Federal Practitioner

A recent review by Hadanny and colleagues recommends hyperbaric oxygen therapy (HBOT) for acute moderate to severe traumatic brain injury (TBI) and selected patients with prolonged postconcussive syndrome.

This article piqued my curiosity because I trained in HBOT more than 20 years ago. As a passionate scuba diver, my motivation was to master treatment for air embolism and decompression illness. Thankfully, these diving accidents are rare. However, I used HBOT for nonhealing wounds, and its efficacy was sometimes remarkable.
 

Paradoxical results with oxygen therapy

Although it may seem self-evident that “more oxygen is better” for medical illness, this is not necessarily true. I recently interviewed Ola Didrik Saugstad, MD, who demonstrated that the traditional practice of resuscitating newborns with 100% oxygen was more toxic than resuscitation with air (which contains 21% oxygen). His counterintuitive discovery led to a lifesaving change in the international newborn resuscitation guidelines.

The Food and Drug Administration has approved HBOT for a wide variety of conditions, but some practitioners enthusiastically promote it for off-label indications. These include antiaging, autism, multiple sclerosis, and the aforementioned TBI.

More than 50 years ago, HBOT was proposed for stroke, another disorder where the brain has been deprived of oxygen. Despite obvious logic, clinical trials have been unconvincing. The FDA has not approved HBOT for stroke.
 

HBOT in practice

During HBOT, the patient breathes 100% oxygen while the whole body is pressurized within a hyperbaric chamber. The chamber’s construction allows pressures above normal sea level of 1.0 atmosphere absolute (ATA). For example, The U.S. Navy Treatment Table for decompression sickness recommends 100% oxygen at 2.8 ATA. Chambers may hold one or more patients at a time.

The frequency of therapy varies but often consists of 20-60 sessions lasting 90-120 minutes. For off-label use like TBI, patients usually pay out of pocket. Given the multiple treatments, costs can add up.
 

Inconsistent evidence and sham controls

The unwieldy 33-page evidence review by Hadanny and colleagues cites multiple studies supporting HBOT for TBI. However, many, if not all, suffer from methodological flaws. These include vague inclusion criteria, lack of a control group, small patient numbers, treatment at different times since injury, poorly defined or varying HBOT protocols, varying outcome measures, and superficial results analysis.

A sham or control arm is essential for HBOT research trials, given the potential placebo effect of placing a human being inside a large, high-tech, sealed tube for an hour or more. In some sham-controlled studies, which consisted of low-pressure oxygen (that is, 1.3 ATA as sham vs. 2.4 ATA as treatment), all groups experienced symptom improvement. The review authors argue that the low-dose HBOT sham arms were biologically active and that the improvements seen mean that both high- and low-dose HBOT is therapeutic. The alternative explanation is that the placebo effect accounted for improvement in both groups.

The late Michael Bennett, a world authority on hyperbaric and underwater medicine, doubted that conventional HBOT sham controls could genuinely have a therapeutic effect, and I agree. The upcoming HOT-POCS trial (discussed below) should answer the question more definitively.
 

Mechanisms of action and safety

Mechanisms of benefit for HBOT include increased oxygen availability and angiogenesis. Animal research suggests that it may reduce secondary cell death from TBI, through stabilization of the blood-brain barrier and inflammation reduction.

HBOT is generally safe and well tolerated. A retrospective analysis of 1.5 million outpatient hyperbaric treatments revealed that less than 1% were associated with adverse events. The most common were ear and sinus barotrauma. Because HBOT uses increased air pressure, patients must equalize their ears and sinuses. Those who cannot because of altered consciousness, anatomical defects, or congestion must undergo myringotomy or terminate therapy. Claustrophobia was the second most common adverse effect. Convulsions and tension pneumocephalus were rare.

Perhaps the most concerning risk of HBOT for patients with TBI is the potential waste of human and financial resources.
 

Desperate physicians and patients

As a neurologist who regularly treats patients with TBI, I share the review authors’ frustration regarding the limited efficacy of available treatments. However, the suboptimal efficacy of currently available therapy is insufficient justification to recommend HBOT.

With respect to chronic TBI, it is difficult to imagine how HBOT could reverse brain injury that has been present for months or years. No other therapy exists that reliably encourages neuronal regeneration or prevents the development of posttraumatic epilepsy.

Frank Conidi, MD, a board-certified sports neurologist and headache specialist, shared his thoughts via email. He agrees that HBOT may have a role in TBI, but after reviewing Hadanny and colleagues’ paper, he concluded that there is insufficient evidence for the use of HBOT in all forms of TBI. He would like to see large multicenter, well-designed studies with standardized pressures and duration and a standard definition of the various types of head injury.
 

Ongoing research

There are at least five ongoing trials on HBOT for TBI or postconcussive syndrome, including the well-designed placebo-controlled HOT-POCS study. The latter has a novel placebo gas system that addresses Hadanny and colleagues’ contention that even low-dose HBOT might be effective.

The placebo arm in HOT-POCS mimics the HBO environment but provides only 0.21 ATA of oxygen, the same as room air. The active arm provides 100% oxygen at 2.0 ATA. If patients in both arms improve, the benefit will be caused by a placebo response, not HBOT.
 

Conflict of interest

Another concern with the review is that all three authors are affiliated with Aviv Scientific. This company has an exclusive partnership with the world’s largest hyperbaric medicine and research facility, the Sagol Center at Shamir Medical Center in Be’er Ya’akov, Israel.

This conflict of interest does not a priori invalidate their conclusions. However, official HBOT guidelines from a leading organization like the Undersea and Hyperbaric Medicine Society or the American Academy of Neurology would be preferable.
 

Conclusion

There is an urgent unmet need for more effective treatments for postconcussive syndrome and chronic TBI. Despite tantalizing theoretical mechanisms as to why HBOT might promote brain healing after trauma, its efficacy remains unproven.

The review authors’ recommendations for HBOT seem premature. They are arguably a disservice to the many desperate patients and their families who will be tempted to expend valuable resources of time and money for an appealing but unproven therapy. Appropriately designed placebo-controlled studies such as HOT-POCS will help separate fact from wishful thinking.

Dr. Wilner is associate professor of neurology at University of Tennessee Health Science Center, Memphis. He reported a conflict of interest with Accordant Health Services.

A version of this article first appeared on Medscape.com.

A recent review by Hadanny and colleagues recommends hyperbaric oxygen therapy (HBOT) for acute moderate to severe traumatic brain injury (TBI) and selected patients with prolonged postconcussive syndrome.

This article piqued my curiosity because I trained in HBOT more than 20 years ago. As a passionate scuba diver, my motivation was to master treatment for air embolism and decompression illness. Thankfully, these diving accidents are rare. However, I used HBOT for nonhealing wounds, and its efficacy was sometimes remarkable.
 

Paradoxical results with oxygen therapy

Although it may seem self-evident that “more oxygen is better” for medical illness, this is not necessarily true. I recently interviewed Ola Didrik Saugstad, MD, who demonstrated that the traditional practice of resuscitating newborns with 100% oxygen was more toxic than resuscitation with air (which contains 21% oxygen). His counterintuitive discovery led to a lifesaving change in the international newborn resuscitation guidelines.

The Food and Drug Administration has approved HBOT for a wide variety of conditions, but some practitioners enthusiastically promote it for off-label indications. These include antiaging, autism, multiple sclerosis, and the aforementioned TBI.

More than 50 years ago, HBOT was proposed for stroke, another disorder where the brain has been deprived of oxygen. Despite obvious logic, clinical trials have been unconvincing. The FDA has not approved HBOT for stroke.
 

HBOT in practice

During HBOT, the patient breathes 100% oxygen while the whole body is pressurized within a hyperbaric chamber. The chamber’s construction allows pressures above normal sea level of 1.0 atmosphere absolute (ATA). For example, The U.S. Navy Treatment Table for decompression sickness recommends 100% oxygen at 2.8 ATA. Chambers may hold one or more patients at a time.

The frequency of therapy varies but often consists of 20-60 sessions lasting 90-120 minutes. For off-label use like TBI, patients usually pay out of pocket. Given the multiple treatments, costs can add up.
 

Inconsistent evidence and sham controls

The unwieldy 33-page evidence review by Hadanny and colleagues cites multiple studies supporting HBOT for TBI. However, many, if not all, suffer from methodological flaws. These include vague inclusion criteria, lack of a control group, small patient numbers, treatment at different times since injury, poorly defined or varying HBOT protocols, varying outcome measures, and superficial results analysis.

A sham or control arm is essential for HBOT research trials, given the potential placebo effect of placing a human being inside a large, high-tech, sealed tube for an hour or more. In some sham-controlled studies, which consisted of low-pressure oxygen (that is, 1.3 ATA as sham vs. 2.4 ATA as treatment), all groups experienced symptom improvement. The review authors argue that the low-dose HBOT sham arms were biologically active and that the improvements seen mean that both high- and low-dose HBOT is therapeutic. The alternative explanation is that the placebo effect accounted for improvement in both groups.

The late Michael Bennett, a world authority on hyperbaric and underwater medicine, doubted that conventional HBOT sham controls could genuinely have a therapeutic effect, and I agree. The upcoming HOT-POCS trial (discussed below) should answer the question more definitively.
 

Mechanisms of action and safety

Mechanisms of benefit for HBOT include increased oxygen availability and angiogenesis. Animal research suggests that it may reduce secondary cell death from TBI, through stabilization of the blood-brain barrier and inflammation reduction.

HBOT is generally safe and well tolerated. A retrospective analysis of 1.5 million outpatient hyperbaric treatments revealed that less than 1% were associated with adverse events. The most common were ear and sinus barotrauma. Because HBOT uses increased air pressure, patients must equalize their ears and sinuses. Those who cannot because of altered consciousness, anatomical defects, or congestion must undergo myringotomy or terminate therapy. Claustrophobia was the second most common adverse effect. Convulsions and tension pneumocephalus were rare.

Perhaps the most concerning risk of HBOT for patients with TBI is the potential waste of human and financial resources.
 

Desperate physicians and patients

As a neurologist who regularly treats patients with TBI, I share the review authors’ frustration regarding the limited efficacy of available treatments. However, the suboptimal efficacy of currently available therapy is insufficient justification to recommend HBOT.

With respect to chronic TBI, it is difficult to imagine how HBOT could reverse brain injury that has been present for months or years. No other therapy exists that reliably encourages neuronal regeneration or prevents the development of posttraumatic epilepsy.

Frank Conidi, MD, a board-certified sports neurologist and headache specialist, shared his thoughts via email. He agrees that HBOT may have a role in TBI, but after reviewing Hadanny and colleagues’ paper, he concluded that there is insufficient evidence for the use of HBOT in all forms of TBI. He would like to see large multicenter, well-designed studies with standardized pressures and duration and a standard definition of the various types of head injury.
 

Ongoing research

There are at least five ongoing trials on HBOT for TBI or postconcussive syndrome, including the well-designed placebo-controlled HOT-POCS study. The latter has a novel placebo gas system that addresses Hadanny and colleagues’ contention that even low-dose HBOT might be effective.

The placebo arm in HOT-POCS mimics the HBO environment but provides only 0.21 ATA of oxygen, the same as room air. The active arm provides 100% oxygen at 2.0 ATA. If patients in both arms improve, the benefit will be caused by a placebo response, not HBOT.
 

Conflict of interest

Another concern with the review is that all three authors are affiliated with Aviv Scientific. This company has an exclusive partnership with the world’s largest hyperbaric medicine and research facility, the Sagol Center at Shamir Medical Center in Be’er Ya’akov, Israel.

This conflict of interest does not a priori invalidate their conclusions. However, official HBOT guidelines from a leading organization like the Undersea and Hyperbaric Medicine Society or the American Academy of Neurology would be preferable.
 

Conclusion

There is an urgent unmet need for more effective treatments for postconcussive syndrome and chronic TBI. Despite tantalizing theoretical mechanisms as to why HBOT might promote brain healing after trauma, its efficacy remains unproven.

The review authors’ recommendations for HBOT seem premature. They are arguably a disservice to the many desperate patients and their families who will be tempted to expend valuable resources of time and money for an appealing but unproven therapy. Appropriately designed placebo-controlled studies such as HOT-POCS will help separate fact from wishful thinking.

Dr. Wilner is associate professor of neurology at University of Tennessee Health Science Center, Memphis. He reported a conflict of interest with Accordant Health Services.

A version of this article first appeared on Medscape.com.

A recent review by Hadanny and colleagues recommends hyperbaric oxygen therapy (HBOT) for acute moderate to severe traumatic brain injury (TBI) and selected patients with prolonged postconcussive syndrome.

This article piqued my curiosity because I trained in HBOT more than 20 years ago. As a passionate scuba diver, my motivation was to master treatment for air embolism and decompression illness. Thankfully, these diving accidents are rare. However, I used HBOT for nonhealing wounds, and its efficacy was sometimes remarkable.
 

Paradoxical results with oxygen therapy

Although it may seem self-evident that “more oxygen is better” for medical illness, this is not necessarily true. I recently interviewed Ola Didrik Saugstad, MD, who demonstrated that the traditional practice of resuscitating newborns with 100% oxygen was more toxic than resuscitation with air (which contains 21% oxygen). His counterintuitive discovery led to a lifesaving change in the international newborn resuscitation guidelines.

The Food and Drug Administration has approved HBOT for a wide variety of conditions, but some practitioners enthusiastically promote it for off-label indications. These include antiaging, autism, multiple sclerosis, and the aforementioned TBI.

More than 50 years ago, HBOT was proposed for stroke, another disorder where the brain has been deprived of oxygen. Despite obvious logic, clinical trials have been unconvincing. The FDA has not approved HBOT for stroke.
 

HBOT in practice

During HBOT, the patient breathes 100% oxygen while the whole body is pressurized within a hyperbaric chamber. The chamber’s construction allows pressures above normal sea level of 1.0 atmosphere absolute (ATA). For example, The U.S. Navy Treatment Table for decompression sickness recommends 100% oxygen at 2.8 ATA. Chambers may hold one or more patients at a time.

The frequency of therapy varies but often consists of 20-60 sessions lasting 90-120 minutes. For off-label use like TBI, patients usually pay out of pocket. Given the multiple treatments, costs can add up.
 

Inconsistent evidence and sham controls

The unwieldy 33-page evidence review by Hadanny and colleagues cites multiple studies supporting HBOT for TBI. However, many, if not all, suffer from methodological flaws. These include vague inclusion criteria, lack of a control group, small patient numbers, treatment at different times since injury, poorly defined or varying HBOT protocols, varying outcome measures, and superficial results analysis.

A sham or control arm is essential for HBOT research trials, given the potential placebo effect of placing a human being inside a large, high-tech, sealed tube for an hour or more. In some sham-controlled studies, which consisted of low-pressure oxygen (that is, 1.3 ATA as sham vs. 2.4 ATA as treatment), all groups experienced symptom improvement. The review authors argue that the low-dose HBOT sham arms were biologically active and that the improvements seen mean that both high- and low-dose HBOT is therapeutic. The alternative explanation is that the placebo effect accounted for improvement in both groups.

The late Michael Bennett, a world authority on hyperbaric and underwater medicine, doubted that conventional HBOT sham controls could genuinely have a therapeutic effect, and I agree. The upcoming HOT-POCS trial (discussed below) should answer the question more definitively.
 

Mechanisms of action and safety

Mechanisms of benefit for HBOT include increased oxygen availability and angiogenesis. Animal research suggests that it may reduce secondary cell death from TBI, through stabilization of the blood-brain barrier and inflammation reduction.

HBOT is generally safe and well tolerated. A retrospective analysis of 1.5 million outpatient hyperbaric treatments revealed that less than 1% were associated with adverse events. The most common were ear and sinus barotrauma. Because HBOT uses increased air pressure, patients must equalize their ears and sinuses. Those who cannot because of altered consciousness, anatomical defects, or congestion must undergo myringotomy or terminate therapy. Claustrophobia was the second most common adverse effect. Convulsions and tension pneumocephalus were rare.

Perhaps the most concerning risk of HBOT for patients with TBI is the potential waste of human and financial resources.
 

Desperate physicians and patients

As a neurologist who regularly treats patients with TBI, I share the review authors’ frustration regarding the limited efficacy of available treatments. However, the suboptimal efficacy of currently available therapy is insufficient justification to recommend HBOT.

With respect to chronic TBI, it is difficult to imagine how HBOT could reverse brain injury that has been present for months or years. No other therapy exists that reliably encourages neuronal regeneration or prevents the development of posttraumatic epilepsy.

Frank Conidi, MD, a board-certified sports neurologist and headache specialist, shared his thoughts via email. He agrees that HBOT may have a role in TBI, but after reviewing Hadanny and colleagues’ paper, he concluded that there is insufficient evidence for the use of HBOT in all forms of TBI. He would like to see large multicenter, well-designed studies with standardized pressures and duration and a standard definition of the various types of head injury.
 

Ongoing research

There are at least five ongoing trials on HBOT for TBI or postconcussive syndrome, including the well-designed placebo-controlled HOT-POCS study. The latter has a novel placebo gas system that addresses Hadanny and colleagues’ contention that even low-dose HBOT might be effective.

The placebo arm in HOT-POCS mimics the HBO environment but provides only 0.21 ATA of oxygen, the same as room air. The active arm provides 100% oxygen at 2.0 ATA. If patients in both arms improve, the benefit will be caused by a placebo response, not HBOT.
 

Conflict of interest

Another concern with the review is that all three authors are affiliated with Aviv Scientific. This company has an exclusive partnership with the world’s largest hyperbaric medicine and research facility, the Sagol Center at Shamir Medical Center in Be’er Ya’akov, Israel.

This conflict of interest does not a priori invalidate their conclusions. However, official HBOT guidelines from a leading organization like the Undersea and Hyperbaric Medicine Society or the American Academy of Neurology would be preferable.
 

