II.

Screening for carcinoma of the cervix

tively unselective screening one should sugar levels and other biochemical fea¬ tures of diabetes, and patients with reason to believe that the screen¬ process ing procedure will be worth while.3 The borderline hypertension. Similar prob¬ be ethically, scienti¬ lems are now coming to light as a In order to evaluate the impact of a procedures should if and, justi- result of breast cancer screening. Not possible, fically screening program one must be aware fied before they are financially introduced into only may the importance of such con¬ of what it can be expected to achieve. medical Screening for carci¬ ditions be disputed, but their natural This requires an appreciation of the noma ofpractice. the cervix has not raised history may be unknown and their the screening ethical difficulties, but the other aspects proper management in doubt. Only philosophy underlying process. have been subject to controversy. The careful programs of surveillance, fol¬ condition being screened for should be low-up and sometimes research into Definitions alternative therapies can correctly deli¬ an important health problem and there Screening is generally considered to should be an acceptable treatment for neate the proper management of such be a medical investigation that does not it. The natural history of the condition conditions. The possible necessity for arise from a patient's request for ad¬ should be understood. If, as is the case such research should not be overlooked vice on specific complaints. The aim for cancer of the cervix, there is a rec- in the setting up of screening programs. is to diagnose disease at a stage when ognizable latent or early symptomatic Because there has been controversy the treatment is likely to be most ef¬ stage, there should be a suitable and over the justification for screening for fective, in the hope that disability and acceptable test and treatment for such cancer of the cervix, it is worth con¬ mortality from the disease will be a stage. The facilities required for full sidering the ways in which the scientific reduced. However, these statements do diagnosis and treatment in patients with basis of screening can be established. not sufficiently characterize screening a positive screening test should be avail¬ and it is therefore necessary to adopt able. There is no point in detecting a Measures of validity a specific definition. A recommended condition if it cannot then be treated. one is that screening is "the presumpThe validity of a screening test has It is desirable that there be an agreed tive identification of unrecognized dis¬ policy on the categories of lesions been defined as the frequency with re¬ ease or defect by the application of quiring treatment. This has not always which the result of the test was later tests, examinations or other procedures been so for the precursors of cancer of confirmed by an acceptable diagnostic which can be applied rapidly".1 The the cervix. Treatment of the presympto- procedure.1 Two useful measures of screening tests used are designed to matic stage of the disease should validity are sensitivity and specificity. sort out apparently well persons who favourably influence its course and Sensitivity is defined as the ability of probably have a disease from those who The cost of the total pro¬ a test to give a positive finding when probably do not. However, it is im¬ prognosis. should be reasonable in relation the person tested truly has the disease gram portant to recognize that a screening to overall expenditures on medical and under study. An insensitive test will test is not intended to be fully diagnos¬ hospital care. Finally, it is important to result in a high proportion of falsetic. This implies that persons with posi¬ appreciate that having established a negatives. If these are in individuals tive or suspicious findings must be program and created a public who have a poor prognosis the screening studied further for a final diagnosis screening it will usually be necessary to test will rapidly fail into disrepute. Spe¬ demand, leading to treatment if necessary. maintain the program. cificity of a screening test is defined as Mass screening is an extension of the One aspect of screening that may be the ability of a test to give a negative screening activity so that it is conducted overlooked at the time programs are finding when the person tested is free on the whole population or a major initiated is that the process of screening of the disease under study. A test of subgroup of it (for example, all adults).2 may identify a new of disease, low specificity will result in a high Selective screening is screening con¬ previously unrecognizedtype because it does proportion of false-positives. This may ducted on a segment of the population not give rise to symptoms. The signi¬ cause considerable anxiety and eco¬ at relatively high risk. Risk may be ficance of such a disease may initially nomic cost to those who have to be defined by age, sex, family history, pre¬ be in some doubt. Screening for carci¬ evaluated in order to confirm that they vious medical history, occupation or noma of the cervix brought to light a do not have the disease. Generally other defined parameters established, number of cases of preclinical speaking, sensitivity and specificity tend by prior epidemiologic investigation, to large to behave in an inverse fashion and the some of which was not defini¬ disease, be predictors of high risk. Mass screen¬ tely malignant (e.g., dysplasia). It also risk of missing a condition may well ing, even when somewhat selective, can brought to light two conditions justify a lower order of specificity than be expensive, and highly selective namely, microinvasive and occult in¬ one might otherwise wish. In the case screening should be aimed for when¬ vasive cancer of the cervix with of malignant disease most people would ever possible. A further relative reduc¬ features definable pathologically as in¬ prefer a highly sensitive test and be tion in expense might be achieved if vasive cancer, but which had not given prepared to put up with some reduction one could screen for different diseases rise to symptoms and were relatively of specificity. at the same session. This is the prin¬ limited in extent. The relations between sensitivity, Appropriate treatment ciple behind multiphasic screening. for these conditions had not been estab¬ specificity, false-positive rate and falseProblems in relation to this and cancer lished because there had not, prior to negative rate are illustrated in Table I. of the cervix are considered in part IV the development of cytologic testing, May4 discussed the relation between of this report. been any way of detecting them except these variables. He pointed out the er¬ by chance. Similar problems have rors often made in considering falseJustification arisen in other screening programs; for positive and false-negative rates, be¬ Before setting up a program of rela¬ example, patients with raised blood cause those members of the population

