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Mammographic breast cancer screening —a randomized trial in Malmö, Sweden
21
Mururiras, 7 (1985) 21-29 Elsevrer
MAT 00341
Mammographic breast cancer screening a randomized trial in Malm6, Sweden I. Andersson ‘, L. Janzon * and B.F. Sigfbsson ’ Departmenrs of’ Radiology and Preventive Medicme, and ’ Communrfy Medicine, Universrty of Lund Maim6 General Hospital, S - 214 01 Malmii, Sweden (Received
26 December
1984; accepted
8 January
1985)
A randomized trial is presented on the effect of repeated invitation to breast cancer screening with mammography on mortality from breast cancer. The invited group and the control group each consisted of approximately 21,000 women aged 45-69 yr at the start of the screening. The attendance rate was 74% at the first screening and 70% at the two subsequent screening rounds. The cancer detection rate was 7.5 per 1000 women examined in the first screening round and 2.2 and 2.0 per 1000 woman-years in the second and third screenings with an incidence of 0.9 in the intervals. The incidence in the control group was 2.7 per 1000 woman-years. The proportion of positive biopsies was 61% ‘in the first screening round, 33% in the second, and 58% in the third. After the prevalence screening, the stage distribution was more favourable in the invited group (including non-attenders) than in the control group. In the two most recent periods of the programme, 62 out of 160 women with cancer (39%) in the invited group were in stage II-IV compared with 91 out of 159 (57%) in the control group. More than 60% of cancers detected at screening were either non-invasive or invasive with a diameter of 1 cm. The corresponding percentage in the control group was 27%. The importance of sampling bias is discussed. Although data on mortality still have to be awaited, the results so far clearly indicate a positive effect of screening. (Key words:
Breast cancer
screening,
Mammography,
Randomized
study)
Study design and population At the end of 1976 a breast cancer screening programme was initiated in the city of Malmo in southern Sweden with 235,000 residents. The programme was designed as a controlled study to investigate whether repeated invitation to breast screening with mammography might reduce mortality due to breast cancer. The invited cohort was offered 6 screening examinations during a lo-yr period. A random sample consisting of 50% of all women in Malmo born between 1908 and 1932 and aged 45 to 69 yr at the start of the screening, was invited. The identification of the women was based on the population registry of the city. The randomization was done on an individual basis. The invited groups and the control group each consisted of approximately 21.000 women.
Correspondence to: 1. Andersson, Department of Radiology Malmo General Hospital, S-214 04 Malmo, Sweden.
0378-5122/85/$03.30
0 1985 Elsevier Science Publishers
and Preventive
B.V.
Medicine.
University
of Lund.
22
Organization and technique
The mammographic screening unit is localized in the Department of Preventive Medicine in Malm6, a free-standing facility outside Malm6 General Hospital, the only hospital in this city. In the mailed invitation women were offered a free mammographic examination for early detection of breast cancer. The staff consisted of one technician, one assistant, one secretary and one part-time radiologist. The capacity of the screening centre was 50 examinations per day. Film mammography was the only screening modality used. Thus, physical examination was not a part of the screening procedure. In the first two screening rounds, two views, the crania-caudal and the oblique, were obtained. In subsequent rounds, either the oblique only or both views were obtained depending on the parenchymal pattern as classified according to Wolfe; Nl and Pl breasts getting the oblique view only, P2 and DY breasts getting both views. Details of the mammographic technique have been described elsewhere [1,2]. The daily routines have been simplified as much as possible, and the amount of paperwork was minimized. The screening mammograms were classified as either suspicious or not suspicious for cancer, the classification being indicated on a diagram on the film chart. No formal reports were dictated on the screening mammograms. If considered suspicious, the patient is recalled for a complete mammogram. If the suspicion can be ruled out on complete examination, the patient is informed immediately and sent home. If there is still a suspicion after the complete examination, the patient is referred on the same day to the team surgeon for further evaluation and information. Presently four screening rounds have been completed. The data in the present paper are preliminary and refer mostly to the first three screening rounds, but sometimes results from the fourth round are included. Number of deaths from breast cancer as well as total mortality are followed by record linkage with the Central Register for Causes of Death in Sweden. All cases were referred to the same Department of Surgery. During the course of the study there has been a relative shift from modified mastectomy to conservative, breast-saving surgery for early stages of the disease.
