Commentary

My wife thinks I am a little morbid, because I still read the local Sunday newspaper not to catch up on the news, and certainly not for the ads, but mostly to read the obituaries.

All of us have elderly patients, and I am growing old with many of my older patients. Now after treating many thousands of patients whom I have grown to know well, it is not unusual to see an obituary of someone my office staff and I know in the newspaper on a weekly basis.

We send sympathy cards, sometimes I write a personal note to the spouse or family, and several times a year, some of my staff and I will go to the funeral or memorial ceremony.

I usually ask if they died well, comfortably with family, or better yet, suddenly, dropping dead like a stone. This is the unspoken, though usually unrealized, goal of many of us from the world of medicine.

All physicians who have been surrounded by death, some horrible deaths, want to die well. I think it is difficult to do, although my mother came close.

One day when dropping off her best little friend (my 10-year-old daughter), she said “look here, I’ve got a knot in my belly button.” I felt the blood rushing to my head and before I could stop her, she showed me her Sister Mary Joseph nodule, a sign of metastatic internal malignancy. I sat stunned as she looked at me; her eyes showed she already knew my answer.

She lasted at home for 6 weeks, went into hospice, and died 36 hours later.

The last morning before she died, I took my daughter to see her before school. She woke up and called her “sugar” and had her climb into bed with her and snuggle. I got choked up and tearful and started telling her how much I loved her and how sorry I was and how much we would miss her. She looked over at me, and with anger in her voice, told me to be quiet, and explained that death comes to everyone eventually and just to get over it. In retrospect, I understand now that I was not helping her die well.

I am telling this story to bring up a point about professionalism. A crucial part of professionalism is a responsiveness to patients’ needs that supersedes self interest. As dermatologists who treat skin cancer, this becomes important as the life cycle ends. Aged patients sometimes start blossoming with skin cancers. You must carefully gauge how much “treatment” a patient really needs.

You have a conflict. You get paid to diagnose and treat skin cancers. You must shift roles and become the patient’s protector, and treat the patient as if he or she was your parent. Less, sometimes much less, is often more. Perhaps you only biopsy and treat rapidly growing cancers that endanger crucial structures. You ignore the noninvasive tumors on the trunk and extremities. It is a fine and difficult line to walk.

Patients know they are dying, and at certain stages of grieving will want everything possible done, especially if it is visible. Skin wounds, even from curetting, salves, and cryotherapy, can be painful and sometimes disabling. You must resist unnecessary treatments, temporize if possible, discuss quality time with the patient and the family, and reach a consensus on how aggressive not to be. You must help them die well.

You are not only a healer, but as a master physician you – yes, even you the dermatologist – must also be a helpful guide at the end of life. I am sad to see patients, my old friends, in the newspaper, but feel secretly satisfied if I have spared them unnecessary suffering.
 

Dr. Coldiron is in private practice but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. He is a past president of the American Academy of Dermatology. Write to him at [email protected].

My wife thinks I am a little morbid, because I still read the local Sunday newspaper not to catch up on the news, and certainly not for the ads, but mostly to read the obituaries.

All of us have elderly patients, and I am growing old with many of my older patients. Now after treating many thousands of patients whom I have grown to know well, it is not unusual to see an obituary of someone my office staff and I know in the newspaper on a weekly basis.

We send sympathy cards, sometimes I write a personal note to the spouse or family, and several times a year, some of my staff and I will go to the funeral or memorial ceremony.

I usually ask if they died well, comfortably with family, or better yet, suddenly, dropping dead like a stone. This is the unspoken, though usually unrealized, goal of many of us from the world of medicine.

All physicians who have been surrounded by death, some horrible deaths, want to die well. I think it is difficult to do, although my mother came close.

One day when dropping off her best little friend (my 10-year-old daughter), she said “look here, I’ve got a knot in my belly button.” I felt the blood rushing to my head and before I could stop her, she showed me her Sister Mary Joseph nodule, a sign of metastatic internal malignancy. I sat stunned as she looked at me; her eyes showed she already knew my answer.

She lasted at home for 6 weeks, went into hospice, and died 36 hours later.

The last morning before she died, I took my daughter to see her before school. She woke up and called her “sugar” and had her climb into bed with her and snuggle. I got choked up and tearful and started telling her how much I loved her and how sorry I was and how much we would miss her. She looked over at me, and with anger in her voice, told me to be quiet, and explained that death comes to everyone eventually and just to get over it. In retrospect, I understand now that I was not helping her die well.

I am telling this story to bring up a point about professionalism. A crucial part of professionalism is a responsiveness to patients’ needs that supersedes self interest. As dermatologists who treat skin cancer, this becomes important as the life cycle ends. Aged patients sometimes start blossoming with skin cancers. You must carefully gauge how much “treatment” a patient really needs.

You have a conflict. You get paid to diagnose and treat skin cancers. You must shift roles and become the patient’s protector, and treat the patient as if he or she was your parent. Less, sometimes much less, is often more. Perhaps you only biopsy and treat rapidly growing cancers that endanger crucial structures. You ignore the noninvasive tumors on the trunk and extremities. It is a fine and difficult line to walk.

Patients know they are dying, and at certain stages of grieving will want everything possible done, especially if it is visible. Skin wounds, even from curetting, salves, and cryotherapy, can be painful and sometimes disabling. You must resist unnecessary treatments, temporize if possible, discuss quality time with the patient and the family, and reach a consensus on how aggressive not to be. You must help them die well.

You are not only a healer, but as a master physician you – yes, even you the dermatologist – must also be a helpful guide at the end of life. I am sad to see patients, my old friends, in the newspaper, but feel secretly satisfied if I have spared them unnecessary suffering.
 

Dr. Coldiron is in private practice but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. He is a past president of the American Academy of Dermatology. Write to him at [email protected].

My wife thinks I am a little morbid, because I still read the local Sunday newspaper not to catch up on the news, and certainly not for the ads, but mostly to read the obituaries.

All of us have elderly patients, and I am growing old with many of my older patients. Now after treating many thousands of patients whom I have grown to know well, it is not unusual to see an obituary of someone my office staff and I know in the newspaper on a weekly basis.

We send sympathy cards, sometimes I write a personal note to the spouse or family, and several times a year, some of my staff and I will go to the funeral or memorial ceremony.

I usually ask if they died well, comfortably with family, or better yet, suddenly, dropping dead like a stone. This is the unspoken, though usually unrealized, goal of many of us from the world of medicine.

All physicians who have been surrounded by death, some horrible deaths, want to die well. I think it is difficult to do, although my mother came close.

One day when dropping off her best little friend (my 10-year-old daughter), she said “look here, I’ve got a knot in my belly button.” I felt the blood rushing to my head and before I could stop her, she showed me her Sister Mary Joseph nodule, a sign of metastatic internal malignancy. I sat stunned as she looked at me; her eyes showed she already knew my answer.

She lasted at home for 6 weeks, went into hospice, and died 36 hours later.

The last morning before she died, I took my daughter to see her before school. She woke up and called her “sugar” and had her climb into bed with her and snuggle. I got choked up and tearful and started telling her how much I loved her and how sorry I was and how much we would miss her. She looked over at me, and with anger in her voice, told me to be quiet, and explained that death comes to everyone eventually and just to get over it. In retrospect, I understand now that I was not helping her die well.

I am telling this story to bring up a point about professionalism. A crucial part of professionalism is a responsiveness to patients’ needs that supersedes self interest. As dermatologists who treat skin cancer, this becomes important as the life cycle ends. Aged patients sometimes start blossoming with skin cancers. You must carefully gauge how much “treatment” a patient really needs.

You have a conflict. You get paid to diagnose and treat skin cancers. You must shift roles and become the patient’s protector, and treat the patient as if he or she was your parent. Less, sometimes much less, is often more. Perhaps you only biopsy and treat rapidly growing cancers that endanger crucial structures. You ignore the noninvasive tumors on the trunk and extremities. It is a fine and difficult line to walk.

Patients know they are dying, and at certain stages of grieving will want everything possible done, especially if it is visible. Skin wounds, even from curetting, salves, and cryotherapy, can be painful and sometimes disabling. You must resist unnecessary treatments, temporize if possible, discuss quality time with the patient and the family, and reach a consensus on how aggressive not to be. You must help them die well.

You are not only a healer, but as a master physician you – yes, even you the dermatologist – must also be a helpful guide at the end of life. I am sad to see patients, my old friends, in the newspaper, but feel secretly satisfied if I have spared them unnecessary suffering.
 

Dr. Coldiron is in private practice but maintains a clinical assistant professorship at the University of Cincinnati. He cares for patients, teaches medical students and residents, and has several active clinical research projects. Dr. Coldiron is the author of more than 80 scientific letters, papers, and several book chapters, and he speaks frequently on a variety of topics. He is a past president of the American Academy of Dermatology. Write to him at [email protected].

Most of us did our postgraduate training in tertiary medical centers, ivory towers of medicine often attached to or closely affiliated with medical schools. These are the places where the buck stops. Occasionally, a very complex patient might be sent to another tertiary center that claims to have a supersubspecialist, a one-of-a-kind physician with nationally recognized expertise. But for most patients, the tertiary medical center is the end of the line, and his or her physicians must manage with the resources at hand. They may confer with one another but there is no place for them to pass the buck.

Yuri_Arcurs/DigitalVision/Getty Images

But most of us who chose primary care left the comforting cocoon of the teaching hospital complex when we finished our training. Those first few months and years in the hinterland can be angst producing. Until we have established our own personal networks of consultants and mentors, patients with more than run-of-the-mill complaints may prompt us to reach for the phone or fire off an email call for help to our recently departed mother ship.

It can take awhile to establish the self-confidence – or at least the appearance of self-confidence – that physicians are expected to exude. But even after years of experience, none of us wants to watch a patient die or suffer preventable complications under our care when we know there is another facility that can provide a higher lever of care just an ambulance ride or short helicopter trip away.

Our primary concern is of course assuring that our patient is receiving the best care. How quickly we reach for the phone to refer out the most fragile patients depends on several factors. Do we practice in a community that has a historic reputation of having a low threshold for malpractice suits? How well do we know the patient and her family? Have we had time to establish bidirectional trust?

Is the patient’s diagnosis one that we feel comfortable with or is the diagnosis one that we believe could quickly deteriorate without warning? For example, a recently published study revealed that 20% of pediatric trauma patients were overtriaged and that the mechanism of injury – firearms or motor vehicle accidents – appeared to have an outsized influence in the triage decision (Trauma Surg Acute Care Open. 2019 Dec 29. doi: 10.1136/tsaco-2019-000300).

Courtesy Dr. William G. Wilkoff

Because I have no experience with firearm injuries and minimal experience with motor vehicle injuries I can understand why the emergency medical technicians might be quick to ship these patients to the trauma center. However, I hope that, were I offered better training and more opportunities to gain experience with these types of injuries, I would have a lower overtriage percentage.

Which begs the question of what is an acceptable rate of overtriage or overreferral? It’s the same old question of how many normal appendixes should one remove to avoid a fatal outcome. Each of us arrives at a given clinical crossroads with our own level of experience and comfort level. Our level of confidence in our local peer and specialty support network helps us decide when it is time to transfer a patient to a higher-level facility.

But in the final analysis it boils down to a personal decision and our own basic level of anxiety. Let’s face it, some of us worry more than others. Physicians come in all shades of anxiety. A hot potato in your hands may feel only room temperature to me.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

Most of us did our postgraduate training in tertiary medical centers, ivory towers of medicine often attached to or closely affiliated with medical schools. These are the places where the buck stops. Occasionally, a very complex patient might be sent to another tertiary center that claims to have a supersubspecialist, a one-of-a-kind physician with nationally recognized expertise. But for most patients, the tertiary medical center is the end of the line, and his or her physicians must manage with the resources at hand. They may confer with one another but there is no place for them to pass the buck.

Yuri_Arcurs/DigitalVision/Getty Images

But most of us who chose primary care left the comforting cocoon of the teaching hospital complex when we finished our training. Those first few months and years in the hinterland can be angst producing. Until we have established our own personal networks of consultants and mentors, patients with more than run-of-the-mill complaints may prompt us to reach for the phone or fire off an email call for help to our recently departed mother ship.

It can take awhile to establish the self-confidence – or at least the appearance of self-confidence – that physicians are expected to exude. But even after years of experience, none of us wants to watch a patient die or suffer preventable complications under our care when we know there is another facility that can provide a higher lever of care just an ambulance ride or short helicopter trip away.

Our primary concern is of course assuring that our patient is receiving the best care. How quickly we reach for the phone to refer out the most fragile patients depends on several factors. Do we practice in a community that has a historic reputation of having a low threshold for malpractice suits? How well do we know the patient and her family? Have we had time to establish bidirectional trust?

Is the patient’s diagnosis one that we feel comfortable with or is the diagnosis one that we believe could quickly deteriorate without warning? For example, a recently published study revealed that 20% of pediatric trauma patients were overtriaged and that the mechanism of injury – firearms or motor vehicle accidents – appeared to have an outsized influence in the triage decision (Trauma Surg Acute Care Open. 2019 Dec 29. doi: 10.1136/tsaco-2019-000300).

Courtesy Dr. William G. Wilkoff

Because I have no experience with firearm injuries and minimal experience with motor vehicle injuries I can understand why the emergency medical technicians might be quick to ship these patients to the trauma center. However, I hope that, were I offered better training and more opportunities to gain experience with these types of injuries, I would have a lower overtriage percentage.

Which begs the question of what is an acceptable rate of overtriage or overreferral? It’s the same old question of how many normal appendixes should one remove to avoid a fatal outcome. Each of us arrives at a given clinical crossroads with our own level of experience and comfort level. Our level of confidence in our local peer and specialty support network helps us decide when it is time to transfer a patient to a higher-level facility.

But in the final analysis it boils down to a personal decision and our own basic level of anxiety. Let’s face it, some of us worry more than others. Physicians come in all shades of anxiety. A hot potato in your hands may feel only room temperature to me.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

Most of us did our postgraduate training in tertiary medical centers, ivory towers of medicine often attached to or closely affiliated with medical schools. These are the places where the buck stops. Occasionally, a very complex patient might be sent to another tertiary center that claims to have a supersubspecialist, a one-of-a-kind physician with nationally recognized expertise. But for most patients, the tertiary medical center is the end of the line, and his or her physicians must manage with the resources at hand. They may confer with one another but there is no place for them to pass the buck.

Yuri_Arcurs/DigitalVision/Getty Images

But most of us who chose primary care left the comforting cocoon of the teaching hospital complex when we finished our training. Those first few months and years in the hinterland can be angst producing. Until we have established our own personal networks of consultants and mentors, patients with more than run-of-the-mill complaints may prompt us to reach for the phone or fire off an email call for help to our recently departed mother ship.

It can take awhile to establish the self-confidence – or at least the appearance of self-confidence – that physicians are expected to exude. But even after years of experience, none of us wants to watch a patient die or suffer preventable complications under our care when we know there is another facility that can provide a higher lever of care just an ambulance ride or short helicopter trip away.

Our primary concern is of course assuring that our patient is receiving the best care. How quickly we reach for the phone to refer out the most fragile patients depends on several factors. Do we practice in a community that has a historic reputation of having a low threshold for malpractice suits? How well do we know the patient and her family? Have we had time to establish bidirectional trust?

Is the patient’s diagnosis one that we feel comfortable with or is the diagnosis one that we believe could quickly deteriorate without warning? For example, a recently published study revealed that 20% of pediatric trauma patients were overtriaged and that the mechanism of injury – firearms or motor vehicle accidents – appeared to have an outsized influence in the triage decision (Trauma Surg Acute Care Open. 2019 Dec 29. doi: 10.1136/tsaco-2019-000300).

Courtesy Dr. William G. Wilkoff

Because I have no experience with firearm injuries and minimal experience with motor vehicle injuries I can understand why the emergency medical technicians might be quick to ship these patients to the trauma center. However, I hope that, were I offered better training and more opportunities to gain experience with these types of injuries, I would have a lower overtriage percentage.

Which begs the question of what is an acceptable rate of overtriage or overreferral? It’s the same old question of how many normal appendixes should one remove to avoid a fatal outcome. Each of us arrives at a given clinical crossroads with our own level of experience and comfort level. Our level of confidence in our local peer and specialty support network helps us decide when it is time to transfer a patient to a higher-level facility.

But in the final analysis it boils down to a personal decision and our own basic level of anxiety. Let’s face it, some of us worry more than others. Physicians come in all shades of anxiety. A hot potato in your hands may feel only room temperature to me.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

I agree wholeheartedly with Dr. William G. Wilkoff’s doubts that an increase in medical schools/students and/or foreign medical graduates is the answer to the physician shortage felt by many areas of the country (Letters From Maine, “Help Wanted,” Nov. 2019, page 19). All you have to do is look at the glut of physicians – and just about any other profession – in metropolitan areas versus rural America, and ask basic questions regarding why those doctors practice where they do. You will quickly discover that most are willing to trade the possibility of a higher salary in areas where their presence is more needed to achieve more school choices, jobs for a spouse, and likely a more favorable call schedule. Something more attractive than salary or the prospect of more “elbow room” is desired.

Here in Mississippi we may have found an answer to the problem. A few years ago our state legislature started the Mississippi Rural Health Scholarship Program that pays for recipients to attend a state-run medical school on scholarship in exchange for agreeing to practice at least 4 years in a rural area of the state (less than 20k population) following their primary care residency (family medicine, pediatrics, ob.gyn., med-peds, internal medicine, and, recently added, psychiatry). Although a recent increase in the number of pediatric residency slots at our state’s sole program will no doubt also have a positive effect to this end, such a scholarship program as the one implemented by Mississippi is the best way to compete with the various intangibles that lead people to choose bigger cities over rural areas of the state to practice their trade. Once there, many – like myself – will find that such a practice is not only a good business decision but often is a wonderful place to raise a family. Meanwhile, our own practice just added a fourth physician as a result of said Rural Health Scholarship Program, and we could not be more satisfied with the result.
 

I agree wholeheartedly with Dr. William G. Wilkoff’s doubts that an increase in medical schools/students and/or foreign medical graduates is the answer to the physician shortage felt by many areas of the country (Letters From Maine, “Help Wanted,” Nov. 2019, page 19). All you have to do is look at the glut of physicians – and just about any other profession – in metropolitan areas versus rural America, and ask basic questions regarding why those doctors practice where they do. You will quickly discover that most are willing to trade the possibility of a higher salary in areas where their presence is more needed to achieve more school choices, jobs for a spouse, and likely a more favorable call schedule. Something more attractive than salary or the prospect of more “elbow room” is desired.

Here in Mississippi we may have found an answer to the problem. A few years ago our state legislature started the Mississippi Rural Health Scholarship Program that pays for recipients to attend a state-run medical school on scholarship in exchange for agreeing to practice at least 4 years in a rural area of the state (less than 20k population) following their primary care residency (family medicine, pediatrics, ob.gyn., med-peds, internal medicine, and, recently added, psychiatry). Although a recent increase in the number of pediatric residency slots at our state’s sole program will no doubt also have a positive effect to this end, such a scholarship program as the one implemented by Mississippi is the best way to compete with the various intangibles that lead people to choose bigger cities over rural areas of the state to practice their trade. Once there, many – like myself – will find that such a practice is not only a good business decision but often is a wonderful place to raise a family. Meanwhile, our own practice just added a fourth physician as a result of said Rural Health Scholarship Program, and we could not be more satisfied with the result.
 

I agree wholeheartedly with Dr. William G. Wilkoff’s doubts that an increase in medical schools/students and/or foreign medical graduates is the answer to the physician shortage felt by many areas of the country (Letters From Maine, “Help Wanted,” Nov. 2019, page 19). All you have to do is look at the glut of physicians – and just about any other profession – in metropolitan areas versus rural America, and ask basic questions regarding why those doctors practice where they do. You will quickly discover that most are willing to trade the possibility of a higher salary in areas where their presence is more needed to achieve more school choices, jobs for a spouse, and likely a more favorable call schedule. Something more attractive than salary or the prospect of more “elbow room” is desired.

Here in Mississippi we may have found an answer to the problem. A few years ago our state legislature started the Mississippi Rural Health Scholarship Program that pays for recipients to attend a state-run medical school on scholarship in exchange for agreeing to practice at least 4 years in a rural area of the state (less than 20k population) following their primary care residency (family medicine, pediatrics, ob.gyn., med-peds, internal medicine, and, recently added, psychiatry). Although a recent increase in the number of pediatric residency slots at our state’s sole program will no doubt also have a positive effect to this end, such a scholarship program as the one implemented by Mississippi is the best way to compete with the various intangibles that lead people to choose bigger cities over rural areas of the state to practice their trade. Once there, many – like myself – will find that such a practice is not only a good business decision but often is a wonderful place to raise a family. Meanwhile, our own practice just added a fourth physician as a result of said Rural Health Scholarship Program, and we could not be more satisfied with the result.
 

The time has come for good men and women to unite and rise up against a common foe. For too long nurses and doctors have labored under the tyranny of a dictator who claimed to help them provide high-quality care for their patients while at the same time cutting their paperwork to nil. But like most autocrats he failed to engage his subjects in a meaningful dialogue as each new version of his promised improvements rolled off the drawing board. When the caregivers were slow to adopt these new nonsystems he offered them financial incentives and issued threats to their survival. Although they were warned that there might be uncomfortable adjustment periods, the caregivers were promised that the steep learning curves would level out and their professional lives would again be valued and productive.

Of course, the dictator is not a single person but a motley and disorganized conglomerate of user- and patient-unfriendly electronic health record nonsystems. Ask almost any nurse or physician for her feelings about computer-based medical record systems, and you will hear tales of long hours, disengagement, and frustration. Caregivers are unhappy at all levels, and patients have grown tired of their nurses and physicians spending most of their time looking at computer screens.

You certainly have heard this all before. But you are hearing it in hospital hallways and grocery store checkout lines as a low rumble of discontent emerging from separate individuals, not as a well-articulated and widely distributed voice of physicians as a group. To some extent this relative silence is because there is no such group, at least not in same mold as a labor union. The term “labor union” may make you uncomfortable. But given the current climate in medicine, unionizing may be the best and only way to effect change.

But organizing to effect change in the workplace isn’t part of the physician genome. In the 1960s, a group of house officers in Boston engaged in a heal-in to successfully improve their salaries and working conditions. But over the ensuing half century physicians have remained tragically silent in the face of a changing workplace landscape in which they have gone from being independent owner operators in control of their destinies to becoming employees feeling powerless to improve their working conditions. This perceived impotence has escalated in the face of the challenge posed by the introduction of dysfunctional EHRs.

Ironically, a solution is at almost every physician’s elbow. In a recent New York Times opinion piece Theresa Brown and Stephen Bergman acknowledge that physicians don’t seem prepared to mount a meaningful response to the challenge to the failed promise of EHRs (“Doctors, Nurses and the Paperwork Crisis That Could Unite Them,” Dec. 31, 2019). They point out that, over the last half century, physicians have remained isolated on the sidelines, finding just enough voice to grumble. Nurses have in a variety of situations organized to effect change in their working conditions – in some cases by forming labor unions.

The authors of this op-ed piece, a physician and a nurse, make a strong argument that the time has come for nurses and doctors shake off the shackles of their stereotypic roles and join in creating a loud, forceful, and effective voice to demand a working environment in which the computer functions as an asset and no longer as the terrible burden it has become. Neither group has the power to do it alone, but together they may be able to turn the tide. For physicians it will probably mean venturing several steps outside of their comfort zone. But working shoulder to shoulder with nurses may provide the courage to speak out.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

The time has come for good men and women to unite and rise up against a common foe. For too long nurses and doctors have labored under the tyranny of a dictator who claimed to help them provide high-quality care for their patients while at the same time cutting their paperwork to nil. But like most autocrats he failed to engage his subjects in a meaningful dialogue as each new version of his promised improvements rolled off the drawing board. When the caregivers were slow to adopt these new nonsystems he offered them financial incentives and issued threats to their survival. Although they were warned that there might be uncomfortable adjustment periods, the caregivers were promised that the steep learning curves would level out and their professional lives would again be valued and productive.

Of course, the dictator is not a single person but a motley and disorganized conglomerate of user- and patient-unfriendly electronic health record nonsystems. Ask almost any nurse or physician for her feelings about computer-based medical record systems, and you will hear tales of long hours, disengagement, and frustration. Caregivers are unhappy at all levels, and patients have grown tired of their nurses and physicians spending most of their time looking at computer screens.

You certainly have heard this all before. But you are hearing it in hospital hallways and grocery store checkout lines as a low rumble of discontent emerging from separate individuals, not as a well-articulated and widely distributed voice of physicians as a group. To some extent this relative silence is because there is no such group, at least not in same mold as a labor union. The term “labor union” may make you uncomfortable. But given the current climate in medicine, unionizing may be the best and only way to effect change.

But organizing to effect change in the workplace isn’t part of the physician genome. In the 1960s, a group of house officers in Boston engaged in a heal-in to successfully improve their salaries and working conditions. But over the ensuing half century physicians have remained tragically silent in the face of a changing workplace landscape in which they have gone from being independent owner operators in control of their destinies to becoming employees feeling powerless to improve their working conditions. This perceived impotence has escalated in the face of the challenge posed by the introduction of dysfunctional EHRs.

