Ajr 05 0088

Chest Imaging Original Research
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Mascalchi et al.
RiskBenefit Analysis of
Lung Cancer Screening
C E N T U
R Y
MEDICAL
O F
IMAGING
Mario Mascalchi1
Giacomo Belli2
Marco Zappa3
Giulia Picozzi1
Massimo Falchini1
Riccardo Della Nave1
Germana Allescia1
Andrea Masi4
Andrea Lopes Pegna5
Natale Villari1
Eugenio Paci3
Mascalchi M, Belli G, Zappa M, et al.
Keywords: cancer screening, CT, lung cancer, MDCT,

radiation exposure, single-detector CT
RiskBenefit Analysis of X-Ray

Exposure Associated with
Lung Cancer Screening in the
Italung-CT Trial
OBJECTIVE. Prior analyses of X-ray exposures in lung cancer screening with CT considered the basic acquisition technique in single-detector scanners and the effects of a lifetime
screening regimen, whereas the potential benefit in terms of lives saved was not addressed.
MATERIALS AND METHODS. We determined the total-body effective dose of different acquisition techniques for one single-detector and one MDCT scanner and made projections about the cumulative radiation exposure to smokers undergoing four annual CT examinations on the same scanners in the Italung-CT Trial. Combining these data with estimates of
radiation-induced fatal cancer and of the benefit of screening, we calculated the riskbenefit
ratio for participants in the trial, ex-smokers, and never-smokers.
RESULTS. The cumulative effective doses per 1,000 subjects were 3.3 Sv using an MDCT
scanner and 5.8 or 7.1 Sv using a single-detector scanner. Potential fatal cancers associated with
radiation exposure were 0.11 per 1,000 subjects for MDCT scanners and 0.20 or 0.24 for singledetector scanners, which is about 10100 times lower than the number of expected lives saved
by screening assuming a 2030% lung cancerspecific mortality reduction in current smokers.
They were, however, of similar magnitude to the lives saved by screening in never-smokers and
former smokers assuming a 10% efficacy of screening.
CONCLUSION. MDCT is associated with lower radiation doses than single-detector CT
technology. The risk of radiation dose in the Italung-CT Trial is compensated for by the expected benefit. CT screening for lung cancer should not be offered to never-smokers, whereas
its recommendation in former smokers is debatable.
DOI:10.2214/AJR.05.0088
Received January 18, 2005; accepted after revision
June 24, 2005.
The Italung-CT Trial is supported by the Health Department of
the Tuscany Region, Italy; and the Ministry of Instruction,
University and Scientific Research of Italy (grant 2003068017).
1Sezione di Radiodiagnostica, Dipartimento di Fisiopatologia
Clinica, Universit di Firenze, Viale Morgagni 85, 50134 Firenze,
Italia. Address correspondence to M. Mascalchi
(m.mascalchi@dfc.unifi.it).
2Fisica
Sanitaria, Azienda Ospedaliera Careggi, Firenze,
Italia.
3Centro di Studio e Prevenzione Oncologica, Firenze, Italia.
4U.O. Radiologia Diagnostica, Azienda Ospedaliera
Careggi, Firenze, Italia.

5U.O. Pneumologia, Azienda Ospedaliera Careggi, Firenze,
Italia.
AJR 2006; 187:421429
0361803X/06/1872421
American Roentgen Ray Society
AJR:187, August 2006
T is capable of revealing peripheral

lung tumors in the early stages [1,
2]. Observational studies [39] and
randomized trials [1013] involving thousands of individuals are in progress
worldwide to assess whether CT screening is
effective in reducing mortality due to lung cancer. In the available accounts of the dose exposure associated with lung cancer screening using CT, only the basic low-dose techniques
with single-detector helical scanners similar to
that originally used in the Early Lung Cancer
Action Project (ELCAP) study [1] were considered [14, 15], whereas the dose associated
with additional full-dose high-resolution acquisitions and repeated low-dose examinations
recommended in the same study [1, 16] for
characterization and follow-up of suspicious
noncalcified nodules was not addressed. As
well, only the dose associated with the basic
low-dose technique was used in the analyses of
the risk of radiation-induced lung cancer associated with CT screening [17, 18].
The advent of MDCT scanners and updates

to the protocol [15, 19] prompted us to investigate the cumulative dose currently delivered
to the screened population. For this purpose,
we calculated the radiation dose in a pilot
study and made projections of the radiation
exposure to smokers undergoing four annual
CT examinations in a randomized clinical
trial named Italung-CT [13], currently in
progress. Moreover, we performed a
riskbenefit analysis of radiation exposure associated with lung cancer screening for participants in the Italung-CT Trial and for exsmokers and never-smokers.
Materials and Methods
The Pilot Study
Between November 2000 and November 2003,
we performed a pilot observational study of 60
smokers that was approved by the local ethics committee; the results of that study are reported elsewhere [13]. Twenty-four subjects were examined on
a single-detector scanner (Somatom Plus, Siemens
421
Mascalchi et al.
Medical Solutions) with a 1-second rotation time
and 36 subjects, on an MDCT scanner (Somatom
Plus 4 VZ, Siemens) with a 0.5-second rotation time
and 4 rows of detectors. The study included one
baseline and two annual repeat low-dose CT examinations for a total of three screening rounds. In case
of suspicious nodules, additional follow-up CT examinations were performed according to the initial
ELCAP protocol [1]. The CT acquisition techniques
were those recommended in the same study [1].
Italung-CT Trial
The Italung-CT Trial is a multicenter randomized controlled study, which was approved by the
local ethics committees of the participating centers,
aiming to evaluate reduction of mortality from lung
cancer with CT screening [13]. It started in 2004
and will enroll 3,000 smokers 5070 years old who
will be randomized in an active arm (1,500 subjects) undergoing annual low-dose CT for 4 years
and a control arm (1,500 subjects) who will receive
usual care [13].
RiskBenefit Analysis
The riskbenefit analysis was performed by
two epidemiologists after approval of the local
ethics committee.
Experimental Dose Measurements

