Screening for Lung Cancer Based on 'Strongest Evidence'

Zosia Chustecka

November 17, 2011

November 17, 2011 — The brand-new guidelines from the National Comprehensive Cancer Network (NCCN), the first to be published by a national advisory group, strongly recommend the use of low-dose computed tomography (LDCT) screening for select individuals at high risk for the disease. For the target group of heavy smokers 55 to 74 years of age, regular annual LDCT scans are recommended.

This is a category 1 recommendation, which is based on high-level evidence (i.e., a randomized controlled trial) and uniform NCCN consensus that the intervention is appropriate.

"A category 1 recommendation is very uncommon," said Arnold J. Rotter, MD, from the City of Hope Hospital in Duarte, California, who was one of the members of the NCCN panel that wrote the guidelines. "The vast majority of clinical medicine wouldn't be considered category 1," he told Medscape Medical News. "Both mammography and colonoscopy, commonly performed cancer screenings, are only category 2A per the NCCN," he pointed out.

For high-risk individuals, the recommendation is the strongest that it can be because it is based on a large randomized clinical trial, Dr. Rotter explained.

These high-risk individuals are defined as adults 55 to 74 years of age with a 30 pack-year or more history of smoking tobacco (i.e., smoking 1 pack a day for 30 years), even if they have stopped smoking within the past 15 years.

This is the same as the inclusion criteria for the National Lung Screening Trial (NLST), which was halted early last year after showing a significant lung-cancer-specific mortality benefit. An interim analysis from this trial showed that screening heavy smokers with LDCT significantly reduced deaths from lung cancer, compared with screening with chest x-ray. In the LDCT group, the reduction in lung-cancer-specific death was 20%, and there was a 7% reduction in all-cause mortality, Dr. Rotter noted.

"This was a large randomized clinical trial and it provides the strongest level of evidence that can be obtained," Dr. Rotter emphasized.

The answer is yes.

"The question of CT screening for people at high risk for lung cancer has been answered, and the answer is yes," he told Medscape Medical News. "Of course, further research can be done to clarify the optimal timing, size, criteria for follow-up, and many other details, but the crucial issue of lung cancer mortality has been answered in the affirmative," he said.

The guidelines recommend regular LDCT screening for another group of high-risk individuals — those who are slightly less-heavy smokers (a 20 pack-year or more history of smoking) but who have an additional risk factor, such as cancer history, lung disease history, family history of lung cancer, radon exposure, and occupational exposure. This is a category 2B recommendation for LDCT screening. It is based on lower-level evidence and NCCN consensus, but not uniform consensus (as in category 2A), which signifies that there was some debate about this recommendation.

Concern Over How to Proceed

Earlier this year at the World Lung Cancer Conference in Amsterdam, the Netherlands, lung cancer experts heaped praise on the NLST results, but at the same time expressed concern about how to proceed with this finding in clinical practice. Who should be screened? How often? What should be done about unclear findings? How should intervention be minimized for patients who turn out not to have lung cancer? One issue specific to lung cancer screening is that the lung is a vital organ, so biopsies carry a greater risk than biopsies of other organs that are screened for cancer, such as the breast, cervix, and prostate.

More recently, at the Tenth Annual American Association for Cancer Research International Conference on Frontiers in Cancer Prevention Research, experts declared that lung cancer screening is "not yet ready for prime time."

There are a number unresolved issues with respect to CT screening for lung cancer, said John L. Field, MA, PhD, BDS, FRCPath, director of research at the Roy Castle Lung Cancer Research Programme, University of Liverpool, United Kingdom. "These need to be resolved before a national screening program can be implemented in any country," he said at that meeting.

"These issues include defining optimal risk populations, cost effectiveness, and harmonization of CT screening protocols; the whole area of work-up techniques is still an open question," he explained. In addition, "optimal surgical management...screening intervals, and screening rounds" must still be defined for Europe, he noted. There are several European studies ongoing, including the NELSON (Nederlands-Leuvens Longkanker Screenings Onderzoek) trial.

I don't know quite what their beef is.

