Most pcp and obgyn quality metrics for reimbursement include documenting mammography. How do we back off when our “quality” of care and reimbursement are dependent on ordering these tests?
- The major counterargument would be that it seems that it also lead to numerical mortality benefit
- The counter-counterargument, which is what is for me the major limitation, is THE INTERVENTION itself - initiation AND uptitration of GMDT (and not each one of them separately):
» At the end, we still don't know if it's either the initiation or uptitration that is leading the benefit. If one believes that the major net benefit seen with most of the drugs in medicine comes with the lower ranges of doses (pharmacology and the evidence supports it most of the times - see and/or read the work if James McCormack and its team), one has the be convinced of the opposite with strong arguments / data.
In this trial, GMDT was both initiated and uptitrated at the same time. Would the initiation in the lower dose be enough for the benefit seen without the harm seen with more adverse events? Maybe. And we can't know it with this trial.
To add to your good points about the mammography study:
Overdiagnosed cases will predominantly be early stages. These overdiagnosed cases will 'artificially' decrease the percentage of late stage cancers amongst those that are screened and are screened more often.
These results would be expected both in cases where breast screening was effectively detecting cancer earlier and improved prognosis AND with a scenario where breast cancer screening caused lots of overdiagnosis and where attending screening was more prominent amongst the well-off, healthier individuals (which it is). Thus, a lower percentage late stage cancers in screenees might as well indicate that screening causes harm (overdiagnosis).
The correct meassure in such studies is not 'percentages of late stage cancers' as this metric assumes there is no overdiagnosis. A slightly better meassure would be 'rates of late stage cancers', say stage 4 cases per 1,000. Even then, this study would be vulnerable to self-selection bias.
These types of studies do not bring our understanding of breast screening forward. They confirm some people in their beliefs and I think that is their main 'value'.
Neither article changed my mind either. I am also an avowed mammogram skeptic. I would go further and admit that I am a "preventive medicine" skeptic, but that is another entirely different topic. The marginal benefits claimed for regular mammograms have always seemed to be more than countered by the life disrupting effects of false positive findings. Unfortunately it is very difficult, if not impossible, to quantitate these negative side effects.. The wording in the conclusion to the abstract gives the game away by stating: "Annual mammographic screening was ASSOCIATED WITH lower rates of late stage cancer and BETTER OS across clinical and demographic subgroups (emphasis added)". This is advocacy, not science.
In addition to your excellent points regarding the mammogram study, there is also the natural experiment which is still running after over thirty years: among the many countries with high quality breast cancer screening programs, the US is the only one doing annual mammograms. Most other countries do screening mammograms every 2 years, a few are every 3 years. All countries have (thankfully) seen similar impressive reductions in breast cancer mortality. The US, despite its more frequent annual screening, has experienced the same, but not better, reduction in breast cancer mortality as other countries performing less frequent screening.
This is so perplexing when one is caring for a patient with a newly detected breast cancer. In that encounter, to the radiologist it really seems like an annual screening would have resulted in a better prognosis finding (emphasis on seems like). I have had that experience many times. But I have also always followed the epidemiology of breast cancer, and if annual mammography really improved breast cancer mortality as compared with less frequent screening, that should have shown up by now, given that it’s been over 30 years.
One thing I like about reading sensible medicine on a Sunday is it keeps my brain from atrophying with the Sunday blues. Funny, how only four years into retirement I still dread Mondays…
Love your thinking. But me, I look forward to Mondays and getting back to the office. Maybe it's my age-78. Or maybe it's having a 3 day weekend in my new job. Still love your thoughts.
Has there ever been an analysis of MRI in Breast Cancer and various intervals of need for repeat study relative to mammogram. More sensitive and more specificity? No radiation and no pain ? Perhaps there could be a longer interval between examinations ? Why do we not follow abnormal mammogram with ultrasound rather than MRI ? More sensitive and if US abnormal, will still go to MRI afterwards often ? All based on $$$ or science ? Only questions not postulations !