Dose measurements were obtained on the single-detector and MDCT scanners used in the pilot
study and in the Italung-CT Trial. The dose at the
isocenter of the scanners was measured using a
pencil ionization chamber (10 cm long) and a readout multimeter (NEROmAX, Victoreen), and the
air CT dose index (CTDI) was calculated. Several
CTDIs at different beam collimations were measured, and the doselength product (DLP) involved
in each acquisition technique was obtained. Finally,
the dose was computed based on the air CTDI measured at the isocenter of the scanner using the software, CT-Dose, which was developed by the Department of Biomedical Engineering, County of
Aarhus and the National Board of Health, Denmark
(www.mta.au.dk/dk/projekter/ctdose/index.htm).
This software provides Monte Carlo simulation
based on an anthropomorphic (Adam and Eve)
phantom. The effective (whole-body) dose, as defined by the International Commission on Radiological Protection (ICRP) 60 [20], and the lung
dose were determined. Three basic CT techniques
were assessed: first, low-dose at thick and thin collimations; second, full-dose at a thin collimation;
and, third, full-dose at a thick collimation. In addition, we estimated the dose of the preliminary scout
anteroposterior view with 120 kVp, 40 mAs, and 2mm beam collimation, which can be considered
computed projection radiography.
422
Dose Estimates
Dose in the pilot studyUsing the previously
described measurements of the dose associated
with the single-detector and MDCT acquisition
techniques, we retrospectively estimated the dose
radiation that was actually delivered to the 60 subjects participating in the pilot study.
Dose projections in the screened arm of the Italung-CT TrialThe dose projections in subjects undergoing screening for lung cancer in the active arm
of the Italung-CT Trial were computed by, first, considering the dose associated with the MDCT and single-detector scanners and protocols used in the Italung-CT Trial [13]; and, second, summing up the dose
to subjects with negative tests, the dose to subjects requiring additional follow-up CT examinations, and
the dose to subjects requiring intervention. The acquisition techniques for single-detector and MDCT
scanners in the Italung-CT Trial are essentially the
same as those recommended in the last available ELCAP protocol (icscreen.med.cornell.edu) with some
minor differences. In particular, the ELCAP protocol
recommends supplemental acquisition of a package
of thin-collimation slices at full dose centered on indeterminate nodules when these are found using lowdose, thick-collimation acquisition on a single-detector scanner. Actually, we observed that even low-dose
3-mm-collimation acquisitions obtained on a singledetector scanner with 1.5-step reconstructions provide images with sufficient spatial resolution, and we
adopted this technique for lung cancer screening with
a single-detector scanner. Nonetheless, for the singledetector scanner, we computed also the dose associated with the previously mentioned ELCAP recommendation. For that purpose, we considered the dose
associated with one 20-mm-thick package of thincollimation slices at full dose centered on a nodule 8
mm in diameter. Additional follow-up CT examinations are recommended in subjects with noncalcified
nodules at baseline screening test that are 5 mm or
more in mean diameter and new nodules at annual repeat test of 3 mm or more in diameter. The number
and the time schedule of such follow-up examinations vary according to the size and the intervening
size change of the nodule. We assumed one follow-up
examination at 3 months after the initial examination
for an indeterminate nodule at baseline and two follow-up examinations at 1, 3, or 6 months for an indeterminate nodule at annual repeat screening examinations.
The frequency of noncalcified nodules at baseline
and hence the proportions of subjects with a negative
screening test and of subjects requiring follow-up reflect the selection criteria of the screened population
and can vary as a function of several factors, including
race, age, smoking habits, incidence of granulomatous diseases, and so on [21]. In the CT series reported
to date, the frequency of noncalcified nodules at base-
line ranged from 5.1% in a Japanese study including