Conclusion

There is an urgent unmet need for more effective treatments for postconcussive syndrome and chronic TBI. Despite tantalizing theoretical mechanisms as to why HBOT might promote brain healing after trauma, its efficacy remains unproven.

The review authors’ recommendations for HBOT seem premature. They are arguably a disservice to the many desperate patients and their families who will be tempted to expend valuable resources of time and money for an appealing but unproven therapy. Appropriately designed placebo-controlled studies such as HOT-POCS will help separate fact from wishful thinking.

Dr. Wilner is associate professor of neurology at University of Tennessee Health Science Center, Memphis. He reported a conflict of interest with Accordant Health Services.

A version of this article first appeared on Medscape.com.

“The doctor won’t see you now.”

The editor of the alumni magazine had succeeded in getting my attention. The shock value of the headline hooked me and I was drawn in to chase down the research. A study by a team of researchers at Harvard Medical School has published a study in the British Medical Journal revealing that “from 2013 to 2019 the share of U.S. health care visits delivered by nonphysicians such as nurse practitioners or physician assistants increased from 14% to 26%.” In other words, at more than a quarter of the health care visits in this country the patient is not seen by a physician. The percent seen by advanced-practice providers varied by complaint and specialty. For example, 47% of patients with a respiratory complaint saw a nurse practitioner or physicians assistant, while for an eye condition only 13% were seen by an advanced-practice provider. However, overall the increase was dramatic.

It doesn’t require much deep thinking to come up with some explanations for this shift in provider involvement. It boils down to supply and demand. Compared with other similar nations, we have fewer physicians. Physicians are leaving the profession for a variety of reasons, including disappointment with their work-life balance and a sense that too much of their day is devoted to meaningless work with user unfriendly computer systems.

The number of nurse practitioners and physician assistants is growing faster than that of physicians. In fact it has been predicted that over the next 2 decades advanced-practice providers will increase by more than 50% while the physician pool will grow by less than 5%.

We can mull over the how-we-got-here ad infinitum, but this recent study suggests that we had better hustle and invest some time rethinking the role of a physician and how we should adapt our education system to better prepare for those choosing the path through medical school. This mirror gazing is particularly critical for those of us doing primary care.

While in years past I often heard a discontented grumble from patients that “I was ‘only’ seen by the nurse practitioner,” this complaint has become much less frequent as patients have gained more experience with advanced-practice providers and have begun to accept the new reality and see the change as inevitable.

When someone tells me that their daughter or nephew or second cousin is planning on becoming a doctor, I pause and listen patiently as they go on proudly about it before asking if the young person has considered becoming a physician assistant. I say, “Ya know, if I were 60 years younger I think I would bypass medical school and become a nurse practitioner because they get to do all the cool things that I enjoyed about seeing patients. Sure, my mother wouldn’t have been able to introduce me as her son the doctor. But, my parents and I would have spent less time and money on my training, and I would have had less administrative hassle heaped on me once I went into practice.”

The essence of good primary care is Availability, Continuity, and Expertise. The first two attributes aren’t taught in medical school and rely on commitment and having enough bodies to deliver the care. When it comes to expertise, how important is the broad and deep education of traditional medical school when the provider is seeing the relatively narrow spectrum of bread-and-butter everyday complaints that fill the day for most primary care providers? Particularly, when the population has already been preselected by age, geography, and socioeconomic factors.

The usual argument against my assertion is that a higher-priced and more arduous education pathway better provides the physician with the tools to deal with the outliers, the diagnostic enigmas. My reply is that any good provider regardless of his or her years spent in training is taught to first admit what they don’t know. When faced with an enigma, call a consultant or, in the near future, access a Chatbot.

If the natural market and economic forces continue to drive the growth of advanced-practice providers, what role(s) remains for the medical school–trained primary care provider? Does she or he remain the leader of a team of providers? Does she or he still see patients and somehow remain the first among equals?

While patients seem to be warming to the notion of seeing a nonphysician provider, I often still hear the complaint but “I see a different provider every time I go to the office.” Continuity is one of those three keystones of quality primary care. It is not incompatible with a team concept of care delivery, but it does require a commitment to the concept and creative scheduling that allows the patient to see the same provider at almost every visit. I’m not sure where having a first-among-equals provider fits into that scheme. Is it just one more “different” provider?

Maybe the medical school–trained provider becomes a consultant physician, much as the British and Canadian systems seem to work. She or he would see patients only after the advanced primary care provider has done an evaluation and is unsure of the next step. Would this be at the same site or electronically? Is there a time lag? In my old-school interpretation, if the visit is not the same day or maybe the next day then it doesn’t satisfy my Availability requirement of primary care.

I’m beginning to believe that the best role for the medical school–trained primary care specialist is someone who has a broad and deep understanding of the organizational issues around primary care. Primarily an educator who generally doesn’t see patients but instead trains advanced primary care providers, organizes them into teams that function to provide care in a timely fashion that emphasizes Continuity, and then performs ongoing, real time assessments to assure that care provided is at the highest level of Expertise.

It sounds like an interesting and challenging job description requiring a deep and broad education. Just not one that appeals to me. I would rather be a nurse practitioner or physician’s assistant who is on the front line and hands on.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com

“The doctor won’t see you now.”

The editor of the alumni magazine had succeeded in getting my attention. The shock value of the headline hooked me and I was drawn in to chase down the research. A study by a team of researchers at Harvard Medical School has published a study in the British Medical Journal revealing that “from 2013 to 2019 the share of U.S. health care visits delivered by nonphysicians such as nurse practitioners or physician assistants increased from 14% to 26%.” In other words, at more than a quarter of the health care visits in this country the patient is not seen by a physician. The percent seen by advanced-practice providers varied by complaint and specialty. For example, 47% of patients with a respiratory complaint saw a nurse practitioner or physicians assistant, while for an eye condition only 13% were seen by an advanced-practice provider. However, overall the increase was dramatic.

It doesn’t require much deep thinking to come up with some explanations for this shift in provider involvement. It boils down to supply and demand. Compared with other similar nations, we have fewer physicians. Physicians are leaving the profession for a variety of reasons, including disappointment with their work-life balance and a sense that too much of their day is devoted to meaningless work with user unfriendly computer systems.

The number of nurse practitioners and physician assistants is growing faster than that of physicians. In fact it has been predicted that over the next 2 decades advanced-practice providers will increase by more than 50% while the physician pool will grow by less than 5%.

We can mull over the how-we-got-here ad infinitum, but this recent study suggests that we had better hustle and invest some time rethinking the role of a physician and how we should adapt our education system to better prepare for those choosing the path through medical school. This mirror gazing is particularly critical for those of us doing primary care.

While in years past I often heard a discontented grumble from patients that “I was ‘only’ seen by the nurse practitioner,” this complaint has become much less frequent as patients have gained more experience with advanced-practice providers and have begun to accept the new reality and see the change as inevitable.

When someone tells me that their daughter or nephew or second cousin is planning on becoming a doctor, I pause and listen patiently as they go on proudly about it before asking if the young person has considered becoming a physician assistant. I say, “Ya know, if I were 60 years younger I think I would bypass medical school and become a nurse practitioner because they get to do all the cool things that I enjoyed about seeing patients. Sure, my mother wouldn’t have been able to introduce me as her son the doctor. But, my parents and I would have spent less time and money on my training, and I would have had less administrative hassle heaped on me once I went into practice.”

The essence of good primary care is Availability, Continuity, and Expertise. The first two attributes aren’t taught in medical school and rely on commitment and having enough bodies to deliver the care. When it comes to expertise, how important is the broad and deep education of traditional medical school when the provider is seeing the relatively narrow spectrum of bread-and-butter everyday complaints that fill the day for most primary care providers? Particularly, when the population has already been preselected by age, geography, and socioeconomic factors.

The usual argument against my assertion is that a higher-priced and more arduous education pathway better provides the physician with the tools to deal with the outliers, the diagnostic enigmas. My reply is that any good provider regardless of his or her years spent in training is taught to first admit what they don’t know. When faced with an enigma, call a consultant or, in the near future, access a Chatbot.

If the natural market and economic forces continue to drive the growth of advanced-practice providers, what role(s) remains for the medical school–trained primary care provider? Does she or he remain the leader of a team of providers? Does she or he still see patients and somehow remain the first among equals?

While patients seem to be warming to the notion of seeing a nonphysician provider, I often still hear the complaint but “I see a different provider every time I go to the office.” Continuity is one of those three keystones of quality primary care. It is not incompatible with a team concept of care delivery, but it does require a commitment to the concept and creative scheduling that allows the patient to see the same provider at almost every visit. I’m not sure where having a first-among-equals provider fits into that scheme. Is it just one more “different” provider?

Maybe the medical school–trained provider becomes a consultant physician, much as the British and Canadian systems seem to work. She or he would see patients only after the advanced primary care provider has done an evaluation and is unsure of the next step. Would this be at the same site or electronically? Is there a time lag? In my old-school interpretation, if the visit is not the same day or maybe the next day then it doesn’t satisfy my Availability requirement of primary care.

I’m beginning to believe that the best role for the medical school–trained primary care specialist is someone who has a broad and deep understanding of the organizational issues around primary care. Primarily an educator who generally doesn’t see patients but instead trains advanced primary care providers, organizes them into teams that function to provide care in a timely fashion that emphasizes Continuity, and then performs ongoing, real time assessments to assure that care provided is at the highest level of Expertise.

It sounds like an interesting and challenging job description requiring a deep and broad education. Just not one that appeals to me. I would rather be a nurse practitioner or physician’s assistant who is on the front line and hands on.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com

“The doctor won’t see you now.”

The editor of the alumni magazine had succeeded in getting my attention. The shock value of the headline hooked me and I was drawn in to chase down the research. A study by a team of researchers at Harvard Medical School has published a study in the British Medical Journal revealing that “from 2013 to 2019 the share of U.S. health care visits delivered by nonphysicians such as nurse practitioners or physician assistants increased from 14% to 26%.” In other words, at more than a quarter of the health care visits in this country the patient is not seen by a physician. The percent seen by advanced-practice providers varied by complaint and specialty. For example, 47% of patients with a respiratory complaint saw a nurse practitioner or physicians assistant, while for an eye condition only 13% were seen by an advanced-practice provider. However, overall the increase was dramatic.

It doesn’t require much deep thinking to come up with some explanations for this shift in provider involvement. It boils down to supply and demand. Compared with other similar nations, we have fewer physicians. Physicians are leaving the profession for a variety of reasons, including disappointment with their work-life balance and a sense that too much of their day is devoted to meaningless work with user unfriendly computer systems.

The number of nurse practitioners and physician assistants is growing faster than that of physicians. In fact it has been predicted that over the next 2 decades advanced-practice providers will increase by more than 50% while the physician pool will grow by less than 5%.

We can mull over the how-we-got-here ad infinitum, but this recent study suggests that we had better hustle and invest some time rethinking the role of a physician and how we should adapt our education system to better prepare for those choosing the path through medical school. This mirror gazing is particularly critical for those of us doing primary care.

While in years past I often heard a discontented grumble from patients that “I was ‘only’ seen by the nurse practitioner,” this complaint has become much less frequent as patients have gained more experience with advanced-practice providers and have begun to accept the new reality and see the change as inevitable.

When someone tells me that their daughter or nephew or second cousin is planning on becoming a doctor, I pause and listen patiently as they go on proudly about it before asking if the young person has considered becoming a physician assistant. I say, “Ya know, if I were 60 years younger I think I would bypass medical school and become a nurse practitioner because they get to do all the cool things that I enjoyed about seeing patients. Sure, my mother wouldn’t have been able to introduce me as her son the doctor. But, my parents and I would have spent less time and money on my training, and I would have had less administrative hassle heaped on me once I went into practice.”

The essence of good primary care is Availability, Continuity, and Expertise. The first two attributes aren’t taught in medical school and rely on commitment and having enough bodies to deliver the care. When it comes to expertise, how important is the broad and deep education of traditional medical school when the provider is seeing the relatively narrow spectrum of bread-and-butter everyday complaints that fill the day for most primary care providers? Particularly, when the population has already been preselected by age, geography, and socioeconomic factors.

The usual argument against my assertion is that a higher-priced and more arduous education pathway better provides the physician with the tools to deal with the outliers, the diagnostic enigmas. My reply is that any good provider regardless of his or her years spent in training is taught to first admit what they don’t know. When faced with an enigma, call a consultant or, in the near future, access a Chatbot.

If the natural market and economic forces continue to drive the growth of advanced-practice providers, what role(s) remains for the medical school–trained primary care provider? Does she or he remain the leader of a team of providers? Does she or he still see patients and somehow remain the first among equals?

While patients seem to be warming to the notion of seeing a nonphysician provider, I often still hear the complaint but “I see a different provider every time I go to the office.” Continuity is one of those three keystones of quality primary care. It is not incompatible with a team concept of care delivery, but it does require a commitment to the concept and creative scheduling that allows the patient to see the same provider at almost every visit. I’m not sure where having a first-among-equals provider fits into that scheme. Is it just one more “different” provider?

Maybe the medical school–trained provider becomes a consultant physician, much as the British and Canadian systems seem to work. She or he would see patients only after the advanced primary care provider has done an evaluation and is unsure of the next step. Would this be at the same site or electronically? Is there a time lag? In my old-school interpretation, if the visit is not the same day or maybe the next day then it doesn’t satisfy my Availability requirement of primary care.

I’m beginning to believe that the best role for the medical school–trained primary care specialist is someone who has a broad and deep understanding of the organizational issues around primary care. Primarily an educator who generally doesn’t see patients but instead trains advanced primary care providers, organizes them into teams that function to provide care in a timely fashion that emphasizes Continuity, and then performs ongoing, real time assessments to assure that care provided is at the highest level of Expertise.

It sounds like an interesting and challenging job description requiring a deep and broad education. Just not one that appeals to me. I would rather be a nurse practitioner or physician’s assistant who is on the front line and hands on.

Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.” Other than a Littman stethoscope he accepted as a first-year medical student in 1966, Dr. Wilkoff reports having nothing to disclose. Email him at pdnews@mdedge.com

SAN DIEGO – Patients with limited-stage small cell lung cancer (LS-SCLC) had improved overall survival and progression-free survival when they received higher-dose thoracic radiotherapy instead of the standard treatment, according to a new multicenter, open-label, randomized phase III trial.

Among 224 patients in China, aged 18-70, those randomly assigned to receive volumetric-modulated arc radiotherapy of high-dose, hypofractionated thoracic radiotherapy of 54 Gy in 30 fractions had a much higher median overall survival (62.4 months) than those who received the standard dose of 45 Gy in 30 fractions (43.1 months, P = .001), reported Jiayi Yu, PhD, of Beijing University Cancer Hospital and Institute and colleagues at the annual meeting of the American Society for Radiation Oncology.

Median progression-free survival was also higher in the 54 Gy group (30.5 months vs. 16.7 months in the 45 Gy group, P = .044).

Kristin Higgins, MD, of Winship Cancer Institute of Emory University, Atlanta, provided perspective at the ASTRO session following Dr. Yu’s presentation. She noted that the study population is quite different than that of LS-SCLC patients in the United States, where patients are often older and more likely to have a history of smoking.

“We need more technical details to understand how to deliver this regimen in clinical practice, and it may not be applicable for all patients,” she said. Still, she added that “a key takeaway here is that optimizing the radiotherapy component of treatment is very important.”

Both groups received chemotherapy. “Higher-dose thoracic radiation therapy concurrently with chemotherapy is an alternative therapeutic option,” Dr. Yu said at an ASTRO presentation.

As Dr. Yu noted, twice-daily thoracic radiotherapy of 45 Gy in 30 fractions and concurrent chemotherapy has been the standard treatment for LS-SCLC for the last 20 years. Trials failed to show benefits for once-daily 66-Gy (33 fractions) or 70-Gy treatment (35 fractions), but a phase 2 trial published in 2023 did indicate that twice-daily treatment of 60 Gy (40 fractions) improved survival without boosting side effects.

For the new study, researchers tracked 224 patients from 2017 to 2021 who were previously untreated or had received specific chemotherapy treatments and had ECOG performance status scores of 0 or 1; 108 patients were randomly assigned to the 54-Gy arm and 116 to the 45-Gy arm. All were recruited at 16 public hospitals in China.

The median age in the two groups were 60 in the 54-Gy arm and 62 in the 45-Gy arm; the percentages of women were similar (45.4% and 45.7%, respectively). Most were current or former smokers (62.0% and 61.2%, respectively).

The researchers closed the trial in April 2021 because of the survival benefit in the 54-Gy arm, and patients were tracked through January 2023 for a median 45 months.

Nearly three-quarters of patients in the 54-Gy arm survived to 2 years (77.7%) vs. 53.4% in the 45-Gy arm, a 41% reduction in risk of death. Adverse events were similar between the groups, with 1 reported treatment-related death (myocardial infarction), in the 54-Gy group.

In an interview, Kenneth Rosenzweig, MD, chairman of the department of radiation oncology at Icahn School of Medicine at Mount Sinai, New York, praised the study. It’s “no surprise” that higher radiation doses are well-tolerated since “our ability to shield normal tissue has improved” over the years, said Dr. Rosenzweig, who served as a moderator of the ASTRO session where the research was presented.

However, he cautioned that hypofractionation is still “intense” and may not be appropriate for certain patients. And he added that some clinics may not be set up to provide twice-daily treatments.

Information about study funding was not provided. The study authors have no disclosures. Dr. Higgins discloses relationships with AstraZeneca and Regeneron (advisory board), Jazz (funded research), and Janssen and Picture Health (consulting). Dr. Rosenzweig has no disclosures.

SAN DIEGO – Patients with limited-stage small cell lung cancer (LS-SCLC) had improved overall survival and progression-free survival when they received higher-dose thoracic radiotherapy instead of the standard treatment, according to a new multicenter, open-label, randomized phase III trial.

