In support of previously published case reports, a study using cross-linked national population data in Denmark has now associated cumulative exposure to high-potency topical steroids with osteoporotic fractures in a dose-response relationship.

In a stepwise manner, the hazard ratios for major osteoporotic fracture (MOF) were found to start climbing incrementally for those with a cumulative topical steroid dose equivalent of more than 500 g of mometasone furoate when compared with exposure of 200-499 g, according to the team of investigators from the University of Copenhagen.

“Use of these drugs is very common, and we found an estimated population-attributable risk of as much as 4.3%,” the investigators reported in the study, published in JAMA Dermatology.

The retrospective cohort study drew data from the Danish National Patient Registry, which covers 99% of the country’s population. It was linked to the Danish National Prescription Registry, which captures data on pharmacy-dispensed medications. Data collected from the beginning of 2003 to the end of 2017 were evaluated.

Exposures to potent or very potent topical corticosteroids were converted into a single standard with potency equivalent to 1 mg/g of mometasone furoate. Four strata of exposure were compared to a reference exposure of 200-499 g. These were 500-999 g, 1,000-1,999 g, 2,000-9,999 g, and 10,000 g or greater.

For the first strata, the small increased risk for MOF did not reach significance (HR, 1.01; 95% confidence interval, 0.99-1.03), but each of the others did. These climbed from a 5% greater risk (HR 1.05 95% CI 1.02-1.08) for a cumulative exposure of 1,000 to 1,999 g, to a 10% greater risk (HR, 1.10; 95% CI, 1.07-1.13) for a cumulative exposure of 2,000-9,999 g, and finally to a 27% greater risk (HR, 1.27; 95% CI, 1.19-1.35) for a cumulative exposure of 10,000 g or higher.

The study included more than 700,000 individuals exposed to topical mometasone at a potency equivalent of 200 g or more over the study period. The reference group (200-499 g) was the largest (317,907 individuals). The first strata (500-999 g) included 186,359 patients; the second (1,000-1,999 g), 111,203 patients; the third (2,000-9,999 g), 94,334 patients; and the fifth (10,000 g or more), 13,448 patients.

“A 3% increase in the relative risk of osteoporosis and MOF was observed per doubling of the TCS dose,” according to the investigators.

Patients exposed to doses of high-potency topical steroids that put them at risk of MOF is limited but substantial, according to the senior author, Alexander Egeberg, MD, PhD, of the department of dermatology and allergy at Herlev and Gentofte Hospital, Copenhagen.

“It is true that the risk is modest for the average user of topical steroids,” Dr. Egeberg said in an interview. However, despite the fact that topical steroids are intended for short-term use, “2% of all our users had been exposed to the equivalent of 10,000 g of mometasone, which mean 100 tubes of 100 g.”

If the other two strata at significantly increased risk of MOF (greater than 1,000 g) are included, an additional 28% of all users are facing the potential for clinically significant osteoporosis, according to the Danish data.

The adverse effect of steroids on bone metabolism has been established previously, and several studies have linked systemic corticosteroid exposure, including inhaled corticosteroids, with increased risk of osteoporotic fracture. For example, one study showed that patients with chronic obstructive pulmonary disease on daily inhaled doses of the equivalent of fluticasone at or above 1,000 mcg for more than 4 years had about a 10% increased risk of MOF relative to those not exposed.

The data associate topical steroids with increased risk of osteoporotic fracture, but Dr. Egeberg said osteoporosis is not the only reason to use topical steroids prudently.

“It is important to keep in mind that osteoporosis and fractures are at the extreme end of the side-effect profile and that other side effects, such as striae formation, skin thinning, and dysregulated diabetes, can occur with much lower quantities of topical steroids,” Dr. Egeberg said

For avoiding this risk, “there are no specific cutoffs” recommended for topical steroids in current guidelines, but dermatologists should be aware that many of the indications for topical steroids, such as psoriasis and atopic dermatitis, involve skin with an impaired barrier function, exposing patients to an increased likelihood of absorption, according to Dr. Egeberg.

“A general rule of thumb that we use is that, if a patient with persistent disease activity requires a new prescription of the equivalent of 100 g mometasone every 1-2 months, it might be worth considering if there is a suitable alternative,” Dr. Egeberg said.

In an accompanying editorial, Rebecca D. Jackson, MD, of the division of endocrinology, diabetes, and metabolism in the department of internal medicine at Ohio State University, Columbus, agreed that no guidelines specific to avoiding the risks of topical corticosteroids are currently available, but she advised clinicians to be considering these risks nonetheless. In general, she suggested that topical steroids, like oral steroids, should be used at “the lowest dose for the shortest duration necessary to manage the underlying medical condition.”

The correlation between topical corticosteroids and increased risk of osteoporotic fracture, although not established previously in a large study, is not surprising, according to Victoria Werth, MD, chief of dermatology at the Philadelphia Veterans Affairs Hospital and professor of dermatology at the University of Pennsylvania, also in Philadelphia.

“Systemic absorption of potent topical steroids has previously been demonstrated with a rapid decrease in serum cortisol levels,” Dr. Werth said in an interview. She indicated that concern about the risk of osteoporosis imposed by use of potent steroids over large body surface areas is appropriate.

To minimize this risk, “it is reasonable to use the lowest dose of steroid possible and to try to substitute other medications when possible,” she said.

Dr. Egeberg reported financial relationships with Abbvie, Almirall, Bristol-Myers Squibb, Dermavant Sciences, Galderma, Janssen Pharmaceuticals, Eli Lilly, Novartis, Pfizer, Samsung, Bioepis, and UCB. Five authors had disclosures related to some of those pharmaceutical companies and/or others. Dr. Jackson had no disclosures.

In support of previously published case reports, a study using cross-linked national population data in Denmark has now associated cumulative exposure to high-potency topical steroids with osteoporotic fractures in a dose-response relationship.

In a stepwise manner, the hazard ratios for major osteoporotic fracture (MOF) were found to start climbing incrementally for those with a cumulative topical steroid dose equivalent of more than 500 g of mometasone furoate when compared with exposure of 200-499 g, according to the team of investigators from the University of Copenhagen.

“Use of these drugs is very common, and we found an estimated population-attributable risk of as much as 4.3%,” the investigators reported in the study, published in JAMA Dermatology.

The retrospective cohort study drew data from the Danish National Patient Registry, which covers 99% of the country’s population. It was linked to the Danish National Prescription Registry, which captures data on pharmacy-dispensed medications. Data collected from the beginning of 2003 to the end of 2017 were evaluated.

Exposures to potent or very potent topical corticosteroids were converted into a single standard with potency equivalent to 1 mg/g of mometasone furoate. Four strata of exposure were compared to a reference exposure of 200-499 g. These were 500-999 g, 1,000-1,999 g, 2,000-9,999 g, and 10,000 g or greater.

For the first strata, the small increased risk for MOF did not reach significance (HR, 1.01; 95% confidence interval, 0.99-1.03), but each of the others did. These climbed from a 5% greater risk (HR 1.05 95% CI 1.02-1.08) for a cumulative exposure of 1,000 to 1,999 g, to a 10% greater risk (HR, 1.10; 95% CI, 1.07-1.13) for a cumulative exposure of 2,000-9,999 g, and finally to a 27% greater risk (HR, 1.27; 95% CI, 1.19-1.35) for a cumulative exposure of 10,000 g or higher.

The study included more than 700,000 individuals exposed to topical mometasone at a potency equivalent of 200 g or more over the study period. The reference group (200-499 g) was the largest (317,907 individuals). The first strata (500-999 g) included 186,359 patients; the second (1,000-1,999 g), 111,203 patients; the third (2,000-9,999 g), 94,334 patients; and the fifth (10,000 g or more), 13,448 patients.

“A 3% increase in the relative risk of osteoporosis and MOF was observed per doubling of the TCS dose,” according to the investigators.

Patients exposed to doses of high-potency topical steroids that put them at risk of MOF is limited but substantial, according to the senior author, Alexander Egeberg, MD, PhD, of the department of dermatology and allergy at Herlev and Gentofte Hospital, Copenhagen.

“It is true that the risk is modest for the average user of topical steroids,” Dr. Egeberg said in an interview. However, despite the fact that topical steroids are intended for short-term use, “2% of all our users had been exposed to the equivalent of 10,000 g of mometasone, which mean 100 tubes of 100 g.”

If the other two strata at significantly increased risk of MOF (greater than 1,000 g) are included, an additional 28% of all users are facing the potential for clinically significant osteoporosis, according to the Danish data.

The adverse effect of steroids on bone metabolism has been established previously, and several studies have linked systemic corticosteroid exposure, including inhaled corticosteroids, with increased risk of osteoporotic fracture. For example, one study showed that patients with chronic obstructive pulmonary disease on daily inhaled doses of the equivalent of fluticasone at or above 1,000 mcg for more than 4 years had about a 10% increased risk of MOF relative to those not exposed.

The data associate topical steroids with increased risk of osteoporotic fracture, but Dr. Egeberg said osteoporosis is not the only reason to use topical steroids prudently.

“It is important to keep in mind that osteoporosis and fractures are at the extreme end of the side-effect profile and that other side effects, such as striae formation, skin thinning, and dysregulated diabetes, can occur with much lower quantities of topical steroids,” Dr. Egeberg said

For avoiding this risk, “there are no specific cutoffs” recommended for topical steroids in current guidelines, but dermatologists should be aware that many of the indications for topical steroids, such as psoriasis and atopic dermatitis, involve skin with an impaired barrier function, exposing patients to an increased likelihood of absorption, according to Dr. Egeberg.

“A general rule of thumb that we use is that, if a patient with persistent disease activity requires a new prescription of the equivalent of 100 g mometasone every 1-2 months, it might be worth considering if there is a suitable alternative,” Dr. Egeberg said.

In an accompanying editorial, Rebecca D. Jackson, MD, of the division of endocrinology, diabetes, and metabolism in the department of internal medicine at Ohio State University, Columbus, agreed that no guidelines specific to avoiding the risks of topical corticosteroids are currently available, but she advised clinicians to be considering these risks nonetheless. In general, she suggested that topical steroids, like oral steroids, should be used at “the lowest dose for the shortest duration necessary to manage the underlying medical condition.”

The correlation between topical corticosteroids and increased risk of osteoporotic fracture, although not established previously in a large study, is not surprising, according to Victoria Werth, MD, chief of dermatology at the Philadelphia Veterans Affairs Hospital and professor of dermatology at the University of Pennsylvania, also in Philadelphia.

“Systemic absorption of potent topical steroids has previously been demonstrated with a rapid decrease in serum cortisol levels,” Dr. Werth said in an interview. She indicated that concern about the risk of osteoporosis imposed by use of potent steroids over large body surface areas is appropriate.

To minimize this risk, “it is reasonable to use the lowest dose of steroid possible and to try to substitute other medications when possible,” she said.

Dr. Egeberg reported financial relationships with Abbvie, Almirall, Bristol-Myers Squibb, Dermavant Sciences, Galderma, Janssen Pharmaceuticals, Eli Lilly, Novartis, Pfizer, Samsung, Bioepis, and UCB. Five authors had disclosures related to some of those pharmaceutical companies and/or others. Dr. Jackson had no disclosures.

In support of previously published case reports, a study using cross-linked national population data in Denmark has now associated cumulative exposure to high-potency topical steroids with osteoporotic fractures in a dose-response relationship.

In a stepwise manner, the hazard ratios for major osteoporotic fracture (MOF) were found to start climbing incrementally for those with a cumulative topical steroid dose equivalent of more than 500 g of mometasone furoate when compared with exposure of 200-499 g, according to the team of investigators from the University of Copenhagen.

“Use of these drugs is very common, and we found an estimated population-attributable risk of as much as 4.3%,” the investigators reported in the study, published in JAMA Dermatology.

The retrospective cohort study drew data from the Danish National Patient Registry, which covers 99% of the country’s population. It was linked to the Danish National Prescription Registry, which captures data on pharmacy-dispensed medications. Data collected from the beginning of 2003 to the end of 2017 were evaluated.

Exposures to potent or very potent topical corticosteroids were converted into a single standard with potency equivalent to 1 mg/g of mometasone furoate. Four strata of exposure were compared to a reference exposure of 200-499 g. These were 500-999 g, 1,000-1,999 g, 2,000-9,999 g, and 10,000 g or greater.

For the first strata, the small increased risk for MOF did not reach significance (HR, 1.01; 95% confidence interval, 0.99-1.03), but each of the others did. These climbed from a 5% greater risk (HR 1.05 95% CI 1.02-1.08) for a cumulative exposure of 1,000 to 1,999 g, to a 10% greater risk (HR, 1.10; 95% CI, 1.07-1.13) for a cumulative exposure of 2,000-9,999 g, and finally to a 27% greater risk (HR, 1.27; 95% CI, 1.19-1.35) for a cumulative exposure of 10,000 g or higher.

The study included more than 700,000 individuals exposed to topical mometasone at a potency equivalent of 200 g or more over the study period. The reference group (200-499 g) was the largest (317,907 individuals). The first strata (500-999 g) included 186,359 patients; the second (1,000-1,999 g), 111,203 patients; the third (2,000-9,999 g), 94,334 patients; and the fifth (10,000 g or more), 13,448 patients.

“A 3% increase in the relative risk of osteoporosis and MOF was observed per doubling of the TCS dose,” according to the investigators.

Patients exposed to doses of high-potency topical steroids that put them at risk of MOF is limited but substantial, according to the senior author, Alexander Egeberg, MD, PhD, of the department of dermatology and allergy at Herlev and Gentofte Hospital, Copenhagen.

“It is true that the risk is modest for the average user of topical steroids,” Dr. Egeberg said in an interview. However, despite the fact that topical steroids are intended for short-term use, “2% of all our users had been exposed to the equivalent of 10,000 g of mometasone, which mean 100 tubes of 100 g.”

If the other two strata at significantly increased risk of MOF (greater than 1,000 g) are included, an additional 28% of all users are facing the potential for clinically significant osteoporosis, according to the Danish data.

The adverse effect of steroids on bone metabolism has been established previously, and several studies have linked systemic corticosteroid exposure, including inhaled corticosteroids, with increased risk of osteoporotic fracture. For example, one study showed that patients with chronic obstructive pulmonary disease on daily inhaled doses of the equivalent of fluticasone at or above 1,000 mcg for more than 4 years had about a 10% increased risk of MOF relative to those not exposed.

The data associate topical steroids with increased risk of osteoporotic fracture, but Dr. Egeberg said osteoporosis is not the only reason to use topical steroids prudently.

“It is important to keep in mind that osteoporosis and fractures are at the extreme end of the side-effect profile and that other side effects, such as striae formation, skin thinning, and dysregulated diabetes, can occur with much lower quantities of topical steroids,” Dr. Egeberg said

For avoiding this risk, “there are no specific cutoffs” recommended for topical steroids in current guidelines, but dermatologists should be aware that many of the indications for topical steroids, such as psoriasis and atopic dermatitis, involve skin with an impaired barrier function, exposing patients to an increased likelihood of absorption, according to Dr. Egeberg.

“A general rule of thumb that we use is that, if a patient with persistent disease activity requires a new prescription of the equivalent of 100 g mometasone every 1-2 months, it might be worth considering if there is a suitable alternative,” Dr. Egeberg said.

In an accompanying editorial, Rebecca D. Jackson, MD, of the division of endocrinology, diabetes, and metabolism in the department of internal medicine at Ohio State University, Columbus, agreed that no guidelines specific to avoiding the risks of topical corticosteroids are currently available, but she advised clinicians to be considering these risks nonetheless. In general, she suggested that topical steroids, like oral steroids, should be used at “the lowest dose for the shortest duration necessary to manage the underlying medical condition.”

The correlation between topical corticosteroids and increased risk of osteoporotic fracture, although not established previously in a large study, is not surprising, according to Victoria Werth, MD, chief of dermatology at the Philadelphia Veterans Affairs Hospital and professor of dermatology at the University of Pennsylvania, also in Philadelphia.

“Systemic absorption of potent topical steroids has previously been demonstrated with a rapid decrease in serum cortisol levels,” Dr. Werth said in an interview. She indicated that concern about the risk of osteoporosis imposed by use of potent steroids over large body surface areas is appropriate.

To minimize this risk, “it is reasonable to use the lowest dose of steroid possible and to try to substitute other medications when possible,” she said.

Dr. Egeberg reported financial relationships with Abbvie, Almirall, Bristol-Myers Squibb, Dermavant Sciences, Galderma, Janssen Pharmaceuticals, Eli Lilly, Novartis, Pfizer, Samsung, Bioepis, and UCB. Five authors had disclosures related to some of those pharmaceutical companies and/or others. Dr. Jackson had no disclosures.

Before the pandemic, the biggest parent-related challenge for Charlie Wray, DO, MS, a hospitalist and assistant clinical professor of medicine at the University of California, San Francisco, was “figuring out what I was going to pack in my kids’ lunches. Like most people, we were very much in our groove – we knew when my wife was going to leave work, and which day I’d pick up the kids,” Dr. Wray said. “I reflect back on that and think how easy it was.”

The old life – the one that seems so comparatively effortless – has been gone for close to a year now. And with the reopening of schools in the fall of 2020, hospitalists with school-age kids felt – and are still feeling – the strain in a variety of ways.
 

‘Podding up’

“The largest struggles that we have had involve dealing with the daily logistics of doing at-home learning,” said Dr. Wray, father to a 6-year-old and a 3-year-old. Dr. Wray and his wife are both physicians and have been juggling full work schedules with virtual school for their older child, who is not old enough to be autonomous. “For parents who have younger children who require one-on-one attention for the vast majority of their learning, that certainly takes more of a toll on your time, energy, and resources.”

Uncertainty has created anxiety about the future. “We have no idea what’s going to be happening next month. How do we plan for that? How do we allocate our time for that? That has been a real struggle for us, especially for a two-physician household where we are both considered front line and are both needing to be at the hospital or the clinic on a fairly regular basis,” he said.

Then there is the never-ending stress. Dr. Wray observed that physicians are used to operating under stress, especially at work. “What I think is gnawing at me, and probably a lot of other physicians out there, is you go home and that stress is still there. It’s really hard to escape it. And you wake up in the morning and it’s there, whereas in the past, you could have a nice day. There’s little separation between work and domestic life right now.”

Having to work later into the evening has eaten into time for himself and time with his wife too. “That’s another side effect of the pandemic – it not only takes your time during the day, it takes the time you used to have at night to relax.”