Results and comments
The average attendance rate in the first screening round was 74% and 70% in the two subsequent rounds. The attendance rate was age-dependent with the highest attendance in the youngest age groups. The entire group invited to the first screening was also invited to the subsequent rounds; thus, not only those women who attended the first screening continued to be invited. Between 3% and 4% of the screened women were selected as suspicious for cancer on the basis of the screening mammograms (Table I). The criteria for selection have been detailed elsewhere [l]. In about half the cases, the original suspicion was
23 TABLE
1
PER CENT
OF SCREENEES
SELECTED,
REFERRED
AND OPERATED
UPON
Screening
Selected
Referred
Operated
I II Ill
3.4 3.8 3.1
1.6 1.5 0.9
1.2 1.3 0.6
considered false-positive as judged from the complete mammogram. In the majority of these cases the reason for the initial suspicion was superimposition of normal structures. The majority of those referred to the team surgeon for further evaluation subsequently underwent a surgical biopsy. The higher figures for selection and operation in the second as compared to the first round is mainly explained by the fact that the criteria for selecting and operating clustered calcifications were extended. This is again reflected in the proportion of positive biopsies which was 61% in the first, 33% in the second, and 58% in the third round. The predictive value of a positive screening mammogram (first screening round) was 22%. By adding a complete mammogram to those initially suspected of malignancy the predictive value increased to 47% due to an increase of the specificity from 97 to 99%. The sensitivity was 92%. For the calculation of the sensitivity the appearance of cancer within 1 yr of a negative screening was considered a falsenegative result. Table II gives the number and rate of carcinoma in various subgroups of the population under study. The interval between the first and second screening, and second and third screening was 22 and 20 mth, respectively. The detection rate at the first screening was approximately three times as high (7.5 per 1000 women) as the incidence of breast cancer in the control group (2.7 per 1000 woman-years). Women belonging to the control group could have a mammogram made either at the hospital
TABLE
11
NUMBER OF WOMEN WITH CARCINOMA FROM DATE OF ENTRY ING IN VARIOUS SUBGROUPS OF THE STUDY POPULATION Figures within parentheses denote detection rates or incidence: screenings II and Ill are per 1000 woman-years, the idea being, more like incidence figures as opposed to the prevalence figure comparable to the other incidence figures given, especially that Screenmg I Screening II Screening III Interval Non-participants Total invited group Control group Total
118 58 46 50 46 318 204 522
UNTIL
THIRD
SCREEN-
screening I is per 1000 women screened, that the rates in screenings II and Ill are of screening I and also to make it more of the control group.
(7.5) (2.2) (2.0) (0.9) (2.0) (2.7)
24 TABLE III PROPORTION OF PATIENTS WITH ‘EARLY’ CARCINOMAS Noninvasive (S)
screening I Screening II Screening III Interval case Non-participants Control groups
16 21 15 14 2 11
Invasive dlOmm (%) 43 48 46 14 9 16
Total (S) 59 69 61 28 11 27
or at a private outpatient clinic in the city, even in the absence of symptoms. It is not known how many women in the control group had a mammogram made, but the number is probably not negligible. Clearly, a number of cancers in the control group were detected by mammography only, which might explain why the incidence figure for the control groups is somewhat higher than expected when compared with historical data from the city of Malmii and contemporary data from other parts of the country. This stresses the fact that once a diagnostic procedure or treatment has been accepted by the public, it is more difficult to evaluate the effect in a controlled trial. The figure for the incidence of interval cancers in Table II is a composite of the first two intervals: in fact the incidence was higher (1.2 per 1000 woman-years) in the first interval than in the second (0.7 per 1000 woman-years). The lower figure for the second interval might reflect increased experience with the interpretation of the screening mammograms or improvement of other factors influencing the sensitivity of the screening procedure. Furthermore, changing the criteria for a positive screening mammogram might have played a role. In the control group, 27% of the cancers were either non-invasive or invasive with a diameter of 10 mm or less (Table III). Among screening-detected cases the proportion of ‘small’ cancers was significantly higher (> 60%), which was mainly due to a larger proportion of small invasive carcinomas. Among interval cases the proportion of small carcinomas was approximately the same as in the control group. In the control group about 50% of the patients were in stage II-IV, which should be compared with < 25% of screening-detected cases (Table IV). The stage distribution of interval carcinomas was slightly more favourable than in the control group, while the stage distribution among non-participants was less favourable. With a study design of two equally large groups of women, one invited and the other not invited, it should be possible to compare directly the number of patients with stage II and over. If screening is effective, the tumours should be detected at an earlier stage, which should be reflected in a reduced number of patients with advanced disease (stage II-IV). In the first round of the screening programme there is an accumulation of stage II-IV carcinomas which in the absence of screening would have surfaced clinically
25 TABLE
IV
PROPORTION
OF PATIENTS
WITH
DISEASE. STAGING ACCORDING TO UICC
ADVANCED
[31
Screening I Screening I1 Screening III Interval cases Non-participants Control group
Axillaiy metastasis
Stage II-IV
($1
(%l
18 18 17 30 61 38
20 26 17 42 65 52
during the following year or years (Fig. 1). Only after three screening rounds did the control group reach the same number of patients with stage II-IV disease as the invited group, and by the end of the fourth screening there was a small excess in the control group. It should be noted that the invited group includes interval cancers and cancers among non-participants. In Fig. 2, the first screening has been excluded. The cumulative difference of patients with stage II-IV at the end of the fourth screening was 36 patients in favour of the invited group. In the two most recent periods of the programme, 62 out of 160 women with cancer (39%) in the invited group were in stage II-IV compared with 91 out of 159 (57%) in the control group. The difference was 14 and 15 cases, Number
Number
-
Study
---
Control
gro”~ group
-
Study
- - -
Control
grow ,144
group
132
/
Screening
Fig. 1. Cumulative screening. Fig. 2. Cumulative
number
number
/
108
Screening
of patients
of patients
with
stage
II-IV
with stage II-IV
carcinoma
carcinoma
from
excluding
date
of entry
first screening.
until
fourth
26
respectively, during the second period (second interval plus third screening) and third period (third interval plus fourth screening). This indicates the new level of diagnosis with screening.
