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A farewell to arms? Drug approvals based on single-arm trials can be flawed
PARIS – with results that should only be used, under certain conditions, for accelerated approvals that should then be followed by confirmatory studies.
In fact, many drugs approved over the last decade based solely on data from single-arm trials have been subsequently withdrawn when put through the rigors of a head-to-head randomized controlled trial, according to Bishal Gyawali, MD, PhD, from the department of oncology at Queen’s University, Kingston, Ont.
“Single-arm trials are not meant to provide confirmatory evidence sufficient for approval; However, that ship has sailed, and we have several drugs that are approved on the basis of single-arm trials, but we need to make sure that those approvals are accelerated or conditional approvals, not regular approval,” he said in a presentation included in a special session on drug approvals at the European Society for Medical Oncology Congress.
“We should not allow premature regular approval based on single-arm trials, because once a drug gets conditional approval, access is not an issue. Patients will have access to the drug anyway, but we should ensure that robust evidence follows, and long-term follow-up data are needed to develop confidence in the efficacy outcomes that are seen in single-arm trials,” he said.
In many cases, single-arm trials are large enough or of long enough duration that investigators could have reasonably performed a randomized controlled trial (RCT) in the first place, Dr. Gyawali added.
Why do single-arm trials?
The term “single-arm registration trial” is something of an oxymoron, he said, noting that the purpose of such trials should be whether to take the drug to a phase 3, randomized trial. But as authors of a 2019 study in JAMA Network Open showed, of a sample of phase 3 RCTs, 42% did not have a prior phase 2 trial, and 28% had a negative phase 2 trial. Single-arm trials may be acceptable for conditional drug approvals if all of the following conditions are met:
- A RCT is not possible because the disease is rare or randomization would be unethical.
- The safety of the drug is established and its potential benefits outweigh its risks.
- The drug is associated with a high and durable overall or objective response rate.
- The mechanism of action is supported by a strong scientific rationale, and if the drug may meet an unmet medical need.
Survival endpoints won’t do
Efficacy endpoints typically used in RCTs, such as progression-free survival (PFS) and overall survival (OS) can be misleading because they may be a result of the natural history of the disease and not the drug being tested, whereas ORRs are almost certainly reflective of the action of the drug itself, because spontaneous tumor regression is a rare phenomenon, Dr. Gyawali said.
He cautioned, however, that the ORR of placebo is not zero percent. For example in a 2018 study of sorafenib (Nexavar) versus placebo for advanced or refractory desmoid tumors, the ORR with the active drug was 33%, and the ORR for placebo was 20%.
It’s also open to question, he said, what constitutes an acceptably high ORR and duration of response, pointing to Food and Drug Administration accelerated approval of an indication for nivolumab (Opdivo) for treatment of patients with hepatocellular carcinoma (HCC) that had progressed on sorafenib. In the single-arm trial used as the basis for approval, the ORRs as assessed by an independent central review committee blinded to the results was 14.3%.
“So, nivolumab in hepatocellular cancer was approved on the basis of a response rate lower than that of placebo, albeit in a different tumor. But the point I’m trying to show here is we don’t have a good definition of what is a good response rate,” he said.
In July 2021, Bristol-Myers Squibb voluntarily withdrew the HCC indication for nivolumab, following negative results of the CheckMate 459 trial and a 5-4 vote against continuing the accelerated approval.
On second thought ...
Citing data compiled by Nathan I. Cherny, MD, from Shaare Zedek Medical Center, Jerusalem, Dr. Gyawali noted that 58 of 161 FDA approvals from 2017 to 2021 of drugs for adult solid tumors were based on single-arm trials. Of the 58 drugs, 39 received accelerated approvals, and 19 received regular approvals; of the 39 that received accelerated approvals, 4 were subsequently withdrawn, 8 were converted to regular approvals, and the remainder continued as accelerated approvals.
Interestingly, the median response rate among all the drugs was 40%, and did not differ between the type of approval received, suggesting that response rates are not predictive of whether a drug will receive a conditional or full-fledged go-ahead.
What’s rare and safe?
The definition of a rare disease in the United States is one that affects fewer than 40,000 per year, and in Europe it’s an incidence rate of less than 6 per 100,000 population, Dr. Gyawali noted. But he argued that even non–small cell lung cancer, the most common form of cancer in the world, could be considered rare if it is broken down into subtypes that are treated according to specific mutations that may occur in a relatively small number of patients.
He also noted that a specific drug’s safety, one of the most important criteria for granting approval to a drug based on a single-arm trial, can be difficult to judge without adequate controls for comparison.
Cherry-picking patients
Winette van der Graaf, MD, president of the European Organization for the Research and Treatment of Cancer, who attended the session where Dr. Gyawali’s presentation was played, said in an interview that clinicians should cast a critical eye on how trials are designed and conducted, including patient selection and choice of endpoints.
“One of the most obvious things to be concerned about is that we’re still having patients with good performance status enrolled, mostly PS 0 or 1, so how representative are these clinical trials for the patients we see in front of us on a daily basis?” she said.
“The other question is radiological endpoints, which we focus on with OS and PFS are most important for patients, especially if you consider that if patients may have asymptomatic disease, and we are only treating them with potentially toxic medication, what are we doing for them? Median overall survival when you look at all of these trials is only 4 months, so we really need to take into account how we affect patients in clinical trials,” she added.
Dr. van der Graaf emphasized that clinical trial investigators need to more routinely incorporate quality of life measures and other patient-reported outcomes in clinical trial results to help regulators and clinicians in practice get a better sense of the true clinical benefit of a new drug.
Dr. Gyawali did not disclose a funding source for his presentation. He reported consulting fees from Vivio Health and research grants from the American Society of Clinical Oncology. Dr. van der Graaf reported no conflicts of interest.
PARIS – with results that should only be used, under certain conditions, for accelerated approvals that should then be followed by confirmatory studies.
In fact, many drugs approved over the last decade based solely on data from single-arm trials have been subsequently withdrawn when put through the rigors of a head-to-head randomized controlled trial, according to Bishal Gyawali, MD, PhD, from the department of oncology at Queen’s University, Kingston, Ont.
“Single-arm trials are not meant to provide confirmatory evidence sufficient for approval; However, that ship has sailed, and we have several drugs that are approved on the basis of single-arm trials, but we need to make sure that those approvals are accelerated or conditional approvals, not regular approval,” he said in a presentation included in a special session on drug approvals at the European Society for Medical Oncology Congress.
“We should not allow premature regular approval based on single-arm trials, because once a drug gets conditional approval, access is not an issue. Patients will have access to the drug anyway, but we should ensure that robust evidence follows, and long-term follow-up data are needed to develop confidence in the efficacy outcomes that are seen in single-arm trials,” he said.
In many cases, single-arm trials are large enough or of long enough duration that investigators could have reasonably performed a randomized controlled trial (RCT) in the first place, Dr. Gyawali added.
Why do single-arm trials?
The term “single-arm registration trial” is something of an oxymoron, he said, noting that the purpose of such trials should be whether to take the drug to a phase 3, randomized trial. But as authors of a 2019 study in JAMA Network Open showed, of a sample of phase 3 RCTs, 42% did not have a prior phase 2 trial, and 28% had a negative phase 2 trial. Single-arm trials may be acceptable for conditional drug approvals if all of the following conditions are met:
- A RCT is not possible because the disease is rare or randomization would be unethical.
- The safety of the drug is established and its potential benefits outweigh its risks.
- The drug is associated with a high and durable overall or objective response rate.
- The mechanism of action is supported by a strong scientific rationale, and if the drug may meet an unmet medical need.
Survival endpoints won’t do
Efficacy endpoints typically used in RCTs, such as progression-free survival (PFS) and overall survival (OS) can be misleading because they may be a result of the natural history of the disease and not the drug being tested, whereas ORRs are almost certainly reflective of the action of the drug itself, because spontaneous tumor regression is a rare phenomenon, Dr. Gyawali said.
He cautioned, however, that the ORR of placebo is not zero percent. For example in a 2018 study of sorafenib (Nexavar) versus placebo for advanced or refractory desmoid tumors, the ORR with the active drug was 33%, and the ORR for placebo was 20%.
It’s also open to question, he said, what constitutes an acceptably high ORR and duration of response, pointing to Food and Drug Administration accelerated approval of an indication for nivolumab (Opdivo) for treatment of patients with hepatocellular carcinoma (HCC) that had progressed on sorafenib. In the single-arm trial used as the basis for approval, the ORRs as assessed by an independent central review committee blinded to the results was 14.3%.
“So, nivolumab in hepatocellular cancer was approved on the basis of a response rate lower than that of placebo, albeit in a different tumor. But the point I’m trying to show here is we don’t have a good definition of what is a good response rate,” he said.
In July 2021, Bristol-Myers Squibb voluntarily withdrew the HCC indication for nivolumab, following negative results of the CheckMate 459 trial and a 5-4 vote against continuing the accelerated approval.
On second thought ...
Citing data compiled by Nathan I. Cherny, MD, from Shaare Zedek Medical Center, Jerusalem, Dr. Gyawali noted that 58 of 161 FDA approvals from 2017 to 2021 of drugs for adult solid tumors were based on single-arm trials. Of the 58 drugs, 39 received accelerated approvals, and 19 received regular approvals; of the 39 that received accelerated approvals, 4 were subsequently withdrawn, 8 were converted to regular approvals, and the remainder continued as accelerated approvals.
Interestingly, the median response rate among all the drugs was 40%, and did not differ between the type of approval received, suggesting that response rates are not predictive of whether a drug will receive a conditional or full-fledged go-ahead.
What’s rare and safe?
The definition of a rare disease in the United States is one that affects fewer than 40,000 per year, and in Europe it’s an incidence rate of less than 6 per 100,000 population, Dr. Gyawali noted. But he argued that even non–small cell lung cancer, the most common form of cancer in the world, could be considered rare if it is broken down into subtypes that are treated according to specific mutations that may occur in a relatively small number of patients.
He also noted that a specific drug’s safety, one of the most important criteria for granting approval to a drug based on a single-arm trial, can be difficult to judge without adequate controls for comparison.
Cherry-picking patients
Winette van der Graaf, MD, president of the European Organization for the Research and Treatment of Cancer, who attended the session where Dr. Gyawali’s presentation was played, said in an interview that clinicians should cast a critical eye on how trials are designed and conducted, including patient selection and choice of endpoints.
“One of the most obvious things to be concerned about is that we’re still having patients with good performance status enrolled, mostly PS 0 or 1, so how representative are these clinical trials for the patients we see in front of us on a daily basis?” she said.
“The other question is radiological endpoints, which we focus on with OS and PFS are most important for patients, especially if you consider that if patients may have asymptomatic disease, and we are only treating them with potentially toxic medication, what are we doing for them? Median overall survival when you look at all of these trials is only 4 months, so we really need to take into account how we affect patients in clinical trials,” she added.
Dr. van der Graaf emphasized that clinical trial investigators need to more routinely incorporate quality of life measures and other patient-reported outcomes in clinical trial results to help regulators and clinicians in practice get a better sense of the true clinical benefit of a new drug.
Dr. Gyawali did not disclose a funding source for his presentation. He reported consulting fees from Vivio Health and research grants from the American Society of Clinical Oncology. Dr. van der Graaf reported no conflicts of interest.
PARIS – with results that should only be used, under certain conditions, for accelerated approvals that should then be followed by confirmatory studies.
In fact, many drugs approved over the last decade based solely on data from single-arm trials have been subsequently withdrawn when put through the rigors of a head-to-head randomized controlled trial, according to Bishal Gyawali, MD, PhD, from the department of oncology at Queen’s University, Kingston, Ont.
“Single-arm trials are not meant to provide confirmatory evidence sufficient for approval; However, that ship has sailed, and we have several drugs that are approved on the basis of single-arm trials, but we need to make sure that those approvals are accelerated or conditional approvals, not regular approval,” he said in a presentation included in a special session on drug approvals at the European Society for Medical Oncology Congress.
