Possible Net Harms of Breast Cancer Screening
Possible Net Harms of Breast Cancer Screening
Objective To assess the claim in a Cochrane review that mammographic breast cancer screening could be doing more harm than good by updating the analysis in the Forrest report, which led to screening in the United Kingdom.
Design Development of a life table model, which replicated Forrest’s results before updating and extending them with data from relevant systematic reviews, trials, and other models based on purposive literature searches.
Participants Women aged 50 and over invited for breast cancer screening.
Main outcome measures Quality adjusted life years (QALYs), combining life years gained from screening with losses of quality of life from false positive diagnoses and surgery.
Results Inclusion of the effects of harms reduced the updated estimate of net cumulative QALYs gained after 20 years from 3301 to 1536 or by more than half. The best estimates from the Cochrane review generated negative QALYs for the first seven years of screening, 70 QALYs after 10 years, and 834 QALYs after 20 years. Sensitivity analysis showed these results were robust to a range of assumptions, particularly up to 10 years. It also indicated the importance of the level and duration of harms from surgery.
Conclusions This analysis supports the claim that the introduction of breast cancer screening might have caused net harm for up to 10 years after the start of screening.
The Forrest report in 1986, which led to the introduction of mammographic breast screening in the United Kingdom, analysed the costs and benefits in terms of quality adjusted life years (QALYs). One of the earliest uses of QALYs to guide policy, it suggested that screening would reduce the death rate from breast cancer by almost one third with few harms and at low cost (for details see appendix on bmj.com).
The key data used in the Forrest report were drawn from two randomised trials, the Swedish two counties trial and the Health Insurance Plan (HIP) New York trial. The Forrest report claimed that overdiagnosis was not a problem, based on the New York trial, but noted that the Swedish trial found possible overdiagnosis of 20%. It stated that "further follow up is required to find out whether this excess persisted." We have updated the Forrest report’s estimates for mortality and extended them to include the effects of false positives and overdiagnosis.
Since the Forrest report, the harms of mammographic breast cancer screening have been acknowledged. A WHO report defined false positives and overdiagnosis:
"The term false positive refers to an abnormal mammogram (one requiring further assessment) in a woman ultimately found to have no evidence of cancer. Overdiagnosis refers to the diagnosis and treatment of cancer that would never have caused symptoms. Thus a false positive result can be found only in a woman without cancer, while overdiagnosis can only be made for women with cancer."
It went on to note that "overdiagnosis is a foreign concept to most prospective screenees (and many clinicians)."
The WHO report noted that a considerable part of overdiagnosis involved ductal carcinoma in situ, which accounts for around a fifth of mammographically detected cancers. While this is a risk factor for breast cancer, only a minority of these develop into breast cancer. Indeed the inclusion of the term "carcinoma" in ductal carcinoma in situ has been questioned.
The WHO report claimed that the success of breast cancer screening programmes should be assessed only in terms of mortality: "Screening programmes should ultimately be monitored in terms of deaths, the measure directly related to the purpose of screening." A focus solely on deaths, however, implies ignoring harms to the living.
Gøtzsche and Nielsen’s Cochrane review raised the disturbing possibility that mammographic breast cancer screening could be doing more harm than good. This was because of their lower estimate of the reduction in mortality from breast cancer and their inclusion of the harms from overtreatment. They said that "this means that for every 2000 women invited for screening throughout 10 years, one will have her life prolonged, and 10 healthy women, who would not have been diagnosed if there had not been screening, will be diagnosed as breast cancer patients and will be treated unnecessarily. Furthermore, more than 200 women will experience important psychological distress for many months because of false positive findings. It is thus not clear whether screening does more good than harm."
Their meta-analysis included eight randomised trials, three of which they considered adequately randomised and five suboptimally randomised. Only the suboptimally randomised trials found a significant effect of screening on deaths ascribed to breast cancer. For all the eight trials taken together the relative risk reduction for mortality from breast cancer was 19% (95% confidence interval 26% to 13%) after 13 years. Given the quality of the evidence, Gøtzsche and Nielsen’s best estimate of the effect of screening was a 15% decline in mortality.
