Head & Neck/Thyroid Cancers

Doug Flora, MD, knows the value of early cancer detection because it helped him survive kidney cancer 5 years ago. But as a medical oncologist and hematologist, and the executive medical director of oncology services at St. Elizabeth Healthcare in Edgewood, Ky., he also knows that a new era of early cancer detection testing poses big challenges for his network of six hospitals and 169 specialty and primary care offices throughout Kentucky, Ohio, and Indiana.

Multicancer early detection (MCED) tests are finally a reality and could be a potential game changer because they can screen for the possibility of up to 50 different cancers in asymptomatic individuals with one blood draw. They represent one of the fastest growing segments in medical diagnostics with a projected value of $2.77 billion by 2030, according to the market research firm Grand View Research.

These tests are different from traditional liquid biopsies, which are designed to identify actionable gene mutations to help inform treatment decisions of patients already diagnosed with cancer. Instead, MCED tests work to detect fragments of circulating free DNA that have been shed by tumors and released into the bloodstream. Detecting these cancer signals could indicate that an individual has cancer well before they ever develop symptoms.

For some cancer types, particularly those commonly diagnosed at advanced stages or those without general population screening tests, MCED testing could have a significant impact.

In its new report, Grand View Research highlights nine “prominent players” active in the MCED market; of these, two have been granted breakthrough device designation by the Food and Drug Administration: OverC MCDBT by Burning Rock on Jan. 3, 2023, and Galleri by Grail in 2019. Galleri was launched in June 2021 and can be obtained with a prescription at a cost of $949.

Yet, while patients are asking for these tests and primary care physicians are prescribing them, oncologists are grappling with how to manage the first patients whose tests tell them they may have cancer.

Ordering the tests may seem straightforward, but in reality, it is not. In fact, they are so new that most health systems have no internal guidelines for physicians. Guidelines would address when the tests should be prescribed, and whether a patient should undergo more testing or be referred to an oncologist.
 

Clinical trials underway

There are currently at least 17 clinical trials underway to investigate the performance and clinical utility of MCED tests. Six of these involve Grail, including NHS-Galleri, the largest study to date of 140,000 participants in the United Kingdom where participants will be followed for 3 years with annual visits at 12 and 24 months. And, the National Cancer Institute is spearheading a clinical trial of its own, according to a search of ClinicalTrials.gov.

In September 2022, Grail presented findings from its pivotal PATHFINDER study at the annual meeting of the European Society of Medical Oncology. Researchers reported that cancer signals were detected in 1.4% (92) of 6,621 participants enrolled in the study. Of the 92, 35 people were diagnosed with 36 cancers: 19 were solid tumors (2 oropharyngeal, 5 breast, l liver, 1 intrahepatic bile duct, 2 colon/rectum, 2 prostate, 1 lung, 1 pancreas, 1 small intestine, 1 uterus, 1 ovary and 1 bone) and 17 hematologic cancers (1 plasma cell myeloma/disorders, 2 lymphoid leukemia, 2 Waldenström’s macroglobulinemia, and 12 lymphoma).

Almost half of newly diagnosed cases were cancers in stage 1 or 2. Of stage 1 cancers, three were solid tumors and four were hematologic cancers. Of stage 2 cancers, three were solid tumors and four were hematologic cancers. All other cancers were in stage 3 and 4 or were listed as recurrent or no stage. Deb Schrag, MD, MPH, chair of the department of medicine at Memorial Sloan Kettering Cancer Center in New York, who presented the results from PATHFINDER at ESMO, reported that, of all diagnosed cancers, only breast, colon/rectum, prostate, and lung have established screening protocols.

The findings were so striking that the meeting scientific co-chair, Fabrice André, MD, PhD, told ESMO the oncology field must prepare for an onslaught of new patients.

“Within the next 5 years, we will need more doctors, surgeons and nurses with more diagnostic and treatment infrastructures to care for the rising number of people who will be identified by multicancer early detection tests,” said Dr. André, who is director of research at Gustave Roussy Cancer Center, Villejuif, France, and future president of ESMO (2025-2026). “We need to involve all stakeholders in deciding new pathways of care. We need to agree who will be tested and when and where tests will be carried out, and to anticipate the changes that will happen as a result of these tests.”

But first, he urged, the need for comparative trials “across all types of cancer to find out if having an early detection test affects morbidity and mortality. We also need to know how the tests benefit patients, and how to discuss the results with them,” Dr. André said.
 

Demand may burden health systems

Dr. Flora suggested that companies like Grail are rushing their product to market without conducting long-term sizable clinical trials.

“These diagnostic companies are a billion dollar publicly traded or venture capital-funded companies that are losing millions of dollars a quarter as they’re scaling up these tests. So, there is some pressure on the sales forces ... to start moving product long before the science has met our lowest areas for entry,” Dr. Flora said. “They are aggressively marketing to a primary care audience that knows nothing about MCEDs. It’s a sales-driven development solving a problem we all believe is real, but we don’t know if it actually solves the problem.”

There are many unanswered questions, he said. Among these include whether the tests do indeed extend survival. “What they’re suggesting – that is if the blood test detects it – that we’re going to save your life. That’s not yet been proven. This is where the providers are pushing back against these industry types to say: ‘This is the wild west right now.’ It’s very irresponsible to go out there and try to sell hundreds of millions of dollars of product to doctors who have never studied genetics,” Dr. Flora said.

Grail’s chief medical officer Jeff Venstrom, MD, however, said physicians don’t need a background in genetic testing to order or interpret Galleri because it’s not a genetic test. Genetic tests look for genetic variants associated with cancer risk, which Galleri does not. MCED tests rely on genomic profiling to identify alterations in tumors.

“Maybe there’s still confusion in the market, which is common for new technologies when they’re initially launched. This is not a 23andMe test. We do not report germline mutations that have implications for cancer risk. We’re using this blood sample to test for the presence or absence of a cancer signal. The test result is very clear and simple: One area of the report says ‘yes’ or ‘no.’ It is a binary result that says if a signal is detected or not. The second provides additional information around where that signal could be coming from,” he said.

Galleri could fill a huge unmet need in cancer prevention, Dr. Venstrom said. Not only could it detect cancer at an earlier stage, but it could serve as a screening tool for cancers like pancreatic cancer in which screening is not available.

The test is not intended to replace standard of care screening, he said. The ordering provider should have a conversation with the patient about overall cancer risk. “Are you smoking? What’s your risk of obesity-associated cancers? Do you have a family history of cancer? I think this should all be in the context of a good conversation around preventative care,” he said.
 

Planning and prep in Boston

In Boston, Aparna Parikh, MD, an oncologist who specializes in gastrointestinal cancers, agreed that MCED testing has forced her team at the Mass General Cancer Center global cancer care program to think outside of the box.

“We’re a major academic center and it’s not easy [because] this is all uncharted territory,” she said. “We all recognize there are more tests coming, and they are here to stay. As a health system, we have to be ready to manage not only the tests, but patient anxieties, and all the complexities that come with it. We just don’t know yet how to best navigate.”

Although Dr. Parikh’s center has set up a working group tasked with organizing an outpatient clinic for patients with positive MCED tests, the current system is haphazard.

“Right now, it gets bounced around between people,” she explained. “Sometimes, patients are getting referred to the oncology team rather than the primary care team to try to sort out where the cancer signal is coming from, that is, if it’s not immediately obvious. No one really knows who should be the right person to own it,” Dr. Parikh said. While the test is supposed to give tissue-specific results, “it’s not perfect” and sometimes imaging and other work-ups are needed to locate the source of the signa.

“A group of four or five oncologists get looped in and then we’re trying to sort it out on a case-by-case basis, but understanding that with more and more tests coming, that kind of ad hoc approach isn’t going to be sufficient. We need a happy medium between the primary care and the disease specific oncologist, someone who can kind of help think through the diagnostic workup until they have a cancer diagnosis to get them to the right place,” Dr. Parikh said.

Dr. Venstrom said Grail is committed to providing support to clinicians in these situations. “We’re doing everything we can with our medical education forums. We have this pretty intense and extensive postpositive suite of resources,” he explained. “Some of our doctors on staff call the ordering provider within 24 hours just to clarify if there are any questions or confusion from the report. For example, if it suggests the signal is coming from the lung, we provide additional support around additional workups.”
 

Out-of-pocket test may widen disparities in care

With the exception of a few health insurance companies that have committed to covering some of the cost for the test, Galleri is an out-of-pocket expense.

Dr. Venstrom acknowledged that broad insurance coverage for the Galleri test remains a hurdle, although “we’ve secured coverage for a handful of companies of self-insured employers and forward-thinking insurers.” This includes partnerships with Point32Health, and Alignment Health, among others, he said.

There is also growing support among more than 400 cancer organizations for the Multi-Cancer Early Detection Screening Coverage Act to accelerate coverage for Medicare beneficiaries. “We are constantly trying to understand the evidence that’s needed for payors to make sure that we get the broadest access possible for this test,” he said.
 

The first positive test result

Back at St. Elizabeth Healthcare where they’ve only seen one positive MCED test result thus far, Dr. Flora is more concerned about patients giving informed consent before they even get the test. “When the reps started hammering our primary care doctors, we sent communiques throughout the system saying that we would very much like to regulate this to make sure that before our patients receive accidental harm, that they at least have a conversation with somebody who understands the test,” he explained.

All 15 patients who requested the test at the hospital were first required to discuss the implications with a genetic counselor who is part of the system. “We are really pro–cancer screening,” he said, but added his hospital is “not pumped” about the Galleri test. “We’re being very cautious about overstatements made by sales guys to our primary care doctors, so we’re letting our own precision medicine people handle it.”

There’s a similar system in place at Community Health Network, a nonprofit health system with nine hospitals and 1,300 employee providers throughout Central Indiana. Patrick McGill, MD, a primary care physician and chief analytics officer for the network says they have streamlined patients with positive tests through their high-risk oncology clinic. “They don’t go straight to a medical oncologist which I know some systems are struggling with,” he said. “They get additional testing, whether it’s imaging they might need or other lab testing. We’ve had a few lung positives, and a few leukemia positives which might go straight to medical oncology. I think we had one breast that was positive so she got additional breast imaging.”

Through its foundation, CHN will offer 2,000 tests free of charge. “We decided to take cost off the table with this funding,” Dr. McGill said. “A lot of health systems I talk to are always concerned that insurance doesn’t cover it and it’s cost prohibitive. Is it creating additional disparities because only people who can afford it can get the test?”

Dr. Schrag serves as an uncompensated advisor for Grail. Previously, while with the Dana-Farber Cancer Institute, she received research funding from Grail.

Doug Flora, MD, knows the value of early cancer detection because it helped him survive kidney cancer 5 years ago. But as a medical oncologist and hematologist, and the executive medical director of oncology services at St. Elizabeth Healthcare in Edgewood, Ky., he also knows that a new era of early cancer detection testing poses big challenges for his network of six hospitals and 169 specialty and primary care offices throughout Kentucky, Ohio, and Indiana.

Multicancer early detection (MCED) tests are finally a reality and could be a potential game changer because they can screen for the possibility of up to 50 different cancers in asymptomatic individuals with one blood draw. They represent one of the fastest growing segments in medical diagnostics with a projected value of $2.77 billion by 2030, according to the market research firm Grand View Research.

These tests are different from traditional liquid biopsies, which are designed to identify actionable gene mutations to help inform treatment decisions of patients already diagnosed with cancer. Instead, MCED tests work to detect fragments of circulating free DNA that have been shed by tumors and released into the bloodstream. Detecting these cancer signals could indicate that an individual has cancer well before they ever develop symptoms.

For some cancer types, particularly those commonly diagnosed at advanced stages or those without general population screening tests, MCED testing could have a significant impact.

In its new report, Grand View Research highlights nine “prominent players” active in the MCED market; of these, two have been granted breakthrough device designation by the Food and Drug Administration: OverC MCDBT by Burning Rock on Jan. 3, 2023, and Galleri by Grail in 2019. Galleri was launched in June 2021 and can be obtained with a prescription at a cost of $949.

Yet, while patients are asking for these tests and primary care physicians are prescribing them, oncologists are grappling with how to manage the first patients whose tests tell them they may have cancer.

Ordering the tests may seem straightforward, but in reality, it is not. In fact, they are so new that most health systems have no internal guidelines for physicians. Guidelines would address when the tests should be prescribed, and whether a patient should undergo more testing or be referred to an oncologist.
 

Clinical trials underway

There are currently at least 17 clinical trials underway to investigate the performance and clinical utility of MCED tests. Six of these involve Grail, including NHS-Galleri, the largest study to date of 140,000 participants in the United Kingdom where participants will be followed for 3 years with annual visits at 12 and 24 months. And, the National Cancer Institute is spearheading a clinical trial of its own, according to a search of ClinicalTrials.gov.

In September 2022, Grail presented findings from its pivotal PATHFINDER study at the annual meeting of the European Society of Medical Oncology. Researchers reported that cancer signals were detected in 1.4% (92) of 6,621 participants enrolled in the study. Of the 92, 35 people were diagnosed with 36 cancers: 19 were solid tumors (2 oropharyngeal, 5 breast, l liver, 1 intrahepatic bile duct, 2 colon/rectum, 2 prostate, 1 lung, 1 pancreas, 1 small intestine, 1 uterus, 1 ovary and 1 bone) and 17 hematologic cancers (1 plasma cell myeloma/disorders, 2 lymphoid leukemia, 2 Waldenström’s macroglobulinemia, and 12 lymphoma).

Almost half of newly diagnosed cases were cancers in stage 1 or 2. Of stage 1 cancers, three were solid tumors and four were hematologic cancers. Of stage 2 cancers, three were solid tumors and four were hematologic cancers. All other cancers were in stage 3 and 4 or were listed as recurrent or no stage. Deb Schrag, MD, MPH, chair of the department of medicine at Memorial Sloan Kettering Cancer Center in New York, who presented the results from PATHFINDER at ESMO, reported that, of all diagnosed cancers, only breast, colon/rectum, prostate, and lung have established screening protocols.

The findings were so striking that the meeting scientific co-chair, Fabrice André, MD, PhD, told ESMO the oncology field must prepare for an onslaught of new patients.

“Within the next 5 years, we will need more doctors, surgeons and nurses with more diagnostic and treatment infrastructures to care for the rising number of people who will be identified by multicancer early detection tests,” said Dr. André, who is director of research at Gustave Roussy Cancer Center, Villejuif, France, and future president of ESMO (2025-2026). “We need to involve all stakeholders in deciding new pathways of care. We need to agree who will be tested and when and where tests will be carried out, and to anticipate the changes that will happen as a result of these tests.”

But first, he urged, the need for comparative trials “across all types of cancer to find out if having an early detection test affects morbidity and mortality. We also need to know how the tests benefit patients, and how to discuss the results with them,” Dr. André said.
 

Demand may burden health systems

Dr. Flora suggested that companies like Grail are rushing their product to market without conducting long-term sizable clinical trials.

“These diagnostic companies are a billion dollar publicly traded or venture capital-funded companies that are losing millions of dollars a quarter as they’re scaling up these tests. So, there is some pressure on the sales forces ... to start moving product long before the science has met our lowest areas for entry,” Dr. Flora said. “They are aggressively marketing to a primary care audience that knows nothing about MCEDs. It’s a sales-driven development solving a problem we all believe is real, but we don’t know if it actually solves the problem.”

There are many unanswered questions, he said. Among these include whether the tests do indeed extend survival. “What they’re suggesting – that is if the blood test detects it – that we’re going to save your life. That’s not yet been proven. This is where the providers are pushing back against these industry types to say: ‘This is the wild west right now.’ It’s very irresponsible to go out there and try to sell hundreds of millions of dollars of product to doctors who have never studied genetics,” Dr. Flora said.

Grail’s chief medical officer Jeff Venstrom, MD, however, said physicians don’t need a background in genetic testing to order or interpret Galleri because it’s not a genetic test. Genetic tests look for genetic variants associated with cancer risk, which Galleri does not. MCED tests rely on genomic profiling to identify alterations in tumors.

“Maybe there’s still confusion in the market, which is common for new technologies when they’re initially launched. This is not a 23andMe test. We do not report germline mutations that have implications for cancer risk. We’re using this blood sample to test for the presence or absence of a cancer signal. The test result is very clear and simple: One area of the report says ‘yes’ or ‘no.’ It is a binary result that says if a signal is detected or not. The second provides additional information around where that signal could be coming from,” he said.

Galleri could fill a huge unmet need in cancer prevention, Dr. Venstrom said. Not only could it detect cancer at an earlier stage, but it could serve as a screening tool for cancers like pancreatic cancer in which screening is not available.

The test is not intended to replace standard of care screening, he said. The ordering provider should have a conversation with the patient about overall cancer risk. “Are you smoking? What’s your risk of obesity-associated cancers? Do you have a family history of cancer? I think this should all be in the context of a good conversation around preventative care,” he said.
 

Planning and prep in Boston

In Boston, Aparna Parikh, MD, an oncologist who specializes in gastrointestinal cancers, agreed that MCED testing has forced her team at the Mass General Cancer Center global cancer care program to think outside of the box.

“We’re a major academic center and it’s not easy [because] this is all uncharted territory,” she said. “We all recognize there are more tests coming, and they are here to stay. As a health system, we have to be ready to manage not only the tests, but patient anxieties, and all the complexities that come with it. We just don’t know yet how to best navigate.”

Although Dr. Parikh’s center has set up a working group tasked with organizing an outpatient clinic for patients with positive MCED tests, the current system is haphazard.

“Right now, it gets bounced around between people,” she explained. “Sometimes, patients are getting referred to the oncology team rather than the primary care team to try to sort out where the cancer signal is coming from, that is, if it’s not immediately obvious. No one really knows who should be the right person to own it,” Dr. Parikh said. While the test is supposed to give tissue-specific results, “it’s not perfect” and sometimes imaging and other work-ups are needed to locate the source of the signa.

“A group of four or five oncologists get looped in and then we’re trying to sort it out on a case-by-case basis, but understanding that with more and more tests coming, that kind of ad hoc approach isn’t going to be sufficient. We need a happy medium between the primary care and the disease specific oncologist, someone who can kind of help think through the diagnostic workup until they have a cancer diagnosis to get them to the right place,” Dr. Parikh said.

Dr. Venstrom said Grail is committed to providing support to clinicians in these situations. “We’re doing everything we can with our medical education forums. We have this pretty intense and extensive postpositive suite of resources,” he explained. “Some of our doctors on staff call the ordering provider within 24 hours just to clarify if there are any questions or confusion from the report. For example, if it suggests the signal is coming from the lung, we provide additional support around additional workups.”
 

Out-of-pocket test may widen disparities in care

With the exception of a few health insurance companies that have committed to covering some of the cost for the test, Galleri is an out-of-pocket expense.

Dr. Venstrom acknowledged that broad insurance coverage for the Galleri test remains a hurdle, although “we’ve secured coverage for a handful of companies of self-insured employers and forward-thinking insurers.” This includes partnerships with Point32Health, and Alignment Health, among others, he said.

There is also growing support among more than 400 cancer organizations for the Multi-Cancer Early Detection Screening Coverage Act to accelerate coverage for Medicare beneficiaries. “We are constantly trying to understand the evidence that’s needed for payors to make sure that we get the broadest access possible for this test,” he said.
 

The first positive test result

Back at St. Elizabeth Healthcare where they’ve only seen one positive MCED test result thus far, Dr. Flora is more concerned about patients giving informed consent before they even get the test. “When the reps started hammering our primary care doctors, we sent communiques throughout the system saying that we would very much like to regulate this to make sure that before our patients receive accidental harm, that they at least have a conversation with somebody who understands the test,” he explained.

All 15 patients who requested the test at the hospital were first required to discuss the implications with a genetic counselor who is part of the system. “We are really pro–cancer screening,” he said, but added his hospital is “not pumped” about the Galleri test. “We’re being very cautious about overstatements made by sales guys to our primary care doctors, so we’re letting our own precision medicine people handle it.”

There’s a similar system in place at Community Health Network, a nonprofit health system with nine hospitals and 1,300 employee providers throughout Central Indiana. Patrick McGill, MD, a primary care physician and chief analytics officer for the network says they have streamlined patients with positive tests through their high-risk oncology clinic. “They don’t go straight to a medical oncologist which I know some systems are struggling with,” he said. “They get additional testing, whether it’s imaging they might need or other lab testing. We’ve had a few lung positives, and a few leukemia positives which might go straight to medical oncology. I think we had one breast that was positive so she got additional breast imaging.”

Through its foundation, CHN will offer 2,000 tests free of charge. “We decided to take cost off the table with this funding,” Dr. McGill said. “A lot of health systems I talk to are always concerned that insurance doesn’t cover it and it’s cost prohibitive. Is it creating additional disparities because only people who can afford it can get the test?”

Dr. Schrag serves as an uncompensated advisor for Grail. Previously, while with the Dana-Farber Cancer Institute, she received research funding from Grail.

Doug Flora, MD, knows the value of early cancer detection because it helped him survive kidney cancer 5 years ago. But as a medical oncologist and hematologist, and the executive medical director of oncology services at St. Elizabeth Healthcare in Edgewood, Ky., he also knows that a new era of early cancer detection testing poses big challenges for his network of six hospitals and 169 specialty and primary care offices throughout Kentucky, Ohio, and Indiana.

Multicancer early detection (MCED) tests are finally a reality and could be a potential game changer because they can screen for the possibility of up to 50 different cancers in asymptomatic individuals with one blood draw. They represent one of the fastest growing segments in medical diagnostics with a projected value of $2.77 billion by 2030, according to the market research firm Grand View Research.

