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Early Detection Research Group (EDRG)

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

 InterventionUsual Care
Lung cancer cases206160
Lung cancer deaths122115
Lung cancer mortality rate (per 1,000 PY)3.23.0

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

 InterventionUsual Care
Lung cancer cases337303
Lung cancer mortality rate (per 1,000 PY) *4.43.9

* 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 calculated using only the participants diagnosed with lung cancer.

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

 InterventionUsual Care
Median survival time: all cancers1.3 years0.9 years
Median survival time: early-stage resected cancers16.0 years5.0 years

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?

Lead time before diagnosis

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

 Spiral CTChest X-ray
Non-calcified nodules233 (23%)68 (7%)
Malignant27 (3%)7 (1%)
-----Stage I23 (85%)4 (60%)

MLP and ELCAP

 MLPELCAP
Greater detection?YesYes
Earlier stage?YesYes
Mortality reduction?No? *

*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 Executive Committee oversees the LSS (contracts) and ACRIN (grants). The NCI Oversight Committee and Data and Safety Monitoring Board oversee the NLST.

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

 20052006200720082009
Mortality reduction52%37%28%24%21%
Statistical power 90%90%90%90%90%

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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