doumat of

J Cancer Res Clin Oncol (1981) 101: 331-337 ~CancerResearch

Clinical Oncology
9 Springer-Verlag1981

Sensitivity Determination
of Cancer Screening Programmes
with the Aid of "Interval Cases"
F.W. Schwartz
Zentralinstitut fiir die kassen/irztlicheVersorgtmgin der Bundesrepublik Deutschland,
Haedenkampstr. 5, D-5000 K61n41, Federal Republic of Germany

Summary. The determination of "interval cases" bears great significance in the

estimation of the diagnostic sensitivity of a cancer screening programme and
the setting of an appropriate periodicity of the screening terms. The concept can
only be applied purposefully with regard to tumor kinetics and its relationships
to the probability of tumor detection through the examination methods applied.
The methodical considerations presented also result in a criticism of the
"length-biased sampling" which has constantly been pointed out in the
screening theory in recent years.

Key words: Cancer screening - Sensitivity - Early detection - Interval cases

The diagnostic effectiveness of screening programmes is generally described with

the terms sensitivity, specificity and with prediction values. Familiarity with these
basic epidemiological terms is assumed in the following paper. Prediction values,
used also in many clinical studies, are inappropriate for objectifying effectiveness
determinations over a long period of time or in comparison with different popula-
tions because they depend on the prevalence of the target disease in the respective
periods of time or populations. Sensitivity or specificity are measurable variables
which are independent of the prevalence of the disease; but their determination
normally presupposes previous and follow-up examination of the screened popu-
lation by means of a better test than the screening test (reference test; criterion va-
lidity). Such a procedure cannot be utilized with a mass screening programme but
is restricted to small-scale studies. However, the results of such studies cannot
automatically be transferred to conditions which are determining for nation-wide
mass screening. For this, the concept of "interval cases" can be applied, as various
authors (e.g., Kirch and Klein 1978) have done for breast cancer screening. It can
be used in those cases where, in one specific region, cancer incidence and, at the
same time, participants and screening results are recorded very reliably.
The basic idea behind this method is, so to speak, to take "the time" as a ref-
erence test: the cancer cases symptomatically developing within a certain interval

0171-5216/81/0101/0331/$1.40
332 F . W . Schwartz

after a screening test has been carried out are evaluated as "false negatives". This
raises the question whether a subsequent case of disease was actually present at the
time of screening (and whether it would have been detectable by means of the best
reference method). Obviously, the answer depends on the interval chosen and the
tumor growth as well as on the relationship between tumor kinetics and detectabil-
ity. The relationships become clear in Fig. 1.
In the model introduced in Fig. 1 we assume that, with increasing growth, each
tumor passes through three phases of ideal type: (1) a "non-detectable preclinical
phase" (So), (2) a "detectable preclinical phase" (Sp) and (3) a "clinical phase" (So).
The transition from Sp to Sc is understood such that, at this point in time, Sp is
regularly ended by the occurrence of clinically manifest symptoms. To simplify
matters, we further presume that this is always the case if the tumor is of the same

TUMOR
SIZE

a a'

r D b I!

C bill

D
c I c3 c2

S = Non-detectable preclinical phase

o
S = Detectable preclinical phase
P
S = Clinical phase
C

Fig. 1. Schematic relationship between tumor kinetics and detectability by screening

SensitivityDeterminationof Cancer ScreeningProgrammeswith the Aid of "Interval Cases" 333

size. Corresponding considerations are assumed for the transition of So to Sp. On