These tests are different from traditional liquid biopsies, which are designed to identify actionable gene mutations to help inform treatment decisions of patients already diagnosed with cancer. Instead, MCED tests work to detect fragments of circulating free DNA that have been shed by tumors and released into the bloodstream. Detecting these cancer signals could indicate that an individual has cancer well before they ever develop symptoms.

For some cancer types, particularly those commonly diagnosed at advanced stages or those without general population screening tests, MCED testing could have a significant impact.

In its new report, Grand View Research highlights nine “prominent players” active in the MCED market; of these, two have been granted breakthrough device designation by the Food and Drug Administration: OverC MCDBT by Burning Rock on Jan. 3, 2023, and Galleri by Grail in 2019. Galleri was launched in June 2021 and can be obtained with a prescription at a cost of $949.

Yet, while patients are asking for these tests and primary care physicians are prescribing them, oncologists are grappling with how to manage the first patients whose tests tell them they may have cancer.

Ordering the tests may seem straightforward, but in reality, it is not. In fact, they are so new that most health systems have no internal guidelines for physicians. Guidelines would address when the tests should be prescribed, and whether a patient should undergo more testing or be referred to an oncologist.
 

Clinical trials underway

There are currently at least 17 clinical trials underway to investigate the performance and clinical utility of MCED tests. Six of these involve Grail, including NHS-Galleri, the largest study to date of 140,000 participants in the United Kingdom where participants will be followed for 3 years with annual visits at 12 and 24 months. And, the National Cancer Institute is spearheading a clinical trial of its own, according to a search of ClinicalTrials.gov.

In September 2022, Grail presented findings from its pivotal PATHFINDER study at the annual meeting of the European Society of Medical Oncology. Researchers reported that cancer signals were detected in 1.4% (92) of 6,621 participants enrolled in the study. Of the 92, 35 people were diagnosed with 36 cancers: 19 were solid tumors (2 oropharyngeal, 5 breast, l liver, 1 intrahepatic bile duct, 2 colon/rectum, 2 prostate, 1 lung, 1 pancreas, 1 small intestine, 1 uterus, 1 ovary and 1 bone) and 17 hematologic cancers (1 plasma cell myeloma/disorders, 2 lymphoid leukemia, 2 Waldenström’s macroglobulinemia, and 12 lymphoma).

Almost half of newly diagnosed cases were cancers in stage 1 or 2. Of stage 1 cancers, three were solid tumors and four were hematologic cancers. Of stage 2 cancers, three were solid tumors and four were hematologic cancers. All other cancers were in stage 3 and 4 or were listed as recurrent or no stage. Deb Schrag, MD, MPH, chair of the department of medicine at Memorial Sloan Kettering Cancer Center in New York, who presented the results from PATHFINDER at ESMO, reported that, of all diagnosed cancers, only breast, colon/rectum, prostate, and lung have established screening protocols.

The findings were so striking that the meeting scientific co-chair, Fabrice André, MD, PhD, told ESMO the oncology field must prepare for an onslaught of new patients.

“Within the next 5 years, we will need more doctors, surgeons and nurses with more diagnostic and treatment infrastructures to care for the rising number of people who will be identified by multicancer early detection tests,” said Dr. André, who is director of research at Gustave Roussy Cancer Center, Villejuif, France, and future president of ESMO (2025-2026). “We need to involve all stakeholders in deciding new pathways of care. We need to agree who will be tested and when and where tests will be carried out, and to anticipate the changes that will happen as a result of these tests.”

But first, he urged, the need for comparative trials “across all types of cancer to find out if having an early detection test affects morbidity and mortality. We also need to know how the tests benefit patients, and how to discuss the results with them,” Dr. André said.
 

Demand may burden health systems

Dr. Flora suggested that companies like Grail are rushing their product to market without conducting long-term sizable clinical trials.

“These diagnostic companies are a billion dollar publicly traded or venture capital-funded companies that are losing millions of dollars a quarter as they’re scaling up these tests. So, there is some pressure on the sales forces ... to start moving product long before the science has met our lowest areas for entry,” Dr. Flora said. “They are aggressively marketing to a primary care audience that knows nothing about MCEDs. It’s a sales-driven development solving a problem we all believe is real, but we don’t know if it actually solves the problem.”

There are many unanswered questions, he said. Among these include whether the tests do indeed extend survival. “What they’re suggesting – that is if the blood test detects it – that we’re going to save your life. That’s not yet been proven. This is where the providers are pushing back against these industry types to say: ‘This is the wild west right now.’ It’s very irresponsible to go out there and try to sell hundreds of millions of dollars of product to doctors who have never studied genetics,” Dr. Flora said.

Grail’s chief medical officer Jeff Venstrom, MD, however, said physicians don’t need a background in genetic testing to order or interpret Galleri because it’s not a genetic test. Genetic tests look for genetic variants associated with cancer risk, which Galleri does not. MCED tests rely on genomic profiling to identify alterations in tumors.

“Maybe there’s still confusion in the market, which is common for new technologies when they’re initially launched. This is not a 23andMe test. We do not report germline mutations that have implications for cancer risk. We’re using this blood sample to test for the presence or absence of a cancer signal. The test result is very clear and simple: One area of the report says ‘yes’ or ‘no.’ It is a binary result that says if a signal is detected or not. The second provides additional information around where that signal could be coming from,” he said.

Galleri could fill a huge unmet need in cancer prevention, Dr. Venstrom said. Not only could it detect cancer at an earlier stage, but it could serve as a screening tool for cancers like pancreatic cancer in which screening is not available.

The test is not intended to replace standard of care screening, he said. The ordering provider should have a conversation with the patient about overall cancer risk. “Are you smoking? What’s your risk of obesity-associated cancers? Do you have a family history of cancer? I think this should all be in the context of a good conversation around preventative care,” he said.
 

Planning and prep in Boston

In Boston, Aparna Parikh, MD, an oncologist who specializes in gastrointestinal cancers, agreed that MCED testing has forced her team at the Mass General Cancer Center global cancer care program to think outside of the box.

“We’re a major academic center and it’s not easy [because] this is all uncharted territory,” she said. “We all recognize there are more tests coming, and they are here to stay. As a health system, we have to be ready to manage not only the tests, but patient anxieties, and all the complexities that come with it. We just don’t know yet how to best navigate.”

Although Dr. Parikh’s center has set up a working group tasked with organizing an outpatient clinic for patients with positive MCED tests, the current system is haphazard.

“Right now, it gets bounced around between people,” she explained. “Sometimes, patients are getting referred to the oncology team rather than the primary care team to try to sort out where the cancer signal is coming from, that is, if it’s not immediately obvious. No one really knows who should be the right person to own it,” Dr. Parikh said. While the test is supposed to give tissue-specific results, “it’s not perfect” and sometimes imaging and other work-ups are needed to locate the source of the signa.

“A group of four or five oncologists get looped in and then we’re trying to sort it out on a case-by-case basis, but understanding that with more and more tests coming, that kind of ad hoc approach isn’t going to be sufficient. We need a happy medium between the primary care and the disease specific oncologist, someone who can kind of help think through the diagnostic workup until they have a cancer diagnosis to get them to the right place,” Dr. Parikh said.

Dr. Venstrom said Grail is committed to providing support to clinicians in these situations. “We’re doing everything we can with our medical education forums. We have this pretty intense and extensive postpositive suite of resources,” he explained. “Some of our doctors on staff call the ordering provider within 24 hours just to clarify if there are any questions or confusion from the report. For example, if it suggests the signal is coming from the lung, we provide additional support around additional workups.”
 

Out-of-pocket test may widen disparities in care

With the exception of a few health insurance companies that have committed to covering some of the cost for the test, Galleri is an out-of-pocket expense.

Dr. Venstrom acknowledged that broad insurance coverage for the Galleri test remains a hurdle, although “we’ve secured coverage for a handful of companies of self-insured employers and forward-thinking insurers.” This includes partnerships with Point32Health, and Alignment Health, among others, he said.

There is also growing support among more than 400 cancer organizations for the Multi-Cancer Early Detection Screening Coverage Act to accelerate coverage for Medicare beneficiaries. “We are constantly trying to understand the evidence that’s needed for payors to make sure that we get the broadest access possible for this test,” he said.
 

The first positive test result

Back at St. Elizabeth Healthcare where they’ve only seen one positive MCED test result thus far, Dr. Flora is more concerned about patients giving informed consent before they even get the test. “When the reps started hammering our primary care doctors, we sent communiques throughout the system saying that we would very much like to regulate this to make sure that before our patients receive accidental harm, that they at least have a conversation with somebody who understands the test,” he explained.

All 15 patients who requested the test at the hospital were first required to discuss the implications with a genetic counselor who is part of the system. “We are really pro–cancer screening,” he said, but added his hospital is “not pumped” about the Galleri test. “We’re being very cautious about overstatements made by sales guys to our primary care doctors, so we’re letting our own precision medicine people handle it.”

There’s a similar system in place at Community Health Network, a nonprofit health system with nine hospitals and 1,300 employee providers throughout Central Indiana. Patrick McGill, MD, a primary care physician and chief analytics officer for the network says they have streamlined patients with positive tests through their high-risk oncology clinic. “They don’t go straight to a medical oncologist which I know some systems are struggling with,” he said. “They get additional testing, whether it’s imaging they might need or other lab testing. We’ve had a few lung positives, and a few leukemia positives which might go straight to medical oncology. I think we had one breast that was positive so she got additional breast imaging.”

Through its foundation, CHN will offer 2,000 tests free of charge. “We decided to take cost off the table with this funding,” Dr. McGill said. “A lot of health systems I talk to are always concerned that insurance doesn’t cover it and it’s cost prohibitive. Is it creating additional disparities because only people who can afford it can get the test?”

Dr. Schrag serves as an uncompensated advisor for Grail. Previously, while with the Dana-Farber Cancer Institute, she received research funding from Grail.

A healthier lifestyle mitigated the impact of genetic factors on the risk of thyroid cancer, in a study based on data from more than 260,000 individuals.

Thyroid cancer has increased globally in recent years and ranks 9th among 36 cancers worldwide, at a considerable cost to health care systems, wrote Xiuming Feng of Guangxi Medical University, Nanning, Guangxi, China, and colleagues.

SciePro/Science Source

Both genetic and lifestyle factors are related to thyroid cancer; previous research suggests a heritability of about 50%, but data on the impact of modifiable lifestyle factors on thyroid cancer are limited, the researchers said.

In a prospective cohort study published in JAMA Network Open, the researchers used data from the UK Biobank and recruited adults aged 40-69 years during March 2006–October 2010. The final study population included 264,956 individuals of European descent. The median age of the participants was 57 years, and 52% were women.

Data on lifestyle behaviors were collected using interviews and questionnaires. The researchers constructed a total lifestyle score based on five variables: diet, physical activity, weight, smoking, and alcohol consumption. Each variable was assigned a score of 0 or 1, with 1 being favorable lifestyle behavior. Lifestyle was divided into three categories: unfavorable (scores 0-1), intermediate (score 2), and favorable (scores 3-5).

Each individual’s polygenic risk score (PRS) was categorized as low, intermediate, or high based on a meta–genome-wide association study of three cohorts.

The main outcome was the development of thyroid cancer.

The researchers identified 423 incident thyroid cancer cases over a median follow-up of 11.1 years.

Overall, higher PRSs were significantly associated with thyroid cancer (hazard ratio, 2.25; 95% confidence interval [CI], 1.91-2.64; P < .00001) as was an unfavorable lifestyle score (HR, 1.93; 95% CI, 1.50-2.49; P < .001 for trend).

An unfavorable lifestyle was significantly associated with thyroid cancer in the highest PRS group, and individuals with high PRS and unfavorable lifestyle had a nearly fivefold increased risk of thyroid cancer (HR, 4.89; 95% CI, 3.03-7.91; P < .001). By extension, “Adherence to a healthier lifestyle could decrease the incidence of thyroid cancer in individuals with a higher PRS,” the researchers wrote in their discussion.

The findings were limited by several factors, including the availability of only baseline lifestyle data, and lack of data on iodine intake, radiation exposure, experience, and family history, the researchers noted. Other limitations include the potential lack of generalizability to populations other than the individuals of European descent in the current study, they said.

However, the study is the first known to address the association among lifestyle, genetic factors, and risk of thyroid cancer, and was strengthened by the large study population, and the results suggest that lifestyle interventions may help reduce the risk of thyroid cancer in those with a genetic predisposition, they concluded.

Healthy living can make a difference

The incidence of thyroid cancer has increased annually, and exploring the possible risk factors could prevent the occurrence of thyroid cancer, corresponding author Xiaobo Yang, PhD, said in an interview.

Previous studies have reported that thyroid cancer is related to genetics and lifestyle, said Dr. Yang. “However, whether healthy lifestyle was associated with thyroid cancer risk and could attenuate the impact of genetic variants on thyroid cancer remains equivocal; therefore, it is crucial to determine the associations between genetic and lifestyle with thyroid cancer,” he said.

“To our surprise, we found that adherence to healthier lifestyle also could reduce the risk of thyroid cancer in those with high genetic predispositions,” said Dr. Yang. “The findings highlight the potential role of lifestyle interventions on thyroid cancer, especially in those with high genetic risk, because the heritability of thyroid cancer was very high, approximately 50%,” he said. “More attention should be paid to the role of healthier lifestyle in the prevention of cancer,” he added.

“Adherence to a healthier lifestyle could decrease the risk of thyroid cancer, which is the important message for clinicians,” said Dr. Yang. “It is not too soon to comment on implications for clinical practice, because many studies have maintained the consistent comment that healthier lifestyle could prevent the occurrence of cancer,” he said.

The relationship between sex-specific lifestyle factors such as smoking and alcohol use and thyroid cancer remains uncertain, and more research is needed to validate these associations, Dr. Yang said. More research also is needed to confirm the complex mechanism between lifestyle and genetics in thyroid cancer, he added.

The study was supported by the National Key R&D Program of China and the National Natural Science Foundation of China. The researchers had no financial conflicts to disclose.

A healthier lifestyle mitigated the impact of genetic factors on the risk of thyroid cancer, in a study based on data from more than 260,000 individuals.

Thyroid cancer has increased globally in recent years and ranks 9th among 36 cancers worldwide, at a considerable cost to health care systems, wrote Xiuming Feng of Guangxi Medical University, Nanning, Guangxi, China, and colleagues.

SciePro/Science Source

Both genetic and lifestyle factors are related to thyroid cancer; previous research suggests a heritability of about 50%, but data on the impact of modifiable lifestyle factors on thyroid cancer are limited, the researchers said.

In a prospective cohort study published in JAMA Network Open, the researchers used data from the UK Biobank and recruited adults aged 40-69 years during March 2006–October 2010. The final study population included 264,956 individuals of European descent. The median age of the participants was 57 years, and 52% were women.

Data on lifestyle behaviors were collected using interviews and questionnaires. The researchers constructed a total lifestyle score based on five variables: diet, physical activity, weight, smoking, and alcohol consumption. Each variable was assigned a score of 0 or 1, with 1 being favorable lifestyle behavior. Lifestyle was divided into three categories: unfavorable (scores 0-1), intermediate (score 2), and favorable (scores 3-5).

Each individual’s polygenic risk score (PRS) was categorized as low, intermediate, or high based on a meta–genome-wide association study of three cohorts.

The main outcome was the development of thyroid cancer.

The researchers identified 423 incident thyroid cancer cases over a median follow-up of 11.1 years.

Overall, higher PRSs were significantly associated with thyroid cancer (hazard ratio, 2.25; 95% confidence interval [CI], 1.91-2.64; P < .00001) as was an unfavorable lifestyle score (HR, 1.93; 95% CI, 1.50-2.49; P < .001 for trend).

An unfavorable lifestyle was significantly associated with thyroid cancer in the highest PRS group, and individuals with high PRS and unfavorable lifestyle had a nearly fivefold increased risk of thyroid cancer (HR, 4.89; 95% CI, 3.03-7.91; P < .001). By extension, “Adherence to a healthier lifestyle could decrease the incidence of thyroid cancer in individuals with a higher PRS,” the researchers wrote in their discussion.

The findings were limited by several factors, including the availability of only baseline lifestyle data, and lack of data on iodine intake, radiation exposure, experience, and family history, the researchers noted. Other limitations include the potential lack of generalizability to populations other than the individuals of European descent in the current study, they said.

However, the study is the first known to address the association among lifestyle, genetic factors, and risk of thyroid cancer, and was strengthened by the large study population, and the results suggest that lifestyle interventions may help reduce the risk of thyroid cancer in those with a genetic predisposition, they concluded.

Healthy living can make a difference

The incidence of thyroid cancer has increased annually, and exploring the possible risk factors could prevent the occurrence of thyroid cancer, corresponding author Xiaobo Yang, PhD, said in an interview.

Previous studies have reported that thyroid cancer is related to genetics and lifestyle, said Dr. Yang. “However, whether healthy lifestyle was associated with thyroid cancer risk and could attenuate the impact of genetic variants on thyroid cancer remains equivocal; therefore, it is crucial to determine the associations between genetic and lifestyle with thyroid cancer,” he said.

“To our surprise, we found that adherence to healthier lifestyle also could reduce the risk of thyroid cancer in those with high genetic predispositions,” said Dr. Yang. “The findings highlight the potential role of lifestyle interventions on thyroid cancer, especially in those with high genetic risk, because the heritability of thyroid cancer was very high, approximately 50%,” he said. “More attention should be paid to the role of healthier lifestyle in the prevention of cancer,” he added.

“Adherence to a healthier lifestyle could decrease the risk of thyroid cancer, which is the important message for clinicians,” said Dr. Yang. “It is not too soon to comment on implications for clinical practice, because many studies have maintained the consistent comment that healthier lifestyle could prevent the occurrence of cancer,” he said.

The relationship between sex-specific lifestyle factors such as smoking and alcohol use and thyroid cancer remains uncertain, and more research is needed to validate these associations, Dr. Yang said. More research also is needed to confirm the complex mechanism between lifestyle and genetics in thyroid cancer, he added.

The study was supported by the National Key R&D Program of China and the National Natural Science Foundation of China. The researchers had no financial conflicts to disclose.

A healthier lifestyle mitigated the impact of genetic factors on the risk of thyroid cancer, in a study based on data from more than 260,000 individuals.

Thyroid cancer has increased globally in recent years and ranks 9th among 36 cancers worldwide, at a considerable cost to health care systems, wrote Xiuming Feng of Guangxi Medical University, Nanning, Guangxi, China, and colleagues.

SciePro/Science Source

Both genetic and lifestyle factors are related to thyroid cancer; previous research suggests a heritability of about 50%, but data on the impact of modifiable lifestyle factors on thyroid cancer are limited, the researchers said.

In a prospective cohort study published in JAMA Network Open, the researchers used data from the UK Biobank and recruited adults aged 40-69 years during March 2006–October 2010. The final study population included 264,956 individuals of European descent. The median age of the participants was 57 years, and 52% were women.

Data on lifestyle behaviors were collected using interviews and questionnaires. The researchers constructed a total lifestyle score based on five variables: diet, physical activity, weight, smoking, and alcohol consumption. Each variable was assigned a score of 0 or 1, with 1 being favorable lifestyle behavior. Lifestyle was divided into three categories: unfavorable (scores 0-1), intermediate (score 2), and favorable (scores 3-5).

Each individual’s polygenic risk score (PRS) was categorized as low, intermediate, or high based on a meta–genome-wide association study of three cohorts.

The main outcome was the development of thyroid cancer.

The researchers identified 423 incident thyroid cancer cases over a median follow-up of 11.1 years.

Overall, higher PRSs were significantly associated with thyroid cancer (hazard ratio, 2.25; 95% confidence interval [CI], 1.91-2.64; P < .00001) as was an unfavorable lifestyle score (HR, 1.93; 95% CI, 1.50-2.49; P < .001 for trend).

An unfavorable lifestyle was significantly associated with thyroid cancer in the highest PRS group, and individuals with high PRS and unfavorable lifestyle had a nearly fivefold increased risk of thyroid cancer (HR, 4.89; 95% CI, 3.03-7.91; P < .001). By extension, “Adherence to a healthier lifestyle could decrease the incidence of thyroid cancer in individuals with a higher PRS,” the researchers wrote in their discussion.

The findings were limited by several factors, including the availability of only baseline lifestyle data, and lack of data on iodine intake, radiation exposure, experience, and family history, the researchers noted. Other limitations include the potential lack of generalizability to populations other than the individuals of European descent in the current study, they said.

However, the study is the first known to address the association among lifestyle, genetic factors, and risk of thyroid cancer, and was strengthened by the large study population, and the results suggest that lifestyle interventions may help reduce the risk of thyroid cancer in those with a genetic predisposition, they concluded.

Healthy living can make a difference

The incidence of thyroid cancer has increased annually, and exploring the possible risk factors could prevent the occurrence of thyroid cancer, corresponding author Xiaobo Yang, PhD, said in an interview.

Previous studies have reported that thyroid cancer is related to genetics and lifestyle, said Dr. Yang. “However, whether healthy lifestyle was associated with thyroid cancer risk and could attenuate the impact of genetic variants on thyroid cancer remains equivocal; therefore, it is crucial to determine the associations between genetic and lifestyle with thyroid cancer,” he said.

“To our surprise, we found that adherence to healthier lifestyle also could reduce the risk of thyroid cancer in those with high genetic predispositions,” said Dr. Yang. “The findings highlight the potential role of lifestyle interventions on thyroid cancer, especially in those with high genetic risk, because the heritability of thyroid cancer was very high, approximately 50%,” he said. “More attention should be paid to the role of healthier lifestyle in the prevention of cancer,” he added.

