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Int. J. Cancer: 71, 4–8 (1997)
r 1997 Wiley-Liss, Inc.
Publication of the International Union Against Cancer
Publication de l’Union Internationale Contre le Cancer
TREATMENT OF PRE-INVASIVE CONDITIONS DURING OPPORTUNISTIC
SCREENING AND ITS EFFECTIVENESS ON CERVICAL CANCER INCIDENCE
IN ONE NORWEGIAN COUNTY
Siri FORSMO1*, Harald BUHAUG1, Finn Egil SKJELDESTAD2 and Olav A. HAUGEN3
Institute for Hospital Research, Trondheim, Norway
2Department of Obstetrics and Gynecology, University Hospital of Trondheim, Trondheim, Norway
3Department of Pathology, University Hospital of Trondheim, Trondheim, Norway
1Norwegian
Norway had until recently no organized screening programme for cervical cancer, but opportunistic screening was
common. This study focuses on the effectiveness of treatment of pre-malignant cervical conditions (CIN III) on cervicalcancer incidence in the county of Sør-Trøndelag in Norway,
prior to the introduction of organized mass screening. The
study is based on cervical-cancer incidence rates during the
years 1965–92 and treatment data for CIN III. The expected
number of cervical-cancer cases prevented due to early
intervention was expressed in a regression model with 2
unknown parameters: the probability, p, of cancer development in case of CIN III, and the time lag, t, between
treatment and when clinical cancer would otherwise have
been diagnosed. The estimated probability that a patient
treated for CIN III would have developed cervical cancer if
not treated was found to be approximately 20%, and the
mean time delay was around 16 years. In the last period of
study (1988–92), the incidence was reduced by nearly 40% of
what would have been expected without early intervention.
Based on equal treatment rates as in 1990, parameter
estimates were used to predict future incidence reduction.
Maximum effectiveness will be achieved around the year
2005, with a nearly 70% reduction. Opportunistic screening
and treatment of CIN III seems to have had considerable
influence on cervical-cancer incidence. The costs, however,
are substantial over-treatment, since our results indicate that
4 of 5 women treated for CIN III would not progress into the
invasive state. Int. J. Cancer, 71:4–8, 1997.
r 1997 Wiley-Liss, Inc.
In most industrialized countries, the incidence and mortality of
cervical cancer have been declining over the last 25 to 30 years
(Hakama, 1982; Parkin et al., 1993). It is commonly believed that
regular Pap testing, which makes possible the diagnosis and
treatment of pre-malignant cervical conditions, is the main reason
for this reduction (Hakama et al., 1985; Miller, 1986). Although the
effectiveness of Pap testing has never been evaluated in any
randomized trial, it seems that the observed reduction has been
most noticeable in populations subject to organized mass screening
(Hakama et al., 1985; Miller, 1986). Reduced incidence of cervical
cancer also has been observed in populations without a screening
program, as is the case in Norway.
It is assumed that the majority of the cervical cancers develop via
a pre-malignant and reversible stage, cervical intraepithelial neoplasia (CIN), graded CIN I–III, according to severity (Richart, 1968).
Without detection and treatment of precursor lesions, the maximum
prevalence rate of carcinoma in situ (included in CIN III) is
believed to manifest itself in women around the age of 35 years
(Boyes et al., 1962), and the maximum incidence rate of invasive
cancer appears about 10 years later.
Development from a pre-malignant condition into invasive
cancer is usually a slow process affecting only a minority of women
with CIN. Hence, it will take many years to observe the effectiveness on cervical-cancer incidence rates of tracing and treating
pre-invasive disease. An indirect approach to evaluating the
efficiency and effectiveness of screening and early intervention is
the estimation of progression time and transition rates from the
pre-malignant to the malignant state in simulation models of the
natural history of cervical cancer (Gustafsson and Adami, 1989,
1992; Yu, 1982; Parkin, 1985; Prorok, 1986; Van Oortmarssen and
Habbema, 1995).
Until 1992, there was no organized nation-wide screening
program for cervical cancer in Norway. During the period 1965–85,
however, a 10-fold increase in the annual number of Pap smears
was observed (Norges Offentlige Utredninger, 1987). This was due
mainly to frequent opportunistic Pap testing, especially of women
of child-bearing age (Forsmo et al., 1994). In most of the other
Nordic countries, organized screening was introduced about 30
years ago, and cervical-cancer incidence has been decreasing since
the mid-1960s (Hakama, 1982). In Norway, the decline in cervicalcancer incidence occurred about 10 years later than in the
neighbouring countries, and has been slower. Lack of a preventive
strategy such as organized mass screening has been held as the
most plausible explanation of this difference (Anonymous, 1985).