Philosophy of the screening

have

.

.

CMA JOURNAL/JUNE 5, 1976/VOL. 114 1013

without disease (the true-negatives) and those with the disease (the true-positives) cannot be identified immediately but only after careful investigation and long-term follow-up. There is a temptation to calculate false-negative and false-positive rates using the test results to define the denominators. Thus, May's "pseudo-rate of false-positives" is the number falsely screened positive di¬ vided by the total number positive on the test, or b/a + b, while the "pseudorate of false-negatives" is the number falsely screened negative divided by the total number negative on the test, or c/c + d. May advocates the use of two

practical (and readily obtainable) rates as approximations to the truth. The "apparent positive rate", defined as the proportion of the total population with positive test results, or a + b/a + b + c -f d, is the only initially available estimate of the true positive rate, or a + c/a + b-f-c + d. The "apparent rate of false-negatives" is the number of false-negatives expressed as a pro¬ portion of the sum of the numbers of positives and false-negatives, or c/a +

of such indices,

must be taken to only that the type of test is specified, but also that the disease being sought is carefully defined, so that even if authors do not use the same definition, at least discrepancies can be understood. For example, if "disease" were to be defined only as clinical invasive carcinoma of the cer¬ vix (an absurdity in the context of a cervical cancer screening program) nearly all the abnormalities that are currently sought in screening programs in Canada would be defined as falsepositive. Thus, it is more realistic to include, within the definition of "dis¬ ease", at least carcinoma in situ, to¬ gether with all three types of invasive carcinoma microinvasive, occult in¬ vasive and clinical invasive. Many cytologists would also include patients with care

.

dysplasia. In interpreting false-negative rates it is important to realize that in cervical cytology there are two components to the problem of false-negatives. The first comprises laboratory error, the cytotechnologist failing to detect cells that b 4- c. This is a useful measure of are truly abnormal and that are present the extent to which disease that should in the smear. An estimate of the extent be treated is being missed. The extent of this error can be reached by appro¬ to which this is occurring in the Man- priate quality-control procedures within chester, England cytology program is the laboratory. The other component, currently being assessed by a policy of due to errors in taking a smear, can only be estimated by appropriate fol¬ planned recall.5 low-up of individuals. It is well recog¬ nized that, if the smear is not correctly Sources of error in interpretation taken, lesions that are present may

In order that there should be unifor¬ mity of presentation and understanding Tablo I.Relations between sensitivity,

false-negative

Other criteria for

screening programs

ensure not

not be detected because cells exfoliated from them are not included in the smear.

specificity, false-positive

rates

rates and

Other evaluation criteria of

screen¬

ing tests apart from specificity and sensitivity also have to be borne in mind.3 Some of these include: 1. Simpiicity. The test should be easy to perform. 2. Acceptability. The test should be acceptable to the subjects. 3. Accuracy. The test should give a true measurement of the attribute under investigation. 4. Precision. The test should give consistent results in repeated trials. 5. Cost. The expense of screening should be reasonable in relation to the benefits resulting from the (early) de¬ tection of disease. Problems in

conducting screening

programs

There are additional problems.

Many

program attenders are self-selected. For cancer of the cervix this may mean that they tend to have a better progno¬

sis than usual, segment of the

they come from the population that is most

as

health-conscious and may be least liable exposed to the risk factors for cancer of the cervix. Furthermore, the to be

nature of the screening process, de¬ pendent as it is on examinations of asymptomatic people, tends to result in cases detected on screening having a higher proportion of long-term sur¬

vivors than usual. Two mechanisms operate to bring this about. Firstly, people with more advanced disease and with more rapidly progressive disease are more likely to have symptoms and to present themselves for diagnosis through procedures other than screen¬ ing. Thus, those with a naturally poorer prognosis may completely escape the screening net. Secondly, if the test per¬ mits detection of disease at an earlier point in the natural history than usual (the lead time), the survival from the time of diagnosis following screening will inevitably be longer than if the disease were not to be diagnosed until symptoms had been allowed to de¬

velop.6 Both these mechanisms will operate in a screening program even if the treatment procedures do not result in any true benefit. The implication is that standard survival-time or case-fatality comparisons may be fallacious; it is necessary to assess changes in popula¬ tion mortality rates. These aspects are further discussed later in this part of the report. Further difficulties arise in a situa¬ tion where other changes may be oc¬ curring at the same time as the intro¬ duction of screening. These could either be improved methods of therapy or

