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GIHN’s Crystal Anniversary: Reflecting on the future of GI
Our December 2022 issue marks the conclusion of GIHN’s 15th Anniversary Series. We hope you have enjoyed these special articles intended to celebrate the success of AGA’s official newspaper since its launch in 2007, mirroring equally rapid advances in our field. Over the past year, GIHN’s esteemed Associate Editors and former Editors-in-Chief have helped us “look back” on how the fields of gastroenterology and hepatology have changed since the newspaper’s inception, including advances in our understanding of the microbiome, innovations in endoscopic practice, changes in the demographics of the GI workforce, and breakthroughs in the treatment of hepatitis C. Now, as we conclude our 15th-anniversary year, it is only fitting that we “look forward” and consider the type of innovative coverage that will grace GIHN’s pages in the future. To that end, we asked a distinguished group of AGA thought leaders, representing various backgrounds and practice settings, to share their perspectives on what are likely to be the biggest change(s) in the field of GI over the next 15 years. We hope you find their answers inspiring as you consider your own reflections on this question.
As we close out 2022, we also wish to extend a big “thank you” to all the individuals who have provided thoughtful commentary to our coverage, helping us to understand the implications of innovative research findings on clinical practice and how changes in health policy impact our practices and our patients. I would also like to acknowledge our hardworking AGA and Frontline Medical Communications editorial teams, without whom this publication would not be possible. We wish you all a restful holiday season with your family and friends and look forward to reconnecting in 2023 – stay tuned for the launch of an exciting new GIHN initiative as part of our January issue!
Megan A. Adams, MD, JD, MSc
Editor-in-Chief
Our December 2022 issue marks the conclusion of GIHN’s 15th Anniversary Series. We hope you have enjoyed these special articles intended to celebrate the success of AGA’s official newspaper since its launch in 2007, mirroring equally rapid advances in our field. Over the past year, GIHN’s esteemed Associate Editors and former Editors-in-Chief have helped us “look back” on how the fields of gastroenterology and hepatology have changed since the newspaper’s inception, including advances in our understanding of the microbiome, innovations in endoscopic practice, changes in the demographics of the GI workforce, and breakthroughs in the treatment of hepatitis C. Now, as we conclude our 15th-anniversary year, it is only fitting that we “look forward” and consider the type of innovative coverage that will grace GIHN’s pages in the future. To that end, we asked a distinguished group of AGA thought leaders, representing various backgrounds and practice settings, to share their perspectives on what are likely to be the biggest change(s) in the field of GI over the next 15 years. We hope you find their answers inspiring as you consider your own reflections on this question.
As we close out 2022, we also wish to extend a big “thank you” to all the individuals who have provided thoughtful commentary to our coverage, helping us to understand the implications of innovative research findings on clinical practice and how changes in health policy impact our practices and our patients. I would also like to acknowledge our hardworking AGA and Frontline Medical Communications editorial teams, without whom this publication would not be possible. We wish you all a restful holiday season with your family and friends and look forward to reconnecting in 2023 – stay tuned for the launch of an exciting new GIHN initiative as part of our January issue!
Megan A. Adams, MD, JD, MSc
Editor-in-Chief
Our December 2022 issue marks the conclusion of GIHN’s 15th Anniversary Series. We hope you have enjoyed these special articles intended to celebrate the success of AGA’s official newspaper since its launch in 2007, mirroring equally rapid advances in our field. Over the past year, GIHN’s esteemed Associate Editors and former Editors-in-Chief have helped us “look back” on how the fields of gastroenterology and hepatology have changed since the newspaper’s inception, including advances in our understanding of the microbiome, innovations in endoscopic practice, changes in the demographics of the GI workforce, and breakthroughs in the treatment of hepatitis C. Now, as we conclude our 15th-anniversary year, it is only fitting that we “look forward” and consider the type of innovative coverage that will grace GIHN’s pages in the future. To that end, we asked a distinguished group of AGA thought leaders, representing various backgrounds and practice settings, to share their perspectives on what are likely to be the biggest change(s) in the field of GI over the next 15 years. We hope you find their answers inspiring as you consider your own reflections on this question.
As we close out 2022, we also wish to extend a big “thank you” to all the individuals who have provided thoughtful commentary to our coverage, helping us to understand the implications of innovative research findings on clinical practice and how changes in health policy impact our practices and our patients. I would also like to acknowledge our hardworking AGA and Frontline Medical Communications editorial teams, without whom this publication would not be possible. We wish you all a restful holiday season with your family and friends and look forward to reconnecting in 2023 – stay tuned for the launch of an exciting new GIHN initiative as part of our January issue!
Megan A. Adams, MD, JD, MSc
Editor-in-Chief
The surprising failure of vitamin D in deficient kids
Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr F. Perry Wilson of the Yale School of Medicine.
My basic gripe is that you’ve got all these observational studies linking lower levels of vitamin D to everything from dementia to falls to cancer to COVID infection, and then you do a big randomized trial of supplementation and don’t see an effect.
And the explanation is that vitamin D is not necessarily the thing causing these bad outcomes; it’s a bystander – a canary in the coal mine. Your vitamin D level is a marker of your lifestyle; it’s higher in people who eat healthier foods, who exercise, and who spend more time out in the sun.
And yet ... if you were to ask me whether supplementing vitamin D in children with vitamin D deficiency would help them grow better and be healthier, I probably would have been on board for the idea.
And, it looks like, I would have been wrong.
Yes, it’s another negative randomized trial of vitamin D supplementation to add to the seemingly ever-growing body of literature suggesting that your money is better spent on a day at the park rather than buying D3 from your local GNC.
We are talking about this study, appearing in JAMA Pediatrics.
Briefly, 8,851 children from around Ulaanbaatar, Mongolia, were randomized to receive 14,000 international units of vitamin D3 or placebo every week for 3 years.
Before we get into the results of the study, I need to point out that this part of Mongolia has a high rate of vitamin D deficiency. Beyond that, a prior observational study by these authors had shown that lower vitamin D levels were linked to the risk of acquiring latent tuberculosis infection in this area. Other studies have linked vitamin D deficiency with poorer growth metrics in children. Given the global scourge that is TB (around 2 million deaths a year) and childhood malnutrition (around 10% of children around the world), vitamin D supplementation is incredibly attractive as a public health intervention. It is relatively low on side effects and, importantly, it is cheap – and thus scalable.
Back to the study. These kids had pretty poor vitamin D levels at baseline; 95% of them were deficient, based on the accepted standard of levels less than 20 ng/mL. Over 30% were severely deficient, with levels less than 10 ng/mL.
The initial purpose of this study was to see if supplementation would prevent TB, but that analysis, which was published a few months ago, was negative. Vitamin D levels went up dramatically in the intervention group – they were taking their pills – but there was no difference in the rate of latent TB infection, active TB, other respiratory infections, or even serum interferon gamma levels.
Nothing.
But to be fair, the TB seroconversion rate was lower than expected, potentially leading to an underpowered study.
Which brings us to the just-published analysis which moves away from infectious disease to something where vitamin D should have some stronger footing: growth.
Would the kids who were randomized to vitamin D, those same kids who got their vitamin D levels into the normal range over 3 years of supplementation, grow more or grow better than the kids who didn’t?
And, unfortunately, the answer is still no.
At the end of follow-up, height z scores were not different between the groups. BMI z scores were not different between the groups. Pubertal development was not different between the groups. This was true not only overall, but across various subgroups, including analyses of those kids who had vitamin D levels less than 10 ng/mL to start with.
So, what’s going on? There are two very broad possibilities we can endorse. First, there’s the idea that vitamin D supplementation simply doesn’t do much for health. This is supported, now, by a long string of large clinical trials that show no effect across a variety of disease states and predisease states. In other words, the observational data linking low vitamin D to bad outcomes is correlation, not causation.
Or we can take the tack of some vitamin D apologists and decide that this trial just got it wrong. Perhaps the dose wasn’t given correctly, or 3 years isn’t long enough to see a real difference, or the growth metrics were wrong, or vitamin D needs to be given alongside something else to really work and so on. This is fine; no study is perfect and there is always something to criticize, believe me. But we need to be careful not to fall into the baby-and-bathwater fallacy. Just because we think a study could have done something better, or differently, doesn’t mean we can ignore all the results. And as each new randomized trial of vitamin D supplementation comes out, it’s getting harder and harder to believe that these trialists keep getting their methods wrong. Maybe they are just testing something that doesn’t work.
What to do? Well, it should be obvious. If low vitamin D levels are linked to TB rates and poor growth but supplementation doesn’t fix the problem, then we have to fix what is upstream of the problem. We need to boost vitamin D levels not through supplements, but through nutrition, exercise, activity, and getting outside. That’s a randomized trial you can sign me up for any day.
Dr. Wilson is associate professor, department of medicine, Yale University, New Haven, Conn. He reported no relevant conflicts of interest.
A version of this video transcript first appeared on Medscape.com.
Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr F. Perry Wilson of the Yale School of Medicine.
My basic gripe is that you’ve got all these observational studies linking lower levels of vitamin D to everything from dementia to falls to cancer to COVID infection, and then you do a big randomized trial of supplementation and don’t see an effect.
And the explanation is that vitamin D is not necessarily the thing causing these bad outcomes; it’s a bystander – a canary in the coal mine. Your vitamin D level is a marker of your lifestyle; it’s higher in people who eat healthier foods, who exercise, and who spend more time out in the sun.
And yet ... if you were to ask me whether supplementing vitamin D in children with vitamin D deficiency would help them grow better and be healthier, I probably would have been on board for the idea.
And, it looks like, I would have been wrong.
Yes, it’s another negative randomized trial of vitamin D supplementation to add to the seemingly ever-growing body of literature suggesting that your money is better spent on a day at the park rather than buying D3 from your local GNC.
We are talking about this study, appearing in JAMA Pediatrics.
Briefly, 8,851 children from around Ulaanbaatar, Mongolia, were randomized to receive 14,000 international units of vitamin D3 or placebo every week for 3 years.
Before we get into the results of the study, I need to point out that this part of Mongolia has a high rate of vitamin D deficiency. Beyond that, a prior observational study by these authors had shown that lower vitamin D levels were linked to the risk of acquiring latent tuberculosis infection in this area. Other studies have linked vitamin D deficiency with poorer growth metrics in children. Given the global scourge that is TB (around 2 million deaths a year) and childhood malnutrition (around 10% of children around the world), vitamin D supplementation is incredibly attractive as a public health intervention. It is relatively low on side effects and, importantly, it is cheap – and thus scalable.
Back to the study. These kids had pretty poor vitamin D levels at baseline; 95% of them were deficient, based on the accepted standard of levels less than 20 ng/mL. Over 30% were severely deficient, with levels less than 10 ng/mL.
The initial purpose of this study was to see if supplementation would prevent TB, but that analysis, which was published a few months ago, was negative. Vitamin D levels went up dramatically in the intervention group – they were taking their pills – but there was no difference in the rate of latent TB infection, active TB, other respiratory infections, or even serum interferon gamma levels.
Nothing.
But to be fair, the TB seroconversion rate was lower than expected, potentially leading to an underpowered study.
Which brings us to the just-published analysis which moves away from infectious disease to something where vitamin D should have some stronger footing: growth.
Would the kids who were randomized to vitamin D, those same kids who got their vitamin D levels into the normal range over 3 years of supplementation, grow more or grow better than the kids who didn’t?
And, unfortunately, the answer is still no.
At the end of follow-up, height z scores were not different between the groups. BMI z scores were not different between the groups. Pubertal development was not different between the groups. This was true not only overall, but across various subgroups, including analyses of those kids who had vitamin D levels less than 10 ng/mL to start with.
So, what’s going on? There are two very broad possibilities we can endorse. First, there’s the idea that vitamin D supplementation simply doesn’t do much for health. This is supported, now, by a long string of large clinical trials that show no effect across a variety of disease states and predisease states. In other words, the observational data linking low vitamin D to bad outcomes is correlation, not causation.
Or we can take the tack of some vitamin D apologists and decide that this trial just got it wrong. Perhaps the dose wasn’t given correctly, or 3 years isn’t long enough to see a real difference, or the growth metrics were wrong, or vitamin D needs to be given alongside something else to really work and so on. This is fine; no study is perfect and there is always something to criticize, believe me. But we need to be careful not to fall into the baby-and-bathwater fallacy. Just because we think a study could have done something better, or differently, doesn’t mean we can ignore all the results. And as each new randomized trial of vitamin D supplementation comes out, it’s getting harder and harder to believe that these trialists keep getting their methods wrong. Maybe they are just testing something that doesn’t work.
What to do? Well, it should be obvious. If low vitamin D levels are linked to TB rates and poor growth but supplementation doesn’t fix the problem, then we have to fix what is upstream of the problem. We need to boost vitamin D levels not through supplements, but through nutrition, exercise, activity, and getting outside. That’s a randomized trial you can sign me up for any day.
Dr. Wilson is associate professor, department of medicine, Yale University, New Haven, Conn. He reported no relevant conflicts of interest.
A version of this video transcript first appeared on Medscape.com.
Welcome to Impact Factor, your weekly dose of commentary on a new medical study. I’m Dr F. Perry Wilson of the Yale School of Medicine.
My basic gripe is that you’ve got all these observational studies linking lower levels of vitamin D to everything from dementia to falls to cancer to COVID infection, and then you do a big randomized trial of supplementation and don’t see an effect.
And the explanation is that vitamin D is not necessarily the thing causing these bad outcomes; it’s a bystander – a canary in the coal mine. Your vitamin D level is a marker of your lifestyle; it’s higher in people who eat healthier foods, who exercise, and who spend more time out in the sun.
And yet ... if you were to ask me whether supplementing vitamin D in children with vitamin D deficiency would help them grow better and be healthier, I probably would have been on board for the idea.
And, it looks like, I would have been wrong.
Yes, it’s another negative randomized trial of vitamin D supplementation to add to the seemingly ever-growing body of literature suggesting that your money is better spent on a day at the park rather than buying D3 from your local GNC.
We are talking about this study, appearing in JAMA Pediatrics.
Briefly, 8,851 children from around Ulaanbaatar, Mongolia, were randomized to receive 14,000 international units of vitamin D3 or placebo every week for 3 years.
Before we get into the results of the study, I need to point out that this part of Mongolia has a high rate of vitamin D deficiency. Beyond that, a prior observational study by these authors had shown that lower vitamin D levels were linked to the risk of acquiring latent tuberculosis infection in this area. Other studies have linked vitamin D deficiency with poorer growth metrics in children. Given the global scourge that is TB (around 2 million deaths a year) and childhood malnutrition (around 10% of children around the world), vitamin D supplementation is incredibly attractive as a public health intervention. It is relatively low on side effects and, importantly, it is cheap – and thus scalable.
Back to the study. These kids had pretty poor vitamin D levels at baseline; 95% of them were deficient, based on the accepted standard of levels less than 20 ng/mL. Over 30% were severely deficient, with levels less than 10 ng/mL.
The initial purpose of this study was to see if supplementation would prevent TB, but that analysis, which was published a few months ago, was negative. Vitamin D levels went up dramatically in the intervention group – they were taking their pills – but there was no difference in the rate of latent TB infection, active TB, other respiratory infections, or even serum interferon gamma levels.
Nothing.
But to be fair, the TB seroconversion rate was lower than expected, potentially leading to an underpowered study.
Which brings us to the just-published analysis which moves away from infectious disease to something where vitamin D should have some stronger footing: growth.
Would the kids who were randomized to vitamin D, those same kids who got their vitamin D levels into the normal range over 3 years of supplementation, grow more or grow better than the kids who didn’t?
And, unfortunately, the answer is still no.
At the end of follow-up, height z scores were not different between the groups. BMI z scores were not different between the groups. Pubertal development was not different between the groups. This was true not only overall, but across various subgroups, including analyses of those kids who had vitamin D levels less than 10 ng/mL to start with.
So, what’s going on? There are two very broad possibilities we can endorse. First, there’s the idea that vitamin D supplementation simply doesn’t do much for health. This is supported, now, by a long string of large clinical trials that show no effect across a variety of disease states and predisease states. In other words, the observational data linking low vitamin D to bad outcomes is correlation, not causation.
Or we can take the tack of some vitamin D apologists and decide that this trial just got it wrong. Perhaps the dose wasn’t given correctly, or 3 years isn’t long enough to see a real difference, or the growth metrics were wrong, or vitamin D needs to be given alongside something else to really work and so on. This is fine; no study is perfect and there is always something to criticize, believe me. But we need to be careful not to fall into the baby-and-bathwater fallacy. Just because we think a study could have done something better, or differently, doesn’t mean we can ignore all the results. And as each new randomized trial of vitamin D supplementation comes out, it’s getting harder and harder to believe that these trialists keep getting their methods wrong. Maybe they are just testing something that doesn’t work.
What to do? Well, it should be obvious. If low vitamin D levels are linked to TB rates and poor growth but supplementation doesn’t fix the problem, then we have to fix what is upstream of the problem. We need to boost vitamin D levels not through supplements, but through nutrition, exercise, activity, and getting outside. That’s a randomized trial you can sign me up for any day.
