LUNG CANCER SCREENING Albert A. Rizzo, MD FACP FCCP Section Chief Pulmonary/ Critical Care Medicine Christiana Care Health System, Newark De & Immediate Past-Chair National Board of Directors American Lung Association September 2012

Disclosures Pfizer – Speakers’ Bureau and Research Novartis – Speakers’ Bureau and Research Boehringer Ingelheim – Researach CSL Behring – Consulting Intermune - Research

Some initial facts In the year 2012, ACS estimates 260,000 new cases of lung cancer and 160,000 lung cancer related deaths Worldwide in 2008, 1.4 million lung cancer deaths 75% of patients with lung cancer present with symptoms due to advanced local or metastatic disease not amenable to cure 5 yr survival of 16%

What is Screening? Screening for cancer means testing for cancer before there are any symptoms. Screening for some types of cancer has reduced deaths by early detection and treatment. Now there is a test that can reduce death from lung cancer through early detection. The best way to prevent lung cancer is to never smoke or stop smoking now. If your patients are still smoking, talk to them about ways you can help them quit smoking. Smoking felt to be causal in 90% of lung cancers 24% smoking rate in US, growing worldwide Former smokers Second hand smokers

Reasons That Screening in Lung Cancer would be effective High morbidity and mortality Significant prevalence (0.5-2.2%) Identifiable risk factors (allow targeting) Lengthy pre-clinical phase Therapy is more effective in early stage disease

A Guiding Principle of Lung Cancer Screening Make sure that the benefits of treating the smaller number of patients who will receive a lung cancer diagnosis through screening outweigh the harms that could occur from screening a large population of healthy individuals.

Ideal Screening Test High Sensitivity High Specificity Safe and Acceptable Low Cost Decrease mortality and/or improve quality of life Sens = TP/TP +FN positive test prob in ill patient Spec = TN/TN + FP negative test prob in well patient PPV = TP/TP + FP NPV = TN/TN +FN

Outcomes to be assessed Cancer detection rates Stage at detection Survival Disease-specific mortality Overall mortality If disease specific mortality declines but general mortality does not, there is a concern that the screening process may have led to inadvertent deaths

Potential Harms of Screening Detection of benign abnormalities Radiation risks Prolonged follow-up Overdiagnosis In addition to prolonged follow up, consider the appropriateness of the screen process in general and the “best practices” of the follow up. CXR no longer have a role in screening. 60% of PCPs still feel CXR is appropriate for screening for CXR In follow up clinic, low mortality when done by thoracic or cardiothoracic surgeon. In US , 30% of lung resections are done by non-thoracic or cardiac surgeons with higher compliacation rate.

Lung Cancer Screening Trials In the early 50’s, several studies were done to see if CXR surveillance could improve detection and survival in lung cancer in a similar way that it had done for TB Some trials enrolled from 6,000 to 1.8 million Patients. CXR was performed every 6 months. There was no control group. Although lung cancer was found with increased frequency, and patient who were found to have early stage cancer and who received surgery had improved survival, there was no evidence of improved mortality.

Understanding terms… # alive with lung cancer Survival = # lung cancer deaths # screened Mortality =

The problem with survival Lead time bias: In screening, survival is confounded by lead-time Earlier detection increases survival even if death is not delayed CT DX Sx DX Lead time Cancer D Lead time bias is easiest to understand if we consider a hypothetical disease for which there is no effective rx. Suppose an individual is first diagnosed with this deadly disease after he becomes symptomatic and dies some time later. The length of his survival is represented by the distance between when he was diagnosed because of symptoms and when he dies. However, suppose the same individual had been screened and his disease were detected earlier. Even though he dies at the same time, his survival time from diagnosis has been increased by the lead time afforded by screening but screening has not prolonged his life. Lead time bias would not be much of a problem if we could accurately estimate lead time. However, we cannot accurately estimate lead time and it varies considerably, depending on the aggressiveness of the tumor. This variability introduces another bias. Survival Survival

