Med. Oncol. & Tumor Pharmacother, Vot. 8, No. 3, pp. 175-181, 1991
0736-0t 18/91 $3.00 + .00 Pergamon Press plc
Printed in Great Britain
EFFICACY
OF CERVICAL
CANCER
SCREENING
FOLKE PETTERSSON Department of Gynaecological Oncology, Radiumhemmet, Karolinska Hospital, S-104 01 Stockholm, Sweden (Received 7 May 1991; accepted 12 May 1991) The earlier optimistic predictions that invasive carcinoma of the uterine cervix could be totally eradicated by means of Pap screening have failed. Experiences from different countries give evidence, however, that a considerable reduction of incidence and mortality can be gained with this type of secondary prevention, Improved knowledge of the epidemiology of carcinoma of the uterine cervix and of its natural history could be anticipated to give a better basis for the planning of preventive measures. Maintenance of a high laboratory standard, a good technique for taking of smears, and improved communications between laboratories and the doctor or nurse taking the smear and the doctor or clinic performing the treatment and an adequate reaction to the report from the laboratory with adequate treatment of the precancerous stages is supposed to improve the effect of the screening programmes.
Key words: Screening, Cervix, Cancer, Efficacy.
clinics for that treatment. There is no doubt that carcinoma of the uterine cervix fulfils the criteria of being fin important health care problem, that is, this disease fulfils the first condition one claims for a disease suitable for secondary prevention in the form of screening. The second main condition for a disease suitable for the screening method is that the precancerous cases detected can be offered a treatment which is more successful than the treatment which is given when the disease is invasive and symptomatic. A third condition is that the prevalence of the preclinical disease should be fairly high, otherwise the cost of identifying them will be too high. The conditions given above lead immediately to the need for knowledge about the epidemiology of carcinoma of t h e uterine cervix and its natural history.
INTRODUCTION Carcinoma of the uterine cervix should be a classical case for preventive medicine. It is a well-defined lifethreatening disease which is possible to treat with fairly high costs b u t which could be prevented through a cheap screening technique. When the Papanicolaou screening technique had proved to be efficacious in tracing the precancerous stage, it seemed possible to eradicate this tumour. However, still more than 60 years after the introduction of the Papanicolaou screening technique, a great number of women fall victims and die of this disease. This is true for the E u r o p e a n countries and for the United States, as well as for all other countries in the world. Thus, carcinoma of the uterine cervix is still an important health problem all over the world, even in countries where screening programmes have been practised. For practical reasons, we can count 100% deaths for untreated cases of invasive carcinoma of the uterine cervix. With the best current therapy, that is, local brachytherapy with radium or caesium and external radiation and, in suitable cases, radical operation, an overall 5-year survival rate of about 60% is obtainable, t The results of treatment are highly dependent on the stage at which the tumour is treated and are far better in the early stages compared with the more advanced stages. The treatment is often time-consuming and there is a need for expensive, specialized and well-equipped
EPIDEMIOLOGY OF CARCINOMA OF T H E UTERINE CERVIX A number of observations show that the risk of getting carcinoma of the uterine cervix is not evenly distributed among the female population. Thus, women living under severe socioeconomic circumstances, especially in the large cities, run a higher risk for this disease. Factors connected with sexual activity influence the risk of this disease, Carcinoma of the uterine cervix is practically unknown among 175
176
Folke Pertersson
women without sexual contacts but is more common among women with several partners and several pregnancies. Early sexual debut increases the risk. Suspicion was aroused early that some infectious agent was responsible for the disease; more specifically, a sexually transmitted infection. Since the late 1960s, many observations have pointed out an infection with herpes hominis virus No. 2 as a possible cause. Recent studies focus on the papilloma virus. -~ Furthermore, it seems cigarette smoking plays a role in the genesis of this disease)
THE NATURAL HISTORY OF CARCINOMA OF THE UTERINE CERVIX
The common belief about the natural history of carcinoma of the uterine cervix is that it is a slowly progrediating process from early precancerous stages, in the form of dysplasia via carcinoma in situ, to invasive carcinoma of the uterine cervix, A few classical works (e.g. Pedersen 4 and Kottmeier 5) observed a number of carcinoma in situ cases during the course of several years and found that this lesion, in 30-70% of cases had, after 10 years' observation, gone over to invasive carcinoma of the uterine cervix. There are many difficulties with this type of study. Extensive and repeated biopsies may, in some cases, have cured the precancerous disease and stopped it. Furthermore, is it not impossible that there might have been invasive carcinomatous changes in connection with the precancerous lesion from the beginning. The time-span between the early precancerous-stage dysplasia, carcinoma in s#u, and the invasive carcinoma is not completely known. Time periods of between 8 and up to 20 years have been given as the mean interval between in situ and invasive carcinoma of the uterine cervix in different investigations. It is possible that the latency period from the pre-invasive to the invasive carcinoma may vary with ages, and this progress may be more rapid in elderly women compared with the younger ones. An important number of these precancerous stages probably regress. We have also to count the possibility that there are a number of cancer cases where the precancerous stage is very short, or may be lacking. It could be concluded that our common knowledge about the epidemiology as well as of the natural history of the carcinoma of the uterine cervix is still incomplete, which will influence the preventive measures undertaken. It is also necessary to take into account that carcinoma of the uterine cervix presents itself in different histopathological types and what has been said is principally based on the knowledge of squamous epithelial carcinoma,
which in different hospital materials represents 8()95% of the total cases of cervical carcinomas. ~' It is, above all, the squamous epithelial carcinoma, which is apt for early diagnosis in precancerous stages with the Papanicolaou test.
PRIMARY PREVENTION
Although the body of knowledge about aetiology of the cervical cancer disease is growing, we still have no firm basis for primary prevention. However, the epidemiological knowledge, speaking for sexually transmitted agents, should be used more extensively for teaching of the importance of sexual hygiene.
SECONDARY PREVENTION - - SCREENING
The scope of this paper is to discuss further the efficacy of secondary prevention of carcinoma of the uterine cervix by means of early detection of precancerous stages, thus inhibiting the development of invasive carcinomas.
