst (2010) 102 (23): 1771-1779.

29. Comparing NLST with US census population Aberle DR, et al. Natl Cancer Inst (2010) 102 (23): 1771-1779.

30. Comparing NLST with US census population • 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 Aberle DR, et al. Natl Cancer Inst (2010) 102 (23): 1771-1779.

31. Screening exam compliance

32. Screen positivity rate by screening round & arm * 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 Data reflect the final interpretation, including benefit of historical comparison exams.

34. Interim analysis: lung cancer mortality 10-20-2010 p = 0.0041 Deficit of lung cancer deaths in CT arm exceeds that expected by chance, even allowing for multiple looks at the data.

35. Interim analysis: all-cause mortality 10-20-2010 • Lung cancer: 25% of all deaths in NLST • Lung cancer: 56% of 126 excessdeaths in CXR arm p = 0.023

36. Kaplan-Meier curves for lung cancer mortality 1.00 0.99 0.98 0.97 0.96 0.95 0.94 Probability of survival: ALL participants 0.93 0.92 0.91 0.90 0 1 2 3 4 5 6 7 CT arm Years from randomization CXR arm

37. Kaplan-Meier curves for all-cause mortality 1.00 0.99 0.98 0.97 0.96 0.95 0.94 Probability of survival: ALL participants 0.93 0.92 0.91 0.90 0 1 2 3 4 5 6 7 8 CT arm Years from randomization 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 1Hendrick RE, et al. Am J Roentgenol. 2012 Mar;198(3):723-8. 2Hewitson P, et al. Cochrane Database Syst Rev. 2007;(1):CD001216. 3Barrett B et al. Fam Med 2011;43(4):248-53. 4Benedet JL, et al. Am J Obstet Gynecol. 1992;166:1254–9. 5Berg 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

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