There is plenty of research that shows that heart failure can be stopped and reversed with T3, triiodothyronine. And T4 can cause A fib. In fact, most a fib and hear failure may be iatrogenic anyway. I have found so many people suffering from it are only on T4, which is a huge medical travesty.
More severe heart failure was associated with higher thyroid-stimulating hormone (TSH), higher free thyroxine (FT4), and lower total triiodothyronine (TT3) concentrations (P<0.001 all models). Atrial fibrillation was positively associated with higher levels of FT4 alone (P≤0.01 all models).
Cardiac output increased with a reduction in systemic vascular resistance in patients receiving the largest dose, consistent with a peripheral vasodilatory effect. Acute intravenous administration of triiodothyronine is well tolerated in patients with advanced heart failure, establishing the basis for further investigation into the safety and potential hemodynamic benefits of longer infusions, combined infusion with inotropic agents, oral triiodothyronine replacement therapy, and new triiodothyronine analogs.
short-term synthetic L-T3 replacement therapy significantly improved neuroendocrine profile and ventricular performance. These data encourage further controlled trials with more patients and longer periods of synthetic L-T3 administration.
A very weak trial, my personal conclusion is the same as you did. The problem is that this trial is an argument to recommend intensive treatment over a step by step approach.
The issue is always scientific method. Making trials and collecting data is not investigation or science: putting brains reflecting, thinking and making a serious analysis of data with clinical argumentation is essential. The strong hf (if we follow a step by step analysis) doesn´t survive to the primary hypothesis.
The last week I made a challenge to the residents: "please, tell me if this situation is true: A and B drugs are well established in the treatment of certain condition called X, I make a trial with patients who are not doing well and randomized to drug C or placebo. The primary endpoint is met, and then I conclude: in ALL patients with the condition X we recommend A + B + C. Then I designed a trial with patients with the condition X who are not doing well with A + B + C and randomized them to drug D or placebo, the primary endpoint is met, then I conclude: to ALL patients with the condition X we must indicate drugs A +B + C + D. I made exactly the same process with drug E..."
We can replace the letters for real drugs such as beta blockers, IECA/ARNI, antialdosteronics, SLGT2 or even Omecamtiv Mecarbil...
SCIENTIFIC METHOD....since the ancient greeks to nowadays... 2.500 years...we learned nothing.
I don’t understand your statement disconnecting detection of early cancer from improving mortality. Even if it is a possibility.
And take away mammograms- what do we women do? 1 in 8 of which may face that diagnosis. Keep their fingers crossed? Wait for masses to get larger so it’s obvious? Europe doesn’t do annual screening right? Any data to compare there?
It’s easy to be critical of various studies but offer real life solutions please. RCTs take a loooong time. Disease doesn’t wait.
It's pretty complex yet pretty simple. As Dr. Cifu points out it's not about finding cancer or finding cancer early. Does mammography prolong the patient's. A lot of very intelligent people believe it doesn't. Today's treatments (mostly non surgical adjuvants) are so good that finding breast cancer a year earlier offers no advantage.
As an international comparison, Switzerland does not have a mammogram screening recommendation. They live longer than us.
Hippocrates said "life is short and the Art long and difficult." We need to do long detailed studies to prove what is best.
You said it. Wait for masses to get larger so it's obvious. When you notice symptoms, then treat the disease. Acknowledge that you are going to die of something, and it'll likely be either heart disease, cancer, or dementia - no amount of screening is going to change that inexorable fact. Stop trying to live forever and reconcile yourself to your mortality. Accept that you're going to die of something, and by not dying of infectious disease etc, you've increased your chances of dying of breast cancer. Make peace with your humanity. There's no need to desperately do something - you seem to believe that doing something is better than nothing - rather, what is needed to be done is in the spiritual or therapeutic realm, in helping people to adjust to their mortal condition and accept their death as a natural part of life. And yeah, my mother had a screening detected breast cancer she survived to die of dementia, (she'd have been better off dying from the cancer) and my stepmother died of a non screening detected breast cancer.
In addition to the problems you discuss, a fundamental problem with the breast cancer screening study is that it only analyzes those subjects who actually developed breast cancer, not the entire screened population. As I commented elsewhere (Doximity):
“The conclusion in the abstract states, “Annual mammographic screening was associated with lower risk of late-stage cancer and better OS across clinical and demographic subgroups. Our study suggests benefit of annual screening for women 40 years and older.”
