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The Biology of ‘Precancer’: Stopping Cancer Before It Starts
Some breast cancer types are more likely than others to recur. Researchers have known this for more than a decade.
But they have long wondered why.
“How did those tumor types arise?” said Christina Curtis, PhD, a professor of medicine, genetics and biomedical data science at Stanford University in California. “They’re all breast cancers. They’re all estrogen receptor positive. But these groups are different. When did they become different, and how is that determined?”
Dr. Curtis and colleagues are finally starting to answer these questions. They recently broke new ground in a study linking differences in cancer-related genes to disease subtype and aggressiveness.
DNA inherited from our parents is known as the germline genome. It affects whether the immune system attacks or retreats when confronted with variations that may lead to breast cancer.
“It turns out, the germline genome sculpts tumor evolution,” said Dr. Curtis.
The study is part of a growing effort to understand “precancer” — the critical period after cells have started to grow abnormally but before they’ve developed into cancer — a research trend that could trigger a decisive shift in how cancer treatments are realized. Therapeutics could be designed on the basis of the biology of these precancerous cells.
While biotech start-ups push new tests to catch cancer early, researchers like Dr. Curtis hope to stop cancer before it even starts.
“This is a really exciting area of research,” said Susan Domchek, MD, executive director of the Basser Center for BRCA at the University of Pennsylvania, Philadelphia, who was not involved in the study. “What we hope for is that, over time, we’re going to have more and more biologically driven interception.”
‘We’re Basically Unearthing the Dark Matter of the Human Genome’
Of course, we already have mechanical ways of heading off cancer, like having a precancerous polyp removed. But for the Stanford researchers, biologic interception is the goal. They hope to figure out how to use the immune system to stop the cancer.
In their study, they looked at DNA variabilities known as somatic aberrations or single-nucleotide protein sequences (SNPs). The HER2 gene, for example, can contain SNPs — possibly affecting how the HER2 protein regulates breast cell growth and division.
“There’s been a huge effort through genomewide association studies to link SNPs to cancer outcomes and risk,” Dr. Curtis said.
Focusing on people with a genetic predisposition for breast cancer, Dr. Curtis used machine learning to show that these variabilities can occur in specific epitopes (protein features that can trigger an immune response).
They also found that heightened variability can show up in a region of the genome called the human leukocyte antigen (HLA). Each HLA molecule can contain many epitopes.
“We developed a whole new algorithm to compute this ‘germline epitope burden,’ ” Dr. Curtis said. “We’re basically unearthing the dark matter of the human genome to ask about the interplay between SNPs and HLA class one presentation.”
These aberration-rich regions can grab the immune system’s attention. Sometimes the immune system identifies and eradicates those epitopes.
In that case: “I have immunosurveillance. I’ve cured my cancer,” said Nora Disis, PhD, director of the Cancer Vaccine Institute and a professor of medicine at the University of Washington, Seattle. Dr. Disis was not involved in the study.
But other times, the immune system finds a way around the high “epitope burden,” and the tumors become more aggressive and immunosuppressive. That’s when cancer forms.
This suggests a “critical juncture between preinvasive and invasive disease,” Dr. Curtis said.
And that “critical juncture” may very well be the optimal time for intervention.
The Precancer Push
Stanford’s findings add information to prior biomarkers and may provide a way to identify “bad-acting tumors” from a simple blood draw measuring germline epitope burden, Dr. Curtis said. Looking further ahead, “this also reveals a new source of epitopes that might be immunogenic and might be informative for the development of vaccines.”
Many labs are trying to understand the biology of precancer and exploring possible vaccines.
The National Cancer Institute’s Human Tumor Atlas Network is building three-dimensional models of the evolution from precancerous to advanced disease. And researchers at the Cancer Vaccine Institute at the University of Washington are developing a vaccine for a precancerous lesion linked to many ovarian cancers.
Dr. Domchek’s research explores whether breast cancers caused by mutations in the BRCA 1 and 2 genes can be intercepted at very early stages. In a clinical trial of healthy people with those mutations, Dr. Domchek and colleagues are attempting to “rev up the immune system to tackle telomerase,” an enzyme that’s over-expressed in 95% of cancers. The hope is for this experimental vaccine to lower their risk of developing cancer.
At the Fred Hutch Cancer Center, Seattle, Ming Yu, PhD, is studying how senescent cells affect immune cells in precancer. As cells age and stop dividing, she said, they can accumulate and create a “tumor-promoting microenvironment” in older people.
Dr. Yu has found that the antiaging drug rapamycin can eliminate those “zombie cells” in mice. She’s studying whether the “cleanup” can help prevent cancer and expects results in a few months.
In the years and decades to come, all of this could lead to a new era in cancer treatment.
“Most drug development starts with people with advanced cancer and then goes into the earlier and earlier spaces,” said Dr. Domchek. “But it may be that we’re thinking about it all wrong and that you really have to understand the unique biology of early lesions to go after them.”
A version of this article first appeared on Medscape.com.
Some breast cancer types are more likely than others to recur. Researchers have known this for more than a decade.
But they have long wondered why.
“How did those tumor types arise?” said Christina Curtis, PhD, a professor of medicine, genetics and biomedical data science at Stanford University in California. “They’re all breast cancers. They’re all estrogen receptor positive. But these groups are different. When did they become different, and how is that determined?”
Dr. Curtis and colleagues are finally starting to answer these questions. They recently broke new ground in a study linking differences in cancer-related genes to disease subtype and aggressiveness.
DNA inherited from our parents is known as the germline genome. It affects whether the immune system attacks or retreats when confronted with variations that may lead to breast cancer.
“It turns out, the germline genome sculpts tumor evolution,” said Dr. Curtis.
The study is part of a growing effort to understand “precancer” — the critical period after cells have started to grow abnormally but before they’ve developed into cancer — a research trend that could trigger a decisive shift in how cancer treatments are realized. Therapeutics could be designed on the basis of the biology of these precancerous cells.
While biotech start-ups push new tests to catch cancer early, researchers like Dr. Curtis hope to stop cancer before it even starts.
“This is a really exciting area of research,” said Susan Domchek, MD, executive director of the Basser Center for BRCA at the University of Pennsylvania, Philadelphia, who was not involved in the study. “What we hope for is that, over time, we’re going to have more and more biologically driven interception.”
‘We’re Basically Unearthing the Dark Matter of the Human Genome’
Of course, we already have mechanical ways of heading off cancer, like having a precancerous polyp removed. But for the Stanford researchers, biologic interception is the goal. They hope to figure out how to use the immune system to stop the cancer.
In their study, they looked at DNA variabilities known as somatic aberrations or single-nucleotide protein sequences (SNPs). The HER2 gene, for example, can contain SNPs — possibly affecting how the HER2 protein regulates breast cell growth and division.
“There’s been a huge effort through genomewide association studies to link SNPs to cancer outcomes and risk,” Dr. Curtis said.
Focusing on people with a genetic predisposition for breast cancer, Dr. Curtis used machine learning to show that these variabilities can occur in specific epitopes (protein features that can trigger an immune response).
They also found that heightened variability can show up in a region of the genome called the human leukocyte antigen (HLA). Each HLA molecule can contain many epitopes.
“We developed a whole new algorithm to compute this ‘germline epitope burden,’ ” Dr. Curtis said. “We’re basically unearthing the dark matter of the human genome to ask about the interplay between SNPs and HLA class one presentation.”
These aberration-rich regions can grab the immune system’s attention. Sometimes the immune system identifies and eradicates those epitopes.
In that case: “I have immunosurveillance. I’ve cured my cancer,” said Nora Disis, PhD, director of the Cancer Vaccine Institute and a professor of medicine at the University of Washington, Seattle. Dr. Disis was not involved in the study.
But other times, the immune system finds a way around the high “epitope burden,” and the tumors become more aggressive and immunosuppressive. That’s when cancer forms.
This suggests a “critical juncture between preinvasive and invasive disease,” Dr. Curtis said.
And that “critical juncture” may very well be the optimal time for intervention.
The Precancer Push
Stanford’s findings add information to prior biomarkers and may provide a way to identify “bad-acting tumors” from a simple blood draw measuring germline epitope burden, Dr. Curtis said. Looking further ahead, “this also reveals a new source of epitopes that might be immunogenic and might be informative for the development of vaccines.”
Many labs are trying to understand the biology of precancer and exploring possible vaccines.
The National Cancer Institute’s Human Tumor Atlas Network is building three-dimensional models of the evolution from precancerous to advanced disease. And researchers at the Cancer Vaccine Institute at the University of Washington are developing a vaccine for a precancerous lesion linked to many ovarian cancers.
Dr. Domchek’s research explores whether breast cancers caused by mutations in the BRCA 1 and 2 genes can be intercepted at very early stages. In a clinical trial of healthy people with those mutations, Dr. Domchek and colleagues are attempting to “rev up the immune system to tackle telomerase,” an enzyme that’s over-expressed in 95% of cancers. The hope is for this experimental vaccine to lower their risk of developing cancer.
At the Fred Hutch Cancer Center, Seattle, Ming Yu, PhD, is studying how senescent cells affect immune cells in precancer. As cells age and stop dividing, she said, they can accumulate and create a “tumor-promoting microenvironment” in older people.
Dr. Yu has found that the antiaging drug rapamycin can eliminate those “zombie cells” in mice. She’s studying whether the “cleanup” can help prevent cancer and expects results in a few months.
In the years and decades to come, all of this could lead to a new era in cancer treatment.
“Most drug development starts with people with advanced cancer and then goes into the earlier and earlier spaces,” said Dr. Domchek. “But it may be that we’re thinking about it all wrong and that you really have to understand the unique biology of early lesions to go after them.”
A version of this article first appeared on Medscape.com.
Some breast cancer types are more likely than others to recur. Researchers have known this for more than a decade.
But they have long wondered why.
“How did those tumor types arise?” said Christina Curtis, PhD, a professor of medicine, genetics and biomedical data science at Stanford University in California. “They’re all breast cancers. They’re all estrogen receptor positive. But these groups are different. When did they become different, and how is that determined?”
Dr. Curtis and colleagues are finally starting to answer these questions. They recently broke new ground in a study linking differences in cancer-related genes to disease subtype and aggressiveness.
DNA inherited from our parents is known as the germline genome. It affects whether the immune system attacks or retreats when confronted with variations that may lead to breast cancer.
“It turns out, the germline genome sculpts tumor evolution,” said Dr. Curtis.
The study is part of a growing effort to understand “precancer” — the critical period after cells have started to grow abnormally but before they’ve developed into cancer — a research trend that could trigger a decisive shift in how cancer treatments are realized. Therapeutics could be designed on the basis of the biology of these precancerous cells.
While biotech start-ups push new tests to catch cancer early, researchers like Dr. Curtis hope to stop cancer before it even starts.
“This is a really exciting area of research,” said Susan Domchek, MD, executive director of the Basser Center for BRCA at the University of Pennsylvania, Philadelphia, who was not involved in the study. “What we hope for is that, over time, we’re going to have more and more biologically driven interception.”
‘We’re Basically Unearthing the Dark Matter of the Human Genome’
Of course, we already have mechanical ways of heading off cancer, like having a precancerous polyp removed. But for the Stanford researchers, biologic interception is the goal. They hope to figure out how to use the immune system to stop the cancer.
In their study, they looked at DNA variabilities known as somatic aberrations or single-nucleotide protein sequences (SNPs). The HER2 gene, for example, can contain SNPs — possibly affecting how the HER2 protein regulates breast cell growth and division.
“There’s been a huge effort through genomewide association studies to link SNPs to cancer outcomes and risk,” Dr. Curtis said.
Focusing on people with a genetic predisposition for breast cancer, Dr. Curtis used machine learning to show that these variabilities can occur in specific epitopes (protein features that can trigger an immune response).
They also found that heightened variability can show up in a region of the genome called the human leukocyte antigen (HLA). Each HLA molecule can contain many epitopes.
“We developed a whole new algorithm to compute this ‘germline epitope burden,’ ” Dr. Curtis said. “We’re basically unearthing the dark matter of the human genome to ask about the interplay between SNPs and HLA class one presentation.”
These aberration-rich regions can grab the immune system’s attention. Sometimes the immune system identifies and eradicates those epitopes.
In that case: “I have immunosurveillance. I’ve cured my cancer,” said Nora Disis, PhD, director of the Cancer Vaccine Institute and a professor of medicine at the University of Washington, Seattle. Dr. Disis was not involved in the study.
But other times, the immune system finds a way around the high “epitope burden,” and the tumors become more aggressive and immunosuppressive. That’s when cancer forms.
This suggests a “critical juncture between preinvasive and invasive disease,” Dr. Curtis said.
And that “critical juncture” may very well be the optimal time for intervention.
The Precancer Push
Stanford’s findings add information to prior biomarkers and may provide a way to identify “bad-acting tumors” from a simple blood draw measuring germline epitope burden, Dr. Curtis said. Looking further ahead, “this also reveals a new source of epitopes that might be immunogenic and might be informative for the development of vaccines.”
Many labs are trying to understand the biology of precancer and exploring possible vaccines.
The National Cancer Institute’s Human Tumor Atlas Network is building three-dimensional models of the evolution from precancerous to advanced disease. And researchers at the Cancer Vaccine Institute at the University of Washington are developing a vaccine for a precancerous lesion linked to many ovarian cancers.
Dr. Domchek’s research explores whether breast cancers caused by mutations in the BRCA 1 and 2 genes can be intercepted at very early stages. In a clinical trial of healthy people with those mutations, Dr. Domchek and colleagues are attempting to “rev up the immune system to tackle telomerase,” an enzyme that’s over-expressed in 95% of cancers. The hope is for this experimental vaccine to lower their risk of developing cancer.
At the Fred Hutch Cancer Center, Seattle, Ming Yu, PhD, is studying how senescent cells affect immune cells in precancer. As cells age and stop dividing, she said, they can accumulate and create a “tumor-promoting microenvironment” in older people.
Dr. Yu has found that the antiaging drug rapamycin can eliminate those “zombie cells” in mice. She’s studying whether the “cleanup” can help prevent cancer and expects results in a few months.
In the years and decades to come, all of this could lead to a new era in cancer treatment.
“Most drug development starts with people with advanced cancer and then goes into the earlier and earlier spaces,” said Dr. Domchek. “But it may be that we’re thinking about it all wrong and that you really have to understand the unique biology of early lesions to go after them.”
A version of this article first appeared on Medscape.com.
Are Targeted Drugs the Future in Colorectal Cancer?
This transcript has been edited for clarity.
Welcome back, everybody, from the European Society for Medical Oncology (ESMO) Congress in the wonderful city of Barcelona in Spain. I was coming from ESMO drenched in huge amounts of new data.
They looked at molecularly targeted drugs, some early-stage and a later-stage study in which there’s some evidence of promise.
She talked a little about the preliminary results from three trials suggesting some benefits, pretty marginal, of cetuximab plus irinotecan in patients who’d already had epidermal growth factor receptor (EGFR) receptor inhibitory treatment.
Amivantamab plus FOLFOX or FOLFIRI was also discussed. This is a bispecific antibody against EGFR and MET. Again, very early, but there are some potential marginal benefits coming through. She also discussed the results of a larger phase 3 randomized trial with an old friend, ramucirumab, the anti-angiogenic agent, in which the ramucirumab in combination with trifluridine-tipiracil failed to meet its primary endpoint of improving overall survival.
There were some interesting post hoc subgroup analyses showing potential benefits for women, left-sided tumors, and so on. She made an excellent presentation, which she summarized by saying that the future of colorectal cancer treatment lies in further defining molecularly targeted treatment.
Nobody would disagree with that. What is interesting, though, is that, if I were to use the analogy of mining, the more deeply we mine, perhaps the lower marginal the benefits are becoming. There’s no doubt that we’re understanding better the exquisite machinery of cell signaling. We understand that there’s redundancy, there’s repeatability, and the possibility of emergence of resistance can come quite quickly.
Although we can develop ever more precise molecularly targeted drugs, it does seem as if the clinical benefits of these, in some cases, are marginally small. I’d like to suggest that, in addition to Sara’s call for more molecularly targeted drugs, we should think about cellular targets.
We did a large amount of work (as have many others, of course) looking at the immune tumor microenvironment and trying to, in a way, separate and understand the contribution of the individual component cells — of which there are many, including cancer-associated fibroblasts, natural killer (NK) cells, whole hosts of different types of T-cell subsets, B cells, tumor-associated neutrophils, and so on — and how these interact together and of interact with the epithelial colorectal cancer cells.
We are collaborating with Patrick Soon-Shiong, a clever chap, who believes in combination immunotherapy, dissecting and understanding the individual role of these different cells, and coming up with cellular therapies or targeted therapies that either inhibit or stimulate some of the different cell components to be the way ahead for an immunologically cold tumor such as microsatellite-stable colorectal cancer.
For example, we’re looking at combinations of our histone deacetylase (HDAC) inhibitor, which switches on the machinery of antigen presentation, up-regulating major histocompatibility complex (MHC) class 1 and class 2, and some other of the molecules involved in antigen chopping and presentation; it’s like turning a microsatellite-stable immunologically cold tumor hot; an interleukin-15 superagonist that stimulates NK cells; and we’ve found a way to manipulate and reduce the number of Treg cells.