the one hand, this point in time is defined by the size of the tumor and, on the other
hand, by the ability of the applied detection method to recognize the tumor with
the size it has at this point in time. Accordingly, the detectability of all tumors lies
between the beginning of Sp and the beginning of So, in other words during Sp. If
we consider a long interexamination interval, i.e. a screening which is carried out
at C1, and then at Cz, it becomes obvious that it is mainly the slowly developing
tumors (a", a"; b") which are detected at these two points in time, whereas the in-
terval cases, viz. those which were overlooked at the first examination although the
tumors were in phase Sv, consist of the rapid developments (b, b'). Of course, it
must be stated here that, with these considerations, the detection methods are as-
sumed to exhibit a sensitivity of one in phase Sp for the time being.
If I reduce the interexamination interval, I can expect to have no interval
cases at a certain position (C3). However, if after a first screening a tumor which
was overlooked initially and which is now clinically manifest should occur within
this short observation period (C1 to C3), this would most probably indicate inad-
equate sensitivity of my first examination at date C1. Accordingly, this would be
a means of estimating the sensitivity of my examination method.
The obvious difficulty with this method is the choice of the correct interval, for
which the mean sojourn time in Sp is decisive. This time is not defined in chrono-
logical and uniform terms, but it is dependent on the tumor growth and the type
of detection. In the case of a short tumor doubling time (with constant detection
modalities), it is shorter (A C) than in the case of slower developments (A" C").
With increasing sojourn time, it becomes more probable that the tumor will be
detected by a given screening method. Consequently, the screening does not detect
carriers of a disease by accident, but prefers those with the extended preclinical so-
journ time (length-biased sampling) (Zelen and Feinleib 1969).
By means of Fig. 1 a further term can be discussed. The extent by which the
point in time of detection of a tumor can be brought forward by screening before
phase So is reached is called "lead time". In Fig. 1, for the tumor development a",
it is represented by the line B" C". Thus, it is dependent on the screening date dur-
ing the sojourn time in Sp. If the screening dates in a population are chosen rand-
omly, only ttie duration of the sojourn time is decisive. Two important conclusions
can be drawn from these considerations.
1. A screening predominantly detects tumor forms which have a slow develop-
ment (long sojourn time).
2. The slower the development (increasing sojourn time), the greater the pos-
sible advance of the date of diagnosis (increasing lead time).
If, among other things, we want to use these considerations to estimate the sen-
sitivity of our examination method, it follows that
3. the shorter the sojourn time, the shorter my observation interval must be.
For complete assessment, however, it is necessary to consider another factor.
The sensitivity of the currently applied, morphologically orientated observation
methods generally improves as the tumor increases in size, i.e. the closer time Sc
approaches, the more probable the detection by a given screening. By analogy with
the introduced term "length-biased sampling", this could be called "longitudinal
detection bias". From these considerations, it follows that
334 F. W. Schwartz

Table 1 a, b.
a Extent of the carcinoma in the testing material
Cases %

I Less than 10% 42 29.8

II More than 10% 68 48.2
III In the total material 22 15.6
Not sufficientlyassessable 9 6.4
Total 141 100.0

b Histological classification of the prostate carcinomas

of Groups I and III

Group I Group III

Highly differentiated 29 0
Slightly differentiated 2 2
Cribriform 1 2
Solid and anaplastic 0 1
Highly and slightly 5 5
differentiated
Cribriform, and solid 0 0
and anaplastic
Cribriform in others 4 7
Other combinations 1 5
Total 42 22

(Dohm et al. 1979)

4. tumors which grow rapidly and have a short sojourn time are, during screen-
ing, detectable with a higher sensitivity than those with slower growth (if the in-
terexamination intervals are shorter than the average sojourn time, or if we con-
sider only one screening date).
This fact is clearly illustrated by developments b and a", respectively, in Fig. 1.
At the screening date Cs, b is more easily detectable than a". Consequently, the
length-biased sampling, which is often emphasized, is counteracted by this longi-
tudinal detection bias effect. This effect will be the more pronounced, the more the
sensitivity of the detection method depends on tumor growth.
In practice, this becomes particularly noticeable with prostate carcinomas.
Whereas the recorded prostate carcinomas in Saarland especially detected by
palpation only show a proportion of 11.8% of differentiated, slowly developing
carcinomas, these carcinomas detected by accident (incidental carcinomas) show a
proportion of 41.8% ( D o h m and H a u t n m m 1979). A further breakdown of the
latter material clarifies the relationship: Within the group of those carcinomas
which constitute less than 10 % of the testing material, the proportion of the highly
differentiated forms was 69%. In the group of those histological samples which
were completely overrun by the tumor, this proportion was 0% (Tables 1 a, b).
These findings can, of course, be interpreted only with great caution since they
do not originate from a clearly defined population. The term "incidental car-
SensitivityDetermination of Cancer ScreeningProgrammeswith the Aid of "Interval Cases" 335