Ironically, a solution is at almost every physician’s elbow. In a recent New York Times opinion piece Theresa Brown and Stephen Bergman acknowledge that physicians don’t seem prepared to mount a meaningful response to the challenge to the failed promise of EHRs (“Doctors, Nurses and the Paperwork Crisis That Could Unite Them,” Dec. 31, 2019). They point out that, over the last half century, physicians have remained isolated on the sidelines, finding just enough voice to grumble. Nurses have in a variety of situations organized to effect change in their working conditions – in some cases by forming labor unions.

The authors of this op-ed piece, a physician and a nurse, make a strong argument that the time has come for nurses and doctors shake off the shackles of their stereotypic roles and join in creating a loud, forceful, and effective voice to demand a working environment in which the computer functions as an asset and no longer as the terrible burden it has become. Neither group has the power to do it alone, but together they may be able to turn the tide. For physicians it will probably mean venturing several steps outside of their comfort zone. But working shoulder to shoulder with nurses may provide the courage to speak out.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

The time has come for good men and women to unite and rise up against a common foe. For too long nurses and doctors have labored under the tyranny of a dictator who claimed to help them provide high-quality care for their patients while at the same time cutting their paperwork to nil. But like most autocrats he failed to engage his subjects in a meaningful dialogue as each new version of his promised improvements rolled off the drawing board. When the caregivers were slow to adopt these new nonsystems he offered them financial incentives and issued threats to their survival. Although they were warned that there might be uncomfortable adjustment periods, the caregivers were promised that the steep learning curves would level out and their professional lives would again be valued and productive.

Of course, the dictator is not a single person but a motley and disorganized conglomerate of user- and patient-unfriendly electronic health record nonsystems. Ask almost any nurse or physician for her feelings about computer-based medical record systems, and you will hear tales of long hours, disengagement, and frustration. Caregivers are unhappy at all levels, and patients have grown tired of their nurses and physicians spending most of their time looking at computer screens.

You certainly have heard this all before. But you are hearing it in hospital hallways and grocery store checkout lines as a low rumble of discontent emerging from separate individuals, not as a well-articulated and widely distributed voice of physicians as a group. To some extent this relative silence is because there is no such group, at least not in same mold as a labor union. The term “labor union” may make you uncomfortable. But given the current climate in medicine, unionizing may be the best and only way to effect change.

But organizing to effect change in the workplace isn’t part of the physician genome. In the 1960s, a group of house officers in Boston engaged in a heal-in to successfully improve their salaries and working conditions. But over the ensuing half century physicians have remained tragically silent in the face of a changing workplace landscape in which they have gone from being independent owner operators in control of their destinies to becoming employees feeling powerless to improve their working conditions. This perceived impotence has escalated in the face of the challenge posed by the introduction of dysfunctional EHRs.

Ironically, a solution is at almost every physician’s elbow. In a recent New York Times opinion piece Theresa Brown and Stephen Bergman acknowledge that physicians don’t seem prepared to mount a meaningful response to the challenge to the failed promise of EHRs (“Doctors, Nurses and the Paperwork Crisis That Could Unite Them,” Dec. 31, 2019). They point out that, over the last half century, physicians have remained isolated on the sidelines, finding just enough voice to grumble. Nurses have in a variety of situations organized to effect change in their working conditions – in some cases by forming labor unions.

The authors of this op-ed piece, a physician and a nurse, make a strong argument that the time has come for nurses and doctors shake off the shackles of their stereotypic roles and join in creating a loud, forceful, and effective voice to demand a working environment in which the computer functions as an asset and no longer as the terrible burden it has become. Neither group has the power to do it alone, but together they may be able to turn the tide. For physicians it will probably mean venturing several steps outside of their comfort zone. But working shoulder to shoulder with nurses may provide the courage to speak out.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Email him at [email protected].

While the frequency of dense breasts decreases with age, approximately 10% of women in the United States have extremely dense breasts (Breast Imaging, Reporting, and Data System [BI-RADS] category D), and another 40% have heterogeneously dense breasts (BI-RADS category C).¹ Women with dense breasts have both an increased risk for developing breast cancer and reduced mammographic sensitivity for breast cancer detection compared with women who have nondense breasts.²

These 2 observations have led the majority of states to pass legislation requiring that women with dense breasts be informed of their breast density, and most require that providers discuss these results with their patients. Thoughtful clinicians who review the available literature, however, will find sparse evidence on which to counsel patients as to next steps.

Now, a recent trial adds to our knowledge about supplemental magnetic resonance imaging (MRI) breast screening in women with extremely dense breasts.

DENSE trial offers high-quality data

Bakker and colleagues studied women aged 50 to 74 who were participating in a Netherlands population-based biennial mammography screening program.³ They enrolled average-risk women with extremely dense breasts who had a negative screening digital mammogram into the Dense Tissue and Early Breast Neoplasm Screening (DENSE) multicenter trial. The women were randomly assigned to receive either continued biennial digital mammography or supplemental breast MRI.

The primary outcome was the between-group difference in the development of interval breast cancers—that is, breast cancers detected by women or their providers between rounds of screening mammography. Interval breast cancers were chosen as the primary outcome for 2 reasons:

• interval cancers appear to be more aggressive tumors than those cancers detected by screening mammography
• interval cancers can be identified over a shorter time interval, making them easier to study than outcomes such as breast cancer mortality, which typically require more than a decade to identify.

The DENSE trial’s secondary outcomes included recall rates from MRI, cancer detection rates on MRI, positive predictive value of MRIs requiring biopsy, and breast cancer characteristics (size, stage) diagnosed in the different groups.

Between-group difference in incidence of interval cancers

A total of 40,373 women with extremely dense breasts were screened; 8,061 of these were randomly assigned to receive breast MRI and 32,312 to continued mammography only (1:4 cluster randomization) across 12 mammography centers in the Netherlands. Among the women assigned to the MRI group, 59% actually underwent MRI (4,783 of the 8,061).

The interval cancer rate in the mammography-only group was 5.0 per 1,000 screenings (95% confidence interval [CI], 4.3–5.8), while the interval cancer rate in the MRI-assigned group was 2.5 per 1,000 screenings (95% CI, 1.6–3.8) (TABLE 1).³

Key secondary outcomes

Of the women who underwent supplemental MRI, 9.49% were recalled for additional imaging, follow-up, or biopsy. Of the 4,783 women who had an MRI, 300 (6.3%) underwent a breast biopsy, and 79 breast cancers (1.65%) were detected. Sixty-four of these cancers were invasive, and 15 were ductal carcinoma in situ (DCIS). Among women who underwent a biopsy for an MRI-detected abnormality, the positive predictive value was 26.3%.

Tumor characteristics. For women who developed breast cancer during the study, both tumor size at diagnosis and tumor stage (early vs late) were described. TABLE 2 shows these results in the women who had their breast cancer detected on MRI, those in the MRI-assigned group who developed interval cancer, and those in the mammography-only group who had interval cancers.³ Overall, tumor size was smaller in the interval group who underwent MRI compared with those who underwent mammography only.

Continue to: Study contributes valuable data, but we need more on long-term outcomes...

Study contributes valuable data, but we need more on long-term outcomes

The trial by Bakker and colleagues employed a solid study design as women were randomly assigned to supplemental MRI screening or ongoing biennial mammography, and nearly all cancers were identified in the short-term of follow-up. In addition, very few women were lost to follow-up, and secondary outcomes, including false-positive rates, were collected to help providers and patients better understand some of the potential downsides of supplemental screening.

The substantial reduction in interval cancers (50% in the intent-to-screen analysis and 84% in the women who actually underwent supplemental MRI) was highly statistically significant (P<.001). While there were substantially fewer interval cancers in the MRI-assigned group, the interval cancers that did occur were of similar stage as those in the women assigned to the mammography-only group (TABLE 2).

Data demonstrate that interval cancers appear to be more aggressive than screen-detected cancers.⁴ While reducing interval cancers should be a good thing overall, it remains unproven that using supplemental MRI in all women with dense breasts would reduce breast cancer specific mortality, all-cause mortality, or the risk of more invasive treatments (for example, the need for chemotherapy or requirement for mastectomy).

On the other hand, using routine supplemental breast MRI in women with extremely dense breasts would result in very substantial use of resources, including cost, radiologist time, provider time, and machine time. In the United States, approximately 49 million women are aged 50 to 74.⁵ Breast MRI charges commonly range from $1,000 to $4,000. If the 4.9 million women with extremely dense breasts underwent supplemental MRI this year, the approximate cost would be somewhere between $4.9 and $19.5 billion for imaging alone. This does not include callbacks, biopsies, or provider time for ordering, interpreting, and arranging for follow-up.

While the reduction in interval cancers seen in this study is promising, more assurance of improvement in important outcomes—such as reduced mortality or reduced need for more invasive breast cancer treatments—should precede any routine change in practice.

Unanswered questions

This study did not address a number of other important questions, including:

Should MRI be done with every round of breast cancer screening given the possibility of prevalence bias? Prevalence bias can be defined as more cancers detected in the first round of MRI screening with possible reduced benefit in future rounds of screening. The study authors indicated that they will continue to analyze the study results to see what occurs in the next round of screening.

Is there a similar impact on decreased interval cancers in women undergoing annual mammography or in women screened between ages 40 and 49? This study was conducted in women aged 50 to 74 undergoing mammography every 2 years. In the United States, annual mammography in women aged 40 to 49 is frequently recommended.

What effect does supplemental MRI screening have in women with heterogeneously dense breasts, which represents 40% of the population? The US Food and Drug Administration recommends that all women with dense breasts be counseled regarding options for management.⁶

Do these results translate to the more racially and ethnically diverse populations of the United States? In the Netherlands, where this study was conducted, 85% to 90% of women are either Dutch or of western European origin. Women of different racial and ancestral backgrounds have biologically different breast cancers and cancer risk (for example, higher rates of triple-negative breast cancers in African American women; 10-fold higher rates of BRCA pathogenic variants in Ashkenazi Jewish women).

Continue to: Use validated tools to assess risk comprehensively...

Use validated tools to assess risk comprehensively

Women aged 50 to 74 with extremely dense breasts have reduced interval cancers following a normal biennial mammogram if supplemental MRI is offered, but the long-term benefit of identifying these cancers earlier is unclear. Until more data are available on important long-term outcomes (such as breast cancer mortality and need for more invasive treatments), providers should consider breast density in the context of a more comprehensive assessment of breast cancer risk using a validated breast cancer risk assessment tool.

I prefer the modified version of the International Breast Cancer Intervention Study (IBIS) tool, which is readily available online (https://ibis.ikonopedia.com/).⁷ This tool incorporates several breast cancer risk factors, including reproductive risk factors, body mass index, BRCA gene status, breast density, and family history. The tool takes 1 to 2 minutes to complete and provides an estimate of a woman’s 10-year risk and lifetime risk of breast cancer.

If the lifetime risk exceeds 20%, I offer the patient supplemental MRI screening, consistent with current recommendations of the National Comprehensive Cancer Network and the American Cancer Society.^8,9 I generally recommend starting breast imaging screening 7 to 10 years prior to the youngest breast cancer occurrence in the family, with mammography starting no earlier than age 30 and MRI no earlier than age 25. Other validated tools also can be used.^10-13

Incorporating breast density and other important risk factors allows a more comprehensive analysis upon which to counsel women about the value (benefits and harms) of breast imaging.⁸

While the frequency of dense breasts decreases with age, approximately 10% of women in the United States have extremely dense breasts (Breast Imaging, Reporting, and Data System [BI-RADS] category D), and another 40% have heterogeneously dense breasts (BI-RADS category C).¹ Women with dense breasts have both an increased risk for developing breast cancer and reduced mammographic sensitivity for breast cancer detection compared with women who have nondense breasts.²

These 2 observations have led the majority of states to pass legislation requiring that women with dense breasts be informed of their breast density, and most require that providers discuss these results with their patients. Thoughtful clinicians who review the available literature, however, will find sparse evidence on which to counsel patients as to next steps.

Now, a recent trial adds to our knowledge about supplemental magnetic resonance imaging (MRI) breast screening in women with extremely dense breasts.

DENSE trial offers high-quality data

Bakker and colleagues studied women aged 50 to 74 who were participating in a Netherlands population-based biennial mammography screening program.³ They enrolled average-risk women with extremely dense breasts who had a negative screening digital mammogram into the Dense Tissue and Early Breast Neoplasm Screening (DENSE) multicenter trial. The women were randomly assigned to receive either continued biennial digital mammography or supplemental breast MRI.

The primary outcome was the between-group difference in the development of interval breast cancers—that is, breast cancers detected by women or their providers between rounds of screening mammography. Interval breast cancers were chosen as the primary outcome for 2 reasons:

• interval cancers appear to be more aggressive tumors than those cancers detected by screening mammography
• interval cancers can be identified over a shorter time interval, making them easier to study than outcomes such as breast cancer mortality, which typically require more than a decade to identify.

The DENSE trial’s secondary outcomes included recall rates from MRI, cancer detection rates on MRI, positive predictive value of MRIs requiring biopsy, and breast cancer characteristics (size, stage) diagnosed in the different groups.

Between-group difference in incidence of interval cancers

A total of 40,373 women with extremely dense breasts were screened; 8,061 of these were randomly assigned to receive breast MRI and 32,312 to continued mammography only (1:4 cluster randomization) across 12 mammography centers in the Netherlands. Among the women assigned to the MRI group, 59% actually underwent MRI (4,783 of the 8,061).

The interval cancer rate in the mammography-only group was 5.0 per 1,000 screenings (95% confidence interval [CI], 4.3–5.8), while the interval cancer rate in the MRI-assigned group was 2.5 per 1,000 screenings (95% CI, 1.6–3.8) (TABLE 1).³

Key secondary outcomes

Of the women who underwent supplemental MRI, 9.49% were recalled for additional imaging, follow-up, or biopsy. Of the 4,783 women who had an MRI, 300 (6.3%) underwent a breast biopsy, and 79 breast cancers (1.65%) were detected. Sixty-four of these cancers were invasive, and 15 were ductal carcinoma in situ (DCIS). Among women who underwent a biopsy for an MRI-detected abnormality, the positive predictive value was 26.3%.

Tumor characteristics. For women who developed breast cancer during the study, both tumor size at diagnosis and tumor stage (early vs late) were described. TABLE 2 shows these results in the women who had their breast cancer detected on MRI, those in the MRI-assigned group who developed interval cancer, and those in the mammography-only group who had interval cancers.³ Overall, tumor size was smaller in the interval group who underwent MRI compared with those who underwent mammography only.

Continue to: Study contributes valuable data, but we need more on long-term outcomes...

Study contributes valuable data, but we need more on long-term outcomes

The trial by Bakker and colleagues employed a solid study design as women were randomly assigned to supplemental MRI screening or ongoing biennial mammography, and nearly all cancers were identified in the short-term of follow-up. In addition, very few women were lost to follow-up, and secondary outcomes, including false-positive rates, were collected to help providers and patients better understand some of the potential downsides of supplemental screening.

The substantial reduction in interval cancers (50% in the intent-to-screen analysis and 84% in the women who actually underwent supplemental MRI) was highly statistically significant (P<.001). While there were substantially fewer interval cancers in the MRI-assigned group, the interval cancers that did occur were of similar stage as those in the women assigned to the mammography-only group (TABLE 2).

Data demonstrate that interval cancers appear to be more aggressive than screen-detected cancers.⁴ While reducing interval cancers should be a good thing overall, it remains unproven that using supplemental MRI in all women with dense breasts would reduce breast cancer specific mortality, all-cause mortality, or the risk of more invasive treatments (for example, the need for chemotherapy or requirement for mastectomy).

On the other hand, using routine supplemental breast MRI in women with extremely dense breasts would result in very substantial use of resources, including cost, radiologist time, provider time, and machine time. In the United States, approximately 49 million women are aged 50 to 74.⁵ Breast MRI charges commonly range from $1,000 to $4,000. If the 4.9 million women with extremely dense breasts underwent supplemental MRI this year, the approximate cost would be somewhere between $4.9 and $19.5 billion for imaging alone. This does not include callbacks, biopsies, or provider time for ordering, interpreting, and arranging for follow-up.

While the reduction in interval cancers seen in this study is promising, more assurance of improvement in important outcomes—such as reduced mortality or reduced need for more invasive breast cancer treatments—should precede any routine change in practice.

Unanswered questions

This study did not address a number of other important questions, including:

Should MRI be done with every round of breast cancer screening given the possibility of prevalence bias? Prevalence bias can be defined as more cancers detected in the first round of MRI screening with possible reduced benefit in future rounds of screening. The study authors indicated that they will continue to analyze the study results to see what occurs in the next round of screening.

Is there a similar impact on decreased interval cancers in women undergoing annual mammography or in women screened between ages 40 and 49? This study was conducted in women aged 50 to 74 undergoing mammography every 2 years. In the United States, annual mammography in women aged 40 to 49 is frequently recommended.

What effect does supplemental MRI screening have in women with heterogeneously dense breasts, which represents 40% of the population? The US Food and Drug Administration recommends that all women with dense breasts be counseled regarding options for management.⁶

Do these results translate to the more racially and ethnically diverse populations of the United States? In the Netherlands, where this study was conducted, 85% to 90% of women are either Dutch or of western European origin. Women of different racial and ancestral backgrounds have biologically different breast cancers and cancer risk (for example, higher rates of triple-negative breast cancers in African American women; 10-fold higher rates of BRCA pathogenic variants in Ashkenazi Jewish women).

Continue to: Use validated tools to assess risk comprehensively...

Use validated tools to assess risk comprehensively

Women aged 50 to 74 with extremely dense breasts have reduced interval cancers following a normal biennial mammogram if supplemental MRI is offered, but the long-term benefit of identifying these cancers earlier is unclear. Until more data are available on important long-term outcomes (such as breast cancer mortality and need for more invasive treatments), providers should consider breast density in the context of a more comprehensive assessment of breast cancer risk using a validated breast cancer risk assessment tool.

I prefer the modified version of the International Breast Cancer Intervention Study (IBIS) tool, which is readily available online (https://ibis.ikonopedia.com/).⁷ This tool incorporates several breast cancer risk factors, including reproductive risk factors, body mass index, BRCA gene status, breast density, and family history. The tool takes 1 to 2 minutes to complete and provides an estimate of a woman’s 10-year risk and lifetime risk of breast cancer.

If the lifetime risk exceeds 20%, I offer the patient supplemental MRI screening, consistent with current recommendations of the National Comprehensive Cancer Network and the American Cancer Society.^8,9 I generally recommend starting breast imaging screening 7 to 10 years prior to the youngest breast cancer occurrence in the family, with mammography starting no earlier than age 30 and MRI no earlier than age 25. Other validated tools also can be used.^10-13

Incorporating breast density and other important risk factors allows a more comprehensive analysis upon which to counsel women about the value (benefits and harms) of breast imaging.⁸

While the frequency of dense breasts decreases with age, approximately 10% of women in the United States have extremely dense breasts (Breast Imaging, Reporting, and Data System [BI-RADS] category D), and another 40% have heterogeneously dense breasts (BI-RADS category C).¹ Women with dense breasts have both an increased risk for developing breast cancer and reduced mammographic sensitivity for breast cancer detection compared with women who have nondense breasts.²

These 2 observations have led the majority of states to pass legislation requiring that women with dense breasts be informed of their breast density, and most require that providers discuss these results with their patients. Thoughtful clinicians who review the available literature, however, will find sparse evidence on which to counsel patients as to next steps.

Now, a recent trial adds to our knowledge about supplemental magnetic resonance imaging (MRI) breast screening in women with extremely dense breasts.

DENSE trial offers high-quality data

Bakker and colleagues studied women aged 50 to 74 who were participating in a Netherlands population-based biennial mammography screening program.³ They enrolled average-risk women with extremely dense breasts who had a negative screening digital mammogram into the Dense Tissue and Early Breast Neoplasm Screening (DENSE) multicenter trial. The women were randomly assigned to receive either continued biennial digital mammography or supplemental breast MRI.

The primary outcome was the between-group difference in the development of interval breast cancers—that is, breast cancers detected by women or their providers between rounds of screening mammography. Interval breast cancers were chosen as the primary outcome for 2 reasons:

• interval cancers appear to be more aggressive tumors than those cancers detected by screening mammography
• interval cancers can be identified over a shorter time interval, making them easier to study than outcomes such as breast cancer mortality, which typically require more than a decade to identify.

The DENSE trial’s secondary outcomes included recall rates from MRI, cancer detection rates on MRI, positive predictive value of MRIs requiring biopsy, and breast cancer characteristics (size, stage) diagnosed in the different groups.

Between-group difference in incidence of interval cancers

A total of 40,373 women with extremely dense breasts were screened; 8,061 of these were randomly assigned to receive breast MRI and 32,312 to continued mammography only (1:4 cluster randomization) across 12 mammography centers in the Netherlands. Among the women assigned to the MRI group, 59% actually underwent MRI (4,783 of the 8,061).

The interval cancer rate in the mammography-only group was 5.0 per 1,000 screenings (95% confidence interval [CI], 4.3–5.8), while the interval cancer rate in the MRI-assigned group was 2.5 per 1,000 screenings (95% CI, 1.6–3.8) (TABLE 1).³

Key secondary outcomes

Of the women who underwent supplemental MRI, 9.49% were recalled for additional imaging, follow-up, or biopsy. Of the 4,783 women who had an MRI, 300 (6.3%) underwent a breast biopsy, and 79 breast cancers (1.65%) were detected. Sixty-four of these cancers were invasive, and 15 were ductal carcinoma in situ (DCIS). Among women who underwent a biopsy for an MRI-detected abnormality, the positive predictive value was 26.3%.

Tumor characteristics. For women who developed breast cancer during the study, both tumor size at diagnosis and tumor stage (early vs late) were described. TABLE 2 shows these results in the women who had their breast cancer detected on MRI, those in the MRI-assigned group who developed interval cancer, and those in the mammography-only group who had interval cancers.³ Overall, tumor size was smaller in the interval group who underwent MRI compared with those who underwent mammography only.

Continue to: Study contributes valuable data, but we need more on long-term outcomes...

Study contributes valuable data, but we need more on long-term outcomes

The trial by Bakker and colleagues employed a solid study design as women were randomly assigned to supplemental MRI screening or ongoing biennial mammography, and nearly all cancers were identified in the short-term of follow-up. In addition, very few women were lost to follow-up, and secondary outcomes, including false-positive rates, were collected to help providers and patients better understand some of the potential downsides of supplemental screening.

The substantial reduction in interval cancers (50% in the intent-to-screen analysis and 84% in the women who actually underwent supplemental MRI) was highly statistically significant (P<.001). While there were substantially fewer interval cancers in the MRI-assigned group, the interval cancers that did occur were of similar stage as those in the women assigned to the mammography-only group (TABLE 2).

Data demonstrate that interval cancers appear to be more aggressive than screen-detected cancers.⁴ While reducing interval cancers should be a good thing overall, it remains unproven that using supplemental MRI in all women with dense breasts would reduce breast cancer specific mortality, all-cause mortality, or the risk of more invasive treatments (for example, the need for chemotherapy or requirement for mastectomy).

On the other hand, using routine supplemental breast MRI in women with extremely dense breasts would result in very substantial use of resources, including cost, radiologist time, provider time, and machine time. In the United States, approximately 49 million women are aged 50 to 74.⁵ Breast MRI charges commonly range from $1,000 to $4,000. If the 4.9 million women with extremely dense breasts underwent supplemental MRI this year, the approximate cost would be somewhere between $4.9 and $19.5 billion for imaging alone. This does not include callbacks, biopsies, or provider time for ordering, interpreting, and arranging for follow-up.

While the reduction in interval cancers seen in this study is promising, more assurance of improvement in important outcomes—such as reduced mortality or reduced need for more invasive breast cancer treatments—should precede any routine change in practice.

Unanswered questions

This study did not address a number of other important questions, including:

Should MRI be done with every round of breast cancer screening given the possibility of prevalence bias? Prevalence bias can be defined as more cancers detected in the first round of MRI screening with possible reduced benefit in future rounds of screening. The study authors indicated that they will continue to analyze the study results to see what occurs in the next round of screening.

Is there a similar impact on decreased interval cancers in women undergoing annual mammography or in women screened between ages 40 and 49? This study was conducted in women aged 50 to 74 undergoing mammography every 2 years. In the United States, annual mammography in women aged 40 to 49 is frequently recommended.

What effect does supplemental MRI screening have in women with heterogeneously dense breasts, which represents 40% of the population? The US Food and Drug Administration recommends that all women with dense breasts be counseled regarding options for management.⁶

Do these results translate to the more racially and ethnically diverse populations of the United States? In the Netherlands, where this study was conducted, 85% to 90% of women are either Dutch or of western European origin. Women of different racial and ancestral backgrounds have biologically different breast cancers and cancer risk (for example, higher rates of triple-negative breast cancers in African American women; 10-fold higher rates of BRCA pathogenic variants in Ashkenazi Jewish women).

Continue to: Use validated tools to assess risk comprehensively...

Use validated tools to assess risk comprehensively

Women aged 50 to 74 with extremely dense breasts have reduced interval cancers following a normal biennial mammogram if supplemental MRI is offered, but the long-term benefit of identifying these cancers earlier is unclear. Until more data are available on important long-term outcomes (such as breast cancer mortality and need for more invasive treatments), providers should consider breast density in the context of a more comprehensive assessment of breast cancer risk using a validated breast cancer risk assessment tool.