We have various approaches to reducing the microenvironment transforming growth factor beta and some of the downstream elements from that. We can look at combinatorial immunotherapy, but thinking at a cellular level and developing anticancer agents that either activate or inhibit these different cell components. I’d bring the two together.
Of course, the future has got to be better molecularly targeted drugs, but let’s think at a macro level as to how we can look at the different cellular interactions within the tumor microenvironment, and perhaps through that, come up with synergistic immunotherapeutic combinations.
Dr. Kerr is Professor, Nuffield Department of Clinical Laboratory Science, University of Oxford, and Professor of Cancer Medicine, Oxford Cancer Centre, both in England. He reported conflicts of interest with Celleron Therapeutics, Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Genomic Health, and Merck Serono.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Welcome back, everybody, from the European Society for Medical Oncology (ESMO) Congress in the wonderful city of Barcelona in Spain. I was coming from ESMO drenched in huge amounts of new data.
They looked at molecularly targeted drugs, some early-stage and a later-stage study in which there’s some evidence of promise.
She talked a little about the preliminary results from three trials suggesting some benefits, pretty marginal, of cetuximab plus irinotecan in patients who’d already had epidermal growth factor receptor (EGFR) receptor inhibitory treatment.
Amivantamab plus FOLFOX or FOLFIRI was also discussed. This is a bispecific antibody against EGFR and MET. Again, very early, but there are some potential marginal benefits coming through. She also discussed the results of a larger phase 3 randomized trial with an old friend, ramucirumab, the anti-angiogenic agent, in which the ramucirumab in combination with trifluridine-tipiracil failed to meet its primary endpoint of improving overall survival.
There were some interesting post hoc subgroup analyses showing potential benefits for women, left-sided tumors, and so on. She made an excellent presentation, which she summarized by saying that the future of colorectal cancer treatment lies in further defining molecularly targeted treatment.
Nobody would disagree with that. What is interesting, though, is that, if I were to use the analogy of mining, the more deeply we mine, perhaps the lower marginal the benefits are becoming. There’s no doubt that we’re understanding better the exquisite machinery of cell signaling. We understand that there’s redundancy, there’s repeatability, and the possibility of emergence of resistance can come quite quickly.
Although we can develop ever more precise molecularly targeted drugs, it does seem as if the clinical benefits of these, in some cases, are marginally small. I’d like to suggest that, in addition to Sara’s call for more molecularly targeted drugs, we should think about cellular targets.
We did a large amount of work (as have many others, of course) looking at the immune tumor microenvironment and trying to, in a way, separate and understand the contribution of the individual component cells — of which there are many, including cancer-associated fibroblasts, natural killer (NK) cells, whole hosts of different types of T-cell subsets, B cells, tumor-associated neutrophils, and so on — and how these interact together and of interact with the epithelial colorectal cancer cells.
We are collaborating with Patrick Soon-Shiong, a clever chap, who believes in combination immunotherapy, dissecting and understanding the individual role of these different cells, and coming up with cellular therapies or targeted therapies that either inhibit or stimulate some of the different cell components to be the way ahead for an immunologically cold tumor such as microsatellite-stable colorectal cancer.
For example, we’re looking at combinations of our histone deacetylase (HDAC) inhibitor, which switches on the machinery of antigen presentation, up-regulating major histocompatibility complex (MHC) class 1 and class 2, and some other of the molecules involved in antigen chopping and presentation; it’s like turning a microsatellite-stable immunologically cold tumor hot; an interleukin-15 superagonist that stimulates NK cells; and we’ve found a way to manipulate and reduce the number of Treg cells.
We have various approaches to reducing the microenvironment transforming growth factor beta and some of the downstream elements from that. We can look at combinatorial immunotherapy, but thinking at a cellular level and developing anticancer agents that either activate or inhibit these different cell components. I’d bring the two together.
Of course, the future has got to be better molecularly targeted drugs, but let’s think at a macro level as to how we can look at the different cellular interactions within the tumor microenvironment, and perhaps through that, come up with synergistic immunotherapeutic combinations.
Dr. Kerr is Professor, Nuffield Department of Clinical Laboratory Science, University of Oxford, and Professor of Cancer Medicine, Oxford Cancer Centre, both in England. He reported conflicts of interest with Celleron Therapeutics, Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Genomic Health, and Merck Serono.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Welcome back, everybody, from the European Society for Medical Oncology (ESMO) Congress in the wonderful city of Barcelona in Spain. I was coming from ESMO drenched in huge amounts of new data.
They looked at molecularly targeted drugs, some early-stage and a later-stage study in which there’s some evidence of promise.
She talked a little about the preliminary results from three trials suggesting some benefits, pretty marginal, of cetuximab plus irinotecan in patients who’d already had epidermal growth factor receptor (EGFR) receptor inhibitory treatment.
Amivantamab plus FOLFOX or FOLFIRI was also discussed. This is a bispecific antibody against EGFR and MET. Again, very early, but there are some potential marginal benefits coming through. She also discussed the results of a larger phase 3 randomized trial with an old friend, ramucirumab, the anti-angiogenic agent, in which the ramucirumab in combination with trifluridine-tipiracil failed to meet its primary endpoint of improving overall survival.
There were some interesting post hoc subgroup analyses showing potential benefits for women, left-sided tumors, and so on. She made an excellent presentation, which she summarized by saying that the future of colorectal cancer treatment lies in further defining molecularly targeted treatment.
Nobody would disagree with that. What is interesting, though, is that, if I were to use the analogy of mining, the more deeply we mine, perhaps the lower marginal the benefits are becoming. There’s no doubt that we’re understanding better the exquisite machinery of cell signaling. We understand that there’s redundancy, there’s repeatability, and the possibility of emergence of resistance can come quite quickly.
Although we can develop ever more precise molecularly targeted drugs, it does seem as if the clinical benefits of these, in some cases, are marginally small. I’d like to suggest that, in addition to Sara’s call for more molecularly targeted drugs, we should think about cellular targets.
We did a large amount of work (as have many others, of course) looking at the immune tumor microenvironment and trying to, in a way, separate and understand the contribution of the individual component cells — of which there are many, including cancer-associated fibroblasts, natural killer (NK) cells, whole hosts of different types of T-cell subsets, B cells, tumor-associated neutrophils, and so on — and how these interact together and of interact with the epithelial colorectal cancer cells.
We are collaborating with Patrick Soon-Shiong, a clever chap, who believes in combination immunotherapy, dissecting and understanding the individual role of these different cells, and coming up with cellular therapies or targeted therapies that either inhibit or stimulate some of the different cell components to be the way ahead for an immunologically cold tumor such as microsatellite-stable colorectal cancer.
For example, we’re looking at combinations of our histone deacetylase (HDAC) inhibitor, which switches on the machinery of antigen presentation, up-regulating major histocompatibility complex (MHC) class 1 and class 2, and some other of the molecules involved in antigen chopping and presentation; it’s like turning a microsatellite-stable immunologically cold tumor hot; an interleukin-15 superagonist that stimulates NK cells; and we’ve found a way to manipulate and reduce the number of Treg cells.
We have various approaches to reducing the microenvironment transforming growth factor beta and some of the downstream elements from that. We can look at combinatorial immunotherapy, but thinking at a cellular level and developing anticancer agents that either activate or inhibit these different cell components. I’d bring the two together.
Of course, the future has got to be better molecularly targeted drugs, but let’s think at a macro level as to how we can look at the different cellular interactions within the tumor microenvironment, and perhaps through that, come up with synergistic immunotherapeutic combinations.
Dr. Kerr is Professor, Nuffield Department of Clinical Laboratory Science, University of Oxford, and Professor of Cancer Medicine, Oxford Cancer Centre, both in England. He reported conflicts of interest with Celleron Therapeutics, Oxford Cancer Biomarkers, Afrox, GlaxoSmithKline, Genomic Health, and Merck Serono.
A version of this article first appeared on Medscape.com.
Adding Short-term ADT to High-Dose Radiotherapy Benefits Some Prostate Cancers
according to results of the phase 3 GETUG 14 trial.
The 5-year disease-free survival rate was 84% in patients who received short-term ADT plus radiotherapy, compared with 76% in those who received radiotherapy alone.
In addition, short-term ADT with high-dose radiotherapy didn’t increase genitourinary or gastrointestinal toxicities, said Nicolas Demogeot, MD, with the Cancer Institute of Lorraine, Vandœuvre-lès-Nancy, France, who presented the results at the annual meeting of the American Society for Radiation Oncology (ASTRO).
Adding short-term ADT to standard-dose radiotherapy has been shown to improve all clinical outcomes, Dr. Demogeot noted, but few trials have tested it with high-dose radiotherapy. GETUG 14 was designed to do just that.
The multicenter, randomized, phase 3 trial enrolled 376 patients with intermediate- or high-risk localized prostate cancer who had PSA levels under 30 ng/mL and no clinical involvement of the seminal vesicles.
Patients were randomly allocated to high-dose radiotherapy (80 Gy) alone or high-dose radiotherapy plus monthly triptorelin and daily flutamide for a total duration of 4 months, starting 2 months prior to radiotherapy.
Disease-free survival was the primary endpoint. Secondary endpoints were overall survival, biochemical failure, metastasis failure, toxicity, and quality of life.
The modified intention-to-treat cohort included 191 patients in the radiotherapy-only group and 179 in the short-term ADT plus radiotherapy group. The two groups were well balanced. In both, patients ranged in age from 64 to 73 years; about two thirds had intermediate-risk disease; 70% received three-dimensional conformal radiotherapy, and 30% received intensity-modulated radiotherapy.
Overall, adding short-term ADT to high-dose radiotherapy was associated with a 36% relative improvement in 5-year disease-free survival (84% vs 76% with radiotherapy alone, hazard ratio [HR], 0.64; P = .02).
In subgroup analyses, intermediate-risk patients who received short-term ADT with high-dose radiotherapy demonstrated a significant improvement in disease-free survival (87% vs 74% with radiotherapy alone; HR, 0.55; P = .02). However, there was no significant disease-free survival benefit with short-term ADT with high-dose radiotherapy in high-risk patients (79% vs 75%; HR, 0.76; P = .40).
On multivariable analysis, short-term ADT with high-dose radiotherapy was associated with significant disease-free survival benefits (HR, 0.66; P = .038).
Patients who received short-term ADT with high-dose radiotherapy were significantly less likely to experience biochemical failure (10% vs 21%; HR, 0.45; P = .001), but there was no significant difference in metastasis failure (HR, 0.5; P = .09) or overall survival (HR, 1.22; P = .54).
As for adverse events, the two groups did not demonstrate significant differences in the proportions of early or late grade 2 or higher gastrointestinal or genitourinary toxicities.
Patients in the short-term ADT with high-dose radiotherapy group did experience a greater frequency of early grade 2 or higher erectile dysfunction (31% vs 6%; P < .001), but not late grade 2 or higher erectile dysfunction (63% vs 61%; P = .89).
Limitations of the study include a low power to detect differences between intermediate- and high-risk patients and the short follow-up period.
The GETUG 14 trial “confirms that short-term ADT improves disease-free survival when combined with dose-escalated radiation therapy for intermediate-risk prostate cancer,” Mark A. Hallman, MD, PhD, with Fox Chase Cancer Center, Philadelphia, Pennsylvania, who was not involved in the study, said in an interview. “However, there was not a similar benefit among the smaller subpopulation with high-risk disease.”
Outside expert Amar Kishan, MD, radiation oncologist, UCLA Jonsson Comprehensive Cancer Center, agreed, adding that “it is also reassuring to see no increase in genitourinary or gastrointestinal toxicity and no longer-term impact on erectile dysfunction.”
The GETUG-14 trial was supported by the French Ministry of Health and Ipsen. Dr. Demogeot has disclosed relationships with Ipsen, Janssen, Accord Healthcare, Astellas, and Bayer. Dr. Hallman had no relevant disclosures. Dr. Kishan has disclosed relationships with Boston Scientific, Janssen, Varian Medical Systems, ViewRay, and POINT Biopharma.
A version of this article first appeared on Medscape.com.
according to results of the phase 3 GETUG 14 trial.
The 5-year disease-free survival rate was 84% in patients who received short-term ADT plus radiotherapy, compared with 76% in those who received radiotherapy alone.
In addition, short-term ADT with high-dose radiotherapy didn’t increase genitourinary or gastrointestinal toxicities, said Nicolas Demogeot, MD, with the Cancer Institute of Lorraine, Vandœuvre-lès-Nancy, France, who presented the results at the annual meeting of the American Society for Radiation Oncology (ASTRO).
Adding short-term ADT to standard-dose radiotherapy has been shown to improve all clinical outcomes, Dr. Demogeot noted, but few trials have tested it with high-dose radiotherapy. GETUG 14 was designed to do just that.
The multicenter, randomized, phase 3 trial enrolled 376 patients with intermediate- or high-risk localized prostate cancer who had PSA levels under 30 ng/mL and no clinical involvement of the seminal vesicles.
Patients were randomly allocated to high-dose radiotherapy (80 Gy) alone or high-dose radiotherapy plus monthly triptorelin and daily flutamide for a total duration of 4 months, starting 2 months prior to radiotherapy.
Disease-free survival was the primary endpoint. Secondary endpoints were overall survival, biochemical failure, metastasis failure, toxicity, and quality of life.
The modified intention-to-treat cohort included 191 patients in the radiotherapy-only group and 179 in the short-term ADT plus radiotherapy group. The two groups were well balanced. In both, patients ranged in age from 64 to 73 years; about two thirds had intermediate-risk disease; 70% received three-dimensional conformal radiotherapy, and 30% received intensity-modulated radiotherapy.
Overall, adding short-term ADT to high-dose radiotherapy was associated with a 36% relative improvement in 5-year disease-free survival (84% vs 76% with radiotherapy alone, hazard ratio [HR], 0.64; P = .02).
In subgroup analyses, intermediate-risk patients who received short-term ADT with high-dose radiotherapy demonstrated a significant improvement in disease-free survival (87% vs 74% with radiotherapy alone; HR, 0.55; P = .02). However, there was no significant disease-free survival benefit with short-term ADT with high-dose radiotherapy in high-risk patients (79% vs 75%; HR, 0.76; P = .40).
On multivariable analysis, short-term ADT with high-dose radiotherapy was associated with significant disease-free survival benefits (HR, 0.66; P = .038).
Patients who received short-term ADT with high-dose radiotherapy were significantly less likely to experience biochemical failure (10% vs 21%; HR, 0.45; P = .001), but there was no significant difference in metastasis failure (HR, 0.5; P = .09) or overall survival (HR, 1.22; P = .54).
As for adverse events, the two groups did not demonstrate significant differences in the proportions of early or late grade 2 or higher gastrointestinal or genitourinary toxicities.
Patients in the short-term ADT with high-dose radiotherapy group did experience a greater frequency of early grade 2 or higher erectile dysfunction (31% vs 6%; P < .001), but not late grade 2 or higher erectile dysfunction (63% vs 61%; P = .89).
Limitations of the study include a low power to detect differences between intermediate- and high-risk patients and the short follow-up period.
The GETUG 14 trial “confirms that short-term ADT improves disease-free survival when combined with dose-escalated radiation therapy for intermediate-risk prostate cancer,” Mark A. Hallman, MD, PhD, with Fox Chase Cancer Center, Philadelphia, Pennsylvania, who was not involved in the study, said in an interview. “However, there was not a similar benefit among the smaller subpopulation with high-risk disease.”
Outside expert Amar Kishan, MD, radiation oncologist, UCLA Jonsson Comprehensive Cancer Center, agreed, adding that “it is also reassuring to see no increase in genitourinary or gastrointestinal toxicity and no longer-term impact on erectile dysfunction.”
The GETUG-14 trial was supported by the French Ministry of Health and Ipsen. Dr. Demogeot has disclosed relationships with Ipsen, Janssen, Accord Healthcare, Astellas, and Bayer. Dr. Hallman had no relevant disclosures. Dr. Kishan has disclosed relationships with Boston Scientific, Janssen, Varian Medical Systems, ViewRay, and POINT Biopharma.
A version of this article first appeared on Medscape.com.
according to results of the phase 3 GETUG 14 trial.
The 5-year disease-free survival rate was 84% in patients who received short-term ADT plus radiotherapy, compared with 76% in those who received radiotherapy alone.
In addition, short-term ADT with high-dose radiotherapy didn’t increase genitourinary or gastrointestinal toxicities, said Nicolas Demogeot, MD, with the Cancer Institute of Lorraine, Vandœuvre-lès-Nancy, France, who presented the results at the annual meeting of the American Society for Radiation Oncology (ASTRO).
Adding short-term ADT to standard-dose radiotherapy has been shown to improve all clinical outcomes, Dr. Demogeot noted, but few trials have tested it with high-dose radiotherapy. GETUG 14 was designed to do just that.
The multicenter, randomized, phase 3 trial enrolled 376 patients with intermediate- or high-risk localized prostate cancer who had PSA levels under 30 ng/mL and no clinical involvement of the seminal vesicles.