Among 224 patients in China, aged 18-70, those randomly assigned to receive volumetric-modulated arc radiotherapy of high-dose, hypofractionated thoracic radiotherapy of 54 Gy in 30 fractions had a much higher median overall survival (62.4 months) than those who received the standard dose of 45 Gy in 30 fractions (43.1 months, P = .001), reported Jiayi Yu, PhD, of Beijing University Cancer Hospital and Institute and colleagues at the annual meeting of the American Society for Radiation Oncology.

Median progression-free survival was also higher in the 54 Gy group (30.5 months vs. 16.7 months in the 45 Gy group, P = .044).

Kristin Higgins, MD, of Winship Cancer Institute of Emory University, Atlanta, provided perspective at the ASTRO session following Dr. Yu’s presentation. She noted that the study population is quite different than that of LS-SCLC patients in the United States, where patients are often older and more likely to have a history of smoking.

“We need more technical details to understand how to deliver this regimen in clinical practice, and it may not be applicable for all patients,” she said. Still, she added that “a key takeaway here is that optimizing the radiotherapy component of treatment is very important.”

Both groups received chemotherapy. “Higher-dose thoracic radiation therapy concurrently with chemotherapy is an alternative therapeutic option,” Dr. Yu said at an ASTRO presentation.

As Dr. Yu noted, twice-daily thoracic radiotherapy of 45 Gy in 30 fractions and concurrent chemotherapy has been the standard treatment for LS-SCLC for the last 20 years. Trials failed to show benefits for once-daily 66-Gy (33 fractions) or 70-Gy treatment (35 fractions), but a phase 2 trial published in 2023 did indicate that twice-daily treatment of 60 Gy (40 fractions) improved survival without boosting side effects.

For the new study, researchers tracked 224 patients from 2017 to 2021 who were previously untreated or had received specific chemotherapy treatments and had ECOG performance status scores of 0 or 1; 108 patients were randomly assigned to the 54-Gy arm and 116 to the 45-Gy arm. All were recruited at 16 public hospitals in China.

The median age in the two groups were 60 in the 54-Gy arm and 62 in the 45-Gy arm; the percentages of women were similar (45.4% and 45.7%, respectively). Most were current or former smokers (62.0% and 61.2%, respectively).

The researchers closed the trial in April 2021 because of the survival benefit in the 54-Gy arm, and patients were tracked through January 2023 for a median 45 months.

Nearly three-quarters of patients in the 54-Gy arm survived to 2 years (77.7%) vs. 53.4% in the 45-Gy arm, a 41% reduction in risk of death. Adverse events were similar between the groups, with 1 reported treatment-related death (myocardial infarction), in the 54-Gy group.

In an interview, Kenneth Rosenzweig, MD, chairman of the department of radiation oncology at Icahn School of Medicine at Mount Sinai, New York, praised the study. It’s “no surprise” that higher radiation doses are well-tolerated since “our ability to shield normal tissue has improved” over the years, said Dr. Rosenzweig, who served as a moderator of the ASTRO session where the research was presented.

However, he cautioned that hypofractionation is still “intense” and may not be appropriate for certain patients. And he added that some clinics may not be set up to provide twice-daily treatments.

Information about study funding was not provided. The study authors have no disclosures. Dr. Higgins discloses relationships with AstraZeneca and Regeneron (advisory board), Jazz (funded research), and Janssen and Picture Health (consulting). Dr. Rosenzweig has no disclosures.

SAN DIEGO – Patients with limited-stage small cell lung cancer (LS-SCLC) had improved overall survival and progression-free survival when they received higher-dose thoracic radiotherapy instead of the standard treatment, according to a new multicenter, open-label, randomized phase III trial.

Among 224 patients in China, aged 18-70, those randomly assigned to receive volumetric-modulated arc radiotherapy of high-dose, hypofractionated thoracic radiotherapy of 54 Gy in 30 fractions had a much higher median overall survival (62.4 months) than those who received the standard dose of 45 Gy in 30 fractions (43.1 months, P = .001), reported Jiayi Yu, PhD, of Beijing University Cancer Hospital and Institute and colleagues at the annual meeting of the American Society for Radiation Oncology.

Median progression-free survival was also higher in the 54 Gy group (30.5 months vs. 16.7 months in the 45 Gy group, P = .044).

Kristin Higgins, MD, of Winship Cancer Institute of Emory University, Atlanta, provided perspective at the ASTRO session following Dr. Yu’s presentation. She noted that the study population is quite different than that of LS-SCLC patients in the United States, where patients are often older and more likely to have a history of smoking.

“We need more technical details to understand how to deliver this regimen in clinical practice, and it may not be applicable for all patients,” she said. Still, she added that “a key takeaway here is that optimizing the radiotherapy component of treatment is very important.”

Both groups received chemotherapy. “Higher-dose thoracic radiation therapy concurrently with chemotherapy is an alternative therapeutic option,” Dr. Yu said at an ASTRO presentation.

As Dr. Yu noted, twice-daily thoracic radiotherapy of 45 Gy in 30 fractions and concurrent chemotherapy has been the standard treatment for LS-SCLC for the last 20 years. Trials failed to show benefits for once-daily 66-Gy (33 fractions) or 70-Gy treatment (35 fractions), but a phase 2 trial published in 2023 did indicate that twice-daily treatment of 60 Gy (40 fractions) improved survival without boosting side effects.

For the new study, researchers tracked 224 patients from 2017 to 2021 who were previously untreated or had received specific chemotherapy treatments and had ECOG performance status scores of 0 or 1; 108 patients were randomly assigned to the 54-Gy arm and 116 to the 45-Gy arm. All were recruited at 16 public hospitals in China.

The median age in the two groups were 60 in the 54-Gy arm and 62 in the 45-Gy arm; the percentages of women were similar (45.4% and 45.7%, respectively). Most were current or former smokers (62.0% and 61.2%, respectively).

The researchers closed the trial in April 2021 because of the survival benefit in the 54-Gy arm, and patients were tracked through January 2023 for a median 45 months.

Nearly three-quarters of patients in the 54-Gy arm survived to 2 years (77.7%) vs. 53.4% in the 45-Gy arm, a 41% reduction in risk of death. Adverse events were similar between the groups, with 1 reported treatment-related death (myocardial infarction), in the 54-Gy group.

In an interview, Kenneth Rosenzweig, MD, chairman of the department of radiation oncology at Icahn School of Medicine at Mount Sinai, New York, praised the study. It’s “no surprise” that higher radiation doses are well-tolerated since “our ability to shield normal tissue has improved” over the years, said Dr. Rosenzweig, who served as a moderator of the ASTRO session where the research was presented.

However, he cautioned that hypofractionation is still “intense” and may not be appropriate for certain patients. And he added that some clinics may not be set up to provide twice-daily treatments.

Information about study funding was not provided. The study authors have no disclosures. Dr. Higgins discloses relationships with AstraZeneca and Regeneron (advisory board), Jazz (funded research), and Janssen and Picture Health (consulting). Dr. Rosenzweig has no disclosures.

For patients with up to 10 brain metastases from small cell lung cancer (SCLC), stereotactic radiosurgery was associated with less cognitive impairment than whole-brain radiation therapy (WBRT) without compromising overall survival, results of the randomized ENCEPHALON (ARO 2018-9) trial suggest.

Among 56 patients with one to 10 SCLC brain metastases, 24% of those who received WBRT demonstrated significant declines in memory function 3 months after treatment, compared with 7% of patients whose metastases were treated with stereotactic radiosurgery alone. Preliminary data showed no significant differences in overall survival between the treatment groups at 6 months of follow-up, Denise Bernhardt, MD, from the Technical University of Munich, reported at the American Society of Radiation Oncology (ASTRO) annual meeting.

“We propose stereotactic radiosurgery should be an option for patients with up to 10 brain metastases in small cell lung cancer,” Dr. Bernhardt said during her presentation.

Vinai Gondi, MD, who was not involved in the study, said that the primary results from the trial – while limited by the study’s small size and missing data – are notable.

Patients with brain metastases from most cancer types typically receive stereotactic radiosurgery but WBRT has remained the standard of care to control brain metastases among patients with SCLC.

“This is the first prospective trial of radiosurgery versus whole-brain radiotherapy for small cell lung cancer brain metastases, and it’s important to recognize how important this is,” said Dr. Gondi, director of Radiation Oncology and codirector of the Brain Tumor Center at Northwestern Medicine Cancer Center, Warrenville, Ill.

Prior trials that have asked the same question did not include SCLC because many of those patients received prophylactic cranial irradiation, Dr. Gondi explained. Prophylactic cranial irradiation, however, has been on the decline among patients with brain metastases from SCLC, following a study from Japan showing no difference in survival among those who received the therapy and those followed with observation as well as evidence demonstrating significant toxicities associated with the technique.

Now “with the declining use of prophylactic cranial irradiation, the emergence of brain metastases is increasing significantly in volume in the small cell lung cancer population,” said Dr. Gondi, who is principal investigator on a phase 3 trial exploring stereotactic radiosurgery versus WBRT in a similar patient population.

In a previous retrospective trial), Dr. Bernhardt and colleagues found that first-line stereotactic radiosurgery did not compromise survival, compared with WBRT, but patients receiving stereotactic radiosurgery did have a higher risk for intracranial failure.

In the current study, the investigators compared the neurocognitive responses in patients with brain metastases from SCLC treated with stereotactic radiosurgery or WBRT.

Enrolled patients had histologically confirmed extensive disease with up to 10 metastatic brain lesions and had not previously received either therapeutic or prophylactic brain irradiation. After stratifying patients by synchronous versus metachronous disease, 56 patients were randomly assigned to either WBRT, at a total dose of 30 Gy delivered in 10 fractions, or to stereotactic radiosurgery with 20 Gy, 18 Gy, or fractionated stereotactic radiosurgery with 30 Gy in 5 Gy fractions for lesions larger than 3 cm.

The primary endpoint was neurocognition after radiation therapy as defined by a decline from baseline of at least five points on the Hopkins Verbal Learning Test-Revised (HVLT-R) total recall subscale at 3 months. Secondary endpoints included survival outcomes, additional neurocognitive assessments of motor skills, executive function, attention, memory, and processing as well as quality-of-life measures.

The investigators expected a high rate of study dropout and planned their statistical analysis accordingly, using a method for estimating the likely values of missing data based on observed data.

Among 26 patients who eventually underwent stereotactic radiosurgery, 18 did not meet the primary endpoint and 2 (7%) demonstrated declines on the HVLT-R subscale of 5 or more points. Data for the remaining 6 patients were missing.

Among the 25 who underwent WBRT, 13 did not meet the primary endpoint and 6 (24%) demonstrated declines of at least 5 points. Data for 6 of the remaining patients were missing.

Although more patients in the WBRT arm had significant declines in neurocognitive function, the difference between the groups was not significant, due to the high proportion of study dropouts – approximately one-fourth of patients in each arm. But the analysis suggested that the neuroprotective effect of stereotactic radiosurgery was notable, Dr. Bernhardt said.

At 6 months, the team also found no significant difference in the survival probability between the treatment groups (P = .36). The median time to death was 124 days among patients who received stereotactic radiosurgery and 131 days among patients who received WBRT. 

Dr. Gondi said the data from ENCEPHALON, while promising, need to be carefully scrutinized because of the small sample sizes and the possibility for unintended bias.

ARO 2018-9 is an investigator-initiated trial funded by Accuray. Dr. Bernhardt disclosed consulting actives, fees, travel expenses, and research funding from Accuray and others. Dr. Gondi disclosed honoraria from UpToDate.

A version of this article appeared on Medscape.com.

For patients with up to 10 brain metastases from small cell lung cancer (SCLC), stereotactic radiosurgery was associated with less cognitive impairment than whole-brain radiation therapy (WBRT) without compromising overall survival, results of the randomized ENCEPHALON (ARO 2018-9) trial suggest.

Among 56 patients with one to 10 SCLC brain metastases, 24% of those who received WBRT demonstrated significant declines in memory function 3 months after treatment, compared with 7% of patients whose metastases were treated with stereotactic radiosurgery alone. Preliminary data showed no significant differences in overall survival between the treatment groups at 6 months of follow-up, Denise Bernhardt, MD, from the Technical University of Munich, reported at the American Society of Radiation Oncology (ASTRO) annual meeting.

“We propose stereotactic radiosurgery should be an option for patients with up to 10 brain metastases in small cell lung cancer,” Dr. Bernhardt said during her presentation.

Vinai Gondi, MD, who was not involved in the study, said that the primary results from the trial – while limited by the study’s small size and missing data – are notable.

Patients with brain metastases from most cancer types typically receive stereotactic radiosurgery but WBRT has remained the standard of care to control brain metastases among patients with SCLC.

“This is the first prospective trial of radiosurgery versus whole-brain radiotherapy for small cell lung cancer brain metastases, and it’s important to recognize how important this is,” said Dr. Gondi, director of Radiation Oncology and codirector of the Brain Tumor Center at Northwestern Medicine Cancer Center, Warrenville, Ill.

Prior trials that have asked the same question did not include SCLC because many of those patients received prophylactic cranial irradiation, Dr. Gondi explained. Prophylactic cranial irradiation, however, has been on the decline among patients with brain metastases from SCLC, following a study from Japan showing no difference in survival among those who received the therapy and those followed with observation as well as evidence demonstrating significant toxicities associated with the technique.

Now “with the declining use of prophylactic cranial irradiation, the emergence of brain metastases is increasing significantly in volume in the small cell lung cancer population,” said Dr. Gondi, who is principal investigator on a phase 3 trial exploring stereotactic radiosurgery versus WBRT in a similar patient population.

In a previous retrospective trial), Dr. Bernhardt and colleagues found that first-line stereotactic radiosurgery did not compromise survival, compared with WBRT, but patients receiving stereotactic radiosurgery did have a higher risk for intracranial failure.

In the current study, the investigators compared the neurocognitive responses in patients with brain metastases from SCLC treated with stereotactic radiosurgery or WBRT.

Enrolled patients had histologically confirmed extensive disease with up to 10 metastatic brain lesions and had not previously received either therapeutic or prophylactic brain irradiation. After stratifying patients by synchronous versus metachronous disease, 56 patients were randomly assigned to either WBRT, at a total dose of 30 Gy delivered in 10 fractions, or to stereotactic radiosurgery with 20 Gy, 18 Gy, or fractionated stereotactic radiosurgery with 30 Gy in 5 Gy fractions for lesions larger than 3 cm.

The primary endpoint was neurocognition after radiation therapy as defined by a decline from baseline of at least five points on the Hopkins Verbal Learning Test-Revised (HVLT-R) total recall subscale at 3 months. Secondary endpoints included survival outcomes, additional neurocognitive assessments of motor skills, executive function, attention, memory, and processing as well as quality-of-life measures.

The investigators expected a high rate of study dropout and planned their statistical analysis accordingly, using a method for estimating the likely values of missing data based on observed data.

Among 26 patients who eventually underwent stereotactic radiosurgery, 18 did not meet the primary endpoint and 2 (7%) demonstrated declines on the HVLT-R subscale of 5 or more points. Data for the remaining 6 patients were missing.

Among the 25 who underwent WBRT, 13 did not meet the primary endpoint and 6 (24%) demonstrated declines of at least 5 points. Data for 6 of the remaining patients were missing.

Although more patients in the WBRT arm had significant declines in neurocognitive function, the difference between the groups was not significant, due to the high proportion of study dropouts – approximately one-fourth of patients in each arm. But the analysis suggested that the neuroprotective effect of stereotactic radiosurgery was notable, Dr. Bernhardt said.

At 6 months, the team also found no significant difference in the survival probability between the treatment groups (P = .36). The median time to death was 124 days among patients who received stereotactic radiosurgery and 131 days among patients who received WBRT. 

Dr. Gondi said the data from ENCEPHALON, while promising, need to be carefully scrutinized because of the small sample sizes and the possibility for unintended bias.

ARO 2018-9 is an investigator-initiated trial funded by Accuray. Dr. Bernhardt disclosed consulting actives, fees, travel expenses, and research funding from Accuray and others. Dr. Gondi disclosed honoraria from UpToDate.

A version of this article appeared on Medscape.com.

For patients with up to 10 brain metastases from small cell lung cancer (SCLC), stereotactic radiosurgery was associated with less cognitive impairment than whole-brain radiation therapy (WBRT) without compromising overall survival, results of the randomized ENCEPHALON (ARO 2018-9) trial suggest.

Among 56 patients with one to 10 SCLC brain metastases, 24% of those who received WBRT demonstrated significant declines in memory function 3 months after treatment, compared with 7% of patients whose metastases were treated with stereotactic radiosurgery alone. Preliminary data showed no significant differences in overall survival between the treatment groups at 6 months of follow-up, Denise Bernhardt, MD, from the Technical University of Munich, reported at the American Society of Radiation Oncology (ASTRO) annual meeting.

“We propose stereotactic radiosurgery should be an option for patients with up to 10 brain metastases in small cell lung cancer,” Dr. Bernhardt said during her presentation.

Vinai Gondi, MD, who was not involved in the study, said that the primary results from the trial – while limited by the study’s small size and missing data – are notable.

Patients with brain metastases from most cancer types typically receive stereotactic radiosurgery but WBRT has remained the standard of care to control brain metastases among patients with SCLC.

“This is the first prospective trial of radiosurgery versus whole-brain radiotherapy for small cell lung cancer brain metastases, and it’s important to recognize how important this is,” said Dr. Gondi, director of Radiation Oncology and codirector of the Brain Tumor Center at Northwestern Medicine Cancer Center, Warrenville, Ill.

