The Randomized Controlled Trials
Population-Based Screening Programs, Including Studies of Effectiveness of Screening

The Randomized Controlled Trials

Randomized controlled trials (RCTs), with participation by nearly half a million women from four countries, examined the breast cancer mortality of women who were offered regular screening. One trial (the Canadian National Breast Screening Study [NBSS]-2) compared mammogram plus clinical breast examination (CBE) with CBE alone, but the other eight compared screening mammogram (MMG) with or without CBE with a control consisting of usual care. The trials differed in design, recruitment of participants, interventions (both screening and treatment), management of the control group, compliance with assignment to screening and control groups, and analysis of outcomes. Some trials used individual randomization while others used cluster randomization in which cohorts were identified and then offered screening, and in one case, nonrandomized allocation by day-of-birth in any given month. Cluster randomization sometimes led to imbalances between the intervention and control groups. Age differences have been identified in several trials, although the differences were probably too small to have a major effect on the trial outcome.[1] In the Edinburgh Trial, socioeconomic status differed markedly between the intervention and control groups. Since socioeconomic status is associated with the risk of breast cancer mortality, this difference makes it difficult, if not impossible, to interpret the trial results.

Since breast cancer mortality is the major outcome parameter for each of these trials, the methods used to determine cause of death is critically important. Efforts to reduce bias in the attribution of mortality cause have been made, including the use of a blinded monitoring committee (New York) and a linkage to independent data sources, such as national mortality registries (Swedish trials). Unfortunately, even these attempts may be unable to avoid prior knowledge of women’s assignment to screening or control arms. Evidence of possible misclassification of breast cancer deaths in the Two-County trial that could bias results in favor of screening has been reviewed.[2]

Differences exist in the methodology used to analyze the results of these trials. Four of the five Swedish trials were designed to include a single screening mammogram in the control group, timed to correspond with the end of the series of screening mammograms in the study group. The initial analysis of these trials used an “evaluation” analysis, tallying only the breast cancer deaths that occurred in women whose cancer was discovered at or before the last study mammogram. In some of the trials a delay occurred in the performance of the end-of-study mammogram, resulting in more time for control group women to develop or be diagnosed with breast cancer. Other trials used a “follow-up” analysis, which counts all deaths attributed to breast cancer, regardless of the time of diagnosis. This type of analysis was used in a meta-analysis of four of the five Swedish trials in response to previously expressed concerns about the effect of a delay in control group mammograms upon evaluation analyses.

The accessibility of the data for international audit and verification also varies, with formal audit having been undertaken only in the Canadian trials. In fact, the author of one trial (Kopparberg) refused to respond to queries about methodology or to submit raw data for independent review.[3]

All of these studies are designed to study breast cancer mortality rather than all-cause mortality, because of the infrequency of breast cancer deaths relative to the total number of deaths. When all-cause mortality in these trials was examined retrospectively, only the Edinburgh trial showed a significant difference, which could be attributed to socioeconomic differences. The meta-analysis (follow-up methods) of the four Swedish trials also showed a small but significant improvement of all-cause mortality.

The trials are listed chronologically.

Health Insurance Plan, United States 1963 [4,5]

Age at entry: 40 to 64 years.

Randomization: Individual, but with significant imbalances in the distribution of women between assigned arms, as evidenced by menopausal status (P < .0001) and education (P = .05).

Sample size: 30,000 to 31,092 in study group and 30,565 to 30,765 in control group.

Consistency of reports: Variation in sample size reports.

Intervention: Annual two-view MMG and CBE for 3 years.

Control: Usual care.

Compliance: Nonattenders to first screening (35% of the screened population) were not reinvited.

Contamination: Screening mammography was not available outside the trial, but frequency of CBE performance among control women is unknown.

Cause of death attribution: Women who died of breast cancer that had been diagnosed before entry into the study were excluded from the comparison between the screening and control groups. However, these exclusions were determined differently within the two groups. Women in the screening group were excluded based on determinations made during the study period at their initial screening visits. These women were dropped from all further consideration in the study. By design, controls did not have regular clinic visits, so the prestudy cancer status of control patients was not determined. When a control patient died and her cause of death was determined to be breast cancer, a retrospective examination was made to determine the date of diagnosis of her disease. If this was prior to the study period then she was excluded from the analysis. This difference in methodology has the potential for a substantial bias in comparing breast cancer mortality between the two groups, and this bias is likely to favor screening.

