Low-Dose Computed Tomography Screening: Experiences from the Randomized Population-Based Nelson Screening Trial

NELSON TRIAL DESIGN
The Dutch–Belgian lung cancer screening trial (NELSON)
investigates whether 16-detector, low-dose, multislice computed
tomography (MSCT) screening in year 1, 2, and 4 will
decrease lung cancer mortality compared to a control group
without screening. Secondary end points of the study are
to estimate the cost-effectiveness of this screening program
and to assess the impact on quality of life. The design of the
NELSON trial is shown in Figure 17.1. NELSON is the only
large-scale, randomized, controlled, population-based lung
cancer CT-screening trial in Europe, with 15,523 participants.
Recruitment started in the second half of 2003, and the first
CT screenings were made in April 2004. As of October 2007,
the baseline-screening round has been completed, the second
round is near its completion, and the third round has recently
been started. The screening part of the trial will be finished by
the end of 2009, but the follow-up period will continue until
the end of 2015. During the first round, lung function tests
have been performed, and biosamples (blood, plasma, serum,
and sputum cytology) have been taken. The blood sampling
and lung function test are repeated during the last screening
round.
Recruitment During the first recruitment phase (second
half of 2003), addresses of all men born between January 1, 1928
and January 1, 1953 were obtained from the population registries
in seven districts in the Netherlands (Groningen, Drenthe,
Utrecht, Eemland, Midden-Nederland, Kennemerland, and
Amstelland-de Meerlanden) (Fig. 17.1). In addition, addresses
of all men and women of the same age were obtained from
the population registries of 14 municipalities around Leuven
in Belgium. They received a first questionnaire about general
health, alcohol consumption, physical exercise, cancer history,
family history of lung cancer, body weight and length,
education, and their opinion on screening programs in general.
The questionnaire contained 11 questions on smo king from
the Minimum Common Dataset (May 2002) of the EU–U.S.
Collaborative Spiral CT-working group, adapted from the
National Cancer Institutes Cancer Data Standards Registry,
the recommended smoking measures of the Behavior Change
Consortium of the U.S. National Institutes of Health, and from
Pistelli et al. 1–3 The most important questions were: “When you
last smoked every day, on average, how many cigarettes (shag)
do/did you smoke a day?” ( 5, 5 to 10, 11 to 15, 16 to 20, 21
to 25, 26 to 30, 31 to 40, 41 to 50, 51 to 60, 60); “What is
the total number of years you have smoked/smoke cigarettes or
shag every day? Do not include any time you stayed off cigarettes
or shag for 6 months or longer.” (0 to 5, 6 to 10, 11 to 15,
16 to 20, 21 to 25, 26 to 30, 31 to 35, 36 to 40, 41 to 45, 46 to
50, 50 years) and; “If you have quit smoking, how long has it
been since you quit?” ( 1 month, 1 to 6 months, 7 months to
1 year, 1 to 3 years, 3 to 5 years, 6 to 10 years, 11 to 15 years,
16 to 20 years, 20 years, not applicable). The questionnaire
was accompanied by brief information about the trial.
During this first recruitment phase, 106,931 of the 335,441
subjects (32%) who received the first NELSON questionnaire
responded. Mean age of the respondents was 61 (standard deviation:
6.8 years). Response rates were lower in Belgium where
we approached more women than in the Netherlands, but were
overall equally distributed over the age categories (Table 17.1).
Table 17.2 shows the number of respondents for each level of
smoking duration, the number of cigarettes smoked per day,
and the duration of smoking cessation. Nearly one third of the
106,931 respondents (33,909 [32%]) never smoked, 26,733
(25%) has been smoking for less than 20 years, and 24,783
(23%) quit smoking for more than 20 years.
Selection of Potential Participants In the Netherlands,
at present, 23% of women smoke compared to 32%
of men. 4 In the past, this difference was greater when even
fewer women and more men smoked. Therefore, fewer
women in the Dutch population have accrued a long-term
exposure to cigarettes compared to men. Because of the lower
fraction of high-risk subjects among women, we anticipated
before start of the trial that recruiting an equal number of
high-risk women and men would require an enormous effort.