“Adherence to a healthier lifestyle could decrease the risk of thyroid cancer, which is the important message for clinicians,” said Dr. Yang. “It is not too soon to comment on implications for clinical practice, because many studies have maintained the consistent comment that healthier lifestyle could prevent the occurrence of cancer,” he said.

The relationship between sex-specific lifestyle factors such as smoking and alcohol use and thyroid cancer remains uncertain, and more research is needed to validate these associations, Dr. Yang said. More research also is needed to confirm the complex mechanism between lifestyle and genetics in thyroid cancer, he added.

The study was supported by the National Key R&D Program of China and the National Natural Science Foundation of China. The researchers had no financial conflicts to disclose.

Children and young adults who are exposed to a single CT scan of the head or neck before age 22 years are at significantly increased risk of developing a brain tumor, particularly glioma, after at least 5 years, according to results of the large EPI-CT study.

“Translation of our risk estimates to the clinical setting indicates that per 10,000 children who received one head CT examination, about one radiation-induced brain cancer is expected during the 5-15 years following the CT examination,” noted lead author Michael Hauptmann, PhD, from the Institute of Biostatistics and Registry Research, Brandenburg Medical School, Neuruppin, Germany, and coauthors.

“Next to the clinical benefit of most CT scans, there is a small risk of cancer from the radiation exposure,” Dr. Hauptmann told this news organization.

“So, CT examinations should only be used when necessary, and if they are used, the lowest achievable dose should be applied,” he said.

The study was published online in The Lancet Oncology.

“This is a thoughtful and well-conducted study by an outstanding multinational team of scientists that adds further weight to the growing body of evidence that has found exposure to CT scanning increases a child’s risk of developing brain cancer,” commented Rebecca Bindman-Smith, MD, from the University of California, San Francisco, who was not involved in the research.

“The results are real, and important,” she told this news organization, adding that “the authors were conservative in their assumptions, and performed a very large number of sensitivity analyses ... to check that the results were robust to a large range of assumptions – and the results changed relatively little.”

“I do not think there is enough awareness [about this risk],” Dr. Hauptmann said. “There is evidence that a nonnegligible number of CTs is unjustified according to guidelines, and there is evidence that doses vary substantially for the same CT between institutions in the same or different countries.”

Indeed, particularly in the United States, “we perform many CT scans in children and even more so in adults that are simply unnecessary,” agreed Dr. Bindman-Smith, who is professor of epidemiology and biostatistics at the University of California, San Francisco. “It is important for patients and providers to understand that nothing we do in medicine is risk free, including CT scanning. If a CT is necessary, the benefit almost certainly outweighs the risk. But if [not], then it should not be obtained. Both patients and providers must make thoroughly considered decisions before asking for or agreeing to a CT.”

She also pointed out that while this study evaluated the risk only for brain cancer, children who undergo head CTs are also at increased risk for leukemia.
 

Dose/response relationship

The study included 658,752 individuals from nine European countries and 276 hospitals. Each patient had received at least one CT scan between 1977 and 2014 before they turned 22 years of age. Eligibility requirements included their being alive at least 5 years after the first scan and that they had not previously been diagnosed with cancer or benign brain tumor.

The radiation dose absorbed to the brain and 33 other organs and tissues was estimated for each participant using a dose reconstruction model that included historical information on CT machine settings, questionnaire data, and Digital Imaging and Communication in Medicine header metadata. “Mean brain dose per head or neck CT examination increased from 1984 until about 1991, following the introduction of multislice CT scanners at which point thereafter the mean dose decreased and then stabilized around 2010,” note the authors.

During a median follow-up of 5.6 years (starting 5 years after the first scan), 165 brain cancers occurred, including 121 (73%) gliomas, as well as a variety of other morphologic changes.

The mean cumulative brain dose, which lagged by 5 years, was 47.4 mGy overall and 76.0 mGy among people with brain cancer.

“We observed a significant positive association between the cumulative number of head or neck CT examinations and the risk of all brain cancers combined (P < .0001), and of gliomas separately (P = .0002),” the team reports, adding that, for a brain dose of 38 mGy, which was the average dose per head or neck CT in 2012-2014, the relative risk of developing brain cancer was 1.5, compared with not undergoing a CT scan, and the excess absolute risk per 100,000 person-years was 1.1.

These findings “can be used to give the patients and their parents important information on the risks of CT examination to balance against the known benefits,” noted Nobuyuki Hamada, PhD, from the Central Research Institute of Electric Power Industry, Tokyo, and Lydia B. Zablotska, MD, PhD, from the University of California, San Francisco, writing in a linked commentary.

“In recent years, rates of CT use have been steady or declined, and various efforts (for instance, in terms of diagnostic reference levels) have been made to justify and optimize CT examinations. Such continued efforts, along with extended epidemiological investigations, would be needed to minimize the risk of brain cancer after pediatric CT examination,” they add.
 

Keeping dose to a minimum

The study’s finding of a dose-response relationship underscores the importance of keeping doses to a minimum, Dr. Bindman-Smith commented. “I do not believe we are doing this nearly enough,” she added.

“In the UCSF International CT Dose Registry, where we have collected CT scans from 165 hospitals on many millions of patients, we found that the average brain dose for a head CT in a 1-year-old is 42 mGy but that this dose varies tremendously, where some children receive a dose of 100 mGy.

“So, a second message is that not only should CT scans be justified and used judiciously, but also they should be optimized, meaning using the lowest dose possible. I personally think there should be regulatory oversight to ensure that patients receive the absolutely lowest doses possible,” she added. “My team at UCSF has written quality measures endorsed by the National Quality Forum as a start for setting explicit standards for how CT should be performed in order to ensure the cancer risks are as low as possible.”

The study was funded through the Belgian Cancer Registry; La Ligue contre le Cancer, L’Institut National du Cancer, France; the Ministry of Health, Labour and Welfare of Japan; the German Federal Ministry of Education and Research; Worldwide Cancer Research; the Dutch Cancer Society; the Research Council of Norway; Consejo de Seguridad Nuclear, Generalitat deCatalunya, Spain; the U.S. National Cancer Institute; the U.K. National Institute for Health Research; and Public Health England. Dr. Hauptmann has disclosed no relevant financial relationships. Other investigators’ relevant financial relationships are listed in the original article. Dr. Hamada and Dr. Zablotska disclosed no relevant financial relationships.

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

Children and young adults who are exposed to a single CT scan of the head or neck before age 22 years are at significantly increased risk of developing a brain tumor, particularly glioma, after at least 5 years, according to results of the large EPI-CT study.

“Translation of our risk estimates to the clinical setting indicates that per 10,000 children who received one head CT examination, about one radiation-induced brain cancer is expected during the 5-15 years following the CT examination,” noted lead author Michael Hauptmann, PhD, from the Institute of Biostatistics and Registry Research, Brandenburg Medical School, Neuruppin, Germany, and coauthors.

“Next to the clinical benefit of most CT scans, there is a small risk of cancer from the radiation exposure,” Dr. Hauptmann told this news organization.

“So, CT examinations should only be used when necessary, and if they are used, the lowest achievable dose should be applied,” he said.

The study was published online in The Lancet Oncology.

“This is a thoughtful and well-conducted study by an outstanding multinational team of scientists that adds further weight to the growing body of evidence that has found exposure to CT scanning increases a child’s risk of developing brain cancer,” commented Rebecca Bindman-Smith, MD, from the University of California, San Francisco, who was not involved in the research.

“The results are real, and important,” she told this news organization, adding that “the authors were conservative in their assumptions, and performed a very large number of sensitivity analyses ... to check that the results were robust to a large range of assumptions – and the results changed relatively little.”

“I do not think there is enough awareness [about this risk],” Dr. Hauptmann said. “There is evidence that a nonnegligible number of CTs is unjustified according to guidelines, and there is evidence that doses vary substantially for the same CT between institutions in the same or different countries.”

Indeed, particularly in the United States, “we perform many CT scans in children and even more so in adults that are simply unnecessary,” agreed Dr. Bindman-Smith, who is professor of epidemiology and biostatistics at the University of California, San Francisco. “It is important for patients and providers to understand that nothing we do in medicine is risk free, including CT scanning. If a CT is necessary, the benefit almost certainly outweighs the risk. But if [not], then it should not be obtained. Both patients and providers must make thoroughly considered decisions before asking for or agreeing to a CT.”

She also pointed out that while this study evaluated the risk only for brain cancer, children who undergo head CTs are also at increased risk for leukemia.
 

Dose/response relationship

The study included 658,752 individuals from nine European countries and 276 hospitals. Each patient had received at least one CT scan between 1977 and 2014 before they turned 22 years of age. Eligibility requirements included their being alive at least 5 years after the first scan and that they had not previously been diagnosed with cancer or benign brain tumor.

The radiation dose absorbed to the brain and 33 other organs and tissues was estimated for each participant using a dose reconstruction model that included historical information on CT machine settings, questionnaire data, and Digital Imaging and Communication in Medicine header metadata. “Mean brain dose per head or neck CT examination increased from 1984 until about 1991, following the introduction of multislice CT scanners at which point thereafter the mean dose decreased and then stabilized around 2010,” note the authors.

During a median follow-up of 5.6 years (starting 5 years after the first scan), 165 brain cancers occurred, including 121 (73%) gliomas, as well as a variety of other morphologic changes.

The mean cumulative brain dose, which lagged by 5 years, was 47.4 mGy overall and 76.0 mGy among people with brain cancer.

“We observed a significant positive association between the cumulative number of head or neck CT examinations and the risk of all brain cancers combined (P < .0001), and of gliomas separately (P = .0002),” the team reports, adding that, for a brain dose of 38 mGy, which was the average dose per head or neck CT in 2012-2014, the relative risk of developing brain cancer was 1.5, compared with not undergoing a CT scan, and the excess absolute risk per 100,000 person-years was 1.1.

These findings “can be used to give the patients and their parents important information on the risks of CT examination to balance against the known benefits,” noted Nobuyuki Hamada, PhD, from the Central Research Institute of Electric Power Industry, Tokyo, and Lydia B. Zablotska, MD, PhD, from the University of California, San Francisco, writing in a linked commentary.

“In recent years, rates of CT use have been steady or declined, and various efforts (for instance, in terms of diagnostic reference levels) have been made to justify and optimize CT examinations. Such continued efforts, along with extended epidemiological investigations, would be needed to minimize the risk of brain cancer after pediatric CT examination,” they add.
 

Keeping dose to a minimum

The study’s finding of a dose-response relationship underscores the importance of keeping doses to a minimum, Dr. Bindman-Smith commented. “I do not believe we are doing this nearly enough,” she added.

“In the UCSF International CT Dose Registry, where we have collected CT scans from 165 hospitals on many millions of patients, we found that the average brain dose for a head CT in a 1-year-old is 42 mGy but that this dose varies tremendously, where some children receive a dose of 100 mGy.

“So, a second message is that not only should CT scans be justified and used judiciously, but also they should be optimized, meaning using the lowest dose possible. I personally think there should be regulatory oversight to ensure that patients receive the absolutely lowest doses possible,” she added. “My team at UCSF has written quality measures endorsed by the National Quality Forum as a start for setting explicit standards for how CT should be performed in order to ensure the cancer risks are as low as possible.”

The study was funded through the Belgian Cancer Registry; La Ligue contre le Cancer, L’Institut National du Cancer, France; the Ministry of Health, Labour and Welfare of Japan; the German Federal Ministry of Education and Research; Worldwide Cancer Research; the Dutch Cancer Society; the Research Council of Norway; Consejo de Seguridad Nuclear, Generalitat deCatalunya, Spain; the U.S. National Cancer Institute; the U.K. National Institute for Health Research; and Public Health England. Dr. Hauptmann has disclosed no relevant financial relationships. Other investigators’ relevant financial relationships are listed in the original article. Dr. Hamada and Dr. Zablotska disclosed no relevant financial relationships.

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

Children and young adults who are exposed to a single CT scan of the head or neck before age 22 years are at significantly increased risk of developing a brain tumor, particularly glioma, after at least 5 years, according to results of the large EPI-CT study.

“Translation of our risk estimates to the clinical setting indicates that per 10,000 children who received one head CT examination, about one radiation-induced brain cancer is expected during the 5-15 years following the CT examination,” noted lead author Michael Hauptmann, PhD, from the Institute of Biostatistics and Registry Research, Brandenburg Medical School, Neuruppin, Germany, and coauthors.

“Next to the clinical benefit of most CT scans, there is a small risk of cancer from the radiation exposure,” Dr. Hauptmann told this news organization.

“So, CT examinations should only be used when necessary, and if they are used, the lowest achievable dose should be applied,” he said.

The study was published online in The Lancet Oncology.

“This is a thoughtful and well-conducted study by an outstanding multinational team of scientists that adds further weight to the growing body of evidence that has found exposure to CT scanning increases a child’s risk of developing brain cancer,” commented Rebecca Bindman-Smith, MD, from the University of California, San Francisco, who was not involved in the research.

“The results are real, and important,” she told this news organization, adding that “the authors were conservative in their assumptions, and performed a very large number of sensitivity analyses ... to check that the results were robust to a large range of assumptions – and the results changed relatively little.”

“I do not think there is enough awareness [about this risk],” Dr. Hauptmann said. “There is evidence that a nonnegligible number of CTs is unjustified according to guidelines, and there is evidence that doses vary substantially for the same CT between institutions in the same or different countries.”

Indeed, particularly in the United States, “we perform many CT scans in children and even more so in adults that are simply unnecessary,” agreed Dr. Bindman-Smith, who is professor of epidemiology and biostatistics at the University of California, San Francisco. “It is important for patients and providers to understand that nothing we do in medicine is risk free, including CT scanning. If a CT is necessary, the benefit almost certainly outweighs the risk. But if [not], then it should not be obtained. Both patients and providers must make thoroughly considered decisions before asking for or agreeing to a CT.”

She also pointed out that while this study evaluated the risk only for brain cancer, children who undergo head CTs are also at increased risk for leukemia.
 

Dose/response relationship

The study included 658,752 individuals from nine European countries and 276 hospitals. Each patient had received at least one CT scan between 1977 and 2014 before they turned 22 years of age. Eligibility requirements included their being alive at least 5 years after the first scan and that they had not previously been diagnosed with cancer or benign brain tumor.

The radiation dose absorbed to the brain and 33 other organs and tissues was estimated for each participant using a dose reconstruction model that included historical information on CT machine settings, questionnaire data, and Digital Imaging and Communication in Medicine header metadata. “Mean brain dose per head or neck CT examination increased from 1984 until about 1991, following the introduction of multislice CT scanners at which point thereafter the mean dose decreased and then stabilized around 2010,” note the authors.

During a median follow-up of 5.6 years (starting 5 years after the first scan), 165 brain cancers occurred, including 121 (73%) gliomas, as well as a variety of other morphologic changes.

The mean cumulative brain dose, which lagged by 5 years, was 47.4 mGy overall and 76.0 mGy among people with brain cancer.

“We observed a significant positive association between the cumulative number of head or neck CT examinations and the risk of all brain cancers combined (P < .0001), and of gliomas separately (P = .0002),” the team reports, adding that, for a brain dose of 38 mGy, which was the average dose per head or neck CT in 2012-2014, the relative risk of developing brain cancer was 1.5, compared with not undergoing a CT scan, and the excess absolute risk per 100,000 person-years was 1.1.

These findings “can be used to give the patients and their parents important information on the risks of CT examination to balance against the known benefits,” noted Nobuyuki Hamada, PhD, from the Central Research Institute of Electric Power Industry, Tokyo, and Lydia B. Zablotska, MD, PhD, from the University of California, San Francisco, writing in a linked commentary.

“In recent years, rates of CT use have been steady or declined, and various efforts (for instance, in terms of diagnostic reference levels) have been made to justify and optimize CT examinations. Such continued efforts, along with extended epidemiological investigations, would be needed to minimize the risk of brain cancer after pediatric CT examination,” they add.
 

Keeping dose to a minimum

The study’s finding of a dose-response relationship underscores the importance of keeping doses to a minimum, Dr. Bindman-Smith commented. “I do not believe we are doing this nearly enough,” she added.

“In the UCSF International CT Dose Registry, where we have collected CT scans from 165 hospitals on many millions of patients, we found that the average brain dose for a head CT in a 1-year-old is 42 mGy but that this dose varies tremendously, where some children receive a dose of 100 mGy.

“So, a second message is that not only should CT scans be justified and used judiciously, but also they should be optimized, meaning using the lowest dose possible. I personally think there should be regulatory oversight to ensure that patients receive the absolutely lowest doses possible,” she added. “My team at UCSF has written quality measures endorsed by the National Quality Forum as a start for setting explicit standards for how CT should be performed in order to ensure the cancer risks are as low as possible.”

The study was funded through the Belgian Cancer Registry; La Ligue contre le Cancer, L’Institut National du Cancer, France; the Ministry of Health, Labour and Welfare of Japan; the German Federal Ministry of Education and Research; Worldwide Cancer Research; the Dutch Cancer Society; the Research Council of Norway; Consejo de Seguridad Nuclear, Generalitat deCatalunya, Spain; the U.S. National Cancer Institute; the U.K. National Institute for Health Research; and Public Health England. Dr. Hauptmann has disclosed no relevant financial relationships. Other investigators’ relevant financial relationships are listed in the original article. Dr. Hamada and Dr. Zablotska disclosed no relevant financial relationships.

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

It had only been 3 weeks since I first met this patient. She presented with an advanced case of colon cancer, but instead of treatment, we had to have a serious talk about death and dying and the goals of care. She died soon after our talk.

Within the course of 2 weeks I saw another new patient, but this time with pancreatic cancer that metastasized to the liver. “When can we start treatment?” he asked. Like my female patient with colon cancer, he was diagnosed too late as he was already in an incurable stage. He was shocked to learn that his condition was in stage 4, that achieving remission would be difficult and a cure, not likely. Certainly, standard of care treatments and clinical trials offered him hope, but they were unlikely to change the outcome.

We take a course in this – that is, in giving bad news, but every doctor has his or her own approach. Some are so uncomfortable with the talk, they choose avoidance and adopt the “look like you gotta go approach.” Or, the doctor may schedule another treatment or another test with the intention of avoiding end-of-life discussions. Other doctors opt for straight talk: “I think you should get your affairs in order. You’ve got 3 months to live.” These are extreme behaviors I wouldn’t recommend.

In my practice, I sit with my patients and explain the diagnosis. After discussing all options and the advanced stage and diagnosis, it ultimately comes down to “Win or lose, I will be here to take care of you.” Sometimes there is therapy that may help, but either way, the patient understands that death is a real possibility.

I find that people just want to know if there is hope. A different treatment regimen or a clinical trial may (or may not) extend their life. And while we cannot predict outcomes, we can give them hope. You can’t shut down hope. True for some people the cup is always half empty, but most people want to live and are optimistic no matter how small the chances are.

These conversations are very difficult. I don’t like them, but then I don’t avoid them either. Fortunately, patients don’t usually come to my office for the first visit presenting with advanced disease. In the cases I described above, one patient had been experiencing unexplained weight loss, but didn’t share it with a physician. And, for the patient with pancreatic cancer, other than some discomfort in the last couple of weeks, the disease was not associated with other symptoms. But the absence of symptoms should not in any way rule out a malignant disease. A diagnosis should be based on a complete evaluation of signs and symptoms followed by testing.

We’ve got to be able to take the time to listen to our patients during these encounters. We may not spend as much time as we should because we’re so busy now and we’re slaves to EMRs. It helps if we take more time to probe symptoms a little longer, especially in the primary care setting.

It is possible for a patient with cancer to be asymptomatic up until the later stages of the disease. A study published in ESMO Open in 2020 found that fewer than half of patients with stage 4 non–small cell lung cancer have only one or two symptoms at diagnosis regardless of whether the patient was a smoker. In this study only 33% of patients reported having a cough and 25% had chest pain.

A study presented in October at the United European Gastroenterology Week found that of 600 pancreatic cancer cases, 46 of these were not detected by CT or MRI conducted 3-18 months prior to diagnosis. Of the 46 cases, 26% were not picked up by the radiologist and the rest were largely as a result of imaging changes over time. Radiology techniques are good, but they cannot pick up lesions that are too small. And some lesions, particularly in pancreatic cancer, can grow and metastasize rather quickly.

When a patient is diagnosed with advanced disease, it is most often simply because of the nature of the disease. But sometimes patients put off scheduling a doctor visit because of fear of the potential for bad news or fear of the doctor belittling their symptoms. Some tell me they were “just hoping the symptoms would disappear.” Waiting too long to see a doctor is never a good idea because timing is crucial. In many cases, there is a small window of opportunity to treat disease if remission is to be achieved.


Dr. Henry is a practicing clinical oncologist with PennMedicine in Philadelphia where he also serves as Vice Chair of the Department of Medicine at Pennsylvania Hospital.
 

This article was updated 12/7/22.

It had only been 3 weeks since I first met this patient. She presented with an advanced case of colon cancer, but instead of treatment, we had to have a serious talk about death and dying and the goals of care. She died soon after our talk.

Within the course of 2 weeks I saw another new patient, but this time with pancreatic cancer that metastasized to the liver. “When can we start treatment?” he asked. Like my female patient with colon cancer, he was diagnosed too late as he was already in an incurable stage. He was shocked to learn that his condition was in stage 4, that achieving remission would be difficult and a cure, not likely. Certainly, standard of care treatments and clinical trials offered him hope, but they were unlikely to change the outcome.