nonsmokers [2] to 51% in a Mayo Clinic study [6].
More importantly, this frequency is reduced up to
more than one half if a cutoff of 5 mm in mean diameter is used for the baseline screening examination [4,
6, 9, 13, 22]. The incidence of new nodules at annual
repeat examinations (all sizes) ranged from 5% in the
ELCAP study [3] to 13% in a Mayo Clinic study [6].
For computation of the dose projections in the active arm of the Italung-CT Trial, we used arbitrary values of 10% frequency of subjects showing indeterminate nodules requiring follow-up at baseline and
annual repeat screening rounds. Also, the percentage
of subjects enrolled in CT screening for lung cancer
requiring intervention varies [12, 21]. In the studies of
heavy smokers in Western countries, the percentage is
consistently below 3% at baseline and repeat screening rounds and is usually lower in the latter [1, 3, 8,
13]. We used an arbitrary value of 1% for the baseline
test and 0.5% for the annual repeat test. Before intervention, these subjects usually undergo examinations
with additional radiation exposure, including fulldose chest CT before and after IV contrast administration, CT-guided biopsy, and 18F-FDG PET. Although
the dose associated with those examinations differs
from center to center and from subject to subject, we
considered an average effective dose of 15 mSv for
subjects examined with MDCT and 20 mSv for subjects examined with single-detector CT, including 7
mSv for the chest PET examination [23]. Computation of the dose in this small fraction of subjects is justified by the fact that benign lesions are definitely
found in up to 25% of the subjects undergoing intervention in the context of CT lung cancer screening [8].
The Risk
The radiation-induced risk associated with the CT
screening procedure was assessed combining the experimental dose measurements, the theoretic dose
projections, and the estimates of the radiation-induced cancer deaths calculated from the English National Radiological Protection Board (NRPB) data
for different age groups [24]. In the same report, sex
differences were minor and were neglected here.
Estimate of the Benefit from CT

Screening for Lung Cancer
The estimate of the benefit from screening was
derived from the expected incidence of lung cancer
in the absence of screening and from the available
predictions of lung cancerspecific reduction of
mortality associated with CT screening [25, 26].
The following assumptions were made. First, we
considered a population of 100,000 subjects with one
third ranging in age from 55 to 59 years; one third,
6064 years; and one third, 6569 years. Second, we
performed separate analyses for men and women.
Third, we considered a screening program of 4 years
RiskBenefit Analysis of Lung Cancer Screening

with four rounds (one CT screening examination per
year), as in the Italung-CT Trial. Fourth, we assumed
that the benefit of early diagnosis was limited to all the
cancers that would have developed during the years of
the screening tests and over the ensuing 4 years,
whereas no benefit is assumed after that period. Fifth,
we estimated the incidence in our population by smoking attitude (current smokers, ex-smokers, and neversmokers) taking into account the following: first, the
age and sex incidence rate of lung cancer in the general
population as derived from the local tumor registry for
the 19982000 period [27] (Table 1); second, the proportion of smokers, ex-smokers, and never-smokers in
the Tuscany population (Table 2) [28]; and third, the
relative risk for lung cancer of smokers and former
smokers in comparison with never-smokers [29]
(Table 3). Former smokers were defined as individuals
TABLE 1: Lung Cancer Annual

Incidence Rates (per 100,000)
in Florence, Tuscany, Italy
[27], 19982000
Annual Incidence Rate
Age (y)
Men
Women
5559
147.8
32.1
6064
227.9
50.7
6569
391
55.4
7074
478.4
77.1
TABLE 2: Proportion of Smokers,

Ex-Smokers, and
Never-Smokers in the
Tuscany Population [28]:
Estimates for 19982000
% in Tuscany Population
Risk Category
Men
Women
Never-smokers
37.4
57.0
Ex-smokersa
32.3
17.8
Smokers
32.4
25.2
a Defined as
individuals who smoked at least 100

cigarettes over their lives and who now never smoke
at all [29].
TABLE 3: Relative Risk of Lung

Cancer Among Current
Smokers, Ex-Smokers, and
Never-Smokers [35]
Relative Risk
Risk Category
Men
Women
Never smokers
0.042
0.196
Ex-smokersa
0.089
0.370
Smokers
1.00
1.00
a Defined as
individuals who smoked at least 100

cigarettes over their lives and who now never smoke
at all [29].
who smoked at least 100 cigarettes over their lives and

who now never smoke at all [29].
To minimize the healthy screening effect for
which people undergoing screening have a lower
risk in the first years, we assumed that in the first
year the expected incidence is one third of that in
the general population and in the second year, two
thirds. We considered that, without screening, the
patients with lung cancer diagnosed in the 8-year
period since the beginning of the screening program would have died according to the observed
relative survival at 15 years. In this way, we estimated the cumulative number of deaths in the
population cohort. We arbitrarily applied to the
cumulative number of deaths expected in the population cohort (in the absence of screening) a reduction of mortality of 30%, 20%, 10%, and 0%
associated with early diagnosis due to active
screening with CT.
Our predictions extend the most favorable and
unfavorable sets assumed in a cost-effective analysis by Mahadevia et al. [25]. Those researchers
hypothesized a 50% stage shift associated with
lung cancer screening and, by weighting the possible influence of confounding factors such as
variable adherence to the annual screening regimen and the degree of length bias and overdiagnosis bias, constructed three fundamental scenariosnamely, a base case scenario implying a 13%
reduction of mortality, a favorable estimate scenario with a 16% reduction, and an unfavorable
estimate scenario with a 4% reduction. Otherwise,
based on an analysis of the stages of all cancers
detected in the ELCAP and Mayo Clinic observational studies, Patz et al. [26] anticipated that no
lung cancerspecific mortality change with
screening is expected. It is noteworthy that if CT
screening does not modify mortality, the specific
lung cancer mortality reduction is 0%.
The number of deaths potentially prevented by
screening was estimated taking into account patient
sex and smoking habits.
The net benefit of screening was computed as
the difference of the number of lives saved minus
the number of estimated radiation-induced fatal
cancers. This was expressed as a riskbenefit ratio,
where a value of 1 implies that the number of lives
saved with screening is equal to the number of radiation-induced deaths; a value of 0.1, that the number of lives saved exceeds 10 times the number of
radiation-induced deaths; and so on.
Results
Experimental Dose Measurements
Table 4 reports the estimates of the effective dose to the whole body and of the dose to
the lung for the single-detector and MDCT
scanners and the different techniques.
Dose Delivered in the Pilot Study