Prior trials that have asked the same question did not include SCLC because many of those patients received prophylactic cranial irradiation, Dr. Gondi explained. Prophylactic cranial irradiation, however, has been on the decline among patients with brain metastases from SCLC, following a study from Japan showing no difference in survival among those who received the therapy and those followed with observation as well as evidence demonstrating significant toxicities associated with the technique.

Now “with the declining use of prophylactic cranial irradiation, the emergence of brain metastases is increasing significantly in volume in the small cell lung cancer population,” said Dr. Gondi, who is principal investigator on a phase 3 trial exploring stereotactic radiosurgery versus WBRT in a similar patient population.

In a previous retrospective trial), Dr. Bernhardt and colleagues found that first-line stereotactic radiosurgery did not compromise survival, compared with WBRT, but patients receiving stereotactic radiosurgery did have a higher risk for intracranial failure.

In the current study, the investigators compared the neurocognitive responses in patients with brain metastases from SCLC treated with stereotactic radiosurgery or WBRT.

Enrolled patients had histologically confirmed extensive disease with up to 10 metastatic brain lesions and had not previously received either therapeutic or prophylactic brain irradiation. After stratifying patients by synchronous versus metachronous disease, 56 patients were randomly assigned to either WBRT, at a total dose of 30 Gy delivered in 10 fractions, or to stereotactic radiosurgery with 20 Gy, 18 Gy, or fractionated stereotactic radiosurgery with 30 Gy in 5 Gy fractions for lesions larger than 3 cm.

The primary endpoint was neurocognition after radiation therapy as defined by a decline from baseline of at least five points on the Hopkins Verbal Learning Test-Revised (HVLT-R) total recall subscale at 3 months. Secondary endpoints included survival outcomes, additional neurocognitive assessments of motor skills, executive function, attention, memory, and processing as well as quality-of-life measures.

The investigators expected a high rate of study dropout and planned their statistical analysis accordingly, using a method for estimating the likely values of missing data based on observed data.

Among 26 patients who eventually underwent stereotactic radiosurgery, 18 did not meet the primary endpoint and 2 (7%) demonstrated declines on the HVLT-R subscale of 5 or more points. Data for the remaining 6 patients were missing.

Among the 25 who underwent WBRT, 13 did not meet the primary endpoint and 6 (24%) demonstrated declines of at least 5 points. Data for 6 of the remaining patients were missing.

Although more patients in the WBRT arm had significant declines in neurocognitive function, the difference between the groups was not significant, due to the high proportion of study dropouts – approximately one-fourth of patients in each arm. But the analysis suggested that the neuroprotective effect of stereotactic radiosurgery was notable, Dr. Bernhardt said.

At 6 months, the team also found no significant difference in the survival probability between the treatment groups (P = .36). The median time to death was 124 days among patients who received stereotactic radiosurgery and 131 days among patients who received WBRT. 

Dr. Gondi said the data from ENCEPHALON, while promising, need to be carefully scrutinized because of the small sample sizes and the possibility for unintended bias.

ARO 2018-9 is an investigator-initiated trial funded by Accuray. Dr. Bernhardt disclosed consulting actives, fees, travel expenses, and research funding from Accuray and others. Dr. Gondi disclosed honoraria from UpToDate.

A version of this article appeared on Medscape.com.

SAN DIEGO – With just five fractions of stereotactic body radiation therapy (SBRT), men with low- or intermediate-risk prostate cancer can have 5-year disease control as good as that provided by conventional external-beam radiation therapy delivered at higher doses in 20-39 fractions, according to new data from the phase 3 randomized PACE-B trial.

Overall, the 5-year event-free survival rates were 95.8% among patients who received SBRT and 94.6% among those who had conventional radiation. The incidence of adverse events was also low in both groups, with no significant differences observed between the trial arms.

The similar event-free survival and toxicity profiles in both groups provide more support for SBRT, which treats prostate cancer with larger radiation fractions over a shorter time period.

“I think we can also say now with a high level of confidence that SBRT can be considered a new standard of care for low and favorable intermediate-risk prostate cancer,” said Nicholas van As, MD, MB, from the Royal Marsden NHS Foundation Trust and Institute of Cancer Research in London, who presented efficacy and safety results from the noninferiority trial at the American Society for Radiation Oncology (ASTRO) annual meeting. SBRT is more convenient for patients and more cost-effective for health care providers, Dr. Van As added.

Invited discussant Alejandro Berlin, MD, MSc, from Princess Margaret Cancer Centre and the University of Toronto, agreed “that this should be a standard of care for low and favorable intermediate-risk prostate cancer,” an option already endorsed by relevant guidelines.

But, Dr. Berlin noted, SBRT requires careful attention to technique to achieve the desired results. Further research will be needed to identify and potentially reduce variability among radiation oncology practice regarding margins, dosimetry goals, dose heterogeneity, treatment schedules, and other factors, he said.
 

An international trial

PACE-B is one of three branches of a multi-center collaboration among 37 radiation therapy centers in the United Kingdom, Ireland, and Canada.

In the trial, investigators enrolled 874 patients with T1c or T2c prostate cancer, Gleason score of 3+4 or less, prostate-specific antigen (PSA) level no higher than 20 ng/mL, MRI staging, and no prior androgen deprivation therapy. Investigators then randomly assigned them on a 1:1 basis to receive either conventional radiation (n = 441) or SBRT (n = 433).

At the start of the trial, patients who were assigned to the conventional radiation group received 78 Gy in 39 fractions over 4-8 weeks. However, after results from the CHHiP trial, which showed that a 60-Gy, 20-fraction regimen was not inferior to a 74-Gy, 37-fraction regimen, the PACE-B investigators modified the protocol to 62 Gy delivered in 20 fractions.

Patients assigned to SBRT received 36.25 Gy divided into give fractions delivered over 1-2 weeks, with 40 Gy to the clinical target volume.

The primary outcome was noninferiority of SBRT, measured as whether patients remained free of biochemical clinical failure. Biochemical clinical failure was defined as evidence that the cancer was returning, such as an increase in PSA levels or distant metastases or death from prostate cancer.

At a median follow-up of 73.1 months, 5-year event-free survival rates were 94.6% for patients who received conventional radiation therapy and 95.8% for patients who received SBRT, meeting the prespecified criteria for noninferiority of SBRT (P = .007).

Freedom from biochemical and clinical failure, the trial’s primary endpoint, “was significantly better on both arms than our original power calculation, where we expected control rates of approximately 85%,” Dr. Van As said in an ASTRO plenary session.

Toxicity rates were also low in both study arms. The rate of grade 2 or greater urogenital side effects at 5 years was 5.5% in the SBRT arm and 3.2% in the conventional therapy arm. Grade 2 or greater gastrointestinal side effects occurred in only two patients, one in each study arm.

Given the findings, “I think it’s now imperative that our surgeons discuss this data with their patients before they perform prostatectomies,” Dr. Van As said.

Neha Vapiwala, MD, president-elect of ASTRO who moderated a media briefing where Dr. Van As summarized the PACE-B data, commented that “this study was conducted very rigorously, with excellent quality assurance.”

The study also highlights that clinicians in the United States have considerable catching up to do, said Dr. Vapiwala, from the Hospital of the University of Pennsylvania, Philadelphia.

In the United States, “we are way behind our colleagues on the other side of the pond,” she said. “We are way behind in our uptake of ultra-hypofractionated radiation [such as SBRT], and I do believe that some of that comes from the lack of feeling comfortable with the techniques that are needed and the expertise that is needed.”

PACE-B was funded by Accuray. Dr. Van As disclosed research grants from the company and consulting fees from Varian. Dr. Berlin reported no conflict of interest relevant to the study. Dr. Vapiwala has disclosed a consulting or advisory role with Bayer.

A version of this article first appeared on Medscape.com.

SAN DIEGO – With just five fractions of stereotactic body radiation therapy (SBRT), men with low- or intermediate-risk prostate cancer can have 5-year disease control as good as that provided by conventional external-beam radiation therapy delivered at higher doses in 20-39 fractions, according to new data from the phase 3 randomized PACE-B trial.

Overall, the 5-year event-free survival rates were 95.8% among patients who received SBRT and 94.6% among those who had conventional radiation. The incidence of adverse events was also low in both groups, with no significant differences observed between the trial arms.

The similar event-free survival and toxicity profiles in both groups provide more support for SBRT, which treats prostate cancer with larger radiation fractions over a shorter time period.

“I think we can also say now with a high level of confidence that SBRT can be considered a new standard of care for low and favorable intermediate-risk prostate cancer,” said Nicholas van As, MD, MB, from the Royal Marsden NHS Foundation Trust and Institute of Cancer Research in London, who presented efficacy and safety results from the noninferiority trial at the American Society for Radiation Oncology (ASTRO) annual meeting. SBRT is more convenient for patients and more cost-effective for health care providers, Dr. Van As added.

Invited discussant Alejandro Berlin, MD, MSc, from Princess Margaret Cancer Centre and the University of Toronto, agreed “that this should be a standard of care for low and favorable intermediate-risk prostate cancer,” an option already endorsed by relevant guidelines.

But, Dr. Berlin noted, SBRT requires careful attention to technique to achieve the desired results. Further research will be needed to identify and potentially reduce variability among radiation oncology practice regarding margins, dosimetry goals, dose heterogeneity, treatment schedules, and other factors, he said.
 

An international trial

PACE-B is one of three branches of a multi-center collaboration among 37 radiation therapy centers in the United Kingdom, Ireland, and Canada.

In the trial, investigators enrolled 874 patients with T1c or T2c prostate cancer, Gleason score of 3+4 or less, prostate-specific antigen (PSA) level no higher than 20 ng/mL, MRI staging, and no prior androgen deprivation therapy. Investigators then randomly assigned them on a 1:1 basis to receive either conventional radiation (n = 441) or SBRT (n = 433).

At the start of the trial, patients who were assigned to the conventional radiation group received 78 Gy in 39 fractions over 4-8 weeks. However, after results from the CHHiP trial, which showed that a 60-Gy, 20-fraction regimen was not inferior to a 74-Gy, 37-fraction regimen, the PACE-B investigators modified the protocol to 62 Gy delivered in 20 fractions.

Patients assigned to SBRT received 36.25 Gy divided into give fractions delivered over 1-2 weeks, with 40 Gy to the clinical target volume.

The primary outcome was noninferiority of SBRT, measured as whether patients remained free of biochemical clinical failure. Biochemical clinical failure was defined as evidence that the cancer was returning, such as an increase in PSA levels or distant metastases or death from prostate cancer.

At a median follow-up of 73.1 months, 5-year event-free survival rates were 94.6% for patients who received conventional radiation therapy and 95.8% for patients who received SBRT, meeting the prespecified criteria for noninferiority of SBRT (P = .007).

Freedom from biochemical and clinical failure, the trial’s primary endpoint, “was significantly better on both arms than our original power calculation, where we expected control rates of approximately 85%,” Dr. Van As said in an ASTRO plenary session.

Toxicity rates were also low in both study arms. The rate of grade 2 or greater urogenital side effects at 5 years was 5.5% in the SBRT arm and 3.2% in the conventional therapy arm. Grade 2 or greater gastrointestinal side effects occurred in only two patients, one in each study arm.

Given the findings, “I think it’s now imperative that our surgeons discuss this data with their patients before they perform prostatectomies,” Dr. Van As said.

Neha Vapiwala, MD, president-elect of ASTRO who moderated a media briefing where Dr. Van As summarized the PACE-B data, commented that “this study was conducted very rigorously, with excellent quality assurance.”

The study also highlights that clinicians in the United States have considerable catching up to do, said Dr. Vapiwala, from the Hospital of the University of Pennsylvania, Philadelphia.

In the United States, “we are way behind our colleagues on the other side of the pond,” she said. “We are way behind in our uptake of ultra-hypofractionated radiation [such as SBRT], and I do believe that some of that comes from the lack of feeling comfortable with the techniques that are needed and the expertise that is needed.”

PACE-B was funded by Accuray. Dr. Van As disclosed research grants from the company and consulting fees from Varian. Dr. Berlin reported no conflict of interest relevant to the study. Dr. Vapiwala has disclosed a consulting or advisory role with Bayer.

A version of this article first appeared on Medscape.com.

SAN DIEGO – With just five fractions of stereotactic body radiation therapy (SBRT), men with low- or intermediate-risk prostate cancer can have 5-year disease control as good as that provided by conventional external-beam radiation therapy delivered at higher doses in 20-39 fractions, according to new data from the phase 3 randomized PACE-B trial.

Overall, the 5-year event-free survival rates were 95.8% among patients who received SBRT and 94.6% among those who had conventional radiation. The incidence of adverse events was also low in both groups, with no significant differences observed between the trial arms.

The similar event-free survival and toxicity profiles in both groups provide more support for SBRT, which treats prostate cancer with larger radiation fractions over a shorter time period.

“I think we can also say now with a high level of confidence that SBRT can be considered a new standard of care for low and favorable intermediate-risk prostate cancer,” said Nicholas van As, MD, MB, from the Royal Marsden NHS Foundation Trust and Institute of Cancer Research in London, who presented efficacy and safety results from the noninferiority trial at the American Society for Radiation Oncology (ASTRO) annual meeting. SBRT is more convenient for patients and more cost-effective for health care providers, Dr. Van As added.

Invited discussant Alejandro Berlin, MD, MSc, from Princess Margaret Cancer Centre and the University of Toronto, agreed “that this should be a standard of care for low and favorable intermediate-risk prostate cancer,” an option already endorsed by relevant guidelines.

But, Dr. Berlin noted, SBRT requires careful attention to technique to achieve the desired results. Further research will be needed to identify and potentially reduce variability among radiation oncology practice regarding margins, dosimetry goals, dose heterogeneity, treatment schedules, and other factors, he said.
 

An international trial

PACE-B is one of three branches of a multi-center collaboration among 37 radiation therapy centers in the United Kingdom, Ireland, and Canada.

In the trial, investigators enrolled 874 patients with T1c or T2c prostate cancer, Gleason score of 3+4 or less, prostate-specific antigen (PSA) level no higher than 20 ng/mL, MRI staging, and no prior androgen deprivation therapy. Investigators then randomly assigned them on a 1:1 basis to receive either conventional radiation (n = 441) or SBRT (n = 433).

At the start of the trial, patients who were assigned to the conventional radiation group received 78 Gy in 39 fractions over 4-8 weeks. However, after results from the CHHiP trial, which showed that a 60-Gy, 20-fraction regimen was not inferior to a 74-Gy, 37-fraction regimen, the PACE-B investigators modified the protocol to 62 Gy delivered in 20 fractions.

Patients assigned to SBRT received 36.25 Gy divided into give fractions delivered over 1-2 weeks, with 40 Gy to the clinical target volume.

The primary outcome was noninferiority of SBRT, measured as whether patients remained free of biochemical clinical failure. Biochemical clinical failure was defined as evidence that the cancer was returning, such as an increase in PSA levels or distant metastases or death from prostate cancer.

At a median follow-up of 73.1 months, 5-year event-free survival rates were 94.6% for patients who received conventional radiation therapy and 95.8% for patients who received SBRT, meeting the prespecified criteria for noninferiority of SBRT (P = .007).

Freedom from biochemical and clinical failure, the trial’s primary endpoint, “was significantly better on both arms than our original power calculation, where we expected control rates of approximately 85%,” Dr. Van As said in an ASTRO plenary session.

Toxicity rates were also low in both study arms. The rate of grade 2 or greater urogenital side effects at 5 years was 5.5% in the SBRT arm and 3.2% in the conventional therapy arm. Grade 2 or greater gastrointestinal side effects occurred in only two patients, one in each study arm.

Given the findings, “I think it’s now imperative that our surgeons discuss this data with their patients before they perform prostatectomies,” Dr. Van As said.

Neha Vapiwala, MD, president-elect of ASTRO who moderated a media briefing where Dr. Van As summarized the PACE-B data, commented that “this study was conducted very rigorously, with excellent quality assurance.”

The study also highlights that clinicians in the United States have considerable catching up to do, said Dr. Vapiwala, from the Hospital of the University of Pennsylvania, Philadelphia.

In the United States, “we are way behind our colleagues on the other side of the pond,” she said. “We are way behind in our uptake of ultra-hypofractionated radiation [such as SBRT], and I do believe that some of that comes from the lack of feeling comfortable with the techniques that are needed and the expertise that is needed.”

PACE-B was funded by Accuray. Dr. Van As disclosed research grants from the company and consulting fees from Varian. Dr. Berlin reported no conflict of interest relevant to the study. Dr. Vapiwala has disclosed a consulting or advisory role with Bayer.

A version of this article first appeared on Medscape.com.

SAN DIEGO – Women with breast cancer who underwent postmastectomy breast reconstruction benefited from shorter bursts of higher-dose radiation, compared with the standard therapy, according to a new prospective, randomized study.

Side effects and physical well-being scores were similar among 400 women who received the two treatment regimens, and outcomes were similar or slightly better in the higher-dose group, reported Rinaa Punglia, MD, MPH, an associate professor of radiation oncology at Dana-Farber Brigham Cancer Center in Boston and colleagues at the annual meeting of the American Society for Radiation Oncology. In a press statement, Dr. Punglia noted that the outcomes weren’t as impressive as researchers had hoped, but it’s positive that higher doses didn’t cause more side effects.

The use of the higher-dose approach, known as hypofractionation, “resulted in fewer treatment breaks and less financial toxicity” vs. conventional fractionation, Dr. Punglia said at a news briefing. The findings of the FABREC study “support the use of hypofractionated postmastectomy radiation for patients with basic reconstruction.”

According to Dr. Punglia, “postmastectomy radiation therapy is indicated for almost one-third of mastectomy patients and improves the lives of patients who are at an elevated risk for recurrence.” However, “the addition of radiation therapy greatly increases the risk of reconstruction complications.”