THE PAPANICOLAOU TEST
The Pap smear, or the Papanicolaou test, is the international name of the test which was presented by George N. Papanicolaou more than 60 years ago. It has been proven that cytologists, with fairly good accuracy, can identify the degree of cell changes and thus identify cases of dysplasia and carcinoma in situo which are the precancerous stage for the invasive carcinoma, and which can then, by a fairly simple operation, be treated. Already by the beginning of 1950s, this screening procedure came into systematic use and pioneers were parts of the United States and Canada. Early extensive screening was performed in British Columbia, Canada and in Louisville, Kentucky, and from these places came early reports regarding the effects, 7,s.~ Severe objections were, however, raised against the early optimistic reports, m-i'~
HOW SHOULD THE EFFECT OF THE CERVICAL CANCER SCREENING BE EVALUATED?
A look at the literature shows that no randomized trial has ever been performed for the evaluation of the effect of cervical cancer screening.iS The belief that the natural history of this disease was welldefined and that the detection and the treatment of these precancerous stages ought to lead to a favour-
Cervical cancer scree~zing
able result, that is, save the individual woman from the invasive carcinoma of the cervix, made it impossible and unethical to perform controlled trials. The remaining possibilities to evaluate the effect of screening included a study of time trends of incidence and mortality and stage distribution of the inwlsive carcinoma of the uterine cervix in relation to the intensity of screening in different geographical regions. Another approach is so-called simulation models, where one - - with the aid of known facts regarding the natural history for cervix c a n c e r tries to predict the result in terms of incidence and mortality in carcinoma of the uterine cervix provided different preventive measures are used. The model is then adapted to known screening projects.
SOME CRITICAL VIEWPOINTS ON GIVEN INCIDENCE AND MORTALITY RATES FOR CARCINOMA OF THE UTERINE CERVIX In all types of evaluation it is necessary to have careful estimates of the incidence and the mortality in carcinoma of the uterine cervix. Incidence, as well as mortality rates, contain a numerator giving the number of cancer cases of deaths in the disease and a denominator giving the female population within which the cases occurred. The difficulties one encountcrs in different parts of the world when studying incidence and mortality rates are: (1) the lack of national cancer registers covering the whole population; (2) changes in reporting and registration routines, (3) changes in definitions and changes in nomenclature; (4) time trends in incidence which might have been going on before the mass screening; (5) trends in incidence rates bound to different birth cohorts, so-called cohort effects; (6) difficulties in defining and delineating the population from which the cases are recruited, problems with migration, A completeness in reporting of incident cases necessitates in practice the existence of national cancer registers of high quality, and only a few countries have such registers. The number of cases giving the numerator are apparently small and are liable to errors in reporting. Even a small refinement in diagnosis and reporting during the time period can simulate trends. The population registration and the control of m o v e m e n t s of the population beyond borders may not be accurate in all countries. Defects in vital statistics can thus also simulate trends. Even certified trends can have other causes than effects of preventive m e a s u r e s . The first optimistic reports from British Columbia and from different parts in the United States were later disputed due to the above-mentioned sources of error. It should, however, be noticed that an increase in
177
the registered new cases of carcinoma of the cervix may be seen the years immediately following the start of the screening p r o g r a m m e , d e p e n d e n t on diagnosis in an earlier stage. After this increase there follows a decrease in incidence rate. Only if we can show that the diagnosis in precancerous stages gives an effect in terms of a decreased cumulative incidence and mortality rate over a longer period, can we talk about the benefits of screening. It does not necessarily follow that the treatment in earlier stages will be beneficial in tile long run, An investigation in Wales (West, 1977) ~(' showed that the mean age in cases of carcinoma in the uterine cervix stage I was 51 years, in stage II 54.5 years, in stage Ill 58 years, and in stage IV 58.9 years. It was found that the mean age at death for cases diagnosed in stage I was 57.7 years, for stage I1 57.4 years, in stage llI 59.1 years, and in stage IV 60.4 years. This study included all cases of carcinoma of the cervix registered in South Wales in 1960-t974o and it should also be noticed that the investigation which was performed in 1975 showed that 48% of the women diagnosed in stage I lived that year, while 3{}% of stage II and 12% of stage Ill and only 6% Of stage IV survived 1975. A conclusion from this study is that an important part of the observed better healing after 5 and 10 years for the earlier stages c o m p a r e d with the advanced stages, respectively, may be explained by a more favourable age distribution for the early stages. Not less than 5{}% of the observed benefit of early diagnosis disappeared in t h e longer perspective according to this study.
MORTALITY IN C A R C I N O M A OF THE UTERINE CERVIX Data on mortality in a disease are found in vital statistical reports founded on death certificates. T o the weakness and sources of error in deathstatistics may be said that generally, a cancer diagnosis gives a h e a v y weight as a cause of death, If a doctor gives a death certificate and if the circumstances are not fairly clear, there is a tendency that an anamnestic note regarding earlier cancer disease gives tile role of cause of death even if there is no evidence that the patient still suffers from the disease. A n o t h e r difficulty in death certificates and death statistics is that carcinoma of the uterine cervix in the earlier years was not separated from carcinoma of the corpus uteri, and even when one started to separate these diagnoses, there may have existed an important group of unspecified cases, There are also important possibilities that errors exist in the d e n o m i n a t o r in
178
Folke Pettersson
the mortality rates due to difficulties in describing the relevant population at risk.
