Strategies for global control of cervical cancer

Int. J. Cancer: 60, 1-26 (1995) 0 1995 Wiley-Liss, Inc.

Publication of the International Union Against Cancer Publication de I Union Internationale Contre le Cancer i

STRATEGIES FOR GLOBAL CONTROL OF CERVICAL CANCER Jan PONTkN',2.9, Hans-Olov ADAM12,3, Reinhold BERGSTROM2,4, Joakim DILLNER~, Lars-Costa F R I B E R ~ , Leif GUSTAFSSON~, Anthony B. MILLER7, D. Max PARKIN8, Par SPAREN? and Dimitrios TRICHOPOULOS3

'Department of Pathology and 2Departrnent of Cancer Epidemiology, Uppsala University, Uppsala, Sweden; 3Department of Epidemiology, Haward School of Public Health, Boston, M A , USA; 4Department of Statistics, Uppsala University, Uppsala; SDepartment of Krology, Karolinska Institute, Stockholm; hDepartment of Gynecologic Oncology, Sahlgrenska Hospital, Gothenbutg, Sweden; 7Depaflment of Preventive Medicine and Biostatistics, University of Toronto, Toronto, Canada; RDescriptive Epidemiology Unit, International Agency for Research on Cancer, Lyon, France.

TUMOR BIOLOGY AND NATURAL HISTOR Tumor biology ...................................................... Definition of disease entities ................................

Precursors of invasive cancer ........................... Clinical stages ................................................................... 4

Natural history ...................................................................... 5 Incidence and prevalence ................................................. 5 Regression ........................................................................ 5 Quantitative models ......................................................... 6 Generalization of the natural history .............................. 7

ETIOLOGY ............................................................................. 7 Papillomavirus ...................................................................... 7

Subtypes of HPV .............................................................. 7 Diagnostic methods .......................................................... 8

Immunohistochemistry ................................................. 8 Nucleic acid analysis ..................................................... 8

Immunity to HPV ............................................................. 8 Papillomaviruses and sexual behavior ............................. 8 Causal models ................................................................... 9

HPV as risk factor for dysplasia and cancer ................ 9 HPV and cervical lesions .................................................. 9

Normal mucosa ............................................................. 9 Koilocytosis ................................................................... 9

Slight and moderate dysplasia ...................................... 9 Severe dysplasia/CIS .................................................... 9 Invasive cancer .............................................................. 9

Condyloma .................................................................... 9

Summary of HPV and cervi Herpesvirus ............................. Smoking .................... Oral contraceptives .. Diet ......................................... Inheritance ............... ................................. 1 I

T SCREENING ..... 11 Primary prevention ............................................................... 11

REDUCING MORTA

Assessment of effects of early diagnosis and treatment ..... 12 Detection at earlier clinical stages ................................... 12 Improved stage-specific survival ...................................... 13 Combined and separate effects of early detection

Factors underlying successful public information in and improved stage-specific treatment ........................ 13

.................................... 13 Clinical downstaging ............................................................ 14

CYTOLOGICAL SCREENING ............................................ 14 Effectiveness of screening ............ Natural history of cervical cancer

Over-treatment ......................... Starting age, frequency and termination of screening .... 16 Optimization ..................................................................... 17 HPV testing ...................................................................... 17

Virological typing of dysplasia to predict risk of progression ...................................................................... 17

Increasing sensitivity of cytological screening programs by addition of HPV testing ............................ 17

RECOMMENDED ACTIONS .............................................. 17 General background ............................................................. 17 Basic treatment and early clinical detection of invasive

cancer ............................................................................ 18 Prerequisites ..................................................................... 18 Implementation ................................................................ 19 Assessment ...................................................................... 19

Clinical down-staging ........................................................... 19 Implementation ................................................................ 19 Assessment ....................................................................... 19

Cytological screening ........................................................... 20 Implementation ................................................................ 20

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Carcinoma of the uterine cervix is one of the leading causes of death from cancer among women (Parkin et al., 1993; Pisani et al., 1993). Since it frequently afflicts relatively young women, its toll in reduced life span is considerable. The wide global variation in incidence (Brinton, 1992; Parkin et al., 1993) (Fig. 1) indicates that the impact of this cancer would be much reduced by application of current knowledge to populations with high incidence and death rates. On a global scale, carcinoma of the cervix may be the most preventable major form of cancer.

Suggested or implemented means of control include alter- ation of life style (sexual behavior), vaccination against human papillomavirus (HPV), testing for HPV infection, cytological screening, early clinical detection and improved therapy. We underscore the need for a thorough appreciation of tumor biology and of the natural history of cervical cancer to understand the effect of any intervention. Our final goal is to lay down scientifically sound schemes of how this disease should best be dealt with to reduce incidence and mortality in global terms.

We have several reasons for concentrating on data from Scandinavian countries and particularly Sweden: (i) To en- hance the consistency in any description of the natural history of a cancer with a wide geographical variation in incidence and in the prevalence of risk factors, it is useful to focus on data from a few populations with well-defined epidemiological parameters, rather than to compile results from numerous locations. (ii) Scandinavian data have been extensively used and have provided many of the most reliable reports on this subject. The population-based registries of the Nordic countries have been invaluable in the present context. (iii) Histori- cally, Sweden has played a leading role in the introduction of

9To whom correspondence should be addressed, at Department of Pathology, University Hospital, S-751 85 Uppsala, Sweden. Fax: 46 18 552739.

Received: October 22,1993 and in revised form May 2, 1994.

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FIGURE 1 - Estimated age-standardized (‘World’ population) incidence rates of invasive cancer (per 100.000) by world area (from Parkin er al., 1993).

strict follow-up schemes and diagnostic recordings (Heyman, 1937-1952). These data have helped immensely in elucidating effects of early detection and improvement of stage-specific treatment. Data collection continued during World War I1 without interruption.

Although most registries do not discriminate between adenocarcinoma and squamous cell carcinoma, our discussion focuses on the latter. Adenocarcinomas constitute a relatively small proportion of cervical cancers and have not attracted much separate attention compared to the squamous cell type. Our conclusions do not therefore automatically have a bearing on adenocarcinoma.

TUMOR BIOLOGY AND NATURAL HISTORY Tumor biology

Advances in molecular biology in recent years have supported the multi-step somatic mutation theory of carcinogenesis (Armitage and Doll, 1954; Friendet al., 1988; Knudson Jr., 1980; Vogelstein et al., 1988). The majority of models indicate that at least 2 “hits” are required to produce cancer. These events may be mediated by ( i ) mutations in host genes (proto-oncogenes), which result in gene products promoting the neoplastic process; ( i i ) inactivation of regulatory genes (suppressor genes) by mutation or allelic loss; and (i i i) host events mediated by immunological or hormonal phenomena (Friend et al., 1988; Vogelstein et af., 1989).

It is logical to divide the life history of cancers in general into two parts: induction and proliferation of transformed cells. The borderline, termed “malignant”, transformation, generally considered a qualitative permanent cell change, is defined as the point in time when the founder cells of the cancer have permanently acquired the capacity to multiply outside normal growth control (Fig. 2).

Induction encompasses all persisting (genetic and possibly epigcnetic) changes occurring in one or more originally normal cells, which subsequently become the founder cells of the

malignant cell population of the proliferation stage. In most cases, the bulk of all changes will occur post-embryonically; however, in hereditary cases some are already present in the germ line. In this latter case the length of the induction period will last from fertilization until malignant transformation. Induction will not be complete until the last event of a multi-hit sequence has ensued.

Induction may or may not be accompanied by morphological abnormalities. The most common sign may be pathological proliferation and/or differentiation. Examples of this are the hyperplasias which precede malignant transformation in mice exposed to certain chemical carcinogens or transfected by oncogenes. In the human situation “pre-neoplasia”, such as atrophic gastritis, intestinal gastric metaplasia and atypical mammary epithelial hyperplasia, may be given as additional examples.

Definition of disease entities Precursors of invasive cancer. Classification issues enter in a

profound manner into any discussion of the natural history of cervical cancer and its elucidation.

Cancer in situ (CIS) was not appreciated as a separate entity until the 1940s (Papanicolaou and Traut, 1943). Interest was stimulated by Papanicolaou’s discovery of shed atypical cells in the vagina of women, who did not have invasive cancer (Papanicolaou, 1946). Unfortunately, no consensus has been reached in defining structural criteria for relevant morphological entities in spite of some very detailed and well illustrated texts (Burghardt, 1973). From combined morphological, cyto- genetic and clinical evidence, the following picture appears to conform best with available data (Ferenczy, 1982).

Neoplasia of cervical squamous epithelium (papilloma/ condyloma, dysplasia, carcinoma) can be defined and distinguished from hyperplasia. Sharp morphological borders to surrounding epithelia suggest partly autonomous, possibly clonal multiplication (Burghardt, 1973).

CONTROL OF CERVICAL CANCER 3

I n d u c t i o n P r o l i f e r a t i o n of t r a n s f o r m e d c e l l s

FTCURE 2 - Schematic outline of carcinogenesis. During the first phase, induction, mutations (“hits”) will accumulate in the genome of the nomal cells, shown as rounded rectangles with regular oval nuclei. Some of the mutations may have profound influence on the phenotype of the subsequently developing population of cancer cells. During the second phase, proliferation of transformed cells, which follows after malignant transformation has taken place, at least 3 alternatives are possible. Alternative A implies that the cancer progresses because of further mutations and selection of increasingly more malignant subclones. Different patterns are used for the nuclei to illustrate such an event. Alternative B implies that such progression is not common but that, instead, the basic characteristics (such as degree of differentiation, capacity for metastasizing, hormone sensitivity) were laid down already during induction and before malignant transformation. This is indicated by maintaining the same nuclear shapes and staining pattern. Alternative C is spontaneous regression. Induction may either be accompanied by hyperplasia (or other “nonspecific” morphological manifestations) as outlined in the lower left part of the figure or occur without visible cell changes (upper left). Malignant transformation is defined as loss of proliferation control permitting the cancer cell population to increase its size beyond physiological limits. It is accompanied by cytological atypia.

Within the broad category of neoplasia, a biological dividing line extends between non-invasive and invasive neoplasia. The ambiguous term “benign neoplasia” (of squamous epithelium) should be avoided and if used. restricted to papillomas and condylomata, which have virtually no tendency to progress further.

Four categories of non-invasive neoplasia (mild dysplasia, moderate dysplasia, severe dysplasia, CIS), which are all considered part of a morphological continuum, have conven- tionally been separated. Within each category differences exist among individual cases. The distinction between the categories is subjective but fairly reproducible in the hands of experi- enced specialists (Burghardt, 1973).

The morphological criteria used to differentiate the respective subclasses of non-invasive neoplasia are based on the degree of epithelial differentiation. In mild dysplasia, the basal layer of neoplastic cells gives rise to increasingly mature squamous cells as the mucosal surface is approached. In CIS no or. at most, slight differentiation may be discerned as cells get closer to the surface. Degree of atypia, i.e., departure from

normal cell morphology, generally becomes progressively obvious along a scale from mild dysplasia to CIS.

Cells shed from mild dysplasia are often cytologically indis- tinguishable from normal surface epithelia but presumably contain the same putative “neoplastic” somatic genetic lesions as the basal cells from which they have differentiated.

Condyloma, different degrees of dysplasia, CIS and invasive cancer can only with sufficient scientific stringency be distinguished from each other in histological slides. Only then can details of intercellular relations be ascertained.

There is commonly a gradient toward lower degrees of dysplasia from the endocervix to the periphery of the ectocer- vix when dysplasia of different degrees co-exist (Burghardt, 1973).

Each non-invasive type of neoplasia has in principle 3 options for further development: (i) regression, (ii) progression to the next higher step in the sequence of dysplasia -+ CIS, or (iii) development into invasive squamous cell cancer. The likelihood of (i) and (ii), respectively, has not been established but may be roughly equal for each type of non-invasive

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neoplasia. The likelihood of (i i i) is, however, different. It has been claimed that it is high and almost identical in severe dysplasia and CIS. This is the basic reason for lumping these two together as CIS or as cervical intra-epithelial neoplasia (CIN) I11 (Richart, 1973). That this may have been an unfortunate choice is indicated by indirect evidence suggesting considerable over-diagnosis because of inclusion of severe and possibly also moderate dysplasia into the category CIS in Sweden (Bergstrom l’t al., 1993). In contrast, slight and moderate dysplasia appear to have a low probability of direct progression to invasive canccr (Ferenczy, 1982).

Figure 3 outlines some of the alternatives for the relations between invasive cancer and its precursors.

In spite of the clinical value of the CIN classification (Richart, 1973) and the existence of further simplifications which subdivide “pre-cancers” into low and high grade (Solo- mon, 1989). we have chosen to employ the older terminology based on the terms dysplasia, CIS and invasive cancer (Ander- son et al., 1991), notwithstanding potential problems in interpretation of “dysplasia” (Table I). The 2 main reasons for this choice arc (i) the possibility of including articles published before the introduction of the CIN classification and (ii) to avoid the confusion introduced into the CIN system by including cellular signs of viral infection among the diagnostic criteria (Anderson et al., 1991).