Two hundred ten CT examinations were
performed in the pilot study over 3 years and
the low-dose 3-mm-collimation technique
was used in 14 examinations performed on a
single-detector scanner.
The cumulative 3-year doses were 53.9
mSv in the 36 subjects screened with the
MDCT system (mean exposure per subject,
1.49 mSv/3 y and 0.49 mSv/y) and 141.6 mSv
in the 24 subjects screened with the single-detector system (mean exposure per subject, 5.9
mSv/3 y and 1.9 mSv/y).
Dose Projections in the Active Arm of the ItalungCT Trial
The dose projections are detailed in Table 5.
The cumulative effective dose to the active arm
of the Italung-CT Trial was 3.35 Sv per 1,000
subjects over 4 years (0.83 mSv per subject/y)
using the MDCT scanner (low-dose 4-mm collimation, yielding four 1-mm-thick sections)
and 5.87 Sv (1.46 mSv/y) (low-dose 3-mm collimation only) or 7.12 Sv (1.78 mSv/y) (lowdose 10-mm collimation and one full-dose thincollimation package) per 1,000 subjects over 4
years using the single-detector scanner.
The Risk
With the previously described cumulative
doses and the estimate of 0.035 fatal cancers
for each Sievert for subjects ranging in age
from 50 to 70 years (men and women altogether) [24], the numbers of lifetime fatal
cancers associated with 4 years of CT screening programs for lung cancer for subjects
5070 years old were 11.7 per 100,000 (0.11
per 1,000) for the MDCT scanner and 20.5 or
24.9 per 100,000 (0.20 or 0.24 per 1,000) for
the single-detector scanner.
The Benefit
Table 6 details the lung cancer incidence
rates in our area estimated for current smokers, ex-smokers, and never-smokers and different age groups and sex. Table 7 reports the
expected number of lung cancers in 8 years in
a cohort of 100,000 subjects. Based on a probability of dying within 15 years after the diagnosis of lung cancer equal to 91% in men and
90% in women [27], Table 8 reports the number of expected deaths from lung cancer in the
same area and the same period in the absence
of screening. Table 9 shows the estimates of
deaths from lung cancer saved assuming a
10%, 20%, and 30% reduction of specific
lung cancer mortality with CT screening according to sex and smoking habits.
423
Mascalchi et al.
TABLE 4: Doses of Radiation for Scanners and Techniques Used in CT Screening for Lung Cancer in the Italung-CT Trial [13]
CT Parameter
Technique
kVp
mAs
Table
Feed
(mm)
120
20
40
Scan
Length
(mm)
360
Beam
Slice
Effective
CTDI
DLP
Lung Dose
Rotations Collimation Thickness
Dose
(no.)
(mm)
(mm)
(mGy/mAs) (mGy cm)
(mGy)
(mSv)
4-MDCT (rotation time, 0.5 s)

Low-dose
Full-dose, thin-collimation
120
Full-dose, thick-collimation
80
20
0.17
61
0.89
0.36
20
360
18
10
2.5
0.18
64
1.20
0.45
360
51
0.21
86
1.60
0.59
10
0.194
16
0.50a
0.17
15
0.194
23
0.68a
0.22
0.33
20
0.194
31
1.00a
120
90
20
360
18
20
0.135
437
8.00
3.1
140
43
20
360
18
10
10
0.221
171
3.20
1.2
Single-detector (rotation time, 1 s)

Low-dose
Two breath-holds
10
360
36
0.214
166
3.10
1.15
Two breath-holds
360
60
0.202
156
2.90
1.1
10
10
0.236
40
1.20a
0.4
15
15
0.236
61
1.60a
0.55
2.20a
Full-dose, thin-collimation
140
Full-dose, thick-collimation, two