Dr. Wilson is associate professor, department of medicine, Yale University, New Haven, Conn. He reported no relevant conflicts of interest.
A version of this video transcript first appeared on Medscape.com.
New studies change beliefs about cardiovascular disease
This transcript has been edited for clarity.
I’m going to review a few of these.
The first is the TIME study. The TIME study looked at whether it matters if you give antihypertensive agents in the morning or the evening. This was a prospective, pragmatic, parallel-group study that was performed in the U.K. and published in The Lancet.
Their question was whether evening dosing of antihypertensives has benefit in cardiovascular outcomes in adults. They enrolled over 21,000 people with hypertension who were taking at least one antihypertensive medication. Patients were randomized to morning or evening dosing.
The primary outcome was death or hospitalization due to myocardial infarction or stroke. There was no difference. It doesn’t matter if you take your antihypertensive agent in the morning or the evening. I think this is important because, clinically, the simpler the regimen for the patient, the greater the adherence, leading to better outcomes.
I know I can safely ask a patient when they would rather take their medicine. For many people, that may be the morning because they’re brushing their teeth and they remember. If they want to take it in the evening, that’s fine, too. We’re no longer slave to telling a patient to take their antihypertensive medications in the evening.
At the meeting of the American Society of Nephrology, results from a study on the use of renin-angiotensin system (RAS) inhibitors in advanced CKD was presented, called the STOP ACEi trial. Again, another interesting trial asking a simple question. This was a randomized controlled trial (RCT) in patients who had an estimated glomerular filtration rate (eGFR) less than 30, and they were randomized to stop or continue therapy with their RAS inhibitors.
The primary outcome was the eGFR at 3 years. They enrolled 411 patients with a median baseline eGFR of 18. At 3 years, there was no difference in the eGFR between the groups. In the discontinuation group, the eGFR was 12.6 versus 13.3 in the continuation group. There were no differences in complications or anything else. Their conclusion was that among patients with advanced and progressive CKD, the discontinuation of a RAS inhibitor was not associated with a significant difference in the long-term rate of decrease in eGFR.
I think this is important because it changes our paradigm a bit. You can stop the RAS inhibitor; reduce the need for excessive medication in these patients; and, hopefully, focus on some newer medications that have been shown to prevent the decline in eGFR that are now available.
Next is from a letter published in JAMA, which asks the following question: Is diabetes itself an equivalent cardiovascular risk factor to those who have had a prior cardiovascular event?
We used to put having diabetes in that same high-risk category as people who’d already had a cardiovascular disease event. Well, have we made that any different? These authors are from Canada, and they did a retrospective population-based study looking at administrative health claims from Ontario, Canada, to assess the association of diabetes and prior cardiovascular disease with cardiovascular events from 1994 to 2014.
What I think is kind of cool, because I’m a diabetologist, is that over time the magnitude of the association between diabetes and cardiovascular event rates decreased. In somebody with diabetes, they don’t have the same high risk that a person who’s already had a cardiovascular event rate does. Diabetes is less of a risk factor for cardiovascular disease than having established cardiovascular disease, which means we’re treating diabetes better and reducing the risk for cardiovascular disease.
If you look at people with diabetes and a prior cardiovascular event, that’s still the very highest risk. The risk of people having another event who have established cardiovascular disease is pretty flat. Those people didn’t get better and the people with preexisting diabetes and cardiovascular events at baseline didn’t get much better, but those who had diabetes alone did improve in terms of looking at cardiovascular event rates.
I think this is good news because diabetes itself isn’t as high a cardiovascular risk factor as we once thought. It doesn’t mean that it isn’t a cardiovascular risk factor, but I think we’ve done better at mitigating the risk.
Finally, there is a relatively small study that was presented at the American Heart Association and published in the Journal of the American College of Cardiology, which asks whether supplements that are often used to lower LDL cholesterol are equivalent to a statin.
They compared six supplements with a placebo and with rosuvastatin, and looked to see what happened. This is not an outcome study, but a very short study, at 28 days, that used a placebo. They included 190 people with no history of cardiovascular disease but an increased 10-year risk for sclerotic cardiovascular disease.
The agents studied were rosuvastatin, placebo, fish oil, cinnamon, garlic, turmeric, plant sterols, and red yeast rice. Well, not surprisingly, rosuvastatin worked. It showed a 35% reduction in LDL cholesterol, and there was no significant impact on cholesterol levels with any of the other agents. The supplements yielded a similar response, as did the placebo. Side effects were similar, but they were most common with plant sterols and red yeast rice.
Clearly, a statin is better if you want to lower cholesterol levels. My approach, when patients want to take supplements, is to tell them what I know factually, which basically is that they don’t really cause much in the way of LDL cholesterol lowering. If I think the supplement isn’t going to hurt someone, I don’t tell them not to use it. I certainly tell them that they need to use agents that we know can actually reduce cardiovascular risk.
I think these studies really go through the gamut of asking questions. When can we stop an agent? What time of day do we need to give an agent? What, really, is the risk for type 2 diabetes with regard to cardiovascular events? What’s the value of supplements?
I think this is interesting, because I really encourage researchers to ask and answer these kinds of questions because it helps us clinically decide what’s best for treating our patients.
Thank you.
Dr. Peters is a professor of medicine at the University of Southern California, Los Angeles, and director of the USC clinical diabetes programs. She reported conflicts of interest with numerous pharmaceutical companies.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
I’m going to review a few of these.
The first is the TIME study. The TIME study looked at whether it matters if you give antihypertensive agents in the morning or the evening. This was a prospective, pragmatic, parallel-group study that was performed in the U.K. and published in The Lancet.
Their question was whether evening dosing of antihypertensives has benefit in cardiovascular outcomes in adults. They enrolled over 21,000 people with hypertension who were taking at least one antihypertensive medication. Patients were randomized to morning or evening dosing.
The primary outcome was death or hospitalization due to myocardial infarction or stroke. There was no difference. It doesn’t matter if you take your antihypertensive agent in the morning or the evening. I think this is important because, clinically, the simpler the regimen for the patient, the greater the adherence, leading to better outcomes.
I know I can safely ask a patient when they would rather take their medicine. For many people, that may be the morning because they’re brushing their teeth and they remember. If they want to take it in the evening, that’s fine, too. We’re no longer slave to telling a patient to take their antihypertensive medications in the evening.
At the meeting of the American Society of Nephrology, results from a study on the use of renin-angiotensin system (RAS) inhibitors in advanced CKD was presented, called the STOP ACEi trial. Again, another interesting trial asking a simple question. This was a randomized controlled trial (RCT) in patients who had an estimated glomerular filtration rate (eGFR) less than 30, and they were randomized to stop or continue therapy with their RAS inhibitors.
The primary outcome was the eGFR at 3 years. They enrolled 411 patients with a median baseline eGFR of 18. At 3 years, there was no difference in the eGFR between the groups. In the discontinuation group, the eGFR was 12.6 versus 13.3 in the continuation group. There were no differences in complications or anything else. Their conclusion was that among patients with advanced and progressive CKD, the discontinuation of a RAS inhibitor was not associated with a significant difference in the long-term rate of decrease in eGFR.
I think this is important because it changes our paradigm a bit. You can stop the RAS inhibitor; reduce the need for excessive medication in these patients; and, hopefully, focus on some newer medications that have been shown to prevent the decline in eGFR that are now available.
Next is from a letter published in JAMA, which asks the following question: Is diabetes itself an equivalent cardiovascular risk factor to those who have had a prior cardiovascular event?
We used to put having diabetes in that same high-risk category as people who’d already had a cardiovascular disease event. Well, have we made that any different? These authors are from Canada, and they did a retrospective population-based study looking at administrative health claims from Ontario, Canada, to assess the association of diabetes and prior cardiovascular disease with cardiovascular events from 1994 to 2014.
What I think is kind of cool, because I’m a diabetologist, is that over time the magnitude of the association between diabetes and cardiovascular event rates decreased. In somebody with diabetes, they don’t have the same high risk that a person who’s already had a cardiovascular event rate does. Diabetes is less of a risk factor for cardiovascular disease than having established cardiovascular disease, which means we’re treating diabetes better and reducing the risk for cardiovascular disease.
If you look at people with diabetes and a prior cardiovascular event, that’s still the very highest risk. The risk of people having another event who have established cardiovascular disease is pretty flat. Those people didn’t get better and the people with preexisting diabetes and cardiovascular events at baseline didn’t get much better, but those who had diabetes alone did improve in terms of looking at cardiovascular event rates.
I think this is good news because diabetes itself isn’t as high a cardiovascular risk factor as we once thought. It doesn’t mean that it isn’t a cardiovascular risk factor, but I think we’ve done better at mitigating the risk.
Finally, there is a relatively small study that was presented at the American Heart Association and published in the Journal of the American College of Cardiology, which asks whether supplements that are often used to lower LDL cholesterol are equivalent to a statin.
They compared six supplements with a placebo and with rosuvastatin, and looked to see what happened. This is not an outcome study, but a very short study, at 28 days, that used a placebo. They included 190 people with no history of cardiovascular disease but an increased 10-year risk for sclerotic cardiovascular disease.
The agents studied were rosuvastatin, placebo, fish oil, cinnamon, garlic, turmeric, plant sterols, and red yeast rice. Well, not surprisingly, rosuvastatin worked. It showed a 35% reduction in LDL cholesterol, and there was no significant impact on cholesterol levels with any of the other agents. The supplements yielded a similar response, as did the placebo. Side effects were similar, but they were most common with plant sterols and red yeast rice.
Clearly, a statin is better if you want to lower cholesterol levels. My approach, when patients want to take supplements, is to tell them what I know factually, which basically is that they don’t really cause much in the way of LDL cholesterol lowering. If I think the supplement isn’t going to hurt someone, I don’t tell them not to use it. I certainly tell them that they need to use agents that we know can actually reduce cardiovascular risk.
I think these studies really go through the gamut of asking questions. When can we stop an agent? What time of day do we need to give an agent? What, really, is the risk for type 2 diabetes with regard to cardiovascular events? What’s the value of supplements?
I think this is interesting, because I really encourage researchers to ask and answer these kinds of questions because it helps us clinically decide what’s best for treating our patients.
Thank you.
Dr. Peters is a professor of medicine at the University of Southern California, Los Angeles, and director of the USC clinical diabetes programs. She reported conflicts of interest with numerous pharmaceutical companies.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
I’m going to review a few of these.
The first is the TIME study. The TIME study looked at whether it matters if you give antihypertensive agents in the morning or the evening. This was a prospective, pragmatic, parallel-group study that was performed in the U.K. and published in The Lancet.
Their question was whether evening dosing of antihypertensives has benefit in cardiovascular outcomes in adults. They enrolled over 21,000 people with hypertension who were taking at least one antihypertensive medication. Patients were randomized to morning or evening dosing.
The primary outcome was death or hospitalization due to myocardial infarction or stroke. There was no difference. It doesn’t matter if you take your antihypertensive agent in the morning or the evening. I think this is important because, clinically, the simpler the regimen for the patient, the greater the adherence, leading to better outcomes.
I know I can safely ask a patient when they would rather take their medicine. For many people, that may be the morning because they’re brushing their teeth and they remember. If they want to take it in the evening, that’s fine, too. We’re no longer slave to telling a patient to take their antihypertensive medications in the evening.
At the meeting of the American Society of Nephrology, results from a study on the use of renin-angiotensin system (RAS) inhibitors in advanced CKD was presented, called the STOP ACEi trial. Again, another interesting trial asking a simple question. This was a randomized controlled trial (RCT) in patients who had an estimated glomerular filtration rate (eGFR) less than 30, and they were randomized to stop or continue therapy with their RAS inhibitors.
The primary outcome was the eGFR at 3 years. They enrolled 411 patients with a median baseline eGFR of 18. At 3 years, there was no difference in the eGFR between the groups. In the discontinuation group, the eGFR was 12.6 versus 13.3 in the continuation group. There were no differences in complications or anything else. Their conclusion was that among patients with advanced and progressive CKD, the discontinuation of a RAS inhibitor was not associated with a significant difference in the long-term rate of decrease in eGFR.
I think this is important because it changes our paradigm a bit. You can stop the RAS inhibitor; reduce the need for excessive medication in these patients; and, hopefully, focus on some newer medications that have been shown to prevent the decline in eGFR that are now available.
Next is from a letter published in JAMA, which asks the following question: Is diabetes itself an equivalent cardiovascular risk factor to those who have had a prior cardiovascular event?
We used to put having diabetes in that same high-risk category as people who’d already had a cardiovascular disease event. Well, have we made that any different? These authors are from Canada, and they did a retrospective population-based study looking at administrative health claims from Ontario, Canada, to assess the association of diabetes and prior cardiovascular disease with cardiovascular events from 1994 to 2014.
What I think is kind of cool, because I’m a diabetologist, is that over time the magnitude of the association between diabetes and cardiovascular event rates decreased. In somebody with diabetes, they don’t have the same high risk that a person who’s already had a cardiovascular event rate does. Diabetes is less of a risk factor for cardiovascular disease than having established cardiovascular disease, which means we’re treating diabetes better and reducing the risk for cardiovascular disease.
If you look at people with diabetes and a prior cardiovascular event, that’s still the very highest risk. The risk of people having another event who have established cardiovascular disease is pretty flat. Those people didn’t get better and the people with preexisting diabetes and cardiovascular events at baseline didn’t get much better, but those who had diabetes alone did improve in terms of looking at cardiovascular event rates.
I think this is good news because diabetes itself isn’t as high a cardiovascular risk factor as we once thought. It doesn’t mean that it isn’t a cardiovascular risk factor, but I think we’ve done better at mitigating the risk.
Finally, there is a relatively small study that was presented at the American Heart Association and published in the Journal of the American College of Cardiology, which asks whether supplements that are often used to lower LDL cholesterol are equivalent to a statin.
They compared six supplements with a placebo and with rosuvastatin, and looked to see what happened. This is not an outcome study, but a very short study, at 28 days, that used a placebo. They included 190 people with no history of cardiovascular disease but an increased 10-year risk for sclerotic cardiovascular disease.
The agents studied were rosuvastatin, placebo, fish oil, cinnamon, garlic, turmeric, plant sterols, and red yeast rice. Well, not surprisingly, rosuvastatin worked. It showed a 35% reduction in LDL cholesterol, and there was no significant impact on cholesterol levels with any of the other agents. The supplements yielded a similar response, as did the placebo. Side effects were similar, but they were most common with plant sterols and red yeast rice.
Clearly, a statin is better if you want to lower cholesterol levels. My approach, when patients want to take supplements, is to tell them what I know factually, which basically is that they don’t really cause much in the way of LDL cholesterol lowering. If I think the supplement isn’t going to hurt someone, I don’t tell them not to use it. I certainly tell them that they need to use agents that we know can actually reduce cardiovascular risk.
I think these studies really go through the gamut of asking questions. When can we stop an agent? What time of day do we need to give an agent? What, really, is the risk for type 2 diabetes with regard to cardiovascular events? What’s the value of supplements?
I think this is interesting, because I really encourage researchers to ask and answer these kinds of questions because it helps us clinically decide what’s best for treating our patients.
Thank you.
Dr. Peters is a professor of medicine at the University of Southern California, Los Angeles, and director of the USC clinical diabetes programs. She reported conflicts of interest with numerous pharmaceutical companies.
A version of this article first appeared on Medscape.com.
Jump starting thankfulness
One night, at the beginning of Thanksgiving week, my son called from his place across town. His car was having trouble starting, so I went to see what was up.
I got to his place to find his car wouldn’t start, even though the battery was only a few months old. I used my car to jump his, left him mine, and headed back. My plan was to leave it at our usual repair place and walk home.
Easier said than done.
I’d just gotten on the 101, the main loop freeway for the Phoenix metro area, when his car completely died. The lights flickered, the gauges stopped working, and then the engine cut out. Mercifully I was able to pull over into the right emergency lane as it did so. I was nowhere near an exit.
Not even the emergency flashers worked. It was dark. I was on a major freeway. I couldn’t make myself visible. Cars and trucks were whizzing by 2-3 feet to my left, and I was hoping they’d see me.
I called AAA and explained the situation. They were sending a tow truck, but it could take up to another 3 hours. I sent some quick texts to family to let them know what was up. I called the AZ highway patrol to let them know my predicament, in case they wanted to come put a flare or two behind me (they didn’t).
And then I settled in. Seatbelt on, staring at the road in front of me ... and had nothing to do.
When was the last time you had absolutely nothing to do?
It’s pretty rare these days. I mean, we all have breaks in the action, so we watch a cute animal video, or play a round of Wordle, or whatever.
But I had none of that. No books, iPad, or computer. Sure, I had my phone, but it was less than 50% charged with no way to charge it, and so I wanted to conserve that in case I needed it.
I don’t think I’ve ever had a moment like this since I began carrying a phone in 1998. There was, literally, nothing to do but wait. I couldn’t even try to nod off with the seat unadjustable and cars whizzing by.
So my mind wandered, and I thought. I turned over office cases. I went through year-end finances. I thought about my current predicament. I stared endlessly at the road ahead and cars passing me.