I prefer the modified version of the International Breast Cancer Intervention Study (IBIS) tool, which is readily available online (https://ibis.ikonopedia.com/).⁷ This tool incorporates several breast cancer risk factors, including reproductive risk factors, body mass index, BRCA gene status, breast density, and family history. The tool takes 1 to 2 minutes to complete and provides an estimate of a woman’s 10-year risk and lifetime risk of breast cancer.

If the lifetime risk exceeds 20%, I offer the patient supplemental MRI screening, consistent with current recommendations of the National Comprehensive Cancer Network and the American Cancer Society.^8,9 I generally recommend starting breast imaging screening 7 to 10 years prior to the youngest breast cancer occurrence in the family, with mammography starting no earlier than age 30 and MRI no earlier than age 25. Other validated tools also can be used.^10-13

Incorporating breast density and other important risk factors allows a more comprehensive analysis upon which to counsel women about the value (benefits and harms) of breast imaging.⁸

The connection between psoriasis and increased major adverse cardiovascular events (MACEs) has been well studied. ^1,2 Although treatment of psoriasis can improve skin and joint symptoms, it is less clear whether therapies may mitigate the increased risk for cardiovascular comorbidities. Tumor necrosis factor (TNF) inhibitors in particular have been studied with great interest given the role of TNF in vascular and metabolic functions. ³ Using a retrospective cohort design, Wu and colleagues ⁴ examined if treatment with TNF inhibitors in patients with psoriasis would be associated with a lower risk for MACEs compared to phototherapy. Results suggested a significantly lower hazard of MACEs in patients using TNF inhibitors vs patients treated with phototherapy (adjusted hazard ratio, 0.77; P = .046). Moreover, based on these findings, they calculated that treating approximately 161 patients with TNF inhibitors rather than phototherapy would result in 1 less MACE per year overall. ⁴

Patients with psoriasis have been shown to have a greater noncalcified coronary plaque burden and prevalence of high-risk plaque compared to healthy patients.⁵ Lerman and colleagues⁵ measured the coronary plaque burden of 105 patients with psoriasis and 25 healthy volunteers using coronary computed tomography angiography. Although the patients were on average 10 years younger and had lower cardiovascular risk as measured by traditional risk scores, patients with psoriasis were found to have a greater noncalcified coronary plaque burden compared to 100 patients with hyperlipidemia. This burden was associated with an increased prevalence of high-risk plaques. Furthermore, in patients followed for 1 year, improvements in psoriasis severity were associated with reductions in noncalcified coronary plaque burden, though this finding was across all treatment modalities. However, there was no significant difference in calcified coronary plaque burden associated with reduced psoriasis severity.⁵

Moreover, Pina et al⁶ conducted a prospective study evaluating the use of the TNF inhibitor adalimumab to improve endothelial function and arterial stiffness in patients with moderate to severe psoriasis. Among 29 patients, they found a significant improvement in endothelial function as measured by flow-mediated dilatation after 6 months of adalimumab therapy, with a mean increase from 6.19% to 7.46% (P=.008). They also reported decreases in arterial stiffness by pulse wave velocity (P=.03). Despite a small sample size, these findings provide 2 potential mechanisms by which TNF inhibitor therapy may reduce the risk for cardiovascular events.⁶

A retrospective cohort study evaluating data from the Kaiser Permanente Southern California health plan assessed whether TNF inhibitor therapy was associated with a lower risk for MACE in patients with psoriasis.⁷ A total of 18,194 patients were included; of these, 1463 received TNF inhibitor therapy for at least 2 months. After controlling for other variables, including age at psoriasis diagnosis, sex, race/ethnicity, and other cardiovascular risk factors (eg, history of smoking or alcohol use; use of clopidogrel, antihypertensive agents, antihyperlipidemics, or anticoagulants), patients in the TNF inhibitor cohort demonstrated a significantly lower MACE hazard ratio compared to patients treated with topicals (hazard ratio, 0.80; 95% confidence interval, 0.66-0.98; P<.05).⁷

Conversely, a randomized, placebo-controlled trial of 107 patients found no difference in vascular inflammation of the ascending aorta and the carotids after 16 weeks of adalimumab treatment vs placebo. In this study, however, most patients had only moderate psoriasis based on a mean psoriasis area and severity index score of 9.8.⁸ Given studies finding higher risk burden in patients with more severe skin disease,² it is possible that the effect of TNF inhibitor therapy may not be as pronounced in patients with less skin involvement. There was a significant effect on C-reactive protein levels in patients receiving TNF inhibitor therapy compared to placebo at 16 weeks (P=.012), suggesting TNF does play some role in systemic inflammation, and it is possible it may exert cardiovascular effects through a mechanism other than vascular inflammation.⁸

A second double-blind, randomized trial reported similar results.⁹ Among 97 patients randomized to receive adalimumab, placebo, or phototherapy, no significant difference in vascular inflammation was found after 12 weeks of therapy. In contrast, levels of C-reactive protein, IL-6, and glycoprotein acetylation were markedly reduced. The authors also reported adverse effects of adalimumab therapy on lipid metabolism with reduced cholesterol efflux capacity, a marker of ability of high-density-lipoprotein particles to perform reverse cholesterol transport, and high-density-lipoprotein particles, suggesting these effects may counteract some of the anti-inflammatory effects of TNF inhibitors.⁹

A growing body of data regarding the effect of TNF inhibitors on cardiovascular morbidity in patients with psoriasis is being collected, but no strong conclusions can be made. Given the disconnect of findings across these studies, it is possible that we have yet to elucidate the full mechanism by which TNF inhibitors may affect cardiovascular health. However, there may be additional confounding factors or patient characteristics at play. More large, prospective, randomized, controlled studies are needed to further understand this relationship.

The connection between psoriasis and increased major adverse cardiovascular events (MACEs) has been well studied. ^1,2 Although treatment of psoriasis can improve skin and joint symptoms, it is less clear whether therapies may mitigate the increased risk for cardiovascular comorbidities. Tumor necrosis factor (TNF) inhibitors in particular have been studied with great interest given the role of TNF in vascular and metabolic functions. ³ Using a retrospective cohort design, Wu and colleagues ⁴ examined if treatment with TNF inhibitors in patients with psoriasis would be associated with a lower risk for MACEs compared to phototherapy. Results suggested a significantly lower hazard of MACEs in patients using TNF inhibitors vs patients treated with phototherapy (adjusted hazard ratio, 0.77; P = .046). Moreover, based on these findings, they calculated that treating approximately 161 patients with TNF inhibitors rather than phototherapy would result in 1 less MACE per year overall. ⁴

Patients with psoriasis have been shown to have a greater noncalcified coronary plaque burden and prevalence of high-risk plaque compared to healthy patients.⁵ Lerman and colleagues⁵ measured the coronary plaque burden of 105 patients with psoriasis and 25 healthy volunteers using coronary computed tomography angiography. Although the patients were on average 10 years younger and had lower cardiovascular risk as measured by traditional risk scores, patients with psoriasis were found to have a greater noncalcified coronary plaque burden compared to 100 patients with hyperlipidemia. This burden was associated with an increased prevalence of high-risk plaques. Furthermore, in patients followed for 1 year, improvements in psoriasis severity were associated with reductions in noncalcified coronary plaque burden, though this finding was across all treatment modalities. However, there was no significant difference in calcified coronary plaque burden associated with reduced psoriasis severity.⁵

Moreover, Pina et al⁶ conducted a prospective study evaluating the use of the TNF inhibitor adalimumab to improve endothelial function and arterial stiffness in patients with moderate to severe psoriasis. Among 29 patients, they found a significant improvement in endothelial function as measured by flow-mediated dilatation after 6 months of adalimumab therapy, with a mean increase from 6.19% to 7.46% (P=.008). They also reported decreases in arterial stiffness by pulse wave velocity (P=.03). Despite a small sample size, these findings provide 2 potential mechanisms by which TNF inhibitor therapy may reduce the risk for cardiovascular events.⁶

A retrospective cohort study evaluating data from the Kaiser Permanente Southern California health plan assessed whether TNF inhibitor therapy was associated with a lower risk for MACE in patients with psoriasis.⁷ A total of 18,194 patients were included; of these, 1463 received TNF inhibitor therapy for at least 2 months. After controlling for other variables, including age at psoriasis diagnosis, sex, race/ethnicity, and other cardiovascular risk factors (eg, history of smoking or alcohol use; use of clopidogrel, antihypertensive agents, antihyperlipidemics, or anticoagulants), patients in the TNF inhibitor cohort demonstrated a significantly lower MACE hazard ratio compared to patients treated with topicals (hazard ratio, 0.80; 95% confidence interval, 0.66-0.98; P<.05).⁷

Conversely, a randomized, placebo-controlled trial of 107 patients found no difference in vascular inflammation of the ascending aorta and the carotids after 16 weeks of adalimumab treatment vs placebo. In this study, however, most patients had only moderate psoriasis based on a mean psoriasis area and severity index score of 9.8.⁸ Given studies finding higher risk burden in patients with more severe skin disease,² it is possible that the effect of TNF inhibitor therapy may not be as pronounced in patients with less skin involvement. There was a significant effect on C-reactive protein levels in patients receiving TNF inhibitor therapy compared to placebo at 16 weeks (P=.012), suggesting TNF does play some role in systemic inflammation, and it is possible it may exert cardiovascular effects through a mechanism other than vascular inflammation.⁸

A second double-blind, randomized trial reported similar results.⁹ Among 97 patients randomized to receive adalimumab, placebo, or phototherapy, no significant difference in vascular inflammation was found after 12 weeks of therapy. In contrast, levels of C-reactive protein, IL-6, and glycoprotein acetylation were markedly reduced. The authors also reported adverse effects of adalimumab therapy on lipid metabolism with reduced cholesterol efflux capacity, a marker of ability of high-density-lipoprotein particles to perform reverse cholesterol transport, and high-density-lipoprotein particles, suggesting these effects may counteract some of the anti-inflammatory effects of TNF inhibitors.⁹

A growing body of data regarding the effect of TNF inhibitors on cardiovascular morbidity in patients with psoriasis is being collected, but no strong conclusions can be made. Given the disconnect of findings across these studies, it is possible that we have yet to elucidate the full mechanism by which TNF inhibitors may affect cardiovascular health. However, there may be additional confounding factors or patient characteristics at play. More large, prospective, randomized, controlled studies are needed to further understand this relationship.

The connection between psoriasis and increased major adverse cardiovascular events (MACEs) has been well studied. ^1,2 Although treatment of psoriasis can improve skin and joint symptoms, it is less clear whether therapies may mitigate the increased risk for cardiovascular comorbidities. Tumor necrosis factor (TNF) inhibitors in particular have been studied with great interest given the role of TNF in vascular and metabolic functions. ³ Using a retrospective cohort design, Wu and colleagues ⁴ examined if treatment with TNF inhibitors in patients with psoriasis would be associated with a lower risk for MACEs compared to phototherapy. Results suggested a significantly lower hazard of MACEs in patients using TNF inhibitors vs patients treated with phototherapy (adjusted hazard ratio, 0.77; P = .046). Moreover, based on these findings, they calculated that treating approximately 161 patients with TNF inhibitors rather than phototherapy would result in 1 less MACE per year overall. ⁴

Patients with psoriasis have been shown to have a greater noncalcified coronary plaque burden and prevalence of high-risk plaque compared to healthy patients.⁵ Lerman and colleagues⁵ measured the coronary plaque burden of 105 patients with psoriasis and 25 healthy volunteers using coronary computed tomography angiography. Although the patients were on average 10 years younger and had lower cardiovascular risk as measured by traditional risk scores, patients with psoriasis were found to have a greater noncalcified coronary plaque burden compared to 100 patients with hyperlipidemia. This burden was associated with an increased prevalence of high-risk plaques. Furthermore, in patients followed for 1 year, improvements in psoriasis severity were associated with reductions in noncalcified coronary plaque burden, though this finding was across all treatment modalities. However, there was no significant difference in calcified coronary plaque burden associated with reduced psoriasis severity.⁵

Moreover, Pina et al⁶ conducted a prospective study evaluating the use of the TNF inhibitor adalimumab to improve endothelial function and arterial stiffness in patients with moderate to severe psoriasis. Among 29 patients, they found a significant improvement in endothelial function as measured by flow-mediated dilatation after 6 months of adalimumab therapy, with a mean increase from 6.19% to 7.46% (P=.008). They also reported decreases in arterial stiffness by pulse wave velocity (P=.03). Despite a small sample size, these findings provide 2 potential mechanisms by which TNF inhibitor therapy may reduce the risk for cardiovascular events.⁶

A retrospective cohort study evaluating data from the Kaiser Permanente Southern California health plan assessed whether TNF inhibitor therapy was associated with a lower risk for MACE in patients with psoriasis.⁷ A total of 18,194 patients were included; of these, 1463 received TNF inhibitor therapy for at least 2 months. After controlling for other variables, including age at psoriasis diagnosis, sex, race/ethnicity, and other cardiovascular risk factors (eg, history of smoking or alcohol use; use of clopidogrel, antihypertensive agents, antihyperlipidemics, or anticoagulants), patients in the TNF inhibitor cohort demonstrated a significantly lower MACE hazard ratio compared to patients treated with topicals (hazard ratio, 0.80; 95% confidence interval, 0.66-0.98; P<.05).⁷

Conversely, a randomized, placebo-controlled trial of 107 patients found no difference in vascular inflammation of the ascending aorta and the carotids after 16 weeks of adalimumab treatment vs placebo. In this study, however, most patients had only moderate psoriasis based on a mean psoriasis area and severity index score of 9.8.⁸ Given studies finding higher risk burden in patients with more severe skin disease,² it is possible that the effect of TNF inhibitor therapy may not be as pronounced in patients with less skin involvement. There was a significant effect on C-reactive protein levels in patients receiving TNF inhibitor therapy compared to placebo at 16 weeks (P=.012), suggesting TNF does play some role in systemic inflammation, and it is possible it may exert cardiovascular effects through a mechanism other than vascular inflammation.⁸

A second double-blind, randomized trial reported similar results.⁹ Among 97 patients randomized to receive adalimumab, placebo, or phototherapy, no significant difference in vascular inflammation was found after 12 weeks of therapy. In contrast, levels of C-reactive protein, IL-6, and glycoprotein acetylation were markedly reduced. The authors also reported adverse effects of adalimumab therapy on lipid metabolism with reduced cholesterol efflux capacity, a marker of ability of high-density-lipoprotein particles to perform reverse cholesterol transport, and high-density-lipoprotein particles, suggesting these effects may counteract some of the anti-inflammatory effects of TNF inhibitors.⁹

A growing body of data regarding the effect of TNF inhibitors on cardiovascular morbidity in patients with psoriasis is being collected, but no strong conclusions can be made. Given the disconnect of findings across these studies, it is possible that we have yet to elucidate the full mechanism by which TNF inhibitors may affect cardiovascular health. However, there may be additional confounding factors or patient characteristics at play. More large, prospective, randomized, controlled studies are needed to further understand this relationship.

It has now been 30 years since the first total laparoscopic hysterectomy was performed. The benefits of minimally invasive gynecologic surgery (MIGS) – and of minimally invasive hysterectomy specifically – are now well documented. Since this milestone procedure, both instrumentation and technique have improved significantly.

Physician experience is the most important determinant for which minimally invasive approach is used to perform hysterectomy. This includes traditional laparoscopy, as well as the robotically assisted laparoscopic approach. However, certain patient characteristics also may influence the choice. A uterus that is undescended, combined with a narrow introitus, for instance, can be a contributory factor in choosing to perform laparoscopic hysterectomy. Additionally, so can an extremely large uterus and an extremely high body mass index (BMI).

These latter two factors – a very large uterus (which we define as more than 15-16 weeks’ gestational size) and a BMI over 60 kg/m² – historically were considered to be contraindications to laparoscopic hysterectomy. But as the proficiency, comfort, and skill of a new generation of laparoscopic surgeons increases, the tide is shifting with respect to both morbid obesity and the very large uterus.

With growing experience and improved instrumentation, the majority of gynecologists who are fellowship-trained in MIGS are able to routinely and safely perform laparoscopic hysterectomy for uteri weighing 1-2 kg and in patients who have extreme morbid obesity. The literature, moreover, increasingly features case reports of laparoscopic removal of very large uteri and reviews/discussions of total laparoscopic hysterectomy being feasible.

In our own experience, total laparoscopic hysterectomy (TLH) of the very large uterus can be safely and advantageously performed using key instruments and refinements in technique, as well as thorough patient counseling regarding the risk of unexpected sarcomas. Recently, we safely performed total laparoscopic hysterectomy for a patient with a uterus that – somewhat unexpectedly – weighed 7.4 kg.
 

Surgical pearls

Performing safe and effective total laparoscopic hysterectomy for large uteri – and for morbidly obese patients – hinges largely on modifications in entry and port placement, patient positioning, and choice of instrumentation. With these modifications, we can achieve adequate visualization of critical anatomy and can minimize bleeding. Otherwise, the surgery itself is largely the same. Here are the principles we find most helpful.

Entry and port placement

Traditionally, for TLHs, a camera port is placed at the umbilicus to provide a full view of the pelvis. For the larger uterus – and in women who are extremely obese – we aim to introduce the laparoscope higher. A reliable landmark is the Palmer’s point in the left upper quadrant. From here, we can identify areas for the placement of additional trocars.

In general, we place ancillary 5-mm ports more cephalad and lateral to the uterus than we otherwise would. Such placement facilitates effective visualization while accommodating manipulation of the uterus and allows us to avoid bleeding around the vascular upper pedicles. Overall, we have much better control through all parts of the surgery when we operate lateral to the uterus.
 

Patient positioning

In addition to the Trendelenburg position, we have adopted an “airplaning” technique for patients with a very large uterus in which the bed is tilted from side to side so that the left and right sides of the body are rotated upward as needed. This allows for gravitational-assisted retraction when it otherwise is not possible.

Instrumentation

For morbidly obese patients, we use Kii Fios advanced fixation trocars. These come in 5- and 10-mm sizes and are equipped with an intraperitoneal balloon that can be inflated to prevent sliding of the trocar out of the abdominal wall.

By far the most valuable instrument for the morbidly obese and the very large uterus is a 30-degree laparoscope. With our higher port placement as described, the 30-degree scope provides visualization of critical structures that wouldn’t be possible with a 0-degree scope.

The Rumi uterine manipulator comes with cups that come in different sizes and can fit around the cervix and help delineate the cervicouterine junction. We use this manipulator for all laparoscopic hysterectomies, but it is a must for the very large uterus.

Extensive desiccation of the utero-ovarian pedicles and uterine arteries is critical, and for this we advise using the rotating bipolar RoBi instrument. Use of the conventional bipolar instrument allows us to use targeted and anatomically guided application of energy. This ensures certainty that vessels whose limits exceed the diameter for advanced bipolar devices (typically 7 mm) are completely sealed. In-depth knowledge of pelvic anatomy and advanced laparoscopic dissection is paramount during these steps to ensure that vital structures are not damaged by the wider thermal spread of the traditional bipolar device. For cutting, the use of ultrasonic energy is important to prevent energy from spreading laterally.

Lastly, we recommend a good suction irrigator because, if bleeding occurs, it tends to be heavy because of the enlarged nature of feeding vasculature. When placed through an umbilical or suprapubic port, the suction irrigator also may be used to help with the rotational vectors and traction for further uterine manipulation.
 

Technique

Courtesy Dr. Paya Pasic

We usually operate from top to bottom, transecting the upper pedicles such as the infundibulopelvic (IP) ligaments or utero-ovarian ligaments first, rather than the round ligaments. This helps us achieve additional mobility of the uterus. Some surgeons believe that retroperitoneal dissection and ligation of the uterine arteries at their origin is essential, but we find that, with good uterine manipulation and the use of a 30-degree scope, we achieve adequate visualization for identifying the ureter and uterine artery on the sidewall and consequently do not need to dissect retroperitoneally.

When using the uterine manipulator with the colpotomy cup, the uterus is pushed upward, increasing the distance between the vaginal fornix and the ureters. Uterine arteries can easily be identified and desiccated using conventional bipolar energy. When the colpotomy cup is pushed cephalad, the application of the bipolar energy within the limits of the cup is safe. The thermal spread does not pose a threat to the ureters, which are displaced 1.5-2 cm laterally. Large fibroids often contribute to distorted anatomical planes, and a colpotomy cup provides a firm palpable surface between the cervix and vagina during dissection.

When dealing with large uteri, one must sometimes think outside the box and deviate from standard technique. For instance, in patients with distorted anatomy because of large fibroids, it helps to first control the pedicles that are most easily accessible. Sometimes it is acceptable to perform oophorectomy if the IP ligament is more accessible and the utero-ovarian pedicle is distorted by dilated veins and adherent to the uterus. After transection of each pedicle, we gain more mobility of the uterus and better visualization for the next step.

Inserting the camera through ancillary ports – a technique known as “port hopping” – helps to visualize and take down adhesions much better and more safely than using the camera from the umbilical port only. Port hopping with a 30-degree laparoscope helps to obtain a 360-degree view of adhesions and anatomy, which is exceedingly helpful in cases in which crucial anatomical structures are within close proximity of one another.

In general it is more challenging to perform TLH on a patient with a broad uterus or a patient with low posterior fibroids that are occupying the pelvis than on a patient with fibroids in the upper abdomen. The main challenge for the surgeon is to safely secure the uterine arteries and control the blood supply to the uterus.

Access to the pelvic sidewall is obtained with the combination of 30-degree scope, uterine manipulator, and the suction irrigator introduced through the midline port; the cervix and uterus are deviated upward. Instead of the suction irrigator or blunt dissector used for internal uterine manipulation, some surgeons use myoma screws or a 5-mm single-tooth tenaculum to manipulate a large uterus. Both of those instruments are valuable and work well, but often a large uterus requires extensive manipulation. Repositioning of any sharp instruments that pierce the serosa can often lead to additional blood loss. It is preferable to avoid this blood loss on a large uterus at all costs because it can be brisk and stains the surgical pedicles, making the remainder of the procedure unnecessarily difficult.

Once the uterine arteries are desiccated, if fibroids are obscuring the view, the corpus of the uterus can be detached from the cervix as in supracervical hysterectomy fashion. From there, the uterus can be placed in the upper abdomen while colpotomy can be performed.

In patients with multiple fibroids, we do not recommend performing myomectomy first, unless the fibroid is pedunculated and on a very small stalk. Improved uterine manipulation and retroperitoneal dissection are preferred over myomectomy to safely complete hysterectomy for the broad uterus. In our opinion, any attempt at myomectomy would lead to unnecessary blood loss and additional operative time with minimal benefit.

In patients with fibroids that grow into the broad ligament and pelvic sidewall, the natural course of the ureter becomes displaced laterally. This is contrary to the popular misconception that the ureter is more medially located in the setting of broad-ligament fibroids. To ensure safe access to the uterine arteries, the vesicouterine peritoneum can be incised and extended cephalad along the broad ligament and, then, using the above-mentioned technique, by pushing the uterus and the fibroid to the contralateral side via the suction irrigator, the uterine arteries can be easily accessed.

Another useful technique is to use diluted vasopressin injected into the lower pole of the uterus to cause vasoconstriction and minimize the bleeding. The concentration is 1 cc of 20 units of vasopressin in 100-400 cc of saline. This technique is very useful for myomectomies, and some surgeons find it also helpful for hysterectomy. The plasma half-life of vasopressin is 10-20 minutes, and a large quantity is needed to help with vasoconstriction in a big uterus. The safe upper limits of vasopressin dosing are not firmly established. A fibroid uterus with aberrant vasculature may require a greater-than-acceptable dose to control bleeding.

It is important to ensure that patients have an optimized hemoglobin level preoperatively. We use a hemoglobin level of 8 g/dL as a lowest cutoff value for performing TLH without preoperative transfusion. Regarding bowel preparation, neither the literature nor our own experience support its value, so we typically do not use it.
 

Morcellation and patient counseling

Courtesy Dr. Paya Pasic

Uteri up to 12 weeks’ gestational size usually can be extracted transvaginally, and most uteri regardless of size can be morcellated and extracted through the vagina, providing that the vaginal fornix is accessible from below. In some cases, such as when the apex is too high, a minilaparotomic incision is needed to extract the uterus, or when available, power morcellation can be performed.

A major challenge, given our growing ability to laparoscopically remove very larger uteri, is that uteri heavier than about 2.5 kg in weight cannot be morcellated inside a morcellation bag. The risk of upstaging a known or suspected uterine malignancy, or of spreading an unknown malignant sarcoma (presumed benign myoma), should be incorporated in each patient’s decision making.

Thorough counseling about surgical options and on the risks of morcellating a very large uterus without containment in a bag is essential. Each patient must understand the risks and decide whether the benefits of minimally invasive surgery outweigh these risks. While MRI can sometimes provide increased suspicion of a leiomyosarcoma, malignancy can never be completed excluded preoperatively.
 

Removal of a 7.4-kg uterus

Our patient was a 44-year-old with a markedly enlarged fibroid uterus. Having been told by other providers that she was not a candidate for minimally invasive hysterectomy, she had delayed surgical management for a number of years, allowing for such a generous uterine size to develop.

The patient was knowledgeable about her condition and, given her comorbid obesity, she requested a minimally invasive approach. Preoperative imaging included an ultrasound, which had to be completed abdominally because of the size of her uterus, and an additional MRI was needed to further characterize the extent and nature of her uterus. A very detailed discussion regarding risk of leiomyosarcoma, operative complications, and conversion to laparotomy ensued.