The problem with survival Length time bias: Screening tends to detect more slowly growing cancers Aggressive cancer Short biological life span 1- 2 of 8 Indolent cancer Longer biological life span 3 - 4 of 8 Length bias, where “length” refers to the duration of the detectable preclinical phase. Suppose we have two types of a certain tumor, a rapidly progressing form and a slowly progressing form , which grows half as fast. The arrows represent the duration of the detectable pre-clinical phase (DPCPs) for the tumors, that is, the time from which a tumor is first detectable thru screening to the time at which it becomes symptomatic. The slowly progressing tumors have a longer arrow -twice as long - because they exist in the DPCP for a longer period of time. Let us also suppose that these two types of tumor have the same incidence so that we have an equal number of short (R) and long (R) arrows. If we perform a screening test (R) at some random moment in time (R) we will detect twice as many slowly progressing forms as rapidly progressing forms because the slowly progressing forms are detectable for twice as long. Time

Growth Rate of Lung Cancer RSNA 2005 11/30/05 Growth Rate of Lung Cancer Winer-Muram. Radiology 2002;223(3):798-805. Median DT 181 days 22% DT >= 465 days 94% >= 1 yr grow 0.5-3.0 cm A recent study that accurately assessed the growth rate of lung cancer using CT found that the median doubling time was… The study also found that …. This study suggests that many pt with CT detectable lung cancer may die of other causes before their lung cancers would have become clinically sign 50 VA pts Stage I NSCLC1996-2001 w 2 CTs Tumors meas volumetrically Page

Overdiagnosis Bias (Pseudodisease) Death Other causes Autopsy Dx No screen Screen CT Dx Overdiagnosis refers to the detection of cancers that would never result in death. It can occur under different conditions. For example, overdiagnosis occurs when screening detects a cancer, but co-morbidity (COPD, cardiovascular disease) is the actual cause of death. More often, we refer to overdiagnosis when screening detects a cancer that is histologically malignant, but biologically so indolent that it would never cause death. Take this example….. The bottom figure shows the effect of screening detection. The “cancer” is diagnosed, the patient is treated, and we ascribe the cure of the patient to screening, when in fact the cancer would never have become symptomatic. Screening detects cancer (pseudodisease) that would remain subclinical before death from other causes

Effects of Overdiagnosis RSNA 2005 11/30/05 Effects of Overdiagnosis Falsely increases sensitivity of test Falsely increases PPV of test Falsely increases incidence Falsely improves stage distribution Falsely improves case survival Does not decrease pop mortality Overdx cause much confusion in cancer screening Major rationale for population based stats Page

Volunteer Bias May not represent general population More concerned they have increased risk More than usually health conscious (lower risk)

Screening WILL prolong survival.. regardless of mortality benefit Dx Average Test A N =100 Years 0 2 4 6 8 10 Sensitive Test B N =100 Test A Prevalence: 3/100 = 3% 5 Yr Survival: 2 living / 4 with known cancer = 50% 10 Yr Survival: 1 living / 4 with lung cancer = 25% Mortality at 10 yrs: 3 deaths / 100 screened = 3% mortality Screening will prolong survival regardless of mortality benefits. Lets look at an example to better understand this concept. Lets look at a cohort of 100 patients with 10 lung cancers. = aggressive cancer = non-significant cancer = average cancer = cancer DEATH = screen diagnosed cancer Test B Baseline Prevalence: 10/100 = 10% 5 Yr Survival: 8 living / 10 with lung cancer = 80% 10 Yr Survival: 7 living / 10 with lung cancer = 70% Mortality at 10 yrs: 3 deaths / 100 screened = 3% mortality

Screening WILL prolong survival.. regardless of mortality benefit Dx Average Test A N =100 Years 0 2 4 6 8 10 Sensitive Test B N =100 Test A Prevalence: 3/100 = 3% 5 Yr Survival: 2 living / 4 with known cancer = 50% 10 Yr Survival: 1 living / 4 with lung cancer = 25% Mortality at 10 yrs: 3 deaths / 100 screened = 3% mortality = aggressive cancer = non-significant cancer = average cancer = cancer DEATH = screen diagnosed cancer Test B Baseline Prevalence: 10/100 = 10% 5 Yr Survival: 8 living / 10 with lung cancer = 80% 10 Yr Survival: 7 living / 10 with lung cancer = 70% Mortality at 10 yrs: 3 deaths / 100 screened = 3% mortality