“We should not allow premature regular approval based on single-arm trials, because once a drug gets conditional approval, access is not an issue. Patients will have access to the drug anyway, but we should ensure that robust evidence follows, and long-term follow-up data are needed to develop confidence in the efficacy outcomes that are seen in single-arm trials,” he said.
In many cases, single-arm trials are large enough or of long enough duration that investigators could have reasonably performed a randomized controlled trial (RCT) in the first place, Dr. Gyawali added.
Why do single-arm trials?
The term “single-arm registration trial” is something of an oxymoron, he said, noting that the purpose of such trials should be whether to take the drug to a phase 3, randomized trial. But as authors of a 2019 study in JAMA Network Open showed, of a sample of phase 3 RCTs, 42% did not have a prior phase 2 trial, and 28% had a negative phase 2 trial. Single-arm trials may be acceptable for conditional drug approvals if all of the following conditions are met:
- A RCT is not possible because the disease is rare or randomization would be unethical.
- The safety of the drug is established and its potential benefits outweigh its risks.
- The drug is associated with a high and durable overall or objective response rate.
- The mechanism of action is supported by a strong scientific rationale, and if the drug may meet an unmet medical need.
Survival endpoints won’t do
Efficacy endpoints typically used in RCTs, such as progression-free survival (PFS) and overall survival (OS) can be misleading because they may be a result of the natural history of the disease and not the drug being tested, whereas ORRs are almost certainly reflective of the action of the drug itself, because spontaneous tumor regression is a rare phenomenon, Dr. Gyawali said.
He cautioned, however, that the ORR of placebo is not zero percent. For example in a 2018 study of sorafenib (Nexavar) versus placebo for advanced or refractory desmoid tumors, the ORR with the active drug was 33%, and the ORR for placebo was 20%.
It’s also open to question, he said, what constitutes an acceptably high ORR and duration of response, pointing to Food and Drug Administration accelerated approval of an indication for nivolumab (Opdivo) for treatment of patients with hepatocellular carcinoma (HCC) that had progressed on sorafenib. In the single-arm trial used as the basis for approval, the ORRs as assessed by an independent central review committee blinded to the results was 14.3%.
“So, nivolumab in hepatocellular cancer was approved on the basis of a response rate lower than that of placebo, albeit in a different tumor. But the point I’m trying to show here is we don’t have a good definition of what is a good response rate,” he said.
In July 2021, Bristol-Myers Squibb voluntarily withdrew the HCC indication for nivolumab, following negative results of the CheckMate 459 trial and a 5-4 vote against continuing the accelerated approval.
On second thought ...
Citing data compiled by Nathan I. Cherny, MD, from Shaare Zedek Medical Center, Jerusalem, Dr. Gyawali noted that 58 of 161 FDA approvals from 2017 to 2021 of drugs for adult solid tumors were based on single-arm trials. Of the 58 drugs, 39 received accelerated approvals, and 19 received regular approvals; of the 39 that received accelerated approvals, 4 were subsequently withdrawn, 8 were converted to regular approvals, and the remainder continued as accelerated approvals.
Interestingly, the median response rate among all the drugs was 40%, and did not differ between the type of approval received, suggesting that response rates are not predictive of whether a drug will receive a conditional or full-fledged go-ahead.
What’s rare and safe?
The definition of a rare disease in the United States is one that affects fewer than 40,000 per year, and in Europe it’s an incidence rate of less than 6 per 100,000 population, Dr. Gyawali noted. But he argued that even non–small cell lung cancer, the most common form of cancer in the world, could be considered rare if it is broken down into subtypes that are treated according to specific mutations that may occur in a relatively small number of patients.
He also noted that a specific drug’s safety, one of the most important criteria for granting approval to a drug based on a single-arm trial, can be difficult to judge without adequate controls for comparison.
Cherry-picking patients
Winette van der Graaf, MD, president of the European Organization for the Research and Treatment of Cancer, who attended the session where Dr. Gyawali’s presentation was played, said in an interview that clinicians should cast a critical eye on how trials are designed and conducted, including patient selection and choice of endpoints.
“One of the most obvious things to be concerned about is that we’re still having patients with good performance status enrolled, mostly PS 0 or 1, so how representative are these clinical trials for the patients we see in front of us on a daily basis?” she said.
“The other question is radiological endpoints, which we focus on with OS and PFS are most important for patients, especially if you consider that if patients may have asymptomatic disease, and we are only treating them with potentially toxic medication, what are we doing for them? Median overall survival when you look at all of these trials is only 4 months, so we really need to take into account how we affect patients in clinical trials,” she added.
Dr. van der Graaf emphasized that clinical trial investigators need to more routinely incorporate quality of life measures and other patient-reported outcomes in clinical trial results to help regulators and clinicians in practice get a better sense of the true clinical benefit of a new drug.
Dr. Gyawali did not disclose a funding source for his presentation. He reported consulting fees from Vivio Health and research grants from the American Society of Clinical Oncology. Dr. van der Graaf reported no conflicts of interest.
AT ESMO CONGRESS 2022
Time to cancer diagnoses in U.S. averages 5 months
Time to diagnosis is a crucial factor in cancer. Delays can lead to diagnosis at later stages and prevent optimal therapeutic strategies, both of which have the potential to reduce survival. An estimated 63%-82% of cancers get diagnosed as a result of symptom presentation, and delays in diagnosis can hamper treatment efforts. Diagnosis can be challenging because common symptoms – such as weight loss, weakness, poor appetite, and shortness of breath – are nonspecific.
A new analysis of U.S.-based data shows that the average time to diagnosis is 5.2 months for patients with solid tumors. The authors of the study call for better cancer diagnosis pathways in the U.S.
“Several countries, including the UK, Denmark, Sweden, Canada and Australia, have identified the importance and potential impact of more timely diagnosis by establishing national guidelines, special programs, and treatment pathways. However, in the U.S., there’s relatively little research and effort focused on streamlining the diagnostic pathway. Currently, the U.S. does not have established cancer diagnostic pathways that are used consistently,” Matthew Gitlin, PharmD, said during a presentation at the annual meeting of the European Society for Medical Oncology.
“That is often associated with worse clinical outcomes, increased economic burden, and decreased health related quality of life,” said Dr. Gitlin, founder and managing director of the health economics consulting firm BluePath Solutions, which conducted the analysis.
The study retrospectively examined administrative billing data drawn from the Clinformatics for Managed Markets longitudinal database. The data represent individuals in Medicare Advantage and a large, U.S.-based private insurance plan. Between 2018 and 2019, there were 458,818 cancer diagnoses. The mean age was 70.6 years and 49.6% of the patients were female. Sixty-five percent were White, 11.1% Black, 8.3% Hispanic, and 2.5% Asian. No race data were available for 13.2%. Medicare Advantage was the primary insurance carrier for 74.0%, and 24.0% had a commercial plan.
The mean time to diagnosis across all tumors was 5.2 months (standard deviation, 5.5 months). There was significant variation across different tumor types, as well as within the same tumor type. The median value was 3.9 months (interquartile range, 1.1-7.2 months).
Mean time to diagnosis ranged from 121.6 days for bladder cancer to as high as 229 days for multiple myeloma. Standard deviations were nearly as large or even larger than the mean values. The study showed that 15.8% of patients waited 6 months or longer for a diagnosis. Delays were most common in kidney cancer, colorectal cancer, gallbladder cancer, esophageal cancer, stomach cancer, lymphoma, and multiple myeloma: More than 25% of patients had a time to diagnosis of at least 6 months in these tumors.
“Although there is limited research in the published literature, our findings are consistent with that literature that does exist. Development or modification of policies, guidelines or medical interventions that streamline the diagnostic pathway are needed to optimize patient outcomes and reduce resource burden and cost to the health care system,” Dr. Gitlin said.
Previous literature on this topic has seen wide variation in how time to diagnosis is defined, and most research is conducted in high-income countries, according to Felipe Roitberg, PhD, who served as a discussant during the session. “Most of the countries and patients in need are localized in low- and middle-income countries, so that is a call to action (for more research),” said Dr. Roitberg, a clinical oncologist at Hospital Sírio Libanês in São Paulo, Brazil.
The study did not look at the associations between race and time to diagnosis. “This is a source of analysis could further be explored,” said Dr. Roitberg.
He noted that the ABC-DO prospective cohort study in sub-Saharan Africa found large variations in breast cancer survival by country, and its authors predicted that downstaging and improvements in treatment could prevent up to one-third of projected breast cancer deaths over the next decade. “So these are the drivers of populational gain in terms of overall survival – not more drugs, not more services available, but coordination of services and making sure the patient has a right pathway (to diagnosis and treatment),” Dr. Roitberg said.
Dr. Gitlin has received consulting fees from GRAIL LLC, which is a subsidiary of Illumina. Dr. Roitberg has received honoraria from Boehringer Ingelheim, Sanofi, Roche, MSD Oncology, AstraZeneca, Nestle Health Science, Dr Reddy’s, and Oncologia Brazil. He has consulted for MSD Oncology. He has received research funding from Roche, Boehringer Ingelheim, MSD, Bayer, AstraZeneca, and Takeda.
Time to diagnosis is a crucial factor in cancer. Delays can lead to diagnosis at later stages and prevent optimal therapeutic strategies, both of which have the potential to reduce survival. An estimated 63%-82% of cancers get diagnosed as a result of symptom presentation, and delays in diagnosis can hamper treatment efforts. Diagnosis can be challenging because common symptoms – such as weight loss, weakness, poor appetite, and shortness of breath – are nonspecific.
A new analysis of U.S.-based data shows that the average time to diagnosis is 5.2 months for patients with solid tumors. The authors of the study call for better cancer diagnosis pathways in the U.S.
“Several countries, including the UK, Denmark, Sweden, Canada and Australia, have identified the importance and potential impact of more timely diagnosis by establishing national guidelines, special programs, and treatment pathways. However, in the U.S., there’s relatively little research and effort focused on streamlining the diagnostic pathway. Currently, the U.S. does not have established cancer diagnostic pathways that are used consistently,” Matthew Gitlin, PharmD, said during a presentation at the annual meeting of the European Society for Medical Oncology.
“That is often associated with worse clinical outcomes, increased economic burden, and decreased health related quality of life,” said Dr. Gitlin, founder and managing director of the health economics consulting firm BluePath Solutions, which conducted the analysis.
The study retrospectively examined administrative billing data drawn from the Clinformatics for Managed Markets longitudinal database. The data represent individuals in Medicare Advantage and a large, U.S.-based private insurance plan. Between 2018 and 2019, there were 458,818 cancer diagnoses. The mean age was 70.6 years and 49.6% of the patients were female. Sixty-five percent were White, 11.1% Black, 8.3% Hispanic, and 2.5% Asian. No race data were available for 13.2%. Medicare Advantage was the primary insurance carrier for 74.0%, and 24.0% had a commercial plan.
The mean time to diagnosis across all tumors was 5.2 months (standard deviation, 5.5 months). There was significant variation across different tumor types, as well as within the same tumor type. The median value was 3.9 months (interquartile range, 1.1-7.2 months).
Mean time to diagnosis ranged from 121.6 days for bladder cancer to as high as 229 days for multiple myeloma. Standard deviations were nearly as large or even larger than the mean values. The study showed that 15.8% of patients waited 6 months or longer for a diagnosis. Delays were most common in kidney cancer, colorectal cancer, gallbladder cancer, esophageal cancer, stomach cancer, lymphoma, and multiple myeloma: More than 25% of patients had a time to diagnosis of at least 6 months in these tumors.
“Although there is limited research in the published literature, our findings are consistent with that literature that does exist. Development or modification of policies, guidelines or medical interventions that streamline the diagnostic pathway are needed to optimize patient outcomes and reduce resource burden and cost to the health care system,” Dr. Gitlin said.
Previous literature on this topic has seen wide variation in how time to diagnosis is defined, and most research is conducted in high-income countries, according to Felipe Roitberg, PhD, who served as a discussant during the session. “Most of the countries and patients in need are localized in low- and middle-income countries, so that is a call to action (for more research),” said Dr. Roitberg, a clinical oncologist at Hospital Sírio Libanês in São Paulo, Brazil.
