NEWS

Larger Debate Underlies Spiral CT Screening for Lung Cancer

Laura Newman

Disagreement over spiral computed tomography’s place in lung cancer screening continues. Nine months after results from the Early Lung Cancer Action Project were published, some proponents say that the technology could be the single most important advance in decades, with some claiming that it could ratchet up lung cancer survival to 80%. Others say that the exact benefits and risks have yet to be determined and are asking for better proof. The argument appears to reflect a much larger divide over what evidence is required and how it should be obtained before an emerging early cancer detection technology is broadly adopted.

Claudia I. Henschke, M.D., Ph.D., principal investigator of the ELCAP study and division chief of chest imaging at Cornell University Medical Center in New York, considers spiral CT a breakthrough in lung cancer screening. But as positive as her study’s data look, many critics are calling for more data and a different study design to answer what they see as important unresolved questions about the test’s specificity, sensitivity, false negative rate, false positive rate, positive predictive value, as well as whether it can decrease lung cancer mortality.



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Dr. Claudia I. Henschke

 
Christine D. Berg, M.D., chief of the National Cancer Institute’s Lung and Upper Aerodigestive Cancer Research Group, said that although she thinks spiral CT represents one of the most exciting new imaging techniques, "this really needs to be studied and done very well if the technology is to be translated into an effective screening strategy" that protects the public’s health, while targeting the strategy to individuals most likely to benefit.

Small Cancers

In Henschke’s baseline prevalence study of individuals at elevated risk for developing lung cancer (current or former smokers age 60 and above with a 10 or more pack-year history) reported in The Lancet on July 10, 1999, she and her colleagues showed that spiral CT could detect "substantially smaller, mainly early-stage [stage I] cancers," she said. More than half of the CT-detected tumors were 10 millimeters or smaller, and all but one CT-detected lung cancer was deemed resectable. In contrast, the study showed that chest x-rays tended to pick up larger, more advanced-stage, unresectable cancers.

Earlier detection raises the specter of overdiagnosis, Henschke acknowledged. To guard against it, she said investigators studied not only growth but also the doubling times of tumors with high-resolution CT. Henschke is convinced that if surgery had not been performed in patients with CT-detected lesions and biopsy-confirmed malignancies, patients would become symptomatic and die from their disease. Armed with spiral CT as a screening tool, "our estimate is that there will be a dramatic difference in lung cancer mortality within the next 5 to 10 years," said Henschke. "We can’t afford to wait 15 years for further studies."

For Henschke and others close to the developing technology, it is unthinkable to consider performing a randomized controlled trial. "If you really believe that spiral CT inverts the usual pyramid and picks up mainly early-stage cancers, how could you possibly enroll patients into a randomized trial?" she said. "How would you write the informed consent?"

She favors expanding the ELCAP study design—evaluating the use of spiral CT by a single-arm study with an active intervention and surveillance component. "It is the best way to get a time-relevant answer to patients," Henschke said. Besides using data from Cornell and McGill University in Montreal, she invites others to pool their data with hers.

However, some question whether this is the most objective viewpoint. "Every great innovation has a proud parent, which is certainly something we want," said Simon Whitney, M.D., J.D., an ethicist in the Department of Family Medicine at Baylor College of Medicine in Houston. "Although this preliminary data suggests that spiral CT could prove to be a very important tool for the early detection of lung cancer, there is not yet enough data to show who it will help, how it will help, or if it will cause harm."



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Dr. Simon Whitney

 
"She is looking to a future when deaths from lung cancer are dramatically different," he added. "I am looking to the past—either its proven effectiveness and ability to tell us up front which cancers to worry about—or remembering that some techniques that were once innovative are now standard care, while others have been shown to be ineffective and have been dropped."