Clinical stages. As early as 1914, with incredible foresight, James Heyman at the Radiumhemmet in Stockholm introduced a classification of invasive cervical cancer involving 4 stages. This classification was officially adopted by the Health Organization of the League of Nations in 1935. It was slightly

modified (Heyman, 1938) and has become the international gold standard (Table 11). It has remained virtually unchanged except for subdivisions of stages I-IV and the addition of stage 0 (CIS). The stages are based on the same clinical criteria now (inspection, palpation) as when they were introduced. Addi- tional modes of inspection such as colposcopy have been added.

Possible shifts over time in the staging procedure may be regarded as small and, if present, probably go in the direction of “worse” staging as a result of addition of better methods for clinical examination.

A series of annual reports created a scientific international basis for evaluation of progress in gynecological oncology. The series contained guidelines of undiminished value. Examples follow: “The importance of the subject is such that it is imperative that the agreed rules for stage-grouping shall be faithfully observed by the collaborating clinicians. There is no easy road to secure the comparability of stage-rates”; “in the present Report microscopic verification is lacking in less than 2%. . .”; “it may be remarked that the proportion of patients ‘lost sight of constitutes one of the indications as to the reliability or otherwise of statements of results’’; “The ‘absolute’ (recovery) rate. This is the proportion of recovered patients expressed as a percentage of the total number examined . . . whether treated or not”. An atlas depicting all the important features of staging was published in 1950 (N. Einhorn, data not shown).

Historically, it has been presumed that the majority of squamous cell carcinomas of the cervix are preceded by a precursor lesion. Screening strategies which are targeted on

A

B

C

D

Dysplasia Ll

FIGURE 3 - Schematic representation of 4 alternatives of interrelation between dysplasia, in sitrr carcinoma and invasive cancer. Alternative A shows how progression takes place from “fields” with scattered dysplastic cells where polyclonal expansions of the dysplastic cell populations will take place. Later on, CIS develops in several scattered dysplastic cells, which then multiply into a polyclonal cell population, in which invasive properties are acquired by several individual cells, which in turn proliferate into many clones of infiltrating cancer. In this scenario the pedigree of each invasive cancer cell will be complicated depending on its derivation from individual clones of dysplastic and/or in situ cancer cells. In alternative B each successive step in the progression chain occurs via monoclonal expansions from one “founder cell”. Dysplasia is monoclonal in the sense that a single normal cell gave rise to the entire dysplastic cell population. Carcinoma in situ is likewise derived from a single altered dysplastic cell and invasive cancer is in its turn monoclonally derived from a single CIS cell. The pedigree of any invasive cancer cell can be traced back to a single dysplastic cell. Alternative C shows “monoclonal” dysplasia with spontaneous regression. Alternative D illustrates “direct” transformation of a normal cell to invasive cancer without any precursor stages. In such a model dysplasia and CIS are thought to develop in parallel with cancer. Their removal would therefore not perse prevent subsequent development of invasive cancer. The text attempts to make clear that the 4 alternatives of the figure are but a few of the different theoretically possible combinations of tumor biological events in cervical cancer. The weight of evidence favors either A or B as the most probable avenues toward invasive cervical cancer. In both, removal of precursor lesions would prevent development of invasive cancer.

CONTROL OF CERVICAL CAhCER 5 TABLE 1 - TERMINOLOGY FOR SQUAMOUS CELL CERVICAL LESIONS

Present LSI L / HSILZ terminology

Classical histology

CIN’ Non-neoplastic nor- Neg.

CIN I Neoplastic slight dys- LSIL including koilo- Dysplasia”

CIN I1 Moderate dysplasia LSIL including koilo- Dysplasia

CIN 111 Severe dysplasia, car- HSIL Carcinoma in situ

Invasive cancer Invasive cancer Invasive cancer Invasive cancer

mal-reactive

plasia cytosis

cytosis

cinoma in situ

TIN, cervical intraepithelial neoplasia.-?LSIL, low-grade squamous intraepithelial lesion; HSIL, high-grade squamous intraepithelial lesion.-’Koilocytosis only is excluded from the category of dysplasia, the definition of which is based on classical criteria (Burghardt, 1973).-4Reports of carcinoma in situ to The Swedish Cancer Registry are based on the following definition: cancer in situ and severe dysplasia, which are borderline cases of the former.

TABLE 11 ~ DEFINITION OF TI IE STAGES OF INVASIVE CANCER OF THE CERVIX UTERI’

Stage I. Growth is strictly limited to the cervix. Stage 11. Carcinoma extends beyond the cervix but does not reach the

pelvic wall and/or involves the vagina but not its lower third.

Stage 111. Carcinoma reaches the pelvic wall and/or involves the lower

Stage IV. Carcinoma involves the bladder or rectum and/or extends

third of the vagina.

bevond limits alreadv described.

‘“The staging should be based on careful clinical examination and should be performed before any definitive therapy. . . . The clinical stage must under no circumstances be changed on the basis of subsequent findings.” Excerpt from the original definitions (Heyman, 1938).

intraepithelial lesions of the cervix should prevent subsequent invasive carcinoma in a substantial portion of the population (Richart, 1973).

Development from dysplasia to CIS via incremental arrest of differentiation may be enhanced by extension of the precursor lesion deeper into the stroma of the transformation zone, accompanied by a loss of maturation (Crum et al., 1983). It is conceivable that morphological progression in the cervix is partially related to expansion into regions of the transformation zone that do not permit epithelial maturation (Koss et al., 1963).

Natitral history Incidence and prevalence. The prevalence and incidence of

dysplasia, CIS and invasive cancer categories in different age groups have been estimated in many studies. Data reported to routine surveillance systems (eg., cancer registries) may be related to the size of the population at risk. The rates thus obtained are not, however, incidence rates, since they will depend on the intensity of screening in the population. Since pre-invasive lesions are only detected by screening, prevalence of dysplasia and CIS should be expressed in relation to number of tests performed. Such prevalences will be determined by the nature of the sample of women tested (ie., is it truly representative?). They are cross-sectional in nature, making no allowance for possible changes in risk by birth cohort.

Incidence of dysplasia or CIS has to be estimated from screening program data, by recording number of cases detected in previously screened women (assumed to be negative) and relating these to person-years of follow-up (Parkin and Hodgson, 1982). Comprehensive estimates of prevalence and

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ETGURE 4-Shape of age distribution of all cases of mild (n = 2,147), moderate (n = 4,548) and severe (n = 6,463) dysplasia and of cancer in situ (n = 8,435) registered in Denmark 1981-1988 Quadratic B splines were used. Curves are scaled in percent of peak values.

incidence in specific cohorts have been published (Boyes et al., 1982; Koutsky et al., 1992).

Incidence and prevalence rates are mathematically strictly inter-related. To utilize these, the cross-sectional data time series has to be transferred into individual birth cohort data.

In Denmark, dysplasias of different degrees, in addition to CIS, are registered (Storm et al., 1989). These data, taken from a population that has been screened for many years, show that the distribution curves of mild, moderate and severe dysplasia and of CIS have virtually the same shape as a function of age; the sequence in time at which they peak supports the idea of successive progression (Fig. 4). The difference in peak age between the categories is small, about 3 years.

Figure 5 presents an estimate of the age-specific incidence of new (see legend to Fig. 5 for definition) cases of CIS in Sweden based on a dynamic model which was fitted to empirical results (Gustafsson and Adami, 1989). The new incidence rose from age 15 to peak at about age 30. This was followed by a rather fast decline, which after some years only became slower than the original rise. After menopause the incidence of CIS was only about one-third of the peak value.

Figure 6 shows the age-specific prevalence curve of in situ cervical cancer in Sweden corresponding to the same dynamic model as in Figure 5 (Gustafsson and Adami, 1989). Preva- lence attained its peak at age 35, with about 3,S00/100,000 women from about 20 years of age. Prevalence did not reach half of the peak value until about age 60.

Regression. Dysplasia can be studied by monitoring without treatment. In a Swedish series of 555 women with mild dysplasia followed up for an average of 39 months, progression to severe dysplasia or CIS took place in 16% of the cases,

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FIGURE 5 - Estimate of age-specific incidence of new cases of CIS. See text for details. We use the term “new” to denote the true incidence rate of CIS, i.e., the number of new cases arising during a given time interval, usually one year. The true incidence rate cannot be directly observed since CIS does not announce its beginning by any symptoms. It can, however, be estimated, eg., through identification and simulation (Gustafsson and Adami, 1989). The true incidence rate of new CIS should be distinguished from the rate of CIS detected and reported by cancer registries, which is highly dependent on screening activity and also inevitably is a mixture of true incidence and prevalence.

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FIGURE 6 - Estimate of age-specific prevalence of CIS. See text for details.

whereas 62% regressed and 22% persisted (Nasiell et al., 1986). In another study, 894 women with moderate dysplasia were followed for 78 months. Here, progression to severe dysplasia or cancer in situ occurred in 30%, regression in 54% and persistence in 16% (Nasiell et al., 1983). The time from discovery of mild or moderate dysplasia to observation of severe dysplasia or CIS was around 3.54.5 years. These figures are compatible with the shifts in peak incidence values in Figure 4.

CIS, where the cells exhibit the same cytological hallmarks as invasive cancer cells, has been shown to be reversible in many studies; i.e., those cell populations will not always show indefinite progressive growth in the absence of treatment. Direct observation of a small number of untreated cases of CIS also appeared to demonstrate that some would regress spontaneously (Kottmeier, 1955). Thorough re-analysis of reported cases has, however, shown that rate of regression may have been over-estimated (Burghardt, 1973). Additional series of follow-up without intervention have been published (Koss, 1993). Taken together, these observations indicate that, in the absence of intervention, roughly one-third of lesions considered precursors of invasive cancer disappear spontaneously, one-third persist and one-third progress from dysplasia to CIS or from CIS to invasive cancer (Koss, 1993).

Since there are no cell biological or molecular markers, the transition from reversible to irreversible growth cannot be determined in individual cases.

LTE---aO@ HtALTHY + DYSPLASIA -+ INSITU + INVASIVE +

FIGURE 7 - Natural history of cervical cancer and its precursor stages as a compartmental model.

The mechanism(s) of regression remains unknown. It is very unlikely that cells of the atypical clone will normalize pheno- typically in the presence of widespread genotypic alterations. Theoretically, it is more attractive to assume that the atypical clone dies out because of “terminal differentiation”.

However, nothing contradicts the notion that invasive cancer is essentially irreversible. It remains an enigma as to why the capacity for invasion of stroma and vessels appears to require that the cancer cell population should also be capable of limitless proliferation. An interesting possibility is that to maintain a potential for indefinite proliferation a malignant population of cells has to form a network of inter-dependent cancer and stromal cells (Folkman and Haudenschild, 1980).

Quantitative models. A compartmental model of the natural history process that takes evolution into account is shown in Figure 7. The model is dynamic, based on states (stages, prevalence) and flows (incidence). Detection of any cervical abnormality will usually lead to interference, ranging from repeated checking to removal of the lesion. This precludes direct observation of the individual natural course of the progressive phase of cervical cancer. Aggregate methods can be applied, however, by studying the propagation of a perturbation of the flow of cases through the stages. If a number of CIS cases are detected at screening and removed at one stage, the time delay and effect of this perturbation as attenuation of invasive cancer can be observed at a later stage (Gustafsson and Adami, 1990).

As seen in Figure 8, the introduction of screening in the early 1960s led to an increase in the number of reported cases of CIS, which leveled out and decreased slightly from about 1968. Invasive cancer showed a small rise, reaching a maximum in 1965 following the introduction of cervical screening. A steady decline was then noted, and the incidence in 1989 was approximately half of that before screening. Mortality from invasive cancer was stable from 1960 to 1970 but fell later. The death rate in 1988-1990 was about SO% of that in 1970.

In a comprehensive attempt to delineate the natural history of pre-invasive and invasive cancer (Gustafsson and Adami, 1989), population-based Swedish Cancer Registry data from 1958 to 1981 were used. The study comprised 8 age cohorts, with birth dates ranging from 1904 to 1943, of which the 5 youngest were extensively screened. Table Ill summarizes percent progression, sojourn times of cancer in situ and total sojourn time from beginning of in situ to clinical detection of invasive cancer. These parameters did not differ between the 8 birth cohorts. Only about 12% of new incident cases of CIS would have progressed to invasive cancer. The average sojourn time for CIS was about 13 years, while the pre-clinical phase of invasive cancer, i.e., the length of time that elapsed before invasive cancer was detected, was estimated to be 3-4 years. The total sojourn time in the fraction of in situ cancers that progressed was about 17 years from the appearance of progressing “new” in situ cancer to the diagnosis of invasive cancer.

Swedish Registry data contain an unusually high fraction of pre-invasive cancer cases. This may be the result of the rather intensive Swedish screening and a liberal classification practice for CIS (Bergstrom et al., 1993). An over-estimate of CIS cases would lead to a directly proportional over-estimation of the likelihood of spontaneous regression of pre-invasive cancer. Sojourn times would remain unchanged.

CONTROL OF CERVICAL CANCER

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FIGURE 8 - Age-standardized (1970) numbers of CIS, invasive cancer and mortality in Sweden 1958-1988.