At some point I began to realize that I’m actually pretty lucky, and that nothing was nearly as bad as it had seemed earlier in the day. As the initial adrenaline rush drained out of me I calmed down and the things I’d been worrying about that afternoon seemed workable.
The tow truck pulled in front of me, ending my reverie. Mercifully, it had only taken them an hour. I was home 45 minutes later.
I was thankful to be home and I was thankful that nothing more serious had happened in a potentially bad situation.
And, somewhere in there,
In today’s world of endless screens and texts and calls and notifications, it’s easy to lose track of that.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
One night, at the beginning of Thanksgiving week, my son called from his place across town. His car was having trouble starting, so I went to see what was up.
I got to his place to find his car wouldn’t start, even though the battery was only a few months old. I used my car to jump his, left him mine, and headed back. My plan was to leave it at our usual repair place and walk home.
Easier said than done.
I’d just gotten on the 101, the main loop freeway for the Phoenix metro area, when his car completely died. The lights flickered, the gauges stopped working, and then the engine cut out. Mercifully I was able to pull over into the right emergency lane as it did so. I was nowhere near an exit.
Not even the emergency flashers worked. It was dark. I was on a major freeway. I couldn’t make myself visible. Cars and trucks were whizzing by 2-3 feet to my left, and I was hoping they’d see me.
I called AAA and explained the situation. They were sending a tow truck, but it could take up to another 3 hours. I sent some quick texts to family to let them know what was up. I called the AZ highway patrol to let them know my predicament, in case they wanted to come put a flare or two behind me (they didn’t).
And then I settled in. Seatbelt on, staring at the road in front of me ... and had nothing to do.
When was the last time you had absolutely nothing to do?
It’s pretty rare these days. I mean, we all have breaks in the action, so we watch a cute animal video, or play a round of Wordle, or whatever.
But I had none of that. No books, iPad, or computer. Sure, I had my phone, but it was less than 50% charged with no way to charge it, and so I wanted to conserve that in case I needed it.
I don’t think I’ve ever had a moment like this since I began carrying a phone in 1998. There was, literally, nothing to do but wait. I couldn’t even try to nod off with the seat unadjustable and cars whizzing by.
So my mind wandered, and I thought. I turned over office cases. I went through year-end finances. I thought about my current predicament. I stared endlessly at the road ahead and cars passing me.
At some point I began to realize that I’m actually pretty lucky, and that nothing was nearly as bad as it had seemed earlier in the day. As the initial adrenaline rush drained out of me I calmed down and the things I’d been worrying about that afternoon seemed workable.
The tow truck pulled in front of me, ending my reverie. Mercifully, it had only taken them an hour. I was home 45 minutes later.
I was thankful to be home and I was thankful that nothing more serious had happened in a potentially bad situation.
And, somewhere in there,
In today’s world of endless screens and texts and calls and notifications, it’s easy to lose track of that.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
One night, at the beginning of Thanksgiving week, my son called from his place across town. His car was having trouble starting, so I went to see what was up.
I got to his place to find his car wouldn’t start, even though the battery was only a few months old. I used my car to jump his, left him mine, and headed back. My plan was to leave it at our usual repair place and walk home.
Easier said than done.
I’d just gotten on the 101, the main loop freeway for the Phoenix metro area, when his car completely died. The lights flickered, the gauges stopped working, and then the engine cut out. Mercifully I was able to pull over into the right emergency lane as it did so. I was nowhere near an exit.
Not even the emergency flashers worked. It was dark. I was on a major freeway. I couldn’t make myself visible. Cars and trucks were whizzing by 2-3 feet to my left, and I was hoping they’d see me.
I called AAA and explained the situation. They were sending a tow truck, but it could take up to another 3 hours. I sent some quick texts to family to let them know what was up. I called the AZ highway patrol to let them know my predicament, in case they wanted to come put a flare or two behind me (they didn’t).
And then I settled in. Seatbelt on, staring at the road in front of me ... and had nothing to do.
When was the last time you had absolutely nothing to do?
It’s pretty rare these days. I mean, we all have breaks in the action, so we watch a cute animal video, or play a round of Wordle, or whatever.
But I had none of that. No books, iPad, or computer. Sure, I had my phone, but it was less than 50% charged with no way to charge it, and so I wanted to conserve that in case I needed it.
I don’t think I’ve ever had a moment like this since I began carrying a phone in 1998. There was, literally, nothing to do but wait. I couldn’t even try to nod off with the seat unadjustable and cars whizzing by.
So my mind wandered, and I thought. I turned over office cases. I went through year-end finances. I thought about my current predicament. I stared endlessly at the road ahead and cars passing me.
At some point I began to realize that I’m actually pretty lucky, and that nothing was nearly as bad as it had seemed earlier in the day. As the initial adrenaline rush drained out of me I calmed down and the things I’d been worrying about that afternoon seemed workable.
The tow truck pulled in front of me, ending my reverie. Mercifully, it had only taken them an hour. I was home 45 minutes later.
I was thankful to be home and I was thankful that nothing more serious had happened in a potentially bad situation.
And, somewhere in there,
In today’s world of endless screens and texts and calls and notifications, it’s easy to lose track of that.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Discontinuing immunotherapy: Is the infusion bag half empty or half full?
It’s a “champagne problem” many of us have encountered over the past few years in the clinic.
A patient with advanced non–small cell lung cancer (NSCLC) is fortunate enough to continue to do well for 2 years on ongoing pembrolizumab or perhaps pemetrexed and pembrolizumab as maintenance therapy. The latest CT shows a residual but far smaller primary tumor than what she started with.
In this instance, you may be considering stopping treatment but are concerned about doing so with evidence of disease still present.
Clinical trials of immunotherapy or chemoimmunotherapy have generally terminated treatment in nonprogressing patients after 2 years. We also know that some patients in early trials of immunotherapy stopped treatment after a fixed period of 1 or 2 years and continued to show no evidence of progression many years later.
The reason some patients experience this kind of success: Unlike the mechanism of action of conventional chemotherapy or targeted therapies, where ongoing treatment would be important to continue to exert an inhibitory effect, the active substrate of immunotherapy is the patient’s immune system, which can potentially have a self-sustaining efficacy beyond the stimulatory effect of the checkpoint inhibitor.
One trial directly addressed this question of stopping vs. continuing treatment in patients on immunotherapy. The CheckMate 153 trial, published in 2020, randomly assigned 252 previously treated patients who hadn’t demonstrated progression after 1 year on nivolumab to either discontinue nivolumab or continue nivolumab on an ongoing basis. The results were strongly in favor of ongoing therapy. Both progression-free survival (PFS) and overall survival (OS) were significantly longer in patients who continued therapy: PFS of 24.7 months vs. 9.4 months and OS not reached vs. 32.5 months.
This finding is important, but there’s an important caveat. The study population included many heavily pretreated patients, but, in practice, immunotherapy has generally moved into the first-line setting, where we see dramatic responses in a significant subset of patients.
Even more recent data are emerging that may help us evaluate who will do well off therapy and who should continue treatment.
We now have a growing collection of long-term data on patients who are more likely to have good outcomes with immunotherapy, specifically those with high tumor programmed death-ligand 1 (PD-L1) expression (≥ 50%), from the KEYNOTE-024 trial. In this study, 39 of 151 (25.8%) patients assigned to pembrolizumab completed the planned maximum of 2 years of treatment, among whom 82.1% achieved an objective response; but, only 10% (4 patients) achieved a complete response. The proportion of patients without progression and remaining off therapy wasn’t reported, but the OS rate 3 years after completing treatment was 81.4%.
In addition, restarting immunotherapy after discontinuing appears to be a moderately effective strategy. In the KEYNOTE-024 trial, 12 patients received a second course of pembrolizumab because of disease progression a median of 15.2 months after discontinuing pembrolizumab. In this small cohort, eight of these patients (66.7%) were alive at the data cutoff, and six (50%) achieved stable disease.
Recently, we received additional insight in the follow-up from two chemoimmunotherapy trials that have most shaped my practice for patients with advanced NSCLC and any level of PD-L1 expression. These are the KEYNOTE-189 trial of platinum-pemetrexed with pembrolizumab vs. placebo in those with nonsquamous NSCLC, and the KEYNOTE-407 trial of carboplatin-taxane with pembrolizumab vs. placebo in patients with advanced squamous NSCLC. The National Comprehensive Cancer Network has designated each as a “preferred regimen” for patients with advanced NSCLC.
Both regimens have demonstrated sustained efficacy benefits with prolonged follow-up, including significantly superior objective response rate, PFS, and OS with the addition of pembrolizumab. These findings merely cemented the role of these regimens in our practice, but the trials also reported on the cohort of patients who completed 35 cycles of treatment over 2 years then discontinued therapy. In both, the majority of patients showed an objective response (86% in KEYNOTE-189 and 90% in KEYNOTE-407), with most patients alive at 3 years after 2 years of treatment (71.9% in KEYNOTE-189 and 69.5% in KEYNOTE-407). In addition, the proportion of patients alive without disease progression or subsequent therapy was notable – 40.4% in KEYNOTE-189 and 43.6% KEYNOTE-407.
How should we interpret these data for the patient who is in the exam room with us?
The short answer is that we don’t know. I see this as a half-empty, half-full conundrum.
I’m disappointed that more patients who responded for 2 years will experience disease progression in the 1-3 years that follow. This signals that their immune systems have not perpetuated their initial response over the long-term. But these patients may have demonstrated disease progression even if they had continued therapy.
We also know that some patients can be rechallenged and will respond again. Some of these patients will show stable disease, whereas others will progress with repeat treatment. I would love to be able to better predict which patients are destined to do well without treatment vs. those who benefit from treatment beyond 2 years.
Might the level of PD-L1 expression tell us? Can PET imaging discriminate those with residual hypermetabolism who may need continued treatment from those with no residual uptake who could be spared it? Would serial measurement of circulating tumor DNA (ctDNA) in responding patients identify when they have achieved a point of diminishing returns, potentially indicating that some can safely discontinue treatment after 2 years, whereas others need to continue to suppress on prolonged maintenance therapy?
These questions have yet to be studied systematically. In the meantime, I take an individualized approach with my patients facing this decision. Some have experienced escalating arthralgias and myalgias, cost concerns, or other issues related to immunotherapy that may dissuade us from continuing treatment. But several others have been grateful to continue with their treatment, hesitant to do anything that could change the path of their disease.
In my patients who tolerate therapy well, I’m more worried about potential undertreatment than overtreatment. I tend to favor having my patients continue therapy in the absence of problematic toxicity or practical challenges. There is certainly room for debate here while we await data to better guide these decisions. How do you approach these patients?
Dr. West is Clinical Associate Professor, Department of Medical Oncology, City of Hope Comprehensive Cancer Care, Duarte, Calif. He reported conflicts of interest with Ariad/Takeda, Bristol-Myers Squibb, Boehringer Ingelheim, Spectrum, AstraZeneca, Celgene, Genentech/Roche, Pfizer, Merck, and Eli Lilly.
A version of this article first appeared on Medscape.com.
It’s a “champagne problem” many of us have encountered over the past few years in the clinic.
A patient with advanced non–small cell lung cancer (NSCLC) is fortunate enough to continue to do well for 2 years on ongoing pembrolizumab or perhaps pemetrexed and pembrolizumab as maintenance therapy. The latest CT shows a residual but far smaller primary tumor than what she started with.
In this instance, you may be considering stopping treatment but are concerned about doing so with evidence of disease still present.
Clinical trials of immunotherapy or chemoimmunotherapy have generally terminated treatment in nonprogressing patients after 2 years. We also know that some patients in early trials of immunotherapy stopped treatment after a fixed period of 1 or 2 years and continued to show no evidence of progression many years later.
The reason some patients experience this kind of success: Unlike the mechanism of action of conventional chemotherapy or targeted therapies, where ongoing treatment would be important to continue to exert an inhibitory effect, the active substrate of immunotherapy is the patient’s immune system, which can potentially have a self-sustaining efficacy beyond the stimulatory effect of the checkpoint inhibitor.
One trial directly addressed this question of stopping vs. continuing treatment in patients on immunotherapy. The CheckMate 153 trial, published in 2020, randomly assigned 252 previously treated patients who hadn’t demonstrated progression after 1 year on nivolumab to either discontinue nivolumab or continue nivolumab on an ongoing basis. The results were strongly in favor of ongoing therapy. Both progression-free survival (PFS) and overall survival (OS) were significantly longer in patients who continued therapy: PFS of 24.7 months vs. 9.4 months and OS not reached vs. 32.5 months.
This finding is important, but there’s an important caveat. The study population included many heavily pretreated patients, but, in practice, immunotherapy has generally moved into the first-line setting, where we see dramatic responses in a significant subset of patients.
Even more recent data are emerging that may help us evaluate who will do well off therapy and who should continue treatment.
We now have a growing collection of long-term data on patients who are more likely to have good outcomes with immunotherapy, specifically those with high tumor programmed death-ligand 1 (PD-L1) expression (≥ 50%), from the KEYNOTE-024 trial. In this study, 39 of 151 (25.8%) patients assigned to pembrolizumab completed the planned maximum of 2 years of treatment, among whom 82.1% achieved an objective response; but, only 10% (4 patients) achieved a complete response. The proportion of patients without progression and remaining off therapy wasn’t reported, but the OS rate 3 years after completing treatment was 81.4%.
In addition, restarting immunotherapy after discontinuing appears to be a moderately effective strategy. In the KEYNOTE-024 trial, 12 patients received a second course of pembrolizumab because of disease progression a median of 15.2 months after discontinuing pembrolizumab. In this small cohort, eight of these patients (66.7%) were alive at the data cutoff, and six (50%) achieved stable disease.
Recently, we received additional insight in the follow-up from two chemoimmunotherapy trials that have most shaped my practice for patients with advanced NSCLC and any level of PD-L1 expression. These are the KEYNOTE-189 trial of platinum-pemetrexed with pembrolizumab vs. placebo in those with nonsquamous NSCLC, and the KEYNOTE-407 trial of carboplatin-taxane with pembrolizumab vs. placebo in patients with advanced squamous NSCLC. The National Comprehensive Cancer Network has designated each as a “preferred regimen” for patients with advanced NSCLC.
Both regimens have demonstrated sustained efficacy benefits with prolonged follow-up, including significantly superior objective response rate, PFS, and OS with the addition of pembrolizumab. These findings merely cemented the role of these regimens in our practice, but the trials also reported on the cohort of patients who completed 35 cycles of treatment over 2 years then discontinued therapy. In both, the majority of patients showed an objective response (86% in KEYNOTE-189 and 90% in KEYNOTE-407), with most patients alive at 3 years after 2 years of treatment (71.9% in KEYNOTE-189 and 69.5% in KEYNOTE-407). In addition, the proportion of patients alive without disease progression or subsequent therapy was notable – 40.4% in KEYNOTE-189 and 43.6% KEYNOTE-407.
How should we interpret these data for the patient who is in the exam room with us?
The short answer is that we don’t know. I see this as a half-empty, half-full conundrum.
I’m disappointed that more patients who responded for 2 years will experience disease progression in the 1-3 years that follow. This signals that their immune systems have not perpetuated their initial response over the long-term. But these patients may have demonstrated disease progression even if they had continued therapy.
We also know that some patients can be rechallenged and will respond again. Some of these patients will show stable disease, whereas others will progress with repeat treatment. I would love to be able to better predict which patients are destined to do well without treatment vs. those who benefit from treatment beyond 2 years.
Might the level of PD-L1 expression tell us? Can PET imaging discriminate those with residual hypermetabolism who may need continued treatment from those with no residual uptake who could be spared it? Would serial measurement of circulating tumor DNA (ctDNA) in responding patients identify when they have achieved a point of diminishing returns, potentially indicating that some can safely discontinue treatment after 2 years, whereas others need to continue to suppress on prolonged maintenance therapy?
These questions have yet to be studied systematically. In the meantime, I take an individualized approach with my patients facing this decision. Some have experienced escalating arthralgias and myalgias, cost concerns, or other issues related to immunotherapy that may dissuade us from continuing treatment. But several others have been grateful to continue with their treatment, hesitant to do anything that could change the path of their disease.
In my patients who tolerate therapy well, I’m more worried about potential undertreatment than overtreatment. I tend to favor having my patients continue therapy in the absence of problematic toxicity or practical challenges. There is certainly room for debate here while we await data to better guide these decisions. How do you approach these patients?
Dr. West is Clinical Associate Professor, Department of Medical Oncology, City of Hope Comprehensive Cancer Care, Duarte, Calif. He reported conflicts of interest with Ariad/Takeda, Bristol-Myers Squibb, Boehringer Ingelheim, Spectrum, AstraZeneca, Celgene, Genentech/Roche, Pfizer, Merck, and Eli Lilly.
A version of this article first appeared on Medscape.com.
It’s a “champagne problem” many of us have encountered over the past few years in the clinic.
A patient with advanced non–small cell lung cancer (NSCLC) is fortunate enough to continue to do well for 2 years on ongoing pembrolizumab or perhaps pemetrexed and pembrolizumab as maintenance therapy. The latest CT shows a residual but far smaller primary tumor than what she started with.