The study did not look at the associations between race and time to diagnosis. “This is a source of analysis could further be explored,” said Dr. Roitberg.
He noted that the ABC-DO prospective cohort study in sub-Saharan Africa found large variations in breast cancer survival by country, and its authors predicted that downstaging and improvements in treatment could prevent up to one-third of projected breast cancer deaths over the next decade. “So these are the drivers of populational gain in terms of overall survival – not more drugs, not more services available, but coordination of services and making sure the patient has a right pathway (to diagnosis and treatment),” Dr. Roitberg said.
Dr. Gitlin has received consulting fees from GRAIL LLC, which is a subsidiary of Illumina. Dr. Roitberg has received honoraria from Boehringer Ingelheim, Sanofi, Roche, MSD Oncology, AstraZeneca, Nestle Health Science, Dr Reddy’s, and Oncologia Brazil. He has consulted for MSD Oncology. He has received research funding from Roche, Boehringer Ingelheim, MSD, Bayer, AstraZeneca, and Takeda.
Time to diagnosis is a crucial factor in cancer. Delays can lead to diagnosis at later stages and prevent optimal therapeutic strategies, both of which have the potential to reduce survival. An estimated 63%-82% of cancers get diagnosed as a result of symptom presentation, and delays in diagnosis can hamper treatment efforts. Diagnosis can be challenging because common symptoms – such as weight loss, weakness, poor appetite, and shortness of breath – are nonspecific.
A new analysis of U.S.-based data shows that the average time to diagnosis is 5.2 months for patients with solid tumors. The authors of the study call for better cancer diagnosis pathways in the U.S.
“Several countries, including the UK, Denmark, Sweden, Canada and Australia, have identified the importance and potential impact of more timely diagnosis by establishing national guidelines, special programs, and treatment pathways. However, in the U.S., there’s relatively little research and effort focused on streamlining the diagnostic pathway. Currently, the U.S. does not have established cancer diagnostic pathways that are used consistently,” Matthew Gitlin, PharmD, said during a presentation at the annual meeting of the European Society for Medical Oncology.
“That is often associated with worse clinical outcomes, increased economic burden, and decreased health related quality of life,” said Dr. Gitlin, founder and managing director of the health economics consulting firm BluePath Solutions, which conducted the analysis.
The study retrospectively examined administrative billing data drawn from the Clinformatics for Managed Markets longitudinal database. The data represent individuals in Medicare Advantage and a large, U.S.-based private insurance plan. Between 2018 and 2019, there were 458,818 cancer diagnoses. The mean age was 70.6 years and 49.6% of the patients were female. Sixty-five percent were White, 11.1% Black, 8.3% Hispanic, and 2.5% Asian. No race data were available for 13.2%. Medicare Advantage was the primary insurance carrier for 74.0%, and 24.0% had a commercial plan.
The mean time to diagnosis across all tumors was 5.2 months (standard deviation, 5.5 months). There was significant variation across different tumor types, as well as within the same tumor type. The median value was 3.9 months (interquartile range, 1.1-7.2 months).
Mean time to diagnosis ranged from 121.6 days for bladder cancer to as high as 229 days for multiple myeloma. Standard deviations were nearly as large or even larger than the mean values. The study showed that 15.8% of patients waited 6 months or longer for a diagnosis. Delays were most common in kidney cancer, colorectal cancer, gallbladder cancer, esophageal cancer, stomach cancer, lymphoma, and multiple myeloma: More than 25% of patients had a time to diagnosis of at least 6 months in these tumors.
“Although there is limited research in the published literature, our findings are consistent with that literature that does exist. Development or modification of policies, guidelines or medical interventions that streamline the diagnostic pathway are needed to optimize patient outcomes and reduce resource burden and cost to the health care system,” Dr. Gitlin said.
Previous literature on this topic has seen wide variation in how time to diagnosis is defined, and most research is conducted in high-income countries, according to Felipe Roitberg, PhD, who served as a discussant during the session. “Most of the countries and patients in need are localized in low- and middle-income countries, so that is a call to action (for more research),” said Dr. Roitberg, a clinical oncologist at Hospital Sírio Libanês in São Paulo, Brazil.
The study did not look at the associations between race and time to diagnosis. “This is a source of analysis could further be explored,” said Dr. Roitberg.
He noted that the ABC-DO prospective cohort study in sub-Saharan Africa found large variations in breast cancer survival by country, and its authors predicted that downstaging and improvements in treatment could prevent up to one-third of projected breast cancer deaths over the next decade. “So these are the drivers of populational gain in terms of overall survival – not more drugs, not more services available, but coordination of services and making sure the patient has a right pathway (to diagnosis and treatment),” Dr. Roitberg said.
Dr. Gitlin has received consulting fees from GRAIL LLC, which is a subsidiary of Illumina. Dr. Roitberg has received honoraria from Boehringer Ingelheim, Sanofi, Roche, MSD Oncology, AstraZeneca, Nestle Health Science, Dr Reddy’s, and Oncologia Brazil. He has consulted for MSD Oncology. He has received research funding from Roche, Boehringer Ingelheim, MSD, Bayer, AstraZeneca, and Takeda.
FROM ESMO CONGRESS 2022
Pembro/chemo combo fails to improve event-free survival in head and neck cancer
PARIS – compared with CRT plus placebo as first-line therapy for patients with locally advanced head and neck squamous cell cancers (HNSCC), reported investigators of the KEYNOTE-412 trial.
Among 804 patients with newly diagnosed, pathologically proven, unresected locally advanced head and neck squamous cell carcinomas who were followed for a median of 47.7 months, the event-free survival (EFS) rate with the pembrolizumab/CRT combination followed by maintenance pembrolizumab was 63.2%, compared with 56.2% for CRT plus placebo. This translated into a nonsignificant hazard ratio of 0.83, said Jean-Pascal Machiels, MD, PhD, at the annual meeting of the European Society for Medical Oncology.
Despite the trial failing to meet its primary endpoint, Dr. Machiels expressed optimism about the results.
“Pembrolizumab with chemoradiation was associated with a favorable trend toward improved event-free survival versus placebo plus chemoradiation in patients with locally advanced head and neck cancer,” he said.
He noted that the 2-year EFS rate was 63% with pembrolizumab, compared with 56% with placebo.
The data also support the hypothesis that programmed death–ligand 1 (PD-L1) expression as measured by a combined positive score (CPS) could be a predictive biomarker for identifying those patients most likely to respond to the immune checkpoint inhibitor, he added.
KEYNOTE-412 details
The rationale for combining the checkpoint inhibitors pembrolizumab with chemoradiotherapy comes from the KEYNOTE-048 trial results of which showed a survival improvement for the use of pembrolizumab plus a platinum-containing regimen as a first-line therapy for recurrent or metastatic HNSCC, as well as pembrolizumab monotherapy for patients with PD-L1 CPS of 1 or greater.
In the current study, Dr. Machiels and colleagues studied whether adding pembrolizumab to CRT could benefit patients with treatment-naive unresected, locally advanced HNSCC.
Eligible patients included those with stage T3 or T4, N0-N3 or any N2a-3 (T1-T4) cancers of the larynx, hypopharynx, or oral cavity, and either p16-negative oropharynx cancers or T4 or N3 p16-positive oropharynx cancer. Patients were required to be eligible for high-dose cisplatin-based CRT.
A total of 804 patients were randomized, 402 in each arm, to receive either pembrolizumab 200 mg intravenously every 3 weeks for 3 cycles plus CRT followed by maintenance pembrolizumab for 14 cycles, or to placebo plus CRT followed by placebo maintenance.
As noted before, there was no significant difference between the study arms for the primary endpoint of EFS. The 24-month EFS rate was 63.2% for the pembrolizumab group, compared with 56.2% for controls. The respective 6-month EFS rates were 57.4% versus 52.1%.
In a post hoc analysis, both EFS and overall survival were numerically with pembrolizumab among patients with PD-L1 CPS of 20 or greater. The respective 2- and 3-year EFS rates were 71.2% versus 62.6%, and 66.7% versus 57.2%.
The 24-months overall survival rates were 83.3% with pembrolizumab and 79.9% with placebo, and 36-month rates were 79.1% and 73%, respectively.
Neither EFS rates nor OS rates among patients in this subgroup differed significantly; however, there were no new safety signals with the combination, Dr. Machiels said. The incidence of grade 3 or greater adverse events was 92.2% in the pembrolizumab arm versus 88.4% in the placebo arm. Four patients in the pembrolizumab arm and six in the control arm died from treatment-related causes.
Benefit still to be proven
In a media briefing held prior to his presentation, Dr. Machiels was asked how he could justify his conclusions about a benefit for adding pembrolizumab given that there was no difference between the treatment groups for the primary endpoint.
He said that when the investigators designed the trial 7 years ago, the CPS score for PD-L1 expression had not yet been developed, and that if it had been they might have designed the trial to explore the effect of the pembrolizumab chemoradiation combination according to CPS subgroups.
He also pointed to the numerically superior 2-year EFS and overall rates.
In the presidential symposium, James Larkin, MD, PhD, an invited discussant from the Royal Marsden Hospital, London, said that chemotherapy and anti–PD-1 therapies are known to offer benefit in advanced cancers despite the trial’s failure.
“There is a signal, particularly as we’ve seen in the high PD-L1 group,” he said, noting that the signal was consistent with that seen in the JAVELIN 100 study, which was also a negative trial. He cautioned against relying too heavily on the comparison, however, as JAVELIN 100 was conducted with avelumab, a PD-L1 inhibitor, whereas pembrolizumab is a PD-1 inhibitor.
“Could there be an issue here with treatment schedule? An example and a comparison might be the PACIFIC study in non–small cell lung cancer, which is a positive trial, where actually the checkpoint inhibit with durvalumab was given immediately after the chemoradiotherapy, leading to benefit, rather than being concurrent,” he said.
Dr. Larkin also questioned whether, as codiscussant Sherene Loi, MD, PhD, from the Peter MacCallum Cancer Center, Melbourne, suggested radiotherapy to lymph nodes might alter the immune response to checkpoint inhibitors.
“Clearly radiotherapy is the central component of treatment in this setting, so it would be quite difficult to scale too much on that, but the question is: ‘Could it be modified?’ For example, just to irradiate the primary tumor and involved lymph nodes and potentially spare noninvolved lymph nodes,” he said.
The KEYNOTE-412 study was funded by Merck Sharp & Dohme. Dr. Machiels reported uncompensated consulting to the company. Dr. Larkin reported consulting for and receiving honoraria from Merck and others. Dr. Loi reported uncompensated advisory board activity for Merck and others.
PARIS – compared with CRT plus placebo as first-line therapy for patients with locally advanced head and neck squamous cell cancers (HNSCC), reported investigators of the KEYNOTE-412 trial.
Among 804 patients with newly diagnosed, pathologically proven, unresected locally advanced head and neck squamous cell carcinomas who were followed for a median of 47.7 months, the event-free survival (EFS) rate with the pembrolizumab/CRT combination followed by maintenance pembrolizumab was 63.2%, compared with 56.2% for CRT plus placebo. This translated into a nonsignificant hazard ratio of 0.83, said Jean-Pascal Machiels, MD, PhD, at the annual meeting of the European Society for Medical Oncology.
Despite the trial failing to meet its primary endpoint, Dr. Machiels expressed optimism about the results.
“Pembrolizumab with chemoradiation was associated with a favorable trend toward improved event-free survival versus placebo plus chemoradiation in patients with locally advanced head and neck cancer,” he said.
He noted that the 2-year EFS rate was 63% with pembrolizumab, compared with 56% with placebo.
The data also support the hypothesis that programmed death–ligand 1 (PD-L1) expression as measured by a combined positive score (CPS) could be a predictive biomarker for identifying those patients most likely to respond to the immune checkpoint inhibitor, he added.