Some aspects on sampling bias
It is apparent that a large proportion of the cancers detected by mammographic screening are small without axillary metastatis. A substantial amount of clinical experience indicates that the prognosis of breast cancer is related to the size of the tumour and the state of the axillary nodes at the time of treatment [4-61. Thus, by parameters established in clinical practice the screened group should have a better than average prognosis. Such a conclusion would, however, be based on the assumption that the sample obtained by screening with mammography is representative of the general clinical breast cancer population. Basically, there are two reasons why such an assumption is not valid. First, breast cancer is not a uniform disease but rather a spectrum of diseases ranging from slow-growing (less malignant) to rapidly growing (more malignant). Secondly, there are mechanisms inherent in the screening procedure which tend to bias the sample, the most important being the length bias which is related to the distribution of growth rates of the tumours [7], and the detection bias which is related to the detection system used for screening. Another factor is self-selection within the invited group. The overrepresentation of advanced disease among non-attenders might reflect such a mechanism. This is also illustrated by the relatively lower attendance rate of older women. Length-biased sampling refers to the tendency of screening to pick up preferably slow-growing tumours while fast-growing tumours tend to surface in the interval to the subsequent screening. As mentioned above, 50 women appeared with carcinoma in the first two intervals. Forty-three of these 50 carcinomas were invasive, and 7 non-invasive. Twenty of 43 invasive cancers had a calculated tumour volume doubling time of 100 days or less which may be considered a rapid growth rate. We do not know the distribution of tumour volume doubling times in the other subsets of the population under study. There are investigations indicating that the average tumour volume doubling time of breast cancer is approximately 200 days with a considerable range of variation [8,9]. After a relatively short follow-up (27 months on the average), 7 patients among those with interval carcinomas had died from breast cancer and another 7 had metastatic disease (Table V). Interestingly, three of these 14 patients had no axillary metastatis at the time of the initial treatment. Twelve of the patients had rapidly growing tumours as compared to 8 of the remaining 29 cases with interval carcinoma who had no evidence of recurrence. A case fatality/recurrence rate of 28% among patients with interval cancer during the average follow-up time period of 27 months is much higher than among patients with screening-detected cancer. It is also worth mentioning that only 3 of the 20 rapidly growing tumours retrospectively showed an abnormality that would have been possible to detect on
27 TABLE
V
FOLLOW-UP (AVERAGE 27 MONTHS) OF PATIENTS APPEARING WITH CARCINOMA IN THE INTERVAL BETWEEN SCREENINGS. NUMBER OF PATIENTS WITH TUMOUR VOLUME DOUBLING TIME < 100 DAYS WITHIN PARENTHESES.
Dead from breast cancer Alive with metastatic disease Dead without metastasis Alive without metastatic disease
7 (6)
7 (6) 1 (0) 28 (8)
the preceding screening mammogram. Furthermore, 9 of them appeared within 12 months of the preceding screening. There is, therefore, a group of very aggressive tumours which cannot be picked up at screening unless the screening is repeated at very short intervals which seems unrealistic. Still, this group represents only a small fraction of all cancers detected in the screened population and therefore does not necessarily influence the total outcome of the screening programme in a significant way. The length-time bias associated with screening could imply that a small tumour detected at screening is not an ‘early’ fast growing one. Data from our own study do not support this view, however. Traditionally there are some histologic types of breast cancer that are considered less malignant than other types. This applies to tubular cancer and non-invasive intraductal cancer. If these were very slow-growing cancers (as compared with other histologic types of cancer) we would expect to find them mainly in the first screening, but it is evident from Table VI that tubular cancer as well as intraductal non-invasive cancer made up about the same proportion in the second and third screenings as in the first one. This indicates that the transition from a radiographically non-detectable to detectable stage occurred within a rather short period of time, which in turn indicates that progression is not very
TABLE
VI
DISTRIBUTION OF CARCINOMAS ING TO LINELL ET AL. [lo] Type of carcinoma
Tubular Tubuioductal Medullary + mucmous + ductal of comedo type Lobular Non-invasive Intraductal Lobular
??
BY MICROSCOPIC
Clinical * series (n = 238)
TYPE (S). CLASSIFICATION
Screening I (II -116)
II (n = 58)
III (n=46)
15 34 33
35 23 15
22 22 26
26 28 22
11
10
9
9
5 3
14 3
16 5
13 2
The control group plus all clinical cases diagnosed the screening.
