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Rapid Responses: Rapid Responses published:
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Over-detection or spontaneous regression of breast cancer?
- Per-Henrik Zahl, Professor Jan Mæhlen (11 March 2005)
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Outcomes of screening mammography: information to support informed choices
- Peter C Gøtzsche, Karsten J. Jørgensen, physician, Nordic Cochrane Centre (15 March 2005)
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What is important to women making decisions about screening?
- Sue M Lockwood, Nicola Bruce, Rosetta Manaszewicz (26 April 2005)
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Is the desired effect of mammography screening dwindling away before our eyes?
- Friederike M. Perl (6 May 2005)
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Does screening mammography cause cancers?
- Jayant S Vaidya (16 May 2005)
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Per-Henrik Zahl, Senior Statistician Norwegian Institute of Public Health, PO Box 4404 Nydalen, N-0403 Oslo, Norway, Professor Jan Mæhlen
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Dear Editor, The results of the interesting model study by Barratt et al. [1] suggest that more breast cancer are diagnosed among screened than unscreened women. For women aged 50 who have five biennial mammography screenings, 40% higher cumulative 10-year cumulative incidence of breast cancer was observed (and 67% higher if ductal carcinoma in-situ (DCIS) was included). For women screened from other ages, the model predicted a similar relative increase over ten year. Two important underlying assumptions in mammography screening are i) the sensitivity at the screening is relatively high (>75%) and ii) most invasive tumours grow monotonously; i.e. spontaneous tumour regression is uncommon. From these assumptions it emerges that most of the difference in the cumulative incidences between the screened and the unscreened women should disappear if a prevalence screening of the previously unscreened women had been performed at the end of the 10-year period. However, a prevalence screening can only compensate for a part of this difference. The reason for this is that the detection rate at a prevalence screening repeatedly has been shown to be only about 3 times higher than the background incidence at age 60 or 70 [2]. Moreover, the model by Barratt et al. predicts that if 1000 women aged 40 have 15 biennial mammography screenings from age 40 to 69, the cumulative difference between screened and unscreened for the three 10- year periods is (17.6 – 13.2) + (28.1 – 19.8) + (32.5 – 23.9) = 21.3 invasive breast cancers [1]. This calculation leads to the conclusion that the model predicts the detection rate at a prevalence screening of women aged 70 to be twice that observed in screening programmes [3, 4]. This result suggests that at least one of the two assumptions above should be modified. The prevalence screening detects most of the slow- growing cancers, and the detection rate at the following screenings is stable at a lower level. This indicates that it is true that the sensitivity at the screening is relatively high. We conclude that the other assumption is false. It is not true that spontaneous tumour regression is uncommon. 1. Barrratt A, Howard K, Irwig L, Salkeld G, Houssami N. Model of outcomes of screening: information to support informed choices. Br Med J doi:10.1136/bmj.38398.469479.8F. 2. Zahl PH, Andersen JM, Maehlen, J. Spontaneous regression of cancerous tumours detected by mammography screening. JAMA 2004; 292: 2579- 80. 3. Tabár L, Fagerberg G, Duffy SW, Day NE, Gad A, Gröntoft O. Update of the Swedish Two-County program of mammographic screening for breast cancer. Radiol Clin North Am 1992; 30: 187-210. 4. Smith-Bindman R, Chu PW, Miglioretti Dl, Sickles EA, Blanks R, et al. Comparison of screening mammography in the United States and the United Kingdom. JAMA 2003; 290: 2129-38. Competing interests: None declared |
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Peter C Gøtzsche, Director The Nordic Cochrane Centre, Rigshospitalet Dept. 7112, Blegdamsvej 9, DK-2100 Copenhagen, Denmark, Karsten J. Jørgensen, physician, Nordic Cochrane Centre
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Barratt et al. report that for every 1000 women screened from the age of 50 over 10 years, 2 fewer will die from breast cancer and 13 more will be diagnosed with breast cancer (corresponding to 63% more cancers, which mostly constitute overdiagnosis) (1). Similarly, we found that for every woman who has her life prolonged, 5 healthy women, who would not have received a breast cancer diagnosis in their lifetime if there had not been screening, will be converted into cancer patients unnecessarily (2). However, it is important to inform women that the frequently used estimate of 25-30% for the survival benefit is uncertain and rather optimistic (2,3). Barratt et al. even used 37% since they adjusted their estimate of 25% for non-compliance. This procedure is doubtful since, as noted by two of the investigators in the screening trials, women who refuse to be screened have a worse prognosis, presumably because some of them are afraid of having a suspicion of breast cancer confirmed (4). They also have a much higher death rate from all causes (4). We disagree that one can equate 2 fewer women who will die from breast cancer with 2 fewer who will die from any cause (1). An effect of screening on all-cause mortality has not been demonstrated (2,3); breast cancer mortality is an unreliable outcome that is biased in favour of screening (4); and the extra treatment due to overdiagnosis would be expected to lead to excess mortality in the screened group (5). 1. Barratt A, Howard K, Irwing L, Salkeld G, Houssami N. Model of outcomes of screening mammography: information to support informed choices. BMJ, doi:10.1136/bmj.38398.469479.8F (published 8 March 2005) 2. Olsen O, Gøtzsche PC. Systematic review of screening for breast cancer with mammography. 2001. http://image.thelancet.com/lancet/extra/fullreport.pdf (accessed 8 Jan 2004). 3. Humphrey LL, Helfand M, Chan BK, Woolf SH. Breast cancer screening: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2002; 137(5 Part 1):347-60. 4. Gøtzsche PC. On the benefits and harms of screening for breast cancer. Int J Epidemiol 2004;33:56-64. 5. Early Breast Cancer Trialists' Collaborative Group. Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: An overview of the randomised trials. Lancet 2000;355:1757- 70. Competing interests: None declared |