KEYNOTE-412 details
The rationale for combining the checkpoint inhibitors pembrolizumab with chemoradiotherapy comes from the KEYNOTE-048 trial results of which showed a survival improvement for the use of pembrolizumab plus a platinum-containing regimen as a first-line therapy for recurrent or metastatic HNSCC, as well as pembrolizumab monotherapy for patients with PD-L1 CPS of 1 or greater.
In the current study, Dr. Machiels and colleagues studied whether adding pembrolizumab to CRT could benefit patients with treatment-naive unresected, locally advanced HNSCC.
Eligible patients included those with stage T3 or T4, N0-N3 or any N2a-3 (T1-T4) cancers of the larynx, hypopharynx, or oral cavity, and either p16-negative oropharynx cancers or T4 or N3 p16-positive oropharynx cancer. Patients were required to be eligible for high-dose cisplatin-based CRT.
A total of 804 patients were randomized, 402 in each arm, to receive either pembrolizumab 200 mg intravenously every 3 weeks for 3 cycles plus CRT followed by maintenance pembrolizumab for 14 cycles, or to placebo plus CRT followed by placebo maintenance.
As noted before, there was no significant difference between the study arms for the primary endpoint of EFS. The 24-month EFS rate was 63.2% for the pembrolizumab group, compared with 56.2% for controls. The respective 6-month EFS rates were 57.4% versus 52.1%.
In a post hoc analysis, both EFS and overall survival were numerically with pembrolizumab among patients with PD-L1 CPS of 20 or greater. The respective 2- and 3-year EFS rates were 71.2% versus 62.6%, and 66.7% versus 57.2%.
The 24-months overall survival rates were 83.3% with pembrolizumab and 79.9% with placebo, and 36-month rates were 79.1% and 73%, respectively.
Neither EFS rates nor OS rates among patients in this subgroup differed significantly; however, there were no new safety signals with the combination, Dr. Machiels said. The incidence of grade 3 or greater adverse events was 92.2% in the pembrolizumab arm versus 88.4% in the placebo arm. Four patients in the pembrolizumab arm and six in the control arm died from treatment-related causes.
Benefit still to be proven
In a media briefing held prior to his presentation, Dr. Machiels was asked how he could justify his conclusions about a benefit for adding pembrolizumab given that there was no difference between the treatment groups for the primary endpoint.
He said that when the investigators designed the trial 7 years ago, the CPS score for PD-L1 expression had not yet been developed, and that if it had been they might have designed the trial to explore the effect of the pembrolizumab chemoradiation combination according to CPS subgroups.
He also pointed to the numerically superior 2-year EFS and overall rates.
In the presidential symposium, James Larkin, MD, PhD, an invited discussant from the Royal Marsden Hospital, London, said that chemotherapy and anti–PD-1 therapies are known to offer benefit in advanced cancers despite the trial’s failure.
“There is a signal, particularly as we’ve seen in the high PD-L1 group,” he said, noting that the signal was consistent with that seen in the JAVELIN 100 study, which was also a negative trial. He cautioned against relying too heavily on the comparison, however, as JAVELIN 100 was conducted with avelumab, a PD-L1 inhibitor, whereas pembrolizumab is a PD-1 inhibitor.
“Could there be an issue here with treatment schedule? An example and a comparison might be the PACIFIC study in non–small cell lung cancer, which is a positive trial, where actually the checkpoint inhibit with durvalumab was given immediately after the chemoradiotherapy, leading to benefit, rather than being concurrent,” he said.
Dr. Larkin also questioned whether, as codiscussant Sherene Loi, MD, PhD, from the Peter MacCallum Cancer Center, Melbourne, suggested radiotherapy to lymph nodes might alter the immune response to checkpoint inhibitors.
“Clearly radiotherapy is the central component of treatment in this setting, so it would be quite difficult to scale too much on that, but the question is: ‘Could it be modified?’ For example, just to irradiate the primary tumor and involved lymph nodes and potentially spare noninvolved lymph nodes,” he said.
The KEYNOTE-412 study was funded by Merck Sharp & Dohme. Dr. Machiels reported uncompensated consulting to the company. Dr. Larkin reported consulting for and receiving honoraria from Merck and others. Dr. Loi reported uncompensated advisory board activity for Merck and others.
PARIS – compared with CRT plus placebo as first-line therapy for patients with locally advanced head and neck squamous cell cancers (HNSCC), reported investigators of the KEYNOTE-412 trial.
Among 804 patients with newly diagnosed, pathologically proven, unresected locally advanced head and neck squamous cell carcinomas who were followed for a median of 47.7 months, the event-free survival (EFS) rate with the pembrolizumab/CRT combination followed by maintenance pembrolizumab was 63.2%, compared with 56.2% for CRT plus placebo. This translated into a nonsignificant hazard ratio of 0.83, said Jean-Pascal Machiels, MD, PhD, at the annual meeting of the European Society for Medical Oncology.
Despite the trial failing to meet its primary endpoint, Dr. Machiels expressed optimism about the results.
“Pembrolizumab with chemoradiation was associated with a favorable trend toward improved event-free survival versus placebo plus chemoradiation in patients with locally advanced head and neck cancer,” he said.
He noted that the 2-year EFS rate was 63% with pembrolizumab, compared with 56% with placebo.
The data also support the hypothesis that programmed death–ligand 1 (PD-L1) expression as measured by a combined positive score (CPS) could be a predictive biomarker for identifying those patients most likely to respond to the immune checkpoint inhibitor, he added.
KEYNOTE-412 details
The rationale for combining the checkpoint inhibitors pembrolizumab with chemoradiotherapy comes from the KEYNOTE-048 trial results of which showed a survival improvement for the use of pembrolizumab plus a platinum-containing regimen as a first-line therapy for recurrent or metastatic HNSCC, as well as pembrolizumab monotherapy for patients with PD-L1 CPS of 1 or greater.
In the current study, Dr. Machiels and colleagues studied whether adding pembrolizumab to CRT could benefit patients with treatment-naive unresected, locally advanced HNSCC.
Eligible patients included those with stage T3 or T4, N0-N3 or any N2a-3 (T1-T4) cancers of the larynx, hypopharynx, or oral cavity, and either p16-negative oropharynx cancers or T4 or N3 p16-positive oropharynx cancer. Patients were required to be eligible for high-dose cisplatin-based CRT.
A total of 804 patients were randomized, 402 in each arm, to receive either pembrolizumab 200 mg intravenously every 3 weeks for 3 cycles plus CRT followed by maintenance pembrolizumab for 14 cycles, or to placebo plus CRT followed by placebo maintenance.
As noted before, there was no significant difference between the study arms for the primary endpoint of EFS. The 24-month EFS rate was 63.2% for the pembrolizumab group, compared with 56.2% for controls. The respective 6-month EFS rates were 57.4% versus 52.1%.
In a post hoc analysis, both EFS and overall survival were numerically with pembrolizumab among patients with PD-L1 CPS of 20 or greater. The respective 2- and 3-year EFS rates were 71.2% versus 62.6%, and 66.7% versus 57.2%.
The 24-months overall survival rates were 83.3% with pembrolizumab and 79.9% with placebo, and 36-month rates were 79.1% and 73%, respectively.
Neither EFS rates nor OS rates among patients in this subgroup differed significantly; however, there were no new safety signals with the combination, Dr. Machiels said. The incidence of grade 3 or greater adverse events was 92.2% in the pembrolizumab arm versus 88.4% in the placebo arm. Four patients in the pembrolizumab arm and six in the control arm died from treatment-related causes.
Benefit still to be proven
In a media briefing held prior to his presentation, Dr. Machiels was asked how he could justify his conclusions about a benefit for adding pembrolizumab given that there was no difference between the treatment groups for the primary endpoint.
He said that when the investigators designed the trial 7 years ago, the CPS score for PD-L1 expression had not yet been developed, and that if it had been they might have designed the trial to explore the effect of the pembrolizumab chemoradiation combination according to CPS subgroups.
He also pointed to the numerically superior 2-year EFS and overall rates.
In the presidential symposium, James Larkin, MD, PhD, an invited discussant from the Royal Marsden Hospital, London, said that chemotherapy and anti–PD-1 therapies are known to offer benefit in advanced cancers despite the trial’s failure.
“There is a signal, particularly as we’ve seen in the high PD-L1 group,” he said, noting that the signal was consistent with that seen in the JAVELIN 100 study, which was also a negative trial. He cautioned against relying too heavily on the comparison, however, as JAVELIN 100 was conducted with avelumab, a PD-L1 inhibitor, whereas pembrolizumab is a PD-1 inhibitor.
“Could there be an issue here with treatment schedule? An example and a comparison might be the PACIFIC study in non–small cell lung cancer, which is a positive trial, where actually the checkpoint inhibit with durvalumab was given immediately after the chemoradiotherapy, leading to benefit, rather than being concurrent,” he said.
Dr. Larkin also questioned whether, as codiscussant Sherene Loi, MD, PhD, from the Peter MacCallum Cancer Center, Melbourne, suggested radiotherapy to lymph nodes might alter the immune response to checkpoint inhibitors.
“Clearly radiotherapy is the central component of treatment in this setting, so it would be quite difficult to scale too much on that, but the question is: ‘Could it be modified?’ For example, just to irradiate the primary tumor and involved lymph nodes and potentially spare noninvolved lymph nodes,” he said.
The KEYNOTE-412 study was funded by Merck Sharp & Dohme. Dr. Machiels reported uncompensated consulting to the company. Dr. Larkin reported consulting for and receiving honoraria from Merck and others. Dr. Loi reported uncompensated advisory board activity for Merck and others.
AT ESMO CONGRESS 2022
First drug for desmoid tumors: ‘Impressive’ data for nirogacestat
PARIS –
Nirogacestat, under development by Connecticut-based SpringWorks Therapeutics, is an oral, selective, small-molecule gamma secretase inhibitor that targets the Notch signaling pathway, which is involved in cell differentiation. Desmoid tumors express high levels of Notch, so there is a “clear mechanistic rationale” for using such drugs in these patients.
Now, nirogacestat has shown a significant improvement in progression-free survival (PFS) and also a reduction in symptoms and better quality of life, when compared with placebo in the phase 3 DeFi trial.
The company has said that, by the end of this year, it will file these data for U.S. Food and Drug Administration approval of the drug for use in desmoid tumors.
Trial results were presented at the annual meeting of the European Society for Medical Oncology.
Overall, nirogacestat demonstrated “rapid, sustained, and statistically significant improvements in all primary and secondary endpoints,” study presenter Bernd Kasper, MD, PhD, sarcoma unit, Mannheim (Germany) Cancer Center, told a press conference.
There were “really impressive” reductions in pain scores and symptom burden, as well as improvements in health-related quality of life.
Dr. Kasper highlighted that this is the “first phase 3 trial … to demonstrate a clinical benefit with a gamma secretase inhibitor in any indication.”
With the drug showing a “manageable safety profile,” despite a high rate of ovarian dysfunction, Dr. Kasper believes it “has the potential to become the standard of care for patients with desmoid tumors requiring systemic treatment.”
Asked how long patients could take the drug, he replied, “Usually you take a drug as long as the patient benefits” from it.
“That means as long as there is no progression,” Dr. Kasper said, noting that there are patients from the earlier phase trials of nirogacestat who have been taking the drug “for years.”
However, there is a “very important question that is not answered” by the current study: “How long should we treat our patients?”
Dr. Kasper said to answer that question will require further trials, including those focused on treatment discontinuation.
Large trial in rare cancer
DeFi is a “unique study” and “very important in many aspects,” commented Jean-Yves Blay, MD, PhD, professor of medicine at the University Claude Bernard in Lyon, France, in an ESMO press release. Dr. Blay was not involved with the DeFi research.
“The results show benefit for the first time with a novel treatment with a new mode of action in patients where treatment options are currently limited,” he said, adding that the findings are “practice changing.”