ACCORD-
in the same birth cohort
1 yr before the beginning
of
28
slow. As mentioned above, the average interval between the screenings was 22 and 20 mth, respectively. One also has to consider the probability of tubular cancer evolving into another histologic type. This problem has been addressed by the pathologists in our group, Drs. Line11 and Ljungberg. In a comprehensive histologic study they identified many transitional forms between pure tubular cancer and ductal cancer with productive fibrosis [lo]. Furthermore, transitional forms between so-called radial scars (non-encapsulated sclerosing lesions [ll]) and tubular cancer were identified, indicating that some radial scars might progress into tubular cancer. The cancers could be classified into subgroups thought to reflect the progression from tubular cancer to less differentiated forms. These subgroups showed an increasing tumour size and frequency of axillary metastasis with decreasing amount of tubules and increasing amount of less differentiated, so-called ductal structures [lo]. It was concluded that tubular cancer probably should not be regarded as a static entity but rather as representing one stage in the progression towards a more malignant type of cancer. Clinically, this is a very important issue. If tubular cancer is to be regarded as a more or less static entity, then the large number of patients with tubular cancer found at screening are probably treated more radically and earlier than is necessary. If, on the other hand, tubular cancer. is a progressive disease, it represents an early finding of a clinically significant cancer. Our data support the latter possibility. The varying sensitivity of mammography to different morphologic types of cancer is another source of sampling bias. Different histologic types of breast cancer produce different morphologic changes, some of which are easier to detect radiographically than others. Thus, cancers with productive fibrosis (tubular and tubuloductal) tend to form spiculated masses which, even when small and located in dense tissue, are relatively easy to detect. On the other hand, medullary and mutinous cancers as well as some intraductal invasive cancers of the comedo type tend to form well-marginated masses which, when small and located in dense tissue, are difficult or impossible to detect. Also, their appearance is similar to that of benign tumours. If this factor is really operating, we would expect to find a larger proportion of tubular carcinomas at screening than in the control group, and few would appear in the intervals between screenings. For the well-marginated type of cancer, the distribution should be the opposite with relatively few detected at screening as compared with the control group, and relatively many appearing in the intervals. The data given in Table VII on the distribution of histologic types of cancer are in accordance with these considerations. Thus, it is reasonable to conclude that the varying sensitivity of mammography to different histologic types of cancer is another source of sampling bias. If the different histologic types have a different prognosis there is a possibility of a biased sampling towards more than average malignant or more than average benign. Our knowledge of the prognosis of the different histologic types of the classification used is insufficient. A study on this particular subject is in progress. The problem is further complicated by the possibility of progression of tubular cancer as discussed above. It is not possible at present to assess the net effect of the different types of bias. Clearly, prognostic parameters such as the proportion of small or ‘early’ cancers might be substantially affected while the other end of the
29 TABLE
VII
DISTRIBUTION OF CARCINOMAS ING TO LINELL ET AL. [lo]
BY MICROSCOPIC
TYPE (‘%). CLASSIFICATION
Type of carcinoma
Clinical series (n=238)
Screenings I-III (n-220)
Intervals (n =50)
Tubular Medullary + mutinous + ductal of comedo type Other invasive Non-invasive
15 33
30 19
8 42
45 8
34 17
36 14
ACCORD-
range, i.e. stage II and over, should be much less so. However, even in a controlled trial using endpoints such as metastatic disease or death from breast cancer, sampling bias might influence the results. Once the patient has a diagnosis of breast cancer, there is a risk that if she gets metastatic disease the metastases are considered to be due to the breast cancer even if the origin actually is a different cancer. The same applies to death from breast cancer. In the absence of autopsy, patients with known breast cancer are more likely to be classified as dead from breast cancer, even if they in fact died from a different disease.
References 1 Andersson I. Radiographic screening for breast carcinoma. I. Program and primary findings in 45-69 year-old women. Acta Radio1 (Diagn) 1981; 22: 185-194. 2 Andersson I. Radiographic screening for breast carcinoma. III. Appearance of carcinoma and number of proJections to be used at screening. Acta Radio1 (Diagn) 1981; 22: 407-420. of mahgnant tumors. 3rd edition. Geneva 1978. 3 UICC. TNM classification 4 Adair F, Berg J, Joubert L, Robbins GF. Long-term follow-up of breast cancer patients: the 30-year report. Cancer 1974; 33: 1145-1150. 5 Duncan W, Kerr GR. The curability of breast cancer. Br Med J 1976; 2: 781-783. 6 Wallgren A. Silfversw’ard C, Eklund G. Prognostic factors in mammary carcinoma. Acta Radio1 Oncol Radiat Phys Biol 1976; 15: 1-16. 7 Feinleib M, Zelen M. Some pitfalls in the evaluation of screening programs. Arch Environ Health 1969; 19: 412-415. 8 Foumier DV, Weber E, Hoeffken W, Bauer M, Kubli F, Bart V. Growth rate of 147 mammary carcinomas. Cancer 1980; 45: 2198-2207. 9 Lundgren B. Observations on growth rate of breast carcinomas and its possible implications for lead-time. Cancer 1977; 40: 1722-1725. 10 Line11 F, Ljungberg 0, Andersson I. Breast carcinoma. Aspects of early stages, progression and related problems. Acta Pathol Microbial Scand Suppl 1980; 272. 11 Fisher ER, Palekar AS, Kotwal N, Lipana N. A non-encapsulated sclerosing lesion of the breast. Am J CIin Pathol 1979; 71: 240-246.
