- Email: [email protected]
How the USPSTF's Mammographic Screening Guidelines Should Be Interpreted
Accepted Manuscript How the USPSTF’s Mammographic Screening Guidelines Should be Interpreted Vinay Prasad, MD MPH PII:
S0002-9343(17)30246-2
DOI:
10.1016/j.amjmed.2017.02.021
Reference:
AJM 13962
To appear in:
The American Journal of Medicine
Received Date: 2 February 2017 Revised Date:
13 February 2017
Accepted Date: 14 February 2017
Please cite this article as: Prasad V, How the USPSTF’s Mammographic Screening Guidelines Should be Interpreted, The American Journal of Medicine (2017), doi: 10.1016/j.amjmed.2017.02.021. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
How the USPSTF’s Mammographic Screening Guidelines Should be Interpreted
RI PT
Vinay Prasad MD MPH 1,2,3 1 Division of Hematology Oncology/ Knight Cancer Institute/ Oregon Health & Science University 2 Department of Public Health and Preventive Medicine/ Oregon Health & Science University 3 Senior Scholar in the Center for Health Care Ethics / Oregon Health & Science University
M AN U
TE D
Corresponding author: Vinay Prasad, MD MPH Assistant Professor of Medicine Oregon Health & Science University 3181 SW Sam Jackson Park Road Portland, Oregon 97239 Tel: 503-494-3159 Fax 503-494-3257 [email protected]
SC
Reference: 9 Word count: 1200
EP
Funding sources: I received no funding for this work Conflict of interest: I am the author of a book Ending Medical Reversal, which has one chapter on cancer screening
AC C
Vinay Prasad had access to the data and a role in writing the manuscript; Key words: USPSTF, mammographic screening, guidelines, pay for performance; Running Header:
How should screening guidelines be interpreted?
1
ACCEPTED MANUSCRIPT
How the USPSTF’s Mammographic Screening Guidelines Should be Interpreted
In 2016, the United States Preventive Services Task Force (USPSTF) issued their final
RI PT
recommendation for mammographic screening for breast cancer, advising women to undergo biennial screening between the ages of 50 to 74 (B recommendation), and that the decision to undergo screening for women aged 40 – 49 should be an individual one,
SC
and a woman may wish to undergo biennial screening (C recommendation). The group based these recommendations on a 2016 evidence review that included 8 randomized
M AN U
trials rated to be of fair-quality from their prior analysis, and supplemented these with new results from 1 trial1. The new review also assessed, for the first time, all cause mortality, and how disease specific mortality benefits may vary by risk factors and
TE D
frequency of screening.
The USPSTF estimated, based on a pooled analysis of breast cancer deaths during the accrual and follow up period of 9 randomized trials, that mammography screening for
EP
women between the ages of 39 to 49 is associated with a relative risk reduction in
AC C
breast cancer mortality of 0.88 (95% CI, 0.73 to 1.003), though confidence intervals of all trials and this pooled estimate crossed 1. Based on 7 randomized trials, reviewers found a 14% disease specific mortality reduction for women age 50-59 years (RR 0.86; 95% CrI, 0.68-0.97)1. Based on 5 randomized trials, researchers find a 33% disease specific mortality reduction for women age 60-69 years (RR 0.67; 95% CrI, 0.54-0.83). For women aged 70-74, three trials found a pooled RR of 0.80 (95%CI .51-1.28)1. Absolute
3
ACCEPTED MANUSCRIPT
reduction in breast cancer mortality ranged from 4.1 – 21.3 per 10000 women screened
RI PT
for 10 years, depending on age of subjects.
Despite this fair and impartial summary of the evidence, the issue of mammographic screening remains controversial, and, must remain a choice. In their review, the
SC
USPSTF found considerable harms of screening, including false positives and over
diagnosis—detecting and treating a cancer that would otherwise not cause harm.
M AN U
Estimates of over diagnosis ranged from 11 to 22 in randomized trials.1 Moreover, irrespective of age, mammographic screening failed to demonstrate statistically significant improvements in overall survival. For all age groups, pooled analysis of 9
TE D
RCTs yielded a RR of 0.99 (95% CI, 0.97 to 1.003).1
For these reasons, the USPSTF guidelines, in the 50-74 year old cohort, should be used to identify women for whom a discussion of mammographic screening should take
EP
place, but it should not be taken to mean that mammographic screening must subsequently take place. An informed decision to decline screening is reasonable. Such
AC C
an interpretation runs counter to many hospital and insurer based programs that provide financial incentives for higher screening rates2.