The typical radiation treatment period is 5-6 weeks in these patients, a major hardship for patients that can take them away from their families for extended periods of time. The researchers sought to understand whether another approach – hypofractionation over 3-4 weeks – is a better option. The strategy is widely used after breast-conserving surgery, she said, and has been linked to similar cancer outcomes, improved quality of life, and improved breast appearance.

From 2018 to 2021, the researchers recruited 400 patients with stage 0-III breast cancer who were treated with mastectomy and immediately underwent implant-based reconstruction (median age = 47.0, 23-79). None had tumors growing into the chest wall or skin.

The patients, spread nationwide across 16 institutions, were randomized to receive conventional fractionation (n = 201, 25 fractions, 5 days a week for 5 weeks of 200 cGy) or hypofractionation (n=199, 16 fractions, 5 days a week, for about 3 weeks of 266 cGy).

The researchers tracked 385 patients over a median follow-up of 40.4 months. There was no statistically significant difference in distant recurrence (12 in conventional fractionation arm, 11 in hypofractionation arm), death (2 in each arm), local recurrence (1 in each arm), or toxicity in the chest wall area (20 in conventional fractionation arm, 19 in hypofractionation arm). Changes in physical well-being scores, the primary endpoint, were similar after controlling for age.

“We found that younger patients randomized to hypofractionation were less bothered by side effects of treatment at 6 months relative to their counterparts who received conventional fractionation,” Dr. Punglia said.

Treatment breaks were more common in the conventional fractionation arm (7.7%, mean = 3.3 days) vs. the hypofractionation arm (2.7%, mean = 2.8 days, P = .03).

Among 51 patients who took unpaid time off work, those who underwent hypofractionation took fewer mean days off (73.7 days vs. 125.8 days for conventional fractionation, P = .046).

The study is the first of its kind to compare conventional fractionation to hypofractionation in this population in a randomized, phase III study, Dr. Punglia said.

At the news briefing, an independent expert – Lori Pierce, MD, a professor of radiation oncology at the University of Michigan – said the new study is a “game changer.”

The findings about the benefits of hypofractionation “will potentially impact thousands of women,” said Dr. Pierce, former president of the American Society of Clinical Oncology. The shorter course of radiation is more convenient for patients, she said, and reduces hardship.

“Without a doubt, these results should be discussed with all patients who have had mastectomy and implant-based reconstruction,” she said.

In an interview, Bruce G. Haffty, MD, MS, professor and chair of Radiation Oncology at Rutgers Cancer Institute of New Jersey, said the study adds to existing data suggesting that shorter courses of therapy “are probably OK.” The new findings “give people a little more confidence that [short courses are] safe in terms of well-being and toxicity.”

However, the follow-up in the trial is relatively short, he said, and longer-term research will be needed to change the standard of care in these patients. “It’ll be an evolving story over the next 5-10 years,” he said.

The study was funded by the Patient-Centered Outcomes Research Institute. Dr. Punglia has no disclosures; disclosures for other authors were not provided. Disclosure information for Dr. Pierce was not provided. Dr. Haffty is an investigator in a similar study called RT CHARM.

SAN DIEGO – Women with breast cancer who underwent postmastectomy breast reconstruction benefited from shorter bursts of higher-dose radiation, compared with the standard therapy, according to a new prospective, randomized study.

Side effects and physical well-being scores were similar among 400 women who received the two treatment regimens, and outcomes were similar or slightly better in the higher-dose group, reported Rinaa Punglia, MD, MPH, an associate professor of radiation oncology at Dana-Farber Brigham Cancer Center in Boston and colleagues at the annual meeting of the American Society for Radiation Oncology. In a press statement, Dr. Punglia noted that the outcomes weren’t as impressive as researchers had hoped, but it’s positive that higher doses didn’t cause more side effects.

The use of the higher-dose approach, known as hypofractionation, “resulted in fewer treatment breaks and less financial toxicity” vs. conventional fractionation, Dr. Punglia said at a news briefing. The findings of the FABREC study “support the use of hypofractionated postmastectomy radiation for patients with basic reconstruction.”

According to Dr. Punglia, “postmastectomy radiation therapy is indicated for almost one-third of mastectomy patients and improves the lives of patients who are at an elevated risk for recurrence.” However, “the addition of radiation therapy greatly increases the risk of reconstruction complications.”

The typical radiation treatment period is 5-6 weeks in these patients, a major hardship for patients that can take them away from their families for extended periods of time. The researchers sought to understand whether another approach – hypofractionation over 3-4 weeks – is a better option. The strategy is widely used after breast-conserving surgery, she said, and has been linked to similar cancer outcomes, improved quality of life, and improved breast appearance.

From 2018 to 2021, the researchers recruited 400 patients with stage 0-III breast cancer who were treated with mastectomy and immediately underwent implant-based reconstruction (median age = 47.0, 23-79). None had tumors growing into the chest wall or skin.

The patients, spread nationwide across 16 institutions, were randomized to receive conventional fractionation (n = 201, 25 fractions, 5 days a week for 5 weeks of 200 cGy) or hypofractionation (n=199, 16 fractions, 5 days a week, for about 3 weeks of 266 cGy).

The researchers tracked 385 patients over a median follow-up of 40.4 months. There was no statistically significant difference in distant recurrence (12 in conventional fractionation arm, 11 in hypofractionation arm), death (2 in each arm), local recurrence (1 in each arm), or toxicity in the chest wall area (20 in conventional fractionation arm, 19 in hypofractionation arm). Changes in physical well-being scores, the primary endpoint, were similar after controlling for age.

“We found that younger patients randomized to hypofractionation were less bothered by side effects of treatment at 6 months relative to their counterparts who received conventional fractionation,” Dr. Punglia said.

Treatment breaks were more common in the conventional fractionation arm (7.7%, mean = 3.3 days) vs. the hypofractionation arm (2.7%, mean = 2.8 days, P = .03).

Among 51 patients who took unpaid time off work, those who underwent hypofractionation took fewer mean days off (73.7 days vs. 125.8 days for conventional fractionation, P = .046).

The study is the first of its kind to compare conventional fractionation to hypofractionation in this population in a randomized, phase III study, Dr. Punglia said.

At the news briefing, an independent expert – Lori Pierce, MD, a professor of radiation oncology at the University of Michigan – said the new study is a “game changer.”

The findings about the benefits of hypofractionation “will potentially impact thousands of women,” said Dr. Pierce, former president of the American Society of Clinical Oncology. The shorter course of radiation is more convenient for patients, she said, and reduces hardship.

“Without a doubt, these results should be discussed with all patients who have had mastectomy and implant-based reconstruction,” she said.

In an interview, Bruce G. Haffty, MD, MS, professor and chair of Radiation Oncology at Rutgers Cancer Institute of New Jersey, said the study adds to existing data suggesting that shorter courses of therapy “are probably OK.” The new findings “give people a little more confidence that [short courses are] safe in terms of well-being and toxicity.”

However, the follow-up in the trial is relatively short, he said, and longer-term research will be needed to change the standard of care in these patients. “It’ll be an evolving story over the next 5-10 years,” he said.

The study was funded by the Patient-Centered Outcomes Research Institute. Dr. Punglia has no disclosures; disclosures for other authors were not provided. Disclosure information for Dr. Pierce was not provided. Dr. Haffty is an investigator in a similar study called RT CHARM.

SAN DIEGO – Women with breast cancer who underwent postmastectomy breast reconstruction benefited from shorter bursts of higher-dose radiation, compared with the standard therapy, according to a new prospective, randomized study.

Side effects and physical well-being scores were similar among 400 women who received the two treatment regimens, and outcomes were similar or slightly better in the higher-dose group, reported Rinaa Punglia, MD, MPH, an associate professor of radiation oncology at Dana-Farber Brigham Cancer Center in Boston and colleagues at the annual meeting of the American Society for Radiation Oncology. In a press statement, Dr. Punglia noted that the outcomes weren’t as impressive as researchers had hoped, but it’s positive that higher doses didn’t cause more side effects.

The use of the higher-dose approach, known as hypofractionation, “resulted in fewer treatment breaks and less financial toxicity” vs. conventional fractionation, Dr. Punglia said at a news briefing. The findings of the FABREC study “support the use of hypofractionated postmastectomy radiation for patients with basic reconstruction.”

According to Dr. Punglia, “postmastectomy radiation therapy is indicated for almost one-third of mastectomy patients and improves the lives of patients who are at an elevated risk for recurrence.” However, “the addition of radiation therapy greatly increases the risk of reconstruction complications.”

The typical radiation treatment period is 5-6 weeks in these patients, a major hardship for patients that can take them away from their families for extended periods of time. The researchers sought to understand whether another approach – hypofractionation over 3-4 weeks – is a better option. The strategy is widely used after breast-conserving surgery, she said, and has been linked to similar cancer outcomes, improved quality of life, and improved breast appearance.

From 2018 to 2021, the researchers recruited 400 patients with stage 0-III breast cancer who were treated with mastectomy and immediately underwent implant-based reconstruction (median age = 47.0, 23-79). None had tumors growing into the chest wall or skin.

The patients, spread nationwide across 16 institutions, were randomized to receive conventional fractionation (n = 201, 25 fractions, 5 days a week for 5 weeks of 200 cGy) or hypofractionation (n=199, 16 fractions, 5 days a week, for about 3 weeks of 266 cGy).

The researchers tracked 385 patients over a median follow-up of 40.4 months. There was no statistically significant difference in distant recurrence (12 in conventional fractionation arm, 11 in hypofractionation arm), death (2 in each arm), local recurrence (1 in each arm), or toxicity in the chest wall area (20 in conventional fractionation arm, 19 in hypofractionation arm). Changes in physical well-being scores, the primary endpoint, were similar after controlling for age.

“We found that younger patients randomized to hypofractionation were less bothered by side effects of treatment at 6 months relative to their counterparts who received conventional fractionation,” Dr. Punglia said.

Treatment breaks were more common in the conventional fractionation arm (7.7%, mean = 3.3 days) vs. the hypofractionation arm (2.7%, mean = 2.8 days, P = .03).

Among 51 patients who took unpaid time off work, those who underwent hypofractionation took fewer mean days off (73.7 days vs. 125.8 days for conventional fractionation, P = .046).

The study is the first of its kind to compare conventional fractionation to hypofractionation in this population in a randomized, phase III study, Dr. Punglia said.

At the news briefing, an independent expert – Lori Pierce, MD, a professor of radiation oncology at the University of Michigan – said the new study is a “game changer.”

The findings about the benefits of hypofractionation “will potentially impact thousands of women,” said Dr. Pierce, former president of the American Society of Clinical Oncology. The shorter course of radiation is more convenient for patients, she said, and reduces hardship.

“Without a doubt, these results should be discussed with all patients who have had mastectomy and implant-based reconstruction,” she said.

In an interview, Bruce G. Haffty, MD, MS, professor and chair of Radiation Oncology at Rutgers Cancer Institute of New Jersey, said the study adds to existing data suggesting that shorter courses of therapy “are probably OK.” The new findings “give people a little more confidence that [short courses are] safe in terms of well-being and toxicity.”

However, the follow-up in the trial is relatively short, he said, and longer-term research will be needed to change the standard of care in these patients. “It’ll be an evolving story over the next 5-10 years,” he said.

The study was funded by the Patient-Centered Outcomes Research Institute. Dr. Punglia has no disclosures; disclosures for other authors were not provided. Disclosure information for Dr. Pierce was not provided. Dr. Haffty is an investigator in a similar study called RT CHARM.

Multicancer early-detection blood (MCED) tests are the focus of intensive development. What techniques do these tests use? What potential do they show? Suzette Delaloge, MD, MSc, oncologist, breast cancer specialist, and director of the individualized cancer prevention program (Interception) at the Gustave Roussy Institute in Villejuif, France, looks into these “liquid biopsies” and shares her reservations about their potential marketing, especially to the organized care plans.

Question: What are the general principles underpinning these MCED tests?

Suzette Delaloge, MD, MSc: Despite their specificities, the general idea is to detect certain cancer markers in various body fluids (blood, urine, saliva, etc.), for example, molecules released by cancer cells (cytokines, inflammatory proteins, leptin, etc.) or distinctive features of the DNA in tumor cells. In blood, these molecules can be found in plasma or in serum. In urine, it’s more about detecting kidney, bladder, and urinary tract cancers.

Q: What sort of time frame are we looking at for these MCED tests to be used in routine practice?

Dr. Delaloge: They first appeared around 10 years ago. Development of these tests has intensified in recent years. There are numerous research laboratories, both public and private, that are developing different early-detection tests for cancer.

Some of these development processes are about to come to an end and are expected to be in regular, concrete use within 5-10 years. For the most advanced developments, the main biologic material researched and analyzed is DNA from cancer cells. We all have fragments of DNA from dead cells in our plasma (apoptosis), but cancer cells release more of these than others, and most importantly, their DNA has distinctive characteristics. The idea is to develop tests capable of detecting these characteristics.

Liquid biopsies based on genomic biomarkers could make MCED a reality, especially for cancers for which there is no standard screening process. But at this stage of the research, there are limitations, including low sensitivity for detecting stage I cancers in validation studies and an increased risk for overdiagnosis.

Q: What specific set of characteristics are the most advanced approaches based on?

Dr. Delaloge: They’re based on the analysis of DNA methylation, a biological process by which CH3 methyl groups are added to the DNA molecule and that determines gene expression. This phenomenon differs depending on whether the cell is cancerous. Among the tests currently under development making use of this specific characteristic is the Galleri test, which is the most advanced of them all.

A previous British National Health Service study, SYMPLIFY, which was published in 2023 by researchers at the University of Oxford, was conducted in symptomatic patients attending a health center. It offers promising results in a diagnostic situation. It has nothing at all to do with screening here. A large, randomized English study, NHS-Galleri, is underway, this time involving the general population, with the aim of assessing the potential benefit of the same test as screening in 140,000 people between ages 50 and 77 years.

In the SYMPLIFY study, which was carried out in symptomatic patients attending a health center, the Galleri MCED test had a positive predictive value of 75.5%, a negative predictive value of 97.6%, a sensitivity of 66.3%, and a specificity of 98.4%. Sensitivity increased with age and cancer stage from 24.2% at stage I to 95.3% at stage IV. For cases for which a cancer signal was detected in patients with cancer, the prediction of the original site of the cancer by the MCED test was accurate in 85.2% of cases. This large-scale prospective evaluation of an MCED diagnostic test confirms its feasibility in a symptomatic population but is not yet sufficiently accurate to “confirm or rule out the presence of cancer.” According to the authors, “in cases in which the MCED test detects a cancer signal in this context, the probability of a diagnosis of cancer being made is considerably higher and may identify cancers at sites other than those suspected during the initial referral phase, thus reducing delays in diagnosis.” A negative test means a lower likelihood of cancer but not so low that proper investigation can be ruled out. Further tests will be needed to optimize use of a negative predictive value.

Q: Does MCED testing concern all types of cancer?

Dr. Delaloge: The Galleri test is based on full profiling of DNA methylation. This allows for early diagnosis of cancer even before it can be seen on imaging tests. The issue with these tests is that they aren’t that good at early diagnosis of the most common types of cancer (breast, colorectal, cervical, etc.) for which we already have more efficient means such as the fecal immunochemical test for colorectal cancer, mammography, HPV testing, and so on.

These blood tests would thus not be aimed at replacing routine screening but rather at screening asymptomatic individuals or those with nonspecific signs for cancers for which we have few or no screening measures and which are on the rise, such as deep tumors and cancer diagnosed at a late stage, namely pancreas, bile duct, ovarian, esophageal, lung, stomach, etc.

The results from the studies published are promising, but others are underway to confirm the benefit of these MCEDs. The challenge is to identify cancer at an early stage, at a stage where it will be easier to cure the patient and control its growth using treatments that are less onerous for the patient and that have fewer aftereffects but not at the expense of a massive increase in overdiagnosis, as seen with prostate-specific antigen levels in prostate cancer a few years ago!

Q: What would be the focus of these MCED tests?

Dr. Delaloge: We must be alert to the risk for the market development of MCED tests. For now, they are mostly, especially the Galleri test, developed in the general population to screen for types of cancer that could not be detected in any other way but also because it’s the most financially beneficial situation. The designers want to position themselves in the general population, regardless of whether this means they’ll have to test hundreds of people to find one for whom the test is beneficial. What’s more, developing tests in isolation, without considering their place in ad hoc treatment pathways, is not realistic. It’s likely that some of these tests will be marketed within the next 10 years, but the health care systems destined to receive them are not remotely ready to do so.

Q: An even more recent publication, from late July 2023, is even more exciting in relation to early detection of lung cancer using circulating DNA sequencing. What are your thoughts on it?

Dr. Delaloge: Initially overtaken by other technologies in favor of MCED approaches, DNA sequencing as a technique to detect somatic mutations seems to have reentered the competition with this new-generation research. The authors published some very interesting results, especially for stage I lung cancer with a very high sensitivity of 75%. [Editor’s note: A machine-learning model using genome-wide mutational profiles combined with other features and followed by CT imaging detected more than 90% of patients with lung cancer, including those with stage I and II disease.]

This research illustrates the difficulty of providing high performance while covering a broad range of cancers. Here, the good results mainly concern lung cancer. Researchers and health care authorities must be alert to ensuring that MCED tests prove themselves in terms of sensitivity and specificity in responding to a medical need and in their impact on specific mortality. This craze for MCED tests must not hinder the development of “single-cancer” technologies that may be much better for detecting specific cancers. This recent publication is interesting in this respect, because this sequencing test seems to be particularly good at detecting lung cancer.

Q: Another approach used in MCED tests is based on analyzing the size of DNA fragments in the blood. Can you explain how this works?

Dr. Delaloge: When cancer is not present, the size of DNA fragments in cells is much more homogeneous. Here also, the benefit of MCED based on this technique rests on the very early detection of cancers that are less common than those for which we already have good screening methods available.