THE INTERPRETATION OF TRENDS IN MORTALITY FROM CARCINOMA OF THE UTERINE CERVIX The death statistics probably have considerable errors in different countries. Changes in diagnosis and routines of registration may simulate trends. This has realistically been described from the Finnish Cancer Registry where a considerable discrepancy was found between data on death in carcinoma of the uterine cervix from the official cause of death statistics compared with data from the Cancer Registry. 17 The differences were large in the beginning of the study period and less important in the end of the study period. Thus, these two sources of information gave completely different trends regarding mortality in carcinoma of the uterine cervix. Cohort-bound differences in carcinoma of the uterine cervix mortality have been described from different countries. Improved facilities and resources for health care and for treatment have contributed to a more favourable stage distribution of cases of carcinoma of the uterine cervix as shown from the F I G O Annual Report.~ Improved treatment resources and treatment facilities in combination with high voltage technique, intracavitary radiation and major surgery, have contributed to a better healing which also resulted in an improvement in mortality. The importance of improvement in treatment technique with regard to improved survival is also shown in data from Radiumhemmet (Table 1). With the 5year survival doubled from the 1920s up to the 1970s, and with unchanged incidence, the result should be a reduction in the cervix cancer mortality within the whole population of about 50% during this period of observation. The conclusion is that trends in mortality rates for carcinoma of the uterine cervix must be judged with great care and that there may be other explanations than the effects of mass screening programmes. Table 1. Carcinoma of the uterine cervix: treatment results, Radiumhemmet Stockholm, Sweden Year 1915-1930 1935-1950 1955-t970
5-year survival (%)
10-year survival (%)
25 44 60
19 39 52
From many countries there has been reported a decreasing trend in mortality for carcinoma of the uterine cervix, a trend which seems to have been in action long before the start of the screening for cancer of the uterine cervix. This is true for parts of Canada, British Columbia and the United States. 1~
INCIDENCE AND MORTALITY TRENDS FOR CARCINOMA OF THE UTERINE CERVIX WITHIN THE NORDIC COUNTRIES In the Nordic countries, Norway, Finland, Denmark, Sweden and Iceland, national cancer registers have been functioning for more than 30 years and the population in these countries has also been well-registered for a long time. The Nordic countries introduced slightly different types of screening programmes. Finland, Iceland and Sweden have programmes covering the whole population. All women in certain age groups are invited by personal letters. The programmes started during 1960s and were extended to cover all of the countries in the beginning of 1970s. In Sweden smears are taken every 4 years in women in the age-group 3 0 4 9 and in Finland every 5 years in women aged 30-59~ In Iceland, the programme covers women aged 2570 with 2-3 year intervals. In Denmark, screening was organized in a few counties. In Norway, screening organization was tested in a small part of the country. The experience which we have had in the Scandinavian countries may serve as an illustration of how different systems work. tSAg"2~ The experience regarding incidence trends for carcinoma of the uterine cervix is very much the same in Finland, Denmark, Iceland and Sweden, where, since the end of the 1960s a notable decrease in incidence rates was observed which could not be seen in Norway. This decrease in incidence of carcinoma of the uterine cervix fits well in as an effect of the mass screening performed within these countries. Parallel to the decrease in incidence rates is seen a corresponding decrease in mortality rates. 18.20
EXPERIENCES FROM THE SWEDISH CERVICAL SCREENING PROGRAMMES Organized screening programmes were, in Sweden, initiated in a few counties in 1964 and were fully developed all over Sweden in 1973.1s'~9 About 200,000 smears have since been taken annually in the organized programmes. The total Swedish female population is approximately 4 million. Women aged 30-49 years were invited to attend at
Cervical cancer s'creening intervals of 4 years. In a d d i t i o n , f o u r t i m e s as m a n y s m e a r s were t a k e n a n n u a l l y since 1970 in an o p p o r tunistic way. D u r i n g the p e r i o d 1958-1985, 19,9t)0 cases of invasive c a r c i n o m a o f the u t e r i n e cervix in w o m e n b o r n b e t w e e n 1879 a n d 1964 w e r e n o t i f i e d to the Swedish C a n c e r Registry, In the s a m e p e r i o d almost 80,000 cases of cervical c a r c i n o m a in situ were r e p o r t e d . T h e a g e - s t a n d a r d i z e d i n c i d e n c e rates o f invasive c a r c i n o m a s c o n t i n u o u s l y d r o p p e d after 1965, a l t o g e t h e r n e a r l y a 50% r e d u c t i o n . T h e i m p a c t , in t e r m s of i n c i d e n c e fall, was m o s t p r o n o u n c e d in t h e age g r o u p 35-60. T h e r e was a c o r r e s p o n d i n g d e c r e a s e in m o r t a l i t y rate in the s c r e e n e d age g r o u p s a n d c o h o r t s (Figs 1, 2). Parallel to the d e c r e a s e in i n c i d e n c e rate o f cervical c a r c i n o m a t h e r e was s e e n a r e l a t i v e i n c r e a s e in a d e n o c a r c i n o m a s o f the u t e r i n e cervix ( T a b l e 2).~ T a b l e 3 shows that t h e r e is an indirect r e l a t i o n s h i p b e t w e e n the c u m u l a t i v e n u m b e r s o f c a n c e r in situ d e t e c t e d within o n e birth c o h o r t a n d the following incidence rate of invasive c a r c i n o m a of the u t e r i n e cervix. T a b l e 4 s h o w s a d i r e c t r e l a t i o n s h i p b e t w e e n the r e g i s t e r e d i n c i d e n c e rate within o n e birth c o h o r t
25 2O84
w d
O .~.. 10
I
I
1960
1955
1965
I
1970
t t975
179
Table 2. Percentage of adenocarcinomas in all carcinomas of the uterine cervix by birth cohorts and age groups Year of birth 192(1-1924 1925-1929 1930-1934 1935-1939 1940-1944 1945-1949
Age 25-29
10.6 4,0 9.2
3(1-34
4.6 7.7 t0.8
35-39
6.0 7.5 11,3
40-44 5.4 6.4 11.5
Table 3. Five-year cumulative reported rate of cancer in situ and incidence of invasive cancer of the uterine cervix per 100,000 women in different year-of-birth cohorts Year of birth
Cancer in situ
Invasive carcinoma
1915-1919 192(t- 1924
age 45-49 years 352 74/)
age 50-54 years 209 125
1925-1929 1930-1934
age 35-39 years 575 1397
age 40-44 years 230 102
1935-1939 1940.1944
age 25-29 years 435 1298
age 3(1-34 years 106 78
, ,J
I
1980 1885
Fig. 1o Carcinoma of the uterine cervix in Sweden. Agestandardized incidence rates per 100,000. (World Standard pop. )
Age 50-54 Age 4.5-48 Age 40..44
Table 4, Five-year cumulative incidence rate for cancer of the uterine cervix per ll)0,000 and five-year cumulative mortality rate for cancer of the uterine cervix per t0(),()t)0
100
o
8.
75
O O
w.,," ) 50
\.2,.,
13. r'r"
I
,
25 0 190
I
1910
I
1915 t 9 2 0
t
t925
t930
1935
1940
Year of birth
Fig. 2. Carcinoma of the uterine cervix in Sweden. Agespecific incidence rates in different birth cohorts per 100,000.