The problem No side of the mammogram debate contests the problem. Advanced breast cancer is an incurable and often fatal condition. In 2015 approximately 230,000 women were
4
ACCEPTED MANUSCRIPT
diagnosed with breast cancer and over 40,000 women died of the disease.1 Outcomes in breast cancer are strongly related to stage of the disease at diagnosis, with disease
RI PT
confined to breast and axilla being potentially curable with some combination of surgery, radiation, chemotherapy, and hormonal therapy. Disease that has spread
beyond the axilla is considered metastatic and incurable. The purpose of screening
SC
mammography is to identify localized breast cancers that would otherwise metastasize
M AN U
to distant sites causing death or disability were it not for early detection and treatment.
Over the last 3 decades mammography has been accepted as a standard screening tool. Since its adoption the annual incidence of early breast cancer has doubled, while the rate of advanced breast cancer has declined by only 8%3. Population data suggest
TE D
mammographic screening leads to sizable over diagnosis, with some estimating that more than 30% of all diagnosed breast cancers are over diagnosed cancers3.
EP
Modeling data
Based upon modeling, the USPSTF researchers concludes that biennial screening among
AC C
women aged 50 to 74 is estimated to reduce breast cancer specific mortality by 25.8% over a lifetime, translating into 7.1 breast cancer specific deaths averted per 1,000 women.4 Extending the lower age of screening to 40 and endorsing annual mammography would avert 3 deaths from breast cancer, but yields 1988 more false positives and 11 more over diagnoses per 1000 women4.
5
ACCEPTED MANUSCRIPT
The controversy Mammography as a screening test for breast cancer remains controversial. In their
RI PT
review of the evidence for mammography, the Swiss Medical Board, an independent health technology assessment initiative, found that the average woman expectations of the benefits of mammography far outweigh the reality. The board felt however that the net harms of the test outweigh the benefits5, and as such it should not be
SC
recommended5. These researchers and others argue that randomized trials showing
M AN U
large reductions in disease specific mortality occurred prior to advances in adjuvant and metastatic therapy, which have likely eroded the benefits of early detection with mammography6.
TE D
Others have noted that several randomized trials of mammography contain imbalances in death from non-breast cancer causes7. These experts believe that the effects of mammography are unlikely to truly affect death from non-breast cancer causes, and
EP
thus imbalances in these type of death suggest inadequate randomization, or errors in the ascertainment or adjudication of death7. When such imbalanced trials are removed
AC C
from pooled analyses, the benefits of mammography on disease specific mortality are attenuated7. The Cochrane meta-analysis argues that when “adequately” randomized trials are solely considered, mammography has no effect on breast cancer mortality8. Thus, the evidence for, and recommendations to undergo mammography are subject of varied opinions.
6
ACCEPTED MANUSCRIPT
Some researchers believe that so much has changed in the landscape of treatment for breast cancer from the early randomized trials of mammography till today, that a new
RI PT
trial is needed7. Improvements in the adjuvant treatment of breast cancer, and improved mammographic screening techniques may have altered the potential benefits and harms of the intervention5,6. Both sadly, may work to undermine mammography’s
SC
potential benefits, as improved adjuvant therapy in part diminishes the gains from very early detection, and improved sensitivity may paradoxically increase ascertainment of
M AN U
over diagnosed versus clinical harmful cancers. However, the practical ability to conduct such a trial, without heavy control arm contamination, in the modern age, particularly in the United States, seems impossible. Others contend that such trials are needed, but should prioritize women at higher risk of breast cancer death, adding that
TE D
disease specific mortality is an inadequate surrogate, and such trials should target demonstration of overall mortality benefit9.
EP
Conclusion
Although the USPSTF fairly summarizes the best available mammography data, there is
AC C
considerable debate and nuance to its interpretation. Whether or not the older, strongly positive studies apply today is uncertain. Simultaneously, women’s conception of the risk and benefits is consistently more favorable than even the most optimistic trial estimates. I contend that the USPSTF recommendation must serve as starting point and not a finish line. Women should not be screened more aggressively than the USPSTF advises, but the recommendation to screen is not a mandate. Efforts to standardized
7
ACCEPTED MANUSCRIPT
screening and incentivize providers to reach target screening levels should be abandoned, as mammographic choices must be made, without pressure or coercion, by
RI PT
informed women. As of 2016, based on the evidence, there is simply no ‘right’ answer to whether a woman should undergo mammographic screening.