Big Expectations

Anthony Miller, M.D., has other concerns. He worries that "there are big expectations being created with this technology." Miller, professor emeritus in the Department of Public Health Sciences at the University of Toronto and head of clinical epidemiology at the German Cancer Research Center in Heidelberg, said that recommending spiral CT now presumes that the cancers found have not spread and that local therapy, thoracotomy, and lobectomy work.



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Dr. Anthony Miller

 
"If the lung cancer is curable by local therapy, that is one thing—but in fact, if the lung cancer has already metastasized, that is another," Miller said. "These are really big ‘ifs’ and we should seize every opportunity to make people informed about them."

Miller said that there are other important drawbacks to the technology. In detecting central lesions, particularly small cell lung cancers and squamous cell cancers, CT detection falls down. "CT can pick up these lesions, but not early—more likely at the level of advanced local spread, or metastases," he said. He added that CT is probably no better than chest x-rays in discovering these lesions, so with these types of cancers, "CT will offer no mortality reduction."

What CT is very good at is "in picking up peripheral adenocarcinomas at an early stage and this could lead to a mortality reduction due to them," Miller pointed out. However, there is one important caveat: adenocarcinomas comprise less than 50% of lung cancers—and patients with adenocarcinomas tend to have better survival than the rest, he added.

Study Design Concerns

William C. Black, M.D., associate professor of radiology and community and family medicine at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., has other reservations about going full-steam ahead based on Henschke’s results. He worries that there is "sparse" evidence on the natural history of CT screen-detected lung cancer.

"We don’t know much about doubling times," he pointed out. "We are not sure how accurate they are. Black also said that the issue "gets a bit fuzzy because people have different thresholds for what they call a nodule. Because they are difficult to characterize, people may not be thinking about the same thing."

Miller also takes issue with the ELCAP case series study design. "Screening trials do not commence with cases, but with those at risk for cancer detection." Proceeding without a randomized controlled trial "not only risks selection bias, but lead time bias, length bias, and overdiagnosis bias," Miller said. "These biases can only be overcome if the comparison groups are assembled after randomization to eliminate selection bias, and by using disease-specific mortality to eliminate lead time bias, length bias, and overdiagnosis bias."

Yet some clinicians say that advocating a cautious approach and calling for randomized controlled trials comes with a price. "Within my own profession and with the public, asking for a randomized controlled trial comes across as anti-intellectual and anti-patient," said Peter Bates, M.D., chief of medicine and pulmonologist at Maine Medical Center in Portland. "Consequently, it becomes very attractive to fast-track the technology using a noncontrolled study design."

Pushing the technology out too fast has hazards, he said. "It could give the public false reassurance and people will go on smoking. I’d hate to see more money go into screening for lung cancer than into prevention."

Getting Answers

Reconciling these disparate points of view could prove formidable, but this is precisely the condition under which a clinical trial should be performed, said Whitney. "When opinions are deeply polarized between the proponents and the naysayers, this is the time to invest some time and money to see whether this works," he said. Indeed, not to do it when you could—and to treat people before you have the data—Whitney considers unethical.

Black pointed out other cautions. There is only a narrow window of opportunity before people are convinced that the technology works, he observed. Later, it will be hard to get a good control group, and people may challenge the ethics of randomization, he pointed out. Indeed, the National Cancer Institute recently conducted consumer research to get an idea of smokers’ and ex-smokers’ perceptions of benefits, risks, and barriers to participating in a clinical trial of spiral CT scanning (see sidebar, p. 593).

If a prospective randomized controlled trial goes ahead soon, observed Black, "this controversy could offer an excellent opportunity to clear up misconceptions about how to evaluate early detection and screening."

And Whitney sees other benefits in moving ahead with a prospective randomized controlled trial. "You have to balance how much time it would take to do a randomized controlled trial versus living with decades of uncertainty and continuous disagreement," said Whitney. "Without a trial," he predicted, "there will be endless wrangling over who should be screened and who should pay for it. It will take a long time—much longer than it would take to conduct a trial."


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