CT Screening Evolves Amid Questions and Controversy

Denise R. Aberle, MD

Nearly 2 years after a landmark study supported computed tomography (CT) screening for people at high risk of developing lung cancer, questions persist about the complexities of implementing an early detection program and potentially conflicting results from European clinical trials now under way.

Denise R. Aberle, MD, who led the National Lung Screening Trial (NLST), remains convinced of the importance and validity of adding CT testing to the menu of preventive cancer screenings, yet notes that significant challenges loom in building a broad public health initiative.

“I think we’re looking at the beginning of a moderately long and evolving implementation for lung cancer screening,” Aberle said during an interview at the 13th International Lung Cancer Congress in Huntington Beach, California. “And I think it would probably be naïve of us to assume that this could happen easily over the course of a couple of years.”

In fact, Aberle believes that academic medical centers working through referrals from primary care physicians and pulmonology specialists will be best equipped to conduct screening programs.

Aberle, a professor of Radiology and Bioengineering at the David Geffen School of Medicine at the University of California, Los Angeles, discussed major issues facing CT screening during a presentation at the congress. Her key points included:

• There is a need to reduce the rate of falsepositives in CT screening and the emphasis should be on better identifying individuals who should undergo testing. Strategies would include developing risk prediction models that include biomarkers, considering other health indicators such as cardiopulmonary disease, and integrating other imaging analyses into a diagnosis.
• Screening programs should be designed that cut across disciplines, standardize radiology protocols, educate primary care physicians and pulmonologists, and integrate risk assessment into smoking cessation and chemoprevention therapies.
• Clinical trial results from Europe Union (EU) nations are raising questions about CT screening programs. Initial results from approximately seven or eight randomized clinical trials conducted in Europe have not shown a mortality benefit or trend toward reducing the numbers of advanced lung cancers.

Conflicting European Trial Results Puzzling

While the challenges of setting up screening programs may be considerable, Aberle acknowledged conflicting trial results from Europe are concerning.

“You can imagine this is relatively disconcerting to those of us who did the National Lung Screening Trial, and I think we’re all, including in the United States and European Union, trying to figure out why that may be,” Aberle said.

Small sample sizes (typically <6000 participants), different risk factors among cohorts, and participant selection issues are among the factors that may account for the disparity in findings, said Aberle.

Another factor may be the experience level of surgeons removing lesions found through screenings. “In the NLST, the majority of the surgeons performing resections are dedicated lung cancer surgeons,” Aberle noted. “That is not necessarily the case in the EU trials, and this might also account for some of the differences in mortality.”

Aberle noted that findings from a larger cohort, the NELSON trial in the Netherlands involving approximately 20,000 participants, are expected in 2014 or later. Results from that trial and meta-analysis of aggregated data from the smaller trials might shed light on the outcomes.

“There is one other explanation and that is that screening doesn’t work, but I’m not ready to concede that because we’ve clearly shown a significant efficacy with both lung cancer—specific mortality and all-cause mortality in the NLST,” Aberle said.

NLST Findings Show Clear Benefits

The NLST involved 53,454 people randomized to receive three annual screenings with either low-dose helical CT or single-view chest x-ray (N Engl J Med. 2011;365:395-409.) The participants, aged 55-74 years, had a cigarette-smoking history of ≥30 packyears and, if former heavy smokers, had quit within the prior 15 years.

The trial, which took place from August 2002 through September 2007, was conducted at two sets of centers consisting of one network for screening and another for imaging. The median follow-up period was 6.5 years.

In all, the screening effort resulted in the diagnosis of 1060 lung cancers among participants in the CT group, compared with 941 in the x-ray group. There were fewer deaths attributable to lung cancer and to all-cause mortality among those who were screened with CT versus x-ray.

When analyzed in terms of deaths per 100,000 person years, the NLST found that there was a 20% relative decrease in lung cancer—specific mortality in the CT arm, and a 6.7% decrease in all-cause mortality.

“The major observations are the fact that there was a more than two-fold increase in the numbers of early-stage lung cancers that were observed with low-dose helical CT,” said Aberle. “Most of these were actually screen-detected.”

“We did realize a decrease in the absolute numbers of late-stage lung cancers, which tells us that we did see a stage shift with the screening,” she added.

At the same time, there was a high rate of falsepositives with both screening methods. A positive screen for the CT group was defined as evidence of a nodule ≥4 mm or some other abnormality; for the x-ray group, it was any abnormality that might be attributable to lung cancer, Aberle said.

Of the total number of screening tests in the three rounds, 24.2% of the CT tests and 6.9% of the chest xrays were positive and led to a diagnostic evaluation. After evaluation, the rates of false-positives for the CT group were 96.4% versus 94.5% for the x-ray group.

Aberle said positive findings were followed first with further imaging, particularly diagnostic chest CTs, and later with noninvasive or invasive surgery. Although the rate of false-positives was high, Aberle said, “Overall complications were low and are extremely low even in patients with false-positive screens.”

Establishing Guidelines and Protocols

Since the initial findings of the NLST were released in November 2010, the question of whether CT screening programs should be established for highrisk populations has been much discussed.