To manage these challenges, Dr. Wray said he and his wife regularly double check their schedules. The family has also created a pod – “I think ‘podded up’ is a verb now,” he laughed – with another family and hired a recent college graduate to help the kids with their virtual learning. “Is it as good as being at school and amongst friends and having an actual teacher there? Of course not. But I think it’s the best that we can do.”

Dr. Wray said his employers have been flexible and understanding regarding scheduling conflicts that parents can have. “It’s really difficult for us, so oftentimes I struggle to see how other people are pulling this off. We recognize how fortunate we are, so that’s something I never want to overlook.”
 

Dividing and conquering

The biggest prepandemic issue for Sridevi Alla, MD, a hospitalist at Baptist Memorial Health in Jackson, Miss., and mother to four children – a 10-year-old, 6-year-old, 2-year-old, and a 9-month-old – was finding a babysitter on the weekend to take her kids out somewhere to burn off energy.

That’s a noticeable departure from the current demand to be not just a parent, but a teacher and a counselor too, thanks to virtual school, noted Dr. Alla. “You are their everything now,” she said. “They don’t have friends. They don’t have any other atmosphere or learning environment to let out their energy, their emotions. You have become their world.”

The beginning of the pandemic was particularly stressful for Dr. Alla, who is in the United States on an H-1B visa. “It was totally worrisome because you’re putting yourself at risk with patients who have the coronavirus, despite not knowing what your future itself is going to be like or what your family’s future is going to be like if anything happens to you,” she said. “We are fortunate we have our jobs. A lot of my immigrant friends lost theirs in the middle of this and they’re still trying to find jobs.”

Dr. Alla’s first challenge was whether to send her older two children to school or keep them at home to do virtual learning. The lack of information from the schools at first did not help that process, but she and her husband ended up choosing virtual school, a decision they still occasionally question.

Next, they had to find child care, and not just someone who could look after the younger two kids – they needed someone with the ability to also help the older ones with their homework.

Though initially the family had help, their first nanny had to quit because her roommate contracted COVID. “After that, we didn’t have help and my husband decided to work from home,” said Dr. Alla. “As of now, we’re still looking for child care. And the main issues are the late hours and the hospitalist week-on, week-off schedule.”

“It’s extremely hard,” she reflected. “At home, there’s no line. A 2-year-old doesn’t understand office time or personal time.” Still, Dr. Alla and her husband are maintaining by dividing up responsibilities and making sure they are always planning ahead.
 

Maintaining a routine

The greatest challenge for Heather Nye, MD, PhD, a hospitalist and professor of clinical medicine at UCSF, has been “maintaining normalcy for the kids.” She mourns the loss of a normal childhood for her kids, however temporary. “Living with abandon, feeling like you’re invincible, going out there and breaking your arm, meeting people, not fearing the world – those are not things we can instill in them right now,” she said.

The mother of an eighth grader and a second grader, Dr. Nye said their school district did not communicate well about how school would proceed. The district ended up offering only virtual school, with no plans for even hybrid learning in the future, leaving parents scrambling to plan.

Dr. Nye lucked out when her youngest child was accepted for a slot at a day camp offered through a partnership between the YMCA and UCSF. However, her eighth grader did not do well with distance learning in the spring, so having that virtual school as the only option has been difficult.

“Neither of the kids are doing really well in school,” she said. Her older one is overwhelmed by all the disparate online platforms and her youngest is having a hard time adjusting to differences like using a virtual pen. “The learning itself without question has suffered. You wonder about evaluation and this whole cohort of children in what will probably be more or less a lost year.”

Routines are the backbone of the family’s survival. “I think one of the most important things for kids in any stage of development is having a routine and being comfortable with that routine because that creates a sense of wellbeing in this time of uncertainty,” Dr. Nye said.

Neither Dr. Nye nor her husband, a geriatrician, have cut back on their work, so they are balancing a full plate of activities with parenting. Though their family is managing, “there are streaks of days where we’re like: ‘Are we failing our children?’ I’m sure every parent out there is asking themselves: ‘Am I doing enough?’” But she said, “We’re very, very lucky. We got that [camp] slot, we have the money to pay for it, and we both have flexible jobs.”
 

Rallying resources

Avital O’Glasser, MD, a hospitalist and associate professor of medicine at Oregon Health and Science University, Portland, fervently wished she could clone herself when the pandemic first started. Not only were her kids suddenly thrown into online classes, but she was pulled in to create a new service line for the COVID response at her clinic.

“The number of times that I said I think I need a time turner from Harry Potter. ... I felt that nothing was getting done even close to adequately because we were cutting corners left and right,” she said.

Thankfully, things have simmered down and Dr. O’Glasser is now working from home 5 or 6 days a week while her husband, a lawyer, goes to his job. “I think stress is lower now, but that’s in large part because, by the end of June, I really had to just stop and acknowledge how stressed I was and do a dramatic realignment of what I was doing for myself in terms of mental health support and bandwidth,” she said. Part of that involved realizing that the family needed a homeschool nanny for their 10-year-old and 7-year-old. “It’s been a lifesaver,” said Dr. O’Glasser.

Though life is on more of an even keel now, stress pops up in unexpected ways. “My youngest has pretty intense separation anxiety from me. Even with getting attention all day from our homeschool nanny, the day after I’m out of the house at the hospital, he really clings to me,” Dr. O’Glasser said. There’s sibling rivalry too, in an attempt to get parental attention.

Setting boundaries between work and home was her biggest challenge prepandemic, and that has not changed. “You’re trying to find that happy balance between professional development and family,” Dr. O’Glasser said. “Where do I cut corners? Do I try to multitask but spread myself thin? How do I say no to things? When am I going to find time to do laundry? When am I disconnecting? I think that now it’s facets of the same conundrum, but just manifested in different ways.”

She emphasized that parents should go easy on themselves right now. “A lot of parenting rules went out the window. My kids have had more screen time…and the amount of junk food they eat right now? Celebrate the wins.” Dr. O’Glasser chuckled about how her definition of a “win” has changed. “The bar now is something that I may never have considered a win before. Just seize those small moments. If my 7-year-old needs to do reading at my feet while I’m finishing notes from the day before, that’s okay,” she said.
 

How hospitalist groups can help

All four hospitalists had ideas about how hospitalist groups can help parents with school-age kids during the pandemic.

Providing child care at health care systems gives employees additional support, said Dr. Alla. Some of her friends have been unable to find child care because they are physicians who care for COVID patients and people do not want the extra risk. “I think any institution should think about this option because it’s very beneficial for an employee, especially for the long hours.”

Dr. Wray said he saw a program that matches up a hospitalist who has kids with one who does not in a type of buddy system, and they check in with each other. Then, if the parent has something come up, the other hospitalist can fill in and the parent can “pay it back” at another time. “This doesn’t put all the impetus on the schedule or on a single individual but spreads the risk out a little more and gives parents a bit of a parachute to make them feel like the system is supporting them,” he said.

“I would encourage groups to reach appropriate accommodations that are equitable and that don’t create discord because they’re perceived as unfair,” said Dr. O’Glasser. For instance, giving child care stipends, but limiting them to care at a licensed facility when some people might need to pay for a homeschool tutor. “Some of the policies that I saw seem to leave out the elementary school lot. You can’t just lump all kids together.”

Dr. Nye thought group leaders should take unseen pressures into account when evaluating employee performance. “I think we’re going to need to shift our yardstick because we can’t do everything now,” she said. “I’m talking about the extra things that people do that they’re evaluated on at the end of the year like volunteering for more shifts, sitting on committees, the things that likely aren’t in their job description. We’re going to have times when people are filling every last minute for their families. Face it with kindness and understanding and know that, in future years, things are going to go back to normal.”
 

Before the pandemic, the biggest parent-related challenge for Charlie Wray, DO, MS, a hospitalist and assistant clinical professor of medicine at the University of California, San Francisco, was “figuring out what I was going to pack in my kids’ lunches. Like most people, we were very much in our groove – we knew when my wife was going to leave work, and which day I’d pick up the kids,” Dr. Wray said. “I reflect back on that and think how easy it was.”

The old life – the one that seems so comparatively effortless – has been gone for close to a year now. And with the reopening of schools in the fall of 2020, hospitalists with school-age kids felt – and are still feeling – the strain in a variety of ways.
 

‘Podding up’

“The largest struggles that we have had involve dealing with the daily logistics of doing at-home learning,” said Dr. Wray, father to a 6-year-old and a 3-year-old. Dr. Wray and his wife are both physicians and have been juggling full work schedules with virtual school for their older child, who is not old enough to be autonomous. “For parents who have younger children who require one-on-one attention for the vast majority of their learning, that certainly takes more of a toll on your time, energy, and resources.”

Uncertainty has created anxiety about the future. “We have no idea what’s going to be happening next month. How do we plan for that? How do we allocate our time for that? That has been a real struggle for us, especially for a two-physician household where we are both considered front line and are both needing to be at the hospital or the clinic on a fairly regular basis,” he said.

Then there is the never-ending stress. Dr. Wray observed that physicians are used to operating under stress, especially at work. “What I think is gnawing at me, and probably a lot of other physicians out there, is you go home and that stress is still there. It’s really hard to escape it. And you wake up in the morning and it’s there, whereas in the past, you could have a nice day. There’s little separation between work and domestic life right now.”

Having to work later into the evening has eaten into time for himself and time with his wife too. “That’s another side effect of the pandemic – it not only takes your time during the day, it takes the time you used to have at night to relax.”

To manage these challenges, Dr. Wray said he and his wife regularly double check their schedules. The family has also created a pod – “I think ‘podded up’ is a verb now,” he laughed – with another family and hired a recent college graduate to help the kids with their virtual learning. “Is it as good as being at school and amongst friends and having an actual teacher there? Of course not. But I think it’s the best that we can do.”

Dr. Wray said his employers have been flexible and understanding regarding scheduling conflicts that parents can have. “It’s really difficult for us, so oftentimes I struggle to see how other people are pulling this off. We recognize how fortunate we are, so that’s something I never want to overlook.”
 

Dividing and conquering

The biggest prepandemic issue for Sridevi Alla, MD, a hospitalist at Baptist Memorial Health in Jackson, Miss., and mother to four children – a 10-year-old, 6-year-old, 2-year-old, and a 9-month-old – was finding a babysitter on the weekend to take her kids out somewhere to burn off energy.

That’s a noticeable departure from the current demand to be not just a parent, but a teacher and a counselor too, thanks to virtual school, noted Dr. Alla. “You are their everything now,” she said. “They don’t have friends. They don’t have any other atmosphere or learning environment to let out their energy, their emotions. You have become their world.”

The beginning of the pandemic was particularly stressful for Dr. Alla, who is in the United States on an H-1B visa. “It was totally worrisome because you’re putting yourself at risk with patients who have the coronavirus, despite not knowing what your future itself is going to be like or what your family’s future is going to be like if anything happens to you,” she said. “We are fortunate we have our jobs. A lot of my immigrant friends lost theirs in the middle of this and they’re still trying to find jobs.”

Dr. Alla’s first challenge was whether to send her older two children to school or keep them at home to do virtual learning. The lack of information from the schools at first did not help that process, but she and her husband ended up choosing virtual school, a decision they still occasionally question.

Next, they had to find child care, and not just someone who could look after the younger two kids – they needed someone with the ability to also help the older ones with their homework.

Though initially the family had help, their first nanny had to quit because her roommate contracted COVID. “After that, we didn’t have help and my husband decided to work from home,” said Dr. Alla. “As of now, we’re still looking for child care. And the main issues are the late hours and the hospitalist week-on, week-off schedule.”

“It’s extremely hard,” she reflected. “At home, there’s no line. A 2-year-old doesn’t understand office time or personal time.” Still, Dr. Alla and her husband are maintaining by dividing up responsibilities and making sure they are always planning ahead.
 

Maintaining a routine

The greatest challenge for Heather Nye, MD, PhD, a hospitalist and professor of clinical medicine at UCSF, has been “maintaining normalcy for the kids.” She mourns the loss of a normal childhood for her kids, however temporary. “Living with abandon, feeling like you’re invincible, going out there and breaking your arm, meeting people, not fearing the world – those are not things we can instill in them right now,” she said.

The mother of an eighth grader and a second grader, Dr. Nye said their school district did not communicate well about how school would proceed. The district ended up offering only virtual school, with no plans for even hybrid learning in the future, leaving parents scrambling to plan.

Dr. Nye lucked out when her youngest child was accepted for a slot at a day camp offered through a partnership between the YMCA and UCSF. However, her eighth grader did not do well with distance learning in the spring, so having that virtual school as the only option has been difficult.

“Neither of the kids are doing really well in school,” she said. Her older one is overwhelmed by all the disparate online platforms and her youngest is having a hard time adjusting to differences like using a virtual pen. “The learning itself without question has suffered. You wonder about evaluation and this whole cohort of children in what will probably be more or less a lost year.”

Routines are the backbone of the family’s survival. “I think one of the most important things for kids in any stage of development is having a routine and being comfortable with that routine because that creates a sense of wellbeing in this time of uncertainty,” Dr. Nye said.

Neither Dr. Nye nor her husband, a geriatrician, have cut back on their work, so they are balancing a full plate of activities with parenting. Though their family is managing, “there are streaks of days where we’re like: ‘Are we failing our children?’ I’m sure every parent out there is asking themselves: ‘Am I doing enough?’” But she said, “We’re very, very lucky. We got that [camp] slot, we have the money to pay for it, and we both have flexible jobs.”
 

Rallying resources

Avital O’Glasser, MD, a hospitalist and associate professor of medicine at Oregon Health and Science University, Portland, fervently wished she could clone herself when the pandemic first started. Not only were her kids suddenly thrown into online classes, but she was pulled in to create a new service line for the COVID response at her clinic.

“The number of times that I said I think I need a time turner from Harry Potter. ... I felt that nothing was getting done even close to adequately because we were cutting corners left and right,” she said.

Thankfully, things have simmered down and Dr. O’Glasser is now working from home 5 or 6 days a week while her husband, a lawyer, goes to his job. “I think stress is lower now, but that’s in large part because, by the end of June, I really had to just stop and acknowledge how stressed I was and do a dramatic realignment of what I was doing for myself in terms of mental health support and bandwidth,” she said. Part of that involved realizing that the family needed a homeschool nanny for their 10-year-old and 7-year-old. “It’s been a lifesaver,” said Dr. O’Glasser.

Though life is on more of an even keel now, stress pops up in unexpected ways. “My youngest has pretty intense separation anxiety from me. Even with getting attention all day from our homeschool nanny, the day after I’m out of the house at the hospital, he really clings to me,” Dr. O’Glasser said. There’s sibling rivalry too, in an attempt to get parental attention.

Setting boundaries between work and home was her biggest challenge prepandemic, and that has not changed. “You’re trying to find that happy balance between professional development and family,” Dr. O’Glasser said. “Where do I cut corners? Do I try to multitask but spread myself thin? How do I say no to things? When am I going to find time to do laundry? When am I disconnecting? I think that now it’s facets of the same conundrum, but just manifested in different ways.”

She emphasized that parents should go easy on themselves right now. “A lot of parenting rules went out the window. My kids have had more screen time…and the amount of junk food they eat right now? Celebrate the wins.” Dr. O’Glasser chuckled about how her definition of a “win” has changed. “The bar now is something that I may never have considered a win before. Just seize those small moments. If my 7-year-old needs to do reading at my feet while I’m finishing notes from the day before, that’s okay,” she said.
 

How hospitalist groups can help

All four hospitalists had ideas about how hospitalist groups can help parents with school-age kids during the pandemic.

Providing child care at health care systems gives employees additional support, said Dr. Alla. Some of her friends have been unable to find child care because they are physicians who care for COVID patients and people do not want the extra risk. “I think any institution should think about this option because it’s very beneficial for an employee, especially for the long hours.”

Dr. Wray said he saw a program that matches up a hospitalist who has kids with one who does not in a type of buddy system, and they check in with each other. Then, if the parent has something come up, the other hospitalist can fill in and the parent can “pay it back” at another time. “This doesn’t put all the impetus on the schedule or on a single individual but spreads the risk out a little more and gives parents a bit of a parachute to make them feel like the system is supporting them,” he said.

“I would encourage groups to reach appropriate accommodations that are equitable and that don’t create discord because they’re perceived as unfair,” said Dr. O’Glasser. For instance, giving child care stipends, but limiting them to care at a licensed facility when some people might need to pay for a homeschool tutor. “Some of the policies that I saw seem to leave out the elementary school lot. You can’t just lump all kids together.”

Dr. Nye thought group leaders should take unseen pressures into account when evaluating employee performance. “I think we’re going to need to shift our yardstick because we can’t do everything now,” she said. “I’m talking about the extra things that people do that they’re evaluated on at the end of the year like volunteering for more shifts, sitting on committees, the things that likely aren’t in their job description. We’re going to have times when people are filling every last minute for their families. Face it with kindness and understanding and know that, in future years, things are going to go back to normal.”
 

Before the pandemic, the biggest parent-related challenge for Charlie Wray, DO, MS, a hospitalist and assistant clinical professor of medicine at the University of California, San Francisco, was “figuring out what I was going to pack in my kids’ lunches. Like most people, we were very much in our groove – we knew when my wife was going to leave work, and which day I’d pick up the kids,” Dr. Wray said. “I reflect back on that and think how easy it was.”

The old life – the one that seems so comparatively effortless – has been gone for close to a year now. And with the reopening of schools in the fall of 2020, hospitalists with school-age kids felt – and are still feeling – the strain in a variety of ways.
 

‘Podding up’

“The largest struggles that we have had involve dealing with the daily logistics of doing at-home learning,” said Dr. Wray, father to a 6-year-old and a 3-year-old. Dr. Wray and his wife are both physicians and have been juggling full work schedules with virtual school for their older child, who is not old enough to be autonomous. “For parents who have younger children who require one-on-one attention for the vast majority of their learning, that certainly takes more of a toll on your time, energy, and resources.”

Uncertainty has created anxiety about the future. “We have no idea what’s going to be happening next month. How do we plan for that? How do we allocate our time for that? That has been a real struggle for us, especially for a two-physician household where we are both considered front line and are both needing to be at the hospital or the clinic on a fairly regular basis,” he said.

Then there is the never-ending stress. Dr. Wray observed that physicians are used to operating under stress, especially at work. “What I think is gnawing at me, and probably a lot of other physicians out there, is you go home and that stress is still there. It’s really hard to escape it. And you wake up in the morning and it’s there, whereas in the past, you could have a nice day. There’s little separation between work and domestic life right now.”

