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Screening for Lung Cancer What the PCP Needs to Know

Screening for Lung Cancer What the PCP Needs to Know. Eric Rich, MD St. Luke’s Idaho Pulmonary Associates. Outline. Lung cancer impact Background: Where have we been? CXR and sputum screening Low dose CT/NLST: Where are we going? Pro’s and con’s of screening

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Screening for Lung Cancer What the PCP Needs to Know

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  1. Screening for Lung CancerWhat the PCP Needs to Know Eric Rich, MD St. Luke’s Idaho Pulmonary Associates

  2. Outline • Lung cancer impact • Background: Where have we been? • CXR and sputum screening • Low dose CT/NLST: Where are we going? • Pro’s and con’s of screening • Cost effectiveness and comparison to other screening tests • Future directions

  3. Lung Cancer • Lung Cancer • Leading cause of cancer deaths • 2011 estimates • 221,130 new cases will be diagnosed (Breast 230,480) • >150,000 deaths due to lung cancer (Breast 39,970) • Survival • 1-year relative survival 43% • 5-year survival • All stages combined 16% • Localized disease 53% (only 15% detected are early stage)

  4. NIH Funding 2010 • Funding does not reflect epidemiology • Cancer $5,823 (Millions) • Breast $763 • Prostate $331 • Lung $201 • Lymphoma $195

  5. Principles of early disease detection J ThoracDis 2013;5(S5)

  6. Screening: CXR and Sputum Cytology • Philadelphia Pulmonary Neoplasm Research Project 1951 • Veterans Administration study 1958-1961 • South London Lung Cancer Study 1955-1963 • Nonrandomized, uncontrolled studies • North London Cancer Study 1960’s. • Randomized to screening vs. no screening • Kaiser Foundation Health Plan screening trial 1964-1979 • Annual CXR, spiro, questionnaire. Controlled. • Mayo Lung Project (MLP) • Randomized to sputum cytology and CXR every 4 months vs. advised to seek annual screening • No difference in mortality (median 20.5 years follow-up)

  7. Screening: CXR and Sputum Cytology • No benefit of screening on mortality • Small studies, majority of follow-up less than 10 years • Self-selection bias, lead-time bias, overdiagnosis bias

  8. Early Lung Cancer Action Project (ELCAP). • 31,567 at risk patients 1993-2005 screened with low-dose CT (LDCT), and 27,456 repeat screenings 7-18 months after previous screening. • Smokers and nonsmokers, exposures, aged 40-86 • Evaluated outcome of stage I cancers diagnosed by screening CT • Prevelance study: • Initial CT: 21% positive tests, 13% required additional work-up • Follow-up CT: 5% positive • 484 lung cancers • 412 (85%) stage I

  9. Estimated 10 year survival 88%, regardless of treatment • Survival rate 92% if surgical resection in 1 month

  10. Conclusion: Annual spiral CT screening can detect lung cancer that is curable • “In a population at risk for lung cancer, such screening could prevent some 80% of deaths from lung cancer.”

  11. Concerns Raised • Not randomized • No control group • Lacked unbiased outcome measure • Did not address harms from screening • Survival always increased by early detection • Deaths are not delayed Arch Intern Med. 2007 Nov 26;167(21):2289-95.

  12. “Study Sees Gain on Lung Cancer” 2006 • “Cigarette Company Paid for Lung Cancer Study” • Disclosure line reported no conflicts of interest • Authors received royalties from GE, makes CT scanners (2007) • Stock ownership and consulting for company that makes biopsy needles for lung cancer diagnosis • Inventors on 27 patents and applications: Lung cancer (2006) screening technology embedded in I-ELCAP protocol • “Review Casts More Doubts on a Lung Cancer Study” • 90% of consent forms cannot be located

  13. Contradictory results in different publications using same data • Statistically unlikely results • Percentage of “Early” stage diagnoses unlikely • Outlier results • Stage at screen detection inconsistent with other studies • Were patients with advanced disease excluded or reclassified? • Lung cancer survival is not consistent with other data. Raises question of poor capture of lung cancer death. “I believe that in the case of ELCAP data, the findings cannot be properly interpreted without understanding the basis of some of the conflicting, improbable, and outlier findings.” J NatlCancer Inst. 2011 Jul 6;103(13):1002-6.