cinoma" presupposes that, in the cases presented, indicative palpation results were
not or have not yet been obtained. 1
This example is mentioned simply to show that - assuming this is not a highly se-
lected population of cases - the slightly differentiated tumor developments, i.e. the
more rapid ones, because of their expansion which is greater on the average, would
have stood a better chance than the others of being detected by the screening
method of palpation.
If we return to the beginning of our considerations, viz. the influence of the in-
terexamination intervals, the following can be stated: When we use the method of
estimating the sensitivity of a screening program by interval cases (I), I is not just
a function of the sensitivity of the given screening method, but also of the average
sojourn time of the observed tumors (tsp) and of the observation interval chosen
(ti), i.e. I (q, tsp). If t~ approaches tsp, the proportion of more slowly developing tu-
mors with I will be high, and that of rapidly developing tumors will be small. This
trend is reversed if t~ tends to zero, or if ti is far larger than tsv.
Before discussing some practical applications of these considerations, it should
be pointed out that the sojourn time in the given definition can be inappropriate
for various diseases or cancer forms. In the case of breast cancer screening, for in-
stance, it is obviously much more important not to take So as the upper limit, i.e.
the entry into the clinically manifest stage, but the point in time of metastatic
lymph node affection. However, this time is then no longer correlated with a uni-
form tumor size, as assumed in Fig. 1, but, with some forms of development, can
be present with as little as a few millimetres of tumor diameter, yet with other
forms, large tumors measuring several centimetres do not exhibit any lymph node
affection (Heuser et al. 1979; Duncan and Kerr 1976). This consideration alone
shows that setting the screening interval at 1 year, as is the case under the legal pro-
gramme of early detection of cancer in the Federal Republic of Germany, is largely
an arbitrary measure. Therefore, in the case of breast cancer, Heuser et al. (1979)
advocate individual setting of the intervals according to the patients' risk factors
and earlier suspect findings, although, and this must be emphasized, a clear con-
cept of distinguishing women with the risk of rapidly growing tumors would first
have to be developed 2.
All these considerations show how difficult realistic estimation of sensitivity is
when applying the method of interval cases to cancer screening. Nevertheless, this
method is popular because an efficient definite diagnostic reference test, which
could be applied to a screening population, is not available here (Chamberlain et
al. 1979). Whereas a series of studies on breast cancer pursues this approach in a
relatively simple way (e.g. Fox et al. 1978; Heuser et al. 1979; Chamberlain et al.
1979), Kirch and Klein (1978) tried to examine the relationships between interval
cases and varying periodic examinations in a quantitative model. Using data of ex-
tensive American studies, they arrived at the result that the proportion of interval

1 For 95 of the 141 cases, the study presents data on rectal palpation findings at the most recent
routine examination. Seventy-tbur(77%) of these were inconspicuous. Obviously, the remaining
palpation findings were not interpreted as indicating the possibility of carcinomas; otherwise, the
term incidentalcarcinoma could not be applied purposefully.
2 Gautherie and Gros (1980)proposed the use of thermographyto distinguish risk groups for rapid
neoplasms
336 F. W. Schwartz

Table 2. Expected proportion of interval cases in peri-

odic programs

Proportion. Interexaminafion interval (months)

of false
negatives 3 6 12 24

A. Physical examination programs

0 01 07 29 57
10 02 11 34 61
20 03 16 40 66
30 04 20 46 70
40 06 24 52 74
B. Joint physical-mammographic examinations a
0 -- 04 18 42
10 -- 07 23 47
20 -- 10 27 52
30 -- 12 32 57
40 -- 15 37 62

" 50% of cancers detected by each modality; (cf.