Intraoperatively, we placed the first 5 mm port in the left upper quadrant initially to survey the anatomy for feasibility of laparoscopic hysterectomy. The left utero-ovarian pedicle was easily viewed by airplaning the bed alone. While the right utero-ovarian pedicle was much more skewed and enlarged, the right IP was easily accessible and the ureter well visualized.

The decision was made to place additional ports and proceed with laparoscopic hysterectomy. The 5-mm assistant ports were placed lateral and directly above the upper vascular pedicles. Operative time was 4 hours and 12 minutes, and blood loss was only 700 cc. Her preoperative hemoglobin was optimized at 13.3 g/dL and dropped to 11.3 g/dL postoperatively. The patient was discharged home the next morning and had a normal recovery with no complications.
 

Dr. Pasic is professor of obstetrics, gynecology & women’s health; director of the section of advanced gynecologic endoscopy; and codirector of the AAGL fellowship in minimally invasive gynecologic surgery at the University of Louisville (Ky.). Dr. Pasic is the current president of the International Society of Gynecologic Endoscopy. He is also a past president of the AAGL (2009). Dr. Cesta is Dr. Pasic’s current fellow in minimally invasive gynecologic surgery as well as an instructor in obstetrics and gynecology at the University of Louisville. Dr. Pasic disclosed he is a consultant for Ethicon Endo, Medtronic, and Olympus and is a speaker for Cooper Surgical, which manufactures some of the instruments mentioned in this article. Dr. Cesta had no relevant financial disclosures.

It has now been 30 years since the first total laparoscopic hysterectomy was performed. The benefits of minimally invasive gynecologic surgery (MIGS) – and of minimally invasive hysterectomy specifically – are now well documented. Since this milestone procedure, both instrumentation and technique have improved significantly.

Physician experience is the most important determinant for which minimally invasive approach is used to perform hysterectomy. This includes traditional laparoscopy, as well as the robotically assisted laparoscopic approach. However, certain patient characteristics also may influence the choice. A uterus that is undescended, combined with a narrow introitus, for instance, can be a contributory factor in choosing to perform laparoscopic hysterectomy. Additionally, so can an extremely large uterus and an extremely high body mass index (BMI).

These latter two factors – a very large uterus (which we define as more than 15-16 weeks’ gestational size) and a BMI over 60 kg/m² – historically were considered to be contraindications to laparoscopic hysterectomy. But as the proficiency, comfort, and skill of a new generation of laparoscopic surgeons increases, the tide is shifting with respect to both morbid obesity and the very large uterus.

With growing experience and improved instrumentation, the majority of gynecologists who are fellowship-trained in MIGS are able to routinely and safely perform laparoscopic hysterectomy for uteri weighing 1-2 kg and in patients who have extreme morbid obesity. The literature, moreover, increasingly features case reports of laparoscopic removal of very large uteri and reviews/discussions of total laparoscopic hysterectomy being feasible.

In our own experience, total laparoscopic hysterectomy (TLH) of the very large uterus can be safely and advantageously performed using key instruments and refinements in technique, as well as thorough patient counseling regarding the risk of unexpected sarcomas. Recently, we safely performed total laparoscopic hysterectomy for a patient with a uterus that – somewhat unexpectedly – weighed 7.4 kg.
 

Surgical pearls

Performing safe and effective total laparoscopic hysterectomy for large uteri – and for morbidly obese patients – hinges largely on modifications in entry and port placement, patient positioning, and choice of instrumentation. With these modifications, we can achieve adequate visualization of critical anatomy and can minimize bleeding. Otherwise, the surgery itself is largely the same. Here are the principles we find most helpful.

Entry and port placement

Traditionally, for TLHs, a camera port is placed at the umbilicus to provide a full view of the pelvis. For the larger uterus – and in women who are extremely obese – we aim to introduce the laparoscope higher. A reliable landmark is the Palmer’s point in the left upper quadrant. From here, we can identify areas for the placement of additional trocars.

In general, we place ancillary 5-mm ports more cephalad and lateral to the uterus than we otherwise would. Such placement facilitates effective visualization while accommodating manipulation of the uterus and allows us to avoid bleeding around the vascular upper pedicles. Overall, we have much better control through all parts of the surgery when we operate lateral to the uterus.
 

Patient positioning

In addition to the Trendelenburg position, we have adopted an “airplaning” technique for patients with a very large uterus in which the bed is tilted from side to side so that the left and right sides of the body are rotated upward as needed. This allows for gravitational-assisted retraction when it otherwise is not possible.

Instrumentation

For morbidly obese patients, we use Kii Fios advanced fixation trocars. These come in 5- and 10-mm sizes and are equipped with an intraperitoneal balloon that can be inflated to prevent sliding of the trocar out of the abdominal wall.

By far the most valuable instrument for the morbidly obese and the very large uterus is a 30-degree laparoscope. With our higher port placement as described, the 30-degree scope provides visualization of critical structures that wouldn’t be possible with a 0-degree scope.

The Rumi uterine manipulator comes with cups that come in different sizes and can fit around the cervix and help delineate the cervicouterine junction. We use this manipulator for all laparoscopic hysterectomies, but it is a must for the very large uterus.

Extensive desiccation of the utero-ovarian pedicles and uterine arteries is critical, and for this we advise using the rotating bipolar RoBi instrument. Use of the conventional bipolar instrument allows us to use targeted and anatomically guided application of energy. This ensures certainty that vessels whose limits exceed the diameter for advanced bipolar devices (typically 7 mm) are completely sealed. In-depth knowledge of pelvic anatomy and advanced laparoscopic dissection is paramount during these steps to ensure that vital structures are not damaged by the wider thermal spread of the traditional bipolar device. For cutting, the use of ultrasonic energy is important to prevent energy from spreading laterally.

Lastly, we recommend a good suction irrigator because, if bleeding occurs, it tends to be heavy because of the enlarged nature of feeding vasculature. When placed through an umbilical or suprapubic port, the suction irrigator also may be used to help with the rotational vectors and traction for further uterine manipulation.
 

Technique

Courtesy Dr. Paya Pasic

We usually operate from top to bottom, transecting the upper pedicles such as the infundibulopelvic (IP) ligaments or utero-ovarian ligaments first, rather than the round ligaments. This helps us achieve additional mobility of the uterus. Some surgeons believe that retroperitoneal dissection and ligation of the uterine arteries at their origin is essential, but we find that, with good uterine manipulation and the use of a 30-degree scope, we achieve adequate visualization for identifying the ureter and uterine artery on the sidewall and consequently do not need to dissect retroperitoneally.

When using the uterine manipulator with the colpotomy cup, the uterus is pushed upward, increasing the distance between the vaginal fornix and the ureters. Uterine arteries can easily be identified and desiccated using conventional bipolar energy. When the colpotomy cup is pushed cephalad, the application of the bipolar energy within the limits of the cup is safe. The thermal spread does not pose a threat to the ureters, which are displaced 1.5-2 cm laterally. Large fibroids often contribute to distorted anatomical planes, and a colpotomy cup provides a firm palpable surface between the cervix and vagina during dissection.

When dealing with large uteri, one must sometimes think outside the box and deviate from standard technique. For instance, in patients with distorted anatomy because of large fibroids, it helps to first control the pedicles that are most easily accessible. Sometimes it is acceptable to perform oophorectomy if the IP ligament is more accessible and the utero-ovarian pedicle is distorted by dilated veins and adherent to the uterus. After transection of each pedicle, we gain more mobility of the uterus and better visualization for the next step.

Inserting the camera through ancillary ports – a technique known as “port hopping” – helps to visualize and take down adhesions much better and more safely than using the camera from the umbilical port only. Port hopping with a 30-degree laparoscope helps to obtain a 360-degree view of adhesions and anatomy, which is exceedingly helpful in cases in which crucial anatomical structures are within close proximity of one another.

In general it is more challenging to perform TLH on a patient with a broad uterus or a patient with low posterior fibroids that are occupying the pelvis than on a patient with fibroids in the upper abdomen. The main challenge for the surgeon is to safely secure the uterine arteries and control the blood supply to the uterus.

Access to the pelvic sidewall is obtained with the combination of 30-degree scope, uterine manipulator, and the suction irrigator introduced through the midline port; the cervix and uterus are deviated upward. Instead of the suction irrigator or blunt dissector used for internal uterine manipulation, some surgeons use myoma screws or a 5-mm single-tooth tenaculum to manipulate a large uterus. Both of those instruments are valuable and work well, but often a large uterus requires extensive manipulation. Repositioning of any sharp instruments that pierce the serosa can often lead to additional blood loss. It is preferable to avoid this blood loss on a large uterus at all costs because it can be brisk and stains the surgical pedicles, making the remainder of the procedure unnecessarily difficult.

Once the uterine arteries are desiccated, if fibroids are obscuring the view, the corpus of the uterus can be detached from the cervix as in supracervical hysterectomy fashion. From there, the uterus can be placed in the upper abdomen while colpotomy can be performed.

In patients with multiple fibroids, we do not recommend performing myomectomy first, unless the fibroid is pedunculated and on a very small stalk. Improved uterine manipulation and retroperitoneal dissection are preferred over myomectomy to safely complete hysterectomy for the broad uterus. In our opinion, any attempt at myomectomy would lead to unnecessary blood loss and additional operative time with minimal benefit.

In patients with fibroids that grow into the broad ligament and pelvic sidewall, the natural course of the ureter becomes displaced laterally. This is contrary to the popular misconception that the ureter is more medially located in the setting of broad-ligament fibroids. To ensure safe access to the uterine arteries, the vesicouterine peritoneum can be incised and extended cephalad along the broad ligament and, then, using the above-mentioned technique, by pushing the uterus and the fibroid to the contralateral side via the suction irrigator, the uterine arteries can be easily accessed.

Another useful technique is to use diluted vasopressin injected into the lower pole of the uterus to cause vasoconstriction and minimize the bleeding. The concentration is 1 cc of 20 units of vasopressin in 100-400 cc of saline. This technique is very useful for myomectomies, and some surgeons find it also helpful for hysterectomy. The plasma half-life of vasopressin is 10-20 minutes, and a large quantity is needed to help with vasoconstriction in a big uterus. The safe upper limits of vasopressin dosing are not firmly established. A fibroid uterus with aberrant vasculature may require a greater-than-acceptable dose to control bleeding.

It is important to ensure that patients have an optimized hemoglobin level preoperatively. We use a hemoglobin level of 8 g/dL as a lowest cutoff value for performing TLH without preoperative transfusion. Regarding bowel preparation, neither the literature nor our own experience support its value, so we typically do not use it.
 

Morcellation and patient counseling

Courtesy Dr. Paya Pasic

Uteri up to 12 weeks’ gestational size usually can be extracted transvaginally, and most uteri regardless of size can be morcellated and extracted through the vagina, providing that the vaginal fornix is accessible from below. In some cases, such as when the apex is too high, a minilaparotomic incision is needed to extract the uterus, or when available, power morcellation can be performed.

A major challenge, given our growing ability to laparoscopically remove very larger uteri, is that uteri heavier than about 2.5 kg in weight cannot be morcellated inside a morcellation bag. The risk of upstaging a known or suspected uterine malignancy, or of spreading an unknown malignant sarcoma (presumed benign myoma), should be incorporated in each patient’s decision making.

Thorough counseling about surgical options and on the risks of morcellating a very large uterus without containment in a bag is essential. Each patient must understand the risks and decide whether the benefits of minimally invasive surgery outweigh these risks. While MRI can sometimes provide increased suspicion of a leiomyosarcoma, malignancy can never be completed excluded preoperatively.
 

Removal of a 7.4-kg uterus

Our patient was a 44-year-old with a markedly enlarged fibroid uterus. Having been told by other providers that she was not a candidate for minimally invasive hysterectomy, she had delayed surgical management for a number of years, allowing for such a generous uterine size to develop.

The patient was knowledgeable about her condition and, given her comorbid obesity, she requested a minimally invasive approach. Preoperative imaging included an ultrasound, which had to be completed abdominally because of the size of her uterus, and an additional MRI was needed to further characterize the extent and nature of her uterus. A very detailed discussion regarding risk of leiomyosarcoma, operative complications, and conversion to laparotomy ensued.

Intraoperatively, we placed the first 5 mm port in the left upper quadrant initially to survey the anatomy for feasibility of laparoscopic hysterectomy. The left utero-ovarian pedicle was easily viewed by airplaning the bed alone. While the right utero-ovarian pedicle was much more skewed and enlarged, the right IP was easily accessible and the ureter well visualized.

The decision was made to place additional ports and proceed with laparoscopic hysterectomy. The 5-mm assistant ports were placed lateral and directly above the upper vascular pedicles. Operative time was 4 hours and 12 minutes, and blood loss was only 700 cc. Her preoperative hemoglobin was optimized at 13.3 g/dL and dropped to 11.3 g/dL postoperatively. The patient was discharged home the next morning and had a normal recovery with no complications.
 

Dr. Pasic is professor of obstetrics, gynecology & women’s health; director of the section of advanced gynecologic endoscopy; and codirector of the AAGL fellowship in minimally invasive gynecologic surgery at the University of Louisville (Ky.). Dr. Pasic is the current president of the International Society of Gynecologic Endoscopy. He is also a past president of the AAGL (2009). Dr. Cesta is Dr. Pasic’s current fellow in minimally invasive gynecologic surgery as well as an instructor in obstetrics and gynecology at the University of Louisville. Dr. Pasic disclosed he is a consultant for Ethicon Endo, Medtronic, and Olympus and is a speaker for Cooper Surgical, which manufactures some of the instruments mentioned in this article. Dr. Cesta had no relevant financial disclosures.

It has now been 30 years since the first total laparoscopic hysterectomy was performed. The benefits of minimally invasive gynecologic surgery (MIGS) – and of minimally invasive hysterectomy specifically – are now well documented. Since this milestone procedure, both instrumentation and technique have improved significantly.

Physician experience is the most important determinant for which minimally invasive approach is used to perform hysterectomy. This includes traditional laparoscopy, as well as the robotically assisted laparoscopic approach. However, certain patient characteristics also may influence the choice. A uterus that is undescended, combined with a narrow introitus, for instance, can be a contributory factor in choosing to perform laparoscopic hysterectomy. Additionally, so can an extremely large uterus and an extremely high body mass index (BMI).

These latter two factors – a very large uterus (which we define as more than 15-16 weeks’ gestational size) and a BMI over 60 kg/m² – historically were considered to be contraindications to laparoscopic hysterectomy. But as the proficiency, comfort, and skill of a new generation of laparoscopic surgeons increases, the tide is shifting with respect to both morbid obesity and the very large uterus.

With growing experience and improved instrumentation, the majority of gynecologists who are fellowship-trained in MIGS are able to routinely and safely perform laparoscopic hysterectomy for uteri weighing 1-2 kg and in patients who have extreme morbid obesity. The literature, moreover, increasingly features case reports of laparoscopic removal of very large uteri and reviews/discussions of total laparoscopic hysterectomy being feasible.

In our own experience, total laparoscopic hysterectomy (TLH) of the very large uterus can be safely and advantageously performed using key instruments and refinements in technique, as well as thorough patient counseling regarding the risk of unexpected sarcomas. Recently, we safely performed total laparoscopic hysterectomy for a patient with a uterus that – somewhat unexpectedly – weighed 7.4 kg.
 

Surgical pearls

Performing safe and effective total laparoscopic hysterectomy for large uteri – and for morbidly obese patients – hinges largely on modifications in entry and port placement, patient positioning, and choice of instrumentation. With these modifications, we can achieve adequate visualization of critical anatomy and can minimize bleeding. Otherwise, the surgery itself is largely the same. Here are the principles we find most helpful.

Entry and port placement

Traditionally, for TLHs, a camera port is placed at the umbilicus to provide a full view of the pelvis. For the larger uterus – and in women who are extremely obese – we aim to introduce the laparoscope higher. A reliable landmark is the Palmer’s point in the left upper quadrant. From here, we can identify areas for the placement of additional trocars.

In general, we place ancillary 5-mm ports more cephalad and lateral to the uterus than we otherwise would. Such placement facilitates effective visualization while accommodating manipulation of the uterus and allows us to avoid bleeding around the vascular upper pedicles. Overall, we have much better control through all parts of the surgery when we operate lateral to the uterus.
 

Patient positioning

In addition to the Trendelenburg position, we have adopted an “airplaning” technique for patients with a very large uterus in which the bed is tilted from side to side so that the left and right sides of the body are rotated upward as needed. This allows for gravitational-assisted retraction when it otherwise is not possible.

Instrumentation

For morbidly obese patients, we use Kii Fios advanced fixation trocars. These come in 5- and 10-mm sizes and are equipped with an intraperitoneal balloon that can be inflated to prevent sliding of the trocar out of the abdominal wall.

By far the most valuable instrument for the morbidly obese and the very large uterus is a 30-degree laparoscope. With our higher port placement as described, the 30-degree scope provides visualization of critical structures that wouldn’t be possible with a 0-degree scope.

The Rumi uterine manipulator comes with cups that come in different sizes and can fit around the cervix and help delineate the cervicouterine junction. We use this manipulator for all laparoscopic hysterectomies, but it is a must for the very large uterus.

Extensive desiccation of the utero-ovarian pedicles and uterine arteries is critical, and for this we advise using the rotating bipolar RoBi instrument. Use of the conventional bipolar instrument allows us to use targeted and anatomically guided application of energy. This ensures certainty that vessels whose limits exceed the diameter for advanced bipolar devices (typically 7 mm) are completely sealed. In-depth knowledge of pelvic anatomy and advanced laparoscopic dissection is paramount during these steps to ensure that vital structures are not damaged by the wider thermal spread of the traditional bipolar device. For cutting, the use of ultrasonic energy is important to prevent energy from spreading laterally.

Lastly, we recommend a good suction irrigator because, if bleeding occurs, it tends to be heavy because of the enlarged nature of feeding vasculature. When placed through an umbilical or suprapubic port, the suction irrigator also may be used to help with the rotational vectors and traction for further uterine manipulation.
 

Technique

Courtesy Dr. Paya Pasic

We usually operate from top to bottom, transecting the upper pedicles such as the infundibulopelvic (IP) ligaments or utero-ovarian ligaments first, rather than the round ligaments. This helps us achieve additional mobility of the uterus. Some surgeons believe that retroperitoneal dissection and ligation of the uterine arteries at their origin is essential, but we find that, with good uterine manipulation and the use of a 30-degree scope, we achieve adequate visualization for identifying the ureter and uterine artery on the sidewall and consequently do not need to dissect retroperitoneally.

When using the uterine manipulator with the colpotomy cup, the uterus is pushed upward, increasing the distance between the vaginal fornix and the ureters. Uterine arteries can easily be identified and desiccated using conventional bipolar energy. When the colpotomy cup is pushed cephalad, the application of the bipolar energy within the limits of the cup is safe. The thermal spread does not pose a threat to the ureters, which are displaced 1.5-2 cm laterally. Large fibroids often contribute to distorted anatomical planes, and a colpotomy cup provides a firm palpable surface between the cervix and vagina during dissection.

When dealing with large uteri, one must sometimes think outside the box and deviate from standard technique. For instance, in patients with distorted anatomy because of large fibroids, it helps to first control the pedicles that are most easily accessible. Sometimes it is acceptable to perform oophorectomy if the IP ligament is more accessible and the utero-ovarian pedicle is distorted by dilated veins and adherent to the uterus. After transection of each pedicle, we gain more mobility of the uterus and better visualization for the next step.

Inserting the camera through ancillary ports – a technique known as “port hopping” – helps to visualize and take down adhesions much better and more safely than using the camera from the umbilical port only. Port hopping with a 30-degree laparoscope helps to obtain a 360-degree view of adhesions and anatomy, which is exceedingly helpful in cases in which crucial anatomical structures are within close proximity of one another.

In general it is more challenging to perform TLH on a patient with a broad uterus or a patient with low posterior fibroids that are occupying the pelvis than on a patient with fibroids in the upper abdomen. The main challenge for the surgeon is to safely secure the uterine arteries and control the blood supply to the uterus.

Access to the pelvic sidewall is obtained with the combination of 30-degree scope, uterine manipulator, and the suction irrigator introduced through the midline port; the cervix and uterus are deviated upward. Instead of the suction irrigator or blunt dissector used for internal uterine manipulation, some surgeons use myoma screws or a 5-mm single-tooth tenaculum to manipulate a large uterus. Both of those instruments are valuable and work well, but often a large uterus requires extensive manipulation. Repositioning of any sharp instruments that pierce the serosa can often lead to additional blood loss. It is preferable to avoid this blood loss on a large uterus at all costs because it can be brisk and stains the surgical pedicles, making the remainder of the procedure unnecessarily difficult.

Once the uterine arteries are desiccated, if fibroids are obscuring the view, the corpus of the uterus can be detached from the cervix as in supracervical hysterectomy fashion. From there, the uterus can be placed in the upper abdomen while colpotomy can be performed.

In patients with multiple fibroids, we do not recommend performing myomectomy first, unless the fibroid is pedunculated and on a very small stalk. Improved uterine manipulation and retroperitoneal dissection are preferred over myomectomy to safely complete hysterectomy for the broad uterus. In our opinion, any attempt at myomectomy would lead to unnecessary blood loss and additional operative time with minimal benefit.

In patients with fibroids that grow into the broad ligament and pelvic sidewall, the natural course of the ureter becomes displaced laterally. This is contrary to the popular misconception that the ureter is more medially located in the setting of broad-ligament fibroids. To ensure safe access to the uterine arteries, the vesicouterine peritoneum can be incised and extended cephalad along the broad ligament and, then, using the above-mentioned technique, by pushing the uterus and the fibroid to the contralateral side via the suction irrigator, the uterine arteries can be easily accessed.

Another useful technique is to use diluted vasopressin injected into the lower pole of the uterus to cause vasoconstriction and minimize the bleeding. The concentration is 1 cc of 20 units of vasopressin in 100-400 cc of saline. This technique is very useful for myomectomies, and some surgeons find it also helpful for hysterectomy. The plasma half-life of vasopressin is 10-20 minutes, and a large quantity is needed to help with vasoconstriction in a big uterus. The safe upper limits of vasopressin dosing are not firmly established. A fibroid uterus with aberrant vasculature may require a greater-than-acceptable dose to control bleeding.

It is important to ensure that patients have an optimized hemoglobin level preoperatively. We use a hemoglobin level of 8 g/dL as a lowest cutoff value for performing TLH without preoperative transfusion. Regarding bowel preparation, neither the literature nor our own experience support its value, so we typically do not use it.
 

Morcellation and patient counseling

Courtesy Dr. Paya Pasic

Uteri up to 12 weeks’ gestational size usually can be extracted transvaginally, and most uteri regardless of size can be morcellated and extracted through the vagina, providing that the vaginal fornix is accessible from below. In some cases, such as when the apex is too high, a minilaparotomic incision is needed to extract the uterus, or when available, power morcellation can be performed.

A major challenge, given our growing ability to laparoscopically remove very larger uteri, is that uteri heavier than about 2.5 kg in weight cannot be morcellated inside a morcellation bag. The risk of upstaging a known or suspected uterine malignancy, or of spreading an unknown malignant sarcoma (presumed benign myoma), should be incorporated in each patient’s decision making.

Thorough counseling about surgical options and on the risks of morcellating a very large uterus without containment in a bag is essential. Each patient must understand the risks and decide whether the benefits of minimally invasive surgery outweigh these risks. While MRI can sometimes provide increased suspicion of a leiomyosarcoma, malignancy can never be completed excluded preoperatively.
 

Removal of a 7.4-kg uterus

Our patient was a 44-year-old with a markedly enlarged fibroid uterus. Having been told by other providers that she was not a candidate for minimally invasive hysterectomy, she had delayed surgical management for a number of years, allowing for such a generous uterine size to develop.

The patient was knowledgeable about her condition and, given her comorbid obesity, she requested a minimally invasive approach. Preoperative imaging included an ultrasound, which had to be completed abdominally because of the size of her uterus, and an additional MRI was needed to further characterize the extent and nature of her uterus. A very detailed discussion regarding risk of leiomyosarcoma, operative complications, and conversion to laparotomy ensued.

Intraoperatively, we placed the first 5 mm port in the left upper quadrant initially to survey the anatomy for feasibility of laparoscopic hysterectomy. The left utero-ovarian pedicle was easily viewed by airplaning the bed alone. While the right utero-ovarian pedicle was much more skewed and enlarged, the right IP was easily accessible and the ureter well visualized.

The decision was made to place additional ports and proceed with laparoscopic hysterectomy. The 5-mm assistant ports were placed lateral and directly above the upper vascular pedicles. Operative time was 4 hours and 12 minutes, and blood loss was only 700 cc. Her preoperative hemoglobin was optimized at 13.3 g/dL and dropped to 11.3 g/dL postoperatively. The patient was discharged home the next morning and had a normal recovery with no complications.
 

Dr. Pasic is professor of obstetrics, gynecology & women’s health; director of the section of advanced gynecologic endoscopy; and codirector of the AAGL fellowship in minimally invasive gynecologic surgery at the University of Louisville (Ky.). Dr. Pasic is the current president of the International Society of Gynecologic Endoscopy. He is also a past president of the AAGL (2009). Dr. Cesta is Dr. Pasic’s current fellow in minimally invasive gynecologic surgery as well as an instructor in obstetrics and gynecology at the University of Louisville. Dr. Pasic disclosed he is a consultant for Ethicon Endo, Medtronic, and Olympus and is a speaker for Cooper Surgical, which manufactures some of the instruments mentioned in this article. Dr. Cesta had no relevant financial disclosures.

