Thoracic Imaging 2003 - Society of Thoracic Radiology

Lung Cancer Screening Trials: An Update
Thomas E. Hartman, M.D.
Objective:
1. Identify the strengths and limitations of previous trials of
imaging in lung cancer screening.
2. Identify the strengths and limitations of currently ongoing
lung cancer screening trials.
3. Identify strengths and weaknesses of randomized control
trials.
In order to make informed decisions regarding a screening
CT practice, individuals need to be familiar with the history of
lung cancer screening as well as the risks and benefits of the
current lung cancer screening trials.
Background
Lung cancer is now the most common cause of cancer death
in the United States. More individuals will die from a lung cancer
than colon, breast, and prostate cancers combined. Overall
5 year survivor from lung cancer is less than 15%. However,
patients with Stage I non-small cell lung cancer who undergo
curative resection have a 5 year survival rate of up to 70% (1) .
The improved survival seen with early stage non-small cell lung
cancer has formed the rationale for lung cancer screening.
Historical Lung Cancer Screening Trials.
In the 1970s there were four major prospective randomized
controlled trials (2-5) which concluded that screening did not
reduce lung cancer specific mortality. Although the trials
showed advantages to the screened group with respect to earlier
stage at diagnosis, resectability and survival, they also demonstrated
increases in cumulative lung cancer incidence above that
of the control groups. Therefore significant improvements in
case fatality (number of cancer deaths/number of individuals
with cancer) did not translate into significant reductions in lung
cancer mortality (number of cancer deaths/number of individuals
screened).
Biases in Screening
There are three biases which need to be addressed in regard
to screening trials. These biases are lead time, length, and over
diagnosis biases.
Lead Time Bias
Early detection of disease with screening may result in
increased survival time even if there is no change in the time to
death from the disease process. Therefore survival is an inadequate
measure of the effectiveness of screening and has no predictable
relationship to mortality.
Length Bias
The likelihood of detection by screening is directly related to
how quickly a cancer grows. The more slowing growing the
neoplasm, the longer it is present without symptoms and the
greater likelihood of detection. Overall, screening will tend to
detect more indolent tumors. This increased detection of indolent
tumors will skew the survival results in favor of the screening
group.
Over Diagnosis Bias
This is basically the detection of pseudo disease (a lung cancer
that would have remained subclinical before the individual's
death from other causes). The idea of over diagnosis is controversial,
but if over diagnosis bias exists it would manifest as a
study which showed increased number of cancers detected,
down staging of the detected cancers, increased resectability and
increased survival, but no change in the number of advanced
cancers and no change in mortality. This is exactly what was
seen in the Mayo Lung Project (6) .
Lung Cancer Screening with Helical CT
Screening trials using low dose CT are in progress in many
countries throughout the world (7-9) . Many of these single arm
(no control) trials have demonstrated increases in the detection
of early stage lung cancer. These findings confirm the sensitivity
of CT over chest radiography in detecting smaller, earlier
stage lung cancers. Unfortunately because these trials are single
arm trials, it will be very difficult to determine whether CT
screening can achieve a true decrease in lung cancer specific
mortality or whether the "improved survival" seen with these trials
was simply due to the screening biases of lead time, length,
and over diagnosis.
PLCO
The Prostate, Lung, Colorectal, Ovarian (PLCO) trial is a
randomized control screening trial sponsored by the National
Cancer Institute (10) . One objective of the trial is to see if using
chest radiographs for lung cancer screening can reduce lung
cancer specific mortality by at least 10% relative to the
unscreened group. The reason for this objective was that the
previous trials of lung cancer screening, particularly the Mayo
Lung Project, did not prove that chest radiographs are ineffective
for lung cancer screening, but merely that chest x-ray
screening could not be endorsed without a better demonstration
of a screening benefit. Therefore it is hoped that this PLCO
trial will resolve lingering questions about the utility of chest
radiographic screening.
National Lung Cancer Screening Trial
The National Lung Cancer Screening Trial (NLST) sponsored
by ACRIN recently began enrolling participants. A total
of 50,000 participants will be enrolled and randomized in a one
to one ratio to the experimental and control arms of the study.
The experimental arm will receive a baseline low dose helical
CT and two annual incidence screening CTs. The control arm
will receive a baseline PA chest radiograph and two annual incidence
screening PA chest radiographs. Samples of blood, sputum,
and urine will be obtained from both arms of the study.
The prime eligibility criteria will include an age between 55-74
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