The most important incidence reduction over the last 20 years has
taken place in the 40-to-55-year age group, and maximum incidence rates are now observed in women aged 60 to 65 years
(Bjørge et al., 1993).
This study focuses on the effect of early intervention on cervical
cancer in one Norwegian county (Sør-Trøndelag, mid-Norway)
during the period 1965–92. In the mid-1960s, cervical-cancer
incidence in Sør-Trøndelag was among the highest in Norway
(relative rate 1.4), but has been decreasing since then. The
incidence of cervical cancer in the county today is approximately
equal to the national cervical-cancer incidence (Cancer Registry of
Norway, 1995). In a regression model, we aimed to estimate the
effectiveness of treatment of cervical premalignancies prior to the
introduction of organized mass screening, measured as cervical
cancer incidence reduction.
MATERIAL AND METHODS
The study is based on incidence data on pre-invasive and
invasive cervical cancer and on treatment records from the county
of Sør-Trøndelag, which had a total female population of 127,000
in 1990. Cervical-cancer incidence data for the years 1965 to 1992
were provided by the Norwegian Cancer Registry. For the analyses,
the cases were grouped by age in 5-year increments.
Effect on cervical-cancer incidence of treatment for pre-invasive
cervical conditions was measured in 3 periods of 5 years from 1978
to 1992. The years 1965 to 1977 were used as a reference period to
measure incidence rates before intervention had had any major
influence. The length of the reference period is necessary in order
to obtain precise estimates, and also a period close in time to the
study periods in order to minimize the effect of possible incidence
trends.
Surgical intervention records, e.g., cervical conization and
hysterectomies during the years 1986 to 1992 were collected from
*Correspondence to: SINTEF UNIMED Norwegian Institute for Hospital Research, N-7034 Trondheim, Norway. Fax: 1 47 73596361. E-mail:
sirif@unimed.sintef.no.
Received 25 July 1996; revised 14 November 1996
EFFECTIVENESS OF TREATING CERVICAL PRE-CANCER
5
TABLE I – AGE-SPECIFIC INCIDENCE OF CERVICAL CANCER IN THE COUNTY OF SØR-TRØNDELAG, 1965 TO 1992,
AND MEAN AGE AT DIAGNOSIS1
Age
(years)
20–29
30–39
40–49
50–59
60–69
70–79
801
Total
Age-adjusted
Mean age
1The
1965–1977
N
6
51
98
104
69
46
16
390
54.8
1/100,000
2.3
37.7
59.1
56.5
34.8
44.0
32.9
25.3
21.2
1978–1982
N
1/100,000
10
15
19
24
26
21
8
123
10.9
18.1
32.9
35.5
34.3
43.2
35.9
19.9
15.1
56.2
1983–1987
N
7
17
26
12
22
24
14
122
57.3
1/100,000
7.5
19.2
38.5
20.4
32.5
46.1
51.8
19.5
14.1
1988–1992
N
5
29
11
18
28
14
12
116
1/100,000
5.1
32.2
13.1
32.3
43.3
25.6
39.5
18.2
13.4
55.8
years 1965 to 1977 represent the baseline period.
computerized registries and medical records at the University
Hospital of Trondheim. As part of a larger project, a record linkage
between the computerized registry at the Department of Pathology
and the surgery records was established in order to create a
complete registry of all Pap smears, histological investigations,
conizations and hysterectomies for the period 1986 to 1992. As the
only pathology laboratory in the region, the coverage is virtually
complete for women resident in Sør-Trøndelag. A system of
automatic calls for follow-up smears at specific intervals in the
event of a positive smear result was introduced in 1986.
From the registry records we know that virtually all histologically confirmed cases of CIN III were treated, and we assumed that
this was also the case for patients prior to 1986. Annual rates of
CIN III (severe dysplasia and carcinoma in situ) diagnosed at the
laboratory between 1975 and 1985 were used to estimate annual
treatment rates. In the years 1975 to 1992, the annual number of
carcinomas in situ varied in proportion with the number of CIN-III
cases, and accounted for about 50% of the cases treated for CIN III.