In his excellent treatise on the history of hysterectomy, Chris Sutton, MBBch, noted that, while Themison of Athens in 50 bc and Soranus of Ephesus in 120 ad were reported to have performed vaginal hysterectomy, these cases essentially were emergency amputation of severely prolapsed uteri, which usually involved cutting both ureters and the bladder (J Minim Invas Gynecol. 2010 Jul;17[4]:421–35). It was not until 1801 that the first planned elective vaginal hysterectomy was performed, and it was not until the mid 19th century, in 1853, that Walter Burnham, MD, in Lowell, Mass., performed the first abdominal hysterectomy resulting in patient survival.

Seemingly incredible, it was only 125 years later, in autumn of 1988 at William Nesbitt Memorial Hospital in Kingston, Pa., that Harry Reich, MD, performed the first total laparoscopically assisted hysterectomy.

Since Dr. Reich’s groundbreaking procedure, the performance of laparoscopic hysterectomy has advanced at a feverish pace. In my own practice, I have not performed an abdominal hysterectomy since 1998. My two partners, who are both fellowship-trained in minimally invasive gynecologic surgery (MIGS), Aarathi Cholkeri-Singh, MD, who joined my practice in 2007, and Kristen Sasaki, MD, who joined my practice in 2014, have never performed an open hysterectomy since starting practice. Despite these advances, a minimally invasive approach to hysterectomy is not without challenge. One of the most difficult situations is the truly large uterus – greater than 2,500 grams.

For this edition of the Master Class in Gynecologic Surgery, I have enlisted the assistance of Paya Pasic, MD, and Megan Cesta, MD, to discuss the next frontier: the removal of the multiple kilogram uterus.

Dr. Pasic is an internationally recognized leader in laparoscopic MIGS. He is professor of obstetrics, gynecology & women’s health; director, section of advanced gynecologic endoscopy, and codirector of the AAGL fellowship in MIGS at the University of Louisville (Ky.). Dr. Pasic is the current president of the International Society of Gynecologic Endoscopy. He is also a past president of the AAGL (2009). Dr. Pasic is published in the field of MIGS, having authored many publications, book chapters, monographs, and textbooks.

Dr. Cesta is Dr. Pasic’s current fellow in MIGS and an instructor in obstetrics and gynecology at the university.

It is truly a pleasure to welcome Dr. Pasic and Dr. Cesta to this edition of the Master Class in Gynecologic Surgery.

Dr. Miller is a clinical associate professor at the University of Illinois in Chicago and past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in metropolitan Chicago and the director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill. He has no disclosures relevant to this Master Class. Email him at [email protected].

In his excellent treatise on the history of hysterectomy, Chris Sutton, MBBch, noted that, while Themison of Athens in 50 bc and Soranus of Ephesus in 120 ad were reported to have performed vaginal hysterectomy, these cases essentially were emergency amputation of severely prolapsed uteri, which usually involved cutting both ureters and the bladder (J Minim Invas Gynecol. 2010 Jul;17[4]:421–35). It was not until 1801 that the first planned elective vaginal hysterectomy was performed, and it was not until the mid 19th century, in 1853, that Walter Burnham, MD, in Lowell, Mass., performed the first abdominal hysterectomy resulting in patient survival.

Seemingly incredible, it was only 125 years later, in autumn of 1988 at William Nesbitt Memorial Hospital in Kingston, Pa., that Harry Reich, MD, performed the first total laparoscopically assisted hysterectomy.

Since Dr. Reich’s groundbreaking procedure, the performance of laparoscopic hysterectomy has advanced at a feverish pace. In my own practice, I have not performed an abdominal hysterectomy since 1998. My two partners, who are both fellowship-trained in minimally invasive gynecologic surgery (MIGS), Aarathi Cholkeri-Singh, MD, who joined my practice in 2007, and Kristen Sasaki, MD, who joined my practice in 2014, have never performed an open hysterectomy since starting practice. Despite these advances, a minimally invasive approach to hysterectomy is not without challenge. One of the most difficult situations is the truly large uterus – greater than 2,500 grams.

For this edition of the Master Class in Gynecologic Surgery, I have enlisted the assistance of Paya Pasic, MD, and Megan Cesta, MD, to discuss the next frontier: the removal of the multiple kilogram uterus.

Dr. Pasic is an internationally recognized leader in laparoscopic MIGS. He is professor of obstetrics, gynecology & women’s health; director, section of advanced gynecologic endoscopy, and codirector of the AAGL fellowship in MIGS at the University of Louisville (Ky.). Dr. Pasic is the current president of the International Society of Gynecologic Endoscopy. He is also a past president of the AAGL (2009). Dr. Pasic is published in the field of MIGS, having authored many publications, book chapters, monographs, and textbooks.

Dr. Cesta is Dr. Pasic’s current fellow in MIGS and an instructor in obstetrics and gynecology at the university.

It is truly a pleasure to welcome Dr. Pasic and Dr. Cesta to this edition of the Master Class in Gynecologic Surgery.

Dr. Miller is a clinical associate professor at the University of Illinois in Chicago and past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in metropolitan Chicago and the director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill. He has no disclosures relevant to this Master Class. Email him at [email protected].

In his excellent treatise on the history of hysterectomy, Chris Sutton, MBBch, noted that, while Themison of Athens in 50 bc and Soranus of Ephesus in 120 ad were reported to have performed vaginal hysterectomy, these cases essentially were emergency amputation of severely prolapsed uteri, which usually involved cutting both ureters and the bladder (J Minim Invas Gynecol. 2010 Jul;17[4]:421–35). It was not until 1801 that the first planned elective vaginal hysterectomy was performed, and it was not until the mid 19th century, in 1853, that Walter Burnham, MD, in Lowell, Mass., performed the first abdominal hysterectomy resulting in patient survival.

Seemingly incredible, it was only 125 years later, in autumn of 1988 at William Nesbitt Memorial Hospital in Kingston, Pa., that Harry Reich, MD, performed the first total laparoscopically assisted hysterectomy.

Since Dr. Reich’s groundbreaking procedure, the performance of laparoscopic hysterectomy has advanced at a feverish pace. In my own practice, I have not performed an abdominal hysterectomy since 1998. My two partners, who are both fellowship-trained in minimally invasive gynecologic surgery (MIGS), Aarathi Cholkeri-Singh, MD, who joined my practice in 2007, and Kristen Sasaki, MD, who joined my practice in 2014, have never performed an open hysterectomy since starting practice. Despite these advances, a minimally invasive approach to hysterectomy is not without challenge. One of the most difficult situations is the truly large uterus – greater than 2,500 grams.

For this edition of the Master Class in Gynecologic Surgery, I have enlisted the assistance of Paya Pasic, MD, and Megan Cesta, MD, to discuss the next frontier: the removal of the multiple kilogram uterus.

Dr. Pasic is an internationally recognized leader in laparoscopic MIGS. He is professor of obstetrics, gynecology & women’s health; director, section of advanced gynecologic endoscopy, and codirector of the AAGL fellowship in MIGS at the University of Louisville (Ky.). Dr. Pasic is the current president of the International Society of Gynecologic Endoscopy. He is also a past president of the AAGL (2009). Dr. Pasic is published in the field of MIGS, having authored many publications, book chapters, monographs, and textbooks.

Dr. Cesta is Dr. Pasic’s current fellow in MIGS and an instructor in obstetrics and gynecology at the university.

It is truly a pleasure to welcome Dr. Pasic and Dr. Cesta to this edition of the Master Class in Gynecologic Surgery.

Dr. Miller is a clinical associate professor at the University of Illinois in Chicago and past president of the AAGL. He is a reproductive endocrinologist and minimally invasive gynecologic surgeon in metropolitan Chicago and the director of minimally invasive gynecologic surgery at Advocate Lutheran General Hospital, Park Ridge, Ill. He has no disclosures relevant to this Master Class. Email him at [email protected].

Sequencing Therapies

Mark Klein, MD. The last few years, there have been several new trials in prostate cancer for people in a metastatic setting or more advanced local setting, such as the STAMPEDE, LATITUDE, and CHAARTED trials.^1-4 In addition, recently a few trials have examined apalutamide and enzalutamide for people who have had PSA (prostate-specific antigen) levels rapidly rising within about 10 months or so. One of the questions that arises is, how do we wrap our heads around sequencing these therapies. Is there a sequence that we should be doing and thinking about upfront and how do the different trials compare?

Julie Graff, MD. It just got more complicated. There was news today (December 20, 2018) that using enzalutamide early on in newly diagnosed metastatic prostate cancer may have positive results. It is not yet approved by the US Food and Drug Administration (FDA), but for patients who present with metastatic prostate cancer, we may have 4 potential treatments. We could have androgen deprivation therapy (ADT) alone, ADT plus docetaxel, enzalutamide, or abiraterone.

When I see patients in this situation, I talk to them about their options, the pros and cons of each option, and try to cover all the trials that look at these combinations. It can be quite a long visit. I talk to the patient about who benefits most, whether it is patients with high-risk factors or high-volume cancers. Also, I talk with the patient about all the adverse effects (AEs), and I look at my patients’ comorbid conditions and come up with a plan.

I encourage any patient who has high-volume or high-risk disease to consider more than just ADT alone. For many patients, I have been using abiraterone plus ADT. I have a wonderful pharmacist. As a medical oncologist, I can’t do it on my own. I need someone to follow patients’ laboratory results and to be available for medication questions and complications.

Elizabeth Hansen, PharmD. With the increasing number of patients on oral antineoplastics, monitoring patients in the outpatient setting has become an increasing priority and one of my major roles as a pharmacist in the clinic at the Chalmers P. Wylie VA Ambulatory Care Center in Columbus, Ohio. This is especially important as some of these treatments require frequent laboratory monitoring, such as abiraterone with liver function tests every 2 weeks for the first 3 months of treatment and monthly thereafter. Without frequent-follow up it’s easy for these patients to get lost in the shuffle.

Abhishek Solanki, MD. You could argue that a fifth option is prostate-directed radiation for patients who have limited metastases based on the STAMPEDE trial, which we’ve started integrating into our practice at the Edward Hines, Jr. Veterans Affairs Hospital in Chicago, Illinois.⁴

Mark Klein. Do you have a feel for the data and using radiation in oligometastatic (≤ 5 metastatic tumors) disease in prostate cancer and how well that might work?

Abhishek Solanki. The best data we have are from the multi-arm, multistage STAMPEDE trial systemic therapies and local therapy in the setting of high-risk localized disease and metastatic disease.⁶ The most recent publication looked specifically at the population with newly diagnosed metastatic disease and compared standard ADT (and docetaxel in about 18% of the patients) with or without prostate-directed radiation therapy. There was no survival benefit with radiation in the overall population, but in the subgroup of patients with low metastatic burden, there was an 8% survival benefit at 3 years.

It’s difficult to know what to make of that information because, as we’ve discussed already, there are other systemic therapy options that are being used more and more upfront such as abiraterone. Can you see the same benefit of radiation in that setting? The flip side is that in this study, radiation just targeted the prostate; could survival be improved even more by targeting all sites of disease in patients with oligometastatic disease? These are still open questions in prostate cancer and there are clinical trials attempting to define the clinical benefit of radiation in the metastatic setting for patients with limited metastases.

Mark Klein. How do you select patients for radiation in this particular situation; How do you approach stratification when radiation is started upfront?

Abhishek Solanki. In the STAMPEDE trial, low metastatic burden was defined based on the definition in the CHAARTED trial, which was those patients who did not have ≥ 4 bone metastases with ≥ 1 outside the vertebral bodies or pelvis, and did not have visceral metastases.⁷ That’s tough, because this definition could be a patient with a solitary bone metastasis but also could include some patients who have involved nodes extending all the way up to the retroperitoneal nodes—that is a fairly heterogeneous population. What we have done at our institution is select patients who have 3 to 5 metastases, administer prostate radiation therapy, and add stereotactic body radiation therapy (SBRT) for the other sites of disease, invoking the oligometastasis approach.

We have been doing this more frequently in the last few months. Typically, we’ll do 3 to 5 fractions of SBRT to metastases. For the primary, if the patient chooses SBRT, we’ll take that approach. If the patient chooses a more standard fractionation, we’ll do 20 treatments, but from a logistic perspective, most patients would rather come in for 5 treatments than 20. We also typically would start these patients on systemic hormonal therapy.

Mark Klein. At that point, are they referred back to medical oncology for surveillance?

Abhishek Solanki. Yes, they are followed by medical oncology and radiation oncology, and typically would continue hormonal therapy.

Mark Klein. Julie, how have you thought about presenting the therapeutic options for those patients who would be either eligible for docetaxel with high-bulk disease or abiraterone? Do you find patients prefer one or the other?

Julie Graff. I try to be very open about all the possibilities, and I present both. I don’t just decide for the patient chemotherapy vs abiraterone, but after we talk about it, most of my patients do opt for the abiraterone. I had a patient referred from the community—we are seeing more and more of this because abiraterone is so expensive—whose ejection fraction was about 38%. I said to that patient, “we could do chemotherapy, but we shouldn’t do abiraterone.” But usually it’s not that clear-cut.

Elizabeth Hansen. There was also an update from the STAMPEDE trial published recently comparing upfront abiraterone and prednisone to docetaxel (18 weeks) in advanced or metastatic prostate cancer. Results from this trial indicated a nearly identical overall survival (OS) (hazard ratio [HR] = 1.16; 95% CI, 0.82-1.65; P = .40). However, the failure-free survival (HR = 0.51; 95% CI, 0.39-0.67; P < .001) and progression-free survival (PFS) (HR= 0.65; 95% CI, 0.0.48-0.88; P = .005) favored abiraterone.^8,9 The authors argue that while there was no change in OS, this trial demonstrates an important difference in the pattern of treatment failure.

Julie, do you think there will be any change in the treatment paradigm between docetaxel and abiraterone with this new update?

Julie Graff. I wasn’t that impressed by that study. I do not see it as practice changing, and it makes sense to me that the PFS is different in the 2 arms because we give chemotherapy and take a break vs giving abiraterone indefinitely. For me, there’s not really a shift.

Patients With Rising PSAs

Mark Klein. Let’s discuss the data from the recent studies on enzalutamide and apalutamide for the patients with fast-rising PSAs. In your discussions with other prostate researchers, will this become a standard part of practice or not?

Julie Graff. I was one of the authors on the SPARTAN apalutamide study.¹⁰ For a long time, we have had patients without metastatic disease but with a PSA relapse after surgery or radiation; and the PSA levels climb when the cancer becomes resistant to ADT. We haven’t had many options in that setting except to use bicalutamide and some older androgen receptor (AR) antagonists. We used to use estrogen and ketoconazole as well.

But now 2 studies have come out looking at a primary endpoint of metastases-free survival. Patients whose PSA was doubling every 10 months or shorter were randomized to either apalutamide (SPARTAN¹⁰) or enzalutamide (PROSPER¹¹), both second-generation AR antagonists. There was a placebo control arm in each of the studies. Both studies found that adding the second-generation AR targeting agent delayed the time to metastatic disease by about 2 years. There is not any signal yet for statistically significant OS benefit, so it is not entirely clear if you could wait for the first metastasis to develop and then give 1 of these treatments and have the same OS benefit.

At the VA Portland Health Care System (VAPORHCS), it took a while to make these drugs available. My fellows were excited to give these drugs right away, but I often counsel patients that we don’t know if the second-generation AR targeting agents will improve survival. They almost certainly will bring down PSAs, which helps with peace of mind, but anything we add to the ADT can cause more AEs.

I have been cautious with second-generation AR antagonists because patients, when they take one of these drugs, are going to be on it for a long time. The FDA has approved those 2 drugs regardless of PSA doubling time, but I would not give it for a PSA doubling time > 10 months. In my practice about a quarter of patients who would qualify for apalutamide or enzalutamide are actually taking one, and the others are monitored closely with computed tomography (CT) and bone scans. When the disease becomes metastatic, then we start those drugs.

Mark Klein. Why 10 months, why not 6 months, a year, or 18 months? Is there reasoning behind that?

Julie Graff. There was a publication by Matthew Smith showing that the PSA doubling time was predictive of the development of metastatic disease and cancer death or prostate cancer death, and that 10 months seemed to be the cutoff between when the prostate cancer was going to become deadly vs not.¹² If you actually look at the trial data, I think the PSA doubling time was between 3 and 4 months for the participants, so pretty short.

Adverse Effects

Mark Klein. What are the AEs people are seeing from using apalutamide, enzalutamide, and abiraterone? What are they seeing in their practice vs what is in the studies? When I have had to stop people on abiraterone or drop down the dose, almost always it has been for fatigue. We check liver function tests (LFTs) repeatedly, but I can’t remember ever having to drop down the dose or take it away even for that reason.

Elizabeth Hansen. The toxicities of these 3 agents are very different. In my practice I have seen a few patients develop hepatotoxicity with abiraterone, and I think this reflects the known incidence of transaminitis (grade 3/4) seen in clinical trials, reported at 6%. Generally, we’ve been able to restart treatment by withholding abiraterone until liver function returns to baseline and then subsequently dose reducing. Like Julie mentioned, abiraterone should be used with caution and/or avoided in patients with serious cardiac disease, recent myocardial infarction, or heart failure. I also always check blood pressure history, to ensure it is well controlled prior to initiation, and order a home blood pressure cuff for monitoring. With enzalutamide one of the main concerns is fatigue, which occurred in > 10% of patients in clinical trials. In my experience this has been dose limiting and can be managed with dose reductions. Seizures also occurred in 0.4% of patients on enzalutamide, so I always ask about seizure history and screen the medication list for concomitant medications that may lower the seizure threshold or other risk factors such as brain metastasis. Last, enzalutamide is a strong CYP3A4 inducer, so there is a strong possibility for drug interactions with other medications, and it is associated with increased cardiac events. With apalutamide you have the cardiac concerns, thyroid dysfunction, fracture risk, and drug interactions to worry about as well. To be honest, we have not used this agent yet at my practice.

Mark Klein. At the Minneapolis VA Health Care System (MVAHCS) when apalutamide first came out, for the PSA rapid doubling, there had already been an abstract presenting the enzalutamide data. We have chosen to recommend enzalutamide as our choice for the people with PSA doubling based on the cost. It’s significantly cheaper for the VA. Between the 2 papers there is very little difference in the efficacy data. I’m wondering what other sites have done with regard to that specific point at their VAs?

Elizabeth Hansen. In Columbus, we prefer to use either abiraterone and enzalutamide because they’re essentially cost neutral. However, this may change with generic abiraterone coming to market. Apalutamide is really cost prohibitive currently.

Julie Graff. I agree.

Patient Education

Mark Klein. At MVAHCS, the navigators handle a lot of upfront education. We have 3 navigators, including Kathleen Nelson who is on this roundtable. She works with patients and provides much of the patient education. How have you handled education for patients?

Kathleen Nelson. For the most part, our pharmacists do the drug-specific education for the oral agents, and the nurse navigators provide more generic education. We did a trial for patients on IV therapies. We learned that patients really don’t report in much detail, but if you call and ask them specific questions, then you can tease out some more detail.

Elizabeth Hansen. It is interesting that every site is different. One of my main roles is oral antineoplastic monitoring, which includes many patients on enzalutamide or abiraterone. At least initially with these patients, I try to follow them closely—abiraterone more so than enzalutamide. I typically call every 2 to 4 weeks, in between clinic visits, to follow up the laboratory tests and manage the AEs. I always try to ask direct and open-ended questions: How often are you checking your blood pressure? What is your current weight? How has your energy level changed since therapy initiation?

The VA telehealth system is amazing. For patients who need to monitor blood pressure regularly, it’s really nice for them to have those numbers come directly back to me in CPRS (Computerized Patient Record System). That has worked wonders for some of our patients to get them through therapy.

Mark Klein. What do you tend to use when the prostate cancer is progressing for a patient? And how do you determine that progression? Some studies will use PSA rise only as a marker for progression. Other studies have not used PSA rise as the only marker for progression and oftentimes require some sort of bone scan criteria or CT imaging criteria for progression.

Julie Graff. We have a limited number of treatment options. Providers typically use enzalutamide or abiraterone as there is a high degree of resistance between the 2. Then there is chemotherapy and then radium, which quite a few people don’t qualify for. We need to be very thoughtful when we change treatments. I look at the 3 factors of biochemical progression or response—PSA, radiographic progression, and clinical progression. If I don’t see 2 out of 3, I typically don’t change treatments. Then after enzalutamide or abiraterone, I wait until there are cancer-related symptoms before I consider chemotherapy and closely monitor my patients.

Imaging Modalities

Abhishek Solanki. Over the last few years the Hines VA Hospital has used fluciclovine positron emission tomography (PET), which is one of the novel imaging modalities for prostate cancer. Really the 2 novel imaging modalities that have gained the most excitement are prostate-specific membrane antigen (PSMA) PET and fluciclovine PET. Fluciclovine PET is based on a synthetic amino acid that’s taken up in multiple tissues, including prostate cancer. It has changed our practice in the localized setting for patients who have developed recurrence after radiation or radical prostatectomy. We have incorporated the scan into our workup of patients with recurrent disease, which can give us some more information at lower PSAs than historically we could get with CT, bone scan, or magnetic resonance imaging.

Our medical oncologists have started using it more and more as well. We are getting a lot of patients who have a negative CT or bone scan but have a positive fluciclovine PET. There are a few different disease settings where that becomes relevant. In patients who develop biochemical recurrence after radiation or salvage radiation after radical, we are finding that a lot of these patients who have no CT or bone scan findings of disease ultimately are found to have a PET-positive lesion. Sometimes it’s difficult to know how best to help patients with PET-only disease. Should you target the disease with an oligometastasis approach or just pursue systemic therapy or surveillance? It is challenging but more and more we are moving toward metastasis-directed therapy. There are multiple randomized trials in progress testing whether metastasis-directed therapy to the PET areas of recurrence can improve outcomes or delay systemic ADT. The STOMP trial randomized surveillance vs SBRT or surgery for patients with oligometastatic disease that showed improvement in biochemical control and ADT-free survival.¹³ However this was a small trial that tried to identify a signal. More definitive trials are necessary.

The other setting where we have found novel PET imaging to be helpful is in patients who have become castration resistant but don’t have clear metastases on conventional imaging. We’re identifying more patients who have only a few sites of progression, and we’ll pursue metastasis-directed therapy to those areas to try to get more mileage out of the systemic therapy that the patient is currently on and to try to avoid having to switch to the next line with the idea that, potentially, the progression site is just a limited clone that is progressing despite the current systemic therapy.
 

Mark Klein. I find that to be a very attractive approach. I’m assuming you do that for any systemic therapy where people have maybe 1 or 2 sites and they do not have a big PSA jump. Do you have a number of sites that you’re willing to radiate? And then, when you do that, what radiation fractionation and dosing do you use? Is there any observational data behind that for efficacy?

Abhishek Solanki. It is a patient by patient decision. Some patients, if they have a very rapid pace of progression shortly after starting systemic therapy and metastases have grown in several areas, we think that perhaps this person may benefit less from aggressive local therapy. But if it’s somebody who has been on systemic therapy for a while and has up to 3 sites of disease growth, we consider SBRT for oligoprogressive disease. Typically, we’ll use SBRT, which delivers a high dose of radiation over 3 to 5 treatments. With SBRT you can give a higher biologic dose and use more sophisticated treatment machines and image guidance for treatments to focus the radiation on the tumor area and limit exposure to normal tissue structures.

In prostate cancer to the primary site, we will typically do around 35 to 40 Gy in 5 fractions. For metastases, it depends on the site. If it’s in the lung, typically we will do 3 to 5 treatments, giving approximately 50 to 60 Gy in that course. In the spine, we use lower doses near the spinal cord and the cauda equina, typically about 30 Gy in 3 fractions. In the liver, similar to the lung, we’ll typically do 50-54 Gy in 3-5 fractions. There aren’t a lot of high-level data guiding the optimal dose/fractionation to metastases, but these are the doses we’ll use for various malignancies.

Treatment Options for Patients With Adverse Events

Mark Klein. I was just reviewing the 2004 study that randomized patients to mitoxantrone or docetaxel for up to 10 cycles.^14,15 Who are good candidates for docetaxel after they have exhausted abiraterone and enzalutamide? How long do you hold to the 10-cycle rule, or do you go beyond that if they’re doing well? And if they’re not a good candidate, what are some options?

Julie Graff. The best candidates are those who are having a cancer-related AE, particularly pain, because docetaxel only improves survival over mitoxantrone by about 2.5 months. I don’t talk to patients about it as though it is a life extender, but it seems to help control pain—about 70% of patients benefited in terms of pain or some other cancer-related symptom.¹⁴

I have a lot of patients who say, “Never will I do chemotherapy.” I refer those patients to hospice, or if they’re appropriate for radium-223, I consider that. I typically give about 6 cycles of chemotherapy and then see how they’re doing. In some patients, the cancer just doesn’t respond to it.

I do tell patients about the papers that you mentioned, the 2 studies of docetaxel vs mitoxantrone where they use about 10 cycles, and some of my patients go all 10.^14,15 Sometimes we have to stop because of neuropathy or some other AE. I believe in taking breaks and that you can probably start it later.