Other approaches, still at the experimental stage, detect certain proteins, certain inflammatory molecules, RNA, etc. But for many researchers, the future will involve pairing tests on the basis of circulating DNA in the blood with the detection of specific molecules indicating the presence of cancer to obtain early screening tests that are even more effective or that possibly even allow us to identify an appropriate treatment at an early stage.

The development of a simple test based on a blood draw that allows us to screen early for all cancers and that would replace all current screening measures is, therefore, not imminent, although it could potentially be on the horizon in years to come. Alongside this, an important issue is the benefit of cancer screening in the general population vs. in a targeted population with a specific risk. The latter option is in development but requires an individualized screening pathway based on blood testing and current screening methods: imaging, etc. It also depends on an individual’s cancer risk profile such as age, personal and family medical history, genetic predisposition, and so on.

According to recent modeling, these multicancer tests could theoretically prevent a minimum of 2,000 deaths from cancer per 100,000 people between ages 50 and 79 years screened per year (17% fewer deaths from cancer per year).

This article was translated from the Medscape French Edition. A version appeared on Medscape.com.

Multicancer early-detection blood (MCED) tests are the focus of intensive development. What techniques do these tests use? What potential do they show? Suzette Delaloge, MD, MSc, oncologist, breast cancer specialist, and director of the individualized cancer prevention program (Interception) at the Gustave Roussy Institute in Villejuif, France, looks into these “liquid biopsies” and shares her reservations about their potential marketing, especially to the organized care plans.

Question: What are the general principles underpinning these MCED tests?

Suzette Delaloge, MD, MSc: Despite their specificities, the general idea is to detect certain cancer markers in various body fluids (blood, urine, saliva, etc.), for example, molecules released by cancer cells (cytokines, inflammatory proteins, leptin, etc.) or distinctive features of the DNA in tumor cells. In blood, these molecules can be found in plasma or in serum. In urine, it’s more about detecting kidney, bladder, and urinary tract cancers.

Q: What sort of time frame are we looking at for these MCED tests to be used in routine practice?

Dr. Delaloge: They first appeared around 10 years ago. Development of these tests has intensified in recent years. There are numerous research laboratories, both public and private, that are developing different early-detection tests for cancer.

Some of these development processes are about to come to an end and are expected to be in regular, concrete use within 5-10 years. For the most advanced developments, the main biologic material researched and analyzed is DNA from cancer cells. We all have fragments of DNA from dead cells in our plasma (apoptosis), but cancer cells release more of these than others, and most importantly, their DNA has distinctive characteristics. The idea is to develop tests capable of detecting these characteristics.

Liquid biopsies based on genomic biomarkers could make MCED a reality, especially for cancers for which there is no standard screening process. But at this stage of the research, there are limitations, including low sensitivity for detecting stage I cancers in validation studies and an increased risk for overdiagnosis.

Q: What specific set of characteristics are the most advanced approaches based on?

Dr. Delaloge: They’re based on the analysis of DNA methylation, a biological process by which CH3 methyl groups are added to the DNA molecule and that determines gene expression. This phenomenon differs depending on whether the cell is cancerous. Among the tests currently under development making use of this specific characteristic is the Galleri test, which is the most advanced of them all.

A previous British National Health Service study, SYMPLIFY, which was published in 2023 by researchers at the University of Oxford, was conducted in symptomatic patients attending a health center. It offers promising results in a diagnostic situation. It has nothing at all to do with screening here. A large, randomized English study, NHS-Galleri, is underway, this time involving the general population, with the aim of assessing the potential benefit of the same test as screening in 140,000 people between ages 50 and 77 years.

In the SYMPLIFY study, which was carried out in symptomatic patients attending a health center, the Galleri MCED test had a positive predictive value of 75.5%, a negative predictive value of 97.6%, a sensitivity of 66.3%, and a specificity of 98.4%. Sensitivity increased with age and cancer stage from 24.2% at stage I to 95.3% at stage IV. For cases for which a cancer signal was detected in patients with cancer, the prediction of the original site of the cancer by the MCED test was accurate in 85.2% of cases. This large-scale prospective evaluation of an MCED diagnostic test confirms its feasibility in a symptomatic population but is not yet sufficiently accurate to “confirm or rule out the presence of cancer.” According to the authors, “in cases in which the MCED test detects a cancer signal in this context, the probability of a diagnosis of cancer being made is considerably higher and may identify cancers at sites other than those suspected during the initial referral phase, thus reducing delays in diagnosis.” A negative test means a lower likelihood of cancer but not so low that proper investigation can be ruled out. Further tests will be needed to optimize use of a negative predictive value.

Q: Does MCED testing concern all types of cancer?

Dr. Delaloge: The Galleri test is based on full profiling of DNA methylation. This allows for early diagnosis of cancer even before it can be seen on imaging tests. The issue with these tests is that they aren’t that good at early diagnosis of the most common types of cancer (breast, colorectal, cervical, etc.) for which we already have more efficient means such as the fecal immunochemical test for colorectal cancer, mammography, HPV testing, and so on.

These blood tests would thus not be aimed at replacing routine screening but rather at screening asymptomatic individuals or those with nonspecific signs for cancers for which we have few or no screening measures and which are on the rise, such as deep tumors and cancer diagnosed at a late stage, namely pancreas, bile duct, ovarian, esophageal, lung, stomach, etc.

The results from the studies published are promising, but others are underway to confirm the benefit of these MCEDs. The challenge is to identify cancer at an early stage, at a stage where it will be easier to cure the patient and control its growth using treatments that are less onerous for the patient and that have fewer aftereffects but not at the expense of a massive increase in overdiagnosis, as seen with prostate-specific antigen levels in prostate cancer a few years ago!

Q: What would be the focus of these MCED tests?

Dr. Delaloge: We must be alert to the risk for the market development of MCED tests. For now, they are mostly, especially the Galleri test, developed in the general population to screen for types of cancer that could not be detected in any other way but also because it’s the most financially beneficial situation. The designers want to position themselves in the general population, regardless of whether this means they’ll have to test hundreds of people to find one for whom the test is beneficial. What’s more, developing tests in isolation, without considering their place in ad hoc treatment pathways, is not realistic. It’s likely that some of these tests will be marketed within the next 10 years, but the health care systems destined to receive them are not remotely ready to do so.

Q: An even more recent publication, from late July 2023, is even more exciting in relation to early detection of lung cancer using circulating DNA sequencing. What are your thoughts on it?

Dr. Delaloge: Initially overtaken by other technologies in favor of MCED approaches, DNA sequencing as a technique to detect somatic mutations seems to have reentered the competition with this new-generation research. The authors published some very interesting results, especially for stage I lung cancer with a very high sensitivity of 75%. [Editor’s note: A machine-learning model using genome-wide mutational profiles combined with other features and followed by CT imaging detected more than 90% of patients with lung cancer, including those with stage I and II disease.]

This research illustrates the difficulty of providing high performance while covering a broad range of cancers. Here, the good results mainly concern lung cancer. Researchers and health care authorities must be alert to ensuring that MCED tests prove themselves in terms of sensitivity and specificity in responding to a medical need and in their impact on specific mortality. This craze for MCED tests must not hinder the development of “single-cancer” technologies that may be much better for detecting specific cancers. This recent publication is interesting in this respect, because this sequencing test seems to be particularly good at detecting lung cancer.

Q: Another approach used in MCED tests is based on analyzing the size of DNA fragments in the blood. Can you explain how this works?

Dr. Delaloge: When cancer is not present, the size of DNA fragments in cells is much more homogeneous. Here also, the benefit of MCED based on this technique rests on the very early detection of cancers that are less common than those for which we already have good screening methods available.

Other approaches, still at the experimental stage, detect certain proteins, certain inflammatory molecules, RNA, etc. But for many researchers, the future will involve pairing tests on the basis of circulating DNA in the blood with the detection of specific molecules indicating the presence of cancer to obtain early screening tests that are even more effective or that possibly even allow us to identify an appropriate treatment at an early stage.

The development of a simple test based on a blood draw that allows us to screen early for all cancers and that would replace all current screening measures is, therefore, not imminent, although it could potentially be on the horizon in years to come. Alongside this, an important issue is the benefit of cancer screening in the general population vs. in a targeted population with a specific risk. The latter option is in development but requires an individualized screening pathway based on blood testing and current screening methods: imaging, etc. It also depends on an individual’s cancer risk profile such as age, personal and family medical history, genetic predisposition, and so on.

According to recent modeling, these multicancer tests could theoretically prevent a minimum of 2,000 deaths from cancer per 100,000 people between ages 50 and 79 years screened per year (17% fewer deaths from cancer per year).

This article was translated from the Medscape French Edition. A version appeared on Medscape.com.

Multicancer early-detection blood (MCED) tests are the focus of intensive development. What techniques do these tests use? What potential do they show? Suzette Delaloge, MD, MSc, oncologist, breast cancer specialist, and director of the individualized cancer prevention program (Interception) at the Gustave Roussy Institute in Villejuif, France, looks into these “liquid biopsies” and shares her reservations about their potential marketing, especially to the organized care plans.

Question: What are the general principles underpinning these MCED tests?

Suzette Delaloge, MD, MSc: Despite their specificities, the general idea is to detect certain cancer markers in various body fluids (blood, urine, saliva, etc.), for example, molecules released by cancer cells (cytokines, inflammatory proteins, leptin, etc.) or distinctive features of the DNA in tumor cells. In blood, these molecules can be found in plasma or in serum. In urine, it’s more about detecting kidney, bladder, and urinary tract cancers.

Q: What sort of time frame are we looking at for these MCED tests to be used in routine practice?

Dr. Delaloge: They first appeared around 10 years ago. Development of these tests has intensified in recent years. There are numerous research laboratories, both public and private, that are developing different early-detection tests for cancer.

Some of these development processes are about to come to an end and are expected to be in regular, concrete use within 5-10 years. For the most advanced developments, the main biologic material researched and analyzed is DNA from cancer cells. We all have fragments of DNA from dead cells in our plasma (apoptosis), but cancer cells release more of these than others, and most importantly, their DNA has distinctive characteristics. The idea is to develop tests capable of detecting these characteristics.

Liquid biopsies based on genomic biomarkers could make MCED a reality, especially for cancers for which there is no standard screening process. But at this stage of the research, there are limitations, including low sensitivity for detecting stage I cancers in validation studies and an increased risk for overdiagnosis.

Q: What specific set of characteristics are the most advanced approaches based on?

Dr. Delaloge: They’re based on the analysis of DNA methylation, a biological process by which CH3 methyl groups are added to the DNA molecule and that determines gene expression. This phenomenon differs depending on whether the cell is cancerous. Among the tests currently under development making use of this specific characteristic is the Galleri test, which is the most advanced of them all.

A previous British National Health Service study, SYMPLIFY, which was published in 2023 by researchers at the University of Oxford, was conducted in symptomatic patients attending a health center. It offers promising results in a diagnostic situation. It has nothing at all to do with screening here. A large, randomized English study, NHS-Galleri, is underway, this time involving the general population, with the aim of assessing the potential benefit of the same test as screening in 140,000 people between ages 50 and 77 years.

In the SYMPLIFY study, which was carried out in symptomatic patients attending a health center, the Galleri MCED test had a positive predictive value of 75.5%, a negative predictive value of 97.6%, a sensitivity of 66.3%, and a specificity of 98.4%. Sensitivity increased with age and cancer stage from 24.2% at stage I to 95.3% at stage IV. For cases for which a cancer signal was detected in patients with cancer, the prediction of the original site of the cancer by the MCED test was accurate in 85.2% of cases. This large-scale prospective evaluation of an MCED diagnostic test confirms its feasibility in a symptomatic population but is not yet sufficiently accurate to “confirm or rule out the presence of cancer.” According to the authors, “in cases in which the MCED test detects a cancer signal in this context, the probability of a diagnosis of cancer being made is considerably higher and may identify cancers at sites other than those suspected during the initial referral phase, thus reducing delays in diagnosis.” A negative test means a lower likelihood of cancer but not so low that proper investigation can be ruled out. Further tests will be needed to optimize use of a negative predictive value.

Q: Does MCED testing concern all types of cancer?

Dr. Delaloge: The Galleri test is based on full profiling of DNA methylation. This allows for early diagnosis of cancer even before it can be seen on imaging tests. The issue with these tests is that they aren’t that good at early diagnosis of the most common types of cancer (breast, colorectal, cervical, etc.) for which we already have more efficient means such as the fecal immunochemical test for colorectal cancer, mammography, HPV testing, and so on.

These blood tests would thus not be aimed at replacing routine screening but rather at screening asymptomatic individuals or those with nonspecific signs for cancers for which we have few or no screening measures and which are on the rise, such as deep tumors and cancer diagnosed at a late stage, namely pancreas, bile duct, ovarian, esophageal, lung, stomach, etc.

The results from the studies published are promising, but others are underway to confirm the benefit of these MCEDs. The challenge is to identify cancer at an early stage, at a stage where it will be easier to cure the patient and control its growth using treatments that are less onerous for the patient and that have fewer aftereffects but not at the expense of a massive increase in overdiagnosis, as seen with prostate-specific antigen levels in prostate cancer a few years ago!

Q: What would be the focus of these MCED tests?

Dr. Delaloge: We must be alert to the risk for the market development of MCED tests. For now, they are mostly, especially the Galleri test, developed in the general population to screen for types of cancer that could not be detected in any other way but also because it’s the most financially beneficial situation. The designers want to position themselves in the general population, regardless of whether this means they’ll have to test hundreds of people to find one for whom the test is beneficial. What’s more, developing tests in isolation, without considering their place in ad hoc treatment pathways, is not realistic. It’s likely that some of these tests will be marketed within the next 10 years, but the health care systems destined to receive them are not remotely ready to do so.

Q: An even more recent publication, from late July 2023, is even more exciting in relation to early detection of lung cancer using circulating DNA sequencing. What are your thoughts on it?

Dr. Delaloge: Initially overtaken by other technologies in favor of MCED approaches, DNA sequencing as a technique to detect somatic mutations seems to have reentered the competition with this new-generation research. The authors published some very interesting results, especially for stage I lung cancer with a very high sensitivity of 75%. [Editor’s note: A machine-learning model using genome-wide mutational profiles combined with other features and followed by CT imaging detected more than 90% of patients with lung cancer, including those with stage I and II disease.]

This research illustrates the difficulty of providing high performance while covering a broad range of cancers. Here, the good results mainly concern lung cancer. Researchers and health care authorities must be alert to ensuring that MCED tests prove themselves in terms of sensitivity and specificity in responding to a medical need and in their impact on specific mortality. This craze for MCED tests must not hinder the development of “single-cancer” technologies that may be much better for detecting specific cancers. This recent publication is interesting in this respect, because this sequencing test seems to be particularly good at detecting lung cancer.

Q: Another approach used in MCED tests is based on analyzing the size of DNA fragments in the blood. Can you explain how this works?

Dr. Delaloge: When cancer is not present, the size of DNA fragments in cells is much more homogeneous. Here also, the benefit of MCED based on this technique rests on the very early detection of cancers that are less common than those for which we already have good screening methods available.

Other approaches, still at the experimental stage, detect certain proteins, certain inflammatory molecules, RNA, etc. But for many researchers, the future will involve pairing tests on the basis of circulating DNA in the blood with the detection of specific molecules indicating the presence of cancer to obtain early screening tests that are even more effective or that possibly even allow us to identify an appropriate treatment at an early stage.

The development of a simple test based on a blood draw that allows us to screen early for all cancers and that would replace all current screening measures is, therefore, not imminent, although it could potentially be on the horizon in years to come. Alongside this, an important issue is the benefit of cancer screening in the general population vs. in a targeted population with a specific risk. The latter option is in development but requires an individualized screening pathway based on blood testing and current screening methods: imaging, etc. It also depends on an individual’s cancer risk profile such as age, personal and family medical history, genetic predisposition, and so on.

According to recent modeling, these multicancer tests could theoretically prevent a minimum of 2,000 deaths from cancer per 100,000 people between ages 50 and 79 years screened per year (17% fewer deaths from cancer per year).

This article was translated from the Medscape French Edition. A version appeared on Medscape.com.

The updated draft recommendation from the U.S. Preventive Services Task Force that would lower the recommended start age for routine screening mammograms by a decade for all average-risk women is not justified, experts argue in a “dissenting view” published in the New England Journal of Medicine.

The proposed change would affect more than 20 million U.S. women, and it’s “hard to see any potential benefits associated with lowering the starting age,” coauthor Steven Woloshin, MD, with Dartmouth Cancer Center, Lebanon, N.H., said in an NEJM podcast.

Back in May, when USPSTF released the draft recommendation, task force member John Wong, MD, with Tufts Medical Center, Boston, said in an interview, “It is now clear that screening every other year starting at age 40 has the potential to save about 20% more lives among all women.”

But, according to Dr. Woloshin, there is no recent evidence that mortality from breast cancer is increasing in young women.

In fact, the United States has seen a steady decrease in breast cancer mortality, especially among younger women. Breast cancer mortality among women under 50 “has been cut in half over the past 30 years,” Dr. Woloshin and coauthors explained.

Another wrinkle: The task force did not base its recent recommendation on randomized trial data. In fact, there have been no new randomized trials of screening mammography for women in their 40s since 2016. Instead, the task force relied on statistical models to “estimate what might happen if the starting age were lowered,” Dr. Woloshin and colleagues said.

Relying on a statistical model, however, “is problematic because it has some very optimistic assumptions about the benefit of mammography,” Dr. Woloshin said in the podcast. For instance, the models assume that screening mammography reduces breast cancer mortality by about 25%.