Dr. Blay also praised the study for being “smart,” as it showed that large, placebo-controlled trials can be conducted in a rare cancer, and demonstrated the “importance of targeting the right patients with right drug.”
“The success of this study puts even more emphasis on the concept of having patients with rare cancers referred into reference centers, where clinical studies can be accomplished in record times, with the potential to deliver new treatments to patients with orphan diseases,” he said.
Discussing the results following their presentation, Dr. Blay said there are nevertheless a number of different treatment options for desmoid tumors, including sorafenib (Nexavar), and it is not clear whether patients with nonprogressive disease would experience any symptomatic benefit with nirogacestat.
Biomarkers of treatment efficacy and resistance are also required, he continued, and the drug’s long-term toxicity profile needs to be understood. In addition, its impact on ovarian dysfunction, as well as on future pregnancies, is currently unclear.
Details of the results
Presenting the study, Dr. Kasper explained that desmoid tumors have a variable presentation and an “unpredictable disease course,” and this together with the lack of approved therapies means they are “challenging to manage.”
Moreover, “due to local and aggressive growth, desmoid tumors can cause pain, disfigurement, and functional problems that can be a real burden for patients,” Dr. Kasper stressed.
Treatment should therefore be individualized to each patient to “optimize tumor control and improve the symptom burden,” he told the audience, including the impact on pain, physical function, and overall quality of life.
Indeed, a recent global consensus-based guideline for the management of desmoid tumors recommended a five-step model for treatment selection based on the level of evidence, overall response rate, PFS rate, ease of administration, and expected toxicity.
The DeFi trial enrolled patients with progressive desmoid tumors, stratified by target tumor location (intra-/extra-abdominal), who either were treatment-naive and not amenable to surgery, or were treatment refractory, or had recurrent disease after one prior line of therapy.
Dr. Kasper said in an interview that they required the patient to have at least 20% disease progression at the tumor sites so that they would include only those “who are in need of treatment.”
He explained that requirement was “quite strict” to ensure they excluded patients with “smaller-scale disease” and those with spontaneous regression, which can occur in desmoid tumors.
In all, 142 patients from 37 sites worldwide were randomly assigned to receive either nirogacestat 150 mg or placebo twice daily in 28-day cycles until radiographic progression, at which point patients were moved into an open-label phase and placebo patients could switch to nirogacestat.
The median age of the patients was 34 years, and two-thirds were female. Dr. Kasper underlined that there was a “rather high” prevalence of multifocal disease, at around 40%.
At the data cutoff for the primary analysis on April 7, nirogacestat was associated with a significant reduction in disease progression, at a median PFS that was not reached vs. 15.1 months for placebo, or a hazard ratio of 0.29 (P < .001).
This effect was seen across all subgroups included in the analysis, including when stratifying patients by age, gender, tumor characteristics, and prior treatment.
The objective response rate was also significantly higher with nirogacestat, at 41% vs. 8% in patients assigned to placebo (P < .001). A complete response was seen in 7% of patients given active treatment vs. 0% of those in the placebo group.
The median time to response was 5.6 months with nirogacestat and 11.1 months for patients given placebo.
Dr. Kasper also showed that nirogacestat was associated with significant reductions in pain severity, compared with placebo at treatment cycle 10, as measured on the Brief Pain Index-Short Form of –1.5 (P < .001).
There were also significant improvements with nirogacestat over placebo in the DT Symptom and DT Impact Scales (P < .001 for both), and on the global health status/quality of life scale (P = .007), physical functioning scale (P < .001), and role functioning scale (P < .001) of the EORTC Quality of Life Questionnaire-Core 30.
After a median exposure of 20.6 months, grade 3 or higher treatment-emergent adverse events were observed in 57% of patients treated with nirogacestat vs. 17% of those given placebo, who had a median treatment exposure of 11.4 months.
The most commonly reported adverse events of any grade with the active drug were diarrhea (84%), nausea (54%), fatigue (51%), and hypophosphatemia (42%), but Dr. Kasper noted that 95% of treatment-emergent adverse events were grade 1 or 2, with the first onset typically during cycle 1.
Ovarian dysfunction was observed in 75% of women of childbearing age, at a median onset at 9 weeks and a median duration of 21 weeks. However, the dysfunction resolved in 74% of patients, including those who continued active therapy.
The study was funded by SpringWorks Therapeutics. Dr. Kasper declares relationships with Bayer, Blueprint, Boehringer Ingelheim, SpringWorks, GSK, PharmaMar, and Ayala.
A version of this article first appeared on Medscape.com.
PARIS –
Nirogacestat, under development by Connecticut-based SpringWorks Therapeutics, is an oral, selective, small-molecule gamma secretase inhibitor that targets the Notch signaling pathway, which is involved in cell differentiation. Desmoid tumors express high levels of Notch, so there is a “clear mechanistic rationale” for using such drugs in these patients.
Now, nirogacestat has shown a significant improvement in progression-free survival (PFS) and also a reduction in symptoms and better quality of life, when compared with placebo in the phase 3 DeFi trial.
The company has said that, by the end of this year, it will file these data for U.S. Food and Drug Administration approval of the drug for use in desmoid tumors.
Trial results were presented at the annual meeting of the European Society for Medical Oncology.
Overall, nirogacestat demonstrated “rapid, sustained, and statistically significant improvements in all primary and secondary endpoints,” study presenter Bernd Kasper, MD, PhD, sarcoma unit, Mannheim (Germany) Cancer Center, told a press conference.
There were “really impressive” reductions in pain scores and symptom burden, as well as improvements in health-related quality of life.
Dr. Kasper highlighted that this is the “first phase 3 trial … to demonstrate a clinical benefit with a gamma secretase inhibitor in any indication.”
With the drug showing a “manageable safety profile,” despite a high rate of ovarian dysfunction, Dr. Kasper believes it “has the potential to become the standard of care for patients with desmoid tumors requiring systemic treatment.”
Asked how long patients could take the drug, he replied, “Usually you take a drug as long as the patient benefits” from it.
“That means as long as there is no progression,” Dr. Kasper said, noting that there are patients from the earlier phase trials of nirogacestat who have been taking the drug “for years.”
However, there is a “very important question that is not answered” by the current study: “How long should we treat our patients?”
Dr. Kasper said to answer that question will require further trials, including those focused on treatment discontinuation.
Large trial in rare cancer
DeFi is a “unique study” and “very important in many aspects,” commented Jean-Yves Blay, MD, PhD, professor of medicine at the University Claude Bernard in Lyon, France, in an ESMO press release. Dr. Blay was not involved with the DeFi research.
“The results show benefit for the first time with a novel treatment with a new mode of action in patients where treatment options are currently limited,” he said, adding that the findings are “practice changing.”
Dr. Blay also praised the study for being “smart,” as it showed that large, placebo-controlled trials can be conducted in a rare cancer, and demonstrated the “importance of targeting the right patients with right drug.”
“The success of this study puts even more emphasis on the concept of having patients with rare cancers referred into reference centers, where clinical studies can be accomplished in record times, with the potential to deliver new treatments to patients with orphan diseases,” he said.
Discussing the results following their presentation, Dr. Blay said there are nevertheless a number of different treatment options for desmoid tumors, including sorafenib (Nexavar), and it is not clear whether patients with nonprogressive disease would experience any symptomatic benefit with nirogacestat.
Biomarkers of treatment efficacy and resistance are also required, he continued, and the drug’s long-term toxicity profile needs to be understood. In addition, its impact on ovarian dysfunction, as well as on future pregnancies, is currently unclear.
Details of the results
Presenting the study, Dr. Kasper explained that desmoid tumors have a variable presentation and an “unpredictable disease course,” and this together with the lack of approved therapies means they are “challenging to manage.”
Moreover, “due to local and aggressive growth, desmoid tumors can cause pain, disfigurement, and functional problems that can be a real burden for patients,” Dr. Kasper stressed.
Treatment should therefore be individualized to each patient to “optimize tumor control and improve the symptom burden,” he told the audience, including the impact on pain, physical function, and overall quality of life.
Indeed, a recent global consensus-based guideline for the management of desmoid tumors recommended a five-step model for treatment selection based on the level of evidence, overall response rate, PFS rate, ease of administration, and expected toxicity.
The DeFi trial enrolled patients with progressive desmoid tumors, stratified by target tumor location (intra-/extra-abdominal), who either were treatment-naive and not amenable to surgery, or were treatment refractory, or had recurrent disease after one prior line of therapy.
Dr. Kasper said in an interview that they required the patient to have at least 20% disease progression at the tumor sites so that they would include only those “who are in need of treatment.”
He explained that requirement was “quite strict” to ensure they excluded patients with “smaller-scale disease” and those with spontaneous regression, which can occur in desmoid tumors.
In all, 142 patients from 37 sites worldwide were randomly assigned to receive either nirogacestat 150 mg or placebo twice daily in 28-day cycles until radiographic progression, at which point patients were moved into an open-label phase and placebo patients could switch to nirogacestat.
The median age of the patients was 34 years, and two-thirds were female. Dr. Kasper underlined that there was a “rather high” prevalence of multifocal disease, at around 40%.
At the data cutoff for the primary analysis on April 7, nirogacestat was associated with a significant reduction in disease progression, at a median PFS that was not reached vs. 15.1 months for placebo, or a hazard ratio of 0.29 (P < .001).
This effect was seen across all subgroups included in the analysis, including when stratifying patients by age, gender, tumor characteristics, and prior treatment.
The objective response rate was also significantly higher with nirogacestat, at 41% vs. 8% in patients assigned to placebo (P < .001). A complete response was seen in 7% of patients given active treatment vs. 0% of those in the placebo group.
The median time to response was 5.6 months with nirogacestat and 11.1 months for patients given placebo.
Dr. Kasper also showed that nirogacestat was associated with significant reductions in pain severity, compared with placebo at treatment cycle 10, as measured on the Brief Pain Index-Short Form of –1.5 (P < .001).
There were also significant improvements with nirogacestat over placebo in the DT Symptom and DT Impact Scales (P < .001 for both), and on the global health status/quality of life scale (P = .007), physical functioning scale (P < .001), and role functioning scale (P < .001) of the EORTC Quality of Life Questionnaire-Core 30.
After a median exposure of 20.6 months, grade 3 or higher treatment-emergent adverse events were observed in 57% of patients treated with nirogacestat vs. 17% of those given placebo, who had a median treatment exposure of 11.4 months.
The most commonly reported adverse events of any grade with the active drug were diarrhea (84%), nausea (54%), fatigue (51%), and hypophosphatemia (42%), but Dr. Kasper noted that 95% of treatment-emergent adverse events were grade 1 or 2, with the first onset typically during cycle 1.
Ovarian dysfunction was observed in 75% of women of childbearing age, at a median onset at 9 weeks and a median duration of 21 weeks. However, the dysfunction resolved in 74% of patients, including those who continued active therapy.
The study was funded by SpringWorks Therapeutics. Dr. Kasper declares relationships with Bayer, Blueprint, Boehringer Ingelheim, SpringWorks, GSK, PharmaMar, and Ayala.
A version of this article first appeared on Medscape.com.
PARIS –
Nirogacestat, under development by Connecticut-based SpringWorks Therapeutics, is an oral, selective, small-molecule gamma secretase inhibitor that targets the Notch signaling pathway, which is involved in cell differentiation. Desmoid tumors express high levels of Notch, so there is a “clear mechanistic rationale” for using such drugs in these patients.
Now, nirogacestat has shown a significant improvement in progression-free survival (PFS) and also a reduction in symptoms and better quality of life, when compared with placebo in the phase 3 DeFi trial.
The company has said that, by the end of this year, it will file these data for U.S. Food and Drug Administration approval of the drug for use in desmoid tumors.
Trial results were presented at the annual meeting of the European Society for Medical Oncology.
Overall, nirogacestat demonstrated “rapid, sustained, and statistically significant improvements in all primary and secondary endpoints,” study presenter Bernd Kasper, MD, PhD, sarcoma unit, Mannheim (Germany) Cancer Center, told a press conference.