In this instance, you may be considering stopping treatment but are concerned about doing so with evidence of disease still present.
Clinical trials of immunotherapy or chemoimmunotherapy have generally terminated treatment in nonprogressing patients after 2 years. We also know that some patients in early trials of immunotherapy stopped treatment after a fixed period of 1 or 2 years and continued to show no evidence of progression many years later.
The reason some patients experience this kind of success: Unlike the mechanism of action of conventional chemotherapy or targeted therapies, where ongoing treatment would be important to continue to exert an inhibitory effect, the active substrate of immunotherapy is the patient’s immune system, which can potentially have a self-sustaining efficacy beyond the stimulatory effect of the checkpoint inhibitor.
One trial directly addressed this question of stopping vs. continuing treatment in patients on immunotherapy. The CheckMate 153 trial, published in 2020, randomly assigned 252 previously treated patients who hadn’t demonstrated progression after 1 year on nivolumab to either discontinue nivolumab or continue nivolumab on an ongoing basis. The results were strongly in favor of ongoing therapy. Both progression-free survival (PFS) and overall survival (OS) were significantly longer in patients who continued therapy: PFS of 24.7 months vs. 9.4 months and OS not reached vs. 32.5 months.
This finding is important, but there’s an important caveat. The study population included many heavily pretreated patients, but, in practice, immunotherapy has generally moved into the first-line setting, where we see dramatic responses in a significant subset of patients.
Even more recent data are emerging that may help us evaluate who will do well off therapy and who should continue treatment.
We now have a growing collection of long-term data on patients who are more likely to have good outcomes with immunotherapy, specifically those with high tumor programmed death-ligand 1 (PD-L1) expression (≥ 50%), from the KEYNOTE-024 trial. In this study, 39 of 151 (25.8%) patients assigned to pembrolizumab completed the planned maximum of 2 years of treatment, among whom 82.1% achieved an objective response; but, only 10% (4 patients) achieved a complete response. The proportion of patients without progression and remaining off therapy wasn’t reported, but the OS rate 3 years after completing treatment was 81.4%.
In addition, restarting immunotherapy after discontinuing appears to be a moderately effective strategy. In the KEYNOTE-024 trial, 12 patients received a second course of pembrolizumab because of disease progression a median of 15.2 months after discontinuing pembrolizumab. In this small cohort, eight of these patients (66.7%) were alive at the data cutoff, and six (50%) achieved stable disease.
Recently, we received additional insight in the follow-up from two chemoimmunotherapy trials that have most shaped my practice for patients with advanced NSCLC and any level of PD-L1 expression. These are the KEYNOTE-189 trial of platinum-pemetrexed with pembrolizumab vs. placebo in those with nonsquamous NSCLC, and the KEYNOTE-407 trial of carboplatin-taxane with pembrolizumab vs. placebo in patients with advanced squamous NSCLC. The National Comprehensive Cancer Network has designated each as a “preferred regimen” for patients with advanced NSCLC.
Both regimens have demonstrated sustained efficacy benefits with prolonged follow-up, including significantly superior objective response rate, PFS, and OS with the addition of pembrolizumab. These findings merely cemented the role of these regimens in our practice, but the trials also reported on the cohort of patients who completed 35 cycles of treatment over 2 years then discontinued therapy. In both, the majority of patients showed an objective response (86% in KEYNOTE-189 and 90% in KEYNOTE-407), with most patients alive at 3 years after 2 years of treatment (71.9% in KEYNOTE-189 and 69.5% in KEYNOTE-407). In addition, the proportion of patients alive without disease progression or subsequent therapy was notable – 40.4% in KEYNOTE-189 and 43.6% KEYNOTE-407.
How should we interpret these data for the patient who is in the exam room with us?
The short answer is that we don’t know. I see this as a half-empty, half-full conundrum.
I’m disappointed that more patients who responded for 2 years will experience disease progression in the 1-3 years that follow. This signals that their immune systems have not perpetuated their initial response over the long-term. But these patients may have demonstrated disease progression even if they had continued therapy.
We also know that some patients can be rechallenged and will respond again. Some of these patients will show stable disease, whereas others will progress with repeat treatment. I would love to be able to better predict which patients are destined to do well without treatment vs. those who benefit from treatment beyond 2 years.
Might the level of PD-L1 expression tell us? Can PET imaging discriminate those with residual hypermetabolism who may need continued treatment from those with no residual uptake who could be spared it? Would serial measurement of circulating tumor DNA (ctDNA) in responding patients identify when they have achieved a point of diminishing returns, potentially indicating that some can safely discontinue treatment after 2 years, whereas others need to continue to suppress on prolonged maintenance therapy?
These questions have yet to be studied systematically. In the meantime, I take an individualized approach with my patients facing this decision. Some have experienced escalating arthralgias and myalgias, cost concerns, or other issues related to immunotherapy that may dissuade us from continuing treatment. But several others have been grateful to continue with their treatment, hesitant to do anything that could change the path of their disease.
In my patients who tolerate therapy well, I’m more worried about potential undertreatment than overtreatment. I tend to favor having my patients continue therapy in the absence of problematic toxicity or practical challenges. There is certainly room for debate here while we await data to better guide these decisions. How do you approach these patients?
Dr. West is Clinical Associate Professor, Department of Medical Oncology, City of Hope Comprehensive Cancer Care, Duarte, Calif. He reported conflicts of interest with Ariad/Takeda, Bristol-Myers Squibb, Boehringer Ingelheim, Spectrum, AstraZeneca, Celgene, Genentech/Roche, Pfizer, Merck, and Eli Lilly.
A version of this article first appeared on Medscape.com.
Hormonal management of gender-diverse patients: SOC8 updates
In September, the World Professional Association for Transgender Health released its much-anticipated standards of care (SOC8). While this update has unfortunately received intense scrutiny for its guidance about gender-diverse adolescents and youth, the SOC8 is their most evidence-based version to date. Recommendations were developed based on data from independent systematic literature reviews, background reviews, and expert opinions.1 These guidelines also recognize knowledge deficits and are intended to be flexible to meet the individual needs of transgender patients. While the scope of this column will not delve into all 258 pages of these new standards, it will highlight pertinent information on hormonal management.
Ever since the original publication of the standards of care in 1979, gender-affirming hormone therapy (GAHT) has been considered medically necessary. The approach to GAHT depends on the patient’s goals and the age at which the patient is seeking to medically transition. Given the complexity of GAHT for transgender youth and adolescents, this article will focus primarily on adult patients.
There are a few pertinent differences in the management and monitoring of GAHT in adults. For patients assigned female at birth, testosterone is the primary modality by which patients can achieve masculinizing features. GAHT for patients assigned male at birth often consists of estrogen and an androgen-lowering medication. Like its predecessor, SOC8 recommends against prescribing ethinyl estradiol because of its marked association with thromboembolic events.
While the formulations of estrogen (oral, injectable, and patches) and hormone blockers (finasteride, spironolactone, gonadotropin-releasing hormone agonists, and bicalutamide) are discussed in prior standards of care, SOC8 further delineates their utilization. It suggests that transdermal estrogen should be considered in transgender women over the age of 45 who are at high risk for developing a venous thromboembolism or have a previous history of thromboembolism. Furthermore, SOC8 establishes spironolactone as the mainstay for androgen blockage and discourages routine usage of bicalutamide and finasteride because of a lack of safety data and questionable efficacy.1 Even though some patients anecdotally report increased breast growth with progesterone supplementation, there is insufficient evidence to regularly prescribe progesterone for breast development.1
Both WPATH and the Endocrine Society recommend checking serum levels of sex hormones every 3 months during the first year until stable levels are achieved, then once or twice a year thereafter.1 Hormone levels should be maintained at physiologic concentrations of the targeted gender. Some patients on feminizing GAHT often request evaluation of estrone/estradiol ratios as there was an assumption that higher ratios were associated with antagonistic effects on breast development. However, recent published evidence refutes this claim and estrone/estradiol ratios need not be measured.1
In addition to monitoring sex hormone levels, providers should check the metabolic effects that can be associated with GAHT. Both testosterone and estrogen can influence lipid panels: Testosterone can increase the red blood cell count, and spironolactone may cause hyperkalemia. While the SOC7 previously encouraged assessment of these laboratory values every 3 months, the new guidelines are more flexible in the frequency of testing of asymptomatic individuals as there is no strong evidence from published studies that supports these 3-month intervals.1
Providers are responsible for informing patients about the possible effects of GAHT on fertility. Estrogen often will cause a reduction in spermatogenesis, which may be irreversible. Patients who plan on taking estrogen should be counseled regarding sperm cryopreservation prior to starting GAHT. Even though testosterone inhibits ovulation and induces menstrual suppression, patients often regain their fertility after cessation of testosterone therapy. However, given the significant knowledge deficit about long-term fertility in transmasculine patients, providers should still offer oocyte or embryo cryopreservation.
Health care providers should collaborate with surgeons regarding preoperative and postoperative GAHT. To mitigate the risk of thromboembolism, many surgeons would stop hormones 1-4 weeks before and after gender-affirming surgery. Recent evidence does not support this practice, as studies indicate no increased risk for venous thromboembolism in individuals on GAHT undergoing surgery. These studies are consistent with other well-established guidelines on preoperative management of cisgender women taking estrogen or progestins. As exogenous sex steroids are necessary for bone health in patients who undergo gonadectomy, surgeons and other health care providers should educate patients on the importance of continuing GAHT.
There are many procedures available for gender-affirming surgery. Many of these surgeries involve three regions: the face, chest/breast, and/or genitalia (both internal and external). Prior to making a surgical referral, providers should be familiar with the surgeon’s scope of practice, performance measures, and surgical outcomes.1 For the first time, the SOC8 also addresses the surgical training of the providers who offer these procedures. While gender-affirming surgery can be performed by a variety of different specialists, training and documented supervision (often by an existing expert in gender-affirming surgery) is essential. Maintaining an active practice in these procedures, tracking surgical outcomes, and continuing education within the field of gender-affirming surgery are additional requirements for surgeons performing these complex operations.1
As their name implies, the SOC8 attempts to create a standardized guide to assist practitioners caring for gender-diverse patients. It’s important for providers to be familiar with updates while also recognizing the evolving nature of this rapidly growing field.
Dr. Brandt is an ob.gyn. and fellowship-trained gender-affirming surgeon in West Reading, Pa.
Reference
1. World Professional Association for Transgender Health. Standards of care for the health of transgender and gender diverse people, Version 8. Int J Transgend Health. 2022 Sep 15. doi: 10.1080/26895269.2022.2100644.
In September, the World Professional Association for Transgender Health released its much-anticipated standards of care (SOC8). While this update has unfortunately received intense scrutiny for its guidance about gender-diverse adolescents and youth, the SOC8 is their most evidence-based version to date. Recommendations were developed based on data from independent systematic literature reviews, background reviews, and expert opinions.1 These guidelines also recognize knowledge deficits and are intended to be flexible to meet the individual needs of transgender patients. While the scope of this column will not delve into all 258 pages of these new standards, it will highlight pertinent information on hormonal management.
Ever since the original publication of the standards of care in 1979, gender-affirming hormone therapy (GAHT) has been considered medically necessary. The approach to GAHT depends on the patient’s goals and the age at which the patient is seeking to medically transition. Given the complexity of GAHT for transgender youth and adolescents, this article will focus primarily on adult patients.
There are a few pertinent differences in the management and monitoring of GAHT in adults. For patients assigned female at birth, testosterone is the primary modality by which patients can achieve masculinizing features. GAHT for patients assigned male at birth often consists of estrogen and an androgen-lowering medication. Like its predecessor, SOC8 recommends against prescribing ethinyl estradiol because of its marked association with thromboembolic events.
While the formulations of estrogen (oral, injectable, and patches) and hormone blockers (finasteride, spironolactone, gonadotropin-releasing hormone agonists, and bicalutamide) are discussed in prior standards of care, SOC8 further delineates their utilization. It suggests that transdermal estrogen should be considered in transgender women over the age of 45 who are at high risk for developing a venous thromboembolism or have a previous history of thromboembolism. Furthermore, SOC8 establishes spironolactone as the mainstay for androgen blockage and discourages routine usage of bicalutamide and finasteride because of a lack of safety data and questionable efficacy.1 Even though some patients anecdotally report increased breast growth with progesterone supplementation, there is insufficient evidence to regularly prescribe progesterone for breast development.1
Both WPATH and the Endocrine Society recommend checking serum levels of sex hormones every 3 months during the first year until stable levels are achieved, then once or twice a year thereafter.1 Hormone levels should be maintained at physiologic concentrations of the targeted gender. Some patients on feminizing GAHT often request evaluation of estrone/estradiol ratios as there was an assumption that higher ratios were associated with antagonistic effects on breast development. However, recent published evidence refutes this claim and estrone/estradiol ratios need not be measured.1
In addition to monitoring sex hormone levels, providers should check the metabolic effects that can be associated with GAHT. Both testosterone and estrogen can influence lipid panels: Testosterone can increase the red blood cell count, and spironolactone may cause hyperkalemia. While the SOC7 previously encouraged assessment of these laboratory values every 3 months, the new guidelines are more flexible in the frequency of testing of asymptomatic individuals as there is no strong evidence from published studies that supports these 3-month intervals.1
Providers are responsible for informing patients about the possible effects of GAHT on fertility. Estrogen often will cause a reduction in spermatogenesis, which may be irreversible. Patients who plan on taking estrogen should be counseled regarding sperm cryopreservation prior to starting GAHT. Even though testosterone inhibits ovulation and induces menstrual suppression, patients often regain their fertility after cessation of testosterone therapy. However, given the significant knowledge deficit about long-term fertility in transmasculine patients, providers should still offer oocyte or embryo cryopreservation.
Health care providers should collaborate with surgeons regarding preoperative and postoperative GAHT. To mitigate the risk of thromboembolism, many surgeons would stop hormones 1-4 weeks before and after gender-affirming surgery. Recent evidence does not support this practice, as studies indicate no increased risk for venous thromboembolism in individuals on GAHT undergoing surgery. These studies are consistent with other well-established guidelines on preoperative management of cisgender women taking estrogen or progestins. As exogenous sex steroids are necessary for bone health in patients who undergo gonadectomy, surgeons and other health care providers should educate patients on the importance of continuing GAHT.
There are many procedures available for gender-affirming surgery. Many of these surgeries involve three regions: the face, chest/breast, and/or genitalia (both internal and external). Prior to making a surgical referral, providers should be familiar with the surgeon’s scope of practice, performance measures, and surgical outcomes.1 For the first time, the SOC8 also addresses the surgical training of the providers who offer these procedures. While gender-affirming surgery can be performed by a variety of different specialists, training and documented supervision (often by an existing expert in gender-affirming surgery) is essential. Maintaining an active practice in these procedures, tracking surgical outcomes, and continuing education within the field of gender-affirming surgery are additional requirements for surgeons performing these complex operations.1
As their name implies, the SOC8 attempts to create a standardized guide to assist practitioners caring for gender-diverse patients. It’s important for providers to be familiar with updates while also recognizing the evolving nature of this rapidly growing field.
Dr. Brandt is an ob.gyn. and fellowship-trained gender-affirming surgeon in West Reading, Pa.
Reference
1. World Professional Association for Transgender Health. Standards of care for the health of transgender and gender diverse people, Version 8. Int J Transgend Health. 2022 Sep 15. doi: 10.1080/26895269.2022.2100644.
In September, the World Professional Association for Transgender Health released its much-anticipated standards of care (SOC8). While this update has unfortunately received intense scrutiny for its guidance about gender-diverse adolescents and youth, the SOC8 is their most evidence-based version to date. Recommendations were developed based on data from independent systematic literature reviews, background reviews, and expert opinions.1 These guidelines also recognize knowledge deficits and are intended to be flexible to meet the individual needs of transgender patients. While the scope of this column will not delve into all 258 pages of these new standards, it will highlight pertinent information on hormonal management.
Ever since the original publication of the standards of care in 1979, gender-affirming hormone therapy (GAHT) has been considered medically necessary. The approach to GAHT depends on the patient’s goals and the age at which the patient is seeking to medically transition. Given the complexity of GAHT for transgender youth and adolescents, this article will focus primarily on adult patients.
There are a few pertinent differences in the management and monitoring of GAHT in adults. For patients assigned female at birth, testosterone is the primary modality by which patients can achieve masculinizing features. GAHT for patients assigned male at birth often consists of estrogen and an androgen-lowering medication. Like its predecessor, SOC8 recommends against prescribing ethinyl estradiol because of its marked association with thromboembolic events.