Elizabeth Hansen. I agree, our practice is similar. A lot of our patients are not very interested in chemotherapy. You have to take into consideration their ECOG (Eastern Cooperative Oncology Group) status, their goals, and quality of life when talking to them about these medications. And a lot of them tend to choose more of a palliative route. Depending on their AEs and how things are going, we will dose reduce, hold treatment, or give treatment holidays.

Mark Klein. If patients are progressing on docetaxel, what are options that people would use? Radium-223 certainly is available for patients with nonvisceral metastases, as well as cabazitaxel, mitoxantrone, estramustine and other older drugs.

Julie Graff. We have some clinical trials for patients postdocetaxel. We have the TRITON2 and TRITON3 studies open at the VA. (NCT02952534 and NCT02975934, respectively) A lot of patients would get a biopsy, and we’d look for a BRCA 1 or 2 and ATM mutation. For those patients who don’t have those mutations—and maybe 80% of them don’t—we talk about radium-223 for the patients without visceral metastases and bone pain. I have had a fair number of patients go on cabazitaxel, but I have not used mitoxantrone since cabazitaxel came out. It’s not off the table, but it hasn’t shown improvement in survival.

Elizabeth Hansen. One of our challenges, because we’re an ambulatory care center, is that we are unable to give radium-223 in house, and these services have to be sent out to a non-VA facility. It is doable, but it takes more legwork and organization on our part.

Julie Graff. We have not had radium-223, although we’re working to get that online. And we are physically connected to Oregon Health Science University (OHSU), so we send our patients there for radium. It is a pain because the doctors at OHSU don’t have CPRS access. I’m often in the middle of making sure the complete blood counts (CBCs) are sent to OHSU and to get my patients their treatments.

Mark Klein. The Minneapolis VAMC has radium-223 on site, and we have used it for patients whose cancer has progressed while on docetaxel without visceral metastases. Katie, have you had an opportunity to coordinate that care for patients?

Kathleen Nelson. Radium is administered at our facility by one of our nuclear medicine physicians. A complete blood count is checked at least 3 days prior to the infusion date but no sooner than 6 days. Due to the cost of the material, ordering without knowing the patient’s counts are within a safe range to administer is prohibitive. This adds an additional burden of 2 visits (lab with return visit) to the patient. We have treated 12 patients. Four patients stopped treatment prior to completing the 6 planned treatments citing debilitating fatigue and/or nonresolution of symptoms as their reason to stop treatment. One patient died. The 7 remaining patients subjectively reported varying degrees of pain relief.

Elizabeth Hansen. Another thing to mention is the lack of a PSA response from radium-223 as well. Patients are generally very diligent about monitoring their PSA, so this can be a bit distressing.

Mark Klein. Julie, have you noticed a PSA flare with radium-223? I know it has been reported.

Julie Graff. I haven’t. But I put little stock in PSAs in these patients. I spend 20 minutes explaining to patients that the PSA is not helpful in determining whether or not the radium is working. I tell them that the bone marker alkaline phosphatase may decrease. And I think it’s important to note, too, that radium-223 is not a treatment we have on the shelf. We order it from Denver I believe. It is weight based, and it takes 5 days to get.

Clinical Trials

Mark Klein. That leads us into clinical trials. What is the role for precision oncology in prostate cancer right now, specifically looking at particular panels? One would be the DNA repair enzyme-based genes and/or also the AR variants and any other markers.

Elizabeth Hansen. The National Comprehensive Cancer Network came out with a statement recommending germ-line and somatic-mutation testing in all patients with metastatic prostate cancer. This highlights the need to offer patients the availability of clinical trials.

Julie Graff. I agree. We occasionally get to a place in the disease where patients are feeling fine, but we don’t have anything else to offer. The studies by Robinson¹⁶ and then Matteo¹⁷ showed that (a) these DNA repair defects are present in about a quarter of patients; and (b) that PARP inhibitors can help these patients. At least it has an anticancer effect.

What’s interesting is that we have TRITON2, and TRITON3, which are sponsored by Clovis,for patients with BRCA 1/2 and ATM mutations and using the PARP-inhibitor rucaparib. Based on the data we have available, we thought a quarter of patients would have the mutation in the tumor, but they’re finding that it is more like 10% to 15%. They are screening many patients but not finding it.

I agree that clinical trials are the way to go. I am hopeful that we’ll get more treatments based on molecular markers. The approval for pembrolizumab in any tumor type with microsatellite instability is interesting, but in prostate cancer, I believe that’s about 3%. I haven’t seen anyone qualify for pembrolizumab based on that. Another plug for clinical trials: Let’s learn more and offer our patients potentially beneficial treatments earlier.

Mark Klein. The first interim analysis from the TRITON2 study found about 12% of patients had alterations in BRCA 1/2. But in those that met the RECIST criteria, they were able to have evaluable disease via that standard with about a 44% response rate so far and a 51% PSA response rate. It is promising data, but it’s only 85 patients so far. We’ll know more because the TRITON2 study is of a more pretreated population than the TRITION3 study at this point. Are there any data on precision medicine and radiation in prostate cancer?

Abhishek Solanki. In the prostate cancer setting, there are not a lot of emerging data specifically looking at using precision oncology biomarkers to help guide decisions in radiation therapy. For example, genomic classifiers, like GenomeDx Decipher (Vancouver, BC) and Myriad Genetics Prolaris (Salt Lake City, UT) are increasingly being utilized in patients with localized disease. Decipher can help predict the risk of recurrence after radical prostatectomy. The difficulty is that there are limited data that show that by using these genomic classifiers, one can improve outcomes in patients over traditional clinical characteristics.

There are 2 trials currently ongoing through NRG Oncology that are using Decipher. The GU002 is a trial for patients who had a radical prostatectomy and had a postoperative PSA that never nadired below 0.2. These patients are randomized between salvage radiation with hormone therapy with or without docetaxel. This trial is collecting Decipher results for patients enrolled in the study. The GU006 is a trial for a slightly more favorable group of patients who do nadir but still have biochemical recurrence and relatively low PSAs. This trial randomizes between radiotherapy alone and radiotherapy and 6 months of apalutamide, stratifying patients based on Decipher results, specially differentiating between patients who have a luminal vs basal subtype of prostate cancer. There are data that suggest that patients who have a luminal subtype may benefit more from the combination of radiation and hormone therapy vs patients who have basal subtype.¹⁸ However this hasn’t been validated in a prospective setting, and that’s what this trial will hopefully do.

Immunotherapies

Mark Klein. Outside of prostate cancer, there has been a lot of research trying to determine how to improve PD-L1 expression. Where are immunotherapy trials moving? How radiation might play a role in conjunction with immunotherapy.

Julie Graff. Two phase 3 studies did not show statistically improved survival or statistically significant survival improvement on ipilimumab, an immunotherapy agent that targets CTLA4. Some early studies of the PD-1 drugs nivolumab and pembrolizumab did not show much response with monotherapy. Despite the negative phase 3 studies for ipilimumab, we periodically see exceptional responses.

In prostate cancer, enzalutamide is FDA approved. And there’s currently a phase 3 study of the PD-L1 inhibitor atezolizumab plus enzalutamide in patients who have progressed on abiraterone. That trial is fully accrued, but the results are not yet known. Soon a study will compare pembrolizumab plus enzalutamide vs enzalutamide alone. So the combinations are getting more interesting.

I just received a Prostate Cancer Foundation Challenge Award to open a VA-only study looking at fecal microbiota transplant from responders to nonresponders to see how manipulating host factors can increase potential responses to PD-1 inhibition.

Abhishek Solanki. The classic mechanism by which radiation therapy works is direct DNA damage and indirect DNA damage through hydroxyl radicals that leads to cytotoxicity. But preclinical and clinical data suggest that radiation therapy can augment the local and systemic immunotherapy response. The radiation oncologist’s dream is what is called the abscopal effect, which is the idea that when you treat one site of disease with radiation, it can induce a response at other sites that didn’t get radiation therapy through reactivation of the immune system. I like to think of the abscopal effect like bigfoot—it’s elusive. However, it seems that the setting it is most likely to happen in is in combination with immunotherapy.

One of the ways that radiation fails locally is that it can upregulate PD-1 expression, and as a result, you can have progression of the tumor because of local immune suppression. We know that T cells are important for the activity of radiation therapy. If you combine checkpoint inhibition with radiation therapy, you can not only have better local control in the area of the tumor, but perhaps you can release tumor antigens that will then induce a systemic response.

The other potential mechanism by which radiation may work synergistically with immunotherapy is as a debulking agent. There are some data that suggest that the ratio of T-cell reinvigoration to bulk of disease, or the volume of tumor burden, is important. That is, having T-cell reinvigoration may not be sufficient to have a response to immunotherapy in patients with a large burden of disease. By using radiation to debulk disease, perhaps you could help make checkpoint inhibition more effective. Ultimately, in the setting of prostate cancer, there are not a lot of data yet showing meaningful benefits with the combination of immunotherapy and radiotherapy, but there are trials that are ongoing that will educate on potential synergy.

Pharmacy

Julie Graff. Before we end I want to make sure that we applaud the amazing pharmacists and patient care navigation teams in the VA who do such a great job of getting veterans the appropriate treatment expeditiously and keeping them safe. It’s something that is truly unique to the VA. And I want to thank the people on this call who do this every day.

Elizabeth Hansen. Thank you Julie. Compared with working in the community, at the VA I’m honestly amazed by the ease of access to these medications for our patients. Being able to deliver medications sometimes the same day to the patient is just not something that happens in the community. It’s nice to see that our veterans are getting cared for in that manner.

Author disclosures
Dr. Solanki participated in advisory boards for Blue Earth Diagnostics’ fluciclovine PET and was previously paid as a consultant. Dr. Graff is a consultant for Sanofi (docetaxel) and Astellas (enzalutamide), and has received research funding (no personal funding)from Sanofi, Merck (pembrolizumab), Astellas, and Jannsen (abiraterone, apalutamide). The other authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Sequencing Therapies

Mark Klein, MD. The last few years, there have been several new trials in prostate cancer for people in a metastatic setting or more advanced local setting, such as the STAMPEDE, LATITUDE, and CHAARTED trials.^1-4 In addition, recently a few trials have examined apalutamide and enzalutamide for people who have had PSA (prostate-specific antigen) levels rapidly rising within about 10 months or so. One of the questions that arises is, how do we wrap our heads around sequencing these therapies. Is there a sequence that we should be doing and thinking about upfront and how do the different trials compare?

Julie Graff, MD. It just got more complicated. There was news today (December 20, 2018) that using enzalutamide early on in newly diagnosed metastatic prostate cancer may have positive results. It is not yet approved by the US Food and Drug Administration (FDA), but for patients who present with metastatic prostate cancer, we may have 4 potential treatments. We could have androgen deprivation therapy (ADT) alone, ADT plus docetaxel, enzalutamide, or abiraterone.

When I see patients in this situation, I talk to them about their options, the pros and cons of each option, and try to cover all the trials that look at these combinations. It can be quite a long visit. I talk to the patient about who benefits most, whether it is patients with high-risk factors or high-volume cancers. Also, I talk with the patient about all the adverse effects (AEs), and I look at my patients’ comorbid conditions and come up with a plan.

I encourage any patient who has high-volume or high-risk disease to consider more than just ADT alone. For many patients, I have been using abiraterone plus ADT. I have a wonderful pharmacist. As a medical oncologist, I can’t do it on my own. I need someone to follow patients’ laboratory results and to be available for medication questions and complications.

Elizabeth Hansen, PharmD. With the increasing number of patients on oral antineoplastics, monitoring patients in the outpatient setting has become an increasing priority and one of my major roles as a pharmacist in the clinic at the Chalmers P. Wylie VA Ambulatory Care Center in Columbus, Ohio. This is especially important as some of these treatments require frequent laboratory monitoring, such as abiraterone with liver function tests every 2 weeks for the first 3 months of treatment and monthly thereafter. Without frequent-follow up it’s easy for these patients to get lost in the shuffle.

Abhishek Solanki, MD. You could argue that a fifth option is prostate-directed radiation for patients who have limited metastases based on the STAMPEDE trial, which we’ve started integrating into our practice at the Edward Hines, Jr. Veterans Affairs Hospital in Chicago, Illinois.⁴

Mark Klein. Do you have a feel for the data and using radiation in oligometastatic (≤ 5 metastatic tumors) disease in prostate cancer and how well that might work?

Abhishek Solanki. The best data we have are from the multi-arm, multistage STAMPEDE trial systemic therapies and local therapy in the setting of high-risk localized disease and metastatic disease.⁶ The most recent publication looked specifically at the population with newly diagnosed metastatic disease and compared standard ADT (and docetaxel in about 18% of the patients) with or without prostate-directed radiation therapy. There was no survival benefit with radiation in the overall population, but in the subgroup of patients with low metastatic burden, there was an 8% survival benefit at 3 years.

It’s difficult to know what to make of that information because, as we’ve discussed already, there are other systemic therapy options that are being used more and more upfront such as abiraterone. Can you see the same benefit of radiation in that setting? The flip side is that in this study, radiation just targeted the prostate; could survival be improved even more by targeting all sites of disease in patients with oligometastatic disease? These are still open questions in prostate cancer and there are clinical trials attempting to define the clinical benefit of radiation in the metastatic setting for patients with limited metastases.

Mark Klein. How do you select patients for radiation in this particular situation; How do you approach stratification when radiation is started upfront?

Abhishek Solanki. In the STAMPEDE trial, low metastatic burden was defined based on the definition in the CHAARTED trial, which was those patients who did not have ≥ 4 bone metastases with ≥ 1 outside the vertebral bodies or pelvis, and did not have visceral metastases.⁷ That’s tough, because this definition could be a patient with a solitary bone metastasis but also could include some patients who have involved nodes extending all the way up to the retroperitoneal nodes—that is a fairly heterogeneous population. What we have done at our institution is select patients who have 3 to 5 metastases, administer prostate radiation therapy, and add stereotactic body radiation therapy (SBRT) for the other sites of disease, invoking the oligometastasis approach.

We have been doing this more frequently in the last few months. Typically, we’ll do 3 to 5 fractions of SBRT to metastases. For the primary, if the patient chooses SBRT, we’ll take that approach. If the patient chooses a more standard fractionation, we’ll do 20 treatments, but from a logistic perspective, most patients would rather come in for 5 treatments than 20. We also typically would start these patients on systemic hormonal therapy.

Mark Klein. At that point, are they referred back to medical oncology for surveillance?

Abhishek Solanki. Yes, they are followed by medical oncology and radiation oncology, and typically would continue hormonal therapy.

Mark Klein. Julie, how have you thought about presenting the therapeutic options for those patients who would be either eligible for docetaxel with high-bulk disease or abiraterone? Do you find patients prefer one or the other?

Julie Graff. I try to be very open about all the possibilities, and I present both. I don’t just decide for the patient chemotherapy vs abiraterone, but after we talk about it, most of my patients do opt for the abiraterone. I had a patient referred from the community—we are seeing more and more of this because abiraterone is so expensive—whose ejection fraction was about 38%. I said to that patient, “we could do chemotherapy, but we shouldn’t do abiraterone.” But usually it’s not that clear-cut.

Elizabeth Hansen. There was also an update from the STAMPEDE trial published recently comparing upfront abiraterone and prednisone to docetaxel (18 weeks) in advanced or metastatic prostate cancer. Results from this trial indicated a nearly identical overall survival (OS) (hazard ratio [HR] = 1.16; 95% CI, 0.82-1.65; P = .40). However, the failure-free survival (HR = 0.51; 95% CI, 0.39-0.67; P < .001) and progression-free survival (PFS) (HR= 0.65; 95% CI, 0.0.48-0.88; P = .005) favored abiraterone.^8,9 The authors argue that while there was no change in OS, this trial demonstrates an important difference in the pattern of treatment failure.

Julie, do you think there will be any change in the treatment paradigm between docetaxel and abiraterone with this new update?

Julie Graff. I wasn’t that impressed by that study. I do not see it as practice changing, and it makes sense to me that the PFS is different in the 2 arms because we give chemotherapy and take a break vs giving abiraterone indefinitely. For me, there’s not really a shift.

Patients With Rising PSAs

Mark Klein. Let’s discuss the data from the recent studies on enzalutamide and apalutamide for the patients with fast-rising PSAs. In your discussions with other prostate researchers, will this become a standard part of practice or not?

Julie Graff. I was one of the authors on the SPARTAN apalutamide study.¹⁰ For a long time, we have had patients without metastatic disease but with a PSA relapse after surgery or radiation; and the PSA levels climb when the cancer becomes resistant to ADT. We haven’t had many options in that setting except to use bicalutamide and some older androgen receptor (AR) antagonists. We used to use estrogen and ketoconazole as well.

But now 2 studies have come out looking at a primary endpoint of metastases-free survival. Patients whose PSA was doubling every 10 months or shorter were randomized to either apalutamide (SPARTAN¹⁰) or enzalutamide (PROSPER¹¹), both second-generation AR antagonists. There was a placebo control arm in each of the studies. Both studies found that adding the second-generation AR targeting agent delayed the time to metastatic disease by about 2 years. There is not any signal yet for statistically significant OS benefit, so it is not entirely clear if you could wait for the first metastasis to develop and then give 1 of these treatments and have the same OS benefit.

At the VA Portland Health Care System (VAPORHCS), it took a while to make these drugs available. My fellows were excited to give these drugs right away, but I often counsel patients that we don’t know if the second-generation AR targeting agents will improve survival. They almost certainly will bring down PSAs, which helps with peace of mind, but anything we add to the ADT can cause more AEs.

I have been cautious with second-generation AR antagonists because patients, when they take one of these drugs, are going to be on it for a long time. The FDA has approved those 2 drugs regardless of PSA doubling time, but I would not give it for a PSA doubling time > 10 months. In my practice about a quarter of patients who would qualify for apalutamide or enzalutamide are actually taking one, and the others are monitored closely with computed tomography (CT) and bone scans. When the disease becomes metastatic, then we start those drugs.

Mark Klein. Why 10 months, why not 6 months, a year, or 18 months? Is there reasoning behind that?

Julie Graff. There was a publication by Matthew Smith showing that the PSA doubling time was predictive of the development of metastatic disease and cancer death or prostate cancer death, and that 10 months seemed to be the cutoff between when the prostate cancer was going to become deadly vs not.¹² If you actually look at the trial data, I think the PSA doubling time was between 3 and 4 months for the participants, so pretty short.

Adverse Effects

Mark Klein. What are the AEs people are seeing from using apalutamide, enzalutamide, and abiraterone? What are they seeing in their practice vs what is in the studies? When I have had to stop people on abiraterone or drop down the dose, almost always it has been for fatigue. We check liver function tests (LFTs) repeatedly, but I can’t remember ever having to drop down the dose or take it away even for that reason.

Elizabeth Hansen. The toxicities of these 3 agents are very different. In my practice I have seen a few patients develop hepatotoxicity with abiraterone, and I think this reflects the known incidence of transaminitis (grade 3/4) seen in clinical trials, reported at 6%. Generally, we’ve been able to restart treatment by withholding abiraterone until liver function returns to baseline and then subsequently dose reducing. Like Julie mentioned, abiraterone should be used with caution and/or avoided in patients with serious cardiac disease, recent myocardial infarction, or heart failure. I also always check blood pressure history, to ensure it is well controlled prior to initiation, and order a home blood pressure cuff for monitoring. With enzalutamide one of the main concerns is fatigue, which occurred in > 10% of patients in clinical trials. In my experience this has been dose limiting and can be managed with dose reductions. Seizures also occurred in 0.4% of patients on enzalutamide, so I always ask about seizure history and screen the medication list for concomitant medications that may lower the seizure threshold or other risk factors such as brain metastasis. Last, enzalutamide is a strong CYP3A4 inducer, so there is a strong possibility for drug interactions with other medications, and it is associated with increased cardiac events. With apalutamide you have the cardiac concerns, thyroid dysfunction, fracture risk, and drug interactions to worry about as well. To be honest, we have not used this agent yet at my practice.

Mark Klein. At the Minneapolis VA Health Care System (MVAHCS) when apalutamide first came out, for the PSA rapid doubling, there had already been an abstract presenting the enzalutamide data. We have chosen to recommend enzalutamide as our choice for the people with PSA doubling based on the cost. It’s significantly cheaper for the VA. Between the 2 papers there is very little difference in the efficacy data. I’m wondering what other sites have done with regard to that specific point at their VAs?

Elizabeth Hansen. In Columbus, we prefer to use either abiraterone and enzalutamide because they’re essentially cost neutral. However, this may change with generic abiraterone coming to market. Apalutamide is really cost prohibitive currently.

Julie Graff. I agree.

Patient Education

Mark Klein. At MVAHCS, the navigators handle a lot of upfront education. We have 3 navigators, including Kathleen Nelson who is on this roundtable. She works with patients and provides much of the patient education. How have you handled education for patients?

Kathleen Nelson. For the most part, our pharmacists do the drug-specific education for the oral agents, and the nurse navigators provide more generic education. We did a trial for patients on IV therapies. We learned that patients really don’t report in much detail, but if you call and ask them specific questions, then you can tease out some more detail.

Elizabeth Hansen. It is interesting that every site is different. One of my main roles is oral antineoplastic monitoring, which includes many patients on enzalutamide or abiraterone. At least initially with these patients, I try to follow them closely—abiraterone more so than enzalutamide. I typically call every 2 to 4 weeks, in between clinic visits, to follow up the laboratory tests and manage the AEs. I always try to ask direct and open-ended questions: How often are you checking your blood pressure? What is your current weight? How has your energy level changed since therapy initiation?

The VA telehealth system is amazing. For patients who need to monitor blood pressure regularly, it’s really nice for them to have those numbers come directly back to me in CPRS (Computerized Patient Record System). That has worked wonders for some of our patients to get them through therapy.

Mark Klein. What do you tend to use when the prostate cancer is progressing for a patient? And how do you determine that progression? Some studies will use PSA rise only as a marker for progression. Other studies have not used PSA rise as the only marker for progression and oftentimes require some sort of bone scan criteria or CT imaging criteria for progression.

Julie Graff. We have a limited number of treatment options. Providers typically use enzalutamide or abiraterone as there is a high degree of resistance between the 2. Then there is chemotherapy and then radium, which quite a few people don’t qualify for. We need to be very thoughtful when we change treatments. I look at the 3 factors of biochemical progression or response—PSA, radiographic progression, and clinical progression. If I don’t see 2 out of 3, I typically don’t change treatments. Then after enzalutamide or abiraterone, I wait until there are cancer-related symptoms before I consider chemotherapy and closely monitor my patients.

Imaging Modalities

Abhishek Solanki. Over the last few years the Hines VA Hospital has used fluciclovine positron emission tomography (PET), which is one of the novel imaging modalities for prostate cancer. Really the 2 novel imaging modalities that have gained the most excitement are prostate-specific membrane antigen (PSMA) PET and fluciclovine PET. Fluciclovine PET is based on a synthetic amino acid that’s taken up in multiple tissues, including prostate cancer. It has changed our practice in the localized setting for patients who have developed recurrence after radiation or radical prostatectomy. We have incorporated the scan into our workup of patients with recurrent disease, which can give us some more information at lower PSAs than historically we could get with CT, bone scan, or magnetic resonance imaging.

Our medical oncologists have started using it more and more as well. We are getting a lot of patients who have a negative CT or bone scan but have a positive fluciclovine PET. There are a few different disease settings where that becomes relevant. In patients who develop biochemical recurrence after radiation or salvage radiation after radical, we are finding that a lot of these patients who have no CT or bone scan findings of disease ultimately are found to have a PET-positive lesion. Sometimes it’s difficult to know how best to help patients with PET-only disease. Should you target the disease with an oligometastasis approach or just pursue systemic therapy or surveillance? It is challenging but more and more we are moving toward metastasis-directed therapy. There are multiple randomized trials in progress testing whether metastasis-directed therapy to the PET areas of recurrence can improve outcomes or delay systemic ADT. The STOMP trial randomized surveillance vs SBRT or surgery for patients with oligometastatic disease that showed improvement in biochemical control and ADT-free survival.¹³ However this was a small trial that tried to identify a signal. More definitive trials are necessary.

The other setting where we have found novel PET imaging to be helpful is in patients who have become castration resistant but don’t have clear metastases on conventional imaging. We’re identifying more patients who have only a few sites of progression, and we’ll pursue metastasis-directed therapy to those areas to try to get more mileage out of the systemic therapy that the patient is currently on and to try to avoid having to switch to the next line with the idea that, potentially, the progression site is just a limited clone that is progressing despite the current systemic therapy.
 

Mark Klein. I find that to be a very attractive approach. I’m assuming you do that for any systemic therapy where people have maybe 1 or 2 sites and they do not have a big PSA jump. Do you have a number of sites that you’re willing to radiate? And then, when you do that, what radiation fractionation and dosing do you use? Is there any observational data behind that for efficacy?

Abhishek Solanki. It is a patient by patient decision. Some patients, if they have a very rapid pace of progression shortly after starting systemic therapy and metastases have grown in several areas, we think that perhaps this person may benefit less from aggressive local therapy. But if it’s somebody who has been on systemic therapy for a while and has up to 3 sites of disease growth, we consider SBRT for oligoprogressive disease. Typically, we’ll use SBRT, which delivers a high dose of radiation over 3 to 5 treatments. With SBRT you can give a higher biologic dose and use more sophisticated treatment machines and image guidance for treatments to focus the radiation on the tumor area and limit exposure to normal tissue structures.