Birth cohort
Incidence rate
Mortality rate
1915-1919 1920.1924
age 45-49 years 268 224
age 5(1-54 years 84 55
1920-1924 1925-1929
age 40-44 years 280 230
age 45-49 years 68 54
t925-1929 1930-1934
age 35-39 years 207 163
age 40-44 years 66 36
180
Folke Pettersson
and the following mortality rate within the same birth cohort.
SENSITIVITY OF T H E SCREENING PROCEDURE, O P T I M A L INTERVALS AND AGES TO BE SCREENED The I A R C collaborative study on the evaluation of cervical cancers screening programmes made use of material from organized screening programmes in many European and North American states, 2~ The study concentrated on the question of whom to screen, that is, whom to invite initially for screening and how often to rescreen those with only negative screening test. A comparison of different screening strategies can be made in terms of the reduction in risk of invasive disease that each strategy might be expected to produce. The risk associated with the particular screening pattern is given by the cumulative incidence of invasive disease during each interscreening interval, together with the risks that accumulate before the age scheduled for the first screening test and after that scheduled for the last screening test. The individual screening programmes and their results were analysed either as case control studies done within the records of a centrally organized screening programme or cohort studies done within the records of a centrally organized programme or case control studies done in areas without a mass screening programme. Table 5 gives a summary of the relative protection calculated from the different materials. Table 6 gives the percentage reduction in the cumulative rate of invasive cervical cancer of the age range 35-65 with different frequencies of screening. ~-~ Table 5~ Summary of relative protections, geometric mean values over the centres Time since last Relative protection negative smear (number of cases 95% confidence (months) in parentheses) intervals 0-1 l 12-23 24-35 36-47 48-59 60-71 72-119 I20+ Never screened
15.3 11.9 8.0 5.3 2.8 3.6 1.6 0.8 1.0
(25) (23) (25) (30) (3/)) (16) (6) (7)
10.0-22.6 7.5-18.3 5.2-11.8 3.6- 7.6 1.9- 4.0 2.1- 5.9 0.6- 3,5 0.3- 1.6
{From Screening)or Cancer of the Uterine Cervix. IARC, Lyon 1986.)
Table 6. Percentage reduction in the cumulative rate of invasive cervical cancer over the age range 35-65, with different frequencies of screening
Screening frequency I 2 3 5 10
year years years years years
Reduction in the cumulative rate* (%)
No. of tests
93.3 92.5 91.4 83.9 64.2
30 15 10 6 3
*Assuming a screen occurs at age 35, and that a previous screen has been performed. (From Screening /br Cancer of the Uterine Cervix. IARC, Lyon 1986.)
REFERENCES 1. Pettersson F (ed.): Annual Report on the Results of Treamwnt in Gynecological Cancer, Vol. 20. Stockholm (1988)~ 2. Munoz N, Bosch F X, Jensen O M: Human Papillomavirus and Cervical Cancer. IARC Scientific Publication No. 94, Lyon (1989). 3~ Hellberg D, Valentin J, Nilsson S: Smoking and cervical intra-epithelial neoplasia. An association independent of sexual or other risk factors. Acta Obstet Gynecol Scand 65, 625 (1986). 4. Pedersen O: Precancerous stages of the cervical epithelium in relation to manifest cervical carcinoma. Acta Radiol Suppl 127 (1955). 5. Kottmeier H L: Evolution et traitement des epithetiomas. Rev Fr Gynec Obstet 56, 821 (1961). 6. Pettersson F: Adenocarcinoma of the uterine cervix. Changes in incidence. 38th Annual Meeting of the Society of Pelvic Surgeons, October 5-8, 1988, Toronto, Canada. 7, Christopherson W M, Lundin Jr. F E, Mendez W M, Parker J E: Cervical cancer control. A study of morbidity and mortality trends over a twenty-oneyear period. Cancer 38, 1357 (1976). 8. Christopherson W M, Parker J E, Mendez W M, Lundin F E Jr: Cervix cancer death rates and mass cytologic screening. Cancer 26, 808 (1970). 9. Boyes D A, Knowelden J, Phillips A J: The evaluation of cancer control measures. Summary of the conclusion of U[CC Symposium held in Sheffield in September 1.972. Br J Cancer 28, 105 (1973). 10. Cramer D W: The role of cervical cytology in the declining morbidity and mortality of cervical cancer. Cancer 34, 2018 (1974). 11. Gardner J W, Lyon J L: Efficacy of cervical cytologic screening in the control of cervical cancer, Prevent Med 6, 487 (1977). 12. Shulman J J, Leyton M, Hamilton R: The Papanicolaou smear: an insensitive case4inding procedure. Am J Obstet Gynecol 120, 446 (1974).
(k'rvica! cancer screenilzg 13, Sackett D L: Can screening programs for serious diseases really improve health? Science Forum IS, 9 (t970). 14, Martin P L: [tow preventable is invasive cervical cancer? A community study of preventable factors, A m J Obstet G'ynecot 113, 541 (1972), 15. Guzick D S: Efficacy of screening for cervical cancer: A review. A m J Public Health ,68, 125 (t978). 16, West R R: Cervical cancer: Age at registration and age at death. Br J Cancer 35, 236 (1977), 17. SaxOn E A: Trends: facts or fallacy, in Magnus K (ed): Trends in Catlcer lncideJwe. Causes and Practical Implications, p. 5. New York, Hemisphere Pubfishing Corporation (1982). 18. Pettersson F, Bj6rkholm E, Ntislund I: Evaluation of
t8l
screening for cervical cancer in Sweden: trends in incidence and mortality 1958-198{). lnt J Epidemiot
14, 52i (1985). 19. Pettersson F, N/islund I, Malker B: Evcduation of the Effect or Pal)cmicohlou Screening in Sweden: Record Linkage Between a Central Screeptin~ Registry and the National Cancer Registry', IARC Scientific Pubt No. 76, Lyon (1986), 20. Hakama M, Magnus K, Pettersson F, Storm H, Tulinius H: Effect of the organized screening in the Nordic countries on the risk of cervical cancer. 21. Hakama M, Miller A B, Day N E: Screening j o t Cancer of the Uterine Cervix. IARC Scientific Publ No. 76, Lyon (t986).