While the formulations of estrogen (oral, injectable, and patches) and hormone blockers (finasteride, spironolactone, gonadotropin-releasing hormone agonists, and bicalutamide) are discussed in prior standards of care, SOC8 further delineates their utilization. It suggests that transdermal estrogen should be considered in transgender women over the age of 45 who are at high risk for developing a venous thromboembolism or have a previous history of thromboembolism. Furthermore, SOC8 establishes spironolactone as the mainstay for androgen blockage and discourages routine usage of bicalutamide and finasteride because of a lack of safety data and questionable efficacy.1 Even though some patients anecdotally report increased breast growth with progesterone supplementation, there is insufficient evidence to regularly prescribe progesterone for breast development.1
Both WPATH and the Endocrine Society recommend checking serum levels of sex hormones every 3 months during the first year until stable levels are achieved, then once or twice a year thereafter.1 Hormone levels should be maintained at physiologic concentrations of the targeted gender. Some patients on feminizing GAHT often request evaluation of estrone/estradiol ratios as there was an assumption that higher ratios were associated with antagonistic effects on breast development. However, recent published evidence refutes this claim and estrone/estradiol ratios need not be measured.1
In addition to monitoring sex hormone levels, providers should check the metabolic effects that can be associated with GAHT. Both testosterone and estrogen can influence lipid panels: Testosterone can increase the red blood cell count, and spironolactone may cause hyperkalemia. While the SOC7 previously encouraged assessment of these laboratory values every 3 months, the new guidelines are more flexible in the frequency of testing of asymptomatic individuals as there is no strong evidence from published studies that supports these 3-month intervals.1
Providers are responsible for informing patients about the possible effects of GAHT on fertility. Estrogen often will cause a reduction in spermatogenesis, which may be irreversible. Patients who plan on taking estrogen should be counseled regarding sperm cryopreservation prior to starting GAHT. Even though testosterone inhibits ovulation and induces menstrual suppression, patients often regain their fertility after cessation of testosterone therapy. However, given the significant knowledge deficit about long-term fertility in transmasculine patients, providers should still offer oocyte or embryo cryopreservation.
Health care providers should collaborate with surgeons regarding preoperative and postoperative GAHT. To mitigate the risk of thromboembolism, many surgeons would stop hormones 1-4 weeks before and after gender-affirming surgery. Recent evidence does not support this practice, as studies indicate no increased risk for venous thromboembolism in individuals on GAHT undergoing surgery. These studies are consistent with other well-established guidelines on preoperative management of cisgender women taking estrogen or progestins. As exogenous sex steroids are necessary for bone health in patients who undergo gonadectomy, surgeons and other health care providers should educate patients on the importance of continuing GAHT.
There are many procedures available for gender-affirming surgery. Many of these surgeries involve three regions: the face, chest/breast, and/or genitalia (both internal and external). Prior to making a surgical referral, providers should be familiar with the surgeon’s scope of practice, performance measures, and surgical outcomes.1 For the first time, the SOC8 also addresses the surgical training of the providers who offer these procedures. While gender-affirming surgery can be performed by a variety of different specialists, training and documented supervision (often by an existing expert in gender-affirming surgery) is essential. Maintaining an active practice in these procedures, tracking surgical outcomes, and continuing education within the field of gender-affirming surgery are additional requirements for surgeons performing these complex operations.1
As their name implies, the SOC8 attempts to create a standardized guide to assist practitioners caring for gender-diverse patients. It’s important for providers to be familiar with updates while also recognizing the evolving nature of this rapidly growing field.
Dr. Brandt is an ob.gyn. and fellowship-trained gender-affirming surgeon in West Reading, Pa.
Reference
1. World Professional Association for Transgender Health. Standards of care for the health of transgender and gender diverse people, Version 8. Int J Transgend Health. 2022 Sep 15. doi: 10.1080/26895269.2022.2100644.
Earlier diagnosis of Alzheimer’s: A good start, but then what?
In the October 2022 issue of JAMA Neurology was a research article and accompanying editorial on the ATN (amyloid/tau/neurodegeneration) framework for diagnosing and treating Alzheimer’s disease.
If the new generation of Alzheimer’s treatments can reverse pathology before the symptoms are apparent, it certainly makes sense to treat people as early as possible. In a terrible disease with only partially effective treatments now, this is encouraging news.
So this testing, as it stands now, would involve amyloid PET and tau PET scans, not to mention other screening tests such as MRI, labs, and the occasional lumbar puncture or EEG.
But it raises new questions.
Who should we be testing? If the new agents work on a presymptomatic basis, should we test everyone over 50, or 60, or 70? Or just those with memory concerns? Realistically, a lot of people come to general neurologists with memory worries, the majority of whom have nothing ominous. Those numbers are going to skyrocket as soon as the “have you been forgetting things? Ask your doctor” ads hit the airwaves. They’ll suggest, as much as the FDA will allow, that if you can’t find your car keys, you may have early dementia and need to be worked up promptly to keep from getting worse.
Who’s going to see these people? I’m sure it’s good for business, which I have no problem with, but most neurology practices are booked out a bit as it is. The influx of people panicked because they forgot their Netflix password will add to that.
How are we going to treat them? Even if we ignore aducanumab, which has more than enough baggage, lecanemab, donanemab, and gantenerumab are all waiting in the wings. Is one drug better for patients with certain scan findings? Or clearly safer? Keep in mind that, even at this early stage, we are already grappling with the potentially serious complication of ARIA [amyloid related imaging abnormalities]. The incidence is only going to go up as these new drugs enter the market. These questions rapidly move the drug outside the comfort zone of many general neurologists, and there aren’t nearly enough dementia subspecialists out there to handle the number of patients involved.
And lastly, from the more practical view, who’s going to pay for this? I’m not trying to prioritize money over people, but it’s a legitimate question that will have to be answered. PET scans aren’t cheap, and we’re talking about doing two of them. Neither are MRIs, or lumbar punctures. If we’re going to put guidelines out (like we do for mammograms and colonoscopies) for screening asymptomatic people over 70, or even mildly forgetful patients ... that’s a lot of dollars. Is there going to be some limitation on the testing based on who would benefit the most? What do we tell the patients and families outside of that range? And that’s even before we start factoring in the drug costs. In October, Forbes listed potential lecanemab prices as being anywhere from $9,000 to $35,000 per year.
I’m not trying to be Debbie Downer here. The fact that these drugs are here is, hopefully, the start of a new era in treatment of what will still be an incurable disease. Aricept (and its cousins) and Namenda were stepping stones in their day, and these are the next ones.
But these are questions that need to be answered. And soon.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
In the October 2022 issue of JAMA Neurology was a research article and accompanying editorial on the ATN (amyloid/tau/neurodegeneration) framework for diagnosing and treating Alzheimer’s disease.
If the new generation of Alzheimer’s treatments can reverse pathology before the symptoms are apparent, it certainly makes sense to treat people as early as possible. In a terrible disease with only partially effective treatments now, this is encouraging news.
So this testing, as it stands now, would involve amyloid PET and tau PET scans, not to mention other screening tests such as MRI, labs, and the occasional lumbar puncture or EEG.
But it raises new questions.
Who should we be testing? If the new agents work on a presymptomatic basis, should we test everyone over 50, or 60, or 70? Or just those with memory concerns? Realistically, a lot of people come to general neurologists with memory worries, the majority of whom have nothing ominous. Those numbers are going to skyrocket as soon as the “have you been forgetting things? Ask your doctor” ads hit the airwaves. They’ll suggest, as much as the FDA will allow, that if you can’t find your car keys, you may have early dementia and need to be worked up promptly to keep from getting worse.
Who’s going to see these people? I’m sure it’s good for business, which I have no problem with, but most neurology practices are booked out a bit as it is. The influx of people panicked because they forgot their Netflix password will add to that.
How are we going to treat them? Even if we ignore aducanumab, which has more than enough baggage, lecanemab, donanemab, and gantenerumab are all waiting in the wings. Is one drug better for patients with certain scan findings? Or clearly safer? Keep in mind that, even at this early stage, we are already grappling with the potentially serious complication of ARIA [amyloid related imaging abnormalities]. The incidence is only going to go up as these new drugs enter the market. These questions rapidly move the drug outside the comfort zone of many general neurologists, and there aren’t nearly enough dementia subspecialists out there to handle the number of patients involved.
And lastly, from the more practical view, who’s going to pay for this? I’m not trying to prioritize money over people, but it’s a legitimate question that will have to be answered. PET scans aren’t cheap, and we’re talking about doing two of them. Neither are MRIs, or lumbar punctures. If we’re going to put guidelines out (like we do for mammograms and colonoscopies) for screening asymptomatic people over 70, or even mildly forgetful patients ... that’s a lot of dollars. Is there going to be some limitation on the testing based on who would benefit the most? What do we tell the patients and families outside of that range? And that’s even before we start factoring in the drug costs. In October, Forbes listed potential lecanemab prices as being anywhere from $9,000 to $35,000 per year.
I’m not trying to be Debbie Downer here. The fact that these drugs are here is, hopefully, the start of a new era in treatment of what will still be an incurable disease. Aricept (and its cousins) and Namenda were stepping stones in their day, and these are the next ones.
But these are questions that need to be answered. And soon.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
In the October 2022 issue of JAMA Neurology was a research article and accompanying editorial on the ATN (amyloid/tau/neurodegeneration) framework for diagnosing and treating Alzheimer’s disease.
If the new generation of Alzheimer’s treatments can reverse pathology before the symptoms are apparent, it certainly makes sense to treat people as early as possible. In a terrible disease with only partially effective treatments now, this is encouraging news.
So this testing, as it stands now, would involve amyloid PET and tau PET scans, not to mention other screening tests such as MRI, labs, and the occasional lumbar puncture or EEG.
But it raises new questions.
Who should we be testing? If the new agents work on a presymptomatic basis, should we test everyone over 50, or 60, or 70? Or just those with memory concerns? Realistically, a lot of people come to general neurologists with memory worries, the majority of whom have nothing ominous. Those numbers are going to skyrocket as soon as the “have you been forgetting things? Ask your doctor” ads hit the airwaves. They’ll suggest, as much as the FDA will allow, that if you can’t find your car keys, you may have early dementia and need to be worked up promptly to keep from getting worse.
Who’s going to see these people? I’m sure it’s good for business, which I have no problem with, but most neurology practices are booked out a bit as it is. The influx of people panicked because they forgot their Netflix password will add to that.
How are we going to treat them? Even if we ignore aducanumab, which has more than enough baggage, lecanemab, donanemab, and gantenerumab are all waiting in the wings. Is one drug better for patients with certain scan findings? Or clearly safer? Keep in mind that, even at this early stage, we are already grappling with the potentially serious complication of ARIA [amyloid related imaging abnormalities]. The incidence is only going to go up as these new drugs enter the market. These questions rapidly move the drug outside the comfort zone of many general neurologists, and there aren’t nearly enough dementia subspecialists out there to handle the number of patients involved.
And lastly, from the more practical view, who’s going to pay for this? I’m not trying to prioritize money over people, but it’s a legitimate question that will have to be answered. PET scans aren’t cheap, and we’re talking about doing two of them. Neither are MRIs, or lumbar punctures. If we’re going to put guidelines out (like we do for mammograms and colonoscopies) for screening asymptomatic people over 70, or even mildly forgetful patients ... that’s a lot of dollars. Is there going to be some limitation on the testing based on who would benefit the most? What do we tell the patients and families outside of that range? And that’s even before we start factoring in the drug costs. In October, Forbes listed potential lecanemab prices as being anywhere from $9,000 to $35,000 per year.
I’m not trying to be Debbie Downer here. The fact that these drugs are here is, hopefully, the start of a new era in treatment of what will still be an incurable disease. Aricept (and its cousins) and Namenda were stepping stones in their day, and these are the next ones.
But these are questions that need to be answered. And soon.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
Long-term behavioral follow-up of children exposed to mood stabilizers and antidepressants: A look forward
Much of the focus of reproductive psychiatry over the last 1 to 2 decades has been on issues regarding risk of fetal exposure to psychiatric medications in the context of the specific risk for teratogenesis or organ malformation. Concerns and questions are mostly focused on exposure to any number of medications that women take during the first trimester, as it is during that period that the major organs are formed.
More recently, there has been appropriate interest in the effect of fetal exposure to psychiatric medications with respect to risk for obstetrical and neonatal complications. This particularly has been the case with respect to antidepressants where fetal exposure to these medications, which while associated with symptoms of transient jitteriness and irritability about 20% of the time, have not been associated with symptoms requiring frank clinical intervention.
Concerning mood stabilizers, the risk for organ dysgenesis following fetal exposure to sodium valproate has been very well established, and we’ve known for over a decade about the adverse effects of fetal exposure to sodium valproate on behavioral outcomes (Lancet Neurol. 2013 Mar;12[3]:244-52). We also now have ample data on lamotrigine, one of the most widely used medicines by reproductive-age women for treatment of bipolar disorder that supports the absence of a risk of organ malformation in first-trimester exposure.
Most recently, in a study of 292 children of women with epilepsy, an evaluation of women being treated with more modern anticonvulsants such as lamotrigine and levetiracetam alone or as polytherapy was performed. The results showed no difference in language, motor, cognitive, social, emotional, and general adaptive functioning in children exposed to either lamotrigine or levetiracetam relative to unexposed children of women with epilepsy. However, the researchers found an increase in anti-epileptic drug plasma level appeared to be associated with decreased motor and sensory function. These are reassuring data that really confirm earlier work, which failed to reveal a signal of concern for lamotrigine and now provide some of the first data on levetiracetam, which is widely used by reproductive-age women with epilepsy (JAMA Neurol. 2021 Aug 1;78[8]:927-936). While one caveat of the study is a short follow-up of 2 years, the absence of a signal of concern is reassuring. With more and more data demonstrating bipolar disorder is an illness that requires chronic treatment for many people, and that discontinuation is associated with high risk for relapse, it is an advance in the field to have data on risk for teratogenesis and data on longer-term neurobehavioral outcomes.
There is vast information regarding reproductive safety, organ malformation, and acute neonatal outcomes for antidepressants. The last decade has brought interest in and analysis of specific reports of increased risk of both autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) following fetal exposure to antidepressants. What can be said based on reviews of pooled meta-analyses is that the risk for ASD and ADHD has been put to rest for most clinicians and patients (J Clin Psychiatry. 2020 May 26;81[3]:20f13463). With other neurodevelopmental disorders, results have been somewhat inconclusive. Over the last 5-10 years, there have been sporadic reports of concerns about problems in a specific domain of neurodevelopment in offspring of women who have used antidepressants during pregnancy, whether it be speech, language, or motor functioning, but no signal of concern has been consistent.
In a previous column, I addressed a Danish study that showed no increased risk of longer-term sequelae after fetal exposure to antidepressants. Now, a new study has examined 1.93 million pregnancies in the Medicaid Analytic eXtract and 1.25 million pregnancies in the IBM MarketScan Research Database with follow-up up to 14 years of age where the specific interval for fetal exposure was from gestational age of 19 weeks to delivery, as that is the period that corresponds most to synaptogenesis in the brain. The researchers examined a spectrum of neurodevelopmental disorders such as developmental speech issues, ADHD, ASD, dyslexia, and learning disorders, among others. They found a twofold increased risk for neurodevelopmental disorders in the unadjusted models that flattened to no finding when factoring in environmental and genetic risk variables, highlighting the importance of dealing appropriately with confounders when performing these analyses. Those confounders examined include the mother’s use of alcohol and tobacco, and her body mass index and overall general health (JAMA Intern Med. 2022;182[11]:1149-60).
Given the consistency of these results with earlier data, patients can be increasingly comfortable as they weigh the benefits and risks of antidepressant use during pregnancy, factoring in the risk of fetal exposure with added data on long-term neurobehavioral sequelae. With that said, we need to remember the importance of initiatives to address alcohol consumption, poor nutrition, tobacco use, elevated BMI, and general health during pregnancy. These are modifiable risks that we as clinicians should focus on in order to optimize outcomes during pregnancy.
We have come so far in knowledge about fetal exposure to antidepressants relative to other classes of medications women take during pregnancy, about which, frankly, we are still starved for data. As use of psychiatric medications during pregnancy continues to grow, we can rest a bit more comfortably. But we should also address some of the other behaviors that have adverse effects on maternal and child well-being.
Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].
Much of the focus of reproductive psychiatry over the last 1 to 2 decades has been on issues regarding risk of fetal exposure to psychiatric medications in the context of the specific risk for teratogenesis or organ malformation. Concerns and questions are mostly focused on exposure to any number of medications that women take during the first trimester, as it is during that period that the major organs are formed.
More recently, there has been appropriate interest in the effect of fetal exposure to psychiatric medications with respect to risk for obstetrical and neonatal complications. This particularly has been the case with respect to antidepressants where fetal exposure to these medications, which while associated with symptoms of transient jitteriness and irritability about 20% of the time, have not been associated with symptoms requiring frank clinical intervention.
Concerning mood stabilizers, the risk for organ dysgenesis following fetal exposure to sodium valproate has been very well established, and we’ve known for over a decade about the adverse effects of fetal exposure to sodium valproate on behavioral outcomes (Lancet Neurol. 2013 Mar;12[3]:244-52). We also now have ample data on lamotrigine, one of the most widely used medicines by reproductive-age women for treatment of bipolar disorder that supports the absence of a risk of organ malformation in first-trimester exposure.