  14. Longitudinal analysis 3246 current or former smokers • Annual CT scans, comprehensive evaluation and treatment of detected nodules • Compared predicted to observed number of new cases, lung cancer resections, advanced lung cancer cases, and deaths from lung cancer • 144 cases of lung cancer compared to 44.5 expected cases (RR 3.2) • 109 lung resections compared to 10.9 expected (RR 10) • No decline in number of advanced lung cancer or deaths from lung cancer “Screening for lung cancer with LDCT may increase the rate of lung cancer diagnosis and treatment, but may not meaningfully reduce the risk of advanced lung cancer or death from lung cancer.”

  15. LDCT detects more nodule and lung cancers, including early stage cancers, than CXR. • No randomized, controlled trial has shown that this leads to a mortality benefit • Therefore, in 2002 the NCI funded the NLST.

  16. Methods • Randomized comparison of screening with LDCT vs. screening with CXR. • 33 participating centers in the USA. • 10 Lung Screening Study sites (LSS) • 23 American College of Radiology Imaging Network (ACRIN)

  17. Participants • Eligible participants • Age 55-74 at randomization • History of cigarette smoking of at least 30 pack-years • If former smoker, quit within last 15 years • Exclusion criteria • Diagnosis of lung cancer • CT of the chest in prior 18 months • Hemoptysis • Unexplained weight loss > 6.8 Kg in previous year • August 2002-April 2004 patients enrolled • Screening from August 2002 through September 2007 • Followed for events through December 31, 2009

  18. Participating Sites • ACRIN centers collected additional data for cost-effectiveness, quality of life, and smoking cessation. • 15 ACRIN centers collected serial blood, sputum, and urine specimens. • Lung-cancer and other tissue specimens were obtained at ACRIN and LSS centers and used to construct tissue microarrays.

  19. Screening • Three screenings (T0, T1, T2) at 1-year intervals. • Screenings outside NLST estimated by questionaires to 500 participants annually • Low-dose CT exposure average 0.6-1.5 mSv • Average effective dose with diagnostic CT 8 mSv. • LDCT • Noncalcified nodule >4mm labeled as “suspicious” for lung cancer. • Adenopathy or effusion could be classified as positive • At T2 stable abnormalities could be classified as minor • Guidelines for nodule follow-up were provided by radiologists, but not mandated.

  20. Data Collection • Medical records • Diagnostic procedures and complications for patients with positive screening tests and in those with lung cancer diagnosis • Pathology and tumor-staging reports • Operative procedures and initial treatments • Vital Status • Questionnaire annually (LSS) or semiannually (ACRIN) • Lost to follow-up patients names and SSN submitted to National Death Index for probable vital status • End-point verification team • Death caused by lung cancer and a death resulting from treatment of lung cancer counted as lung-cancer deaths • Intention-to-screen analysis • Estimated 90% power to detect 21% decrease in mortality • Secondary analyses compared rate of death from any cause and incidence of lung cancer

  21. Trial stopped early by DSMB on October 20, 2010. Definitive result reached for primary end point. • Vital status known for 97% of patients • Median duration of follow-up 6.5 years • Maximum duration 7.4 years • Adherence to screening high • 95% LDCT • 93% CXR

  22. At least one positive result during screening • LDCT 39.1% • CXR 16% • Clinically significant abnormality other than suspicious for lung cancer • LDCT: 7.5% • CXR: 2.1%

  23. What happens to patients with positive screening tests? • First round of screening • 90% of positives led to a diagnostic evaluation • Screening rounds combined • LDCT: 24.2% positive results, 23.3% false positive • 96.4% false positives • CXR: 6.9% positive results, 6.5% false positive • 94.5% false positives

  24. Complications • Adverse Events • All patients: LDCT 1.4%, CXR 1.6% • Major complication from procedure • 0.06% in those without lung cancer confirmation • 11.6% in those with lung cancer confirmation • 16 patients died within 60 days after invasive procedure

  25. Lung Cancer • LDCT: 1060 lung cancers (645 per 100,000 person-years) • 649 diagnosed after positive screening test • 44 diagnosed after negative screening test • 367 after missing screening or after screening complete • CXR: 941 lung cancers (572 per 100,000 person-years) • 279 diagnosed after positive screening test • 137 after negative screening test • 525 after missing screening or after screening complete • Rate ratio 1.13 (95% [CI] 1.03-1.23)

  26. Stage I at Diagnosis • LDCT: 50% • CXR: 31.1% • Stage III or IV at Diagnosis • LDCT: 32.9% • CXR: 40.9%

  27. Mortality • Lung-Cancer specific mortality • LDCT: 356 deaths in 144,103 person years • 247 per 100,000 person years • CXR: 443 deaths in 143,368 person years • 309 per 100,000 person years • Relative rate reduction: 20.0% (95% [CI] 6.8 to 26.7, P=0.004) • Number needed to screen to prevent one death • 320 people

