Feature

Widely considered the father of cancer immunotherapy, Steven A. Rosenberg MD, PhD, FAACR, has spent nearly 50 years analyzing the link between patients’ immune reaction and their cancer response.

His pioneering research established interleukin-2 (IL-2) as the first U.S. Food and Drug Administration–approved cancer immunotherapy in 1992.

To recognize his trailblazing work and other achievements, the American Association for Cancer Research (AACR) will award Dr. Rosenberg with the 2024 AACR Award for Lifetime Achievement in Cancer Research at its annual meeting in April.

Dr. Rosenberg: I grew up in the Bronx. My parents both immigrated to the United States from Poland as teenagers.


As a young boy, did you always want to become a doctor?

Dr. Rosenberg: I think some defining moments on why I decided to go into medicine occurred when I was 6 or 7 years old. The second world war was over, and many of the horrors of the Holocaust became apparent to me. I was brought up as an Orthodox Jew. My parents were quite religious, and I remember postcards coming in one after another about relatives that had died in the death camps. That had a profound influence on me.


How did that experience impact your aspirations?

Dr. Rosenberg: It was an example to me of how evil certain people and groups can be toward one another. I decided at that point, that I wanted to do something good for people, and medicine seemed the most likely way to do that. But also, I was developing a broad scientific interest. I ended up at the Bronx High School of Science and knew that I not only wanted to practice the medicine of today, but I wanted to play a role in helping develop the medicine.


What led to your interest in cancer treatment?

Dr. Rosenberg: Well, as a medical student and resident, it became clear that the field of cancer needed major improvement. We had three major ways to treat cancer: surgery, radiation therapy, and chemotherapy. That could cure about half of the people [who] had cancer. But despite the best application of those three specialties, there were over 600,000 deaths from cancer each year in the United States alone. It was clear to me that new approaches were needed, and I became very interested in taking advantage of the body’s immune system as a source of information to try to make progress.


Were there patients who inspired your research?

Dr. Rosenberg: There were two patients that I saw early in my career that impressed me a great deal. One was a patient that I saw when working in the emergency ward as a resident. A patient came in with right upper quadrant pain that looked like a gallbladder attack. That’s what it was. But when I went through his chart, I saw that he had been at that hospital 12 years earlier with a metastatic gastric cancer. The surgeons had operated. They saw tumor had spread to the liver and could not be removed. They closed the belly, not expecting him to survive. Yet he kept showing up for follow-up visits.
Here he was 12 years later. When I helped operate to take out his gallbladder, there was no evidence of any cancer. The cancer had disappeared in the absence of any external treatment. One of the rarest events in medicine, the spontaneous regression of a cancer. Somehow his body had learned how to destroy the tumor.
 

Was the second patient’s case as impressive?

Dr. Rosenberg: This patient had received a kidney transplant from a gentleman who died in an auto accident. [The donor’s] kidney contained a cancer deposit, a kidney cancer, unbeknownst to the transplant surgeons. [When the kidney was transplanted], the recipient developed widespread metastatic kidney cancer.
[The recipient] was on immunosuppressive drugs, and so the drugs had to be stopped. [When the immunosuppressive drugs were stopped], the patient’s body rejected the kidney and his cancer disappeared.
That showed me that, in fact, if you could stimulate a strong enough immune reaction, in this case, an [allogeneic] reaction, against foreign tissues from a different individual, that you could make large vascularized, invasive cancers disappear based on immune reactivities. Those were clues that led me toward studying the immune system’s impact on cancer.


From there, how did your work evolve?

Dr. Rosenberg: As chief of the surgery branch at NIH, I began doing research. It was very difficult to manipulate immune cells in the laboratory. They wouldn’t stay alive. But I tried to study immune reactions in patients with cancer to see if there was such a thing as an immune reaction against the cancer. There was no such thing known at the time. There were no cancer antigens and no known immune reactions against the disease in the human.


Around this time, investigators were publishing studies about interleukin-2 (IL-2), or white blood cells known as leukocytes. How did interleukin-2 further your research?

Dr. Rosenberg: The advent of interleukin-2 enabled scientists to grow lymphocytes outside the body. [This] enabled us to grow t-lymphocytes, which are some of the major warriors of the immune system against foreign tissue. After [studying] 66 patients in which we studied interleukin-2 and cells that would develop from it, we finally saw a disappearance of melanoma in a patient that received interleukin-2. And we went on to treat hundreds of patients with that hormone, interleukin-2. In fact, interleukin-2 became the first immunotherapy ever approved by the Food and Drug Administration for the treatment of cancer in humans.

Dr. Rosenberg: [It] led to studies of the mechanism of action of interleukin-2 and to do that, we identified a kind of cell called a tumor infiltrating lymphocyte. What better place, intuitively to look for cells doing battle against the cancer than within the cancer itself?
In 1988, we demonstrated for the first time that transfer of lymphocytes with antitumor activity could cause the regression of melanoma. This was a living drug obtained from melanoma deposits that could be grown outside the body and then readministered to the patient under suitable conditions. Interestingly, [in February the FDA approved that drug as treatment for patients with melanoma]. A company developed it to the point where in multi-institutional studies, they reproduced our results.
And we’ve now emphasized the value of using T cell therapy, t cell transfer, for the treatment of patients with the common solid cancers, the cancers that start anywhere from the colon up through the intestine, the stomach, the pancreas, and the esophagus. Solid tumors such as ovarian cancer, uterine cancer and so on, are also potentially susceptible to this T cell therapy.
We’ve published several papers showing in isolated patients that you could cause major regressions, if not complete regressions, of these solid cancers in the liver, in the breast, the cervix, the colon. That’s a major aspect of what we’re doing now.
I think immunotherapy has come to be recognized as a major fourth arm that can be used to attack cancers, adding to surgery, radiation, and chemotherapy.


What guidance would you have for other physician-investigators or young doctors who want to follow in your path?

Dr. Rosenberg: You have to have a broad base of knowledge. You have to be willing to immerse yourself in a problem so that your mind is working on it when you’re doing things where you can only think. [When] you’re taking a shower, [or] waiting at a red light, your mind is working on this problem because you’re immersed in trying to understand it.
You need to have a laser focus on the goals that you have and not get sidetracked by issues that may be interesting but not directly related to the goals that you’re attempting to achieve.

Widely considered the father of cancer immunotherapy, Steven A. Rosenberg MD, PhD, FAACR, has spent nearly 50 years analyzing the link between patients’ immune reaction and their cancer response.

His pioneering research established interleukin-2 (IL-2) as the first U.S. Food and Drug Administration–approved cancer immunotherapy in 1992.

To recognize his trailblazing work and other achievements, the American Association for Cancer Research (AACR) will award Dr. Rosenberg with the 2024 AACR Award for Lifetime Achievement in Cancer Research at its annual meeting in April.

Dr. Rosenberg: I grew up in the Bronx. My parents both immigrated to the United States from Poland as teenagers.


As a young boy, did you always want to become a doctor?

Dr. Rosenberg: I think some defining moments on why I decided to go into medicine occurred when I was 6 or 7 years old. The second world war was over, and many of the horrors of the Holocaust became apparent to me. I was brought up as an Orthodox Jew. My parents were quite religious, and I remember postcards coming in one after another about relatives that had died in the death camps. That had a profound influence on me.


How did that experience impact your aspirations?

Dr. Rosenberg: It was an example to me of how evil certain people and groups can be toward one another. I decided at that point, that I wanted to do something good for people, and medicine seemed the most likely way to do that. But also, I was developing a broad scientific interest. I ended up at the Bronx High School of Science and knew that I not only wanted to practice the medicine of today, but I wanted to play a role in helping develop the medicine.


What led to your interest in cancer treatment?

Dr. Rosenberg: Well, as a medical student and resident, it became clear that the field of cancer needed major improvement. We had three major ways to treat cancer: surgery, radiation therapy, and chemotherapy. That could cure about half of the people [who] had cancer. But despite the best application of those three specialties, there were over 600,000 deaths from cancer each year in the United States alone. It was clear to me that new approaches were needed, and I became very interested in taking advantage of the body’s immune system as a source of information to try to make progress.


Were there patients who inspired your research?

Dr. Rosenberg: There were two patients that I saw early in my career that impressed me a great deal. One was a patient that I saw when working in the emergency ward as a resident. A patient came in with right upper quadrant pain that looked like a gallbladder attack. That’s what it was. But when I went through his chart, I saw that he had been at that hospital 12 years earlier with a metastatic gastric cancer. The surgeons had operated. They saw tumor had spread to the liver and could not be removed. They closed the belly, not expecting him to survive. Yet he kept showing up for follow-up visits.
Here he was 12 years later. When I helped operate to take out his gallbladder, there was no evidence of any cancer. The cancer had disappeared in the absence of any external treatment. One of the rarest events in medicine, the spontaneous regression of a cancer. Somehow his body had learned how to destroy the tumor.
 

Was the second patient’s case as impressive?

Dr. Rosenberg: This patient had received a kidney transplant from a gentleman who died in an auto accident. [The donor’s] kidney contained a cancer deposit, a kidney cancer, unbeknownst to the transplant surgeons. [When the kidney was transplanted], the recipient developed widespread metastatic kidney cancer.
[The recipient] was on immunosuppressive drugs, and so the drugs had to be stopped. [When the immunosuppressive drugs were stopped], the patient’s body rejected the kidney and his cancer disappeared.
That showed me that, in fact, if you could stimulate a strong enough immune reaction, in this case, an [allogeneic] reaction, against foreign tissues from a different individual, that you could make large vascularized, invasive cancers disappear based on immune reactivities. Those were clues that led me toward studying the immune system’s impact on cancer.


From there, how did your work evolve?

Dr. Rosenberg: As chief of the surgery branch at NIH, I began doing research. It was very difficult to manipulate immune cells in the laboratory. They wouldn’t stay alive. But I tried to study immune reactions in patients with cancer to see if there was such a thing as an immune reaction against the cancer. There was no such thing known at the time. There were no cancer antigens and no known immune reactions against the disease in the human.


Around this time, investigators were publishing studies about interleukin-2 (IL-2), or white blood cells known as leukocytes. How did interleukin-2 further your research?

Dr. Rosenberg: The advent of interleukin-2 enabled scientists to grow lymphocytes outside the body. [This] enabled us to grow t-lymphocytes, which are some of the major warriors of the immune system against foreign tissue. After [studying] 66 patients in which we studied interleukin-2 and cells that would develop from it, we finally saw a disappearance of melanoma in a patient that received interleukin-2. And we went on to treat hundreds of patients with that hormone, interleukin-2. In fact, interleukin-2 became the first immunotherapy ever approved by the Food and Drug Administration for the treatment of cancer in humans.

Dr. Rosenberg: [It] led to studies of the mechanism of action of interleukin-2 and to do that, we identified a kind of cell called a tumor infiltrating lymphocyte. What better place, intuitively to look for cells doing battle against the cancer than within the cancer itself?
In 1988, we demonstrated for the first time that transfer of lymphocytes with antitumor activity could cause the regression of melanoma. This was a living drug obtained from melanoma deposits that could be grown outside the body and then readministered to the patient under suitable conditions. Interestingly, [in February the FDA approved that drug as treatment for patients with melanoma]. A company developed it to the point where in multi-institutional studies, they reproduced our results.
And we’ve now emphasized the value of using T cell therapy, t cell transfer, for the treatment of patients with the common solid cancers, the cancers that start anywhere from the colon up through the intestine, the stomach, the pancreas, and the esophagus. Solid tumors such as ovarian cancer, uterine cancer and so on, are also potentially susceptible to this T cell therapy.
We’ve published several papers showing in isolated patients that you could cause major regressions, if not complete regressions, of these solid cancers in the liver, in the breast, the cervix, the colon. That’s a major aspect of what we’re doing now.
I think immunotherapy has come to be recognized as a major fourth arm that can be used to attack cancers, adding to surgery, radiation, and chemotherapy.


What guidance would you have for other physician-investigators or young doctors who want to follow in your path?

Dr. Rosenberg: You have to have a broad base of knowledge. You have to be willing to immerse yourself in a problem so that your mind is working on it when you’re doing things where you can only think. [When] you’re taking a shower, [or] waiting at a red light, your mind is working on this problem because you’re immersed in trying to understand it.
You need to have a laser focus on the goals that you have and not get sidetracked by issues that may be interesting but not directly related to the goals that you’re attempting to achieve.

Widely considered the father of cancer immunotherapy, Steven A. Rosenberg MD, PhD, FAACR, has spent nearly 50 years analyzing the link between patients’ immune reaction and their cancer response.

His pioneering research established interleukin-2 (IL-2) as the first U.S. Food and Drug Administration–approved cancer immunotherapy in 1992.

To recognize his trailblazing work and other achievements, the American Association for Cancer Research (AACR) will award Dr. Rosenberg with the 2024 AACR Award for Lifetime Achievement in Cancer Research at its annual meeting in April.

Dr. Rosenberg: I grew up in the Bronx. My parents both immigrated to the United States from Poland as teenagers.


As a young boy, did you always want to become a doctor?

Dr. Rosenberg: I think some defining moments on why I decided to go into medicine occurred when I was 6 or 7 years old. The second world war was over, and many of the horrors of the Holocaust became apparent to me. I was brought up as an Orthodox Jew. My parents were quite religious, and I remember postcards coming in one after another about relatives that had died in the death camps. That had a profound influence on me.


How did that experience impact your aspirations?

Dr. Rosenberg: It was an example to me of how evil certain people and groups can be toward one another. I decided at that point, that I wanted to do something good for people, and medicine seemed the most likely way to do that. But also, I was developing a broad scientific interest. I ended up at the Bronx High School of Science and knew that I not only wanted to practice the medicine of today, but I wanted to play a role in helping develop the medicine.


What led to your interest in cancer treatment?

Dr. Rosenberg: Well, as a medical student and resident, it became clear that the field of cancer needed major improvement. We had three major ways to treat cancer: surgery, radiation therapy, and chemotherapy. That could cure about half of the people [who] had cancer. But despite the best application of those three specialties, there were over 600,000 deaths from cancer each year in the United States alone. It was clear to me that new approaches were needed, and I became very interested in taking advantage of the body’s immune system as a source of information to try to make progress.


Were there patients who inspired your research?

Dr. Rosenberg: There were two patients that I saw early in my career that impressed me a great deal. One was a patient that I saw when working in the emergency ward as a resident. A patient came in with right upper quadrant pain that looked like a gallbladder attack. That’s what it was. But when I went through his chart, I saw that he had been at that hospital 12 years earlier with a metastatic gastric cancer. The surgeons had operated. They saw tumor had spread to the liver and could not be removed. They closed the belly, not expecting him to survive. Yet he kept showing up for follow-up visits.
Here he was 12 years later. When I helped operate to take out his gallbladder, there was no evidence of any cancer. The cancer had disappeared in the absence of any external treatment. One of the rarest events in medicine, the spontaneous regression of a cancer. Somehow his body had learned how to destroy the tumor.
 

Was the second patient’s case as impressive?

Dr. Rosenberg: This patient had received a kidney transplant from a gentleman who died in an auto accident. [The donor’s] kidney contained a cancer deposit, a kidney cancer, unbeknownst to the transplant surgeons. [When the kidney was transplanted], the recipient developed widespread metastatic kidney cancer.
[The recipient] was on immunosuppressive drugs, and so the drugs had to be stopped. [When the immunosuppressive drugs were stopped], the patient’s body rejected the kidney and his cancer disappeared.
That showed me that, in fact, if you could stimulate a strong enough immune reaction, in this case, an [allogeneic] reaction, against foreign tissues from a different individual, that you could make large vascularized, invasive cancers disappear based on immune reactivities. Those were clues that led me toward studying the immune system’s impact on cancer.


From there, how did your work evolve?

Dr. Rosenberg: As chief of the surgery branch at NIH, I began doing research. It was very difficult to manipulate immune cells in the laboratory. They wouldn’t stay alive. But I tried to study immune reactions in patients with cancer to see if there was such a thing as an immune reaction against the cancer. There was no such thing known at the time. There were no cancer antigens and no known immune reactions against the disease in the human.


Around this time, investigators were publishing studies about interleukin-2 (IL-2), or white blood cells known as leukocytes. How did interleukin-2 further your research?

Dr. Rosenberg: The advent of interleukin-2 enabled scientists to grow lymphocytes outside the body. [This] enabled us to grow t-lymphocytes, which are some of the major warriors of the immune system against foreign tissue. After [studying] 66 patients in which we studied interleukin-2 and cells that would develop from it, we finally saw a disappearance of melanoma in a patient that received interleukin-2. And we went on to treat hundreds of patients with that hormone, interleukin-2. In fact, interleukin-2 became the first immunotherapy ever approved by the Food and Drug Administration for the treatment of cancer in humans.

Dr. Rosenberg: [It] led to studies of the mechanism of action of interleukin-2 and to do that, we identified a kind of cell called a tumor infiltrating lymphocyte. What better place, intuitively to look for cells doing battle against the cancer than within the cancer itself?
In 1988, we demonstrated for the first time that transfer of lymphocytes with antitumor activity could cause the regression of melanoma. This was a living drug obtained from melanoma deposits that could be grown outside the body and then readministered to the patient under suitable conditions. Interestingly, [in February the FDA approved that drug as treatment for patients with melanoma]. A company developed it to the point where in multi-institutional studies, they reproduced our results.
And we’ve now emphasized the value of using T cell therapy, t cell transfer, for the treatment of patients with the common solid cancers, the cancers that start anywhere from the colon up through the intestine, the stomach, the pancreas, and the esophagus. Solid tumors such as ovarian cancer, uterine cancer and so on, are also potentially susceptible to this T cell therapy.
We’ve published several papers showing in isolated patients that you could cause major regressions, if not complete regressions, of these solid cancers in the liver, in the breast, the cervix, the colon. That’s a major aspect of what we’re doing now.
I think immunotherapy has come to be recognized as a major fourth arm that can be used to attack cancers, adding to surgery, radiation, and chemotherapy.


What guidance would you have for other physician-investigators or young doctors who want to follow in your path?

Dr. Rosenberg: You have to have a broad base of knowledge. You have to be willing to immerse yourself in a problem so that your mind is working on it when you’re doing things where you can only think. [When] you’re taking a shower, [or] waiting at a red light, your mind is working on this problem because you’re immersed in trying to understand it.
You need to have a laser focus on the goals that you have and not get sidetracked by issues that may be interesting but not directly related to the goals that you’re attempting to achieve.

In 2019, we interviewed Andrea Prince, MD, who was completing her internship in the Inuit village of Puvirnituq, a town of 2000 inhabitants located in Nunavik, in the Canadian Far North. Five years later, still in her position, what perspective does she have on her practice? Have the challenges of practicing medicine in a remote region within the Inuit community affected her vocation? Would she recommend this experience to young doctors?

Question: What position do you currently hold?

Dr. Prince: I am a full-time general practitioner at Puvirnituq Hospital. My responsibilities range from following up on hospitalized patients to those seen in outpatient clinics for chronic illnesses. Within our medical team, I receive patients in the emergency department (day and night shifts), and I travel to smaller dispensaries nearby, especially to the village of Akulivik. So, it’s quite a varied practice.

More recently, I have been involved in remote continuing medical education projects in collaboration with specialists based in Montreal. In this context, we are increasingly trying to collaborate with doctors from other indigenous communities, such as the Grand Council of the Cree, because our practices are quite similar.



Q: What is the patient volume you see?

Dr. Prince: We see approximately 20-30 patients per day in the clinic, plus about 10 by appointment, and dozens of calls from dispensaries, in addition to patients transferred from other villages. There are four daytime doctors (one at night) and about 15 nurses stationed full-time at Puvirnituq Hospital.

Our practice relies heavily on collaboration with the nursing team, which has an expanded role — they can manage certain patients according to the treatment plan established by the doctor and prescribe treatments (eg, antibiotics for uncomplicated otitis).



Q: Access to care in these isolated regions is considered difficult. Have you observed any improvement in the situation over the past 5 years? What about new material and human resources?

Dr. Prince: For the past year, we have had a Starlink internet connection at the hospital, which facilitates telemedicine exchanges with specialists; we can now send data and medical images to Montreal to obtain expertise much more easily. Previously, everything was done by phone or with significant delays. We do not yet have a cellular network, and all records are currently in paper format.

But the challenges remain numerous. Progress is very slow. Like everywhere in the country, we are experiencing a shortage of staff, particularly an insufficient number of nurses. But the impact is even more dramatic in these isolated territories. We have had to close dispensaries on the coast due to a lack of personnel and only offer emergency services. However, patients have no other options; they cannot drive to another hospital. In Nunavik, the road network is practically nonexistent, and travel to other regions is by plane (about a 2.5-hour medical evacuation trip).

So, sometimes, patients do not seek care in time, and when we finally see them, unfortunately, the issue can be quite advanced.



Q: What are the most pressing logistical needs?

Dr. Prince: We still do not have a scanner in the Far North. This has a significant impact on mortality, especially in the case of accidents and trauma, which are very common in these regions. “Residents of Nunavik are four times more likely to suffer trauma than the rest of Quebec’s population and 40 times more likely to die from it,” as recently reported in La Presse.

There has also been much discussion about cancer mortality, with a risk for death about 70% higher following a lung cancer diagnosis (reported by Medscape Medical News). We do not have a mammogram machine to diagnose breast cancer. Before the COVID-19 pandemic, equipped diagnostic teams sometimes traveled to the region, but this is no longer the case. Today, a patient needing a mammogram will have to travel to Montreal. The same goes for colonoscopies, but visits are becoming less frequent. Therefore, campaigns to screen for certain common types of cancer are practically nonexistent.

As for urgent surgeries (appendicitis, cesarean sections, trauma, etc.), patients must be transferred to Montreal by medical evacuation. We have a visiting surgeon twice a year.



Q: What improvement strategies do you foresee despite the lack of resources?

Dr. Prince: The saying “prevention is better than cure” makes perfect sense in such remote regions under extreme conditions (it is impossible to fly a medevac when it is too windy or during a snowstorm!). That’s why my colleagues and I believe that prevention should be the top priority in terms of healthcare intervention. It may seem obvious, but nothing is simple in the Far North.



Q: In which areas should prevention campaigns be prioritized in your opinion?

Dr. Prince: An example is wearing helmets. Practically no one wears this type of protection in the Far North. They use all-terrain vehicles that are dangerous and for which helmet use is crucial. But they are simply not available in stores. So, communication is difficult: We tell people, “you need a helmet for the ATV, another for the bike, for the snowmobile, for playing hockey, etc.” when it is difficult to obtain one. With traumatologists in Montreal, we had a project to create multifunctional helmets for children — to protect them but also to develop a culture of helmet use, which is not common practice in the community — but these are projects that take a lot of time and are more complex than they seem.

Villages still do not have running water. Therefore, it is difficult to give recommendations to patients as they live in sanitary conditions that are unseen elsewhere in Canada. Without clean water, we cannot ensure that wound care is done properly. Not to mention the occurrence of hepatitis A epidemics, like the one we had to face.

Residents also grapple with significant alcohol and smoking problems, but there is no detox center or dedicated psychological help on site. To follow a detox program, patients would have to leave, move away from their families, and that can be psychologically very destabilizing. I try, in my practice, to talk to my patients about this, especially pregnant women — because many continue to smoke or drink during their pregnancy — but we need more resources.



Q: What about women’s health in this region?

Dr. Prince: We are fortunate to have a team of midwives, several of whom are Inuit, who are of great help in accessing contraception, performing cervical cancer screening tests, etc. But some patients with high-risk pregnancies who should be transferred to Montreal refuse to give birth away from their families. Again, if we had the means to allow high-risk women — or those for whom continuous monitoring or a cesarean section may be necessary — to give birth here safely, it would be a big step. As for abortion, it is feasible but remains a very taboo subject in the community.

Regarding violence against women, I have not observed any particularly encouraging developments in the past 5 years, but recently, we met with the mayor about this, hoping that concrete actions will be taken to help victims of violence.
 

Q: What is the predominant feeling in your daily life in a situation that is slow to evolve?

Dr. Prince: I remain hopeful for my patients. We must continue to fight! Initiatives must also come from the communities themselves; they must be involved in developing solutions. Because patients, too, need to have hope. They have the right to be cared for like other inhabitants of Canada.

On my part, I try to find a balance between feeling good about my caregiving profession and not burning out professionally. But burnout is a subject that concerns many doctors around the world and is increasingly being discussed. We should all have psychological support when entering medicine!



Q: Would you recommend colleagues to come and work in the Far North? What would you tell them?

Dr. Prince: I would tell them they will have no regrets! Yes, it’s difficult, but it’s a unique type of practice and very rewarding on a human level.

Professionally, it is a general practice that is no longer seen in the city today. The spectrum is very broad, ranging from neonatology to geriatrics, from the simplest to the most complex. It’s very stimulating. Diagnostically, practice is also very different from what is done in the metropolis. Without a scanner, you really have to question and investigate to evaluate whether a patient should be evacuated by plane to Montreal or not. It’s not trivial. Decisions must be made judiciously and quickly.

The human experience is also unique. Inuit communities are little known, and the aspects relayed in the media are often negative due to their increased risk for addiction. However, they are cheerful and very warm people, with an extraordinary culture. I have learned a lot from them, including reconsidering the notion of time, reviewing my priorities, and approaching life one day at a time.