1014 CMA JOURNAL/JUNE 5, 1976/VOL. 114

even declining incidence of the disease. Controversy exists over whether or not

these circumstances obtained in relation cervix; the available data are discussed later in this part. Finally, it may be difficult to persuade people to attend for screening. This difficulty obviously becomes pro¬ gressively more severe as the program to cancer of the

to reaching complete cov¬ erage. It has to be appreciated that it is impossible to reach 100% of the comes nearer

population. This is because of the changing nature of human populations. As women age they enter the risk group; and they leave it both through ageing and through death from other causes. In addition, migration patterns can seriously interfere with the cover¬ age achieved by screening programs particularly, migration to a well screened region from an area where the coverage of the population may have been less than optimal. It has been cal¬ culated that in British Columbia, be¬ cause of these problems, the practical maximum for population coverage is 82 to 85%. For this reason, however ef¬ fective the screening test and however efficient the procedures that are carried out after the test has been found to be positive, it may be impossible to elim¬ inate morbidity and mortality from a disease by screening.

.

Conclusion It should be recognized that screening for cancer of the cervix has a par¬

ticularly important advantage over screening for many other malignant conditions. The procedure is based on the detection of precursors of the truly

invasive condition. As discussed in part I, there is time for these pre¬ cursors to be detected and treated before invasive malignant disease supervenes. Therefore, this is one of the instances in which screening can be expected to result in a reduction of incidence of clinical disease. This can¬ not occur in those conditions, such as carcinoma of the breast, in which one has to wait for invasive disease to be present before it can be recognized by a screening procedure. One can expect prevention of invasive cancer of the

cervix,

not

merely early diagnosis.

Elsewhere in this part of the report the achievements of cervical cancer screening programs, as far as they can be measured, are discussed. At this point it has to be emphasized that it can be extremely difficult to measure such achievements and to utilize them in planning programs. Increasingly, health statisticians and economists are turning to computer simulation in order to try to solve some of the problems of planning. Though very often the real-life data needed in order to pro¬

duce an appropriate model may not be available, the endeavours that are going on in this area could well result in substantial guidance in planning screening programs in the future. The interested reader is referred to a paper by Knox7 for further details of one such model.

Screening activity in Canada Screening for carcinoma of the cer¬ vix in Canada has developed as a result of two complementary requirements: firstly, a demand for skilled cytologic diagnosis of the precursor of invasive carcinoma of the cervix, created ini¬ tially by gynecologists and subsequently by informed members of the public; and secondly, a realization, mainly on the part of gynecologists and cytopathologists, that the full potential benefit of cervical cytology in terms of reduc¬ tion in both morbidity and mortality of carcinoma of the cervix would not be achieved unless programs were designed to screen large numbers of asympto¬ matic women. In British Columbia this process re¬ sulted in the provision of a provincially

organized cervical cytology service based on one large central laboratory. The program began in 1949 as a diag¬ nostic laboratory. It gradually expanded its activities to population screening in the 1950s; and in the early 1960s, with the assistance of the Canadian Cancer Society (CCS) and the opportunity pro¬ vided by large numbers of women requesting prescriptions for oral contra¬ ceptives, the program became provincewide.8 It is against this program that the achievements of other programs in Canada and elsewhere tend to be measured. Sources of information There is no centralized source of data on cervical cytology screening for

Table II.Numbers of laboratories Canada and the provinces, 1971|

cancer

of the cervix in Canada. Data

however, available, up to 1974, from a number of sources. First, the Canadian Society of Cy¬ tology (CSC) has published the results of two surveys.910 A third, covering the years 1968 to 1971, and a fourth, cov¬ ering 1972 to 1975, both as yet unare,

published, have been made available to the task force in the form of the original questionnaires and replies. Sec¬