Most recently, in a study of 292 children of women with epilepsy, an evaluation of women being treated with more modern anticonvulsants such as lamotrigine and levetiracetam alone or as polytherapy was performed. The results showed no difference in language, motor, cognitive, social, emotional, and general adaptive functioning in children exposed to either lamotrigine or levetiracetam relative to unexposed children of women with epilepsy. However, the researchers found an increase in anti-epileptic drug plasma level appeared to be associated with decreased motor and sensory function. These are reassuring data that really confirm earlier work, which failed to reveal a signal of concern for lamotrigine and now provide some of the first data on levetiracetam, which is widely used by reproductive-age women with epilepsy (JAMA Neurol. 2021 Aug 1;78[8]:927-936). While one caveat of the study is a short follow-up of 2 years, the absence of a signal of concern is reassuring. With more and more data demonstrating bipolar disorder is an illness that requires chronic treatment for many people, and that discontinuation is associated with high risk for relapse, it is an advance in the field to have data on risk for teratogenesis and data on longer-term neurobehavioral outcomes.
There is vast information regarding reproductive safety, organ malformation, and acute neonatal outcomes for antidepressants. The last decade has brought interest in and analysis of specific reports of increased risk of both autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) following fetal exposure to antidepressants. What can be said based on reviews of pooled meta-analyses is that the risk for ASD and ADHD has been put to rest for most clinicians and patients (J Clin Psychiatry. 2020 May 26;81[3]:20f13463). With other neurodevelopmental disorders, results have been somewhat inconclusive. Over the last 5-10 years, there have been sporadic reports of concerns about problems in a specific domain of neurodevelopment in offspring of women who have used antidepressants during pregnancy, whether it be speech, language, or motor functioning, but no signal of concern has been consistent.
In a previous column, I addressed a Danish study that showed no increased risk of longer-term sequelae after fetal exposure to antidepressants. Now, a new study has examined 1.93 million pregnancies in the Medicaid Analytic eXtract and 1.25 million pregnancies in the IBM MarketScan Research Database with follow-up up to 14 years of age where the specific interval for fetal exposure was from gestational age of 19 weeks to delivery, as that is the period that corresponds most to synaptogenesis in the brain. The researchers examined a spectrum of neurodevelopmental disorders such as developmental speech issues, ADHD, ASD, dyslexia, and learning disorders, among others. They found a twofold increased risk for neurodevelopmental disorders in the unadjusted models that flattened to no finding when factoring in environmental and genetic risk variables, highlighting the importance of dealing appropriately with confounders when performing these analyses. Those confounders examined include the mother’s use of alcohol and tobacco, and her body mass index and overall general health (JAMA Intern Med. 2022;182[11]:1149-60).
Given the consistency of these results with earlier data, patients can be increasingly comfortable as they weigh the benefits and risks of antidepressant use during pregnancy, factoring in the risk of fetal exposure with added data on long-term neurobehavioral sequelae. With that said, we need to remember the importance of initiatives to address alcohol consumption, poor nutrition, tobacco use, elevated BMI, and general health during pregnancy. These are modifiable risks that we as clinicians should focus on in order to optimize outcomes during pregnancy.
We have come so far in knowledge about fetal exposure to antidepressants relative to other classes of medications women take during pregnancy, about which, frankly, we are still starved for data. As use of psychiatric medications during pregnancy continues to grow, we can rest a bit more comfortably. But we should also address some of the other behaviors that have adverse effects on maternal and child well-being.
Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].
Much of the focus of reproductive psychiatry over the last 1 to 2 decades has been on issues regarding risk of fetal exposure to psychiatric medications in the context of the specific risk for teratogenesis or organ malformation. Concerns and questions are mostly focused on exposure to any number of medications that women take during the first trimester, as it is during that period that the major organs are formed.
More recently, there has been appropriate interest in the effect of fetal exposure to psychiatric medications with respect to risk for obstetrical and neonatal complications. This particularly has been the case with respect to antidepressants where fetal exposure to these medications, which while associated with symptoms of transient jitteriness and irritability about 20% of the time, have not been associated with symptoms requiring frank clinical intervention.
Concerning mood stabilizers, the risk for organ dysgenesis following fetal exposure to sodium valproate has been very well established, and we’ve known for over a decade about the adverse effects of fetal exposure to sodium valproate on behavioral outcomes (Lancet Neurol. 2013 Mar;12[3]:244-52). We also now have ample data on lamotrigine, one of the most widely used medicines by reproductive-age women for treatment of bipolar disorder that supports the absence of a risk of organ malformation in first-trimester exposure.
Most recently, in a study of 292 children of women with epilepsy, an evaluation of women being treated with more modern anticonvulsants such as lamotrigine and levetiracetam alone or as polytherapy was performed. The results showed no difference in language, motor, cognitive, social, emotional, and general adaptive functioning in children exposed to either lamotrigine or levetiracetam relative to unexposed children of women with epilepsy. However, the researchers found an increase in anti-epileptic drug plasma level appeared to be associated with decreased motor and sensory function. These are reassuring data that really confirm earlier work, which failed to reveal a signal of concern for lamotrigine and now provide some of the first data on levetiracetam, which is widely used by reproductive-age women with epilepsy (JAMA Neurol. 2021 Aug 1;78[8]:927-936). While one caveat of the study is a short follow-up of 2 years, the absence of a signal of concern is reassuring. With more and more data demonstrating bipolar disorder is an illness that requires chronic treatment for many people, and that discontinuation is associated with high risk for relapse, it is an advance in the field to have data on risk for teratogenesis and data on longer-term neurobehavioral outcomes.
There is vast information regarding reproductive safety, organ malformation, and acute neonatal outcomes for antidepressants. The last decade has brought interest in and analysis of specific reports of increased risk of both autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) following fetal exposure to antidepressants. What can be said based on reviews of pooled meta-analyses is that the risk for ASD and ADHD has been put to rest for most clinicians and patients (J Clin Psychiatry. 2020 May 26;81[3]:20f13463). With other neurodevelopmental disorders, results have been somewhat inconclusive. Over the last 5-10 years, there have been sporadic reports of concerns about problems in a specific domain of neurodevelopment in offspring of women who have used antidepressants during pregnancy, whether it be speech, language, or motor functioning, but no signal of concern has been consistent.
In a previous column, I addressed a Danish study that showed no increased risk of longer-term sequelae after fetal exposure to antidepressants. Now, a new study has examined 1.93 million pregnancies in the Medicaid Analytic eXtract and 1.25 million pregnancies in the IBM MarketScan Research Database with follow-up up to 14 years of age where the specific interval for fetal exposure was from gestational age of 19 weeks to delivery, as that is the period that corresponds most to synaptogenesis in the brain. The researchers examined a spectrum of neurodevelopmental disorders such as developmental speech issues, ADHD, ASD, dyslexia, and learning disorders, among others. They found a twofold increased risk for neurodevelopmental disorders in the unadjusted models that flattened to no finding when factoring in environmental and genetic risk variables, highlighting the importance of dealing appropriately with confounders when performing these analyses. Those confounders examined include the mother’s use of alcohol and tobacco, and her body mass index and overall general health (JAMA Intern Med. 2022;182[11]:1149-60).
Given the consistency of these results with earlier data, patients can be increasingly comfortable as they weigh the benefits and risks of antidepressant use during pregnancy, factoring in the risk of fetal exposure with added data on long-term neurobehavioral sequelae. With that said, we need to remember the importance of initiatives to address alcohol consumption, poor nutrition, tobacco use, elevated BMI, and general health during pregnancy. These are modifiable risks that we as clinicians should focus on in order to optimize outcomes during pregnancy.
We have come so far in knowledge about fetal exposure to antidepressants relative to other classes of medications women take during pregnancy, about which, frankly, we are still starved for data. As use of psychiatric medications during pregnancy continues to grow, we can rest a bit more comfortably. But we should also address some of the other behaviors that have adverse effects on maternal and child well-being.
Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].
Top 10 unproven infertility tests and treatments
In 2019, a New York Times opinion piece titled, “The Big IVF Add-On Racket – This is no way to treat patients desperate for a baby”1 alleged exploitation of infertility patients based on a Fertility and Sterility article, “Do à la carte menus serve infertility patients? The ethics and regulation of in vitro fertility add-ons.”2 The desperation of infertility patients combined with their financial burden, caused by inconsistent insurance coverage, has resulted in a perfect storm of frustration and overzealous recommendations for a successful outcome. Since the inception of in vitro fertilization (IVF) itself, infertility patients have been subjected to many unproven tests and procedures that enter the mainstream of care before unequivocal efficacy and safety have been shown.
From ovarian stimulation with intrauterine insemination (IUI) or IVF along with intracytoplasmic sperm injection (ICSI), assisted hatching, and preimplantation genetic testing for aneuploidy (PGT-A), a multitude of options with varying success can overwhelm fertility patients as they walk the tightrope of wanting “the kitchen sink” of treatment while experiencing sticker shock. This month’s article examines the top 10 infertility add-ons that have yet to be shown to improve pregnancy outcomes.
1. Blood testing: Prolactin and FSH
In a woman with ovulatory monthly menstrual cycles, a serum prolactin level provides no elucidation of the cause of infertility. If obtained following ovulation, prolactin can often be physiologically elevated, thereby compelling a repeat blood level, which is ideally performed during the early proliferative phase. False elevations of prolactin can be caused by an early morning blood sample, eating, and stress – which may result from worry caused by having to repeat the unnecessary initial blood test!
Follicle-stimulating hormone (FSH) was a first-line hormone test to assess for ovarian age. For nearly 15 years now, FSH has been replaced by anti-Müllerian hormone as a more reliable and earlier test for diminished ovarian reserve. However, FSH is still the hormone test of choice to diagnose primary ovarian insufficiency. Note that the use of ovarian age testing in a woman without infertility can result in both unnecessary patient anxiety and additional testing.
2. Endometrial scratch
The concept was understandable, that is, induce endometrial trauma by a biopsy or “scratch,” that results in an inflammatory and immunologic response to increase implantation. Endometrial sampling was recommended to be performed during the month prior to the embryo transfer cycle. While the procedure is brief, the pain response of women varies from minimal to severe. Unfortunately, a randomized controlled trial of over 1,300 patients did not show any improvement in the IVF live birth rate from the scratch procedure.3
3. Diagnostic laparoscopy
In years past, a diagnosis of unexplained infertility was not accepted until a laparoscopy was performed that revealed a normal pelvis. This approach subjected many women to an unindicated and a potentially risky surgery that has not shown benefit. The American Society for Reproductive Medicine’s ReproductiveFacts.org website states: “Routine diagnostic laparoscopy should not be performed unless there is a suspicion of pelvic pathology based on clinical history, an abnormal pelvic exam, or abnormalities identified with less invasive testing. In patients with a normal hysterosalpingogram or the presence of a unilaterally patent tube, diagnostic laparoscopy typically will not change the initial recommendation for treatment.”
4. Prescribing clomiphene citrate without IUI
Ovulation dysfunction is found in 40% of female factors for fertility. Provided testing reveals a reasonably normal sperm analysis and hysterosalpingogram, ovulation induction medication with ultrasound monitoring along with an hCG trigger is appropriate. In women who ovulate with unexplained infertility and/or mild male factor, the use of clomiphene citrate or letrozole with timed intercourse is often prescribed, particularly in clinics when IUI preparation is not available. Unfortunately, without including IUI, the use of oral ovarian stimulation has been shown by good evidence to be no more effective than natural cycle attempts at conception.4
5. Thrombophilia testing
Recurrent miscarriage, defined by the spontaneous loss of two or more pregnancies (often during the first trimester but may include up to 20 weeks estimated gestational age), has remained an ill-defined problem that lacks a consensus on the most optimal evaluation and treatment. In 2006, an international consensus statement provided guidance on laboratory testing for antiphospholipid syndrome limited to lupus anticoagulant, anticardiolipin IgG and IgM, and IgG and IgM anti–beta2-glycoprotein I assays.5 ASRM does not recommend additional thrombophilia tests as they are unproven causative factors of recurrent miscarriage.
6. Screening hysteroscopy
A standard infertility evaluation includes ovulation testing, assessment of fallopian tube patency, and a sperm analysis. In a subfertile women with a normal ultrasound or hysterosalpingogram in the basic fertility work‐up, a Cochrane data review concluded there is no definitive evidence for improved outcome with a screening hysteroscopy prior to IUI or IVF.6,7 Two large trials included in the Cochrane review, confirmed similar live birth rates whether or not hysteroscopy was performed before IVF. There may value in screening patients with recurrent implantation failure.
7. PGT-A for all
As the efficacy of the first generation of embryo preimplantation genetic testing, i.e., FISH (fluorescence in situ hybridization) was disproven, so has the same result been determined for PGT-A, specifically in women younger than 35.8 In an elegant randomized prospective trial, Munne and colleagues showed no improvement in the ongoing pregnancy rate (OPR) of study patients of all ages who were enrolled with the intention to treat. However, a subanalysis of patients aged 35-40 who completed the protocol did show an improved OPR and lower miscarriage rate per embryo transfer. While there is no evidence to support improved outcomes with the universal application of PGT-A, there may be some benefit in women older than 35 as well as in certain individual patient circumstances.
8. ICSI for nonmale factor infertility; assisted hatching
In an effort to reduce the risk of fertilization failure, programs have broadened the use of ICSI to nonmale factor infertility. While it has been used in PGT to reduce the risk of DNA contamination, particularly in PGT-M (monogenic disorder) and PGT-SR (structural rearrangement) cases, ICSI has not been shown to improve outcomes when there is a normal sperm analysis.9 During IVF embryo development, assisted hatching involves the thinning and/or opening of the zona pellucida either by chemical, mechanical, or laser means around the embryo before transfer with the intention of facilitating implantation. The routine use of assisted hatching is not recommended based on the lack of increase in live birth rates and because it may increase multiple pregnancy and monozygotic twinning rates.10
9. Acupuncture
Four meta-analyses showed no evidence of the overall benefit of acupuncture for improving live birth rates regardless of whether acupuncture was performed around the time of oocyte retrieval or around the day of embryo transfer. Consequently, acupuncture cannot be recommended routinely to improve IVF outcomes.11
10. Immunologic tests/treatments
Given the “foreign” genetic nature of a fetus, attempts to suppress the maternal immunologic response to sustain the pregnancy have been made for decades, especially for recurrent miscarriage and recurrent implantation failure with IVF. Testing has included natural killer (NK) cells, human leukocyte antigen (HLA) genotypes, and cytokines. While NK cells can be examined by endometrial biopsy, levels fluctuate based on the cycle phase, and no correlation between peripheral blood testing and uterine NK cell levels has been shown. Further, no consensus has been reached on reliable normal reference ranges in uterine NK cells.12
Several treatments have been proposed to somehow modulate the immune system during the implantation process thereby improving implantation and live birth, including lipid emulsion (intralipid) infusion, intravenous immunoglobulin, leukocyte immunization therapy, tacrolimus, anti–tumor necrosis factor agents, and granulocyte colony-stimulating factor. A recent systematic review and meta-analysis cited low-quality studies and did not recommend the use of any of these immune treatments.13 Further, immunomodulation has many known side effects, some of which are serious (including hepatosplenomegaly, thrombocytopenia, leukopenia, renal failure, thromboembolism, and anaphylactic reactions). Excluding women with autoimmune disease, taking glucocorticoids or other immune treatments to improve fertility has not been proven.13
Conclusion
To quote the New York Times opinion piece, “IVF remains an under-regulated arena, and entrepreneurial doctors and pharmaceutical and life science companies are eager to find new ways to cash in on a growing global market that is projected to be as large as $40 billion by 2024.” While this bold statement compels a huge “Ouch!”, it reminds us of our obligation to provide evidence-based medicine and to include emotional and financial harm to our oath of Primum non nocere.
References
1. The News York Times. 2019 Dec 12. Opinion.
2. Wilkinson J et al. Fertil Steril. 2019;112(6):973-7.
3. Lensen S et al. N Engl J Med. 2019 Jan 24;380(4):325-34.
4. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2020;113(2):305-22.
5. Miyakis S et al. J Thromb Haemost. 2006;4(2):295-306.
6. Kamath MS et al. Cochrane Database Syst Rev. 2019 Apr 16;4(4):CD012856.
7. Bosteels J et al. Cochrane Database Syst Rev. 2013 Jan 31;(1):CD009461.
8. Munne S et al. Fertil Steril. 2019;112(6):1071-9.
9. Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. Fertil Steril. 2020;114(2):239-45.
10. Lacey L et al. Cochrane Database Syst Rev. March 7 2021;3:2199.
11. Coyle ME et al. Acupunct Med. 2021;39(1):20-9.
12. Von Woon E et al. Hum Reprod Update. 2022;30;28(4):548-82.
13. Achilli C et al. Fertil Steril. 2018;110(6):1089-100.
In 2019, a New York Times opinion piece titled, “The Big IVF Add-On Racket – This is no way to treat patients desperate for a baby”1 alleged exploitation of infertility patients based on a Fertility and Sterility article, “Do à la carte menus serve infertility patients? The ethics and regulation of in vitro fertility add-ons.”2 The desperation of infertility patients combined with their financial burden, caused by inconsistent insurance coverage, has resulted in a perfect storm of frustration and overzealous recommendations for a successful outcome. Since the inception of in vitro fertilization (IVF) itself, infertility patients have been subjected to many unproven tests and procedures that enter the mainstream of care before unequivocal efficacy and safety have been shown.