TABLE 111 ~ RISK OF PROGRESSION AND SOJOURN TIMES OF CANCER IN SITU AND TOTAL SOJOURN TIME FROM BEGINNING OF IN SITU TO

CLINICAL DETECTION OF INVASIVE CANCER

c< Sojourn time

Progrswon I n SlI1t Total Cohort born

1939-1943 14.7 12.1 19.9 1934-1938 10.8 11.8 14.5 1929-1933 11.0 11.9 1.5.1 1924-1928 12.4 12.3 15.5 1919-1923 12.7 12.6 15.7 191 4-1 91 8 12.6 13.6 17.4 1909-191 3 11.6 14.1 19.7 1904-1908 11.6 17.8 19.5 Mean (S.D.) 12.2 (1.3) 13.3 (2.0) 17.7 (2.3)

Sojourn times refer solely to those cases which progress.

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Age

FIGURE 9 -Weighted age-specific incidence of invasive cancer from 12 European countries (Denmark, former East Germany, England and Wales, Finland, Hungary, Norway, Poland, Roma- nia, Scotland, Slovenia, Sweden, former West Germany). Curves with the largest irregularities contain only a few cases. To facilitate shape comparisons, quotients are computed by dividing age- specific incidence by cumulated age-specific incidence up to age 70.

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Generalization of the natural history. It is not known when the basic features determining the course of any type of cancer are laid down. The somatic genetic cell changes which govern the subsequent clinical behavior of the cancer cell population (including the capacity for genetic progression and selection of increasingly malignant cell clones) may partially be embodied in the first transformed cell (Ponten et al., 1990). This does not, of course, rule out the possibility that superimposed changes induccd by external carcinogens may also occur during the phase of proliferation of transformed cells or that absence of HPV may be associated with a clinically more malignant course (DeBritton et al., 1993). The important implication from this point of view is that the collection of natural histories of cervical cancer may be biologically comparable even in areas with large differences in incidence, as the impact of the basic changes (dominant proto-oncogene mutations and homozy- gotic loss of recessive suppressor genes?) underlying malignant transformation of any single cell may be qualitatively independent of types of exposure.

The parameters describing the basic features of the process of progression from CIS to invasive carcinoma did not differ between birth cohorts from the beginning of this century and those emanating from the 1930s, suggesting that the natural history has been invariant (Table III), in spite of differences in incidence. The basic shapes of the age-specific incidence curves of invasive cancer before screening are also similar in most countries. Figure 9 shows data for 12 European countries from the time period 1962-1965, before the incidence of invasive cancer was reduced through screening measures. All curves started about the age of 20 and increased rapidly, to reach a peak around age 45, followed by a slow decrease. A similar pattern was also found in statistics from other parts of the world (L. Gustafsson, data not shown).

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Age

F~GURE 10 - Age-specific prevalence rates of CIS in 5 different geographical locations: Barbados (Barron, 1978), USA (Sadeghi et al., 1988). LeeddWakefield, UK (Parkin et al., 1981), British Columbia, Canada (Fiddler et a[., 1968), Chicago (Bibbo et a/., 1971) and Sweden (Gustafsson and Adami, 1990) as percentage of peak values. Smoothed by quadratic B splines.

Scaled estimates of CIS prevalence varied slightly only between different geographical locations (Fig. lo), supporting the existence of a global natural history.

In the absence of any contradictory evidence, we have concluded that the findings concerning the natural history in one geographic area, time period or age of the afflicted woman can most likely be generalized to other areas and times.

ETIOLOGY

Established or proposed risk factors for cancer of the cervix include early age at first intercourse; large number of sexual partners; a male partner himself with many sexual partners; tobacco smoking; diet poor in fruit, vegetables and some micronutrients (vitamin C, beta-carotene, folate); use of oral contraceptives; infection by HPV; presence of HPV DNA in cervical specimens; infection by genital herpes virus; and presence of certain histocompatibility types. This review focuses on the role of HPV.

Papillomavirus

Subtypes of HPV As a group, papillomaviruses are widespread in nature,

typically causing benign, regressing squamous cell papillomata

8 PONTEN ETAL.

in the skin or mucosa in a large number of animal species (Sundberg, 1987). For example, in rabbits, squamous cell carcinomas may develop from benign papilloma cells harhor- ing papillomavirus (PV) DNA (Ito, 197.5; Shope, 1933). Pio- neering studies (see zur Hausen, 1988) drew attention to the role of HPV in human genital cancer.

Out of over 60 subtypes of HPV, about 20 have been found to be associated with genital infections. Types 6, 11, 16, 18, 31, 33 and 3.5 predominantly infect genital mucosa. These types have been the main focus of interest and will be used as prototypes for further discussion. Extensive reviews have been published concerning these and other types of HPV in relation to cervical cancer (see Bronner et al., 1994).

Molecular biology results have related putative transformation genes to the early E6-E7 transcription units. For the high-risk HPV types 16 and 18, E6 and E7 proteins bind to the p53 and Rb suppressor gene products respectively. Such binding to proteins permits cells to multiply in spite of damage to DNA and will thus make mutations permanent (Lane, 1992).

The low-risk types of HPV (mostly HPV 6, HPV 11 or HPV 42) cause classical, easily detected exophytic condyloma acuminata (CA). HPV 16, 18, 31, 33 or 35 are not normally associated with CA but rather with flat or inverted condylomata.

The koilocyte, which represents a cytopathic change in differentiated keratinocytes, either normal or dysplastic, is the most easily distinguished morphological marker of PV accumu- lation (Koss and Durfee, 1956; Meisels et al., 1976). HPV particles, as demonstrated by electron microscopy, as well as the HPV capsid antigen can be detected in most koilocytes.

Diagnostic methods Immrrnohistochemistr. Immunohistochemistry is frequently

used to detect PV structural group-specific capsid antigens (Kurman et al., 1988), preferentially expressed in koilocytes in the upper, differentiated layers of the epithelium. Condyloma- tous tissue and dysplasias are often positive for the capsid antigen, but in situ and invasive cancers are usually not permissive for virus replication and will therefore not express the capsid antigen (Syrjanen, 1983). No antibodies that would detect non-structural HPV antigens under routine circumstances are available.

Nucleic acid analysis. In filter in situ or dot blot hybridization, DNA from a cell sample is denatured and spotted onto a filter membrane. Viral DNA is detected by hybridization using radioactive, enzymatically or biotin-labeled probes followed by autoradiography or color development. About SO HPV gc- nome copies per cell are needed for unequivocal detection (Wagner et al., 1984).

In sit" hybridization can be performed on sections of formalin-lixed paraffin-embedded tissue (Hagmar et al., 1992). Morphology can be correlated with presence of viral DNA. A major advantage is that archival material can be analyzed. Detection limit is 10-50 genome copies per cell (de Villiers et al., 1986; Stoler et al., 1990). Consensus as well as type-specific probes are available.

In Southern blotting, total cellular DNA, either intact or digested with restriction enzymes, separated by gel electropho- resis, denatured and transferred onto a nylon membrane is hybridized under stringent conditions with labeled viral probes of a known HPV type; 10-100 cells are required to detect one HPV copy under non-stringent conditions (de Villiers, 1992). Southern blotting is a most reliable, specific test which has been widely used as a gold standard for detecting HPV.

Polymerase chain reaction (PCR) utilizes primer-directed enzymatic amplification of specific target DNA sequences. For each amplification cycle, after denaturation of target DNA, 2

sequence-specific probes of opposite direction are allowed to anneal to single-stranded DNA. A heat stable DNA polymerase starts to synthesize a new DNA strand, using the probes as primers (Evander and Wadell, 1991; Manos et al., 1989). The resulting amplification product can be detected by hybridization. The theoretical detection limit is one genome copy in 100,000 cells (de Villiers, 1992). PCR performed under carefully controlled conditions is rapidly becoming the technique most widely used for detecting HPV DNA.

Immunity to HPV Studies using proteins produced in vitro or oligopeptides

corresponding to regions of the PV coding region indicate that a large proportion of the population is exposed to PVs (Jenison et al., 1990; Jochmus-Kudielka et al., 1989). Although some of the antigens used are apparently broadly cross- reactive among PVs (Dillner et al., 1991), several studies indicate that immune responses to certain HPV proteins are more commonly detected in patients with cancer than in normal controls (Dillner, 1990; Jenison et al., 1990; Jochmus- Kudielka et al., 1989; Miiller et al., 1992). Improvements in developing more type-restricted serological assays have found seropositivity for genital HPV types in a majority of patients with cervical cancer or dysplasia. Only < l o % of normal women are seropositive (Dillner et al., 1994; Kirnbauer et al., 1994).

Enhanced papilloma cell proliferation was observed after immunosuppression specifically involving cell-mediated immunity (Reid et al., 1976). Patients with warts may have a depressed cellular immune system (Kienzler et al., 1983; Laga et al., 1992; Morison, 1975; Spencer and Andersen, 1970). HPV infections were shown to be 9 times more common among renal transplant recipients compared to the general population (Halpert et al., 1986). Immunosuppressed patients have also been shown to be susceptible to multiple infections with rare types of HPV (Lutzner et al., 1983). An increased incidence of dysplasia and CIS in renal transplant recipients has been reported (Alloub et al., 1989). Trauma to one wart sometimes results in regression of other warts, suggesting that a general immune response is triggered by released antigen (Shah, 1992). The majority of the infiltrating cells in regressing warts (Oguchi rt ab, 1981; Tagami et al., 1977) are CD4+ T cells (Aiba et al., 1986).

An unequivocal biological function of antibodies to PV has not been demonstrated in humans. Neutralizing antibodies can, however, confer immunity against infection in animals (Ghim et al., 1991; Kidd, 1938) but do not influence the rate of growth or regression of already established papillomas (Evans et aL, 1962; Ito, 1975; Spradbrow, 1987).

Papillomaviruses and .sexual behavior Several investigations have suggested that the prevalence of

HPV infection has increased since 1960 (Becker et al., 1987; Chuang et al., 1984), perhaps because of an increasing frequency of contagious sexual contacts, probably facilitated by use of oral rather than barrier contraceptives. The correlation between sexual activity and HPV was found by Kiviat et al. (1989) to be especially related to recent rather than past behavior, probably because HPV tends to disappear with time (Schneider and Koutsky, 1992). Presence of HPV DNA and number of sexual partners also correlate. Longitudinal follow-up has disclosed a complex dynamic pattern of infection, often by different subtypes which occur and vanish apparently without any inter-correlation (Kiviat et al., 1989; Syrjanen et al., 1988). Types 6/11 belong to the class which may become undetectable after only 1 year or so, in contrast to type 16, which tends to persist. The genital types of HPV are mostly transmitted via sexual contacts, indirectly demonstrating that male partners play a critical role in transmission.


Causal models HPV as risk factor for dysplasia and cancer. Proof of a causal

role for HPV can probably only be obtained after recording a protective influence of vaccination on cervical cancer and its precursors. Indirect evidence has, however, strongly impli- cated genital HPV as an important risk factor for the various lesions incriminated in cervical carcinogenesis (zur Hausen, 1991). The role of viruses as risk factors for the plethora of cervical lesions needs to be discussed individually for each type of pathology. Rapid technological advance has made comparisons between studies difficult, as has indiscriminate use of poorly defincd criteria for the various lesions.

Alterations strongly associated with PV nucleic acids are CA, dysplasia, in situ and invasive cancer (Crum et al., 1984; Durst et al., 1983; Gissman et a/., 1983). Acanthosis, or “mild papillomatosis”, is only weakly correlated with the presence of HPV nucleic acids (Nuovo, 1988) and will not be further discussed. The role of HPV as a cause of non-specific cervical inflammation will also not be elaborated upon.

HPV 6 and 11 (and the rarer types 13,42,43,44) have been associated with CA. This assembly of subtypes will be referred to as 6/11 or “CA types”. HPV 16 and 18 (and the less studied rarer types 31, 33, 35, 39, 45, 51, 52, 56, 58) have been predominantly associated with dysplasia, CIS and invasive cancer. They will be referred to as 16/18 or “high-risk types”.

HPV and cervical lesions Normal mucosa. Since the advent of the PCR technique, it

has become apparent that a proportion of the young, sexually active population harbors some type of PV DNA in the genital tract (Schiffman et a/., 1991). Determination of HPV prevalence is hampered by difficulties in obtaining samples from representative segments of the population and presence of unidentified HPV sequences (“HPV X”), when general primers are used. An inverse correlation with age exists, as exemplified by Melkert et al. (1993), who found 14% HPV positivity before and 7% positivity after the age of 35 in a large study, which is essentially in agreement with the results of Lorincz et al. (1992) and Schiffman et al. (1993).

Prevalence of HPV has consistently been found to be higher than that of dysplasia by at least one order of magnitude. A substantial proportion of women with genital HPV therefore never develop any disease related to their infection (Schneider et al., 1992). A 4-year prospective follow-up study indicated that only 30% of women infected with high-risk HPV will develop dysplasia (Koutsky et al., 1992).

When PCR tests have been repeated, the prevalence of HPV DNA was higher than that of koilocytosis in similar populations (Schneider and Koutsky, 1992). Thus infection by HPV can probably exist in the absence of demonstrable koilocytosis or other light-microscopic signs of infection.