0736-0t 18/91 $3.00 + .00 Pergamon Press plc
Printed in Great Britain
EFFICACY
OF CERVICAL
CANCER
SCREENING
FOLKE PETTERSSON Department of Gynaecological Oncology, Radiumhemmet, Karolinska Hospital, S-104 01 Stockholm, Sweden (Received 7 May 1991; accepted 12 May 1991) The earlier optimistic predictions that invasive carcinoma of the uterine cervix could be totally eradicated by means of Pap screening have failed. Experiences from different countries give evidence, however, that a considerable reduction of incidence and mortality can be gained with this type of secondary prevention, Improved knowledge of the epidemiology of carcinoma of the uterine cervix and of its natural history could be anticipated to give a better basis for the planning of preventive measures. Maintenance of a high laboratory standard, a good technique for taking of smears, and improved communications between laboratories and the doctor or nurse taking the smear and the doctor or clinic performing the treatment and an adequate reaction to the report from the laboratory with adequate treatment of the precancerous stages is supposed to improve the effect of the screening programmes.
Key words: Screening, Cervix, Cancer, Efficacy.
clinics for that treatment. There is no doubt that carcinoma of the uterine cervix fulfils the criteria of being fin important health care problem, that is, this disease fulfils the first condition one claims for a disease suitable for secondary prevention in the form of screening. The second main condition for a disease suitable for the screening method is that the precancerous cases detected can be offered a treatment which is more successful than the treatment which is given when the disease is invasive and symptomatic. A third condition is that the prevalence of the preclinical disease should be fairly high, otherwise the cost of identifying them will be too high. The conditions given above lead immediately to the need for knowledge about the epidemiology of carcinoma of t h e uterine cervix and its natural history.
INTRODUCTION Carcinoma of the uterine cervix should be a classical case for preventive medicine. It is a well-defined lifethreatening disease which is possible to treat with fairly high costs b u t which could be prevented through a cheap screening technique. When the Papanicolaou screening technique had proved to be efficacious in tracing the precancerous stage, it seemed possible to eradicate this tumour. However, still more than 60 years after the introduction of the Papanicolaou screening technique, a great number of women fall victims and die of this disease. This is true for the E u r o p e a n countries and for the United States, as well as for all other countries in the world. Thus, carcinoma of the uterine cervix is still an important health problem all over the world, even in countries where screening programmes have been practised. For practical reasons, we can count 100% deaths for untreated cases of invasive carcinoma of the uterine cervix. With the best current therapy, that is, local brachytherapy with radium or caesium and external radiation and, in suitable cases, radical operation, an overall 5-year survival rate of about 60% is obtainable, t The results of treatment are highly dependent on the stage at which the tumour is treated and are far better in the early stages compared with the more advanced stages. The treatment is often time-consuming and there is a need for expensive, specialized and well-equipped
EPIDEMIOLOGY OF CARCINOMA OF T H E UTERINE CERVIX A number of observations show that the risk of getting carcinoma of the uterine cervix is not evenly distributed among the female population. Thus, women living under severe socioeconomic circumstances, especially in the large cities, run a higher risk for this disease. Factors connected with sexual activity influence the risk of this disease, Carcinoma of the uterine cervix is practically unknown among 175
176
Folke Pertersson
women without sexual contacts but is more common among women with several partners and several pregnancies. Early sexual debut increases the risk. Suspicion was aroused early that some infectious agent was responsible for the disease; more specifically, a sexually transmitted infection. Since the late 1960s, many observations have pointed out an infection with herpes hominis virus No. 2 as a possible cause. Recent studies focus on the papilloma virus. -~ Furthermore, it seems cigarette smoking plays a role in the genesis of this disease)
THE NATURAL HISTORY OF CARCINOMA OF THE UTERINE CERVIX
The common belief about the natural history of carcinoma of the uterine cervix is that it is a slowly progrediating process from early precancerous stages, in the form of dysplasia via carcinoma in situ, to invasive carcinoma of the uterine cervix, A few classical works (e.g. Pedersen 4 and Kottmeier 5) observed a number of carcinoma in situ cases during the course of several years and found that this lesion, in 30-70% of cases had, after 10 years' observation, gone over to invasive carcinoma of the uterine cervix. There are many difficulties with this type of study. Extensive and repeated biopsies may, in some cases, have cured the precancerous disease and stopped it. Furthermore, is it not impossible that there might have been invasive carcinomatous changes in connection with the precancerous lesion from the beginning. The time-span between the early precancerous-stage dysplasia, carcinoma in s#u, and the invasive carcinoma is not completely known. Time periods of between 8 and up to 20 years have been given as the mean interval between in situ and invasive carcinoma of the uterine cervix in different investigations. It is possible that the latency period from the pre-invasive to the invasive carcinoma may vary with ages, and this progress may be more rapid in elderly women compared with the younger ones. An important number of these precancerous stages probably regress. We have also to count the possibility that there are a number of cancer cases where the precancerous stage is very short, or may be lacking. It could be concluded that our common knowledge about the epidemiology as well as of the natural history of the carcinoma of the uterine cervix is still incomplete, which will influence the preventive measures undertaken. It is also necessary to take into account that carcinoma of the uterine cervix presents itself in different histopathological types and what has been said is principally based on the knowledge of squamous epithelial carcinoma,
which in different hospital materials represents 8()95% of the total cases of cervical carcinomas. ~' It is, above all, the squamous epithelial carcinoma, which is apt for early diagnosis in precancerous stages with the Papanicolaou test.
PRIMARY PREVENTION
Although the body of knowledge about aetiology of the cervical cancer disease is growing, we still have no firm basis for primary prevention. However, the epidemiological knowledge, speaking for sexually transmitted agents, should be used more extensively for teaching of the importance of sexual hygiene.
SECONDARY PREVENTION - - SCREENING
The scope of this paper is to discuss further the efficacy of secondary prevention of carcinoma of the uterine cervix by means of early detection of precancerous stages, thus inhibiting the development of invasive carcinomas.
