LUNG CANCER SCREENING

Albert A. Rizzo, MD FACP FCCP

Section Chief Pulmonary/ Critical Care MedicineChristiana 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.

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

Outcomes to be assessed

Cancer detection rates

Stage at detection

Survival

Disease-specific mortality

Overall mortality

Potential Harms of Screening

Detection of benign abnormalities

Radiation risks

Prolonged follow-up

Overdiagnosis

Lung Cancer Screening Trials

Understanding terms…

# lung cancer deaths# screened

Mortality =

Survival = # alive with lung cancer # with lung cancer

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

Survival

Sx DX

DCancer

CT DXLead time

Survival

Time

Indolent cancerLonger biological life span

1- 2 of 8

3 - 4 of 8

Aggressive cancerShort biological life span

Screen

The problem with survival

Length time bias: Screening tends to detect more slowly growing cancers

Growth Rate of Lung Cancer

• Median DT 181 days• 22% DT >= 465 days• 94% >= 1 yr grow 0.5-3.0 cm

Winer-Muram. Radiology 2002;223(3):798-805.

DeathOther causes

AutopsyDxNo screen

Screen

Screening detects cancer (pseudodisease) that would remain subclinical before death from other causes

Overdiagnosis Bias (Pseudodisease)

CT Dx

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

Volunteer Bias

May not represent general population

More concerned they have increased risk

More than usually health conscious (lower risk)

0 2 4 6 8 10Years

AverageTest A

N =100

Test APrevalence: 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

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

SensitiveTest B

N =100

= aggressive cancer

= non-significant cancer= average cancer

= cancer DEATH

= screen diagnosed cancer

0 2 4 6 8 10Years

AverageTest A

N =100

Test APrevalence: 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

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

SensitiveTest B

N =100

= aggressive cancer

= non-significant cancer= average cancer

= cancer DEATH

= screen diagnosed cancer

• 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

CT-detected Lung Cancers will Have ↑ survival

History of lung cancer screeningEarly lung cancer screening with sputum and CXRs in 1970’s

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.

• 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

CXR lung cancer screening

Mayo Lung Project Incidence Screening Control

No of patients4618 4593

Lung cancers detected 206160

Resectable cancers, % 46 32

5-year survival, % 33 15

Lung cancer deaths 122115

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

Early low dose CT screening: Single arm studies

• 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

US Trial N [+] Screens Total Lung Ca

Stage INSCLC

ELCAP CT Prevalence 1000 233 (23%) 27 (2.7%) 23 (85%)

ELCAP CXR Prevalence 1000 68 (7%) * 7(0.3%) 4 (57%)

Incidence Year 1-2 1184 2.5% 7(2 interval) 5

Henschke CI et al. Lancet 1999; 354:99-105Henschke CI et al. Cancer 2001; 92:153-159

* 50% were false shadows ; positive screens are actually 3.5%

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 Lung Screening Trial National Cancer Institute

TSLN

2002 03 04 05 06 07 08 09 10T0

NLST design and time posts• RCT• 1:1 randomization to CT or CXR• Launched in 08-2002 across ~ 33 sites

Final A

nalysis

CXR

CT

53,476High-Risk

SubjectsT2

T1Follow up

Interim analyses

National Lung

Screening Trial

National Cancer Institute

TSLN

Standardized Eligibility

National Lung Screening Trial

National Cancer Institute

TSLN

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

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 1N (%)

Round 2N (%)

Round 3N (%)

Round 1N (%)

Round 2N (%)

Round 3N (%)

Total Positives

Lung cancerNo 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 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

Screen positivity rate by screening round & arm

Low dose helical CT CXR

Number screened

Number positive

% Positive

Number screened

Number 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.

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

CT Screens (1040 cancers) CXR Screens (929 cancers)

Numbers reflect only lung cancers of known stage

Years post randomization

LDCT

CXR

500

400

300

200

100

0 0 1 2 3 4 5 6 7

Cum

ulati

ve n

umbe

r of l

ung

canc

er d

eath

s

cumulative lung cancer deaths by time from randomization

diagnostic follow-up of positive screens

CategoryLDCT CXR

T0 (%) T1 (%) T2 (%) Total (%) 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%

Invasive Procedures T0 (%) T1 (%) T2 (%) Total (%) T0 (%) T1 (%) T2 (%) Total (%)

Percutaneous FNA/Core 2.2% 1.1% 2.4% 1.8% 3.5% 2.5% 4.5% 3.5%Bronchoscopy 4.6% 2.6% 4.8% 3.8% 4.6% 3.8% 5.4% 4.5%Surgical procedure(s) 4.2% 2.9% 5.6% 4.0% 5.2% 3.5% 5.8% 4.8%

Mediastinoscopy 0.9% 0.5% 0.6% 0.7% 0.9% 0.8% 1.7% 1.1%Thoracoscopy 1.2% 0.8% 2.5% 1.3% 0.9% 0.8% 1.7% 1.1%Thoracotomy 2.8% 2.2% 4.2% 2.9% 4.1% 3.0% 3.8% 3.7%

screening-related complications from invasive procedures

CTlung cancer

CTNO cancer

CXRlung cancer

CXRNo cancer

N % N % N % N %

Positive screens 649 100 17,053 100 279 100 4,674 100

Major complication 75 11.6 12 0.1 24 8.6 4 < 0.1

Death 60 days after any procedure 10 1.5 11 < 0.1 11 3.9 3 < 0.1

Death 60 days after invasive procedure 10 1.5 6 < 0.1 10 3.8 0 0

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

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.

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

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 yearHeathcare 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 CostHEALTH 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 18,862

LDCT (Lowest Cost Scenario)

11,708 2012 11,708

LDCT (Highest Cost Scenario)

26,016 2012 26,016

NCCN Guidelines: Lung Cancer Screening

• 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.

October 26, 2011

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.

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 yearsa 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– 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

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

Multi-disciplinary Approach

Risks Risks

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?