Having to work later into the evening has eaten into time for himself and time with his wife too. “That’s another side effect of the pandemic – it not only takes your time during the day, it takes the time you used to have at night to relax.”

To manage these challenges, Dr. Wray said he and his wife regularly double check their schedules. The family has also created a pod – “I think ‘podded up’ is a verb now,” he laughed – with another family and hired a recent college graduate to help the kids with their virtual learning. “Is it as good as being at school and amongst friends and having an actual teacher there? Of course not. But I think it’s the best that we can do.”

Dr. Wray said his employers have been flexible and understanding regarding scheduling conflicts that parents can have. “It’s really difficult for us, so oftentimes I struggle to see how other people are pulling this off. We recognize how fortunate we are, so that’s something I never want to overlook.”
 

Dividing and conquering

The biggest prepandemic issue for Sridevi Alla, MD, a hospitalist at Baptist Memorial Health in Jackson, Miss., and mother to four children – a 10-year-old, 6-year-old, 2-year-old, and a 9-month-old – was finding a babysitter on the weekend to take her kids out somewhere to burn off energy.

That’s a noticeable departure from the current demand to be not just a parent, but a teacher and a counselor too, thanks to virtual school, noted Dr. Alla. “You are their everything now,” she said. “They don’t have friends. They don’t have any other atmosphere or learning environment to let out their energy, their emotions. You have become their world.”

The beginning of the pandemic was particularly stressful for Dr. Alla, who is in the United States on an H-1B visa. “It was totally worrisome because you’re putting yourself at risk with patients who have the coronavirus, despite not knowing what your future itself is going to be like or what your family’s future is going to be like if anything happens to you,” she said. “We are fortunate we have our jobs. A lot of my immigrant friends lost theirs in the middle of this and they’re still trying to find jobs.”

Dr. Alla’s first challenge was whether to send her older two children to school or keep them at home to do virtual learning. The lack of information from the schools at first did not help that process, but she and her husband ended up choosing virtual school, a decision they still occasionally question.

Next, they had to find child care, and not just someone who could look after the younger two kids – they needed someone with the ability to also help the older ones with their homework.

Though initially the family had help, their first nanny had to quit because her roommate contracted COVID. “After that, we didn’t have help and my husband decided to work from home,” said Dr. Alla. “As of now, we’re still looking for child care. And the main issues are the late hours and the hospitalist week-on, week-off schedule.”

“It’s extremely hard,” she reflected. “At home, there’s no line. A 2-year-old doesn’t understand office time or personal time.” Still, Dr. Alla and her husband are maintaining by dividing up responsibilities and making sure they are always planning ahead.
 

Maintaining a routine

The greatest challenge for Heather Nye, MD, PhD, a hospitalist and professor of clinical medicine at UCSF, has been “maintaining normalcy for the kids.” She mourns the loss of a normal childhood for her kids, however temporary. “Living with abandon, feeling like you’re invincible, going out there and breaking your arm, meeting people, not fearing the world – those are not things we can instill in them right now,” she said.

The mother of an eighth grader and a second grader, Dr. Nye said their school district did not communicate well about how school would proceed. The district ended up offering only virtual school, with no plans for even hybrid learning in the future, leaving parents scrambling to plan.

Dr. Nye lucked out when her youngest child was accepted for a slot at a day camp offered through a partnership between the YMCA and UCSF. However, her eighth grader did not do well with distance learning in the spring, so having that virtual school as the only option has been difficult.

“Neither of the kids are doing really well in school,” she said. Her older one is overwhelmed by all the disparate online platforms and her youngest is having a hard time adjusting to differences like using a virtual pen. “The learning itself without question has suffered. You wonder about evaluation and this whole cohort of children in what will probably be more or less a lost year.”

Routines are the backbone of the family’s survival. “I think one of the most important things for kids in any stage of development is having a routine and being comfortable with that routine because that creates a sense of wellbeing in this time of uncertainty,” Dr. Nye said.

Neither Dr. Nye nor her husband, a geriatrician, have cut back on their work, so they are balancing a full plate of activities with parenting. Though their family is managing, “there are streaks of days where we’re like: ‘Are we failing our children?’ I’m sure every parent out there is asking themselves: ‘Am I doing enough?’” But she said, “We’re very, very lucky. We got that [camp] slot, we have the money to pay for it, and we both have flexible jobs.”
 

Rallying resources

Avital O’Glasser, MD, a hospitalist and associate professor of medicine at Oregon Health and Science University, Portland, fervently wished she could clone herself when the pandemic first started. Not only were her kids suddenly thrown into online classes, but she was pulled in to create a new service line for the COVID response at her clinic.

“The number of times that I said I think I need a time turner from Harry Potter. ... I felt that nothing was getting done even close to adequately because we were cutting corners left and right,” she said.

Thankfully, things have simmered down and Dr. O’Glasser is now working from home 5 or 6 days a week while her husband, a lawyer, goes to his job. “I think stress is lower now, but that’s in large part because, by the end of June, I really had to just stop and acknowledge how stressed I was and do a dramatic realignment of what I was doing for myself in terms of mental health support and bandwidth,” she said. Part of that involved realizing that the family needed a homeschool nanny for their 10-year-old and 7-year-old. “It’s been a lifesaver,” said Dr. O’Glasser.

Though life is on more of an even keel now, stress pops up in unexpected ways. “My youngest has pretty intense separation anxiety from me. Even with getting attention all day from our homeschool nanny, the day after I’m out of the house at the hospital, he really clings to me,” Dr. O’Glasser said. There’s sibling rivalry too, in an attempt to get parental attention.

Setting boundaries between work and home was her biggest challenge prepandemic, and that has not changed. “You’re trying to find that happy balance between professional development and family,” Dr. O’Glasser said. “Where do I cut corners? Do I try to multitask but spread myself thin? How do I say no to things? When am I going to find time to do laundry? When am I disconnecting? I think that now it’s facets of the same conundrum, but just manifested in different ways.”

She emphasized that parents should go easy on themselves right now. “A lot of parenting rules went out the window. My kids have had more screen time…and the amount of junk food they eat right now? Celebrate the wins.” Dr. O’Glasser chuckled about how her definition of a “win” has changed. “The bar now is something that I may never have considered a win before. Just seize those small moments. If my 7-year-old needs to do reading at my feet while I’m finishing notes from the day before, that’s okay,” she said.
 

How hospitalist groups can help

All four hospitalists had ideas about how hospitalist groups can help parents with school-age kids during the pandemic.

Providing child care at health care systems gives employees additional support, said Dr. Alla. Some of her friends have been unable to find child care because they are physicians who care for COVID patients and people do not want the extra risk. “I think any institution should think about this option because it’s very beneficial for an employee, especially for the long hours.”

Dr. Wray said he saw a program that matches up a hospitalist who has kids with one who does not in a type of buddy system, and they check in with each other. Then, if the parent has something come up, the other hospitalist can fill in and the parent can “pay it back” at another time. “This doesn’t put all the impetus on the schedule or on a single individual but spreads the risk out a little more and gives parents a bit of a parachute to make them feel like the system is supporting them,” he said.

“I would encourage groups to reach appropriate accommodations that are equitable and that don’t create discord because they’re perceived as unfair,” said Dr. O’Glasser. For instance, giving child care stipends, but limiting them to care at a licensed facility when some people might need to pay for a homeschool tutor. “Some of the policies that I saw seem to leave out the elementary school lot. You can’t just lump all kids together.”

Dr. Nye thought group leaders should take unseen pressures into account when evaluating employee performance. “I think we’re going to need to shift our yardstick because we can’t do everything now,” she said. “I’m talking about the extra things that people do that they’re evaluated on at the end of the year like volunteering for more shifts, sitting on committees, the things that likely aren’t in their job description. We’re going to have times when people are filling every last minute for their families. Face it with kindness and understanding and know that, in future years, things are going to go back to normal.”
 

When early-stage seminoma metastasizes to one or two retroperitoneal lymph nodes, surgical excision is an “attractive” alternative to standard chemotherapy or radiation, according to an investigator from the phase 2 SEMS trial.

The trial enrolled 55 men with early-stage seminoma and isolated retroperitoneal disease, and all of them underwent retroperitoneal lymph node dissection (RPLND). At 2 years, the recurrence rate was 18%, the recurrence-free survival rate was 84%, and the overall survival rate was 100%. Surgical complications occurred in 13% of patients.

“The SEMS trial establishes RPLND as a first-line treatment alternative for testicular seminoma with isolated retroperitoneal lymphadenopathy up to 3 cm ... It’s an attractive option given the favorable long-term morbidity of RPLND,” said co-principal investigator Siamak Daneshmand, MD, of the University of Southern California (USC), Los Angeles.

“The whole point is to offer an alternative treatment that will avoid long-term toxicity ... It makes no sense treating isolated retroperitoneal lymphadenopathy with strong chemotherapy that’s meant for more widely disseminated disease,” Dr. Daneshmand said.

He presented results from the SEMS trial at the 2021 Genitourinary Cancers Symposium (Abstract 375).
 

Practice-changing?

Dr. Daneshmand called the trial results “practice-changing” and noted that surgery “makes sense” to patients and providers, especially because RPLND is already an established option for early-stage non-seminoma testicular cancer. In fact, USC has continued to offer RPLND for early-stage seminoma since this trial ended 2 years ago, Dr. Daneshmand said.

Study discussant Pilar Laguna, MD, PhD, of Istanbul Medipol University in Turkey, offered a different viewpoint. She said the SEMS trial had an “excellent” design, but, due to the relatively short follow-up, she would recommend caution.

“We in Europe do not recommend primary retroperitoneal lymph node dissection in seminoma outside a trial or institutional study,” Dr. Laguna said.

Still, she said the SEMS trial “establishes a solid base” for ongoing prospective trials of primary RPLND in early-stage seminoma.
 

Trial details

The SEMS trial enrolled 55 patients with pure testicular seminoma. They had stage I disease with 1-3 cm relapse (25%) or stage IIA/B disease with no more than two lymph nodes in any dimension (75%). Imaging was done within 6 weeks of surgery to avoid under staging, and serum tumor markers could be no more than 1.5 times the upper limit of normal.

The majority of subjects were White, and the median age was 34 years (range, 21-64 years). Including USC, the trial was conducted at 12 North American sites.

Patients had open modified-template surgeries by surgeons who had performed at least eight open RPLNDs in 1 year or more than 24 in 3 years. Surgeries at USC used a midline approach, with a typical hospital stay of 1 day.

The median follow-up was 2 years. The overall recurrence rate was 18% (10/55), with a median time to recurrence of 8 months.

All 10 cases of recurrence were salvageable – 8 with chemotherapy and 2 with surgical resection. All of the recurrences were retroperitoneal.

“If you can cure 80% [of men] without radiation or chemotherapy, that’s very significant. These are young patients, and chemotherapy and radiation have long-term side effects. The important thing to remember is if men do recur, they are salvageable,” Dr. Daneshmand said.

Seven patients (13%) had surgical complications that were largely minor. The exceptions were one case of pulmonary embolism and one case of chylous ascites that required drainage. There were no long-term complications, including retrograde ejaculation.

The SEMS study was funded by the Think Different Foundation. Dr. Daneshmand and Dr. Laguna said they have no relevant disclosures.

[email protected]

When early-stage seminoma metastasizes to one or two retroperitoneal lymph nodes, surgical excision is an “attractive” alternative to standard chemotherapy or radiation, according to an investigator from the phase 2 SEMS trial.

The trial enrolled 55 men with early-stage seminoma and isolated retroperitoneal disease, and all of them underwent retroperitoneal lymph node dissection (RPLND). At 2 years, the recurrence rate was 18%, the recurrence-free survival rate was 84%, and the overall survival rate was 100%. Surgical complications occurred in 13% of patients.

“The SEMS trial establishes RPLND as a first-line treatment alternative for testicular seminoma with isolated retroperitoneal lymphadenopathy up to 3 cm ... It’s an attractive option given the favorable long-term morbidity of RPLND,” said co-principal investigator Siamak Daneshmand, MD, of the University of Southern California (USC), Los Angeles.

“The whole point is to offer an alternative treatment that will avoid long-term toxicity ... It makes no sense treating isolated retroperitoneal lymphadenopathy with strong chemotherapy that’s meant for more widely disseminated disease,” Dr. Daneshmand said.

He presented results from the SEMS trial at the 2021 Genitourinary Cancers Symposium (Abstract 375).
 

Practice-changing?

Dr. Daneshmand called the trial results “practice-changing” and noted that surgery “makes sense” to patients and providers, especially because RPLND is already an established option for early-stage non-seminoma testicular cancer. In fact, USC has continued to offer RPLND for early-stage seminoma since this trial ended 2 years ago, Dr. Daneshmand said.

Study discussant Pilar Laguna, MD, PhD, of Istanbul Medipol University in Turkey, offered a different viewpoint. She said the SEMS trial had an “excellent” design, but, due to the relatively short follow-up, she would recommend caution.

“We in Europe do not recommend primary retroperitoneal lymph node dissection in seminoma outside a trial or institutional study,” Dr. Laguna said.

Still, she said the SEMS trial “establishes a solid base” for ongoing prospective trials of primary RPLND in early-stage seminoma.
 

Trial details

The SEMS trial enrolled 55 patients with pure testicular seminoma. They had stage I disease with 1-3 cm relapse (25%) or stage IIA/B disease with no more than two lymph nodes in any dimension (75%). Imaging was done within 6 weeks of surgery to avoid under staging, and serum tumor markers could be no more than 1.5 times the upper limit of normal.

The majority of subjects were White, and the median age was 34 years (range, 21-64 years). Including USC, the trial was conducted at 12 North American sites.

Patients had open modified-template surgeries by surgeons who had performed at least eight open RPLNDs in 1 year or more than 24 in 3 years. Surgeries at USC used a midline approach, with a typical hospital stay of 1 day.

The median follow-up was 2 years. The overall recurrence rate was 18% (10/55), with a median time to recurrence of 8 months.

All 10 cases of recurrence were salvageable – 8 with chemotherapy and 2 with surgical resection. All of the recurrences were retroperitoneal.

“If you can cure 80% [of men] without radiation or chemotherapy, that’s very significant. These are young patients, and chemotherapy and radiation have long-term side effects. The important thing to remember is if men do recur, they are salvageable,” Dr. Daneshmand said.

Seven patients (13%) had surgical complications that were largely minor. The exceptions were one case of pulmonary embolism and one case of chylous ascites that required drainage. There were no long-term complications, including retrograde ejaculation.

The SEMS study was funded by the Think Different Foundation. Dr. Daneshmand and Dr. Laguna said they have no relevant disclosures.

[email protected]

When early-stage seminoma metastasizes to one or two retroperitoneal lymph nodes, surgical excision is an “attractive” alternative to standard chemotherapy or radiation, according to an investigator from the phase 2 SEMS trial.

The trial enrolled 55 men with early-stage seminoma and isolated retroperitoneal disease, and all of them underwent retroperitoneal lymph node dissection (RPLND). At 2 years, the recurrence rate was 18%, the recurrence-free survival rate was 84%, and the overall survival rate was 100%. Surgical complications occurred in 13% of patients.

“The SEMS trial establishes RPLND as a first-line treatment alternative for testicular seminoma with isolated retroperitoneal lymphadenopathy up to 3 cm ... It’s an attractive option given the favorable long-term morbidity of RPLND,” said co-principal investigator Siamak Daneshmand, MD, of the University of Southern California (USC), Los Angeles.

“The whole point is to offer an alternative treatment that will avoid long-term toxicity ... It makes no sense treating isolated retroperitoneal lymphadenopathy with strong chemotherapy that’s meant for more widely disseminated disease,” Dr. Daneshmand said.

He presented results from the SEMS trial at the 2021 Genitourinary Cancers Symposium (Abstract 375).
 

Practice-changing?

Dr. Daneshmand called the trial results “practice-changing” and noted that surgery “makes sense” to patients and providers, especially because RPLND is already an established option for early-stage non-seminoma testicular cancer. In fact, USC has continued to offer RPLND for early-stage seminoma since this trial ended 2 years ago, Dr. Daneshmand said.

Study discussant Pilar Laguna, MD, PhD, of Istanbul Medipol University in Turkey, offered a different viewpoint. She said the SEMS trial had an “excellent” design, but, due to the relatively short follow-up, she would recommend caution.

“We in Europe do not recommend primary retroperitoneal lymph node dissection in seminoma outside a trial or institutional study,” Dr. Laguna said.

Still, she said the SEMS trial “establishes a solid base” for ongoing prospective trials of primary RPLND in early-stage seminoma.
 

Trial details

The SEMS trial enrolled 55 patients with pure testicular seminoma. They had stage I disease with 1-3 cm relapse (25%) or stage IIA/B disease with no more than two lymph nodes in any dimension (75%). Imaging was done within 6 weeks of surgery to avoid under staging, and serum tumor markers could be no more than 1.5 times the upper limit of normal.

The majority of subjects were White, and the median age was 34 years (range, 21-64 years). Including USC, the trial was conducted at 12 North American sites.

Patients had open modified-template surgeries by surgeons who had performed at least eight open RPLNDs in 1 year or more than 24 in 3 years. Surgeries at USC used a midline approach, with a typical hospital stay of 1 day.

The median follow-up was 2 years. The overall recurrence rate was 18% (10/55), with a median time to recurrence of 8 months.

All 10 cases of recurrence were salvageable – 8 with chemotherapy and 2 with surgical resection. All of the recurrences were retroperitoneal.

“If you can cure 80% [of men] without radiation or chemotherapy, that’s very significant. These are young patients, and chemotherapy and radiation have long-term side effects. The important thing to remember is if men do recur, they are salvageable,” Dr. Daneshmand said.

Seven patients (13%) had surgical complications that were largely minor. The exceptions were one case of pulmonary embolism and one case of chylous ascites that required drainage. There were no long-term complications, including retrograde ejaculation.

The SEMS study was funded by the Think Different Foundation. Dr. Daneshmand and Dr. Laguna said they have no relevant disclosures.

[email protected]

A novel drug that offers multilineage protection from chemotherapy-induced myelosuppression has been approved by the Food and Drug Administration.

The drug, trilaciclib (Cosela, G1 Therapeutics) is administered intravenously as a 30-minute infusion within 4 hours prior to the start of chemotherapy. It is indicated specifically for use in adults with extensive-stage small-cell lung cancer (ES-SCLC) who are receiving chemotherapy.