Patients were randomly allocated to high-dose radiotherapy (80 Gy) alone or high-dose radiotherapy plus monthly triptorelin and daily flutamide for a total duration of 4 months, starting 2 months prior to radiotherapy.
Disease-free survival was the primary endpoint. Secondary endpoints were overall survival, biochemical failure, metastasis failure, toxicity, and quality of life.
The modified intention-to-treat cohort included 191 patients in the radiotherapy-only group and 179 in the short-term ADT plus radiotherapy group. The two groups were well balanced. In both, patients ranged in age from 64 to 73 years; about two thirds had intermediate-risk disease; 70% received three-dimensional conformal radiotherapy, and 30% received intensity-modulated radiotherapy.
Overall, adding short-term ADT to high-dose radiotherapy was associated with a 36% relative improvement in 5-year disease-free survival (84% vs 76% with radiotherapy alone, hazard ratio [HR], 0.64; P = .02).
In subgroup analyses, intermediate-risk patients who received short-term ADT with high-dose radiotherapy demonstrated a significant improvement in disease-free survival (87% vs 74% with radiotherapy alone; HR, 0.55; P = .02). However, there was no significant disease-free survival benefit with short-term ADT with high-dose radiotherapy in high-risk patients (79% vs 75%; HR, 0.76; P = .40).
On multivariable analysis, short-term ADT with high-dose radiotherapy was associated with significant disease-free survival benefits (HR, 0.66; P = .038).
Patients who received short-term ADT with high-dose radiotherapy were significantly less likely to experience biochemical failure (10% vs 21%; HR, 0.45; P = .001), but there was no significant difference in metastasis failure (HR, 0.5; P = .09) or overall survival (HR, 1.22; P = .54).
As for adverse events, the two groups did not demonstrate significant differences in the proportions of early or late grade 2 or higher gastrointestinal or genitourinary toxicities.
Patients in the short-term ADT with high-dose radiotherapy group did experience a greater frequency of early grade 2 or higher erectile dysfunction (31% vs 6%; P < .001), but not late grade 2 or higher erectile dysfunction (63% vs 61%; P = .89).
Limitations of the study include a low power to detect differences between intermediate- and high-risk patients and the short follow-up period.
The GETUG 14 trial “confirms that short-term ADT improves disease-free survival when combined with dose-escalated radiation therapy for intermediate-risk prostate cancer,” Mark A. Hallman, MD, PhD, with Fox Chase Cancer Center, Philadelphia, Pennsylvania, who was not involved in the study, said in an interview. “However, there was not a similar benefit among the smaller subpopulation with high-risk disease.”
Outside expert Amar Kishan, MD, radiation oncologist, UCLA Jonsson Comprehensive Cancer Center, agreed, adding that “it is also reassuring to see no increase in genitourinary or gastrointestinal toxicity and no longer-term impact on erectile dysfunction.”
The GETUG-14 trial was supported by the French Ministry of Health and Ipsen. Dr. Demogeot has disclosed relationships with Ipsen, Janssen, Accord Healthcare, Astellas, and Bayer. Dr. Hallman had no relevant disclosures. Dr. Kishan has disclosed relationships with Boston Scientific, Janssen, Varian Medical Systems, ViewRay, and POINT Biopharma.
A version of this article first appeared on Medscape.com.
FROM ASTRO 2024
IMRT vs Proton Therapy for Early Prostate Cancer?
With both techniques, disease control rates were over 90%, with virtually no difference in bowel function or other quality-of-life ratings after 2 years, reported Jason Efstathiou, MD, PhD, with Massachusetts General Hospital, Boston, at the annual meeting of the American Society for Radiation Oncology (ASTRO).
“This is a tremendous study [that] really shows us we have two great options, with equal results across the board for both control rates and toxicity rates,” said Sameer Keole, MD, incoming ASTRO president, during a press briefing.
“These control rates are phenomenal, and the complication rates were very low,” continued Dr. Keole, with the Mayo Clinic in Phoenix, Arizona. “I think men can go and seek definitive treatment when it’s appropriate with a radiation oncologist and know that whether it’s proton therapy or IMRT; it’s an excellent treatment option.”
Overall, about 70% of new cases of prostate cancer each year are localized disease, which represents about 200,000 patients in the United States each year, Dr. Efstathiou explained. These patients have several treatment options, including different choices for external beam radiation therapy.
“Because many of these patients are going to survive their cancer and live many years after treatment, quality of life becomes paramount because they’re at risk for long-term posttreatment morbidity,” Dr. Efstathiou said. “Quality of life will inform their decision-making.”
Dr. Efstathiou noted that proton beam therapy comes with certain dosimetric advantages with the potential to reduce morbidity and improve cancer outcomes, but it is generally more resource intensive and costly than IMRT.
The PARTIQoL multicenter, phase 3, randomized trial compared patient-reported quality of life after external beam radiation using either IMRT or proton beam therapy to determine whether one performs better on the local control and toxicity fronts.
After stratifying by institution, age (< 65 years vs ≥ 65 years), rectal spacer use (no vs yes), and moderate hypofractionation (no vs yes), participants were randomized to either proton beam therapy or IMRT.
Patients were followed longitudinally for 60 months after completing radiotherapy. The primary endpoint was bowel function at 24 months using the Expanded Prostate Cancer Index Composite (EPIC) instrument. Secondary outcomes included urinary and erectile function, sexual function, toxicity and efficacy, or disease control endpoints.
Of the 450 patients randomized, 221 of 226 (97.8%) randomized to proton beam therapy and 216 of 224 (96.4%) randomized to IMRT started on their respective treatments, and 167 and 162, respectively, completed the EPIC at 24 months. This represents about a 27% rate of missing data, which “was much better than anticipated,” Dr. Efstathiou noted.
For the primary endpoint, there was no difference between proton beam therapy and IMRT in mean change of the EPIC bowel score at 24 months, with both treatment groups showing only a small, clinically nonrelevant decline from baseline. There was only about a 2% decrease on a 100-point scale in bowel quality of life after 2 years, Dr. Efstathiou reported.
Similarly, the team noted no difference in bowel function at earlier or later time points. “We see some small fluctuations, but at no time point did these reach statistical significance,” he noted.
There were also no differences observed in the other domains at any point, including urinary incontinence, urinary irritation, or sexual function.
Turning to disease control, Dr. Efstathiou and colleagues found no difference between the two groups in progression-free survival. The progression-free survival rate was 99% at 24 months and 93.7% at 60 months with IMRT, compared with 98.1% at 24 months and 93.4% at 60 months with proton beam therapy.
When looking at key subgroups or factors, the team reported no sustained difference in any quality-of-life domain or in cancer control.
Patient monitoring over a longer follow-up period is ongoing. Dr. Efstathiou noted that the PARTIQoL trial was limited to localized low- and intermediate-risk prostate cancer patients receiving either conventionally or moderately hypofractionated therapy. The trial also did not address the full range of disease scope, including higher risk disease, nodal therapy, concurrent use of hormonal therapy or other systemic therapy, local recurrent situations, or retreatment situations.
Dr. Efstathiou noted that because both proton therapy and IMRT continue to evolve, there is ongoing work to optimize the delivery of both.
Overall, the PARTIQoL trial results demonstrate “equivalent outcomes, with superb cancer control rates and extremely low toxicity from both treatments,” Jessica Karen Wong, MD, MEng, who wasn’t involved in the study, told this news organization.
“Both are excellent treatments for low- and intermediate-risk prostate cancer patients,” said Dr. Wong, Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania. “This study corroborates prior single and multi-institutional experiences with the statistical power and rigorous methods of a clinical trial. Dr Efstathiou and authors should be commended for this comprehensive and well-run trial.”
Discussant for the study, Curtiland Deville, MD, of Johns Hopkins University School of Medicine, Baltimore, Maryland, agreed that patients in the trial did “exceedingly well,” regardless of whether patients received IMRT or proton therapy.
Dr. Deville said the “fundamental question regarding the use of proton therapy for prostate cancer remains — is there a clinical benefit to protons that justifies their increased costs in this setting? In a cost-neutral setting, it may still be considered very reasonable to deliver proton therapy for prostate cancer.”
In his view, this study is “practice informing” but not yet “practice changing as we await the imminent findings of the COMPARE trial,” which uses a pragmatic design powered to assess the co-primary patient-reported outcome endpoints of EPIC bowel summary, urinary function, and sexual function scores at 2 years, and which enrolled over 2500 patients.
The study has no commercial funding. Dr. Efstathiou disclosed various relationships with IBA Proton Therapy, Blue Earth Diagnostics, Boston Scientific, AstraZeneca, Genentech, Lantheus/Progenics, Astellas/Pfizer, Elekta, Uptodate, Merck, Roivant Pharma, Myovant Sciences, EMD Serono, Bayer Healthcare, Janssen, Pfizer, Progenics Pharmaceuticals, Gilead, Angiodynamics, and Clarity Pharmaceuticals. Dr. Keole and Dr. Wong had no relevant disclosures. Dr. Deville is deputy editor of the ASTRO Red Journal.
A version of this article appeared on Medscape.com.
With both techniques, disease control rates were over 90%, with virtually no difference in bowel function or other quality-of-life ratings after 2 years, reported Jason Efstathiou, MD, PhD, with Massachusetts General Hospital, Boston, at the annual meeting of the American Society for Radiation Oncology (ASTRO).
“This is a tremendous study [that] really shows us we have two great options, with equal results across the board for both control rates and toxicity rates,” said Sameer Keole, MD, incoming ASTRO president, during a press briefing.
“These control rates are phenomenal, and the complication rates were very low,” continued Dr. Keole, with the Mayo Clinic in Phoenix, Arizona. “I think men can go and seek definitive treatment when it’s appropriate with a radiation oncologist and know that whether it’s proton therapy or IMRT; it’s an excellent treatment option.”
Overall, about 70% of new cases of prostate cancer each year are localized disease, which represents about 200,000 patients in the United States each year, Dr. Efstathiou explained. These patients have several treatment options, including different choices for external beam radiation therapy.
“Because many of these patients are going to survive their cancer and live many years after treatment, quality of life becomes paramount because they’re at risk for long-term posttreatment morbidity,” Dr. Efstathiou said. “Quality of life will inform their decision-making.”
Dr. Efstathiou noted that proton beam therapy comes with certain dosimetric advantages with the potential to reduce morbidity and improve cancer outcomes, but it is generally more resource intensive and costly than IMRT.
The PARTIQoL multicenter, phase 3, randomized trial compared patient-reported quality of life after external beam radiation using either IMRT or proton beam therapy to determine whether one performs better on the local control and toxicity fronts.
After stratifying by institution, age (< 65 years vs ≥ 65 years), rectal spacer use (no vs yes), and moderate hypofractionation (no vs yes), participants were randomized to either proton beam therapy or IMRT.
Patients were followed longitudinally for 60 months after completing radiotherapy. The primary endpoint was bowel function at 24 months using the Expanded Prostate Cancer Index Composite (EPIC) instrument. Secondary outcomes included urinary and erectile function, sexual function, toxicity and efficacy, or disease control endpoints.
Of the 450 patients randomized, 221 of 226 (97.8%) randomized to proton beam therapy and 216 of 224 (96.4%) randomized to IMRT started on their respective treatments, and 167 and 162, respectively, completed the EPIC at 24 months. This represents about a 27% rate of missing data, which “was much better than anticipated,” Dr. Efstathiou noted.
For the primary endpoint, there was no difference between proton beam therapy and IMRT in mean change of the EPIC bowel score at 24 months, with both treatment groups showing only a small, clinically nonrelevant decline from baseline. There was only about a 2% decrease on a 100-point scale in bowel quality of life after 2 years, Dr. Efstathiou reported.
Similarly, the team noted no difference in bowel function at earlier or later time points. “We see some small fluctuations, but at no time point did these reach statistical significance,” he noted.
There were also no differences observed in the other domains at any point, including urinary incontinence, urinary irritation, or sexual function.
Turning to disease control, Dr. Efstathiou and colleagues found no difference between the two groups in progression-free survival. The progression-free survival rate was 99% at 24 months and 93.7% at 60 months with IMRT, compared with 98.1% at 24 months and 93.4% at 60 months with proton beam therapy.
When looking at key subgroups or factors, the team reported no sustained difference in any quality-of-life domain or in cancer control.
Patient monitoring over a longer follow-up period is ongoing. Dr. Efstathiou noted that the PARTIQoL trial was limited to localized low- and intermediate-risk prostate cancer patients receiving either conventionally or moderately hypofractionated therapy. The trial also did not address the full range of disease scope, including higher risk disease, nodal therapy, concurrent use of hormonal therapy or other systemic therapy, local recurrent situations, or retreatment situations.
Dr. Efstathiou noted that because both proton therapy and IMRT continue to evolve, there is ongoing work to optimize the delivery of both.
Overall, the PARTIQoL trial results demonstrate “equivalent outcomes, with superb cancer control rates and extremely low toxicity from both treatments,” Jessica Karen Wong, MD, MEng, who wasn’t involved in the study, told this news organization.
“Both are excellent treatments for low- and intermediate-risk prostate cancer patients,” said Dr. Wong, Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania. “This study corroborates prior single and multi-institutional experiences with the statistical power and rigorous methods of a clinical trial. Dr Efstathiou and authors should be commended for this comprehensive and well-run trial.”
Discussant for the study, Curtiland Deville, MD, of Johns Hopkins University School of Medicine, Baltimore, Maryland, agreed that patients in the trial did “exceedingly well,” regardless of whether patients received IMRT or proton therapy.
Dr. Deville said the “fundamental question regarding the use of proton therapy for prostate cancer remains — is there a clinical benefit to protons that justifies their increased costs in this setting? In a cost-neutral setting, it may still be considered very reasonable to deliver proton therapy for prostate cancer.”
In his view, this study is “practice informing” but not yet “practice changing as we await the imminent findings of the COMPARE trial,” which uses a pragmatic design powered to assess the co-primary patient-reported outcome endpoints of EPIC bowel summary, urinary function, and sexual function scores at 2 years, and which enrolled over 2500 patients.
The study has no commercial funding. Dr. Efstathiou disclosed various relationships with IBA Proton Therapy, Blue Earth Diagnostics, Boston Scientific, AstraZeneca, Genentech, Lantheus/Progenics, Astellas/Pfizer, Elekta, Uptodate, Merck, Roivant Pharma, Myovant Sciences, EMD Serono, Bayer Healthcare, Janssen, Pfizer, Progenics Pharmaceuticals, Gilead, Angiodynamics, and Clarity Pharmaceuticals. Dr. Keole and Dr. Wong had no relevant disclosures. Dr. Deville is deputy editor of the ASTRO Red Journal.
A version of this article appeared on Medscape.com.
With both techniques, disease control rates were over 90%, with virtually no difference in bowel function or other quality-of-life ratings after 2 years, reported Jason Efstathiou, MD, PhD, with Massachusetts General Hospital, Boston, at the annual meeting of the American Society for Radiation Oncology (ASTRO).
“This is a tremendous study [that] really shows us we have two great options, with equal results across the board for both control rates and toxicity rates,” said Sameer Keole, MD, incoming ASTRO president, during a press briefing.
“These control rates are phenomenal, and the complication rates were very low,” continued Dr. Keole, with the Mayo Clinic in Phoenix, Arizona. “I think men can go and seek definitive treatment when it’s appropriate with a radiation oncologist and know that whether it’s proton therapy or IMRT; it’s an excellent treatment option.”
Overall, about 70% of new cases of prostate cancer each year are localized disease, which represents about 200,000 patients in the United States each year, Dr. Efstathiou explained. These patients have several treatment options, including different choices for external beam radiation therapy.
“Because many of these patients are going to survive their cancer and live many years after treatment, quality of life becomes paramount because they’re at risk for long-term posttreatment morbidity,” Dr. Efstathiou said. “Quality of life will inform their decision-making.”
Dr. Efstathiou noted that proton beam therapy comes with certain dosimetric advantages with the potential to reduce morbidity and improve cancer outcomes, but it is generally more resource intensive and costly than IMRT.
The PARTIQoL multicenter, phase 3, randomized trial compared patient-reported quality of life after external beam radiation using either IMRT or proton beam therapy to determine whether one performs better on the local control and toxicity fronts.
After stratifying by institution, age (< 65 years vs ≥ 65 years), rectal spacer use (no vs yes), and moderate hypofractionation (no vs yes), participants were randomized to either proton beam therapy or IMRT.
Patients were followed longitudinally for 60 months after completing radiotherapy. The primary endpoint was bowel function at 24 months using the Expanded Prostate Cancer Index Composite (EPIC) instrument. Secondary outcomes included urinary and erectile function, sexual function, toxicity and efficacy, or disease control endpoints.
Of the 450 patients randomized, 221 of 226 (97.8%) randomized to proton beam therapy and 216 of 224 (96.4%) randomized to IMRT started on their respective treatments, and 167 and 162, respectively, completed the EPIC at 24 months. This represents about a 27% rate of missing data, which “was much better than anticipated,” Dr. Efstathiou noted.