breath-holds
120
171
150
20
20
0.236
81
360
72
0.15
810
15.0
0.73
5.5
NoteCTDI = CT dose index in air at the isocenter, DLP = doselength product in air at the isocenter.
a The dose is related to partially irradiated lung.
TABLE 5: Cumulative Doses for 1,000 Subjects Screened for Lung Cancer with Low-Dose CT in the Italung-CT Trial [13]
% of
Subjects at
Baseline
Dose from
Baseline
Examination
(mSv)
% of Subjects
at Annual
Repeat
Examination
Dose from
Annual Repeat
Examination
3 (mSv)
Cumulative
4-y Dose
(Sv)
Negative findings
89
0.64 (D1)
89.5
0.64 (D1)
2.28
Follow-upa
10
1.28 (D2)
10
1.92 (D2)
0.70
15 (D3)
0.5
15 (D3)
0.37
Negative findings
89
1.15 (D1)
89.5
1.15 (D1)
4.11
Follow-upa
10
2.30 (D2)
10
3.45 (D2)
1.26
20 (D3)
0.5
20 (D3)
0.50
Negative findings
89
1.25 (D1)
89.5
1.25 (D1)
4.46
Follow-upa
10
3.98 (D2)
10
5.94 (D2)
2.18
20 (D3)
20 (D3)
0.48
Technique
MDCT scanner
Low-dose, 4 1 mm collimation
Interventiona
Single-detector scanner
Low-dose, 3-mm collimation
Interventiona
Low-dose, 10-mm collimation low-dose; and one full-dose, thin-collimation
package
Interventiona
0.5
NoteThe 0.05-mSv dose associated with scout acquisition obtained using low milliamperage setting (mA) and 2-mm collimation is included in dose estimate for each
examination. D1 = dose for subjects with negative findings; D2 = dose for subjects with noncalcified nodules 5 mm in mean diameter requiring one follow-up at 3 months
for initial detection at baseline screening or two follow-up examinations at 1, 3, or 6 months for initial detection at annual repeat examinations; D3 = dose for intervention,
which includes radiation exposure associated with full-dose diagnostic chest CT before and after IV contrast administration, CT-guided biopsy or fine-needle aspiration,
and 18F-FDG PET.
a Arbitrary frequency assumed for the cumulative calculation.
424

TABLE 6: Estimated Annual Lung Cancer Incidence for 100,000 in Florence,
Tuscany, Italy, by Age, Sex, and Smoking Habits
Men
Age (y)
Smokers
Women
Ex-Smokersa Never-Smokers
Smokers
5559
401.8
35.8
16.9
74.7
27.7
14.6
6064
618.3
55.2
26.1
118.0
43.7
23.1
6569
1,060.7
94.7
44.8
128.9
47.8
25.3
7074
1,297.8
115.9
54.8
179.4
66.5
35.2
NoteEquation for estimate of rates is as follows: L(T) = L(0) p(0) + p(1) r(1) + L(2) p(2) r(2), where L(T) =
lung cancer rate for whole population; L(0) = lung cancer rate for never-smokers (unknown); p = proportion of
never-smokers (0), ex-smokers (1), and current smokers (2) in general population; and r = relative risk of exsmokers (1) and current smokers (2) as compared with never-smokers.
a Defined as individuals who smoked at least 100 cigarettes over their lives and who now never smoke at all [29].
TABLE 7: Estimated Incidence of Lung Cancer for 100,000 Subjects in 8 Years

in Florence, Italy
Men
Women
Age at
Entry (y)
Smokers
5559
1,152
103
49
217
81
43
6064
1,883
168
79
286
106
56
Ex-Smokersa Never-Smokers Smokers
6569
2,708
242
114
351
130
69
Total
5,743
513
242
854
317
168
TABLE 8: Numbers of Expected Deaths from Lung Cancer for 100,000 Subjects
in 8 Years in Florence, Italy
Age at
Entry (y)
Men
Women
Smokers Ex-Smokersa Never-Smokers
Smokers
5559
1,048
94
44
196
73
38
6064
1,713
153
72
257
95
50
6569
2,465
220
104
316
117
62
Total
5,226
467
220
769
285
150
TABLE 9: Estimates of Deaths from Lung Cancer Potentially Saved by CT

Screening in Florence, Italy in a Cohort of 100,000 Subjects
Undergoing Annual Screening Examination for 4 Years
Assumed
Reduction of
Mortality (%)
Men
Women
Smokers
30
1,568
140
66
231
85
45
20
1,045
93
44
154
57
30
10
523
47
22
77
28
15
Smokers
NoteOne third of subjects were 5559 years old, one third were 6064 years old, and one third were 6569
years old.
The Risk-to-Benefit Ratio

Different scenarios may be drawn according to efficacy of screening, smoking habits,
sex of the screened subject, use of single-detector or MDCT technology, and patient age
at the commencement of screening.
In Figure 1, the riskbenefit ratios associated with undergoing four annual screening
examinations with the MDCT and single-detector scanners (low-dose plus full-dose highresolution CT) used in the Italung-CT Trial
assuming 10%, 20%, and 30% lung cancer
mortality reduction are reported for male and
female never-smokers, ex-smokers, and current smokers. Assuming a 10% reduction of
mortality, the riskbenefit ratio is higher than
1 for male and female never-smokers examined with a single-detector scanner. At the
same level of efficacy, the ratio is between 1
and 0.1 for male and female never-smokers
examined with MDCT and for male or female
former smokers examined with a single-detector or MDCT scanner. The risk-to-benefit
ratio for current smokers, assuming a 10%
screening efficacy, ranges between 0.32 (females examined on a single-detector scanner)
and 0.02 (males examined on an MDCTscanner). Assuming 20% or 30% screening efficacy, the ratio is around or below 0.1 for male
and female current smokers examined with
either a single-detector or an MDCT scanner.
In Figure 2, the variation of the riskbenefit ratios as a function of patient age at the
commencement of screening is displayed assuming a 20% efficacy of screening. The riskto-benefit ratio decreases with advancing age
and is lower in men.
Discussion
The increase in diagnostic radiology activity is emerging as a main concern in medicine due to the risk of radiation-induced fatal cancers [30].
The estimation of this radiation-induced
cancer risk is difficult. In fact, it is fundamentally based on observational studies of the
atomic bomb survivors and radiation workers
chronically exposed to low radiation doses
and implies several assumptions. In particular, the cancer risk from low-level radiation
such as that used for diagnostic radiology procedures has been extrapolated by observations obtained at moderate and high doses using a linear no-threshold relation between the
radiation dose and the risk of cancer [31].
However, other scenariosincluding the possibility that the linear no-threshold relation
underestimates or overestimates the cancer
425
risk from a low radiation dose, the presence of