I am very grateful to them for accepting me. I am sometimes even greeted with a “Welcome home!” when I return from vacation...Being told that in Nunavik, I am also “at home,” touches me immensely. I have seen children grow up, adolescents become adults. A bond of trust has developed.

Of course, all of this comes with sacrifices like being away from family and loved ones. We miss birthdays, weddings, etc. But without hesitation, it’s worth it!



Q: What are the next steps in your career in Nunavik? Will you stay for a long time?

Dr. Prince: I take it one day at a time, especially since I am about to take maternity leave very soon. But if a full-time return to Nunavik is difficult with a newborn, I know that the Nunavummiuts [inhabitants of Nunavik] will always be part of my life and my practice.

I want to remain involved with these communities, whether on-site (by practicing there a few months a year) or in Montreal where many patients are transferred. Coming to be treated in a big city (Montreal, 1.7M inhabitants), in very large hospitals, can be very stressful for them. They express themselves much less verbally than Westerners, so we must know how to listen to them, dedicate the necessary time to them, consider their culture and beliefs. I would like to be the familiar face they will encounter when they are cared for away from home. It’s a bond I want to preserve.

This story was translated from Medscape France using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

In 2019, we interviewed Andrea Prince, MD, who was completing her internship in the Inuit village of Puvirnituq, a town of 2000 inhabitants located in Nunavik, in the Canadian Far North. Five years later, still in her position, what perspective does she have on her practice? Have the challenges of practicing medicine in a remote region within the Inuit community affected her vocation? Would she recommend this experience to young doctors?

Question: What position do you currently hold?

Dr. Prince: I am a full-time general practitioner at Puvirnituq Hospital. My responsibilities range from following up on hospitalized patients to those seen in outpatient clinics for chronic illnesses. Within our medical team, I receive patients in the emergency department (day and night shifts), and I travel to smaller dispensaries nearby, especially to the village of Akulivik. So, it’s quite a varied practice.

More recently, I have been involved in remote continuing medical education projects in collaboration with specialists based in Montreal. In this context, we are increasingly trying to collaborate with doctors from other indigenous communities, such as the Grand Council of the Cree, because our practices are quite similar.



Q: What is the patient volume you see?

Dr. Prince: We see approximately 20-30 patients per day in the clinic, plus about 10 by appointment, and dozens of calls from dispensaries, in addition to patients transferred from other villages. There are four daytime doctors (one at night) and about 15 nurses stationed full-time at Puvirnituq Hospital.

Our practice relies heavily on collaboration with the nursing team, which has an expanded role — they can manage certain patients according to the treatment plan established by the doctor and prescribe treatments (eg, antibiotics for uncomplicated otitis).



Q: Access to care in these isolated regions is considered difficult. Have you observed any improvement in the situation over the past 5 years? What about new material and human resources?

Dr. Prince: For the past year, we have had a Starlink internet connection at the hospital, which facilitates telemedicine exchanges with specialists; we can now send data and medical images to Montreal to obtain expertise much more easily. Previously, everything was done by phone or with significant delays. We do not yet have a cellular network, and all records are currently in paper format.

But the challenges remain numerous. Progress is very slow. Like everywhere in the country, we are experiencing a shortage of staff, particularly an insufficient number of nurses. But the impact is even more dramatic in these isolated territories. We have had to close dispensaries on the coast due to a lack of personnel and only offer emergency services. However, patients have no other options; they cannot drive to another hospital. In Nunavik, the road network is practically nonexistent, and travel to other regions is by plane (about a 2.5-hour medical evacuation trip).

So, sometimes, patients do not seek care in time, and when we finally see them, unfortunately, the issue can be quite advanced.



Q: What are the most pressing logistical needs?

Dr. Prince: We still do not have a scanner in the Far North. This has a significant impact on mortality, especially in the case of accidents and trauma, which are very common in these regions. “Residents of Nunavik are four times more likely to suffer trauma than the rest of Quebec’s population and 40 times more likely to die from it,” as recently reported in La Presse.

There has also been much discussion about cancer mortality, with a risk for death about 70% higher following a lung cancer diagnosis (reported by Medscape Medical News). We do not have a mammogram machine to diagnose breast cancer. Before the COVID-19 pandemic, equipped diagnostic teams sometimes traveled to the region, but this is no longer the case. Today, a patient needing a mammogram will have to travel to Montreal. The same goes for colonoscopies, but visits are becoming less frequent. Therefore, campaigns to screen for certain common types of cancer are practically nonexistent.

As for urgent surgeries (appendicitis, cesarean sections, trauma, etc.), patients must be transferred to Montreal by medical evacuation. We have a visiting surgeon twice a year.



Q: What improvement strategies do you foresee despite the lack of resources?

Dr. Prince: The saying “prevention is better than cure” makes perfect sense in such remote regions under extreme conditions (it is impossible to fly a medevac when it is too windy or during a snowstorm!). That’s why my colleagues and I believe that prevention should be the top priority in terms of healthcare intervention. It may seem obvious, but nothing is simple in the Far North.



Q: In which areas should prevention campaigns be prioritized in your opinion?

Dr. Prince: An example is wearing helmets. Practically no one wears this type of protection in the Far North. They use all-terrain vehicles that are dangerous and for which helmet use is crucial. But they are simply not available in stores. So, communication is difficult: We tell people, “you need a helmet for the ATV, another for the bike, for the snowmobile, for playing hockey, etc.” when it is difficult to obtain one. With traumatologists in Montreal, we had a project to create multifunctional helmets for children — to protect them but also to develop a culture of helmet use, which is not common practice in the community — but these are projects that take a lot of time and are more complex than they seem.

Villages still do not have running water. Therefore, it is difficult to give recommendations to patients as they live in sanitary conditions that are unseen elsewhere in Canada. Without clean water, we cannot ensure that wound care is done properly. Not to mention the occurrence of hepatitis A epidemics, like the one we had to face.

Residents also grapple with significant alcohol and smoking problems, but there is no detox center or dedicated psychological help on site. To follow a detox program, patients would have to leave, move away from their families, and that can be psychologically very destabilizing. I try, in my practice, to talk to my patients about this, especially pregnant women — because many continue to smoke or drink during their pregnancy — but we need more resources.



Q: What about women’s health in this region?

Dr. Prince: We are fortunate to have a team of midwives, several of whom are Inuit, who are of great help in accessing contraception, performing cervical cancer screening tests, etc. But some patients with high-risk pregnancies who should be transferred to Montreal refuse to give birth away from their families. Again, if we had the means to allow high-risk women — or those for whom continuous monitoring or a cesarean section may be necessary — to give birth here safely, it would be a big step. As for abortion, it is feasible but remains a very taboo subject in the community.

Regarding violence against women, I have not observed any particularly encouraging developments in the past 5 years, but recently, we met with the mayor about this, hoping that concrete actions will be taken to help victims of violence.
 

Q: What is the predominant feeling in your daily life in a situation that is slow to evolve?

Dr. Prince: I remain hopeful for my patients. We must continue to fight! Initiatives must also come from the communities themselves; they must be involved in developing solutions. Because patients, too, need to have hope. They have the right to be cared for like other inhabitants of Canada.

On my part, I try to find a balance between feeling good about my caregiving profession and not burning out professionally. But burnout is a subject that concerns many doctors around the world and is increasingly being discussed. We should all have psychological support when entering medicine!



Q: Would you recommend colleagues to come and work in the Far North? What would you tell them?

Dr. Prince: I would tell them they will have no regrets! Yes, it’s difficult, but it’s a unique type of practice and very rewarding on a human level.

Professionally, it is a general practice that is no longer seen in the city today. The spectrum is very broad, ranging from neonatology to geriatrics, from the simplest to the most complex. It’s very stimulating. Diagnostically, practice is also very different from what is done in the metropolis. Without a scanner, you really have to question and investigate to evaluate whether a patient should be evacuated by plane to Montreal or not. It’s not trivial. Decisions must be made judiciously and quickly.

The human experience is also unique. Inuit communities are little known, and the aspects relayed in the media are often negative due to their increased risk for addiction. However, they are cheerful and very warm people, with an extraordinary culture. I have learned a lot from them, including reconsidering the notion of time, reviewing my priorities, and approaching life one day at a time.

I am very grateful to them for accepting me. I am sometimes even greeted with a “Welcome home!” when I return from vacation...Being told that in Nunavik, I am also “at home,” touches me immensely. I have seen children grow up, adolescents become adults. A bond of trust has developed.

Of course, all of this comes with sacrifices like being away from family and loved ones. We miss birthdays, weddings, etc. But without hesitation, it’s worth it!



Q: What are the next steps in your career in Nunavik? Will you stay for a long time?

Dr. Prince: I take it one day at a time, especially since I am about to take maternity leave very soon. But if a full-time return to Nunavik is difficult with a newborn, I know that the Nunavummiuts [inhabitants of Nunavik] will always be part of my life and my practice.

I want to remain involved with these communities, whether on-site (by practicing there a few months a year) or in Montreal where many patients are transferred. Coming to be treated in a big city (Montreal, 1.7M inhabitants), in very large hospitals, can be very stressful for them. They express themselves much less verbally than Westerners, so we must know how to listen to them, dedicate the necessary time to them, consider their culture and beliefs. I would like to be the familiar face they will encounter when they are cared for away from home. It’s a bond I want to preserve.

This story was translated from Medscape France using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

In 2019, we interviewed Andrea Prince, MD, who was completing her internship in the Inuit village of Puvirnituq, a town of 2000 inhabitants located in Nunavik, in the Canadian Far North. Five years later, still in her position, what perspective does she have on her practice? Have the challenges of practicing medicine in a remote region within the Inuit community affected her vocation? Would she recommend this experience to young doctors?

Question: What position do you currently hold?

Dr. Prince: I am a full-time general practitioner at Puvirnituq Hospital. My responsibilities range from following up on hospitalized patients to those seen in outpatient clinics for chronic illnesses. Within our medical team, I receive patients in the emergency department (day and night shifts), and I travel to smaller dispensaries nearby, especially to the village of Akulivik. So, it’s quite a varied practice.

More recently, I have been involved in remote continuing medical education projects in collaboration with specialists based in Montreal. In this context, we are increasingly trying to collaborate with doctors from other indigenous communities, such as the Grand Council of the Cree, because our practices are quite similar.



Q: What is the patient volume you see?

Dr. Prince: We see approximately 20-30 patients per day in the clinic, plus about 10 by appointment, and dozens of calls from dispensaries, in addition to patients transferred from other villages. There are four daytime doctors (one at night) and about 15 nurses stationed full-time at Puvirnituq Hospital.

Our practice relies heavily on collaboration with the nursing team, which has an expanded role — they can manage certain patients according to the treatment plan established by the doctor and prescribe treatments (eg, antibiotics for uncomplicated otitis).



Q: Access to care in these isolated regions is considered difficult. Have you observed any improvement in the situation over the past 5 years? What about new material and human resources?

Dr. Prince: For the past year, we have had a Starlink internet connection at the hospital, which facilitates telemedicine exchanges with specialists; we can now send data and medical images to Montreal to obtain expertise much more easily. Previously, everything was done by phone or with significant delays. We do not yet have a cellular network, and all records are currently in paper format.

But the challenges remain numerous. Progress is very slow. Like everywhere in the country, we are experiencing a shortage of staff, particularly an insufficient number of nurses. But the impact is even more dramatic in these isolated territories. We have had to close dispensaries on the coast due to a lack of personnel and only offer emergency services. However, patients have no other options; they cannot drive to another hospital. In Nunavik, the road network is practically nonexistent, and travel to other regions is by plane (about a 2.5-hour medical evacuation trip).

So, sometimes, patients do not seek care in time, and when we finally see them, unfortunately, the issue can be quite advanced.



Q: What are the most pressing logistical needs?

Dr. Prince: We still do not have a scanner in the Far North. This has a significant impact on mortality, especially in the case of accidents and trauma, which are very common in these regions. “Residents of Nunavik are four times more likely to suffer trauma than the rest of Quebec’s population and 40 times more likely to die from it,” as recently reported in La Presse.

There has also been much discussion about cancer mortality, with a risk for death about 70% higher following a lung cancer diagnosis (reported by Medscape Medical News). We do not have a mammogram machine to diagnose breast cancer. Before the COVID-19 pandemic, equipped diagnostic teams sometimes traveled to the region, but this is no longer the case. Today, a patient needing a mammogram will have to travel to Montreal. The same goes for colonoscopies, but visits are becoming less frequent. Therefore, campaigns to screen for certain common types of cancer are practically nonexistent.

As for urgent surgeries (appendicitis, cesarean sections, trauma, etc.), patients must be transferred to Montreal by medical evacuation. We have a visiting surgeon twice a year.



Q: What improvement strategies do you foresee despite the lack of resources?

Dr. Prince: The saying “prevention is better than cure” makes perfect sense in such remote regions under extreme conditions (it is impossible to fly a medevac when it is too windy or during a snowstorm!). That’s why my colleagues and I believe that prevention should be the top priority in terms of healthcare intervention. It may seem obvious, but nothing is simple in the Far North.



Q: In which areas should prevention campaigns be prioritized in your opinion?

Dr. Prince: An example is wearing helmets. Practically no one wears this type of protection in the Far North. They use all-terrain vehicles that are dangerous and for which helmet use is crucial. But they are simply not available in stores. So, communication is difficult: We tell people, “you need a helmet for the ATV, another for the bike, for the snowmobile, for playing hockey, etc.” when it is difficult to obtain one. With traumatologists in Montreal, we had a project to create multifunctional helmets for children — to protect them but also to develop a culture of helmet use, which is not common practice in the community — but these are projects that take a lot of time and are more complex than they seem.

Villages still do not have running water. Therefore, it is difficult to give recommendations to patients as they live in sanitary conditions that are unseen elsewhere in Canada. Without clean water, we cannot ensure that wound care is done properly. Not to mention the occurrence of hepatitis A epidemics, like the one we had to face.

Residents also grapple with significant alcohol and smoking problems, but there is no detox center or dedicated psychological help on site. To follow a detox program, patients would have to leave, move away from their families, and that can be psychologically very destabilizing. I try, in my practice, to talk to my patients about this, especially pregnant women — because many continue to smoke or drink during their pregnancy — but we need more resources.



Q: What about women’s health in this region?

Dr. Prince: We are fortunate to have a team of midwives, several of whom are Inuit, who are of great help in accessing contraception, performing cervical cancer screening tests, etc. But some patients with high-risk pregnancies who should be transferred to Montreal refuse to give birth away from their families. Again, if we had the means to allow high-risk women — or those for whom continuous monitoring or a cesarean section may be necessary — to give birth here safely, it would be a big step. As for abortion, it is feasible but remains a very taboo subject in the community.

Regarding violence against women, I have not observed any particularly encouraging developments in the past 5 years, but recently, we met with the mayor about this, hoping that concrete actions will be taken to help victims of violence.
 

Q: What is the predominant feeling in your daily life in a situation that is slow to evolve?

Dr. Prince: I remain hopeful for my patients. We must continue to fight! Initiatives must also come from the communities themselves; they must be involved in developing solutions. Because patients, too, need to have hope. They have the right to be cared for like other inhabitants of Canada.

On my part, I try to find a balance between feeling good about my caregiving profession and not burning out professionally. But burnout is a subject that concerns many doctors around the world and is increasingly being discussed. We should all have psychological support when entering medicine!



Q: Would you recommend colleagues to come and work in the Far North? What would you tell them?

Dr. Prince: I would tell them they will have no regrets! Yes, it’s difficult, but it’s a unique type of practice and very rewarding on a human level.

Professionally, it is a general practice that is no longer seen in the city today. The spectrum is very broad, ranging from neonatology to geriatrics, from the simplest to the most complex. It’s very stimulating. Diagnostically, practice is also very different from what is done in the metropolis. Without a scanner, you really have to question and investigate to evaluate whether a patient should be evacuated by plane to Montreal or not. It’s not trivial. Decisions must be made judiciously and quickly.

The human experience is also unique. Inuit communities are little known, and the aspects relayed in the media are often negative due to their increased risk for addiction. However, they are cheerful and very warm people, with an extraordinary culture. I have learned a lot from them, including reconsidering the notion of time, reviewing my priorities, and approaching life one day at a time.

I am very grateful to them for accepting me. I am sometimes even greeted with a “Welcome home!” when I return from vacation...Being told that in Nunavik, I am also “at home,” touches me immensely. I have seen children grow up, adolescents become adults. A bond of trust has developed.

Of course, all of this comes with sacrifices like being away from family and loved ones. We miss birthdays, weddings, etc. But without hesitation, it’s worth it!



Q: What are the next steps in your career in Nunavik? Will you stay for a long time?

Dr. Prince: I take it one day at a time, especially since I am about to take maternity leave very soon. But if a full-time return to Nunavik is difficult with a newborn, I know that the Nunavummiuts [inhabitants of Nunavik] will always be part of my life and my practice.

I want to remain involved with these communities, whether on-site (by practicing there a few months a year) or in Montreal where many patients are transferred. Coming to be treated in a big city (Montreal, 1.7M inhabitants), in very large hospitals, can be very stressful for them. They express themselves much less verbally than Westerners, so we must know how to listen to them, dedicate the necessary time to them, consider their culture and beliefs. I would like to be the familiar face they will encounter when they are cared for away from home. It’s a bond I want to preserve.

This story was translated from Medscape France using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Targeted treatments, including antibody-drug conjugates and immunotherapy agents, are now standard of care for breast cancer, but there are limited data on the safety of combining these newer agents alongside radiotherapy.

One reason is studies of new drugs typically exclude concurrent radiotherapy, said Kathy Miller, MD, a contributor to this news organization and professor of oncology and medicine at the Indiana University School of Medicine, Indianapolis, Indiana.

If trials evaluating new targeted therapies included concurrent radiotherapy, it would be challenging to identify whether toxicities came from the drug itself, the radiation, or the combination, Dr. Miller explained.

Given the limited evidence, “we tend to be cautious and conservative” and not combine therapies that “we don’t know are safe or appropriate for patients,” said Chirag Shah, MD, director of breast radiology at the Cleveland Clinic, Cleveland, Ohio.

Below is a guide to what we do and don’t know about combining radiotherapy and systemic treatments in breast cancer.

1. Immunotherapy plus radiotherapy likely safe but evidence is limited

Safety data on combining immune checkpoint inhibitors and radiotherapy in breast cancer are limited because concurrent radiotherapy has typically been excluded in pivotal trials.

The 2020 KEYNOTE-522 trial did provide a rare look at concurrent radiotherapy and immunotherapy in early triple-negative breast cancer. The analysis found “no safety concerns” with concurrent radiotherapy and pembrolizumab, lead investigator Peter Schmid, MD, of Queen Mary University of London, England, told this news organization.

Research on other solid tumor types also suggests that radiotherapy “can be considered safe” alongside immunotherapy, the authors of a recent ESTRO consensus said.

Despite evidence indicating radiotherapy alongside immunotherapy can be safe in patients with breast cancer, “certain aspects, such as patient selection, total dose, and dose per fraction, remain open for debate to achieve the best therapeutic outcomes,” the ESTRO experts cautioned.

2. CDK4/6 inhibitors may be offered with radiotherapy in some settings, not others

CDK4/6 inhibitors are now standard of care for first- or second-line treatment in patients with advanced or metastatic hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer.

“Unfortunately, we found no information regarding concurrent radiotherapy in the adjuvant setting” in pivotal trials for palbociclib, abemaciclib, and ribociclib, the ESTRO authors said. In the pivotal trials for palbociclib and abemaciclib, patients had to discontinue immunotherapy before initiating radiotherapy, and in the trial for ribociclib, palliative radiotherapy was allowed for relieving bone pain only.

However, in 2023, a team of experts from 12 countries attempted to piece together the available evidence, publishing a meta-analysis of 11 retrospective studies on the safety of CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic disease.

Although most of these studies had small patient populations, the analysis revealed that CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic breast cancer led to a similar side-effect profile to that observed in trials of the inhibitors given sequentially with adjuvant radiotherapy.

“These findings suggest that the simultaneous administration of CDK4/6 inhibitors and radiotherapy is generally well tolerated,” the ESTRO authors concluded but added that CDK4/6 inhibitors and concomitant radiotherapy should be investigated more in the adjuvant locoregional, whole brain, and intracranial stereotactic radiotherapy settings.

The expert panel did note, however, that CDK4/6 inhibitors and concomitant radiotherapy “could be offered” during palliative and ablative extracranial radiotherapy.

3. Only offer poly (ADP-ribose) polymerase (PARP) inhibitors plus radiotherapy in clinical trial setting

PARP inhibitors olaparib (Lynparza) and talazoprib (Talzenna) are standard of care in patients with metastatic breast cancer who have BRCA1/2 gene mutations. Olaparib is also indicated for high-risk early breast cancer following neoadjuvant or adjuvant chemotherapy.

But data on combining PARP inhibitors with radiotherapy in breast cancer also remain limited.

One ongoing phase 2 trial, comparing olaparib plus radiotherapy to radiotherapy alone in 300 people with inflammatory breast cancer, is aiming to tease out the safety of the combination and whether it improves local control in patients with aggressive disease.

“The desire is to explore the exciting possibility that low doses of PARP inhibition may radiosensitize tumor cells more than normal tissues,” Reshma Jagsi, MD, chair of the Department of Radiation Oncology at Emory University School of Medicine in Atlanta, Georgia, who is leading the study.

Because of potential good or bad interactions between new systemic therapies and radiotherapy, “intentional trial design” is important, Dr. Jagsi said, so we “know the best way to combine treatments in practice to optimize outcomes.”

But given the evidence to date, the ESTRO experts advised waiting until “further research provides more comprehensive safety and efficacy data” in the primary, adjuvant, and metastatic settings. The experts also advised not offering PARP inhibitors and concomitant radiotherapy to treat advanced breast cancer outside of clinical trials.

4. Phosphoinositide 3-kinase inhibitors (PI3K) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and newer targeted agents should not be offered concurrently with radiotherapy

Clinical trial data on the safety of combining PI3K and mTOR inhibitors with radiation are thin, especially in advanced breast cancer. Typically, radiotherapy within 4 weeks before randomization, or 2 weeks for palliative radiation, was excluded in pivotal trials.

For this reason, the ESTRO team recommended that concurrent radiation with either PI3K inhibitors or mTOR inhibitors “should not be offered.”

ESTRO also cautioned against providing radiation concurrently with newer anti-HER2 tyrosine-kinase drugs, such as neratinib or tucatinib, or newer antibody-drug conjugates such as trastuzumab deruxtecan, until more data emerge on the safety of these combinations.

5. Combining older HER2-targeted drugs and radiotherapy generally safe

The ESTRO authors agreed that older anti-HER2 drugs trastuzumab (Herceptin), pertuzumab (Perjeta), and lapatinib (Tykerb) can be safely used concurrently with locoregional radiotherapy as well.

One of the biggest concerns in the field is how to combine radiation with systemic therapies in the setting of brain metastases, and the data on these older anti-HER2 drugs are relatively clear that it’s safe, Dr. Miller said.

For instance, in a 2019 study of 84 patients with 487 brain metastases, stereotactic radiosurgery given alongside lapatinib led to significantly higher rates of complete responses than stereotactic radiosurgery alone (35% vs 11%) with no increased risk for radiation necrosis.

The ESTRO team agreed, noting that the latest evidence supports the use of trastuzumab, pertuzumab, or lapatinib alongside radiotherapy for whole brain and ablative intracranial stereotactic radiotherapy.

As for older antibody-drug conjugates, trastuzumab emtansine (T-DM1) plus radiotherapy “might be considered” during adjuvant locoregional radiotherapy for breast cancer but should not be offered for whole brain and ablative intracranial stereotactic radiotherapy, the ESTRO team said.

Dr. Jagsi declared the following conflicts in a recent 2024 publication: Stock options for advisory board role in Equity Quotient; grants or contracts from Genentech; and expert witness for Kleinbard, LLC, and Hawks Quindel Law. In the Keynote-522 trial publication Dr. Schmid declared relationships with AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Hoffmann-La Roche, Genetech, Merck, Novartis, and Pfizer. Dr. Shah reported consulting for Impedimed, Videra Surgical, and PreludeDX.

A version of this article appeared on Medscape.com.

Targeted treatments, including antibody-drug conjugates and immunotherapy agents, are now standard of care for breast cancer, but there are limited data on the safety of combining these newer agents alongside radiotherapy.

One reason is studies of new drugs typically exclude concurrent radiotherapy, said Kathy Miller, MD, a contributor to this news organization and professor of oncology and medicine at the Indiana University School of Medicine, Indianapolis, Indiana.

If trials evaluating new targeted therapies included concurrent radiotherapy, it would be challenging to identify whether toxicities came from the drug itself, the radiation, or the combination, Dr. Miller explained.

Given the limited evidence, “we tend to be cautious and conservative” and not combine therapies that “we don’t know are safe or appropriate for patients,” said Chirag Shah, MD, director of breast radiology at the Cleveland Clinic, Cleveland, Ohio.

Below is a guide to what we do and don’t know about combining radiotherapy and systemic treatments in breast cancer.

1. Immunotherapy plus radiotherapy likely safe but evidence is limited

Safety data on combining immune checkpoint inhibitors and radiotherapy in breast cancer are limited because concurrent radiotherapy has typically been excluded in pivotal trials.