Trilaciclib is a CDK4/6 inhibitor, and this action appears to protect normal bone marrow cells from the harmful effects of chemotherapy.

“For patients with extensive-stage small-cell lung cancer, protecting bone marrow function may help make their chemotherapy safer and allow them to complete their course of treatment on time and according to plan,” Albert Deisseroth, MD, PhD, of the FDA’s Center for Drug Evaluation and Research, said in an FDA press release.
 

First drug of its type

Trilaciclib “is the first and only therapy designed to help protect bone marrow (myeloprotection) when administered prior to treatment with chemotherapy,” according to the drug’s manufacturer.

Myelosuppression is one of the most severe adverse effects of chemotherapy, and it can be life-threatening. It can increase the risk of infection and lead to severe anemia and/or bleeding.

“These complications impact patients’ quality of life and may also result in chemotherapy dose reductions and delays,” Jeffrey Crawford, MD, of Duke Cancer Institute, Durham, N.C., said in a company press release.

“To date, approaches have included the use of growth factor agents to accelerate blood cell recovery after the bone marrow injury has occurred, along with antibiotics and transfusions as needed. By contrast, trilaciclib provides the first proactive approach to myelosuppression through a unique mechanism of action that helps protect the bone marrow from damage by chemotherapy.”
 

Approval based on randomized, placebo-controlled trials

The approval of trilaciclib is based on data from three randomized, double-blind, placebo-controlled studies, involving a total of 245 patients with ES-SCLC.

These patients were being treated with chemotherapy regimens that were based on the combination of carboplatin and etoposide (with or without the immunotherapy atezolizumab) or regimens that were based on topotecan.

Before receiving the chemotherapy, patients were randomly assigned to receive trilaciclib or placebo.

Results showed that patients who had received an infusion of trilaciclib before receiving chemotherapy had a lower chance of developing severe neutropenia compared with patients who received a placebo, the FDA noted. In addition, among the patients who did develop severe neutropenia, this had a shorter duration among patients who received trilaciclib than among those who received placebo.

The most common side effects of trilaciclib were fatigue; low levels of calcium, potassium, and phosphate in the blood; increased levels of aspartate aminotransferase; headache; and pneumonia.

The FDA noted that patients should also be advised about injection site reactions, acute drug hypersensitivity, interstitial lung disease/pneumonitis, and embryo-fetal toxicity.

The approval received a priority review, based on the drug’s breakthrough therapy designation. As is common for such products, the company plans postmarketing activities that will assess the effects of trilaciclib on disease progression or survival with at least a 2-year follow up. This clinical trial is scheduled to start in 2022.

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

A novel drug that offers multilineage protection from chemotherapy-induced myelosuppression has been approved by the Food and Drug Administration.

The drug, trilaciclib (Cosela, G1 Therapeutics) is administered intravenously as a 30-minute infusion within 4 hours prior to the start of chemotherapy. It is indicated specifically for use in adults with extensive-stage small-cell lung cancer (ES-SCLC) who are receiving chemotherapy.

Trilaciclib is a CDK4/6 inhibitor, and this action appears to protect normal bone marrow cells from the harmful effects of chemotherapy.

“For patients with extensive-stage small-cell lung cancer, protecting bone marrow function may help make their chemotherapy safer and allow them to complete their course of treatment on time and according to plan,” Albert Deisseroth, MD, PhD, of the FDA’s Center for Drug Evaluation and Research, said in an FDA press release.
 

First drug of its type

Trilaciclib “is the first and only therapy designed to help protect bone marrow (myeloprotection) when administered prior to treatment with chemotherapy,” according to the drug’s manufacturer.

Myelosuppression is one of the most severe adverse effects of chemotherapy, and it can be life-threatening. It can increase the risk of infection and lead to severe anemia and/or bleeding.

“These complications impact patients’ quality of life and may also result in chemotherapy dose reductions and delays,” Jeffrey Crawford, MD, of Duke Cancer Institute, Durham, N.C., said in a company press release.

“To date, approaches have included the use of growth factor agents to accelerate blood cell recovery after the bone marrow injury has occurred, along with antibiotics and transfusions as needed. By contrast, trilaciclib provides the first proactive approach to myelosuppression through a unique mechanism of action that helps protect the bone marrow from damage by chemotherapy.”
 

Approval based on randomized, placebo-controlled trials

The approval of trilaciclib is based on data from three randomized, double-blind, placebo-controlled studies, involving a total of 245 patients with ES-SCLC.

These patients were being treated with chemotherapy regimens that were based on the combination of carboplatin and etoposide (with or without the immunotherapy atezolizumab) or regimens that were based on topotecan.

Before receiving the chemotherapy, patients were randomly assigned to receive trilaciclib or placebo.

Results showed that patients who had received an infusion of trilaciclib before receiving chemotherapy had a lower chance of developing severe neutropenia compared with patients who received a placebo, the FDA noted. In addition, among the patients who did develop severe neutropenia, this had a shorter duration among patients who received trilaciclib than among those who received placebo.

The most common side effects of trilaciclib were fatigue; low levels of calcium, potassium, and phosphate in the blood; increased levels of aspartate aminotransferase; headache; and pneumonia.

The FDA noted that patients should also be advised about injection site reactions, acute drug hypersensitivity, interstitial lung disease/pneumonitis, and embryo-fetal toxicity.

The approval received a priority review, based on the drug’s breakthrough therapy designation. As is common for such products, the company plans postmarketing activities that will assess the effects of trilaciclib on disease progression or survival with at least a 2-year follow up. This clinical trial is scheduled to start in 2022.

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

A novel drug that offers multilineage protection from chemotherapy-induced myelosuppression has been approved by the Food and Drug Administration.

The drug, trilaciclib (Cosela, G1 Therapeutics) is administered intravenously as a 30-minute infusion within 4 hours prior to the start of chemotherapy. It is indicated specifically for use in adults with extensive-stage small-cell lung cancer (ES-SCLC) who are receiving chemotherapy.

Trilaciclib is a CDK4/6 inhibitor, and this action appears to protect normal bone marrow cells from the harmful effects of chemotherapy.

“For patients with extensive-stage small-cell lung cancer, protecting bone marrow function may help make their chemotherapy safer and allow them to complete their course of treatment on time and according to plan,” Albert Deisseroth, MD, PhD, of the FDA’s Center for Drug Evaluation and Research, said in an FDA press release.
 

First drug of its type

Trilaciclib “is the first and only therapy designed to help protect bone marrow (myeloprotection) when administered prior to treatment with chemotherapy,” according to the drug’s manufacturer.

Myelosuppression is one of the most severe adverse effects of chemotherapy, and it can be life-threatening. It can increase the risk of infection and lead to severe anemia and/or bleeding.

“These complications impact patients’ quality of life and may also result in chemotherapy dose reductions and delays,” Jeffrey Crawford, MD, of Duke Cancer Institute, Durham, N.C., said in a company press release.

“To date, approaches have included the use of growth factor agents to accelerate blood cell recovery after the bone marrow injury has occurred, along with antibiotics and transfusions as needed. By contrast, trilaciclib provides the first proactive approach to myelosuppression through a unique mechanism of action that helps protect the bone marrow from damage by chemotherapy.”
 

Approval based on randomized, placebo-controlled trials

The approval of trilaciclib is based on data from three randomized, double-blind, placebo-controlled studies, involving a total of 245 patients with ES-SCLC.

These patients were being treated with chemotherapy regimens that were based on the combination of carboplatin and etoposide (with or without the immunotherapy atezolizumab) or regimens that were based on topotecan.

Before receiving the chemotherapy, patients were randomly assigned to receive trilaciclib or placebo.

Results showed that patients who had received an infusion of trilaciclib before receiving chemotherapy had a lower chance of developing severe neutropenia compared with patients who received a placebo, the FDA noted. In addition, among the patients who did develop severe neutropenia, this had a shorter duration among patients who received trilaciclib than among those who received placebo.

The most common side effects of trilaciclib were fatigue; low levels of calcium, potassium, and phosphate in the blood; increased levels of aspartate aminotransferase; headache; and pneumonia.

The FDA noted that patients should also be advised about injection site reactions, acute drug hypersensitivity, interstitial lung disease/pneumonitis, and embryo-fetal toxicity.

The approval received a priority review, based on the drug’s breakthrough therapy designation. As is common for such products, the company plans postmarketing activities that will assess the effects of trilaciclib on disease progression or survival with at least a 2-year follow up. This clinical trial is scheduled to start in 2022.

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

John G. Bartlett, MD, professor emeritus at Johns Hopkins University School of Medicine, Baltimore, and a prominent leader and instructor in infectious disease medicine, died Jan. 19 at age 83. The cause of death was not immediately disclosed.

Dr. Bartlett is remembered by colleagues for his wide range of infectious disease expertise, an ability to repeatedly predict emerging issues in the field, and for inspiring students and trainees to choose the same specialty. 

“What I consistently found so extraordinary about John was his excitement for ID – the whole field. He had a wonderful sixth sense about what was going to be the next ‘big thing,’” Paul Edward Sax, MD, clinical director of the Infectious Disease Clinic at Brigham and Women’s Hospital in Boston, told this news organization.

“He thoroughly absorbed the emerging research on the topic and then provided the most wonderful clinical summaries,” Dr. Sax said. “His range of expert content areas was unbelievably broad.” Dr. Bartlett was “a true ID polymath.”

Dr. Bartlett was “a giant in the field of infectious diseases,” David Lee Thomas, MD, MPH, said in an interview. He agreed that Dr. Bartlett was a visionary who could anticipate the most exciting developments in the specialty.

Dr. Bartlett also “led the efforts to combat the foes, from HIV to antimicrobial resistance,” said Dr. Thomas, director of the division of infectious diseases and professor of medicine at Johns Hopkins University.
 

A pioneer in HIV research and care

Dr. Bartlett’s early research focused on anaerobic pulmonary and other infections, Bacteroides fragilis pathogenesis, and colitis caused by Clostridioides difficile.

Shortly after joining Johns Hopkins in 1980, he focused on HIV/AIDS research and caring for people with HIV. Dr. Bartlett led clinical trials of new treatments and developed years of HIV clinical treatment guidelines.

“Back when most hospitals, university medical centers, and ID divisions were running away from the AIDS epidemic, John took it on, both as a scientific priority and a moral imperative,” Dr. Sax writes in a blog post for NEJM Journal Watch. “With the help of Frank Polk and the Hopkins president, he established an outpatient AIDS clinic and an inpatient AIDS ward – both of which were way ahead of their time.”

In the same post, Dr. Sax points out that Dr. Bartlett was an expert in multiple areas – any one of which could be a sole career focus. “How many ID doctors are true experts in all of the following distinct topics? HIV, Clostridium difficile, respiratory tract infections, antimicrobial resistance, and anaerobic pulmonary infections.” Dr. Sax writes.
 

Expertise that defined an era

In a piece reviewing the long history of infectious disease medicine at Johns Hopkins published in Clinical Infectious Diseases in 2014, Paul Auwaerter, MD, and colleagues describe his tenure at the institution from 1980 to 2006 as “The Bartlett Era,” notable for the many advances he spearheaded.

“It is nearly impossible to find someone trained in infectious diseases in the past 30 years who has not been impacted by John Bartlett,” Dr. Auwaerter and colleagues note. “His tireless devotion to scholarship, teaching, and patient care remains an inspiration to his faculty members at Johns Hopkins, his colleagues, and coworkers around the world.”

Dr. Bartlett was not only a faculty member in the division of infectious diseases, he also helped establish it. When he joined Johns Hopkins, the infectious disease department featured just three faculty members with a research budget of less than $285,000. By the time he left 26 years later, the division had 44 faculty members on tenure track and a research budget exceeding $40 million.
 

Sharing memories via social media

Reactions to Dr. Bartlett’s passing on Twitter were swift.

“We have lost one of the greatest physicians I have ever met or had the privilege to learn from. Saddened to hear of Dr. John G. Bartlett’s passing. He inspired so many, including me, to choose the field of infectious diseases,” David Fisk, MD, infectious disease specialist in Santa Barbara, Calif., wrote on Twitter.

“John Bartlett just died – a true visionary and the classic ‘Renaissance’ person in clinical ID. Such a nice guy, too! His IDSA/IDWeek literature summaries (among other things) were amazing. We’ll miss him!” Dr. Sax tweeted on Jan. 19.

A colleague at Johns Hopkins, transplant infectious disease specialist Shmuel Shoham, MD, shared an anecdote about Dr. Bartlett on Twitter: “Year ago. My office is across from his. I ask him what he is doing. He tells me he is reviewing a file from the Vatican to adjudicate whether a miracle happened. True story.”

Infectious disease specialist Graeme Forrest, MBBS, also shared a story about Dr. Bartlett via Twitter. “He described to me in 2001 how the U.S. model of health care would not cope with a pandemic or serious bioterror attack as it’s not connected to disseminate information. How prescient from 20 years ago.”

Dr. Bartlett shared his expertise at many national and international infectious disease conferences over the years. He also authored 470 articles, 282 book chapters, and 61 editions of 14 books.

Dr. Bartlett was also a regular contributor to this news organization. For example, he shared his expertise in perspective pieces that addressed priorities in antibiotic stewardship, upcoming infectious disease predictions, and critical infectious disease topics in a three-part series.

Dr. Bartlett’s education includes a bachelor’s degree from Dartmouth College in Hanover, N.H., in 1959 and an MD from Upstate Medical Center in Syracuse, N.Y., in 1963. He did his first 2 years of residency at Brigham and Women’s Hospital.

He also served as an Army captain from 1965 to 1967, treating patients in fever wards in Vietnam. He then returned to the United States to finish his internal medicine training at the University of Alabama in 1968.

Dr. Bartlett completed his fellowship in infectious diseases at the University of California, Los Angeles. In 1975, he joined the faculty at Tufts University, Boston.
 

Leaving a legacy

Dr. Bartlett’s influence will likely live on in many ways at Johns Hopkins.

“John is a larger-than-life legend whose impact will endure and after whom we are so proud to have named our clinical service, The Bartlett Specialty Practice,” Dr. Thomas said.

The specialty practice clinic named for him has 23 exam rooms and features multidisciplinary care for people with HIV, hepatitis, bone infections, general infectious diseases, and more. Furthermore, friends, family, and colleagues joined forces to create the “Dr. John G. Bartlett HIV/AIDS Fund.”

They note that it is “only appropriate that we honor him by creating an endowment that will provide support for young trainees and junior faculty in the division, helping them transition to their independent careers.”

In addition to all his professional accomplishments, “He was also a genuinely nice person, approachable and humble,” Dr. Sax said. “We really lost a great one!”

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

John G. Bartlett, MD, professor emeritus at Johns Hopkins University School of Medicine, Baltimore, and a prominent leader and instructor in infectious disease medicine, died Jan. 19 at age 83. The cause of death was not immediately disclosed.

Dr. Bartlett is remembered by colleagues for his wide range of infectious disease expertise, an ability to repeatedly predict emerging issues in the field, and for inspiring students and trainees to choose the same specialty. 

“What I consistently found so extraordinary about John was his excitement for ID – the whole field. He had a wonderful sixth sense about what was going to be the next ‘big thing,’” Paul Edward Sax, MD, clinical director of the Infectious Disease Clinic at Brigham and Women’s Hospital in Boston, told this news organization.

“He thoroughly absorbed the emerging research on the topic and then provided the most wonderful clinical summaries,” Dr. Sax said. “His range of expert content areas was unbelievably broad.” Dr. Bartlett was “a true ID polymath.”

Dr. Bartlett was “a giant in the field of infectious diseases,” David Lee Thomas, MD, MPH, said in an interview. He agreed that Dr. Bartlett was a visionary who could anticipate the most exciting developments in the specialty.

Dr. Bartlett also “led the efforts to combat the foes, from HIV to antimicrobial resistance,” said Dr. Thomas, director of the division of infectious diseases and professor of medicine at Johns Hopkins University.
 

A pioneer in HIV research and care

Dr. Bartlett’s early research focused on anaerobic pulmonary and other infections, Bacteroides fragilis pathogenesis, and colitis caused by Clostridioides difficile.

Shortly after joining Johns Hopkins in 1980, he focused on HIV/AIDS research and caring for people with HIV. Dr. Bartlett led clinical trials of new treatments and developed years of HIV clinical treatment guidelines.

“Back when most hospitals, university medical centers, and ID divisions were running away from the AIDS epidemic, John took it on, both as a scientific priority and a moral imperative,” Dr. Sax writes in a blog post for NEJM Journal Watch. “With the help of Frank Polk and the Hopkins president, he established an outpatient AIDS clinic and an inpatient AIDS ward – both of which were way ahead of their time.”

In the same post, Dr. Sax points out that Dr. Bartlett was an expert in multiple areas – any one of which could be a sole career focus. “How many ID doctors are true experts in all of the following distinct topics? HIV, Clostridium difficile, respiratory tract infections, antimicrobial resistance, and anaerobic pulmonary infections.” Dr. Sax writes.
 

Expertise that defined an era

In a piece reviewing the long history of infectious disease medicine at Johns Hopkins published in Clinical Infectious Diseases in 2014, Paul Auwaerter, MD, and colleagues describe his tenure at the institution from 1980 to 2006 as “The Bartlett Era,” notable for the many advances he spearheaded.

“It is nearly impossible to find someone trained in infectious diseases in the past 30 years who has not been impacted by John Bartlett,” Dr. Auwaerter and colleagues note. “His tireless devotion to scholarship, teaching, and patient care remains an inspiration to his faculty members at Johns Hopkins, his colleagues, and coworkers around the world.”

Dr. Bartlett was not only a faculty member in the division of infectious diseases, he also helped establish it. When he joined Johns Hopkins, the infectious disease department featured just three faculty members with a research budget of less than $285,000. By the time he left 26 years later, the division had 44 faculty members on tenure track and a research budget exceeding $40 million.
 

Sharing memories via social media

Reactions to Dr. Bartlett’s passing on Twitter were swift.

“We have lost one of the greatest physicians I have ever met or had the privilege to learn from. Saddened to hear of Dr. John G. Bartlett’s passing. He inspired so many, including me, to choose the field of infectious diseases,” David Fisk, MD, infectious disease specialist in Santa Barbara, Calif., wrote on Twitter.

“John Bartlett just died – a true visionary and the classic ‘Renaissance’ person in clinical ID. Such a nice guy, too! His IDSA/IDWeek literature summaries (among other things) were amazing. We’ll miss him!” Dr. Sax tweeted on Jan. 19.

