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The rationale for developing effective lung cancer screening stems from the fact that lung cancer is the most
common cause of cancer death in the United States and accounts for more cancer deaths than do breast, prostate
and colon cancers combined. We know that overall, the 5-year survival with lung cancer is 15 percent, whereas
the 5-year survival for those with surgically resected early stage disease is 60 percent to 80 percent. This
strong difference in lung cancer survival between treated early stage and late stage lung cancer has formed the
rationale for lung cancer screening with CT. One source of confusion centers on the use of "survival" as a
measure of screening effectiveness. From a population perspective, the accepted measure of screening effectiveness
is "mortality" -- whether screening for the disease saves lives.
What is the NLST?
The National Lung Screening Trial (NLST) is the largest lung cancer specific screening trial ever conducted.
It is sponsored by the National Cancer Institute, and U-M is one of 30 centers across the country that enrolled
participants. The trial is a randomized, controlled trial in which spiral CT will be compared with chest X-ray
(CXR) to determine which screening test will result in fewer lung cancer deaths among individuals at high risk of
lung cancer. Subjects will receive three annual screens and will be observed thereafter for medical outcomes for
up to 5 years. Currently, we anticipate the final analysis will be completed in 2009.
The trial was launched in September of 2002 and accrual finished ahead of schedule in April of 2004 with more
than 53,000 individuals enrolled. While no trial can address all questions concerning lung cancer screening,
the methodology of this trial is rigorous and will be able to address the single most important question about
screening efficacy: does screening save lives?
If it's been reported that people whose lung cancer is found early by SCT scans have a five-year survival
rate of 80 percent as opposed to 15 percent for the typical lung-cancer patient whose condition is detected later,
isn't this enough proof SCT works?
The short answer is no. You have to consider exactly how a five-year survival rate is figured. It is a fraction.
Imagine 1,000 people diagnosed with lung cancer five years ago. If 150 are alive today, the five year survival is
150/1000, or 15 percent. A screening test that detects cancers before signs of symptoms develop is bound to improve
survival, if only because the time of diagnosis is advanced, independent of whether the time of death is delayed.
Because survival cannot distinguish between true benefit and the "pseudo" benefit of a lead in the time of diagnosis,
it is not an acceptable measure of the goodness of screening. Indeed, even if a screening test increases the five
year survival to 90 percent, it is entirely possible that none of the patients with screened-detected lung cancer
will live even an extra day.
Give me an example of this paradox.
The best way to understand this is to work through a thought experiment. First, consider a group of people with
lung cancer who will all die at age 70. If they first receive the diagnosis when they are 67, their five-year
survival rate would be zero percent. But if these same people had received their diagnoses earlier - at, say, age
63 - the five-year survival rate would be 100 percent. Yet death would still come at 70 for all of them. Earlier
diagnosis always increases survival statistics, but it doesn't necessarily mean that death is postponed.
What do we currently know about CT screening for lung cancer?
There have been a number of single-arm, observational studies in the United States, Europe and Japan
that have collected important information about CT screening for lung cancer. The results vary somewhat
because the risk factors in the groups studied have varied. However, some trends are emerging:
- The vast majority of lung nodules detected by either CT or CXR are benign; CT detects many more
lung nodules than CXR. A high number of CT-detected nodules require some form of additional follow-up
to ensure that they are not cancerous.
- CT detects more lung cancers than does CXR. Most of these excess cancers are early stage cancers.
However, there is no evidence yet that the number of late stage cancers is dropping with CT.
- There is no evidence of mortality benefit with CT.
- The potential for screening-related morbidity must be considered along with the potential, as yet
unproven, benefit of early diagnosis.
What is the downside to screening?
Screening tests alone do not provide a definite cancer diagnosis. If screening tests find something
suspicious, additional medical procedures may be necessary to determine if the person has cancer. These
procedures may be uncomfortable and may result in anxiety or medical complications. In addition, screening
may detect abnormalities (both cancerous and non-cancerous) that are unimportant or whose importance is
unknown. We do not know if finding lung cancer through screening will actually result in saving lives, but
we do know that screening will result in additional procedures and treatments. Some may be unnecessary, and
all carry the risk of medical complications. Some medical complications can be life-threatening.
What have previous studies found?
Some studies have shown that spiral CT detects smaller abnormalities than chest X-ray. However, smaller
cancers are not always "early" cancers, and we do not know if detecting these small abnormalities and
treating them will reduce lung cancer deaths. To address this question, it is necessary to conduct a
randomized, controlled trial as we are doing in NLST.
What have previous studies found?
In general, it is better to find cancers when they are smaller. This applies to those cancers that are
potentially fatal. However, we don't know the fatal potential of lung cancers that are found when they
are smaller than a quarter. And size is only one factor in the ability of a tumor to spread or metastasize.
One major difference between lung and other tissues is that all of the blood in the body goes through the
lungs to get oxygen. It only takes one lung cancer cell to break away and enter the bloodstream for lung cancer
to metastasize. So, by the time we can see a lung cancer on a radiology exam, cells may already have entered the
bloodstream and spread throughout the body. The other cancers are different because only a limited amount of blood
flows through those organs. With those cancers, a small cancer may well be limited to the tumor seen on a radiology
exam.
There are other, more significant factors besides tumor size that determine the behavior of lung cancer and
whether it will spread quickly or not. That explains why many small tumors (meaning cancers less than about the
size of a quarter) have already spread when we find them, and why some cancers that are early stage at the time
of surgery develop metastases later.
The important message is that small tumors are NOT necessarily early cancers that can be cured, nor are they
necessarily cancers that have a fatal potential. The goal of this trial is to determine which screening test-chest
X-ray or spiral CT - leads to fewer lung cancer deaths.
What are the risks of screening spiral CT?
First, screening spiral CT scans are abnormal in 25 percent to 50 percent or more of individuals, depending on what
part of the country they live in and the particular kinds of infections to which they have been exposed. Although
the great majority of these positive screens will end up being benign lesions such as scars, many individuals will
need to undergo additional diagnostic tests. These additional tests range from repeat CT scans over several months,
to PET scans, to percutaneous biopsy (where a needle is placed in the lung through the skin), to open-chest surgery.
These procedures are not without risk. With screening, a large group of people will undergo these tests
because of a positive screening result, yet the vast majority of them will have benign lesions. It is possible
that the downstream complications of these diagnostic procedures, including death, may outweigh the benefit of
screening.
Even if there are risks, don't individuals have the right to decide for themselves whether the risks are worth it?
YES, individuals have the right to decide whether the risks are worth it. The challenge is to ensure that
individuals are truly informed, that they truly understand that screening may or may NOT reduce their changes
of dying from lung cancer, and that screening may expose them to other more intrusive diagnostic and therapeutic
procedures that pose a similar risk of morbidity or mortality. When they have all of the facts, many people opt
to be screened within the confines of a controlled trial such as the NLST.
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