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Sue M Lockwood, Chair Breast Cancer Action Group Melbourne Australia 3130, Nicola Bruce, Rosetta Manaszewicz
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All women would like accurate and balanced information to help them decide whether or not to participate in screening programs. So the question is: does the information presented by Barratt et al in this article actually provide accurate or balanced information? We have our doubts about this for the following reasons: This article is based on assumptions about the “harms” associated with false positive results from screening. Although we acknowledge these “harms”, we would argue that the “harms” associated with false negative results are even greater. False negatives may lead to death. Most women would be prepared to cope with the problems of anxiety etc, if they understood that there was a trade-off with the possibility of death. So the next issue is how accurate are these “estimates”. We are not in a position to argue this at the present time, the statisticians will need to get to work to be able to determine the answer to this question. But be reminded that they are estimates. And the “estimates” are just a little rubbery. If the range of “estimates” for overdetection ranges from 2-30% just how much value can be placed on this concept. Indeed we would argue that overdetection is not the issue; the main problem is the overwhelming desire by clinicians to treat women, that is, overtreatment is more of a problem than overdetection. Even if these “estimates” are accurate, will this information actually assist women in making their decisions. We would argue that these figures are only of partial value to women. Although women will take these estimates into account, they also base decisions on factors such as their own personal value systems, their fears of developing breast cancer, and their personal circumstances. “Estimates” such as this play a limited role in their decision making. Competing interests: None declared |
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Friederike M. Perl, Consultant surgeon breast centre Diakonie Klinikum Stuttgart Germany
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Barrat et al. compared screening compliers and refusers in their incidence and mortality from breast cancer and their overall mortality. They express surprise at the small difference in mortality between these two groups. Indeed, it should be expected that the refusers have a much higher mortality because of their higher background of health problems. Therefore, it is likely that comparable groups (which these are not) would make it even more difficult to detect a difference. If even one of the world's flagships of mammography screening is apparently needing magnifying glasses to detect the desired effects, then the ordinary rest of us will face even greater difficulties in finding support for women's hope of a mortality benefit through screening mammography. Furthermore, neither Barratt et al. nor the editorial by Taylor consider the additional x-ray exposures required to localize screening abnormalities for histology. Radiographically directed fine needle biopsy requires an additional 7 to 9 x-ray exposures of the incriminated breast during the procedure. There is no estimate as yet to take these additional cancerogenic factors into account. They might obliterate any mortality benefit teased out by screening as such, or even increase mortality by a larger margin than we fear. Given the uncontrolled nature of the study and the lack of comparability between the two groups, one should be cautious in attributing causality to any of the observed phenomena. Even the word "reduction" may be misleading as it implies a directed activity. This study does not allow such a conclusion. Friederike M. Perl DRCOG
Competing interests: None declared |
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Jayant S Vaidya, Senior Lecturer/ Consultant Surgeon University of Dundee, Ninewells Hospital and Medical School, DD1 9SY
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The recent model of screening mammography by Alexandra Barratt (1) has some very interesting data. We could use their data to predict what might happen in the breast of a woman from the age of 40 to 69 if not disturbed by the consequences of mammographic screening. Let us wipe our slates clean and look at it sans-prejudice. The basis of screening is to
detect cancers before they became invasive or big enough to metastasise and
kill. So in theory, the total number of cancers should remain the same in the
screened and unscreened population, but the screened women would have smaller
ones. Or, perhaps the detection of ductal carcinoma in situ (DCIS) should
increase whilst as a corollary to that, invasive cancers should reduce in
incidence, if not in the first 10 years then at least over a 30 year period. Looking at table 2 from the
original paper (1) and concentrating on the 3 columns from the ages of 40-69.