That 25% reduction is “far greater than what’s reported in the meta-analyses of the available randomized trials,” Dr. Woloshin explained. The meta-analyses report about a 16% reduction for all the trials combined and an estimated 13% for trials at low risk of bias. But “even these meta-analyses are likely to overstate the effect of screening since the trials were done before the major advances in treatment.”

In their own calculations, Dr. Woloshin and colleagues found that lowering the screening age to 40 came with a small potential benefit and a substantial risk for harm.

Combing data from the National Cancer Institute, the team reported that the risk for death for women in their 40s from any cause over the next 10 years was about 3% whether or not they received their biennial mammogram.

The risk for death from breast cancer in that time was 0.23% with mammograms – about 2 in every 1,000 women – and 0.31% without. “That’s 1 less breast cancer death per 1,000 women screened for 10 years,” Dr. Woloshin said.

Put another way, with mammography screening, “the chance of not dying from breast cancer over the next 10 years increases from 99.7% to 99.8%,” Dr. Woloshin said.

The benefit is arguably small, while the harms appear quite significant, Dr. Woloshin said. About 36% of women who begin screening at age 40 would have at least one false alarm over 10 years, and almost 7% would have a false alarm requiring a biopsy in that time frame.
 

Ease or exacerbate racial disparity?

Another argument that the USPSTF highlighted for lowering the screening age: Research indicates that Black women get breast cancer at younger ages and are more likely to die of the disease, compared with White women.

Dr. Woloshin and coauthors, however, also took issue with the view that lowering the screening age could reduce disparities between Black and White women.

“There’s no question that there are substantial differences between Black and White women in terms of breast cancer mortality, but there’s actually very little disparity in breast cancer screening – about 60% of Black and White women in their 40s are screened regularly in the United States,” Dr. Woloshin explained in the podcast.

Therefore, it’s “really hard to imagine” how recommending the same intervention to both groups could possibly reduce the disparity, he said.

“The disparity is not a reflection of screening. It reflects differences in cancer biology,” he added. “Black women are at higher risk for more aggressive, fast-growing cancers that are less likely to be caught by screening and unfortunately are less likely to benefit from treatment.”

Earlier screening would also not address the problems facing poor women, who tend to be disproportionately Black, such as lower quality of available medical services, follow-up delays after abnormal scans, treatment delays, and less use of adjuvant therapy, Dr. Woloshin cautioned.

In Dr. Woloshin’s view, lowering the screening age, which broadens the eligible population, may actually “exacerbate problems contributing to disparity by diverting resources toward expanded screening rather than doing what we know works by ensuring that high-quality treatments are more readily accessible to poor women with breast cancer.”
 

Reconsider the change?

Because task force recommendations are so influential, Dr. Woloshin and colleagues worry that mammography screening for women in their 40s will probably become a performance measure.

“Our concern is that, rather than fostering informed decisions, clinicians and practices are going to be judged and rewarded and punished based on compliance with this quality metric,” Dr. Woloshin said.

That’s a problem, he noted, “because women should be able to make the decision for themselves rather than having this be a public health imperative, which is imposed by physicians and practices who are incentivized to meet a quality metric.”

The hope, said Dr. Woloshin, is that this prospective piece will help influence the task force to “reconsider the recommendation, because we think that the bottom line is that their models are insufficient to support a new imperative. The benefits are really limited, and there are really common and important harms for healthy women.”

The comment period for the draft recommendation is now closed, and a final decision from the task force is forthcoming.

The research had no funding. Dr. Woloshin has no relevant disclosures.

A version of this article first appeared on Medscape.com.

The updated draft recommendation from the U.S. Preventive Services Task Force that would lower the recommended start age for routine screening mammograms by a decade for all average-risk women is not justified, experts argue in a “dissenting view” published in the New England Journal of Medicine.

The proposed change would affect more than 20 million U.S. women, and it’s “hard to see any potential benefits associated with lowering the starting age,” coauthor Steven Woloshin, MD, with Dartmouth Cancer Center, Lebanon, N.H., said in an NEJM podcast.

Back in May, when USPSTF released the draft recommendation, task force member John Wong, MD, with Tufts Medical Center, Boston, said in an interview, “It is now clear that screening every other year starting at age 40 has the potential to save about 20% more lives among all women.”

But, according to Dr. Woloshin, there is no recent evidence that mortality from breast cancer is increasing in young women.

In fact, the United States has seen a steady decrease in breast cancer mortality, especially among younger women. Breast cancer mortality among women under 50 “has been cut in half over the past 30 years,” Dr. Woloshin and coauthors explained.

Another wrinkle: The task force did not base its recent recommendation on randomized trial data. In fact, there have been no new randomized trials of screening mammography for women in their 40s since 2016. Instead, the task force relied on statistical models to “estimate what might happen if the starting age were lowered,” Dr. Woloshin and colleagues said.

Relying on a statistical model, however, “is problematic because it has some very optimistic assumptions about the benefit of mammography,” Dr. Woloshin said in the podcast. For instance, the models assume that screening mammography reduces breast cancer mortality by about 25%.

That 25% reduction is “far greater than what’s reported in the meta-analyses of the available randomized trials,” Dr. Woloshin explained. The meta-analyses report about a 16% reduction for all the trials combined and an estimated 13% for trials at low risk of bias. But “even these meta-analyses are likely to overstate the effect of screening since the trials were done before the major advances in treatment.”

In their own calculations, Dr. Woloshin and colleagues found that lowering the screening age to 40 came with a small potential benefit and a substantial risk for harm.

Combing data from the National Cancer Institute, the team reported that the risk for death for women in their 40s from any cause over the next 10 years was about 3% whether or not they received their biennial mammogram.

The risk for death from breast cancer in that time was 0.23% with mammograms – about 2 in every 1,000 women – and 0.31% without. “That’s 1 less breast cancer death per 1,000 women screened for 10 years,” Dr. Woloshin said.

Put another way, with mammography screening, “the chance of not dying from breast cancer over the next 10 years increases from 99.7% to 99.8%,” Dr. Woloshin said.

The benefit is arguably small, while the harms appear quite significant, Dr. Woloshin said. About 36% of women who begin screening at age 40 would have at least one false alarm over 10 years, and almost 7% would have a false alarm requiring a biopsy in that time frame.
 

Ease or exacerbate racial disparity?

Another argument that the USPSTF highlighted for lowering the screening age: Research indicates that Black women get breast cancer at younger ages and are more likely to die of the disease, compared with White women.

Dr. Woloshin and coauthors, however, also took issue with the view that lowering the screening age could reduce disparities between Black and White women.

“There’s no question that there are substantial differences between Black and White women in terms of breast cancer mortality, but there’s actually very little disparity in breast cancer screening – about 60% of Black and White women in their 40s are screened regularly in the United States,” Dr. Woloshin explained in the podcast.

Therefore, it’s “really hard to imagine” how recommending the same intervention to both groups could possibly reduce the disparity, he said.

“The disparity is not a reflection of screening. It reflects differences in cancer biology,” he added. “Black women are at higher risk for more aggressive, fast-growing cancers that are less likely to be caught by screening and unfortunately are less likely to benefit from treatment.”

Earlier screening would also not address the problems facing poor women, who tend to be disproportionately Black, such as lower quality of available medical services, follow-up delays after abnormal scans, treatment delays, and less use of adjuvant therapy, Dr. Woloshin cautioned.

In Dr. Woloshin’s view, lowering the screening age, which broadens the eligible population, may actually “exacerbate problems contributing to disparity by diverting resources toward expanded screening rather than doing what we know works by ensuring that high-quality treatments are more readily accessible to poor women with breast cancer.”
 

Reconsider the change?

Because task force recommendations are so influential, Dr. Woloshin and colleagues worry that mammography screening for women in their 40s will probably become a performance measure.

“Our concern is that, rather than fostering informed decisions, clinicians and practices are going to be judged and rewarded and punished based on compliance with this quality metric,” Dr. Woloshin said.

That’s a problem, he noted, “because women should be able to make the decision for themselves rather than having this be a public health imperative, which is imposed by physicians and practices who are incentivized to meet a quality metric.”

The hope, said Dr. Woloshin, is that this prospective piece will help influence the task force to “reconsider the recommendation, because we think that the bottom line is that their models are insufficient to support a new imperative. The benefits are really limited, and there are really common and important harms for healthy women.”

The comment period for the draft recommendation is now closed, and a final decision from the task force is forthcoming.

The research had no funding. Dr. Woloshin has no relevant disclosures.

A version of this article first appeared on Medscape.com.

The updated draft recommendation from the U.S. Preventive Services Task Force that would lower the recommended start age for routine screening mammograms by a decade for all average-risk women is not justified, experts argue in a “dissenting view” published in the New England Journal of Medicine.

The proposed change would affect more than 20 million U.S. women, and it’s “hard to see any potential benefits associated with lowering the starting age,” coauthor Steven Woloshin, MD, with Dartmouth Cancer Center, Lebanon, N.H., said in an NEJM podcast.

Back in May, when USPSTF released the draft recommendation, task force member John Wong, MD, with Tufts Medical Center, Boston, said in an interview, “It is now clear that screening every other year starting at age 40 has the potential to save about 20% more lives among all women.”

But, according to Dr. Woloshin, there is no recent evidence that mortality from breast cancer is increasing in young women.

In fact, the United States has seen a steady decrease in breast cancer mortality, especially among younger women. Breast cancer mortality among women under 50 “has been cut in half over the past 30 years,” Dr. Woloshin and coauthors explained.

Another wrinkle: The task force did not base its recent recommendation on randomized trial data. In fact, there have been no new randomized trials of screening mammography for women in their 40s since 2016. Instead, the task force relied on statistical models to “estimate what might happen if the starting age were lowered,” Dr. Woloshin and colleagues said.

Relying on a statistical model, however, “is problematic because it has some very optimistic assumptions about the benefit of mammography,” Dr. Woloshin said in the podcast. For instance, the models assume that screening mammography reduces breast cancer mortality by about 25%.

That 25% reduction is “far greater than what’s reported in the meta-analyses of the available randomized trials,” Dr. Woloshin explained. The meta-analyses report about a 16% reduction for all the trials combined and an estimated 13% for trials at low risk of bias. But “even these meta-analyses are likely to overstate the effect of screening since the trials were done before the major advances in treatment.”

In their own calculations, Dr. Woloshin and colleagues found that lowering the screening age to 40 came with a small potential benefit and a substantial risk for harm.

Combing data from the National Cancer Institute, the team reported that the risk for death for women in their 40s from any cause over the next 10 years was about 3% whether or not they received their biennial mammogram.

The risk for death from breast cancer in that time was 0.23% with mammograms – about 2 in every 1,000 women – and 0.31% without. “That’s 1 less breast cancer death per 1,000 women screened for 10 years,” Dr. Woloshin said.

Put another way, with mammography screening, “the chance of not dying from breast cancer over the next 10 years increases from 99.7% to 99.8%,” Dr. Woloshin said.

The benefit is arguably small, while the harms appear quite significant, Dr. Woloshin said. About 36% of women who begin screening at age 40 would have at least one false alarm over 10 years, and almost 7% would have a false alarm requiring a biopsy in that time frame.
 

Ease or exacerbate racial disparity?

Another argument that the USPSTF highlighted for lowering the screening age: Research indicates that Black women get breast cancer at younger ages and are more likely to die of the disease, compared with White women.

Dr. Woloshin and coauthors, however, also took issue with the view that lowering the screening age could reduce disparities between Black and White women.

“There’s no question that there are substantial differences between Black and White women in terms of breast cancer mortality, but there’s actually very little disparity in breast cancer screening – about 60% of Black and White women in their 40s are screened regularly in the United States,” Dr. Woloshin explained in the podcast.

Therefore, it’s “really hard to imagine” how recommending the same intervention to both groups could possibly reduce the disparity, he said.

“The disparity is not a reflection of screening. It reflects differences in cancer biology,” he added. “Black women are at higher risk for more aggressive, fast-growing cancers that are less likely to be caught by screening and unfortunately are less likely to benefit from treatment.”

Earlier screening would also not address the problems facing poor women, who tend to be disproportionately Black, such as lower quality of available medical services, follow-up delays after abnormal scans, treatment delays, and less use of adjuvant therapy, Dr. Woloshin cautioned.

In Dr. Woloshin’s view, lowering the screening age, which broadens the eligible population, may actually “exacerbate problems contributing to disparity by diverting resources toward expanded screening rather than doing what we know works by ensuring that high-quality treatments are more readily accessible to poor women with breast cancer.”
 

Reconsider the change?

Because task force recommendations are so influential, Dr. Woloshin and colleagues worry that mammography screening for women in their 40s will probably become a performance measure.

“Our concern is that, rather than fostering informed decisions, clinicians and practices are going to be judged and rewarded and punished based on compliance with this quality metric,” Dr. Woloshin said.

That’s a problem, he noted, “because women should be able to make the decision for themselves rather than having this be a public health imperative, which is imposed by physicians and practices who are incentivized to meet a quality metric.”

The hope, said Dr. Woloshin, is that this prospective piece will help influence the task force to “reconsider the recommendation, because we think that the bottom line is that their models are insufficient to support a new imperative. The benefits are really limited, and there are really common and important harms for healthy women.”

The comment period for the draft recommendation is now closed, and a final decision from the task force is forthcoming.

The research had no funding. Dr. Woloshin has no relevant disclosures.

A version of this article first appeared on Medscape.com.

HAMBURG, GERMANY – Once-weekly tirzepatide (Mounjaro, Lilly) added to insulin glargine resulted in greater reductions in hemoglobin A1c along with more weight loss and less hypoglycemia, compared with prandial insulin lispro (Humalog, Sanofi), for patients with inadequately controlled type 2 diabetes, show data from the SURPASS-6 randomized clinical trial.

Tirzepatide led to a statistically and clinically significant reduction in mean A1c, at −2.1%, compared with insulin lispro, at −1.1%, by week 52. It also resulted in a higher percentage of participants meeting an A1c target of less than 7.0%, wrote the researchers, whose study was presented at the annual meeting of the European Association for the Study of Diabetes and was published simultaneously in JAMA.

Also, daily insulin glargine use was substantially lower among participants who received tirzepatide, compared with insulin lispro. Insulin glargine was administered at a dosage 13 IU/day; insulin lispro was administered at a dosage of 62 IU/day. “At the highest dose, some patients stopped their insulin [glargine] in the tirzepatide arm,” said Juan Pablo Frias, MD, medical director and principal investigator of Velocity Clinical Research, Los Angeles, who presented the findings. “We demonstrated clinically meaningful and superior glycemic and body weight control with tirzepatide compared with insulin lispro, while tirzepatide was also associated with less clinically significant hypoglycemia.”

Weight improved for participants who received tirzepatide compared with those who received insulin lispro, at –10 kg and +4 kg respectively. The rate of clinically significant hypoglycemia (blood glucose < 54 mg/dL) or severe hypoglycemia was tenfold lower with tirzepatide, compared with insulin lispro.

The session dedicated to tirzepatide was comoderated by Apostolos Tsapas, MD, professor of medicine and diabetes, Aristotle University, Thessaloniki, Greece, and Konstantinos Toulis, MD, consultant in endocrinology and diabetes, General Military Hospital, Thessaloniki, Greece. Dr. Toulis remarked that, in the chronic disease setting, management and treatment intensification are challenging to integrate, and there are barriers to adoption in routine practice. “This is particularly true when it adds complexity, as in the case of multiple prandial insulin injections on top of basal insulin in suboptimally treated individuals with type 2 diabetes.

“Demonstrating superiority over insulin lispro in terms of the so-called trio of A1c, weight loss, and hypoglycemic events, tirzepatide offers both a simpler to adhere to and a more efficacious treatment intensification option.” He noted that, while long-term safety data are awaited, “this seems to be a definite step forward from any viewpoint, with the possible exception of the taxpayer’s perspective.”

Dr. Tsapas added: “These data further support the very high dual glucose and weight efficacy of tirzepatide and the primary role of incretin-related therapies amongst the injectables for the treatment of type 2 diabetes.”
 

Tirzepatide 5, 10, 15 mg vs. insulin lispro in addition to insulin glargine

The researchers aimed to assess the efficacy and safety of adding once-weekly tirzepatide, compared with thrice-daily prandial insulin lispro, as an adjunctive therapy to insulin glargine for patients with type 2 diabetes that was inadequately controlled with basal insulin.

Tirzepatide activates the body’s receptors for glucose-dependent insulinotropic polypeptide and glucagonlike peptide–1 (GLP-1). The study authors noted that “recent guidelines support adding an injectable incretin-related therapy such as GLP-1 receptor agonist for glycemic control, rather than basal insulin, when oral medications are inadequate.”

The open-label, phase 3b clinical trial drew data from 135 sites across 15 countries and included 1,428 adults with type 2 diabetes who were taking basal insulin. Participants were randomly assigned in a 1:1:1:3 ratio to receive once-weekly subcutaneous injections of tirzepatide (5 mg [n = 243], 10 mg [n = 238], or 15 mg [n = 236]) or prandial thrice-daily insulin lispro (n = 708).

Both arms were well matched. The average age was 60 years, and 60% of participants were women. The average amount of time patients had type 2 diabetes was 14 years; 85% of participants continued taking metformin. The average A1c level was 8.8% at baseline. Patients were categorized as having obesity (average body mass index, 33 kg/m²). The average insulin glargine dose was 46 units, or 0.5 units/kg.

Outcomes included noninferiority of tirzepatide (pooled cohort) compared with insulin lispro, both in addition to insulin glargine; and A1c change from baseline to week 52 (noninferiority margin, 0.3%). Key secondary endpoints included change in body weight and percentage of participants who achieved an A1c target of less than 7.0%.

About 90% of participants who received the study drug completed the study, said Dr. Frias. “Only 0.5% of tirzepatide patients needed rescue therapy, while only 2% of the insulin lispro did.”