SC
References: 1.
Nelson HD, Cantor A, Humphrey L, Fu R, Pappas M, Daeges M, Griffin J.
M AN U
Screening for Breast Cancer: A Systematic Review to Update the 2009 U.S. Preventive Services Task Force Recommendation. Evidence Synthesis No. 124. AHRQ Publication No. 14-05201-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2016. 2.
Schmidt H. The ethics of incentivizing mammography screening. JAMA.
TE D
2015;314(10):995-996. 3.
Bleyer A, Welch HG. Effect of Three Decades of Screening Mammography on
2005.
EP
Breast-Cancer Incidence. New England Journal of Medicine. 2012;367(21):1998-
AC C
4. Writing Committee of the Breast Cancer Working Group Cancer Intervention and Surveillance Modeling Network (CISNET) and the Breast Cancer Surveillance Consortium (BCSC). Collaborative Modeling of U.S. Breast Cancer Screening Strategies. AHRQ Publication No. 14-05201-EF-4 December 2015 5.
Biller-Andorno N, Jüni P. Abolishing Mammography Screening Programs? A
View from the Swiss Medical Board. New England Journal of Medicine. 2014;370(21):1965-1967.
8
ACCEPTED MANUSCRIPT
6.
Harris R. Screening Is Only Part of the Answer to Breast CancerScreening Is
Only Part of the Answer to Breast Cancer. Annals of Internal Medicine. 2014;160(12):861-863. Jüni P, Zwahlen M. It Is Time to Initiate Another Breast Cancer Screening
RI PT
7.
TrialIt Is Time to Initiate Another Breast Cancer Screening Trial. Annals of Internal Medicine. 2014;160(12):864-866. Screening for breast cancer with mammography
Peter C Gøtzsche, Karsten Juhl Jørgensen
SC
8.
Website:
M AN U
Article first published online: 4 Jun 2013 | DOI: 10.1002/14651858.CD001877.pub5.
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001877.pub5/full Accessed February 10, 2017.
Prasad V, Lenzer J, Newman DH. Why cancer screening has never been
TE D
9.
AC C
EP
shown to “save lives”—and what we can do about it. BMJ. 2016;352.
9
S0002-9343(17)30246-2
DOI:
10.1016/j.amjmed.2017.02.021
Reference:
AJM 13962
To appear in:
The American Journal of Medicine
Received Date: 2 February 2017 Revised Date:
13 February 2017
Accepted Date: 14 February 2017
Please cite this article as: Prasad V, How the USPSTF’s Mammographic Screening Guidelines Should be Interpreted, The American Journal of Medicine (2017), doi: 10.1016/j.amjmed.2017.02.021. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
How the USPSTF’s Mammographic Screening Guidelines Should be Interpreted
RI PT
Vinay Prasad MD MPH 1,2,3 1 Division of Hematology Oncology/ Knight Cancer Institute/ Oregon Health & Science University 2 Department of Public Health and Preventive Medicine/ Oregon Health & Science University 3 Senior Scholar in the Center for Health Care Ethics / Oregon Health & Science University
M AN U
TE D
Corresponding author: Vinay Prasad, MD MPH Assistant Professor of Medicine Oregon Health & Science University 3181 SW Sam Jackson Park Road Portland, Oregon 97239 Tel: 503-494-3159 Fax 503-494-3257 [email protected]
SC
Reference: 9 Word count: 1200
EP
Funding sources: I received no funding for this work Conflict of interest: I am the author of a book Ending Medical Reversal, which has one chapter on cancer screening
AC C
Vinay Prasad had access to the data and a role in writing the manuscript; Key words: USPSTF, mammographic screening, guidelines, pay for performance; Running Header:
How should screening guidelines be interpreted?
1
ACCEPTED MANUSCRIPT
How the USPSTF’s Mammographic Screening Guidelines Should be Interpreted
In 2016, the United States Preventive Services Task Force (USPSTF) issued their final
RI PT
recommendation for mammographic screening for breast cancer, advising women to undergo biennial screening between the ages of 50 to 74 (B recommendation), and that the decision to undergo screening for women aged 40 – 49 should be an individual one,
SC
and a woman may wish to undergo biennial screening (C recommendation). The group based these recommendations on a 2016 evidence review that included 8 randomized
M AN U
trials rated to be of fair-quality from their prior analysis, and supplemented these with new results from 1 trial1. The new review also assessed, for the first time, all cause mortality, and how disease specific mortality benefits may vary by risk factors and
TE D
frequency of screening.