Mururiras, 7 (1985) 21-29 Elsevrer
MAT 00341
Mammographic breast cancer screening a randomized trial in Malm6, Sweden I. Andersson ‘, L. Janzon * and B.F. Sigfbsson ’ Departmenrs of’ Radiology and Preventive Medicme, and ’ Communrfy Medicine, Universrty of Lund Maim6 General Hospital, S - 214 01 Malmii, Sweden (Received
26 December
1984; accepted
8 January
1985)
A randomized trial is presented on the effect of repeated invitation to breast cancer screening with mammography on mortality from breast cancer. The invited group and the control group each consisted of approximately 21,000 women aged 45-69 yr at the start of the screening. The attendance rate was 74% at the first screening and 70% at the two subsequent screening rounds. The cancer detection rate was 7.5 per 1000 women examined in the first screening round and 2.2 and 2.0 per 1000 woman-years in the second and third screenings with an incidence of 0.9 in the intervals. The incidence in the control group was 2.7 per 1000 woman-years. The proportion of positive biopsies was 61% ‘in the first screening round, 33% in the second, and 58% in the third. After the prevalence screening, the stage distribution was more favourable in the invited group (including non-attenders) than in the control group. In the two most recent periods of the programme, 62 out of 160 women with cancer (39%) in the invited group were in stage II-IV compared with 91 out of 159 (57%) in the control group. More than 60% of cancers detected at screening were either non-invasive or invasive with a diameter of 1 cm. The corresponding percentage in the control group was 27%. The importance of sampling bias is discussed. Although data on mortality still have to be awaited, the results so far clearly indicate a positive effect of screening. (Key words:
Breast cancer
screening,
Mammography,
Randomized
study)
Study design and population At the end of 1976 a breast cancer screening programme was initiated in the city of Malmo in southern Sweden with 235,000 residents. The programme was designed as a controlled study to investigate whether repeated invitation to breast screening with mammography might reduce mortality due to breast cancer. The invited cohort was offered 6 screening examinations during a lo-yr period. A random sample consisting of 50% of all women in Malmo born between 1908 and 1932 and aged 45 to 69 yr at the start of the screening, was invited. The identification of the women was based on the population registry of the city. The randomization was done on an individual basis. The invited groups and the control group each consisted of approximately 21.000 women.
Correspondence to: 1. Andersson, Department of Radiology Malmo General Hospital, S-214 04 Malmo, Sweden.
0378-5122/85/$03.30
0 1985 Elsevier Science Publishers
and Preventive
B.V.
Medicine.
University
of Lund.
22
Organization and technique
The mammographic screening unit is localized in the Department of Preventive Medicine in Malm6, a free-standing facility outside Malm6 General Hospital, the only hospital in this city. In the mailed invitation women were offered a free mammographic examination for early detection of breast cancer. The staff consisted of one technician, one assistant, one secretary and one part-time radiologist. The capacity of the screening centre was 50 examinations per day. Film mammography was the only screening modality used. Thus, physical examination was not a part of the screening procedure. In the first two screening rounds, two views, the crania-caudal and the oblique, were obtained. In subsequent rounds, either the oblique only or both views were obtained depending on the parenchymal pattern as classified according to Wolfe; Nl and Pl breasts getting the oblique view only, P2 and DY breasts getting both views. Details of the mammographic technique have been described elsewhere [1,2]. The daily routines have been simplified as much as possible, and the amount of paperwork was minimized. The screening mammograms were classified as either suspicious or not suspicious for cancer, the classification being indicated on a diagram on the film chart. No formal reports were dictated on the screening mammograms. If considered suspicious, the patient is recalled for a complete mammogram. If the suspicion can be ruled out on complete examination, the patient is informed immediately and sent home. If there is still a suspicion after the complete examination, the patient is referred on the same day to the team surgeon for further evaluation and information. Presently four screening rounds have been completed. The data in the present paper are preliminary and refer mostly to the first three screening rounds, but sometimes results from the fourth round are included. Number of deaths from breast cancer as well as total mortality are followed by record linkage with the Central Register for Causes of Death in Sweden. All cases were referred to the same Department of Surgery. During the course of the study there has been a relative shift from modified mastectomy to conservative, breast-saving surgery for early stages of the disease.