This is misleading, since the study analyzes data only for the subset of women in the screening population who actually developed and were diagnosed with breast cancer during the study duration. One would need to analyze data from the entire screened population to draw any conclusions as to whether there is an overall statistically or clinically significant benefit to screening and if so how it compares to the risks and costs of overdiagnosis.
If such a poorly designed study were actually accepted for publication, the limited conclusion actually supported by the study data should be modified to read as follows:
“Conclusion
Among the subset of subjects who developed and were diagnosed with breast cancer annual mammographic screening was associated with lower risk of late-stage cancer and better OS across clinical and demographic subgroups. Our study suggests benefit of annual screening for those women 40 years and older who actually develop breast cancer but does not assess the benefit, if any, of screening all women 40 years and older.”
In my view, the study authors, peer reviewers, and journal editor(s) all share the responsibility for adding such a misleading study conclusion to the literature on this important and highly controversial topic.
Excellent piece. I need to learn more about the issue of lead time bias in observational studies of “screening”.
Agree that there will always be limitations with observational studies, and that RCT are required. You mentioned difficulties with doing RCT in breast cancer screening….what are the barriers? If there have not been RCT showing mammography to causally improve hard outcomes, then clinical equipoise must exist.
To wit, Nordicc (colonoscopy)and Dancavas (cardiac multimodality) fit that bill. Importantly, however, RCT of screening strategies need to analyze at the level of “invitation to screening” to be analogous to ITT. Both Nordicc (by some margin) and Dancavas (very barely) were negative for overall survival, but screening proponents have continued to argue for analysis of those “actually screened” which would be akin to an on-treatment analysis.
I think Strong HF is a great study. However, I agree it is NOT a study of GDMT per se, but rather one of care systems. If you worked in a system capable of providing 4 medical visits within 2 months of discharge from HF hospitalization (and another visit within 1 week of each Med titration)(avg number of visits in study =5), AND your pts look like theirs (avg age 63), then this is a fantastic treatment strategy to reduce subsequent HF hospitalizations. I don’t know about you, but I don’t work in such a system, and my typical pt is not 63. However, for younger pts, I have started to try more rapid uptitration of therapies on the basis of this study (although I find the guideline mantra that all HFrEF pts need to be on all 4 drugs to be idiotic, and I continue to apply the criteria from individual landmark studies for the respective agents).
2) This is not a case-cohort study. This is a specific retrospective study designed to address the hypothesis that excess cancers after mammography screening may be related to radiation.
Since we have no explanation for the failure of mammography screening to reduce breast cancer mortality and since mammography screening is ALWAYS associated with an excess of breast cancers, a single study (in the UK) where it is possible to analyze when these cancers occur is relevant. The fact that the same conclusion can be drawn from the effect of mammography screening in the USA and in France (Corcos & Bleyer, NEJM, 2020) removes all doubt on this subject. There have been NO studies since then to suggest that it could be otherwise.
Most pcp and obgyn quality metrics for reimbursement include documenting mammography. How do we back off when our “quality” of care and reimbursement are dependent on ordering these tests?
STRONG-HF:
- The major counterargument would be that it seems that it also lead to numerical mortality benefit
- The counter-counterargument, which is what is for me the major limitation, is THE INTERVENTION itself - initiation AND uptitration of GMDT (and not each one of them separately):
» At the end, we still don't know if it's either the initiation or uptitration that is leading the benefit. If one believes that the major net benefit seen with most of the drugs in medicine comes with the lower ranges of doses (pharmacology and the evidence supports it most of the times - see and/or read the work if James McCormack and its team), one has the be convinced of the opposite with strong arguments / data.
In this trial, GMDT was both initiated and uptitrated at the same time. Would the initiation in the lower dose be enough for the benefit seen without the harm seen with more adverse events? Maybe. And we can't know it with this trial.