The USPSTF estimated, based on a pooled analysis of breast cancer deaths during the accrual and follow up period of 9 randomized trials, that mammography screening for
EP
women between the ages of 39 to 49 is associated with a relative risk reduction in
AC C
breast cancer mortality of 0.88 (95% CI, 0.73 to 1.003), though confidence intervals of all trials and this pooled estimate crossed 1. Based on 7 randomized trials, reviewers found a 14% disease specific mortality reduction for women age 50-59 years (RR 0.86; 95% CrI, 0.68-0.97)1. Based on 5 randomized trials, researchers find a 33% disease specific mortality reduction for women age 60-69 years (RR 0.67; 95% CrI, 0.54-0.83). For women aged 70-74, three trials found a pooled RR of 0.80 (95%CI .51-1.28)1. Absolute
3
ACCEPTED MANUSCRIPT
reduction in breast cancer mortality ranged from 4.1 – 21.3 per 10000 women screened
RI PT
for 10 years, depending on age of subjects.
Despite this fair and impartial summary of the evidence, the issue of mammographic screening remains controversial, and, must remain a choice. In their review, the
SC
USPSTF found considerable harms of screening, including false positives and over
diagnosis—detecting and treating a cancer that would otherwise not cause harm.
M AN U
Estimates of over diagnosis ranged from 11 to 22 in randomized trials.1 Moreover, irrespective of age, mammographic screening failed to demonstrate statistically significant improvements in overall survival. For all age groups, pooled analysis of 9
TE D
RCTs yielded a RR of 0.99 (95% CI, 0.97 to 1.003).1
For these reasons, the USPSTF guidelines, in the 50-74 year old cohort, should be used to identify women for whom a discussion of mammographic screening should take
EP
place, but it should not be taken to mean that mammographic screening must subsequently take place. An informed decision to decline screening is reasonable. Such
AC C
an interpretation runs counter to many hospital and insurer based programs that provide financial incentives for higher screening rates2.
The problem No side of the mammogram debate contests the problem. Advanced breast cancer is an incurable and often fatal condition. In 2015 approximately 230,000 women were
4
ACCEPTED MANUSCRIPT
diagnosed with breast cancer and over 40,000 women died of the disease.1 Outcomes in breast cancer are strongly related to stage of the disease at diagnosis, with disease
RI PT
confined to breast and axilla being potentially curable with some combination of surgery, radiation, chemotherapy, and hormonal therapy. Disease that has spread
beyond the axilla is considered metastatic and incurable. The purpose of screening
SC
mammography is to identify localized breast cancers that would otherwise metastasize
M AN U
to distant sites causing death or disability were it not for early detection and treatment.
Over the last 3 decades mammography has been accepted as a standard screening tool. Since its adoption the annual incidence of early breast cancer has doubled, while the rate of advanced breast cancer has declined by only 8%3. Population data suggest
TE D
mammographic screening leads to sizable over diagnosis, with some estimating that more than 30% of all diagnosed breast cancers are over diagnosed cancers3.
EP
Modeling data
Based upon modeling, the USPSTF researchers concludes that biennial screening among
AC C
women aged 50 to 74 is estimated to reduce breast cancer specific mortality by 25.8% over a lifetime, translating into 7.1 breast cancer specific deaths averted per 1,000 women.4 Extending the lower age of screening to 40 and endorsing annual mammography would avert 3 deaths from breast cancer, but yields 1988 more false positives and 11 more over diagnoses per 1000 women4.
5
ACCEPTED MANUSCRIPT
The controversy Mammography as a screening test for breast cancer remains controversial. In their
RI PT
review of the evidence for mammography, the Swiss Medical Board, an independent health technology assessment initiative, found that the average woman expectations of the benefits of mammography far outweigh the reality. The board felt however that the net harms of the test outweigh the benefits5, and as such it should not be
SC
recommended5. These researchers and others argue that randomized trials showing
M AN U
large reductions in disease specific mortality occurred prior to advances in adjuvant and metastatic therapy, which have likely eroded the benefits of early detection with mammography6.