Therefore, the Dutch Health Council and the Ministry
of Health agreed to invite first men and only in the second
phase also women. In that way, we would still be able to
demonstrate possible differences in lung cancer detection
between men and women, and at the same time limit our
recruitment efforts.
Because the smoking exposure history of all respondents
on the first NELSON questionnaire was available, a careful
decision could be made on whom to invite for the trial. First,
the estimated lung cancer mortality risk of the respondents was
determined. Next, the required sample size to show a mortality
benefit of screening of 20%, 25%, and 30%, and the
corresponding number of eligible subjects was determined for
various selection scenarios, and finally, the required participation
rate was determined, defined as the required response of
eligible subjects to reach the required sample size. In the optimal
selection scenario, the required participation rate was
as low as possible, and the required sample size was within
the ranges of our capacity in the Netherlands and Belgium
( 16,000 participants).
Our estimates of lung cancer mortality were based on
the U.S. Cancer Prevention Study II (CPS II), a cohort study
that started in 1982 and followed 508,579 men and 676,527
women, aged 30 years or older for 6 years. 5 The CPS II reports
lung cancer mortality rates per 100,000 person-years
(PY) for groups of men with attained ages 50 to 79 (50 to
59, 60 to 69, and 70 to 79 years), smoking duration of 20
years or more (20 to 29, 30 to 39, 40 to 49, and 50 years),
and one or more cigarettes smoked per day (1 to 19, 20, 21
to 39, 40, and 41 cigarettes per day). Because the CPS II
monograph included only data on current smokers, the U.S.
Cancer Prevention Study I (CPS I) was used to estimate the
effect of smoking cessation. This prospective cohort study
started following up 456,491 men and 594,551 women older
than 30 years on July 1, 1960. Follow-up was a maximum of
12 years. 6 By varying the thresholds for duration of smoking,
the duration of smoking cessation, and the number of
cigarettes smoked per day, the mean-estimated expected lung
cancer mortality rate (per 1000 PY) for various selection scenarios
was determined. Based on the most optimal selection
scenario, current and former smokers with 10 years or less
of cessation, who smoked more than 15 cigarettes a day for
more than 25 years or 10 cigarettes a day for more than 30
years, were selected. 7 Persons with a moderate or bad selfreported
health who were unable to climb two flights of stairs
and persons with a body weight greater than or equal to 140
kg were excluded from participation. Lung cancer patients
diagnosed less than 5 years ago, subjects symptomatic for
lung cancer, and persons who had a chest-CT examination
less than 1 year before they filled in the first NELSON questionnaire
were excluded as well.
Power and Required Sample Size The required
sam ple sizes to demonstrate a lung cancer mortality reduction
of 20%, 25%, or 30% were calculated for the various
selection scenarios. A 1:1 randomization, a power of 80%,
a one-sided -significance level of 0.05, 95% compliance
in the screen group, 5% contamination rate in the control
group, and 10 years of follow-up after randomization were
assumed. 8 With a power of 80%, enrolment of 17,300
subjects in NELSON is required to demonstrate a lung
cancer mortality reduction of 25% or more and 27,900
subjects to demonstrate a lung cancer mortality reduction
of 20% or more 10 years of follow-up. In Denmark,
4100 men and women, current and former smokers (quit
10 years), aged 50 to 70, with at least 20 pack-years of
smoking have been recruited through the public media. It
is planned to pool mortality data with the Danish trial,
so that the total number of participants in the NELSON
trial will be more than 20,000. NELSON will then be the
only trial without screening in controls that is expected to
have an 80% power to show a lung cancer mortality reduction
of at least 25% 10 years after randomization. When
pooling with the Danish trial data, the fraction of women,
which comprises 45% of all Danish trial participants, will
also increase.
Our population-based recruitment gave insight in the
risk profiles of the general population and we estimated that
about 15% to 25% of the general (Dutch) population, age
50 to 75 would be the target for routine screening if our eligibility
criteria would be applied. We, therefore, believe that
our results are generalizable to a sufficiently large part of our
population. Another advantage of a population-based recruitment
approach is that it is less likely that potential participants
exaggerated their smoking history to increase their chance to
be invited for the trial, because they were unaware of the selection
criteria.