We take a course in this – that is, in giving bad news, but every doctor has his or her own approach. Some are so uncomfortable with the talk, they choose avoidance and adopt the “look like you gotta go approach.” Or, the doctor may schedule another treatment or another test with the intention of avoiding end-of-life discussions. Other doctors opt for straight talk: “I think you should get your affairs in order. You’ve got 3 months to live.” These are extreme behaviors I wouldn’t recommend.

In my practice, I sit with my patients and explain the diagnosis. After discussing all options and the advanced stage and diagnosis, it ultimately comes down to “Win or lose, I will be here to take care of you.” Sometimes there is therapy that may help, but either way, the patient understands that death is a real possibility.

I find that people just want to know if there is hope. A different treatment regimen or a clinical trial may (or may not) extend their life. And while we cannot predict outcomes, we can give them hope. You can’t shut down hope. True for some people the cup is always half empty, but most people want to live and are optimistic no matter how small the chances are.

These conversations are very difficult. I don’t like them, but then I don’t avoid them either. Fortunately, patients don’t usually come to my office for the first visit presenting with advanced disease. In the cases I described above, one patient had been experiencing unexplained weight loss, but didn’t share it with a physician. And, for the patient with pancreatic cancer, other than some discomfort in the last couple of weeks, the disease was not associated with other symptoms. But the absence of symptoms should not in any way rule out a malignant disease. A diagnosis should be based on a complete evaluation of signs and symptoms followed by testing.

We’ve got to be able to take the time to listen to our patients during these encounters. We may not spend as much time as we should because we’re so busy now and we’re slaves to EMRs. It helps if we take more time to probe symptoms a little longer, especially in the primary care setting.

It is possible for a patient with cancer to be asymptomatic up until the later stages of the disease. A study published in ESMO Open in 2020 found that fewer than half of patients with stage 4 non–small cell lung cancer have only one or two symptoms at diagnosis regardless of whether the patient was a smoker. In this study only 33% of patients reported having a cough and 25% had chest pain.

A study presented in October at the United European Gastroenterology Week found that of 600 pancreatic cancer cases, 46 of these were not detected by CT or MRI conducted 3-18 months prior to diagnosis. Of the 46 cases, 26% were not picked up by the radiologist and the rest were largely as a result of imaging changes over time. Radiology techniques are good, but they cannot pick up lesions that are too small. And some lesions, particularly in pancreatic cancer, can grow and metastasize rather quickly.

When a patient is diagnosed with advanced disease, it is most often simply because of the nature of the disease. But sometimes patients put off scheduling a doctor visit because of fear of the potential for bad news or fear of the doctor belittling their symptoms. Some tell me they were “just hoping the symptoms would disappear.” Waiting too long to see a doctor is never a good idea because timing is crucial. In many cases, there is a small window of opportunity to treat disease if remission is to be achieved.


Dr. Henry is a practicing clinical oncologist with PennMedicine in Philadelphia where he also serves as Vice Chair of the Department of Medicine at Pennsylvania Hospital.
 

This article was updated 12/7/22.

It had only been 3 weeks since I first met this patient. She presented with an advanced case of colon cancer, but instead of treatment, we had to have a serious talk about death and dying and the goals of care. She died soon after our talk.

Within the course of 2 weeks I saw another new patient, but this time with pancreatic cancer that metastasized to the liver. “When can we start treatment?” he asked. Like my female patient with colon cancer, he was diagnosed too late as he was already in an incurable stage. He was shocked to learn that his condition was in stage 4, that achieving remission would be difficult and a cure, not likely. Certainly, standard of care treatments and clinical trials offered him hope, but they were unlikely to change the outcome.

We take a course in this – that is, in giving bad news, but every doctor has his or her own approach. Some are so uncomfortable with the talk, they choose avoidance and adopt the “look like you gotta go approach.” Or, the doctor may schedule another treatment or another test with the intention of avoiding end-of-life discussions. Other doctors opt for straight talk: “I think you should get your affairs in order. You’ve got 3 months to live.” These are extreme behaviors I wouldn’t recommend.

In my practice, I sit with my patients and explain the diagnosis. After discussing all options and the advanced stage and diagnosis, it ultimately comes down to “Win or lose, I will be here to take care of you.” Sometimes there is therapy that may help, but either way, the patient understands that death is a real possibility.

I find that people just want to know if there is hope. A different treatment regimen or a clinical trial may (or may not) extend their life. And while we cannot predict outcomes, we can give them hope. You can’t shut down hope. True for some people the cup is always half empty, but most people want to live and are optimistic no matter how small the chances are.

These conversations are very difficult. I don’t like them, but then I don’t avoid them either. Fortunately, patients don’t usually come to my office for the first visit presenting with advanced disease. In the cases I described above, one patient had been experiencing unexplained weight loss, but didn’t share it with a physician. And, for the patient with pancreatic cancer, other than some discomfort in the last couple of weeks, the disease was not associated with other symptoms. But the absence of symptoms should not in any way rule out a malignant disease. A diagnosis should be based on a complete evaluation of signs and symptoms followed by testing.

We’ve got to be able to take the time to listen to our patients during these encounters. We may not spend as much time as we should because we’re so busy now and we’re slaves to EMRs. It helps if we take more time to probe symptoms a little longer, especially in the primary care setting.

It is possible for a patient with cancer to be asymptomatic up until the later stages of the disease. A study published in ESMO Open in 2020 found that fewer than half of patients with stage 4 non–small cell lung cancer have only one or two symptoms at diagnosis regardless of whether the patient was a smoker. In this study only 33% of patients reported having a cough and 25% had chest pain.

A study presented in October at the United European Gastroenterology Week found that of 600 pancreatic cancer cases, 46 of these were not detected by CT or MRI conducted 3-18 months prior to diagnosis. Of the 46 cases, 26% were not picked up by the radiologist and the rest were largely as a result of imaging changes over time. Radiology techniques are good, but they cannot pick up lesions that are too small. And some lesions, particularly in pancreatic cancer, can grow and metastasize rather quickly.

When a patient is diagnosed with advanced disease, it is most often simply because of the nature of the disease. But sometimes patients put off scheduling a doctor visit because of fear of the potential for bad news or fear of the doctor belittling their symptoms. Some tell me they were “just hoping the symptoms would disappear.” Waiting too long to see a doctor is never a good idea because timing is crucial. In many cases, there is a small window of opportunity to treat disease if remission is to be achieved.


Dr. Henry is a practicing clinical oncologist with PennMedicine in Philadelphia where he also serves as Vice Chair of the Department of Medicine at Pennsylvania Hospital.
 

This article was updated 12/7/22.

In human papillomavirus (HPV)-positive, locally advanced oropharyngeal squamous cell carcinoma, an immune checkpoint blockade regimen combined with radiotherapy led to good survival with a reduction in radiation exposure.

First-line therapy for HPV-positive oropharynx cancer is generally high-dose cisplatin combined with high-dose radiotherapy, but this regimen is associated with significant acute and long-term toxicity.

In previous studies among patients with recurrent or metastatic squamous cell carcinoma, nivolumab (Opdiva, Bristol Myers Squibb) improved survival when combined with platinum-based chemotherapy, and pembrolizumab (Keytruda, Merck) improved survival in recurrent disease compared with chemotherapy plus cetuximab.

Those precedents predicted success for HPV-positive oropharynx cancer, according to Maura Gillison, MD, PhD, who presented the results at a press briefing held in November in advance of the Society for Immunotherapy of Cancer’s 37th Annual Meeting. “Given that HPV-positive oropharynx cancers are characterized by an inflamed tumor microenvironment and HPV oncoproteins are omnipresent, required for cancer survival, and are ideal tumor-specific antigens – we hypothesized that induction and concurrent CTLA-4 and PD-1 immune checkpoint blockade, followed by volume- and dose-adapted IMRT (intensity-modulated radiotherapy), would be an effective alternative to the current standard of care,” said Dr. Gillison, who is a professor of medicine at the University of Texas MD Anderson Cancer Center, Houston.

Anti–PD-L1 therapy is approved for head and neck cancer, but the frontier is moving it into the locally advanced setting in combination with CTLA-4 inhibitors, according to Robert Ferris, MD, PhD, who moderated the press briefing and was lead author of the nivolumab in metastatic squamous cell carcinoma study. He added that recent trial data suggest this approach should be more effective and create more durable responses.

The new data support the approach. “The trial provides compelling data to support a new approach for treating newly diagnosed HPV-positive head and neck cancers. Our goal is to treat this cancer with immunotherapy alone. The results of this trial make me optimistic that this will be achievable,” Dr. Gillison said.
 

The study details

The researchers conducted a phase 2 clinical trial, enrolling 35 patients with newly diagnosed HPV-positive oropharynx cancer who were positive for PD-L1 expression.

Patients received 1 mg/kg ipilimumab (Yervoy, Bristol Myers Squibb) and 3 mg/kg nivolumab over a 6-week cycle, followed by a second cycle that was accompanied by 40-44 Gy radiotherapy for patients with a complete response in their primary tumor, and a boost to 50-66 based on postinduction treatment volume. The protocol reduced dose to the neck from 52 to 36 Gy. The radiation was delivered to only one nodal echelon beyond the involved node. Standard care delivers radiotherapy to essentially the entire neck, Dr. Gillison said.

Grade 3 or higher adverse events occurred in 66% of patients, the majority of which were attributable to radiotherapy. The complete response rate was 94% at 6 months as assessed by PET scan, and 2-year progression-free survival was 86%. After a median follow-up of 14.9 months, all patients were alive and cancer-free.

Overall response rate was 14% following induction, but 96% showed a histologic treatment effect. Tumor viability was less than 5% in 48% of patients, and a molecular complete response was observed in 30% as measured by plasma cell-free HPV. Patients received 36% less radiation than typical of standard of care, and the dose to critical areas was reduced by 50%.

At the press conference, Dr. Ferris asked Dr. Gillison whether the researchers observed a spike in cell-free HPV DNA before the decline occurred, suggesting evidence of tumor death and DNA release.

“We did see in a remarkable number of patients within 2 weeks of the first dose, a very strong peak in the cell-free HPV DNA, followed by a rapid decline. In those patients who still have viable tumor at the end of induction immunotherapy, we saw a second robust peak in cell-free HPV DNA at the start of radiation, with rapid clearance. So that gave us confidence that (among) those patients who had cell-free HPV clearance by the end of induction, followed by no further detection through radiation, that it’s an excellent surrogate for tumor control,” Dr. Gillison said.

Dr. Gillison has financial relationships with Eisai, Exilixis, Caladrius, iTeos, Istari, Seagen, Sensei, Bicara, Mirati, Coherus, Debiopharm, Kura, Shattuck, Nektar, Ipsen, EMD Serono, Gilead, LXS, BioNTech, Merck, Bristol Myers Squibb, Bayer, Roche, Genocea, NewLink Genetics, Aspyrian, TRM Oncology, Amgen, AstraZeneca, Celgene, and Agenus. Dr. Ferris has financial relationships with Bristol Myers Squibb, AstraZeneca/MedImmune, Merck, and Celgene.

In human papillomavirus (HPV)-positive, locally advanced oropharyngeal squamous cell carcinoma, an immune checkpoint blockade regimen combined with radiotherapy led to good survival with a reduction in radiation exposure.

First-line therapy for HPV-positive oropharynx cancer is generally high-dose cisplatin combined with high-dose radiotherapy, but this regimen is associated with significant acute and long-term toxicity.

In previous studies among patients with recurrent or metastatic squamous cell carcinoma, nivolumab (Opdiva, Bristol Myers Squibb) improved survival when combined with platinum-based chemotherapy, and pembrolizumab (Keytruda, Merck) improved survival in recurrent disease compared with chemotherapy plus cetuximab.

Those precedents predicted success for HPV-positive oropharynx cancer, according to Maura Gillison, MD, PhD, who presented the results at a press briefing held in November in advance of the Society for Immunotherapy of Cancer’s 37th Annual Meeting. “Given that HPV-positive oropharynx cancers are characterized by an inflamed tumor microenvironment and HPV oncoproteins are omnipresent, required for cancer survival, and are ideal tumor-specific antigens – we hypothesized that induction and concurrent CTLA-4 and PD-1 immune checkpoint blockade, followed by volume- and dose-adapted IMRT (intensity-modulated radiotherapy), would be an effective alternative to the current standard of care,” said Dr. Gillison, who is a professor of medicine at the University of Texas MD Anderson Cancer Center, Houston.

Anti–PD-L1 therapy is approved for head and neck cancer, but the frontier is moving it into the locally advanced setting in combination with CTLA-4 inhibitors, according to Robert Ferris, MD, PhD, who moderated the press briefing and was lead author of the nivolumab in metastatic squamous cell carcinoma study. He added that recent trial data suggest this approach should be more effective and create more durable responses.

The new data support the approach. “The trial provides compelling data to support a new approach for treating newly diagnosed HPV-positive head and neck cancers. Our goal is to treat this cancer with immunotherapy alone. The results of this trial make me optimistic that this will be achievable,” Dr. Gillison said.
 

The study details

The researchers conducted a phase 2 clinical trial, enrolling 35 patients with newly diagnosed HPV-positive oropharynx cancer who were positive for PD-L1 expression.

Patients received 1 mg/kg ipilimumab (Yervoy, Bristol Myers Squibb) and 3 mg/kg nivolumab over a 6-week cycle, followed by a second cycle that was accompanied by 40-44 Gy radiotherapy for patients with a complete response in their primary tumor, and a boost to 50-66 based on postinduction treatment volume. The protocol reduced dose to the neck from 52 to 36 Gy. The radiation was delivered to only one nodal echelon beyond the involved node. Standard care delivers radiotherapy to essentially the entire neck, Dr. Gillison said.

Grade 3 or higher adverse events occurred in 66% of patients, the majority of which were attributable to radiotherapy. The complete response rate was 94% at 6 months as assessed by PET scan, and 2-year progression-free survival was 86%. After a median follow-up of 14.9 months, all patients were alive and cancer-free.

Overall response rate was 14% following induction, but 96% showed a histologic treatment effect. Tumor viability was less than 5% in 48% of patients, and a molecular complete response was observed in 30% as measured by plasma cell-free HPV. Patients received 36% less radiation than typical of standard of care, and the dose to critical areas was reduced by 50%.

At the press conference, Dr. Ferris asked Dr. Gillison whether the researchers observed a spike in cell-free HPV DNA before the decline occurred, suggesting evidence of tumor death and DNA release.

“We did see in a remarkable number of patients within 2 weeks of the first dose, a very strong peak in the cell-free HPV DNA, followed by a rapid decline. In those patients who still have viable tumor at the end of induction immunotherapy, we saw a second robust peak in cell-free HPV DNA at the start of radiation, with rapid clearance. So that gave us confidence that (among) those patients who had cell-free HPV clearance by the end of induction, followed by no further detection through radiation, that it’s an excellent surrogate for tumor control,” Dr. Gillison said.

Dr. Gillison has financial relationships with Eisai, Exilixis, Caladrius, iTeos, Istari, Seagen, Sensei, Bicara, Mirati, Coherus, Debiopharm, Kura, Shattuck, Nektar, Ipsen, EMD Serono, Gilead, LXS, BioNTech, Merck, Bristol Myers Squibb, Bayer, Roche, Genocea, NewLink Genetics, Aspyrian, TRM Oncology, Amgen, AstraZeneca, Celgene, and Agenus. Dr. Ferris has financial relationships with Bristol Myers Squibb, AstraZeneca/MedImmune, Merck, and Celgene.

In human papillomavirus (HPV)-positive, locally advanced oropharyngeal squamous cell carcinoma, an immune checkpoint blockade regimen combined with radiotherapy led to good survival with a reduction in radiation exposure.

First-line therapy for HPV-positive oropharynx cancer is generally high-dose cisplatin combined with high-dose radiotherapy, but this regimen is associated with significant acute and long-term toxicity.

In previous studies among patients with recurrent or metastatic squamous cell carcinoma, nivolumab (Opdiva, Bristol Myers Squibb) improved survival when combined with platinum-based chemotherapy, and pembrolizumab (Keytruda, Merck) improved survival in recurrent disease compared with chemotherapy plus cetuximab.

Those precedents predicted success for HPV-positive oropharynx cancer, according to Maura Gillison, MD, PhD, who presented the results at a press briefing held in November in advance of the Society for Immunotherapy of Cancer’s 37th Annual Meeting. “Given that HPV-positive oropharynx cancers are characterized by an inflamed tumor microenvironment and HPV oncoproteins are omnipresent, required for cancer survival, and are ideal tumor-specific antigens – we hypothesized that induction and concurrent CTLA-4 and PD-1 immune checkpoint blockade, followed by volume- and dose-adapted IMRT (intensity-modulated radiotherapy), would be an effective alternative to the current standard of care,” said Dr. Gillison, who is a professor of medicine at the University of Texas MD Anderson Cancer Center, Houston.

Anti–PD-L1 therapy is approved for head and neck cancer, but the frontier is moving it into the locally advanced setting in combination with CTLA-4 inhibitors, according to Robert Ferris, MD, PhD, who moderated the press briefing and was lead author of the nivolumab in metastatic squamous cell carcinoma study. He added that recent trial data suggest this approach should be more effective and create more durable responses.

The new data support the approach. “The trial provides compelling data to support a new approach for treating newly diagnosed HPV-positive head and neck cancers. Our goal is to treat this cancer with immunotherapy alone. The results of this trial make me optimistic that this will be achievable,” Dr. Gillison said.
 

The study details

The researchers conducted a phase 2 clinical trial, enrolling 35 patients with newly diagnosed HPV-positive oropharynx cancer who were positive for PD-L1 expression.

Patients received 1 mg/kg ipilimumab (Yervoy, Bristol Myers Squibb) and 3 mg/kg nivolumab over a 6-week cycle, followed by a second cycle that was accompanied by 40-44 Gy radiotherapy for patients with a complete response in their primary tumor, and a boost to 50-66 based on postinduction treatment volume. The protocol reduced dose to the neck from 52 to 36 Gy. The radiation was delivered to only one nodal echelon beyond the involved node. Standard care delivers radiotherapy to essentially the entire neck, Dr. Gillison said.

Grade 3 or higher adverse events occurred in 66% of patients, the majority of which were attributable to radiotherapy. The complete response rate was 94% at 6 months as assessed by PET scan, and 2-year progression-free survival was 86%. After a median follow-up of 14.9 months, all patients were alive and cancer-free.

Overall response rate was 14% following induction, but 96% showed a histologic treatment effect. Tumor viability was less than 5% in 48% of patients, and a molecular complete response was observed in 30% as measured by plasma cell-free HPV. Patients received 36% less radiation than typical of standard of care, and the dose to critical areas was reduced by 50%.

At the press conference, Dr. Ferris asked Dr. Gillison whether the researchers observed a spike in cell-free HPV DNA before the decline occurred, suggesting evidence of tumor death and DNA release.

“We did see in a remarkable number of patients within 2 weeks of the first dose, a very strong peak in the cell-free HPV DNA, followed by a rapid decline. In those patients who still have viable tumor at the end of induction immunotherapy, we saw a second robust peak in cell-free HPV DNA at the start of radiation, with rapid clearance. So that gave us confidence that (among) those patients who had cell-free HPV clearance by the end of induction, followed by no further detection through radiation, that it’s an excellent surrogate for tumor control,” Dr. Gillison said.

Dr. Gillison has financial relationships with Eisai, Exilixis, Caladrius, iTeos, Istari, Seagen, Sensei, Bicara, Mirati, Coherus, Debiopharm, Kura, Shattuck, Nektar, Ipsen, EMD Serono, Gilead, LXS, BioNTech, Merck, Bristol Myers Squibb, Bayer, Roche, Genocea, NewLink Genetics, Aspyrian, TRM Oncology, Amgen, AstraZeneca, Celgene, and Agenus. Dr. Ferris has financial relationships with Bristol Myers Squibb, AstraZeneca/MedImmune, Merck, and Celgene.

It’s a “champagne problem” many of us have encountered over the past few years in the clinic.

A patient with advanced non–small cell lung cancer (NSCLC) is fortunate enough to continue to do well for 2 years on ongoing pembrolizumab or perhaps pemetrexed and pembrolizumab as maintenance therapy. The latest CT shows a residual but far smaller primary tumor than what she started with.

In this instance, you may be considering stopping treatment but are concerned about doing so with evidence of disease still present.

Clinical trials of immunotherapy or chemoimmunotherapy have generally terminated treatment in nonprogressing patients after 2 years. We also know that some patients in early trials of immunotherapy stopped treatment after a fixed period of 1 or 2 years and continued to show no evidence of progression many years later.

The reason some patients experience this kind of success: Unlike the mechanism of action of conventional chemotherapy or targeted therapies, where ongoing treatment would be important to continue to exert an inhibitory effect, the active substrate of immunotherapy is the patient’s immune system, which can potentially have a self-sustaining efficacy beyond the stimulatory effect of the checkpoint inhibitor.

Though we don’t want to overtreat our patients, the question remains: Will patients do just as well off treatment, with the potential to resume as needed?

One trial directly addressed this question of stopping vs. continuing treatment in patients on immunotherapy. The CheckMate 153 trial, published in 2020, randomly assigned 252 previously treated patients who hadn’t demonstrated progression after 1 year on nivolumab to either discontinue nivolumab or continue nivolumab on an ongoing basis. The results were strongly in favor of ongoing therapy. Both progression-free survival (PFS) and overall survival (OS) were significantly longer in patients who continued therapy: PFS of 24.7 months vs. 9.4 months and OS not reached vs. 32.5 months.