There were “really impressive” reductions in pain scores and symptom burden, as well as improvements in health-related quality of life.
Dr. Kasper highlighted that this is the “first phase 3 trial … to demonstrate a clinical benefit with a gamma secretase inhibitor in any indication.”
With the drug showing a “manageable safety profile,” despite a high rate of ovarian dysfunction, Dr. Kasper believes it “has the potential to become the standard of care for patients with desmoid tumors requiring systemic treatment.”
Asked how long patients could take the drug, he replied, “Usually you take a drug as long as the patient benefits” from it.
“That means as long as there is no progression,” Dr. Kasper said, noting that there are patients from the earlier phase trials of nirogacestat who have been taking the drug “for years.”
However, there is a “very important question that is not answered” by the current study: “How long should we treat our patients?”
Dr. Kasper said to answer that question will require further trials, including those focused on treatment discontinuation.
Large trial in rare cancer
DeFi is a “unique study” and “very important in many aspects,” commented Jean-Yves Blay, MD, PhD, professor of medicine at the University Claude Bernard in Lyon, France, in an ESMO press release. Dr. Blay was not involved with the DeFi research.
“The results show benefit for the first time with a novel treatment with a new mode of action in patients where treatment options are currently limited,” he said, adding that the findings are “practice changing.”
Dr. Blay also praised the study for being “smart,” as it showed that large, placebo-controlled trials can be conducted in a rare cancer, and demonstrated the “importance of targeting the right patients with right drug.”
“The success of this study puts even more emphasis on the concept of having patients with rare cancers referred into reference centers, where clinical studies can be accomplished in record times, with the potential to deliver new treatments to patients with orphan diseases,” he said.
Discussing the results following their presentation, Dr. Blay said there are nevertheless a number of different treatment options for desmoid tumors, including sorafenib (Nexavar), and it is not clear whether patients with nonprogressive disease would experience any symptomatic benefit with nirogacestat.
Biomarkers of treatment efficacy and resistance are also required, he continued, and the drug’s long-term toxicity profile needs to be understood. In addition, its impact on ovarian dysfunction, as well as on future pregnancies, is currently unclear.
Details of the results
Presenting the study, Dr. Kasper explained that desmoid tumors have a variable presentation and an “unpredictable disease course,” and this together with the lack of approved therapies means they are “challenging to manage.”
Moreover, “due to local and aggressive growth, desmoid tumors can cause pain, disfigurement, and functional problems that can be a real burden for patients,” Dr. Kasper stressed.
Treatment should therefore be individualized to each patient to “optimize tumor control and improve the symptom burden,” he told the audience, including the impact on pain, physical function, and overall quality of life.
Indeed, a recent global consensus-based guideline for the management of desmoid tumors recommended a five-step model for treatment selection based on the level of evidence, overall response rate, PFS rate, ease of administration, and expected toxicity.
The DeFi trial enrolled patients with progressive desmoid tumors, stratified by target tumor location (intra-/extra-abdominal), who either were treatment-naive and not amenable to surgery, or were treatment refractory, or had recurrent disease after one prior line of therapy.
Dr. Kasper said in an interview that they required the patient to have at least 20% disease progression at the tumor sites so that they would include only those “who are in need of treatment.”
He explained that requirement was “quite strict” to ensure they excluded patients with “smaller-scale disease” and those with spontaneous regression, which can occur in desmoid tumors.
In all, 142 patients from 37 sites worldwide were randomly assigned to receive either nirogacestat 150 mg or placebo twice daily in 28-day cycles until radiographic progression, at which point patients were moved into an open-label phase and placebo patients could switch to nirogacestat.
The median age of the patients was 34 years, and two-thirds were female. Dr. Kasper underlined that there was a “rather high” prevalence of multifocal disease, at around 40%.
At the data cutoff for the primary analysis on April 7, nirogacestat was associated with a significant reduction in disease progression, at a median PFS that was not reached vs. 15.1 months for placebo, or a hazard ratio of 0.29 (P < .001).
This effect was seen across all subgroups included in the analysis, including when stratifying patients by age, gender, tumor characteristics, and prior treatment.
The objective response rate was also significantly higher with nirogacestat, at 41% vs. 8% in patients assigned to placebo (P < .001). A complete response was seen in 7% of patients given active treatment vs. 0% of those in the placebo group.
The median time to response was 5.6 months with nirogacestat and 11.1 months for patients given placebo.
Dr. Kasper also showed that nirogacestat was associated with significant reductions in pain severity, compared with placebo at treatment cycle 10, as measured on the Brief Pain Index-Short Form of –1.5 (P < .001).
There were also significant improvements with nirogacestat over placebo in the DT Symptom and DT Impact Scales (P < .001 for both), and on the global health status/quality of life scale (P = .007), physical functioning scale (P < .001), and role functioning scale (P < .001) of the EORTC Quality of Life Questionnaire-Core 30.
After a median exposure of 20.6 months, grade 3 or higher treatment-emergent adverse events were observed in 57% of patients treated with nirogacestat vs. 17% of those given placebo, who had a median treatment exposure of 11.4 months.
The most commonly reported adverse events of any grade with the active drug were diarrhea (84%), nausea (54%), fatigue (51%), and hypophosphatemia (42%), but Dr. Kasper noted that 95% of treatment-emergent adverse events were grade 1 or 2, with the first onset typically during cycle 1.
Ovarian dysfunction was observed in 75% of women of childbearing age, at a median onset at 9 weeks and a median duration of 21 weeks. However, the dysfunction resolved in 74% of patients, including those who continued active therapy.
The study was funded by SpringWorks Therapeutics. Dr. Kasper declares relationships with Bayer, Blueprint, Boehringer Ingelheim, SpringWorks, GSK, PharmaMar, and Ayala.
A version of this article first appeared on Medscape.com.
FROM ESMO 2022
Trends in Palliative Care Utilization and Facility Type for Stage IV Esophageal Cancer: A National Cancer Database Analysis
Background
Palliative Care (PC) addresses quality of life and patient satisfaction with care. Recognized as a board-certified subspeciality in 2006, the utilization and implementation of PC has been evolving. Stage IV esophageal cancer has a 5-year survival rate of 15% to 20%, making it a good candidate for PC. This study aims to look at trends in PC interventions and facility type.
Methods
This study looked at 8808 patients with stage IV esophageal cancer who received PC interventions from 2004 to 2018 in the National Cancer Database (NCDB). The NCDB codes 4 different kinds of PC: surgical, radiation, chemotherapy/hormone therapy, and pain management. All PC interventions function to “alleviate symptoms, but no attempt to diagnose, stage, or treat the primary tumor is made.” Data was grouped into 5-year time increments: 2004- 2008 (time 1), 2009-2013 (time 2), 2014-2018 (time 3). Exclusion criteria was concurrent tumors and missing data. Cross tabulation analysis was performed using Pearson chi-square and ANOVA tests.
Results
For all PC interventions, 9.0% were surgical, 42.5% radiation, 41.1% chemotherapy, and 7.4% pain management. Surgical interventions decreased over time, indicated by interventions administered at times 1 (n = 360), 2 (n = 228), and 3 (n = 200). Radiation PC utilization remained nearly constant (n = 1157, n = 1147, n = 1397) over the same time increments. Chemotherapy/hormone therapy and pain management increased over time, indicated by interventions administered at times 1 (n = 713), 2 (n = 1053), and 3 (n = 1795) and times 1 (n = 129) 2 (n = 224), and 3 (n = 291), respectively. For surgical PC, facility type shifted from academic institutions, occurring 45% of all cases in time 1 to 30% by time 3. Radiation PC remained constant with a slight predominance of comprehensive cancer community facilities. Chemotherapy/hormone therapy PC facility type also remained constant, with a slight preference for comprehensive cancer community facilities. Pain management shifted from a predominance of academic/research facilities in time 1 (38.0%) to comprehensive cancer community facilities by time 3 (38.1%).
Conclusions
Radiation, chemotherapy/hormone therapy, and pain management have been growing in utilization, while there has been a downtrend in surgical PC. All PC interventions (besides surgery) have been increasing across all facility locations, with PC predominantly being implemented in community cancer programs.
Background
Palliative Care (PC) addresses quality of life and patient satisfaction with care. Recognized as a board-certified subspeciality in 2006, the utilization and implementation of PC has been evolving. Stage IV esophageal cancer has a 5-year survival rate of 15% to 20%, making it a good candidate for PC. This study aims to look at trends in PC interventions and facility type.
Methods
This study looked at 8808 patients with stage IV esophageal cancer who received PC interventions from 2004 to 2018 in the National Cancer Database (NCDB). The NCDB codes 4 different kinds of PC: surgical, radiation, chemotherapy/hormone therapy, and pain management. All PC interventions function to “alleviate symptoms, but no attempt to diagnose, stage, or treat the primary tumor is made.” Data was grouped into 5-year time increments: 2004- 2008 (time 1), 2009-2013 (time 2), 2014-2018 (time 3). Exclusion criteria was concurrent tumors and missing data. Cross tabulation analysis was performed using Pearson chi-square and ANOVA tests.
Results
For all PC interventions, 9.0% were surgical, 42.5% radiation, 41.1% chemotherapy, and 7.4% pain management. Surgical interventions decreased over time, indicated by interventions administered at times 1 (n = 360), 2 (n = 228), and 3 (n = 200). Radiation PC utilization remained nearly constant (n = 1157, n = 1147, n = 1397) over the same time increments. Chemotherapy/hormone therapy and pain management increased over time, indicated by interventions administered at times 1 (n = 713), 2 (n = 1053), and 3 (n = 1795) and times 1 (n = 129) 2 (n = 224), and 3 (n = 291), respectively. For surgical PC, facility type shifted from academic institutions, occurring 45% of all cases in time 1 to 30% by time 3. Radiation PC remained constant with a slight predominance of comprehensive cancer community facilities. Chemotherapy/hormone therapy PC facility type also remained constant, with a slight preference for comprehensive cancer community facilities. Pain management shifted from a predominance of academic/research facilities in time 1 (38.0%) to comprehensive cancer community facilities by time 3 (38.1%).
Conclusions
Radiation, chemotherapy/hormone therapy, and pain management have been growing in utilization, while there has been a downtrend in surgical PC. All PC interventions (besides surgery) have been increasing across all facility locations, with PC predominantly being implemented in community cancer programs.
Background
Palliative Care (PC) addresses quality of life and patient satisfaction with care. Recognized as a board-certified subspeciality in 2006, the utilization and implementation of PC has been evolving. Stage IV esophageal cancer has a 5-year survival rate of 15% to 20%, making it a good candidate for PC. This study aims to look at trends in PC interventions and facility type.
Methods
This study looked at 8808 patients with stage IV esophageal cancer who received PC interventions from 2004 to 2018 in the National Cancer Database (NCDB). The NCDB codes 4 different kinds of PC: surgical, radiation, chemotherapy/hormone therapy, and pain management. All PC interventions function to “alleviate symptoms, but no attempt to diagnose, stage, or treat the primary tumor is made.” Data was grouped into 5-year time increments: 2004- 2008 (time 1), 2009-2013 (time 2), 2014-2018 (time 3). Exclusion criteria was concurrent tumors and missing data. Cross tabulation analysis was performed using Pearson chi-square and ANOVA tests.
Results
For all PC interventions, 9.0% were surgical, 42.5% radiation, 41.1% chemotherapy, and 7.4% pain management. Surgical interventions decreased over time, indicated by interventions administered at times 1 (n = 360), 2 (n = 228), and 3 (n = 200). Radiation PC utilization remained nearly constant (n = 1157, n = 1147, n = 1397) over the same time increments. Chemotherapy/hormone therapy and pain management increased over time, indicated by interventions administered at times 1 (n = 713), 2 (n = 1053), and 3 (n = 1795) and times 1 (n = 129) 2 (n = 224), and 3 (n = 291), respectively. For surgical PC, facility type shifted from academic institutions, occurring 45% of all cases in time 1 to 30% by time 3. Radiation PC remained constant with a slight predominance of comprehensive cancer community facilities. Chemotherapy/hormone therapy PC facility type also remained constant, with a slight preference for comprehensive cancer community facilities. Pain management shifted from a predominance of academic/research facilities in time 1 (38.0%) to comprehensive cancer community facilities by time 3 (38.1%).