Results and comments
The average attendance rate in the first screening round was 74% and 70% in the two subsequent rounds. The attendance rate was age-dependent with the highest attendance in the youngest age groups. The entire group invited to the first screening was also invited to the subsequent rounds; thus, not only those women who attended the first screening continued to be invited. Between 3% and 4% of the screened women were selected as suspicious for cancer on the basis of the screening mammograms (Table I). The criteria for selection have been detailed elsewhere [l]. In about half the cases, the original suspicion was
23 TABLE
1
PER CENT
OF SCREENEES
SELECTED,
REFERRED
AND OPERATED
UPON
Screening
Selected
Referred
Operated
I II Ill
3.4 3.8 3.1
1.6 1.5 0.9
1.2 1.3 0.6
considered false-positive as judged from the complete mammogram. In the majority of these cases the reason for the initial suspicion was superimposition of normal structures. The majority of those referred to the team surgeon for further evaluation subsequently underwent a surgical biopsy. The higher figures for selection and operation in the second as compared to the first round is mainly explained by the fact that the criteria for selecting and operating clustered calcifications were extended. This is again reflected in the proportion of positive biopsies which was 61% in the first, 33% in the second, and 58% in the third round. The predictive value of a positive screening mammogram (first screening round) was 22%. By adding a complete mammogram to those initially suspected of malignancy the predictive value increased to 47% due to an increase of the specificity from 97 to 99%. The sensitivity was 92%. For the calculation of the sensitivity the appearance of cancer within 1 yr of a negative screening was considered a falsenegative result. Table II gives the number and rate of carcinoma in various subgroups of the population under study. The interval between the first and second screening, and second and third screening was 22 and 20 mth, respectively. The detection rate at the first screening was approximately three times as high (7.5 per 1000 women) as the incidence of breast cancer in the control group (2.7 per 1000 woman-years). Women belonging to the control group could have a mammogram made either at the hospital
TABLE
11
NUMBER OF WOMEN WITH CARCINOMA FROM DATE OF ENTRY ING IN VARIOUS SUBGROUPS OF THE STUDY POPULATION Figures within parentheses denote detection rates or incidence: screenings II and Ill are per 1000 woman-years, the idea being, more like incidence figures as opposed to the prevalence figure comparable to the other incidence figures given, especially that Screenmg I Screening II Screening III Interval Non-participants Total invited group Control group Total
118 58 46 50 46 318 204 522
UNTIL
THIRD
SCREEN-
screening I is per 1000 women screened, that the rates in screenings II and Ill are of screening I and also to make it more of the control group.
(7.5) (2.2) (2.0) (0.9) (2.0) (2.7)
24 TABLE III PROPORTION OF PATIENTS WITH ‘EARLY’ CARCINOMAS Noninvasive (S)
screening I Screening II Screening III Interval case Non-participants Control groups
16 21 15 14 2 11
Invasive dlOmm (%) 43 48 46 14 9 16
Total (S) 59 69 61 28 11 27
or at a private outpatient clinic in the city, even in the absence of symptoms. It is not known how many women in the control group had a mammogram made, but the number is probably not negligible. Clearly, a number of cancers in the control group were detected by mammography only, which might explain why the incidence figure for the control groups is somewhat higher than expected when compared with historical data from the city of Malmii and contemporary data from other parts of the country. This stresses the fact that once a diagnostic procedure or treatment has been accepted by the public, it is more difficult to evaluate the effect in a controlled trial. The figure for the incidence of interval cancers in Table II is a composite of the first two intervals: in fact the incidence was higher (1.2 per 1000 woman-years) in the first interval than in the second (0.7 per 1000 woman-years). The lower figure for the second interval might reflect increased experience with the interpretation of the screening mammograms or improvement of other factors influencing the sensitivity of the screening procedure. Furthermore, changing the criteria for a positive screening mammogram might have played a role. In the control group, 27% of the cancers were either non-invasive or invasive with a diameter of 10 mm or less (Table III). Among screening-detected cases the proportion of ‘small’ cancers was significantly higher (> 60%), which was mainly due to a larger proportion of small invasive carcinomas. Among interval cases the proportion of small carcinomas was approximately the same as in the control group. In the control group about 50% of the patients were in stage II-IV, which should be compared with < 25% of screening-detected cases (Table IV). The stage distribution of interval carcinomas was slightly more favourable than in the control group, while the stage distribution among non-participants was less favourable. With a study design of two equally large groups of women, one invited and the other not invited, it should be possible to compare directly the number of patients with stage II and over. If screening is effective, the tumours should be detected at an earlier stage, which should be reflected in a reduced number of patients with advanced disease (stage II-IV). In the first round of the screening programme there is an accumulation of stage II-IV carcinomas which in the absence of screening would have surfaced clinically
25 TABLE
IV
PROPORTION
OF PATIENTS
WITH
DISEASE. STAGING ACCORDING TO UICC
ADVANCED
[31
Screening I Screening I1 Screening III Interval cases Non-participants Control group
Axillaiy metastasis
Stage II-IV
($1
(%l
18 18 17 30 61 38
20 26 17 42 65 52
during the following year or years (Fig. 1). Only after three screening rounds did the control group reach the same number of patients with stage II-IV disease as the invited group, and by the end of the fourth screening there was a small excess in the control group. It should be noted that the invited group includes interval cancers and cancers among non-participants. In Fig. 2, the first screening has been excluded. The cumulative difference of patients with stage II-IV at the end of the fourth screening was 36 patients in favour of the invited group. In the two most recent periods of the programme, 62 out of 160 women with cancer (39%) in the invited group were in stage II-IV compared with 91 out of 159 (57%) in the control group. The difference was 14 and 15 cases, Number
Number
-
Study
---
Control
gro”~ group
-
Study
- - -
Control
grow ,144
group
132
/
Screening
Fig. 1. Cumulative screening. Fig. 2. Cumulative
number
number
/
108
Screening
of patients
of patients
with
stage
II-IV
with stage II-IV
carcinoma
carcinoma
from
excluding
date
of entry
first screening.
until
fourth
26
respectively, during the second period (second interval plus third screening) and third period (third interval plus fourth screening). This indicates the new level of diagnosis with screening.