For the primary endpoint, there was no difference between proton beam therapy and IMRT in mean change of the EPIC bowel score at 24 months, with both treatment groups showing only a small, clinically nonrelevant decline from baseline. There was only about a 2% decrease on a 100-point scale in bowel quality of life after 2 years, Dr. Efstathiou reported.
Similarly, the team noted no difference in bowel function at earlier or later time points. “We see some small fluctuations, but at no time point did these reach statistical significance,” he noted.
There were also no differences observed in the other domains at any point, including urinary incontinence, urinary irritation, or sexual function.
Turning to disease control, Dr. Efstathiou and colleagues found no difference between the two groups in progression-free survival. The progression-free survival rate was 99% at 24 months and 93.7% at 60 months with IMRT, compared with 98.1% at 24 months and 93.4% at 60 months with proton beam therapy.
When looking at key subgroups or factors, the team reported no sustained difference in any quality-of-life domain or in cancer control.
Patient monitoring over a longer follow-up period is ongoing. Dr. Efstathiou noted that the PARTIQoL trial was limited to localized low- and intermediate-risk prostate cancer patients receiving either conventionally or moderately hypofractionated therapy. The trial also did not address the full range of disease scope, including higher risk disease, nodal therapy, concurrent use of hormonal therapy or other systemic therapy, local recurrent situations, or retreatment situations.
Dr. Efstathiou noted that because both proton therapy and IMRT continue to evolve, there is ongoing work to optimize the delivery of both.
Overall, the PARTIQoL trial results demonstrate “equivalent outcomes, with superb cancer control rates and extremely low toxicity from both treatments,” Jessica Karen Wong, MD, MEng, who wasn’t involved in the study, told this news organization.
“Both are excellent treatments for low- and intermediate-risk prostate cancer patients,” said Dr. Wong, Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania. “This study corroborates prior single and multi-institutional experiences with the statistical power and rigorous methods of a clinical trial. Dr Efstathiou and authors should be commended for this comprehensive and well-run trial.”
Discussant for the study, Curtiland Deville, MD, of Johns Hopkins University School of Medicine, Baltimore, Maryland, agreed that patients in the trial did “exceedingly well,” regardless of whether patients received IMRT or proton therapy.
Dr. Deville said the “fundamental question regarding the use of proton therapy for prostate cancer remains — is there a clinical benefit to protons that justifies their increased costs in this setting? In a cost-neutral setting, it may still be considered very reasonable to deliver proton therapy for prostate cancer.”
In his view, this study is “practice informing” but not yet “practice changing as we await the imminent findings of the COMPARE trial,” which uses a pragmatic design powered to assess the co-primary patient-reported outcome endpoints of EPIC bowel summary, urinary function, and sexual function scores at 2 years, and which enrolled over 2500 patients.
The study has no commercial funding. Dr. Efstathiou disclosed various relationships with IBA Proton Therapy, Blue Earth Diagnostics, Boston Scientific, AstraZeneca, Genentech, Lantheus/Progenics, Astellas/Pfizer, Elekta, Uptodate, Merck, Roivant Pharma, Myovant Sciences, EMD Serono, Bayer Healthcare, Janssen, Pfizer, Progenics Pharmaceuticals, Gilead, Angiodynamics, and Clarity Pharmaceuticals. Dr. Keole and Dr. Wong had no relevant disclosures. Dr. Deville is deputy editor of the ASTRO Red Journal.
A version of this article appeared on Medscape.com.
FROM ASTRO 2024
NCCRT Confirmed as Best Approach in Locally Advanced, Resectable ESCC
confirmed the first randomized trial to directly compare the two approaches.
Yaoyao Zhu, MD, Department of Radiation Oncology, Shanghai Pulmonary Hospital, Shanghai, China, presented the new research at the annual World Conference on Lung Cancer on September 10.
Based on the findings, neoadjuvant concurrent chemoradiotherapy (NCCRT) followed by surgical resection “should be regarded as the standard of care for patients with locally advanced esophageal squamous cell carcinoma (ESCC) in the Chinese population,” Dr. Zhu said.
Different Approaches in ESCC
Dr. Zhu began her presentation by underscoring that in Western countries, NCCRT followed by surgery has been the standard treatment for locally advanced, resectable esophageal cancer since the publication of the CROSS trial in 2012, which compared neoadjuvant therapy plus surgery with surgery alone.
This demonstrated that preoperative chemoradiotherapy improved survival by 34% in patients with potentially curable esophageal or esophagogastric junction cancer, while adverse event rates were deemed “acceptable.”
In contrast, in most centers in China, clinicians opt for performing surgery followed by ASCRT.
Dr. Zhu pointed out that as previous randomized controlled trials have used surgery alone as the comparator arm, it has not been shown definitively that NCCRT plus surgery is superior to surgery followed by ASCRT.
The researchers, therefore, conducted the NEOTERIC trial, which enrolled patients with clinically resectable, locally advanced ESCC, defined as clinical stage T1-2N1M0 or T3-4N0-1M0.
They were randomized to one of two arms. The NCCRT arm involved 6 weeks of carboplatin plus paclitaxel chemotherapy alongside radiotherapy delivered as 50.4 Gy over 28 fractions. After an interval of 4-6 weeks, the patients underwent surgery, followed by an optional two cycles of carboplatin plus paclitaxel 4-6 weeks later.
In the ASCRT arm, patients underwent surgery straightaway, waited for 4-6 weeks, then had two cycles of carboplatin plus paclitaxel 3 weeks apart, followed by the same radiotherapy regimen as in the first arm. About 2-4 weeks later, patients could then undergo another two cycles of carboplatin plus paclitaxel.
More Than Doubling of Survival Outcomes
One hundred patients were assigned to NCCRT and 104 to ASCRT. There were no significant differences between the groups in terms of their baseline characteristics.
The vast majority of patients were men, just over two thirds were smokers, and the median age was around 60 years. The median tumor length was approximately 5 cm, and around half of tumors were located in the middle third of the esophagus.
Median disease-free survival was markedly longer with NCCRT, at 51.0 months vs 14.0 months in the ASCRT arm (P = .01). Similarly, median overall survival was far longer with neoadjuvant therapy, at 79.0 months, vs 38.0 months when waiting until after surgery to provide chemoradiotherapy (P = .025).
There were no significant differences in postsurgical complications between the two arms, and no significant differences in rates of grade 3-4 hematologic and nonhematologic toxicities. There were also no chemoradiotherapy-related deaths.
The most common toxicities across the two study arms were esophagitis, neutropenia, thrombocytopenia, and leukopenia.
Overall, the rates of recurrence were significantly lower with NCCRT than with ASCRT (58.0% vs 66.3%; P = .020). This included significant reductions in both locoregional (P = .012) and distant recurrence (P = .009).
Jaffer A. Ajani, MD, University of Texas MD Anderson Cancer Center, Houston, underlined that the experimental arm of the trial, with neoadjuvant chemoradiotherapy, “has been the standard of care in the United States for a long time, particularly for squamous carcinoma.”
However, he said in an interview that it is not a standard of care in China and clinicians continue with adjuvant therapy. This is despite a recent study conducted in Hong Kong that concluded that patients should not be given any treatment after surgery “because they do worse” than those given neoadjuvant therapy, he continued.
While Dr. Ajani noted that the current analysis is underpowered to provide a definitive conclusion, it remains “an important study for Chinese patients.
“Hopefully, it will be well advertised in China, and all the providers switch [to NCCRT]. This could push them to abandon what in the West was considered harmful.”
Dr. Ajani explained the reason neoadjuvant therapy performs better than adjuvant chemoradiotherapy is it “may be mopping up some of the micro metastatic disease, which is difficult to do after surgery,” especially as many patients cannot tolerate postoperative treatment.
“It may be that the majority of patients don’t even get [adjuvant therapy], and those who get it don’t seem to benefit.”
Vishwanath Sathyanarayanan, MD, PhD, Senior Consultant, Professor and Academic Advisor, Department of Medical Oncology, Apollo Cancer Centers, Bangalore, India, agreed that the study reinforces that “NCCRT continues to remain the standard of care in locally advanced resectable esophageal squamous cell carcinoma.”
Consequently, there are “no implications for clinical practice” for providers in the West from these study results, “particularly as NCCRT significantly improves outcomes vs ASCRT with a similar toxicity profile,” he said in an interview.
No funding was declared. Dr. Zhu declared no relevant financial relationships.
A version of this article appeared on Medscape.com.
confirmed the first randomized trial to directly compare the two approaches.
Yaoyao Zhu, MD, Department of Radiation Oncology, Shanghai Pulmonary Hospital, Shanghai, China, presented the new research at the annual World Conference on Lung Cancer on September 10.
Based on the findings, neoadjuvant concurrent chemoradiotherapy (NCCRT) followed by surgical resection “should be regarded as the standard of care for patients with locally advanced esophageal squamous cell carcinoma (ESCC) in the Chinese population,” Dr. Zhu said.
Different Approaches in ESCC
Dr. Zhu began her presentation by underscoring that in Western countries, NCCRT followed by surgery has been the standard treatment for locally advanced, resectable esophageal cancer since the publication of the CROSS trial in 2012, which compared neoadjuvant therapy plus surgery with surgery alone.
This demonstrated that preoperative chemoradiotherapy improved survival by 34% in patients with potentially curable esophageal or esophagogastric junction cancer, while adverse event rates were deemed “acceptable.”
In contrast, in most centers in China, clinicians opt for performing surgery followed by ASCRT.
Dr. Zhu pointed out that as previous randomized controlled trials have used surgery alone as the comparator arm, it has not been shown definitively that NCCRT plus surgery is superior to surgery followed by ASCRT.
The researchers, therefore, conducted the NEOTERIC trial, which enrolled patients with clinically resectable, locally advanced ESCC, defined as clinical stage T1-2N1M0 or T3-4N0-1M0.
They were randomized to one of two arms. The NCCRT arm involved 6 weeks of carboplatin plus paclitaxel chemotherapy alongside radiotherapy delivered as 50.4 Gy over 28 fractions. After an interval of 4-6 weeks, the patients underwent surgery, followed by an optional two cycles of carboplatin plus paclitaxel 4-6 weeks later.
In the ASCRT arm, patients underwent surgery straightaway, waited for 4-6 weeks, then had two cycles of carboplatin plus paclitaxel 3 weeks apart, followed by the same radiotherapy regimen as in the first arm. About 2-4 weeks later, patients could then undergo another two cycles of carboplatin plus paclitaxel.
More Than Doubling of Survival Outcomes
One hundred patients were assigned to NCCRT and 104 to ASCRT. There were no significant differences between the groups in terms of their baseline characteristics.
The vast majority of patients were men, just over two thirds were smokers, and the median age was around 60 years. The median tumor length was approximately 5 cm, and around half of tumors were located in the middle third of the esophagus.
Median disease-free survival was markedly longer with NCCRT, at 51.0 months vs 14.0 months in the ASCRT arm (P = .01). Similarly, median overall survival was far longer with neoadjuvant therapy, at 79.0 months, vs 38.0 months when waiting until after surgery to provide chemoradiotherapy (P = .025).
There were no significant differences in postsurgical complications between the two arms, and no significant differences in rates of grade 3-4 hematologic and nonhematologic toxicities. There were also no chemoradiotherapy-related deaths.
The most common toxicities across the two study arms were esophagitis, neutropenia, thrombocytopenia, and leukopenia.
Overall, the rates of recurrence were significantly lower with NCCRT than with ASCRT (58.0% vs 66.3%; P = .020). This included significant reductions in both locoregional (P = .012) and distant recurrence (P = .009).
Jaffer A. Ajani, MD, University of Texas MD Anderson Cancer Center, Houston, underlined that the experimental arm of the trial, with neoadjuvant chemoradiotherapy, “has been the standard of care in the United States for a long time, particularly for squamous carcinoma.”
However, he said in an interview that it is not a standard of care in China and clinicians continue with adjuvant therapy. This is despite a recent study conducted in Hong Kong that concluded that patients should not be given any treatment after surgery “because they do worse” than those given neoadjuvant therapy, he continued.
While Dr. Ajani noted that the current analysis is underpowered to provide a definitive conclusion, it remains “an important study for Chinese patients.
“Hopefully, it will be well advertised in China, and all the providers switch [to NCCRT]. This could push them to abandon what in the West was considered harmful.”
Dr. Ajani explained the reason neoadjuvant therapy performs better than adjuvant chemoradiotherapy is it “may be mopping up some of the micro metastatic disease, which is difficult to do after surgery,” especially as many patients cannot tolerate postoperative treatment.
“It may be that the majority of patients don’t even get [adjuvant therapy], and those who get it don’t seem to benefit.”
Vishwanath Sathyanarayanan, MD, PhD, Senior Consultant, Professor and Academic Advisor, Department of Medical Oncology, Apollo Cancer Centers, Bangalore, India, agreed that the study reinforces that “NCCRT continues to remain the standard of care in locally advanced resectable esophageal squamous cell carcinoma.”
Consequently, there are “no implications for clinical practice” for providers in the West from these study results, “particularly as NCCRT significantly improves outcomes vs ASCRT with a similar toxicity profile,” he said in an interview.
No funding was declared. Dr. Zhu declared no relevant financial relationships.
A version of this article appeared on Medscape.com.
confirmed the first randomized trial to directly compare the two approaches.
Yaoyao Zhu, MD, Department of Radiation Oncology, Shanghai Pulmonary Hospital, Shanghai, China, presented the new research at the annual World Conference on Lung Cancer on September 10.
Based on the findings, neoadjuvant concurrent chemoradiotherapy (NCCRT) followed by surgical resection “should be regarded as the standard of care for patients with locally advanced esophageal squamous cell carcinoma (ESCC) in the Chinese population,” Dr. Zhu said.
Different Approaches in ESCC
Dr. Zhu began her presentation by underscoring that in Western countries, NCCRT followed by surgery has been the standard treatment for locally advanced, resectable esophageal cancer since the publication of the CROSS trial in 2012, which compared neoadjuvant therapy plus surgery with surgery alone.
This demonstrated that preoperative chemoradiotherapy improved survival by 34% in patients with potentially curable esophageal or esophagogastric junction cancer, while adverse event rates were deemed “acceptable.”
In contrast, in most centers in China, clinicians opt for performing surgery followed by ASCRT.
Dr. Zhu pointed out that as previous randomized controlled trials have used surgery alone as the comparator arm, it has not been shown definitively that NCCRT plus surgery is superior to surgery followed by ASCRT.
The researchers, therefore, conducted the NEOTERIC trial, which enrolled patients with clinically resectable, locally advanced ESCC, defined as clinical stage T1-2N1M0 or T3-4N0-1M0.
They were randomized to one of two arms. The NCCRT arm involved 6 weeks of carboplatin plus paclitaxel chemotherapy alongside radiotherapy delivered as 50.4 Gy over 28 fractions. After an interval of 4-6 weeks, the patients underwent surgery, followed by an optional two cycles of carboplatin plus paclitaxel 4-6 weeks later.
In the ASCRT arm, patients underwent surgery straightaway, waited for 4-6 weeks, then had two cycles of carboplatin plus paclitaxel 3 weeks apart, followed by the same radiotherapy regimen as in the first arm. About 2-4 weeks later, patients could then undergo another two cycles of carboplatin plus paclitaxel.
More Than Doubling of Survival Outcomes
One hundred patients were assigned to NCCRT and 104 to ASCRT. There were no significant differences between the groups in terms of their baseline characteristics.
The vast majority of patients were men, just over two thirds were smokers, and the median age was around 60 years. The median tumor length was approximately 5 cm, and around half of tumors were located in the middle third of the esophagus.
Median disease-free survival was markedly longer with NCCRT, at 51.0 months vs 14.0 months in the ASCRT arm (P = .01). Similarly, median overall survival was far longer with neoadjuvant therapy, at 79.0 months, vs 38.0 months when waiting until after surgery to provide chemoradiotherapy (P = .025).
There were no significant differences in postsurgical complications between the two arms, and no significant differences in rates of grade 3-4 hematologic and nonhematologic toxicities. There were also no chemoradiotherapy-related deaths.
The most common toxicities across the two study arms were esophagitis, neutropenia, thrombocytopenia, and leukopenia.
Overall, the rates of recurrence were significantly lower with NCCRT than with ASCRT (58.0% vs 66.3%; P = .020). This included significant reductions in both locoregional (P = .012) and distant recurrence (P = .009).
Jaffer A. Ajani, MD, University of Texas MD Anderson Cancer Center, Houston, underlined that the experimental arm of the trial, with neoadjuvant chemoradiotherapy, “has been the standard of care in the United States for a long time, particularly for squamous carcinoma.”
However, he said in an interview that it is not a standard of care in China and clinicians continue with adjuvant therapy. This is despite a recent study conducted in Hong Kong that concluded that patients should not be given any treatment after surgery “because they do worse” than those given neoadjuvant therapy, he continued.
While Dr. Ajani noted that the current analysis is underpowered to provide a definitive conclusion, it remains “an important study for Chinese patients.