(The numbers for unscreened population between 70-79
are not available and hence are not included.) To estimate the natural history of
breast cancer over 30 years, one just adds up the numbers to get Table 1, in
which one can compare what happens to unscreened breasts to those subjected to
two-yearly screening mammography Table 1
*The
interval cancers appear in between the two-yearly mammograms so they are in
fact symptomatic cancers. Let us assume that they are not “caused” by the
screening process itself and ignore them at present. Let us now interrogate the data with two obvious questions: Does mammography “cause” cancers? And is mammography dangerous to life? Thus we start off with 28 invasive cancers and 1 DCIS that develops among 1000 women whose breasts are not screened over 30 years. If these breasts are subjected to mammography, then they are found to have 49 invasive cancers and 14 DCIS, over the same period. That is 34 extra cancers. More than doubling of risk of diagnosis of cancer. The unscreened women never seem to catch up with the cancer diagnosis over 30 years, until they are 69. Table 2 shows the same numbers for calculation of odds ratios for testing alleged causality of invasive cancers, DCIS and total cancers by mammography. Table 2
So it appears that two-yearly mammography more than doubles the risk of breast cancer diagnosis and increases the risk of DCIS diagnosis 14 times. Even if we include the interval cancers, the Odds ratio is 1.65 (95% CI – 1.15 to 2.35, p=0.003). Fortunately, risk of remaining alive is not statistically significantly altered (OR=1.05, 95% CI= 0.79-1.39, p=0.72). So does mammographic screening
“cause” breast cancers? Yes, it either directly causes cancers from ionising radiation or more likely
unearths cancers that would never surface in those 30 years if left to nature.
Is mammographic screening dangerous to life? Perhaps not,- there is no
statistically significant detrimental effect on life, suggesting that either
the cancers it induces or unearths are harmless or would have regressed anyway
(see Zahl et al above), or it detects other cancers
early enough to favourably influence their natural history, so negating the
harmful effect. This unequivocal evidence from a
human experiment correlates well with
laboratory evidence that low dose radiation such as with mammography has
a carcinogenic effect in laboratory animals and cell cultures(2). The other, more plausible hypothesis (see Zahl et al above), to explain this phenomenon is that the extra cancers are also present in unscreened women, but they either don’t progress or regress spontaneously. However there is some evidence to the contrary. A study of untreated DCIS cases in the Nurses health study (3), in which 13 DCIS cases were wrongly labelled as benign. Six of these developed invasive cancers and 4 more were diagnosed as DCIS suggesting that probably half of DCIS progresses to invasive cancer. In the classic study by David Page and colleagues(4), 28 women with DCIS were treated with biopsy only. Eleven of these women developed invasive carcinoma in a 30 year follow up. Applying this to the table 1, Of the 28 cancers in the unscreened group, 6 would have resulted from the 13 cases of undetected DCIS. This gives us an estimate that 22 of the 49 cancers detected by screening become clinically apparent- a proportion similar to DCIS! (NB Many of these women being screened and having biopsies and this may confound the issue). The proportion of screen detected invasive cancers that may have progressed to clinically evident cancers is not known. Let us now estimate how many cancers would need to be diagnosed during screening to account for these 22 cases, for different probabilities of progression to clinical cancers. Then the number of cancers caused by screening can be calculated by subtracting this number from the 49 cancers that are actually detected by screening. This is shown in Table 3 Table 3 shows the results of 4 possible proportions of invasive cancers detected at screening that may progress to clinical cancers over 30 years. Please read this table, column by column
So one has to either believe that more than half of invasive cancers detected by screening would never have become clinically evident, at least until the age of 69, (column 1 of table 3), or, if a larger proportion (60%, 80% or 100%) of these invasive cancers progress to clinical tumours, then screening mammography actually causes extra cancers(13, 22 or 27, respectively), as in columns 2, 3 or 4 of Table 3. Neither of these hypotheses is easily testable. Women should be made aware that mammographic screening would double the chance of their being diagnosed with cancer, although it is unlikely that this will adversely affect their chance of remaining alive at the age of 69. The relevance of this may be more sinister in women with family history of breast cancer because tissues of women with BRCA1 or BRCA 2 gene mutations are even more sensitive to low dose of radiation (5). Yours sincerely, Jayant S Vaidya References 1. Alexandra Barratt, Kirsten Howard, Les Irwig, Glenn Salkeld, Nehmat Houssami Model of outcomes of screening mammography: information to support informed choices 2005; 330 (7497): 936. 2. Frankenberg D,
Kelnhofer K, Bar K, Frankenberg-Schwager M. Enhanced neoplastic transformation by mammography X rays relative to 200 kVp X rays: indication for a strong dependence on photon energy of the RBE(M) for various end points. Radiat Res. 2002 Jan;157(1):99-105. 3. Collins LC, Tamimi RM, Baer HJ, Connolly JL, Colditz GA, Schnitt SJ Cancer. Outcome of patients with ductal carcinoma in situ untreated after diagnostic biopsy. 2005 May 1;103(9):1778-84. 4. Sanders ME, Schuyler PA, Dupont WD, Page DL The natural history of low-grade ductal carcinoma in situ of the breast in women treated by biopsy only revealed over 30 years of long-term follow-up. Cancer. 2005 May 9; [Epub ahead of print]
5. Vaidya JS, Baum M. Benefits and risks of screening mammography in women with BRCA1 and BRCA2 mutations. JAMA. 1997 Jul 23-30;278(4):290 Competing interests: None declared |
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