THE PAPANICOLAOU TEST
The Pap smear, or the Papanicolaou test, is the international name of the test which was presented by George N. Papanicolaou more than 60 years ago. It has been proven that cytologists, with fairly good accuracy, can identify the degree of cell changes and thus identify cases of dysplasia and carcinoma in situo which are the precancerous stage for the invasive carcinoma, and which can then, by a fairly simple operation, be treated. Already by the beginning of 1950s, this screening procedure came into systematic use and pioneers were parts of the United States and Canada. Early extensive screening was performed in British Columbia, Canada and in Louisville, Kentucky, and from these places came early reports regarding the effects, 7,s.~ Severe objections were, however, raised against the early optimistic reports, m-i'~
HOW SHOULD THE EFFECT OF THE CERVICAL CANCER SCREENING BE EVALUATED?
A look at the literature shows that no randomized trial has ever been performed for the evaluation of the effect of cervical cancer screening.iS The belief that the natural history of this disease was welldefined and that the detection and the treatment of these precancerous stages ought to lead to a favour-
Cervical cancer scree~zing
able result, that is, save the individual woman from the invasive carcinoma of the cervix, made it impossible and unethical to perform controlled trials. The remaining possibilities to evaluate the effect of screening included a study of time trends of incidence and mortality and stage distribution of the inwlsive carcinoma of the uterine cervix in relation to the intensity of screening in different geographical regions. Another approach is so-called simulation models, where one - - with the aid of known facts regarding the natural history for cervix c a n c e r tries to predict the result in terms of incidence and mortality in carcinoma of the uterine cervix provided different preventive measures are used. The model is then adapted to known screening projects.
SOME CRITICAL VIEWPOINTS ON GIVEN INCIDENCE AND MORTALITY RATES FOR CARCINOMA OF THE UTERINE CERVIX In all types of evaluation it is necessary to have careful estimates of the incidence and the mortality in carcinoma of the uterine cervix. Incidence, as well as mortality rates, contain a numerator giving the number of cancer cases of deaths in the disease and a denominator giving the female population within which the cases occurred. The difficulties one encountcrs in different parts of the world when studying incidence and mortality rates are: (1) the lack of national cancer registers covering the whole population; (2) changes in reporting and registration routines, (3) changes in definitions and changes in nomenclature; (4) time trends in incidence which might have been going on before the mass screening; (5) trends in incidence rates bound to different birth cohorts, so-called cohort effects; (6) difficulties in defining and delineating the population from which the cases are recruited, problems with migration, A completeness in reporting of incident cases necessitates in practice the existence of national cancer registers of high quality, and only a few countries have such registers. The number of cases giving the numerator are apparently small and are liable to errors in reporting. Even a small refinement in diagnosis and reporting during the time period can simulate trends. The population registration and the control of m o v e m e n t s of the population beyond borders may not be accurate in all countries. Defects in vital statistics can thus also simulate trends. Even certified trends can have other causes than effects of preventive m e a s u r e s . The first optimistic reports from British Columbia and from different parts in the United States were later disputed due to the above-mentioned sources of error. It should, however, be noticed that an increase in
177
the registered new cases of carcinoma of the cervix may be seen the years immediately following the start of the screening p r o g r a m m e , d e p e n d e n t on diagnosis in an earlier stage. After this increase there follows a decrease in incidence rate. Only if we can show that the diagnosis in precancerous stages gives an effect in terms of a decreased cumulative incidence and mortality rate over a longer period, can we talk about the benefits of screening. It does not necessarily follow that the treatment in earlier stages will be beneficial in tile long run, An investigation in Wales (West, 1977) ~(' showed that the mean age in cases of carcinoma in the uterine cervix stage I was 51 years, in stage II 54.5 years, in stage Ill 58 years, and in stage IV 58.9 years. It was found that the mean age at death for cases diagnosed in stage I was 57.7 years, for stage I1 57.4 years, in stage llI 59.1 years, and in stage IV 60.4 years. This study included all cases of carcinoma of the cervix registered in South Wales in 1960-t974o and it should also be noticed that the investigation which was performed in 1975 showed that 48% of the women diagnosed in stage I lived that year, while 3{}% of stage II and 12% of stage Ill and only 6% Of stage IV survived 1975. A conclusion from this study is that an important part of the observed better healing after 5 and 10 years for the earlier stages c o m p a r e d with the advanced stages, respectively, may be explained by a more favourable age distribution for the early stages. Not less than 5{}% of the observed benefit of early diagnosis disappeared in t h e longer perspective according to this study.
MORTALITY IN C A R C I N O M A OF THE UTERINE CERVIX Data on mortality in a disease are found in vital statistical reports founded on death certificates. T o the weakness and sources of error in deathstatistics may be said that generally, a cancer diagnosis gives a h e a v y weight as a cause of death, If a doctor gives a death certificate and if the circumstances are not fairly clear, there is a tendency that an anamnestic note regarding earlier cancer disease gives tile role of cause of death even if there is no evidence that the patient still suffers from the disease. A n o t h e r difficulty in death certificates and death statistics is that carcinoma of the uterine cervix in the earlier years was not separated from carcinoma of the corpus uteri, and even when one started to separate these diagnoses, there may have existed an important group of unspecified cases, There are also important possibilities that errors exist in the d e n o m i n a t o r in
178
Folke Pettersson
the mortality rates due to difficulties in describing the relevant population at risk.