“Hopefully, it will be well advertised in China, and all the providers switch [to NCCRT]. This could push them to abandon what in the West was considered harmful.”
Dr. Ajani explained the reason neoadjuvant therapy performs better than adjuvant chemoradiotherapy is it “may be mopping up some of the micro metastatic disease, which is difficult to do after surgery,” especially as many patients cannot tolerate postoperative treatment.
“It may be that the majority of patients don’t even get [adjuvant therapy], and those who get it don’t seem to benefit.”
Vishwanath Sathyanarayanan, MD, PhD, Senior Consultant, Professor and Academic Advisor, Department of Medical Oncology, Apollo Cancer Centers, Bangalore, India, agreed that the study reinforces that “NCCRT continues to remain the standard of care in locally advanced resectable esophageal squamous cell carcinoma.”
Consequently, there are “no implications for clinical practice” for providers in the West from these study results, “particularly as NCCRT significantly improves outcomes vs ASCRT with a similar toxicity profile,” he said in an interview.
No funding was declared. Dr. Zhu declared no relevant financial relationships.
A version of this article appeared on Medscape.com.
FROM WCLC 2024
‘Cancer Doesn’t Wait’: How Prior Authorization Harms Care
Fantine Giap, MD, sat across from a 21-year-old with a rare sarcoma at the base of her skull.
Despite the large tumor, nestled in a sensitive area, the Boston-based radiation oncologist could envision a bright future for her patient.
She and the other members of the patient’s care team had an impressive cancer-fighting arsenal at her fingertips. The team had recommended surgery, followed by proton therapy — a sophisticated tool able to deliver concentrated, razor-focused radiation to the once apple-sized growth, while sparing the fragile brain stem, optic nerve, and spinal cord.
Surgery went as planned. But as the days and weeks wore on and insurance prior authorization for the proton therapy never came, the tumor roared back, leading to more surgeries and more complications. Ultimately, the young woman needed a tracheostomy and a feeding tube.
By the time insurance said yes, more than 1 year from her initial visit, the future the team had envisioned seemed out of reach.
“Unfortunately for this patient, it went from a potentially curable situation to a likely not curable situation,” recalled Dr. Giap, a clinician at Massachusetts General Hospital and instructor at Harvard Medical School, Boston. “I wanted to cry every day that she waited.’’
While a stark example, such insurance delays are not uncommon, according to new research published in JAMA Network Open.
Other studies have found that number to be even higher, with more than 86% of prior authorization requests ultimately approved with few changes.
‘’It gives you the idea that this entire process might be a little futile — that it’s just wasting people’s time,’’ said Fumiko Chino, MD, coauthor on the JAMA study and now an assistant professor in radiation oncology at MD Anderson Cancer Center in Houston. ‘’The problem is cancer doesn’t wait for bureaucracy.’’
Barriers at Every Step
As Dr. Chino and her study coauthors explained, advancements like intensity-modulated radiation therapy and stereotactic radiosurgery have allowed a new generation of specialists to treat previously untreatable cancers in ways that maximize tumor-killing power while minimizing collateral damage. But these tools require sophisticated planning, imaging, simulations and execution — all of which are subject to increased insurance scrutiny.
‘’We face barriers pretty much every step of the way for every patient,’’ said Dr. Chino.
To investigate how such barriers impact care, Dr. Chino and colleagues at Memorial Sloan Kettering Cancer Center — where she worked until July — looked at 206 cases in which payers denied prior authorization for radiation therapy from November 1, 2021 to December 8, 2022.
The team found that 62% were ultimately approved without any change to technique or dose, while 28% were authorized, but with lower doses or less sophisticated techniques. Four people, however, never got authorization at all — three abandoned treatment altogether, and one sought treatment at another institution.
Treatment delays ranged from 1 day to 49 days. Eighty-three patients died.
Would some of them have lived if it weren’t for prior authorization?
Dr. Chino cannot say for sure, but did note that certain cancers, like cervical cancer, can grow so quickly that every day of delayed treatment makes them harder to control.
Patients with metastatic or late-stage cancers are often denied more aggressive treatments by insurers who, in essence, “assume that they are going to die from their disease anyway,” Dr. Chino said.
She views this as tragically shortsighted.
‘’There’s actually a strong body of evidence to show that if you treat even metastatic stage IV diseases aggressively, you can prolong not just quality of life but also quantity,’’ she said.
In cases where the cancer is more localized and insurance mandates lower doses or cheaper techniques, the consequences can be equally heartbreaking.
‘’It’s like saying instead of taking an extra-strength Tylenol you can only have a baby aspirin,’’ she said. ‘’Their pain is less likely to be controlled, their disease is less likely to be controlled, and they are more likely to need retreatment.’’
Prior authorization delays can also significantly stress patients at the most vulnerable point of their lives.
In another recent study, Dr. Chino found that 69% of patients with cancer reported prior authorization-related delays in care, with one-third waiting a month or longer. One in five never got the care their doctors recommended, and 20% reported spending more than 11 hours on the phone haggling with their insurance companies.
Most patients rated the process as ‘’bad’’ or ‘’horrible,’’ and said it fueled anxiety.
Such delays can be hard on clinicians and the healthcare system too.
One 2022 study found that a typical academic radiation oncology practice spent about a half-million dollars per year seeking insurance preauthorization. Nationally, that number exceeds $40 million.
Then there is the burnout factor.
Dr. Giap, an early-career physician who specializes in rare, aggressive sarcomas, works at an institution that helped pioneer proton therapy. She says it pains her to tell a desperate patient, like the 21-year-old, who has traveled to her from out of state that they have to wait.
‘’Knowing that the majority of the cases are ultimately approved and that this wait is often unnecessary makes it even tougher,’’ she said.
Dr. Chino, a breast cancer specialist, has taken to warning patients before the alarming insurance letter arrives in the mail that their insurance may delay authorizing their care. But she tells patients that she will do everything she can to fight for them and develops a back-up plan to pivot to quickly, if needed.
‘’No one goes into medicine to spend their time talking to insurance companies,’’ said Dr. Chino.
The national trade group, America’s Health Insurance Plans (AHIP), did not return repeated requests for an interview for this story. But their official position, as stated on their website, is that “prior authorization is one of many tools health insurance providers use to promote safe, timely, evidence-based, affordable, and efficient care.”
Both Dr. Giap and Dr. Chino believe that prior authorization was developed with good intentions: to save healthcare costs and rein in treatments that don’t necessarily benefit patients.
But, in their specialty, the burden has proliferated to a point that Dr. Chino characterizes as ‘’unconscionable.’’
She believes that policy changes like the proposed Improving Seniors’ Timely Access to Care Act — which would require real-time decisions for procedures that are routinely approved — could go a long way in improving patient care.
Meanwhile, Dr. Giap said, more research and professional guidelines are necessary to bolster insurance company confidence in newer technologies, particularly for rare cancers.
Her patient ultimately got her proton therapy and is ‘’doing relatively well, all things considered.’’
But not all the stories end like this.
Dr. Chino will never forget a patient with a cancer growing so rapidly she could see it protruding through her chest wall. She called for an urgent PET scan to see where else in the body the cancer might be brewing and rushed the planning process for radiation therapy, both of which faced prior authorization barriers. That scan — which ultimately showed the cancer had spread — was delayed for months.*
If the team had had those imaging results upfront, she said, they would have recommended a completely different course of treatment.
And her patient might be alive today.
‘’Unfortunately,” Dr. Chino said, “the people with the very worst prior authorization stories aren’t here anymore to tell you about them.”
*Correction, 10/4/24: An earlier version of this article erroneously stated that Dr. Chino called for surgery for her patient. She actually called for a PET scan and an urgent radiation start.
A version of this article first appeared on Medscape.com.
Fantine Giap, MD, sat across from a 21-year-old with a rare sarcoma at the base of her skull.
Despite the large tumor, nestled in a sensitive area, the Boston-based radiation oncologist could envision a bright future for her patient.
She and the other members of the patient’s care team had an impressive cancer-fighting arsenal at her fingertips. The team had recommended surgery, followed by proton therapy — a sophisticated tool able to deliver concentrated, razor-focused radiation to the once apple-sized growth, while sparing the fragile brain stem, optic nerve, and spinal cord.
Surgery went as planned. But as the days and weeks wore on and insurance prior authorization for the proton therapy never came, the tumor roared back, leading to more surgeries and more complications. Ultimately, the young woman needed a tracheostomy and a feeding tube.
By the time insurance said yes, more than 1 year from her initial visit, the future the team had envisioned seemed out of reach.
“Unfortunately for this patient, it went from a potentially curable situation to a likely not curable situation,” recalled Dr. Giap, a clinician at Massachusetts General Hospital and instructor at Harvard Medical School, Boston. “I wanted to cry every day that she waited.’’
While a stark example, such insurance delays are not uncommon, according to new research published in JAMA Network Open.
Other studies have found that number to be even higher, with more than 86% of prior authorization requests ultimately approved with few changes.
‘’It gives you the idea that this entire process might be a little futile — that it’s just wasting people’s time,’’ said Fumiko Chino, MD, coauthor on the JAMA study and now an assistant professor in radiation oncology at MD Anderson Cancer Center in Houston. ‘’The problem is cancer doesn’t wait for bureaucracy.’’
Barriers at Every Step
As Dr. Chino and her study coauthors explained, advancements like intensity-modulated radiation therapy and stereotactic radiosurgery have allowed a new generation of specialists to treat previously untreatable cancers in ways that maximize tumor-killing power while minimizing collateral damage. But these tools require sophisticated planning, imaging, simulations and execution — all of which are subject to increased insurance scrutiny.
‘’We face barriers pretty much every step of the way for every patient,’’ said Dr. Chino.
To investigate how such barriers impact care, Dr. Chino and colleagues at Memorial Sloan Kettering Cancer Center — where she worked until July — looked at 206 cases in which payers denied prior authorization for radiation therapy from November 1, 2021 to December 8, 2022.
The team found that 62% were ultimately approved without any change to technique or dose, while 28% were authorized, but with lower doses or less sophisticated techniques. Four people, however, never got authorization at all — three abandoned treatment altogether, and one sought treatment at another institution.
Treatment delays ranged from 1 day to 49 days. Eighty-three patients died.
Would some of them have lived if it weren’t for prior authorization?
Dr. Chino cannot say for sure, but did note that certain cancers, like cervical cancer, can grow so quickly that every day of delayed treatment makes them harder to control.
Patients with metastatic or late-stage cancers are often denied more aggressive treatments by insurers who, in essence, “assume that they are going to die from their disease anyway,” Dr. Chino said.
She views this as tragically shortsighted.
‘’There’s actually a strong body of evidence to show that if you treat even metastatic stage IV diseases aggressively, you can prolong not just quality of life but also quantity,’’ she said.
In cases where the cancer is more localized and insurance mandates lower doses or cheaper techniques, the consequences can be equally heartbreaking.
‘’It’s like saying instead of taking an extra-strength Tylenol you can only have a baby aspirin,’’ she said. ‘’Their pain is less likely to be controlled, their disease is less likely to be controlled, and they are more likely to need retreatment.’’
Prior authorization delays can also significantly stress patients at the most vulnerable point of their lives.
In another recent study, Dr. Chino found that 69% of patients with cancer reported prior authorization-related delays in care, with one-third waiting a month or longer. One in five never got the care their doctors recommended, and 20% reported spending more than 11 hours on the phone haggling with their insurance companies.
Most patients rated the process as ‘’bad’’ or ‘’horrible,’’ and said it fueled anxiety.
Such delays can be hard on clinicians and the healthcare system too.
One 2022 study found that a typical academic radiation oncology practice spent about a half-million dollars per year seeking insurance preauthorization. Nationally, that number exceeds $40 million.
Then there is the burnout factor.
Dr. Giap, an early-career physician who specializes in rare, aggressive sarcomas, works at an institution that helped pioneer proton therapy. She says it pains her to tell a desperate patient, like the 21-year-old, who has traveled to her from out of state that they have to wait.
‘’Knowing that the majority of the cases are ultimately approved and that this wait is often unnecessary makes it even tougher,’’ she said.
Dr. Chino, a breast cancer specialist, has taken to warning patients before the alarming insurance letter arrives in the mail that their insurance may delay authorizing their care. But she tells patients that she will do everything she can to fight for them and develops a back-up plan to pivot to quickly, if needed.
‘’No one goes into medicine to spend their time talking to insurance companies,’’ said Dr. Chino.
The national trade group, America’s Health Insurance Plans (AHIP), did not return repeated requests for an interview for this story. But their official position, as stated on their website, is that “prior authorization is one of many tools health insurance providers use to promote safe, timely, evidence-based, affordable, and efficient care.”
Both Dr. Giap and Dr. Chino believe that prior authorization was developed with good intentions: to save healthcare costs and rein in treatments that don’t necessarily benefit patients.
But, in their specialty, the burden has proliferated to a point that Dr. Chino characterizes as ‘’unconscionable.’’
She believes that policy changes like the proposed Improving Seniors’ Timely Access to Care Act — which would require real-time decisions for procedures that are routinely approved — could go a long way in improving patient care.
Meanwhile, Dr. Giap said, more research and professional guidelines are necessary to bolster insurance company confidence in newer technologies, particularly for rare cancers.
Her patient ultimately got her proton therapy and is ‘’doing relatively well, all things considered.’’
But not all the stories end like this.
Dr. Chino will never forget a patient with a cancer growing so rapidly she could see it protruding through her chest wall. She called for an urgent PET scan to see where else in the body the cancer might be brewing and rushed the planning process for radiation therapy, both of which faced prior authorization barriers. That scan — which ultimately showed the cancer had spread — was delayed for months.*
If the team had had those imaging results upfront, she said, they would have recommended a completely different course of treatment.
And her patient might be alive today.
‘’Unfortunately,” Dr. Chino said, “the people with the very worst prior authorization stories aren’t here anymore to tell you about them.”
*Correction, 10/4/24: An earlier version of this article erroneously stated that Dr. Chino called for surgery for her patient. She actually called for a PET scan and an urgent radiation start.
A version of this article first appeared on Medscape.com.
Fantine Giap, MD, sat across from a 21-year-old with a rare sarcoma at the base of her skull.
Despite the large tumor, nestled in a sensitive area, the Boston-based radiation oncologist could envision a bright future for her patient.
She and the other members of the patient’s care team had an impressive cancer-fighting arsenal at her fingertips. The team had recommended surgery, followed by proton therapy — a sophisticated tool able to deliver concentrated, razor-focused radiation to the once apple-sized growth, while sparing the fragile brain stem, optic nerve, and spinal cord.
Surgery went as planned. But as the days and weeks wore on and insurance prior authorization for the proton therapy never came, the tumor roared back, leading to more surgeries and more complications. Ultimately, the young woman needed a tracheostomy and a feeding tube.
By the time insurance said yes, more than 1 year from her initial visit, the future the team had envisioned seemed out of reach.
“Unfortunately for this patient, it went from a potentially curable situation to a likely not curable situation,” recalled Dr. Giap, a clinician at Massachusetts General Hospital and instructor at Harvard Medical School, Boston. “I wanted to cry every day that she waited.’’
While a stark example, such insurance delays are not uncommon, according to new research published in JAMA Network Open.
Other studies have found that number to be even higher, with more than 86% of prior authorization requests ultimately approved with few changes.
‘’It gives you the idea that this entire process might be a little futile — that it’s just wasting people’s time,’’ said Fumiko Chino, MD, coauthor on the JAMA study and now an assistant professor in radiation oncology at MD Anderson Cancer Center in Houston. ‘’The problem is cancer doesn’t wait for bureaucracy.’’
Barriers at Every Step
As Dr. Chino and her study coauthors explained, advancements like intensity-modulated radiation therapy and stereotactic radiosurgery have allowed a new generation of specialists to treat previously untreatable cancers in ways that maximize tumor-killing power while minimizing collateral damage. But these tools require sophisticated planning, imaging, simulations and execution — all of which are subject to increased insurance scrutiny.
‘’We face barriers pretty much every step of the way for every patient,’’ said Dr. Chino.
To investigate how such barriers impact care, Dr. Chino and colleagues at Memorial Sloan Kettering Cancer Center — where she worked until July — looked at 206 cases in which payers denied prior authorization for radiation therapy from November 1, 2021 to December 8, 2022.
The team found that 62% were ultimately approved without any change to technique or dose, while 28% were authorized, but with lower doses or less sophisticated techniques. Four people, however, never got authorization at all — three abandoned treatment altogether, and one sought treatment at another institution.
Treatment delays ranged from 1 day to 49 days. Eighty-three patients died.
Would some of them have lived if it weren’t for prior authorization?
Dr. Chino cannot say for sure, but did note that certain cancers, like cervical cancer, can grow so quickly that every day of delayed treatment makes them harder to control.
Patients with metastatic or late-stage cancers are often denied more aggressive treatments by insurers who, in essence, “assume that they are going to die from their disease anyway,” Dr. Chino said.
She views this as tragically shortsighted.
‘’There’s actually a strong body of evidence to show that if you treat even metastatic stage IV diseases aggressively, you can prolong not just quality of life but also quantity,’’ she said.