ond, the British Columbia program has been well documented in a number of publications over the years,11"13 and the most current data have been made available to the task force. Third, On¬ tario programs were reviewed recently by a provincial task force, and the report of this has been published.14 Fourth, data on the Quebec program are maintained by the ministere des Affaires sociales de la province du Quebec, and these data have been made available to us. Fifth, individual en¬ quiries have been made of some labo¬ ratories to obtain previously missing information. The provinces of Nova Scotia and Newfoundland have recently set up pro¬ vincial cytology registries. The province of Manitoba has had a registry since 1963; it publishes information in the reports of the Manitoba Cancer Treat¬ ment and Research Foundation. It is to be hoped that other provinces will follow suit. Distribution of

cytology services

.In Table II are shown the numbers of laboratories providing cervical cy¬ tology services in 1971, classified ac¬ cording to the number of specimens examined. Table III shows the propor¬ tion of specimens examined in labo¬ ratories of different sizes. It is ap¬ parent that there is a tendency in most provinces for a major proportion of specimens to be examined in the

larger laboratories, the size of these

providing

cervical

cytology services, by size,*

Laboratory size Province British Columbia Alberta Saskatchewan Manitoba Ontario

< 499

5004999

500024999

25 00099999

£ 100000

Quebec

New Brunswick Nova Scotia Prince Edward Island

Newfoundland 39 75 100 15 Canada ?Defined by numbers of specimens examined per year. fSource: unpublished data from the Canadian Society of Cytology 1971 survey. CMA JOURNAL/JUNE 5, 1976/VOL. 114 1015

being compatible with the size of the population of the province. In British Columbia and Prince Edward Island virtually all cytology screening is done in a single laboratory. One laboratory clearly carries the major load in Saskatchewan, in Manitoba and in Nova Scotia. In Quebec and Ontario the pattern is predominantly one of screening in numerous laboratories, most of which examine fewer than 25 000 specimens annually. Coverage

population Table IV gives an indication of the degree of coverage achieved in the Canadian population in three reference years during the decade 1962 to 1971. The figures are based on the number of gynecologic examinations conducted in each province, derived from the data of the surveys of the CSC, shown as a percentage of the population of women aged 20 and over. It is appreciated that "no. of cyto¬ logic examinations" is a less informa¬ tive numerator than "no. of women examined". Unfortunately the latter in¬ formation can be readily obtained only for British Columbia and Manitoba. To ensure comparability, therefore, the same type of numerator has been used throughout the table. It can be seen that during this period the coverage of the province by cervical cytology was greatest in British Columbia, but that the increase in proportion examined was greater in some other provinces notably, Saskatchewan, Manitoba, On¬ tario, Nova Scotia and Newfoundland. Preliminary data from the CSC survey for the period 1972-74 indicate that the amount of screening activity had reached a plateau in most provinces. As the coverage of the population increases, the proportion of examina¬ tions that are re-examinations of pre¬ viously screened women also increases. Eventually such re-examinations form

Table IV.Extent of cervical screening, Canada and the provinces, 1962, 1967 and 1971* No. of cytologic examina¬ tions as % of female popu¬ lation more

aged 20

years

or

of

.

Table lll.Distribution of cervical and the provinces, 1971|

?Source: unpublished data from the Canadian Society of Cytology 1971 survey and references 9 and 10.

the major part of the laboratories' work. Only some provinces are able to supply data of this type. In 1970 the proportion of examinations that were first examinations was 27% in British Columbia, 43% in Alberta, 37% in Saskatchewan, 65% in Ontario and 74% in Newfoundland. It is estimated that 80% or more of the eligible popu¬ lation of Manitoba and British Colum¬ bia has been screened at least once. Similar estimates are not available from the rest of the country. Even with a well organized central registry such es¬ timates are difficult to derive with pre¬ cision because of problems of undetected duplication in the files when women change their names through marriage or when names are incorrectly spelled or recorded. Such errors result in women attending for repeat screen¬ ing being incorrectly regarded as first attenders, thus inflating the proportion of the population regarded as having been screened at least once. Migration from a province and undetected death of previously screened individuals also result in an overestimate of the propor¬ tion of the current population that has

cytology

services

by laboratory size,* Canada

'Defined by numbers of specimens examined per year. tSource: unpublished data from the Canadian Society of Cytology 1971 survey. 1016 CMA JOURNAL/JUNE 5, 1976/VOL. 114

been screened at least once. The existence of such errors is par¬ ticularly important if data on numbers of individuals screened are used to es¬ timate the incidence of invasive carci¬ noma in the unscreened population. The errors result in the denominator for the unscreened population being too small, thus making the incidence of invasive carcinoma in unscreened wom¬ en appear to be higher than it really is. A related difficulty arises when women migrate from poorly screened areas to well screened areas and arrive with carcinoma of the cervix not de¬ tected by the immigration physician. Such women, even if identified as re¬ cent migrants, are usually left in the incidence tables of the receiving prov¬ ince to counterbalance those women who have left and have subsequently had carcinoma of the cervix diagnosed elsewhere. This procedure will adverse¬ ly affect the statistics in a well screened area because invasive disease is less likely to develop in women migrating from such an area than in women migrating into it from an area that is less well screened.