The 2020 KEYNOTE-522 trial did provide a rare look at concurrent radiotherapy and immunotherapy in early triple-negative breast cancer. The analysis found “no safety concerns” with concurrent radiotherapy and pembrolizumab, lead investigator Peter Schmid, MD, of Queen Mary University of London, England, told this news organization.

Research on other solid tumor types also suggests that radiotherapy “can be considered safe” alongside immunotherapy, the authors of a recent ESTRO consensus said.

Despite evidence indicating radiotherapy alongside immunotherapy can be safe in patients with breast cancer, “certain aspects, such as patient selection, total dose, and dose per fraction, remain open for debate to achieve the best therapeutic outcomes,” the ESTRO experts cautioned.

2. CDK4/6 inhibitors may be offered with radiotherapy in some settings, not others

CDK4/6 inhibitors are now standard of care for first- or second-line treatment in patients with advanced or metastatic hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer.

“Unfortunately, we found no information regarding concurrent radiotherapy in the adjuvant setting” in pivotal trials for palbociclib, abemaciclib, and ribociclib, the ESTRO authors said. In the pivotal trials for palbociclib and abemaciclib, patients had to discontinue immunotherapy before initiating radiotherapy, and in the trial for ribociclib, palliative radiotherapy was allowed for relieving bone pain only.

However, in 2023, a team of experts from 12 countries attempted to piece together the available evidence, publishing a meta-analysis of 11 retrospective studies on the safety of CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic disease.

Although most of these studies had small patient populations, the analysis revealed that CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic breast cancer led to a similar side-effect profile to that observed in trials of the inhibitors given sequentially with adjuvant radiotherapy.

“These findings suggest that the simultaneous administration of CDK4/6 inhibitors and radiotherapy is generally well tolerated,” the ESTRO authors concluded but added that CDK4/6 inhibitors and concomitant radiotherapy should be investigated more in the adjuvant locoregional, whole brain, and intracranial stereotactic radiotherapy settings.

The expert panel did note, however, that CDK4/6 inhibitors and concomitant radiotherapy “could be offered” during palliative and ablative extracranial radiotherapy.

3. Only offer poly (ADP-ribose) polymerase (PARP) inhibitors plus radiotherapy in clinical trial setting

PARP inhibitors olaparib (Lynparza) and talazoprib (Talzenna) are standard of care in patients with metastatic breast cancer who have BRCA1/2 gene mutations. Olaparib is also indicated for high-risk early breast cancer following neoadjuvant or adjuvant chemotherapy.

But data on combining PARP inhibitors with radiotherapy in breast cancer also remain limited.

One ongoing phase 2 trial, comparing olaparib plus radiotherapy to radiotherapy alone in 300 people with inflammatory breast cancer, is aiming to tease out the safety of the combination and whether it improves local control in patients with aggressive disease.

“The desire is to explore the exciting possibility that low doses of PARP inhibition may radiosensitize tumor cells more than normal tissues,” Reshma Jagsi, MD, chair of the Department of Radiation Oncology at Emory University School of Medicine in Atlanta, Georgia, who is leading the study.

Because of potential good or bad interactions between new systemic therapies and radiotherapy, “intentional trial design” is important, Dr. Jagsi said, so we “know the best way to combine treatments in practice to optimize outcomes.”

But given the evidence to date, the ESTRO experts advised waiting until “further research provides more comprehensive safety and efficacy data” in the primary, adjuvant, and metastatic settings. The experts also advised not offering PARP inhibitors and concomitant radiotherapy to treat advanced breast cancer outside of clinical trials.

4. Phosphoinositide 3-kinase inhibitors (PI3K) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and newer targeted agents should not be offered concurrently with radiotherapy

Clinical trial data on the safety of combining PI3K and mTOR inhibitors with radiation are thin, especially in advanced breast cancer. Typically, radiotherapy within 4 weeks before randomization, or 2 weeks for palliative radiation, was excluded in pivotal trials.

For this reason, the ESTRO team recommended that concurrent radiation with either PI3K inhibitors or mTOR inhibitors “should not be offered.”

ESTRO also cautioned against providing radiation concurrently with newer anti-HER2 tyrosine-kinase drugs, such as neratinib or tucatinib, or newer antibody-drug conjugates such as trastuzumab deruxtecan, until more data emerge on the safety of these combinations.

5. Combining older HER2-targeted drugs and radiotherapy generally safe

The ESTRO authors agreed that older anti-HER2 drugs trastuzumab (Herceptin), pertuzumab (Perjeta), and lapatinib (Tykerb) can be safely used concurrently with locoregional radiotherapy as well.

One of the biggest concerns in the field is how to combine radiation with systemic therapies in the setting of brain metastases, and the data on these older anti-HER2 drugs are relatively clear that it’s safe, Dr. Miller said.

For instance, in a 2019 study of 84 patients with 487 brain metastases, stereotactic radiosurgery given alongside lapatinib led to significantly higher rates of complete responses than stereotactic radiosurgery alone (35% vs 11%) with no increased risk for radiation necrosis.

The ESTRO team agreed, noting that the latest evidence supports the use of trastuzumab, pertuzumab, or lapatinib alongside radiotherapy for whole brain and ablative intracranial stereotactic radiotherapy.

As for older antibody-drug conjugates, trastuzumab emtansine (T-DM1) plus radiotherapy “might be considered” during adjuvant locoregional radiotherapy for breast cancer but should not be offered for whole brain and ablative intracranial stereotactic radiotherapy, the ESTRO team said.

Dr. Jagsi declared the following conflicts in a recent 2024 publication: Stock options for advisory board role in Equity Quotient; grants or contracts from Genentech; and expert witness for Kleinbard, LLC, and Hawks Quindel Law. In the Keynote-522 trial publication Dr. Schmid declared relationships with AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Hoffmann-La Roche, Genetech, Merck, Novartis, and Pfizer. Dr. Shah reported consulting for Impedimed, Videra Surgical, and PreludeDX.

A version of this article appeared on Medscape.com.

Targeted treatments, including antibody-drug conjugates and immunotherapy agents, are now standard of care for breast cancer, but there are limited data on the safety of combining these newer agents alongside radiotherapy.

One reason is studies of new drugs typically exclude concurrent radiotherapy, said Kathy Miller, MD, a contributor to this news organization and professor of oncology and medicine at the Indiana University School of Medicine, Indianapolis, Indiana.

If trials evaluating new targeted therapies included concurrent radiotherapy, it would be challenging to identify whether toxicities came from the drug itself, the radiation, or the combination, Dr. Miller explained.

Given the limited evidence, “we tend to be cautious and conservative” and not combine therapies that “we don’t know are safe or appropriate for patients,” said Chirag Shah, MD, director of breast radiology at the Cleveland Clinic, Cleveland, Ohio.

Below is a guide to what we do and don’t know about combining radiotherapy and systemic treatments in breast cancer.

1. Immunotherapy plus radiotherapy likely safe but evidence is limited

Safety data on combining immune checkpoint inhibitors and radiotherapy in breast cancer are limited because concurrent radiotherapy has typically been excluded in pivotal trials.

The 2020 KEYNOTE-522 trial did provide a rare look at concurrent radiotherapy and immunotherapy in early triple-negative breast cancer. The analysis found “no safety concerns” with concurrent radiotherapy and pembrolizumab, lead investigator Peter Schmid, MD, of Queen Mary University of London, England, told this news organization.

Research on other solid tumor types also suggests that radiotherapy “can be considered safe” alongside immunotherapy, the authors of a recent ESTRO consensus said.

Despite evidence indicating radiotherapy alongside immunotherapy can be safe in patients with breast cancer, “certain aspects, such as patient selection, total dose, and dose per fraction, remain open for debate to achieve the best therapeutic outcomes,” the ESTRO experts cautioned.

2. CDK4/6 inhibitors may be offered with radiotherapy in some settings, not others

CDK4/6 inhibitors are now standard of care for first- or second-line treatment in patients with advanced or metastatic hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer.

“Unfortunately, we found no information regarding concurrent radiotherapy in the adjuvant setting” in pivotal trials for palbociclib, abemaciclib, and ribociclib, the ESTRO authors said. In the pivotal trials for palbociclib and abemaciclib, patients had to discontinue immunotherapy before initiating radiotherapy, and in the trial for ribociclib, palliative radiotherapy was allowed for relieving bone pain only.

However, in 2023, a team of experts from 12 countries attempted to piece together the available evidence, publishing a meta-analysis of 11 retrospective studies on the safety of CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic disease.

Although most of these studies had small patient populations, the analysis revealed that CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic breast cancer led to a similar side-effect profile to that observed in trials of the inhibitors given sequentially with adjuvant radiotherapy.

“These findings suggest that the simultaneous administration of CDK4/6 inhibitors and radiotherapy is generally well tolerated,” the ESTRO authors concluded but added that CDK4/6 inhibitors and concomitant radiotherapy should be investigated more in the adjuvant locoregional, whole brain, and intracranial stereotactic radiotherapy settings.

The expert panel did note, however, that CDK4/6 inhibitors and concomitant radiotherapy “could be offered” during palliative and ablative extracranial radiotherapy.

3. Only offer poly (ADP-ribose) polymerase (PARP) inhibitors plus radiotherapy in clinical trial setting

PARP inhibitors olaparib (Lynparza) and talazoprib (Talzenna) are standard of care in patients with metastatic breast cancer who have BRCA1/2 gene mutations. Olaparib is also indicated for high-risk early breast cancer following neoadjuvant or adjuvant chemotherapy.

But data on combining PARP inhibitors with radiotherapy in breast cancer also remain limited.

One ongoing phase 2 trial, comparing olaparib plus radiotherapy to radiotherapy alone in 300 people with inflammatory breast cancer, is aiming to tease out the safety of the combination and whether it improves local control in patients with aggressive disease.

“The desire is to explore the exciting possibility that low doses of PARP inhibition may radiosensitize tumor cells more than normal tissues,” Reshma Jagsi, MD, chair of the Department of Radiation Oncology at Emory University School of Medicine in Atlanta, Georgia, who is leading the study.

Because of potential good or bad interactions between new systemic therapies and radiotherapy, “intentional trial design” is important, Dr. Jagsi said, so we “know the best way to combine treatments in practice to optimize outcomes.”

But given the evidence to date, the ESTRO experts advised waiting until “further research provides more comprehensive safety and efficacy data” in the primary, adjuvant, and metastatic settings. The experts also advised not offering PARP inhibitors and concomitant radiotherapy to treat advanced breast cancer outside of clinical trials.

4. Phosphoinositide 3-kinase inhibitors (PI3K) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and newer targeted agents should not be offered concurrently with radiotherapy

Clinical trial data on the safety of combining PI3K and mTOR inhibitors with radiation are thin, especially in advanced breast cancer. Typically, radiotherapy within 4 weeks before randomization, or 2 weeks for palliative radiation, was excluded in pivotal trials.

For this reason, the ESTRO team recommended that concurrent radiation with either PI3K inhibitors or mTOR inhibitors “should not be offered.”

ESTRO also cautioned against providing radiation concurrently with newer anti-HER2 tyrosine-kinase drugs, such as neratinib or tucatinib, or newer antibody-drug conjugates such as trastuzumab deruxtecan, until more data emerge on the safety of these combinations.

5. Combining older HER2-targeted drugs and radiotherapy generally safe

The ESTRO authors agreed that older anti-HER2 drugs trastuzumab (Herceptin), pertuzumab (Perjeta), and lapatinib (Tykerb) can be safely used concurrently with locoregional radiotherapy as well.

One of the biggest concerns in the field is how to combine radiation with systemic therapies in the setting of brain metastases, and the data on these older anti-HER2 drugs are relatively clear that it’s safe, Dr. Miller said.

For instance, in a 2019 study of 84 patients with 487 brain metastases, stereotactic radiosurgery given alongside lapatinib led to significantly higher rates of complete responses than stereotactic radiosurgery alone (35% vs 11%) with no increased risk for radiation necrosis.

The ESTRO team agreed, noting that the latest evidence supports the use of trastuzumab, pertuzumab, or lapatinib alongside radiotherapy for whole brain and ablative intracranial stereotactic radiotherapy.

As for older antibody-drug conjugates, trastuzumab emtansine (T-DM1) plus radiotherapy “might be considered” during adjuvant locoregional radiotherapy for breast cancer but should not be offered for whole brain and ablative intracranial stereotactic radiotherapy, the ESTRO team said.

Dr. Jagsi declared the following conflicts in a recent 2024 publication: Stock options for advisory board role in Equity Quotient; grants or contracts from Genentech; and expert witness for Kleinbard, LLC, and Hawks Quindel Law. In the Keynote-522 trial publication Dr. Schmid declared relationships with AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Hoffmann-La Roche, Genetech, Merck, Novartis, and Pfizer. Dr. Shah reported consulting for Impedimed, Videra Surgical, and PreludeDX.

A version of this article appeared on Medscape.com.

A wise medical precept is attributed to Theodore Woodward, MD (1914-2005): “When you hear hoofbeats, think of horses, not zebras.” Primary care pediatricians, however, often find themselves confronting so-called rare or uncommon diseases (“zebras”) in their offices. The pressing challenge is to know when to suspect them. How can one reconcile the need to dispel uncertainty with the use of diagnostic tests that can be costly and invasive? When can the desire to reassure parents mean delaying the detection of a potentially treatable condition?

“It may seem like wordplay, but it’s not uncommon to have a rare disease,” noted Alejandro Fainboim, MD, a specialist in rare diseases and head of the Multivalent Day Hospital at the Ricardo Gutiérrez Children’s Hospital in Buenos Aires, Argentina. “And pediatricians are the first line of defense in detecting these types of pathologies. To make the diagnosis, we have to consider them. And to consider them, we must be knowledgeable. That’s why sometimes, ignorance slows down the diagnosis,” Dr. Fainboim made his remarks during an online seminar organized for the press on the eve of Rare Disease Day, which is commemorated on February 29th.

There are more than 8000 rare diseases, which generally are defined as those affecting fewer than five people per 10,000. But collectively, one in every 13 people has one of these diseases, and one in every two diagnosed patients is a child. Dr. Fainboim emphasized that most of these rare diseases are severe or very severe, hereditary, degenerative, and potentially fatal. And although they are pediatric pathologies, some manifest later in adulthood.

“The major problem we pediatricians face is that we’re handed a model from adults to solve pediatric diseases. So, signs and symptoms are described that we won’t find early on, but we have to anticipate and learn to decode some that are hidden,” he remarked.

Diagnostic delays and repeated consultations with various doctors before identification are common. Dr. Fainboim added that in industrialized countries, the diagnosis of these diseases takes between 5 and 10 years, and in low-income countries, up to 30 years or more. However, “this has improved significantly in recent years,” he said.
 

Unnoticed Signs

Specialists who treat patients with rare diseases often feel that there were obvious signs that went unnoticed and should have aroused the suspicion of the primary care physician. An example is paroxysmal nocturnal hemoglobinuria, which affects 13-14 people per million inhabitants and can appear at any age, although the incidence is higher in the third decade of life.

“In my 50 years as a doctor, I’ve seen seven or eight patients with paroxysmal nocturnal hemoglobinuria,” said Elsa Nucifora, MD, a hematologist at the Italian Hospital of Buenos Aires, Argentina. But “the diagnosis is so easy” that doctors could make it if they “were to think instead of acting automatically because they’re in a hurry,” she added. The diagnosis should be considered “every time anemia occurs in a young person, with certain characteristics, instead of giving them iron like everyone else and ‘we’ll see later’…the diagnosis is in two or three steps, so it’s not complicated.”

Similar situations occur with more than 1000 neuromuscular diseases involving mutations in more than 600 genes, including spinal muscular atrophy and muscular dystrophies.

“What are the most common manifestations? The hypotonic infant, the child who walks late, who falls frequently, who can’t climb stairs, who later may have difficulty breathing, who loses strength: These are presentations often unrecognized by doctors not in the specialty,” said Alberto Dubrovsky, MD, director of the Department of Neurology and the Neuromuscular Diseases Unit at the Favaloro University Neuroscience Institute in Buenos Aires, Argentina, during the seminar. “And considering that these diseases are diagnosed based on genetic mutations that need to be known to search for and request them, we are faced with a truly complex scenario that requires subspecialization.”

In a study recently published in the Argentine Archives of Pediatrics, Dr. Dubrovsky and colleagues interviewed 112 families of Argentine patients with molecular diagnoses of spinal muscular atrophy types I, II, and III and found that in 75%-85% of cases, the first signs of the disease (such as hypotonia, developmental delay, inability to achieve bipedal standing, or frequent falls) were recognized by parents. For type I, the most severe and early onset, in only 17.5% of cases did a neonatologist or pediatrician first notice something. Of the 72 patients with types II and III, where routine checks are less frequent than in the first months of life, only one doctor detected the first signs of the disease before parents or other relatives.

In the same study, the median time elapsed between the first sign and confirmed molecular diagnosis was 2, 10, and 31.5 months for types I, II, and III, respectively. The delay “is primarily due to the lack of clinical suspicion on the part of the intervening physician, who often dismisses or misinterprets the signs reported by parents, as reflected in the alternative diagnoses invoked,” the authors wrote.

“I don’t even ask for suspicion of a specific rare disease because that requires specialization. What I ask for is a kind of recognition or realization that something is happening and then request a consultation with the specialist to ensure proper care,” said Dr. Dubrovsky.

In another study conducted among 70 Argentine patients under age 13 years who were diagnosed with Duchenne muscular dystrophy (one of the most severe forms of muscular dystrophy), 82% of the pediatricians who were initially consulted for any problem in motor agility that parents, other relatives, or teachers had detected dismissed the observation. “They’re told to wait, that it will mature a little more,” said Dr. Dubrovsky. This explains why the time to diagnosis in Argentina from the first signs is around 2 years. The delays are unfortunate because “today we have treatments capable of interfering with the disease’s progression slope, reducing its progression, or eventually stopping it,” he said.

“Do you mind that primary care pediatricians don’t notice or dismiss signs and symptoms strongly suggestive of one of these rare diseases? Does it frustrate you?” this news organization asked asked Dr. Dubrovsky. “Sometimes it does make me angry, but many times it’s understood that there can’t be highly trained specialists everywhere to realize and request diagnostic tests. One must consider the circumstances in each case, and that’s why we work in education,” he replied.
 

Rules and Experience

In an interview, Dr. Fainboim highlighted key factors that should prompt a pediatrician’s suspicion. One is common symptoms expressed in a more intense or complicated way or when many symptoms coexist in the same patient, even if each one separately is benign or not so severe.

Dr. Fainboim also recommended establishing a therapeutic alliance with parents. “We shouldn’t undermine what parents say, especially those who have other children and already know what normal child development is like. This is a very important milestone.

“We have to strengthen the suspicion clue, and for that, we rely on standards and our experience, which we keep refining. As Wilde said, experience is the sum of our mistakes. But there’s no universal answer. Not all families are the same. Not all diseases manifest in the same way. And unless there’s an imminent risk to life or function, one can wait and take the time to evaluate it. For example, if I have a child with slowed developmental milestones, what I have to do is teach how to stimulate them or send them for stimulation with another professional. And I observe the response to this initial basic treatment. If I see no response, the alarms start to grow louder,” said Dr. Fainboim.

Pablo Barvosa, MD, the principal physician in the outpatient area of the Juan P. Garrahan Pediatric Hospital in Buenos Aires, Argentina, and a member of the Working Group on Genetics and Rare Diseases of the Argentine Society of Pediatrics, told this news organization about other factors that should be considered for detecting these pathologies. Dr. Barvosa did not participate in the online seminar.

“Patients with rare diseases have common symptoms. What needs to be done is to prioritize those symptoms that behave abnormally, that have an unusual evolution compared with normal situations. For example, children who go into a coma after a fasting episode or after eating a certain food,” he said.

Dr. Barvosa also suggested considering when patients belong to certain communities where there is a lot of endogamy, due to the higher incidence of hereditary diseases. “Attention should be heightened when parents are cousins or relatives,” he pointed out.

“My view is that doctors should think more and better, be rational, sequential. If a disease is treated and resolved, but we find out that the child had 26 previous hospitalizations in the last 2 years, something is wrong. We have to look at the patient’s and family’s life histories. If a mother had 15 miscarriages, that’s a warning sign. We have to find a common thread. Be a sharp-witted pediatrician,” said Dr. Barvosa.

The suspicion and diagnosis of a rare disease can be devastating for families and painful for the professional, but even if there is no specific treatment, “something can always be done for patients,” he added.

And in certain circumstances, identifying a rare disease can reverse the ominous “stamp” of a wrong diagnosis. Dr. Barvosa commented on the case of a 7-year-old boy he attended at the hospital in 2014. The boy presented as quadriplegic, with no mobility in his limbs, and the parents were convinced he had that condition because he had fallen from the roof of the house. Although imaging techniques did not show a spinal injury, it was assumed to be a case of spinal cord injury without radiographic abnormality. But something caught Dr. Barvosa’s attention: The boy had well-developed abdominal muscles, as if he were an athlete. So, he requested an electromyogram, and the muscle was found to be in permanent contraction.

“The patient didn’t have a spinal cord injury: He had Isaacs’ syndrome,” said Dr. Barvosa. The syndrome also is known as acquired neuromyotonia, a rare condition of hyperexcitability of peripheral nerves that activate muscle fibers. “That is treated with anticonvulsants, such as phenytoin. Within a week, he was walking again, and shortly after, he was playing soccer. When I presented the case at a conference, I cried with emotion. That’s why the pediatrician must be insistent, be like the gadfly that stings in the ear” when there are clinical elements that don’t quite fit into a clear diagnosis, he added.

In recent publications, Dr. Dubrovsky has reported receiving fees for consultations or research from PTC, Sarepta, Biogen, Sanofi Genzyme, Takeda Avexis, Novartis, Raffo, and Roche. Dr. Nucifora has received fees from Jansen LATAM. Dr. Fainboim reported receiving fees from Sanofi. Dr. Barvosa has declared no relevant financial conflicts of interest. The webinar was organized by Urban Comunicaciones.
 

This story was translated from the Medscape Spanish edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

A wise medical precept is attributed to Theodore Woodward, MD (1914-2005): “When you hear hoofbeats, think of horses, not zebras.” Primary care pediatricians, however, often find themselves confronting so-called rare or uncommon diseases (“zebras”) in their offices. The pressing challenge is to know when to suspect them. How can one reconcile the need to dispel uncertainty with the use of diagnostic tests that can be costly and invasive? When can the desire to reassure parents mean delaying the detection of a potentially treatable condition?

“It may seem like wordplay, but it’s not uncommon to have a rare disease,” noted Alejandro Fainboim, MD, a specialist in rare diseases and head of the Multivalent Day Hospital at the Ricardo Gutiérrez Children’s Hospital in Buenos Aires, Argentina. “And pediatricians are the first line of defense in detecting these types of pathologies. To make the diagnosis, we have to consider them. And to consider them, we must be knowledgeable. That’s why sometimes, ignorance slows down the diagnosis,” Dr. Fainboim made his remarks during an online seminar organized for the press on the eve of Rare Disease Day, which is commemorated on February 29th.

There are more than 8000 rare diseases, which generally are defined as those affecting fewer than five people per 10,000. But collectively, one in every 13 people has one of these diseases, and one in every two diagnosed patients is a child. Dr. Fainboim emphasized that most of these rare diseases are severe or very severe, hereditary, degenerative, and potentially fatal. And although they are pediatric pathologies, some manifest later in adulthood.

“The major problem we pediatricians face is that we’re handed a model from adults to solve pediatric diseases. So, signs and symptoms are described that we won’t find early on, but we have to anticipate and learn to decode some that are hidden,” he remarked.

Diagnostic delays and repeated consultations with various doctors before identification are common. Dr. Fainboim added that in industrialized countries, the diagnosis of these diseases takes between 5 and 10 years, and in low-income countries, up to 30 years or more. However, “this has improved significantly in recent years,” he said.
 

Unnoticed Signs

Specialists who treat patients with rare diseases often feel that there were obvious signs that went unnoticed and should have aroused the suspicion of the primary care physician. An example is paroxysmal nocturnal hemoglobinuria, which affects 13-14 people per million inhabitants and can appear at any age, although the incidence is higher in the third decade of life.

“In my 50 years as a doctor, I’ve seen seven or eight patients with paroxysmal nocturnal hemoglobinuria,” said Elsa Nucifora, MD, a hematologist at the Italian Hospital of Buenos Aires, Argentina. But “the diagnosis is so easy” that doctors could make it if they “were to think instead of acting automatically because they’re in a hurry,” she added. The diagnosis should be considered “every time anemia occurs in a young person, with certain characteristics, instead of giving them iron like everyone else and ‘we’ll see later’…the diagnosis is in two or three steps, so it’s not complicated.”

Similar situations occur with more than 1000 neuromuscular diseases involving mutations in more than 600 genes, including spinal muscular atrophy and muscular dystrophies.

“What are the most common manifestations? The hypotonic infant, the child who walks late, who falls frequently, who can’t climb stairs, who later may have difficulty breathing, who loses strength: These are presentations often unrecognized by doctors not in the specialty,” said Alberto Dubrovsky, MD, director of the Department of Neurology and the Neuromuscular Diseases Unit at the Favaloro University Neuroscience Institute in Buenos Aires, Argentina, during the seminar. “And considering that these diseases are diagnosed based on genetic mutations that need to be known to search for and request them, we are faced with a truly complex scenario that requires subspecialization.”