CT-detected Lung Cancers will Have ↑ survival Lead-time: advance time of Dx even absent a delay in death Screening selects for biologically favorable cancers (length bias) Some proportion = overdiagnosis (over-treatment) Biologically benign behavior Death from competing cause True ↑ in longevity indeterminate Even in absence of delay in death

History of lung cancer screening Early lung cancer screening with sputum and CXRs in 1970’s A number of RCTs were conducted in the 1970s in the US and Europe. These trials all evaluated some combination of CXR and sputum for lung cancer screening. Common across all of these trials were increases in the lung cancer detection rates and 5-year survival in the screening arm over controls. However, in NONE was there a mortality benefit. This table shows some of the results of the most studied of the RCTS: Frost JK, Ball WC, Levin ML. Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Johns Hopkins study. Am Rev Respir Dis 1984; 130:549-54. Flehinger BH, Melamed MR, Zaman MB, et al. Early lung cancer detection: results of the initial (prevalence) radiologic and cytologic screening in the Memorial Sloan-Kettering study. Am Rev Respir Dis 1984; 130:555-60. Fontana RS, Sanderson DR, Taylor WF, et al. Early lung cancer detection, results of the initial (prevalence) radiologic and cytologic screening in the Mayo Clinic Study. Am Rev Respir Dis 1984; 130:561-5. Kubik A, Polak J. Lung cancer detection. Results of a randomized prospective study in Czechoslovakia. Cancer 1986; 57:2427-37. Radiology 2011

Limitations of early lung cancer screening trials Studies each had different designs. Combined analysis limited Small sample sizes Primarily addressed the benefit of sputum cytology, not CXR Some degree of contamination (control arm receives the screening intervention. Large number of Lead-time bias predicts an initial excess of cases, reflecting earlier detection through screening. This is due to increased detection of relatively indolent cancers, which, because of length bias, are most likely to be detected by screening.

CXR lung cancer screening CXR RCT screening trials: Mayo | MSK | Johns Hopkins | Czech studies Studied some combination of CXR and sputum cytology Observed increases in lung cancer detection rate over controls Improved survival of screen-detected lung cancers No mortality benefit Long term follow-up: endpoints unchanged Mayo Lung Project Incidence Screening Control No of patients 4618 4593 Lung cancers detected 206 160 Resectable cancers, % 46 32 5-year survival, % 33 15 Lung cancer deaths 122 115 The Mayo lung project. Asymptomatic male smokers aged 45 or older were randomized to receive intensive screening with CXR and sputum cytology at 4 month intervals for 6 years. This table shows the features of the incidence cancers. More lung cancers were observed in the screening arm than control arm. A higher proportion were surgically resectable. There was a doubling of 5-year survival in the screening arm. However, there was no decrease in lung cancer mortality.