Koilocytosis. Koilocytosis (Koss and Durfee, 1956) appears to be a specific sign of replicative infection by HPV (any type). There is no indication that external co-factors are needed. Foci of koilocytosis may appear in otherwise normal squamous epithelium but can also be spotted with increasing ambiguity in dysplasia of increasing severity. Syrjanen et al. (1989) followed up a cohort of Finnish women selected on account of HPV- specific cytological abnormalities (mainly koilocytosis). Of these cases 40% regressed morphologically within 5 years of follow-up, demonstrating reversibility of koilocytosis. Another 45% of the Finnish cohort remained stationary, but 15% showed subsequent development of dysplasia or CIS.

Condyloma. All CA with unambiguous morphology appear to contain HPV. Exophytic CA which exhibit koilocytosis correlate well with the presence of HPV 6 or 11 nucleic acids (Franquement et al., 1989; Willett et al., 1989). A proportion of flat CA, exhibiting the same cellular abnormalities as exophytic CA, contain viral nucleic acids (6111) that are not associated

with cancer; however, some flat CA have been found to contain high-risk HPV types (16/18) (Crum et al., 1985; Franquement et a/., 1989; Schiffman et al., 1991; Willett et al., 1989), suggesting that flat CA, particularly if infected by types 16/18, are precursors of CIS. This is supported by prospective follow-up studies (Nash et al., 1987).

It looks as if CA should be considered a generally transitory response to 6/11 types of HPV, with no or minimal association to dysplasia or cancer, but some flat condylomas, inherently difficult to distinguish morphologically from dysplasia, particularly in the absence of histological examination, may be precursors of CIS.

Slight and moderate dysplasia. To become fully interpretable, studies of HPV prevalence, particularly in slight dysplasia (and its approximate equivalent CIN I), need a clear morphological (unnattainable?) distinction between, on the one hand, dysplasia/CIN I, where koilocytosis is used as an inclusion criterion (Schiffman et al., 1993), and, on the other, those cases where true cellular atypia and disturbed differentiation are used as defining features.

Prevalence of different types of HPV in genuine cases of slight and moderate dysplasia cannot be determined from case-control studies with sufficient precision to warrant firm conclusions about their quantitative role as risk factors in the development of these lesions. Their high prevalence in studies of mixed “koilocytotic atypia” and CIN 1-111 make, however, a causal role plausible (Koutsky et al., 1992; Schiffman et al., 1993) in “non-koilocytotic dysplasia” as well. High-risk types, particularly 16 and 18, showed the highest relative risk ratios (33-51) for presence of condylomatous atypia or CIN 1-3. This can be compared with a relative risk of 8.7 for the CA types (Schiffman et al., 1993).

Severe dysplasia /CIS. Progression from mild/moderate dysplasia to CIS is usually associated with loss of virion produc- tion, while the amount of replicating (episomal) viral DNA is also reduced. HPV 16 and 18 are strongly associated with in situ and invasive cancers (Crum et a/ . , 1984, 1986; Durst et al., 1983; Kurman et al., 1988). In a large case-control study (Bosch et a/., 1993) covering 2 countries with about 10-fold difference in age-adjusted incidence of invasive cervical cancer, 3 different methods, including PCR, were used to establish the association between HPV and CIS (CIN 111). In both countries, 60% to 70% of cases had HPV DNA in contrast to controls, for whom the corresponding figures were 5%-10%. For HPV 16, which was by far the commonest type, odds ratios were 296 in the low-incidence country (Spain) compared to 27 in the high-incidence country (Colombia).

There have been relatively few follow-up studies of patients with lesions known to harbor specific HPV types. In some, mild dysplasia was more likely to progress to higher-grade dysplasia or CIS if the lesions contained HPV 16 but not the CA types (Campion et a/., 1986: Syrjanen et a/., 1989); other inbestigators have claimed poor correlations between progression and type of HPV (Weaver et al., 1990).

Moderate and severe dysplasia showed a stronger association with HPV 16 and 18 than mild dysplasia (Crum et al., 1984). This appears to indicate that the type of HPV associated with the initial infection will determine the risk of progression to severe dysplasia and consequently also to CIS. It does not imply, however, that all intra-epithelial lesions associated with high-risk viruses will progress.

High-risk HPV types, particularly HPV 16, are probably a component cause of severe dysplasia/CIS, though their presence does not necessarily lead to these conditions and HPV- negative cases exist.

Znvasive cancer. The possible role of HPV in the transition from non-invasive to invasive cancer is even more conjectural than that in the progression from slight and moderate dyspla-

10 PONTEN ETAL.

sia to CIS. The fact that HPV 16 accomplishes in vitm immortalization of keratinocytes (Pirisi et al., 1988) suggests that this could be the role of this virus in the chain of events leading to invasiveness. It has been proposed that integration of HPV DNA into the cellular genome could be the cause of progression from in situ to invasive cancer (Cullen et al., 1991). It is, however, possible that integration is a causally irrelevant stochastic event, the likelihood of which increases with time.

Epidemiological evidence of HPV involvement in invasive cancer is largely based on case-control studies, all of which have shown increased prevalence of HPV in cases. This approach cannot, however, solve the fundamental cause-effect problem.

A Danish study (Kjaer and Jensen, 1992) demonstrated the expected relation between sexual activity and risk of invasive cervical cancer in an ecological comparison between women from Denmark and Greenland. But the low-risk population had a higher prevalence of HPV DNA positivity than the high-risk one. These results challenge the concept of HPV as being a dominant cause of cancer of the cervix. The results may be contrasted with findings of a strong association between HPV types 16, 18, 31, 33 and 35 and presence of invasive cancer in Colombia and Spain, with an 8-fold difference in incidence rate (Bosch eta/., 1992; Munoz et a/., 1992).

HPVs, particularly high-risk types 16, 18, 31, 33 and 35, are likely to be component but not necessary or sufficient causal factors for invasive cancer of the cervix. Simmaty of HPV and cervical lesions

Human PVs establish largely innocent relations between host and infectious agent. Most infections go unnoticed and, if not, give rise to usually regressing wart-like manifestations in skin or mucosa. In some instances, however, there appears to be a low but distinct probability of subsequent development of lethal cancer, particularly of mucosa. Immunity is not sufficiently effective to prevent horizontal transmission of, or re-infection by, the virus.

HPV exists in a variety of types with more or less stringent host cell requirements. All are epitheliotropic, particularly in relation to squamous cells. Their maturation and growth is favored by terminal keratinocyte differentiation.

Genital HPV is essentially a sexually transmitted disease, the prevalence of which approaches 100% in women involved in unprotected sexual intercourse with multiple partners. Subtypes exemplified by 6/11 cause CA but are only rarely associated with cancer. Other types, eg., 16/18. show a strong statistical correlation to dysplasia (all grades), CIS and invasive cancer.

The low-risk subtypes of HPV do not appear to play a critical role in the further progression of dysplasias into in situ and invasive cancer (unless they act as initiators whose continued presence is not required). The high-risk (such as 16, 18) types are uncommon in mild-moderate dysplasia but are common (prevalence about 80%) in insitii and invasive cancer. It has not been resolved whether this reflects a tendency to remain as persistent infections, to show an unusual capacity to multiply in cancer cells or to become integrated into the cellular genome. Ingenious suggestions have been proposed to explain how they could be carcinogenic as a result of a capacity to induce genetic instability by complexing with and degrading the p53 tumor suppressor protein (zur Hausen, 1993).

Combined evidence points to HPV (such as types 16/18) as an important but probably not a necessary cause, i.e., as one of several causes of invasive cervical cancer. Unresolved problems have recently been reviewed (Koss, 1993).

If high-risk HPV types are in fact an important cause of invasive cervical cancer, eradication of this virus by vaccination will prevent this neoplastic disease and theoretically lead to a reduction of its incidence and mortality.

Approximately 10% of invasive cervical cancers are not associated with known PVs. These cancers are not expected to disappear after eradication of HPV.

Higgins et nl., (1991) found that patients with non-HPV- associated cancer are more likely to be older and have a poorer prognosis. These results stand in contrast to other reports (Barnes et al., 1988; Rose eta/ . , 1991; Walker et al., 1989).

Herpesvirus There was considerable enthusiasm in support of herpesvi-

ruses as causative agents of cervical cancer in the 1970s (see Fenoglio and Ferenczy, 1982). There has been no conclusive identification of herpesvirus DNA within pre-cancerous or cancerous cervical lesions, and no strong association between viral DNA and neoplastic process has been reported. Notwith- standing the weakness of the current evidence for a causal relationship, herpes simplex virus (HSV) still remains a strong marker of sexual activity and, in some studies, is associated with a risk for cervical neoplasia (Kjaer et al., 1988). The case for HSV has gradually become weaker during the last decade. Scveral initial serological case-control studies found an association between HPV and cervical cancer, but large prospective investigations failed to confirm this (Lehtinen et al., 1993; Vonka et al., 1984). It is now considered doubtful, by most observers, that HSV plays any role other than as a marker of sexual activity (Lacey, 1992). It is in this capacity that it has been mistaken for a causal factor.

Smoking There is evidence that tobacco smoking increases the risk of

invasive cervical cancer (Brinton et al., 1986; Layde and Broste, 1989), though studies showing no association have been reported (Zaninetti et al., 1986). Residual confounding due to misclassification of the reported sexual activity of women and of their partners remains a distinct possibility (in many cultural settings sexually active individuals are more likely to be smokers). Some observations have also suggested that there may be an interaction between HPV and smoking in the causation of cancer of the cervix (Herrero et a/., 1989). It has been reported that the risk of acquiring CA is higher in smokers (Brisson et al., 1988; Daling et a/., 1986).

Oral contraceptives Analysis of the association, if any, between use of oral

contraceptives and risk of invasive cervical cancer is fraught with difficulties (Brinton, 1991). Oral contraceptives are used by sexually active women who are less likely to use barrier methods and are therefore at increased risk for invasive cervical cancer. Furthermore, oral contraceptive users are more likely to be screened for cervical disease. Notwithstand- ing these concerns, it appears that long-term use of oral contraceptives tends to increase the risk of invasive cervical cancer (Brinton, 1991; Reeves et al., 1985; Vessey and Grice, 1989). The same appears to be true with respect to injectable hormonal contraceptives (Herrero et al., 1989). By contrast, women using barrier contraceptives and spermicidal foams or jellies seem to be at lower risk for this cancer (Celentano et a[., 1987).

Diet Earlier studies, reviewed by Rogers and Lnngnecker (1988)

Schneider and Shah (1989) and Ziegler et a/. (1990) have indicated that high dietary intake of fruits and vegetables (and, inferentially, of beta-carotene, vitamin C and folate) tends to reduce the risk of invasive cervical cancer. The results of some recent studies are more equivocal. Several reports suggest that high dietary intake of beta-carotene (Herrero et al., 1991; Potischman et al., 1989; Slattery et al., 1990; Verreault et al., 1989) and vitamin C (Slattery et al., 1990) and consumption of fruits and fruit juices reduce the risk of invasive cervical cancer, but other studies have yielded no evidence of a

CONTROL OF CERVICAL CANCER I 1

protective effect of fruits, vegetables, carotenoids or vitamins A and C and folate (De Vet et al., 1991; Ziegler et al., 1990). The weight of evidence still indicates that consumption of fruit and vegetables and some of the associated micronutrients is protective against invasive cervical cancer, but the findings are not overall conclusive.

Inheritance In one study the likelihood of developing invasive cervical

cancer was increased about 7-fold among fcmale Caucasian carriers of HLA DQw3 compared with women who lacked this antigen (Wank and Thomssen, 1991). Such a high risk figure was not confirmed in a second report from another area (Clew e t a l , 1992). Another report has claimed a protective effect of certain HLA types (Apple et al., 1994). An association between HLA type and cervical cancer could be explained if viral infection is immunologically influenced.

REDUCING MORTALITY WITHOUT SCREENING

Primary prevention

Altered life style The indirect evidence that life style factors heavily influence

the risk of developing invasive cervical cancer is persuasive (Brinton, 1992). The indication that cervical cancer behaves like a sexually transmitted disease, with PV being the most important contagion, is strong. Little has been done, however, to implement this knowledge within preventive efforts. The forces underlying sexual behavior, particularly in high-risk groups, are too strong to be materially influenced, except possibly by general socio-economic improvement. We will not suggest any measures aimed at altering sexual behavior, except to note that prevention of cervical cancer may become an important side benefit of successful campaigns to increase the use of barrier contraceptives to prevent AIDS and other sexually transmitted diseases.

HPV vaccination Preventing infection. Significant inverse associations between

serological reactions to specific PV proteins and presence of disease have been demonstrated (Jochmus-Kudielka et al., 1989). Limited studies using PV typing suggest that healthy individuals who suffer recurrent lesions of the cervix may be the victims of additional PVs, further suggesting that the initial virus is prevented from re-infecting the squamous epithelium after eradication. In contrast, individuals who are immunosuppressed tend to be re-infected by the same HPV types (Nuovo et al., 1991).

As reviewed by Campo (1991) homogenized papillomas or inactivated viral particles have been used as vaccines against the cottontail rabbit PV (Evans et al., 1962), the bovine PV (Olson et al., 1968) or the canine PV (Bergman et al., 1987). Protection against infection correlates with the level of neutralizing serum antibodies (Ghim et al., 1991; Kidd, 1938). The composite neutralizable epitopes are only exposed on intact viral particles, not on the individual capsid proteins (Chris- tensen and Kreider, 1990; Christensen et al., 1991; Jenson et al., 1980). This explains why subunit vaccines containing only Ll or L2 protein gave rise to relatively poor titers of neutralizing antibodies (Ghim etal., 1991; Jenson etal., 1980). Neverthe- less, subunit vaccines containing L1 (Campo, 1991) or L2 (Jarrett et al., 1991) protein have conferred some immunity against infection with bovine or cottontail rabbit PV.