a dose threshold below which the risk is 0, and
the possible protective effect of low-radiation
dose against cancer (so-called hormetic response)can be hypothesized based on observational, experimental, and radiobiologic
data.
Even adopting a linear no-threshold
doserisk relation, which appears to be the
most reasonable and prudent assumption,
other variables that can modify the
doserisk relation, such as a theoretic relationship, need to be considered. First is the

age of the patient at exposure. In fact, the
low-dose radiation-induced cancer incidence generally decreases with advancing
age. It is noteworthy, however, that the risk
of radiation-induced lung cancer does not
seem to show this pattern and peaks at the
age of 5060 years [18]. Second is the temporal profile of the dose exposure. In fact,
protracted exposures are associated with
RiskBenefit Ratio
RiskBenefit Ratio
lower risks of cancer than those of an acute

exposure to the same total dose [18]. This is
particularly relevant, but to date unsettled,
in the context of screening procedures using
X-rays in which a series of low-dose examinations is performed over many years.
Third is that the latent period between radiation exposure and cancer death increases
with decreasing exposure, and it is possible
that for low doses the latent period exceeds
the normal life span [31].
10
10
0.1
0.01
0.1
0.01
0.001
10%
20%
10%
30%
SD never-smokers
MD current smokers
20%
30%
Estimated Mortality Reduction from Screening
Estimated Mortality Reduction from Screening

MD never-smokers
SD ex-smokers
MD ex-smokers
SD current smokers
MD never-smokers
SD ex-smokers
SD never-smokers
MD current smokers
MD ex-smokers
SD current smokers
Fig. 1Risk-to-benefit ratios for study participants.

A and B, Risk-to-benefit ratio (log units) histograms for male (A) and female (B) never-smokers, ex-smokers, and current smokers associated with four annual screening
examinations with MDCT (MD) and single-detector (SD) (low-dose thick-collimation plus one full-dose thin-collimation package) scanners in the Italung-CT Trial. Three
different levels of expected benefitnamely, 10%, 20%, and 30% reduction of lung cancer mortalityare considered. Assuming 10% reduction of mortality, riskbenefit ratio
is over the unitthat is, the number of radiation-induced deaths overcomes the estimated number of lives saved, for male (1.13) and female (1.66) never- smokers examined
with the single-detector scanner. At the same level of screening efficacy, the ratio is between 1 and 0.1 and close to the critic value of 0.5, implying only two lives saved for
one radiation-induced death, for male (0.53) or female (0.78) never-smokers examined with an MDCT scanner, for female former smokers examined with a single-detector
(0.87) or MDCT (0.41) scanner, and for male former smokers examined with a single-detector scanner (0.53). Assuming 20% or 30% screening efficacy, the ratio is around or
below 0.1 for male and female current smokers examined with either a single-detector or MDCT scanner.
RiskBenefit Ratio
RiskBenefit Ratio
Mascalchi et al.
0.1
0.01
0.1
0.01
5559
6064
6569
0.001
5559
6064
6569
Age (y)
Age (y)
MD never-smokers
SD ex-smokers
SD never-smokers
MD current smokers
MD never-smokers
SD ex-smokers
MD ex-smokers
SD current smokers
SD never-smokers
MD current smokers
MD ex-smokers
SD current smokers
Fig. 2Risk-to-benefit histograms for men and women stratified by age.

A and B, Risk-to-benefit ratio (log units) histograms for males (A) and females (B) commencing 4 years of annual screening rounds on an MDCT (MD) or single-detector (SD)
(low-dose thick-collimation plus one full-dose thin-collimation package) scanner in different age categories: 5559, 6064, and 6569 years. Efficacy of screening is assumed
to be 20% in reducing mortality in 8 years after start of program. For current smokers, riskbenefit ratio ranges between 0.21 in women who are 5559 years old examined
on a single-detector scanner and 0.008 in men who are 6569 years old examined on an MDCT scanner.
426