In cases where the cancer is more localized and insurance mandates lower doses or cheaper techniques, the consequences can be equally heartbreaking.
‘’It’s like saying instead of taking an extra-strength Tylenol you can only have a baby aspirin,’’ she said. ‘’Their pain is less likely to be controlled, their disease is less likely to be controlled, and they are more likely to need retreatment.’’
Prior authorization delays can also significantly stress patients at the most vulnerable point of their lives.
In another recent study, Dr. Chino found that 69% of patients with cancer reported prior authorization-related delays in care, with one-third waiting a month or longer. One in five never got the care their doctors recommended, and 20% reported spending more than 11 hours on the phone haggling with their insurance companies.
Most patients rated the process as ‘’bad’’ or ‘’horrible,’’ and said it fueled anxiety.
Such delays can be hard on clinicians and the healthcare system too.
One 2022 study found that a typical academic radiation oncology practice spent about a half-million dollars per year seeking insurance preauthorization. Nationally, that number exceeds $40 million.
Then there is the burnout factor.
Dr. Giap, an early-career physician who specializes in rare, aggressive sarcomas, works at an institution that helped pioneer proton therapy. She says it pains her to tell a desperate patient, like the 21-year-old, who has traveled to her from out of state that they have to wait.
‘’Knowing that the majority of the cases are ultimately approved and that this wait is often unnecessary makes it even tougher,’’ she said.
Dr. Chino, a breast cancer specialist, has taken to warning patients before the alarming insurance letter arrives in the mail that their insurance may delay authorizing their care. But she tells patients that she will do everything she can to fight for them and develops a back-up plan to pivot to quickly, if needed.
‘’No one goes into medicine to spend their time talking to insurance companies,’’ said Dr. Chino.
The national trade group, America’s Health Insurance Plans (AHIP), did not return repeated requests for an interview for this story. But their official position, as stated on their website, is that “prior authorization is one of many tools health insurance providers use to promote safe, timely, evidence-based, affordable, and efficient care.”
Both Dr. Giap and Dr. Chino believe that prior authorization was developed with good intentions: to save healthcare costs and rein in treatments that don’t necessarily benefit patients.
But, in their specialty, the burden has proliferated to a point that Dr. Chino characterizes as ‘’unconscionable.’’
She believes that policy changes like the proposed Improving Seniors’ Timely Access to Care Act — which would require real-time decisions for procedures that are routinely approved — could go a long way in improving patient care.
Meanwhile, Dr. Giap said, more research and professional guidelines are necessary to bolster insurance company confidence in newer technologies, particularly for rare cancers.
Her patient ultimately got her proton therapy and is ‘’doing relatively well, all things considered.’’
But not all the stories end like this.
Dr. Chino will never forget a patient with a cancer growing so rapidly she could see it protruding through her chest wall. She called for an urgent PET scan to see where else in the body the cancer might be brewing and rushed the planning process for radiation therapy, both of which faced prior authorization barriers. That scan — which ultimately showed the cancer had spread — was delayed for months.*
If the team had had those imaging results upfront, she said, they would have recommended a completely different course of treatment.
And her patient might be alive today.
‘’Unfortunately,” Dr. Chino said, “the people with the very worst prior authorization stories aren’t here anymore to tell you about them.”
*Correction, 10/4/24: An earlier version of this article erroneously stated that Dr. Chino called for surgery for her patient. She actually called for a PET scan and an urgent radiation start.
A version of this article first appeared on Medscape.com.
FROM JAMA NETWORK OPEN
Popular Weight Loss Drugs Now for Patients With Cancer?
Demand for new weight loss drugs has surged over the past few years.
Led by the antiobesity drugs semaglutide (Wegovy) and tirzepatide (Zepbound), these popular medications — more commonly known as glucagon-like peptide 1 (GLP-1) agonists — have become game changers for shedding excess pounds.
Aside from obesity indications, both drugs have been approved to treat type 2 diabetes under different brand names and have a growing list of other potential benefits, such as reducing inflammation and depression.
While there’s limited data to support the use of GLP-1 agonists for weight loss in cancer, some oncologists have begun carefully integrating the antiobesity agents into care and studying their effects in this patient population.
The reason: Research suggests that obesity can reduce the effectiveness of cancer therapies, especially in patients with breast cancer, and can increase the risk for treatment-related side effects.
The idea is that managing patients’ weight will improve their cancer outcomes, explained Lajos Pusztai, MD, PhD, a breast cancer specialist and professor of medicine at Yale School of Medicine in New Haven, Connecticut.
Although Dr. Pusztai and his oncology peers at Yale don’t yet use GPL-1 agonists, Neil Iyengar, MD, and colleagues have begun doing so to help some patients with breast cancer manage their weight. Dr. Iyengar estimates that a few hundred — almost 40% — of his patients are on the antiobesity drugs.
“For a patient who has really tried to reduce their weight and who is in the obese range, that’s where I think the use of these medications can be considered,” said Dr. Iyengar, a breast cancer oncologist at Memorial Sloan Kettering Cancer Center in New York City.
Why GLP-1s in Cancer?
GLP-1 is a hormone that the small intestine releases after eating. GLP-1 agonists work by mimicking GLP-1 to trigger the release of insulin and reduce the production of glucagon — two processes that help regulate blood sugar.
These agents, such as Wegovy (or Ozempic when prescribed for diabetes), also slow gastric emptying and can make people feel fuller longer.
Zebound (or Mounjaro for type 2 diabetes) is considered a dual GLP-1 and glucose-dependent insulinotropic polypeptide agonist, which may enhance its weight loss benefits.
In practice, however, these drugs can increase nausea and vomiting from chemotherapy, so Dr. Iyengar typically has patients use them afterwards, during maintenance treatment.
Oncologists don’t prescribe the drugs themselves but instead refer patients to endocrinologists or weight management centers that then write the prescriptions. Taking these drugs involves weekly subcutaneous injections patients can administer themselves.
Endocrinologist Emily Gallagher, MD, PhD, of Mount Sinai Hospital in New York City, estimates she has prescribed the antiobesity drugs to a few hundred patients with cancer and, like Dr. Iyengar, uses the drugs during maintenance treatment with hormone therapy for breast cancer. She also has used these agents in patients with prostate and endometrial cancers and has found the drugs can help counter steroid weight gain in multiple myeloma.
But, to date, the evidence for using GPL-1 agonists in cancer remains limited and the practice has not yet become widespread.
Research largely comes down to a few small retrospective studies in patients with breast cancer receiving aromatase inhibitors. Although no safety issues have emerged so far, these initial reports suggest that the drugs lead to significantly less weight loss in patients with cancer compared to the general population.
Dr. Iyengar led one recent study, presented at the 2024 annual meeting of the American Society of Clinical Oncology, in which he and his team assessed outcomes in 75 women with breast cancer who received a GLP-1 agonist. Almost 80% of patients had diabetes, and 60% received hormone therapy, most commonly an aromatase inhibitor. Patients’ median body mass index (BMI) at baseline was 34 kg/m2 (range, 23-50 kg/m2).
From baseline, patients lost 6.2 kg, on average, or about 5% of their total body weight, 12 months after initiating GLP-1 therapy.
In contrast, phase 3 trials show much higher mean weight loss — about two times — in patients without cancer.
Another recent study also reported modest weight loss results in patients with breast cancer undergoing endocrine therapy. The researchers reported that, at 12 months, Wegovy led to 4.34% reduction in BMI, compared with a 14% change reported in the general population. Zebound, however, was associated with a 2.31% BMI increase overall — though some patients did experience a decrease — compared with a 15% reduction in the general population.
“These findings indicate a substantially reduced weight loss efficacy in breast cancer patients on endocrine therapy compared to the general population,” the authors concluded.
It’s unclear why the drugs appear to not work as well in patients with cancer. It’s possible that hormone therapy or metabolic changes interfere with their effectiveness, given that some cancer therapies lead to weight gain. Steroids and hormone therapies, for instance, often increase appetite, and some treatments can slow patients’ metabolism or lead to fatigue, which can make it harder to exercise.
Patients with cancer may need a higher dose of GLP-1 agonists to achieve similar weight loss to the general population, Dr. Iyengar noted.
However, Dr. Gallagher said, in her own experience, she hasn’t found the drugs to be less effective in patients with cancer, especially the newer agents, like Wegovy and Zepbound.
As for safety, Wegovy and Zepbound both carry a black box warning for thyroid C-cell tumors, including medullary thyroid carcinoma. (Recent research, however, has found that GLP-1 agonists do not increase thyroid cancer risk).
These antiobesity agents are also contraindicated in patients with a personal or family history of medullary thyroid carcinoma and in patients who have multiple endocrine neoplasia syndrome type 2, which is associated with medullary thyroid carcinoma.
Dr. Gallagher hasn’t seen any secondary tumors — thyroid or otherwise — in her patients with cancer, but she follows the labeling contraindications. Dr. Iyengar also noted that more recent and larger data sets have shown no impact on this risk, which may not actually exist, he said
Dr. Gallagher remains cautious about using GPL-1 agonists in patients who have had bariatric surgery because these agents can compound the slower gastric emptying and intestinal transit from surgery, potentially leading to gastrointestinal obstructions.
Looking ahead, GPL-1 manufacturers are interested in adding cancer indications to the drug labeling. Both Dr. Iyengar and Dr. Gallagher said their institutions are in talks with companies to participate in large, multicenter, global phase 3 trials.
Dr. Iyengar welcomes the efforts, not only to test the effectiveness of GPL-1 agonists in oncology but also to “nail down” their safety in cancer.
“I don’t think that there’s mechanistically anything that’s particularly worrisome,” and current observations suggest that these drugs are likely to be safe, Dr. Iyengar said. Even so, “GLP-1 agonists do a lot of things that we don’t fully understand yet.”
The bigger challenge, Dr. Iyengar noted, is that companies will have to show a sizable benefit to using these drugs in patients with cancer to get the Food and Drug Administration’s approval. And to move the needle on cancer-specific outcomes, these antiobesity drugs will need to demonstrate significant, durable weight loss in patients with cancer.
But if these drugs can do that, “I think it’s going to be one of the biggest advances in medicine and oncology given the obesity and cancer epidemic,” Dr. Iyengar said.
Dr. Iyengar has adviser and/or researcher ties with companies that make or are developing GPL-1 agonists, including AstraZeneca, Novartis, Gilead, and Pfizer. Dr. Gallagher is a consultant for Novartis, Flare Therapeutics, Reactive Biosciences, and Seagen.
A version of this article first appeared on Medscape.com.
Demand for new weight loss drugs has surged over the past few years.
Led by the antiobesity drugs semaglutide (Wegovy) and tirzepatide (Zepbound), these popular medications — more commonly known as glucagon-like peptide 1 (GLP-1) agonists — have become game changers for shedding excess pounds.
Aside from obesity indications, both drugs have been approved to treat type 2 diabetes under different brand names and have a growing list of other potential benefits, such as reducing inflammation and depression.
While there’s limited data to support the use of GLP-1 agonists for weight loss in cancer, some oncologists have begun carefully integrating the antiobesity agents into care and studying their effects in this patient population.
The reason: Research suggests that obesity can reduce the effectiveness of cancer therapies, especially in patients with breast cancer, and can increase the risk for treatment-related side effects.
The idea is that managing patients’ weight will improve their cancer outcomes, explained Lajos Pusztai, MD, PhD, a breast cancer specialist and professor of medicine at Yale School of Medicine in New Haven, Connecticut.
Although Dr. Pusztai and his oncology peers at Yale don’t yet use GPL-1 agonists, Neil Iyengar, MD, and colleagues have begun doing so to help some patients with breast cancer manage their weight. Dr. Iyengar estimates that a few hundred — almost 40% — of his patients are on the antiobesity drugs.
“For a patient who has really tried to reduce their weight and who is in the obese range, that’s where I think the use of these medications can be considered,” said Dr. Iyengar, a breast cancer oncologist at Memorial Sloan Kettering Cancer Center in New York City.
Why GLP-1s in Cancer?
GLP-1 is a hormone that the small intestine releases after eating. GLP-1 agonists work by mimicking GLP-1 to trigger the release of insulin and reduce the production of glucagon — two processes that help regulate blood sugar.
These agents, such as Wegovy (or Ozempic when prescribed for diabetes), also slow gastric emptying and can make people feel fuller longer.
Zebound (or Mounjaro for type 2 diabetes) is considered a dual GLP-1 and glucose-dependent insulinotropic polypeptide agonist, which may enhance its weight loss benefits.
In practice, however, these drugs can increase nausea and vomiting from chemotherapy, so Dr. Iyengar typically has patients use them afterwards, during maintenance treatment.
Oncologists don’t prescribe the drugs themselves but instead refer patients to endocrinologists or weight management centers that then write the prescriptions. Taking these drugs involves weekly subcutaneous injections patients can administer themselves.
Endocrinologist Emily Gallagher, MD, PhD, of Mount Sinai Hospital in New York City, estimates she has prescribed the antiobesity drugs to a few hundred patients with cancer and, like Dr. Iyengar, uses the drugs during maintenance treatment with hormone therapy for breast cancer. She also has used these agents in patients with prostate and endometrial cancers and has found the drugs can help counter steroid weight gain in multiple myeloma.
But, to date, the evidence for using GPL-1 agonists in cancer remains limited and the practice has not yet become widespread.
Research largely comes down to a few small retrospective studies in patients with breast cancer receiving aromatase inhibitors. Although no safety issues have emerged so far, these initial reports suggest that the drugs lead to significantly less weight loss in patients with cancer compared to the general population.
Dr. Iyengar led one recent study, presented at the 2024 annual meeting of the American Society of Clinical Oncology, in which he and his team assessed outcomes in 75 women with breast cancer who received a GLP-1 agonist. Almost 80% of patients had diabetes, and 60% received hormone therapy, most commonly an aromatase inhibitor. Patients’ median body mass index (BMI) at baseline was 34 kg/m2 (range, 23-50 kg/m2).
From baseline, patients lost 6.2 kg, on average, or about 5% of their total body weight, 12 months after initiating GLP-1 therapy.
In contrast, phase 3 trials show much higher mean weight loss — about two times — in patients without cancer.
Another recent study also reported modest weight loss results in patients with breast cancer undergoing endocrine therapy. The researchers reported that, at 12 months, Wegovy led to 4.34% reduction in BMI, compared with a 14% change reported in the general population. Zebound, however, was associated with a 2.31% BMI increase overall — though some patients did experience a decrease — compared with a 15% reduction in the general population.
“These findings indicate a substantially reduced weight loss efficacy in breast cancer patients on endocrine therapy compared to the general population,” the authors concluded.
It’s unclear why the drugs appear to not work as well in patients with cancer. It’s possible that hormone therapy or metabolic changes interfere with their effectiveness, given that some cancer therapies lead to weight gain. Steroids and hormone therapies, for instance, often increase appetite, and some treatments can slow patients’ metabolism or lead to fatigue, which can make it harder to exercise.
Patients with cancer may need a higher dose of GLP-1 agonists to achieve similar weight loss to the general population, Dr. Iyengar noted.
However, Dr. Gallagher said, in her own experience, she hasn’t found the drugs to be less effective in patients with cancer, especially the newer agents, like Wegovy and Zepbound.
As for safety, Wegovy and Zepbound both carry a black box warning for thyroid C-cell tumors, including medullary thyroid carcinoma. (Recent research, however, has found that GLP-1 agonists do not increase thyroid cancer risk).
These antiobesity agents are also contraindicated in patients with a personal or family history of medullary thyroid carcinoma and in patients who have multiple endocrine neoplasia syndrome type 2, which is associated with medullary thyroid carcinoma.
Dr. Gallagher hasn’t seen any secondary tumors — thyroid or otherwise — in her patients with cancer, but she follows the labeling contraindications. Dr. Iyengar also noted that more recent and larger data sets have shown no impact on this risk, which may not actually exist, he said
Dr. Gallagher remains cautious about using GPL-1 agonists in patients who have had bariatric surgery because these agents can compound the slower gastric emptying and intestinal transit from surgery, potentially leading to gastrointestinal obstructions.
Looking ahead, GPL-1 manufacturers are interested in adding cancer indications to the drug labeling. Both Dr. Iyengar and Dr. Gallagher said their institutions are in talks with companies to participate in large, multicenter, global phase 3 trials.
Dr. Iyengar welcomes the efforts, not only to test the effectiveness of GPL-1 agonists in oncology but also to “nail down” their safety in cancer.
“I don’t think that there’s mechanistically anything that’s particularly worrisome,” and current observations suggest that these drugs are likely to be safe, Dr. Iyengar said. Even so, “GLP-1 agonists do a lot of things that we don’t fully understand yet.”
The bigger challenge, Dr. Iyengar noted, is that companies will have to show a sizable benefit to using these drugs in patients with cancer to get the Food and Drug Administration’s approval. And to move the needle on cancer-specific outcomes, these antiobesity drugs will need to demonstrate significant, durable weight loss in patients with cancer.
But if these drugs can do that, “I think it’s going to be one of the biggest advances in medicine and oncology given the obesity and cancer epidemic,” Dr. Iyengar said.