THE INTERPRETATION OF TRENDS IN MORTALITY FROM CARCINOMA OF THE UTERINE CERVIX The death statistics probably have considerable errors in different countries. Changes in diagnosis and routines of registration may simulate trends. This has realistically been described from the Finnish Cancer Registry where a considerable discrepancy was found between data on death in carcinoma of the uterine cervix from the official cause of death statistics compared with data from the Cancer Registry. 17 The differences were large in the beginning of the study period and less important in the end of the study period. Thus, these two sources of information gave completely different trends regarding mortality in carcinoma of the uterine cervix. Cohort-bound differences in carcinoma of the uterine cervix mortality have been described from different countries. Improved facilities and resources for health care and for treatment have contributed to a more favourable stage distribution of cases of carcinoma of the uterine cervix as shown from the F I G O Annual Report.~ Improved treatment resources and treatment facilities in combination with high voltage technique, intracavitary radiation and major surgery, have contributed to a better healing which also resulted in an improvement in mortality. The importance of improvement in treatment technique with regard to improved survival is also shown in data from Radiumhemmet (Table 1). With the 5year survival doubled from the 1920s up to the 1970s, and with unchanged incidence, the result should be a reduction in the cervix cancer mortality within the whole population of about 50% during this period of observation. The conclusion is that trends in mortality rates for carcinoma of the uterine cervix must be judged with great care and that there may be other explanations than the effects of mass screening programmes. Table 1. Carcinoma of the uterine cervix: treatment results, Radiumhemmet Stockholm, Sweden Year 1915-1930 1935-1950 1955-t970
5-year survival (%)
10-year survival (%)
25 44 60
19 39 52
From many countries there has been reported a decreasing trend in mortality for carcinoma of the uterine cervix, a trend which seems to have been in action long before the start of the screening for cancer of the uterine cervix. This is true for parts of Canada, British Columbia and the United States. 1~
INCIDENCE AND MORTALITY TRENDS FOR CARCINOMA OF THE UTERINE CERVIX WITHIN THE NORDIC COUNTRIES In the Nordic countries, Norway, Finland, Denmark, Sweden and Iceland, national cancer registers have been functioning for more than 30 years and the population in these countries has also been well-registered for a long time. The Nordic countries introduced slightly different types of screening programmes. Finland, Iceland and Sweden have programmes covering the whole population. All women in certain age groups are invited by personal letters. The programmes started during 1960s and were extended to cover all of the countries in the beginning of 1970s. In Sweden smears are taken every 4 years in women in the age-group 3 0 4 9 and in Finland every 5 years in women aged 30-59~ In Iceland, the programme covers women aged 2570 with 2-3 year intervals. In Denmark, screening was organized in a few counties. In Norway, screening organization was tested in a small part of the country. The experience which we have had in the Scandinavian countries may serve as an illustration of how different systems work. tSAg"2~ The experience regarding incidence trends for carcinoma of the uterine cervix is very much the same in Finland, Denmark, Iceland and Sweden, where, since the end of the 1960s a notable decrease in incidence rates was observed which could not be seen in Norway. This decrease in incidence of carcinoma of the uterine cervix fits well in as an effect of the mass screening performed within these countries. Parallel to the decrease in incidence rates is seen a corresponding decrease in mortality rates. 18.20
EXPERIENCES FROM THE SWEDISH CERVICAL SCREENING PROGRAMMES Organized screening programmes were, in Sweden, initiated in a few counties in 1964 and were fully developed all over Sweden in 1973.1s'~9 About 200,000 smears have since been taken annually in the organized programmes. The total Swedish female population is approximately 4 million. Women aged 30-49 years were invited to attend at
Cervical cancer s'creening intervals of 4 years. In a d d i t i o n , f o u r t i m e s as m a n y s m e a r s were t a k e n a n n u a l l y since 1970 in an o p p o r tunistic way. D u r i n g the p e r i o d 1958-1985, 19,9t)0 cases of invasive c a r c i n o m a o f the u t e r i n e cervix in w o m e n b o r n b e t w e e n 1879 a n d 1964 w e r e n o t i f i e d to the Swedish C a n c e r Registry, In the s a m e p e r i o d almost 80,000 cases of cervical c a r c i n o m a in situ were r e p o r t e d . T h e a g e - s t a n d a r d i z e d i n c i d e n c e rates o f invasive c a r c i n o m a s c o n t i n u o u s l y d r o p p e d after 1965, a l t o g e t h e r n e a r l y a 50% r e d u c t i o n . T h e i m p a c t , in t e r m s of i n c i d e n c e fall, was m o s t p r o n o u n c e d in t h e age g r o u p 35-60. T h e r e was a c o r r e s p o n d i n g d e c r e a s e in m o r t a l i t y rate in the s c r e e n e d age g r o u p s a n d c o h o r t s (Figs 1, 2). Parallel to the d e c r e a s e in i n c i d e n c e rate o f cervical c a r c i n o m a t h e r e was s e e n a r e l a t i v e i n c r e a s e in a d e n o c a r c i n o m a s o f the u t e r i n e cervix ( T a b l e 2).~ T a b l e 3 shows that t h e r e is an indirect r e l a t i o n s h i p b e t w e e n the c u m u l a t i v e n u m b e r s o f c a n c e r in situ d e t e c t e d within o n e birth c o h o r t a n d the following incidence rate of invasive c a r c i n o m a of the u t e r i n e cervix. T a b l e 4 s h o w s a d i r e c t r e l a t i o n s h i p b e t w e e n the r e g i s t e r e d i n c i d e n c e rate within o n e birth c o h o r t
25 2O84
w d
O .~.. 10
I
I
1960
1955
1965
I
1970
t t975
179
Table 2. Percentage of adenocarcinomas in all carcinomas of the uterine cervix by birth cohorts and age groups Year of birth 192(1-1924 1925-1929 1930-1934 1935-1939 1940-1944 1945-1949
Age 25-29
10.6 4,0 9.2
3(1-34
4.6 7.7 t0.8
35-39
6.0 7.5 11,3
40-44 5.4 6.4 11.5
Table 3. Five-year cumulative reported rate of cancer in situ and incidence of invasive cancer of the uterine cervix per 100,000 women in different year-of-birth cohorts Year of birth
Cancer in situ
Invasive carcinoma
1915-1919 192(t- 1924
age 45-49 years 352 74/)
age 50-54 years 209 125
1925-1929 1930-1934
age 35-39 years 575 1397
age 40-44 years 230 102
1935-1939 1940.1944
age 25-29 years 435 1298
age 3(1-34 years 106 78
, ,J
I
1980 1885
Fig. 1o Carcinoma of the uterine cervix in Sweden. Agestandardized incidence rates per 100,000. (World Standard pop. )
Age 50-54 Age 4.5-48 Age 40..44
Table 4, Five-year cumulative incidence rate for cancer of the uterine cervix per ll)0,000 and five-year cumulative mortality rate for cancer of the uterine cervix per t0(),()t)0
100
o
8.
75
O O
w.,," ) 50
\.2,.,
13. r'r"
I
,
25 0 190
I
1910
I
1915 t 9 2 0
t
t925
t930
1935
1940
Year of birth
Fig. 2. Carcinoma of the uterine cervix in Sweden. Agespecific incidence rates in different birth cohorts per 100,000.