Vaccines for human use containing viral DNA would not at present fulfill basic safety requirements. A low percentage of dogs exposed to a viral DNA-containing canine PV vaccine developed PV-carrying squamous cell carcinomas at the inocu- lation site (Sundberg, 1987).

Although it is possible that subunit vaccines of the capsid proteins could be effective, the theoretically most appealing human vaccine for protection against infection is the as- sembled pseudovirions lacking viral DNA that are formed after infection of mammalian cells with vaccinia virus con- structs expressing both L1 and L2 proteins (Zhou et al., 1991).

Vaccination against oncogenic HPV types has not yet been tried in humans. Though vaccination has been accomplished in animal model systems and recent advances in basic immunol- ogy have provided new approaches for rational vaccine design. It is likely that HPV vaccines will soon be tested.

Vaccines to aid rejection or regression. Rejection of murine syngeneic HPV 16-carrying tumors has been induced by immunization with non-malignant cells expressing the HPV 16 E7 protein (Chen er al., 1991) or by vaccinia virus expressing the E6 and E7 proteins (Meneguzzi et al., 1991).

Cytotoxic T cells (CTL) require considerably stronger stimulation for activation than for recognition of target cells. Thus a tumor that expresses minute amounts of antigen at the cell surface may not alone be able to stimulate an efficient CTL response but may be efficiently recognized by a CTL response once it has been activated.

The mechanisms by which the host cell degrades endo- genous cellular or viral proteins and presents them to CTLs as peptides bound in the groove of the major histocompatibility complex (MHC) class I molecule have been elucidated (see review by Murray and McMichael 1992). Vaccination using free peptide with optimal ability to bind MHC class I has been found to induce tumor rejection of adenovirus E l A-carrying tumors (Kast et al., 1989). HPV-carrying cancers express the E6 and E7 virus transforming proteins, on which they are dependent for continued growth (von Knoebel Doeberitz et al., 1988). Stimulation of a CTL response using peptides mimick- ing endogenously degraded E6 and E7 peptides with MHC class I binding ability that also constitute CTL epitopes, would be a comparatively straightforward vaccination approach. The major drawback is that the epitopes would most likely be MHC-restricted, requiring the development of separate antigens for all the major human haplotypes as well as for the different major viral oncogenic types.

Overview of available therapy CIS. Surgery, loop excision, laser therapy and cryotherapy

are currently the most common treatment modalities. They will to a large extent eliminate normal cervical epithelia and thus also reduce the number of target cells for any subsequently developing neoplasia. Surgery and loop excision in particular give adequate histological specimens. Cure rate should be close to 100%.

Invasive cancer. To the original modalities, i.e., surgery and radium therapy, introduced in clinical practice some 80 years ago, advanced radiological (linear accelerators, betatrons, microtrons. race-track microtrons) and cytostatic treatments have been added during the last 4 decades, particularly for stages 11-IV. Table IV lists some important therapeutic advances that have taken place during this century. Cure rate depends on stage (see below).

For a long period of time, intracavitary application of radium was the main method of treatment. Radium (22hRa) has now been largely replaced by cesium (I3’Cs) or cobalt (hoCo). Cesium, with its half-life of 33 years, in particular, has found widespread use. External supervoltage therapy was added in the 1950s.

Surgery competed with irradiation for early stage cancer, until it was finally agreed that the two modalities gave comparable results. A combination of intracavitary irradiation and surgery for stages 1-11 has become the established method in a large number of centers.

12 PONTEN E T A L

TABLE IV - OL’TLIKE O F DF\’FI OPMIVI‘S IN I<,\UIATIOK TI IFL\ I ’ \ ’ I K O M I T S lN(’EI’TI0N IL\STI) ON C’ONOI I IONS IK SWEDFY

. _ _ Sr;lgc

I IB IIA IIB Ill 1v Pcriod - -

-- ..

1905- 1930 Intracavitary ‘?“Ra 193U-lYhS Intracavitary 2?hRa,

7.200 mg hr in 3 fractions with 2-week interval’ ventral and dorsal

and external ortho- voltage (250kV) pel\ ic irradiation in 4

parametrial fields

voltage pelvic irradiation with opposite

1966-1975 Intracavitary 22hRa, 7:200 mgihr in 3 fractions with 2-week

and external high

interval’ fields by liriear accel-

OCo by remote after- h”Co loading technique. and Dose: minimum 4.3 Gy at target surface given in 5 fractions (weekly)

erator 1976-1990 Hi h dose intracavitary Intracavitary ?IhRa or

External pelvic irradiation, 4.2 Gy

and Wertheim-Meigs’ radical pelvic surgery and External pelvic irradiation 5.5 Gy to parame- trium when positive Ivmph nodes

‘Doses in these days were given as “milligram/hours,” i.e., mg of radium times number of hours of exposure to intracavitary application.

With programs for early detection of invasive disease, it is required that effective therapy is ensured for stages I and I1 cancers, the proportions of which should increase. The numbers of advanced stages I11 and IV cancers, however, are expected to decline with an effective early diagnosis program. This in itself will reduce the need for complicated long-term treatment, hospital beds and terminal care. It remains important though that palliative treatment including pain relief is available.

Intracavitary treatment can effectively eradicate local tumor growth and thus cure stage I patients and a majority of those at stage 11. The resources needed for this treatment are domi- nated by storage facilities and personnel competent in han- dling radioactive material. The half-life of radium (1,600 years) is long enough to maintain constant emission of ionizing energy; cesium will require radiophysical re-assessment of dose of irradiation yearly and cobalt monthly. If possible, access to after-loading will be an advantage, since recurrence may be prevented and significant palliation accomplished.

External radiation, eg., using linear accelerators. is a standard component of therapy in stages 11-111 in developed countries, whereas telecobalt machines are extensively used in the developing world. These modalities may eradicate loco- regional tumor growth not reachable by intracavitary irradiation, notably metastases to pelvic nodes, and thereby improve local tumor control. However, introduction of external therapy in the 1960s did not result in significant increases in stage- specific survival (Fig. 11). The efficacy of external treatment in improving survival has never been ascertained in any randomized trial.

We conclude that resources for external irradiation are not crucial. If adequate resources for surgical treatment and brachytherapy ( ie . , short-range irradiation, for instance by local application of radium or cesium) are available, external irradiation is likely to increase only marginally, if at all, long-term survival.

100 1 I

Stage II V L

20 -

n Stage IV

1920 1440 1960 1980 Year

FIGURE 11 -Crude stage-specific 5-year survival compiled from the material followed at the Radiumhemmet (Heyman, 1937- 1952; Heyman, 1953-1955; Kottmeier, 1958-1961; Kottmeier, 1964-1967; Kottmeier, 1973-1976; Kottmeier, 1979-1982; Petters- son, 1988-1991).

Assessment of effects of early diagnosis and treatment

Detection at earlier clinical stages Long before screening was even conceived of, considerable

progress had been made on the basis of early clinical detection largely through public education. Success was based on general information, support by responsible agencies and the medical community and development of improved diagnostic and therapeutic procedures. The progress from this early time has been documented in Sweden by careful statistics with individual 5- or 10-year follow-up of patients categorized into 4 clinical stages (Table 11). An important part of this work was emphasis on histopathological diagnosis, which clearly separated cervical from endometrial cancer and also served to substantiate any clinical suspicion of cancer. An uninterrupted series of data has been published since 1920 based on results from an increasing number of participating centers ( Heyman, 1937-1952; Heyman, 1953-1955; Kottmeier, 1958-1961; Kott- meier, 1964-1967; Kottmeier, 1973-1976; Kottmeier, 1979- 1982; Pettersson, 1988-1991).

Figure 12 shows crude Swedish data on stage distribution at detection as a function of time. Two phases in the dynamic events can be discerned, roughly separated by the middle of the present century. During the first phase there was a shift from stage IV to stage I11 and further to stage I1 (but only to a small degree to stage I ) . The end result was an increase in the proportion of stage I1 cases from about 15% to 50% and a corresponding decline in cases diagnosed in stages 111-IV. During the second phase a major shift took place from stages I1 to I, stage I rising from about 15% to 45%. In the beginning of this phase the decline of stage I11 cancers continued, but after about 1965 the proportion of advanced stages 111-IV remained stable. Since mass screening was not fully developed in Sweden until the late 1960s, the major beneficial effect was noted before this preventive measure. In Sweden the current stage distribution is stage I: 45%, stage 11: 30%, stage 111: 2096, and stage IV: 5%.

The original data have 2 principal drawbacks: ( i ) the age of the patient was not given, and (ii) the size and other demo- graphic characteristics of the population from which the patients derived was not stated. We have chosen material from Gothenburg, Sweden, to obtain more reliable data on stage distribution development over time.

Figure 13 shows stage distribution at detection from 1930 to 1969 (i.e., before mass screening took place in the Gothenburg

13 CONTROL OF CERVICAL CANCER

60

50

40

8 30

20

10

0

c) S

L

2

19iO 1 9b 1660 1680 Year

FIGURE 12 -Data on stage distribution at time of diagnosis at the Radiumhemmet (Heyman, 1937-1952; Heyman, 1953-1955; Kottrneier, 1958-1961; Kottrneier, 1964-1967: Kottmeier, 1973- 1976: Kottmeier, 1979-1982; Pettersson, 1988-1991).

80

60

c) C e,

2 4 0 2

20

0 1890 ' 1910 I930 ' 1950

Year of birth

FIGURE 13 -Stage distribution at detection of invasive cervical cancer for different birth cohorts. The respective curves have been divided into 2 parts, one corresponding to the period without screening (1930-1969) and the second to the period during which screening was in effect (1970-1990). Only women aged 30-49 have been included.

area, which lagged behind other parts of Sweden) and from 1970 to 1990 (i.e., after the start of mass screening) by birth cohort. To avoid giving too much weight to the more recent cohorts during the second period, only women aged 30-49 were taken into account.

During the period with no screening a clear tendency was noted toward an increasing proportion of cases diagnosed in stage I from the birth cohort 1880-1889 up to the cohort of 1920-1929. The proportion of stage I11 cases diminished over all birth cohorts before screening was introduced, while the proportion of stage I1 cases remained stable.

During the screening period 1970-1990, the proportion of stage 111 cancers continued to decline and the proportion of stage I cancers increased even more rapidly than before. Concomitantly, the proportion of stage I1 cases decreased. The accelerated redistribution from stage I1 to stage I can be interpreted as an effect of screening. Extrapolation from the tendency toward an increased proportion of stage I cases suggests that 10%-15% of the additional cases in stage I could have been due to early detection by screening.

We conclude that considerable gains have been made in early detection even without any screening program. The principal effects were an increase in cases diagnosed in stages 1-11, especially the latter, and a corresponding decrease in stage I11 in particular, but also in stage IV. After introduction of screening, the main effect was an accelerated shift from stage I1 to stage I.

Improved stage-specific survival Figure 11 from the Radiumhemmet in Stockholm shows that

crude (not adjusted to age) stage-specific 5-year survival has changed considerably. Two phases can be roughly distinguished. Before the middle of the century, survival increased steadily among stage I and stage I1 cases from about 35% to about 90% and 55%, respectively. During the second phase no further improvement took place in stages 1-11. The curves for stage 111-IV were rather irregular, but no definite tendency toward improved survival was observed over the entire observation period. Survival rate remained about 20% for stage I11 and 10% for stage IV.

A detailed analysis of the Gothenburg data referred to above will be published separately (P. Sparen, personal communication). Multivariate analyses showed that for each stage by which early diagnosis was advanced, the risk of death declined by a factor of about 2.5. Over time, improvement in 5-year survival was evident among women below 50 for stage I and to a lesser extent for stage I1 but not for stages 111-IV, in agreement with the crude data of Figure 11. In older women, a slight improvement only was recorded in stage-specific fatality rates (data not shown). Altogether, our analyses show that stage at detection exerts an independent dominating effect on survival (P. Sparen, data not shown).

As indicated in Table IV, treatment has been modified to include many new modalities. We conclude that institution of radium and surgery in the 1920s was particularly beneficial to stages 1-11 and that sophisticated treatment for advanced cancers introduced in the 1960s did not produce any major additional improvement of 5-year survival.

Combined and separate effects of early detection and improved stage-specific treatment

The data series were taken from Pettersson (1988-1991). In combination, early detection (as reflected by stage redistribution) and improved treatment (as reflected by stage-specific case fatality) caused a 50% reduction of 5-year case fatality (from around 80% to 40%) until 1960. We estimated the effect of treatment separately by standardizing the stage-specific case fatality, assuming the stage distribution of 1930 for all time periods. The isolated effect of stage redistribution was estimated by keeping stage-specific case fatality constant, also using 1930 as the standard period of time.

From Figure 14 it appears that early detection and improved treatment contributed about equally to the combined reduction of case fatality achieved finally. The effect of improved treatment was only noticeable until 1950, whereas earlier detection continued to have an effect until about 1960, after which the effect of this factor also remained constant. The irregularity of the curve for treatment during 1970-1980 is ascribed to statistical variation.