Early Low Dose CT lung cancer screening Trials Early low dose CT screening: Single arm studies ELCAP: Henschke CI et al. Lancet 1999; 354:99-105. Japanese Studies Sobue et al. J Clin Oncol. 2002;20:911-920 Sone et al. British J Cancer 2001; 84:25-32 Nawa et al. Chest. 2002;122:15-20 Mayo Study. Swensen SJ et al. Radiology 2005; 235:259-265 There have been several small observational studies of low dose helical CT screening in the United States, Europe, and Japan. These began in the early 1990s. Here are a few of the most commonly referenced studies. These would ultimately pave the way for the Lung Screening Study, which was a feasibility study to determine whether individuals would allow themselves to be randomized to receive either LDCT vs. CXR. Matsumoto M, Horikoshi H, Moteki T, et al. A pilot study with lung-cancer screening CT (LSCT) at the secondary screening for lung cancer detection. Nippon Igaku Hoshasen Gakkai Zasshi. 1995;55:172-179. Henschke CI, McCauley DI, Yankelevitz DF, et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet. 1999;354:99-105. Sone S, Li F,Yang ZG, et al. Results of three-year mass screening programme for lung cancer using mobile low-dose spiral computed tomography scanner. Br J Cancer. 2001;84:25-32. Diederich S,Wormanns D, Semik M, et al. Screening for early lung cancer with low-dose spiral CT: prevalence in 817 asymptomatic smokers. Radiology. 2002;222:773-781. Nawa T, Nakagawa T, Kusano S, et al. Lung cancer screening using low-dose spiral CT: results of baseline and 1-year follow-up studies. Chest. 2002;122:15-20. Sobue T, Moriyama N, Kaneko M, et al. Screening for lung cancer with low-dose helical computed tomography: anti-lung cancer association project. J Clin Oncol. 2002;20:911-920. Swensen SJ, Jett JR, Sloan JA, et al. Screening for lung cancer with low-dose spiral computed tomography. Am J Respir Crit Care Med. 2002;165:508-513. Tiitola M, Kivisaari L, Huuskonen MS, et al. Computed tomography screening for lung cancer in asbestos-exposed workers. Lung Cancer. 2002;35:17-22.

Early low dose CT screening: Single arm studies US Trial N [+] Screens Total Lung Ca Stage I NSCLC ELCAP CT Prevalence 1000 233 (23%) 27 (2.7%) 23 (85%) ELCAP CXR Prevalence 68 (7%) * 7(0.3%) 4 (57%) Incidence Year 1-2 1184 2.5% 7 (2 interval) 5 * 50% were false shadows ; positive screens are actually 3.5% Trial design: Single arm—subjects received both annual CXR and CT screening Eligibility: Asymptomatic | > 60 yrs | > 10 pack yrs Trial endpoints: The frequencies of Nodule detection Nodules representing malignancy Malignant nodules that are curable ELCAP DID NOT ADDRESS MORTALITY, BUT DEMOSTRATED THE IMPORTANCE OF CT OVER CXR IN LUNG CANCER DETECTION The ELCAP was a single arm trial in which eligible participants received BOTH annual CXR and CT for three years. They showed that CT detected 6-times more nodules and 4 times the number of lung cancers than CXR. They emphasis was on the detection of early stage lung cancers, which were much more commonly seen in the CT arm. They equate this with curability, which is a term commonly misunderstood epidmeiologically, and usually refers to either 3-year, 5-year or 10-year survival times. Henschke CI et al. Lancet 1999; 354:99-105 Henschke CI et al. Cancer 2001; 92:153-159

Early low dose CT screening: CONCLUSIONS CT detection rates CT has ~6-fold higher nodule detection rate than CXR CT has ~3-fold higher cancer detection rate than CXR Benign nodules = majority of detected nodules (> 90%) CT has 5-fold increase in resectable lung cancers No proven benefit in lung cancer mortality True stage shift which requires not only an increase in early-stage disease but a concomitant decrease in late-stage disease when compared with a control population.

National Cancer Institute National Lung Screening Trial National Cancer Institute T S L N

NLST design and time posts National Lung Screening Trial National Cancer Institute T S L N RCT 1:1 randomization to CT or CXR Launched in 08-2002 across ~ 33 sites Final Analysis Interim analyses CT Low dose chest CT yearly for three years 2 mSv vs 7 mSv 33 medical centers 53,476 High-Risk Subjects 2002 03 04 05 06 07 08 09 10 T0 CXR Follow up T1 T2

Standardized Eligibility Males | Females 55-74 Yrs Asymptomatic Current or former smokers ≥ 30 pack yrs Former smokers have quit within ≤ 15 yrs No prior lung cancer No cancer within past 5 yrs No chest CT w/in prior 18 months National Lung Screening Trial National Cancer Institute T S L N Study stopped in Nov 2010 when interim analysis found a statistically significant benefit for CT scanning At 6.5 yrs follow up, 645 /100000 lung cancer in CT group 572/100000 lung cancers in CXR group 247 lung cancer deaths in CT group 309 lung cancer deaths in CXR group Relative mortality reduction of 20% 6.7% reduction in all cause mortality

Endpoints Lung cancer specific mortality 90% power to detect a 20% mortality reduction with LDCT Compliance: 85% CT | 80% CXR Contamination: 5% CT | 10% CXR All cause mortality Medical resource utilization ACRIN secondary aims: Short | long term effects on smoking habits and beliefs Cost-effectiveness Specimen biorepository for molecular biomarkers of risk | early Dz NLST Research Team. Radiology 2011; 258(1):243-253.