Assuming that this was also true prior to 1975, treatment rates in
the period 1961 to 1974 were estimated on the basis of in situ cases
recorded by the Cancer Registry since 1961.
Since 1983, the preferred treatment of pre-malignant cervical
conditions has been laser conization. About 90% of the cases
receiving conization were treated after the diagnosis of CIN III, but
a few cases of CIN I, II and invasive cancer are recorded. This
study includes treatment rates of CIN III only.
Statistical methods
CIN III involves a risk of cancer progression. For the analyses,
we assume a probability that treatment of one case of CIN III will
prevent one case of invasive disease. The time lag between
treatment of a progressive CIN-III case and the time at which
invasive cancer would otherwise have been diagnosed is assumed
to be a random variable, i, with a probable density function f(i).
Thus, we express the expected number of prevented cancer cases in
year t in terms of the number of CIN-III cases treated by
(conization or hysterectomy) in previous years:
Prev(a,t) 5 p S i Con(a-i,t-i) f(t) Surv(a-i,a) 5 p X(a,t)
(1)
where Prev(a,t) is the prevented number of cervix-cancer cases of
age a in year t (1/100,000);
p is the probability that treatment of pre-invasive disease will
prevent a future case of invasive cervical cancer;
Con(a-i,t-i) is the number of cases of age a-i treated for preinvasive cancer in the year t-i (1/100,000);
f(t) is the probability that a case of invasive cancer, prevented due
to intervention, would have been diagnosed t years later if not
prevented;
Surv(a-i,a) is the probability that the patient will survive from age
a-i to age a and will not be subject to a hysterectomy during
this period;
X(a,t) is the result of Si (Con(a-i,t-i) f(t) Surv(a-i,a).
We used a Poisson distribution to represent the ‘‘delay function’’
f(t) after testing series of distributions belonging to the Erlang
family based on an exponential distribution of the time delay. With
the actual parameters, the Poisson distribution is a close approximation to the normal distribution. The survivor function Surv(a-i,a) is
based on female age-specific mortality rates from official statistics
and on hysterectomy rates for reasons other than pre-invasive and
invasive cancer of the cervix. Mortality and hysterectomy rates are
relatively low in the relevant age groups, and the inclusion of this
function has only a minor effect on the final results. There was
practically no net migration to or from the county during the study
years.
Model parameters were estimated by the least-squares method,
using the following equation:
Y(a,t) 5 c 1 p X(a,t) 1 ea,t
(2)
where Y(a,t) is the reduction in the incidence of cervical cancer at
age a, measured as the difference in incidence between the
reference period and the year t. The constant term c represents a
possible general shift in the incidence level from the reference to
the study period. A negative value of c indicates an increase in
cancer incidence. The parameter ea,t is an error term.
X(a,t) depends on the delay function f(t), and the equation is not
linear in the unknown parameter t. Ordinary linear regression
cannot be applied, and the parameters are estimated by minimizing
the sum of squares, using an iterative method. Confidence intervals
are estimated by Monte Carlo simulation (Press et al., 1988). Based
on the model and the parameter estimates, simulation is used to
generate a number of invasive cases for each age group and time
period. The simulated numbers are used to calculate new incidence
rates which are fed back into the model, and new parameter
estimates are computed. This procedure was repeated 100 times,
and the sample of estimates for each parameter was used for the
calculation of 95% confidence intervals (CI).
RESULTS
Age-specific cervical-cancer incidence rates and age-adjusted
incidence throughout the study period 1965 to 1992 are presented
in Table I. There was a marked reduction in incidence, most
pronounced in the first period after the reference period 1965 to
1977 (Table I). Registration rates for carcinoma in situ in women
from Sør-Trøndelag in the Cancer Registry between 1961 and 1992
are presented in Table II. Until the beginning of the 1980’s, there
was a steady increase in carcinoma-in situ registrations, but about
10 years later the registration rates seem to be decreasing. Mean
age of patients with in situ cancer decreased from 44 years in the
early 1960’s to 35 years in the last period, equal to the mean age of
women treated for pre-invasive disease.
Least-square estimates of model parameters with 95% CI for the
3 successive time periods are presented in Table III. Mean time
FORSMO ET AL.