Conclusions
Radiation, chemotherapy/hormone therapy, and pain management have been growing in utilization, while there has been a downtrend in surgical PC. All PC interventions (besides surgery) have been increasing across all facility locations, with PC predominantly being implemented in community cancer programs.
Demographics in Early vs Late-Stage Laryngeal Squamous Cell Carcinoma: A NCDB Review
Purpose
To evaluate how various demographic factors impact the stage of cancer at diagnosis.
Background
Laryngeal squamous cell carcinoma (SCC) is a common cancer with variable clinical presentation. While the probability of cure is high, more advanced tumors are less likely to be cured and more likely to have functional deficits from surgical treatment. Given the worsened prognosis of a later-stage diagnosis, it is important to understand what may contribute to a late presentation.
Method/Analysis
Using the National Cancer Database (NCDB), 73,330 patients were identified between 2004 and 2016 with laryngeal SCC. Early (stage 0 or I) vs late-stage (stage IV) cancers were compared based on demographic variables utilizing descriptive statistics, multivariate, and chi-square analyses on SPSS version 28 with a significance of P < .05.
Results
Women were 27% more likely to have late-stage SCC than men. Black patients were 44% more likely to have late-stage SCC than White patients. No significant difference was found between Hispanic and non-Hispanic patients. Patients with private insurance, Medicare, or other government insurance were less likely (73%, 74%, and 62%, respectively) to have late-stage SCC compared to patients without insurance. Patients with Medicaid were 12% more likely to present later than the uninsured. Patients making $63,000 or greater were 23% less likely to have late-stage SCC than those making less than $38,000. Patients living in more educated areas (< 7% of adults had no high school degree) were 32% less likely to have late-stage SCC compared to less educated areas (> 21% of adults had no high school degree).
Conclusions/Implications
Patients who are Black, uninsured or on Medicaid, have low-socioeconomic status, and live in less educated areas have less favorable diagnoses than their counterparts. These data demonstrates inequities in health care and may lead to a better understanding of social determinants of health that can be used to advocate for improved access and quality of care.
Purpose
To evaluate how various demographic factors impact the stage of cancer at diagnosis.
Background
Laryngeal squamous cell carcinoma (SCC) is a common cancer with variable clinical presentation. While the probability of cure is high, more advanced tumors are less likely to be cured and more likely to have functional deficits from surgical treatment. Given the worsened prognosis of a later-stage diagnosis, it is important to understand what may contribute to a late presentation.
Method/Analysis
Using the National Cancer Database (NCDB), 73,330 patients were identified between 2004 and 2016 with laryngeal SCC. Early (stage 0 or I) vs late-stage (stage IV) cancers were compared based on demographic variables utilizing descriptive statistics, multivariate, and chi-square analyses on SPSS version 28 with a significance of P < .05.
Results
Women were 27% more likely to have late-stage SCC than men. Black patients were 44% more likely to have late-stage SCC than White patients. No significant difference was found between Hispanic and non-Hispanic patients. Patients with private insurance, Medicare, or other government insurance were less likely (73%, 74%, and 62%, respectively) to have late-stage SCC compared to patients without insurance. Patients with Medicaid were 12% more likely to present later than the uninsured. Patients making $63,000 or greater were 23% less likely to have late-stage SCC than those making less than $38,000. Patients living in more educated areas (< 7% of adults had no high school degree) were 32% less likely to have late-stage SCC compared to less educated areas (> 21% of adults had no high school degree).
Conclusions/Implications
Patients who are Black, uninsured or on Medicaid, have low-socioeconomic status, and live in less educated areas have less favorable diagnoses than their counterparts. These data demonstrates inequities in health care and may lead to a better understanding of social determinants of health that can be used to advocate for improved access and quality of care.
Purpose
To evaluate how various demographic factors impact the stage of cancer at diagnosis.
Background
Laryngeal squamous cell carcinoma (SCC) is a common cancer with variable clinical presentation. While the probability of cure is high, more advanced tumors are less likely to be cured and more likely to have functional deficits from surgical treatment. Given the worsened prognosis of a later-stage diagnosis, it is important to understand what may contribute to a late presentation.
Method/Analysis
Using the National Cancer Database (NCDB), 73,330 patients were identified between 2004 and 2016 with laryngeal SCC. Early (stage 0 or I) vs late-stage (stage IV) cancers were compared based on demographic variables utilizing descriptive statistics, multivariate, and chi-square analyses on SPSS version 28 with a significance of P < .05.
Results
Women were 27% more likely to have late-stage SCC than men. Black patients were 44% more likely to have late-stage SCC than White patients. No significant difference was found between Hispanic and non-Hispanic patients. Patients with private insurance, Medicare, or other government insurance were less likely (73%, 74%, and 62%, respectively) to have late-stage SCC compared to patients without insurance. Patients with Medicaid were 12% more likely to present later than the uninsured. Patients making $63,000 or greater were 23% less likely to have late-stage SCC than those making less than $38,000. Patients living in more educated areas (< 7% of adults had no high school degree) were 32% less likely to have late-stage SCC compared to less educated areas (> 21% of adults had no high school degree).
Conclusions/Implications
Patients who are Black, uninsured or on Medicaid, have low-socioeconomic status, and live in less educated areas have less favorable diagnoses than their counterparts. These data demonstrates inequities in health care and may lead to a better understanding of social determinants of health that can be used to advocate for improved access and quality of care.
Nearly 30% of U.S. cancer deaths linked to smoking
Nearly 123,000 cancer deaths – or
That corresponds to more than 2 million person-years of lost life and nearly $21 billion in annual lost earnings.
“During the past few decades, smoking has substantially declined in the U.S., followed by great declines in mortality from lung cancer and some other smoking-related cancers,” said lead author Farhad Islami, MD, senior scientific director of cancer disparity research at the American Cancer Society.
Despite this “remarkable progress, our results indicate that smoking is still associated with about 30% of all cancer deaths and substantial lost earnings in the U.S., and that more work should be done to further reduce smoking in the country,” he said.
The study was published online in the International Journal of Cancer.
Dr. Islami and colleagues had found that lost earnings from cancer deaths in 2015 came to nearly $95 billion. Other research showed that a substantial portion of lost earnings from cancer deaths could be traced to cigarette smoking, but estimates were more than a decade old.
To provide more recent estimates and help guide tobacco control policies, Dr. Islami and colleagues estimated person-years of life lost (PYLL) and lost earnings from cigarette smoking-related cancer deaths in 2019.
Of the 418,563 cancer deaths in adults ages 25-79 years, an estimated 122,951 could be linked to cigarette smoking. That corresponds to 29.4% of all cancer deaths and roughly 2.2 million PYLL. Translated to lost earnings, the authors estimated $20.9 billion total, with average lost earnings of $170,000 per cancer death linked to smoking.
By cancer type, lung cancer accounted for about 62%, or $12.9 billion, of the total lost earnings linked to smoking, followed by esophageal cancer (7%, or $1.5 billion), colorectal cancer (6%, or $1.2 billion), and liver cancer (5%, or $1.1 billion).
Smoking-related death rates were highest in the 13 “tobacco nation” states with weaker tobacco control policies and a higher rate of cigarette smoking. These states are Alabama, Arkansas, Indiana, Kentucky, Louisiana, Michigan, Mississippi, Missouri, Ohio, Oklahoma, South Carolina, Tennessee, and West Virginia.
The lost earnings rate in all 13 tobacco nation states combined was about 44% higher, compared with other states and the District of Columbia combined, and the annual PYLL rate was 47% higher in tobacco nation states.
The researchers estimated that if PYLL and lost earnings rates in all states matched those in Utah, which has the lowest rates, more than half of the total PYLL and lost earnings nationally would have been avoided. In other words, that would mean 1.27 million PYLL and $10.5 billion saved in 2019.
Ending the ‘scourge of tobacco’
To kick the smoking habit, health providers should “screen patients for tobacco use, document tobacco use status, advise people who smoke to quit, and assist in attempts to quit,” Dr. Islami said.
Getting more people to screen for lung cancer in the United States is also important, given that only 6.6% of eligible people in 2019 received screening.
In a statement, Lisa Lacasse, president of the American Cancer Society Cancer Action Network, said this report “further demonstrates just how critical reducing tobacco use is to ending suffering and death from cancer.”
To end the “scourge of tobacco,” local, state, and federal lawmakers need to pass proven tobacco control policies, she said.
These include regular and significant tobacco tax increases, thorough statewide smoke-free laws, and enough funding for state programs to prevent and stop smoking. It also means ensuring all Medicaid enrollees have access to all services that can help smokers quit as well as access to all FDA-approved medications that help users stop smoking.
“We have the tools to get this done, we just need lawmakers to act,” Ms. Lacasse said.
A version of this article first appeared on WebMD.com.
Nearly 123,000 cancer deaths – or
That corresponds to more than 2 million person-years of lost life and nearly $21 billion in annual lost earnings.
“During the past few decades, smoking has substantially declined in the U.S., followed by great declines in mortality from lung cancer and some other smoking-related cancers,” said lead author Farhad Islami, MD, senior scientific director of cancer disparity research at the American Cancer Society.
Despite this “remarkable progress, our results indicate that smoking is still associated with about 30% of all cancer deaths and substantial lost earnings in the U.S., and that more work should be done to further reduce smoking in the country,” he said.
The study was published online in the International Journal of Cancer.
Dr. Islami and colleagues had found that lost earnings from cancer deaths in 2015 came to nearly $95 billion. Other research showed that a substantial portion of lost earnings from cancer deaths could be traced to cigarette smoking, but estimates were more than a decade old.
To provide more recent estimates and help guide tobacco control policies, Dr. Islami and colleagues estimated person-years of life lost (PYLL) and lost earnings from cigarette smoking-related cancer deaths in 2019.
Of the 418,563 cancer deaths in adults ages 25-79 years, an estimated 122,951 could be linked to cigarette smoking. That corresponds to 29.4% of all cancer deaths and roughly 2.2 million PYLL. Translated to lost earnings, the authors estimated $20.9 billion total, with average lost earnings of $170,000 per cancer death linked to smoking.
By cancer type, lung cancer accounted for about 62%, or $12.9 billion, of the total lost earnings linked to smoking, followed by esophageal cancer (7%, or $1.5 billion), colorectal cancer (6%, or $1.2 billion), and liver cancer (5%, or $1.1 billion).
Smoking-related death rates were highest in the 13 “tobacco nation” states with weaker tobacco control policies and a higher rate of cigarette smoking. These states are Alabama, Arkansas, Indiana, Kentucky, Louisiana, Michigan, Mississippi, Missouri, Ohio, Oklahoma, South Carolina, Tennessee, and West Virginia.
The lost earnings rate in all 13 tobacco nation states combined was about 44% higher, compared with other states and the District of Columbia combined, and the annual PYLL rate was 47% higher in tobacco nation states.
The researchers estimated that if PYLL and lost earnings rates in all states matched those in Utah, which has the lowest rates, more than half of the total PYLL and lost earnings nationally would have been avoided. In other words, that would mean 1.27 million PYLL and $10.5 billion saved in 2019.
Ending the ‘scourge of tobacco’
To kick the smoking habit, health providers should “screen patients for tobacco use, document tobacco use status, advise people who smoke to quit, and assist in attempts to quit,” Dr. Islami said.
Getting more people to screen for lung cancer in the United States is also important, given that only 6.6% of eligible people in 2019 received screening.
In a statement, Lisa Lacasse, president of the American Cancer Society Cancer Action Network, said this report “further demonstrates just how critical reducing tobacco use is to ending suffering and death from cancer.”
To end the “scourge of tobacco,” local, state, and federal lawmakers need to pass proven tobacco control policies, she said.