True and false positive screens Screening Result Low Dose Helical CT CXR Round 1 N (%) Round 2 Round 3 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) 649 total CT screen detected lung cancers vs. 279 CXR-detected lung cancers, representing a 2.3 fold increase in lung cancer detection in the CT arm. (Difference = 370 additional cancers) 649 CT-detected lung cancers | 279 CXR-detected lung cancers 370 excess cancers by CT screening: 2.3 fold increase with CT Most positive screens did not have lung cancer 31

Screen positivity rate by screening round & arm Low dose helical CT CXR Number screened Number positive % Positive % Positive Screen 1 (T0) 26,314 7,193 27.3 26,049 2,387 9.2 Screen 2 (T1) 24,718 6,902 27.9 24,097 1,482 6.2 Screen 3 (T2) 24,104 4,054 16.8* 23,353 1,175 5.0* All screens 75,136 18,149 24.2 73,499 5,044 6.9 Positive screen: Nodule ≥ 4 mm or other findings potentially related to lung cancer. * Abnormality stable for 3 rounds could be called negative according to protocol. 3-fold increase in positive screens in CT arm. 32

lung cancers diagnosed in NLST Screen Result and Time Period CT (%) CXR (%) Total T0-T2 Screen-detected lung cancers 649 (61.2%) 279 (29.6%) Total Screen [-] lung cancers T0-T2 44 (4.2%) 137 (14.6%) Total NO screen lung cancers 367 (34.6%) 525 (55.8%) Total lung cancers in arm 1060 (100.0%) 941 (100%) Total Lung Cancers NLST 2001 892 NO screen cancers include: never screened (N = 35) | due for screen (N = 55) post-screen time period (N = 802)

stage distribution for lung cancers by screen status This is a complicated chart. Points to take home: 1. With CT, the great majority of early stage cancers were screen-detected. With CT, most cancers diagnosed in screen [-] patients were advanced stage (goes along with length bias—screening misses aggressive lung cancers. With CXR, early stage cancers were seen equally in those screened and not screened. Overall, there WAS a stage shift. There was an increase in early stage cancer with CT BUT there was a decrease in late stage cancers. There is some component of overdiagnosis, but it appears to be modest. CT Screens (1040 cancers) CXR Screens (929 cancers) Numbers reflect only lung cancers of known stage

cumulative lung cancer deaths by time from randomization Years post randomization LDCT CXR 500 400 300 200 100 0 1 2 3 4 5 6 7 Cumulative number of lung cancer deaths 35

