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Prolonged Lung Cancer Screening Boosts Mortality Benefit

Roxanne Nelson, RN, BSN
April 18, 2019

Extending lung cancer screening in individuals beyond 5 years can significantly impact the survival benefits associated with early disease detection, reports a new study.

The 10-year results of The Multicentric Italian Lung Detection (MILD) study showed a significant 39% reduction in the relative risk of lung cancer mortality among patients who underwent low-dose computed tomography (LDCT).

In addition, there was also a 20% risk reduction in overall mortality.

"The study demonstrates the significance of lung cancer screening in defined high-risk groups," commented Fred Hirsch, MD, PhD, executive director at the Center for Thoracic Oncology in the Tisch Cancer Institute at Mount Sinai, New York City. "That is the main message here."

Hirsch, who was not involved in the study and was asked to comment, noted that the study adds to previous data and addresses the question of how long screening should continue. "The MILD study did not show any significant difference in mortality after 5 years. But after 10 years, there was a difference in lung cancer and overall mortality," he said in an interview. "That is an important message and needs to be discussed."

The results were published online April 1 in the Annals of Oncology.

The landmark National Lung Screening Trial (NLST), which published its principal findings in 2010, is the largest randomized study of lung cancer screening in a high-risk population to date, and reported that LDCT reduces mortality from lung cancer. At a median follow up of 6.5 years, the 53,000-person trial found a 20% reduction in deaths from lung cancer among current and former heavy smokers screened with LDCT as compared with chest x-ray screening.

More recently, a second large trial has also shown that a population-based lung cancer screening program can significantly lower the mortality risk for high-risk former and current smokers. New data from the NELSON study, conducted in the Netherlands and Belgium and presented last fall at the 19th World Conference on Lung Cancer (WCLC), showed an even greater reduction in deaths from lung cancer than was seen in the NLST.

Comprised of about 16,000 participants, NELSON demonstrated that LDCT screening reduced lung cancer deaths by 26% in men and up to 61% in women, compared with the control group at a follow-up of 10 years.

However, the authors of the MILD study note that several small European randomized clinical trials testing LDCT vs observation showed no benefit at the 5-year mark, which may have been partly because of the small number of patients and a short follow-up period. Their own 5-year results showed no evidence of a protective effect of annual or biennial LDCT screening (Eur J Cancer Prev. 2012;21:308-15).

The European studies collectively have also tended to enroll younger patients with a lower lung cancer risk than the NLST and have heterogenous selection criteria. Also, most offered annual LDCT screening rounds for 4 years or less, where the impact of screening duration and intensity is not evaluable.

"In principle, as individual lung cancer risk increases constantly with age, there is no reason to stop LDCT screening after 3 to 5 years," said MILD lead author Ugo Pastorino, MD, Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy. "Prolonged screening can enhance the benefit, if the quality of intervention is adequate."

He noted that a "proper comparison with NELSON requires a full report of their results, and that is still awaited."

Enhanced Results at 10 Years

Pastorino and colleagues designed the MILD study to investigate the efficacy of prolonged LDCT screening beyond 4 years. While the early results showed no mortality reduction in the LDCT group at 5 years, and similar results of annual vs biennial LDCT in terms of detection rates and interval cancers at 7 years, they now reported on the 10-year results.

The study included 4099 participants between the ages of 49 and 75 years, all of whom were current smokers or had quit smoking within the past 10 years, and had at least 20 pack-years.

The cohort was randomly assigned to undergo LDCT lung screening (n = 2376) or no intervention (n = 1723), and the screening group was further randomized to LDCT every 12 months (n = 1190) or 24 months (n= 1186).

The main endpoint was lung cancer mortality at 10 years and secondary endpoints were overall mortality and lung cancer diagnosis.

In the screening group, lung cancer was diagnosed in 98 participants (431/100,000 person-years) and in 60 participants (373/100,000 person-years) in the control group. The 10-year cumulative lung cancer incidence curves showed a nonsignificant difference between intervention and control group (P = .84).

To identify one case of lung cancer, the authors calculated that 154 LDCT scans and 1.4 positron emission tomography (PET) scans, used selectively for differential diagnosis, were required.

Lung cancer specific mortality was 173/100,000 person-years (40 deaths) in the screening group and 247/100,000 person-years among controls (40 deaths, P = .12), and lung cancer comprised 33% of all deaths in the cohort (29% in intervention and 38% in control group). One lung cancer death was preventable by 167 screened individuals, 733 LDCTs and 4.4 PETs.

The cumulative risk of 10-year overall mortality was 5.8% in the intervention group and 6.5% in the control group, and that extrapolated to a 20% relative risk reduction by LDCT (hazard ratio [HR], 0.80, log-rank P = .07). The cumulative risk of 10-year lung cancer mortality was 1.7% vs 2.5%, with a significant 39% relative risk reduction by LDCT screening (HR, 0.61; P = .02).

Pastorino and his colleagues note that the "landmark" analysis beyond 5 years showed a 3.4% cumulative risk of overall mortality in the intervention group and 4.5% among controls, with a significant 32% relative risk reduction by LDCT (HR, 0.68; P = .01). The difference was greater for lung cancer mortality, with a cumulative risk of 0.7% vs. 1.5% that corresponded to a 58% relative risk reduction by LDCT (HR, 0.42; P = .0037).

These results were confirmed in a sensitivity analysis comprised of 3446 individuals, which showed a significant 49% reduction in lung cancer mortality with screening beyond 5 years, even though the statistical power was lower.

Screening Rate Needs a Boost

Hirsch pointed out that there are differences between the MILD study and the two other large studies, one being its smaller size and slightly younger population. But overall, that doesn't take away from the importance of these findings, he reiterated, in that long-term lung cancer screening can reduce mortality.

However, a larger problem is the lack of penetration that lung cancer screening has made into mainstream healthcare. "Lung cancer screening needs to be formally implemented in the US," said Hirsch, "And this is long overdue. Only about 2%-3% of the eligible population is undergoing screening and that is concerning, especially with all of these new results showing the benefit of screening."

"The goal is clearly to significantly increase participation in lung cancer screening efforts," he added.

But lung cancer screening may present more barriers to the patient than other types of cancer screening, such as fewer facilities that offer the service or issues with health insurance coverage. Pastorino explained that the "problem of limited resources can be approached by targeting LDCT intervals/repeats on the basis of individual level of risk," and that was the focus of another study.

"This was the principle of [the] BioMILD trial that we have conducted from 2013 to 2019," he said. "BioMILD results will be reported in the next summer."

The MILD trial was supported by grants from the Italian Ministry of Health, the Italian Association for Cancer Research, Fondazione Cariplo, and the National Cancer Institute. The authors have disclosed no relevant financial relationships.

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Reviewed on 4/19/2019

SOURCE: Medscape, April 18, 2019. Annals of Oncology. Published online April 1, 2019.

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