Dr. Iyengar has adviser and/or researcher ties with companies that make or are developing GPL-1 agonists, including AstraZeneca, Novartis, Gilead, and Pfizer. Dr. Gallagher is a consultant for Novartis, Flare Therapeutics, Reactive Biosciences, and Seagen.
A version of this article first appeared on Medscape.com.
Demand for new weight loss drugs has surged over the past few years.
Led by the antiobesity drugs semaglutide (Wegovy) and tirzepatide (Zepbound), these popular medications — more commonly known as glucagon-like peptide 1 (GLP-1) agonists — have become game changers for shedding excess pounds.
Aside from obesity indications, both drugs have been approved to treat type 2 diabetes under different brand names and have a growing list of other potential benefits, such as reducing inflammation and depression.
While there’s limited data to support the use of GLP-1 agonists for weight loss in cancer, some oncologists have begun carefully integrating the antiobesity agents into care and studying their effects in this patient population.
The reason: Research suggests that obesity can reduce the effectiveness of cancer therapies, especially in patients with breast cancer, and can increase the risk for treatment-related side effects.
The idea is that managing patients’ weight will improve their cancer outcomes, explained Lajos Pusztai, MD, PhD, a breast cancer specialist and professor of medicine at Yale School of Medicine in New Haven, Connecticut.
Although Dr. Pusztai and his oncology peers at Yale don’t yet use GPL-1 agonists, Neil Iyengar, MD, and colleagues have begun doing so to help some patients with breast cancer manage their weight. Dr. Iyengar estimates that a few hundred — almost 40% — of his patients are on the antiobesity drugs.
“For a patient who has really tried to reduce their weight and who is in the obese range, that’s where I think the use of these medications can be considered,” said Dr. Iyengar, a breast cancer oncologist at Memorial Sloan Kettering Cancer Center in New York City.
Why GLP-1s in Cancer?
GLP-1 is a hormone that the small intestine releases after eating. GLP-1 agonists work by mimicking GLP-1 to trigger the release of insulin and reduce the production of glucagon — two processes that help regulate blood sugar.
These agents, such as Wegovy (or Ozempic when prescribed for diabetes), also slow gastric emptying and can make people feel fuller longer.
Zebound (or Mounjaro for type 2 diabetes) is considered a dual GLP-1 and glucose-dependent insulinotropic polypeptide agonist, which may enhance its weight loss benefits.
In practice, however, these drugs can increase nausea and vomiting from chemotherapy, so Dr. Iyengar typically has patients use them afterwards, during maintenance treatment.
Oncologists don’t prescribe the drugs themselves but instead refer patients to endocrinologists or weight management centers that then write the prescriptions. Taking these drugs involves weekly subcutaneous injections patients can administer themselves.
Endocrinologist Emily Gallagher, MD, PhD, of Mount Sinai Hospital in New York City, estimates she has prescribed the antiobesity drugs to a few hundred patients with cancer and, like Dr. Iyengar, uses the drugs during maintenance treatment with hormone therapy for breast cancer. She also has used these agents in patients with prostate and endometrial cancers and has found the drugs can help counter steroid weight gain in multiple myeloma.
But, to date, the evidence for using GPL-1 agonists in cancer remains limited and the practice has not yet become widespread.
Research largely comes down to a few small retrospective studies in patients with breast cancer receiving aromatase inhibitors. Although no safety issues have emerged so far, these initial reports suggest that the drugs lead to significantly less weight loss in patients with cancer compared to the general population.
Dr. Iyengar led one recent study, presented at the 2024 annual meeting of the American Society of Clinical Oncology, in which he and his team assessed outcomes in 75 women with breast cancer who received a GLP-1 agonist. Almost 80% of patients had diabetes, and 60% received hormone therapy, most commonly an aromatase inhibitor. Patients’ median body mass index (BMI) at baseline was 34 kg/m2 (range, 23-50 kg/m2).
From baseline, patients lost 6.2 kg, on average, or about 5% of their total body weight, 12 months after initiating GLP-1 therapy.
In contrast, phase 3 trials show much higher mean weight loss — about two times — in patients without cancer.
Another recent study also reported modest weight loss results in patients with breast cancer undergoing endocrine therapy. The researchers reported that, at 12 months, Wegovy led to 4.34% reduction in BMI, compared with a 14% change reported in the general population. Zebound, however, was associated with a 2.31% BMI increase overall — though some patients did experience a decrease — compared with a 15% reduction in the general population.
“These findings indicate a substantially reduced weight loss efficacy in breast cancer patients on endocrine therapy compared to the general population,” the authors concluded.
It’s unclear why the drugs appear to not work as well in patients with cancer. It’s possible that hormone therapy or metabolic changes interfere with their effectiveness, given that some cancer therapies lead to weight gain. Steroids and hormone therapies, for instance, often increase appetite, and some treatments can slow patients’ metabolism or lead to fatigue, which can make it harder to exercise.
Patients with cancer may need a higher dose of GLP-1 agonists to achieve similar weight loss to the general population, Dr. Iyengar noted.
However, Dr. Gallagher said, in her own experience, she hasn’t found the drugs to be less effective in patients with cancer, especially the newer agents, like Wegovy and Zepbound.
As for safety, Wegovy and Zepbound both carry a black box warning for thyroid C-cell tumors, including medullary thyroid carcinoma. (Recent research, however, has found that GLP-1 agonists do not increase thyroid cancer risk).
These antiobesity agents are also contraindicated in patients with a personal or family history of medullary thyroid carcinoma and in patients who have multiple endocrine neoplasia syndrome type 2, which is associated with medullary thyroid carcinoma.
Dr. Gallagher hasn’t seen any secondary tumors — thyroid or otherwise — in her patients with cancer, but she follows the labeling contraindications. Dr. Iyengar also noted that more recent and larger data sets have shown no impact on this risk, which may not actually exist, he said
Dr. Gallagher remains cautious about using GPL-1 agonists in patients who have had bariatric surgery because these agents can compound the slower gastric emptying and intestinal transit from surgery, potentially leading to gastrointestinal obstructions.
Looking ahead, GPL-1 manufacturers are interested in adding cancer indications to the drug labeling. Both Dr. Iyengar and Dr. Gallagher said their institutions are in talks with companies to participate in large, multicenter, global phase 3 trials.
Dr. Iyengar welcomes the efforts, not only to test the effectiveness of GPL-1 agonists in oncology but also to “nail down” their safety in cancer.
“I don’t think that there’s mechanistically anything that’s particularly worrisome,” and current observations suggest that these drugs are likely to be safe, Dr. Iyengar said. Even so, “GLP-1 agonists do a lot of things that we don’t fully understand yet.”
The bigger challenge, Dr. Iyengar noted, is that companies will have to show a sizable benefit to using these drugs in patients with cancer to get the Food and Drug Administration’s approval. And to move the needle on cancer-specific outcomes, these antiobesity drugs will need to demonstrate significant, durable weight loss in patients with cancer.
But if these drugs can do that, “I think it’s going to be one of the biggest advances in medicine and oncology given the obesity and cancer epidemic,” Dr. Iyengar said.
Dr. Iyengar has adviser and/or researcher ties with companies that make or are developing GPL-1 agonists, including AstraZeneca, Novartis, Gilead, and Pfizer. Dr. Gallagher is a consultant for Novartis, Flare Therapeutics, Reactive Biosciences, and Seagen.
A version of this article first appeared on Medscape.com.
FDA Panel Votes for Limits on Gastric, Esophageal Cancer Immunotherapy
During the meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted in favor of restricting the use of these immunotherapy agents to patients with programmed death-ligand 1 (PD-L1) expression of 1% or higher.
The agency usually follows the ODAC’s advice.
The FDA had originally approved the two immune checkpoint inhibitors for both indications in combination with chemotherapy, regardless of patients’ PD-L1 status. The FDA had also approved nivolumab in combination with ipilimumab for esophageal cancer, regardless of PD-L1 expression. The approvals were based on overall benefit in intent-to-treat populations, not on specific PD-L1 expression subgroups.
Since then, additional studies — including the agency’s own pooled analyses of the approval trials — have found that overall survival benefits are limited to patients with PD-L1 expression of 1% or higher.
These findings have raised concerns that patients with no or low PD-L1 expression face the risks associated with immunotherapy, which include death, but minimal to no benefits.
In response, the FDA has considered changing the labeling for these indications to require a PD-L1 cutoff point of 1% or higher. The move would mirror guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network that already recommend use with chemotherapy only at certain PD-L1 cutoffs.
Before the agency acts, however, the FDA wanted the advice of the ODAC. It asked the 14-member panel whether the risk-benefit assessment is “favorable for the use of PD-1 inhibitors in first line” for the two indications among patients with PD-L1 expression below 1%.
In two nearly unanimous decisions for each indication, the panel voted that risk-benefit assessment was not favorable. In other words, the risks do outweigh the benefits for this patient population with no or low PD-L1 expression.
The determination also applies to tislelizumab (Tevimbra), an immune checkpoint inhibitor under review by the FDA for the same indications.
Voting came after hours of testimony from FDA scientists and the three drug companies involved in the decisions.
Merck, maker of pembrolizumab, was against any labeling change. Nivolumab’s maker, Bristol Myers Squibb (BMS), also wanted to stick with the current PD-L1 agnostic indications but said that any indication change should be class-wide to avoid confusion. BeiGene USA, maker of tislelizumab, had no problem with a PD-L1 cutoff of 1% because its approval trial showed benefit only in patients at that level or higher.
In general, Merck and BMS said the drug benefits correspond with higher PD-L1 expression but noted that patients with low or no PD-L1 expression can sometimes benefit from treatment. The companies had several patients testify to the benefits of the agents and noted patients like this would likely lose access. But an ODAC panelist noted that patients who died from immunotherapy complications weren’t there to respond.
The companies also expressed concern about taking treatment decisions out of the hands of oncologists as well as the need for additional biopsies to determine if tumors cross the proposed PD-L1 threshold at some point during treatment. With this potential new restriction, the companies were worried that insurance companies would be even less likely to pay for their checkpoint inhibitors in low or no PD-L1 expressors.
ODAC wasn’t moved. With consistent findings across multiple trials, the strength of the FDA’s data carried the day.
In a pooled analysis of the three companies’ unresectable or metastatic HER2–negative, microsatellite-stable gastric/gastroesophageal adenocarcinoma approval trials across almost 4000 patients, those with PD-L1 levels below 1% did not demonstrate a significant overall survival benefit (hazard ratio [HR], 0.91; 95% CI, 0.75-1.09). The median overall survival with immunotherapy plus chemotherapy was only 1 month more — 13.4 months vs 12.4 months with chemotherapy alone.
FDA’s pooled analysis for unresectable or metastatic esophageal squamous cell carcinoma also showed no overall survival benefit (HR, 1.1; 95% CI, 0.76-1.58), with a trend suggesting harm. Median overall survival with immunotherapy plus chemotherapy was 14.6 months vs 9.8 months with chemotherapy alone.
Despite the vote on esophageal squamous cell carcinoma, panelists had reservations about making decisions based on just over 160 patients with PD-L1 levels below 1% in the three esophageal squamous cell carcinoma trials.
Still, one panelist said, it’s likely “the best dataset we will get.”
The companies all used different methods to test PD-L1 levels, and attendees called for a single standardized PD-L1 test. Richard Pazdur, MD, head of the FDA’s Oncology Center of Excellence, said the agency has been working with companies for years to get them to agree to such a test, with no luck.
If the FDA ultimately decides to restrict immunotherapy use in this patient population based on PD-L1 levels, insurance company coverage may become more limited. Pazdur asked the companies if they would be willing to expand their patient assistance programs to provide free coverage of immune checkpoint blockers to patients with low or no PD-L1 expression.
BeiGene and BMS seemed open to the idea. Merck said, “We’ll have to ... think about it.”
A version of this article first appeared on Medscape.com.
During the meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted in favor of restricting the use of these immunotherapy agents to patients with programmed death-ligand 1 (PD-L1) expression of 1% or higher.
The agency usually follows the ODAC’s advice.
The FDA had originally approved the two immune checkpoint inhibitors for both indications in combination with chemotherapy, regardless of patients’ PD-L1 status. The FDA had also approved nivolumab in combination with ipilimumab for esophageal cancer, regardless of PD-L1 expression. The approvals were based on overall benefit in intent-to-treat populations, not on specific PD-L1 expression subgroups.
Since then, additional studies — including the agency’s own pooled analyses of the approval trials — have found that overall survival benefits are limited to patients with PD-L1 expression of 1% or higher.
These findings have raised concerns that patients with no or low PD-L1 expression face the risks associated with immunotherapy, which include death, but minimal to no benefits.
In response, the FDA has considered changing the labeling for these indications to require a PD-L1 cutoff point of 1% or higher. The move would mirror guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network that already recommend use with chemotherapy only at certain PD-L1 cutoffs.
Before the agency acts, however, the FDA wanted the advice of the ODAC. It asked the 14-member panel whether the risk-benefit assessment is “favorable for the use of PD-1 inhibitors in first line” for the two indications among patients with PD-L1 expression below 1%.
In two nearly unanimous decisions for each indication, the panel voted that risk-benefit assessment was not favorable. In other words, the risks do outweigh the benefits for this patient population with no or low PD-L1 expression.
The determination also applies to tislelizumab (Tevimbra), an immune checkpoint inhibitor under review by the FDA for the same indications.
Voting came after hours of testimony from FDA scientists and the three drug companies involved in the decisions.
Merck, maker of pembrolizumab, was against any labeling change. Nivolumab’s maker, Bristol Myers Squibb (BMS), also wanted to stick with the current PD-L1 agnostic indications but said that any indication change should be class-wide to avoid confusion. BeiGene USA, maker of tislelizumab, had no problem with a PD-L1 cutoff of 1% because its approval trial showed benefit only in patients at that level or higher.
In general, Merck and BMS said the drug benefits correspond with higher PD-L1 expression but noted that patients with low or no PD-L1 expression can sometimes benefit from treatment. The companies had several patients testify to the benefits of the agents and noted patients like this would likely lose access. But an ODAC panelist noted that patients who died from immunotherapy complications weren’t there to respond.
The companies also expressed concern about taking treatment decisions out of the hands of oncologists as well as the need for additional biopsies to determine if tumors cross the proposed PD-L1 threshold at some point during treatment. With this potential new restriction, the companies were worried that insurance companies would be even less likely to pay for their checkpoint inhibitors in low or no PD-L1 expressors.
ODAC wasn’t moved. With consistent findings across multiple trials, the strength of the FDA’s data carried the day.
In a pooled analysis of the three companies’ unresectable or metastatic HER2–negative, microsatellite-stable gastric/gastroesophageal adenocarcinoma approval trials across almost 4000 patients, those with PD-L1 levels below 1% did not demonstrate a significant overall survival benefit (hazard ratio [HR], 0.91; 95% CI, 0.75-1.09). The median overall survival with immunotherapy plus chemotherapy was only 1 month more — 13.4 months vs 12.4 months with chemotherapy alone.
FDA’s pooled analysis for unresectable or metastatic esophageal squamous cell carcinoma also showed no overall survival benefit (HR, 1.1; 95% CI, 0.76-1.58), with a trend suggesting harm. Median overall survival with immunotherapy plus chemotherapy was 14.6 months vs 9.8 months with chemotherapy alone.
Despite the vote on esophageal squamous cell carcinoma, panelists had reservations about making decisions based on just over 160 patients with PD-L1 levels below 1% in the three esophageal squamous cell carcinoma trials.
Still, one panelist said, it’s likely “the best dataset we will get.”
The companies all used different methods to test PD-L1 levels, and attendees called for a single standardized PD-L1 test. Richard Pazdur, MD, head of the FDA’s Oncology Center of Excellence, said the agency has been working with companies for years to get them to agree to such a test, with no luck.
If the FDA ultimately decides to restrict immunotherapy use in this patient population based on PD-L1 levels, insurance company coverage may become more limited. Pazdur asked the companies if they would be willing to expand their patient assistance programs to provide free coverage of immune checkpoint blockers to patients with low or no PD-L1 expression.
BeiGene and BMS seemed open to the idea. Merck said, “We’ll have to ... think about it.”
A version of this article first appeared on Medscape.com.
During the meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted in favor of restricting the use of these immunotherapy agents to patients with programmed death-ligand 1 (PD-L1) expression of 1% or higher.
The agency usually follows the ODAC’s advice.
The FDA had originally approved the two immune checkpoint inhibitors for both indications in combination with chemotherapy, regardless of patients’ PD-L1 status. The FDA had also approved nivolumab in combination with ipilimumab for esophageal cancer, regardless of PD-L1 expression. The approvals were based on overall benefit in intent-to-treat populations, not on specific PD-L1 expression subgroups.
Since then, additional studies — including the agency’s own pooled analyses of the approval trials — have found that overall survival benefits are limited to patients with PD-L1 expression of 1% or higher.
These findings have raised concerns that patients with no or low PD-L1 expression face the risks associated with immunotherapy, which include death, but minimal to no benefits.