Prior to optimization, the average insulin glargine dose was 42 IU/kg; during optimization, it rose to an average of 46 IU/kg. “At 52 weeks, those on basal-bolus insulin found their insulin glargine dose stayed flat while insulin lispro was 62 units,” reported Dr. Frias. “The three tirzepatide doses show a reduction in insulin glargine, such that the pooled dose reached an average of 11 units, while 20% actually came off their basal insulin altogether [pooled tirzepatide].”

Tirzepatide (pooled) led to the recommended A1c target of less than 7.0% for 68% of patients versus 36% of patients in the insulin lispro group.

About 68% of the patients who received tirzepatide (pooled) achieved the recommended A1c target of less than 7.0% versus 36% of patients in the insulin lispro group.

“Individual tirzepatide doses and pooled doses showed significant reduction in A1c and up to a 2.5% reduction,” Dr. Frias added. “Normoglycemia was obtained by a greater proportion of patients on tirzepatide doses versus basal-bolus insulin – one-third in the 15-mg tirzepatide dose.”
 

Body weight reduction of 10% or more with tirzepatide

Further, at week 52, weight loss of 5% or more was achieved by 75.4% of participants in the pooled tirzepatide group, compared with 6.3% in the prandial lispro group. The weight loss was accompanied by clinically relevant improvements in cardiometabolic parameters.

In an exploratory analysis, weight loss of 10% or more was achieved by a mean of 48.9% of pooled tirzepatide-treated participants at week 52, compared with 2% of those taking insulin lispro, said Dr. Frias.

“It is possible that the body weight loss induced by tirzepatide therapy and its reported effect in reducing liver fat content may have led to an improvement in insulin sensitivity and decreased insulin requirements,” wrote the researchers in their article.

Hypoglycemia risk and the weight gain observed with complex insulin regimens that include prandial insulin have been main limitations to optimally up-titrate insulin therapy in clinical practice, wrote the authors.

Dr. Frias noted that, in this study, 48% of patients who received insulin lispro experienced clinically significant hypoglycemia, while only 10% of patients in the tirzepatide arms did. “This was 0.4 episodes per patient-year versus 4.4 in tirzepatide and insulin lispro respectively.”

There were more reports of adverse events among the tirzepatide groups than the insulin lispro group. “Typically, with tirzepatide, the commonest adverse events were GI in origin and were mild to moderate.” Rates were 14%-26% for nausea, 11%-15% for diarrhea, and 5%-13% for vomiting.

The study was sponsored by Eli Lilly. Dr. Frias has received grants from Eli Lilly paid to his institution during the conduct of the study and grants, personal fees, or nonfinancial support from Boehringer Ingelheim, Pfizer, Merck, Altimmune, 89BIO, Akero, Carmot Therapeutics, Intercept, Janssen, Madrigal, Novartis, Eli Lilly, Sanofi, and Novo Nordisk outside the submitted work. Dr. Toulis and Dr. Tsapas declared no relevant disclosures.

A version of this article first appeared on Medscape.com.

HAMBURG, GERMANY – Once-weekly tirzepatide (Mounjaro, Lilly) added to insulin glargine resulted in greater reductions in hemoglobin A1c along with more weight loss and less hypoglycemia, compared with prandial insulin lispro (Humalog, Sanofi), for patients with inadequately controlled type 2 diabetes, show data from the SURPASS-6 randomized clinical trial.

Tirzepatide led to a statistically and clinically significant reduction in mean A1c, at −2.1%, compared with insulin lispro, at −1.1%, by week 52. It also resulted in a higher percentage of participants meeting an A1c target of less than 7.0%, wrote the researchers, whose study was presented at the annual meeting of the European Association for the Study of Diabetes and was published simultaneously in JAMA.

Also, daily insulin glargine use was substantially lower among participants who received tirzepatide, compared with insulin lispro. Insulin glargine was administered at a dosage 13 IU/day; insulin lispro was administered at a dosage of 62 IU/day. “At the highest dose, some patients stopped their insulin [glargine] in the tirzepatide arm,” said Juan Pablo Frias, MD, medical director and principal investigator of Velocity Clinical Research, Los Angeles, who presented the findings. “We demonstrated clinically meaningful and superior glycemic and body weight control with tirzepatide compared with insulin lispro, while tirzepatide was also associated with less clinically significant hypoglycemia.”

Weight improved for participants who received tirzepatide compared with those who received insulin lispro, at –10 kg and +4 kg respectively. The rate of clinically significant hypoglycemia (blood glucose < 54 mg/dL) or severe hypoglycemia was tenfold lower with tirzepatide, compared with insulin lispro.

The session dedicated to tirzepatide was comoderated by Apostolos Tsapas, MD, professor of medicine and diabetes, Aristotle University, Thessaloniki, Greece, and Konstantinos Toulis, MD, consultant in endocrinology and diabetes, General Military Hospital, Thessaloniki, Greece. Dr. Toulis remarked that, in the chronic disease setting, management and treatment intensification are challenging to integrate, and there are barriers to adoption in routine practice. “This is particularly true when it adds complexity, as in the case of multiple prandial insulin injections on top of basal insulin in suboptimally treated individuals with type 2 diabetes.

“Demonstrating superiority over insulin lispro in terms of the so-called trio of A1c, weight loss, and hypoglycemic events, tirzepatide offers both a simpler to adhere to and a more efficacious treatment intensification option.” He noted that, while long-term safety data are awaited, “this seems to be a definite step forward from any viewpoint, with the possible exception of the taxpayer’s perspective.”

Dr. Tsapas added: “These data further support the very high dual glucose and weight efficacy of tirzepatide and the primary role of incretin-related therapies amongst the injectables for the treatment of type 2 diabetes.”
 

Tirzepatide 5, 10, 15 mg vs. insulin lispro in addition to insulin glargine

The researchers aimed to assess the efficacy and safety of adding once-weekly tirzepatide, compared with thrice-daily prandial insulin lispro, as an adjunctive therapy to insulin glargine for patients with type 2 diabetes that was inadequately controlled with basal insulin.

Tirzepatide activates the body’s receptors for glucose-dependent insulinotropic polypeptide and glucagonlike peptide–1 (GLP-1). The study authors noted that “recent guidelines support adding an injectable incretin-related therapy such as GLP-1 receptor agonist for glycemic control, rather than basal insulin, when oral medications are inadequate.”

The open-label, phase 3b clinical trial drew data from 135 sites across 15 countries and included 1,428 adults with type 2 diabetes who were taking basal insulin. Participants were randomly assigned in a 1:1:1:3 ratio to receive once-weekly subcutaneous injections of tirzepatide (5 mg [n = 243], 10 mg [n = 238], or 15 mg [n = 236]) or prandial thrice-daily insulin lispro (n = 708).

Both arms were well matched. The average age was 60 years, and 60% of participants were women. The average amount of time patients had type 2 diabetes was 14 years; 85% of participants continued taking metformin. The average A1c level was 8.8% at baseline. Patients were categorized as having obesity (average body mass index, 33 kg/m²). The average insulin glargine dose was 46 units, or 0.5 units/kg.

Outcomes included noninferiority of tirzepatide (pooled cohort) compared with insulin lispro, both in addition to insulin glargine; and A1c change from baseline to week 52 (noninferiority margin, 0.3%). Key secondary endpoints included change in body weight and percentage of participants who achieved an A1c target of less than 7.0%.

About 90% of participants who received the study drug completed the study, said Dr. Frias. “Only 0.5% of tirzepatide patients needed rescue therapy, while only 2% of the insulin lispro did.”

Prior to optimization, the average insulin glargine dose was 42 IU/kg; during optimization, it rose to an average of 46 IU/kg. “At 52 weeks, those on basal-bolus insulin found their insulin glargine dose stayed flat while insulin lispro was 62 units,” reported Dr. Frias. “The three tirzepatide doses show a reduction in insulin glargine, such that the pooled dose reached an average of 11 units, while 20% actually came off their basal insulin altogether [pooled tirzepatide].”

Tirzepatide (pooled) led to the recommended A1c target of less than 7.0% for 68% of patients versus 36% of patients in the insulin lispro group.

About 68% of the patients who received tirzepatide (pooled) achieved the recommended A1c target of less than 7.0% versus 36% of patients in the insulin lispro group.

“Individual tirzepatide doses and pooled doses showed significant reduction in A1c and up to a 2.5% reduction,” Dr. Frias added. “Normoglycemia was obtained by a greater proportion of patients on tirzepatide doses versus basal-bolus insulin – one-third in the 15-mg tirzepatide dose.”
 

Body weight reduction of 10% or more with tirzepatide

Further, at week 52, weight loss of 5% or more was achieved by 75.4% of participants in the pooled tirzepatide group, compared with 6.3% in the prandial lispro group. The weight loss was accompanied by clinically relevant improvements in cardiometabolic parameters.

In an exploratory analysis, weight loss of 10% or more was achieved by a mean of 48.9% of pooled tirzepatide-treated participants at week 52, compared with 2% of those taking insulin lispro, said Dr. Frias.

“It is possible that the body weight loss induced by tirzepatide therapy and its reported effect in reducing liver fat content may have led to an improvement in insulin sensitivity and decreased insulin requirements,” wrote the researchers in their article.

Hypoglycemia risk and the weight gain observed with complex insulin regimens that include prandial insulin have been main limitations to optimally up-titrate insulin therapy in clinical practice, wrote the authors.

Dr. Frias noted that, in this study, 48% of patients who received insulin lispro experienced clinically significant hypoglycemia, while only 10% of patients in the tirzepatide arms did. “This was 0.4 episodes per patient-year versus 4.4 in tirzepatide and insulin lispro respectively.”

There were more reports of adverse events among the tirzepatide groups than the insulin lispro group. “Typically, with tirzepatide, the commonest adverse events were GI in origin and were mild to moderate.” Rates were 14%-26% for nausea, 11%-15% for diarrhea, and 5%-13% for vomiting.

The study was sponsored by Eli Lilly. Dr. Frias has received grants from Eli Lilly paid to his institution during the conduct of the study and grants, personal fees, or nonfinancial support from Boehringer Ingelheim, Pfizer, Merck, Altimmune, 89BIO, Akero, Carmot Therapeutics, Intercept, Janssen, Madrigal, Novartis, Eli Lilly, Sanofi, and Novo Nordisk outside the submitted work. Dr. Toulis and Dr. Tsapas declared no relevant disclosures.

A version of this article first appeared on Medscape.com.

HAMBURG, GERMANY – Once-weekly tirzepatide (Mounjaro, Lilly) added to insulin glargine resulted in greater reductions in hemoglobin A1c along with more weight loss and less hypoglycemia, compared with prandial insulin lispro (Humalog, Sanofi), for patients with inadequately controlled type 2 diabetes, show data from the SURPASS-6 randomized clinical trial.

Tirzepatide led to a statistically and clinically significant reduction in mean A1c, at −2.1%, compared with insulin lispro, at −1.1%, by week 52. It also resulted in a higher percentage of participants meeting an A1c target of less than 7.0%, wrote the researchers, whose study was presented at the annual meeting of the European Association for the Study of Diabetes and was published simultaneously in JAMA.

Also, daily insulin glargine use was substantially lower among participants who received tirzepatide, compared with insulin lispro. Insulin glargine was administered at a dosage 13 IU/day; insulin lispro was administered at a dosage of 62 IU/day. “At the highest dose, some patients stopped their insulin [glargine] in the tirzepatide arm,” said Juan Pablo Frias, MD, medical director and principal investigator of Velocity Clinical Research, Los Angeles, who presented the findings. “We demonstrated clinically meaningful and superior glycemic and body weight control with tirzepatide compared with insulin lispro, while tirzepatide was also associated with less clinically significant hypoglycemia.”

Weight improved for participants who received tirzepatide compared with those who received insulin lispro, at –10 kg and +4 kg respectively. The rate of clinically significant hypoglycemia (blood glucose < 54 mg/dL) or severe hypoglycemia was tenfold lower with tirzepatide, compared with insulin lispro.

The session dedicated to tirzepatide was comoderated by Apostolos Tsapas, MD, professor of medicine and diabetes, Aristotle University, Thessaloniki, Greece, and Konstantinos Toulis, MD, consultant in endocrinology and diabetes, General Military Hospital, Thessaloniki, Greece. Dr. Toulis remarked that, in the chronic disease setting, management and treatment intensification are challenging to integrate, and there are barriers to adoption in routine practice. “This is particularly true when it adds complexity, as in the case of multiple prandial insulin injections on top of basal insulin in suboptimally treated individuals with type 2 diabetes.

“Demonstrating superiority over insulin lispro in terms of the so-called trio of A1c, weight loss, and hypoglycemic events, tirzepatide offers both a simpler to adhere to and a more efficacious treatment intensification option.” He noted that, while long-term safety data are awaited, “this seems to be a definite step forward from any viewpoint, with the possible exception of the taxpayer’s perspective.”

Dr. Tsapas added: “These data further support the very high dual glucose and weight efficacy of tirzepatide and the primary role of incretin-related therapies amongst the injectables for the treatment of type 2 diabetes.”
 

Tirzepatide 5, 10, 15 mg vs. insulin lispro in addition to insulin glargine

The researchers aimed to assess the efficacy and safety of adding once-weekly tirzepatide, compared with thrice-daily prandial insulin lispro, as an adjunctive therapy to insulin glargine for patients with type 2 diabetes that was inadequately controlled with basal insulin.

Tirzepatide activates the body’s receptors for glucose-dependent insulinotropic polypeptide and glucagonlike peptide–1 (GLP-1). The study authors noted that “recent guidelines support adding an injectable incretin-related therapy such as GLP-1 receptor agonist for glycemic control, rather than basal insulin, when oral medications are inadequate.”

The open-label, phase 3b clinical trial drew data from 135 sites across 15 countries and included 1,428 adults with type 2 diabetes who were taking basal insulin. Participants were randomly assigned in a 1:1:1:3 ratio to receive once-weekly subcutaneous injections of tirzepatide (5 mg [n = 243], 10 mg [n = 238], or 15 mg [n = 236]) or prandial thrice-daily insulin lispro (n = 708).

Both arms were well matched. The average age was 60 years, and 60% of participants were women. The average amount of time patients had type 2 diabetes was 14 years; 85% of participants continued taking metformin. The average A1c level was 8.8% at baseline. Patients were categorized as having obesity (average body mass index, 33 kg/m²). The average insulin glargine dose was 46 units, or 0.5 units/kg.

Outcomes included noninferiority of tirzepatide (pooled cohort) compared with insulin lispro, both in addition to insulin glargine; and A1c change from baseline to week 52 (noninferiority margin, 0.3%). Key secondary endpoints included change in body weight and percentage of participants who achieved an A1c target of less than 7.0%.

About 90% of participants who received the study drug completed the study, said Dr. Frias. “Only 0.5% of tirzepatide patients needed rescue therapy, while only 2% of the insulin lispro did.”

Prior to optimization, the average insulin glargine dose was 42 IU/kg; during optimization, it rose to an average of 46 IU/kg. “At 52 weeks, those on basal-bolus insulin found their insulin glargine dose stayed flat while insulin lispro was 62 units,” reported Dr. Frias. “The three tirzepatide doses show a reduction in insulin glargine, such that the pooled dose reached an average of 11 units, while 20% actually came off their basal insulin altogether [pooled tirzepatide].”

Tirzepatide (pooled) led to the recommended A1c target of less than 7.0% for 68% of patients versus 36% of patients in the insulin lispro group.

About 68% of the patients who received tirzepatide (pooled) achieved the recommended A1c target of less than 7.0% versus 36% of patients in the insulin lispro group.

“Individual tirzepatide doses and pooled doses showed significant reduction in A1c and up to a 2.5% reduction,” Dr. Frias added. “Normoglycemia was obtained by a greater proportion of patients on tirzepatide doses versus basal-bolus insulin – one-third in the 15-mg tirzepatide dose.”
 

Body weight reduction of 10% or more with tirzepatide

Further, at week 52, weight loss of 5% or more was achieved by 75.4% of participants in the pooled tirzepatide group, compared with 6.3% in the prandial lispro group. The weight loss was accompanied by clinically relevant improvements in cardiometabolic parameters.

In an exploratory analysis, weight loss of 10% or more was achieved by a mean of 48.9% of pooled tirzepatide-treated participants at week 52, compared with 2% of those taking insulin lispro, said Dr. Frias.

“It is possible that the body weight loss induced by tirzepatide therapy and its reported effect in reducing liver fat content may have led to an improvement in insulin sensitivity and decreased insulin requirements,” wrote the researchers in their article.

Hypoglycemia risk and the weight gain observed with complex insulin regimens that include prandial insulin have been main limitations to optimally up-titrate insulin therapy in clinical practice, wrote the authors.

Dr. Frias noted that, in this study, 48% of patients who received insulin lispro experienced clinically significant hypoglycemia, while only 10% of patients in the tirzepatide arms did. “This was 0.4 episodes per patient-year versus 4.4 in tirzepatide and insulin lispro respectively.”

There were more reports of adverse events among the tirzepatide groups than the insulin lispro group. “Typically, with tirzepatide, the commonest adverse events were GI in origin and were mild to moderate.” Rates were 14%-26% for nausea, 11%-15% for diarrhea, and 5%-13% for vomiting.

The study was sponsored by Eli Lilly. Dr. Frias has received grants from Eli Lilly paid to his institution during the conduct of the study and grants, personal fees, or nonfinancial support from Boehringer Ingelheim, Pfizer, Merck, Altimmune, 89BIO, Akero, Carmot Therapeutics, Intercept, Janssen, Madrigal, Novartis, Eli Lilly, Sanofi, and Novo Nordisk outside the submitted work. Dr. Toulis and Dr. Tsapas declared no relevant disclosures.

A version of this article first appeared on Medscape.com.

Click to read more from Federal Health Care Data Trends 2023.

Click to read more from Federal Health Care Data Trends 2023.

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