To add to your good points about the mammography study:
Overdiagnosed cases will predominantly be early stages. These overdiagnosed cases will 'artificially' decrease the percentage of late stage cancers amongst those that are screened and are screened more often.
These results would be expected both in cases where breast screening was effectively detecting cancer earlier and improved prognosis AND with a scenario where breast cancer screening caused lots of overdiagnosis and where attending screening was more prominent amongst the well-off, healthier individuals (which it is). Thus, a lower percentage late stage cancers in screenees might as well indicate that screening causes harm (overdiagnosis).
The correct meassure in such studies is not 'percentages of late stage cancers' as this metric assumes there is no overdiagnosis. A slightly better meassure would be 'rates of late stage cancers', say stage 4 cases per 1,000. Even then, this study would be vulnerable to self-selection bias.
These types of studies do not bring our understanding of breast screening forward. They confirm some people in their beliefs and I think that is their main 'value'.
Neither article changed my mind either. I am also an avowed mammogram skeptic. I would go further and admit that I am a "preventive medicine" skeptic, but that is another entirely different topic. The marginal benefits claimed for regular mammograms have always seemed to be more than countered by the life disrupting effects of false positive findings. Unfortunately it is very difficult, if not impossible, to quantitate these negative side effects.. The wording in the conclusion to the abstract gives the game away by stating: "Annual mammographic screening was ASSOCIATED WITH lower rates of late stage cancer and BETTER OS across clinical and demographic subgroups (emphasis added)". This is advocacy, not science.
In addition to your excellent points regarding the mammogram study, there is also the natural experiment which is still running after over thirty years: among the many countries with high quality breast cancer screening programs, the US is the only one doing annual mammograms. Most other countries do screening mammograms every 2 years, a few are every 3 years. All countries have (thankfully) seen similar impressive reductions in breast cancer mortality. The US, despite its more frequent annual screening, has experienced the same, but not better, reduction in breast cancer mortality as other countries performing less frequent screening.
This is so perplexing when one is caring for a patient with a newly detected breast cancer. In that encounter, to the radiologist it really seems like an annual screening would have resulted in a better prognosis finding (emphasis on seems like). I have had that experience many times. But I have also always followed the epidemiology of breast cancer, and if annual mammography really improved breast cancer mortality as compared with less frequent screening, that should have shown up by now, given that it’s been over 30 years.
One thing I like about reading sensible medicine on a Sunday is it keeps my brain from atrophying with the Sunday blues. Funny, how only four years into retirement I still dread Mondays…
Mondays are bad no matter what surrounds them.
Love your thinking. But me, I look forward to Mondays and getting back to the office. Maybe it's my age-78. Or maybe it's having a 3 day weekend in my new job. Still love your thoughts.
Has there ever been an analysis of MRI in Breast Cancer and various intervals of need for repeat study relative to mammogram. More sensitive and more specificity? No radiation and no pain ? Perhaps there could be a longer interval between examinations ? Why do we not follow abnormal mammogram with ultrasound rather than MRI ? More sensitive and if US abnormal, will still go to MRI afterwards often ? All based on $$$ or science ? Only questions not postulations !
Respectfully
Gerald M Casey MD
There is plenty of research that shows that heart failure can be stopped and reversed with T3, triiodothyronine. And T4 can cause A fib. In fact, most a fib and hear failure may be iatrogenic anyway. I have found so many people suffering from it are only on T4, which is a huge medical travesty.
https://www.ahajournals.org/doi/full/10.1161/CIRCHEARTFAILURE.118.005266
More severe heart failure was associated with higher thyroid-stimulating hormone (TSH), higher free thyroxine (FT4), and lower total triiodothyronine (TT3) concentrations (P<0.001 all models). Atrial fibrillation was positively associated with higher levels of FT4 alone (P≤0.01 all models).
https://www.sciencedirect.com/science/article/abs/pii/S0002914997009508
Cardiac output increased with a reduction in systemic vascular resistance in patients receiving the largest dose, consistent with a peripheral vasodilatory effect. Acute intravenous administration of triiodothyronine is well tolerated in patients with advanced heart failure, establishing the basis for further investigation into the safety and potential hemodynamic benefits of longer infusions, combined infusion with inotropic agents, oral triiodothyronine replacement therapy, and new triiodothyronine analogs.
https://academic.oup.com/jcem/article/93/4/1351/2826632
short-term synthetic L-T3 replacement therapy significantly improved neuroendocrine profile and ventricular performance. These data encourage further controlled trials with more patients and longer periods of synthetic L-T3 administration.