This finding is important, but there’s an important caveat. The study population included many heavily pretreated patients, but, in practice, immunotherapy has generally moved into the first-line setting, where we see dramatic responses in a significant subset of patients.

Even more recent data are emerging that may help us evaluate who will do well off therapy and who should continue treatment.

We now have a growing collection of long-term data on patients who are more likely to have good outcomes with immunotherapy, specifically those with high tumor programmed death-ligand 1 (PD-L1) expression (≥ 50%), from the KEYNOTE-024 trial. In this study, 39 of 151 (25.8%) patients assigned to pembrolizumab completed the planned maximum of 2 years of treatment, among whom 82.1% achieved an objective response; but, only 10% (4 patients) achieved a complete response. The proportion of patients without progression and remaining off therapy wasn’t reported, but the OS rate 3 years after completing treatment was 81.4%.

In addition, restarting immunotherapy after discontinuing appears to be a moderately effective strategy. In the KEYNOTE-024 trial, 12 patients received a second course of pembrolizumab because of disease progression a median of 15.2 months after discontinuing pembrolizumab. In this small cohort, eight of these patients (66.7%) were alive at the data cutoff, and six (50%) achieved stable disease.

Recently, we received additional insight in the follow-up from two chemoimmunotherapy trials that have most shaped my practice for patients with advanced NSCLC and any level of PD-L1 expression. These are the KEYNOTE-189 trial of platinum-pemetrexed with pembrolizumab vs. placebo in those with nonsquamous NSCLC, and the KEYNOTE-407 trial of carboplatin-taxane with pembrolizumab vs. placebo in patients with advanced squamous NSCLC. The National Comprehensive Cancer Network has designated each as a “preferred regimen” for patients with advanced NSCLC.

Both regimens have demonstrated sustained efficacy benefits with prolonged follow-up, including significantly superior objective response rate, PFS, and OS with the addition of pembrolizumab. These findings merely cemented the role of these regimens in our practice, but the trials also reported on the cohort of patients who completed 35 cycles of treatment over 2 years then discontinued therapy. In both, the majority of patients showed an objective response (86% in KEYNOTE-189 and 90% in KEYNOTE-407), with most patients alive at 3 years after 2 years of treatment (71.9% in KEYNOTE-189 and 69.5% in KEYNOTE-407). In addition, the proportion of patients alive without disease progression or subsequent therapy was notable – 40.4% in KEYNOTE-189 and 43.6% KEYNOTE-407.

How should we interpret these data for the patient who is in the exam room with us?

The short answer is that we don’t know. I see this as a half-empty, half-full conundrum.

I’m disappointed that more patients who responded for 2 years will experience disease progression in the 1-3 years that follow. This signals that their immune systems have not perpetuated their initial response over the long-term. But these patients may have demonstrated disease progression even if they had continued therapy.

We also know that some patients can be rechallenged and will respond again. Some of these patients will show stable disease, whereas others will progress with repeat treatment. I would love to be able to better predict which patients are destined to do well without treatment vs. those who benefit from treatment beyond 2 years.

Might the level of PD-L1 expression tell us? Can PET imaging discriminate those with residual hypermetabolism who may need continued treatment from those with no residual uptake who could be spared it? Would serial measurement of circulating tumor DNA (ctDNA) in responding patients identify when they have achieved a point of diminishing returns, potentially indicating that some can safely discontinue treatment after 2 years, whereas others need to continue to suppress on prolonged maintenance therapy?

These questions have yet to be studied systematically. In the meantime, I take an individualized approach with my patients facing this decision. Some have experienced escalating arthralgias and myalgias, cost concerns, or other issues related to immunotherapy that may dissuade us from continuing treatment. But several others have been grateful to continue with their treatment, hesitant to do anything that could change the path of their disease.

In my patients who tolerate therapy well, I’m more worried about potential undertreatment than overtreatment. I tend to favor having my patients continue therapy in the absence of problematic toxicity or practical challenges. There is certainly room for debate here while we await data to better guide these decisions. How do you approach these patients?

Dr. West is Clinical Associate Professor, Department of Medical Oncology, City of Hope Comprehensive Cancer Care, Duarte, Calif. He reported conflicts of interest with Ariad/Takeda, Bristol-Myers Squibb, Boehringer Ingelheim, Spectrum, AstraZeneca, Celgene, Genentech/Roche, Pfizer, Merck, and Eli Lilly.

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

It’s a “champagne problem” many of us have encountered over the past few years in the clinic.

A patient with advanced non–small cell lung cancer (NSCLC) is fortunate enough to continue to do well for 2 years on ongoing pembrolizumab or perhaps pemetrexed and pembrolizumab as maintenance therapy. The latest CT shows a residual but far smaller primary tumor than what she started with.

In this instance, you may be considering stopping treatment but are concerned about doing so with evidence of disease still present.

Clinical trials of immunotherapy or chemoimmunotherapy have generally terminated treatment in nonprogressing patients after 2 years. We also know that some patients in early trials of immunotherapy stopped treatment after a fixed period of 1 or 2 years and continued to show no evidence of progression many years later.

The reason some patients experience this kind of success: Unlike the mechanism of action of conventional chemotherapy or targeted therapies, where ongoing treatment would be important to continue to exert an inhibitory effect, the active substrate of immunotherapy is the patient’s immune system, which can potentially have a self-sustaining efficacy beyond the stimulatory effect of the checkpoint inhibitor.

Though we don’t want to overtreat our patients, the question remains: Will patients do just as well off treatment, with the potential to resume as needed?

One trial directly addressed this question of stopping vs. continuing treatment in patients on immunotherapy. The CheckMate 153 trial, published in 2020, randomly assigned 252 previously treated patients who hadn’t demonstrated progression after 1 year on nivolumab to either discontinue nivolumab or continue nivolumab on an ongoing basis. The results were strongly in favor of ongoing therapy. Both progression-free survival (PFS) and overall survival (OS) were significantly longer in patients who continued therapy: PFS of 24.7 months vs. 9.4 months and OS not reached vs. 32.5 months.

This finding is important, but there’s an important caveat. The study population included many heavily pretreated patients, but, in practice, immunotherapy has generally moved into the first-line setting, where we see dramatic responses in a significant subset of patients.

Even more recent data are emerging that may help us evaluate who will do well off therapy and who should continue treatment.

We now have a growing collection of long-term data on patients who are more likely to have good outcomes with immunotherapy, specifically those with high tumor programmed death-ligand 1 (PD-L1) expression (≥ 50%), from the KEYNOTE-024 trial. In this study, 39 of 151 (25.8%) patients assigned to pembrolizumab completed the planned maximum of 2 years of treatment, among whom 82.1% achieved an objective response; but, only 10% (4 patients) achieved a complete response. The proportion of patients without progression and remaining off therapy wasn’t reported, but the OS rate 3 years after completing treatment was 81.4%.

In addition, restarting immunotherapy after discontinuing appears to be a moderately effective strategy. In the KEYNOTE-024 trial, 12 patients received a second course of pembrolizumab because of disease progression a median of 15.2 months after discontinuing pembrolizumab. In this small cohort, eight of these patients (66.7%) were alive at the data cutoff, and six (50%) achieved stable disease.

Recently, we received additional insight in the follow-up from two chemoimmunotherapy trials that have most shaped my practice for patients with advanced NSCLC and any level of PD-L1 expression. These are the KEYNOTE-189 trial of platinum-pemetrexed with pembrolizumab vs. placebo in those with nonsquamous NSCLC, and the KEYNOTE-407 trial of carboplatin-taxane with pembrolizumab vs. placebo in patients with advanced squamous NSCLC. The National Comprehensive Cancer Network has designated each as a “preferred regimen” for patients with advanced NSCLC.

Both regimens have demonstrated sustained efficacy benefits with prolonged follow-up, including significantly superior objective response rate, PFS, and OS with the addition of pembrolizumab. These findings merely cemented the role of these regimens in our practice, but the trials also reported on the cohort of patients who completed 35 cycles of treatment over 2 years then discontinued therapy. In both, the majority of patients showed an objective response (86% in KEYNOTE-189 and 90% in KEYNOTE-407), with most patients alive at 3 years after 2 years of treatment (71.9% in KEYNOTE-189 and 69.5% in KEYNOTE-407). In addition, the proportion of patients alive without disease progression or subsequent therapy was notable – 40.4% in KEYNOTE-189 and 43.6% KEYNOTE-407.

How should we interpret these data for the patient who is in the exam room with us?

The short answer is that we don’t know. I see this as a half-empty, half-full conundrum.

I’m disappointed that more patients who responded for 2 years will experience disease progression in the 1-3 years that follow. This signals that their immune systems have not perpetuated their initial response over the long-term. But these patients may have demonstrated disease progression even if they had continued therapy.

We also know that some patients can be rechallenged and will respond again. Some of these patients will show stable disease, whereas others will progress with repeat treatment. I would love to be able to better predict which patients are destined to do well without treatment vs. those who benefit from treatment beyond 2 years.

Might the level of PD-L1 expression tell us? Can PET imaging discriminate those with residual hypermetabolism who may need continued treatment from those with no residual uptake who could be spared it? Would serial measurement of circulating tumor DNA (ctDNA) in responding patients identify when they have achieved a point of diminishing returns, potentially indicating that some can safely discontinue treatment after 2 years, whereas others need to continue to suppress on prolonged maintenance therapy?

These questions have yet to be studied systematically. In the meantime, I take an individualized approach with my patients facing this decision. Some have experienced escalating arthralgias and myalgias, cost concerns, or other issues related to immunotherapy that may dissuade us from continuing treatment. But several others have been grateful to continue with their treatment, hesitant to do anything that could change the path of their disease.

In my patients who tolerate therapy well, I’m more worried about potential undertreatment than overtreatment. I tend to favor having my patients continue therapy in the absence of problematic toxicity or practical challenges. There is certainly room for debate here while we await data to better guide these decisions. How do you approach these patients?

Dr. West is Clinical Associate Professor, Department of Medical Oncology, City of Hope Comprehensive Cancer Care, Duarte, Calif. He reported conflicts of interest with Ariad/Takeda, Bristol-Myers Squibb, Boehringer Ingelheim, Spectrum, AstraZeneca, Celgene, Genentech/Roche, Pfizer, Merck, and Eli Lilly.

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

It’s a “champagne problem” many of us have encountered over the past few years in the clinic.

A patient with advanced non–small cell lung cancer (NSCLC) is fortunate enough to continue to do well for 2 years on ongoing pembrolizumab or perhaps pemetrexed and pembrolizumab as maintenance therapy. The latest CT shows a residual but far smaller primary tumor than what she started with.

In this instance, you may be considering stopping treatment but are concerned about doing so with evidence of disease still present.

Clinical trials of immunotherapy or chemoimmunotherapy have generally terminated treatment in nonprogressing patients after 2 years. We also know that some patients in early trials of immunotherapy stopped treatment after a fixed period of 1 or 2 years and continued to show no evidence of progression many years later.

The reason some patients experience this kind of success: Unlike the mechanism of action of conventional chemotherapy or targeted therapies, where ongoing treatment would be important to continue to exert an inhibitory effect, the active substrate of immunotherapy is the patient’s immune system, which can potentially have a self-sustaining efficacy beyond the stimulatory effect of the checkpoint inhibitor.

Though we don’t want to overtreat our patients, the question remains: Will patients do just as well off treatment, with the potential to resume as needed?

One trial directly addressed this question of stopping vs. continuing treatment in patients on immunotherapy. The CheckMate 153 trial, published in 2020, randomly assigned 252 previously treated patients who hadn’t demonstrated progression after 1 year on nivolumab to either discontinue nivolumab or continue nivolumab on an ongoing basis. The results were strongly in favor of ongoing therapy. Both progression-free survival (PFS) and overall survival (OS) were significantly longer in patients who continued therapy: PFS of 24.7 months vs. 9.4 months and OS not reached vs. 32.5 months.

This finding is important, but there’s an important caveat. The study population included many heavily pretreated patients, but, in practice, immunotherapy has generally moved into the first-line setting, where we see dramatic responses in a significant subset of patients.

Even more recent data are emerging that may help us evaluate who will do well off therapy and who should continue treatment.

We now have a growing collection of long-term data on patients who are more likely to have good outcomes with immunotherapy, specifically those with high tumor programmed death-ligand 1 (PD-L1) expression (≥ 50%), from the KEYNOTE-024 trial. In this study, 39 of 151 (25.8%) patients assigned to pembrolizumab completed the planned maximum of 2 years of treatment, among whom 82.1% achieved an objective response; but, only 10% (4 patients) achieved a complete response. The proportion of patients without progression and remaining off therapy wasn’t reported, but the OS rate 3 years after completing treatment was 81.4%.

In addition, restarting immunotherapy after discontinuing appears to be a moderately effective strategy. In the KEYNOTE-024 trial, 12 patients received a second course of pembrolizumab because of disease progression a median of 15.2 months after discontinuing pembrolizumab. In this small cohort, eight of these patients (66.7%) were alive at the data cutoff, and six (50%) achieved stable disease.

Recently, we received additional insight in the follow-up from two chemoimmunotherapy trials that have most shaped my practice for patients with advanced NSCLC and any level of PD-L1 expression. These are the KEYNOTE-189 trial of platinum-pemetrexed with pembrolizumab vs. placebo in those with nonsquamous NSCLC, and the KEYNOTE-407 trial of carboplatin-taxane with pembrolizumab vs. placebo in patients with advanced squamous NSCLC. The National Comprehensive Cancer Network has designated each as a “preferred regimen” for patients with advanced NSCLC.

Both regimens have demonstrated sustained efficacy benefits with prolonged follow-up, including significantly superior objective response rate, PFS, and OS with the addition of pembrolizumab. These findings merely cemented the role of these regimens in our practice, but the trials also reported on the cohort of patients who completed 35 cycles of treatment over 2 years then discontinued therapy. In both, the majority of patients showed an objective response (86% in KEYNOTE-189 and 90% in KEYNOTE-407), with most patients alive at 3 years after 2 years of treatment (71.9% in KEYNOTE-189 and 69.5% in KEYNOTE-407). In addition, the proportion of patients alive without disease progression or subsequent therapy was notable – 40.4% in KEYNOTE-189 and 43.6% KEYNOTE-407.

How should we interpret these data for the patient who is in the exam room with us?

The short answer is that we don’t know. I see this as a half-empty, half-full conundrum.

I’m disappointed that more patients who responded for 2 years will experience disease progression in the 1-3 years that follow. This signals that their immune systems have not perpetuated their initial response over the long-term. But these patients may have demonstrated disease progression even if they had continued therapy.

We also know that some patients can be rechallenged and will respond again. Some of these patients will show stable disease, whereas others will progress with repeat treatment. I would love to be able to better predict which patients are destined to do well without treatment vs. those who benefit from treatment beyond 2 years.

Might the level of PD-L1 expression tell us? Can PET imaging discriminate those with residual hypermetabolism who may need continued treatment from those with no residual uptake who could be spared it? Would serial measurement of circulating tumor DNA (ctDNA) in responding patients identify when they have achieved a point of diminishing returns, potentially indicating that some can safely discontinue treatment after 2 years, whereas others need to continue to suppress on prolonged maintenance therapy?

These questions have yet to be studied systematically. In the meantime, I take an individualized approach with my patients facing this decision. Some have experienced escalating arthralgias and myalgias, cost concerns, or other issues related to immunotherapy that may dissuade us from continuing treatment. But several others have been grateful to continue with their treatment, hesitant to do anything that could change the path of their disease.

In my patients who tolerate therapy well, I’m more worried about potential undertreatment than overtreatment. I tend to favor having my patients continue therapy in the absence of problematic toxicity or practical challenges. There is certainly room for debate here while we await data to better guide these decisions. How do you approach these patients?

Dr. West is Clinical Associate Professor, Department of Medical Oncology, City of Hope Comprehensive Cancer Care, Duarte, Calif. He reported conflicts of interest with Ariad/Takeda, Bristol-Myers Squibb, Boehringer Ingelheim, Spectrum, AstraZeneca, Celgene, Genentech/Roche, Pfizer, Merck, and Eli Lilly.

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

Artificial intelligence (AI) is impacting many aspects of health care, and radiation oncology is no exception. It has the potential to cut costs and streamline work flows ranging from image analysis to treatment plan formulation, but its specific place in clinical practice is still being debated.

In a session at the annual meeting of the American Society for Radiation Oncology, researchers discussed some of the ways that AI is or will soon be relevant to the clinic. The general consensus was that AI provides a useful supplement but is no threat to replace the role of radiation oncologists.

In his talk, Sanjay Aneja, MD focused on practical applications of AI that are in the clinic or close to being ready. One example is image classification. “There has been recent evidence that suggests in a variety of different kind of scenarios, deep-learning models can be very good at image classification in automated ways,” said Dr. Aneja, who is a professor of radiology at Yale University, New Haven, Conn. He described one study that used AI to classify 14 different pathologies on chest x-ray images.

Dr. Aneja described the open-source nnU-net tool, which automatically configures itself and segments biomedical images for research or clinical purposes, including therapy planning support, intraoperative support, and tumor growth monitoring. The researchers who developed it also created a “recipe” to systematize configuration of nnU-net, making it useful as an out-of-the-box tool for image segmentation.

He predicted that AI will improve radiology oncology by assisting in the determination of disease extent, including microscopic areas of disease. It could also help plan treatment volume and monitor treatment response. “I think that these are the types of things that will be moving toward the clinic in the future; very specific applications and models trained on very specific scenarios that will help us answer a very important clinical question,” Dr. Aneja said.

He expects AI to contribute to auto-segmenting and clinical contouring, “but I will caution everyone that these algorithms have not been proven to be better than physician contours. They very frequently fail in the specific use cases when anatomy is distorted by, I don’t know, say a tumor. And so a lot of times, we don’t actually have the ability to just make it an automated process. I think it’ll be something that physicians will use to help them but not necessarily replace their contouring ability,” Dr. Aneja said.

Another, potentially more useful application, is in adaptive radiation planning. “I think that AI auto-contouring will be very helpful in establishing contours in a situation in which a physician doing them would not be feasible. We need to have nimble and computationally efficient auto segmentation algorithms that will be able to be easily deployed at the linear accelerator,” he said.
 

AI in pathology and treatment selection

In another talk, Osama Mohamad, MD talked about AI in pathology, and specifically treatment selection. He described research from his group that digitized pathology data from 5,500 patients drawn from five randomized, clinical trials. They used AI on data from four of the clinical trials to identify a prognostic biomarker for distant metastasis, then validated it on data from the remaining clinical trial, which compared radiation versus radiation plus short-term hormone therapy in prostate cancer.

The results suggested that most patients should receive hormone therapy, but the AI suggested a more nuanced answer. “Patients who had AI biomarker negative do not see any benefit from adding 4 months of hormone therapy ... whereas patients who have biomarker positive have significant difference and improvement in distant metastasis at 10 years and 15 years. This means that we can save a significant proportion of patients from getting [androgen deprivation therapy], which is hormonal therapy and has very well-known side effects, because they simply they will not benefit,” said Dr. Mohamad, who is an assistant professor of radiation oncology at University of California, San Francisco.

That study relied on the ArteraAI prostate cancer test, which is available through a Clinical Laboratory Improvement Amendment–certified laboratory in Florida.

Another example of AI used to plan treatment is On-line Real-time Benchmarking Informatics Technology for Radiotherapy (ORBIT-RT), developed at the University of California, San Diego. It focuses on radiotherapy treatment plan quality control, and has two main components: creating clinically validated plan routines and a free radiotherapy plan quality control system.

No matter how impressive the technical advances may be, AI contributions won’t impact clinical practice if radiation oncologists, physicians, and patients don’t accept AI. Dr. Aneja’s group surveyed patients about which health field they would feel more comfortable with AI having an important role. Most said they were extremely uncomfortable when it came to cancer. “Now, does that mean that we can’t use AI in oncology? No, I think it just means that we have to be a little bit more nuanced in our approach and how we develop AI solutions for cancer patients,” Dr. Aneja said.

Physicians also show reluctance, according to Alejandro Berlin, MD, who is an affiliate scientist at Princess Margaret Cancer Centre in Toronto. He discussed some research looking at physician acceptance of machine learning. His group looked at physician acceptance of treatment plans for prostate cancer that were generated by physicians and in parallel by machine learning. In a theoretical phase, physicians generally agreed that the machine learning plans were better, but when it came to a phase of the study in which physicians chose which plan to implement in a real patient, the acceptance of machine learning-generated plans dropped by 20%.

This tendency to trust humans over machines is what Dr. Berlin called “automation bias,” and he called for a more collaborative approach to implement AI. “In some cases, [machine learning] is going to be good and sufficient. And in some cases, you will need the expertise of a human.”

Dr. Aneja, who also moderated the session, expressed a similar sentiment when summing up the day’s talks: “I do feel like it’s a disruptive technology ... but I think there will still be a need for us to have people who are trained in order to evaluate and make sure that these algorithms are working correctly and efficiently.”

Dr. Aneja, Dr. Mohamad, and Dr. Berlin have no relevant financial disclosures.

* This article was updated on Nov. 15, 2022.

Artificial intelligence (AI) is impacting many aspects of health care, and radiation oncology is no exception. It has the potential to cut costs and streamline work flows ranging from image analysis to treatment plan formulation, but its specific place in clinical practice is still being debated.

In a session at the annual meeting of the American Society for Radiation Oncology, researchers discussed some of the ways that AI is or will soon be relevant to the clinic. The general consensus was that AI provides a useful supplement but is no threat to replace the role of radiation oncologists.