Analysis: Follow-up.

External audit: No.

Follow-up duration: 18 years.

Relative risk of breast cancer death, screening versus control (95% confidence interval [CI]): 0.71 (0.55–0.93) at 10 years and 0.77 (0.61–0.97) at 15 years.

Comments: The mammograms were of poor quality compared with those of later trials, because of outdated equipment and techniques. One should remember that the intervention consisted of both MMG and CBE. Major concerns about trial performance are the validity of the initial randomization and the differential exclusion of women with a prior history of breast cancer.

Malmo, Sweden 1976 [6,7]

Age at entry: 45 to 69 years.

Randomization: Individual, within each birth year cohort for the first phase, mammographic screening trial (MMST I). Individual for the entire birth cohort 1933 to 1945 for MMST II, but with variations imposed by limited resources. Validation by analysis of age in both groups shows no significant difference.

Exclusions: In a Swedish meta-analysis, there were 393 women with pre-existing breast cancer excluded from the intervention group, and 412 from the control group. Overall however, there were 86 more women excluded from the intervention group than from the control group.

Sample size: 21,088 study and 21,195 control.

Consistency of reports: No variation in patient numbers.

Intervention: Two-view MMG every 18 to 24 months × 5.

Control: Usual care, with MMG at study end.

Compliance: Participants migrating from Malmo (2% per year) were not followed. The participation rate of study women was 74% for the first round and 70% for subsequent rounds.

Contamination: 24% of all control women had at least one MMG, as did 35% of the control women aged 45 to 49 years.

Cause of death attribution: 76% autopsy rate in early report, lower rate later. Cause of death assessment blinded for women with a breast cancer diagnosis. Linked to Swedish Cause of Death Registry.

Analysis: Evaluation, initially. Follow-up analysis, as part of the Swedish meta-analysis.[3]

External audit: No.

Follow-up duration: 12 years.

Relative risk of breast cancer death, screening versus control (95% CI): 0.81 (0.62–1.07).

Comments: Evaluation analysis required a correction factor for the delay in the performance of MMG in the control group. The two Malmo trials MMST I and MMST II have been combined for most analyses.

Ostergotland (Part of Two County Trial), Sweden 1977 [8-10]

Age at entry: 40 to 74 years.

Randomization: Geographic cluster, with stratification for residence (urban or rural), socioeconomic factors and size. Baseline breast cancer incidence and mortality were comparable between the randomly assigned geographic clusters. The study women were older than the control women, P < .0001, but this should not have had a major effect on the outcome of the trial.

Exclusions: Women with pre-existing breast cancer were excluded from both groups, but the numbers are reported differently in different publications. The Swedish meta-analysis excluded all women with a prior breast cancer diagnosis, regardless of group assignment.

Sample size: Variably reported, ranging from 38,405 to 39,034 in study and from 37,145 to 37,936 in control.

Consistency of reports: Variable.

Intervention: Three single-view MMGs every 2 years for women younger than 50 years and every 33 months for women 50 years and older.

Control: Usual care, with MMG at study end.

Compliance: 89% screened.

Contamination: 13% of women in the Two County trial had MMG as part of routine care, mostly in 1983 and 1984.

Cause of death attribution: Determined by a team of local physicians. When results were recalculated in the Swedish meta-analysis, using data from the Swedish Cause of Death Registry, there was less benefit for screening than had been previously reported.

Analysis: Evaluation initially, with correction for delay in control group MMG. Follow-up analysis, as part of the Swedish meta-analysis.[3]

External audit: No.

Follow-up duration: 12 years.

Relative risk of breast cancer death, screening versus control (95% CI): 0.82 (0.64–1.05) Ostergotland.

Comments: Concerns were raised about the randomization methodology and the evaluation analysis, which required a correction for late performance of the control group MMG. The Swedish meta-analysis resolved these questions appropriately.

Kopparberg (Part of Two County Trial), Sweden 1977 [8-10]

Age at entry: 40 to 74 years.