A colleague at Johns Hopkins, transplant infectious disease specialist Shmuel Shoham, MD, shared an anecdote about Dr. Bartlett on Twitter: “Year ago. My office is across from his. I ask him what he is doing. He tells me he is reviewing a file from the Vatican to adjudicate whether a miracle happened. True story.”

Infectious disease specialist Graeme Forrest, MBBS, also shared a story about Dr. Bartlett via Twitter. “He described to me in 2001 how the U.S. model of health care would not cope with a pandemic or serious bioterror attack as it’s not connected to disseminate information. How prescient from 20 years ago.”

Dr. Bartlett shared his expertise at many national and international infectious disease conferences over the years. He also authored 470 articles, 282 book chapters, and 61 editions of 14 books.

Dr. Bartlett was also a regular contributor to this news organization. For example, he shared his expertise in perspective pieces that addressed priorities in antibiotic stewardship, upcoming infectious disease predictions, and critical infectious disease topics in a three-part series.

Dr. Bartlett’s education includes a bachelor’s degree from Dartmouth College in Hanover, N.H., in 1959 and an MD from Upstate Medical Center in Syracuse, N.Y., in 1963. He did his first 2 years of residency at Brigham and Women’s Hospital.

He also served as an Army captain from 1965 to 1967, treating patients in fever wards in Vietnam. He then returned to the United States to finish his internal medicine training at the University of Alabama in 1968.

Dr. Bartlett completed his fellowship in infectious diseases at the University of California, Los Angeles. In 1975, he joined the faculty at Tufts University, Boston.
 

Leaving a legacy

Dr. Bartlett’s influence will likely live on in many ways at Johns Hopkins.

“John is a larger-than-life legend whose impact will endure and after whom we are so proud to have named our clinical service, The Bartlett Specialty Practice,” Dr. Thomas said.

The specialty practice clinic named for him has 23 exam rooms and features multidisciplinary care for people with HIV, hepatitis, bone infections, general infectious diseases, and more. Furthermore, friends, family, and colleagues joined forces to create the “Dr. John G. Bartlett HIV/AIDS Fund.”

They note that it is “only appropriate that we honor him by creating an endowment that will provide support for young trainees and junior faculty in the division, helping them transition to their independent careers.”

In addition to all his professional accomplishments, “He was also a genuinely nice person, approachable and humble,” Dr. Sax said. “We really lost a great one!”

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

John G. Bartlett, MD, professor emeritus at Johns Hopkins University School of Medicine, Baltimore, and a prominent leader and instructor in infectious disease medicine, died Jan. 19 at age 83. The cause of death was not immediately disclosed.

Dr. Bartlett is remembered by colleagues for his wide range of infectious disease expertise, an ability to repeatedly predict emerging issues in the field, and for inspiring students and trainees to choose the same specialty. 

“What I consistently found so extraordinary about John was his excitement for ID – the whole field. He had a wonderful sixth sense about what was going to be the next ‘big thing,’” Paul Edward Sax, MD, clinical director of the Infectious Disease Clinic at Brigham and Women’s Hospital in Boston, told this news organization.

“He thoroughly absorbed the emerging research on the topic and then provided the most wonderful clinical summaries,” Dr. Sax said. “His range of expert content areas was unbelievably broad.” Dr. Bartlett was “a true ID polymath.”

Dr. Bartlett was “a giant in the field of infectious diseases,” David Lee Thomas, MD, MPH, said in an interview. He agreed that Dr. Bartlett was a visionary who could anticipate the most exciting developments in the specialty.

Dr. Bartlett also “led the efforts to combat the foes, from HIV to antimicrobial resistance,” said Dr. Thomas, director of the division of infectious diseases and professor of medicine at Johns Hopkins University.
 

A pioneer in HIV research and care

Dr. Bartlett’s early research focused on anaerobic pulmonary and other infections, Bacteroides fragilis pathogenesis, and colitis caused by Clostridioides difficile.

Shortly after joining Johns Hopkins in 1980, he focused on HIV/AIDS research and caring for people with HIV. Dr. Bartlett led clinical trials of new treatments and developed years of HIV clinical treatment guidelines.

“Back when most hospitals, university medical centers, and ID divisions were running away from the AIDS epidemic, John took it on, both as a scientific priority and a moral imperative,” Dr. Sax writes in a blog post for NEJM Journal Watch. “With the help of Frank Polk and the Hopkins president, he established an outpatient AIDS clinic and an inpatient AIDS ward – both of which were way ahead of their time.”

In the same post, Dr. Sax points out that Dr. Bartlett was an expert in multiple areas – any one of which could be a sole career focus. “How many ID doctors are true experts in all of the following distinct topics? HIV, Clostridium difficile, respiratory tract infections, antimicrobial resistance, and anaerobic pulmonary infections.” Dr. Sax writes.
 

Expertise that defined an era

In a piece reviewing the long history of infectious disease medicine at Johns Hopkins published in Clinical Infectious Diseases in 2014, Paul Auwaerter, MD, and colleagues describe his tenure at the institution from 1980 to 2006 as “The Bartlett Era,” notable for the many advances he spearheaded.

“It is nearly impossible to find someone trained in infectious diseases in the past 30 years who has not been impacted by John Bartlett,” Dr. Auwaerter and colleagues note. “His tireless devotion to scholarship, teaching, and patient care remains an inspiration to his faculty members at Johns Hopkins, his colleagues, and coworkers around the world.”

Dr. Bartlett was not only a faculty member in the division of infectious diseases, he also helped establish it. When he joined Johns Hopkins, the infectious disease department featured just three faculty members with a research budget of less than $285,000. By the time he left 26 years later, the division had 44 faculty members on tenure track and a research budget exceeding $40 million.
 

Sharing memories via social media

Reactions to Dr. Bartlett’s passing on Twitter were swift.

“We have lost one of the greatest physicians I have ever met or had the privilege to learn from. Saddened to hear of Dr. John G. Bartlett’s passing. He inspired so many, including me, to choose the field of infectious diseases,” David Fisk, MD, infectious disease specialist in Santa Barbara, Calif., wrote on Twitter.

“John Bartlett just died – a true visionary and the classic ‘Renaissance’ person in clinical ID. Such a nice guy, too! His IDSA/IDWeek literature summaries (among other things) were amazing. We’ll miss him!” Dr. Sax tweeted on Jan. 19.

A colleague at Johns Hopkins, transplant infectious disease specialist Shmuel Shoham, MD, shared an anecdote about Dr. Bartlett on Twitter: “Year ago. My office is across from his. I ask him what he is doing. He tells me he is reviewing a file from the Vatican to adjudicate whether a miracle happened. True story.”

Infectious disease specialist Graeme Forrest, MBBS, also shared a story about Dr. Bartlett via Twitter. “He described to me in 2001 how the U.S. model of health care would not cope with a pandemic or serious bioterror attack as it’s not connected to disseminate information. How prescient from 20 years ago.”

Dr. Bartlett shared his expertise at many national and international infectious disease conferences over the years. He also authored 470 articles, 282 book chapters, and 61 editions of 14 books.

Dr. Bartlett was also a regular contributor to this news organization. For example, he shared his expertise in perspective pieces that addressed priorities in antibiotic stewardship, upcoming infectious disease predictions, and critical infectious disease topics in a three-part series.

Dr. Bartlett’s education includes a bachelor’s degree from Dartmouth College in Hanover, N.H., in 1959 and an MD from Upstate Medical Center in Syracuse, N.Y., in 1963. He did his first 2 years of residency at Brigham and Women’s Hospital.

He also served as an Army captain from 1965 to 1967, treating patients in fever wards in Vietnam. He then returned to the United States to finish his internal medicine training at the University of Alabama in 1968.

Dr. Bartlett completed his fellowship in infectious diseases at the University of California, Los Angeles. In 1975, he joined the faculty at Tufts University, Boston.
 

Leaving a legacy

Dr. Bartlett’s influence will likely live on in many ways at Johns Hopkins.

“John is a larger-than-life legend whose impact will endure and after whom we are so proud to have named our clinical service, The Bartlett Specialty Practice,” Dr. Thomas said.

The specialty practice clinic named for him has 23 exam rooms and features multidisciplinary care for people with HIV, hepatitis, bone infections, general infectious diseases, and more. Furthermore, friends, family, and colleagues joined forces to create the “Dr. John G. Bartlett HIV/AIDS Fund.”

They note that it is “only appropriate that we honor him by creating an endowment that will provide support for young trainees and junior faculty in the division, helping them transition to their independent careers.”

In addition to all his professional accomplishments, “He was also a genuinely nice person, approachable and humble,” Dr. Sax said. “We really lost a great one!”

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

The checkpoint inhibitor nivolumab is efficacious and well tolerated when used as adjuvant therapy in patients who have undergone radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC), first results of the CheckMate 274 trial suggest.

The trial enrolled patients regardless of tumor PD-L1 status and receipt of neoadjuvant chemotherapy. The median disease-free survival was 21.0 months among patients given adjuvant nivolumab, almost double the 10.9 months among counterparts given placebo. Unsurprisingly, treatment-related adverse events were more common with nivolumab, but health-related quality of life was similar to that with placebo.

“Nivolumab is the first systemic immunotherapy to demonstrate a statistically significant and clinically meaningful improvement in outcomes when administered as adjuvant therapy to patients with MIUC,” said study investigator Dean F. Bajorin, MD, of Memorial Sloan Kettering Cancer Center, New York.

“These results support nivolumab monotherapy as a new standard of care in the adjuvant setting for patients with high-risk MIUC after radical surgery regardless of PD-L1 status and prior neoadjuvant chemotherapy,” Dr. Bajorin said when presenting the results at the 2021 Genitourinary Cancers Symposium (Abstract 391).
 

Trial details

The international, phase 3 trial enrolled 709 patients who had undergone radical surgery for high-risk MIUC of the bladder, ureter, or renal pelvis.

By intention, about 20% of the trial population had upper-tract disease, Dr. Bajorin noted. Roughly 43% had received cisplatin-based neoadjuvant chemotherapy, and 40% had tumors that were positive for PD-L1 (defined as ≥1% expression).

The patients were randomized evenly to receive up to 1 year of adjuvant nivolumab or placebo on a double-blind basis.

At a median follow-up of about 20 months, the trial met its primary endpoint, showing significant prolongation of disease-free survival in the intention-to-treat population with nivolumab versus placebo – a median of 21.0 months and 10.9 months, respectively (hazard ratio, 0.70; P < .001).

In subgroup analyses by disease site, benefit appeared restricted to patients with bladder tumors, although this finding is only hypothesis generating, Dr. Bajorin said.

The gain in disease-free survival was greater when analysis was restricted to the patients whose tumors were positive for PD-L1. The median disease-free survival was not reached in the nivolumab group and was 10.8 months in the placebo group (HR, 0.53; P < .001).

Nivolumab also netted significantly better non–urothelial tract recurrence-free survival (an endpoint that excludes common, non–life-threatening second primary urothelial cancers) and distant metastasis–free survival, both in the entire intention-to-treat population and in the subset with PD-L1–positive tumors.

Patients in the nivolumab group had a higher rate of grade 3 or worse treatment-related adverse events (17.9% vs. 7.2%), mainly caused by higher rates of increased amylase levels and lipase levels. But there was no deterioration in health-related quality of life as compared with placebo.

The most common grade 3 or worse treatment-related adverse events with nivolumab that were potentially immune mediated were diarrhea (0.9%), colitis (0.9%), and pneumonitis (0.9%), including two deaths in patients with treatment-related pneumonitis.
 

Awaited findings

Overall survival and biomarker data will require longer follow-up, Dr. Bajorin acknowledged. He defended the choice of disease-free survival as the trial’s primary endpoint, noting that it was selected after discussions with regulators when the trial was designed about 7 years ago.

“We believe that disease-free survival is an appropriate endpoint, that there are a lot of symptoms associated with metastasis in this disease. This is a devastating, symptomatic disease when it’s metastatic,” he elaborated, adding that this fact was also a driver behind selection of the other efficacy endpoints.

“I think that, as we follow this study further, we will see that disease-free survival – like it has in other studies in urothelial cancer – can translate into an overall survival benefit as well,” Dr. Bajorin said.

“This study is one of the most important in the last 5 years,” commented session cochair James M. McKiernan, MD, of the Columbia University Irving Medical Center, New York.

Some questions do arise when comparing the trial’s findings against those of other adjuvant trials in MIUC, he observed in an interview. In addition, it was noteworthy that the benefit of nivolumab was greatest among patients with PD-L1–positive tumors and those who had received neoadjuvant cisplatin.

Nonetheless, “I agree with the overall conclusion of the trial, and these data will establish a new standard of care,” Dr. McKiernan concluded. “The absence of overall survival data is not concerning for me, but we will all await that endpoint.”

The trial was supported by Bristol-Myers Squibb. Dr. Bajorin disclosed relationships with Bristol-Myers Squibb and several other companies. Dr. McKiernan disclosed a relationship with miR Scientific.

The checkpoint inhibitor nivolumab is efficacious and well tolerated when used as adjuvant therapy in patients who have undergone radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC), first results of the CheckMate 274 trial suggest.

The trial enrolled patients regardless of tumor PD-L1 status and receipt of neoadjuvant chemotherapy. The median disease-free survival was 21.0 months among patients given adjuvant nivolumab, almost double the 10.9 months among counterparts given placebo. Unsurprisingly, treatment-related adverse events were more common with nivolumab, but health-related quality of life was similar to that with placebo.

“Nivolumab is the first systemic immunotherapy to demonstrate a statistically significant and clinically meaningful improvement in outcomes when administered as adjuvant therapy to patients with MIUC,” said study investigator Dean F. Bajorin, MD, of Memorial Sloan Kettering Cancer Center, New York.

“These results support nivolumab monotherapy as a new standard of care in the adjuvant setting for patients with high-risk MIUC after radical surgery regardless of PD-L1 status and prior neoadjuvant chemotherapy,” Dr. Bajorin said when presenting the results at the 2021 Genitourinary Cancers Symposium (Abstract 391).
 

Trial details

The international, phase 3 trial enrolled 709 patients who had undergone radical surgery for high-risk MIUC of the bladder, ureter, or renal pelvis.

By intention, about 20% of the trial population had upper-tract disease, Dr. Bajorin noted. Roughly 43% had received cisplatin-based neoadjuvant chemotherapy, and 40% had tumors that were positive for PD-L1 (defined as ≥1% expression).

The patients were randomized evenly to receive up to 1 year of adjuvant nivolumab or placebo on a double-blind basis.

At a median follow-up of about 20 months, the trial met its primary endpoint, showing significant prolongation of disease-free survival in the intention-to-treat population with nivolumab versus placebo – a median of 21.0 months and 10.9 months, respectively (hazard ratio, 0.70; P < .001).

In subgroup analyses by disease site, benefit appeared restricted to patients with bladder tumors, although this finding is only hypothesis generating, Dr. Bajorin said.

The gain in disease-free survival was greater when analysis was restricted to the patients whose tumors were positive for PD-L1. The median disease-free survival was not reached in the nivolumab group and was 10.8 months in the placebo group (HR, 0.53; P < .001).

Nivolumab also netted significantly better non–urothelial tract recurrence-free survival (an endpoint that excludes common, non–life-threatening second primary urothelial cancers) and distant metastasis–free survival, both in the entire intention-to-treat population and in the subset with PD-L1–positive tumors.

Patients in the nivolumab group had a higher rate of grade 3 or worse treatment-related adverse events (17.9% vs. 7.2%), mainly caused by higher rates of increased amylase levels and lipase levels. But there was no deterioration in health-related quality of life as compared with placebo.

The most common grade 3 or worse treatment-related adverse events with nivolumab that were potentially immune mediated were diarrhea (0.9%), colitis (0.9%), and pneumonitis (0.9%), including two deaths in patients with treatment-related pneumonitis.
 

Awaited findings

Overall survival and biomarker data will require longer follow-up, Dr. Bajorin acknowledged. He defended the choice of disease-free survival as the trial’s primary endpoint, noting that it was selected after discussions with regulators when the trial was designed about 7 years ago.

“We believe that disease-free survival is an appropriate endpoint, that there are a lot of symptoms associated with metastasis in this disease. This is a devastating, symptomatic disease when it’s metastatic,” he elaborated, adding that this fact was also a driver behind selection of the other efficacy endpoints.

“I think that, as we follow this study further, we will see that disease-free survival – like it has in other studies in urothelial cancer – can translate into an overall survival benefit as well,” Dr. Bajorin said.

“This study is one of the most important in the last 5 years,” commented session cochair James M. McKiernan, MD, of the Columbia University Irving Medical Center, New York.

Some questions do arise when comparing the trial’s findings against those of other adjuvant trials in MIUC, he observed in an interview. In addition, it was noteworthy that the benefit of nivolumab was greatest among patients with PD-L1–positive tumors and those who had received neoadjuvant cisplatin.

Nonetheless, “I agree with the overall conclusion of the trial, and these data will establish a new standard of care,” Dr. McKiernan concluded. “The absence of overall survival data is not concerning for me, but we will all await that endpoint.”

The trial was supported by Bristol-Myers Squibb. Dr. Bajorin disclosed relationships with Bristol-Myers Squibb and several other companies. Dr. McKiernan disclosed a relationship with miR Scientific.

The checkpoint inhibitor nivolumab is efficacious and well tolerated when used as adjuvant therapy in patients who have undergone radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC), first results of the CheckMate 274 trial suggest.

The trial enrolled patients regardless of tumor PD-L1 status and receipt of neoadjuvant chemotherapy. The median disease-free survival was 21.0 months among patients given adjuvant nivolumab, almost double the 10.9 months among counterparts given placebo. Unsurprisingly, treatment-related adverse events were more common with nivolumab, but health-related quality of life was similar to that with placebo.

“Nivolumab is the first systemic immunotherapy to demonstrate a statistically significant and clinically meaningful improvement in outcomes when administered as adjuvant therapy to patients with MIUC,” said study investigator Dean F. Bajorin, MD, of Memorial Sloan Kettering Cancer Center, New York.

“These results support nivolumab monotherapy as a new standard of care in the adjuvant setting for patients with high-risk MIUC after radical surgery regardless of PD-L1 status and prior neoadjuvant chemotherapy,” Dr. Bajorin said when presenting the results at the 2021 Genitourinary Cancers Symposium (Abstract 391).
 