Factors underlying successful public information in Sweden Even with a relative lack of documentation, it is interesting

to speculate about the factors underlying the successful advent of early clinical detection based solely on public education as noted above.

Access to and faith in treatment, particularly radium therapy, was enthusiastically promoted at the Radiumhemmet. Refer- ence to the results, which were also presented in the lay press, should have convinced many women that invasive cervical cancer was a curable disease.

14 PONTEN ETAL.

100 I I

20 1 I 1910 1950 1970

Year

FIGURE 14 - Development over time of case fatality (100 minus survival). “Treatment” refers to standardized stage-specific case fatality, assuming that the stage distribution found in 1930 also existed at all other points of time. “Early detection” refers to a standardized stage distribution, assuming that the stage-specific case fatality found in 1930 also existed at all other points of time.

Specialist gynecological oncologist groups were created with keen interest in the disease and a desire to document the diagnostic and therapeutic progress by complete follow-up of patients. Rapid acquisition of considerable skill must have created confidence among patients and the medical community at large. Information about the disease presumably spread orally.

Health education was promoted among the population. It was emphasized in articles and brochures that abnormal bleeding, particularly after sexual intercourse, is a signal to seek medical help, as are other types of abnormal discharge. Awareness of cervical cancer and its symptoms within the medical profession was considered a key factor.

A scheme was introduced whereby anybody could travel to and be examined originally at the Radiumhemmet in Stock- holm and later at other Swedish centers. Special contributions were available for those who could not afford the trip. From the very start of the program, socio-economic circumstances were not permitted to hinder access to consultation and treatment.

Treatment of invasive cervical cancer was centralized to a few facilities with similar practice of recording stages and treating patients.

A general awareness developed among the population and the medical profession about cancer being a curable disease, early diagnosis being essential. Results proved that early detection was beneficial. Treatment would also provide means for palliating late incurable stages. Female emancipation presumably played a role. Husbands could not be permitted to discourage wives or daughters from seeking medical advice.

General improvement of the living standards and education probably contributed greatly to the possibility of spreading and acquiring knowledge about cancer and its early symptoms.

Clinical down-staging

The benefit that likely can be obtained by public education directed toward women, informing them of the symptoms of cervical cancer (as discussed above), may be facilitated by a more active attempt to detect the disease at an early stage. This more ambitious approach, as proposed for developing countries without the laboratory facilities or resources to envisage cytological screening, has been termed “down- staging” (Stjernsward. 1990). Down-staging is defined as “de-

tection of the disease in an earlier stage when still curable, by nurses and other nonmedical health workers using a simple speculum for visual inspection of the cervix” (Stjernsward et al., 1987).

Feasibility studies on early visual detection, in which female paramedical workers are being trained to recognize cervical abnormalities, have been started (Stjernsward, 1990). In India, women attending clinics have been examined by direct inspection and Pap smears (Singh et al., 1992). Visual inspection alone identified as high risk 63% ofwomen subsequently found to have cancer. Remarkably, all of these cancer cases were stage I1 or earlier.

Female primary health care workers involved in the examina- tions should be able to distinguish between clinically normal cervix, cervix with a simple erosion. and cervix with suspected cancer by speculum examination. They should understand the symptoms as well as the signs of the disease and be able to take a culture and a cervical smear for diagnostic purposes. Such cultures and/or smears may reduce the number of women who will be referred for gynecological assessment. The objective is to distinguish normal from abnormal, rather than to establish diagnosis. For women with suspected invasive cancer, appropriately directed biopsies are taken. If the facilities for further assessment are limited, women with suspected cancer should receive high priority.

The age group examined is that in which the incidence of cervical cancer is high, i e . , usually 35 and above. When a program of down-staging is first introduced, it would be preferable to restrict the age range to 45-64 to reduce the number of women to be examined and to obtain maximum initial impact.

CYTOLOGICAL SCREENING

Effectiveness of screening

Since screening for cervical cancer was introduced without evaluation via randomized trials, other less valid mechanisms have been used to judge effectiveness. These include correlation studies (time trends or geographical differences in incidence or mortality in relation to screening) and studies of risk in individuals in relation to personal screening.

The simplest studies reviewed by Miller (1986) compare trends in cervical cancer in a given area with the extent of screening. Analyses which correlate change in risk and screening intensity in several populations are more convincing. Cramer (1974) found a positive correlation between the decline in mortality rates and the level of screening at state level in the USA. Miller et al., (1976) related an index of screening intensity (smears/1,000 women/year) with changes in mortality from uterine cancer for Canadian provinces and for counties of census subdivisions. Results suggest that greater levels of screening are associated with larger declines in mortality, even when controlling for various socio-demo- graphic variables of the geographical units. Lynge (1983) analyzed data on cumulative incidence in women from 30 to 59 years of age and intensity of screening for counties of Den- mark; the decline in incidence was greatest in counties where organized screening had been introduced in the 1960s. In the 5 Nordic countries, Laara et al., (1987) observed that the decline in incidence in the 15-year period 1965-1980 correlates well with the coverage offered by the organized mass screening programs. A study of time trends in age-specific rates in these countries shows that the falls in incidence are confined almost entirely to the age groups that have been subjected to screening, and there has been little change or even increase in incidence in women aged 60 or more in all of the countries (Hakama, 1982).

More direct evidence for an effect of screening is obtained by relating cancer risk to screening activity at an individual


level. In Iceland, mortality rate and incidence of advanced tumors were low among women who had at least one negative smear and almost zero after 2 negative tests (Johanncsson et al., 1982). Rates in the unscreened group were slightly higher than before the introduction of screening so that the relative risk compared to the screened group was around 10. Fidler et al. (1968) estimated “ever-screened’’ and “never-screened’’ populations in British Columbia and calculated an age- adjusted relative risk for clinical carcinoma of 6.8 in unscreened women. In such studies, some of the effect may be due to lack of comparability between the groups; however, it is highly improbable that such large differences in risk are solely due to self-selection of low-risk women for scrcening (Breslow and Day, 1980).

Beginning with the pioneering studies of Clarke and Ander- son ( 1 9 7 9 many case-control studies of the effects of screening have been performed (reviewed by Morrison, 1992). There have been 3 studies in developing countries: in Colombia (Aristizabal, 1984), Thailand (Wangsuphachart et al., 1987) and China (Zhang et af., 1989). All confirm the lower risk in screened than in unscreened women, though the component of this which is due simply to selection bias has not been estimated. In a combined analysis of 10 such studies, the size of the protective effect was estimated in relation to time since screening (Hakama et al., 1986). Table V shows the relative protection obtained at different lengths of time following 2 negative smears. The relative protection was, for instance, 5-fold even 3-4 years after the last negative smear.

The effectiveness of screening at the population level will be determined by the proportion of progressive lesions that are successfully detected and treated. This proportion has itself 4 determinants: attendance rate, attendance pattern (self- selection), sensitivity of the test, and completeness of diagnostic work-up and treatment. It can readily be demonstrated that improving attendance rates at screening programs is a much more cost-effective strategy than increasing the frequency of testing on those women who d o attend. Furthermore, non- attenders are more likely to be from lower socio-economic strata and are at higher risk of developing the disease (Parkin et af., 1981). One of the great challenges for any screening program is therefore to reach a high attendance rate and an adequate attendance pattern among high-risk women who are less likely to be compliant. Inclusion of a greater proportion of high-risk women is probably the most important mechanism by which a quantitative impact of screening can be enhanced.

Test sensitivity, ~ e . , the likelihood that pre-clinical disease (notably those that would otherwise progress to invasive cancer) is detected, is difficult to estimate directly. It may be estimated by studying the occurrence of disease in women who initially have a negative smear and who are followed up over a period of years with repeat smears (Boyes et al., 1982). Alternatively, sensitivity may be estimated from the incidence rate of invasive cancers in the absence of screening and in a given interval following a negative test (Day, 1985). In British

T4BLE V - RELATIVE PROTECTION (GEOMETRIC MEAN) AGAINST (INVASIVE?) CERVICAL CANCER IN WOMEN WITH 2 OR MORE

PREVIOUSLY NEGATIVE SMEARS

Relative Conhdencr Months w c e la51 nrgdtive smear protection interval

0-1 1 15.3 10.0-22.6 12-23 11.9 7.5-18.3 24-35 8.0 5.2-11.8 36-47 5.3 3.6-7.6

60-71 3.6 2.1-5.9 72-1 19 1.6 0.6-3.5 120+ 0.8 0.3-1.6 Never screened 1 .0

48-59 2.8 i.wu~

Columbia, sensitivity was estimated as 75% for a laboratory with considerable experience in quality-control procedures, and it is likely that lowcr values are achieved elsewhere.

Since precursors (CIS or dysplasia) of invasive cervical cancer are detected by screening, both reduced incidence of invasive cancer and mortality are valid end points. New evidence concerning the efficacy of screening emerged from a global survey of time trends in incidence of invasive cervical cancer (Muir et ul., 1987). In Figure 15, data from 12 European countries are shown together. A peak age-specific incidence of about 75/100,000 in the age group 45-49 years in the mid 1960s disappeared gradually, i.e., before widespread screening took place. In the period 1978-1982, when fairly extensive (but largely opportunistic) screening was going on, a low broad shoulder remained, which reached a maximal height of 40 cases/100,000 around the age of 65. In contrast, no change in incidence was recorded above the age of 65; all women who presumably benefited from screening were between 35 and 65. We cannot prove that such declining incidence is caused by screening. However, data from Canada, USA and Latin America favor the conclusion that screening is significantly responsible for a declining incidence in large parts of the world (L. Gustafsson, personal communication). Time trends in age-specific rates show that any declining incidence is confined almost entirely to the screened age groups and that there has been little change or even increase in incidence in women aged 60 or more in all countries.

Finally, it should be evident that screening will only be effective if women with positive tests undergo appropriate diagnosis and therapy. Failure to manage screen-detected cases correctly is not uncommon (Chamberlain, 1986).

Natural history of cervical cancer and screening

Over-treatment

It is statistically well established that only a minor proportion, perhaps less than 20%, of all new CIS lesions ever progress to invasive cervical cancer (p. 6). Substantial over- treatment of dysplasia and CIS is the price to be paid for the benefit of intervention. The situation is even worse for moderate or particularly mild dysplasia (Narod et al., 1991), since low probabilities of progression have been established from the longitudinal study of defined cohorts of women who entered screening programs (Boyes et al., 1982; Miller et af., 1991~).

I00

1962.67

10 20 30 40 50 60 70 80 90 Age

FIGURE 15 - Age specific incidence of invasive cervical cancer 1962-1967, 1968-1972, 1973-1977 and 1978-1982 in 12 European countries (Denmark, Finland, former East Germany, Norway, Sweden, Slovenia, Scotland and parts of England, former West Germany, Hungary, Poland, Romania, Wales). Compilation from “Cancer Incidence in Five Continents, Volumes 11-V”. The data points are weighted according to the number of cases reported from the respective countries.

16 PONTEN ETAL.

Little attention has so far been paid to the possibility of reducing over-treatment, other than optimization of screening schedules. Conceivably, it may be possible in the future to apply more refined criteria using light microscopy and/or molecular biology to more accurately identify lesions that are likely to progress (Bergstrom et al., 1993).

Starting age, frequency and temiitiatioti of screening Ideally, screening should take place when the prevalence of

progressing lesions is high. The prevalence curve for CIS rises rapidly from the age of 20 to reach a peak at about 35, followed by a slow decline so that women in their 60s have a lower prevalence than those in their mid-20s. The decline from the age of 35 is partly due to progression to invasive cancer but is largely attributable to regression of lesions that do not progress (Boyeset al., 1982).

There are some indications that the prevalence in young women today may be higher than in older birth cohorts, perhaps as a result of changes in sexual habits at young ages. This does not necessarily mean, however, that the age-specific incidence curve has been shifted to younger ages, just that the incidence of the disease as a whole in the younger cohorts may be higher than in older ones; the shapes of the age-specific prevalence and incidence curves may remain the same, with the same inferences applicable to natural history (Miller et al., 1991b).

Optimal age for starting and stopping screening is connected with the number of screens performed. If only one test is carried out, it should be performed close to the age at which the prevalence of the most proximatc precursor of invasive cancer, i.e., CIS, appears. Since symptom-poor early invasive cancer is also to some extent picked up by screening (Johannes- son et al., 1976), the likelihood of detecting such cases will also enter the picture. Since the effect can be predicted, it is possible to estimate the marginal benefit expected from any change in the age of starting screening and thus to make recommendations that are specific to the age-specific rates in the population.

Prevalence of CIS peaked at around age 35 in our analysis (Fig. 6) and invasive cancer at about age 45 (Fig. 9). If only one smear is affordable, calculation based on the model of Figure 6 showed 36.5 years to be optimal (Gustafsson and Adami. 1992). In view of uncertainties inherent to the models em- ployed, their relative insensitivity to shifts in age and the ambiguity about effects on detection of pre-symptomatic invasive disease, it is reasonable to propose that if only one test is to be taken, this should be done somewhere between the ages of 35 and 45.