From ovarian stimulation with intrauterine insemination (IUI) or IVF along with intracytoplasmic sperm injection (ICSI), assisted hatching, and preimplantation genetic testing for aneuploidy (PGT-A), a multitude of options with varying success can overwhelm fertility patients as they walk the tightrope of wanting “the kitchen sink” of treatment while experiencing sticker shock. This month’s article examines the top 10 infertility add-ons that have yet to be shown to improve pregnancy outcomes.
1. Blood testing: Prolactin and FSH
In a woman with ovulatory monthly menstrual cycles, a serum prolactin level provides no elucidation of the cause of infertility. If obtained following ovulation, prolactin can often be physiologically elevated, thereby compelling a repeat blood level, which is ideally performed during the early proliferative phase. False elevations of prolactin can be caused by an early morning blood sample, eating, and stress – which may result from worry caused by having to repeat the unnecessary initial blood test!
Follicle-stimulating hormone (FSH) was a first-line hormone test to assess for ovarian age. For nearly 15 years now, FSH has been replaced by anti-Müllerian hormone as a more reliable and earlier test for diminished ovarian reserve. However, FSH is still the hormone test of choice to diagnose primary ovarian insufficiency. Note that the use of ovarian age testing in a woman without infertility can result in both unnecessary patient anxiety and additional testing.
2. Endometrial scratch
The concept was understandable, that is, induce endometrial trauma by a biopsy or “scratch,” that results in an inflammatory and immunologic response to increase implantation. Endometrial sampling was recommended to be performed during the month prior to the embryo transfer cycle. While the procedure is brief, the pain response of women varies from minimal to severe. Unfortunately, a randomized controlled trial of over 1,300 patients did not show any improvement in the IVF live birth rate from the scratch procedure.3
3. Diagnostic laparoscopy
In years past, a diagnosis of unexplained infertility was not accepted until a laparoscopy was performed that revealed a normal pelvis. This approach subjected many women to an unindicated and a potentially risky surgery that has not shown benefit. The American Society for Reproductive Medicine’s ReproductiveFacts.org website states: “Routine diagnostic laparoscopy should not be performed unless there is a suspicion of pelvic pathology based on clinical history, an abnormal pelvic exam, or abnormalities identified with less invasive testing. In patients with a normal hysterosalpingogram or the presence of a unilaterally patent tube, diagnostic laparoscopy typically will not change the initial recommendation for treatment.”
4. Prescribing clomiphene citrate without IUI
Ovulation dysfunction is found in 40% of female factors for fertility. Provided testing reveals a reasonably normal sperm analysis and hysterosalpingogram, ovulation induction medication with ultrasound monitoring along with an hCG trigger is appropriate. In women who ovulate with unexplained infertility and/or mild male factor, the use of clomiphene citrate or letrozole with timed intercourse is often prescribed, particularly in clinics when IUI preparation is not available. Unfortunately, without including IUI, the use of oral ovarian stimulation has been shown by good evidence to be no more effective than natural cycle attempts at conception.4
5. Thrombophilia testing
Recurrent miscarriage, defined by the spontaneous loss of two or more pregnancies (often during the first trimester but may include up to 20 weeks estimated gestational age), has remained an ill-defined problem that lacks a consensus on the most optimal evaluation and treatment. In 2006, an international consensus statement provided guidance on laboratory testing for antiphospholipid syndrome limited to lupus anticoagulant, anticardiolipin IgG and IgM, and IgG and IgM anti–beta2-glycoprotein I assays.5 ASRM does not recommend additional thrombophilia tests as they are unproven causative factors of recurrent miscarriage.
6. Screening hysteroscopy
A standard infertility evaluation includes ovulation testing, assessment of fallopian tube patency, and a sperm analysis. In a subfertile women with a normal ultrasound or hysterosalpingogram in the basic fertility work‐up, a Cochrane data review concluded there is no definitive evidence for improved outcome with a screening hysteroscopy prior to IUI or IVF.6,7 Two large trials included in the Cochrane review, confirmed similar live birth rates whether or not hysteroscopy was performed before IVF. There may value in screening patients with recurrent implantation failure.
7. PGT-A for all
As the efficacy of the first generation of embryo preimplantation genetic testing, i.e., FISH (fluorescence in situ hybridization) was disproven, so has the same result been determined for PGT-A, specifically in women younger than 35.8 In an elegant randomized prospective trial, Munne and colleagues showed no improvement in the ongoing pregnancy rate (OPR) of study patients of all ages who were enrolled with the intention to treat. However, a subanalysis of patients aged 35-40 who completed the protocol did show an improved OPR and lower miscarriage rate per embryo transfer. While there is no evidence to support improved outcomes with the universal application of PGT-A, there may be some benefit in women older than 35 as well as in certain individual patient circumstances.
8. ICSI for nonmale factor infertility; assisted hatching
In an effort to reduce the risk of fertilization failure, programs have broadened the use of ICSI to nonmale factor infertility. While it has been used in PGT to reduce the risk of DNA contamination, particularly in PGT-M (monogenic disorder) and PGT-SR (structural rearrangement) cases, ICSI has not been shown to improve outcomes when there is a normal sperm analysis.9 During IVF embryo development, assisted hatching involves the thinning and/or opening of the zona pellucida either by chemical, mechanical, or laser means around the embryo before transfer with the intention of facilitating implantation. The routine use of assisted hatching is not recommended based on the lack of increase in live birth rates and because it may increase multiple pregnancy and monozygotic twinning rates.10
9. Acupuncture
Four meta-analyses showed no evidence of the overall benefit of acupuncture for improving live birth rates regardless of whether acupuncture was performed around the time of oocyte retrieval or around the day of embryo transfer. Consequently, acupuncture cannot be recommended routinely to improve IVF outcomes.11
10. Immunologic tests/treatments
Given the “foreign” genetic nature of a fetus, attempts to suppress the maternal immunologic response to sustain the pregnancy have been made for decades, especially for recurrent miscarriage and recurrent implantation failure with IVF. Testing has included natural killer (NK) cells, human leukocyte antigen (HLA) genotypes, and cytokines. While NK cells can be examined by endometrial biopsy, levels fluctuate based on the cycle phase, and no correlation between peripheral blood testing and uterine NK cell levels has been shown. Further, no consensus has been reached on reliable normal reference ranges in uterine NK cells.12
Several treatments have been proposed to somehow modulate the immune system during the implantation process thereby improving implantation and live birth, including lipid emulsion (intralipid) infusion, intravenous immunoglobulin, leukocyte immunization therapy, tacrolimus, anti–tumor necrosis factor agents, and granulocyte colony-stimulating factor. A recent systematic review and meta-analysis cited low-quality studies and did not recommend the use of any of these immune treatments.13 Further, immunomodulation has many known side effects, some of which are serious (including hepatosplenomegaly, thrombocytopenia, leukopenia, renal failure, thromboembolism, and anaphylactic reactions). Excluding women with autoimmune disease, taking glucocorticoids or other immune treatments to improve fertility has not been proven.13
Conclusion
To quote the New York Times opinion piece, “IVF remains an under-regulated arena, and entrepreneurial doctors and pharmaceutical and life science companies are eager to find new ways to cash in on a growing global market that is projected to be as large as $40 billion by 2024.” While this bold statement compels a huge “Ouch!”, it reminds us of our obligation to provide evidence-based medicine and to include emotional and financial harm to our oath of Primum non nocere.
References
1. The News York Times. 2019 Dec 12. Opinion.
2. Wilkinson J et al. Fertil Steril. 2019;112(6):973-7.
3. Lensen S et al. N Engl J Med. 2019 Jan 24;380(4):325-34.
4. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2020;113(2):305-22.
5. Miyakis S et al. J Thromb Haemost. 2006;4(2):295-306.
6. Kamath MS et al. Cochrane Database Syst Rev. 2019 Apr 16;4(4):CD012856.
7. Bosteels J et al. Cochrane Database Syst Rev. 2013 Jan 31;(1):CD009461.
8. Munne S et al. Fertil Steril. 2019;112(6):1071-9.
9. Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. Fertil Steril. 2020;114(2):239-45.
10. Lacey L et al. Cochrane Database Syst Rev. March 7 2021;3:2199.
11. Coyle ME et al. Acupunct Med. 2021;39(1):20-9.
12. Von Woon E et al. Hum Reprod Update. 2022;30;28(4):548-82.
13. Achilli C et al. Fertil Steril. 2018;110(6):1089-100.
In 2019, a New York Times opinion piece titled, “The Big IVF Add-On Racket – This is no way to treat patients desperate for a baby”1 alleged exploitation of infertility patients based on a Fertility and Sterility article, “Do à la carte menus serve infertility patients? The ethics and regulation of in vitro fertility add-ons.”2 The desperation of infertility patients combined with their financial burden, caused by inconsistent insurance coverage, has resulted in a perfect storm of frustration and overzealous recommendations for a successful outcome. Since the inception of in vitro fertilization (IVF) itself, infertility patients have been subjected to many unproven tests and procedures that enter the mainstream of care before unequivocal efficacy and safety have been shown.
From ovarian stimulation with intrauterine insemination (IUI) or IVF along with intracytoplasmic sperm injection (ICSI), assisted hatching, and preimplantation genetic testing for aneuploidy (PGT-A), a multitude of options with varying success can overwhelm fertility patients as they walk the tightrope of wanting “the kitchen sink” of treatment while experiencing sticker shock. This month’s article examines the top 10 infertility add-ons that have yet to be shown to improve pregnancy outcomes.
1. Blood testing: Prolactin and FSH
In a woman with ovulatory monthly menstrual cycles, a serum prolactin level provides no elucidation of the cause of infertility. If obtained following ovulation, prolactin can often be physiologically elevated, thereby compelling a repeat blood level, which is ideally performed during the early proliferative phase. False elevations of prolactin can be caused by an early morning blood sample, eating, and stress – which may result from worry caused by having to repeat the unnecessary initial blood test!
Follicle-stimulating hormone (FSH) was a first-line hormone test to assess for ovarian age. For nearly 15 years now, FSH has been replaced by anti-Müllerian hormone as a more reliable and earlier test for diminished ovarian reserve. However, FSH is still the hormone test of choice to diagnose primary ovarian insufficiency. Note that the use of ovarian age testing in a woman without infertility can result in both unnecessary patient anxiety and additional testing.
2. Endometrial scratch
The concept was understandable, that is, induce endometrial trauma by a biopsy or “scratch,” that results in an inflammatory and immunologic response to increase implantation. Endometrial sampling was recommended to be performed during the month prior to the embryo transfer cycle. While the procedure is brief, the pain response of women varies from minimal to severe. Unfortunately, a randomized controlled trial of over 1,300 patients did not show any improvement in the IVF live birth rate from the scratch procedure.3
3. Diagnostic laparoscopy
In years past, a diagnosis of unexplained infertility was not accepted until a laparoscopy was performed that revealed a normal pelvis. This approach subjected many women to an unindicated and a potentially risky surgery that has not shown benefit. The American Society for Reproductive Medicine’s ReproductiveFacts.org website states: “Routine diagnostic laparoscopy should not be performed unless there is a suspicion of pelvic pathology based on clinical history, an abnormal pelvic exam, or abnormalities identified with less invasive testing. In patients with a normal hysterosalpingogram or the presence of a unilaterally patent tube, diagnostic laparoscopy typically will not change the initial recommendation for treatment.”
4. Prescribing clomiphene citrate without IUI
Ovulation dysfunction is found in 40% of female factors for fertility. Provided testing reveals a reasonably normal sperm analysis and hysterosalpingogram, ovulation induction medication with ultrasound monitoring along with an hCG trigger is appropriate. In women who ovulate with unexplained infertility and/or mild male factor, the use of clomiphene citrate or letrozole with timed intercourse is often prescribed, particularly in clinics when IUI preparation is not available. Unfortunately, without including IUI, the use of oral ovarian stimulation has been shown by good evidence to be no more effective than natural cycle attempts at conception.4
5. Thrombophilia testing
Recurrent miscarriage, defined by the spontaneous loss of two or more pregnancies (often during the first trimester but may include up to 20 weeks estimated gestational age), has remained an ill-defined problem that lacks a consensus on the most optimal evaluation and treatment. In 2006, an international consensus statement provided guidance on laboratory testing for antiphospholipid syndrome limited to lupus anticoagulant, anticardiolipin IgG and IgM, and IgG and IgM anti–beta2-glycoprotein I assays.5 ASRM does not recommend additional thrombophilia tests as they are unproven causative factors of recurrent miscarriage.
6. Screening hysteroscopy
A standard infertility evaluation includes ovulation testing, assessment of fallopian tube patency, and a sperm analysis. In a subfertile women with a normal ultrasound or hysterosalpingogram in the basic fertility work‐up, a Cochrane data review concluded there is no definitive evidence for improved outcome with a screening hysteroscopy prior to IUI or IVF.6,7 Two large trials included in the Cochrane review, confirmed similar live birth rates whether or not hysteroscopy was performed before IVF. There may value in screening patients with recurrent implantation failure.
7. PGT-A for all
As the efficacy of the first generation of embryo preimplantation genetic testing, i.e., FISH (fluorescence in situ hybridization) was disproven, so has the same result been determined for PGT-A, specifically in women younger than 35.8 In an elegant randomized prospective trial, Munne and colleagues showed no improvement in the ongoing pregnancy rate (OPR) of study patients of all ages who were enrolled with the intention to treat. However, a subanalysis of patients aged 35-40 who completed the protocol did show an improved OPR and lower miscarriage rate per embryo transfer. While there is no evidence to support improved outcomes with the universal application of PGT-A, there may be some benefit in women older than 35 as well as in certain individual patient circumstances.
8. ICSI for nonmale factor infertility; assisted hatching
In an effort to reduce the risk of fertilization failure, programs have broadened the use of ICSI to nonmale factor infertility. While it has been used in PGT to reduce the risk of DNA contamination, particularly in PGT-M (monogenic disorder) and PGT-SR (structural rearrangement) cases, ICSI has not been shown to improve outcomes when there is a normal sperm analysis.9 During IVF embryo development, assisted hatching involves the thinning and/or opening of the zona pellucida either by chemical, mechanical, or laser means around the embryo before transfer with the intention of facilitating implantation. The routine use of assisted hatching is not recommended based on the lack of increase in live birth rates and because it may increase multiple pregnancy and monozygotic twinning rates.10
9. Acupuncture
Four meta-analyses showed no evidence of the overall benefit of acupuncture for improving live birth rates regardless of whether acupuncture was performed around the time of oocyte retrieval or around the day of embryo transfer. Consequently, acupuncture cannot be recommended routinely to improve IVF outcomes.11
10. Immunologic tests/treatments
Given the “foreign” genetic nature of a fetus, attempts to suppress the maternal immunologic response to sustain the pregnancy have been made for decades, especially for recurrent miscarriage and recurrent implantation failure with IVF. Testing has included natural killer (NK) cells, human leukocyte antigen (HLA) genotypes, and cytokines. While NK cells can be examined by endometrial biopsy, levels fluctuate based on the cycle phase, and no correlation between peripheral blood testing and uterine NK cell levels has been shown. Further, no consensus has been reached on reliable normal reference ranges in uterine NK cells.12
Several treatments have been proposed to somehow modulate the immune system during the implantation process thereby improving implantation and live birth, including lipid emulsion (intralipid) infusion, intravenous immunoglobulin, leukocyte immunization therapy, tacrolimus, anti–tumor necrosis factor agents, and granulocyte colony-stimulating factor. A recent systematic review and meta-analysis cited low-quality studies and did not recommend the use of any of these immune treatments.13 Further, immunomodulation has many known side effects, some of which are serious (including hepatosplenomegaly, thrombocytopenia, leukopenia, renal failure, thromboembolism, and anaphylactic reactions). Excluding women with autoimmune disease, taking glucocorticoids or other immune treatments to improve fertility has not been proven.13
Conclusion
To quote the New York Times opinion piece, “IVF remains an under-regulated arena, and entrepreneurial doctors and pharmaceutical and life science companies are eager to find new ways to cash in on a growing global market that is projected to be as large as $40 billion by 2024.” While this bold statement compels a huge “Ouch!”, it reminds us of our obligation to provide evidence-based medicine and to include emotional and financial harm to our oath of Primum non nocere.
References
1. The News York Times. 2019 Dec 12. Opinion.
2. Wilkinson J et al. Fertil Steril. 2019;112(6):973-7.
3. Lensen S et al. N Engl J Med. 2019 Jan 24;380(4):325-34.
4. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2020;113(2):305-22.
5. Miyakis S et al. J Thromb Haemost. 2006;4(2):295-306.
6. Kamath MS et al. Cochrane Database Syst Rev. 2019 Apr 16;4(4):CD012856.
7. Bosteels J et al. Cochrane Database Syst Rev. 2013 Jan 31;(1):CD009461.
8. Munne S et al. Fertil Steril. 2019;112(6):1071-9.
9. Practice Committees of the American Society for Reproductive Medicine and the Society for Assisted Reproductive Technology. Fertil Steril. 2020;114(2):239-45.