diagnostic follow-up of positive screens Category LDCT CXR T0 (%) T1 (%) T2 (%) Total (%) Total positives 7191 (100%) 6901 (100%) 4054 (100%) 18,146 (100%) 2387 (100%) 1482 (100%) 1174 (100%) 5043 (100%) Confirmed lung cancer 270 (3.8%) 168 (2.4%) 211 (5.2%) 649 (3.6%) 136 (5.7%) 65 (4.4%) 78 (6.6%) 279 (5.5%) Participants with complete diagnostic F/U 7049 (98%) 6740 (98%) 3913 (97%) 17,702 (98%) 2348 (98%) 1456 (98%) 1149 (98%) 4953 (98%) Clinical procedure 72.2% 47.3% 55.0% 58.9% 60.2% 49.7% 57.3% 56.4% Imaging Exam 81.1% 37.4% 51.3% 57.9% 85.6% 66.5% 78.9% 78.4% CXR 18.2% 9.1% 16.6% 14.4% 36.9% 26.2% 31.8% 32.6% Chest CT 73.1% 30.4% 41.1% 49.8% 65.8% 51.2% 62.0% 60.6% PET or PET-CT 10.3% 5.2% 10.0% 8.3% 7.6% 7.2% 9.8% 8.0% Confirmed Dark blue row represents the dominator for the percentages of participants undergoing specific diagnostic procedures. Of imaging procedures, the majority of patients underwent diagnostic CT exams. Of interventional procedures: bronchoscopy and surgery (generic) were the most common procedures. Of surgical procedures, thoracotomy was the most common procedure. There are: Significantly fewer participants in CXR arm that undergo diagnostic procedures Typically higher percentage of participants in CXR that undergo diagnostic procedures. Invasive Procedures T0 (%) T1 (%) T2 (%) Total (%) Percutaneous FNA/Core 2.2% 1.1% 2.4% 1.8% 3.5% 2.5% 4.5% Bronchoscopy 4.6% 2.6% 4.8% 3.8% 5.4% Surgical procedure(s) 4.2% 2.9% 5.6% 4.0% 5.2% 5.8% Mediastinoscopy 0.9% 0.5% 0.6% 0.7% 0.8% 1.7% Thoracoscopy 1.2% 1.3% Thoracotomy 2.8% 4.1% 3.0% 3.7%

screening-related complications from invasive procedures CT lung cancer NO cancer CXR No cancer N % Positive screens 649 100 17,053 279 4,674 Major complication 75 11.6 12 0.1 24 8.6 4 < 0.1 Death 60 days after any procedure 10 1.5 11 3.9 3 Death 60 days after invasive procedure 6 3.8 In patients with [+] screens who HAD lung cancer, major complications were seen in 11.6%. Death occurred in only 1.5%. NOTE: most of the literature reports death within 30 days of a procedure. We were conservative and measured death within 60 days of the procedure. Our complication rate was low-likely because the NLST was performed at centers with dedicated oncologic thoracic surgeons. In CT participants with [+] screens and NO lung cancer, the complication rates were VERY low (< 0.1). So, despite the high number of false [+] screens, we did not observe significant complications with CT screening. NOTE ALSO: to avoid ascertainment bias, we counted all complications and death based on timing relative to the intervention. Therefore, included in this would be individuals who died of other causes unrelated to the intervention.

NLST Summary CT-detects more lung cancers than CXR x 2.3 folds True stage shift observed in CT arm 20% lung cancer mortality reduction CT vs. CXR Absolute risk reduction = 0.4% (AR CT= 1.3% | CXR = 1.7%) Few major complications NNS (Number needed to screen) : 320 NNS (Breast Cancer): US: 238, NZ: 781 NCI_2012 and J med Screen, 2001;8(3):114-5 Need for diagnostic algorithm to decrease false positives

Take Away Points from NSLT Population was younger than the general population Population was fairly well educated Population included more former smokers Operative mortality was low (1%)

Rational for Lung Cancer Screening

Lung cancer is, by far, the most common fatal cancer in both men (29%), and woman (26%) . Lung Cancer Accounts for more deaths than prostate, and colon and breast combined. 41

The survival rates for all cancers combined and for certain site-specific cancers have improved significantly since the 1970s, due, in part, to both earlier detection and advances in treatment. Survival rates for lung cancer have remained relatively flat, in part due to delayed detection. 80% of lung cancers are discovered at advanced stage. Survival rates markedly increased for cancers of the prostate, breast, colon, rectum, and for leukemia. With new treatment techniques and increased utilization of screening, there is hope for even greater improvements in the near future. 42

Kaplan–Meier Estimates of Overall Survival (Panel A) and the Time to Progression of Disease (Panel B) in the Study Patients, According to the Assigned Treatment. Figure 2. Kaplan–Meier Estimates of Overall Survival (Panel A) and the Time to Progression of Disease (Panel B) in the Study Patients, According to the Assigned Treatment. Schiller JH et al. N Engl J Med 2002;346:92-98.

FY 2010 Federal Research Dollars Per Death Federal spending from the combined FY2010 research dollars of the National Cancer Institute, Department of Defense and Centers for Disease Control and Prevention.