When the number of screening tests is increased, their dispersion in time becomes critical. Table VI uses the relative protection of screening estimated in the IARC study and the incidence of invasive cervical cancer from Cali, Colombia

(Muir et al., 1987), to illustrate the effects of different test frequencies and starting ages. The number of cases prevented per 100,000 tests provides a crude index of cost-effectiveness. Thus it can be seen that, although increasing the number of tests per lifetime results in fewer cases, there are diminishing returns in terms of cost. A program starting at age 25 is more effective than one starting at 35. but the benefit of moving from age 25 to 20 is negligible, because invasive cancer is rare at young ages. The additional costs of an early start are substantial due to the high prevalence of pre-clinical lesions, the majority of which will regress.

Annual screening is not necessary. Indeed, much of the benefit is obtained by screening at 5-year intervals, and re-screening more frequently than every 3 years cannot be justified. Unfortunately, in many countries resources are over-used in a small segment of the population, with little incremental benefit. More would be achieved by a high coverage of the population and limited numbers of smears in a lifetime than by low coverage and intensive screening of a few. This can be easily shown using the data of Table VI: a program of 5-yearly tests at ages 20-64 attended by one-third of the population would reduce incidence by 28% (84/3), and demand an average of 3 tests per lifetime for the whole population (9/3); the same number of tests per lifetime with 100% attendance can reduce incidence by 55%.

There has been pressure to commence screening at young ages, in part because of some evidence of increasing incidence of invasive cervical cancer in young age groups in some countries (Cook and Draper, 1984; Holman and Armstrong, 1987; Miller et al., 1991~) . However, the number of cases concerned is very small in absolute terms.

Unfortunately, there are no data on the effect of screening at ages above 65 in women who have been previously screened. Because of significant incidence of invasive cancer, women above 65 have been recommended to continue screening until they have had at least 2 negative smears (Miller et al., 1990). Results from a cost-effectiveness analysis have suggested that for women with a history of several negative smears in the previous 10 years and no positive smear, there is little to be gained by extending screening beyond the age of 65 (Fahs et al., 1992). This is reinforced by the problems related to taking smears in elderly women and ensuring their attendance for screening.

Optimization Following proper definition of available resources, of the

natural history of the disease and of the efficiency of the screening program, an optimal lifetime schedule for screening can be defined. Simulation programs can be used for such purposes [eg., see Gustafsson and Adami (1992), Knox (1991), Parkin et al. (1985) and van Oortmarssen and Habbema (1991)l. Such programs may also be used to accommodate

TABLEVI ~ EFFECTS O N INVASIVE CERVICAL CANCER INCIDENCE OF DIFFERENT SCREENING POLICIES STARTING AT AGE 201

Screening schedule Number of cases

per 10' tests Cumulative Reduction in Number prevented rate (9%) of tests rate, 20-64,

Der 10'

None 3312 Every 10 years, age 25-64 1298 61

Every 5 years, age 20-64 544 84 Every 5 years. age 25-64 562 83

Every 3 years, age 20-64 303 91

Every 10 years, age 35-64 1476 55 Every 10 years, age 4 5 4 4 1895 43

Every 5 years, age 30-64 630 81

Every year, age 20-64 216 93

4 503 3 612 2 708 9 308 8 344 7 383

1s 20 1 45 69

'From Parkin, 1991, assuming incidence rates from Cali, Colombia and the relative protections from Table V. The first screening test is assumed to be 70% sensitive.

17 CONTROL OF CERVICAL CANCER

complex individual situations such as prior screening histories and differing screening schedules in women believed to be at high or low risk for developing cervical cancer. Although the screening tests are optimally not distributed at regular intervals throughout a woman’s lifetime and rather tend to “bunch up” at the ages at which the maximum prevalence of precursor lesions occur (Gustafsson and Adami, 1992), considerations of practicality have led to all screening schedules being defined in terms of regular testing (e.g., every 3rd or 5th year). In most countries with sufficient resources for cytological screening, there are, in addition, existing norms or standards which should be considered. In practice this requires that screening starting age, frequency of re-screening and age to stop screening are treated separately. More complex models must be used, however, if the policies to be evaluated include allowance for other factors, for example, testing outside the organized programs or varying compliance in subgroups of the population at different risk.

HPV testing Virological typing of dvsplasia to predict risk of progression.

Arguments indicating that dysplasias carrying high-risk HPV types have an increased risk of progression, as compared to dysplasia without HPV or with low-risk CA HPV types are discussed on page 9. Dysplasias with high-risk HPV could be selected for intensive follow-up and/or treatment, whereas dysplasias which are HPV-negative or carry other HPV types could be left untreated and only monitored in a standard screening program. Calculations suggest that the reduced cost of treatment would outweigh the increased cost of testing (Reid et al., 1991). However, a number of objections may be raised. HPV testing focuses resources on dysplasias which are largely reversible spontaneously. HPV typing of dysplasia in younger women is therefore unlikely to reduce incidence of invasive cancer more than marginally. The psychological trauma of being singled out for closer follow-up because of infection with a potential cancer virus could. however, be substantial.

It is also doubtful whether detection of infection with a CA HPV type could be used to signify that the lesion is harmless. Although there are case reports of invasive tumors carrying low-risk CA HPVs, such tumors are sufficiently rare that infection with a low-risk virus cannot per se be said to constitute a significant risk factor for the development of cancer. However, since the various HPV types have similar routes of transmission and since infection with multiple types of HPV is common, detection of low-risk HPV is an indication that the patient may also be (or become) a likely candidate for infection by a high-risk type (Reeves et a/., 1989). In the absence of definitive data, a prospective evaluation of treat- mentifollow-up regimens with and without HPV typing of dysplasias is warranted.

Increasing sensitivity of cytological screening programs b y addition of HPV testing. HPV testing could be used as an objective independent adjunct for selecting slides for re- examination (Lorincz et al., 1992; Schiffman, 1992). When pathologists have blindly re-examined HPV-positive smears, significant detection of previously neglected dysplasias has ensued (Moscicki et al., 1991). HPV testing has also been used as a quality-control of histopathological diagnoses (Richart and Wright, 1993).

Since HPV testing has some predictive value for CIS or invasive cervical cancer, taking a second smear and/or a colposcopy-directed biopsy from HPV-positive women should improve sensitivity by reducing taker’s error. CIS has been detected colposcopically in HPV-positive women with normal smears (Reid etul., 1991).

The role of HPV screening, if any, as an adjunct to or replacement of cytology remains experimental. Elucidation of its value will be difficult, particularly if medical, psychological

and economic considerations should be taken into account. We believe that a useful answer can only be obtained via prospective randomized studies.

RECOMMENDED ACTIONS General background

Carcinoma of thc cervix is one of the main causes of death from cancer in women. Its victims belong to an age group where decades of healthy and active life are expected to be ahead. It is more common in populations with low socio- economic conditions. These exist in all countries but are most prominent in the developing world, where cervical cancer ranks first in many locations (Parkin, 1993). There is justification for effective measures not only to achieve lower mortality in general but also to give young and middle-aged women with a family and economic responsibilities a longer active life in every country.

Linking together partially unpublished and published data has helped to clarify our image of cervical cancer as being a treatable disease. A logical sequence exists for the combat of cervical cancer, based on available data, modifiable according to the current prevalent medical-economic-social conditions of any society. Fairly simple medical actions, not beyond the economic limitations of many societies, would suffice to bring about substantial reduction of morbidity and mortality. It is not lack of knowledge but rather its proper, equitable and cost-effective use that prevents progress. We d o recognize that there are societies where more pressing needs than combating cervical cancer deserve high priority. We maintain, however, that any country which contemplates a cancer-control program should consider carcinoma of the cervix as a target for concerted efforts.

A recent clinical-epidemiological survey of conditions in Kenya revealed a stage distribution (7% stage I, 58% stages 111-IV) similar to that in Sweden shortly after the turn of the century (Fig. 12). Crude stage-specific survival was difficult to evaluate because of poor follow-up but appeared to be at least as poor as that depicted during the earliest part of this century (Fig. 11) (Rogo, 1990). Conditions in Port Harcourt, Nigeria, were even worse, with 81% of women with cervical cancer presenting in stages 111-IV (Briggs and Katchy, 1990).

The natural history is sufficiently well known to allow scientifically well founded interventions, the effects of which can largely be predicted.

Our interpretation of existing data about the causes and the natural history of cancer of the cervix contains the following: ( i) Cancer of the cervix is predominantly caused by external, avoidable factors connected to life style and exposure to carcinogens. (ii) Causal factors are strongly linked to sexual behavior. Infection by HPV, particularly types 16/18. is likely a component but not a sufficient cause of invasive cervical cancer. (iii) The disease commonly develops as a number of consecutive stages: dysplasia of increasing degree, CIS and invasive cancer. Removal of a prior stage is expected to prevent development of the following one by eliminating a biological precursor and/or a large part of a potential target for subsequent invasive cancer. (iv) Invasive cervical cancer and its precursors develop slowly, thus leaving ample time for intervention. Mean sojourn time in dysplasia and CIS stages lasts about one decade for each entity, with moderate individual variations. Spontaneous regression will occur in over one-half of cases of dysplasia and CIS respectively. Invasive cancer is irreversible and will, if untreated, lead to death within a few years. (v) The development of invasive cancer can be described in 4 successive stages (I-IV) defined by the extension of the cancer in relation to surrounding pelvic tissues. Risk of death increases by a factor of 2.5 per each successive stage; i.e., treatment becomes progressively less

18 PONTEN E TAL.

effective as the cancer advances anatomically. (vi) The natural history of cervical cancer appears to be similar regardless of the time period and geographic location, thus allowing general- izations from one study to another.

Basic treatment and early clinical detection of invasive cancer

Prerequisites

The simplest scientifically well founded approach to prevention of death, i.e., access to basic treatment and early clinical detection, has given surprisingly good results. We refer to the early half of this century when a combination of a few simple measures was remarkably successful, originally in Sweden but later in different centers in Europe, USA, Canada and Latin America as well.

The primary requirement for success, that is delivery of effective information to a large segment of the population, particularly to women at risk, ought to be more easily met now than in the early and mid-periods of this century, given the effectiveness of communication media such as radio and television. The main prerequisite would be a commitment by governments, voluntary cancer organizations and medical personnel to focus on the goal of reducing mortality from cervical cancer. Although a purely informational approach should be the cheapest one, it would require that diagnostic and therapeutic facilities specifically aimed at cervical cancer be singled out.

Cancer of the cervix was considered hopeless at the turn of the century. Afflicted women presented in advanced stages when surgery, the only available type of therapy, could no longer be performed. The advent of radium therapy shortly after 1900 created the possibility of simple but effective treat men t.

Our analysis of the period up until 1960, when radium treatment (or its effective equivalent, local surgery) was the predominant modality and when mass screening was not performed, shows that remarkable progress was possible. Two main factors in association helped to produce these good results: (i) effective detection resulting in initiating treatment at progressively earlier clinical stages; and (ii) improved

stage-specific 5-year survival, predominantly in stages 1-11, which we interpret as being largely due to better therapy.

The 5-year survival increased from 20% to about .SO%, though in reality the improvement may have been greater, since in the early years, cases of advanced disease may not have been admitted for treatment. Nevertheless, these figures are probably representative of the situation in the population, since facilities for radium treatment were concentrated in just a few centers, to which all women with treatable cervical cancer were referred. Staging was performed according to agreed and fixed definitions and individual 5- and in most cases even 10-year follow-up strictly adhered to (Kottmeier, 1953). Five-year survival provides a good evaluation of outcome for cervical cancer, since most of the excess mortality occurs within 5 years of diagnosis (Adami et al., 1994).

Table VII illustrates effects obtainable by early clinical detection combined with improved treatment. Data are based on reported events from the Radiumhemmet, Stockholm (Figs. 11, 12) (Heyman, 1937-1952; Heyman, 1953-1955). Improved treatment alone gave a reduction of case fatality of about 17% from 1920 to 1960 (61 deaths instead of 74/100 women with invasive cervical cancer) and improved stage distribution alone a case fatality reduction of about 14% (64 deaths instead of 74/100 women). Taken together, these types of improvement gave a reduction of 43% (42 deaths/100 instead of 741100). Using the Radiumhemmet data, further improvement in stage distribution (“optimal distribution”) up until 1990 reduced case fatalities among women with invasive cancer marginally, down to 39 deaths per 100 women only.

These figures should be considered indicative rather than absolute. We conclude, however, that a major reduction in case fatality can be accomplished by a simultaneous improvement of treatment and the earlier detection of invasive clinical disease even in the absence of screening. Screening contrib- utes to further reduced mortality, mainly by reducing incidence of invasive cancer (Fig. 8) and to some extent also via early detection of invasive cancer (Adami et al., 1994).

We find that many centers, which report to the main international (FIGO) source of information (Pettersson, 1988- 1991), still have a sub-optimal stage distribution. If these figures could be improved by successful information cam-

Case fatality rate (probability)

Stage Baseline (1920) Improved (1960)

1 11 111 IV I II 111 1V 0.45 0.65 0.80 0.95 0.15 0.40 0.75 0.95

distribution

Baseline (1920) I I1 111 IV

Improved (1960) I I1 111 IV

Optimal (1990) I I1 111 IV

10 4.5 35 22.75 35 20

2s 11.2s 55 35.75 15 5

45 20.25 30 19.5 20

5

1.5 14

28 19

74

3.75 22

12 4.75

64

6.75 12

16 4.75

61

26.25 19

61

11.25 4.75

42

15 4.75

39

The “baseline,” “improved” and “optimal” conditions relate to the results from the Radiumhem- met, Stockholm, in 1920, 1960 and 1990 (as shown in Figs. 5 and 6). Results are expressed per 100 women in each combination.


paigns, a considerable number of deaths due to cancer of the cervix would be prevented. Implementation in areas where adequate treatment facilities already exist should further induce a favorable shift from expensive, complicated therapeutic modalities to simpler, more effective ones, suitable for treatment of stages 1-11.