In his talk, Sanjay Aneja, MD focused on practical applications of AI that are in the clinic or close to being ready. One example is image classification. “There has been recent evidence that suggests in a variety of different kind of scenarios, deep-learning models can be very good at image classification in automated ways,” said Dr. Aneja, who is a professor of radiology at Yale University, New Haven, Conn. He described one study that used AI to classify 14 different pathologies on chest x-ray images.

Dr. Aneja described the open-source nnU-net tool, which automatically configures itself and segments biomedical images for research or clinical purposes, including therapy planning support, intraoperative support, and tumor growth monitoring. The researchers who developed it also created a “recipe” to systematize configuration of nnU-net, making it useful as an out-of-the-box tool for image segmentation.

He predicted that AI will improve radiology oncology by assisting in the determination of disease extent, including microscopic areas of disease. It could also help plan treatment volume and monitor treatment response. “I think that these are the types of things that will be moving toward the clinic in the future; very specific applications and models trained on very specific scenarios that will help us answer a very important clinical question,” Dr. Aneja said.

He expects AI to contribute to auto-segmenting and clinical contouring, “but I will caution everyone that these algorithms have not been proven to be better than physician contours. They very frequently fail in the specific use cases when anatomy is distorted by, I don’t know, say a tumor. And so a lot of times, we don’t actually have the ability to just make it an automated process. I think it’ll be something that physicians will use to help them but not necessarily replace their contouring ability,” Dr. Aneja said.

Another, potentially more useful application, is in adaptive radiation planning. “I think that AI auto-contouring will be very helpful in establishing contours in a situation in which a physician doing them would not be feasible. We need to have nimble and computationally efficient auto segmentation algorithms that will be able to be easily deployed at the linear accelerator,” he said.
 

AI in pathology and treatment selection

In another talk, Osama Mohamad, MD talked about AI in pathology, and specifically treatment selection. He described research from his group that digitized pathology data from 5,500 patients drawn from five randomized, clinical trials. They used AI on data from four of the clinical trials to identify a prognostic biomarker for distant metastasis, then validated it on data from the remaining clinical trial, which compared radiation versus radiation plus short-term hormone therapy in prostate cancer.

The results suggested that most patients should receive hormone therapy, but the AI suggested a more nuanced answer. “Patients who had AI biomarker negative do not see any benefit from adding 4 months of hormone therapy ... whereas patients who have biomarker positive have significant difference and improvement in distant metastasis at 10 years and 15 years. This means that we can save a significant proportion of patients from getting [androgen deprivation therapy], which is hormonal therapy and has very well-known side effects, because they simply they will not benefit,” said Dr. Mohamad, who is an assistant professor of radiation oncology at University of California, San Francisco.

That study relied on the ArteraAI prostate cancer test, which is available through a Clinical Laboratory Improvement Amendment–certified laboratory in Florida.

Another example of AI used to plan treatment is On-line Real-time Benchmarking Informatics Technology for Radiotherapy (ORBIT-RT), developed at the University of California, San Diego. It focuses on radiotherapy treatment plan quality control, and has two main components: creating clinically validated plan routines and a free radiotherapy plan quality control system.

No matter how impressive the technical advances may be, AI contributions won’t impact clinical practice if radiation oncologists, physicians, and patients don’t accept AI. Dr. Aneja’s group surveyed patients about which health field they would feel more comfortable with AI having an important role. Most said they were extremely uncomfortable when it came to cancer. “Now, does that mean that we can’t use AI in oncology? No, I think it just means that we have to be a little bit more nuanced in our approach and how we develop AI solutions for cancer patients,” Dr. Aneja said.

Physicians also show reluctance, according to Alejandro Berlin, MD, who is an affiliate scientist at Princess Margaret Cancer Centre in Toronto. He discussed some research looking at physician acceptance of machine learning. His group looked at physician acceptance of treatment plans for prostate cancer that were generated by physicians and in parallel by machine learning. In a theoretical phase, physicians generally agreed that the machine learning plans were better, but when it came to a phase of the study in which physicians chose which plan to implement in a real patient, the acceptance of machine learning-generated plans dropped by 20%.

This tendency to trust humans over machines is what Dr. Berlin called “automation bias,” and he called for a more collaborative approach to implement AI. “In some cases, [machine learning] is going to be good and sufficient. And in some cases, you will need the expertise of a human.”

Dr. Aneja, who also moderated the session, expressed a similar sentiment when summing up the day’s talks: “I do feel like it’s a disruptive technology ... but I think there will still be a need for us to have people who are trained in order to evaluate and make sure that these algorithms are working correctly and efficiently.”

Dr. Aneja, Dr. Mohamad, and Dr. Berlin have no relevant financial disclosures.

* This article was updated on Nov. 15, 2022.

Artificial intelligence (AI) is impacting many aspects of health care, and radiation oncology is no exception. It has the potential to cut costs and streamline work flows ranging from image analysis to treatment plan formulation, but its specific place in clinical practice is still being debated.

In a session at the annual meeting of the American Society for Radiation Oncology, researchers discussed some of the ways that AI is or will soon be relevant to the clinic. The general consensus was that AI provides a useful supplement but is no threat to replace the role of radiation oncologists.

In his talk, Sanjay Aneja, MD focused on practical applications of AI that are in the clinic or close to being ready. One example is image classification. “There has been recent evidence that suggests in a variety of different kind of scenarios, deep-learning models can be very good at image classification in automated ways,” said Dr. Aneja, who is a professor of radiology at Yale University, New Haven, Conn. He described one study that used AI to classify 14 different pathologies on chest x-ray images.

Dr. Aneja described the open-source nnU-net tool, which automatically configures itself and segments biomedical images for research or clinical purposes, including therapy planning support, intraoperative support, and tumor growth monitoring. The researchers who developed it also created a “recipe” to systematize configuration of nnU-net, making it useful as an out-of-the-box tool for image segmentation.

He predicted that AI will improve radiology oncology by assisting in the determination of disease extent, including microscopic areas of disease. It could also help plan treatment volume and monitor treatment response. “I think that these are the types of things that will be moving toward the clinic in the future; very specific applications and models trained on very specific scenarios that will help us answer a very important clinical question,” Dr. Aneja said.

He expects AI to contribute to auto-segmenting and clinical contouring, “but I will caution everyone that these algorithms have not been proven to be better than physician contours. They very frequently fail in the specific use cases when anatomy is distorted by, I don’t know, say a tumor. And so a lot of times, we don’t actually have the ability to just make it an automated process. I think it’ll be something that physicians will use to help them but not necessarily replace their contouring ability,” Dr. Aneja said.

Another, potentially more useful application, is in adaptive radiation planning. “I think that AI auto-contouring will be very helpful in establishing contours in a situation in which a physician doing them would not be feasible. We need to have nimble and computationally efficient auto segmentation algorithms that will be able to be easily deployed at the linear accelerator,” he said.
 

AI in pathology and treatment selection

In another talk, Osama Mohamad, MD talked about AI in pathology, and specifically treatment selection. He described research from his group that digitized pathology data from 5,500 patients drawn from five randomized, clinical trials. They used AI on data from four of the clinical trials to identify a prognostic biomarker for distant metastasis, then validated it on data from the remaining clinical trial, which compared radiation versus radiation plus short-term hormone therapy in prostate cancer.

The results suggested that most patients should receive hormone therapy, but the AI suggested a more nuanced answer. “Patients who had AI biomarker negative do not see any benefit from adding 4 months of hormone therapy ... whereas patients who have biomarker positive have significant difference and improvement in distant metastasis at 10 years and 15 years. This means that we can save a significant proportion of patients from getting [androgen deprivation therapy], which is hormonal therapy and has very well-known side effects, because they simply they will not benefit,” said Dr. Mohamad, who is an assistant professor of radiation oncology at University of California, San Francisco.

That study relied on the ArteraAI prostate cancer test, which is available through a Clinical Laboratory Improvement Amendment–certified laboratory in Florida.

Another example of AI used to plan treatment is On-line Real-time Benchmarking Informatics Technology for Radiotherapy (ORBIT-RT), developed at the University of California, San Diego. It focuses on radiotherapy treatment plan quality control, and has two main components: creating clinically validated plan routines and a free radiotherapy plan quality control system.

No matter how impressive the technical advances may be, AI contributions won’t impact clinical practice if radiation oncologists, physicians, and patients don’t accept AI. Dr. Aneja’s group surveyed patients about which health field they would feel more comfortable with AI having an important role. Most said they were extremely uncomfortable when it came to cancer. “Now, does that mean that we can’t use AI in oncology? No, I think it just means that we have to be a little bit more nuanced in our approach and how we develop AI solutions for cancer patients,” Dr. Aneja said.

Physicians also show reluctance, according to Alejandro Berlin, MD, who is an affiliate scientist at Princess Margaret Cancer Centre in Toronto. He discussed some research looking at physician acceptance of machine learning. His group looked at physician acceptance of treatment plans for prostate cancer that were generated by physicians and in parallel by machine learning. In a theoretical phase, physicians generally agreed that the machine learning plans were better, but when it came to a phase of the study in which physicians chose which plan to implement in a real patient, the acceptance of machine learning-generated plans dropped by 20%.

This tendency to trust humans over machines is what Dr. Berlin called “automation bias,” and he called for a more collaborative approach to implement AI. “In some cases, [machine learning] is going to be good and sufficient. And in some cases, you will need the expertise of a human.”

Dr. Aneja, who also moderated the session, expressed a similar sentiment when summing up the day’s talks: “I do feel like it’s a disruptive technology ... but I think there will still be a need for us to have people who are trained in order to evaluate and make sure that these algorithms are working correctly and efficiently.”

Dr. Aneja, Dr. Mohamad, and Dr. Berlin have no relevant financial disclosures.

* This article was updated on Nov. 15, 2022.

The American folk hero John Henry pitted his hammer against a mechanical steam drill, only to die of exhaustion after winning the battle. In the legend, John Henry was African American, and it’s a fitting metaphor, according to Justin Xavier Moore, PhD.

It’s a metaphor for accumulated stress over a lifetime, also known as allostatic load. Though it affects everyone, Black, Indigenous, and people of color experience it in excess. “It serves as a symbolism for the plight of African Americans within the United States, that regardless of all the triumph and trying to overcompensate and work just as hard as your counterpart, it oftentimes leads to this overtaxing or exhaustion because your competitor has an unfair advantage. You have Jim Crow laws in the South. We have the history of slavery. We have individuals of racial subgroups that are exposed daily to microaggressions, racial discrimination, stereotypes, redlining, all of these different issues that basically reduce to systemic racism,” said Dr. Moore, who is an assistant professor of medicine at the Medical College of Georgia, Augusta.

Dr. Moore is also a coauthor of a new study published online in SSM–Population Health, which examined the association between increased allostatic load and cancer outcomes among participants in the National Health and Nutrition Examination Survey (NHANES) and the National Death Index. They found that both non-Hispanic Black and non-Hispanic White adults with high allostatic load had about a doubled risk of cancer death.

To determine allostatic load, the researchers looked at nine factors collected in NHANES: abnormal values of BMI, diastolic blood pressure, glycohemoglobin, systolic blood pressure, total cholesterol, serum triglycerides, serum albumin, serum creatinine, and C-reactive protein. “The fact that we’re looking at cardiovascular, metabolic and immune function, all in one gives us a better risk assessment for morbidity and mortality. Allostatic load has actually been associated with cardiovascular disease. I think we are one of the first studies to actually look at whether allostatic load is associated with cancer mortality,” said Dr. Moore.

Previous research coauthored by Dr. Moore showed 20-year old African Americans have an allostatic load comparable with that seen in 30-year-old non-Hispanic Whites. That can lead to a proinflammatory state that might be causing increased cancer risk. But stress isn’t a simple concept to pin down, Dr. Moore said. “One of the founding fathers of public health research and epidemiology, Paracelsus, [said] ‘the dose makes the poison.’ ”

In this case, it means that not all stress is bad. Exercise is good stress. “Your heart rate goes up, you compete, and then it comes back down. That’s healthy. But then there’s those stressful situations like dealing with a horrible job, and a boss that may just be overdemanding. Deadlines, and not having a work-life balance. Too much stress, in this case, can cause cancer death,” Dr. Moore said.

In the study, both non-Hispanic Black adults and non-Hispanic White adults heightened risk of cancer death when dealing with high allostatic load, even though the cause of stress may be different. “It’s almost like the cause of the stress does not matter as much. There are millions of Americans that live in environments that are not conducive to their health. The fact of the matter is that because of racial discrimination, because all these different biases, African Americans may have higher allostatic load, which they did on an average, but high allostatic load for even White people is associated with dying from cancer,” Dr. Moore said.

After adjustment, the researchers found that a high allostatic load was linked to a 14% increased risk of cancer death overall (adjusted subdistributed hazard ratio, 1.14; 95% CI, 1.04-1.26). After stratification by age, high allostatic load was associated with an 80% increased risk of cancer death among adults (SHR, 1.80; 95% CI, 1.35-2.41). Non-Hispanic White adults had a 95% increased risk (SHR, 1.95; 95% CI, 1.22-3.12), non-Hispanic Black adults had a twofold increased risk (SHR, 1.06; 95% CI, 1.27-3.34), and Hispanic adults had a 36% increased risk.

Dr. Moore has no relevant financial disclosures.

The American folk hero John Henry pitted his hammer against a mechanical steam drill, only to die of exhaustion after winning the battle. In the legend, John Henry was African American, and it’s a fitting metaphor, according to Justin Xavier Moore, PhD.

It’s a metaphor for accumulated stress over a lifetime, also known as allostatic load. Though it affects everyone, Black, Indigenous, and people of color experience it in excess. “It serves as a symbolism for the plight of African Americans within the United States, that regardless of all the triumph and trying to overcompensate and work just as hard as your counterpart, it oftentimes leads to this overtaxing or exhaustion because your competitor has an unfair advantage. You have Jim Crow laws in the South. We have the history of slavery. We have individuals of racial subgroups that are exposed daily to microaggressions, racial discrimination, stereotypes, redlining, all of these different issues that basically reduce to systemic racism,” said Dr. Moore, who is an assistant professor of medicine at the Medical College of Georgia, Augusta.

Dr. Moore is also a coauthor of a new study published online in SSM–Population Health, which examined the association between increased allostatic load and cancer outcomes among participants in the National Health and Nutrition Examination Survey (NHANES) and the National Death Index. They found that both non-Hispanic Black and non-Hispanic White adults with high allostatic load had about a doubled risk of cancer death.

To determine allostatic load, the researchers looked at nine factors collected in NHANES: abnormal values of BMI, diastolic blood pressure, glycohemoglobin, systolic blood pressure, total cholesterol, serum triglycerides, serum albumin, serum creatinine, and C-reactive protein. “The fact that we’re looking at cardiovascular, metabolic and immune function, all in one gives us a better risk assessment for morbidity and mortality. Allostatic load has actually been associated with cardiovascular disease. I think we are one of the first studies to actually look at whether allostatic load is associated with cancer mortality,” said Dr. Moore.

Previous research coauthored by Dr. Moore showed 20-year old African Americans have an allostatic load comparable with that seen in 30-year-old non-Hispanic Whites. That can lead to a proinflammatory state that might be causing increased cancer risk. But stress isn’t a simple concept to pin down, Dr. Moore said. “One of the founding fathers of public health research and epidemiology, Paracelsus, [said] ‘the dose makes the poison.’ ”

In this case, it means that not all stress is bad. Exercise is good stress. “Your heart rate goes up, you compete, and then it comes back down. That’s healthy. But then there’s those stressful situations like dealing with a horrible job, and a boss that may just be overdemanding. Deadlines, and not having a work-life balance. Too much stress, in this case, can cause cancer death,” Dr. Moore said.

In the study, both non-Hispanic Black adults and non-Hispanic White adults heightened risk of cancer death when dealing with high allostatic load, even though the cause of stress may be different. “It’s almost like the cause of the stress does not matter as much. There are millions of Americans that live in environments that are not conducive to their health. The fact of the matter is that because of racial discrimination, because all these different biases, African Americans may have higher allostatic load, which they did on an average, but high allostatic load for even White people is associated with dying from cancer,” Dr. Moore said.

After adjustment, the researchers found that a high allostatic load was linked to a 14% increased risk of cancer death overall (adjusted subdistributed hazard ratio, 1.14; 95% CI, 1.04-1.26). After stratification by age, high allostatic load was associated with an 80% increased risk of cancer death among adults (SHR, 1.80; 95% CI, 1.35-2.41). Non-Hispanic White adults had a 95% increased risk (SHR, 1.95; 95% CI, 1.22-3.12), non-Hispanic Black adults had a twofold increased risk (SHR, 1.06; 95% CI, 1.27-3.34), and Hispanic adults had a 36% increased risk.

Dr. Moore has no relevant financial disclosures.

The American folk hero John Henry pitted his hammer against a mechanical steam drill, only to die of exhaustion after winning the battle. In the legend, John Henry was African American, and it’s a fitting metaphor, according to Justin Xavier Moore, PhD.

It’s a metaphor for accumulated stress over a lifetime, also known as allostatic load. Though it affects everyone, Black, Indigenous, and people of color experience it in excess. “It serves as a symbolism for the plight of African Americans within the United States, that regardless of all the triumph and trying to overcompensate and work just as hard as your counterpart, it oftentimes leads to this overtaxing or exhaustion because your competitor has an unfair advantage. You have Jim Crow laws in the South. We have the history of slavery. We have individuals of racial subgroups that are exposed daily to microaggressions, racial discrimination, stereotypes, redlining, all of these different issues that basically reduce to systemic racism,” said Dr. Moore, who is an assistant professor of medicine at the Medical College of Georgia, Augusta.

Dr. Moore is also a coauthor of a new study published online in SSM–Population Health, which examined the association between increased allostatic load and cancer outcomes among participants in the National Health and Nutrition Examination Survey (NHANES) and the National Death Index. They found that both non-Hispanic Black and non-Hispanic White adults with high allostatic load had about a doubled risk of cancer death.

To determine allostatic load, the researchers looked at nine factors collected in NHANES: abnormal values of BMI, diastolic blood pressure, glycohemoglobin, systolic blood pressure, total cholesterol, serum triglycerides, serum albumin, serum creatinine, and C-reactive protein. “The fact that we’re looking at cardiovascular, metabolic and immune function, all in one gives us a better risk assessment for morbidity and mortality. Allostatic load has actually been associated with cardiovascular disease. I think we are one of the first studies to actually look at whether allostatic load is associated with cancer mortality,” said Dr. Moore.

Previous research coauthored by Dr. Moore showed 20-year old African Americans have an allostatic load comparable with that seen in 30-year-old non-Hispanic Whites. That can lead to a proinflammatory state that might be causing increased cancer risk. But stress isn’t a simple concept to pin down, Dr. Moore said. “One of the founding fathers of public health research and epidemiology, Paracelsus, [said] ‘the dose makes the poison.’ ”

In this case, it means that not all stress is bad. Exercise is good stress. “Your heart rate goes up, you compete, and then it comes back down. That’s healthy. But then there’s those stressful situations like dealing with a horrible job, and a boss that may just be overdemanding. Deadlines, and not having a work-life balance. Too much stress, in this case, can cause cancer death,” Dr. Moore said.

In the study, both non-Hispanic Black adults and non-Hispanic White adults heightened risk of cancer death when dealing with high allostatic load, even though the cause of stress may be different. “It’s almost like the cause of the stress does not matter as much. There are millions of Americans that live in environments that are not conducive to their health. The fact of the matter is that because of racial discrimination, because all these different biases, African Americans may have higher allostatic load, which they did on an average, but high allostatic load for even White people is associated with dying from cancer,” Dr. Moore said.

After adjustment, the researchers found that a high allostatic load was linked to a 14% increased risk of cancer death overall (adjusted subdistributed hazard ratio, 1.14; 95% CI, 1.04-1.26). After stratification by age, high allostatic load was associated with an 80% increased risk of cancer death among adults (SHR, 1.80; 95% CI, 1.35-2.41). Non-Hispanic White adults had a 95% increased risk (SHR, 1.95; 95% CI, 1.22-3.12), non-Hispanic Black adults had a twofold increased risk (SHR, 1.06; 95% CI, 1.27-3.34), and Hispanic adults had a 36% increased risk.

Dr. Moore has no relevant financial disclosures.

A third dose of coronavirus booster vaccine is effective in reducing death and hospitalization among people with cancer, though this population still suffers higher risks than those of the general population, according to a new large-scale observational study out of the United Kingdom.

People living with lymphoma and those who underwent recent systemic anti-cancer treatment or radiotherapy are at the highest risk, according to study author Lennard Y.W. Lee, PhD. “Our study is the largest evaluation of a coronavirus third dose vaccine booster effectiveness in people living with cancer in the world. For the first time we have quantified the benefits of boosters for COVID-19 in cancer patients,” said Dr. Lee, UK COVID Cancer program lead and a medical oncologist at the University of Oxford, England.

The research was published in the November issue of the European Journal of Cancer.

Despite the encouraging numbers, those with cancer continue to have a more than threefold increased risk of both hospitalization and death from coronavirus compared to the general population. “More needs to be done to reduce this excess risk, like prophylactic antibody therapies,” Dr. Lee said.

Third dose efficacy was lower among cancer patients who had been diagnosed within the past 12 months, as well as those with lymphoma, and those who had undergone systemic anti-cancer therapy or radiotherapy within the past 12 months.