TE D
Others have noted that several randomized trials of mammography contain imbalances in death from non-breast cancer causes7. These experts believe that the effects of mammography are unlikely to truly affect death from non-breast cancer causes, and
EP
thus imbalances in these type of death suggest inadequate randomization, or errors in the ascertainment or adjudication of death7. When such imbalanced trials are removed
AC C
from pooled analyses, the benefits of mammography on disease specific mortality are attenuated7. The Cochrane meta-analysis argues that when “adequately” randomized trials are solely considered, mammography has no effect on breast cancer mortality8. Thus, the evidence for, and recommendations to undergo mammography are subject of varied opinions.
6
ACCEPTED MANUSCRIPT
Some researchers believe that so much has changed in the landscape of treatment for breast cancer from the early randomized trials of mammography till today, that a new
RI PT
trial is needed7. Improvements in the adjuvant treatment of breast cancer, and improved mammographic screening techniques may have altered the potential benefits and harms of the intervention5,6. Both sadly, may work to undermine mammography’s
SC
potential benefits, as improved adjuvant therapy in part diminishes the gains from very early detection, and improved sensitivity may paradoxically increase ascertainment of
M AN U
over diagnosed versus clinical harmful cancers. However, the practical ability to conduct such a trial, without heavy control arm contamination, in the modern age, particularly in the United States, seems impossible. Others contend that such trials are needed, but should prioritize women at higher risk of breast cancer death, adding that
TE D
disease specific mortality is an inadequate surrogate, and such trials should target demonstration of overall mortality benefit9.
EP
Conclusion
Although the USPSTF fairly summarizes the best available mammography data, there is
AC C
considerable debate and nuance to its interpretation. Whether or not the older, strongly positive studies apply today is uncertain. Simultaneously, women’s conception of the risk and benefits is consistently more favorable than even the most optimistic trial estimates. I contend that the USPSTF recommendation must serve as starting point and not a finish line. Women should not be screened more aggressively than the USPSTF advises, but the recommendation to screen is not a mandate. Efforts to standardized
7
ACCEPTED MANUSCRIPT
screening and incentivize providers to reach target screening levels should be abandoned, as mammographic choices must be made, without pressure or coercion, by
RI PT
informed women. As of 2016, based on the evidence, there is simply no ‘right’ answer to whether a woman should undergo mammographic screening.
SC
References: 1.
Nelson HD, Cantor A, Humphrey L, Fu R, Pappas M, Daeges M, Griffin J.
M AN U
Screening for Breast Cancer: A Systematic Review to Update the 2009 U.S. Preventive Services Task Force Recommendation. Evidence Synthesis No. 124. AHRQ Publication No. 14-05201-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2016. 2.
Schmidt H. The ethics of incentivizing mammography screening. JAMA.
TE D
2015;314(10):995-996. 3.
Bleyer A, Welch HG. Effect of Three Decades of Screening Mammography on
2005.
EP
Breast-Cancer Incidence. New England Journal of Medicine. 2012;367(21):1998-
AC C
4. Writing Committee of the Breast Cancer Working Group Cancer Intervention and Surveillance Modeling Network (CISNET) and the Breast Cancer Surveillance Consortium (BCSC). Collaborative Modeling of U.S. Breast Cancer Screening Strategies. AHRQ Publication No. 14-05201-EF-4 December 2015 5.
Biller-Andorno N, Jüni P. Abolishing Mammography Screening Programs? A
View from the Swiss Medical Board. New England Journal of Medicine. 2014;370(21):1965-1967.
8
ACCEPTED MANUSCRIPT
6.
Harris R. Screening Is Only Part of the Answer to Breast CancerScreening Is
Only Part of the Answer to Breast Cancer. Annals of Internal Medicine. 2014;160(12):861-863. Jüni P, Zwahlen M. It Is Time to Initiate Another Breast Cancer Screening
RI PT
7.
TrialIt Is Time to Initiate Another Breast Cancer Screening Trial. Annals of Internal Medicine. 2014;160(12):864-866. Screening for breast cancer with mammography
Peter C Gøtzsche, Karsten Juhl Jørgensen
SC
8.
Website:
M AN U
Article first published online: 4 Jun 2013 | DOI: 10.1002/14651858.CD001877.pub5.
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001877.pub5/full Accessed February 10, 2017.
Prasad V, Lenzer J, Newman DH. Why cancer screening has never been
TE D
9.
AC C
EP
shown to “save lives”—and what we can do about it. BMJ. 2016;352.
9