85% of all lung cancers are linked to cigarette use.

 Tobacco use is a major preventable cause of death, particularly from lung cancer. The year 2004 marks the anniversary of the release of the first Surgeon General’s report on Tobacco and Health, which initiated a decline in per capita cigarette consumption in the United States. As a result of the cigarette smoking epidemic, lung cancer death rates showed a steady increase through 1990, then began to decline among men. The lung cancer death rate among US women, who began regular cigarette smoking later than men, has begun to plateau after increasing for many decades. 94 million current or former smokers remain at risk 46

Effects of stopping smoking at various ages on the cumulative risk (%) of death from lung cancer up to age 75, at death rates for men in UK in 1990. Nonsmoker rates were taken from US prospective study of mortality Peto R, BMJ, 2000 The effects of smoking cessation are delayed by as much as 20 years and are related to exposure. Up to 505 of newly diagnosed lung cancer cases are among former smokers.

Cost of Lung Cancer Care Annual Cost of Lung Cancer treatment in US $10 billion Estimated Annual treatment cost $21,000 per patient $47,000 per patient for those who live more than one year Heathcare Mang Sci 1999, J Clin Oncol 1997

Actuarial Analysis Shows That Offering Lung Cancer Screening As An Insurance Benefit Would Save Lives At Relatively Low Cost HEALTH AFFAIRS 31,NO. 4 (2012): 770–779 Cancer Type Screening Test Cost/life-year saved (Original Study) Study date Cost/life-year saved (2012 dollers) Cervical Pap Smear 33,000 2000 50,162 - 75,181 Colorectal Colonoscopy 11,900 1999 18,705 - 28,958 Breast mammography 18,800 1997 31,309 – 51,274 Lung LDCT (Baseline) 18,862 2012 LDCT (Lowest Cost Scenario) 11,708 LDCT (Highest Cost Scenario) 26,016 the cost per life-year saved in 2012 dollars was considerably higher for cervical, colorectal, and breast cancer than for lung cancer in the baseline scenario. Assuming that 50 percent of the people ages 50–64 with thirty or more pack-years of smoking were screened, the insurer cost spread across the commercial population would be $0.76 per member per month, with no cost sharing.

NCCN Guidelines: Lung Cancer Screening October 26, 2011 Lung cancer screening with CT should be part of a program of care and should not be performed in isolation as a free standing test. The risks and benefits of lung cancer screening should be discussed with the individual before doing a screening LDCT scan. It is recommended that institutions performing lung cancer screening use a multidisciplinary approach that may include specialties such as radiology, pulmonary medicine, thoracic oncology, and thoracic surgery. Management of downstream testing and follow-up of small nodules are imperative and may require establishment of administrative processes to ensure the adequacy of follow-up. NCCN. Org

Typical Organ Radiation Doses from Various Radiologic Studies. Brenner DJ, Hall EJ. N Engl J Med 2007;357:2277-2284.

Ionizing Radiation Linear No Threshold Model Roentgens (R) vs Grays (Gy) vs Sieverts (Sv) 3 mSv – annual background dose 1000 mSv – 4-5% risk of fatal cancer Myeloma, leukemia, lung, thyroid, breast CXR 0.1 mSv, CT chest 8 mSv, LDCT chest 1.5 mSv

Institute of Medicine Use of CT scanning increased three fold since 1993 Top environmental causes of breast cancer CT scanning Postmenopausal Hormone Therapy 30% of all CT scans “medically unnecessary” Justification, Optimization, Limitation

Estimated Dependence of Lifetime Radiation-Induced Risk of Cancer on Age at Exposure for Two of the Most Common Radiogenic Cancers. Figure 4. Estimated Dependence of Lifetime Radiation-Induced Risk of Cancer on Age at Exposure for Two of the Most Common Radiogenic Cancers. Cancer risks decrease with increasing age both because children have more years of life during which a potential cancer can be expressed (latency periods for solid tumors are typically decades) and because growing children are inherently more radiosensitive, since they have a larger proportion of dividing cells. These risk estimates, applicable to a Western population, are from a 2005 report by the National Academy of Sciences25 and are ultimately derived from studies of the survivors of the atomic bombings. The data have been averaged according to sex. Brenner DJ, Hall EJ. N Engl J Med 2007;357:2277-2284.