The increased vulnerability among individuals with cancer is likely due to compromised immune systems. “Patients with cancer often have impaired B and T cell function and this study provides the largest global clinical study showing the definitive meaningful clinical impact of this,” Dr. Lee said. The greater risk among those with lymphoma likely traces to aberrant white cells or immunosuppressant regimens, he said.

“Vaccination probably should be used in combination with new forms of prevention and in Europe the strategy of using prophylactic antibodies is going to provide additional levels of protection,” Dr. Lee said.

Overall, the study reveals the challenges that cancer patients face in a pandemic that remains a critical health concern, one that can seriously affect quality of life. “Many are still shielding, unable to see family or hug loved ones. Furthermore, looking beyond the direct health risks, there is also the mental health impact. Shielding for nearly 3 years is very difficult. It is important to realize that behind this large-scale study, which is the biggest in the world, there are real people. The pandemic still goes on for them as they remain at higher risk from COVID-19 and we must be aware of the impact on them,” Dr. Lee said.

The study included data from the United Kingdom’s third dose booster vaccine program, representing 361,098 individuals who participated from December 2020 through December 2021. It also include results from all coronavirus tests conducted in the United Kingdom during that period. Among the participants, 97.8% got the Pfizer-BioNTech vaccine as a booster, while 1.5% received the Moderna vaccine. Overall, 8,371,139 individuals received a third dose booster, including 230,666 living with cancer. The researchers used a test-negative case-controlled analysis to estimate vaccine efficacy.

The booster shot had a 59.1% efficacy against breakthrough infections, 62.8% efficacy against symptomatic infections, 80.5% efficacy versus coronavirus hospitalization, and 94.5% efficacy against coronavirus death. Patients with solid tumors benefited from higher efficacy versus breakthrough infections 66.0% versus 53.2%) and symptomatic infections (69.6% versus 56.0%).

Patients with lymphoma experienced just a 10.5% efficacy of the primary dose vaccine versus breakthrough infections and 13.6% versus symptomatic infections, and this did not improve with a third dose. The benefit was greater for hospitalization (23.2%) and death (80.1%).

Despite the additional protection of a third dose, patients with cancer had a higher risk than the population control for coronavirus hospitalization (odds ratio, 3.38; P < .000001) and death (odds ratio, 3.01; P < .000001).

Dr. Lee has no relevant financial disclosures.

A third dose of coronavirus booster vaccine is effective in reducing death and hospitalization among people with cancer, though this population still suffers higher risks than those of the general population, according to a new large-scale observational study out of the United Kingdom.

People living with lymphoma and those who underwent recent systemic anti-cancer treatment or radiotherapy are at the highest risk, according to study author Lennard Y.W. Lee, PhD. “Our study is the largest evaluation of a coronavirus third dose vaccine booster effectiveness in people living with cancer in the world. For the first time we have quantified the benefits of boosters for COVID-19 in cancer patients,” said Dr. Lee, UK COVID Cancer program lead and a medical oncologist at the University of Oxford, England.

The research was published in the November issue of the European Journal of Cancer.

Despite the encouraging numbers, those with cancer continue to have a more than threefold increased risk of both hospitalization and death from coronavirus compared to the general population. “More needs to be done to reduce this excess risk, like prophylactic antibody therapies,” Dr. Lee said.

Third dose efficacy was lower among cancer patients who had been diagnosed within the past 12 months, as well as those with lymphoma, and those who had undergone systemic anti-cancer therapy or radiotherapy within the past 12 months.

The increased vulnerability among individuals with cancer is likely due to compromised immune systems. “Patients with cancer often have impaired B and T cell function and this study provides the largest global clinical study showing the definitive meaningful clinical impact of this,” Dr. Lee said. The greater risk among those with lymphoma likely traces to aberrant white cells or immunosuppressant regimens, he said.

“Vaccination probably should be used in combination with new forms of prevention and in Europe the strategy of using prophylactic antibodies is going to provide additional levels of protection,” Dr. Lee said.

Overall, the study reveals the challenges that cancer patients face in a pandemic that remains a critical health concern, one that can seriously affect quality of life. “Many are still shielding, unable to see family or hug loved ones. Furthermore, looking beyond the direct health risks, there is also the mental health impact. Shielding for nearly 3 years is very difficult. It is important to realize that behind this large-scale study, which is the biggest in the world, there are real people. The pandemic still goes on for them as they remain at higher risk from COVID-19 and we must be aware of the impact on them,” Dr. Lee said.

The study included data from the United Kingdom’s third dose booster vaccine program, representing 361,098 individuals who participated from December 2020 through December 2021. It also include results from all coronavirus tests conducted in the United Kingdom during that period. Among the participants, 97.8% got the Pfizer-BioNTech vaccine as a booster, while 1.5% received the Moderna vaccine. Overall, 8,371,139 individuals received a third dose booster, including 230,666 living with cancer. The researchers used a test-negative case-controlled analysis to estimate vaccine efficacy.

The booster shot had a 59.1% efficacy against breakthrough infections, 62.8% efficacy against symptomatic infections, 80.5% efficacy versus coronavirus hospitalization, and 94.5% efficacy against coronavirus death. Patients with solid tumors benefited from higher efficacy versus breakthrough infections 66.0% versus 53.2%) and symptomatic infections (69.6% versus 56.0%).

Patients with lymphoma experienced just a 10.5% efficacy of the primary dose vaccine versus breakthrough infections and 13.6% versus symptomatic infections, and this did not improve with a third dose. The benefit was greater for hospitalization (23.2%) and death (80.1%).

Despite the additional protection of a third dose, patients with cancer had a higher risk than the population control for coronavirus hospitalization (odds ratio, 3.38; P < .000001) and death (odds ratio, 3.01; P < .000001).

Dr. Lee has no relevant financial disclosures.

A third dose of coronavirus booster vaccine is effective in reducing death and hospitalization among people with cancer, though this population still suffers higher risks than those of the general population, according to a new large-scale observational study out of the United Kingdom.

People living with lymphoma and those who underwent recent systemic anti-cancer treatment or radiotherapy are at the highest risk, according to study author Lennard Y.W. Lee, PhD. “Our study is the largest evaluation of a coronavirus third dose vaccine booster effectiveness in people living with cancer in the world. For the first time we have quantified the benefits of boosters for COVID-19 in cancer patients,” said Dr. Lee, UK COVID Cancer program lead and a medical oncologist at the University of Oxford, England.

The research was published in the November issue of the European Journal of Cancer.

Despite the encouraging numbers, those with cancer continue to have a more than threefold increased risk of both hospitalization and death from coronavirus compared to the general population. “More needs to be done to reduce this excess risk, like prophylactic antibody therapies,” Dr. Lee said.

Third dose efficacy was lower among cancer patients who had been diagnosed within the past 12 months, as well as those with lymphoma, and those who had undergone systemic anti-cancer therapy or radiotherapy within the past 12 months.

The increased vulnerability among individuals with cancer is likely due to compromised immune systems. “Patients with cancer often have impaired B and T cell function and this study provides the largest global clinical study showing the definitive meaningful clinical impact of this,” Dr. Lee said. The greater risk among those with lymphoma likely traces to aberrant white cells or immunosuppressant regimens, he said.

“Vaccination probably should be used in combination with new forms of prevention and in Europe the strategy of using prophylactic antibodies is going to provide additional levels of protection,” Dr. Lee said.

Overall, the study reveals the challenges that cancer patients face in a pandemic that remains a critical health concern, one that can seriously affect quality of life. “Many are still shielding, unable to see family or hug loved ones. Furthermore, looking beyond the direct health risks, there is also the mental health impact. Shielding for nearly 3 years is very difficult. It is important to realize that behind this large-scale study, which is the biggest in the world, there are real people. The pandemic still goes on for them as they remain at higher risk from COVID-19 and we must be aware of the impact on them,” Dr. Lee said.

The study included data from the United Kingdom’s third dose booster vaccine program, representing 361,098 individuals who participated from December 2020 through December 2021. It also include results from all coronavirus tests conducted in the United Kingdom during that period. Among the participants, 97.8% got the Pfizer-BioNTech vaccine as a booster, while 1.5% received the Moderna vaccine. Overall, 8,371,139 individuals received a third dose booster, including 230,666 living with cancer. The researchers used a test-negative case-controlled analysis to estimate vaccine efficacy.

The booster shot had a 59.1% efficacy against breakthrough infections, 62.8% efficacy against symptomatic infections, 80.5% efficacy versus coronavirus hospitalization, and 94.5% efficacy against coronavirus death. Patients with solid tumors benefited from higher efficacy versus breakthrough infections 66.0% versus 53.2%) and symptomatic infections (69.6% versus 56.0%).

Patients with lymphoma experienced just a 10.5% efficacy of the primary dose vaccine versus breakthrough infections and 13.6% versus symptomatic infections, and this did not improve with a third dose. The benefit was greater for hospitalization (23.2%) and death (80.1%).

Despite the additional protection of a third dose, patients with cancer had a higher risk than the population control for coronavirus hospitalization (odds ratio, 3.38; P < .000001) and death (odds ratio, 3.01; P < .000001).

Dr. Lee has no relevant financial disclosures.

Every year, around 7,000 people in Germany develop a brain tumor, and around half of those cases involve a glioblastoma, a particularly aggressive form of the disease. Glioblastomas are incurable, but advances are being made in both diagnostics and therapy. Scientists from the Heidelberg University Hospital (UKHD) and from the German Cancer Research Center (DKFZ) in Heidelberg have discovered a fundamentally new way in which glioblastomas spread within the brain.

This news organization spoke to Wolfgang Wick, MD, medical director of the neurologic clinic at UKHD, about how glioblastomas are treated; the role that vaccinations, recombinant proteins, and parvoviruses play; and what therapeutic approaches might be derived from the discovery of this method by which glioblastomas spread.

Question: Glioblastomas spread through the brain like a fungal network. So how would a glioblastoma currently be treated? The tumor can only be partially removed through surgery.

Answer: Nevertheless, glioblastoma would be operated on. This would have a significant effect. Relieving the strain of the main tumor mass, without generating a new deficit, is prognostically very good for the patient concerned. However, surgery on glioblastoma is never curative.

The reason a cure is not possible is down to the special form and spread of the glioblastoma. Nevertheless, an operation helps. This seems to be because removing the main tumor mass maybe has a positive immunological effect. But it may also be connected to the tumor’s network communication. The surgical intervention stimulates the network by increasing resistance.

If the main tumor mass is decreased through a surgical procedure, this results in an at least temporarily improved starting position for the patient until the mass regenerates. This could also be connected to the fact that tumor communication is not unregulated but is rather in accordance with a certain hierarchy and order, which requires a certain structure and mass.

The other aspect is that support can be requested via this communication. You can imagine that a cell connected to another cell via a conduit receives help from this other cell in the form of organelles by exchanging ions and that, for example, stress or toxicity can be much better balanced out in large networks than in small networks. That means that external attacks, such as a surgical intervention, can be much better balanced by a well-organized network than by isolated cells.
 

Resistance to chemotherapy

Q: How do irradiation and chemotherapy rank in the treatment of glioblastomas?

A: Irradiation is another therapeutic approach. It causes cells to be stuck in the growth phase of the cell cycle. The cells are not killed through radiation, but they are practically halted. And this arrest of the cell cycle is often sufficient to help people with glioblastomas for a very long time. But the same is true for irradiation as for surgery. This deep network of cells cannot be addressed.

Attempts have been made in the past to reduce the radiation dose to the extent that the brain is no longer damaged by it, but this low dose was then not sufficient to exert any control. If you want to control the tumor, the dose must be high and the volume must be correspondingly low, since there is a clear limit.

Every patient is offered alkylating chemotherapy. At the moment, just one substance is used here in the primary therapy: temozolomide. The problem with this is that two-thirds of tumors in all cells exhibit a resistance to this alkylating chemotherapy, which means that the efficacy of this therapy is highly limited in two-thirds of patients.

In the one-third of patients in whom this resistance is not present, the chemotherapy works fairly well. But even then, it is unfortunately only a matter of time until there is a relapse or disease progression. In my practice, this has always been the case, but there are people who have been living with this disease for 20 years now. There seem to be tumor cells that calmly and silently survive this phase of chemotherapy and then restart the cell cycle at some point.

Q: What do you think of alternating electric fields as a therapy option?

A: Therapy with alternating electric fields is currently being used and offered to patients. This means that patients who have survived well through radiochemotherapy should also be offered treatment with alternating electric fields.

However, what happens in this process is not as well understood as with other therapies. It is assumed that the cell cycle, i.e., cell division, is altered by disrupting the mitotic spindle. But you can imagine, and this is now speculation, but quite sound speculation I believe, that alternating electric fields also cause a certain amount of confusion in the previously described networks. But this still needs to be investigated in more detail.

It is not implausible. We know that such alternating electric fields disturb the organization of cell organelles. And we also know that for this communication, we need fairly good order and also organization. This would definitely be a starting point on the way to understanding why this therapy potentially shows a certain effect in some patients.
 

Nerve cell precursors

Q: Scientists from the UKHD and the DKFZ have discovered a new glioblastoma spreading strategy and have learned that the tumor cells imitate the properties and movement patterns of nerve cells. They are labeling the results a “milestone in the field of cancer neuroscience.” Could you explain a bit more?

A: Glioblastoma does not grow on its own as a solid mass, but instead, the entire brain is affected by the disease. The question of how the tumor’s individual cells move the main tumor mass from afar, how they get there, how they continue to be supplied, and what their interaction partners are – an entirely new light has been shed on all of this in our work.

The development of tumor cell mobility has been recognized as a remnant of brain development. The tumor cells have retained properties that the precursor cells for nervous-system development require for an organized nervous system to emerge from just a few cells. This means that the tumor cells copy or eventually retain properties of the nerve-cell precursors that, unlike mature nerve cells, are mobile to a fairly high degree.

Mobility here means that it can advance along a network, despite said network being very densely packed. This also means that certain processes, such as releasing and then continuing to move again, must function and that the communication regarding the original disease must be maintained.

First, we understand what the different glioblastoma cell types do, which molecular properties are associated with which behaviors, and which cell type (namely the swarming cells) is responsible for the invasive tumor growth. In contrast, the network-forming cell type, which only develops from these, is responsible for the resistance.
 

Interrupting communication

Q: Which starting points for new therapies do you see?

A: In terms of new therapies, these movement phenomena are one good starting point. The other starting point – I find this one much more interesting – is that the programming steps that these tumor cells use [are] no longer needed. This is because our mature nervous system no longer requires this program, which was necessary for the mobility of cells in development.

Our central nervous system exhibits little cell movement. This is to do with programs of nervous-system development that are switched off in the mature nervous system. But they are then reactivated or remain active in the tumor cells. This process reveals potential starting points for therapy.

Addressing the movement of cells, that has been investigated for the last 20 years, but it seems to have an extraordinarily high number of side effects, because these movement mechanisms are also important for other, healthy cells in the body. For example, digestive mechanisms and other proliferation mechanisms, on mucous membranes, in the blood system, in the bone marrow, are then affected and no longer function.

There is another possible approach: the more-or-less specific interaction between the nerve cells and the tumor cells also offers starting points for therapies, from our point of view. The key word is epilepsy treatment. We know that people with brain tumors suffer badly, or worse than usual, from epileptic seizures. This was often regarded purely as a pressure problem. There is a disruptive element in the brain, and this causes the electrical activity in the brain to become disorganized. For some people, this can lead to seizures in certain situations.

The communication between tumor cells and nerve cells takes place via transmission substances, e.g., through the neurotransmitter glutamate. Now you can consider whether a “surplus” of communication, such as an excessively strong stimulus, can trigger epileptic seizures.

In this work, we demonstrate that by interrupting this communication, we can also prevent the movement of these cells and the growth, the proliferation, of these cells.

Q: What is the significance of parvoviruses for therapy?

A: The major topic for cancer is immunotherapy. And one option for performing immunotherapies lies with viruses. Parvoviruses are a plausible therapy for proliferating cells.

Parvoviruses are usually administered locally. This means that a surgical cavity is infected with the viruses and the tumor cells that remain after an operation will then hopefully be killed off by these viruses.

This is the first step and the immediate effect of virus therapy. The attempt is made to kill off cells in the same way as with a medication. The advantage of viruses is the high specificity, i.e., only dividing cells will be attacked. In addition, parvoviruses are so small that they can also spread well and circulate through the brain.

The second reason for immunotherapy is that when killing off cells with viruses, antigens are often released that otherwise would not be, depending on the virus. But it’s the case with parvoviruses. They integrate with the virus’s genetic material. When cells rupture, certain proteins are then revealed, hybrids of viruses and the human genome, and these are attractive to the immune system.

There is a whole range of studies on this subject. However, there are currently no randomized studies that directly compare the therapies. But the expectation is that the use of parvoviruses could be a good addition to therapy.

One limitation that should be mentioned is that the use of viruses may be beneficial for some patients, but it will not have an effect in every patient. What is exciting about parvoviruses is that these viruses can be injected via the bloodstream and still achieve a good effect in the brain.
 

Protein APG101

Q: How relevant is the recombinant protein APG101 to therapy?

A: APG101 is a protein that simulates the cell-death receptor CD95 and binds with a stable antibody fragment. By doing so, it blocks the signaling pathway between CD95 ligand and receptor. The interaction between the CD95 ligand and the CD95 receptor activates an intracellular signaling pathway, which in turn stimulates the invasive growth and migration of tumor cells.

APG101 blocks the CD95 ligand and thereby prevents the activation of the CD95 signaling pathway, which leads to a reduction in the invasive cell growth and migration.

Apoptosis, programmed cell death, is a system we have used throughout our evolution to kill off the cell components we no longer need. During tumor development, this system is perverted, so to speak. Here, the stimulation of this system does not actually lead to cell death but rather to cell movement (i.e., to cell mobility). And in principle, APG101 blocks this mobility.

To date, I only know of three studies in which the medication has been used for tumors. One study was published 8 years ago. We demonstrated that we can achieve a relatively good effect with APG101 in connection with repeat irradiation, compared with repeat irradiation alone. We consider this effect to most likely be due to this influence on cell mobility.

There is a study on primary therapy: a four-arm study by the Neuro-Oncological Working Group. The results are still not available, however. In addition, a study on primary therapy with APG101 is currently being conducted in China. It is investigating whether the mechanism of action influences mobility. Whether it will be pushed through as therapy remains to be seen.
 

Vaccinations and antigens

Q: Vaccinations are of course a part of immunotherapy. What is their status?

A: We are looking at the IDH1 protein, which is present in mutated form in a group of brain tumors, as a very good target for a vaccine. The reason is that the protein is present in its mutated form in every cell of the tumor but not in healthy cells. That is a prerequisite for immunotherapy.

We started a study with peptides a few years ago. These peptides are injected under the skin on the stomach and leg. They cause an immune response systemically and in the brain tumor. This immune response may cause an inflammatory reaction (we can demonstrate this inflammatory reaction). And in this noncontrolled study, the approach was successful, at least compared to historical controls. There is no randomized study with treatment-naive control patients.

However, we are cautious because we know that peptide, unlike CAR T cells or RNA-based vaccines, for example, only triggers a relatively small immune response in many patients. The scale of the immune response is important, rather than the specificity. The scale is probably not large enough in most patients for a long-term effect to be expected.

But there are exceptions. Patients we vaccinated many years ago still have a very remarkable immune status. But we also have patients in whom an immune status cannot even be seen anymore, after just a short period of time.

Therefore, our aim is to perform the immune strategy with more effective, stronger measures – not more specific, but stronger. Unfortunately, it is often the case with glioblastomas that there is not a single antigen that can be vaccinated against. Instead, a relatively large cocktail is needed, which unfortunately also often varies from patient to patient. The conditions are difficult.

Q: You mentioned that glioblastomas can be classified into subgroups. Does this improve the prognosis?

A: Yes, in certain subgroups the prognosis improves. That is the case with those usually very small groups that are molecularly well defined. I believe that by better understanding the individual groups, we have succeeded in making major progress in those groups. But where there is light, there is also shadow. We know that there are many groups with which we have not achieved a great deal.

Fundamental research leads to a better understanding, and the next step in this is to be able to adapt the therapy. Instead of it being one therapy for everyone, it will become a part of various differing therapies for these quite different groups. We are making a lot of progress with individual groups. But unfortunately, we have not come quite as far as we want with many patients.

This article was translated from the Medscape German edition. A version of this article first appeared on Medscape.com.

Every year, around 7,000 people in Germany develop a brain tumor, and around half of those cases involve a glioblastoma, a particularly aggressive form of the disease. Glioblastomas are incurable, but advances are being made in both diagnostics and therapy. Scientists from the Heidelberg University Hospital (UKHD) and from the German Cancer Research Center (DKFZ) in Heidelberg have discovered a fundamentally new way in which glioblastomas spread within the brain.

This news organization spoke to Wolfgang Wick, MD, medical director of the neurologic clinic at UKHD, about how glioblastomas are treated; the role that vaccinations, recombinant proteins, and parvoviruses play; and what therapeutic approaches might be derived from the discovery of this method by which glioblastomas spread.

Question: Glioblastomas spread through the brain like a fungal network. So how would a glioblastoma currently be treated? The tumor can only be partially removed through surgery.

Answer: Nevertheless, glioblastoma would be operated on. This would have a significant effect. Relieving the strain of the main tumor mass, without generating a new deficit, is prognostically very good for the patient concerned. However, surgery on glioblastoma is never curative.

The reason a cure is not possible is down to the special form and spread of the glioblastoma. Nevertheless, an operation helps. This seems to be because removing the main tumor mass maybe has a positive immunological effect. But it may also be connected to the tumor’s network communication. The surgical intervention stimulates the network by increasing resistance.