Randomization: Geographic cluster, with stratification for residence (urban or rural), socioeconomic factors and size. The process for randomization has not been described. The study women were older than the control women, P < .0001, but this should not have had a major effect on the outcome of the trial.

Exclusions: Women with pre-existing breast cancer were excluded from both groups, but the numbers are reported differently in different publications.

Sample size: Variably reported, ranging from 38,562 to 39,051 in intervention and from 18,478 to 18,846 in control.

Consistency of reports: Variable.

Intervention: Three single-view MMGs every 2 years for women younger than 50 years and every 33 months for women aged 50 years and older.

Control: Usual care, with MMG at study end.

Compliance: 89% participation.

Contamination: 13% of women in the Two County trial had MMG as part of routine care, mostly between 1983 and 1984.

Cause of death attribution: Determined by a team of local physicians (see Ostergotland).

Analysis: Evaluation.

External audit: No. Primary author has refused to collaborate with several investigators, both internationally [11] and in Sweden.[3]

Follow-up duration: 12 years.

Relative risk of breast cancer death, screening versus control (95% CI): 0.68 (0.52–0.89).

Edinburgh, United Kingdom 1976 [12]

Age at entry: 45 to 64 years.

Randomization: Cluster by physician practices, though many randomization assignments were changed after study start. Within each practice, there was inconsistent recruitment of women, according to the physician’s judgment about each woman’s suitability for the trial. Large differences in socioeconomic status between practices were not recognized until after the study end.

Exclusions: More women (338) with pre-existing breast cancer were excluded from the intervention group than from the control group (177).

Sample size: 23,226 study and 21,904 control.

Consistency of reports: Good.

Intervention: Initially, two-view MMG and CBE; then annual CBE, with single-view MMG in years 3, 5, and 7.

Control: Usual care.

Compliance: 61% screened.

Contamination: None.

Cause of death attribution: Cancer Registry Data.

Analysis: Follow-up.

External audit: No.

Follow-up duration: 10 years.

Relative risk of breast cancer death, screening versus control (95% CI): 0.84 (0.63–1.12).

Comments: Randomization process was flawed. Socioeconomic differences between study and control groups probably account for the higher all-cause mortality in control women compared with screened women. This difference in all-cause mortality was four times greater than the breast cancer mortality in the control group, and therefore, may account for the higher breast cancer mortality in the control group compared with screened women. Although a correction factor was used in the final analysis, this may not adjust the analysis sufficiently.

The study design and conduct make these results difficult to assess or combine with the results of other trials.

NBSS-1, Canada 1980 [13]

Age at entry: 40 to 49 years.

Randomization: Individual volunteers, with names entered successively on allocation lists. Although criticisms of the randomization procedure have been made, a thorough independent review found no evidence of subversion and that subversion on a scale large enough to affect the results was unlikely.[14]

Exclusions: Few, balanced between groups.

Sample size: 25,214 study (100% screened after entry CBE) and 25,216 control.

Consistency of reports: Good.

Intervention: Annual two-view MMG and CBE for 4 to 5 years.

Control: Usual care.

Compliance: Initially 100%, decreased to 85.5% by screen five.

Contamination: 26.4% in usual care group.

Cause of death attribution: Death certificates, with review of questionable cases by a blinded review panel. Also linked with the Canadian Mortality Data Base, Statistics Canada.

Analysis: Follow-up.

External audit: Yes. Independent, with analysis of data by several reviewers.

Follow-up duration: 13 years.

Relative risk of breast cancer death, screening versus control (95% CI): 0.97 (0.74–1.27).

Comments: This is the only trial specifically designed to study women aged 40 to 49 years. Cancers diagnosed at entry in both study and control groups were included. Concerns were expressed prior to completion of the trial about the technical adequacy of the MMGs, the training of the radiologists, and the standardization of the equipment, which prompted an independent external review. The primary deficiency identified by this review was the use of the mediolateral view from 1980 to 1985 instead of the mediolateral oblique view, which was used after 1985.[15] Subsequent analyses found the size and stage of the cancers detected mammographically in this trial to be equivalent to those of other trials.[16] This trial and NBSS-2 differ from the other RCTs in the consistent use of adjuvant hormone and chemotherapy following local breast cancer therapy in women with axillary node-positive disease.