When asked about these opinions, Dr. Rotter said: "There is tremendous push back from all of academia about cancer screening. I don't know quite what their beef is." This applies to all screening, he said, including mammography for breast cancer, colonoscopy for colon cancer, prostate-specific antigen testing for prostate cancer, and LDCT scans for lung cancer.

"Eliminating screening and depending on improved chemotherapy to optimize health for the population does not make sense to me," he said.

Part of the issue is that some of the early evidence supporting these interventions came from nonrandomized clinical trials, Dr. Rotter said. This was the case with lung screening, he admitted, and was the main criticism directed at the International Early Lung Cancer Action Program (I-ELCAP) study, headed by Claudia Henschke, MD, which Dr. Rotter was involved in during the early years.

The I-ELCAP study showed that lung cancer can be diagnosed with LDCT at a much earlier stage than usual, he explained. Without screening, 85% of lung cancers are diagnosed at stage III and IV; only 15% are diagnosed at stage I.

The I-ECLAP study inverted this staging, so that 85% of lung cancers were diagnosed at stage I, he said. "But this wasn't a randomized trial, and that was an issue," he acknowledged. And some researchers suggested that some of the early-stage lung cancers were indolent.

"Our overwhelming experience in every area of cancer is that people with earlier stages do better and have better survival," Dr. Rotter said. There was pressure from the research community to prove that lung-cancer-specific mortality could be reduced with LDCT screening, so the huge NLST, funded by the US National Cancer Institute, was launched. There was some controversy over the comparison of LDCT with chest x-ray; some researchers questioned whether the use of chest x-rays was ethical in light of the benefits already documented for LDCT.

Now that the NLST results are in and are overwhelmingly positive for lung cancer screening with LDCT in high-risk individuals, there should be an end to these debates, Dr. Rotter said. "I think that the antiscreening groups are struggling to find a way to minimize these very significant findings," he added.

"I believe that lung screening is ready for prime time," Dr. Rotter said. "In fact, the recommendations are conservative; they limit screening to only the highest-risk group," he noted, in contrast to screening for other cancer types, which is aimed at all people.

Not a Test, Part of a Process

Lung cancer screening should not be conducted in isolation, Dr. Rotter emphasized. It should be part of a multidisciplinary program with primary care doctors, pulmonologists, radiologists, thoracic surgeons, medical oncologists, and pathologists, as specified in the NCCN guidelines. In addition, smoking-cessation counseling should be an integral part of the screening process, he noted.

This sentiment was echoed by Michael Unger MD, FACP, FCCP, director of the pulmonary cancer detection and prevention program and of the pulmonary endoscopy and high-risk lung cancer program at the Fox Chase Cancer Center in Philadelphia, Pennsylvania.

Screening is not a test but a process.

"I maintain that screening is not a test but a process requiring a multidisciplinary approach with adequate resources for appropriate follow-up and algorithms of the best available additional tests and procedures," Dr. Unger told Medscape Medical News. "Without this, it is a financially driven sham that exploits public ignorance; it has some personal benefits but also potential damage."

Dr. Unger was on the panel of experts that authored the NCCN guidelines. "By definition, it is a consensus, and is not necessarily a rigorous, methodologically strict, and categorically graded guideline. Thus, it has strength and weaknesses," he said. However, he added, the results from the NLST randomized controlled trial "are solid."

"The consensus recommended proceeding with the process of screening in a specific high-risk population that, essentially, is not different from the population criteria for inclusion in the NSLT study," he said.

Dr. Unger agrees that there are many unanswered questions. "For example, assuming a negative study on initial and repeat LDCT in a subject 57 years of age: Do we stop (and if so, on what basis) or continue until age 74? Or should we do it every 2 years? If so, what is the evidence?"

Another important point is that in the United States, where lung cancer screening is already being offered at some centers, the process is not covered by medical insurance companies, Dr. Unger noted. "Patients are asked to pay (around $300 to $350) out of pocket.... This might introduce the problem of disparities."

For the time being, Dr. Unger sees lung cancer screening as more of personalized rather than a population-based approach. "We are dealing then with 2 issues — medical practice and public policy," he said.

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