In May, representatives of several medical societies collaborating on a review of CT screening concluded that high-risk individuals may benefit, “but uncertainty exists about the potential harms of screening and the generalizability of results” (JAMA. 2012;307[22]:2418-2429).

Meanwhile, sentiment for screening programs is taking root in the oncology community. More than 75 medical centers throughout the nation have announced plans to screen high-risk individuals, according to the Lung Cancer Alliance, an advocacy group.

At least four medical associations have embraced CT screening for high-risk populations, while two other organizations have issued interim recommendations while guidelines are studied (Table). The US Preventive Services Task Force (USPSTF) is considering an update to its 2004 guidelines, which recommended against screening programs.

Table. Lung Cancer Screening Guidelines for High-Risk Patients

Medical Organization

Age

Smoking History

Recommendation

Grade

American Society of Clinical Oncology

American College of Chest Physicians

American Thoracic Society^a

55-74

≥30 pack-year history, current and former smokers who have quit in past 15 y

Annual LDCT screening in settings similar to NLST

Category 2B

<55 or

>74

<30 pack-year history, former smokers who quit <15 y, severe comorbidities

LDCT should not be performed

Category 2C

National Comprehensive Cancer Network^b

55-74

≥30 pack-year history, current and former smokers who have quit <15 y

Baseline LDCT

Annual LDCT screenings for 2 y, depending upon findings at baseline

Category 1

≥50

≥20 pack-year history with one additional risk factor such as radon exposure, occupational exposure, cancer history, history of COPD or pulmonary fibrosis

Baseline LDCT

Annual LDCT screenings for 2 y, depending upon findings at baseline

Category 2B

American Lung Association (Interim)^c

55-74

≥30 pack-year history, current and former smokers

No history of lung cancer

Universal lung screening not recommended

Smoking cessation should be emphasized as best form of risk reduction

Hospitals and screening centers should provide multidisciplinary teams to evaluate/follow-up on nodules

Screening facilities should develop ethical guidelines for advertising LDCT

N/A

American Cancer Society (Interim)^d

55-74

≥30 pack-year history, current and former smokers who have quit in past 15 y

Individuals and physicians may consider LDCT screening Adults who choose screening should enter organized program that follows NLST criteria

N/A

LDCT indicates low-dose computed tomography; NLST, National Lung Screening Trial.

A pack-year is the equivalent of 1 pack of cigarettes per day per year, according to the American Cancer Society.

^a Bach PB, Mirkin JN, Oliver TK, et al. Benefits and harms of CT screening for lung cancer: a systematic review (published online ahead of print May 20, 2012). JAMA. 2012;307(22):2418-2429. doi:10.1001/jama.2012.5521.

^b NCCN Clinical Practice Guidelines in Oncology. Lung cancer screening version 1.2013. National Comprehensive Cancer Network website. http://www.nccn.org/ professionals/physician_gls/f_guidelines.asp. Published June 15, 2012. Accessed September 7, 2012.

^c Lung Cancer Screening Committee. Providing guidance on lung cancer screening to patients and physicians. American Lung Association website. http://www.lung.org/lungdisease/lung-cancer/. Published April 23, 2012. Accessed September 7, 2012.

^d Lung Cancer Guidance Workshop. American Cancer Society interim guidance on lung cancer screening. American Cancer Society website. http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-030879.pdf. Published February 17, 2012. Accessed September 7, 2012.

Aberle said the findings of the USPSTF and the Centers for Medicare and Medicaid Services would be important steps for implementation, particularly in terms of insurance coverage. She said the NLST investigators are analyzing the data in terms of the cost of screenings per quality-adjusted life-year.

In order to launch screening programs, Aberle sees many necessary steps. “There will be a number of challenges at the levels of the screening centers, which will be required to standardize their acquisition parameters so that we truly maintain low dose. We’ll be required to standardize the way we interpret these images, the way we communicate the results, and to whom we communicate the results. And most importantly, to make sure that these patients who have positive screens are properly followed,” said Aberle.

Interdisciplinary cooperation also is vital to successful screening programs, Aberle said. “I think, at this point, the academic centers, at which there are subspecialty groups that are already working together with lung cancer programs that have the equipment and also have the physicians who are capable of ensuring standardization and quality, should be undertaking this,” she said.

Aberle believes it will take time for the primary care physicians, and perhaps pulmonologists who would refer patients for CT screenings, to digest the implications of the NLST findings and subsequent recommendations.

In some ways, she sees these challenges as growing pains of a new screening program.

“It’s important to understand that breast cancer and mammography screening, in particular, was probably around for at least 40 or 50 years before it finally became regulated and had federal guidelines that we have to follow in order to screen and manage these patients,” said Aberle. “I frankly anticipate that that will ultimately be a requirement for CT screening in order to maintain quality and to control costs.”

She is adamant about the need to start a similar journey to screen patients at high risk of lung cancer.

“In comparison to other cancers for which we have screening tests, the whole concept of the lung cancer patient is tainted by the perception that this is a preventable disease and that the lung cancer patient had this coming to them,” she said. “We all have that feeling—the primary care physicians, perhaps the medical oncologists, the patients themselves, and the patients’ families and friends. And, frankly, we need to get over that. Nobody deserves to die.”