The increased risk of surgery was the basis of Gøtzsche and Nielsen’s estimate of unnecessary treatment. Four trials provided data on breast operations (mastectomies and lumpectomies), with more performed in the screened groups than in the control groups: the relative risk increase was 31% (22% to 42%) for the two adequately randomised trials and 35% (26% to 44%) for all four trials. For false positive results, Gøtzsche and Nielsen stated "it seems that screening inflicts important psychological distress for many months on more than a 10th of the healthy population of women who attend a screening program."
A systematic review and meta-analysis by Nelson and colleagues for the US Preventive Services Task Force independently analysed the same eight clinical trials in the Cochrane review but by age group. This put the reduction in mortality from breast cancer at 15% for those aged 39-49, 14% for those aged 50-59, and 32% for those aged 60-69. It used US registry data to suggest that about 10% of those screened would have a false positive result requiring further investigation. It differed from the Cochrane review in relation to overdiagnosis. "Rates of overdiagnosis vary from less than 1% to 30% with most from 1% to 10%. Estimates differ by outcome (invasive vs in situ breast cancer), by whether cases are incident or prevalent, and by age. The studies are too heterogeneous to combine statistically." These studies, it should be noted, included both randomised trials and observational studies.
Thus the two systematic reviews agreed that screening reduced mortality from breast cancer but differed in how much. Nelson and colleagues estimated a false positive rate around 10% per round of screening, while Gøtzsche and Nielsen put it at around 10% over 10 years. Only Gøtzsche and Nielsen provided data on the increased relative risk of surgery with screening, with two estimates: 31% based on the better quality trials and 35% based on all trials reporting this outcome.
We assessed the claim of Gotzsche and Nielsen by updating the Forrest report framework, extended to include harms. The Forrest report used life tables to estimate the number of women surviving by year up to 15 years in two cohorts aged 50, only one of which was screened. Deaths could be from breast cancer or all other causes. Baseline mortality and the reduction from triennial breast cancer screening were based on the two randomised controlled trials then available. The difference in life years between the two cohorts after 15 years was expressed in QALYs by reducing their quality of life by 8% to reflect the effects of treatment.
Abstract
Objective To assess the claim in a Cochrane review that mammographic breast cancer screening could be doing more harm than good by updating the analysis in the Forrest report, which led to screening in the United Kingdom.
Design Development of a life table model, which replicated Forrest’s results before updating and extending them with data from relevant systematic reviews, trials, and other models based on purposive literature searches.
Participants Women aged 50 and over invited for breast cancer screening.
Main outcome measures Quality adjusted life years (QALYs), combining life years gained from screening with losses of quality of life from false positive diagnoses and surgery.
Results Inclusion of the effects of harms reduced the updated estimate of net cumulative QALYs gained after 20 years from 3301 to 1536 or by more than half. The best estimates from the Cochrane review generated negative QALYs for the first seven years of screening, 70 QALYs after 10 years, and 834 QALYs after 20 years. Sensitivity analysis showed these results were robust to a range of assumptions, particularly up to 10 years. It also indicated the importance of the level and duration of harms from surgery.
Conclusions This analysis supports the claim that the introduction of breast cancer screening might have caused net harm for up to 10 years after the start of screening.
Introduction
The Forrest report in 1986, which led to the introduction of mammographic breast screening in the United Kingdom, analysed the costs and benefits in terms of quality adjusted life years (QALYs). One of the earliest uses of QALYs to guide policy, it suggested that screening would reduce the death rate from breast cancer by almost one third with few harms and at low cost (for details see appendix on bmj.com).
The key data used in the Forrest report were drawn from two randomised trials, the Swedish two counties trial and the Health Insurance Plan (HIP) New York trial. The Forrest report claimed that overdiagnosis was not a problem, based on the New York trial, but noted that the Swedish trial found possible overdiagnosis of 20%. It stated that "further follow up is required to find out whether this excess persisted." We have updated the Forrest report’s estimates for mortality and extended them to include the effects of false positives and overdiagnosis.
