National Lung Screening Trial: A Giant Leap for Lung Cancer ScreeningAt Baby-step Pace
In November 2010, the National Cancer Institute (NCI) ended one of the largest clinical trials ever conducted, the National Lung Screening Trial (NLST), after annual CT screenings of heavy smokers showed a 20 percent reduction in mortality compared with conventional x-ray screening. One year later, dozens of U.S. cancer centers have begun to offer screening for the nation's deadliest cancer, but few Americans are lining up for a chance at early detection.

NCI's decision to bring the NLST to an early  close after screening 53,000 smokers signaled a major victory in the fight against lung cancer. Despite decades of decline in the number of U.S. smokers, lung cancer continues to kill 160,000 Americans each year. Notwithstanding NCI's abrupt action in response to CT's survival benefit, medical societies have yet to recommend the exam. As secondary analyses of the NLST trickle in, Medicare and private payors have yet to reimburse for CT screening, leaving lung cancer screening on the table at many centers, but patients off the gantry.

"The NLST results will have a significant impact on public health policy," Denise R. Aberle, MD, principal investigator for the NLST and vice chair of research for radiological sciences at University of California, Los Angeles (UCLA), predicted when early results were released in November 2010.

Screening implementation

By the time Aberle and colleagues published a more comprehensive look at the NLST results in the Aug. 4 issue of The  New England Journal of Medicine, cancer centers had already begun preparing, publicizing and, in many cases, implementing screening programs for high-risk patients.

"We had been talking for several months about implementing lung cancer screening. By the time the final report was published, we had already developed our lung CT program and were ready to begin screening," explains Stanton L. Gerson, MD, director of University Hospitals Seidman Cancer Center in Cleveland. University Hospitals' radiologists review approximately 100 low-dose lung CT screenings per month.

University Hospitals is not alone. At UCLA, lung CT screening has been available to the public for more than two years. "Even before the NLST results came out, there was a demand among patients to get screening CTs," points out Jay M. Lee, MD, surgical director of thoracic oncology at UCLA and head of the university's Lung Screening Clinic.

Public demand for lung CT has been the foundation of screening thus far. Without insurance coverage, cancer centers have instituted screening programs partly as services to their communities. "Lung screening can be a major contribution to fighting lung cancer, and we should be participating in anything that's helping reduce the number of people dying from cancer. But it's not going to be a margin-producing project," offers Reginald F. Munden, MD, MBA, head of the lung CT screening program at MD Anderson Cancer Center in Houston. Still, patient demand, or perhaps the ability to pay out of pocket, for CT screening is weak.

"We haven't seen a groundswell of people demanding screening," affirms Ella A. Kazerooni, MD, MS, head of the University of Michigan Comprehensive Cancer Center's lung screening program in Ann Arbor. Across the board, cost is the chief impediment to participation. At roughly $300 to $400 out-of-pocket per exam, the number of smokers getting screened remains low.

Too many false positives

Widespread lung screening hinges on reimbursement, which, experts say, will not come until Aberle and her team publishes a cost-effectiveness analysis of lung CT screening. At the root of the uncertainty is a high rate of false-positive screenings: 96 percent of all positive NLST screenings on CT were non-cancerous.

There is an overarching lack of guidance on how to manage abnormal lung nodules. "CT provides us with a powerful hint in the right direction, but the findings could still be many things, benign or malignant," Lee says.

The issue may come down to a matter of definition. The NLST defined positive screenings as non-calcified nodules 4 mm or larger. Different screening programs, as well as another large lung screening trial ongoing in Europe (NELSON trial), have opted for other definitions of positive findings. Thresholds range from 3D lesion quantifications of 500 mm3 in the NELSON trial to careful clinical judgments combining nodule size, density, borders and appearance.

"Generally speaking, the larger the lesion, the shorter the interval of follow-up," Gerson says.

What is clear is that all successful lung screening programs are interdisciplinary, comprising radiologists, pulmonologists, primary care physicians, surgeons and oncologists. "Without buy-in from these specialties, we would not have launched lung screening," Munden notes.

At UCLA and Seidman Cancer Center, physicians meet weekly to discuss indeterminate findings. Plus, enlisting and educating specialists as well as primary care physicians has been shown to be an essential avenue to establishing viable and appropriate referral patterns.

"It is very important that people realize that lung screening is a process, not a simple test," Kazerooni advises. "A primary obligation of screening centers is to provide enough information to allow individuals to make an informed decision about risks versus benefits," Aberle explains, adding that CT screening must "be positioned within broader programs of smoking cessation, which remains the single most effective way to reduce lung cancer mortality."

Questions linger

Aberle and co-investigators acknowledge the uncertainty surrounding which patient populations would benefit most from screening. The UCLA screening program follows all patients with prior histories of lung cancer, a group excluded from the NLST. Meanwhile, both UCLA and MD Anderson have expanded eligibility criteria with regard to the number of smoking years and the age of participants.

Aberle welcomes questioning of the NLST eligibility specifications. "The NLST answered a specific question: Can CT screening reduce lung cancer mortality relative to chest x-ray? There are a host of other questions we still must answer, such as whether those with a history of significant lung disease, family history of lung cancer or other risk factor should be screened; the frequency and duration of screening; and how better to define a positive screen," she explains.

Her hope is that as screening expands, and additional trials inform the field, varied experiences and careful observations will help to answer these questions.

The heads of screening programs are waiting anxiously for cost-effectiveness analsyis results, which are expected in early 2012.

According to Aberle, an essential criterion for payors to pick up screening is to reach a cost-effectiveness of below $50,000 per quality-adjusted life-year (QALY) saved. "Our crude back-of-the-napkin calculations average around $50,000 per QALY for lung screening, which puts us in that range."

With cost-containment permeating all levels of healthcare, physicians' optimism that Medicare and other payors will cover lung screening is couched in terms of years, not months. Yet, as studies from clinical trials and a growing number of  screening programs come to press, the controversy surrounding lung screening is moving from if toward who and how much.

Snapshot: The NLST Results
  • Participants: 53,454 men and women.
  • Eligibility: 55 to 74 years of age; at least 30 years of smoking a pack of cigarettes per day.
  • Procedure: Random assignment of 26,722 participants to low-dose (1.5 mSv) chest CT and 26,732 to x-ray. Initial exams followed by two annual screenings.
  • Cancer Incidence: 1,060 cancers in the CT group, 941 in x-ray.
  • Cancer-Specific Mortality: 356 patients in the CT group died from lung cancer, 443 in the x-ray group.     
  • False-Positive Rate: 24 percent of all CT screenings were positive, compared with 7 percent of x-ray exams. Overall, 96 percent of positive screenings in the CT group and 95 percent in the x-ray group were not cancer.
  • Conclusion: Lung cancer screening with CT yields a 20 percent mortality reduction compared with conventional x-ray among current and former heavy smokers.
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