Implementation Our simplest minimal proposal for areas or societies where

cervical cancer runs its natural course in most women, without any medical intervention, can be summarized as follows: ( r ) Therapy centers must be created, where the basis would be intracavitary radium or cesium completed by after-loading. Radium may be acquired cheaply from centers where it is no longer used. It lasts long enough to make repeated radioactiv- ity determinations superfluous. Cesium has a shorter half-life and necessitates yearly radiophysical activity assessments. After-loading is more expensive, but equipment, which has been abandoned in favor of more sophisticated machinery (a questionable therapeutic gain, according to our analysis!), could be transferred to such centers at little extra cost. Advanced cases will have to be treated palliatively, with great attention to pain relief and psychological support. (ii) The same centers will have to be equipped with diagnostic facilities including cervical inspection, possibility of biopsy and diagnostic cytology. Clinical staging (I-IV) must be performed for each case and records kept. By following the dynamics of stage distribution, an early idea about the success of the program will be obtained. (iii) The centers must have possibilities for simple curative surgery of stage 0 lesions based on surgery, diathermy loop excision and/or destruction by laser. (iv) A simple follow-up system should be established ensuring that dose and schedule of irradiation treatments are adhered to. If possible, 5-year survival should be ascertained. (v) Intense information should be directed to the general public and the medical community about cervical cancer being a curable disease if early diagnosis is made. We believe that voluntary organizations geared to women’s health are the most suitable channels to disseminate this type of information. Maternity wards, community health centers, midwives and nurses should feel responsible for informing all women about symptoms of cervical cancer. Simple brochures could be produced for mass distribution.

Information campaigns will necessarily be different depending on existing circumstances, which may vary from largely rural population groups and perhaps isolated tribes or commu- nities to sections of cities with social and ethnic mixtures of under-privileged people.

The scheme above is naturally modified if adequate treatment facilities already exist. However, any program which will lead to an increased number of women seeking help at earlier, treatable stages of their disease will necessitate a corresponding increase of existing diagnostic and therapeutic facilities.

One major obstacle to the simplest of all approaches may be of a psychological nature. It will be hard to convince, particularly the medical establishment, of the efficacy of an approach which does not require any sophisticated sampling and analysis of cells or mobilization of active diagnostic measures. It will take great patience and perseverance to keep up enthusiasm for such a non-glamorous scheme, which critics may even call out-dated. No large commercial interest will be attracted.

To be successful a campaign has to be carefully geared to the particular traits and interests of the target population. The conviction that cervical cancer can be detected early because of the symptoms has to infuse into the population. Women should not let inter-menstrual bleeding, bleedings or other discomfort at coitus or other types of abnormal discharge pass without seeking medical aid.

Health care centers, policlinics, private physicians and hospital services should be persuaded to examine women with symptoms with a view to regarding them as having cervical cancer or dysplasia until such conditions have been excluded by cytology, biopsy and/or colposcopy. Participating centers must be encouraged to gather results of their efforts in systematic form and report on their progress also in the lay press.

This type of public and professional educational approach may be applicable in developing countries. This has been indicated by a project largely involving personally directed health education using specially trained workers in a rural area, Barsi, Maharashtra State, India. This appears to produce a favorable effect on the stage distribution of cancers of the cervix (Tata Memorial Centre, 1991).

Assessment Assessment of such intervention by randomized controlled

trials is not realistic. Since the goal is to spread education through all possible mechanisms, the number of women reached by information cannot be readily defined. Contamina- tion of the control group would be unavoidable. Moreover, access to basic treatment, an equally important component of the intervention, cannot be withheld for women in the control group for obvious ethical reasons.

One approach to assessment would be to monitor trends of age-specific and age-standardized mortality before, during and after the introduction of a program, particularly in well- defined pilot areas, where a register for cervical cancer can indeed be introduced (Morrison, 1992). Initial impact will necessarily entail a rise in the number of patients diagnosed and treated for invasive cervical cancer, particularly in early clinical stages. Persistent increase may even occur in populations where women with cervical cancer earlier escaped medical attention until they were beyond curative treatment or indeed died from disease.

In addition to monitoring mortality trends, it would be valuable to have at least a part of the target population covered by a cancer registry, which can monitor disease stages, treatment received and survival rates. This requires patient follow-up for at least 5 years. With such information at hand, stage distribution, stagc-specific survival and trends over time could be readily calculated. At least a crude estimate of the overall impact of public and professional education should thus be possible.

Clinical down-staging

Implementation

We have not found sufficient support for recommending or refuting mass screening by speculum examination, as an isolated method for prevention. The method essentially requires the participation of trained health workers capable of recognizing cervical abnormalities and can only be instituted where adequate diagnostic and therapeutic facilities exist. It should be regarded as an option which requires thorough evaluation before it is introduced as a large-scale procedure.

Assessment At least 3 different levels of ambition are perceived. The

most basic is to characterize the performance of visual inspection. Beside sensitivity and specificity, data on predictive value of a positive test in the general population of mostly asymptom- atic women is particularly informative. Also, the feasibility of a test should be ascertained by studies of costs and resources needed, compliance and possible self-selection of women at low or high risk of cervical cancer among those who partici- pate. Ideally, the ultimate effect of the intervention in terms of

20 PONTEN E T A L .

reduced mortality from cervical cancer should be established and quantified in controlled clinical trials.

Cytological screening

Implernentalion

Screening by cytology is a potentially highly effective procedure. A single cervical smear for all women at age 45 might reduce the incidence of invasive cervical cancer by 25% (Prabhakar, 1992), and 2 tests per lifetime at ages 45 and 55 would reduce incidence by 409645% (Parkin, 1991). These estimates refer to circumstances without other measures to detect cervical cancer early. Even after developing early clinical detection via public information, however, mass screening has produced extra benefit, eg., in Finland and Sweden.

The problem involved in cytological screening lies in implementation, which assures maximum coverage of the target population without wasting resources on frequent testing of women at lower risk, a challenge which no society has met successfully.

The type of program which is appropriate depends on the resources available. An estimate can be prepared in terms of the total number of cytology tests affordable per year and followed up with appropriate control of program quality. These tests must be optimally distributed over the female population. The challenge is then to deliver such a program, an important field for research indeed, into health service delivery.

If routine testing of the population in this way is not possible, due to lack of sufficient resources or to operational problems, alternative deployment of scarce resources can be investigated. One example is to ensure screening of all women who attend gynecology or sexually transmitted disease clinics. Another possibility is to use existing health care centers and to restrict examination by Pap smear to women over age 35. Provided smears are well taken and read and appropriate follow-up and treatment can be accomplished, even such limited programs could have a significant impact on the incidence of cervical cancer.

Cytological screening is costly because of heavy demand on infrastructures, particularly related to taking and reading smears. If contemplated, emphasis should be given to coverage rather than to total number of smears. A program with 80% coverage involving one smear at 30 and one at 45 combined with information about symptoms and adequate diagnostic and therapeutic facilities would perhaps reduce cervical cancer mortality by some 50% (against a background of no or minimal intervention). About half of this reduction would then be due to detection of early clinical stages because of symptoms and employment of effective treatment, and half would depend on removal of screening-detected precursors.

In developed societies with adequate resources for taking and reading smears and adequate therapy, organized programs ought to accomplish significant further reduction of mortality. These imply calling women individually. Where such schemes have worked, compliance. measured, for instance, as at least 3 smears spread over a decade covering the age bracket from 35 and up, has been at least 75%. Unless such a coverage is reached. one should not expect a screening program to work optimally or even adequately. Repeated individual approaches of women above 30 or 35 may be required, backed up by general information about the importance of screening. The expected additional gain in reduced specific mortality is not known, but it has been suggested that it can be reduced to at least 80% of baseline values within a population with minimal or no prior intervention.

The essential features of organized programs have been described extensively (Hakama et al., 1985). Therefore, we

shall provide a brief summary only. Key elements of successful screening include high coverage of the source population, appropriately taken smears, adequate facilities for reading smears and further diagnosis and treatment of confirmed neoplastic lesions. An organized quality-control program and procedures for evaluating and monitoring effects are also important. These goals are not easily met. Indeed, failure of programs in many countries have been largely due to organizational and managerial shortcomings. They relate principally to problems with taking smears, failure to recruit women at high risk into screening and inefficient, poorly organized laboratory services. As many as half of the false-negatives may be due to taker’s error (Boyes et al., 1982), but a useful guide to improve smear taking is available (Thompson, 1989). In too many instances, small laboratories with inadequate routine loads perform substandard cytology.

Organized programs have a potential for major cost saving, as they could prevent over-use or mis-use of services of unorganized programs. Governments must provide the necessary up-front resources for the organizational framework. They must also persuade the medical profession to accept less frequent screening of many women at lower risk, thereby releasing resources to ensure that women at higher risk are brought into the program.

There are 3 possible means of informing women about screening and persuading them to attend: public education campaigns to ensure that women request screening, professional education campaigns to ensure that primary health care workers include their patients in screening programs and an organized program combining these 2 elements with measures to make certain that women are invited to be screened. The first 2 elements have been shown to be insufficiently effective in Canada and the UK for exerting a maximal impact on the disease. Hence, special efforts are required to bring many women at high risk into screening programs. In many countries maternal, child health and family services have been used for initiating cervical screening, but these are not sufficient as they often miss the older high-risk women in the population.

There is a clear need for research to determine the best ways to recruit women for cervical cancer screening in different cultural settings.

Assessment Several measures are needed to ensure basic evaluation of

screening programs. These include: ( i ) the number of smears taken, (ii) the number of positive smears reported, (iii) the number (and proportion) of women referred for diagnosis and therapy, (iv) the number of precursor and benign lesions detected, (v) the number of invasive cancers diagnosed and their stage distribution.

Such data, analyzed by age, can confirm that women in the target groups are screened and receive appropriate management. Population-based cancer registration is needed, however, to evaluate the effectiveness in terms of prevention of invasive cancer and death.

The simplest form of surveillance and evaluation is recording a change in the trend of the incidence rate of invasive cancer, in the number of advanced cases of disease or in mortality from the disease. Case-control comparisons of past screening history may be used to quantitate the protective effects of screening. Screening histories are best taken from registers of screening, but if they are not available, screening histories may be obtained from the individuals themselves, though this is likely to be subject to defects in recall.

Case-control studies usually give an over-optimistic picture of effectiveness because women who attend screening are of lower baseline risk ( ie . , without screening) than those who d o not attend.


Efficient surveillance requires a system of linked records brought together to establish an information system for cervical screening. A population register provides the basis for periodic call-back for re-screening at appropriate intervals. The cytology register, linked with a cancer register, permits active surveillance of women with abnormalities to ensure recall for repeat screening, diagnosis and therapy. The program can then be evaluated with regard to: ( i ) management of women with positive smears, (ii) false-negative smears leading to cancers which have escaped successive screenings, ( i i i ) groups missed in the target population, (iv) failures of attendance for diagnosis and treatment.

An ideal solution is to ensurc that the whole program is integrated with an appropriate information system that can document attendance for diagnosis and therapy of those with abnormal findings on cytology, activate a recall system at appropriate intervals for those with negative smears and evaluate and monitor the total program (Miller et al., 1991~) .

Government agencies, professional organizations and cancer societies frequently issue recommendations with regard to ages for starting and stopping screening and the frequency of re-screening. In principle, such recommendations may have limited impact if the available resources for the program have not been defined and if justification for the recommendations is uncertain. For these purposes it is important to define the optimal number of screenings that a woman should be offered in her lifetime and at what ages, always provided that the

laboratory services are of sufficient quality. Whereas costs tend to increasc linearly with increasing numbers of re-screenings, the marginal benefit for any additional screening decreases rapidly (Gustafsson and Adami 1992; Yu et al., 1982). The qucstion of cost-effectiveness is thus highly relevant. The marginal benefit of additional screens must be assessed in relation to the impact of spending the necessary resources on improving other factors relevant to the success of screening, such as attendance rates, sensitivity of the test and quality of the laboratories.

ACKNOWLEDGEMENTS

We sincerely thank Drs. F.X. Bosch at the Hospital Duran i Reynals, Barcelona, Spain, and C.P. Crum at the Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, for valuable suggestions and constructive comments, particularly concerning HPV and its relation to cervical cancer and its precursors. Deep thanks also go to Dr. 0. Kjellgren, Department of Gyneco- logical Oncology, University of Umei, Sweden, who helped us to sort out the intricacies of different treatment modalities, particularly in relation to the developing world, and offered several other valuable comments. Superb constructive editorial and secreterial help has generously been delivered by L. &an-Nordberg, Depart- ment of Cancer Epidemiology, Uppsala University. Supported by grants from the Swedish Cancer Society.

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Strategies for global control of cervical cancer

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