Key Programs

VA Oncology Conference - January 2002
January 24, 2002, Alexandria Virginia

Pamela M. Marcus, MS, PhD
Division of Cancer Prevention
National Cancer Institute

Lung cancer Screening: History

• 1950's and 60's
  • Small uncontrolled studies
  • No reduction in lung cancer mortality
• 1970's and 80's
  • Three large randomized controlled trials (RCTs)
  • No reduction in lung cancer mortality

Today's Talk

• Evidence underlying "not ready for prime time" view
  • Data from Mayo Lung Project - over-diagnosis
  • Data from Early Lung Cancer Action Project - not sufficient
• Lung Screening Study (LSS)
• National Lung Screening Trial (NLST)

Mayo Lung Project (MLP)

• RCT
• Began in early 1970s
• Nearly 10,000 male smokers
• Two study arms
  • Intervention arm: chest x-ray and sputum cytology every 4 months for 6 years
  • Usual care (control) arm: at trial entry only, a recommendation to receive same tests annually

MLP: Results, 1983

MLP: Reactions

• Validity of finding questioned
• Limitation: follow-up time may have been too short to observe a mortality reduction

MLP: Additional Research

• Extended Lung Cancer Mortality Follow-up
• National Death Index Plus search
  • Matches participant identifiers against state death certificates
  • Provides coded cause of death
• Through 1996

MLP: Mortality - extended follow-up

* p-value = 0.08

MLP: Case survival - extended follow-up

• Lung cancer cases:
  • Intervention arm: 206
  • Usual care arm: 160
• Cases diagnosed before the close of the project (July 1, 1983)

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What is case survival?

Case Survival Vs. Mortality

• Case survival calculated using only the participants diagnosed with lung cancer
• Mortality calculated using all participants: those diagnosed with lung cancer and those who were not

MLP: Case Survival - Extended Follow-up

Case Survival: Interpretations

• Interpreted as some benefit of screening existed in MLP
• Incorrect interpretation
• In the absence of a mortality benefit, an improvement in case survival can only reflect screening biases
• Three possible screening biases: lead-time, length, over-diagnosis

MLP: Lead-time Bias?

MLP: Length Bias?

• Screening reveals a different set of tumors than are diagnosed as a result of symptoms
• "Length" refers to length of pre-clinical detection phase
• Unlikely explanation - total follow-up > 20 years on average

MLP: Over-diagnosis Bias?

• Most likely explanation
• Occurs when: Screening detects lesions that would never have been diagnosed during a person's lifetime in the absence of screening
• Two ways:
  • Non-lung-cancer death prior to symptomatic detection (competing causes of mortality)
  • Detection of indolent lesions

Over-diagnosis

• Value of screening is called into serious question
• Screening will cause harm that would not have occurred in the absence of screening
• Downstream effects may cause serious harm

Over-diagnosis: Is it plausible?

• Smokers also at high risk of other life-threatening events and diseases
• No consensus regarding whether a class of indolent lung cancer lesions exists

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Does a class of indolent lung cancer lesions truly exist?

• High fatality rate of lung cancer - flawed argument
• Experience with other organ sites

MLP: Contributions

• An intense regimen of lung cancer screening may result in identification of lesions with little-to-no clinical relevance
• Particularly relevant information as we look towards spiral CT as a lung cancer screening modality

Spiral CT

• Used to diagnose lung cancer
• Low radiation dose spiral CT - detects abnormalities in asymptomatic high-risk persons
• ELCAP data (Lancet - July, 1999)
  • 1,000 participants
  • Each received low-dose CT and chest x-ray

ELCAP: Baseline Results

MLP and ELCAP

*Not evaluable, due to absence of randomized control group

Randomized Controlled Trials (RCT)

• Most effective and least biased manner to assess screening modalities
• Random assignment of screening regimen
• Internal, yet separate, comparison group - provides the closest representation of what would have happened had screening not occurred

Lung Screening Study (LSS)

• Division of Cancer Prevention (NCI)
• Six PLCO screening centers - Washington DC, Minneapolis, Detroit, St. Louis, Birmingham, Marshfield (WI)
• PLCO: Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial
  • Large RCT (n=154,958)
  • Revisiting annual chest x-ray question
• LSS Participants:
  • Males and females
  • Ages 55-74
  • Current and former (quit < 10 yrs) smokers
  • At least 30 pack-years
  • Not involved in PLCO
• Half randomized to CT; half to x-ray

LSS: Phase I

• Assessed feasibility of RCT
• September 2000 - August 2001
• One screen
• Overwhelming interest
• 3300+ participants
• Less than 2% ineligible due to recent CT
• Compliance greater than 94%

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LSS: Additional Activities

• Began November 1, 2001
• Participants invited to receive second screen
• Same exam as first screening round

NCI Research - Status

• LSS - Inadequate power to detect small reduction in lung cancer mortality
• New project
  • Approved by NCI's BSA (11/01)
  • National Lung Screening Trial (NLST)

NLST Structure, January 2002

NLST - Trial Goals

• Primary: Determine whether lung cancer mortality is reduced by spiral CT compared to chest x-ray screening
• Secondary: Determine all-cause mortality, screening parameters

NLST - Design

• 46,000 participants randomized in 2 years
  • 36,000 at PLCO sites
  • 10,000 at ACRIN sites
• 50,000 in total (LSS included)
• Equal randomization
  • Spiral CT versus chest x-ray
  • Three annual screens
• Refer positives for follow-up

NLST - Statistical Power

NLST - Eligibility Criteria

• 55 to 74 years old
• Smoking history
  • 30 pack-years or more
  • Current or former smoker (less than 15 years since quitting)
• Informed consent

NLST - Major Exclusion Criteria

• Previous lung cancer diagnosis
• Spiral CT scan of lungs or chest within past 18 mo.
• Current treatment for cancer other than non-melanoma skin
• Home oxygen supplementation
• Unexplained Sx: Wt loss > 15 lb. in 12 mo., hemoptysis
• Participation in another cancer screening or primary prevention trial (excluding smoking cessation)

NLST - Screening Results

• Sent to participant and physician within 3 weeks of exam
• Positive (suspicious for LC):
  • Non-calcified nodule/mass - 4 mm
  • Other abnormalities (or constellations of abnormalities) suggestive of lung cancer
• Positive screens: urged to seek medical care from a recognized specialist

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Not Ready For Prime Time

• NLST will answer whether spiral CT can reduce the number of lung cancer deaths
• Until then - not ready for prime time

The Crux Of The Issue

If screening, in the absence of a benefit, were guaranteed to be innocuous, it would not be inappropriate to implement mass screening programs before definitive evidence supporting a mortality reduction was available. Unfortunately, that is not the case.

The "Costs" Of Screening

• Financial and otherwise
• Health care resources
• False positive tests
• Identification of lesions with little-to-no clinical relevance

The Unfortunate Truth

• Cancer screening will always result in harm, harm that would never have occurred in the absence of screening
• Benefit must outweigh harm
• Spiral CT must be properly evaluated

Collaborators

• Richard Fagerstrom
• Phil Prorok
• John Gohagan
• Members of the ACRIN team

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