NLST complications (partial list) Major complications Acute respiratory failure Respiratory arrest Prolonged mechanical ventilation Cardiac arrest | MI | CHF Hemothorax requiring tube Empyema Bronchopulmonary fistula Bronchial stump leak Injury to vital organ | vessel Thromboembolic complications Death Intermediate complications Respiratory distress Mucostasis  bronchoscopy Cardiac arrhythmia needing attention Cardiac ischemia | ST elevation Pleural effusion Pneumothorax needing chest tube Fever | infection | sepsis | pneumonia Transfusion for blood loss Steroid-induced diabetes Hospitalization post procedure Vocal cord paralysis Pain requiring referral to specialist

Lung Cancer Screening: American Lung Association Recommendations Low-dose CT screening should be recommended for those people who meet National Lung Cancer Screening Trail criteria: current or former smokers, aged 55 to 74 years a smoking history of at least one pack a day for 30 years (30 pack-years ) no history of lung cancer Individuals should not receive a chest X-ray for lung cancer screening Low-dose CT screening should NOT be recommended for everyone

Should my patient be screened? Prior to appointment: Questions to think about Does my patient meet the NLST criteria or another high-risk profile that makes them good candidates for screening? What are the benefits/risks for my patient if screened? What are my referral options? Where do I refer? During the average medical visit: ~12 minutes Take a complete health history and determine possible co-morbidities (conduct spirometry?) Advocate smoking cessation Educate about symptoms of underlying lung disease Discuss the benefits /risks and possible procedures associated with the screening process Discuss costs of screening – health insurance reimbursement, time and personal costs If recommending screening, discuss Availability – low dose CT is available and will be done, high quality machine and staff Low Dose CT /qualified center with expertise to follow up after test Follow up care through multidisciplinary approach. Points to Remember: Do not offer a Chest X-ray as an option for screening Refer patients only to qualified centers, those providing low-dose CT scans and a multi-disciplinary team for follow-up Ensure that patients know the difference between a screening test and screening process.

Screening Referrals Refer your patient to institutions that have experience in conducting Low Dose CT scans, as well as, using the latest CT technology. Make sure that the facility uses “best practices” for lung cancer screening There should be a link to an expert multidisciplinary team that can provide follow- up for evaluation of nodules. Discussion of results and follow-up is key.

Understanding Risks Making an Individual Decision to Get Screened: Questions to Ask Your Doctor Understanding Are you considered high risk for lung cancer? NLST high risk group Genetics Smoking History – pack years Other exposures – occupational, etc. What is your current health status? Do you have co-morbidities like COPD? What are my screening options? What does the screening process entail? Risks What are some of the complications of the diagnosis procedure? False Positives Negative results do not absolutely rule out the chance for cancer incidence What is the cumulative exposure to radiation? What are the unknowns?

Making an Individual Decision to Get Screened: Questions to Ask Your Doctor, con’t Costs Does my health insurance company reimburse for CT scans? How much does a CT scan cost? What about the cost of follow up procedures? How will screening affect my quality of life? (living with indeterminate diagnosis) How much time and personal costs will I spend throughout the screening

Screening Flow Chart: What Happens if a Patient Chooses to Be Screened? Low Dose CT Screening Negative Re-Screen Indeterminate Watchful Follow Up Further Imaging Suspicious Further Immediate and Potentially Invasive Procedures Lung Cancer Treatment Possibilities: Surgery, Palliative Care, Clinical Trials, Other No Lung Cancer Continued Screening Smoking Cessation Risks Risks Multi-disciplinary Approach Concerns: Length of Time Intervals

Some Remaining Issues Cost effectiveness Screening frequency Population targets Criteria for “positive” findings Follow up protocols to decrease false-positive evaluations

THANK YOU QUESTIONS?