Overdiagnosis of breast cancer after 14 years of ... · Overdiagnosis of breast cancer after 14...
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Overdiagnosis of breast cancer after 14
years of mammography screening
Per-Henrik Zahl Norwegian Institute of Public Health
January 31, 2013
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Overview
1. What is overdiagnosis?
2. Why are 30-year old RCTs inappropriate to estimate the level of
overdiagnosis?
3. What is rate and life time risk?
4. How is the magnitude of cancer overdiagnosis calculated?
5. What is the underlying incidence increase?
6. What is the decline after age 69 and how do we adjust?
7. Comparison with Kalager et al
8. All DCIS are overdiagnoses when calculating overdiagnosis
9. Life time risk of being overdiagnosed and prevalent overdiagosed
patients
10. The dilution method
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1. What is overdiagnosis?
“Overdiagnosis is detection of a disease that in the
absence of screening would not have been diagnosed
in the patient's lifetime.” Etzioni et al. J Natl Cancer Inst 2002
Overdiagnosis can be explained by:
The detection of tumors
i) that grow very slowly, or
ii) spontaneously would regress
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Overdiagnosed
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2. Why are 30-years old RCTs inappropriate
when estimating the level of overdiagnosis?
2.A Underestimation in the old trials
The Cochrane review reported 30 percent
overdiagnosis when screening with old type
mammography
But screening was going on also in the control
groups:
- CNBSS-2: Physical examination in the control group
- Malmö trial: DCIS rates in the control group were about 20 per 100 000
(and 40 in the screening arm) suggesting extensive screening in the
control group
Gøtzsche, Nielsen. Cochrane Review 2011
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2.B There is a disease reservoir of DCIS
Prevalence of DCIS by number of slides per breast
Number of slides
per breast
Bartlow et al, 1987 9 0
Kramer et al, 1973 40 4.3
Nielsen et al, 1984 95 14.3
Nielsen et al, 1987 275 39
Prevalence of
DCIS
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* Miller et al (CBCSS-2), CMAJ 1992
** Evaluering av prøveprosjektet,1999-2000
*** Skaane et al, Radiology 2013
Detection rates have increased because of: double view, computer assisted
reading, ultrasound, MR and 3D mammography without any decline in the
rate of interval cancer.
2.C Detection rate at screening has increased dramatically
0
1
2
3
4
5
6
7
8
9
10
Canada 1981-85 * Norway 1996-99 ** Norway 2011 ***
Detection rate at screening
Rate first year after a screening
Rate per 1000
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3. What is rate and life time risk?
Rate = number of incident cancers/
100,000 individuals / year
0
50
100
150
200
250
300
350
Rate
1991 2010
Sum of rates over all ages = life time risk
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Zahl, Strand, Mæhlen. BMJ 2004
4. How is the magnitude of overdiagnosis calculated?
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0,0
100,0
200,0
300,0
400,0
500,0
1975
1977
1979
1981
1983
1985
1987
1989
1991
1993
1995
1997
1999
2001
2003
2005
2007
2009
Year
Rate
30-49 70-84
Curves show 1% and 2% annual underlying incidence increase
5. An underlying incidence increase?
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Rates in Sweden, women aged 50-74 years
Zahl et al. Lancet Oncol 2011.
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An increasing use of HRT?
Kalager et al. Ann Intern Med 2012.
Fra 1990 til 2010 vokste befolkningen med 33 % i aldersgruppen 50-69 år
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Breast cancers / 100 000 women