In a study recently published in the Argentine Archives of Pediatrics, Dr. Dubrovsky and colleagues interviewed 112 families of Argentine patients with molecular diagnoses of spinal muscular atrophy types I, II, and III and found that in 75%-85% of cases, the first signs of the disease (such as hypotonia, developmental delay, inability to achieve bipedal standing, or frequent falls) were recognized by parents. For type I, the most severe and early onset, in only 17.5% of cases did a neonatologist or pediatrician first notice something. Of the 72 patients with types II and III, where routine checks are less frequent than in the first months of life, only one doctor detected the first signs of the disease before parents or other relatives.

In the same study, the median time elapsed between the first sign and confirmed molecular diagnosis was 2, 10, and 31.5 months for types I, II, and III, respectively. The delay “is primarily due to the lack of clinical suspicion on the part of the intervening physician, who often dismisses or misinterprets the signs reported by parents, as reflected in the alternative diagnoses invoked,” the authors wrote.

“I don’t even ask for suspicion of a specific rare disease because that requires specialization. What I ask for is a kind of recognition or realization that something is happening and then request a consultation with the specialist to ensure proper care,” said Dr. Dubrovsky.

In another study conducted among 70 Argentine patients under age 13 years who were diagnosed with Duchenne muscular dystrophy (one of the most severe forms of muscular dystrophy), 82% of the pediatricians who were initially consulted for any problem in motor agility that parents, other relatives, or teachers had detected dismissed the observation. “They’re told to wait, that it will mature a little more,” said Dr. Dubrovsky. This explains why the time to diagnosis in Argentina from the first signs is around 2 years. The delays are unfortunate because “today we have treatments capable of interfering with the disease’s progression slope, reducing its progression, or eventually stopping it,” he said.

“Do you mind that primary care pediatricians don’t notice or dismiss signs and symptoms strongly suggestive of one of these rare diseases? Does it frustrate you?” this news organization asked asked Dr. Dubrovsky. “Sometimes it does make me angry, but many times it’s understood that there can’t be highly trained specialists everywhere to realize and request diagnostic tests. One must consider the circumstances in each case, and that’s why we work in education,” he replied.
 

Rules and Experience

In an interview, Dr. Fainboim highlighted key factors that should prompt a pediatrician’s suspicion. One is common symptoms expressed in a more intense or complicated way or when many symptoms coexist in the same patient, even if each one separately is benign or not so severe.

Dr. Fainboim also recommended establishing a therapeutic alliance with parents. “We shouldn’t undermine what parents say, especially those who have other children and already know what normal child development is like. This is a very important milestone.

“We have to strengthen the suspicion clue, and for that, we rely on standards and our experience, which we keep refining. As Wilde said, experience is the sum of our mistakes. But there’s no universal answer. Not all families are the same. Not all diseases manifest in the same way. And unless there’s an imminent risk to life or function, one can wait and take the time to evaluate it. For example, if I have a child with slowed developmental milestones, what I have to do is teach how to stimulate them or send them for stimulation with another professional. And I observe the response to this initial basic treatment. If I see no response, the alarms start to grow louder,” said Dr. Fainboim.

Pablo Barvosa, MD, the principal physician in the outpatient area of the Juan P. Garrahan Pediatric Hospital in Buenos Aires, Argentina, and a member of the Working Group on Genetics and Rare Diseases of the Argentine Society of Pediatrics, told this news organization about other factors that should be considered for detecting these pathologies. Dr. Barvosa did not participate in the online seminar.

“Patients with rare diseases have common symptoms. What needs to be done is to prioritize those symptoms that behave abnormally, that have an unusual evolution compared with normal situations. For example, children who go into a coma after a fasting episode or after eating a certain food,” he said.

Dr. Barvosa also suggested considering when patients belong to certain communities where there is a lot of endogamy, due to the higher incidence of hereditary diseases. “Attention should be heightened when parents are cousins or relatives,” he pointed out.

“My view is that doctors should think more and better, be rational, sequential. If a disease is treated and resolved, but we find out that the child had 26 previous hospitalizations in the last 2 years, something is wrong. We have to look at the patient’s and family’s life histories. If a mother had 15 miscarriages, that’s a warning sign. We have to find a common thread. Be a sharp-witted pediatrician,” said Dr. Barvosa.

The suspicion and diagnosis of a rare disease can be devastating for families and painful for the professional, but even if there is no specific treatment, “something can always be done for patients,” he added.

And in certain circumstances, identifying a rare disease can reverse the ominous “stamp” of a wrong diagnosis. Dr. Barvosa commented on the case of a 7-year-old boy he attended at the hospital in 2014. The boy presented as quadriplegic, with no mobility in his limbs, and the parents were convinced he had that condition because he had fallen from the roof of the house. Although imaging techniques did not show a spinal injury, it was assumed to be a case of spinal cord injury without radiographic abnormality. But something caught Dr. Barvosa’s attention: The boy had well-developed abdominal muscles, as if he were an athlete. So, he requested an electromyogram, and the muscle was found to be in permanent contraction.

“The patient didn’t have a spinal cord injury: He had Isaacs’ syndrome,” said Dr. Barvosa. The syndrome also is known as acquired neuromyotonia, a rare condition of hyperexcitability of peripheral nerves that activate muscle fibers. “That is treated with anticonvulsants, such as phenytoin. Within a week, he was walking again, and shortly after, he was playing soccer. When I presented the case at a conference, I cried with emotion. That’s why the pediatrician must be insistent, be like the gadfly that stings in the ear” when there are clinical elements that don’t quite fit into a clear diagnosis, he added.

In recent publications, Dr. Dubrovsky has reported receiving fees for consultations or research from PTC, Sarepta, Biogen, Sanofi Genzyme, Takeda Avexis, Novartis, Raffo, and Roche. Dr. Nucifora has received fees from Jansen LATAM. Dr. Fainboim reported receiving fees from Sanofi. Dr. Barvosa has declared no relevant financial conflicts of interest. The webinar was organized by Urban Comunicaciones.
 

This story was translated from the Medscape Spanish edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

A wise medical precept is attributed to Theodore Woodward, MD (1914-2005): “When you hear hoofbeats, think of horses, not zebras.” Primary care pediatricians, however, often find themselves confronting so-called rare or uncommon diseases (“zebras”) in their offices. The pressing challenge is to know when to suspect them. How can one reconcile the need to dispel uncertainty with the use of diagnostic tests that can be costly and invasive? When can the desire to reassure parents mean delaying the detection of a potentially treatable condition?

“It may seem like wordplay, but it’s not uncommon to have a rare disease,” noted Alejandro Fainboim, MD, a specialist in rare diseases and head of the Multivalent Day Hospital at the Ricardo Gutiérrez Children’s Hospital in Buenos Aires, Argentina. “And pediatricians are the first line of defense in detecting these types of pathologies. To make the diagnosis, we have to consider them. And to consider them, we must be knowledgeable. That’s why sometimes, ignorance slows down the diagnosis,” Dr. Fainboim made his remarks during an online seminar organized for the press on the eve of Rare Disease Day, which is commemorated on February 29th.

There are more than 8000 rare diseases, which generally are defined as those affecting fewer than five people per 10,000. But collectively, one in every 13 people has one of these diseases, and one in every two diagnosed patients is a child. Dr. Fainboim emphasized that most of these rare diseases are severe or very severe, hereditary, degenerative, and potentially fatal. And although they are pediatric pathologies, some manifest later in adulthood.

“The major problem we pediatricians face is that we’re handed a model from adults to solve pediatric diseases. So, signs and symptoms are described that we won’t find early on, but we have to anticipate and learn to decode some that are hidden,” he remarked.

Diagnostic delays and repeated consultations with various doctors before identification are common. Dr. Fainboim added that in industrialized countries, the diagnosis of these diseases takes between 5 and 10 years, and in low-income countries, up to 30 years or more. However, “this has improved significantly in recent years,” he said.
 

Unnoticed Signs

Specialists who treat patients with rare diseases often feel that there were obvious signs that went unnoticed and should have aroused the suspicion of the primary care physician. An example is paroxysmal nocturnal hemoglobinuria, which affects 13-14 people per million inhabitants and can appear at any age, although the incidence is higher in the third decade of life.

“In my 50 years as a doctor, I’ve seen seven or eight patients with paroxysmal nocturnal hemoglobinuria,” said Elsa Nucifora, MD, a hematologist at the Italian Hospital of Buenos Aires, Argentina. But “the diagnosis is so easy” that doctors could make it if they “were to think instead of acting automatically because they’re in a hurry,” she added. The diagnosis should be considered “every time anemia occurs in a young person, with certain characteristics, instead of giving them iron like everyone else and ‘we’ll see later’…the diagnosis is in two or three steps, so it’s not complicated.”

Similar situations occur with more than 1000 neuromuscular diseases involving mutations in more than 600 genes, including spinal muscular atrophy and muscular dystrophies.

“What are the most common manifestations? The hypotonic infant, the child who walks late, who falls frequently, who can’t climb stairs, who later may have difficulty breathing, who loses strength: These are presentations often unrecognized by doctors not in the specialty,” said Alberto Dubrovsky, MD, director of the Department of Neurology and the Neuromuscular Diseases Unit at the Favaloro University Neuroscience Institute in Buenos Aires, Argentina, during the seminar. “And considering that these diseases are diagnosed based on genetic mutations that need to be known to search for and request them, we are faced with a truly complex scenario that requires subspecialization.”

In a study recently published in the Argentine Archives of Pediatrics, Dr. Dubrovsky and colleagues interviewed 112 families of Argentine patients with molecular diagnoses of spinal muscular atrophy types I, II, and III and found that in 75%-85% of cases, the first signs of the disease (such as hypotonia, developmental delay, inability to achieve bipedal standing, or frequent falls) were recognized by parents. For type I, the most severe and early onset, in only 17.5% of cases did a neonatologist or pediatrician first notice something. Of the 72 patients with types II and III, where routine checks are less frequent than in the first months of life, only one doctor detected the first signs of the disease before parents or other relatives.

In the same study, the median time elapsed between the first sign and confirmed molecular diagnosis was 2, 10, and 31.5 months for types I, II, and III, respectively. The delay “is primarily due to the lack of clinical suspicion on the part of the intervening physician, who often dismisses or misinterprets the signs reported by parents, as reflected in the alternative diagnoses invoked,” the authors wrote.

“I don’t even ask for suspicion of a specific rare disease because that requires specialization. What I ask for is a kind of recognition or realization that something is happening and then request a consultation with the specialist to ensure proper care,” said Dr. Dubrovsky.

In another study conducted among 70 Argentine patients under age 13 years who were diagnosed with Duchenne muscular dystrophy (one of the most severe forms of muscular dystrophy), 82% of the pediatricians who were initially consulted for any problem in motor agility that parents, other relatives, or teachers had detected dismissed the observation. “They’re told to wait, that it will mature a little more,” said Dr. Dubrovsky. This explains why the time to diagnosis in Argentina from the first signs is around 2 years. The delays are unfortunate because “today we have treatments capable of interfering with the disease’s progression slope, reducing its progression, or eventually stopping it,” he said.

“Do you mind that primary care pediatricians don’t notice or dismiss signs and symptoms strongly suggestive of one of these rare diseases? Does it frustrate you?” this news organization asked asked Dr. Dubrovsky. “Sometimes it does make me angry, but many times it’s understood that there can’t be highly trained specialists everywhere to realize and request diagnostic tests. One must consider the circumstances in each case, and that’s why we work in education,” he replied.
 

Rules and Experience

In an interview, Dr. Fainboim highlighted key factors that should prompt a pediatrician’s suspicion. One is common symptoms expressed in a more intense or complicated way or when many symptoms coexist in the same patient, even if each one separately is benign or not so severe.

Dr. Fainboim also recommended establishing a therapeutic alliance with parents. “We shouldn’t undermine what parents say, especially those who have other children and already know what normal child development is like. This is a very important milestone.

“We have to strengthen the suspicion clue, and for that, we rely on standards and our experience, which we keep refining. As Wilde said, experience is the sum of our mistakes. But there’s no universal answer. Not all families are the same. Not all diseases manifest in the same way. And unless there’s an imminent risk to life or function, one can wait and take the time to evaluate it. For example, if I have a child with slowed developmental milestones, what I have to do is teach how to stimulate them or send them for stimulation with another professional. And I observe the response to this initial basic treatment. If I see no response, the alarms start to grow louder,” said Dr. Fainboim.

Pablo Barvosa, MD, the principal physician in the outpatient area of the Juan P. Garrahan Pediatric Hospital in Buenos Aires, Argentina, and a member of the Working Group on Genetics and Rare Diseases of the Argentine Society of Pediatrics, told this news organization about other factors that should be considered for detecting these pathologies. Dr. Barvosa did not participate in the online seminar.

“Patients with rare diseases have common symptoms. What needs to be done is to prioritize those symptoms that behave abnormally, that have an unusual evolution compared with normal situations. For example, children who go into a coma after a fasting episode or after eating a certain food,” he said.

Dr. Barvosa also suggested considering when patients belong to certain communities where there is a lot of endogamy, due to the higher incidence of hereditary diseases. “Attention should be heightened when parents are cousins or relatives,” he pointed out.

“My view is that doctors should think more and better, be rational, sequential. If a disease is treated and resolved, but we find out that the child had 26 previous hospitalizations in the last 2 years, something is wrong. We have to look at the patient’s and family’s life histories. If a mother had 15 miscarriages, that’s a warning sign. We have to find a common thread. Be a sharp-witted pediatrician,” said Dr. Barvosa.

The suspicion and diagnosis of a rare disease can be devastating for families and painful for the professional, but even if there is no specific treatment, “something can always be done for patients,” he added.

And in certain circumstances, identifying a rare disease can reverse the ominous “stamp” of a wrong diagnosis. Dr. Barvosa commented on the case of a 7-year-old boy he attended at the hospital in 2014. The boy presented as quadriplegic, with no mobility in his limbs, and the parents were convinced he had that condition because he had fallen from the roof of the house. Although imaging techniques did not show a spinal injury, it was assumed to be a case of spinal cord injury without radiographic abnormality. But something caught Dr. Barvosa’s attention: The boy had well-developed abdominal muscles, as if he were an athlete. So, he requested an electromyogram, and the muscle was found to be in permanent contraction.

“The patient didn’t have a spinal cord injury: He had Isaacs’ syndrome,” said Dr. Barvosa. The syndrome also is known as acquired neuromyotonia, a rare condition of hyperexcitability of peripheral nerves that activate muscle fibers. “That is treated with anticonvulsants, such as phenytoin. Within a week, he was walking again, and shortly after, he was playing soccer. When I presented the case at a conference, I cried with emotion. That’s why the pediatrician must be insistent, be like the gadfly that stings in the ear” when there are clinical elements that don’t quite fit into a clear diagnosis, he added.

In recent publications, Dr. Dubrovsky has reported receiving fees for consultations or research from PTC, Sarepta, Biogen, Sanofi Genzyme, Takeda Avexis, Novartis, Raffo, and Roche. Dr. Nucifora has received fees from Jansen LATAM. Dr. Fainboim reported receiving fees from Sanofi. Dr. Barvosa has declared no relevant financial conflicts of interest. The webinar was organized by Urban Comunicaciones.
 

This story was translated from the Medscape Spanish edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

While the increased risk of cancer in patients with metabolic syndrome is well established by research, the authors of a new study delve deeper by examining metabolic syndrome trajectories.

The new research finds that adults with persistent metabolic syndrome that worsens over time are at increased risk for any type of cancer.

The conditions that make up metabolic syndrome (high blood pressure, high blood sugar, increased abdominal adiposity, and high cholesterol and triglycerides) have been associated with an increased risk of diseases, including heart disease, stroke, and type 2 diabetes, wrote Li Deng, PhD, of Capital Medical University, Beijing, and colleagues.

However, a single assessment of metabolic syndrome at one point in time is inadequate to show an association with cancer risk over time, they said. In the current study, the researchers used models to examine the association between trajectory patterns of metabolic syndrome over time and the risk of overall and specific cancer types. They also examined the impact of chronic inflammation concurrent with metabolic syndrome.
 

What We Know About Metabolic Syndrome and Cancer Risk

A systematic review and meta-analysis published in Diabetes Care in 2012 showed an association between the presence of metabolic syndrome and an increased risk of various cancers including liver, bladder, pancreatic, breast, and colorectal.

More recently, a 2020 study published in Diabetes showed evidence of increased risk for certain cancers (pancreatic, kidney, uterine, cervical) but no increased risk for cancer overall.

In addition, a 2022 study by some of the current study researchers of the same Chinese cohort focused on the role of inflammation in combination with metabolic syndrome on colorectal cancer specifically, and found an increased risk for cancer when both metabolic syndrome and inflammation were present.

However, the reasons for this association between metabolic syndrome and cancer remain unclear, and the effect of the fluctuating nature of metabolic syndrome over time on long-term cancer risk has not been explored, the researchers wrote.

“There is emerging evidence that even normal weight individuals who are metabolically unhealthy may be at an elevated cancer risk, and we need better metrics to define the underlying metabolic dysfunction in obesity,” Sheetal Hardikar, MBBS, PhD, MPH, an investigator at the Huntsman Cancer Institute, University of Utah, said in an interview.

Dr. Hardikar, who serves as assistant professor in the department of population health sciences at the University of Utah, was not involved in the current study. She and her colleagues published a research paper on data from the National Health and Nutrition Examination Survey in 2023 that showed an increased risk of obesity-related cancer.
 

What New Study Adds to Related Research

Previous studies have consistently reported an approximately 30% increased risk of cancer with metabolic syndrome, Dr. Hardikar said. “What is unique about this study is the examination of metabolic syndrome trajectories over four years, and not just the presence of metabolic syndrome at one point in time,” she said.

In the new study, published in Cancer on March 11 (doi: 10.1002/cncr.35235), 44,115 adults in China were separated into four trajectories based on metabolic syndrome scores for the period from 2006 to 2010. The scores were based on clinical evidence of metabolic syndrome, defined using the International Diabetes Federation criteria of central obesity and the presence of at least two other factors including increased triglycerides, decreased HDL cholesterol, high blood pressure (or treatment for previously diagnosed hypertension), and increased fasting plasma glucose (or previous diagnosis of type 2 diabetes).

The average age of the participants was 49 years; the mean body mass index ranged from approximately 22 kg/m² in the low-stable group to approximately 28 kg/m² in the elevated-increasing group.

The four trajectories of metabolic syndrome were low-stable (10.56% of participants), moderate-low (40.84%), moderate-high (41.46%), and elevated-increasing (7.14%), based on trends from the individuals’ initial physical exams on entering the study.

Over a median follow-up period of 9.4 years (from 2010 to 2021), 2,271 cancer diagnoses were reported in the study population. Those with an elevated-increasing metabolic syndrome trajectory had 1.3 times the risk of any cancer compared with those in the low-stable group. Risk for breast cancer, endometrial cancer, kidney cancer, colorectal cancer, and liver cancer in the highest trajectory group were 2.1, 3.3, 4.5, 2.5, and 1.6 times higher, respectively, compared to the lowest group. The increased risk in the elevated-trajectory group for all cancer types persisted when the low-stable, moderate-low, and moderate-high trajectory pattern groups were combined.

The researchers also examined the impact of chronic inflammation and found that individuals with persistently high metabolic syndrome scores and concurrent chronic inflammation had the highest risks of breast, endometrial, colon, and liver cancer. However, individuals with persistently high metabolic syndrome scores and no concurrent chronic inflammation had the highest risk of kidney cancer.
 

What Are the Limitations of This Research?

The researchers of the current study acknowledged the lack of information on other causes of cancer, including dietary habits, hepatitis C infection, and Helicobacter pylori infection. Other limitations include the focus only on individuals from a single community of mainly middle-aged men in China that may not generalize to other populations.

Also, the metabolic syndrome trajectories did not change much over time, which may be related to the short 4-year study period.

Using the International Diabetes Federation criteria was another limitation, because it prevented the assessment of cancer risk in normal weight individuals with metabolic dysfunction, Dr. Hardikar noted.
 

Does Metabolic Syndrome Cause Cancer?

“This research suggests that proactive and continuous management of metabolic syndrome may serve as an essential strategy in preventing cancer,” senior author Han-Ping Shi, MD, PhD, of Capital Medical University in Beijing, noted in a statement on the study.

More research is needed to assess the impact of these interventions on cancer risk. However, the data from the current study can guide future research that may lead to more targeted treatments and more effective preventive strategies, he continued.

“Current evidence based on this study and many other reports strongly suggests an increased risk for cancer associated with metabolic syndrome,” Dr. Hardikar said in an interview. The data serve as a reminder to clinicians to look beyond BMI as the only measure of obesity, and to consider metabolic factors together to identify individuals at increased risk for cancer, she said.

“We must continue to educate patients about obesity and all the chronic conditions it may lead to, but we cannot ignore this emerging phenotype of being of normal weight but metabolically unhealthy,” Dr. Hardikar emphasized.
 

What Additional Research is Needed?

Looking ahead, “we need well-designed interventions to test causality for metabolic syndrome and cancer risk, though the evidence from the observational studies is very strong,” Dr. Hardikar said.

In addition, a consensus is needed to better define metabolic dysfunction,and to explore cancer risk in normal weight but metabolically unhealthy individuals, she said.

The study was supported by the National Key Research and Development Program of China. The researchers and Dr. Hardikar had no financial conflicts to disclose.

While the increased risk of cancer in patients with metabolic syndrome is well established by research, the authors of a new study delve deeper by examining metabolic syndrome trajectories.

The new research finds that adults with persistent metabolic syndrome that worsens over time are at increased risk for any type of cancer.

The conditions that make up metabolic syndrome (high blood pressure, high blood sugar, increased abdominal adiposity, and high cholesterol and triglycerides) have been associated with an increased risk of diseases, including heart disease, stroke, and type 2 diabetes, wrote Li Deng, PhD, of Capital Medical University, Beijing, and colleagues.

However, a single assessment of metabolic syndrome at one point in time is inadequate to show an association with cancer risk over time, they said. In the current study, the researchers used models to examine the association between trajectory patterns of metabolic syndrome over time and the risk of overall and specific cancer types. They also examined the impact of chronic inflammation concurrent with metabolic syndrome.
 

What We Know About Metabolic Syndrome and Cancer Risk

A systematic review and meta-analysis published in Diabetes Care in 2012 showed an association between the presence of metabolic syndrome and an increased risk of various cancers including liver, bladder, pancreatic, breast, and colorectal.

More recently, a 2020 study published in Diabetes showed evidence of increased risk for certain cancers (pancreatic, kidney, uterine, cervical) but no increased risk for cancer overall.

In addition, a 2022 study by some of the current study researchers of the same Chinese cohort focused on the role of inflammation in combination with metabolic syndrome on colorectal cancer specifically, and found an increased risk for cancer when both metabolic syndrome and inflammation were present.

However, the reasons for this association between metabolic syndrome and cancer remain unclear, and the effect of the fluctuating nature of metabolic syndrome over time on long-term cancer risk has not been explored, the researchers wrote.

“There is emerging evidence that even normal weight individuals who are metabolically unhealthy may be at an elevated cancer risk, and we need better metrics to define the underlying metabolic dysfunction in obesity,” Sheetal Hardikar, MBBS, PhD, MPH, an investigator at the Huntsman Cancer Institute, University of Utah, said in an interview.

Dr. Hardikar, who serves as assistant professor in the department of population health sciences at the University of Utah, was not involved in the current study. She and her colleagues published a research paper on data from the National Health and Nutrition Examination Survey in 2023 that showed an increased risk of obesity-related cancer.
 

What New Study Adds to Related Research

Previous studies have consistently reported an approximately 30% increased risk of cancer with metabolic syndrome, Dr. Hardikar said. “What is unique about this study is the examination of metabolic syndrome trajectories over four years, and not just the presence of metabolic syndrome at one point in time,” she said.

In the new study, published in Cancer on March 11 (doi: 10.1002/cncr.35235), 44,115 adults in China were separated into four trajectories based on metabolic syndrome scores for the period from 2006 to 2010. The scores were based on clinical evidence of metabolic syndrome, defined using the International Diabetes Federation criteria of central obesity and the presence of at least two other factors including increased triglycerides, decreased HDL cholesterol, high blood pressure (or treatment for previously diagnosed hypertension), and increased fasting plasma glucose (or previous diagnosis of type 2 diabetes).

The average age of the participants was 49 years; the mean body mass index ranged from approximately 22 kg/m² in the low-stable group to approximately 28 kg/m² in the elevated-increasing group.

The four trajectories of metabolic syndrome were low-stable (10.56% of participants), moderate-low (40.84%), moderate-high (41.46%), and elevated-increasing (7.14%), based on trends from the individuals’ initial physical exams on entering the study.