To perform a balanced analysis of the harm
and gain of diagnostic radiologyrelated radiation exposure, studies evaluating also the
benefit in terms of reduced mortality are
needed [32, 33].
There is no proof that CT screening is effective in reducing mortality of lung cancer,
but there is consensus that randomized clinical trials should be performed to evaluate this
possibility [15]. Because there is no indication supporting the extension of CT screening
examinations for life, even for heavy smokers
[15, 26], we focused on the risk-to-benefit ratio of radiation exposure in the active arm of
the Italung-CT Trial, which is a 4-year clinical trial and is currently in progress [13]. Accordingly, on the scanners used for the CT
screening program, we experimentally measured the radiation dose related to the CT acquisition techniques and protocols currently
used in this trial. The cumulative dose delivered to subjects undergoing lung cancer
screening was calculated in retrospect for a
pilot study and as projections for the ItalungCT Trial. For the calculation of the risk of fatal cancer, we used the effective dose [20] and
NRPB data [24], whereas for the estimation
of the benefit we assessed the number of expected cancers in our area based on the data
from the local tumor registry [27]. A range of
efficacy of the screening procedure in reducing the mortality of lung cancer of between
0% and 30% was assumed.
For the basic low-dose CT technique, we
measured a dose of 0.36 mSv on the MDCT
scanner using a 1-mm slice collimation, 120
kVp, and 20 mAs and a dose of 1.1 or 1.2
mSv on the single-detector scanner using a
3- or 10-mm collimation, 140 kVp, and 43
mA. Although a small increase in the peak
kilovoltagefor instance, from 120 to 140
kVpimplies an increase in the dose of
about 30% on the single-detector scanner we
used, this change was necessary to improve
the image quality, taking into consideration
the characteristics of the detectors and time
of rotation of the single-detector scanner of
our study. Nishizawa et al. [17] experimentally calculated an effective dose of 3.6 mSv
for the basic CT examination technique.
However, they used a single-detector mobile
scanner with 100 mAs and a table speed of
10 mmthat is, pitch of 1 and 10-mm-collimation slices. Diederich and Lenzen [14] reported an effective dose of 0.3 mSv for men
and 0.55 mSv for women on a single-detector scanner (10- or 5-mm collimation, pitch
of 2, 25 mAs).
Our data indicate that MDCT technology

enables considerable dose savings as compared with single-detector CT technology.
This is especially true if one considers that
low-dose thin-collimation acquisitions with
1- to 1.5-mm reconstruction can obviate supplemental full-dose thin-collimation packages. A similar dose saving can be obtained in
the case of a single-detector scanner if lowdose 3-mm-collimation acquisitions are used.
At variance with prior studies [14, 17, 18]
in the calculation of the radiation dose associated with lung cancer screening, we included
the additional exposure related to follow-up
and interventional CT examinations required
in the management of suspected nodules. The
considerable dose associated with such additional examinations was previously emphasized [26, 34]. To calculate dose projections
for participants in the Italung-CT Trial, we
considered the dose exposures with current
single-detector and multidetector technology,
the percentages of nodules requiring followup and intervention reported in the literature,
and the last ELCAP protocol and management recommendations. In particular, we
adopted a cutoff value of 5 mm in mean diameter for an indeterminate nodule at baseline
requiring follow-up and a restricted number
of follow-up CT examinationsnamely, one
examination for nodules detected at baseline
screening and two examinations for nodules
initially detected at annual repeat screening
rounds. The mean cumulative 4-year doses
for 1,000 screened subjects examined on an
MDCT scanner were 3.3 Sv (0.83 mSv/y per
subject) and 5.8 Sv (1.46 mSv per subject);
the dose was 7.1 Sv (1.78 mSv per subject) for
those examined on a single-detector scanner.
The lower dose exposure associated with
the adoption of MDCT technology for lung
cancer screening programs was confirmed in
the pilot study, in which the mean annual dose
per subject was 0.49 mSv for MDCT and 1.9
mSv for single-detector CT. Although no definite studies are yet available, preliminary
data (personal unpublished observation) indicate that with the newer MDCT scanners (12,
16, > 16 detector rows) low-dose thin-collimation acquisition techniques recommended
for lung cancer screening will provide dose
exposures similar to those of the 4-MDCT
scanner of our study.
To calculate the risk of radiation associated with lung cancer screening with CT, we
used the total-body (effective) dose and
adopted the estimates of lifetime radiationinduced fatal cancer from English NRPB
publications, in which data are stratified according to age at exposure and in which the
effect of sex is minor [24].
Pending results of randomized trials, the estimate of the potential benefit of lung cancer
screening with CT in reducing the specific mortality rate is speculative and controversial [13,
9, 19, 26]. In our analysis of the benefit of
screening in terms of reduction of specific lung
cancer mortality, we covered a range of between 30% and 0% screening efficacy [25, 26],
the most favorable estimate being similar to that
of mammographic screening for breast cancer
[35]. The additional assumption was made that
the 4-year mortality rate of lung cancer outside
a screening program is so high that it can be
considered equivalent to the incidence.
In the present analysis, we applied the assumptions discussed earlier to the expected
number of lung cancers based on current incidence rates in our area provided by the local
tumor registry and on the Italian estimate on
relative risk of current smokers in comparison
to ex-smokers and nonsmokers.
In calculating the riskbenefit ratio related to the radiation exposure in lung cancer screening with CT, besides the estimated
efficacy of the screening procedure in reducing lung cancerspecific mortality, the
interaction of several variables related to
risk and benefit must be taken into account.
In particular, because the incidence of lung
cancer and the potential benefit of screening
differ according to smoking habits, age, and
sex, the risk-to-benefit ratio of radiation exposure related to lung cancer screening with
CT varies accordingly.
For male and female current smokers participating in a 4-year program, such as the
Italung-CT Trial, our data indicate that assuming lung cancerspecific mortality reduction of 1030% with CT screening, the benefit of screening overcomes the risk associated
with the radiation exposure. Our data also indicate that this favorable ratio, ranging from
0.32 (in women examined on a single-detector scanner with a 10% screening efficacy) to
0.007 (in men examined on an MDCT scanner with a 30% screening efficacy), is more
pronounced in elderly smokers who show the
highest incidence of lung cancer.
Conversely, our data indicate that even a
4-year screening program with CT is not indicated for subjects with a low risk of lung
cancer such as never-smokers, with a
riskbenefit ratio ranging from 1.66 (women
examined on a single-detector scanner with a
10% screening efficacy) to 0.08 (men exam-
427
Mascalchi et al.
ined on an MDCT scanner with a 30%
screening efficacy).
In former smokers, the situation is intermediate, but it is noteworthy that for a screening
efficacy of 10% the ratio is between 0.25 and
0.87 with either CT technology for women
and men. The estimate of lung cancer risk in
former smokers is difficult to calculate owing
to the controversial definition of this category
and its presumable heterogeneity and to the
uncertainties about the change over time of
the lung cancer risk in subjects who quit
smoking. Our data seem to indicate that some
caution should be exercised in initiating lung
cancer screening programs in former smokers, and that in such a case a keen understanding of the individual risk and of the specific
risk categories is necessary.
Although it is possible that extension of CT
screening to more than 4 years will increase
the benefit more than the risk in heavy smokers, we did apply our analysis to the typical
regimen of screening used in ongoing randomized clinical trialsnamely, annual CT
examination for a few years [11].
If CT screening does not affect mortality,
subjects participating in CT screening programs have no benefit of radiation exposure
and only a possible detrimental effect due to radiation-induced cancers. This assumption enables us to assess the risk associated with lung
cancer screening in a simpler way than when
some degree of efficacy is assumed. Several
considerations are needed to properly weigh
the risk of radiation-induced cancers in subjects
participating in annual CT screening programs
for lung cancer. In fact, one has to consider the
interaction between radiation exposure for the
lung and other factors in modifying the risk of
lung cancer. In particular, it was reported that
the interaction between X-ray radiation and
smoking could imply a multiplicative effect
[18]. Moreover, recent data showed that the risk
of radiation-induced lung cancer does not decrease with increasing age at exposure [18]. On
the other hand, there is considerable uncertainty about the time needed for development of
radiation-induced cancer after X-ray exposure
for lung cancer screening, but it can reasonably
be estimated in terms of many years. It is conceivable that most subjects will receive in the
meantime considerably higher doses of radiation for diagnostic or therapeutic procedures
due to current diseases [30].
In conclusion, MDCT technology is associated with lower radiation doses than singledetector technology and is recommended for
lung cancer screening with CT. However,
428
even a 4-year annual screening with an