5. What is the decline after age 69?
Boer et al. Lancet 1994
Age 50-69 years: 25% observed increase
In theory: about 35% expected decline in age group 70-79 years
A B
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Zahl, Mæhlen. Tidsskriftet 2012
Age 50-69: observed over 50% increase
Age 70-79: almost no decline
A B
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Invasive breast cancer incidence in Fife, Scotland
Vaidya. BMJ 2004; 339: b2587 (rapid responses)
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250/100,000 ∙ 80,000 ∙ 7% = 14 less cancers after end of screening
Period 25-44 50-69 70-74 75+
1991-5 43 178 250 281
2005 46 285 234 282
2009 44 275 232 260
Age-specific rates of cancer
About 56% increase in the age group 50-69
About 7% reduction in the age group 70-74
178/100,000 ∙ 532,000 ∙ 56% = 530 more cancers when screening
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Adjusting for earlier diagnosis
• Expected number of cancers: 945
• Observed 530 more cancers than expected when screening
• Observed 14 less after age 69
Zahl, Mæhlen. Tidsskriftet 2012
This is adjustment for
earlier diagnosis
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• 1948/2,337,000 = 83 per 100,000
• Zahl et al 2004: 450/430,000 = 105 per 100,000
• Zahl et al 2012: 500/532,000 = 94 per 100,000
7. Comparison with Kalager et al
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8. All DCIS are overdiagnosed when
calculating overdiagnosis
1. All DCIS that regress are overdiagnosed by definition
2. If some DCIS progress, for example 150, then we
would expect 945 - 150 = 795 breast cancers
The absolute differences between numerator and
denominator are 816 in both cases
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• USA: 114/100,000 women over 40
• Norway: 800/1,177,000 = 68/100,000 women over
40
67% more overdiagnosis in USA than in Norway
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9. Life time risk of being overdiagnosed
“How many percent of women will be overdiagnosed
during their life-time”?
• There are 100 overdiagnosed cancers/100,000 women
• There are 50 overdiagnosed DCIS/100,000 women
(100/100,000+ 50/100,000) ∙ 20 years = 3 %
Prevalent overdiagnosed patients: 800 ∙ 5 = 4000
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Dilution of the magnitude of overdiagnosis
occurs when including all incident cancers in a
10-15 year follow up after screening was
terminated.
10.“The dilution method”
50 69 79 years
1473
945
356
370
Screening cohort:
Control cohort:
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Suppose the rate is 232 for the age group 70-
74 (and 250 for the age group 75-79) who have
undergone previous screening and 250 if no
screening has occured, then
By using rates instead of cancer cases, cancers in the age group 70-79
years have larger weights than cancers in the age group 50-69 and this is
making the dilution effect stronger than if we only add cancers after age 69.
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Figure 1. The black curve is the conditional IRR of the cumulative breast cancer incidence rate for a
cohort screened from age 50 to 69 to an un-screened cohort and then followed-op to age 90. The red
curve is the conditional IRR for the same cohorts, but here we assume that both cohorts are screened
from age 70 to 90.
1
1,1
1,2
1,3
1,4
1,5
1,6
55 60 65 70 75 80 85 90
Screening 50-69
Screening 50-89
Conditional IRR/overdiagnosis
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The Marmot Report
• “…the Panel thinks that the best estimate of
overdiagnosis for a population invited to be
screened is roughly 11%, defined as the excess
incidence in the screening population as proportion
of the long-term expected incidence.”
– It is 11% of something that is not defined
– Why not apply the same dilution method to the mortality
reduction to make estimates comparable; i.e. (20%
mortality reduction)/5?
The Marmot Report. Lancet 2012
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Conclusion
1. 30-35 years old RCTs underestimate overdiagnosis
2. The level of overdiagnosis of invasive breast cancer is 50%
• Or at least 95 overdiagnosed cancers for every 100,000 women invited
to screening
• In addition there are 50 overdiagnosed DCIS for every 100,000 women
invited to screening
• Each year there are at least 800 overdiagnosed breast cancer and
DCIS and because they are treated in 5 years, we get at least 4000
more patients who need to be treated in hospitals
• Life time risk of being overdiagnosed is at least 3%
3. These numbers are adjusted for earlier diagnoses (long lead times) and
they are minimum estimates
4. The dilution method cannot be interpreted as any of the numbers above –
conditional IRR is has very little meaning for women, I think
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Slutt