6
TABLE II – REGISTRATION RATES (1/100,000) OF CARCINOMA IN SITU IN THE NORWEGIAN CANCER REGISTRY IN THE COUNTY OF SØR-TRØNDELAG
DURING THE YEARS 1961 TO 19921
1961–1967
Age
N
20–29
30–39
40–49
50–59
60–69
70–79
801
Total
Age-adjusted
Mean age1
1Mean
0
13
17
4
0
2
0
36
1968–1972
1/100,000
0
15.4
16.3
4.1
0
4.3
0
4.7
4.4
44.2
N
1973–1977
1/100,000
21
39
37
9
4
1
0
111
N
24.0
67.1
53.3
12.4
6.6
2.5
0
18.8
20.3
63
83
42
20
6
1
2
217
41.6
1978–1982
1/100,000
68.2
121.0
69.3
27.5
9.4
2.2
11.2
35.7
36.8
N
144
160
55
30
6
0
2
397
37.2
1983–1987
1/100,000
156.0
192.5
95.4
44.5
9.0
0
8.9
64.7
64.4
35.1
N
1988–1992
1/100,000
148
154
45
27
16
7
1
398
157.9
173.7
66.5
45.9
23.7
13.5
3.7
64.1
60.9
N
117
130
50
11
6
4
0
318
35.9
1/100,000
118.4
144.8
61.1
21.1
12.7
7.7
0
46.5
50.5
35.0
age at registration.
TABLE III – OUTCOME OF REGRESSION MODEL FOR 3 SUBSEQUENT 5-YEAR PERIODS
Time periods
1978–1982
1983–1987
1988–1992
Delay before invasive
cancer (T)1
Probability of future cancer
if no treatment2
Constant term
Years
(95% CI)
9.8
16.1
15.3
(7.8–11.7)
(13.5–18.7)
(14.1–16.6)
20.7
1.5
22.7
(95% CI)
p
(95% CI)
R2
(25.4–3.9)
(21.5–4.5)
(25.0–20.4)
0.21
0.27
0.18
(0.08–0.34)
(0.14–0.40)
(0.14–0.22)
0.38
0.27
0.60
1Mean delay between treatment and when invasive disease would have been diagnosed without
intervention.–2Probability that a woman treated for CIN III would have developed invasive disease if not
treated.
TABLE IV – NUMBER OF CERVICAL-CANCER CASES PREVENTED DUE TO
TREATMENT OF CIN III IN WOMEN AGED 25 TO 79 YEARS IN
3 SUCCESSIVE TIME PERIODS
Period
Number observed
Number prevented
Percentage reduction1
1978–1982
1983–1987
1988–1992
112
105
104
37
38
62
24.7
26.8
37.3
1Estimated
percentage incidence reduction due to intervention.
delay until patients treated for CIN III would have developed
invasive cancer was around 16 years for the 2 last periods. In the
first period 1977 to 1982, the mean time delay was significantly
shorter, about 10 years. The estimated probability ( p) that a patient
treated for CIN III would later have developed cancer if not treated
was found to be approximately 20% in the 3 study periods. The
confidence limits were, however, rather broad in the 2 first periods
(Table III). The constant term c measures the change in incidence
from the reference to the study period that would have occurred if
no CIN-III cases had been treated. Only in the last period does c
attain a statistically significant negative value, which indicates that
an increase in expected incidence would have taken place if no
screening or treatment of CIN III had been performed.
Results from the first period should be interpreted bearing in
mind that the incidence of cervical cancer in these years had been
less influenced by pre-invasive treatment than in the later periods.
The minor effect of prevention is probably partly disguised in
random incidence variations. We consider the results from the 2 last
periods, and especially the last one, to be the most valid. For the last
period (1988–92), the estimates had narrow confidence limits, and
the coefficient of determination (R2) improved markedly. This
indicates that the model better fits the data in this period than in
previous periods. Results based on all 3 periods pooled are not
presented, as the results from the periods analyzed individually
differed significantly.
Table IV presents the estimated number of cervical-cancer cases
prevented by treatment of CIN III and the percentage incidence
reduction for women aged 25 to 79 years during the 3 study periods
between 1977 and 1992. In the first period, prevention was most
pronounced in younger age groups, with maximum effect around
45 years (data not shown). In the next periods (1983–92),
maximum effect was skewed towards older age groups, and the
greatest total effect was observed in the last period, with maximum
incidence reduction in women between 40 and 59 years.