In prostate cancer to the primary site, we will typically do around 35 to 40 Gy in 5 fractions. For metastases, it depends on the site. If it’s in the lung, typically we will do 3 to 5 treatments, giving approximately 50 to 60 Gy in that course. In the spine, we use lower doses near the spinal cord and the cauda equina, typically about 30 Gy in 3 fractions. In the liver, similar to the lung, we’ll typically do 50-54 Gy in 3-5 fractions. There aren’t a lot of high-level data guiding the optimal dose/fractionation to metastases, but these are the doses we’ll use for various malignancies.

Treatment Options for Patients With Adverse Events

Mark Klein. I was just reviewing the 2004 study that randomized patients to mitoxantrone or docetaxel for up to 10 cycles.^14,15 Who are good candidates for docetaxel after they have exhausted abiraterone and enzalutamide? How long do you hold to the 10-cycle rule, or do you go beyond that if they’re doing well? And if they’re not a good candidate, what are some options?

Julie Graff. The best candidates are those who are having a cancer-related AE, particularly pain, because docetaxel only improves survival over mitoxantrone by about 2.5 months. I don’t talk to patients about it as though it is a life extender, but it seems to help control pain—about 70% of patients benefited in terms of pain or some other cancer-related symptom.¹⁴

I have a lot of patients who say, “Never will I do chemotherapy.” I refer those patients to hospice, or if they’re appropriate for radium-223, I consider that. I typically give about 6 cycles of chemotherapy and then see how they’re doing. In some patients, the cancer just doesn’t respond to it.

I do tell patients about the papers that you mentioned, the 2 studies of docetaxel vs mitoxantrone where they use about 10 cycles, and some of my patients go all 10.^14,15 Sometimes we have to stop because of neuropathy or some other AE. I believe in taking breaks and that you can probably start it later.

Elizabeth Hansen. I agree, our practice is similar. A lot of our patients are not very interested in chemotherapy. You have to take into consideration their ECOG (Eastern Cooperative Oncology Group) status, their goals, and quality of life when talking to them about these medications. And a lot of them tend to choose more of a palliative route. Depending on their AEs and how things are going, we will dose reduce, hold treatment, or give treatment holidays.

Mark Klein. If patients are progressing on docetaxel, what are options that people would use? Radium-223 certainly is available for patients with nonvisceral metastases, as well as cabazitaxel, mitoxantrone, estramustine and other older drugs.

Julie Graff. We have some clinical trials for patients postdocetaxel. We have the TRITON2 and TRITON3 studies open at the VA. (NCT02952534 and NCT02975934, respectively) A lot of patients would get a biopsy, and we’d look for a BRCA 1 or 2 and ATM mutation. For those patients who don’t have those mutations—and maybe 80% of them don’t—we talk about radium-223 for the patients without visceral metastases and bone pain. I have had a fair number of patients go on cabazitaxel, but I have not used mitoxantrone since cabazitaxel came out. It’s not off the table, but it hasn’t shown improvement in survival.

Elizabeth Hansen. One of our challenges, because we’re an ambulatory care center, is that we are unable to give radium-223 in house, and these services have to be sent out to a non-VA facility. It is doable, but it takes more legwork and organization on our part.

Julie Graff. We have not had radium-223, although we’re working to get that online. And we are physically connected to Oregon Health Science University (OHSU), so we send our patients there for radium. It is a pain because the doctors at OHSU don’t have CPRS access. I’m often in the middle of making sure the complete blood counts (CBCs) are sent to OHSU and to get my patients their treatments.

Mark Klein. The Minneapolis VAMC has radium-223 on site, and we have used it for patients whose cancer has progressed while on docetaxel without visceral metastases. Katie, have you had an opportunity to coordinate that care for patients?

Kathleen Nelson. Radium is administered at our facility by one of our nuclear medicine physicians. A complete blood count is checked at least 3 days prior to the infusion date but no sooner than 6 days. Due to the cost of the material, ordering without knowing the patient’s counts are within a safe range to administer is prohibitive. This adds an additional burden of 2 visits (lab with return visit) to the patient. We have treated 12 patients. Four patients stopped treatment prior to completing the 6 planned treatments citing debilitating fatigue and/or nonresolution of symptoms as their reason to stop treatment. One patient died. The 7 remaining patients subjectively reported varying degrees of pain relief.

Elizabeth Hansen. Another thing to mention is the lack of a PSA response from radium-223 as well. Patients are generally very diligent about monitoring their PSA, so this can be a bit distressing.

Mark Klein. Julie, have you noticed a PSA flare with radium-223? I know it has been reported.

Julie Graff. I haven’t. But I put little stock in PSAs in these patients. I spend 20 minutes explaining to patients that the PSA is not helpful in determining whether or not the radium is working. I tell them that the bone marker alkaline phosphatase may decrease. And I think it’s important to note, too, that radium-223 is not a treatment we have on the shelf. We order it from Denver I believe. It is weight based, and it takes 5 days to get.

Clinical Trials

Mark Klein. That leads us into clinical trials. What is the role for precision oncology in prostate cancer right now, specifically looking at particular panels? One would be the DNA repair enzyme-based genes and/or also the AR variants and any other markers.

Elizabeth Hansen. The National Comprehensive Cancer Network came out with a statement recommending germ-line and somatic-mutation testing in all patients with metastatic prostate cancer. This highlights the need to offer patients the availability of clinical trials.

Julie Graff. I agree. We occasionally get to a place in the disease where patients are feeling fine, but we don’t have anything else to offer. The studies by Robinson¹⁶ and then Matteo¹⁷ showed that (a) these DNA repair defects are present in about a quarter of patients; and (b) that PARP inhibitors can help these patients. At least it has an anticancer effect.

What’s interesting is that we have TRITON2, and TRITON3, which are sponsored by Clovis,for patients with BRCA 1/2 and ATM mutations and using the PARP-inhibitor rucaparib. Based on the data we have available, we thought a quarter of patients would have the mutation in the tumor, but they’re finding that it is more like 10% to 15%. They are screening many patients but not finding it.

I agree that clinical trials are the way to go. I am hopeful that we’ll get more treatments based on molecular markers. The approval for pembrolizumab in any tumor type with microsatellite instability is interesting, but in prostate cancer, I believe that’s about 3%. I haven’t seen anyone qualify for pembrolizumab based on that. Another plug for clinical trials: Let’s learn more and offer our patients potentially beneficial treatments earlier.

Mark Klein. The first interim analysis from the TRITON2 study found about 12% of patients had alterations in BRCA 1/2. But in those that met the RECIST criteria, they were able to have evaluable disease via that standard with about a 44% response rate so far and a 51% PSA response rate. It is promising data, but it’s only 85 patients so far. We’ll know more because the TRITON2 study is of a more pretreated population than the TRITION3 study at this point. Are there any data on precision medicine and radiation in prostate cancer?

Abhishek Solanki. In the prostate cancer setting, there are not a lot of emerging data specifically looking at using precision oncology biomarkers to help guide decisions in radiation therapy. For example, genomic classifiers, like GenomeDx Decipher (Vancouver, BC) and Myriad Genetics Prolaris (Salt Lake City, UT) are increasingly being utilized in patients with localized disease. Decipher can help predict the risk of recurrence after radical prostatectomy. The difficulty is that there are limited data that show that by using these genomic classifiers, one can improve outcomes in patients over traditional clinical characteristics.

There are 2 trials currently ongoing through NRG Oncology that are using Decipher. The GU002 is a trial for patients who had a radical prostatectomy and had a postoperative PSA that never nadired below 0.2. These patients are randomized between salvage radiation with hormone therapy with or without docetaxel. This trial is collecting Decipher results for patients enrolled in the study. The GU006 is a trial for a slightly more favorable group of patients who do nadir but still have biochemical recurrence and relatively low PSAs. This trial randomizes between radiotherapy alone and radiotherapy and 6 months of apalutamide, stratifying patients based on Decipher results, specially differentiating between patients who have a luminal vs basal subtype of prostate cancer. There are data that suggest that patients who have a luminal subtype may benefit more from the combination of radiation and hormone therapy vs patients who have basal subtype.¹⁸ However this hasn’t been validated in a prospective setting, and that’s what this trial will hopefully do.

Immunotherapies

Mark Klein. Outside of prostate cancer, there has been a lot of research trying to determine how to improve PD-L1 expression. Where are immunotherapy trials moving? How radiation might play a role in conjunction with immunotherapy.

Julie Graff. Two phase 3 studies did not show statistically improved survival or statistically significant survival improvement on ipilimumab, an immunotherapy agent that targets CTLA4. Some early studies of the PD-1 drugs nivolumab and pembrolizumab did not show much response with monotherapy. Despite the negative phase 3 studies for ipilimumab, we periodically see exceptional responses.

In prostate cancer, enzalutamide is FDA approved. And there’s currently a phase 3 study of the PD-L1 inhibitor atezolizumab plus enzalutamide in patients who have progressed on abiraterone. That trial is fully accrued, but the results are not yet known. Soon a study will compare pembrolizumab plus enzalutamide vs enzalutamide alone. So the combinations are getting more interesting.

I just received a Prostate Cancer Foundation Challenge Award to open a VA-only study looking at fecal microbiota transplant from responders to nonresponders to see how manipulating host factors can increase potential responses to PD-1 inhibition.

Abhishek Solanki. The classic mechanism by which radiation therapy works is direct DNA damage and indirect DNA damage through hydroxyl radicals that leads to cytotoxicity. But preclinical and clinical data suggest that radiation therapy can augment the local and systemic immunotherapy response. The radiation oncologist’s dream is what is called the abscopal effect, which is the idea that when you treat one site of disease with radiation, it can induce a response at other sites that didn’t get radiation therapy through reactivation of the immune system. I like to think of the abscopal effect like bigfoot—it’s elusive. However, it seems that the setting it is most likely to happen in is in combination with immunotherapy.

One of the ways that radiation fails locally is that it can upregulate PD-1 expression, and as a result, you can have progression of the tumor because of local immune suppression. We know that T cells are important for the activity of radiation therapy. If you combine checkpoint inhibition with radiation therapy, you can not only have better local control in the area of the tumor, but perhaps you can release tumor antigens that will then induce a systemic response.

The other potential mechanism by which radiation may work synergistically with immunotherapy is as a debulking agent. There are some data that suggest that the ratio of T-cell reinvigoration to bulk of disease, or the volume of tumor burden, is important. That is, having T-cell reinvigoration may not be sufficient to have a response to immunotherapy in patients with a large burden of disease. By using radiation to debulk disease, perhaps you could help make checkpoint inhibition more effective. Ultimately, in the setting of prostate cancer, there are not a lot of data yet showing meaningful benefits with the combination of immunotherapy and radiotherapy, but there are trials that are ongoing that will educate on potential synergy.

Pharmacy

Julie Graff. Before we end I want to make sure that we applaud the amazing pharmacists and patient care navigation teams in the VA who do such a great job of getting veterans the appropriate treatment expeditiously and keeping them safe. It’s something that is truly unique to the VA. And I want to thank the people on this call who do this every day.

Elizabeth Hansen. Thank you Julie. Compared with working in the community, at the VA I’m honestly amazed by the ease of access to these medications for our patients. Being able to deliver medications sometimes the same day to the patient is just not something that happens in the community. It’s nice to see that our veterans are getting cared for in that manner.

Author disclosures
Dr. Solanki participated in advisory boards for Blue Earth Diagnostics’ fluciclovine PET and was previously paid as a consultant. Dr. Graff is a consultant for Sanofi (docetaxel) and Astellas (enzalutamide), and has received research funding (no personal funding)from Sanofi, Merck (pembrolizumab), Astellas, and Jannsen (abiraterone, apalutamide). The other authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

Sequencing Therapies

Mark Klein, MD. The last few years, there have been several new trials in prostate cancer for people in a metastatic setting or more advanced local setting, such as the STAMPEDE, LATITUDE, and CHAARTED trials.^1-4 In addition, recently a few trials have examined apalutamide and enzalutamide for people who have had PSA (prostate-specific antigen) levels rapidly rising within about 10 months or so. One of the questions that arises is, how do we wrap our heads around sequencing these therapies. Is there a sequence that we should be doing and thinking about upfront and how do the different trials compare?

Julie Graff, MD. It just got more complicated. There was news today (December 20, 2018) that using enzalutamide early on in newly diagnosed metastatic prostate cancer may have positive results. It is not yet approved by the US Food and Drug Administration (FDA), but for patients who present with metastatic prostate cancer, we may have 4 potential treatments. We could have androgen deprivation therapy (ADT) alone, ADT plus docetaxel, enzalutamide, or abiraterone.

When I see patients in this situation, I talk to them about their options, the pros and cons of each option, and try to cover all the trials that look at these combinations. It can be quite a long visit. I talk to the patient about who benefits most, whether it is patients with high-risk factors or high-volume cancers. Also, I talk with the patient about all the adverse effects (AEs), and I look at my patients’ comorbid conditions and come up with a plan.

I encourage any patient who has high-volume or high-risk disease to consider more than just ADT alone. For many patients, I have been using abiraterone plus ADT. I have a wonderful pharmacist. As a medical oncologist, I can’t do it on my own. I need someone to follow patients’ laboratory results and to be available for medication questions and complications.

Elizabeth Hansen, PharmD. With the increasing number of patients on oral antineoplastics, monitoring patients in the outpatient setting has become an increasing priority and one of my major roles as a pharmacist in the clinic at the Chalmers P. Wylie VA Ambulatory Care Center in Columbus, Ohio. This is especially important as some of these treatments require frequent laboratory monitoring, such as abiraterone with liver function tests every 2 weeks for the first 3 months of treatment and monthly thereafter. Without frequent-follow up it’s easy for these patients to get lost in the shuffle.

Abhishek Solanki, MD. You could argue that a fifth option is prostate-directed radiation for patients who have limited metastases based on the STAMPEDE trial, which we’ve started integrating into our practice at the Edward Hines, Jr. Veterans Affairs Hospital in Chicago, Illinois.⁴

Mark Klein. Do you have a feel for the data and using radiation in oligometastatic (≤ 5 metastatic tumors) disease in prostate cancer and how well that might work?

Abhishek Solanki. The best data we have are from the multi-arm, multistage STAMPEDE trial systemic therapies and local therapy in the setting of high-risk localized disease and metastatic disease.⁶ The most recent publication looked specifically at the population with newly diagnosed metastatic disease and compared standard ADT (and docetaxel in about 18% of the patients) with or without prostate-directed radiation therapy. There was no survival benefit with radiation in the overall population, but in the subgroup of patients with low metastatic burden, there was an 8% survival benefit at 3 years.

It’s difficult to know what to make of that information because, as we’ve discussed already, there are other systemic therapy options that are being used more and more upfront such as abiraterone. Can you see the same benefit of radiation in that setting? The flip side is that in this study, radiation just targeted the prostate; could survival be improved even more by targeting all sites of disease in patients with oligometastatic disease? These are still open questions in prostate cancer and there are clinical trials attempting to define the clinical benefit of radiation in the metastatic setting for patients with limited metastases.

Mark Klein. How do you select patients for radiation in this particular situation; How do you approach stratification when radiation is started upfront?

Abhishek Solanki. In the STAMPEDE trial, low metastatic burden was defined based on the definition in the CHAARTED trial, which was those patients who did not have ≥ 4 bone metastases with ≥ 1 outside the vertebral bodies or pelvis, and did not have visceral metastases.⁷ That’s tough, because this definition could be a patient with a solitary bone metastasis but also could include some patients who have involved nodes extending all the way up to the retroperitoneal nodes—that is a fairly heterogeneous population. What we have done at our institution is select patients who have 3 to 5 metastases, administer prostate radiation therapy, and add stereotactic body radiation therapy (SBRT) for the other sites of disease, invoking the oligometastasis approach.

We have been doing this more frequently in the last few months. Typically, we’ll do 3 to 5 fractions of SBRT to metastases. For the primary, if the patient chooses SBRT, we’ll take that approach. If the patient chooses a more standard fractionation, we’ll do 20 treatments, but from a logistic perspective, most patients would rather come in for 5 treatments than 20. We also typically would start these patients on systemic hormonal therapy.

Mark Klein. At that point, are they referred back to medical oncology for surveillance?

Abhishek Solanki. Yes, they are followed by medical oncology and radiation oncology, and typically would continue hormonal therapy.

Mark Klein. Julie, how have you thought about presenting the therapeutic options for those patients who would be either eligible for docetaxel with high-bulk disease or abiraterone? Do you find patients prefer one or the other?

Julie Graff. I try to be very open about all the possibilities, and I present both. I don’t just decide for the patient chemotherapy vs abiraterone, but after we talk about it, most of my patients do opt for the abiraterone. I had a patient referred from the community—we are seeing more and more of this because abiraterone is so expensive—whose ejection fraction was about 38%. I said to that patient, “we could do chemotherapy, but we shouldn’t do abiraterone.” But usually it’s not that clear-cut.

Elizabeth Hansen. There was also an update from the STAMPEDE trial published recently comparing upfront abiraterone and prednisone to docetaxel (18 weeks) in advanced or metastatic prostate cancer. Results from this trial indicated a nearly identical overall survival (OS) (hazard ratio [HR] = 1.16; 95% CI, 0.82-1.65; P = .40). However, the failure-free survival (HR = 0.51; 95% CI, 0.39-0.67; P < .001) and progression-free survival (PFS) (HR= 0.65; 95% CI, 0.0.48-0.88; P = .005) favored abiraterone.^8,9 The authors argue that while there was no change in OS, this trial demonstrates an important difference in the pattern of treatment failure.

Julie, do you think there will be any change in the treatment paradigm between docetaxel and abiraterone with this new update?

Julie Graff. I wasn’t that impressed by that study. I do not see it as practice changing, and it makes sense to me that the PFS is different in the 2 arms because we give chemotherapy and take a break vs giving abiraterone indefinitely. For me, there’s not really a shift.

Patients With Rising PSAs

Mark Klein. Let’s discuss the data from the recent studies on enzalutamide and apalutamide for the patients with fast-rising PSAs. In your discussions with other prostate researchers, will this become a standard part of practice or not?

Julie Graff. I was one of the authors on the SPARTAN apalutamide study.¹⁰ For a long time, we have had patients without metastatic disease but with a PSA relapse after surgery or radiation; and the PSA levels climb when the cancer becomes resistant to ADT. We haven’t had many options in that setting except to use bicalutamide and some older androgen receptor (AR) antagonists. We used to use estrogen and ketoconazole as well.

But now 2 studies have come out looking at a primary endpoint of metastases-free survival. Patients whose PSA was doubling every 10 months or shorter were randomized to either apalutamide (SPARTAN¹⁰) or enzalutamide (PROSPER¹¹), both second-generation AR antagonists. There was a placebo control arm in each of the studies. Both studies found that adding the second-generation AR targeting agent delayed the time to metastatic disease by about 2 years. There is not any signal yet for statistically significant OS benefit, so it is not entirely clear if you could wait for the first metastasis to develop and then give 1 of these treatments and have the same OS benefit.

At the VA Portland Health Care System (VAPORHCS), it took a while to make these drugs available. My fellows were excited to give these drugs right away, but I often counsel patients that we don’t know if the second-generation AR targeting agents will improve survival. They almost certainly will bring down PSAs, which helps with peace of mind, but anything we add to the ADT can cause more AEs.

I have been cautious with second-generation AR antagonists because patients, when they take one of these drugs, are going to be on it for a long time. The FDA has approved those 2 drugs regardless of PSA doubling time, but I would not give it for a PSA doubling time > 10 months. In my practice about a quarter of patients who would qualify for apalutamide or enzalutamide are actually taking one, and the others are monitored closely with computed tomography (CT) and bone scans. When the disease becomes metastatic, then we start those drugs.

Mark Klein. Why 10 months, why not 6 months, a year, or 18 months? Is there reasoning behind that?

Julie Graff. There was a publication by Matthew Smith showing that the PSA doubling time was predictive of the development of metastatic disease and cancer death or prostate cancer death, and that 10 months seemed to be the cutoff between when the prostate cancer was going to become deadly vs not.¹² If you actually look at the trial data, I think the PSA doubling time was between 3 and 4 months for the participants, so pretty short.

Adverse Effects

Mark Klein. What are the AEs people are seeing from using apalutamide, enzalutamide, and abiraterone? What are they seeing in their practice vs what is in the studies? When I have had to stop people on abiraterone or drop down the dose, almost always it has been for fatigue. We check liver function tests (LFTs) repeatedly, but I can’t remember ever having to drop down the dose or take it away even for that reason.

Elizabeth Hansen. The toxicities of these 3 agents are very different. In my practice I have seen a few patients develop hepatotoxicity with abiraterone, and I think this reflects the known incidence of transaminitis (grade 3/4) seen in clinical trials, reported at 6%. Generally, we’ve been able to restart treatment by withholding abiraterone until liver function returns to baseline and then subsequently dose reducing. Like Julie mentioned, abiraterone should be used with caution and/or avoided in patients with serious cardiac disease, recent myocardial infarction, or heart failure. I also always check blood pressure history, to ensure it is well controlled prior to initiation, and order a home blood pressure cuff for monitoring. With enzalutamide one of the main concerns is fatigue, which occurred in > 10% of patients in clinical trials. In my experience this has been dose limiting and can be managed with dose reductions. Seizures also occurred in 0.4% of patients on enzalutamide, so I always ask about seizure history and screen the medication list for concomitant medications that may lower the seizure threshold or other risk factors such as brain metastasis. Last, enzalutamide is a strong CYP3A4 inducer, so there is a strong possibility for drug interactions with other medications, and it is associated with increased cardiac events. With apalutamide you have the cardiac concerns, thyroid dysfunction, fracture risk, and drug interactions to worry about as well. To be honest, we have not used this agent yet at my practice.

Mark Klein. At the Minneapolis VA Health Care System (MVAHCS) when apalutamide first came out, for the PSA rapid doubling, there had already been an abstract presenting the enzalutamide data. We have chosen to recommend enzalutamide as our choice for the people with PSA doubling based on the cost. It’s significantly cheaper for the VA. Between the 2 papers there is very little difference in the efficacy data. I’m wondering what other sites have done with regard to that specific point at their VAs?

Elizabeth Hansen. In Columbus, we prefer to use either abiraterone and enzalutamide because they’re essentially cost neutral. However, this may change with generic abiraterone coming to market. Apalutamide is really cost prohibitive currently.

Julie Graff. I agree.

Patient Education

Mark Klein. At MVAHCS, the navigators handle a lot of upfront education. We have 3 navigators, including Kathleen Nelson who is on this roundtable. She works with patients and provides much of the patient education. How have you handled education for patients?

Kathleen Nelson. For the most part, our pharmacists do the drug-specific education for the oral agents, and the nurse navigators provide more generic education. We did a trial for patients on IV therapies. We learned that patients really don’t report in much detail, but if you call and ask them specific questions, then you can tease out some more detail.

Elizabeth Hansen. It is interesting that every site is different. One of my main roles is oral antineoplastic monitoring, which includes many patients on enzalutamide or abiraterone. At least initially with these patients, I try to follow them closely—abiraterone more so than enzalutamide. I typically call every 2 to 4 weeks, in between clinic visits, to follow up the laboratory tests and manage the AEs. I always try to ask direct and open-ended questions: How often are you checking your blood pressure? What is your current weight? How has your energy level changed since therapy initiation?

The VA telehealth system is amazing. For patients who need to monitor blood pressure regularly, it’s really nice for them to have those numbers come directly back to me in CPRS (Computerized Patient Record System). That has worked wonders for some of our patients to get them through therapy.

Mark Klein. What do you tend to use when the prostate cancer is progressing for a patient? And how do you determine that progression? Some studies will use PSA rise only as a marker for progression. Other studies have not used PSA rise as the only marker for progression and oftentimes require some sort of bone scan criteria or CT imaging criteria for progression.

Julie Graff. We have a limited number of treatment options. Providers typically use enzalutamide or abiraterone as there is a high degree of resistance between the 2. Then there is chemotherapy and then radium, which quite a few people don’t qualify for. We need to be very thoughtful when we change treatments. I look at the 3 factors of biochemical progression or response—PSA, radiographic progression, and clinical progression. If I don’t see 2 out of 3, I typically don’t change treatments. Then after enzalutamide or abiraterone, I wait until there are cancer-related symptoms before I consider chemotherapy and closely monitor my patients.

Imaging Modalities

Abhishek Solanki. Over the last few years the Hines VA Hospital has used fluciclovine positron emission tomography (PET), which is one of the novel imaging modalities for prostate cancer. Really the 2 novel imaging modalities that have gained the most excitement are prostate-specific membrane antigen (PSMA) PET and fluciclovine PET. Fluciclovine PET is based on a synthetic amino acid that’s taken up in multiple tissues, including prostate cancer. It has changed our practice in the localized setting for patients who have developed recurrence after radiation or radical prostatectomy. We have incorporated the scan into our workup of patients with recurrent disease, which can give us some more information at lower PSAs than historically we could get with CT, bone scan, or magnetic resonance imaging.