Over a median follow-up period of 9.4 years (from 2010 to 2021), 2,271 cancer diagnoses were reported in the study population. Those with an elevated-increasing metabolic syndrome trajectory had 1.3 times the risk of any cancer compared with those in the low-stable group. Risk for breast cancer, endometrial cancer, kidney cancer, colorectal cancer, and liver cancer in the highest trajectory group were 2.1, 3.3, 4.5, 2.5, and 1.6 times higher, respectively, compared to the lowest group. The increased risk in the elevated-trajectory group for all cancer types persisted when the low-stable, moderate-low, and moderate-high trajectory pattern groups were combined.

The researchers also examined the impact of chronic inflammation and found that individuals with persistently high metabolic syndrome scores and concurrent chronic inflammation had the highest risks of breast, endometrial, colon, and liver cancer. However, individuals with persistently high metabolic syndrome scores and no concurrent chronic inflammation had the highest risk of kidney cancer.
 

What Are the Limitations of This Research?

The researchers of the current study acknowledged the lack of information on other causes of cancer, including dietary habits, hepatitis C infection, and Helicobacter pylori infection. Other limitations include the focus only on individuals from a single community of mainly middle-aged men in China that may not generalize to other populations.

Also, the metabolic syndrome trajectories did not change much over time, which may be related to the short 4-year study period.

Using the International Diabetes Federation criteria was another limitation, because it prevented the assessment of cancer risk in normal weight individuals with metabolic dysfunction, Dr. Hardikar noted.
 

Does Metabolic Syndrome Cause Cancer?

“This research suggests that proactive and continuous management of metabolic syndrome may serve as an essential strategy in preventing cancer,” senior author Han-Ping Shi, MD, PhD, of Capital Medical University in Beijing, noted in a statement on the study.

More research is needed to assess the impact of these interventions on cancer risk. However, the data from the current study can guide future research that may lead to more targeted treatments and more effective preventive strategies, he continued.

“Current evidence based on this study and many other reports strongly suggests an increased risk for cancer associated with metabolic syndrome,” Dr. Hardikar said in an interview. The data serve as a reminder to clinicians to look beyond BMI as the only measure of obesity, and to consider metabolic factors together to identify individuals at increased risk for cancer, she said.

“We must continue to educate patients about obesity and all the chronic conditions it may lead to, but we cannot ignore this emerging phenotype of being of normal weight but metabolically unhealthy,” Dr. Hardikar emphasized.
 

What Additional Research is Needed?

Looking ahead, “we need well-designed interventions to test causality for metabolic syndrome and cancer risk, though the evidence from the observational studies is very strong,” Dr. Hardikar said.

In addition, a consensus is needed to better define metabolic dysfunction,and to explore cancer risk in normal weight but metabolically unhealthy individuals, she said.

The study was supported by the National Key Research and Development Program of China. The researchers and Dr. Hardikar had no financial conflicts to disclose.

While the increased risk of cancer in patients with metabolic syndrome is well established by research, the authors of a new study delve deeper by examining metabolic syndrome trajectories.

The new research finds that adults with persistent metabolic syndrome that worsens over time are at increased risk for any type of cancer.

The conditions that make up metabolic syndrome (high blood pressure, high blood sugar, increased abdominal adiposity, and high cholesterol and triglycerides) have been associated with an increased risk of diseases, including heart disease, stroke, and type 2 diabetes, wrote Li Deng, PhD, of Capital Medical University, Beijing, and colleagues.

However, a single assessment of metabolic syndrome at one point in time is inadequate to show an association with cancer risk over time, they said. In the current study, the researchers used models to examine the association between trajectory patterns of metabolic syndrome over time and the risk of overall and specific cancer types. They also examined the impact of chronic inflammation concurrent with metabolic syndrome.
 

What We Know About Metabolic Syndrome and Cancer Risk

A systematic review and meta-analysis published in Diabetes Care in 2012 showed an association between the presence of metabolic syndrome and an increased risk of various cancers including liver, bladder, pancreatic, breast, and colorectal.

More recently, a 2020 study published in Diabetes showed evidence of increased risk for certain cancers (pancreatic, kidney, uterine, cervical) but no increased risk for cancer overall.

In addition, a 2022 study by some of the current study researchers of the same Chinese cohort focused on the role of inflammation in combination with metabolic syndrome on colorectal cancer specifically, and found an increased risk for cancer when both metabolic syndrome and inflammation were present.

However, the reasons for this association between metabolic syndrome and cancer remain unclear, and the effect of the fluctuating nature of metabolic syndrome over time on long-term cancer risk has not been explored, the researchers wrote.

“There is emerging evidence that even normal weight individuals who are metabolically unhealthy may be at an elevated cancer risk, and we need better metrics to define the underlying metabolic dysfunction in obesity,” Sheetal Hardikar, MBBS, PhD, MPH, an investigator at the Huntsman Cancer Institute, University of Utah, said in an interview.

Dr. Hardikar, who serves as assistant professor in the department of population health sciences at the University of Utah, was not involved in the current study. She and her colleagues published a research paper on data from the National Health and Nutrition Examination Survey in 2023 that showed an increased risk of obesity-related cancer.
 

What New Study Adds to Related Research

Previous studies have consistently reported an approximately 30% increased risk of cancer with metabolic syndrome, Dr. Hardikar said. “What is unique about this study is the examination of metabolic syndrome trajectories over four years, and not just the presence of metabolic syndrome at one point in time,” she said.

In the new study, published in Cancer on March 11 (doi: 10.1002/cncr.35235), 44,115 adults in China were separated into four trajectories based on metabolic syndrome scores for the period from 2006 to 2010. The scores were based on clinical evidence of metabolic syndrome, defined using the International Diabetes Federation criteria of central obesity and the presence of at least two other factors including increased triglycerides, decreased HDL cholesterol, high blood pressure (or treatment for previously diagnosed hypertension), and increased fasting plasma glucose (or previous diagnosis of type 2 diabetes).

The average age of the participants was 49 years; the mean body mass index ranged from approximately 22 kg/m² in the low-stable group to approximately 28 kg/m² in the elevated-increasing group.

The four trajectories of metabolic syndrome were low-stable (10.56% of participants), moderate-low (40.84%), moderate-high (41.46%), and elevated-increasing (7.14%), based on trends from the individuals’ initial physical exams on entering the study.

Over a median follow-up period of 9.4 years (from 2010 to 2021), 2,271 cancer diagnoses were reported in the study population. Those with an elevated-increasing metabolic syndrome trajectory had 1.3 times the risk of any cancer compared with those in the low-stable group. Risk for breast cancer, endometrial cancer, kidney cancer, colorectal cancer, and liver cancer in the highest trajectory group were 2.1, 3.3, 4.5, 2.5, and 1.6 times higher, respectively, compared to the lowest group. The increased risk in the elevated-trajectory group for all cancer types persisted when the low-stable, moderate-low, and moderate-high trajectory pattern groups were combined.

The researchers also examined the impact of chronic inflammation and found that individuals with persistently high metabolic syndrome scores and concurrent chronic inflammation had the highest risks of breast, endometrial, colon, and liver cancer. However, individuals with persistently high metabolic syndrome scores and no concurrent chronic inflammation had the highest risk of kidney cancer.
 

What Are the Limitations of This Research?

The researchers of the current study acknowledged the lack of information on other causes of cancer, including dietary habits, hepatitis C infection, and Helicobacter pylori infection. Other limitations include the focus only on individuals from a single community of mainly middle-aged men in China that may not generalize to other populations.

Also, the metabolic syndrome trajectories did not change much over time, which may be related to the short 4-year study period.

Using the International Diabetes Federation criteria was another limitation, because it prevented the assessment of cancer risk in normal weight individuals with metabolic dysfunction, Dr. Hardikar noted.
 

Does Metabolic Syndrome Cause Cancer?

“This research suggests that proactive and continuous management of metabolic syndrome may serve as an essential strategy in preventing cancer,” senior author Han-Ping Shi, MD, PhD, of Capital Medical University in Beijing, noted in a statement on the study.

More research is needed to assess the impact of these interventions on cancer risk. However, the data from the current study can guide future research that may lead to more targeted treatments and more effective preventive strategies, he continued.

“Current evidence based on this study and many other reports strongly suggests an increased risk for cancer associated with metabolic syndrome,” Dr. Hardikar said in an interview. The data serve as a reminder to clinicians to look beyond BMI as the only measure of obesity, and to consider metabolic factors together to identify individuals at increased risk for cancer, she said.

“We must continue to educate patients about obesity and all the chronic conditions it may lead to, but we cannot ignore this emerging phenotype of being of normal weight but metabolically unhealthy,” Dr. Hardikar emphasized.
 

What Additional Research is Needed?

Looking ahead, “we need well-designed interventions to test causality for metabolic syndrome and cancer risk, though the evidence from the observational studies is very strong,” Dr. Hardikar said.

In addition, a consensus is needed to better define metabolic dysfunction,and to explore cancer risk in normal weight but metabolically unhealthy individuals, she said.

The study was supported by the National Key Research and Development Program of China. The researchers and Dr. Hardikar had no financial conflicts to disclose.

The American Society for Radiation Oncology (ASTRO) recently sent a letter to the Centers for Medicare and Medicaid Services (CMS) opposing the extension of virtual supervision for radiation oncology services.

Although serious errors during virtual supervision are rare, ASTRO said radiation treatments (RT) should be done with a radiation oncologist on site to ensure high-quality care. But some radiation oncologists do not agree with the proposal to move back to direct in-person supervision only. 
 

Changes to Direct Supervision

Most radiation oncology treatments are delivered in an outpatient setting under a physician’s direction and control. 

During the COVID-19 pandemic when social distancing mandates were in place, CMS temporarily changed the definition of “direct supervision” to include telehealth, specifying that a physician must be immediately available to assist and direct a procedure virtually using real-time audio and video. In other words, a physician did not need to be physically present in the room when the treatment was being performed. 

CMS has extended this rule until the end of 2024 and is considering making it a permanent change. In the Calendar Year (CY) 2024 Medicare Physician Fee Schedule (PFS) Final Rule, CMS asked for comments on whether to extend the rule. 

“We received input from interested parties on potential patient safety or quality concerns when direct supervision occurs virtually, which we will consider for future rulemaking,” a CMS spokesperson told this news organization. “CMS is currently considering the best approach that will protect patient access and safety as well as quality of care and program integrity concerns following CY 2024.”

CMS also noted its concerns that an abrupt transition back to requiring a physician’s physical presence could interrupt care from practitioners who have established new patterns of practice with telehealth. 
 

What Are ASTRO’s Concerns?

Late last month, ASTRO sent CMS a letter, asking the agency to change the rules back to direct in-person supervision for all radiation services, citing that virtual supervision jeopardizes patient safety and quality of care. 

Jeff Michalski, MD, MBA, chair of the ASTRO Board of Directors, said in an interview that radiation oncologists should be physically present to supervise the treatments.

“ASTRO is concerned that blanket policies of general or virtual supervision could lead to patients not having direct, in-person access to their doctors’ care,” he said. “While serious errors are rare, real-world experiences of radiation oncologists across practice settings demonstrate how an in-person radiation oncology physician is best suited to ensure high-quality care.”
 

What Do Radiation Oncologists Think?

According to ASTRO, most radiation oncologists would agree that in-person supervision is best for patients. 

But that might not be the case. 

Radiation oncologists took to X (formerly Twitter) to voice their opinions about ASTRO’s letter. 

Jason Beckta, MD, PhD, of Rutland Regional’s Foley Cancer Center, Vermont, said “the February 26th ASTRO letter reads like an Onion article.” 

“I’m struggling to understand the Luddite-level myopia around this topic,” he said in another tweet. “Virtual direct/outpatient general supervision has done nothing but boost my productivity and in particular, face-to-face patient contact.”

Join Y. Luh, MD, with the Providence Medical Network in Eureka, California, said he understands the challenges faced by clinicians working in more isolated rural settings. “For them, it’s either having virtual supervision or closing the center,” Dr. Luh said.

“Virtual care is definitely at my clinic and is not only an option but is critical to my patients who are 2+ snowy, mountainous hours away,” Dr. Luh wrote. “But I’m still in the clinic directly supervising treatments.”

Sidney Roberts, MD, with the CHI St. Luke’s Health-Memorial, Texas, tweeted that supervision does require some face-to-face care but contended that “babysitting trained therapists for every routine treatment is a farce.”

Another issue Dr. Luh brought up is reimbursement for virtual supervision, noting that “the elephant in the room is whether that level of service should be reimbursed at the same rate. Reimbursement has not changed — but will it stay that way?”

ASTRO has acknowledged that radiation oncologists will have varying opinions and says it is working to balance these challenges.

CMS has not reached a decision on whether the change will be implemented permanently. The organization will assess concern, patient safety, and quality of care at the end of the year.

A version of this article first appeared on Medscape.com

The American Society for Radiation Oncology (ASTRO) recently sent a letter to the Centers for Medicare and Medicaid Services (CMS) opposing the extension of virtual supervision for radiation oncology services.

Although serious errors during virtual supervision are rare, ASTRO said radiation treatments (RT) should be done with a radiation oncologist on site to ensure high-quality care. But some radiation oncologists do not agree with the proposal to move back to direct in-person supervision only. 
 

Changes to Direct Supervision

Most radiation oncology treatments are delivered in an outpatient setting under a physician’s direction and control. 

During the COVID-19 pandemic when social distancing mandates were in place, CMS temporarily changed the definition of “direct supervision” to include telehealth, specifying that a physician must be immediately available to assist and direct a procedure virtually using real-time audio and video. In other words, a physician did not need to be physically present in the room when the treatment was being performed. 

CMS has extended this rule until the end of 2024 and is considering making it a permanent change. In the Calendar Year (CY) 2024 Medicare Physician Fee Schedule (PFS) Final Rule, CMS asked for comments on whether to extend the rule. 

“We received input from interested parties on potential patient safety or quality concerns when direct supervision occurs virtually, which we will consider for future rulemaking,” a CMS spokesperson told this news organization. “CMS is currently considering the best approach that will protect patient access and safety as well as quality of care and program integrity concerns following CY 2024.”

CMS also noted its concerns that an abrupt transition back to requiring a physician’s physical presence could interrupt care from practitioners who have established new patterns of practice with telehealth. 
 

What Are ASTRO’s Concerns?

Late last month, ASTRO sent CMS a letter, asking the agency to change the rules back to direct in-person supervision for all radiation services, citing that virtual supervision jeopardizes patient safety and quality of care. 

Jeff Michalski, MD, MBA, chair of the ASTRO Board of Directors, said in an interview that radiation oncologists should be physically present to supervise the treatments.

“ASTRO is concerned that blanket policies of general or virtual supervision could lead to patients not having direct, in-person access to their doctors’ care,” he said. “While serious errors are rare, real-world experiences of radiation oncologists across practice settings demonstrate how an in-person radiation oncology physician is best suited to ensure high-quality care.”
 

What Do Radiation Oncologists Think?

According to ASTRO, most radiation oncologists would agree that in-person supervision is best for patients. 

But that might not be the case. 

Radiation oncologists took to X (formerly Twitter) to voice their opinions about ASTRO’s letter. 

Jason Beckta, MD, PhD, of Rutland Regional’s Foley Cancer Center, Vermont, said “the February 26th ASTRO letter reads like an Onion article.” 

“I’m struggling to understand the Luddite-level myopia around this topic,” he said in another tweet. “Virtual direct/outpatient general supervision has done nothing but boost my productivity and in particular, face-to-face patient contact.”

Join Y. Luh, MD, with the Providence Medical Network in Eureka, California, said he understands the challenges faced by clinicians working in more isolated rural settings. “For them, it’s either having virtual supervision or closing the center,” Dr. Luh said.

“Virtual care is definitely at my clinic and is not only an option but is critical to my patients who are 2+ snowy, mountainous hours away,” Dr. Luh wrote. “But I’m still in the clinic directly supervising treatments.”

Sidney Roberts, MD, with the CHI St. Luke’s Health-Memorial, Texas, tweeted that supervision does require some face-to-face care but contended that “babysitting trained therapists for every routine treatment is a farce.”

Another issue Dr. Luh brought up is reimbursement for virtual supervision, noting that “the elephant in the room is whether that level of service should be reimbursed at the same rate. Reimbursement has not changed — but will it stay that way?”

ASTRO has acknowledged that radiation oncologists will have varying opinions and says it is working to balance these challenges.

CMS has not reached a decision on whether the change will be implemented permanently. The organization will assess concern, patient safety, and quality of care at the end of the year.

A version of this article first appeared on Medscape.com

The American Society for Radiation Oncology (ASTRO) recently sent a letter to the Centers for Medicare and Medicaid Services (CMS) opposing the extension of virtual supervision for radiation oncology services.

Although serious errors during virtual supervision are rare, ASTRO said radiation treatments (RT) should be done with a radiation oncologist on site to ensure high-quality care. But some radiation oncologists do not agree with the proposal to move back to direct in-person supervision only. 
 

Changes to Direct Supervision

Most radiation oncology treatments are delivered in an outpatient setting under a physician’s direction and control. 

During the COVID-19 pandemic when social distancing mandates were in place, CMS temporarily changed the definition of “direct supervision” to include telehealth, specifying that a physician must be immediately available to assist and direct a procedure virtually using real-time audio and video. In other words, a physician did not need to be physically present in the room when the treatment was being performed. 

CMS has extended this rule until the end of 2024 and is considering making it a permanent change. In the Calendar Year (CY) 2024 Medicare Physician Fee Schedule (PFS) Final Rule, CMS asked for comments on whether to extend the rule. 

“We received input from interested parties on potential patient safety or quality concerns when direct supervision occurs virtually, which we will consider for future rulemaking,” a CMS spokesperson told this news organization. “CMS is currently considering the best approach that will protect patient access and safety as well as quality of care and program integrity concerns following CY 2024.”

CMS also noted its concerns that an abrupt transition back to requiring a physician’s physical presence could interrupt care from practitioners who have established new patterns of practice with telehealth. 
 

What Are ASTRO’s Concerns?

Late last month, ASTRO sent CMS a letter, asking the agency to change the rules back to direct in-person supervision for all radiation services, citing that virtual supervision jeopardizes patient safety and quality of care. 

Jeff Michalski, MD, MBA, chair of the ASTRO Board of Directors, said in an interview that radiation oncologists should be physically present to supervise the treatments.

“ASTRO is concerned that blanket policies of general or virtual supervision could lead to patients not having direct, in-person access to their doctors’ care,” he said. “While serious errors are rare, real-world experiences of radiation oncologists across practice settings demonstrate how an in-person radiation oncology physician is best suited to ensure high-quality care.”
 

What Do Radiation Oncologists Think?

According to ASTRO, most radiation oncologists would agree that in-person supervision is best for patients. 

But that might not be the case. 

Radiation oncologists took to X (formerly Twitter) to voice their opinions about ASTRO’s letter. 

Jason Beckta, MD, PhD, of Rutland Regional’s Foley Cancer Center, Vermont, said “the February 26th ASTRO letter reads like an Onion article.” 

“I’m struggling to understand the Luddite-level myopia around this topic,” he said in another tweet. “Virtual direct/outpatient general supervision has done nothing but boost my productivity and in particular, face-to-face patient contact.”

Join Y. Luh, MD, with the Providence Medical Network in Eureka, California, said he understands the challenges faced by clinicians working in more isolated rural settings. “For them, it’s either having virtual supervision or closing the center,” Dr. Luh said.

“Virtual care is definitely at my clinic and is not only an option but is critical to my patients who are 2+ snowy, mountainous hours away,” Dr. Luh wrote. “But I’m still in the clinic directly supervising treatments.”

Sidney Roberts, MD, with the CHI St. Luke’s Health-Memorial, Texas, tweeted that supervision does require some face-to-face care but contended that “babysitting trained therapists for every routine treatment is a farce.”

Another issue Dr. Luh brought up is reimbursement for virtual supervision, noting that “the elephant in the room is whether that level of service should be reimbursed at the same rate. Reimbursement has not changed — but will it stay that way?”

ASTRO has acknowledged that radiation oncologists will have varying opinions and says it is working to balance these challenges.

CMS has not reached a decision on whether the change will be implemented permanently. The organization will assess concern, patient safety, and quality of care at the end of the year.

A version of this article first appeared on Medscape.com

Adults with persistent metabolic syndrome that worsens over time are at increased risk for any type of cancer, according to a new study of more than 44,000 individuals.

The conditions that comprise metabolic syndrome (high blood pressure, high blood sugar, increased abdominal adiposity, and high cholesterol and triglycerides) have been associated with an increased risk of diseases, including heart disease, stroke, and type 2 diabetes, wrote Li Deng, PhD, of Capital Medical University, Beijing, China, and colleagues.

A systematic review and meta-analysis published in Diabetes Care in 2012 showed an association between the presence of metabolic syndrome and an increased risk of various cancers including liver, bladder, pancreatic, breast, and colorectal.

More recently, a 2019 study published in Diabetes showed evidence of increased risk for certain cancers (pancreatic, kidney, uterine, cervical) but no increased risk for cancer overall.

However, the reasons for this association between metabolic syndrome and cancer remain unclear, and the effect of the fluctuating nature of metabolic syndrome over time on long-term cancer risk has not been explored, the researchers wrote.
 

What Does New Study Add to Other Research on Metabolic Syndrome and Cancer Risk?

In the new study, published in Cancer on March 11 (doi: 10.1002/cncr.35235), 44,115 adults in China were separated into four trajectories based on metabolic syndrome scores for the period from 2006 to 2010. The scores were based on clinical evidence of metabolic syndrome, defined using the International Diabetes Federation criteria of central obesity and the presence of at least two other factors including increased triglycerides, decreased HDL cholesterol, high blood pressure (or treatment for previously diagnosed hypertension), and increased fasting plasma glucose (or previous diagnosis of type 2 diabetes).

The average age of the participants was 49 years. The four trajectories of metabolic syndrome were low-stable (10.56% of participants), moderate-low (40.84%), moderate-high (41.46%), and elevated-increasing (7.14%), based on trends from the individuals’ initial physical exams on entering the study.

Over a median follow-up period of 9.4 years (from 2010 to 2021), 2,271 cancer diagnoses were reported in the study population. Those with an elevated-increasing metabolic syndrome trajectory had 1.3 times the risk of any cancer compared with those in the low-stable group. Risk for breast cancer, endometrial cancer, kidney cancer, colorectal cancer, and liver cancer in the highest trajectory group were 2.1, 3.3, 4.5, 2.5, and 1.6 times higher, respectively, compared to the lowest group. The increased risk in the elevated-trajectory group for all cancer types persisted when the low-stable, moderate-low, and moderate-high trajectory pattern groups were combined.

The researchers also examined the impact of chronic inflammation and found that individuals with persistently high metabolic syndrome scores and concurrent chronic inflammation had the highest risks of breast, endometrial, colon, and liver cancer. However, individuals with persistently high metabolic syndrome scores and no concurrent chronic inflammation had the highest risk of kidney cancer.
 

 What Are the Limitations of This Research?

The researchers of the current study acknowledged the lack of information on other causes of cancer, including dietary habits, hepatitis C infection, and Helicobacter pylori infection. Other limitations include the focus only on individuals from a single community of mainly middle-aged men in China that may not generalize to other populations.

Also, the metabolic syndrome trajectories did not change much over time, which may be related to the short 4-year study period.
 

What Is the Takeaway Message for Clinical Practice?

The results suggest that monitoring and managing metabolic syndrome could help reduce cancer risk, the researchers concluded. 

“This research suggests that proactive and continuous management of metabolic syndrome may serve as an essential strategy in preventing cancer,” senior author Han-Ping Shi, MD, PhD, of Capital Medical University in Beijing, said in a press release accompanying the study.

More research is needed to assess the impact of these interventions on cancer risk, he noted. However, the data from the current study can guide future research that may lead to more targeted treatments and more effective preventive strategies, he said in a statement.

The study was supported by the National Key Research and Development Program of China. The researchers had no financial conflicts to disclose.

Adults with persistent metabolic syndrome that worsens over time are at increased risk for any type of cancer, according to a new study of more than 44,000 individuals.

The conditions that comprise metabolic syndrome (high blood pressure, high blood sugar, increased abdominal adiposity, and high cholesterol and triglycerides) have been associated with an increased risk of diseases, including heart disease, stroke, and type 2 diabetes, wrote Li Deng, PhD, of Capital Medical University, Beijing, China, and colleagues.

A systematic review and meta-analysis published in Diabetes Care in 2012 showed an association between the presence of metabolic syndrome and an increased risk of various cancers including liver, bladder, pancreatic, breast, and colorectal.

More recently, a 2019 study published in Diabetes showed evidence of increased risk for certain cancers (pancreatic, kidney, uterine, cervical) but no increased risk for cancer overall.

However, the reasons for this association between metabolic syndrome and cancer remain unclear, and the effect of the fluctuating nature of metabolic syndrome over time on long-term cancer risk has not been explored, the researchers wrote.
 

What Does New Study Add to Other Research on Metabolic Syndrome and Cancer Risk?

In the new study, published in Cancer on March 11 (doi: 10.1002/cncr.35235), 44,115 adults in China were separated into four trajectories based on metabolic syndrome scores for the period from 2006 to 2010. The scores were based on clinical evidence of metabolic syndrome, defined using the International Diabetes Federation criteria of central obesity and the presence of at least two other factors including increased triglycerides, decreased HDL cholesterol, high blood pressure (or treatment for previously diagnosed hypertension), and increased fasting plasma glucose (or previous diagnosis of type 2 diabetes).