Trial details

The international, phase 3 trial enrolled 709 patients who had undergone radical surgery for high-risk MIUC of the bladder, ureter, or renal pelvis.

By intention, about 20% of the trial population had upper-tract disease, Dr. Bajorin noted. Roughly 43% had received cisplatin-based neoadjuvant chemotherapy, and 40% had tumors that were positive for PD-L1 (defined as ≥1% expression).

The patients were randomized evenly to receive up to 1 year of adjuvant nivolumab or placebo on a double-blind basis.

At a median follow-up of about 20 months, the trial met its primary endpoint, showing significant prolongation of disease-free survival in the intention-to-treat population with nivolumab versus placebo – a median of 21.0 months and 10.9 months, respectively (hazard ratio, 0.70; P < .001).

In subgroup analyses by disease site, benefit appeared restricted to patients with bladder tumors, although this finding is only hypothesis generating, Dr. Bajorin said.

The gain in disease-free survival was greater when analysis was restricted to the patients whose tumors were positive for PD-L1. The median disease-free survival was not reached in the nivolumab group and was 10.8 months in the placebo group (HR, 0.53; P < .001).

Nivolumab also netted significantly better non–urothelial tract recurrence-free survival (an endpoint that excludes common, non–life-threatening second primary urothelial cancers) and distant metastasis–free survival, both in the entire intention-to-treat population and in the subset with PD-L1–positive tumors.

Patients in the nivolumab group had a higher rate of grade 3 or worse treatment-related adverse events (17.9% vs. 7.2%), mainly caused by higher rates of increased amylase levels and lipase levels. But there was no deterioration in health-related quality of life as compared with placebo.

The most common grade 3 or worse treatment-related adverse events with nivolumab that were potentially immune mediated were diarrhea (0.9%), colitis (0.9%), and pneumonitis (0.9%), including two deaths in patients with treatment-related pneumonitis.
 

Awaited findings

Overall survival and biomarker data will require longer follow-up, Dr. Bajorin acknowledged. He defended the choice of disease-free survival as the trial’s primary endpoint, noting that it was selected after discussions with regulators when the trial was designed about 7 years ago.

“We believe that disease-free survival is an appropriate endpoint, that there are a lot of symptoms associated with metastasis in this disease. This is a devastating, symptomatic disease when it’s metastatic,” he elaborated, adding that this fact was also a driver behind selection of the other efficacy endpoints.

“I think that, as we follow this study further, we will see that disease-free survival – like it has in other studies in urothelial cancer – can translate into an overall survival benefit as well,” Dr. Bajorin said.

“This study is one of the most important in the last 5 years,” commented session cochair James M. McKiernan, MD, of the Columbia University Irving Medical Center, New York.

Some questions do arise when comparing the trial’s findings against those of other adjuvant trials in MIUC, he observed in an interview. In addition, it was noteworthy that the benefit of nivolumab was greatest among patients with PD-L1–positive tumors and those who had received neoadjuvant cisplatin.

Nonetheless, “I agree with the overall conclusion of the trial, and these data will establish a new standard of care,” Dr. McKiernan concluded. “The absence of overall survival data is not concerning for me, but we will all await that endpoint.”

The trial was supported by Bristol-Myers Squibb. Dr. Bajorin disclosed relationships with Bristol-Myers Squibb and several other companies. Dr. McKiernan disclosed a relationship with miR Scientific.

The survival benefit of adding apalutamide to standard care for metastatic castration-sensitive prostate cancer persisted at nearly 4 years of follow-up, according to the final analysis of the phase 3 TITAN trial.

At a median follow-up of 44 months, the median overall survival (OS) was not reached in patients who received apalutamide plus standard androgen deprivation therapy (ADT), but the median OS was 52.2 months in patients who received placebo plus ADT.

“In the final analysis, the risk of death with apalutamide was reduced by 35%, with a hazard ratio of 0.65 and P value of less than .0001. This was similar to the hazard ratio of 0.67 in the primary analysis of TITAN, despite an almost 40% crossover rate from the placebo group to the apalutamide,” said Kim N. Chi, MD, a medical oncologist at BC Cancer Vancouver Prostate Centre.

Dr. Chi reported these results at the 2021 Genitourinary Cancer Symposium (Abstract 11).
 

Study details

The international, double-blind TITAN trial compared apalutamide (240 mg daily) with placebo, both added to standard ADT, in 1,052 patients with metastatic castration-sensitive prostate cancer, including those with high- and low-volume disease, prior docetaxel use, prior treatment for localized disease, and prior ADT for no more than 6 months.

At the primary analysis, reported in the New England Journal of Medicine in 2019, the dual primary endpoints of radiographic progression-free survival and OS met statistical significance at a median follow up of 22.7 months.

At the final analysis, the median treatment duration was 39.3 months for the apalutamide arm, 20.2 months for the placebo arm, and 15.4 months for patients who crossed over from placebo to apalutamide.

After adjusting for crossover, the effect of apalutamide on OS increased (HR, 0.52), indicating a reduction in the risk of death by 48% versus placebo, Dr. Chi said. He noted that the treatment effect on OS favored apalutamide in both high- and low-volume disease.

“Treatment with apalutamide also significantly prolonged second progression-free survival on next subsequent therapy and delayed development of castration resistance,” Dr. Chi said.

The median second progression-free survival was 44.0 months in the placebo arm and was not reached in the apalutamide arm. The median time to castration resistance was 11.4 months in the placebo arm and was not reached in the apalutamide arm.

Health-related quality of life was also maintained in the apalutamide group throughout the study and did not differ from the placebo group. Safety was consistent with previous reports.

“Importantly, the cumulative incidence of treatment-related falls, fracture, and fatigue was similar between groups, as was the cumulative incidence of treatment-related adverse events and serious adverse events,” Dr. Chi said.

An increased incidence of any-grade rash that was seen in the apalutamide group was expected but plateaued after about 6 months.

“These results confirm the favorable risk-benefit profile of apalutamide,” Dr. Chi concluded.
 

Implications for practice

The study results raise questions about how to best incorporate the findings into practice, including how to use docetaxel or other androgen receptor inhibitors in treatment strategies for this patient population and if they should be used in high-volume patients, said Elisabeth Heath, MD, session cochair and associate director of translational science at Wayne State University in Detroit.

Dr. Chi said a number of studies over the past 5 years have demonstrated OS benefit when combining ADT with additional therapy.

“Really, this should be considered the standard of care,” he said. “However, real-world studies ... suggest that only a minority of patients are actually receiving this additional therapy.”

Although there are challenges with comparing outcomes across studies to determine which treatments to use, the TITAN data reinforce apalutamide plus ADT as a good option, including in high-volume patients, Dr. Chi said.

Funding for TITAN was provided by Janssen Research & Development. Dr. Chi and Dr. Heath disclosed relationships with Janssen and many other companies. [email protected]
 

The survival benefit of adding apalutamide to standard care for metastatic castration-sensitive prostate cancer persisted at nearly 4 years of follow-up, according to the final analysis of the phase 3 TITAN trial.

At a median follow-up of 44 months, the median overall survival (OS) was not reached in patients who received apalutamide plus standard androgen deprivation therapy (ADT), but the median OS was 52.2 months in patients who received placebo plus ADT.

“In the final analysis, the risk of death with apalutamide was reduced by 35%, with a hazard ratio of 0.65 and P value of less than .0001. This was similar to the hazard ratio of 0.67 in the primary analysis of TITAN, despite an almost 40% crossover rate from the placebo group to the apalutamide,” said Kim N. Chi, MD, a medical oncologist at BC Cancer Vancouver Prostate Centre.

Dr. Chi reported these results at the 2021 Genitourinary Cancer Symposium (Abstract 11).
 

Study details

The international, double-blind TITAN trial compared apalutamide (240 mg daily) with placebo, both added to standard ADT, in 1,052 patients with metastatic castration-sensitive prostate cancer, including those with high- and low-volume disease, prior docetaxel use, prior treatment for localized disease, and prior ADT for no more than 6 months.

At the primary analysis, reported in the New England Journal of Medicine in 2019, the dual primary endpoints of radiographic progression-free survival and OS met statistical significance at a median follow up of 22.7 months.

At the final analysis, the median treatment duration was 39.3 months for the apalutamide arm, 20.2 months for the placebo arm, and 15.4 months for patients who crossed over from placebo to apalutamide.

After adjusting for crossover, the effect of apalutamide on OS increased (HR, 0.52), indicating a reduction in the risk of death by 48% versus placebo, Dr. Chi said. He noted that the treatment effect on OS favored apalutamide in both high- and low-volume disease.

“Treatment with apalutamide also significantly prolonged second progression-free survival on next subsequent therapy and delayed development of castration resistance,” Dr. Chi said.

The median second progression-free survival was 44.0 months in the placebo arm and was not reached in the apalutamide arm. The median time to castration resistance was 11.4 months in the placebo arm and was not reached in the apalutamide arm.

Health-related quality of life was also maintained in the apalutamide group throughout the study and did not differ from the placebo group. Safety was consistent with previous reports.

“Importantly, the cumulative incidence of treatment-related falls, fracture, and fatigue was similar between groups, as was the cumulative incidence of treatment-related adverse events and serious adverse events,” Dr. Chi said.

An increased incidence of any-grade rash that was seen in the apalutamide group was expected but plateaued after about 6 months.

“These results confirm the favorable risk-benefit profile of apalutamide,” Dr. Chi concluded.
 

Implications for practice

The study results raise questions about how to best incorporate the findings into practice, including how to use docetaxel or other androgen receptor inhibitors in treatment strategies for this patient population and if they should be used in high-volume patients, said Elisabeth Heath, MD, session cochair and associate director of translational science at Wayne State University in Detroit.

Dr. Chi said a number of studies over the past 5 years have demonstrated OS benefit when combining ADT with additional therapy.

“Really, this should be considered the standard of care,” he said. “However, real-world studies ... suggest that only a minority of patients are actually receiving this additional therapy.”

Although there are challenges with comparing outcomes across studies to determine which treatments to use, the TITAN data reinforce apalutamide plus ADT as a good option, including in high-volume patients, Dr. Chi said.

Funding for TITAN was provided by Janssen Research & Development. Dr. Chi and Dr. Heath disclosed relationships with Janssen and many other companies. [email protected]
 

The survival benefit of adding apalutamide to standard care for metastatic castration-sensitive prostate cancer persisted at nearly 4 years of follow-up, according to the final analysis of the phase 3 TITAN trial.

At a median follow-up of 44 months, the median overall survival (OS) was not reached in patients who received apalutamide plus standard androgen deprivation therapy (ADT), but the median OS was 52.2 months in patients who received placebo plus ADT.

“In the final analysis, the risk of death with apalutamide was reduced by 35%, with a hazard ratio of 0.65 and P value of less than .0001. This was similar to the hazard ratio of 0.67 in the primary analysis of TITAN, despite an almost 40% crossover rate from the placebo group to the apalutamide,” said Kim N. Chi, MD, a medical oncologist at BC Cancer Vancouver Prostate Centre.

Dr. Chi reported these results at the 2021 Genitourinary Cancer Symposium (Abstract 11).
 

Study details

The international, double-blind TITAN trial compared apalutamide (240 mg daily) with placebo, both added to standard ADT, in 1,052 patients with metastatic castration-sensitive prostate cancer, including those with high- and low-volume disease, prior docetaxel use, prior treatment for localized disease, and prior ADT for no more than 6 months.

At the primary analysis, reported in the New England Journal of Medicine in 2019, the dual primary endpoints of radiographic progression-free survival and OS met statistical significance at a median follow up of 22.7 months.

At the final analysis, the median treatment duration was 39.3 months for the apalutamide arm, 20.2 months for the placebo arm, and 15.4 months for patients who crossed over from placebo to apalutamide.

After adjusting for crossover, the effect of apalutamide on OS increased (HR, 0.52), indicating a reduction in the risk of death by 48% versus placebo, Dr. Chi said. He noted that the treatment effect on OS favored apalutamide in both high- and low-volume disease.

“Treatment with apalutamide also significantly prolonged second progression-free survival on next subsequent therapy and delayed development of castration resistance,” Dr. Chi said.

The median second progression-free survival was 44.0 months in the placebo arm and was not reached in the apalutamide arm. The median time to castration resistance was 11.4 months in the placebo arm and was not reached in the apalutamide arm.

Health-related quality of life was also maintained in the apalutamide group throughout the study and did not differ from the placebo group. Safety was consistent with previous reports.

“Importantly, the cumulative incidence of treatment-related falls, fracture, and fatigue was similar between groups, as was the cumulative incidence of treatment-related adverse events and serious adverse events,” Dr. Chi said.

An increased incidence of any-grade rash that was seen in the apalutamide group was expected but plateaued after about 6 months.

“These results confirm the favorable risk-benefit profile of apalutamide,” Dr. Chi concluded.
 

Implications for practice

The study results raise questions about how to best incorporate the findings into practice, including how to use docetaxel or other androgen receptor inhibitors in treatment strategies for this patient population and if they should be used in high-volume patients, said Elisabeth Heath, MD, session cochair and associate director of translational science at Wayne State University in Detroit.

Dr. Chi said a number of studies over the past 5 years have demonstrated OS benefit when combining ADT with additional therapy.

“Really, this should be considered the standard of care,” he said. “However, real-world studies ... suggest that only a minority of patients are actually receiving this additional therapy.”

Although there are challenges with comparing outcomes across studies to determine which treatments to use, the TITAN data reinforce apalutamide plus ADT as a good option, including in high-volume patients, Dr. Chi said.

Funding for TITAN was provided by Janssen Research & Development. Dr. Chi and Dr. Heath disclosed relationships with Janssen and many other companies. [email protected]
 

The combined clinical cell-cycle risk (CCR) score – derived from both clinical and genetic factors – can identify patients with intermediate- and high-risk localized prostate cancer who could potentially forgo androgen deprivation therapy (ADT), a retrospective study suggests.

The score can identify patients in whom the risk of metastasis after dose-escalated radiation is so small that adding ADT no longer makes clinical sense, according to investigator Jonathan Tward, MD, PhD, of the Genitourinary Cancer Center at the University of Utah, Salt Lake City.

His group’s study, which included 741 patients, showed that, below a CCR score of 2.112, the 10-year risk of metastasis was 4.2% with radiation therapy (RT) alone and 3.9% with the addition of ADT.

“Whether you have RT alone, RT plus any duration of ADT, insufficient duration ADT, or sufficient ADT duration by guideline standard, the risk of metastasis never exceeds 5% at 10 years” even in high- and very-high-risk men, Dr. Tward said.

He and his team found that half the men in their study with unfavorable intermediate-risk disease, 20% with high-risk disease, and 5% with very-high-risk disease scored below the CCR threshold.

This implies that, for many men, ADT after radiation “adds unnecessary morbidity for an extremely small absolute risk reduction in metastasis-free survival,” Dr. Tward said at the 2021 Genitourinary Cancers Symposium, where he presented the findings (Abstract 195).
 

Value of CCR

The CCR score tells you if the relative metastasis risk reduction with ADT after radiation – about 50% based on clinical trials – translates to an absolute risk reduction that would matter, Dr. Tward said in an interview.

“Each patient has in their own mind what that risk reduction is that works for them,” he added.

For some patients, a 1%-2% drop in absolute risk is worth it, he said, but most patients wouldn’t be willing to endure the side effects of hormone therapy if the absolute benefit is less than 5%.

The CCR score is a validated prognosticator of metastasis and death in localized prostate cancer. It’s an amalgam of traditional clinical risk factors from the Cancer of the Prostate Risk Assessment (CAPRA) score and the cell-cycle progression (CCP) score, which measures expression of cell-cycle proliferation genes for a sense of how quickly tumor cells are dividing.

The CCP test is available commercially as Prolaris. It is used mostly to make the call between active surveillance and treatment, Dr. Tward explained, “but I had a hunch this off-the-shelf test would be very good at” helping with ADT decisions after radiation.
 

‘Uncomfortable’ findings, barriers to acceptance

“People are going to be very uncomfortable with these findings because it’s been ingrained in our heads for the past 20-30 years that you must use hormone therapy with high-risk prostate cancer, and you should use hormone therapy with intermediate risk,” Dr. Tward said.

“It took me a while to believe my own data, but we have used this test for several years to help men decide if they would like to have hormone therapy after radiation. Patients clearly benefit from this information,” he said.

The 2.112 cut point for CCR was determined from a prior study that was presented at GUCS 2020 (Abstract 346) and recently accepted for publication.

In the validation study Dr. Tward presented at GUCS 2021, 70% of patients had intermediate-risk disease, and 30% had high- or very-high-risk disease according to National Comprehensive Cancer Network criteria.

All 741 patients received RT equivalent to at least 75.6 Gy at 1.8 Gy per fraction, with 84% getting or exceeding 79.2 Gy. About half the men (53%) had ADT after RT.

Genetic testing was done on stored biopsy samples years after the men were treated. Half of them were below the CCR threshold of 2.112. For those above it, the 10-year risk of metastasis was 25.3%.

CCR outperformed CCP alone, CAPRA alone, and NCCN risk groupings for predicting metastasis risk after RT.

Though this validation study was “successful,” additional research is needed, according to study discussant Richard Valicenti, MD, of the University of California, Davis.

“Widespread acceptance for routine use faces challenges since no biomarker has been prospectively tested or shown to improve long-term outcome,” Dr. Valicenti said. “Clearly, the CCR score may provide highly precise, personalized estimates and justifies testing in tiered and appropriately powered noninferiority studies according to NCCN risk groups. We eagerly await the completion and reporting of such trials so that we have a more personalized approach to treating men with prostate cancer.”

The current study was funded by Myriad Genetics, the company that developed the Prolaris test. Dr. Tward disclosed relationships with Myriad Genetics, Bayer, Blue Earth Diagnostics, Janssen Scientific Affairs, and Merck. Dr. Valicenti has no disclosures.

[email protected]

The combined clinical cell-cycle risk (CCR) score – derived from both clinical and genetic factors – can identify patients with intermediate- and high-risk localized prostate cancer who could potentially forgo androgen deprivation therapy (ADT), a retrospective study suggests.

The score can identify patients in whom the risk of metastasis after dose-escalated radiation is so small that adding ADT no longer makes clinical sense, according to investigator Jonathan Tward, MD, PhD, of the Genitourinary Cancer Center at the University of Utah, Salt Lake City.

His group’s study, which included 741 patients, showed that, below a CCR score of 2.112, the 10-year risk of metastasis was 4.2% with radiation therapy (RT) alone and 3.9% with the addition of ADT.