In response, the FDA has considered changing the labeling for these indications to require a PD-L1 cutoff point of 1% or higher. The move would mirror guidelines from the American Society of Clinical Oncology and the National Comprehensive Cancer Network that already recommend use with chemotherapy only at certain PD-L1 cutoffs.
Before the agency acts, however, the FDA wanted the advice of the ODAC. It asked the 14-member panel whether the risk-benefit assessment is “favorable for the use of PD-1 inhibitors in first line” for the two indications among patients with PD-L1 expression below 1%.
In two nearly unanimous decisions for each indication, the panel voted that risk-benefit assessment was not favorable. In other words, the risks do outweigh the benefits for this patient population with no or low PD-L1 expression.
The determination also applies to tislelizumab (Tevimbra), an immune checkpoint inhibitor under review by the FDA for the same indications.
Voting came after hours of testimony from FDA scientists and the three drug companies involved in the decisions.
Merck, maker of pembrolizumab, was against any labeling change. Nivolumab’s maker, Bristol Myers Squibb (BMS), also wanted to stick with the current PD-L1 agnostic indications but said that any indication change should be class-wide to avoid confusion. BeiGene USA, maker of tislelizumab, had no problem with a PD-L1 cutoff of 1% because its approval trial showed benefit only in patients at that level or higher.
In general, Merck and BMS said the drug benefits correspond with higher PD-L1 expression but noted that patients with low or no PD-L1 expression can sometimes benefit from treatment. The companies had several patients testify to the benefits of the agents and noted patients like this would likely lose access. But an ODAC panelist noted that patients who died from immunotherapy complications weren’t there to respond.
The companies also expressed concern about taking treatment decisions out of the hands of oncologists as well as the need for additional biopsies to determine if tumors cross the proposed PD-L1 threshold at some point during treatment. With this potential new restriction, the companies were worried that insurance companies would be even less likely to pay for their checkpoint inhibitors in low or no PD-L1 expressors.
ODAC wasn’t moved. With consistent findings across multiple trials, the strength of the FDA’s data carried the day.
In a pooled analysis of the three companies’ unresectable or metastatic HER2–negative, microsatellite-stable gastric/gastroesophageal adenocarcinoma approval trials across almost 4000 patients, those with PD-L1 levels below 1% did not demonstrate a significant overall survival benefit (hazard ratio [HR], 0.91; 95% CI, 0.75-1.09). The median overall survival with immunotherapy plus chemotherapy was only 1 month more — 13.4 months vs 12.4 months with chemotherapy alone.
FDA’s pooled analysis for unresectable or metastatic esophageal squamous cell carcinoma also showed no overall survival benefit (HR, 1.1; 95% CI, 0.76-1.58), with a trend suggesting harm. Median overall survival with immunotherapy plus chemotherapy was 14.6 months vs 9.8 months with chemotherapy alone.
Despite the vote on esophageal squamous cell carcinoma, panelists had reservations about making decisions based on just over 160 patients with PD-L1 levels below 1% in the three esophageal squamous cell carcinoma trials.
Still, one panelist said, it’s likely “the best dataset we will get.”
The companies all used different methods to test PD-L1 levels, and attendees called for a single standardized PD-L1 test. Richard Pazdur, MD, head of the FDA’s Oncology Center of Excellence, said the agency has been working with companies for years to get them to agree to such a test, with no luck.
If the FDA ultimately decides to restrict immunotherapy use in this patient population based on PD-L1 levels, insurance company coverage may become more limited. Pazdur asked the companies if they would be willing to expand their patient assistance programs to provide free coverage of immune checkpoint blockers to patients with low or no PD-L1 expression.
BeiGene and BMS seemed open to the idea. Merck said, “We’ll have to ... think about it.”
A version of this article first appeared on Medscape.com.
Minimal Risks With SBRT in Stage I NSCLC
TOPLINE:
METHODOLOGY:
- SBRT is generally considered a safe treatment option in patients with stage I NSCLC who have medically inoperable tumors or who refuse surgery. Although rare, clinically relevant acute toxicities or early mortality can occur.
- In the current real-world analysis, researchers explored toxicity and 90-day mortality outcomes in patients who received SBRT to develop a better understanding of how often they happen and whether certain patients are at higher risk.
- Researchers analyzed data from the Dutch Lung Cancer Audit for Radiotherapy database, which included 7279 patients with stage I NSCLC who received SBRT between January 2017 and December 2021.
- Participants had a mean age of 72.5 years; 21.6% were older than 80 years. Over half were men (50.7%), most (73.3%) had WHO scores of 0-1, and about two thirds (64.6%) had cT1a-b tumors, mostly in the upper lobes (65.2%).
- Prediction models for acute toxicity and 90-day mortality were developed and internally validated using logistic regression analysis. Acute toxicity was defined as grade 2 or higher radiation pneumonitis or grade 3 or higher non-hematologic toxicity within 90 days after SBRT. The 90-day mortality was defined as mortality from any cause within 90 days after SBRT.
TAKEAWAY:
- Acute toxicity was observed in 3.8% patients, with more common types including dyspnea (1.8%), radiation pneumonitis (1.2%), fatigue (0.3%), and dysphagia (0.2%).
- Predictors for acute toxicity included WHO performance status of 2 or higher (adjusted odds ratio [aOR], 1.89; P = .003), middle or lower lobe tumor location (aOR, 1.38), cT1c-cT2a stage (aOR, 1.66), as well as lower forced expiratory volume in 1 second and higher mean lung dose.
- Overall, 90-day mortality was observed in 1.7% patients, with predictors including male sex, WHO performance status of 2 or higher (aOR, 6.11; P < .001), and acute toxicity (aOR, 8.89; P < .001).
- Advanced age was not associated with a higher risk for acute toxicity or 90-day mortality.
IN PRACTICE:
“This real-world study confirms that clinically relevant acute toxicity after lung SBRT for stage I NSCLC is rare,” and the 90-day mortality rate is low, the authors wrote. “Although these findings could inform clinical practice and enable individualized risk estimations, these parameters (and the others in the presented nomograms) should not serve as contraindication for SBRT as the benefits in terms of local control and survival outweigh the risks in most patients.”
SOURCE:
This study, led by Peter S.N. van Rossum, MD, PhD, Amsterdam UMC in Amsterdam, the Netherlands, was published online in Journal of Thoracic Oncology.
LIMITATIONS:
Patients with ultracentral tumor locations were excluded, which may have limited the generalizability of the findings. The Dutch Lung Cancer Audit for Radiotherapy database does not register whether a patient has interstitial lung disease or whether the treated tumor is at a central location, which carry increased risks for toxicity. The findings may not be applicable to patients receiving combined immunotherapy and SBRT, as this combination was not included in the current analysis. External validation of the prediction models is needed for application outside the Netherlands.
DISCLOSURES:
The authors declared no conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- SBRT is generally considered a safe treatment option in patients with stage I NSCLC who have medically inoperable tumors or who refuse surgery. Although rare, clinically relevant acute toxicities or early mortality can occur.
- In the current real-world analysis, researchers explored toxicity and 90-day mortality outcomes in patients who received SBRT to develop a better understanding of how often they happen and whether certain patients are at higher risk.
- Researchers analyzed data from the Dutch Lung Cancer Audit for Radiotherapy database, which included 7279 patients with stage I NSCLC who received SBRT between January 2017 and December 2021.
- Participants had a mean age of 72.5 years; 21.6% were older than 80 years. Over half were men (50.7%), most (73.3%) had WHO scores of 0-1, and about two thirds (64.6%) had cT1a-b tumors, mostly in the upper lobes (65.2%).
- Prediction models for acute toxicity and 90-day mortality were developed and internally validated using logistic regression analysis. Acute toxicity was defined as grade 2 or higher radiation pneumonitis or grade 3 or higher non-hematologic toxicity within 90 days after SBRT. The 90-day mortality was defined as mortality from any cause within 90 days after SBRT.
TAKEAWAY:
- Acute toxicity was observed in 3.8% patients, with more common types including dyspnea (1.8%), radiation pneumonitis (1.2%), fatigue (0.3%), and dysphagia (0.2%).
- Predictors for acute toxicity included WHO performance status of 2 or higher (adjusted odds ratio [aOR], 1.89; P = .003), middle or lower lobe tumor location (aOR, 1.38), cT1c-cT2a stage (aOR, 1.66), as well as lower forced expiratory volume in 1 second and higher mean lung dose.
- Overall, 90-day mortality was observed in 1.7% patients, with predictors including male sex, WHO performance status of 2 or higher (aOR, 6.11; P < .001), and acute toxicity (aOR, 8.89; P < .001).
- Advanced age was not associated with a higher risk for acute toxicity or 90-day mortality.
IN PRACTICE:
“This real-world study confirms that clinically relevant acute toxicity after lung SBRT for stage I NSCLC is rare,” and the 90-day mortality rate is low, the authors wrote. “Although these findings could inform clinical practice and enable individualized risk estimations, these parameters (and the others in the presented nomograms) should not serve as contraindication for SBRT as the benefits in terms of local control and survival outweigh the risks in most patients.”
SOURCE:
This study, led by Peter S.N. van Rossum, MD, PhD, Amsterdam UMC in Amsterdam, the Netherlands, was published online in Journal of Thoracic Oncology.
LIMITATIONS:
Patients with ultracentral tumor locations were excluded, which may have limited the generalizability of the findings. The Dutch Lung Cancer Audit for Radiotherapy database does not register whether a patient has interstitial lung disease or whether the treated tumor is at a central location, which carry increased risks for toxicity. The findings may not be applicable to patients receiving combined immunotherapy and SBRT, as this combination was not included in the current analysis. External validation of the prediction models is needed for application outside the Netherlands.
DISCLOSURES:
The authors declared no conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- SBRT is generally considered a safe treatment option in patients with stage I NSCLC who have medically inoperable tumors or who refuse surgery. Although rare, clinically relevant acute toxicities or early mortality can occur.
- In the current real-world analysis, researchers explored toxicity and 90-day mortality outcomes in patients who received SBRT to develop a better understanding of how often they happen and whether certain patients are at higher risk.
- Researchers analyzed data from the Dutch Lung Cancer Audit for Radiotherapy database, which included 7279 patients with stage I NSCLC who received SBRT between January 2017 and December 2021.
- Participants had a mean age of 72.5 years; 21.6% were older than 80 years. Over half were men (50.7%), most (73.3%) had WHO scores of 0-1, and about two thirds (64.6%) had cT1a-b tumors, mostly in the upper lobes (65.2%).
- Prediction models for acute toxicity and 90-day mortality were developed and internally validated using logistic regression analysis. Acute toxicity was defined as grade 2 or higher radiation pneumonitis or grade 3 or higher non-hematologic toxicity within 90 days after SBRT. The 90-day mortality was defined as mortality from any cause within 90 days after SBRT.
TAKEAWAY:
- Acute toxicity was observed in 3.8% patients, with more common types including dyspnea (1.8%), radiation pneumonitis (1.2%), fatigue (0.3%), and dysphagia (0.2%).
- Predictors for acute toxicity included WHO performance status of 2 or higher (adjusted odds ratio [aOR], 1.89; P = .003), middle or lower lobe tumor location (aOR, 1.38), cT1c-cT2a stage (aOR, 1.66), as well as lower forced expiratory volume in 1 second and higher mean lung dose.
- Overall, 90-day mortality was observed in 1.7% patients, with predictors including male sex, WHO performance status of 2 or higher (aOR, 6.11; P < .001), and acute toxicity (aOR, 8.89; P < .001).
- Advanced age was not associated with a higher risk for acute toxicity or 90-day mortality.
IN PRACTICE:
“This real-world study confirms that clinically relevant acute toxicity after lung SBRT for stage I NSCLC is rare,” and the 90-day mortality rate is low, the authors wrote. “Although these findings could inform clinical practice and enable individualized risk estimations, these parameters (and the others in the presented nomograms) should not serve as contraindication for SBRT as the benefits in terms of local control and survival outweigh the risks in most patients.”
SOURCE:
This study, led by Peter S.N. van Rossum, MD, PhD, Amsterdam UMC in Amsterdam, the Netherlands, was published online in Journal of Thoracic Oncology.
LIMITATIONS:
Patients with ultracentral tumor locations were excluded, which may have limited the generalizability of the findings. The Dutch Lung Cancer Audit for Radiotherapy database does not register whether a patient has interstitial lung disease or whether the treated tumor is at a central location, which carry increased risks for toxicity. The findings may not be applicable to patients receiving combined immunotherapy and SBRT, as this combination was not included in the current analysis. External validation of the prediction models is needed for application outside the Netherlands.
DISCLOSURES:
The authors declared no conflicts of interest.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.
FDA Okays Osimertinib After CRT in Locally Advanced, Unresectable NSCLC
Specifically, the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) was approved for patients whose disease has not progressed during or after concurrent or sequential platinum-based chemoradiation therapy and whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations. Such EGFR mutations can be detected by an FDA-approved test.
The FDA approved osimertinib in combination with platinum-based chemotherapy as first-line treatment for patients with locally advanced or metastatic NSCLC with the same mutations in February. The EGFR-TKI also carries other indications, including as first-line monotherapy for locally advanced or metastatic EGFR-mutated NSCLC.
Trial Findings Supporting Latest Approval
AstraZeneca announced in June that osimertinib had been granted Priority Review and Breakthrough Therapy Designation for its newest indication.
The September 25 approval was based on findings from the randomized, placebo-controlled LAURA trial of 216 patients, which demonstrated improved median progression-free survival with osimertinib vs placebo (39.1 vs 5.6 months; hazard ratio, 0.16). Overall survival results were immature at the most recent analysis, but “no trend towards a detriment was observed,” with 36% of prespecified deaths for the final analysis reported, according to an FDA press release.
Adverse Events
Study participants were randomized 2:1 to receive the osimertinib recommended dose of 80 mg given orally once daily or placebo until disease progression or unacceptable toxicity. The most common adverse reactions, occurring in at least 20% of patients, were lymphopenia, leukopenia, interstitial lung disease/pneumonitis, thrombocytopenia, neutropenia, rash, diarrhea, nail toxicity, musculoskeletal pain, cough, and COVID-19 infection.
A version of this article first appeared on Medscape.com.
Specifically, the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) was approved for patients whose disease has not progressed during or after concurrent or sequential platinum-based chemoradiation therapy and whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations. Such EGFR mutations can be detected by an FDA-approved test.
The FDA approved osimertinib in combination with platinum-based chemotherapy as first-line treatment for patients with locally advanced or metastatic NSCLC with the same mutations in February. The EGFR-TKI also carries other indications, including as first-line monotherapy for locally advanced or metastatic EGFR-mutated NSCLC.
Trial Findings Supporting Latest Approval
AstraZeneca announced in June that osimertinib had been granted Priority Review and Breakthrough Therapy Designation for its newest indication.
The September 25 approval was based on findings from the randomized, placebo-controlled LAURA trial of 216 patients, which demonstrated improved median progression-free survival with osimertinib vs placebo (39.1 vs 5.6 months; hazard ratio, 0.16). Overall survival results were immature at the most recent analysis, but “no trend towards a detriment was observed,” with 36% of prespecified deaths for the final analysis reported, according to an FDA press release.
Adverse Events
Study participants were randomized 2:1 to receive the osimertinib recommended dose of 80 mg given orally once daily or placebo until disease progression or unacceptable toxicity. The most common adverse reactions, occurring in at least 20% of patients, were lymphopenia, leukopenia, interstitial lung disease/pneumonitis, thrombocytopenia, neutropenia, rash, diarrhea, nail toxicity, musculoskeletal pain, cough, and COVID-19 infection.
A version of this article first appeared on Medscape.com.
Specifically, the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) was approved for patients whose disease has not progressed during or after concurrent or sequential platinum-based chemoradiation therapy and whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations. Such EGFR mutations can be detected by an FDA-approved test.
The FDA approved osimertinib in combination with platinum-based chemotherapy as first-line treatment for patients with locally advanced or metastatic NSCLC with the same mutations in February. The EGFR-TKI also carries other indications, including as first-line monotherapy for locally advanced or metastatic EGFR-mutated NSCLC.
Trial Findings Supporting Latest Approval
AstraZeneca announced in June that osimertinib had been granted Priority Review and Breakthrough Therapy Designation for its newest indication.
The September 25 approval was based on findings from the randomized, placebo-controlled LAURA trial of 216 patients, which demonstrated improved median progression-free survival with osimertinib vs placebo (39.1 vs 5.6 months; hazard ratio, 0.16). Overall survival results were immature at the most recent analysis, but “no trend towards a detriment was observed,” with 36% of prespecified deaths for the final analysis reported, according to an FDA press release.
Adverse Events
Study participants were randomized 2:1 to receive the osimertinib recommended dose of 80 mg given orally once daily or placebo until disease progression or unacceptable toxicity. The most common adverse reactions, occurring in at least 20% of patients, were lymphopenia, leukopenia, interstitial lung disease/pneumonitis, thrombocytopenia, neutropenia, rash, diarrhea, nail toxicity, musculoskeletal pain, cough, and COVID-19 infection.
A version of this article first appeared on Medscape.com.