The earliest of the randomised trials was the Health Insurance Plan (HIP) study performed in the United States in the 1960s, in which women in the intervention arm were offered annual screening by both mammography and clinical breast examination for four rounds. By the end of 5 years from date of entry (about 1.5 years after the last screen) the incidence of breast cancer in the two arms was similar (2.03 per 1,000 women years in the intervention arm, and 1.94 in the control arm [3
]). An earlier report indicates that the percentages of in situ
cancer were 13% and 8%, respectively, in the two arms [4
]. There have been considerable improvements in the sensitivity of mammography since this trial was conducted, and it therefore provides little indication of the potential for overdiagnosis with current techniques.
The four randomised trials conducted in Sweden all used screening by mammography alone, with screening intervals ranging from 18 to 33 months. In all except one of these the control group has subsequently been offered screening.
The Swedish Two County Study, which began in 1977/8, included 143,867 women aged 40 to 74 years at the date of randomisation [5
]. Women in the intervention arm were invited to screening at intervals of 24 to 33 months.
In 1985, after two to four rounds of screening in the intervention arm, women in the control arm were offered screening. After this screen had taken place, rates of invasive cancer have been reported as 16.90 and 17.79 per 1,000 women in the intervention and control arms, respectively; assuming an average of 7 years of follow-up, the estimated rates per 1,000 women years are 2.41 and 2.54, respectively, with rates of DCIS of 0.23 and 0.12 per 1,000 women years, respectively [6
The Gothenberg trial invited women aged between 35 and 59 years, between 1982 and 1991. Again, women in the control arm were offered a single screen at approximately the same time as the final screen in the intervention arm.
The cumulative incidence of invasive breast cancer was greater in the intervention arm than in the control arm until year 6, at about the time of the first screen in the control arm. At the end of the 'screening phase' of the trial (that is, the period up to and including the first screen in the control arm), rates of DCIS were slightly higher in the intervention arm (about 0.22 versus 0.17 per 1,000 women years), with a slightly lower rate of invasive cancers (1.56 versus 1.73 per 1,000 women years) [7
]. The relative risk of overall breast cancer incidence in the intervention arm relative to the control arm at follow-up of up to 14 years is reported as 0.98 (95% confidence interval 0.88 to 1.09).
The first Malmö trial invited women between 45 and 69 years old to five rounds of screening between 1976 and 1978. Women in the control arm were not invited for screening (although those in the youngest cohort were eventually invited in 1992/3). At a mean follow-up of 8.8 years, when screening was still continuing, the rates of invasive breast cancers in the intervention and control arms were 2.62 and 2.12 per 1,000 women years, respectively. The rates of DCIS were 0.50 and 0.27 per 1,000 women years, respectively [8
]. It was estimated that 24% of the control arm had been screened, although most only once. No incidence data have been published on the subsequent (Malmö II) trial.
The Stockholm trial randomised about 60,000 women in 1981; there were two screening rounds using single-view mammography 28 months apart; during 1986 the control group was invited to a single screen. Uptake at first screen was 81% in the intervention arm and 77% in the control arm [9
]. At the end of 1986 there was no difference in overall cancer incidence between the two arms (0.90 versus 0.91 per 1,000 women years). There was a slightly higher rate of DCIS (0.09 versus 0.06) and lower rate of invasive cancers (0.81 versus 0.85) in the intervention arm, but the differences were not significant.
Two trials conducted in Canada both used volunteer populations, resulting in high uptake. The NBSS II trial was designed to compare mammography plus physical examination (MP), with physical examination alone (PO) in women aged 50 to 64 years [10
]. An initial excess of invasive cancers in the MP arm mainly disappeared with continued follow-up; at 13 years of follow-up, rates per 1,000 women years were 2.43 and 2.38 in the MP and PO arms, respectively [11
]. Rates of DCIS were 0.28 and 0.06 per 1,000 women years, respectively. The NBSS I trial was designed to compare breast cancer mortality in women aged 40 to 49 years randomised to either screening by annual mammography, physical examination and instruction on breast self-examination (BSE) or a single physical examination and BSE instruction [12
]. After 13 years of follow-up, the cumulative rates of DCIS were 0.22 and 0.09 per 1,000 women years in the screening and 'usual care' groups, respectively [13
]. The rates of invasive breast cancers were 1.81 and 1.68, respectively, per 1,000 women years.
The Edinburgh trial recruited women aged 45 to 64 years into the initial cohort during 1978 to 1981, with randomisation by general practice. Women in the intervention arm were offered annual screening for 7 years, by mammography and physical examination every 2 years, and physical examination only in the intervening years. At 10 years of follow-up the incidence rates of invasive breast cancer were 2.04 and 1.93 per 1,000 women years in the intervention and control arms, respectively; rates of DCIS were 0.19 and 0.05, respectively, per 1,000 women years [14
However, the cluster randomisation in this trial led to an imbalance in socio-economic status, reflected in all-cause mortality, which is likely to have resulted in an increased risk of breast cancer in the intervention arm. Adjustment for this altered the rate ratio of breast cancer mortality at 14 years of follow-up from 0.87 to 0.79 [15