NBSS-2, Canada 1980 [17]

Age at entry: 50 to 59 years.

Randomization: Individual volunteer (see NBSS-1).

Exclusions: Few, balanced between groups.

Sample size: 19,711 study (100% screened after entry CBE) and 19,694 control.

Intervention: Annual two-view MMG and CBE.

Control: Annual CBE.

Compliance: Initially 100%, decreased to 86.7% by screen five in the MMG and CBE group. Initially 100%, decreased to 85.4% by screen five in the CBE only group.

Contamination: 16.9% of the CBE only group.

Cause of death attribution: Death certificates, with review of questionable cases by a blinded review panel. Also linked with the Canadian Mortality Data Base, Statistics Canada.

Analysis: Follow-up.

External audit: Yes. Independent with analysis of data by several reviewers.

Follow-up duration: 11 to 16 years (mean 13 years).

Relative risk of breast cancer death, screening versus control (95% CI): 1.02 (0.78–1.33).

Comments: This trial is unique in that it compares one screening modality to another, and does not include an unscreened control. Regarding criticisms and comments about this trial, see NBSS-1.

Stockholm, Sweden 1981 [18]

Age at entry: 40 to 64 years.

Randomization: Cluster by birth date. There were two subtrials with balanced randomization in the first and a significant imbalance in the second with 508 more women in the screened group than the control.

Exclusions: Inconsistently reported.

Sample size: Declined from 40,318 to 38,525 in intervention group and rose from 19,943 to 20,978 in control, between published reports.

Consistency of reports: Variable.

Intervention: Single-view MMG every 28 months × 2.

Control: MMG at year 5.

Compliance: 82% screened.

Contamination: 25% of women entering the study had MMG in the 3 years before entry.

Cause of death attribution: Linked to Swedish Cause of Death Registry.

Analysis: Evaluation, with 1-year delay in the posttrial MMG in control group. Follow-up analysis as part of the Swedish meta-analysis.[3]

External audit: No.

Follow-up duration: 8 years.

Relative risk of breast cancer death, screening versus control (95% CI): 0.80 (0.53–1.22).

Comments: There are concerns about randomization, especially in the second subtrial, about exclusions, and about the delay in control group MMG. Inclusion of these data in the Swedish meta-analysis resolves many of these questions.

Gothenberg, Sweden 1982

Age at entry: 39 to 59 years.

Randomization: Complex; cluster randomly assigned within birth year by day of birth for older group (aged 50–59 years) and by individual for younger group (aged 39–49 years); ratio of study to control varied by year depending on mammography availability (randomization took place 1982–1984).

Exclusions: A similar proportion of women were excluded from both groups for prior breast cancer diagnosis (1.2% each).

Sample size: Most recent publication: 21,650 invited; 29,961 control.

Consistency of reports: Variable.

Intervention: Initial two-view MMG, then single-view MMG every 18 months × 4. Single-read first three rounds, then double-read.

Control: Control group received one screening exam approximately 3 to 8 months after the final screen in study group.

Cause of death attribution: Linked to Swedish Cause of Death Registry; also used an independent endpoint committee.

Analysis: Both evaluation and follow-up methods.[3]

External audit: No.

Follow-up duration: 12 to14 years.

Relative risk of breast cancer death, screening versus control (95% CI): Aged 39 to 59 years: 0.79 (0.58–1.08) [evaluation]; 0.77 (0.60–1.00) [follow-up].

Comments: No reduction for women aged 50 to 54 years, but similar reductions for other 5-year age groups.

Conclusions: Delay in the performance of MMG in the control group and unequal numbers of women in invited and control groups (complex randomization process) complicates interpretation.

Screening for breast cancer does not affect overall mortality, and the absolute benefit for breast cancer mortality appears to be small.