Parameter estimates from the period 1988 to 1992 were used to
predict the number of cancer cases prevented in the future,
assuming the same incidence of CIN III and treatment rates as in
1990. Maximum effect of pre-invasive treatment on cervicalcancer incidence will be reached around the year 2005, with almost
70% reduction in the incidence that would be expected without
early intervention.
DISCUSSION
The results of the regression model indicate that opportunistic
screening and treatment of CIN III have led to reduced cervicalcancer incidence in the county of Sør-Trøndelag over the last 15
years. Because of the time delay before the results of pre-invasive
treatment on cervical-cancer incidence can be observed, only part
of the total improvement in incidence reduction has been revealed
so far.
Method
The study is based on a small (6%) and delimited population in
Norway, and random incidence variations of pre-malignant conditions and cervical cancer may influence the outcome of the
regression model. If similar data were available for the whole
nation, we believe our method would be valid for evaluation of
secondary-cervical-cancer prevention on a national scale.
Registration of carcinoma in situ may not have been complete in
the Cancer Registry, especially in the early 1960s. Thus, true
treatment rates may have been higher than those applied in the
model. Increased treatment rates would have given lower probability ( p) of cancer progression and increased time delay before
clinical cancer.
It can be argued that an exponential or Erlang-family distribution
of the time delay would seem more appropriate than the Poisson
distribution. These distributions all came out with consistently
poorer results than the Poisson distribution.
EFFECTIVENESS OF TREATING CERVICAL PRE-CANCER
As indicated by the registration rates of carcinoma in situ, there
was some opportunistic screening during the last years (1968–72)
of the reference period. This may have led to increased detection of
invasive cervical cancer, hence a larger difference in incidence
between the reference period and subsequent time periods than
without screening. However, cervical-cancer incidence in SørTrøndelag during this period was actually lower than during the
previous 5-year period, 1963 to 1967 (Cancer Registry of Norway,
1995). Although it remains a possibility, screening detected cancer
cases during the reference period do not seem to represent a major
bias to the results.
For the analyses, we assumed that previous treatment of
pre-malignant disease had not yet had any major influence on the
cervical-cancer incidence rates in the reference period (1965–77).
This is not necessarily true, especially in the last years of the
reference period. Although treatment rates were very low in the
years prior to this, some prevalent pre-malignant conditions
destined to surface as invasive cancer during the reference years
might have been eliminated. These would have been prevalent
cases close to the point of malignant transition or cases of
fast-progressing pre-invasive disease. The last category is rare
(IARC Working Group, 1986). Probably less than 10% of invasive
cases develop within 5 years (Gustafsson and Adami, 1989; Albert,
1981), and we do not think they represent a major bias in our
results. Because of very low carcinoma-in situ registration and
treatment rates in the early 1960s, we believe that the number of
prevalent CIN-III cases prevented from emerging as invasive
cervical cancer during the reference period was very small. In order
to minimize the effect of general trends in cervical-cancer incidence, we preferred to keep the baseline and study periods close in
time.
Test sensitivity and screening frequency may have varied during
the study periods, and this would affect estimation of the parameters, primarily of p.The actual results indicate that such variation
is small compared with other sources of variation. The mean age of
carcinoma-in situ patients registered was virtually equal throughout
the study periods, which is one argument against important
fluctuations in test validity.
Screening for cervical cancer affects cancer incidence in 2 ways:
(i) reduction is caused by detection and treatment of pre-invasive
conditions; (ii) screening contributes to early detection of invasive
cases. Early detection implies a shift in the age distribution towards
younger age. As the amount of testing was much higher in the study
periods than in the reference period, estimation of time delay
between treatment and diagnosis will be biased by earlier diagnosis. This new parameter was included in an elaborate model.
However, because of limited data in a model that included 2 more
parameters, we were not able to produce precise estimates. We
believe that this factor must be taken into account when evaluating
the time delay.
Natural history
Estimations in mathematical models of the duration of premalignant conditions have yielded values ranging from 5 to nearly
30 years (Prorok, 1986; Eddy, 1987). In more recent studies
(Gustafsson and Adami, 1989; Van Oortmarssen and Habbema,
1995), a mean duration of 16 or 17 years from the onset of
carcinoma in situ until the eventual development of clinical
invasive cancer seems to fit the data on the natural history of
cervical cancer. Our results, comparable to these estimates, represent the mean duration from the diagnosis of CIN III until clinical
cancer. As CIN III includes both severe dysplasia and carcinoma in
situ, it is possible that the average time delay before clinical cancer
is longer than for carcinoma in situ only.