The average age of the participants was 49 years. The four trajectories of metabolic syndrome were low-stable (10.56% of participants), moderate-low (40.84%), moderate-high (41.46%), and elevated-increasing (7.14%), based on trends from the individuals’ initial physical exams on entering the study.

Over a median follow-up period of 9.4 years (from 2010 to 2021), 2,271 cancer diagnoses were reported in the study population. Those with an elevated-increasing metabolic syndrome trajectory had 1.3 times the risk of any cancer compared with those in the low-stable group. Risk for breast cancer, endometrial cancer, kidney cancer, colorectal cancer, and liver cancer in the highest trajectory group were 2.1, 3.3, 4.5, 2.5, and 1.6 times higher, respectively, compared to the lowest group. The increased risk in the elevated-trajectory group for all cancer types persisted when the low-stable, moderate-low, and moderate-high trajectory pattern groups were combined.

The researchers also examined the impact of chronic inflammation and found that individuals with persistently high metabolic syndrome scores and concurrent chronic inflammation had the highest risks of breast, endometrial, colon, and liver cancer. However, individuals with persistently high metabolic syndrome scores and no concurrent chronic inflammation had the highest risk of kidney cancer.
 

 What Are the Limitations of This Research?

The researchers of the current study acknowledged the lack of information on other causes of cancer, including dietary habits, hepatitis C infection, and Helicobacter pylori infection. Other limitations include the focus only on individuals from a single community of mainly middle-aged men in China that may not generalize to other populations.

Also, the metabolic syndrome trajectories did not change much over time, which may be related to the short 4-year study period.
 

What Is the Takeaway Message for Clinical Practice?

The results suggest that monitoring and managing metabolic syndrome could help reduce cancer risk, the researchers concluded. 

“This research suggests that proactive and continuous management of metabolic syndrome may serve as an essential strategy in preventing cancer,” senior author Han-Ping Shi, MD, PhD, of Capital Medical University in Beijing, said in a press release accompanying the study.

More research is needed to assess the impact of these interventions on cancer risk, he noted. However, the data from the current study can guide future research that may lead to more targeted treatments and more effective preventive strategies, he said in a statement.

The study was supported by the National Key Research and Development Program of China. The researchers had no financial conflicts to disclose.

Adults with persistent metabolic syndrome that worsens over time are at increased risk for any type of cancer, according to a new study of more than 44,000 individuals.

The conditions that comprise metabolic syndrome (high blood pressure, high blood sugar, increased abdominal adiposity, and high cholesterol and triglycerides) have been associated with an increased risk of diseases, including heart disease, stroke, and type 2 diabetes, wrote Li Deng, PhD, of Capital Medical University, Beijing, China, and colleagues.

A systematic review and meta-analysis published in Diabetes Care in 2012 showed an association between the presence of metabolic syndrome and an increased risk of various cancers including liver, bladder, pancreatic, breast, and colorectal.

More recently, a 2019 study published in Diabetes showed evidence of increased risk for certain cancers (pancreatic, kidney, uterine, cervical) but no increased risk for cancer overall.

However, the reasons for this association between metabolic syndrome and cancer remain unclear, and the effect of the fluctuating nature of metabolic syndrome over time on long-term cancer risk has not been explored, the researchers wrote.
 

What Does New Study Add to Other Research on Metabolic Syndrome and Cancer Risk?

In the new study, published in Cancer on March 11 (doi: 10.1002/cncr.35235), 44,115 adults in China were separated into four trajectories based on metabolic syndrome scores for the period from 2006 to 2010. The scores were based on clinical evidence of metabolic syndrome, defined using the International Diabetes Federation criteria of central obesity and the presence of at least two other factors including increased triglycerides, decreased HDL cholesterol, high blood pressure (or treatment for previously diagnosed hypertension), and increased fasting plasma glucose (or previous diagnosis of type 2 diabetes).

The average age of the participants was 49 years. The four trajectories of metabolic syndrome were low-stable (10.56% of participants), moderate-low (40.84%), moderate-high (41.46%), and elevated-increasing (7.14%), based on trends from the individuals’ initial physical exams on entering the study.

Over a median follow-up period of 9.4 years (from 2010 to 2021), 2,271 cancer diagnoses were reported in the study population. Those with an elevated-increasing metabolic syndrome trajectory had 1.3 times the risk of any cancer compared with those in the low-stable group. Risk for breast cancer, endometrial cancer, kidney cancer, colorectal cancer, and liver cancer in the highest trajectory group were 2.1, 3.3, 4.5, 2.5, and 1.6 times higher, respectively, compared to the lowest group. The increased risk in the elevated-trajectory group for all cancer types persisted when the low-stable, moderate-low, and moderate-high trajectory pattern groups were combined.

The researchers also examined the impact of chronic inflammation and found that individuals with persistently high metabolic syndrome scores and concurrent chronic inflammation had the highest risks of breast, endometrial, colon, and liver cancer. However, individuals with persistently high metabolic syndrome scores and no concurrent chronic inflammation had the highest risk of kidney cancer.
 

 What Are the Limitations of This Research?

The researchers of the current study acknowledged the lack of information on other causes of cancer, including dietary habits, hepatitis C infection, and Helicobacter pylori infection. Other limitations include the focus only on individuals from a single community of mainly middle-aged men in China that may not generalize to other populations.

Also, the metabolic syndrome trajectories did not change much over time, which may be related to the short 4-year study period.
 

What Is the Takeaway Message for Clinical Practice?

The results suggest that monitoring and managing metabolic syndrome could help reduce cancer risk, the researchers concluded. 

“This research suggests that proactive and continuous management of metabolic syndrome may serve as an essential strategy in preventing cancer,” senior author Han-Ping Shi, MD, PhD, of Capital Medical University in Beijing, said in a press release accompanying the study.

More research is needed to assess the impact of these interventions on cancer risk, he noted. However, the data from the current study can guide future research that may lead to more targeted treatments and more effective preventive strategies, he said in a statement.

The study was supported by the National Key Research and Development Program of China. The researchers had no financial conflicts to disclose.

More Black men with elevated prostate-specific antigen (PSA) counts are diagnosed with prostate cancer than their White counterparts, but incidence of advanced prostate cancer is similar for Black and White men within 1 year of the PSA test, a new study finds.

There was a substantial difference in prostate cancer diagnosis across ethnic groups: 25% of Black men with a raised PSA were diagnosed with prostate cancer within 1 year of being tested, compared with 20% of White men and 13% of Asian men, in the analysis of a large primary care cohort in the United Kingdom.

Incidence of advanced prostate cancer for Asian men with a raised PSA result was 4.5%, compared with 7.5% for White men and 7.0% for Black men.

Men included in the study were aged 40 and older and had no prior cancer diagnosis. Their ethnicity and PSA test result were logged in a national dataset between 2010 and 2017.

The study of more than 730,000 men, published in BMC Medicine, didn’t explore reasons for the differences, but experts offer their thoughts on what led to the findings and what these results imply.

Why the Higher Diagnosis Rates but Not More Advanced Disease in Black Men?

Lead author Liz Down, a graduate research assistant at the University of Exeter, Exeter, England, suggests the higher diagnosis rates but not more advanced disease in Black men may be linked to genetic variations.

Her team’s studies have shown that Black men in the United Kingdom and United States have higher levels of PSA. The PSA value is used to identify patients who might benefit from specialist investigation, and current guidelines in the UK and US don’t distinguish between ethnic groups.

As most men have slow-growing prostate cancer, this may lead to a disproportionately higher number of Black men being diagnosed with prostate cancer, she said.

“One possible interpretation,” Ms. Down notes, “is that prostate cancer follows a similar trajectory in Black and White men. What is different, however, is that Black men have higher PSA levels.”

As to why the advanced-cancer incidence is similar in Black and White patients in the study, Daniel George, MD, director of genitourinary oncology at Duke Cancer Institute in Durham, North Carolina, says it’s important to understand that the Black men in this study “are not necessarily representative of the Black population at large.”

In this study, “they’re a little bit more healthcare inclined,” Dr. George notes. The study population is actively seeking the PSA test. Their socioeconomic profile might be closer to their White counterparts’, and that may make results more similar, he said.

“It’s possible that because this is a screening and not just men coming in for symptoms or cause, that we’re not seeing as much advanced disease,” he continued.

Amar Kishan, MD, chief of the genitourinary oncology service at University of California Los Angeles (UCLA) Health, says the genomic factors and environmental stressors that lead to elevated PSA counts don’t necessarily translate into aggressiveness of disease.

Why do Different Races have Different Prostate Cancer Risk?

Dr. George points out that the study also highlights that Asian men were significantly less likely to be diagnosed with prostate cancer within 1 year of the test.

The reasons for differences in prostate risk by race are complex, he notes. There are some clues that biologic factors may be at work. For instance, early puberty has a link to prostate cancer as it does to breast cancer, and height is also associated with a greater risk of prostate cancer, Dr. George said.

It’s not necessarily a racial association but there are some biological factors associated with prostate cancer later in life, he explained. “These may be enriched in certain populations, including northern Europeans and patients with African ancestries.”

The study also notes that Black men are more likely to die from prostate cancer than are White men, and Asian men are less likely than White or Black men to die from it.

Ms. Down said the difference in prostate cancer mortality between Black vs White men, in particular, may be related to a number of factors, and age, and lifetime risk of prostate cancer may play a major role, at least in the UK.

Should There Be Different ‘Normal’ PSA Levels for Different Races?

Dr. George says there is likely a need to change the system because a PSA level in one race may not signal the same risk it does in another. So medicine probably needs to standardize what a “normal” PSA is by race, he says, adding that he is a coauthor of an upcoming paper regarding that issue.

The lowest instances of prostate cancer were in Asian patients so this isn’t just a Black and White issue, Dr. George notes. “Being able to establish benchmarks by race and ethnicity is something that is probably needed in the field,” he says.

Dr. Kishan, on the other hand, says data from this study are not enough to support differentiating PSA levels based on race. He noted a limitation of the study is that it was not able to calculate the false-negative rate of PSA tests.

What are the Implications for Treating and Screening for Prostate Cancer

Dr. Kishan says there may be a role for increased intensity of screening, whether at an earlier age or with different intervals, but prostate cancer treatment should not differ by race.

“Our prior study, as well as others,” he says, “have shown that when you balance Black and White patients for every factor that might impact prognosis other than race — such as age, disease aggressiveness, etc. — Black men actually tend to have better  outcomes than White men. Thus, it would mean potentially overtreating (i.e., causing unnecessary side effects) to increase treatment intensity purely based on race with the available data.”

According to the paper, prostate cancer incidence in men with higher PSA levels increases with increasing age, even when using age-adjusted thresholds.

Dr. George says we know from this study and other studies as well that Black men are more likely to be diagnosed with prostate at a younger age. “Therefore, we probably need to be thinking about screening Black men starting at a younger age. These are the men who are most likely to benefit from an intervention — patients who have life expectancies of 20 years or more.”

What are the Downsides to Overdiagnosing Prostate Cancer in Men?

“It’s one of the biggest concerns that men have in proactively seeking healthcare,” Dr. George says. “They’re more likely to undergo treatment for this disease if they’re getting screened because (clinicians are) more likely to find it.”

Some of those men, he says, are going to undergo treatment for disease that won’t ultimately kill them, but may cause complications the men shouldn’t have had at all or otherwise may have had later.

“Overtreatment is a real concern. That’s why active surveillance is so important to minimize overtreatment of patients by finding out which cancers are low risk for progression and which are becoming more aggressive,” Dr. George says.

Authors of the study write that “the potential for overdiagnosis and the subsequent psychological and physical impact of diagnosis and treatment is an important consideration.”

All authors of the new paper received financial support from Cancer Research UK, the National Institute for Health and Care Research (NIHR), and the Higgins family for the submitted work.

Dr. George reports no relevant financial relationships.

Dr. Kishan reports consulting fees and speaking honoraria from Varian Medical Systems, Janssen, and Boston Scientific; research funding from PointBioPharma, Lantheus, and Janssen; and serving on advisory boards for Lantheus, Janssen and Boston Scientific.

More Black men with elevated prostate-specific antigen (PSA) counts are diagnosed with prostate cancer than their White counterparts, but incidence of advanced prostate cancer is similar for Black and White men within 1 year of the PSA test, a new study finds.

There was a substantial difference in prostate cancer diagnosis across ethnic groups: 25% of Black men with a raised PSA were diagnosed with prostate cancer within 1 year of being tested, compared with 20% of White men and 13% of Asian men, in the analysis of a large primary care cohort in the United Kingdom.

Incidence of advanced prostate cancer for Asian men with a raised PSA result was 4.5%, compared with 7.5% for White men and 7.0% for Black men.

Men included in the study were aged 40 and older and had no prior cancer diagnosis. Their ethnicity and PSA test result were logged in a national dataset between 2010 and 2017.

The study of more than 730,000 men, published in BMC Medicine, didn’t explore reasons for the differences, but experts offer their thoughts on what led to the findings and what these results imply.

Why the Higher Diagnosis Rates but Not More Advanced Disease in Black Men?

Lead author Liz Down, a graduate research assistant at the University of Exeter, Exeter, England, suggests the higher diagnosis rates but not more advanced disease in Black men may be linked to genetic variations.

Her team’s studies have shown that Black men in the United Kingdom and United States have higher levels of PSA. The PSA value is used to identify patients who might benefit from specialist investigation, and current guidelines in the UK and US don’t distinguish between ethnic groups.

As most men have slow-growing prostate cancer, this may lead to a disproportionately higher number of Black men being diagnosed with prostate cancer, she said.

“One possible interpretation,” Ms. Down notes, “is that prostate cancer follows a similar trajectory in Black and White men. What is different, however, is that Black men have higher PSA levels.”

As to why the advanced-cancer incidence is similar in Black and White patients in the study, Daniel George, MD, director of genitourinary oncology at Duke Cancer Institute in Durham, North Carolina, says it’s important to understand that the Black men in this study “are not necessarily representative of the Black population at large.”

In this study, “they’re a little bit more healthcare inclined,” Dr. George notes. The study population is actively seeking the PSA test. Their socioeconomic profile might be closer to their White counterparts’, and that may make results more similar, he said.

“It’s possible that because this is a screening and not just men coming in for symptoms or cause, that we’re not seeing as much advanced disease,” he continued.

Amar Kishan, MD, chief of the genitourinary oncology service at University of California Los Angeles (UCLA) Health, says the genomic factors and environmental stressors that lead to elevated PSA counts don’t necessarily translate into aggressiveness of disease.

Why do Different Races have Different Prostate Cancer Risk?

Dr. George points out that the study also highlights that Asian men were significantly less likely to be diagnosed with prostate cancer within 1 year of the test.

The reasons for differences in prostate risk by race are complex, he notes. There are some clues that biologic factors may be at work. For instance, early puberty has a link to prostate cancer as it does to breast cancer, and height is also associated with a greater risk of prostate cancer, Dr. George said.

It’s not necessarily a racial association but there are some biological factors associated with prostate cancer later in life, he explained. “These may be enriched in certain populations, including northern Europeans and patients with African ancestries.”

The study also notes that Black men are more likely to die from prostate cancer than are White men, and Asian men are less likely than White or Black men to die from it.

Ms. Down said the difference in prostate cancer mortality between Black vs White men, in particular, may be related to a number of factors, and age, and lifetime risk of prostate cancer may play a major role, at least in the UK.

Should There Be Different ‘Normal’ PSA Levels for Different Races?

Dr. George says there is likely a need to change the system because a PSA level in one race may not signal the same risk it does in another. So medicine probably needs to standardize what a “normal” PSA is by race, he says, adding that he is a coauthor of an upcoming paper regarding that issue.

The lowest instances of prostate cancer were in Asian patients so this isn’t just a Black and White issue, Dr. George notes. “Being able to establish benchmarks by race and ethnicity is something that is probably needed in the field,” he says.

Dr. Kishan, on the other hand, says data from this study are not enough to support differentiating PSA levels based on race. He noted a limitation of the study is that it was not able to calculate the false-negative rate of PSA tests.

What are the Implications for Treating and Screening for Prostate Cancer

Dr. Kishan says there may be a role for increased intensity of screening, whether at an earlier age or with different intervals, but prostate cancer treatment should not differ by race.

“Our prior study, as well as others,” he says, “have shown that when you balance Black and White patients for every factor that might impact prognosis other than race — such as age, disease aggressiveness, etc. — Black men actually tend to have better  outcomes than White men. Thus, it would mean potentially overtreating (i.e., causing unnecessary side effects) to increase treatment intensity purely based on race with the available data.”

According to the paper, prostate cancer incidence in men with higher PSA levels increases with increasing age, even when using age-adjusted thresholds.

Dr. George says we know from this study and other studies as well that Black men are more likely to be diagnosed with prostate at a younger age. “Therefore, we probably need to be thinking about screening Black men starting at a younger age. These are the men who are most likely to benefit from an intervention — patients who have life expectancies of 20 years or more.”

What are the Downsides to Overdiagnosing Prostate Cancer in Men?

“It’s one of the biggest concerns that men have in proactively seeking healthcare,” Dr. George says. “They’re more likely to undergo treatment for this disease if they’re getting screened because (clinicians are) more likely to find it.”

Some of those men, he says, are going to undergo treatment for disease that won’t ultimately kill them, but may cause complications the men shouldn’t have had at all or otherwise may have had later.

“Overtreatment is a real concern. That’s why active surveillance is so important to minimize overtreatment of patients by finding out which cancers are low risk for progression and which are becoming more aggressive,” Dr. George says.

Authors of the study write that “the potential for overdiagnosis and the subsequent psychological and physical impact of diagnosis and treatment is an important consideration.”

All authors of the new paper received financial support from Cancer Research UK, the National Institute for Health and Care Research (NIHR), and the Higgins family for the submitted work.

Dr. George reports no relevant financial relationships.

Dr. Kishan reports consulting fees and speaking honoraria from Varian Medical Systems, Janssen, and Boston Scientific; research funding from PointBioPharma, Lantheus, and Janssen; and serving on advisory boards for Lantheus, Janssen and Boston Scientific.

More Black men with elevated prostate-specific antigen (PSA) counts are diagnosed with prostate cancer than their White counterparts, but incidence of advanced prostate cancer is similar for Black and White men within 1 year of the PSA test, a new study finds.

There was a substantial difference in prostate cancer diagnosis across ethnic groups: 25% of Black men with a raised PSA were diagnosed with prostate cancer within 1 year of being tested, compared with 20% of White men and 13% of Asian men, in the analysis of a large primary care cohort in the United Kingdom.

Incidence of advanced prostate cancer for Asian men with a raised PSA result was 4.5%, compared with 7.5% for White men and 7.0% for Black men.

Men included in the study were aged 40 and older and had no prior cancer diagnosis. Their ethnicity and PSA test result were logged in a national dataset between 2010 and 2017.

The study of more than 730,000 men, published in BMC Medicine, didn’t explore reasons for the differences, but experts offer their thoughts on what led to the findings and what these results imply.

Why the Higher Diagnosis Rates but Not More Advanced Disease in Black Men?

Lead author Liz Down, a graduate research assistant at the University of Exeter, Exeter, England, suggests the higher diagnosis rates but not more advanced disease in Black men may be linked to genetic variations.

Her team’s studies have shown that Black men in the United Kingdom and United States have higher levels of PSA. The PSA value is used to identify patients who might benefit from specialist investigation, and current guidelines in the UK and US don’t distinguish between ethnic groups.

As most men have slow-growing prostate cancer, this may lead to a disproportionately higher number of Black men being diagnosed with prostate cancer, she said.

“One possible interpretation,” Ms. Down notes, “is that prostate cancer follows a similar trajectory in Black and White men. What is different, however, is that Black men have higher PSA levels.”

As to why the advanced-cancer incidence is similar in Black and White patients in the study, Daniel George, MD, director of genitourinary oncology at Duke Cancer Institute in Durham, North Carolina, says it’s important to understand that the Black men in this study “are not necessarily representative of the Black population at large.”

In this study, “they’re a little bit more healthcare inclined,” Dr. George notes. The study population is actively seeking the PSA test. Their socioeconomic profile might be closer to their White counterparts’, and that may make results more similar, he said.

“It’s possible that because this is a screening and not just men coming in for symptoms or cause, that we’re not seeing as much advanced disease,” he continued.

Amar Kishan, MD, chief of the genitourinary oncology service at University of California Los Angeles (UCLA) Health, says the genomic factors and environmental stressors that lead to elevated PSA counts don’t necessarily translate into aggressiveness of disease.

Why do Different Races have Different Prostate Cancer Risk?

Dr. George points out that the study also highlights that Asian men were significantly less likely to be diagnosed with prostate cancer within 1 year of the test.

The reasons for differences in prostate risk by race are complex, he notes. There are some clues that biologic factors may be at work. For instance, early puberty has a link to prostate cancer as it does to breast cancer, and height is also associated with a greater risk of prostate cancer, Dr. George said.

It’s not necessarily a racial association but there are some biological factors associated with prostate cancer later in life, he explained. “These may be enriched in certain populations, including northern Europeans and patients with African ancestries.”

The study also notes that Black men are more likely to die from prostate cancer than are White men, and Asian men are less likely than White or Black men to die from it.

Ms. Down said the difference in prostate cancer mortality between Black vs White men, in particular, may be related to a number of factors, and age, and lifetime risk of prostate cancer may play a major role, at least in the UK.

Should There Be Different ‘Normal’ PSA Levels for Different Races?

Dr. George says there is likely a need to change the system because a PSA level in one race may not signal the same risk it does in another. So medicine probably needs to standardize what a “normal” PSA is by race, he says, adding that he is a coauthor of an upcoming paper regarding that issue.

The lowest instances of prostate cancer were in Asian patients so this isn’t just a Black and White issue, Dr. George notes. “Being able to establish benchmarks by race and ethnicity is something that is probably needed in the field,” he says.

Dr. Kishan, on the other hand, says data from this study are not enough to support differentiating PSA levels based on race. He noted a limitation of the study is that it was not able to calculate the false-negative rate of PSA tests.

What are the Implications for Treating and Screening for Prostate Cancer

Dr. Kishan says there may be a role for increased intensity of screening, whether at an earlier age or with different intervals, but prostate cancer treatment should not differ by race.

“Our prior study, as well as others,” he says, “have shown that when you balance Black and White patients for every factor that might impact prognosis other than race — such as age, disease aggressiveness, etc. — Black men actually tend to have better  outcomes than White men. Thus, it would mean potentially overtreating (i.e., causing unnecessary side effects) to increase treatment intensity purely based on race with the available data.”

According to the paper, prostate cancer incidence in men with higher PSA levels increases with increasing age, even when using age-adjusted thresholds.

Dr. George says we know from this study and other studies as well that Black men are more likely to be diagnosed with prostate at a younger age. “Therefore, we probably need to be thinking about screening Black men starting at a younger age. These are the men who are most likely to benefit from an intervention — patients who have life expectancies of 20 years or more.”

What are the Downsides to Overdiagnosing Prostate Cancer in Men?

“It’s one of the biggest concerns that men have in proactively seeking healthcare,” Dr. George says. “They’re more likely to undergo treatment for this disease if they’re getting screened because (clinicians are) more likely to find it.”

Some of those men, he says, are going to undergo treatment for disease that won’t ultimately kill them, but may cause complications the men shouldn’t have had at all or otherwise may have had later.

“Overtreatment is a real concern. That’s why active surveillance is so important to minimize overtreatment of patients by finding out which cancers are low risk for progression and which are becoming more aggressive,” Dr. George says.

Authors of the study write that “the potential for overdiagnosis and the subsequent psychological and physical impact of diagnosis and treatment is an important consideration.”

All authors of the new paper received financial support from Cancer Research UK, the National Institute for Health and Care Research (NIHR), and the Higgins family for the submitted work.

Dr. George reports no relevant financial relationships.

Dr. Kishan reports consulting fees and speaking honoraria from Varian Medical Systems, Janssen, and Boston Scientific; research funding from PointBioPharma, Lantheus, and Janssen; and serving on advisory boards for Lantheus, Janssen and Boston Scientific.

The US Food and Drug Administration approvals of dupilumab (Dupixent, Regeneron/Sanofi) for adults and children with eosinophilic esophagitis (EoE) affirmed the safety and efficacy of the drug, which is the first product indicated specifically for treatment of this disease.

The recent expanded approval for its use in kids aged 1 year and older imply that clinicians can prescribe it for just about any patient with the immune disorder.

But is dupilumab right for everyone?
 

What the Trials Said

Dupilumab, given by injection, is a recombinant human immunoglobulin-G4 monoclonal antibody that inhibits interleukin 4 (IL-4) and IL-13 signaling.

The first approval for EoE, on May 22, 2022, for adults and children aged 12 years and older weighing at least 40 kg, was based on data from 321 participants in the first two parts of a three-part phase 3 trial involving patients with EoE despite 8 weeks of high-dose proton pump inhibitor (PPI) therapy and with substantial symptom burden.

At 24 weeks, histologic remission occurred in 60% of patients in Part A of the trial and 59% in Part B who received a weekly 300-mg dose of dupilumab compared with 5% and 6% taking placebo. Additionally, Part A and B participants taking the drug weekly experienced a 69% and 64% reduction in disease symptoms, respectively, vs 32% and 41% for placebo. The drug also outperformed placebo in reducing patients’ esophageal eosinophilic counts and abnormal endoscopic findings.