I thought the T3 business had been debunked years ago. Oh, well, I guess it's hard to keep some ideas down.
Nice, something we agree on... "I’m an avowed mammogram skeptic."
Would have been nice to find out if the study asked if the participants did self exams.
Also do you ever suggest thermography?
About the STRONG-HF.
A very weak trial, my personal conclusion is the same as you did. The problem is that this trial is an argument to recommend intensive treatment over a step by step approach.
The issue is always scientific method. Making trials and collecting data is not investigation or science: putting brains reflecting, thinking and making a serious analysis of data with clinical argumentation is essential. The strong hf (if we follow a step by step analysis) doesn´t survive to the primary hypothesis.
The last week I made a challenge to the residents: "please, tell me if this situation is true: A and B drugs are well established in the treatment of certain condition called X, I make a trial with patients who are not doing well and randomized to drug C or placebo. The primary endpoint is met, and then I conclude: in ALL patients with the condition X we recommend A + B + C. Then I designed a trial with patients with the condition X who are not doing well with A + B + C and randomized them to drug D or placebo, the primary endpoint is met, then I conclude: to ALL patients with the condition X we must indicate drugs A +B + C + D. I made exactly the same process with drug E..."
We can replace the letters for real drugs such as beta blockers, IECA/ARNI, antialdosteronics, SLGT2 or even Omecamtiv Mecarbil...
SCIENTIFIC METHOD....since the ancient greeks to nowadays... 2.500 years...we learned nothing.
I don’t understand your statement disconnecting detection of early cancer from improving mortality. Even if it is a possibility.
And take away mammograms- what do we women do? 1 in 8 of which may face that diagnosis. Keep their fingers crossed? Wait for masses to get larger so it’s obvious? Europe doesn’t do annual screening right? Any data to compare there?
It’s easy to be critical of various studies but offer real life solutions please. RCTs take a loooong time. Disease doesn’t wait.
Lis,
It's pretty complex yet pretty simple. As Dr. Cifu points out it's not about finding cancer or finding cancer early. Does mammography prolong the patient's. A lot of very intelligent people believe it doesn't. Today's treatments (mostly non surgical adjuvants) are so good that finding breast cancer a year earlier offers no advantage.
As an international comparison, Switzerland does not have a mammogram screening recommendation. They live longer than us.
Hippocrates said "life is short and the Art long and difficult." We need to do long detailed studies to prove what is best.
You said it. Wait for masses to get larger so it's obvious. When you notice symptoms, then treat the disease. Acknowledge that you are going to die of something, and it'll likely be either heart disease, cancer, or dementia - no amount of screening is going to change that inexorable fact. Stop trying to live forever and reconcile yourself to your mortality. Accept that you're going to die of something, and by not dying of infectious disease etc, you've increased your chances of dying of breast cancer. Make peace with your humanity. There's no need to desperately do something - you seem to believe that doing something is better than nothing - rather, what is needed to be done is in the spiritual or therapeutic realm, in helping people to adjust to their mortal condition and accept their death as a natural part of life. And yeah, my mother had a screening detected breast cancer she survived to die of dementia, (she'd have been better off dying from the cancer) and my stepmother died of a non screening detected breast cancer.
And to the young mother who wants to live to raise her children you would say???
Yeah I think we are just a number here. Gotta die of something, maybe stroke when you're 80 or maybe breast cancer at 45, all the same amirite?
In addition to the problems you discuss, a fundamental problem with the breast cancer screening study is that it only analyzes those subjects who actually developed breast cancer, not the entire screened population. As I commented elsewhere (Doximity):
“The conclusion in the abstract states, “Annual mammographic screening was associated with lower risk of late-stage cancer and better OS across clinical and demographic subgroups. Our study suggests benefit of annual screening for women 40 years and older.”