A way to view the potential benefit of breast cancer screening is to estimate the number of lives extended because of early breast cancer detection.[19,20] Harris [21] estimated the outcomes of 10,000 women aged 50 to 70 years who undergo a single screen. Mammograms will be normal (true negatives and false negatives) in 9,500 women. Of the 500 abnormal screens, between 466 and 479 will be false-positives, and 100 to 200 of these women will undergo invasive procedures. The remaining 21 to 34 abnormal screens will be true positives, indicating breast cancer. Some of these women will die of breast cancer in spite of mammographic detection and optimal therapy, and some may live long enough to die of other causes even if the cancer has not been screen detected. The number of extended lives attributable to mammographic detection is between two and six. Another expression of this analysis is that one life may be extended per 1,700 to 5,000 women screened and followed for 15 years. The same analysis for 10,000 women aged 40 to 49 years, assuming the same 500 abnormal examinations, results in an estimate that 488 of these will be false-positives, and 12 will be breast cancer. Of these 12, there will probably be only one to two lives extended. Thus, for women aged 40 to 49 years, it is estimated that one to two lives may be extended per 5,000 to 10,000 mammograms.

Although the RCTs of screening have addressed the issue of the efficacy of screening (i.e., the extent to which screening reduces breast cancer mortality under the ideal conditions of an RCT), they do not provide information about the effectiveness of screening (i.e., the extent to which screening is reducing breast cancer mortality in the U.S. population). Studies that provide information on this issue include nonrandomized controlled studies of screened versus nonscreened populations, case-control studies of screening in real communities, and modeling studies that examine the impact of screening on large populations. An important issue in all of these studies is the extent to which they can control for additional effects on breast cancer mortality such as improved treatment and heightened awareness of breast cancer in the community.

Two population-based, observational studies from Sweden compared breast cancer mortality in the presence and absence of screening mammography programs. One study compared two adjacent time periods within 7 of the 25 counties in Sweden and concluded a statistically significant breast cancer mortality reduction of 18% to 32% due to screening.[22] The most important bias in this study is that the advent of screening in these counties occurred over a period during which dramatic improvements were being made in the effectiveness of adjuvant breast cancer therapy. The authors do not present data on treatment received, nor do they address differences in treatment that could at least partially explain the observed reduction in breast cancer mortality. The second study considered an 11-year period and compared seven counties that had screening programs with five counties that did not.[23] It concluded that there was a statistically nonsignificant reduction of 16% to 20% in favor of screening. The most important bias in this study was similar to that in the first study. The counties in the control group were rural. Those in the screening group included some urban areas and in general they were largely in the southern, more densely populated part of the country in comparison with the control counties. Participants were accrued over a 7-year period (about 1980–1987) during which effective adjuvant hormonal therapy and chemotherapy were being introduced. The authors do not address differences in treatment in the various geographic areas that could explain the observed reduction in breast cancer mortality.

In Nijmegen, the Netherlands, a population-based screening program was undertaken in 1975, and breast cancer mortality rates were compared with those in the neighboring town Arnhem and to all of the Netherlands. No difference in breast cancer mortality could be identified [24] despite the fact that case-cohort studies showed that screened women have decreased mortality. One such study was performed in Nijmegen itself, with an odds ratio of 0.48, for screened versus unscreened women.[25] Explanations for the lack of demonstrable benefit include earlier diagnosis of breast cancer in the general population (due to increased public awareness) and documented trends for the diagnosis of cancers with favorable prognostic indicators. Furthermore, adjuvant systemic therapy decreases breast cancer mortality, and its use may decrease the impact of early detection.

A community-based case-control study of screening as practiced in excellent U.S. health care systems between 1983 and 1998 found no association between previous screening and reduced breast cancer mortality. Mammography screening rates, however, were generally low.[26]

Since 1990, there has been a sustained reduction in age-adjusted breast cancer mortality in the United States of about 2% per year. Between 1990 and 2000, the cumulative reduction was 24%. To address the contribution of screening and adjuvant therapy to this decline, the National Cancer Institute formed a consortium of seven modeling groups.[27] These groups developed independent statistical models of female breast cancer incidence and breast cancer mortality in the United States. They used common inputs for the dissemination of screening mammography, chemotherapy, and hormonal therapy and for the benefits of treatment interventions. All seven models ascribed some benefit to both screening and adjuvant treatment, but their estimates of the relative and absolute contributions varied considerably. The estimated proportion of the total mortality reduction contributed by screening varied from 28% to 65%, with adjuvant treatment contributing the rest. The variability across models for the absolute contribution of screening was larger than it was for treatment, reflecting the greater uncertainty and higher complexity associated with estimating screening benefit.

References

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