Since the Forrest report, the harms of mammographic breast cancer screening have been acknowledged. A WHO report defined false positives and overdiagnosis:
"The term false positive refers to an abnormal mammogram (one requiring further assessment) in a woman ultimately found to have no evidence of cancer. Overdiagnosis refers to the diagnosis and treatment of cancer that would never have caused symptoms. Thus a false positive result can be found only in a woman without cancer, while overdiagnosis can only be made for women with cancer."
It went on to note that "overdiagnosis is a foreign concept to most prospective screenees (and many clinicians)."
The WHO report noted that a considerable part of overdiagnosis involved ductal carcinoma in situ, which accounts for around a fifth of mammographically detected cancers. While this is a risk factor for breast cancer, only a minority of these develop into breast cancer. Indeed the inclusion of the term "carcinoma" in ductal carcinoma in situ has been questioned.
The WHO report claimed that the success of breast cancer screening programmes should be assessed only in terms of mortality: "Screening programmes should ultimately be monitored in terms of deaths, the measure directly related to the purpose of screening." A focus solely on deaths, however, implies ignoring harms to the living.
Gøtzsche and Nielsen’s Cochrane review raised the disturbing possibility that mammographic breast cancer screening could be doing more harm than good. This was because of their lower estimate of the reduction in mortality from breast cancer and their inclusion of the harms from overtreatment. They said that "this means that for every 2000 women invited for screening throughout 10 years, one will have her life prolonged, and 10 healthy women, who would not have been diagnosed if there had not been screening, will be diagnosed as breast cancer patients and will be treated unnecessarily. Furthermore, more than 200 women will experience important psychological distress for many months because of false positive findings. It is thus not clear whether screening does more good than harm."
Their meta-analysis included eight randomised trials, three of which they considered adequately randomised and five suboptimally randomised. Only the suboptimally randomised trials found a significant effect of screening on deaths ascribed to breast cancer. For all the eight trials taken together the relative risk reduction for mortality from breast cancer was 19% (95% confidence interval 26% to 13%) after 13 years. Given the quality of the evidence, Gøtzsche and Nielsen’s best estimate of the effect of screening was a 15% decline in mortality.
The increased risk of surgery was the basis of Gøtzsche and Nielsen’s estimate of unnecessary treatment. Four trials provided data on breast operations (mastectomies and lumpectomies), with more performed in the screened groups than in the control groups: the relative risk increase was 31% (22% to 42%) for the two adequately randomised trials and 35% (26% to 44%) for all four trials. For false positive results, Gøtzsche and Nielsen stated "it seems that screening inflicts important psychological distress for many months on more than a 10th of the healthy population of women who attend a screening program."
A systematic review and meta-analysis by Nelson and colleagues for the US Preventive Services Task Force independently analysed the same eight clinical trials in the Cochrane review but by age group. This put the reduction in mortality from breast cancer at 15% for those aged 39-49, 14% for those aged 50-59, and 32% for those aged 60-69. It used US registry data to suggest that about 10% of those screened would have a false positive result requiring further investigation. It differed from the Cochrane review in relation to overdiagnosis. "Rates of overdiagnosis vary from less than 1% to 30% with most from 1% to 10%. Estimates differ by outcome (invasive vs in situ breast cancer), by whether cases are incident or prevalent, and by age. The studies are too heterogeneous to combine statistically." These studies, it should be noted, included both randomised trials and observational studies.
Thus the two systematic reviews agreed that screening reduced mortality from breast cancer but differed in how much. Nelson and colleagues estimated a false positive rate around 10% per round of screening, while Gøtzsche and Nielsen put it at around 10% over 10 years. Only Gøtzsche and Nielsen provided data on the increased relative risk of surgery with screening, with two estimates: 31% based on the better quality trials and 35% based on all trials reporting this outcome.
We assessed the claim of Gotzsche and Nielsen by updating the Forrest report framework, extended to include harms. The Forrest report used life tables to estimate the number of women surviving by year up to 15 years in two cohorts aged 50, only one of which was screened. Deaths could be from breast cancer or all other causes. Baseline mortality and the reduction from triennial breast cancer screening were based on the two randomised controlled trials then available. The difference in life years between the two cohorts after 15 years was expressed in QALYs by reducing their quality of life by 8% to reflect the effects of treatment.
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