If the main tumor mass is decreased through a surgical procedure, this results in an at least temporarily improved starting position for the patient until the mass regenerates. This could also be connected to the fact that tumor communication is not unregulated but is rather in accordance with a certain hierarchy and order, which requires a certain structure and mass.

The other aspect is that support can be requested via this communication. You can imagine that a cell connected to another cell via a conduit receives help from this other cell in the form of organelles by exchanging ions and that, for example, stress or toxicity can be much better balanced out in large networks than in small networks. That means that external attacks, such as a surgical intervention, can be much better balanced by a well-organized network than by isolated cells.
 

Resistance to chemotherapy

Q: How do irradiation and chemotherapy rank in the treatment of glioblastomas?

A: Irradiation is another therapeutic approach. It causes cells to be stuck in the growth phase of the cell cycle. The cells are not killed through radiation, but they are practically halted. And this arrest of the cell cycle is often sufficient to help people with glioblastomas for a very long time. But the same is true for irradiation as for surgery. This deep network of cells cannot be addressed.

Attempts have been made in the past to reduce the radiation dose to the extent that the brain is no longer damaged by it, but this low dose was then not sufficient to exert any control. If you want to control the tumor, the dose must be high and the volume must be correspondingly low, since there is a clear limit.

Every patient is offered alkylating chemotherapy. At the moment, just one substance is used here in the primary therapy: temozolomide. The problem with this is that two-thirds of tumors in all cells exhibit a resistance to this alkylating chemotherapy, which means that the efficacy of this therapy is highly limited in two-thirds of patients.

In the one-third of patients in whom this resistance is not present, the chemotherapy works fairly well. But even then, it is unfortunately only a matter of time until there is a relapse or disease progression. In my practice, this has always been the case, but there are people who have been living with this disease for 20 years now. There seem to be tumor cells that calmly and silently survive this phase of chemotherapy and then restart the cell cycle at some point.

Q: What do you think of alternating electric fields as a therapy option?

A: Therapy with alternating electric fields is currently being used and offered to patients. This means that patients who have survived well through radiochemotherapy should also be offered treatment with alternating electric fields.

However, what happens in this process is not as well understood as with other therapies. It is assumed that the cell cycle, i.e., cell division, is altered by disrupting the mitotic spindle. But you can imagine, and this is now speculation, but quite sound speculation I believe, that alternating electric fields also cause a certain amount of confusion in the previously described networks. But this still needs to be investigated in more detail.

It is not implausible. We know that such alternating electric fields disturb the organization of cell organelles. And we also know that for this communication, we need fairly good order and also organization. This would definitely be a starting point on the way to understanding why this therapy potentially shows a certain effect in some patients.
 

Nerve cell precursors

Q: Scientists from the UKHD and the DKFZ have discovered a new glioblastoma spreading strategy and have learned that the tumor cells imitate the properties and movement patterns of nerve cells. They are labeling the results a “milestone in the field of cancer neuroscience.” Could you explain a bit more?

A: Glioblastoma does not grow on its own as a solid mass, but instead, the entire brain is affected by the disease. The question of how the tumor’s individual cells move the main tumor mass from afar, how they get there, how they continue to be supplied, and what their interaction partners are – an entirely new light has been shed on all of this in our work.

The development of tumor cell mobility has been recognized as a remnant of brain development. The tumor cells have retained properties that the precursor cells for nervous-system development require for an organized nervous system to emerge from just a few cells. This means that the tumor cells copy or eventually retain properties of the nerve-cell precursors that, unlike mature nerve cells, are mobile to a fairly high degree.

Mobility here means that it can advance along a network, despite said network being very densely packed. This also means that certain processes, such as releasing and then continuing to move again, must function and that the communication regarding the original disease must be maintained.

First, we understand what the different glioblastoma cell types do, which molecular properties are associated with which behaviors, and which cell type (namely the swarming cells) is responsible for the invasive tumor growth. In contrast, the network-forming cell type, which only develops from these, is responsible for the resistance.
 

Interrupting communication

Q: Which starting points for new therapies do you see?

A: In terms of new therapies, these movement phenomena are one good starting point. The other starting point – I find this one much more interesting – is that the programming steps that these tumor cells use [are] no longer needed. This is because our mature nervous system no longer requires this program, which was necessary for the mobility of cells in development.

Our central nervous system exhibits little cell movement. This is to do with programs of nervous-system development that are switched off in the mature nervous system. But they are then reactivated or remain active in the tumor cells. This process reveals potential starting points for therapy.

Addressing the movement of cells, that has been investigated for the last 20 years, but it seems to have an extraordinarily high number of side effects, because these movement mechanisms are also important for other, healthy cells in the body. For example, digestive mechanisms and other proliferation mechanisms, on mucous membranes, in the blood system, in the bone marrow, are then affected and no longer function.

There is another possible approach: the more-or-less specific interaction between the nerve cells and the tumor cells also offers starting points for therapies, from our point of view. The key word is epilepsy treatment. We know that people with brain tumors suffer badly, or worse than usual, from epileptic seizures. This was often regarded purely as a pressure problem. There is a disruptive element in the brain, and this causes the electrical activity in the brain to become disorganized. For some people, this can lead to seizures in certain situations.

The communication between tumor cells and nerve cells takes place via transmission substances, e.g., through the neurotransmitter glutamate. Now you can consider whether a “surplus” of communication, such as an excessively strong stimulus, can trigger epileptic seizures.

In this work, we demonstrate that by interrupting this communication, we can also prevent the movement of these cells and the growth, the proliferation, of these cells.

Q: What is the significance of parvoviruses for therapy?

A: The major topic for cancer is immunotherapy. And one option for performing immunotherapies lies with viruses. Parvoviruses are a plausible therapy for proliferating cells.

Parvoviruses are usually administered locally. This means that a surgical cavity is infected with the viruses and the tumor cells that remain after an operation will then hopefully be killed off by these viruses.

This is the first step and the immediate effect of virus therapy. The attempt is made to kill off cells in the same way as with a medication. The advantage of viruses is the high specificity, i.e., only dividing cells will be attacked. In addition, parvoviruses are so small that they can also spread well and circulate through the brain.

The second reason for immunotherapy is that when killing off cells with viruses, antigens are often released that otherwise would not be, depending on the virus. But it’s the case with parvoviruses. They integrate with the virus’s genetic material. When cells rupture, certain proteins are then revealed, hybrids of viruses and the human genome, and these are attractive to the immune system.

There is a whole range of studies on this subject. However, there are currently no randomized studies that directly compare the therapies. But the expectation is that the use of parvoviruses could be a good addition to therapy.

One limitation that should be mentioned is that the use of viruses may be beneficial for some patients, but it will not have an effect in every patient. What is exciting about parvoviruses is that these viruses can be injected via the bloodstream and still achieve a good effect in the brain.
 

Protein APG101

Q: How relevant is the recombinant protein APG101 to therapy?

A: APG101 is a protein that simulates the cell-death receptor CD95 and binds with a stable antibody fragment. By doing so, it blocks the signaling pathway between CD95 ligand and receptor. The interaction between the CD95 ligand and the CD95 receptor activates an intracellular signaling pathway, which in turn stimulates the invasive growth and migration of tumor cells.

APG101 blocks the CD95 ligand and thereby prevents the activation of the CD95 signaling pathway, which leads to a reduction in the invasive cell growth and migration.

Apoptosis, programmed cell death, is a system we have used throughout our evolution to kill off the cell components we no longer need. During tumor development, this system is perverted, so to speak. Here, the stimulation of this system does not actually lead to cell death but rather to cell movement (i.e., to cell mobility). And in principle, APG101 blocks this mobility.

To date, I only know of three studies in which the medication has been used for tumors. One study was published 8 years ago. We demonstrated that we can achieve a relatively good effect with APG101 in connection with repeat irradiation, compared with repeat irradiation alone. We consider this effect to most likely be due to this influence on cell mobility.

There is a study on primary therapy: a four-arm study by the Neuro-Oncological Working Group. The results are still not available, however. In addition, a study on primary therapy with APG101 is currently being conducted in China. It is investigating whether the mechanism of action influences mobility. Whether it will be pushed through as therapy remains to be seen.
 

Vaccinations and antigens

Q: Vaccinations are of course a part of immunotherapy. What is their status?

A: We are looking at the IDH1 protein, which is present in mutated form in a group of brain tumors, as a very good target for a vaccine. The reason is that the protein is present in its mutated form in every cell of the tumor but not in healthy cells. That is a prerequisite for immunotherapy.

We started a study with peptides a few years ago. These peptides are injected under the skin on the stomach and leg. They cause an immune response systemically and in the brain tumor. This immune response may cause an inflammatory reaction (we can demonstrate this inflammatory reaction). And in this noncontrolled study, the approach was successful, at least compared to historical controls. There is no randomized study with treatment-naive control patients.

However, we are cautious because we know that peptide, unlike CAR T cells or RNA-based vaccines, for example, only triggers a relatively small immune response in many patients. The scale of the immune response is important, rather than the specificity. The scale is probably not large enough in most patients for a long-term effect to be expected.

But there are exceptions. Patients we vaccinated many years ago still have a very remarkable immune status. But we also have patients in whom an immune status cannot even be seen anymore, after just a short period of time.

Therefore, our aim is to perform the immune strategy with more effective, stronger measures – not more specific, but stronger. Unfortunately, it is often the case with glioblastomas that there is not a single antigen that can be vaccinated against. Instead, a relatively large cocktail is needed, which unfortunately also often varies from patient to patient. The conditions are difficult.

Q: You mentioned that glioblastomas can be classified into subgroups. Does this improve the prognosis?

A: Yes, in certain subgroups the prognosis improves. That is the case with those usually very small groups that are molecularly well defined. I believe that by better understanding the individual groups, we have succeeded in making major progress in those groups. But where there is light, there is also shadow. We know that there are many groups with which we have not achieved a great deal.

Fundamental research leads to a better understanding, and the next step in this is to be able to adapt the therapy. Instead of it being one therapy for everyone, it will become a part of various differing therapies for these quite different groups. We are making a lot of progress with individual groups. But unfortunately, we have not come quite as far as we want with many patients.

This article was translated from the Medscape German edition. A version of this article first appeared on Medscape.com.

Every year, around 7,000 people in Germany develop a brain tumor, and around half of those cases involve a glioblastoma, a particularly aggressive form of the disease. Glioblastomas are incurable, but advances are being made in both diagnostics and therapy. Scientists from the Heidelberg University Hospital (UKHD) and from the German Cancer Research Center (DKFZ) in Heidelberg have discovered a fundamentally new way in which glioblastomas spread within the brain.

This news organization spoke to Wolfgang Wick, MD, medical director of the neurologic clinic at UKHD, about how glioblastomas are treated; the role that vaccinations, recombinant proteins, and parvoviruses play; and what therapeutic approaches might be derived from the discovery of this method by which glioblastomas spread.

Question: Glioblastomas spread through the brain like a fungal network. So how would a glioblastoma currently be treated? The tumor can only be partially removed through surgery.

Answer: Nevertheless, glioblastoma would be operated on. This would have a significant effect. Relieving the strain of the main tumor mass, without generating a new deficit, is prognostically very good for the patient concerned. However, surgery on glioblastoma is never curative.

The reason a cure is not possible is down to the special form and spread of the glioblastoma. Nevertheless, an operation helps. This seems to be because removing the main tumor mass maybe has a positive immunological effect. But it may also be connected to the tumor’s network communication. The surgical intervention stimulates the network by increasing resistance.

If the main tumor mass is decreased through a surgical procedure, this results in an at least temporarily improved starting position for the patient until the mass regenerates. This could also be connected to the fact that tumor communication is not unregulated but is rather in accordance with a certain hierarchy and order, which requires a certain structure and mass.

The other aspect is that support can be requested via this communication. You can imagine that a cell connected to another cell via a conduit receives help from this other cell in the form of organelles by exchanging ions and that, for example, stress or toxicity can be much better balanced out in large networks than in small networks. That means that external attacks, such as a surgical intervention, can be much better balanced by a well-organized network than by isolated cells.
 

Resistance to chemotherapy

Q: How do irradiation and chemotherapy rank in the treatment of glioblastomas?

A: Irradiation is another therapeutic approach. It causes cells to be stuck in the growth phase of the cell cycle. The cells are not killed through radiation, but they are practically halted. And this arrest of the cell cycle is often sufficient to help people with glioblastomas for a very long time. But the same is true for irradiation as for surgery. This deep network of cells cannot be addressed.

Attempts have been made in the past to reduce the radiation dose to the extent that the brain is no longer damaged by it, but this low dose was then not sufficient to exert any control. If you want to control the tumor, the dose must be high and the volume must be correspondingly low, since there is a clear limit.

Every patient is offered alkylating chemotherapy. At the moment, just one substance is used here in the primary therapy: temozolomide. The problem with this is that two-thirds of tumors in all cells exhibit a resistance to this alkylating chemotherapy, which means that the efficacy of this therapy is highly limited in two-thirds of patients.

In the one-third of patients in whom this resistance is not present, the chemotherapy works fairly well. But even then, it is unfortunately only a matter of time until there is a relapse or disease progression. In my practice, this has always been the case, but there are people who have been living with this disease for 20 years now. There seem to be tumor cells that calmly and silently survive this phase of chemotherapy and then restart the cell cycle at some point.

Q: What do you think of alternating electric fields as a therapy option?

A: Therapy with alternating electric fields is currently being used and offered to patients. This means that patients who have survived well through radiochemotherapy should also be offered treatment with alternating electric fields.

However, what happens in this process is not as well understood as with other therapies. It is assumed that the cell cycle, i.e., cell division, is altered by disrupting the mitotic spindle. But you can imagine, and this is now speculation, but quite sound speculation I believe, that alternating electric fields also cause a certain amount of confusion in the previously described networks. But this still needs to be investigated in more detail.

It is not implausible. We know that such alternating electric fields disturb the organization of cell organelles. And we also know that for this communication, we need fairly good order and also organization. This would definitely be a starting point on the way to understanding why this therapy potentially shows a certain effect in some patients.
 

Nerve cell precursors

Q: Scientists from the UKHD and the DKFZ have discovered a new glioblastoma spreading strategy and have learned that the tumor cells imitate the properties and movement patterns of nerve cells. They are labeling the results a “milestone in the field of cancer neuroscience.” Could you explain a bit more?

A: Glioblastoma does not grow on its own as a solid mass, but instead, the entire brain is affected by the disease. The question of how the tumor’s individual cells move the main tumor mass from afar, how they get there, how they continue to be supplied, and what their interaction partners are – an entirely new light has been shed on all of this in our work.

The development of tumor cell mobility has been recognized as a remnant of brain development. The tumor cells have retained properties that the precursor cells for nervous-system development require for an organized nervous system to emerge from just a few cells. This means that the tumor cells copy or eventually retain properties of the nerve-cell precursors that, unlike mature nerve cells, are mobile to a fairly high degree.

Mobility here means that it can advance along a network, despite said network being very densely packed. This also means that certain processes, such as releasing and then continuing to move again, must function and that the communication regarding the original disease must be maintained.

First, we understand what the different glioblastoma cell types do, which molecular properties are associated with which behaviors, and which cell type (namely the swarming cells) is responsible for the invasive tumor growth. In contrast, the network-forming cell type, which only develops from these, is responsible for the resistance.
 

Interrupting communication

Q: Which starting points for new therapies do you see?

A: In terms of new therapies, these movement phenomena are one good starting point. The other starting point – I find this one much more interesting – is that the programming steps that these tumor cells use [are] no longer needed. This is because our mature nervous system no longer requires this program, which was necessary for the mobility of cells in development.

Our central nervous system exhibits little cell movement. This is to do with programs of nervous-system development that are switched off in the mature nervous system. But they are then reactivated or remain active in the tumor cells. This process reveals potential starting points for therapy.

Addressing the movement of cells, that has been investigated for the last 20 years, but it seems to have an extraordinarily high number of side effects, because these movement mechanisms are also important for other, healthy cells in the body. For example, digestive mechanisms and other proliferation mechanisms, on mucous membranes, in the blood system, in the bone marrow, are then affected and no longer function.

There is another possible approach: the more-or-less specific interaction between the nerve cells and the tumor cells also offers starting points for therapies, from our point of view. The key word is epilepsy treatment. We know that people with brain tumors suffer badly, or worse than usual, from epileptic seizures. This was often regarded purely as a pressure problem. There is a disruptive element in the brain, and this causes the electrical activity in the brain to become disorganized. For some people, this can lead to seizures in certain situations.

The communication between tumor cells and nerve cells takes place via transmission substances, e.g., through the neurotransmitter glutamate. Now you can consider whether a “surplus” of communication, such as an excessively strong stimulus, can trigger epileptic seizures.

In this work, we demonstrate that by interrupting this communication, we can also prevent the movement of these cells and the growth, the proliferation, of these cells.

Q: What is the significance of parvoviruses for therapy?

A: The major topic for cancer is immunotherapy. And one option for performing immunotherapies lies with viruses. Parvoviruses are a plausible therapy for proliferating cells.

Parvoviruses are usually administered locally. This means that a surgical cavity is infected with the viruses and the tumor cells that remain after an operation will then hopefully be killed off by these viruses.

This is the first step and the immediate effect of virus therapy. The attempt is made to kill off cells in the same way as with a medication. The advantage of viruses is the high specificity, i.e., only dividing cells will be attacked. In addition, parvoviruses are so small that they can also spread well and circulate through the brain.

The second reason for immunotherapy is that when killing off cells with viruses, antigens are often released that otherwise would not be, depending on the virus. But it’s the case with parvoviruses. They integrate with the virus’s genetic material. When cells rupture, certain proteins are then revealed, hybrids of viruses and the human genome, and these are attractive to the immune system.

There is a whole range of studies on this subject. However, there are currently no randomized studies that directly compare the therapies. But the expectation is that the use of parvoviruses could be a good addition to therapy.

One limitation that should be mentioned is that the use of viruses may be beneficial for some patients, but it will not have an effect in every patient. What is exciting about parvoviruses is that these viruses can be injected via the bloodstream and still achieve a good effect in the brain.
 

Protein APG101

Q: How relevant is the recombinant protein APG101 to therapy?

A: APG101 is a protein that simulates the cell-death receptor CD95 and binds with a stable antibody fragment. By doing so, it blocks the signaling pathway between CD95 ligand and receptor. The interaction between the CD95 ligand and the CD95 receptor activates an intracellular signaling pathway, which in turn stimulates the invasive growth and migration of tumor cells.

APG101 blocks the CD95 ligand and thereby prevents the activation of the CD95 signaling pathway, which leads to a reduction in the invasive cell growth and migration.

Apoptosis, programmed cell death, is a system we have used throughout our evolution to kill off the cell components we no longer need. During tumor development, this system is perverted, so to speak. Here, the stimulation of this system does not actually lead to cell death but rather to cell movement (i.e., to cell mobility). And in principle, APG101 blocks this mobility.

To date, I only know of three studies in which the medication has been used for tumors. One study was published 8 years ago. We demonstrated that we can achieve a relatively good effect with APG101 in connection with repeat irradiation, compared with repeat irradiation alone. We consider this effect to most likely be due to this influence on cell mobility.

There is a study on primary therapy: a four-arm study by the Neuro-Oncological Working Group. The results are still not available, however. In addition, a study on primary therapy with APG101 is currently being conducted in China. It is investigating whether the mechanism of action influences mobility. Whether it will be pushed through as therapy remains to be seen.
 

Vaccinations and antigens

Q: Vaccinations are of course a part of immunotherapy. What is their status?

A: We are looking at the IDH1 protein, which is present in mutated form in a group of brain tumors, as a very good target for a vaccine. The reason is that the protein is present in its mutated form in every cell of the tumor but not in healthy cells. That is a prerequisite for immunotherapy.

We started a study with peptides a few years ago. These peptides are injected under the skin on the stomach and leg. They cause an immune response systemically and in the brain tumor. This immune response may cause an inflammatory reaction (we can demonstrate this inflammatory reaction). And in this noncontrolled study, the approach was successful, at least compared to historical controls. There is no randomized study with treatment-naive control patients.

However, we are cautious because we know that peptide, unlike CAR T cells or RNA-based vaccines, for example, only triggers a relatively small immune response in many patients. The scale of the immune response is important, rather than the specificity. The scale is probably not large enough in most patients for a long-term effect to be expected.

But there are exceptions. Patients we vaccinated many years ago still have a very remarkable immune status. But we also have patients in whom an immune status cannot even be seen anymore, after just a short period of time.

Therefore, our aim is to perform the immune strategy with more effective, stronger measures – not more specific, but stronger. Unfortunately, it is often the case with glioblastomas that there is not a single antigen that can be vaccinated against. Instead, a relatively large cocktail is needed, which unfortunately also often varies from patient to patient. The conditions are difficult.

Q: You mentioned that glioblastomas can be classified into subgroups. Does this improve the prognosis?

A: Yes, in certain subgroups the prognosis improves. That is the case with those usually very small groups that are molecularly well defined. I believe that by better understanding the individual groups, we have succeeded in making major progress in those groups. But where there is light, there is also shadow. We know that there are many groups with which we have not achieved a great deal.

Fundamental research leads to a better understanding, and the next step in this is to be able to adapt the therapy. Instead of it being one therapy for everyone, it will become a part of various differing therapies for these quite different groups. We are making a lot of progress with individual groups. But unfortunately, we have not come quite as far as we want with many patients.

This article was translated from the Medscape German edition. A version of this article first appeared on Medscape.com.