This is misleading, since the study analyzes data only for the subset of women in the screening population who actually developed and were diagnosed with breast cancer during the study duration. One would need to analyze data from the entire screened population to draw any conclusions as to whether there is an overall statistically or clinically significant benefit to screening and if so how it compares to the risks and costs of overdiagnosis.
If such a poorly designed study were actually accepted for publication, the limited conclusion actually supported by the study data should be modified to read as follows:
“Conclusion
Among the subset of subjects who developed and were diagnosed with breast cancer annual mammographic screening was associated with lower risk of late-stage cancer and better OS across clinical and demographic subgroups. Our study suggests benefit of annual screening for those women 40 years and older who actually develop breast cancer but does not assess the benefit, if any, of screening all women 40 years and older.”
In my view, the study authors, peer reviewers, and journal editor(s) all share the responsibility for adding such a misleading study conclusion to the literature on this important and highly controversial topic.
The problem is that it is forbidden to talk about why mammography screening does not reduce breast cancer mortality. This is because it causes cancer. https://danielcorcos.substack.com/p/radiation-the-other-conspiracy-of
It's a big money maker
I agree with every word, comma, and period in your last paragraph.
Excellent piece. I need to learn more about the issue of lead time bias in observational studies of “screening”.
Agree that there will always be limitations with observational studies, and that RCT are required. You mentioned difficulties with doing RCT in breast cancer screening….what are the barriers? If there have not been RCT showing mammography to causally improve hard outcomes, then clinical equipoise must exist.
To wit, Nordicc (colonoscopy)and Dancavas (cardiac multimodality) fit that bill. Importantly, however, RCT of screening strategies need to analyze at the level of “invitation to screening” to be analogous to ITT. Both Nordicc (by some margin) and Dancavas (very barely) were negative for overall survival, but screening proponents have continued to argue for analysis of those “actually screened” which would be akin to an on-treatment analysis.
I think Strong HF is a great study. However, I agree it is NOT a study of GDMT per se, but rather one of care systems. If you worked in a system capable of providing 4 medical visits within 2 months of discharge from HF hospitalization (and another visit within 1 week of each Med titration)(avg number of visits in study =5), AND your pts look like theirs (avg age 63), then this is a fantastic treatment strategy to reduce subsequent HF hospitalizations. I don’t know about you, but I don’t work in such a system, and my typical pt is not 63. However, for younger pts, I have started to try more rapid uptitration of therapies on the basis of this study (although I find the guideline mantra that all HFrEF pts need to be on all 4 drugs to be idiotic, and I continue to apply the criteria from individual landmark studies for the respective agents).
"We so desperately need RCT data for our screening tests. "
Here, you have one:
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(85)92204-4/fulltext
Here's why it's best to detect early:
https://jamanetwork.com/journals/jamaoncology/fullarticle/2474438
And here's why mammography screening has not reduced breast cancer mortality.
https://www.biorxiv.org/content/10.1101/238527v1.full
But you are not allowed to talk about that.
Is a 1985 study of breast cancer screening relevant in 2024?
Is a case- cohort useful for anything but hypothesis forming?
1) Yes, since the benefit of early detection has not changed.
https://www.bmj.com/content/381/bmj-2022-074684.long
Fig 4- 7.
2) This is not a case-cohort study. This is a specific retrospective study designed to address the hypothesis that excess cancers after mammography screening may be related to radiation.
Since we have no explanation for the failure of mammography screening to reduce breast cancer mortality and since mammography screening is ALWAYS associated with an excess of breast cancers, a single study (in the UK) where it is possible to analyze when these cancers occur is relevant. The fact that the same conclusion can be drawn from the effect of mammography screening in the USA and in France (Corcos & Bleyer, NEJM, 2020) removes all doubt on this subject. There have been NO studies since then to suggest that it could be otherwise.
Pretty old stuff: RCT of mammograms in today’s world of better treatments needed
There is no reason to believe that better treatments have diminished the benefits of early detection (fig 4-7, https://www.bmj.com/content/381/bmj-2022-074684.long ).