Kirch and Klein 1978)

cases rises almost linearly with the increase o f the false negatives (insensivity) and
almost linearly with the increase o f the interexamination intervals (Table 2). The
example applies to breast cancer screening.
This table makes it possible to estimate the sensitivity (l-e) at k n o w n values for
interval cases and given screening periodicity. I f the sensitivity is known, this table
can also be used to determine the p r o p o r t i o n o f interval cases which entered the
detectable phase only after the previous screening date. F o r a given interval, I cal-
culate the difference between the values o f m y k n o w n sensitivity and those o f a
screening with the hypothetical sensitivity o f 1 (c~= 0).
Assuming that, at the time o f detection or o f first treatment, a linear relation-
ship can be seen between the p r o p o r t i o n o f patients with axillary lymph node af-
fection and the n u m b e r o f t u m o r doublings f r o m a given basic t u m o r size, Kirch
and Klein (1978) have c o m p o s e d a corresponding table for the expected p r o p o r t i o n
o f positive lymph node cases (Table 3). However, D u n c a n and Kerr (1976) have
proved that this no longer applies to tumors above 6 cm diameter.
Table 2 can be used to estimate the sensitivity, whereas Table 3 n o t only fulfills
the same purpose using a different observation method, but also provides a medi-
cally relevant criterion o f decision for the desired sensitivity and periodicity o f a
screening. Thus, e.g., it becomes obvious that even under different sensitivity as-
sumptions a physical examination at 3-monthly intervals seems to have the same
usefulness 3 as a screening c o m b i n e d with m a m m o g r a p h y , which is carried out ev-
ery 12 months.
3 The authors use the proportion of "lymphatic node negative" patients to define the "primary ben-
efits" of a screening program which is contrasted to different cost assumptions. It is presumed that
this measure'~is accepted to be a prognostically sufficient parameter
Sensitivity Determination of Cancer Screening Programmes with the Aid of "Interval Cases" 337

Table 3. Expected proportion of positive node cases in

periodic programs

Proportion Interexamination interval (months)

of false
negatives 3 6 12 24

A. Physical examinations
0 33 35 37 39
10 34 36 38 40
20 34 36 38 40
30 34 37 39 40
40 35 37 39 40
B. Joint physical-mammographic examinations~
0 -- 29 32 36
10 -- 30 33 37
20 -- 31 34 37
30 -- 32 35 38
40 -- 32 35 38

a 50% of cancers detected by each modality; (cf.

Kirch and Klein 1978)

These considerations show that the concept of sensitivity estimation by means

of interval cases is productive if applied with appropriate consideration. However,
it can only be applied successfully in cases where sufficient empirical data on tumor
kinetics and sojourn time in a detectable preclinical phase are available and, fur-
thermore, on the relationships between tumor size and detectability by the exam-
ination method applied. In this connection, the "length-sampling bias" has to be
regarded more critically than it used to be because, with morphologically oriented
methods of discovery, it ignores the increasing detectability of tumors in lapse of
time. A rational screening strategy today demands a detailed knowledge of ex-
perimental, clinical and epidemiological data.

References
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cidental carcinoma). Urologe A 14:105-111
Duncan W, Kerr GR (1976) The curability of breast cancer. Br Med J 2:781-783
Fox SH, Moskowitz M, Saenger EL (1978) Benefit/risk analysis of aggressive mammographic screen-
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Gautherie M, Gros CM (1980) Breast thermography and cancer risk prediction. Cancer 45:51-56
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intervals between screenings. Cancer 43:857-862
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Received July 8, 1980/Accepted April 25, 1981