The second approval, on January 25, 2024, for children aged 1 year and older weighing at least 15 kg, was based on data from a two-part, placebo-controlled trial involving 102 children, ages 1-11 years, with EoE. The study involved a 16-week treatment period and a 36-week extended period during which eligible children from the dupilumab group continued to receive their weight-based dose level and those who were on placebo switched to active treatment. The trial showed that a greater proportion of children taking the drug achieved histological remission.
 

A Major Advance but Temper Expectations

Dupilumab is a “major advance for EoE that has to find its place but should be looked at with optimism and what I call tempered expectations,” Philip Katz, MD, AGAF, professor of medicine in the gastroenterology division at Weill Cornell Medicine, New York City, said in an interview. “I’ve been using it since The New England Journal of Medicine paper was published about a year and a half ago , and as a slow adopter, I like it.”

Dr. Katz and his colleagues have been prescribing dupilumab mainly for patients who haven’t responded to other medications, mainly PPIs and steroids.

“We start people on it without stopping anything else,” Dr. Katz said. “Then, as symptoms evolve and people have a positive response, we stop the other medications. For example, in one patient who did very well on the drug, we stopped his steroids and now, we’re weaning him off his PPI. It’s a process. This is not a disease where you can rush people.”

The tempered approach is in part because of payer issues, he noted.

“It’s very difficult to get it reimbursed in the US if you haven’t tried something else first,” Dr. Katz said. “And because it’s still relatively new in this field, standard treatment is still used frequently.”

Although Dr. Katz has had “incredible success” with dupilumab so far, “nothing should be considered a miracle drug,” he said. “A couple of people have had injection reactions, and one person couldn’t tolerate the drug. So, while it seems to have an excellent response rate, it’s not 100%. Like any new drug, it will have to find its true success rate.”
 

Taking a Step-Up Approach

Like Dr. Katz, Evan Dellon, MD, MPH, AGAF, director of the Center for Esophageal Diseases and Swallowing at the University of North Carolina at Chapel Hill, North Carolina, is enthusiastic about dupilumab.

“It’s a boon to the field, and now, some real-world data are coming out and looking very much like the clinical trial data, which are reassuring,” said Dr. Dellon, a coauthor of The New England Journal of Medicine paper.

It’s been a “game changer,” particularly for people who weren’t doing well with their current treatments, he said. “In my practice, I’ve been seeing a lowish response rate for PPIs, and about 30%-40% not responding to topical steroids, since we don’t have a standard formulation for that. The diet elimination therapy is effective if people can do it well and adhere to it. But there’s a group of people who don’t respond, and probably, a larger group who can’t really do that treatment long term. So, the drug has been fantastic for those patients.”

Although the drug is approved for patients aged 1 year and older with no caveats, “it’s not the right medicine for every patient,” he said. “Patients in the clinical trials had EoE for 5 years, many of them were treatment refractory, and just under half had dilations and strictures,” he said. “They represent a certain group of patients.”

Dr. Dellon is taking a “step-up approach” to EoE treatment, first trying the standard interventions — PPIs, steroids, and an elimination diet — that many patients do respond to.

For new patients who choose medication therapy, he prescribes PPIs and then topical steroids and then steps up to dupilumab for patients who aren’t responding or who have a strong preference for starting the drug early.

In addition to EoE, the drug is approved for certain patients with atopic dermatitis, asthma, and chronic rhinosinusitis with nasal polyposis. As such, Dr. Dellon said that he will try dupilumab early on in patients with multiple atopic conditions, such as asthma, eczema, or nasal disease.

“Even if their EoE is not that severe, those patients can still benefit from a more streamlined systemic therapy,” he said.
 

Challenges and Questions Still Remain

Not surprisingly, both Dr. Katz and Dr. Dellon pointed to dupilumab’s cost and the related challenge of convincing insurance companies to cover the drug as major challenges to more widespread use. The lack of long-term data also poses a challenge.

Side effects, which often stand in the way of the use of a new drug, are not an issue, for the most part, at least in the short term, according to Dr. Dellon. The most common side effects are discomfort, redness at the injection site, and pain related to the injection.

“Keeping the medication out of the refrigerator for a bit to bring it up to room temperature can help, as can doing the injection in the lower abdomen,” he said. “Otherwise, it’s well tolerated, with no side effects that are unique to EoE.”

Data from the third part of the clinical trial, which followed patients from weeks 24-52 of treatment, indicated that improvements in histological, symptomatic, endoscopic, and molecular features of EoE among patients taking weekly dupilumab continued or improved.

In my practice, “my observations have been that people are maintaining their responses,” said Dr. Dellon, a coauthor of the paper on the study’s third part.

However, one critical question is whether the dose intensity and/or frequency can be decreased over time without reducing the response rate.

“Hopefully, we’ll start getting data on that in the next year or two,” Dr. Dellon said. “It’s hard to do that yet because the drug has only been out for a year or year and a half, and people are just getting to that year of the initial dosing.”

Another question is how to use the drug in people who are different from the clinical trial population, such as those who have been responding to other therapies but want to switch, and people who are newly diagnosed but who have severe disease. Can the drug be used earlier in these populations?

Dr. Dellon would like to see a study that utilizes the new EoE index of severity metric to focus specifically on dupilumab use in patients with severe disease.

Early findings from his recent real-world study of 46 patients with severe disease who would not have qualified for the clinical trials found histologic, endoscopic, and symptom improvement in 91% of patients with refractory and fibrostenotic EoE after 6 months of dupilumab treatment.

While women tend to be well represented in the clinical trial, the drug needs to be tested in a more diverse population, Dr. Dellon noted. Research is underway looking at dupilumab effectiveness in people with different race/ethnicities.

EoE is more common among White people but that may be the result of a “detection issue,” he said. “When clinicians see a Black or Hispanic patient with dysphagia, for example, they may not be thinking of EoE. And there are also some data suggesting that EoE presents slightly differently in non-White populations, which again could decrease the suspicion for it. This is an area we need to learn more about.”
 

Don’t ‘Abandon’ Current Interventions

“We’ve got an exciting drug that is going to help a lot of people with a complex disease,” Dr. Katz said. “But we should not forget that there are other interventions that have been successful, and quite frankly, they don’t need to be abandoned.”

“Learn about the drug if you’ve never used it,” he advised. “Read the studies so you understand who the patients were as a baseline for where you’re going to use it. Be prepared to do the appropriate paperwork requirements to get approvals from insurers. And look for more literature because it’s coming.”

“Overall, dupilumab has really changed care in people with moderate to severe disease who are not responding or are intolerant to the other treatments,” Dr. Dellon said. “That’s the natural place for the medication to go at this point.”

Dr. Katz is a consultant to Phathom Pharma, Sebela Pharma, Medpace (not active), and Medtronic.

Dr. Dellon received research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, and Shire/Takeda. He served as a consultant to Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Dr. Falk Pharma, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, and Upstream Bio. He also received educational grants from Allakos, Aqilion, Holoclara, and Invea.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration approvals of dupilumab (Dupixent, Regeneron/Sanofi) for adults and children with eosinophilic esophagitis (EoE) affirmed the safety and efficacy of the drug, which is the first product indicated specifically for treatment of this disease.

The recent expanded approval for its use in kids aged 1 year and older imply that clinicians can prescribe it for just about any patient with the immune disorder.

But is dupilumab right for everyone?
 

What the Trials Said

Dupilumab, given by injection, is a recombinant human immunoglobulin-G4 monoclonal antibody that inhibits interleukin 4 (IL-4) and IL-13 signaling.

The first approval for EoE, on May 22, 2022, for adults and children aged 12 years and older weighing at least 40 kg, was based on data from 321 participants in the first two parts of a three-part phase 3 trial involving patients with EoE despite 8 weeks of high-dose proton pump inhibitor (PPI) therapy and with substantial symptom burden.

At 24 weeks, histologic remission occurred in 60% of patients in Part A of the trial and 59% in Part B who received a weekly 300-mg dose of dupilumab compared with 5% and 6% taking placebo. Additionally, Part A and B participants taking the drug weekly experienced a 69% and 64% reduction in disease symptoms, respectively, vs 32% and 41% for placebo. The drug also outperformed placebo in reducing patients’ esophageal eosinophilic counts and abnormal endoscopic findings.

The second approval, on January 25, 2024, for children aged 1 year and older weighing at least 15 kg, was based on data from a two-part, placebo-controlled trial involving 102 children, ages 1-11 years, with EoE. The study involved a 16-week treatment period and a 36-week extended period during which eligible children from the dupilumab group continued to receive their weight-based dose level and those who were on placebo switched to active treatment. The trial showed that a greater proportion of children taking the drug achieved histological remission.
 

A Major Advance but Temper Expectations

Dupilumab is a “major advance for EoE that has to find its place but should be looked at with optimism and what I call tempered expectations,” Philip Katz, MD, AGAF, professor of medicine in the gastroenterology division at Weill Cornell Medicine, New York City, said in an interview. “I’ve been using it since The New England Journal of Medicine paper was published about a year and a half ago , and as a slow adopter, I like it.”

Dr. Katz and his colleagues have been prescribing dupilumab mainly for patients who haven’t responded to other medications, mainly PPIs and steroids.

“We start people on it without stopping anything else,” Dr. Katz said. “Then, as symptoms evolve and people have a positive response, we stop the other medications. For example, in one patient who did very well on the drug, we stopped his steroids and now, we’re weaning him off his PPI. It’s a process. This is not a disease where you can rush people.”

The tempered approach is in part because of payer issues, he noted.

“It’s very difficult to get it reimbursed in the US if you haven’t tried something else first,” Dr. Katz said. “And because it’s still relatively new in this field, standard treatment is still used frequently.”

Although Dr. Katz has had “incredible success” with dupilumab so far, “nothing should be considered a miracle drug,” he said. “A couple of people have had injection reactions, and one person couldn’t tolerate the drug. So, while it seems to have an excellent response rate, it’s not 100%. Like any new drug, it will have to find its true success rate.”
 

Taking a Step-Up Approach

Like Dr. Katz, Evan Dellon, MD, MPH, AGAF, director of the Center for Esophageal Diseases and Swallowing at the University of North Carolina at Chapel Hill, North Carolina, is enthusiastic about dupilumab.

“It’s a boon to the field, and now, some real-world data are coming out and looking very much like the clinical trial data, which are reassuring,” said Dr. Dellon, a coauthor of The New England Journal of Medicine paper.

It’s been a “game changer,” particularly for people who weren’t doing well with their current treatments, he said. “In my practice, I’ve been seeing a lowish response rate for PPIs, and about 30%-40% not responding to topical steroids, since we don’t have a standard formulation for that. The diet elimination therapy is effective if people can do it well and adhere to it. But there’s a group of people who don’t respond, and probably, a larger group who can’t really do that treatment long term. So, the drug has been fantastic for those patients.”

Although the drug is approved for patients aged 1 year and older with no caveats, “it’s not the right medicine for every patient,” he said. “Patients in the clinical trials had EoE for 5 years, many of them were treatment refractory, and just under half had dilations and strictures,” he said. “They represent a certain group of patients.”

Dr. Dellon is taking a “step-up approach” to EoE treatment, first trying the standard interventions — PPIs, steroids, and an elimination diet — that many patients do respond to.

For new patients who choose medication therapy, he prescribes PPIs and then topical steroids and then steps up to dupilumab for patients who aren’t responding or who have a strong preference for starting the drug early.

In addition to EoE, the drug is approved for certain patients with atopic dermatitis, asthma, and chronic rhinosinusitis with nasal polyposis. As such, Dr. Dellon said that he will try dupilumab early on in patients with multiple atopic conditions, such as asthma, eczema, or nasal disease.

“Even if their EoE is not that severe, those patients can still benefit from a more streamlined systemic therapy,” he said.
 

Challenges and Questions Still Remain

Not surprisingly, both Dr. Katz and Dr. Dellon pointed to dupilumab’s cost and the related challenge of convincing insurance companies to cover the drug as major challenges to more widespread use. The lack of long-term data also poses a challenge.

Side effects, which often stand in the way of the use of a new drug, are not an issue, for the most part, at least in the short term, according to Dr. Dellon. The most common side effects are discomfort, redness at the injection site, and pain related to the injection.

“Keeping the medication out of the refrigerator for a bit to bring it up to room temperature can help, as can doing the injection in the lower abdomen,” he said. “Otherwise, it’s well tolerated, with no side effects that are unique to EoE.”

Data from the third part of the clinical trial, which followed patients from weeks 24-52 of treatment, indicated that improvements in histological, symptomatic, endoscopic, and molecular features of EoE among patients taking weekly dupilumab continued or improved.

In my practice, “my observations have been that people are maintaining their responses,” said Dr. Dellon, a coauthor of the paper on the study’s third part.

However, one critical question is whether the dose intensity and/or frequency can be decreased over time without reducing the response rate.

“Hopefully, we’ll start getting data on that in the next year or two,” Dr. Dellon said. “It’s hard to do that yet because the drug has only been out for a year or year and a half, and people are just getting to that year of the initial dosing.”

Another question is how to use the drug in people who are different from the clinical trial population, such as those who have been responding to other therapies but want to switch, and people who are newly diagnosed but who have severe disease. Can the drug be used earlier in these populations?

Dr. Dellon would like to see a study that utilizes the new EoE index of severity metric to focus specifically on dupilumab use in patients with severe disease.

Early findings from his recent real-world study of 46 patients with severe disease who would not have qualified for the clinical trials found histologic, endoscopic, and symptom improvement in 91% of patients with refractory and fibrostenotic EoE after 6 months of dupilumab treatment.

While women tend to be well represented in the clinical trial, the drug needs to be tested in a more diverse population, Dr. Dellon noted. Research is underway looking at dupilumab effectiveness in people with different race/ethnicities.

EoE is more common among White people but that may be the result of a “detection issue,” he said. “When clinicians see a Black or Hispanic patient with dysphagia, for example, they may not be thinking of EoE. And there are also some data suggesting that EoE presents slightly differently in non-White populations, which again could decrease the suspicion for it. This is an area we need to learn more about.”
 

Don’t ‘Abandon’ Current Interventions

“We’ve got an exciting drug that is going to help a lot of people with a complex disease,” Dr. Katz said. “But we should not forget that there are other interventions that have been successful, and quite frankly, they don’t need to be abandoned.”

“Learn about the drug if you’ve never used it,” he advised. “Read the studies so you understand who the patients were as a baseline for where you’re going to use it. Be prepared to do the appropriate paperwork requirements to get approvals from insurers. And look for more literature because it’s coming.”

“Overall, dupilumab has really changed care in people with moderate to severe disease who are not responding or are intolerant to the other treatments,” Dr. Dellon said. “That’s the natural place for the medication to go at this point.”

Dr. Katz is a consultant to Phathom Pharma, Sebela Pharma, Medpace (not active), and Medtronic.

Dr. Dellon received research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, and Shire/Takeda. He served as a consultant to Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Dr. Falk Pharma, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, and Upstream Bio. He also received educational grants from Allakos, Aqilion, Holoclara, and Invea.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration approvals of dupilumab (Dupixent, Regeneron/Sanofi) for adults and children with eosinophilic esophagitis (EoE) affirmed the safety and efficacy of the drug, which is the first product indicated specifically for treatment of this disease.

The recent expanded approval for its use in kids aged 1 year and older imply that clinicians can prescribe it for just about any patient with the immune disorder.

But is dupilumab right for everyone?
 

What the Trials Said

Dupilumab, given by injection, is a recombinant human immunoglobulin-G4 monoclonal antibody that inhibits interleukin 4 (IL-4) and IL-13 signaling.

The first approval for EoE, on May 22, 2022, for adults and children aged 12 years and older weighing at least 40 kg, was based on data from 321 participants in the first two parts of a three-part phase 3 trial involving patients with EoE despite 8 weeks of high-dose proton pump inhibitor (PPI) therapy and with substantial symptom burden.

At 24 weeks, histologic remission occurred in 60% of patients in Part A of the trial and 59% in Part B who received a weekly 300-mg dose of dupilumab compared with 5% and 6% taking placebo. Additionally, Part A and B participants taking the drug weekly experienced a 69% and 64% reduction in disease symptoms, respectively, vs 32% and 41% for placebo. The drug also outperformed placebo in reducing patients’ esophageal eosinophilic counts and abnormal endoscopic findings.

The second approval, on January 25, 2024, for children aged 1 year and older weighing at least 15 kg, was based on data from a two-part, placebo-controlled trial involving 102 children, ages 1-11 years, with EoE. The study involved a 16-week treatment period and a 36-week extended period during which eligible children from the dupilumab group continued to receive their weight-based dose level and those who were on placebo switched to active treatment. The trial showed that a greater proportion of children taking the drug achieved histological remission.
 

A Major Advance but Temper Expectations

Dupilumab is a “major advance for EoE that has to find its place but should be looked at with optimism and what I call tempered expectations,” Philip Katz, MD, AGAF, professor of medicine in the gastroenterology division at Weill Cornell Medicine, New York City, said in an interview. “I’ve been using it since The New England Journal of Medicine paper was published about a year and a half ago , and as a slow adopter, I like it.”

Dr. Katz and his colleagues have been prescribing dupilumab mainly for patients who haven’t responded to other medications, mainly PPIs and steroids.

“We start people on it without stopping anything else,” Dr. Katz said. “Then, as symptoms evolve and people have a positive response, we stop the other medications. For example, in one patient who did very well on the drug, we stopped his steroids and now, we’re weaning him off his PPI. It’s a process. This is not a disease where you can rush people.”

The tempered approach is in part because of payer issues, he noted.

“It’s very difficult to get it reimbursed in the US if you haven’t tried something else first,” Dr. Katz said. “And because it’s still relatively new in this field, standard treatment is still used frequently.”

Although Dr. Katz has had “incredible success” with dupilumab so far, “nothing should be considered a miracle drug,” he said. “A couple of people have had injection reactions, and one person couldn’t tolerate the drug. So, while it seems to have an excellent response rate, it’s not 100%. Like any new drug, it will have to find its true success rate.”
 

Taking a Step-Up Approach

Like Dr. Katz, Evan Dellon, MD, MPH, AGAF, director of the Center for Esophageal Diseases and Swallowing at the University of North Carolina at Chapel Hill, North Carolina, is enthusiastic about dupilumab.

“It’s a boon to the field, and now, some real-world data are coming out and looking very much like the clinical trial data, which are reassuring,” said Dr. Dellon, a coauthor of The New England Journal of Medicine paper.

It’s been a “game changer,” particularly for people who weren’t doing well with their current treatments, he said. “In my practice, I’ve been seeing a lowish response rate for PPIs, and about 30%-40% not responding to topical steroids, since we don’t have a standard formulation for that. The diet elimination therapy is effective if people can do it well and adhere to it. But there’s a group of people who don’t respond, and probably, a larger group who can’t really do that treatment long term. So, the drug has been fantastic for those patients.”

Although the drug is approved for patients aged 1 year and older with no caveats, “it’s not the right medicine for every patient,” he said. “Patients in the clinical trials had EoE for 5 years, many of them were treatment refractory, and just under half had dilations and strictures,” he said. “They represent a certain group of patients.”

Dr. Dellon is taking a “step-up approach” to EoE treatment, first trying the standard interventions — PPIs, steroids, and an elimination diet — that many patients do respond to.

For new patients who choose medication therapy, he prescribes PPIs and then topical steroids and then steps up to dupilumab for patients who aren’t responding or who have a strong preference for starting the drug early.

In addition to EoE, the drug is approved for certain patients with atopic dermatitis, asthma, and chronic rhinosinusitis with nasal polyposis. As such, Dr. Dellon said that he will try dupilumab early on in patients with multiple atopic conditions, such as asthma, eczema, or nasal disease.

“Even if their EoE is not that severe, those patients can still benefit from a more streamlined systemic therapy,” he said.
 

Challenges and Questions Still Remain

Not surprisingly, both Dr. Katz and Dr. Dellon pointed to dupilumab’s cost and the related challenge of convincing insurance companies to cover the drug as major challenges to more widespread use. The lack of long-term data also poses a challenge.

Side effects, which often stand in the way of the use of a new drug, are not an issue, for the most part, at least in the short term, according to Dr. Dellon. The most common side effects are discomfort, redness at the injection site, and pain related to the injection.

“Keeping the medication out of the refrigerator for a bit to bring it up to room temperature can help, as can doing the injection in the lower abdomen,” he said. “Otherwise, it’s well tolerated, with no side effects that are unique to EoE.”

Data from the third part of the clinical trial, which followed patients from weeks 24-52 of treatment, indicated that improvements in histological, symptomatic, endoscopic, and molecular features of EoE among patients taking weekly dupilumab continued or improved.

In my practice, “my observations have been that people are maintaining their responses,” said Dr. Dellon, a coauthor of the paper on the study’s third part.

However, one critical question is whether the dose intensity and/or frequency can be decreased over time without reducing the response rate.

“Hopefully, we’ll start getting data on that in the next year or two,” Dr. Dellon said. “It’s hard to do that yet because the drug has only been out for a year or year and a half, and people are just getting to that year of the initial dosing.”

Another question is how to use the drug in people who are different from the clinical trial population, such as those who have been responding to other therapies but want to switch, and people who are newly diagnosed but who have severe disease. Can the drug be used earlier in these populations?

Dr. Dellon would like to see a study that utilizes the new EoE index of severity metric to focus specifically on dupilumab use in patients with severe disease.

Early findings from his recent real-world study of 46 patients with severe disease who would not have qualified for the clinical trials found histologic, endoscopic, and symptom improvement in 91% of patients with refractory and fibrostenotic EoE after 6 months of dupilumab treatment.

While women tend to be well represented in the clinical trial, the drug needs to be tested in a more diverse population, Dr. Dellon noted. Research is underway looking at dupilumab effectiveness in people with different race/ethnicities.

EoE is more common among White people but that may be the result of a “detection issue,” he said. “When clinicians see a Black or Hispanic patient with dysphagia, for example, they may not be thinking of EoE. And there are also some data suggesting that EoE presents slightly differently in non-White populations, which again could decrease the suspicion for it. This is an area we need to learn more about.”
 

Don’t ‘Abandon’ Current Interventions

“We’ve got an exciting drug that is going to help a lot of people with a complex disease,” Dr. Katz said. “But we should not forget that there are other interventions that have been successful, and quite frankly, they don’t need to be abandoned.”

“Learn about the drug if you’ve never used it,” he advised. “Read the studies so you understand who the patients were as a baseline for where you’re going to use it. Be prepared to do the appropriate paperwork requirements to get approvals from insurers. And look for more literature because it’s coming.”

“Overall, dupilumab has really changed care in people with moderate to severe disease who are not responding or are intolerant to the other treatments,” Dr. Dellon said. “That’s the natural place for the medication to go at this point.”

Dr. Katz is a consultant to Phathom Pharma, Sebela Pharma, Medpace (not active), and Medtronic.

Dr. Dellon received research funding from Adare/Ellodi, Allakos, Arena/Pfizer, AstraZeneca, Eupraxia, Ferring, GSK, Meritage, Miraca, Nutricia, Celgene/Receptos/BMS, Regeneron, Revolo, and Shire/Takeda. He served as a consultant to Abbott, AbbVie, Adare/Ellodi, Aimmune, Akesobio, Alfasigma, ALK, Allakos, Amgen, Aqilion, Arena/Pfizer, Aslan, AstraZeneca, Avir, Biorasi, Calypso, Celgene/Receptos/BMS, Celldex, Eli Lilly, EsoCap, Eupraxia, Dr. Falk Pharma, Ferring, GSK, Gossamer Bio, Holoclara, Invea, Knightpoint, Landos, LucidDx, Morphic, Nexstone Immunology/Uniquity, Nutricia, Parexel/Calyx, Phathom, Regeneron, Revolo, Robarts/Alimentiv, Salix, Sanofi, Shire/Takeda, Target RWE, and Upstream Bio. He also received educational grants from Allakos, Aqilion, Holoclara, and Invea.

A version of this article appeared on Medscape.com.

A new drug-device combo aimed at detecting residual cancer in real time during lumpectomy is one step closer to gaining federal approval, but some physicians aren’t convinced the technology is safe — or effective enough — to start using on patients.

A majority of the US Food and Drug Administration’s Medical Imaging Drugs Advisory Committee (MIDAC) on March 5 voted in support of LUMISIGHT’s (pegulicianine) benefit-risk profile.

LUMISIGHT is an optical imaging agent used in combination with Lumicell Direct Visualization System (DVS), a fluorescence-guided imaging system. The technology, developed by Lumicell Inc., helps surgeons identify cancer that may remain in the breast after they’ve completed the main resection of tissue.

Following MIDAC’s positive vote, the FDA will move on to reviewing Lumicell’s new drug application for LUMISIGHT and its premarket approval application for Lumicell DVS.

“We are proud of the efforts and look forward to the next steps as we work with the FDA to finalize the approval process so that women with breast cancer can access the therapy,” Jorge Ferrer, PhD, Lumicell’s chief scientific officer, said in an interview.

However, Freya Schnabel, MD, professor of surgery and director of breast surgery at NYU Perlmutter Cancer Center, said there are some “real concerns” with the technology. She expressed surprise at MIDAC’s overall favorable vote.

