Dutch lung cancer prevention trial shows no benefit of CT screening

The 5-year results of the Danish Lung Cancer Screening Trial (DLCST) were reported in the April 2012 Thorax, and they show no mortality benefit from annual screening for lung cancer with chest CT. Rather, it appeared that more harmless early stage cancers were identified through screening -- "overdiagnosis" of cancers that would never have advanced or been lethal. The results are in discordance with the U.S. National Lung Screening Trial (NLST), which showed a ~20% reduction in mortality with CT screening, although overdiagnosis is also likely to have occurred in the NLST.

What They Did

Investigators randomized 4,104 healthy former or current heavy smokers (20+ pack-years) aged 50-70 to 5 annual chest CTs or no screening. Participants had no cancer diagnosis, could climb 2 flights of stairs, were < 130 kg, and had FEV1 > 30% predicted. In the screening group, CT results were evaluated as follows:

• Nodules < 5 mm were not acted upon (i.e.,  CT screen was repeated in one year.

• Nodules >5 mm were re-scanned every 3 months.

• Nodules > 15 mm, and growing nodules (using volumetric imaging techniques) were referred for further evaluation according to a protocol that favored invasive sampling.

• Patients were followed for 5 years with scans at least annually (more often if nodules were seen), the last patient's data completed in March 2010.

Patients in the control group were diagnosed and treated largely at the same centers, but without screening CT (i.e., for incidentally discovered or symptomatic lung cancers).

What They Found: Increased Early Detection...

• 69 lung cancers were identified in the screening group, vs. 24 in the control group.

• The screening group had many more early stage (I-IIB) theoretically curable lung cancers: 48 of 69 (70%), with 30% advanced stage (IIIA+).

• The control group had only 8 early stage lung cancers discovered (33%), and 16 (67%) higher stage lung cancers.

 ... But no Mortality Benefit

At the end of follow-up, 103 of 4,104 participants had died (~2.5%). Screening did not reduce mortality from all causes or from lung cancer (if anything, it may have worsened outcomes):

• 61 died in the screening group from all causes (2.97%); 42 died in the control group (2.05%), with a strong trend toward increased mortality in the screening group (p=0.059).

• In the screening group, 15 people died of lung cancer (0.73%) vs. 11 in the control group (0.54%), no statistical difference (p=0.49).

The results suggest screening led to earlier detection of lung cancers that were not destined to progress or be lethal; i.e., "stage shift" or overdiagnosis.

Authors plan to report later the number and type of invasive procedures and their outcomes; such analysis will add to an understanding of any adverse effects of screening, or why earlier detection of low-stage "curable" cancers did not lead to improved survival from lung cancer.

 The "biggest" difference between the Dutch DLCST and the U.S. NSLT is of course size: the U.S. lung cancer screening trial enrolled 50,000 people, compared to 4,000 for the DLCST. A ten-times larger sample size would conceivably have changed the DLCST's findings. Other differences were surely present between trials in the protocols for managing large or growing pulmonary nodules. The investigators plan to pool their data with other European lung cancer screening trials (e.g., the Dutch-Belgian NELSON trial) to strengthen their statistical power and conclusions. Saghir Z et al. CT screening for lung cancer brings forward early disease. The randomised Danish Lung Cancer Screening Trial: status after five annual screening rounds with low-dose CT. Thorax 2012;67:296-301.