MDCT scanner implies a nonnegligible dose
exposure and a risk of radiation-induced fatal
cancer. The amount of this riskin consideration of the uncertainties of the benefit of
screening in terms of reduction in specific
lung cancer mortalitycan equal or even
dominate the spontaneous lung cancer incidence and mortality in nonsmokers in Western countries. Studies of lung cancer screening with CT should be restricted to current
smokers, and their extension to former smokers is debatable.
12.
13.
14.
15.
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Chest Imaging Original Research

Keywords: cancer screening, CT, lung cancer, MDCT,

RiskBenefit Analysis of X-Ray

Sanitaria, Azienda Ospedaliera Careggi, Firenze,

Careggi, Firenze, Italia.

AJR:187, August 2006

T is capable of revealing peripheral

The advent of MDCT scanners and updates

Experimental Dose Measurements

line ranged from 5.1% in a Japanese study including

Estimate of the Benefit from CT

AJR:187, August 2006

RiskBenefit Analysis of Lung Cancer Screening

TABLE 1: Lung Cancer Annual

TABLE 2: Proportion of Smokers,

individuals who smoked at least 100

TABLE 3: Relative Risk of Lung

individuals who smoked at least 100

AJR:187, August 2006

who smoked at least 100 cigarettes over their lives and

Dose Delivered in the Pilot Study

4-MDCT (rotation time, 0.5 s)

Single-detector (rotation time, 1 s)

Full-dose, thick-collimation, two

AJR:187, August 2006

RiskBenefit Analysis of Lung Cancer Screening

TABLE 7: Estimated Incidence of Lung Cancer for 100,000 Subjects in 8 Years

Ex-Smokersa Never-Smokers Smokers

Smokers Ex-Smokersa Never-Smokers

TABLE 9: Estimates of Deaths from Lung Cancer Potentially Saved by CT

AJR:187, August 2006

The Risk-to-Benefit Ratio

risk from a low radiation dose, the presence of

doserisk relation, such as a theoretic relationship, need to be considered. First is the

lower risks of cancer than those of an acute

Estimated Mortality Reduction from Screening

Estimated Mortality Reduction from Screening

Fig. 1Risk-to-benefit ratios for study participants.

Fig. 2Risk-to-benefit histograms for men and women stratified by age.

AJR:187, August 2006

RiskBenefit Analysis of Lung Cancer Screening

AJR:187, August 2006

Our data indicate that MDCT technology

even a 4-year annual screening with an

spiral CT scan vs chest radiograph lung screening

AJR:187, August 2006

RiskBenefit Analysis of Lung Cancer Screening

AJR:187, August 2006

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