“Whether you have RT alone, RT plus any duration of ADT, insufficient duration ADT, or sufficient ADT duration by guideline standard, the risk of metastasis never exceeds 5% at 10 years” even in high- and very-high-risk men, Dr. Tward said.

He and his team found that half the men in their study with unfavorable intermediate-risk disease, 20% with high-risk disease, and 5% with very-high-risk disease scored below the CCR threshold.

This implies that, for many men, ADT after radiation “adds unnecessary morbidity for an extremely small absolute risk reduction in metastasis-free survival,” Dr. Tward said at the 2021 Genitourinary Cancers Symposium, where he presented the findings (Abstract 195).
 

Value of CCR

The CCR score tells you if the relative metastasis risk reduction with ADT after radiation – about 50% based on clinical trials – translates to an absolute risk reduction that would matter, Dr. Tward said in an interview.

“Each patient has in their own mind what that risk reduction is that works for them,” he added.

For some patients, a 1%-2% drop in absolute risk is worth it, he said, but most patients wouldn’t be willing to endure the side effects of hormone therapy if the absolute benefit is less than 5%.

The CCR score is a validated prognosticator of metastasis and death in localized prostate cancer. It’s an amalgam of traditional clinical risk factors from the Cancer of the Prostate Risk Assessment (CAPRA) score and the cell-cycle progression (CCP) score, which measures expression of cell-cycle proliferation genes for a sense of how quickly tumor cells are dividing.

The CCP test is available commercially as Prolaris. It is used mostly to make the call between active surveillance and treatment, Dr. Tward explained, “but I had a hunch this off-the-shelf test would be very good at” helping with ADT decisions after radiation.
 

‘Uncomfortable’ findings, barriers to acceptance

“People are going to be very uncomfortable with these findings because it’s been ingrained in our heads for the past 20-30 years that you must use hormone therapy with high-risk prostate cancer, and you should use hormone therapy with intermediate risk,” Dr. Tward said.

“It took me a while to believe my own data, but we have used this test for several years to help men decide if they would like to have hormone therapy after radiation. Patients clearly benefit from this information,” he said.

The 2.112 cut point for CCR was determined from a prior study that was presented at GUCS 2020 (Abstract 346) and recently accepted for publication.

In the validation study Dr. Tward presented at GUCS 2021, 70% of patients had intermediate-risk disease, and 30% had high- or very-high-risk disease according to National Comprehensive Cancer Network criteria.

All 741 patients received RT equivalent to at least 75.6 Gy at 1.8 Gy per fraction, with 84% getting or exceeding 79.2 Gy. About half the men (53%) had ADT after RT.

Genetic testing was done on stored biopsy samples years after the men were treated. Half of them were below the CCR threshold of 2.112. For those above it, the 10-year risk of metastasis was 25.3%.

CCR outperformed CCP alone, CAPRA alone, and NCCN risk groupings for predicting metastasis risk after RT.

Though this validation study was “successful,” additional research is needed, according to study discussant Richard Valicenti, MD, of the University of California, Davis.

“Widespread acceptance for routine use faces challenges since no biomarker has been prospectively tested or shown to improve long-term outcome,” Dr. Valicenti said. “Clearly, the CCR score may provide highly precise, personalized estimates and justifies testing in tiered and appropriately powered noninferiority studies according to NCCN risk groups. We eagerly await the completion and reporting of such trials so that we have a more personalized approach to treating men with prostate cancer.”

The current study was funded by Myriad Genetics, the company that developed the Prolaris test. Dr. Tward disclosed relationships with Myriad Genetics, Bayer, Blue Earth Diagnostics, Janssen Scientific Affairs, and Merck. Dr. Valicenti has no disclosures.

[email protected]

The combined clinical cell-cycle risk (CCR) score – derived from both clinical and genetic factors – can identify patients with intermediate- and high-risk localized prostate cancer who could potentially forgo androgen deprivation therapy (ADT), a retrospective study suggests.

The score can identify patients in whom the risk of metastasis after dose-escalated radiation is so small that adding ADT no longer makes clinical sense, according to investigator Jonathan Tward, MD, PhD, of the Genitourinary Cancer Center at the University of Utah, Salt Lake City.

His group’s study, which included 741 patients, showed that, below a CCR score of 2.112, the 10-year risk of metastasis was 4.2% with radiation therapy (RT) alone and 3.9% with the addition of ADT.

“Whether you have RT alone, RT plus any duration of ADT, insufficient duration ADT, or sufficient ADT duration by guideline standard, the risk of metastasis never exceeds 5% at 10 years” even in high- and very-high-risk men, Dr. Tward said.

He and his team found that half the men in their study with unfavorable intermediate-risk disease, 20% with high-risk disease, and 5% with very-high-risk disease scored below the CCR threshold.

This implies that, for many men, ADT after radiation “adds unnecessary morbidity for an extremely small absolute risk reduction in metastasis-free survival,” Dr. Tward said at the 2021 Genitourinary Cancers Symposium, where he presented the findings (Abstract 195).
 

Value of CCR

The CCR score tells you if the relative metastasis risk reduction with ADT after radiation – about 50% based on clinical trials – translates to an absolute risk reduction that would matter, Dr. Tward said in an interview.

“Each patient has in their own mind what that risk reduction is that works for them,” he added.

For some patients, a 1%-2% drop in absolute risk is worth it, he said, but most patients wouldn’t be willing to endure the side effects of hormone therapy if the absolute benefit is less than 5%.

The CCR score is a validated prognosticator of metastasis and death in localized prostate cancer. It’s an amalgam of traditional clinical risk factors from the Cancer of the Prostate Risk Assessment (CAPRA) score and the cell-cycle progression (CCP) score, which measures expression of cell-cycle proliferation genes for a sense of how quickly tumor cells are dividing.

The CCP test is available commercially as Prolaris. It is used mostly to make the call between active surveillance and treatment, Dr. Tward explained, “but I had a hunch this off-the-shelf test would be very good at” helping with ADT decisions after radiation.
 

‘Uncomfortable’ findings, barriers to acceptance

“People are going to be very uncomfortable with these findings because it’s been ingrained in our heads for the past 20-30 years that you must use hormone therapy with high-risk prostate cancer, and you should use hormone therapy with intermediate risk,” Dr. Tward said.

“It took me a while to believe my own data, but we have used this test for several years to help men decide if they would like to have hormone therapy after radiation. Patients clearly benefit from this information,” he said.

The 2.112 cut point for CCR was determined from a prior study that was presented at GUCS 2020 (Abstract 346) and recently accepted for publication.

In the validation study Dr. Tward presented at GUCS 2021, 70% of patients had intermediate-risk disease, and 30% had high- or very-high-risk disease according to National Comprehensive Cancer Network criteria.

All 741 patients received RT equivalent to at least 75.6 Gy at 1.8 Gy per fraction, with 84% getting or exceeding 79.2 Gy. About half the men (53%) had ADT after RT.

Genetic testing was done on stored biopsy samples years after the men were treated. Half of them were below the CCR threshold of 2.112. For those above it, the 10-year risk of metastasis was 25.3%.

CCR outperformed CCP alone, CAPRA alone, and NCCN risk groupings for predicting metastasis risk after RT.

Though this validation study was “successful,” additional research is needed, according to study discussant Richard Valicenti, MD, of the University of California, Davis.

“Widespread acceptance for routine use faces challenges since no biomarker has been prospectively tested or shown to improve long-term outcome,” Dr. Valicenti said. “Clearly, the CCR score may provide highly precise, personalized estimates and justifies testing in tiered and appropriately powered noninferiority studies according to NCCN risk groups. We eagerly await the completion and reporting of such trials so that we have a more personalized approach to treating men with prostate cancer.”

The current study was funded by Myriad Genetics, the company that developed the Prolaris test. Dr. Tward disclosed relationships with Myriad Genetics, Bayer, Blue Earth Diagnostics, Janssen Scientific Affairs, and Merck. Dr. Valicenti has no disclosures.

[email protected]

The genomic landscape of circulating tumor DNA (ctDNA) was comparable to the landscape of tissue biopsies in a large study of patients with metastatic castration-resistant prostate cancer (mCRPC), according to researchers.

The type and frequency of genomic alterations observed were largely similar in ctDNA and tissue, and there was high concordance for BRCA1/2 alterations. Comprehensive genomic profiling (CGP) of ctDNA detected more acquired resistance alterations, which included novel androgen receptor (AR)–activating variants. In fact, alterations in nine genes were significantly enriched in ctDNA, but some of these alterations may be attributable to clonal hematopoiesis and not the tumor.

Still, the researchers concluded that CGP of ctDNA could complement tissue-based CGP.

“This is the largest study of mCRPC plasma samples conducted to date, and CGP of ctDNA recapitulated the genomic landscape detected in tissue biopsies,” said investigator Hanna Tukachinsky, PhD, from Foundation Medicine, the company that developed the liquid biopsy tests used in this study.

“The large percentage of patients with rich genomic signal from ctDNA and the sensitive, specific detection of BRCA1/2 alterations position liquid biopsy as a compelling clinical complement to tissue CGP for patients with mCRPC.”

Dr. Tukachinsky presented results from this study at the 2021 Genitourinary Cancers Symposium (Abstract 25). The results were also published in Clinical Cancer Research, but the following data are from the meeting presentation.

ctDNA profiling proves feasible, comparable

CGP was performed on 3,334 liquid biopsy samples and 2,006 tissue samples from patients with mCRPC, including patients in the TRITON2 and TRITON3 trials.

The plasma samples were profiled using FoundationACT, which had a panel of 62 genes, or FoundationOne Liquid CDx, which had a panel of 70 genes.

Most of the liquid biopsy samples – 94% – had detectable ctDNA, and the median ctDNA fraction was 7.5%.

“One of the most important findings in this study is the fact that the majority of patients with advanced prostate cancer – 94% of them – have abundant ctDNA,” Dr. Tukachinsky said.

“The overall landscape we detected in ctDNA highly resembles landscapes reported in tissue-based CGP studies of mCRPC,” she added.

ctDNA results showed a high percentage of TP53 and AR alterations, as well as alterations in DNA repair genes (ATM, CHEK2, BRCA2, and CDK12), PI3 kinase components (PTEN, PIK3CA, and AKT1), and WNT components (APC and CTNNB1).

“It should be noted that the two assays did not bait for TMPRSS2-ERT fusions or SPOP ... and we’re missing homozygous deletions, which affects the frequency we detect PTEN, RB1, and BRCA alterations,” Dr. Tukachinsky said.

When the researchers compared results from the 3,334 liquid biopsy samples and the 2,006 tissue samples, they found that most genes were altered at similar rates.

However, nine genes were significantly enriched in ctDNA – AR, TP53, ATM, CHEK2, NF1, TERT, JAK2, IDH2, and GNAS.

Dr. Tukachinsky noted that JAK2, GNAS, and IDH2 alterations are rarely detected in mCRPC tissue and are likely attributable to clonal hematopoiesis. Alterations in TERT and NF1, as well as some of the alterations in ATM and CHEK2, might also be attributed to clonal hematopoiesis, she added.

Rare and novel AR alterations

“ctDNA detected more acquired resistance genomic alterations than tissue, including novel and rare AR-activating variants,” Dr. Tukachinsky said.

She noted that F877L/T878A, a compound mutant that has been shown to confer synergistic resistance to enzalutamide, was found in 11 patients.

Similarly, “completely novel” in-frame mutations spanning residues H875 to T878 were found in 11 patients, and each shifted S885 into the T878 position.

“Although these require more experiments to prove that they are activating, their repeated appearance in different patients with mCRPC and alignment of the serine residues is highly suggestive that they are activating,” Dr. Tukachinsky said.

The researchers also found, in 160 patients, AR rearrangements that truncate the reading frame just after exon 3 to yield a receptor with an intact DNA binding domain but without a ligand binding domain.

“These truncated receptors have been demonstrated to confer resistance to AR signaling inhibitors and drive transcription of the AR target genes,” Dr. Tukachinsky said.

BRCA1/2: High concordance

To further assess concordance between ctDNA and tissue, Dr. Tukachinsky and colleagues evaluated a subset of 837 patients with matched tissue and liquid biopsies.

The researchers observed high concordance in BRCA1/2 short variants and rearrangements. The positive percent agreement was 93.1%, the negative percent agreement was 97.4%, and the overall percent agreement was 97.0%.

There were 5 patients in whom BRCA1/2 alterations were detected in tissue but not ctDNA, and there were 20 patients in whom BRCA1/2 alterations were detected in ctDNA but not tissue.

The false negatives could be the result of low ctDNA fraction, a minor clone, or filtering out by post analytics, said study discussant Silke Gillessen, MD, of the Institute of Oncology of Southern Switzerland in Bellinzona. She also postulated that the false positives could be explained by clonal hematopoiesis or metastases from a subclone.

Implications for practice

This study showed that liquid and tissue biopsies can perform comparably in identifying patients with BRCA1/2 variants who may benefit from PARP inhibition, Dr. Tukachinsky noted. Additionally, ctDNA revealed novel AR variants that may be driving resistance to AR-signaling inhibitors. However, the presence of alterations that may derive from clonal hematopoiesis suggests ctDNA results should be interpreted with some caution, she added.

“NCCN [National Comprehensive Cancer Network] guidelines have recently changed to include liquid biopsy as an option. There’s definitely some skepticism about liquid biopsy …. That said, liquid biopsy is also a pretty powerful tool,” Dr. Tukachinsky said.

“We are not advocating liquid biopsy over tissue. In the cases where tissue’s not available, or if you have a primary, in some cases, liquid could serve as a good complement to give you the full picture of what’s going on in the tumor,” she added.

“For the time being, tissue will still be our gold standard,” Dr. Gillessen said. “And if we can’t get the tissue tested, that will be then maybe a point for the liquid biopsy.”

Dr. Tukachinsky’s research was funded by Foundation Medicine and Clovis Oncology. She and her colleagues disclosed relationships with both companies and a range of other companies. Dr. Gillessen disclosed relationships with Amgen, Astellas Pharma, Bayer, and several other companies as well as a patent for a biomarker method (WO 3752009138392 A1).

The genomic landscape of circulating tumor DNA (ctDNA) was comparable to the landscape of tissue biopsies in a large study of patients with metastatic castration-resistant prostate cancer (mCRPC), according to researchers.

The type and frequency of genomic alterations observed were largely similar in ctDNA and tissue, and there was high concordance for BRCA1/2 alterations. Comprehensive genomic profiling (CGP) of ctDNA detected more acquired resistance alterations, which included novel androgen receptor (AR)–activating variants. In fact, alterations in nine genes were significantly enriched in ctDNA, but some of these alterations may be attributable to clonal hematopoiesis and not the tumor.

Still, the researchers concluded that CGP of ctDNA could complement tissue-based CGP.

“This is the largest study of mCRPC plasma samples conducted to date, and CGP of ctDNA recapitulated the genomic landscape detected in tissue biopsies,” said investigator Hanna Tukachinsky, PhD, from Foundation Medicine, the company that developed the liquid biopsy tests used in this study.

“The large percentage of patients with rich genomic signal from ctDNA and the sensitive, specific detection of BRCA1/2 alterations position liquid biopsy as a compelling clinical complement to tissue CGP for patients with mCRPC.”

Dr. Tukachinsky presented results from this study at the 2021 Genitourinary Cancers Symposium (Abstract 25). The results were also published in Clinical Cancer Research, but the following data are from the meeting presentation.

ctDNA profiling proves feasible, comparable

CGP was performed on 3,334 liquid biopsy samples and 2,006 tissue samples from patients with mCRPC, including patients in the TRITON2 and TRITON3 trials.

The plasma samples were profiled using FoundationACT, which had a panel of 62 genes, or FoundationOne Liquid CDx, which had a panel of 70 genes.

Most of the liquid biopsy samples – 94% – had detectable ctDNA, and the median ctDNA fraction was 7.5%.

“One of the most important findings in this study is the fact that the majority of patients with advanced prostate cancer – 94% of them – have abundant ctDNA,” Dr. Tukachinsky said.

“The overall landscape we detected in ctDNA highly resembles landscapes reported in tissue-based CGP studies of mCRPC,” she added.

ctDNA results showed a high percentage of TP53 and AR alterations, as well as alterations in DNA repair genes (ATM, CHEK2, BRCA2, and CDK12), PI3 kinase components (PTEN, PIK3CA, and AKT1), and WNT components (APC and CTNNB1).

“It should be noted that the two assays did not bait for TMPRSS2-ERT fusions or SPOP ... and we’re missing homozygous deletions, which affects the frequency we detect PTEN, RB1, and BRCA alterations,” Dr. Tukachinsky said.

When the researchers compared results from the 3,334 liquid biopsy samples and the 2,006 tissue samples, they found that most genes were altered at similar rates.

However, nine genes were significantly enriched in ctDNA – AR, TP53, ATM, CHEK2, NF1, TERT, JAK2, IDH2, and GNAS.

Dr. Tukachinsky noted that JAK2, GNAS, and IDH2 alterations are rarely detected in mCRPC tissue and are likely attributable to clonal hematopoiesis. Alterations in TERT and NF1, as well as some of the alterations in ATM and CHEK2, might also be attributed to clonal hematopoiesis, she added.

Rare and novel AR alterations

“ctDNA detected more acquired resistance genomic alterations than tissue, including novel and rare AR-activating variants,” Dr. Tukachinsky said.

She noted that F877L/T878A, a compound mutant that has been shown to confer synergistic resistance to enzalutamide, was found in 11 patients.

Similarly, “completely novel” in-frame mutations spanning residues H875 to T878 were found in 11 patients, and each shifted S885 into the T878 position.

“Although these require more experiments to prove that they are activating, their repeated appearance in different patients with mCRPC and alignment of the serine residues is highly suggestive that they are activating,” Dr. Tukachinsky said.

The researchers also found, in 160 patients, AR rearrangements that truncate the reading frame just after exon 3 to yield a receptor with an intact DNA binding domain but without a ligand binding domain.

“These truncated receptors have been demonstrated to confer resistance to AR signaling inhibitors and drive transcription of the AR target genes,” Dr. Tukachinsky said.

BRCA1/2: High concordance

To further assess concordance between ctDNA and tissue, Dr. Tukachinsky and colleagues evaluated a subset of 837 patients with matched tissue and liquid biopsies.

The researchers observed high concordance in BRCA1/2 short variants and rearrangements. The positive percent agreement was 93.1%, the negative percent agreement was 97.4%, and the overall percent agreement was 97.0%.