  28. “Screening with the use of low-dose CT reduces mortality from lung cancer.” • 20% relative reduction. • Rate of positive results was higher with LDCT • Three times higher (24% positive) • High rate of false positives with LDCT • 96.4% of all positive results • Higher rate of early stage detection • 50% stage I • Major complications are rare for evaluation of positive result • Surgical resection mortality 1% (4% general US)

  29. Pro’s of Study • Randomized controlled trial • Intention-to-screen analysis • Appropriate control group, no concern for systematic differences in two groups • Internal Validity • Standardized reading of CTs • Extremely high adherence to screening (>90%) • Minimal loss to follow-up (3%, 4%) • Collection of data for further study • Tissue, blood, sputum • Cost-effectiveness • Quality of life • First study to show a mortality benefit in lung cancer screening

  30. Concerns • Overdiagnosis • Detection of cancers that never would have become symptomatic. • Follow populations over time for excess cancer diagnoses in screened group. Mayo study suggests ~ 15 years of follow-up. • USPSTF estimates 10-12% • Would the same results be obtained in clinical practice? (external validity) • Radiologists were trained, read large volume of CTs • CT scanners now more advanced • “Healthy volunteer effect”, as patients were younger and more educated • Large variance in risk (age, smoking, family history) • Who is really at highest risk • Does incorporation of sputum, peripheral blood profiles, etc increase benefit?

  31. Risk of radiation? • Effects on quality of life, anxiety? • Cost? • Role for smoking cessation? • Who should really be screened? • How does this compare to other accepted screening tools? • Can we do this on a local level? Infrastructure? Who’s in charge?

  32. Downstream effects • Positive scans and incidental findings require clinical and radiologic follow-up • 50% increase visits per participant (1 visit per participant) • Risk of radiation: • LDCT 0.6-1.5 mSv(Mammography 0.7 mSv, background radiation in US 2.4 mSv per year) • Lifetime excess risk 0.85% (50 yo female smoker, 25 scans) • 2-5 excess deaths per 10,000 screened • 15-100 lives saved per 10,000 screened

  33. Quality of Life • 3 studies • HRQoL, anxiety, lung-cancer specific distress • 2500 screening participants • Transient negative psychological effects with indeterminate or positive result • Effects subsided, no difference at 12-24 months • Improved with minimizing the waiting time for results

  34. Smoking Cessation Is screening a teachable moment?

  35. ELCAP study: 23% of active smokers quit after baseline CT scan! • Background population quit rate: 4% • NLST collected data on smoking cessation with full results pending • Subgroup of 430 NLST participants at 1 year post-study • No change overall in risk perceptions • 9.7% quit, and 6.6% relapsed at 1 year • Changes risk perceptions among current/former smokers? • Opportunity for captive audience, improved motivation? • Smoking cessation counseling and treatment likely improves mortality benefits above screening alone Cancer. 2013 Apr 1;119(7):1306-13. J ThoracDis 2013;5(S5)524-539

  36. Modeling study: LDCT screening annually over 15 years • NLST criteria • Compared with/without smoking cessation • Light smoking cessation intervention • Behavioral treatment • Intensive cessation intervention • Behavioral and pharmacologic treatment • Lung cancer screening is cost effective from a commercial payer perspective • Becomes even more cost effective when linked with smoking cessation interventions PLoS One 2013 Aug 7;8(8)

  37. Mammography is socially and economically accepted. Is this a model to follow in lung cancer? • Relative risk reduction for death 15-20% • Age 40: Absolute mortality benefit 4 per 10,000 (at 10.7 years) • Age 50: Absolute mortality benefit 5 per 1,000. • False positives • 50% over 10 years • 25% with biopsies NCI, USPSTF

  38. Assessed variation in efficacy of NLST participant data according to 5 year risk of lung cancer • Efficacy • False positive rate • Number of lung cancer deaths prevented • Results • Number of lung cancer deaths per 10,000 person years increased across higher risk quartiles • Decreased false-positives in those at higher risk • The 60% at highest risk accounted for 88% of prevented lung cancer deaths!

  39. Higher risk quartiles account for most prevented deaths • Number needed to screen improves dramatically by risk classification

  40. Empirical evidence for targeting highest risk population for LDCT • Potential to narrow the population needing to be screened, limit cost, and limit false positive results

  41. Principles of early disease detection J ThoracDis 2013;5(S5)

  42. ACCP, ASCO, ATS, NCCN, ACS • Recommendations similar to NLST criteria • ACS recommends strongly in screening at an organized program/center with experience in LDCT

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