In a recently published study, she noted that the use of pegulicianine fluorescence-guided surgery (pFGS) did not meet the prespecified threshold for sensitivity.

“It did meet thresholds for removal of residual tumor and specificity — but this is still basically a negative study, and a low sensitivity raises concerns regarding false negative readings,” she said in an interview. “I’m surprised [the committee] is supportive in light of this result. Also, the technique is logistically challenging, as patients need to be injected 2 to 6 hours before their surgeries, very challenging timing for patients having ambulatory procedures.”

The study, published in the April 2023 NEJM Evidence, analyzed 357 patients who received 1.0 mg/kg intravenous pegulicianine followed by lumpectomy. Tumor left behind after standard lumpectomy was removed in 27 of 357 patients through use of pFGS. Of the 27, 22 patients had cavity orientations deemed “negative” on standard margin evaluation, according to the study. A margin is described as negative or clean when there are no further cancer cells at the edge of the tissue, suggesting that all of the cancer has been removed. Second surgeries were avoided by pFGS in 9 of 62 patients with positive margins, the analysis found.

On per-margin analysis, pFGS specificity was 85.2%, and sensitivity was 49.3%. While the sensitivity endpoint missed the lower boundary of the 95% confidence interval, the LUM system exceeded the specificity endpoint of 60% with a point estimate of 86%, and an accuracy of 84% for imaging residual cancer in the lumpectomy cavity, coinvestigator E. Shelley Hwang, MD, MPH, said during the MIDAC meeting.

“The pivotal study was an adequate and well-controlled study demonstrating the effectiveness of the LUM system to detect residual cancer in the lumpectomy cavity, following the standard of care procedure,” she said. “These results also demonstrate clinical benefit that improves the current standard of care. This is the first and only imaging system that provides results in the lumpectomy cavity in real time, allowing surgeons to use this information at the time of the initial procedure.”

Is the Technology Safe?

Pegulicianine is an imaging agent that contains a fluorescent dye. The agent is given to patients as a 3-minute intravenous infusion 2 to 6 hours before surgery.

After removal of the main tumor specimen, the surgeon inserts a handheld probe into the breast cavity and in combination with the detection software, searches for residual cancer that may have been left behind, Dr. Ferrer explained during the MIDAC meeting.

If the software identifies areas suspicious for residual cancer, those areas display in red on an overhead screen. The surgeon then takes a targeted shave to resect the suspicious tissue. Once the tissue has been removed, the surgeon can rescan the cavity with the probe to ensure a more complete resection has been performed. Use of the LUM system typically takes surgeons less than 7 minutes to use, Dr. Ferrer said.

In the study, a total of 406 patients received the intravenous pegulicianine, but 14 patients were withdrawn before randomization. After a standard lumpectomy procedure, 357 patients were assigned to the pFGS group and 35 patients to the control group.

Of the 406 patients, pegulicianine administration was stopped for adverse events in 6 patients (1.5%). Two patients had grade 3 serious adverse events related to pegulicianine; one had hypersensitivity, and one had an anaphylactic reaction. The other four pegulicianine-related adverse events included allergic reaction, milder hypersensitivity, nausea, and pegulicianine extravasation.

Dr. Schnabel said these reactions are worrisome. While any effort to reduce the need for patients to have more than one surgery to complete a breast conserving approach would be a “real advance,” Dr. Schnabel said she would not feel comfortable using pFGS in her own practice if approved by the FDA as is.

“This is clearly a major issue in terms of incorporating this technique into practice,” she said. “I could go on, but in light of the above, I’m surprised that [the committee] is supportive. I would hope for some refinement of the technique to reduce the risks to patients and improve the results before I’d consider utilizing this approach.”

During the MIDAC meeting, Dr. Ferrer said the company takes the safety events seriously and has developed mitigation strategies to further reduce the risk of patient hypersensitivity. These strategies include: clear labeling that informs users of anaphylaxis risk, incorporating a new section into the device training program to address warnings and precautions, an enhanced pharmacovigilance program to closely track and report hypersensitivity events, and a postmarket study to access the incidence rate and risk of such events in a broader population.

Several MIDAC members raised questions about the adverse reactions observed and about the safety of the technology.

David B. Hackney, MD, a neuroradiologist at Beth Israel Deaconess Medical Center in Boston, questioned the recommendation that patients only be monitored for 15 minutes after the injection.

“Since you don’t have enough data to know how long after injection reactions could occur, why not keep them under monitoring until after the surgery is over?” he said.

Barbara Smith, MD, PhD, lead investigator of the study, explained that per the protocol, there would be frequent monitoring, with a nurse at bedside, and patients would be monitored after injection, on their way to the procedure, and afterward.

She suggested, during the meeting, that more intense monitoring early in the process would be beneficial as that is when investigators observed side effects believed to be attributed to LUMISIGHT.

MIDAC member Kimberly E. Applegate, MD, a retired radiology professor, asked about the learning curve for surgeons and how long it generally takes for physicians to become familiar with the system.

Coinvestigator Kelly Hunt, MD, explained that all surgeons who participated in the trial completed a training program.

“Certainly, there’s a learning curve anytime we introduce new technology in the operating room,” she said. “Surgeons said it usually takes about three procedures before they’re comfortable with the system, including the camera and the software.”

During a presentation period by FDA officials, Anil Rajpal, MD, MPH, FDA, Deputy Division Director for Safety, said it’s important that prescribing information for LUMISIGHT communicate the risk of anaphylaxis and other hypersensitivity reactions, the need to monitor patients, and the need for the appropriate available personnel, medications, and equipment.

“This would be done by warnings and precautions and a boxed warning,” he said. “Note, that [such warnings] would only communicate the risks, it would not further characterize the risk.”
 

Committee Expresses Support

During a subsequent vote among committee members, most expressed support for the technology and its benefits. Sixteen members voted in support, one abstained, and two voted against the benefit-risk profile.

Andrea Richardson, MD, PhD, professor of pathology at Johns Hopkins in Baltimore, said she voted yes because the incremental benefits of avoiding additional surgeries outweigh the small risk of anaphylaxis.

Henry Royal, MD, MIDAC chair and professor of radiology at Washington University School of Medicine in St. Louis, agreed.

“Even though the benefit of this is on average, quite small, the benefit to the woman who has positive margins that’s converted to negative margins because of use of [LUMISIGHT] is really quite great,” he said. “The risk from this procedure is certainly very manageable.”

Harold J. Burstein, MD, PhD, a professor of medicine at Harvard Medical School and oncologist at Dana-Farber Cancer Institute in Boston, voted against the benefit-risk profile. He said the technology merits more research and that he does not believe it was proven the technology reduces the risk of reoperation.

“I think it’s a great technology,” he said. “I would like to see a well-conducted, randomized, phase III study with the endpoint of reoperation,” he said. “That would really prove the usefulness and benefit of the intervention in my mind.”

Chengjie Xiong, PhD, professor of biostatistics at Washington University School of Medicine in St. Louis, chose to abstain from voting because he said there was not enough data.

The FDA will now complete its review of Lumicell’s new drug application for LUMISIGHT and review of its premarket approval application for Lumicell DVS. The FDA review team has 6-10 months to make a decision. As part of the process, the FDA will evaluate clinical data, travel to clinical study sites to conduct inspections, and assemble a final action package for a senior FDA official to make a final decision.

If deemed safe and effective, the FDA will then work with Lumicell on developing and refining prescribing information.

Dr. Ferrer said his team expects to receive FDA approval in the coming weeks and will continue to work collaboratively with the FDA to expedite approval where possible.

The purpose of the MIDAC is to review and evaluate data about the safety and effectiveness of marketed and investigational human drug products for use in diagnostic and therapeutic procedures using radioactive pharmaceuticals and make appropriate recommendations to the FDA Commissioner.

A new drug-device combo aimed at detecting residual cancer in real time during lumpectomy is one step closer to gaining federal approval, but some physicians aren’t convinced the technology is safe — or effective enough — to start using on patients.

A majority of the US Food and Drug Administration’s Medical Imaging Drugs Advisory Committee (MIDAC) on March 5 voted in support of LUMISIGHT’s (pegulicianine) benefit-risk profile.

LUMISIGHT is an optical imaging agent used in combination with Lumicell Direct Visualization System (DVS), a fluorescence-guided imaging system. The technology, developed by Lumicell Inc., helps surgeons identify cancer that may remain in the breast after they’ve completed the main resection of tissue.

Following MIDAC’s positive vote, the FDA will move on to reviewing Lumicell’s new drug application for LUMISIGHT and its premarket approval application for Lumicell DVS.

“We are proud of the efforts and look forward to the next steps as we work with the FDA to finalize the approval process so that women with breast cancer can access the therapy,” Jorge Ferrer, PhD, Lumicell’s chief scientific officer, said in an interview.

However, Freya Schnabel, MD, professor of surgery and director of breast surgery at NYU Perlmutter Cancer Center, said there are some “real concerns” with the technology. She expressed surprise at MIDAC’s overall favorable vote.

In a recently published study, she noted that the use of pegulicianine fluorescence-guided surgery (pFGS) did not meet the prespecified threshold for sensitivity.

“It did meet thresholds for removal of residual tumor and specificity — but this is still basically a negative study, and a low sensitivity raises concerns regarding false negative readings,” she said in an interview. “I’m surprised [the committee] is supportive in light of this result. Also, the technique is logistically challenging, as patients need to be injected 2 to 6 hours before their surgeries, very challenging timing for patients having ambulatory procedures.”

The study, published in the April 2023 NEJM Evidence, analyzed 357 patients who received 1.0 mg/kg intravenous pegulicianine followed by lumpectomy. Tumor left behind after standard lumpectomy was removed in 27 of 357 patients through use of pFGS. Of the 27, 22 patients had cavity orientations deemed “negative” on standard margin evaluation, according to the study. A margin is described as negative or clean when there are no further cancer cells at the edge of the tissue, suggesting that all of the cancer has been removed. Second surgeries were avoided by pFGS in 9 of 62 patients with positive margins, the analysis found.

On per-margin analysis, pFGS specificity was 85.2%, and sensitivity was 49.3%. While the sensitivity endpoint missed the lower boundary of the 95% confidence interval, the LUM system exceeded the specificity endpoint of 60% with a point estimate of 86%, and an accuracy of 84% for imaging residual cancer in the lumpectomy cavity, coinvestigator E. Shelley Hwang, MD, MPH, said during the MIDAC meeting.

“The pivotal study was an adequate and well-controlled study demonstrating the effectiveness of the LUM system to detect residual cancer in the lumpectomy cavity, following the standard of care procedure,” she said. “These results also demonstrate clinical benefit that improves the current standard of care. This is the first and only imaging system that provides results in the lumpectomy cavity in real time, allowing surgeons to use this information at the time of the initial procedure.”

Is the Technology Safe?

Pegulicianine is an imaging agent that contains a fluorescent dye. The agent is given to patients as a 3-minute intravenous infusion 2 to 6 hours before surgery.

After removal of the main tumor specimen, the surgeon inserts a handheld probe into the breast cavity and in combination with the detection software, searches for residual cancer that may have been left behind, Dr. Ferrer explained during the MIDAC meeting.

If the software identifies areas suspicious for residual cancer, those areas display in red on an overhead screen. The surgeon then takes a targeted shave to resect the suspicious tissue. Once the tissue has been removed, the surgeon can rescan the cavity with the probe to ensure a more complete resection has been performed. Use of the LUM system typically takes surgeons less than 7 minutes to use, Dr. Ferrer said.

In the study, a total of 406 patients received the intravenous pegulicianine, but 14 patients were withdrawn before randomization. After a standard lumpectomy procedure, 357 patients were assigned to the pFGS group and 35 patients to the control group.

Of the 406 patients, pegulicianine administration was stopped for adverse events in 6 patients (1.5%). Two patients had grade 3 serious adverse events related to pegulicianine; one had hypersensitivity, and one had an anaphylactic reaction. The other four pegulicianine-related adverse events included allergic reaction, milder hypersensitivity, nausea, and pegulicianine extravasation.

Dr. Schnabel said these reactions are worrisome. While any effort to reduce the need for patients to have more than one surgery to complete a breast conserving approach would be a “real advance,” Dr. Schnabel said she would not feel comfortable using pFGS in her own practice if approved by the FDA as is.

“This is clearly a major issue in terms of incorporating this technique into practice,” she said. “I could go on, but in light of the above, I’m surprised that [the committee] is supportive. I would hope for some refinement of the technique to reduce the risks to patients and improve the results before I’d consider utilizing this approach.”

During the MIDAC meeting, Dr. Ferrer said the company takes the safety events seriously and has developed mitigation strategies to further reduce the risk of patient hypersensitivity. These strategies include: clear labeling that informs users of anaphylaxis risk, incorporating a new section into the device training program to address warnings and precautions, an enhanced pharmacovigilance program to closely track and report hypersensitivity events, and a postmarket study to access the incidence rate and risk of such events in a broader population.

Several MIDAC members raised questions about the adverse reactions observed and about the safety of the technology.

David B. Hackney, MD, a neuroradiologist at Beth Israel Deaconess Medical Center in Boston, questioned the recommendation that patients only be monitored for 15 minutes after the injection.

“Since you don’t have enough data to know how long after injection reactions could occur, why not keep them under monitoring until after the surgery is over?” he said.

Barbara Smith, MD, PhD, lead investigator of the study, explained that per the protocol, there would be frequent monitoring, with a nurse at bedside, and patients would be monitored after injection, on their way to the procedure, and afterward.

She suggested, during the meeting, that more intense monitoring early in the process would be beneficial as that is when investigators observed side effects believed to be attributed to LUMISIGHT.

MIDAC member Kimberly E. Applegate, MD, a retired radiology professor, asked about the learning curve for surgeons and how long it generally takes for physicians to become familiar with the system.

Coinvestigator Kelly Hunt, MD, explained that all surgeons who participated in the trial completed a training program.

“Certainly, there’s a learning curve anytime we introduce new technology in the operating room,” she said. “Surgeons said it usually takes about three procedures before they’re comfortable with the system, including the camera and the software.”

During a presentation period by FDA officials, Anil Rajpal, MD, MPH, FDA, Deputy Division Director for Safety, said it’s important that prescribing information for LUMISIGHT communicate the risk of anaphylaxis and other hypersensitivity reactions, the need to monitor patients, and the need for the appropriate available personnel, medications, and equipment.

“This would be done by warnings and precautions and a boxed warning,” he said. “Note, that [such warnings] would only communicate the risks, it would not further characterize the risk.”
 

Committee Expresses Support

During a subsequent vote among committee members, most expressed support for the technology and its benefits. Sixteen members voted in support, one abstained, and two voted against the benefit-risk profile.

Andrea Richardson, MD, PhD, professor of pathology at Johns Hopkins in Baltimore, said she voted yes because the incremental benefits of avoiding additional surgeries outweigh the small risk of anaphylaxis.

Henry Royal, MD, MIDAC chair and professor of radiology at Washington University School of Medicine in St. Louis, agreed.

“Even though the benefit of this is on average, quite small, the benefit to the woman who has positive margins that’s converted to negative margins because of use of [LUMISIGHT] is really quite great,” he said. “The risk from this procedure is certainly very manageable.”

Harold J. Burstein, MD, PhD, a professor of medicine at Harvard Medical School and oncologist at Dana-Farber Cancer Institute in Boston, voted against the benefit-risk profile. He said the technology merits more research and that he does not believe it was proven the technology reduces the risk of reoperation.

“I think it’s a great technology,” he said. “I would like to see a well-conducted, randomized, phase III study with the endpoint of reoperation,” he said. “That would really prove the usefulness and benefit of the intervention in my mind.”

Chengjie Xiong, PhD, professor of biostatistics at Washington University School of Medicine in St. Louis, chose to abstain from voting because he said there was not enough data.

The FDA will now complete its review of Lumicell’s new drug application for LUMISIGHT and review of its premarket approval application for Lumicell DVS. The FDA review team has 6-10 months to make a decision. As part of the process, the FDA will evaluate clinical data, travel to clinical study sites to conduct inspections, and assemble a final action package for a senior FDA official to make a final decision.

If deemed safe and effective, the FDA will then work with Lumicell on developing and refining prescribing information.

Dr. Ferrer said his team expects to receive FDA approval in the coming weeks and will continue to work collaboratively with the FDA to expedite approval where possible.

The purpose of the MIDAC is to review and evaluate data about the safety and effectiveness of marketed and investigational human drug products for use in diagnostic and therapeutic procedures using radioactive pharmaceuticals and make appropriate recommendations to the FDA Commissioner.

A new drug-device combo aimed at detecting residual cancer in real time during lumpectomy is one step closer to gaining federal approval, but some physicians aren’t convinced the technology is safe — or effective enough — to start using on patients.

A majority of the US Food and Drug Administration’s Medical Imaging Drugs Advisory Committee (MIDAC) on March 5 voted in support of LUMISIGHT’s (pegulicianine) benefit-risk profile.

LUMISIGHT is an optical imaging agent used in combination with Lumicell Direct Visualization System (DVS), a fluorescence-guided imaging system. The technology, developed by Lumicell Inc., helps surgeons identify cancer that may remain in the breast after they’ve completed the main resection of tissue.

Following MIDAC’s positive vote, the FDA will move on to reviewing Lumicell’s new drug application for LUMISIGHT and its premarket approval application for Lumicell DVS.

“We are proud of the efforts and look forward to the next steps as we work with the FDA to finalize the approval process so that women with breast cancer can access the therapy,” Jorge Ferrer, PhD, Lumicell’s chief scientific officer, said in an interview.

However, Freya Schnabel, MD, professor of surgery and director of breast surgery at NYU Perlmutter Cancer Center, said there are some “real concerns” with the technology. She expressed surprise at MIDAC’s overall favorable vote.

In a recently published study, she noted that the use of pegulicianine fluorescence-guided surgery (pFGS) did not meet the prespecified threshold for sensitivity.

“It did meet thresholds for removal of residual tumor and specificity — but this is still basically a negative study, and a low sensitivity raises concerns regarding false negative readings,” she said in an interview. “I’m surprised [the committee] is supportive in light of this result. Also, the technique is logistically challenging, as patients need to be injected 2 to 6 hours before their surgeries, very challenging timing for patients having ambulatory procedures.”

The study, published in the April 2023 NEJM Evidence, analyzed 357 patients who received 1.0 mg/kg intravenous pegulicianine followed by lumpectomy. Tumor left behind after standard lumpectomy was removed in 27 of 357 patients through use of pFGS. Of the 27, 22 patients had cavity orientations deemed “negative” on standard margin evaluation, according to the study. A margin is described as negative or clean when there are no further cancer cells at the edge of the tissue, suggesting that all of the cancer has been removed. Second surgeries were avoided by pFGS in 9 of 62 patients with positive margins, the analysis found.

On per-margin analysis, pFGS specificity was 85.2%, and sensitivity was 49.3%. While the sensitivity endpoint missed the lower boundary of the 95% confidence interval, the LUM system exceeded the specificity endpoint of 60% with a point estimate of 86%, and an accuracy of 84% for imaging residual cancer in the lumpectomy cavity, coinvestigator E. Shelley Hwang, MD, MPH, said during the MIDAC meeting.

“The pivotal study was an adequate and well-controlled study demonstrating the effectiveness of the LUM system to detect residual cancer in the lumpectomy cavity, following the standard of care procedure,” she said. “These results also demonstrate clinical benefit that improves the current standard of care. This is the first and only imaging system that provides results in the lumpectomy cavity in real time, allowing surgeons to use this information at the time of the initial procedure.”

Is the Technology Safe?

Pegulicianine is an imaging agent that contains a fluorescent dye. The agent is given to patients as a 3-minute intravenous infusion 2 to 6 hours before surgery.

After removal of the main tumor specimen, the surgeon inserts a handheld probe into the breast cavity and in combination with the detection software, searches for residual cancer that may have been left behind, Dr. Ferrer explained during the MIDAC meeting.

If the software identifies areas suspicious for residual cancer, those areas display in red on an overhead screen. The surgeon then takes a targeted shave to resect the suspicious tissue. Once the tissue has been removed, the surgeon can rescan the cavity with the probe to ensure a more complete resection has been performed. Use of the LUM system typically takes surgeons less than 7 minutes to use, Dr. Ferrer said.

In the study, a total of 406 patients received the intravenous pegulicianine, but 14 patients were withdrawn before randomization. After a standard lumpectomy procedure, 357 patients were assigned to the pFGS group and 35 patients to the control group.

Of the 406 patients, pegulicianine administration was stopped for adverse events in 6 patients (1.5%). Two patients had grade 3 serious adverse events related to pegulicianine; one had hypersensitivity, and one had an anaphylactic reaction. The other four pegulicianine-related adverse events included allergic reaction, milder hypersensitivity, nausea, and pegulicianine extravasation.

Dr. Schnabel said these reactions are worrisome. While any effort to reduce the need for patients to have more than one surgery to complete a breast conserving approach would be a “real advance,” Dr. Schnabel said she would not feel comfortable using pFGS in her own practice if approved by the FDA as is.

“This is clearly a major issue in terms of incorporating this technique into practice,” she said. “I could go on, but in light of the above, I’m surprised that [the committee] is supportive. I would hope for some refinement of the technique to reduce the risks to patients and improve the results before I’d consider utilizing this approach.”

During the MIDAC meeting, Dr. Ferrer said the company takes the safety events seriously and has developed mitigation strategies to further reduce the risk of patient hypersensitivity. These strategies include: clear labeling that informs users of anaphylaxis risk, incorporating a new section into the device training program to address warnings and precautions, an enhanced pharmacovigilance program to closely track and report hypersensitivity events, and a postmarket study to access the incidence rate and risk of such events in a broader population.

Several MIDAC members raised questions about the adverse reactions observed and about the safety of the technology.

David B. Hackney, MD, a neuroradiologist at Beth Israel Deaconess Medical Center in Boston, questioned the recommendation that patients only be monitored for 15 minutes after the injection.

“Since you don’t have enough data to know how long after injection reactions could occur, why not keep them under monitoring until after the surgery is over?” he said.

Barbara Smith, MD, PhD, lead investigator of the study, explained that per the protocol, there would be frequent monitoring, with a nurse at bedside, and patients would be monitored after injection, on their way to the procedure, and afterward.

She suggested, during the meeting, that more intense monitoring early in the process would be beneficial as that is when investigators observed side effects believed to be attributed to LUMISIGHT.

MIDAC member Kimberly E. Applegate, MD, a retired radiology professor, asked about the learning curve for surgeons and how long it generally takes for physicians to become familiar with the system.

Coinvestigator Kelly Hunt, MD, explained that all surgeons who participated in the trial completed a training program.

“Certainly, there’s a learning curve anytime we introduce new technology in the operating room,” she said. “Surgeons said it usually takes about three procedures before they’re comfortable with the system, including the camera and the software.”

During a presentation period by FDA officials, Anil Rajpal, MD, MPH, FDA, Deputy Division Director for Safety, said it’s important that prescribing information for LUMISIGHT communicate the risk of anaphylaxis and other hypersensitivity reactions, the need to monitor patients, and the need for the appropriate available personnel, medications, and equipment.

“This would be done by warnings and precautions and a boxed warning,” he said. “Note, that [such warnings] would only communicate the risks, it would not further characterize the risk.”
 

Committee Expresses Support

During a subsequent vote among committee members, most expressed support for the technology and its benefits. Sixteen members voted in support, one abstained, and two voted against the benefit-risk profile.

Andrea Richardson, MD, PhD, professor of pathology at Johns Hopkins in Baltimore, said she voted yes because the incremental benefits of avoiding additional surgeries outweigh the small risk of anaphylaxis.

Henry Royal, MD, MIDAC chair and professor of radiology at Washington University School of Medicine in St. Louis, agreed.

“Even though the benefit of this is on average, quite small, the benefit to the woman who has positive margins that’s converted to negative margins because of use of [LUMISIGHT] is really quite great,” he said. “The risk from this procedure is certainly very manageable.”

Harold J. Burstein, MD, PhD, a professor of medicine at Harvard Medical School and oncologist at Dana-Farber Cancer Institute in Boston, voted against the benefit-risk profile. He said the technology merits more research and that he does not believe it was proven the technology reduces the risk of reoperation.

“I think it’s a great technology,” he said. “I would like to see a well-conducted, randomized, phase III study with the endpoint of reoperation,” he said. “That would really prove the usefulness and benefit of the intervention in my mind.”

Chengjie Xiong, PhD, professor of biostatistics at Washington University School of Medicine in St. Louis, chose to abstain from voting because he said there was not enough data.

The FDA will now complete its review of Lumicell’s new drug application for LUMISIGHT and review of its premarket approval application for Lumicell DVS. The FDA review team has 6-10 months to make a decision. As part of the process, the FDA will evaluate clinical data, travel to clinical study sites to conduct inspections, and assemble a final action package for a senior FDA official to make a final decision.

If deemed safe and effective, the FDA will then work with Lumicell on developing and refining prescribing information.

Dr. Ferrer said his team expects to receive FDA approval in the coming weeks and will continue to work collaboratively with the FDA to expedite approval where possible.

The purpose of the MIDAC is to review and evaluate data about the safety and effectiveness of marketed and investigational human drug products for use in diagnostic and therapeutic procedures using radioactive pharmaceuticals and make appropriate recommendations to the FDA Commissioner.