The ratio between prevalent and incident cases treated for CIN
III was presumably higher in the first years of opportunistic testing
than later. The cases might have spent longer in the pre-malignant
phase than cases diagnosed later. One indication is the mean age of
patients with carcinoma in situ, which was higher in the 1960s than
7
a decade later. We do not know the proportion of CIN-III cases that
were diagnosed based on genital symptoms. Spontaneous testing of
symptom-free women was infrequent in the 1960s compared with
15 to 20 years later, when the intensity of opportunistic screening
was high, especially in the age groups that empirically show a high
incidence of CIN III. We believe that the relative number of women
tested on indication was much higher in the early years. This
represents a confounder in the estimation of time delay and may
explain, although the estimates were less reliable, the shorter time
delay in the first study period. The elimination of cases with a
longer pre-malignant history may explain the pronounced incidence reduction in the first study period.
In the last period, which produced the most valid results, we
found that 18 of 100 women treated for CIN III would have
developed cervical cancer if left untreated. Treatment affected
prevalent and also incident cases. The likelihood of preventing
cancer when treating a new case of CIN III will be lower, as
demonstrated by Gustafsson and Adami (1989). Where there were
no screening measures, they found that progression to cancer will
occur in 15 to 23% of prevalent in situ cases and in about 12% of
new in situ cases. Age should be included as a possible factor of
progression from CIN to cancer in the study of the natural history
(Morrison et al., 1996). In a mathematical model based on British
Columbia data (Van Oortmarssen and Habbema, 1991), the best fit
was achieved in a model with lower regression rates in women
aged 34 years or more than in women of younger age. Owing to the
organization of our data and a small population in our study, no
conclusive results could be procured when assuming agedependency for the parameter p in our model, which was then
interpreted as an average.
Our results appears to confirm that secondary prevention of
cervical cancer involves substantial overtreatment, as only a
proportion of the patients will develop cancer if left untreated
(Gustafsson and Adami, 1989; Bergström et al., 1993). Besides the
economic aspects of unnecessary treatment, it also represents an
ethical dilemma (Anonymous, 1985; Skegg, 1995).
Reduction in cervical-cancer incidence
According to our study, an incidence reduction of 65 to 70% is
expected with present treatment rates. However, a possible 90%
incidence reduction with screening intervals of 3 years has been
estimated (IARC Working Group, 1986). This must imply increased detection and treatment rates of pre-invasive conditions,
given equal association between the diagnostic criteria of CIN and
the specificity in detecting lesions likely to develop into cancer as
today. The main difference between the automatical recall system
in the event of positive smears and an organized screening
programme, was that a woman was not invited unless she had had a
positive smear registered. Despite the absence of an organized
programme, a substantial proportion of the female population aged
,50 years is already regularly tested, about 73% at least once in a
3-year period (Forsmo et al., 1994). Older women have Pap smears
taken less frequently. Increased detection of pre-invasive disease
relies on higher attendance rates than today, if the prevalence of
CIN in women rarely or never tested is similar to or higher than in
women who regularly have smears taken. We believe that organized screening will lead to an incidence reduction beyond the
predictions in this study, though the greatest reduction will be due
to previous opportunistic screening.
The Pap test has a low level of accuracy (Fahey et al., 1995), and
a negative smear is no guarantee against development of cervical
cancer (Morrison et al., 1996). It has been demonstrated that the
eagerness to trace all cases and avoid false-negative results in
organized screening programs may lead to reduced test specificity
and to increased detection and treatment of minor abnormalities
and conditions at lower risk for malignant transition (Bergström et
8
FORSMO ET AL.
al., 1993; Skegg, 1995; Raffle et al., 1995). This is of particular
concern, since our study indicates that 4 of 5 women treated for
pre-malignant cervical conditions subsequent to opportunistic
screening would not develop invasive cancer.
ACKNOWLEDGEMENTS
We thank Dr. B.K. Jacobsen, Institute of Community Medicine,
University of Tromsø, Norway for valuable comments.
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