Some aspects on sampling bias
It is apparent that a large proportion of the cancers detected by mammographic screening are small without axillary metastatis. A substantial amount of clinical experience indicates that the prognosis of breast cancer is related to the size of the tumour and the state of the axillary nodes at the time of treatment [4-61. Thus, by parameters established in clinical practice the screened group should have a better than average prognosis. Such a conclusion would, however, be based on the assumption that the sample obtained by screening with mammography is representative of the general clinical breast cancer population. Basically, there are two reasons why such an assumption is not valid. First, breast cancer is not a uniform disease but rather a spectrum of diseases ranging from slow-growing (less malignant) to rapidly growing (more malignant). Secondly, there are mechanisms inherent in the screening procedure which tend to bias the sample, the most important being the length bias which is related to the distribution of growth rates of the tumours [7], and the detection bias which is related to the detection system used for screening. Another factor is self-selection within the invited group. The overrepresentation of advanced disease among non-attenders might reflect such a mechanism. This is also illustrated by the relatively lower attendance rate of older women. Length-biased sampling refers to the tendency of screening to pick up preferably slow-growing tumours while fast-growing tumours tend to surface in the interval to the subsequent screening. As mentioned above, 50 women appeared with carcinoma in the first two intervals. Forty-three of these 50 carcinomas were invasive, and 7 non-invasive. Twenty of 43 invasive cancers had a calculated tumour volume doubling time of 100 days or less which may be considered a rapid growth rate. We do not know the distribution of tumour volume doubling times in the other subsets of the population under study. There are investigations indicating that the average tumour volume doubling time of breast cancer is approximately 200 days with a considerable range of variation [8,9]. After a relatively short follow-up (27 months on the average), 7 patients among those with interval carcinomas had died from breast cancer and another 7 had metastatic disease (Table V). Interestingly, three of these 14 patients had no axillary metastatis at the time of the initial treatment. Twelve of the patients had rapidly growing tumours as compared to 8 of the remaining 29 cases with interval carcinoma who had no evidence of recurrence. A case fatality/recurrence rate of 28% among patients with interval cancer during the average follow-up time period of 27 months is much higher than among patients with screening-detected cancer. It is also worth mentioning that only 3 of the 20 rapidly growing tumours retrospectively showed an abnormality that would have been possible to detect on
27 TABLE
V
FOLLOW-UP (AVERAGE 27 MONTHS) OF PATIENTS APPEARING WITH CARCINOMA IN THE INTERVAL BETWEEN SCREENINGS. NUMBER OF PATIENTS WITH TUMOUR VOLUME DOUBLING TIME < 100 DAYS WITHIN PARENTHESES.
Dead from breast cancer Alive with metastatic disease Dead without metastasis Alive without metastatic disease
7 (6)
7 (6) 1 (0) 28 (8)
the preceding screening mammogram. Furthermore, 9 of them appeared within 12 months of the preceding screening. There is, therefore, a group of very aggressive tumours which cannot be picked up at screening unless the screening is repeated at very short intervals which seems unrealistic. Still, this group represents only a small fraction of all cancers detected in the screened population and therefore does not necessarily influence the total outcome of the screening programme in a significant way. The length-time bias associated with screening could imply that a small tumour detected at screening is not an ‘early’ fast growing one. Data from our own study do not support this view, however. Traditionally there are some histologic types of breast cancer that are considered less malignant than other types. This applies to tubular cancer and non-invasive intraductal cancer. If these were very slow-growing cancers (as compared with other histologic types of cancer) we would expect to find them mainly in the first screening, but it is evident from Table VI that tubular cancer as well as intraductal non-invasive cancer made up about the same proportion in the second and third screenings as in the first one. This indicates that the transition from a radiographically non-detectable to detectable stage occurred within a rather short period of time, which in turn indicates that progression is not very
TABLE
VI
DISTRIBUTION OF CARCINOMAS ING TO LINELL ET AL. [lo] Type of carcinoma
Tubular Tubuioductal Medullary + mucmous + ductal of comedo type Lobular Non-invasive Intraductal Lobular
??
BY MICROSCOPIC
Clinical * series (n = 238)
TYPE (S). CLASSIFICATION
Screening I (II -116)
II (n = 58)
III (n=46)
15 34 33
35 23 15
22 22 26
26 28 22
11
10
9
9
5 3
14 3
16 5
13 2
The control group plus all clinical cases diagnosed the screening.