Effects of screening in Canada Incidence In part I of this report the available data on incidence rates for carcinoma of the cervix and the pitfalls in inter¬ preting them were discussed. In this section trends of incidence derived from cancer registries and other data in Canada are presented, and discussed in the light of those pitfalls. In addition, when interpreting the data on trends, it must be constantly borne in mind that most are based on small numbers, and that year-to-year fluctuations can occur by chance. Available data on the change in staging patterns for carcino¬ ma of the cervix are also presented. Incidence rates for carcinoma of the cervix during a period of a decade or more are available from the provincial cancer registries of Quebec, Manitoba and Alberta, and from the Saskatche¬ wan Cancer Commission. In British Columbia a special registry maintained by the provincial cervical cytology la¬ boratory has kept a record of incidence rates since 1955. Age-specific incidence rates, or, failing that, numbers of cases registered as invasive carcinoma of the cervix, were obtained from these sources for the periods for which data are available, either from published data or by special request. These data were used to calculate, wherever possible, age-standardized truncated rates* for the age span 35 to ?For a full description of age-standardized rates, their methods of calculation and the reasons for using truncated rates, the interested reader is referred to chapter 6 in "Cancer Incidence in Five Continents", vol. 2, pages 333-38.1*

64. This age period was chosen for cancer and in situ cancer are combined. comparability with available truncated It is thus apparent that this particular rates from international cancer regis¬ registry failed to distinguish in situ can¬ tries in the publication "Cancer Incid¬ cer in its records until 1969 and its ence in Five Continents". As discussed data are thus not utilizable for ascer¬ in part I, it avoids inclusion of cases taining the effect of screening on trends in which the diagnosis was made at of incidence of invasive cancer. The age 65 or more, a period when, at data from the other provincial sources least for mortality data, imprecision in are reproduced in Figs. 2 to 5. They certification can be expected, and also do not appear to contain the artefact a period when it seems unlikely that seen in Quebec. an early effect of screening could be ascertained. The population base rec¬ Manitoba

ommended in volume 2 of "Cancer Incidence in Five Continents" for cal¬ culating truncated rates was used.15 Fig. 1 shows the incidence rates for Quebec, calculated in this manner. It also shows the annual number of ex¬ aminations reported in the surveys of the CSC,9,10 expressed as a percentage of the female population aged 20 or more. These percentages are used as indices of the screening activity in the province. It appears from the figure that the incidence rose from 1963 to 1968, only to fail dramatically to the present level in 1969, when the registry adopted the coding rules for the eighth revision of the International Classifica¬ tion of Diseases. The earlier, higher level persists if the rates for invasive

The data for Manitoba are presented in Fig. 2. Age-specific rates for invasive carcinoma of the cervix were available by 10-year age groups for the years 1962 to 1973. Thus, the age-standard¬ ized truncated rates are calculated for the age range 30 to 59, using an ap¬ propriate modification of the standard world population. It is apparent that the incidence rate for cancer of the cervix has fallen progressively over the decade for which data are available, while simultaneously the amount of screening has increased. These data are difficult to interpret in the absence of baseline incidence rates for the years preceding the introduction of the screening program.

Saskatchewan The data for the Province of Saskat¬ chewan are presented in Fig. 3. In that province incidence rates are available for the period 1946-73, thus providing several years' experience without screening. It is apparent that, notwith¬ standing the wide fluctuations in rates (probably related to the relatively small numbers of cases), the incidence dropped over the period 1946-60. There is a suspicion that the incidence may well have been relatively stable over the first 10 years of this period, only to fail in the next 5 years. However, the apparent stability may be an arte¬ fact of relatively incomplete datagathering during the early years cov¬ ered by the figure. Over the period 1963 to 1967 the rates show a dramatic upswing, only to fail in 1968 and con¬ tinue failing thereafter to 1973 (the last year for which data are complete at the time of writing). The overall incidence in the period 1963-67 was higher than in the 1st decade shown in the figure. These high rates coincided with the relatively rapid introduction of the screening program in the province. A plausible interpreta¬ tion is that, initially, a high proportion of those screened were either sympto-

Rat« 90

Screening index 60

7^;

Cervical cancer screening programs. II. Screening for carcinoma of the cervix.

II. Screening for carcinoma of the cervix tively unselective screening one should sugar levels and other biochemical fea¬ tures of diabetes, and pat...
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