10. Lacey L et al. Cochrane Database Syst Rev. March 7 2021;3:2199.
11. Coyle ME et al. Acupunct Med. 2021;39(1):20-9.
12. Von Woon E et al. Hum Reprod Update. 2022;30;28(4):548-82.
13. Achilli C et al. Fertil Steril. 2018;110(6):1089-100.
Update on high-grade vulvar interepithelial neoplasia
Vulvar squamous cell carcinomas (VSCC) comprise approximately 90% of all vulvar malignancies. Unlike cervical SCC, which are predominantly human papilloma virus (HPV) positive, only a minority of VSCC are HPV positive – on the order of 15%-25% of cases. Most cases occur in the setting of lichen sclerosus and are HPV negative.
Lichen sclerosus is a chronic inflammatory dermatitis typically involving the anogenital area, which in some cases can become seriously distorted (e.g. atrophy of the labia minora, clitoral phimosis, and introital stenosis). Although most cases are diagnosed in postmenopausal women, LS can affect women of any age. The true prevalence of lichen sclerosus is unknown. Recent studies have shown a prevalence of 1 in 60; among older women, it can even be as high as 1 in 30. While lichen sclerosus is a pruriginous condition, it is often asymptomatic. It is not considered a premalignant condition. The diagnosis is clinical; however, suspicious lesions (erosions/ulcerations, hyperkeratosis, pigmented areas, ecchymosis, warty or papular lesions), particularly when recalcitrant to adequate first-line therapy, should be biopsied.
VSCC arises from precursor lesions or high-grade vulvar intraepithelial neoplasia (VIN). The 2015 International Society for the Study of Vulvovaginal Disease nomenclature classifies high-grade VIN into high-grade squamous intraepithelial lesion (HSIL) and differentiated VIN (dVIN). Most patients with high-grade VIN are diagnosed with HSIL or usual type VIN. A preponderance of these lesions (75%-85%) are HPV positive, predominantly HPV 16. Vulvar HSIL (vHSIL) lesions affect younger women. The lesions tend to be multifocal and extensive. On the other hand, dVIN typically affects older women and commonly develops as a solitary lesion. While dVIN accounts for only a small subset of patients with high-grade VIN, these lesions are HPV negative and associated with lichen sclerosus.
Both disease entities, vHSIL and dVIN, are increasing in incidence. There is a higher risk and shortened period of progression to cancer in patients with dVIN compared to HSIL. The cancer risk of vHSIL is relatively low. The 10-year cumulative VSCC risk reported in the literature is 10.3%; 9.7% for vHSIL and 50% for dVIN. Patients with vHSIL could benefit from less aggressive treatment modalities.
Patients present with a constellation of signs such as itching, pain, burning, bleeding, and discharge. Chronic symptoms portend HPV-independent lesions associated with lichen sclerosus while episodic signs are suggestive of HPV-positive lesions.
The recurrence risk of high-grade VIN is 46%-70%. Risk factors for recurrence include age greater than 50, immunosuppression, metasynchronous HSIL, and multifocal lesions. Recurrences occur in up to 50% of women who have undergone surgery. For those who undergo surgical treatment for high-grade VIN, recurrence is more common in the setting of positive margins, underlying lichen sclerosis, persistent HPV infection, and immunosuppression.
Management of high-grade VIN is determined by the lesion characteristics, patient characteristics, and medical expertise. Given the risk of progression of high-grade VIN to cancer and risk of underlying cancer, surgical therapy is typically recommended. The treatment of choice is surgical excision in cases of dVIN. Surgical treatments include CO2 laser ablation, wide local excision, and vulvectomy. Women who undergo surgical treatment for vHSIL have about a 50% chance of the condition recurring 1 year later, irrespective of whether treatment is by surgical excision or laser vaporization.
Since surgery can be associated with disfigurement and sexual dysfunction, alternatives to surgery should be considered in cases of vHSIL. The potential for effect on sexual function should be part of preoperative counseling and treatment. Women treated for VIN often experience increased inhibition of sexual excitement and increased inhibition of orgasm. One study found that in women undergoing vulvar excision for VIN, the impairment was found to be psychological in nature. Overall, the studies of sexual effect from treatment of VIN have found that women do not return to their pretreatment sexual function. However, the optimal management of vHSIL has not been determined. Nonsurgical options include topical therapies (imiquimod, 5-fluorouracil, cidofovir, and interferon) and nonpharmacologic treatments, such as photodynamic therapy.
Imiquimod, a topical immune modulator, is the most studied pharmacologic treatment of vHSIL. The drug induces secretion of cytokines, creating an immune response that clears the HPV infection. Imiquimod is safe and well tolerated. The clinical response rate varies between 35% and 81%. A recent study demonstrated the efficacy of imiquimod and the treatment was found to be noninferior to surgery. Adverse events differed, with local pain following surgical treatment and local pruritus and erythema associated with imiquimod use. Some patients did not respond to imiquimod; it was thought by the authors of the study that specific immunological factors affect the clinical response.
In conclusion, high-grade VIN is a heterogeneous disease made up of two distinct disease entities with rising incidence. In contrast to dVIN, the cancer risk is low for patients with vHSIL. Treatment should be driven by the clinical characteristics of the vulvar lesions, patients’ preferences, sexual activity, and compliance. Future directions include risk stratification of patients with vHSIL who are most likely to benefit from topical treatments, thus reducing overtreatment. Molecular biomarkers that could identify dVIN at an early stage are needed.
Dr. Jackson-Moore is associate professor in gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Tucker is assistant professor of gynecologic oncology at the university.
References
Cendejas BR et al. Am J Obstet Gynecol. 2015 Mar;212(3):291-7.
Lebreton M et al. J Gynecol Obstet Hum Reprod. 2020 Nov;49(9):101801.
Thuijs NB et al. Int J Cancer. 2021 Jan 1;148(1):90-8. doi: 10.1002/ijc.33198. .
Trutnovsky G et al. Lancet. 2022 May 7;399(10337):1790-8. Erratum in: Lancet. 2022 Oct 8;400(10359):1194.
Vulvar squamous cell carcinomas (VSCC) comprise approximately 90% of all vulvar malignancies. Unlike cervical SCC, which are predominantly human papilloma virus (HPV) positive, only a minority of VSCC are HPV positive – on the order of 15%-25% of cases. Most cases occur in the setting of lichen sclerosus and are HPV negative.
Lichen sclerosus is a chronic inflammatory dermatitis typically involving the anogenital area, which in some cases can become seriously distorted (e.g. atrophy of the labia minora, clitoral phimosis, and introital stenosis). Although most cases are diagnosed in postmenopausal women, LS can affect women of any age. The true prevalence of lichen sclerosus is unknown. Recent studies have shown a prevalence of 1 in 60; among older women, it can even be as high as 1 in 30. While lichen sclerosus is a pruriginous condition, it is often asymptomatic. It is not considered a premalignant condition. The diagnosis is clinical; however, suspicious lesions (erosions/ulcerations, hyperkeratosis, pigmented areas, ecchymosis, warty or papular lesions), particularly when recalcitrant to adequate first-line therapy, should be biopsied.
VSCC arises from precursor lesions or high-grade vulvar intraepithelial neoplasia (VIN). The 2015 International Society for the Study of Vulvovaginal Disease nomenclature classifies high-grade VIN into high-grade squamous intraepithelial lesion (HSIL) and differentiated VIN (dVIN). Most patients with high-grade VIN are diagnosed with HSIL or usual type VIN. A preponderance of these lesions (75%-85%) are HPV positive, predominantly HPV 16. Vulvar HSIL (vHSIL) lesions affect younger women. The lesions tend to be multifocal and extensive. On the other hand, dVIN typically affects older women and commonly develops as a solitary lesion. While dVIN accounts for only a small subset of patients with high-grade VIN, these lesions are HPV negative and associated with lichen sclerosus.
Both disease entities, vHSIL and dVIN, are increasing in incidence. There is a higher risk and shortened period of progression to cancer in patients with dVIN compared to HSIL. The cancer risk of vHSIL is relatively low. The 10-year cumulative VSCC risk reported in the literature is 10.3%; 9.7% for vHSIL and 50% for dVIN. Patients with vHSIL could benefit from less aggressive treatment modalities.
Patients present with a constellation of signs such as itching, pain, burning, bleeding, and discharge. Chronic symptoms portend HPV-independent lesions associated with lichen sclerosus while episodic signs are suggestive of HPV-positive lesions.
The recurrence risk of high-grade VIN is 46%-70%. Risk factors for recurrence include age greater than 50, immunosuppression, metasynchronous HSIL, and multifocal lesions. Recurrences occur in up to 50% of women who have undergone surgery. For those who undergo surgical treatment for high-grade VIN, recurrence is more common in the setting of positive margins, underlying lichen sclerosis, persistent HPV infection, and immunosuppression.
Management of high-grade VIN is determined by the lesion characteristics, patient characteristics, and medical expertise. Given the risk of progression of high-grade VIN to cancer and risk of underlying cancer, surgical therapy is typically recommended. The treatment of choice is surgical excision in cases of dVIN. Surgical treatments include CO2 laser ablation, wide local excision, and vulvectomy. Women who undergo surgical treatment for vHSIL have about a 50% chance of the condition recurring 1 year later, irrespective of whether treatment is by surgical excision or laser vaporization.
Since surgery can be associated with disfigurement and sexual dysfunction, alternatives to surgery should be considered in cases of vHSIL. The potential for effect on sexual function should be part of preoperative counseling and treatment. Women treated for VIN often experience increased inhibition of sexual excitement and increased inhibition of orgasm. One study found that in women undergoing vulvar excision for VIN, the impairment was found to be psychological in nature. Overall, the studies of sexual effect from treatment of VIN have found that women do not return to their pretreatment sexual function. However, the optimal management of vHSIL has not been determined. Nonsurgical options include topical therapies (imiquimod, 5-fluorouracil, cidofovir, and interferon) and nonpharmacologic treatments, such as photodynamic therapy.
Imiquimod, a topical immune modulator, is the most studied pharmacologic treatment of vHSIL. The drug induces secretion of cytokines, creating an immune response that clears the HPV infection. Imiquimod is safe and well tolerated. The clinical response rate varies between 35% and 81%. A recent study demonstrated the efficacy of imiquimod and the treatment was found to be noninferior to surgery. Adverse events differed, with local pain following surgical treatment and local pruritus and erythema associated with imiquimod use. Some patients did not respond to imiquimod; it was thought by the authors of the study that specific immunological factors affect the clinical response.
In conclusion, high-grade VIN is a heterogeneous disease made up of two distinct disease entities with rising incidence. In contrast to dVIN, the cancer risk is low for patients with vHSIL. Treatment should be driven by the clinical characteristics of the vulvar lesions, patients’ preferences, sexual activity, and compliance. Future directions include risk stratification of patients with vHSIL who are most likely to benefit from topical treatments, thus reducing overtreatment. Molecular biomarkers that could identify dVIN at an early stage are needed.
Dr. Jackson-Moore is associate professor in gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Tucker is assistant professor of gynecologic oncology at the university.
References
Cendejas BR et al. Am J Obstet Gynecol. 2015 Mar;212(3):291-7.
Lebreton M et al. J Gynecol Obstet Hum Reprod. 2020 Nov;49(9):101801.
Thuijs NB et al. Int J Cancer. 2021 Jan 1;148(1):90-8. doi: 10.1002/ijc.33198. .
Trutnovsky G et al. Lancet. 2022 May 7;399(10337):1790-8. Erratum in: Lancet. 2022 Oct 8;400(10359):1194.
Vulvar squamous cell carcinomas (VSCC) comprise approximately 90% of all vulvar malignancies. Unlike cervical SCC, which are predominantly human papilloma virus (HPV) positive, only a minority of VSCC are HPV positive – on the order of 15%-25% of cases. Most cases occur in the setting of lichen sclerosus and are HPV negative.
Lichen sclerosus is a chronic inflammatory dermatitis typically involving the anogenital area, which in some cases can become seriously distorted (e.g. atrophy of the labia minora, clitoral phimosis, and introital stenosis). Although most cases are diagnosed in postmenopausal women, LS can affect women of any age. The true prevalence of lichen sclerosus is unknown. Recent studies have shown a prevalence of 1 in 60; among older women, it can even be as high as 1 in 30. While lichen sclerosus is a pruriginous condition, it is often asymptomatic. It is not considered a premalignant condition. The diagnosis is clinical; however, suspicious lesions (erosions/ulcerations, hyperkeratosis, pigmented areas, ecchymosis, warty or papular lesions), particularly when recalcitrant to adequate first-line therapy, should be biopsied.
VSCC arises from precursor lesions or high-grade vulvar intraepithelial neoplasia (VIN). The 2015 International Society for the Study of Vulvovaginal Disease nomenclature classifies high-grade VIN into high-grade squamous intraepithelial lesion (HSIL) and differentiated VIN (dVIN). Most patients with high-grade VIN are diagnosed with HSIL or usual type VIN. A preponderance of these lesions (75%-85%) are HPV positive, predominantly HPV 16. Vulvar HSIL (vHSIL) lesions affect younger women. The lesions tend to be multifocal and extensive. On the other hand, dVIN typically affects older women and commonly develops as a solitary lesion. While dVIN accounts for only a small subset of patients with high-grade VIN, these lesions are HPV negative and associated with lichen sclerosus.
Both disease entities, vHSIL and dVIN, are increasing in incidence. There is a higher risk and shortened period of progression to cancer in patients with dVIN compared to HSIL. The cancer risk of vHSIL is relatively low. The 10-year cumulative VSCC risk reported in the literature is 10.3%; 9.7% for vHSIL and 50% for dVIN. Patients with vHSIL could benefit from less aggressive treatment modalities.
Patients present with a constellation of signs such as itching, pain, burning, bleeding, and discharge. Chronic symptoms portend HPV-independent lesions associated with lichen sclerosus while episodic signs are suggestive of HPV-positive lesions.
The recurrence risk of high-grade VIN is 46%-70%. Risk factors for recurrence include age greater than 50, immunosuppression, metasynchronous HSIL, and multifocal lesions. Recurrences occur in up to 50% of women who have undergone surgery. For those who undergo surgical treatment for high-grade VIN, recurrence is more common in the setting of positive margins, underlying lichen sclerosis, persistent HPV infection, and immunosuppression.
Management of high-grade VIN is determined by the lesion characteristics, patient characteristics, and medical expertise. Given the risk of progression of high-grade VIN to cancer and risk of underlying cancer, surgical therapy is typically recommended. The treatment of choice is surgical excision in cases of dVIN. Surgical treatments include CO2 laser ablation, wide local excision, and vulvectomy. Women who undergo surgical treatment for vHSIL have about a 50% chance of the condition recurring 1 year later, irrespective of whether treatment is by surgical excision or laser vaporization.
Since surgery can be associated with disfigurement and sexual dysfunction, alternatives to surgery should be considered in cases of vHSIL. The potential for effect on sexual function should be part of preoperative counseling and treatment. Women treated for VIN often experience increased inhibition of sexual excitement and increased inhibition of orgasm. One study found that in women undergoing vulvar excision for VIN, the impairment was found to be psychological in nature. Overall, the studies of sexual effect from treatment of VIN have found that women do not return to their pretreatment sexual function. However, the optimal management of vHSIL has not been determined. Nonsurgical options include topical therapies (imiquimod, 5-fluorouracil, cidofovir, and interferon) and nonpharmacologic treatments, such as photodynamic therapy.
Imiquimod, a topical immune modulator, is the most studied pharmacologic treatment of vHSIL. The drug induces secretion of cytokines, creating an immune response that clears the HPV infection. Imiquimod is safe and well tolerated. The clinical response rate varies between 35% and 81%. A recent study demonstrated the efficacy of imiquimod and the treatment was found to be noninferior to surgery. Adverse events differed, with local pain following surgical treatment and local pruritus and erythema associated with imiquimod use. Some patients did not respond to imiquimod; it was thought by the authors of the study that specific immunological factors affect the clinical response.
In conclusion, high-grade VIN is a heterogeneous disease made up of two distinct disease entities with rising incidence. In contrast to dVIN, the cancer risk is low for patients with vHSIL. Treatment should be driven by the clinical characteristics of the vulvar lesions, patients’ preferences, sexual activity, and compliance. Future directions include risk stratification of patients with vHSIL who are most likely to benefit from topical treatments, thus reducing overtreatment. Molecular biomarkers that could identify dVIN at an early stage are needed.
Dr. Jackson-Moore is associate professor in gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Tucker is assistant professor of gynecologic oncology at the university.
References
Cendejas BR et al. Am J Obstet Gynecol. 2015 Mar;212(3):291-7.
Lebreton M et al. J Gynecol Obstet Hum Reprod. 2020 Nov;49(9):101801.
Thuijs NB et al. Int J Cancer. 2021 Jan 1;148(1):90-8. doi: 10.1002/ijc.33198. .
Trutnovsky G et al. Lancet. 2022 May 7;399(10337):1790-8. Erratum in: Lancet. 2022 Oct 8;400(10359):1194.