There were 5 patients in whom BRCA1/2 alterations were detected in tissue but not ctDNA, and there were 20 patients in whom BRCA1/2 alterations were detected in ctDNA but not tissue.

The false negatives could be the result of low ctDNA fraction, a minor clone, or filtering out by post analytics, said study discussant Silke Gillessen, MD, of the Institute of Oncology of Southern Switzerland in Bellinzona. She also postulated that the false positives could be explained by clonal hematopoiesis or metastases from a subclone.

Implications for practice

This study showed that liquid and tissue biopsies can perform comparably in identifying patients with BRCA1/2 variants who may benefit from PARP inhibition, Dr. Tukachinsky noted. Additionally, ctDNA revealed novel AR variants that may be driving resistance to AR-signaling inhibitors. However, the presence of alterations that may derive from clonal hematopoiesis suggests ctDNA results should be interpreted with some caution, she added.

“NCCN [National Comprehensive Cancer Network] guidelines have recently changed to include liquid biopsy as an option. There’s definitely some skepticism about liquid biopsy …. That said, liquid biopsy is also a pretty powerful tool,” Dr. Tukachinsky said.

“We are not advocating liquid biopsy over tissue. In the cases where tissue’s not available, or if you have a primary, in some cases, liquid could serve as a good complement to give you the full picture of what’s going on in the tumor,” she added.

“For the time being, tissue will still be our gold standard,” Dr. Gillessen said. “And if we can’t get the tissue tested, that will be then maybe a point for the liquid biopsy.”

Dr. Tukachinsky’s research was funded by Foundation Medicine and Clovis Oncology. She and her colleagues disclosed relationships with both companies and a range of other companies. Dr. Gillessen disclosed relationships with Amgen, Astellas Pharma, Bayer, and several other companies as well as a patent for a biomarker method (WO 3752009138392 A1).

The genomic landscape of circulating tumor DNA (ctDNA) was comparable to the landscape of tissue biopsies in a large study of patients with metastatic castration-resistant prostate cancer (mCRPC), according to researchers.

The type and frequency of genomic alterations observed were largely similar in ctDNA and tissue, and there was high concordance for BRCA1/2 alterations. Comprehensive genomic profiling (CGP) of ctDNA detected more acquired resistance alterations, which included novel androgen receptor (AR)–activating variants. In fact, alterations in nine genes were significantly enriched in ctDNA, but some of these alterations may be attributable to clonal hematopoiesis and not the tumor.

Still, the researchers concluded that CGP of ctDNA could complement tissue-based CGP.

“This is the largest study of mCRPC plasma samples conducted to date, and CGP of ctDNA recapitulated the genomic landscape detected in tissue biopsies,” said investigator Hanna Tukachinsky, PhD, from Foundation Medicine, the company that developed the liquid biopsy tests used in this study.

“The large percentage of patients with rich genomic signal from ctDNA and the sensitive, specific detection of BRCA1/2 alterations position liquid biopsy as a compelling clinical complement to tissue CGP for patients with mCRPC.”

Dr. Tukachinsky presented results from this study at the 2021 Genitourinary Cancers Symposium (Abstract 25). The results were also published in Clinical Cancer Research, but the following data are from the meeting presentation.

ctDNA profiling proves feasible, comparable

CGP was performed on 3,334 liquid biopsy samples and 2,006 tissue samples from patients with mCRPC, including patients in the TRITON2 and TRITON3 trials.

The plasma samples were profiled using FoundationACT, which had a panel of 62 genes, or FoundationOne Liquid CDx, which had a panel of 70 genes.

Most of the liquid biopsy samples – 94% – had detectable ctDNA, and the median ctDNA fraction was 7.5%.

“One of the most important findings in this study is the fact that the majority of patients with advanced prostate cancer – 94% of them – have abundant ctDNA,” Dr. Tukachinsky said.

“The overall landscape we detected in ctDNA highly resembles landscapes reported in tissue-based CGP studies of mCRPC,” she added.

ctDNA results showed a high percentage of TP53 and AR alterations, as well as alterations in DNA repair genes (ATM, CHEK2, BRCA2, and CDK12), PI3 kinase components (PTEN, PIK3CA, and AKT1), and WNT components (APC and CTNNB1).

“It should be noted that the two assays did not bait for TMPRSS2-ERT fusions or SPOP ... and we’re missing homozygous deletions, which affects the frequency we detect PTEN, RB1, and BRCA alterations,” Dr. Tukachinsky said.

When the researchers compared results from the 3,334 liquid biopsy samples and the 2,006 tissue samples, they found that most genes were altered at similar rates.

However, nine genes were significantly enriched in ctDNA – AR, TP53, ATM, CHEK2, NF1, TERT, JAK2, IDH2, and GNAS.

Dr. Tukachinsky noted that JAK2, GNAS, and IDH2 alterations are rarely detected in mCRPC tissue and are likely attributable to clonal hematopoiesis. Alterations in TERT and NF1, as well as some of the alterations in ATM and CHEK2, might also be attributed to clonal hematopoiesis, she added.

Rare and novel AR alterations

“ctDNA detected more acquired resistance genomic alterations than tissue, including novel and rare AR-activating variants,” Dr. Tukachinsky said.

She noted that F877L/T878A, a compound mutant that has been shown to confer synergistic resistance to enzalutamide, was found in 11 patients.

Similarly, “completely novel” in-frame mutations spanning residues H875 to T878 were found in 11 patients, and each shifted S885 into the T878 position.

“Although these require more experiments to prove that they are activating, their repeated appearance in different patients with mCRPC and alignment of the serine residues is highly suggestive that they are activating,” Dr. Tukachinsky said.

The researchers also found, in 160 patients, AR rearrangements that truncate the reading frame just after exon 3 to yield a receptor with an intact DNA binding domain but without a ligand binding domain.

“These truncated receptors have been demonstrated to confer resistance to AR signaling inhibitors and drive transcription of the AR target genes,” Dr. Tukachinsky said.

BRCA1/2: High concordance

To further assess concordance between ctDNA and tissue, Dr. Tukachinsky and colleagues evaluated a subset of 837 patients with matched tissue and liquid biopsies.

The researchers observed high concordance in BRCA1/2 short variants and rearrangements. The positive percent agreement was 93.1%, the negative percent agreement was 97.4%, and the overall percent agreement was 97.0%.

There were 5 patients in whom BRCA1/2 alterations were detected in tissue but not ctDNA, and there were 20 patients in whom BRCA1/2 alterations were detected in ctDNA but not tissue.

The false negatives could be the result of low ctDNA fraction, a minor clone, or filtering out by post analytics, said study discussant Silke Gillessen, MD, of the Institute of Oncology of Southern Switzerland in Bellinzona. She also postulated that the false positives could be explained by clonal hematopoiesis or metastases from a subclone.

Implications for practice

This study showed that liquid and tissue biopsies can perform comparably in identifying patients with BRCA1/2 variants who may benefit from PARP inhibition, Dr. Tukachinsky noted. Additionally, ctDNA revealed novel AR variants that may be driving resistance to AR-signaling inhibitors. However, the presence of alterations that may derive from clonal hematopoiesis suggests ctDNA results should be interpreted with some caution, she added.

“NCCN [National Comprehensive Cancer Network] guidelines have recently changed to include liquid biopsy as an option. There’s definitely some skepticism about liquid biopsy …. That said, liquid biopsy is also a pretty powerful tool,” Dr. Tukachinsky said.

“We are not advocating liquid biopsy over tissue. In the cases where tissue’s not available, or if you have a primary, in some cases, liquid could serve as a good complement to give you the full picture of what’s going on in the tumor,” she added.

“For the time being, tissue will still be our gold standard,” Dr. Gillessen said. “And if we can’t get the tissue tested, that will be then maybe a point for the liquid biopsy.”

Dr. Tukachinsky’s research was funded by Foundation Medicine and Clovis Oncology. She and her colleagues disclosed relationships with both companies and a range of other companies. Dr. Gillessen disclosed relationships with Amgen, Astellas Pharma, Bayer, and several other companies as well as a patent for a biomarker method (WO 3752009138392 A1).

The U.S. Preventive Services Task Force is planning to update its breast cancer screening guidelines, which were last issued in 2016. For transparency, it has released the draft research plan it will use for formulating the update, and this draft plan is open for comment until Feb. 17.

However, an expert in breast screening has taken issue with the whole plan.

Daniel Kopans, MD, professor of radiology at Harvard Medical School and founder of the Breast Imaging Division at Massachusetts General Hospital, Boston, argues that previous USPSTF guidelines on breast cancer screening “have been based on flawed analyses of scientific data” and the research plan, as outlined, perpetuates this.

He has also objected, yet again, to the USPSTF panel not having any experts in breast screening on the panel.

Writing in a commentary on Aunt Minnie, a radiology website, he warns about the dangers of not listening to experts: “The COVID-19 pandemic has demonstrated the tragic consequences that result from ignoring science, evidence, and the analysis and advice of experts while being guided by inexpert advice.”
 

Controversy over previous guidelines

The current USPSTF guidelines on breast cancer screening, which were issued in 2016, were largely unchanged from the previous guidelines that had been issued in 2009. They recommended mammography screening every 2 years for women 50-74 years of age but said that women aged 40-49 should make individual decisions about screening in partnership with their doctors.

The guidance on younger women was met with severe criticism from many experts, as previously reported by this news organization, and the every-2-year interval has also been questioned.

The American College of Radiology and Society of Breast Imaging both recommend annual mammograms starting at age 40.

In the update the USPSTF is now planning, it has an opportunity to “revisit the group’s flawed decision in 2009” about not recommending screening for women in their 40s, argues Dr. Kopans.  

But to do that, a number of factors need to be addressed to present a fair and impartial review of the science and evidence in favor of breast screening, he continues, while worrying the draft plan, as currently outlined, will not do so.

One big problem, he argues, is that USPSTF, in its draft plan, has not included statistical models from the U.S. National Cancer Institute and Cancer Intervention and Surveillance Modeling Network to project the potential outcomes of various screening protocols. These NCI/CISNET models all predict that the most lives are saved by annual screening starting at age 40, he points out.

Without these models, the USPSTF will be “guessing in their predictions,” he argues.

Second, even though a reduction in advanced-stage disease is a potentially useful “surrogate endpoint,” Dr. Kopans points out that it is still crucial to remember that women diagnosed at all stages of breast cancer die of the disease. “It has been shown that reducing the size of cancers within stages is also a major benefit from screening that reduces deaths,” he says.

Third, he contends in his commentary that there is a “false claim that the background incidence of breast cancer has not increased over time.” Dr. Kopans says this has been the primary source of misinformation that has been used to promote “the false concepts of massive overdiagnosis” as well as a “false claim that there has not been a reduction in advanced cancers.”

To emphasize his point, Dr. Kopans explains that data clearly demonstrate that the baseline incidence of breast cancer has steadily risen by 1%-1.3% per year, going back at least 80 years. This increase predates screening, which didn’t really begin until the mid-1980s.

“If the correct increasing baseline is used, not only is there no apparent ‘overdiagnosis’ of invasive cancers, but it appears that there has been a major reduction in the incidence of invasive cancers,” he writes. “By using the correct baseline incidence and extrapolation, it is also clear that there has been a major reduction in the rate of advanced cancers.”

To date, there have not been any randomized controlled trials comparing screening intervals (for example, annual vs. every second or third year). But based on the CISNET models, Dr. Kopans emphasized that annual screening is estimated to provide the greatest reduction in deaths. “All women ages 40-74 should be encouraged to be screened every year,” he says.

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

The U.S. Preventive Services Task Force is planning to update its breast cancer screening guidelines, which were last issued in 2016. For transparency, it has released the draft research plan it will use for formulating the update, and this draft plan is open for comment until Feb. 17.

However, an expert in breast screening has taken issue with the whole plan.

Daniel Kopans, MD, professor of radiology at Harvard Medical School and founder of the Breast Imaging Division at Massachusetts General Hospital, Boston, argues that previous USPSTF guidelines on breast cancer screening “have been based on flawed analyses of scientific data” and the research plan, as outlined, perpetuates this.

He has also objected, yet again, to the USPSTF panel not having any experts in breast screening on the panel.

Writing in a commentary on Aunt Minnie, a radiology website, he warns about the dangers of not listening to experts: “The COVID-19 pandemic has demonstrated the tragic consequences that result from ignoring science, evidence, and the analysis and advice of experts while being guided by inexpert advice.”
 

Controversy over previous guidelines

The current USPSTF guidelines on breast cancer screening, which were issued in 2016, were largely unchanged from the previous guidelines that had been issued in 2009. They recommended mammography screening every 2 years for women 50-74 years of age but said that women aged 40-49 should make individual decisions about screening in partnership with their doctors.

The guidance on younger women was met with severe criticism from many experts, as previously reported by this news organization, and the every-2-year interval has also been questioned.

The American College of Radiology and Society of Breast Imaging both recommend annual mammograms starting at age 40.

In the update the USPSTF is now planning, it has an opportunity to “revisit the group’s flawed decision in 2009” about not recommending screening for women in their 40s, argues Dr. Kopans.  

But to do that, a number of factors need to be addressed to present a fair and impartial review of the science and evidence in favor of breast screening, he continues, while worrying the draft plan, as currently outlined, will not do so.

One big problem, he argues, is that USPSTF, in its draft plan, has not included statistical models from the U.S. National Cancer Institute and Cancer Intervention and Surveillance Modeling Network to project the potential outcomes of various screening protocols. These NCI/CISNET models all predict that the most lives are saved by annual screening starting at age 40, he points out.

Without these models, the USPSTF will be “guessing in their predictions,” he argues.

Second, even though a reduction in advanced-stage disease is a potentially useful “surrogate endpoint,” Dr. Kopans points out that it is still crucial to remember that women diagnosed at all stages of breast cancer die of the disease. “It has been shown that reducing the size of cancers within stages is also a major benefit from screening that reduces deaths,” he says.

Third, he contends in his commentary that there is a “false claim that the background incidence of breast cancer has not increased over time.” Dr. Kopans says this has been the primary source of misinformation that has been used to promote “the false concepts of massive overdiagnosis” as well as a “false claim that there has not been a reduction in advanced cancers.”

To emphasize his point, Dr. Kopans explains that data clearly demonstrate that the baseline incidence of breast cancer has steadily risen by 1%-1.3% per year, going back at least 80 years. This increase predates screening, which didn’t really begin until the mid-1980s.

“If the correct increasing baseline is used, not only is there no apparent ‘overdiagnosis’ of invasive cancers, but it appears that there has been a major reduction in the incidence of invasive cancers,” he writes. “By using the correct baseline incidence and extrapolation, it is also clear that there has been a major reduction in the rate of advanced cancers.”

To date, there have not been any randomized controlled trials comparing screening intervals (for example, annual vs. every second or third year). But based on the CISNET models, Dr. Kopans emphasized that annual screening is estimated to provide the greatest reduction in deaths. “All women ages 40-74 should be encouraged to be screened every year,” he says.

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

The U.S. Preventive Services Task Force is planning to update its breast cancer screening guidelines, which were last issued in 2016. For transparency, it has released the draft research plan it will use for formulating the update, and this draft plan is open for comment until Feb. 17.

However, an expert in breast screening has taken issue with the whole plan.

Daniel Kopans, MD, professor of radiology at Harvard Medical School and founder of the Breast Imaging Division at Massachusetts General Hospital, Boston, argues that previous USPSTF guidelines on breast cancer screening “have been based on flawed analyses of scientific data” and the research plan, as outlined, perpetuates this.

He has also objected, yet again, to the USPSTF panel not having any experts in breast screening on the panel.

Writing in a commentary on Aunt Minnie, a radiology website, he warns about the dangers of not listening to experts: “The COVID-19 pandemic has demonstrated the tragic consequences that result from ignoring science, evidence, and the analysis and advice of experts while being guided by inexpert advice.”
 

Controversy over previous guidelines

The current USPSTF guidelines on breast cancer screening, which were issued in 2016, were largely unchanged from the previous guidelines that had been issued in 2009. They recommended mammography screening every 2 years for women 50-74 years of age but said that women aged 40-49 should make individual decisions about screening in partnership with their doctors.

The guidance on younger women was met with severe criticism from many experts, as previously reported by this news organization, and the every-2-year interval has also been questioned.

The American College of Radiology and Society of Breast Imaging both recommend annual mammograms starting at age 40.

In the update the USPSTF is now planning, it has an opportunity to “revisit the group’s flawed decision in 2009” about not recommending screening for women in their 40s, argues Dr. Kopans.  

But to do that, a number of factors need to be addressed to present a fair and impartial review of the science and evidence in favor of breast screening, he continues, while worrying the draft plan, as currently outlined, will not do so.

One big problem, he argues, is that USPSTF, in its draft plan, has not included statistical models from the U.S. National Cancer Institute and Cancer Intervention and Surveillance Modeling Network to project the potential outcomes of various screening protocols. These NCI/CISNET models all predict that the most lives are saved by annual screening starting at age 40, he points out.

Without these models, the USPSTF will be “guessing in their predictions,” he argues.

Second, even though a reduction in advanced-stage disease is a potentially useful “surrogate endpoint,” Dr. Kopans points out that it is still crucial to remember that women diagnosed at all stages of breast cancer die of the disease. “It has been shown that reducing the size of cancers within stages is also a major benefit from screening that reduces deaths,” he says.

Third, he contends in his commentary that there is a “false claim that the background incidence of breast cancer has not increased over time.” Dr. Kopans says this has been the primary source of misinformation that has been used to promote “the false concepts of massive overdiagnosis” as well as a “false claim that there has not been a reduction in advanced cancers.”

To emphasize his point, Dr. Kopans explains that data clearly demonstrate that the baseline incidence of breast cancer has steadily risen by 1%-1.3% per year, going back at least 80 years. This increase predates screening, which didn’t really begin until the mid-1980s.

“If the correct increasing baseline is used, not only is there no apparent ‘overdiagnosis’ of invasive cancers, but it appears that there has been a major reduction in the incidence of invasive cancers,” he writes. “By using the correct baseline incidence and extrapolation, it is also clear that there has been a major reduction in the rate of advanced cancers.”

To date, there have not been any randomized controlled trials comparing screening intervals (for example, annual vs. every second or third year). But based on the CISNET models, Dr. Kopans emphasized that annual screening is estimated to provide the greatest reduction in deaths. “All women ages 40-74 should be encouraged to be screened every year,” he says.

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