Are Most Lung Cancer Deaths Among Long-Term Smokers Preventable with Affordable Screening?

Lung tumors are the leading cancer killer, striking down more than 160,000 Americans each year. A large majority of lung cancer deaths might be prevented by screening exams. At least that's what the principal investigator of a recent, controversial study says. Interim results of the ongoing study - the International Early Lung Cancer Action Program (I-ELCAP) - were reported on Oct. 26 in the New England Journal of Medicine.

Claudia Henschke, MD, PhD, at Weill Medical College of Cornell University and her I-ELCAP colleagues suggest that periodic screening of smokers and ex-smokers with an imaging technique called spiral CT - a high-tech kind of X-ray - may be as cost-effective in saving lives of those with lung cancer as current mammography screening is in detecting early breast cancer.

Lung cancer is usually deadly by the time it is diagnosed. But I-ELCAP researchers estimate that 88 percent of I-ELCAP study participants diagnosed with and treated for early-stage lung cancer will survive the disease for 10 years or more. Already, the eight patients diagnosed with early-stage lung cancer during I-ELCAP who were not treated have died.

Robert A. Hiatt, MD, PhD, is director of population sciences for the UCSF Comprehensive Cancer Center. Hiatt served as deputy director of the Division of Cancer Control and Population Sciences at the National Cancer Institute (NCI) during the time when Henschke made waves with her first major study results on CT screening in 1999, and while the NCI deliberated about whether to expand efforts to evaluate spiral CT for lung cancer screening. The NCI eventually launched a separate randomized, controlled trial, for which patients have been recruited.

Q. Screening by X-ray imaging already has been thoroughly evaluated and adopted for breast cancer screening. Why are these techniques still being evaluated for lung cancer?

A. All cancers are different in terms of their imaging characteristics, and in the sensitivity and specificity of the imaging exam. What we have learned from mammography doesn't translate directly into other types of screening.

The biological characteristics of the tumors are different. A lung cancer, when imaged at the same size as a breast cancer, may be at a more advanced stage. The breast is an external body organ, and can be looked at more carefully and biopsied more easily than the lung. With conventional X-ray imaging, when you can see lung cancer, it may be too late.

Q. Do the I-ELCAP survival estimates seem valid?

A. As far as they go, yes. The model they used to make estimates seems valid. I'm sure that the amount of time between the identification of the tumor by screening and the survival was accurately calculated in I-ELCAP. It's a well-performed study.

But what does it mean? Someone with a persistent cough might be diagnosed with a tumor and die five years later. Alternatively, the same person might have been diagnosed via a screening spiral CT exam two years earlier.

Even if whatever treatment was given following the earlier diagnosis made no difference - and the person were to die on the same calendar date in either scenario - diagnosing the cancer early would add two years to the measure of survival. It would seem like the survival had gone from five years to seven years, but there was no real difference to the patient. This is called lead time bias. It's why a randomized trial is needed, in which a control, or comparison, group does not receive the same intervention.

Q. Similarly, is it valid to conclude that spiral CT screening for lung cancer is as cost-effective as mammography?

A. I think it's premature to say that. In order to assess cost-effectiveness, you have to first assess the effectiveness in preventing death from lung cancer. That cannot be done on the basis of this recently published study. The only way you can do that in an unbiased way is with a randomized, controlled trial.

Furthermore, they do not account for the fairly large number of people who had benign lesions detected that would have needed biopsies - and maybe lobectomies - to really get at the diagnosis. They didn't really go into the morbidity associated with the workup - and that it is a real cost.

Q. What can be concluded now - and what more can be learned - from the I-ELCAP study?

A. After the clinical investigators follow these individuals for a longer period of time, they will have more real data, and they won't be relying on modeling to calculate long-term survival.

Despite the caveats I mentioned about this study, spiral CT scanning is an exciting technology. Lung cancer is the major cause of cancer mortality. There is no other screening option out there. The I-ELCAP results help to rationalize the additional investment the government is making to do a randomized trial.

Q. What other questions need to be addressed when it comes to spiral CT screening for lung cancer, and what is being done to answer them?

A. What you have here with spiral CT is a technique that is very sensitive in picking up small lung abnormalities. When there really is a cancer, you can measure how likely it is that it will be picked up. However, to accurately assess its benefits, one needs a randomized trial and to learn more about cost and cost-effectiveness.

The NCI-sponsored National Lung Screening Trial (NLST) is comparing spiral CT and chest X-ray in 50,000 smokers and former smokers to determine which offers a stronger reduction in mortality as a screening tool.

There was a debate at the National Cancer Institute about funding it, because choosing to do this very expensive study meant the NCI would not be able to do certain other studies. I think I would agree with the decision to go forward with the NLST because of the promise of the technology in reducing lung cancer deaths.

If all we had to go by was this New England Journal of Medicine paper, we might be tempted to adopt a national screening policy prematurely that ultimately might do more harm than good. With something this important, it's critical to do the proper efficacy trial.

Q. Don't the I-ELCAP study results already indicate that lung cancers detected early are destined to be deadly without treatment, and that it is important to detect and treat them?

A. The fact that the eight people who were untreated, despite being diagnosed with early-stage cancer, all died suggests that the answer is yes. But while it is suggestive and promising, we don't really know. There is nothing reported about the reasons why these people were diagnosed, but not treated. If they had been randomly assigned to spiral CT or X-ray screening, as they would have been in the NLST trial, it is likely that some would have ended up in each arm of the study, with little effect on the study outcome.

Q. How long will it take before we know for sure whether spiral CT is a cost-effective screening method for diagnosing lung cancer in high-risk groups?

A. Enrollment in NLST is complete, and participants will be tracked yearly through 2009. The trial could end early if it becomes clear from interim data that one form of screening saves more lives than the other.

Spiral CT is a promising, impressive technology. But until results from a randomized trial are available, as a society we need to wait before adopting widespread screening - even if many who can afford to pay for it out of their own pockets are already choosing to go ahead and have a spiral CT scan. There are real risks of harm as a consequence of working up individuals with positive results who will turn out not to have cancer. That needs to be assessed in greater depth.

Q. If we do not adopt CT screening for lung cancer, are there other diagnostic techniques on the horizon that raise hopes for detecting lung cancers at an early stage?

A. There are advances in PET imaging that may become valuable in staging already diagnosed lung cancers, but these highly experimental techniques will remain too expensive for broad-based screening.

There is hope that proteomic studies may lead to the identification of protein markers for lung cancer that can be used to sensitively and specifically diagnose lung cancer, using blood samples. But that has not happened yet, and that research is at a very early stage.

"Survival of Patients with Stage I Lung Cancer Detected on CT Screening"
The International Early Lung Cancer Action Program Investigators The New England Journal of Medicine 355:1763-1771 October 26, 2006 Abstract | Full Text | Full Text (PDF)

Related Links:

Robert A. Hiatt, MD, PhD Comprehensive Cancer Center

Robert A. Hiatt, MD, PhD Faculty Profile UCSF Department of Epidemiology & Biostatistics

National Lung Screening Trial (NLST) National Cancer Institute, U.S. National Institutes of Health


Related Links

Robert A. Hiatt, MD, PhD
Comprehensive Cancer Center
Robert A. Hiatt, MD, PhD Faculty Profile
UCSF Department of Epidemiology & Biostatistics
National Lung Screening Trial (NLST)
National Cancer Institute, U.S. National Institutes of Health