ACCORD-
in the same birth cohort
1 yr before the beginning
of
28
slow. As mentioned above, the average interval between the screenings was 22 and 20 mth, respectively. One also has to consider the probability of tubular cancer evolving into another histologic type. This problem has been addressed by the pathologists in our group, Drs. Line11 and Ljungberg. In a comprehensive histologic study they identified many transitional forms between pure tubular cancer and ductal cancer with productive fibrosis [lo]. Furthermore, transitional forms between so-called radial scars (non-encapsulated sclerosing lesions [ll]) and tubular cancer were identified, indicating that some radial scars might progress into tubular cancer. The cancers could be classified into subgroups thought to reflect the progression from tubular cancer to less differentiated forms. These subgroups showed an increasing tumour size and frequency of axillary metastasis with decreasing amount of tubules and increasing amount of less differentiated, so-called ductal structures [lo]. It was concluded that tubular cancer probably should not be regarded as a static entity but rather as representing one stage in the progression towards a more malignant type of cancer. Clinically, this is a very important issue. If tubular cancer is to be regarded as a more or less static entity, then the large number of patients with tubular cancer found at screening are probably treated more radically and earlier than is necessary. If, on the other hand, tubular cancer. is a progressive disease, it represents an early finding of a clinically significant cancer. Our data support the latter possibility. The varying sensitivity of mammography to different morphologic types of cancer is another source of sampling bias. Different histologic types of breast cancer produce different morphologic changes, some of which are easier to detect radiographically than others. Thus, cancers with productive fibrosis (tubular and tubuloductal) tend to form spiculated masses which, even when small and located in dense tissue, are relatively easy to detect. On the other hand, medullary and mutinous cancers as well as some intraductal invasive cancers of the comedo type tend to form well-marginated masses which, when small and located in dense tissue, are difficult or impossible to detect. Also, their appearance is similar to that of benign tumours. If this factor is really operating, we would expect to find a larger proportion of tubular carcinomas at screening than in the control group, and few would appear in the intervals between screenings. For the well-marginated type of cancer, the distribution should be the opposite with relatively few detected at screening as compared with the control group, and relatively many appearing in the intervals. The data given in Table VII on the distribution of histologic types of cancer are in accordance with these considerations. Thus, it is reasonable to conclude that the varying sensitivity of mammography to different histologic types of cancer is another source of sampling bias. If the different histologic types have a different prognosis there is a possibility of a biased sampling towards more than average malignant or more than average benign. Our knowledge of the prognosis of the different histologic types of the classification used is insufficient. A study on this particular subject is in progress. The problem is further complicated by the possibility of progression of tubular cancer as discussed above. It is not possible at present to assess the net effect of the different types of bias. Clearly, prognostic parameters such as the proportion of small or ‘early’ cancers might be substantially affected while the other end of the
29 TABLE
VII
DISTRIBUTION OF CARCINOMAS ING TO LINELL ET AL. [lo]
BY MICROSCOPIC
TYPE (‘%). CLASSIFICATION
Type of carcinoma
Clinical series (n=238)
Screenings I-III (n-220)
Intervals (n =50)
Tubular Medullary + mutinous + ductal of comedo type Other invasive Non-invasive
15 33
30 19
8 42
45 8
34 17
36 14
ACCORD-
range, i.e. stage II and over, should be much less so. However, even in a controlled trial using endpoints such as metastatic disease or death from breast cancer, sampling bias might influence the results. Once the patient has a diagnosis of breast cancer, there is a risk that if she gets metastatic disease the metastases are considered to be due to the breast cancer even if the origin actually is a different cancer. The same applies to death from breast cancer. In the absence of autopsy, patients with known breast cancer are more likely to be classified as dead from breast cancer, even if they in fact died from a different disease.
References 1 Andersson I. Radiographic screening for breast carcinoma. I. Program and primary findings in 45-69 year-old women. Acta Radio1 (Diagn) 1981; 22: 185-194. 2 Andersson I. Radiographic screening for breast carcinoma. III. Appearance of carcinoma and number of proJections to be used at screening. Acta Radio1 (Diagn) 1981; 22: 407-420. of mahgnant tumors. 3rd edition. Geneva 1978. 3 UICC. TNM classification 4 Adair F, Berg J, Joubert L, Robbins GF. Long-term follow-up of breast cancer patients: the 30-year report. Cancer 1974; 33: 1145-1150. 5 Duncan W, Kerr GR. The curability of breast cancer. Br Med J 1976; 2: 781-783. 6 Wallgren A. Silfversw’ard C, Eklund G. Prognostic factors in mammary carcinoma. Acta Radio1 Oncol Radiat Phys Biol 1976; 15: 1-16. 7 Feinleib M, Zelen M. Some pitfalls in the evaluation of screening programs. Arch Environ Health 1969; 19: 412-415. 8 Foumier DV, Weber E, Hoeffken W, Bauer M, Kubli F, Bart V. Growth rate of 147 mammary carcinomas. Cancer 1980; 45: 2198-2207. 9 Lundgren B. Observations on growth rate of breast carcinomas and its possible implications for lead-time. Cancer 1977; 40: 1722-1725. 10 Line11 F, Ljungberg 0, Andersson I. Breast carcinoma. Aspects of early stages, progression and related problems. Acta Pathol Microbial Scand Suppl 1980; 272. 11 Fisher ER, Palekar AS, Kotwal N, Lipana N. A non-encapsulated sclerosing lesion of the breast. Am J CIin Pathol 1979; 71: 240-246.