Birth cohort
Incidence rate
Mortality rate
1915-1919 1920.1924
age 45-49 years 268 224
age 5(1-54 years 84 55
1920-1924 1925-1929
age 40-44 years 280 230
age 45-49 years 68 54
t925-1929 1930-1934
age 35-39 years 207 163
age 40-44 years 66 36
180
Folke Pettersson
and the following mortality rate within the same birth cohort.
SENSITIVITY OF T H E SCREENING PROCEDURE, O P T I M A L INTERVALS AND AGES TO BE SCREENED The I A R C collaborative study on the evaluation of cervical cancers screening programmes made use of material from organized screening programmes in many European and North American states, 2~ The study concentrated on the question of whom to screen, that is, whom to invite initially for screening and how often to rescreen those with only negative screening test. A comparison of different screening strategies can be made in terms of the reduction in risk of invasive disease that each strategy might be expected to produce. The risk associated with the particular screening pattern is given by the cumulative incidence of invasive disease during each interscreening interval, together with the risks that accumulate before the age scheduled for the first screening test and after that scheduled for the last screening test. The individual screening programmes and their results were analysed either as case control studies done within the records of a centrally organized screening programme or cohort studies done within the records of a centrally organized programme or case control studies done in areas without a mass screening programme. Table 5 gives a summary of the relative protection calculated from the different materials. Table 6 gives the percentage reduction in the cumulative rate of invasive cervical cancer of the age range 35-65 with different frequencies of screening. ~-~ Table 5~ Summary of relative protections, geometric mean values over the centres Time since last Relative protection negative smear (number of cases 95% confidence (months) in parentheses) intervals 0-1 l 12-23 24-35 36-47 48-59 60-71 72-119 I20+ Never screened
15.3 11.9 8.0 5.3 2.8 3.6 1.6 0.8 1.0
(25) (23) (25) (30) (3/)) (16) (6) (7)
10.0-22.6 7.5-18.3 5.2-11.8 3.6- 7.6 1.9- 4.0 2.1- 5.9 0.6- 3,5 0.3- 1.6
{From Screening)or Cancer of the Uterine Cervix. IARC, Lyon 1986.)
Table 6. Percentage reduction in the cumulative rate of invasive cervical cancer over the age range 35-65, with different frequencies of screening
Screening frequency I 2 3 5 10
year years years years years
Reduction in the cumulative rate* (%)
No. of tests
93.3 92.5 91.4 83.9 64.2
30 15 10 6 3
*Assuming a screen occurs at age 35, and that a previous screen has been performed. (From Screening /br Cancer of the Uterine Cervix. IARC, Lyon 1986.)
REFERENCES 1. Pettersson F (ed.): Annual Report on the Results of Treamwnt in Gynecological Cancer, Vol. 20. Stockholm (1988)~ 2. Munoz N, Bosch F X, Jensen O M: Human Papillomavirus and Cervical Cancer. IARC Scientific Publication No. 94, Lyon (1989). 3~ Hellberg D, Valentin J, Nilsson S: Smoking and cervical intra-epithelial neoplasia. An association independent of sexual or other risk factors. Acta Obstet Gynecol Scand 65, 625 (1986). 4. Pedersen O: Precancerous stages of the cervical epithelium in relation to manifest cervical carcinoma. Acta Radiol Suppl 127 (1955). 5. Kottmeier H L: Evolution et traitement des epithetiomas. Rev Fr Gynec Obstet 56, 821 (1961). 6. Pettersson F: Adenocarcinoma of the uterine cervix. Changes in incidence. 38th Annual Meeting of the Society of Pelvic Surgeons, October 5-8, 1988, Toronto, Canada. 7, Christopherson W M, Lundin Jr. F E, Mendez W M, Parker J E: Cervical cancer control. A study of morbidity and mortality trends over a twenty-oneyear period. Cancer 38, 1357 (1976). 8. Christopherson W M, Parker J E, Mendez W M, Lundin F E Jr: Cervix cancer death rates and mass cytologic screening. Cancer 26, 808 (1970). 9. Boyes D A, Knowelden J, Phillips A J: The evaluation of cancer control measures. Summary of the conclusion of U[CC Symposium held in Sheffield in September 1.972. Br J Cancer 28, 105 (1973). 10. Cramer D W: The role of cervical cytology in the declining morbidity and mortality of cervical cancer. Cancer 34, 2018 (1974). 11. Gardner J W, Lyon J L: Efficacy of cervical cytologic screening in the control of cervical cancer, Prevent Med 6, 487 (1977). 12. Shulman J J, Leyton M, Hamilton R: The Papanicolaou smear: an insensitive case4inding procedure. Am J Obstet Gynecol 120, 446 (1974).
(k'rvica! cancer screenilzg 13, Sackett D L: Can screening programs for serious diseases really improve health? Science Forum IS, 9 (t970). 14, Martin P L: [tow preventable is invasive cervical cancer? A community study of preventable factors, A m J Obstet G'ynecot 113, 541 (1972), 15. Guzick D S: Efficacy of screening for cervical cancer: A review. A m J Public Health ,68, 125 (t978). 16, West R R: Cervical cancer: Age at registration and age at death. Br J Cancer 35, 236 (1977), 17. SaxOn E A: Trends: facts or fallacy, in Magnus K (ed): Trends in Catlcer lncideJwe. Causes and Practical Implications, p. 5. New York, Hemisphere Pubfishing Corporation (1982). 18. Pettersson F, Bj6rkholm E, Ntislund I: Evaluation of
t8l
screening for cervical cancer in Sweden: trends in incidence and mortality 1958-198{). lnt J Epidemiot
14, 52i (1985). 19. Pettersson F, N/islund I, Malker B: Evcduation of the Effect or Pal)cmicohlou Screening in Sweden: Record Linkage Between a Central Screeptin~ Registry and the National Cancer Registry', IARC Scientific Pubt No. 76, Lyon (1986), 20. Hakama M, Magnus K, Pettersson F, Storm H, Tulinius H: Effect of the organized screening in the Nordic countries on the risk of cervical cancer. 21. Hakama M, Miller A B, Day N E: Screening j o t Cancer of the Uterine Cervix. IARC Scientific Publ No. 76, Lyon (t986).