Our medical oncologists have started using it more and more as well. We are getting a lot of patients who have a negative CT or bone scan but have a positive fluciclovine PET. There are a few different disease settings where that becomes relevant. In patients who develop biochemical recurrence after radiation or salvage radiation after radical, we are finding that a lot of these patients who have no CT or bone scan findings of disease ultimately are found to have a PET-positive lesion. Sometimes it’s difficult to know how best to help patients with PET-only disease. Should you target the disease with an oligometastasis approach or just pursue systemic therapy or surveillance? It is challenging but more and more we are moving toward metastasis-directed therapy. There are multiple randomized trials in progress testing whether metastasis-directed therapy to the PET areas of recurrence can improve outcomes or delay systemic ADT. The STOMP trial randomized surveillance vs SBRT or surgery for patients with oligometastatic disease that showed improvement in biochemical control and ADT-free survival.¹³ However this was a small trial that tried to identify a signal. More definitive trials are necessary.

The other setting where we have found novel PET imaging to be helpful is in patients who have become castration resistant but don’t have clear metastases on conventional imaging. We’re identifying more patients who have only a few sites of progression, and we’ll pursue metastasis-directed therapy to those areas to try to get more mileage out of the systemic therapy that the patient is currently on and to try to avoid having to switch to the next line with the idea that, potentially, the progression site is just a limited clone that is progressing despite the current systemic therapy.
 

Mark Klein. I find that to be a very attractive approach. I’m assuming you do that for any systemic therapy where people have maybe 1 or 2 sites and they do not have a big PSA jump. Do you have a number of sites that you’re willing to radiate? And then, when you do that, what radiation fractionation and dosing do you use? Is there any observational data behind that for efficacy?

Abhishek Solanki. It is a patient by patient decision. Some patients, if they have a very rapid pace of progression shortly after starting systemic therapy and metastases have grown in several areas, we think that perhaps this person may benefit less from aggressive local therapy. But if it’s somebody who has been on systemic therapy for a while and has up to 3 sites of disease growth, we consider SBRT for oligoprogressive disease. Typically, we’ll use SBRT, which delivers a high dose of radiation over 3 to 5 treatments. With SBRT you can give a higher biologic dose and use more sophisticated treatment machines and image guidance for treatments to focus the radiation on the tumor area and limit exposure to normal tissue structures.

In prostate cancer to the primary site, we will typically do around 35 to 40 Gy in 5 fractions. For metastases, it depends on the site. If it’s in the lung, typically we will do 3 to 5 treatments, giving approximately 50 to 60 Gy in that course. In the spine, we use lower doses near the spinal cord and the cauda equina, typically about 30 Gy in 3 fractions. In the liver, similar to the lung, we’ll typically do 50-54 Gy in 3-5 fractions. There aren’t a lot of high-level data guiding the optimal dose/fractionation to metastases, but these are the doses we’ll use for various malignancies.

Treatment Options for Patients With Adverse Events

Mark Klein. I was just reviewing the 2004 study that randomized patients to mitoxantrone or docetaxel for up to 10 cycles.^14,15 Who are good candidates for docetaxel after they have exhausted abiraterone and enzalutamide? How long do you hold to the 10-cycle rule, or do you go beyond that if they’re doing well? And if they’re not a good candidate, what are some options?

Julie Graff. The best candidates are those who are having a cancer-related AE, particularly pain, because docetaxel only improves survival over mitoxantrone by about 2.5 months. I don’t talk to patients about it as though it is a life extender, but it seems to help control pain—about 70% of patients benefited in terms of pain or some other cancer-related symptom.¹⁴

I have a lot of patients who say, “Never will I do chemotherapy.” I refer those patients to hospice, or if they’re appropriate for radium-223, I consider that. I typically give about 6 cycles of chemotherapy and then see how they’re doing. In some patients, the cancer just doesn’t respond to it.

I do tell patients about the papers that you mentioned, the 2 studies of docetaxel vs mitoxantrone where they use about 10 cycles, and some of my patients go all 10.^14,15 Sometimes we have to stop because of neuropathy or some other AE. I believe in taking breaks and that you can probably start it later.

Elizabeth Hansen. I agree, our practice is similar. A lot of our patients are not very interested in chemotherapy. You have to take into consideration their ECOG (Eastern Cooperative Oncology Group) status, their goals, and quality of life when talking to them about these medications. And a lot of them tend to choose more of a palliative route. Depending on their AEs and how things are going, we will dose reduce, hold treatment, or give treatment holidays.

Mark Klein. If patients are progressing on docetaxel, what are options that people would use? Radium-223 certainly is available for patients with nonvisceral metastases, as well as cabazitaxel, mitoxantrone, estramustine and other older drugs.

Julie Graff. We have some clinical trials for patients postdocetaxel. We have the TRITON2 and TRITON3 studies open at the VA. (NCT02952534 and NCT02975934, respectively) A lot of patients would get a biopsy, and we’d look for a BRCA 1 or 2 and ATM mutation. For those patients who don’t have those mutations—and maybe 80% of them don’t—we talk about radium-223 for the patients without visceral metastases and bone pain. I have had a fair number of patients go on cabazitaxel, but I have not used mitoxantrone since cabazitaxel came out. It’s not off the table, but it hasn’t shown improvement in survival.

Elizabeth Hansen. One of our challenges, because we’re an ambulatory care center, is that we are unable to give radium-223 in house, and these services have to be sent out to a non-VA facility. It is doable, but it takes more legwork and organization on our part.

Julie Graff. We have not had radium-223, although we’re working to get that online. And we are physically connected to Oregon Health Science University (OHSU), so we send our patients there for radium. It is a pain because the doctors at OHSU don’t have CPRS access. I’m often in the middle of making sure the complete blood counts (CBCs) are sent to OHSU and to get my patients their treatments.

Mark Klein. The Minneapolis VAMC has radium-223 on site, and we have used it for patients whose cancer has progressed while on docetaxel without visceral metastases. Katie, have you had an opportunity to coordinate that care for patients?

Kathleen Nelson. Radium is administered at our facility by one of our nuclear medicine physicians. A complete blood count is checked at least 3 days prior to the infusion date but no sooner than 6 days. Due to the cost of the material, ordering without knowing the patient’s counts are within a safe range to administer is prohibitive. This adds an additional burden of 2 visits (lab with return visit) to the patient. We have treated 12 patients. Four patients stopped treatment prior to completing the 6 planned treatments citing debilitating fatigue and/or nonresolution of symptoms as their reason to stop treatment. One patient died. The 7 remaining patients subjectively reported varying degrees of pain relief.

Elizabeth Hansen. Another thing to mention is the lack of a PSA response from radium-223 as well. Patients are generally very diligent about monitoring their PSA, so this can be a bit distressing.

Mark Klein. Julie, have you noticed a PSA flare with radium-223? I know it has been reported.

Julie Graff. I haven’t. But I put little stock in PSAs in these patients. I spend 20 minutes explaining to patients that the PSA is not helpful in determining whether or not the radium is working. I tell them that the bone marker alkaline phosphatase may decrease. And I think it’s important to note, too, that radium-223 is not a treatment we have on the shelf. We order it from Denver I believe. It is weight based, and it takes 5 days to get.

Clinical Trials

Mark Klein. That leads us into clinical trials. What is the role for precision oncology in prostate cancer right now, specifically looking at particular panels? One would be the DNA repair enzyme-based genes and/or also the AR variants and any other markers.

Elizabeth Hansen. The National Comprehensive Cancer Network came out with a statement recommending germ-line and somatic-mutation testing in all patients with metastatic prostate cancer. This highlights the need to offer patients the availability of clinical trials.

Julie Graff. I agree. We occasionally get to a place in the disease where patients are feeling fine, but we don’t have anything else to offer. The studies by Robinson¹⁶ and then Matteo¹⁷ showed that (a) these DNA repair defects are present in about a quarter of patients; and (b) that PARP inhibitors can help these patients. At least it has an anticancer effect.

What’s interesting is that we have TRITON2, and TRITON3, which are sponsored by Clovis,for patients with BRCA 1/2 and ATM mutations and using the PARP-inhibitor rucaparib. Based on the data we have available, we thought a quarter of patients would have the mutation in the tumor, but they’re finding that it is more like 10% to 15%. They are screening many patients but not finding it.

I agree that clinical trials are the way to go. I am hopeful that we’ll get more treatments based on molecular markers. The approval for pembrolizumab in any tumor type with microsatellite instability is interesting, but in prostate cancer, I believe that’s about 3%. I haven’t seen anyone qualify for pembrolizumab based on that. Another plug for clinical trials: Let’s learn more and offer our patients potentially beneficial treatments earlier.

Mark Klein. The first interim analysis from the TRITON2 study found about 12% of patients had alterations in BRCA 1/2. But in those that met the RECIST criteria, they were able to have evaluable disease via that standard with about a 44% response rate so far and a 51% PSA response rate. It is promising data, but it’s only 85 patients so far. We’ll know more because the TRITON2 study is of a more pretreated population than the TRITION3 study at this point. Are there any data on precision medicine and radiation in prostate cancer?

Abhishek Solanki. In the prostate cancer setting, there are not a lot of emerging data specifically looking at using precision oncology biomarkers to help guide decisions in radiation therapy. For example, genomic classifiers, like GenomeDx Decipher (Vancouver, BC) and Myriad Genetics Prolaris (Salt Lake City, UT) are increasingly being utilized in patients with localized disease. Decipher can help predict the risk of recurrence after radical prostatectomy. The difficulty is that there are limited data that show that by using these genomic classifiers, one can improve outcomes in patients over traditional clinical characteristics.

There are 2 trials currently ongoing through NRG Oncology that are using Decipher. The GU002 is a trial for patients who had a radical prostatectomy and had a postoperative PSA that never nadired below 0.2. These patients are randomized between salvage radiation with hormone therapy with or without docetaxel. This trial is collecting Decipher results for patients enrolled in the study. The GU006 is a trial for a slightly more favorable group of patients who do nadir but still have biochemical recurrence and relatively low PSAs. This trial randomizes between radiotherapy alone and radiotherapy and 6 months of apalutamide, stratifying patients based on Decipher results, specially differentiating between patients who have a luminal vs basal subtype of prostate cancer. There are data that suggest that patients who have a luminal subtype may benefit more from the combination of radiation and hormone therapy vs patients who have basal subtype.¹⁸ However this hasn’t been validated in a prospective setting, and that’s what this trial will hopefully do.

Immunotherapies

Mark Klein. Outside of prostate cancer, there has been a lot of research trying to determine how to improve PD-L1 expression. Where are immunotherapy trials moving? How radiation might play a role in conjunction with immunotherapy.

Julie Graff. Two phase 3 studies did not show statistically improved survival or statistically significant survival improvement on ipilimumab, an immunotherapy agent that targets CTLA4. Some early studies of the PD-1 drugs nivolumab and pembrolizumab did not show much response with monotherapy. Despite the negative phase 3 studies for ipilimumab, we periodically see exceptional responses.

In prostate cancer, enzalutamide is FDA approved. And there’s currently a phase 3 study of the PD-L1 inhibitor atezolizumab plus enzalutamide in patients who have progressed on abiraterone. That trial is fully accrued, but the results are not yet known. Soon a study will compare pembrolizumab plus enzalutamide vs enzalutamide alone. So the combinations are getting more interesting.

I just received a Prostate Cancer Foundation Challenge Award to open a VA-only study looking at fecal microbiota transplant from responders to nonresponders to see how manipulating host factors can increase potential responses to PD-1 inhibition.

Abhishek Solanki. The classic mechanism by which radiation therapy works is direct DNA damage and indirect DNA damage through hydroxyl radicals that leads to cytotoxicity. But preclinical and clinical data suggest that radiation therapy can augment the local and systemic immunotherapy response. The radiation oncologist’s dream is what is called the abscopal effect, which is the idea that when you treat one site of disease with radiation, it can induce a response at other sites that didn’t get radiation therapy through reactivation of the immune system. I like to think of the abscopal effect like bigfoot—it’s elusive. However, it seems that the setting it is most likely to happen in is in combination with immunotherapy.

One of the ways that radiation fails locally is that it can upregulate PD-1 expression, and as a result, you can have progression of the tumor because of local immune suppression. We know that T cells are important for the activity of radiation therapy. If you combine checkpoint inhibition with radiation therapy, you can not only have better local control in the area of the tumor, but perhaps you can release tumor antigens that will then induce a systemic response.

The other potential mechanism by which radiation may work synergistically with immunotherapy is as a debulking agent. There are some data that suggest that the ratio of T-cell reinvigoration to bulk of disease, or the volume of tumor burden, is important. That is, having T-cell reinvigoration may not be sufficient to have a response to immunotherapy in patients with a large burden of disease. By using radiation to debulk disease, perhaps you could help make checkpoint inhibition more effective. Ultimately, in the setting of prostate cancer, there are not a lot of data yet showing meaningful benefits with the combination of immunotherapy and radiotherapy, but there are trials that are ongoing that will educate on potential synergy.

Pharmacy

Julie Graff. Before we end I want to make sure that we applaud the amazing pharmacists and patient care navigation teams in the VA who do such a great job of getting veterans the appropriate treatment expeditiously and keeping them safe. It’s something that is truly unique to the VA. And I want to thank the people on this call who do this every day.

Elizabeth Hansen. Thank you Julie. Compared with working in the community, at the VA I’m honestly amazed by the ease of access to these medications for our patients. Being able to deliver medications sometimes the same day to the patient is just not something that happens in the community. It’s nice to see that our veterans are getting cared for in that manner.

Author disclosures
Dr. Solanki participated in advisory boards for Blue Earth Diagnostics’ fluciclovine PET and was previously paid as a consultant. Dr. Graff is a consultant for Sanofi (docetaxel) and Astellas (enzalutamide), and has received research funding (no personal funding)from Sanofi, Merck (pembrolizumab), Astellas, and Jannsen (abiraterone, apalutamide). The other authors report no actual or potential conflicts of interest with regard to this article.

Disclaimer
The opinions expressed herein are those of the authors and do not necessarily reflect those of Federal Practitioner, Frontline Medical Communications Inc., the US Government, or any of its agencies. This article may discuss unlabeled or investigational use of certain drugs. Please review the complete prescribing information for specific drugs or drug combinations—including indications, contraindications, warnings, and adverse effects—before administering pharmacologic therapy to patients.

The general public may have been led to believe that by decoding genes into their constituent parts, clinicians can prevent or predict serious illnesses and personalize treatment. While this may be true in some areas of medicine, such as oncology, using a pharmacogenetic testing-based “lookup table” to prescribe psychiatric medications is disturbing. This practice could lead to incorrect prescriptions, as well as a lack of follow-up or appropriate dosage titration or medication switching. These problems could put a patient’s life at risk and, consequently, bring the field of psychiatry into disrepute.

In the last few years, using pharmacogenetics to predict or prevent illness and personalize treatment has become very attractive. A 2019 meta-analysis of 5 randomized controlled trials examined the use of pharmacogenetic-guided decision support tools for major depressive disorder (MDD). Researchers randomized 1,737 participants with MDD to either pharmacogenetic-guided decision support tools or treatment as usual.¹ Patients were assessed using the Hamilton Depression Rating Scale–17 three times over 8 weeks. Compared with those who received treatment as usual, those who were managed using pharmacogenetic-guided decision support tools were more likely to achieve remission from depressive symptoms (relative risk = 1.71; 95% CI, 1.17 to 2.48; P = .005). However, these results are controversial because the included studies were industry-funded, and proprietary algorithms were used to interpret the results. (Editor's note: For more information about this study and pharma­cogenetic testing, see “Pharmacogenomics testing: What the FDA says,” Savvy Psychopharmacology, Current Psych­­iatry. April 2019, p. 29-33.)

In a policy statement on the use of pharmacogenetic testing in psychiatry, the International Society of Psychiatric Genetics (ISPG) explained that such testing should be viewed as a decision support tool to assist in implementing good clinical care, rather than as an alternative to standard protocols.² Furthermore, the ISPG stated that “common genetic variants are not sufficient to cause psychiatric disorders such as depression, bipolar disorder, substance dependence, or schizophrenia.”²

Some manufacturers have claimed that their pharmacogenetic tests can provide information on how a patient will respond to medications for treating depression and other conditions, and when a clinician can or should change a patient’s medication. However, the relationship between DNA variations and the effectiveness of antidepressant medications has not been established, and basing clinical decisions on the results of these tests may lead to inappropriate medication changes.

Pharmacogenetic tests are being advertised to both clinicians and patients, but the FDA has not approved the use of any test for providing information on a patient’s ability to respond to any specific medication.³ Therefore, psychiatrists should discuss the use of pharmacogenetic testing with their patients, and advise patients to avoid stopping or changing their medications based on the results of any pharmacogenetic test. Clinicians should not change a patient’s medication regimen solely based on the results of pharmacogenetic testing. These tests are not supported by scientific or clinical evidence, and using these tests for clinical decisions may put the patient at risk for potentially serious health consequences.

Aneela Jafri, MD, MS
Research Volunteer
Ocean Medical Center
Nutley, New Jersey

Ramon Solhkhah, MD
Founding Chair and Professor
Department of Psychiatry and Behavioral Health
Hackensack Meridian School of Medicine at Seton Hall University
Nutley, New Jersey
Chair
Department of Psychiatry
Jersey Shore University Medical Center
Neptune, New Jersey
Residency Training Director
General Psychiatry
Ocean Medical Center
Brick, New Jersey

Stacy Doumas, MD
Vice Chair
Associate Professor
Department of Psychiatry and Behavioral Health
Hackensack Meridian School of Medicine at Seton Hall University
Nutley, New Jersey
Vice Chair for Education & Research
Residency Training Director
General Psychiatry
Jersey Shore University Medical Center Neptune, New Jersey

Saba Afzal, MD
Assistant Professor
Department of Psychiatry and Behavioral Health
Hackensack Meridian School of Medicine at Seton Hall University
Nutley, New Jersey
Associate Residency Training Director General Psychiatry
Ocean Medical Center
Brick, New Jersey

Disclosures: The authors report no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

The general public may have been led to believe that by decoding genes into their constituent parts, clinicians can prevent or predict serious illnesses and personalize treatment. While this may be true in some areas of medicine, such as oncology, using a pharmacogenetic testing-based “lookup table” to prescribe psychiatric medications is disturbing. This practice could lead to incorrect prescriptions, as well as a lack of follow-up or appropriate dosage titration or medication switching. These problems could put a patient’s life at risk and, consequently, bring the field of psychiatry into disrepute.

In the last few years, using pharmacogenetics to predict or prevent illness and personalize treatment has become very attractive. A 2019 meta-analysis of 5 randomized controlled trials examined the use of pharmacogenetic-guided decision support tools for major depressive disorder (MDD). Researchers randomized 1,737 participants with MDD to either pharmacogenetic-guided decision support tools or treatment as usual.¹ Patients were assessed using the Hamilton Depression Rating Scale–17 three times over 8 weeks. Compared with those who received treatment as usual, those who were managed using pharmacogenetic-guided decision support tools were more likely to achieve remission from depressive symptoms (relative risk = 1.71; 95% CI, 1.17 to 2.48; P = .005). However, these results are controversial because the included studies were industry-funded, and proprietary algorithms were used to interpret the results. (Editor's note: For more information about this study and pharma­cogenetic testing, see “Pharmacogenomics testing: What the FDA says,” Savvy Psychopharmacology, Current Psych­­iatry. April 2019, p. 29-33.)

In a policy statement on the use of pharmacogenetic testing in psychiatry, the International Society of Psychiatric Genetics (ISPG) explained that such testing should be viewed as a decision support tool to assist in implementing good clinical care, rather than as an alternative to standard protocols.² Furthermore, the ISPG stated that “common genetic variants are not sufficient to cause psychiatric disorders such as depression, bipolar disorder, substance dependence, or schizophrenia.”²

Some manufacturers have claimed that their pharmacogenetic tests can provide information on how a patient will respond to medications for treating depression and other conditions, and when a clinician can or should change a patient’s medication. However, the relationship between DNA variations and the effectiveness of antidepressant medications has not been established, and basing clinical decisions on the results of these tests may lead to inappropriate medication changes.

Pharmacogenetic tests are being advertised to both clinicians and patients, but the FDA has not approved the use of any test for providing information on a patient’s ability to respond to any specific medication.³ Therefore, psychiatrists should discuss the use of pharmacogenetic testing with their patients, and advise patients to avoid stopping or changing their medications based on the results of any pharmacogenetic test. Clinicians should not change a patient’s medication regimen solely based on the results of pharmacogenetic testing. These tests are not supported by scientific or clinical evidence, and using these tests for clinical decisions may put the patient at risk for potentially serious health consequences.

Aneela Jafri, MD, MS
Research Volunteer
Ocean Medical Center
Nutley, New Jersey

Ramon Solhkhah, MD
Founding Chair and Professor
Department of Psychiatry and Behavioral Health
Hackensack Meridian School of Medicine at Seton Hall University
Nutley, New Jersey
Chair
Department of Psychiatry
Jersey Shore University Medical Center
Neptune, New Jersey
Residency Training Director
General Psychiatry
Ocean Medical Center
Brick, New Jersey

Stacy Doumas, MD
Vice Chair
Associate Professor
Department of Psychiatry and Behavioral Health
Hackensack Meridian School of Medicine at Seton Hall University
Nutley, New Jersey
Vice Chair for Education & Research
Residency Training Director
General Psychiatry
Jersey Shore University Medical Center Neptune, New Jersey

Saba Afzal, MD
Assistant Professor
Department of Psychiatry and Behavioral Health
Hackensack Meridian School of Medicine at Seton Hall University
Nutley, New Jersey
Associate Residency Training Director General Psychiatry
Ocean Medical Center
Brick, New Jersey

Disclosures: The authors report no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.

The general public may have been led to believe that by decoding genes into their constituent parts, clinicians can prevent or predict serious illnesses and personalize treatment. While this may be true in some areas of medicine, such as oncology, using a pharmacogenetic testing-based “lookup table” to prescribe psychiatric medications is disturbing. This practice could lead to incorrect prescriptions, as well as a lack of follow-up or appropriate dosage titration or medication switching. These problems could put a patient’s life at risk and, consequently, bring the field of psychiatry into disrepute.

In the last few years, using pharmacogenetics to predict or prevent illness and personalize treatment has become very attractive. A 2019 meta-analysis of 5 randomized controlled trials examined the use of pharmacogenetic-guided decision support tools for major depressive disorder (MDD). Researchers randomized 1,737 participants with MDD to either pharmacogenetic-guided decision support tools or treatment as usual.¹ Patients were assessed using the Hamilton Depression Rating Scale–17 three times over 8 weeks. Compared with those who received treatment as usual, those who were managed using pharmacogenetic-guided decision support tools were more likely to achieve remission from depressive symptoms (relative risk = 1.71; 95% CI, 1.17 to 2.48; P = .005). However, these results are controversial because the included studies were industry-funded, and proprietary algorithms were used to interpret the results. (Editor's note: For more information about this study and pharma­cogenetic testing, see “Pharmacogenomics testing: What the FDA says,” Savvy Psychopharmacology, Current Psych­­iatry. April 2019, p. 29-33.)

In a policy statement on the use of pharmacogenetic testing in psychiatry, the International Society of Psychiatric Genetics (ISPG) explained that such testing should be viewed as a decision support tool to assist in implementing good clinical care, rather than as an alternative to standard protocols.² Furthermore, the ISPG stated that “common genetic variants are not sufficient to cause psychiatric disorders such as depression, bipolar disorder, substance dependence, or schizophrenia.”²

Some manufacturers have claimed that their pharmacogenetic tests can provide information on how a patient will respond to medications for treating depression and other conditions, and when a clinician can or should change a patient’s medication. However, the relationship between DNA variations and the effectiveness of antidepressant medications has not been established, and basing clinical decisions on the results of these tests may lead to inappropriate medication changes.

Pharmacogenetic tests are being advertised to both clinicians and patients, but the FDA has not approved the use of any test for providing information on a patient’s ability to respond to any specific medication.³ Therefore, psychiatrists should discuss the use of pharmacogenetic testing with their patients, and advise patients to avoid stopping or changing their medications based on the results of any pharmacogenetic test. Clinicians should not change a patient’s medication regimen solely based on the results of pharmacogenetic testing. These tests are not supported by scientific or clinical evidence, and using these tests for clinical decisions may put the patient at risk for potentially serious health consequences.

Aneela Jafri, MD, MS
Research Volunteer
Ocean Medical Center
Nutley, New Jersey

Ramon Solhkhah, MD
Founding Chair and Professor
Department of Psychiatry and Behavioral Health
Hackensack Meridian School of Medicine at Seton Hall University
Nutley, New Jersey
Chair
Department of Psychiatry
Jersey Shore University Medical Center
Neptune, New Jersey
Residency Training Director
General Psychiatry
Ocean Medical Center
Brick, New Jersey

Stacy Doumas, MD
Vice Chair
Associate Professor
Department of Psychiatry and Behavioral Health
Hackensack Meridian School of Medicine at Seton Hall University
Nutley, New Jersey
Vice Chair for Education & Research
Residency Training Director
General Psychiatry
Jersey Shore University Medical Center Neptune, New Jersey

Saba Afzal, MD
Assistant Professor
Department of Psychiatry and Behavioral Health
Hackensack Meridian School of Medicine at Seton Hall University
Nutley, New Jersey
Associate Residency Training Director General Psychiatry
Ocean Medical Center
Brick, New Jersey

Disclosures: The authors report no financial relationships with any companies whose products are mentioned in this article, or with manufacturers of competing products.