These include regular and significant tobacco tax increases, thorough statewide smoke-free laws, and enough funding for state programs to prevent and stop smoking. It also means ensuring all Medicaid enrollees have access to all services that can help smokers quit as well as access to all FDA-approved medications that help users stop smoking.
“We have the tools to get this done, we just need lawmakers to act,” Ms. Lacasse said.
A version of this article first appeared on WebMD.com.
Nearly 123,000 cancer deaths – or
That corresponds to more than 2 million person-years of lost life and nearly $21 billion in annual lost earnings.
“During the past few decades, smoking has substantially declined in the U.S., followed by great declines in mortality from lung cancer and some other smoking-related cancers,” said lead author Farhad Islami, MD, senior scientific director of cancer disparity research at the American Cancer Society.
Despite this “remarkable progress, our results indicate that smoking is still associated with about 30% of all cancer deaths and substantial lost earnings in the U.S., and that more work should be done to further reduce smoking in the country,” he said.
The study was published online in the International Journal of Cancer.
Dr. Islami and colleagues had found that lost earnings from cancer deaths in 2015 came to nearly $95 billion. Other research showed that a substantial portion of lost earnings from cancer deaths could be traced to cigarette smoking, but estimates were more than a decade old.
To provide more recent estimates and help guide tobacco control policies, Dr. Islami and colleagues estimated person-years of life lost (PYLL) and lost earnings from cigarette smoking-related cancer deaths in 2019.
Of the 418,563 cancer deaths in adults ages 25-79 years, an estimated 122,951 could be linked to cigarette smoking. That corresponds to 29.4% of all cancer deaths and roughly 2.2 million PYLL. Translated to lost earnings, the authors estimated $20.9 billion total, with average lost earnings of $170,000 per cancer death linked to smoking.
By cancer type, lung cancer accounted for about 62%, or $12.9 billion, of the total lost earnings linked to smoking, followed by esophageal cancer (7%, or $1.5 billion), colorectal cancer (6%, or $1.2 billion), and liver cancer (5%, or $1.1 billion).
Smoking-related death rates were highest in the 13 “tobacco nation” states with weaker tobacco control policies and a higher rate of cigarette smoking. These states are Alabama, Arkansas, Indiana, Kentucky, Louisiana, Michigan, Mississippi, Missouri, Ohio, Oklahoma, South Carolina, Tennessee, and West Virginia.
The lost earnings rate in all 13 tobacco nation states combined was about 44% higher, compared with other states and the District of Columbia combined, and the annual PYLL rate was 47% higher in tobacco nation states.
The researchers estimated that if PYLL and lost earnings rates in all states matched those in Utah, which has the lowest rates, more than half of the total PYLL and lost earnings nationally would have been avoided. In other words, that would mean 1.27 million PYLL and $10.5 billion saved in 2019.
Ending the ‘scourge of tobacco’
To kick the smoking habit, health providers should “screen patients for tobacco use, document tobacco use status, advise people who smoke to quit, and assist in attempts to quit,” Dr. Islami said.
Getting more people to screen for lung cancer in the United States is also important, given that only 6.6% of eligible people in 2019 received screening.
In a statement, Lisa Lacasse, president of the American Cancer Society Cancer Action Network, said this report “further demonstrates just how critical reducing tobacco use is to ending suffering and death from cancer.”
To end the “scourge of tobacco,” local, state, and federal lawmakers need to pass proven tobacco control policies, she said.
These include regular and significant tobacco tax increases, thorough statewide smoke-free laws, and enough funding for state programs to prevent and stop smoking. It also means ensuring all Medicaid enrollees have access to all services that can help smokers quit as well as access to all FDA-approved medications that help users stop smoking.
“We have the tools to get this done, we just need lawmakers to act,” Ms. Lacasse said.
A version of this article first appeared on WebMD.com.
FROM THE INTERNATIONAL JOURNAL OF CANCER
At-home test for oral/throat cancer launched in U.S.
Recently, a home test for oral and throat cancer was launched in the United States, and it is being marketed directly to the general public, aimed at former or current tobacco users and anyone 50 years or older.
Individuals can order the test – CancerDetect Test for Oral & Throat Cancer – directly from its maker, Viome Life Sciences, for $399.
The test is being marketed under the agency’s “laboratory developed test” rubric.
People who qualify and buy the test are mailed a saliva collection tube, which they fill and mail back. The company then analyzes the RNA for changes in human cells and the oropharyngeal microbiome that are associated with cancer. During a 15-minute telemedicine conference – included in the $399 cost – those who test positive are told to follow up with a secondary care center for a definitive diagnosis.
For people who test positive but have no visible lesion to biopsy, doctors will likely opt for surveillance, computer scientist Guruduth Banavar, PhD, Viome’s chief technology officer, told this news organization.
Dr. Banavar said people have been buying the test every day since it was launched in early August, but he declined to give specific sales figures.
CancerDetect’s tagline is “test at home for peace of mind.” The test “brings unprecedented accuracy to early cancer detection and prevention,” the company said in a press release announcing the launch.
The test showed an overall specificity of 94% and sensitivity of 84.2%-90% for cancer in Viome’s latest study, which is posted on medRxiv.org as a preprint. Banavar said it has been submitted to a top-tier medical journal.
Viome plans to market CancerDetect “in every possible way” to consumers, including social media, Dr. Banavar said. CancerDetect is not sold on Amazon at the moment, but the company sells another at-home test for gut microbiome plus cellular health on the website.
As for outreach to the medical community, “we will start doing that with dentists first” and then eventually oncologists and other doctors, but “our primary target is to get out to the consumers themselves,” Dr. Banavar said.
Viome’s main goal is to help consumers be proactive regarding their health, he said.
An expert opinion
The marketing push means that sooner or later, oncologists will likely have to deal with a patient who tests positive on CancerDetect, so this news organization turned to numerous experts for their thoughts. None had heard about the test, but one responded with comments.
“I am happy to see industry working on strategies for the early detection of oral and throat cancers,” and CancerDetect has “potential,” said surgical oncologist Saral Mehra, MD, MBA, chief of head and neck surgery at Yale University, New Haven, Conn.
However, after reviewing the study posted on medRxiv, Dr. Mehra advised caution. He said he was concerned about false negative results leading to missed cancers and false positives leading to unnecessary anxiety and testing.
According to the medRxiv preprint, the test was developed and validated using saliva samples from 1,175 people 50 years or older as well as adults with a history of tobacco use.
In the 230-sample validation cohort, CancerDetect correctly classified 18 out of 20 people with oral squamous cell carcinoma (OSCC) and 64/76 with oropharyngeal squamous cell carcinoma (OPSCC), yielding sensitivities of 90% and 84.2%, respectively.
The test also correctly identified 126/134 people as cancer free, for a specificity of 94%.
Results were similar between early and late-stage disease, but mixed in subgroups. Among people younger than age 50, for instance, 4/4 (100%) with OSCC and 2/3 (66.7%) with OPSCC were correctly classified as positive. Among older people, 15/17 (88.2%) with OSCC and 62/73 (84.9%) with OPSCC were correctly classified
Commenting on the results, Dr. Mehra noted that “the power of the study, especially for subgroup analysis, was low,” and investigators “used both advanced-stage and early-stage cancer patients in the model, while the target population for this test is early stage.
“The research needs to be tightened significantly on specific target populations, the models adjusted to really limit false negatives, and a plan [put in place] to act upon positive results,” he said.
Also, the ability of CancerDetect to pick up premalignant lesions – “the greatest value in a screening test” – is not clear, he added.
Viome’s Dr. Banavar said that CancerDetect is in its first iteration, and the test uses machine learning, so its diagnostic performance will improve with the ongoing addition of real-world data.
The company is organizing a pivotal trial to gain formal FDA approval, with results expected in a year and a half or so, he said.
Viome is pushing ahead with its RNA diagnosis technology for the entire range of alimentary canal cancers and disorders, including inflammatory bowel disease. The company has partnered with pharmaceutical companies, including GSK, for vaccines, Dr. Banavar said.
Dr. Mehra reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Recently, a home test for oral and throat cancer was launched in the United States, and it is being marketed directly to the general public, aimed at former or current tobacco users and anyone 50 years or older.
Individuals can order the test – CancerDetect Test for Oral & Throat Cancer – directly from its maker, Viome Life Sciences, for $399.
The test is being marketed under the agency’s “laboratory developed test” rubric.
People who qualify and buy the test are mailed a saliva collection tube, which they fill and mail back. The company then analyzes the RNA for changes in human cells and the oropharyngeal microbiome that are associated with cancer. During a 15-minute telemedicine conference – included in the $399 cost – those who test positive are told to follow up with a secondary care center for a definitive diagnosis.
For people who test positive but have no visible lesion to biopsy, doctors will likely opt for surveillance, computer scientist Guruduth Banavar, PhD, Viome’s chief technology officer, told this news organization.
Dr. Banavar said people have been buying the test every day since it was launched in early August, but he declined to give specific sales figures.
CancerDetect’s tagline is “test at home for peace of mind.” The test “brings unprecedented accuracy to early cancer detection and prevention,” the company said in a press release announcing the launch.
The test showed an overall specificity of 94% and sensitivity of 84.2%-90% for cancer in Viome’s latest study, which is posted on medRxiv.org as a preprint. Banavar said it has been submitted to a top-tier medical journal.
Viome plans to market CancerDetect “in every possible way” to consumers, including social media, Dr. Banavar said. CancerDetect is not sold on Amazon at the moment, but the company sells another at-home test for gut microbiome plus cellular health on the website.
As for outreach to the medical community, “we will start doing that with dentists first” and then eventually oncologists and other doctors, but “our primary target is to get out to the consumers themselves,” Dr. Banavar said.
Viome’s main goal is to help consumers be proactive regarding their health, he said.
An expert opinion
The marketing push means that sooner or later, oncologists will likely have to deal with a patient who tests positive on CancerDetect, so this news organization turned to numerous experts for their thoughts. None had heard about the test, but one responded with comments.
“I am happy to see industry working on strategies for the early detection of oral and throat cancers,” and CancerDetect has “potential,” said surgical oncologist Saral Mehra, MD, MBA, chief of head and neck surgery at Yale University, New Haven, Conn.
However, after reviewing the study posted on medRxiv, Dr. Mehra advised caution. He said he was concerned about false negative results leading to missed cancers and false positives leading to unnecessary anxiety and testing.
According to the medRxiv preprint, the test was developed and validated using saliva samples from 1,175 people 50 years or older as well as adults with a history of tobacco use.
In the 230-sample validation cohort, CancerDetect correctly classified 18 out of 20 people with oral squamous cell carcinoma (OSCC) and 64/76 with oropharyngeal squamous cell carcinoma (OPSCC), yielding sensitivities of 90% and 84.2%, respectively.
The test also correctly identified 126/134 people as cancer free, for a specificity of 94%.
Results were similar between early and late-stage disease, but mixed in subgroups. Among people younger than age 50, for instance, 4/4 (100%) with OSCC and 2/3 (66.7%) with OPSCC were correctly classified as positive. Among older people, 15/17 (88.2%) with OSCC and 62/73 (84.9%) with OPSCC were correctly classified
Commenting on the results, Dr. Mehra noted that “the power of the study, especially for subgroup analysis, was low,” and investigators “used both advanced-stage and early-stage cancer patients in the model, while the target population for this test is early stage.
“The research needs to be tightened significantly on specific target populations, the models adjusted to really limit false negatives, and a plan [put in place] to act upon positive results,” he said.
Also, the ability of CancerDetect to pick up premalignant lesions – “the greatest value in a screening test” – is not clear, he added.
Viome’s Dr. Banavar said that CancerDetect is in its first iteration, and the test uses machine learning, so its diagnostic performance will improve with the ongoing addition of real-world data.
The company is organizing a pivotal trial to gain formal FDA approval, with results expected in a year and a half or so, he said.
Viome is pushing ahead with its RNA diagnosis technology for the entire range of alimentary canal cancers and disorders, including inflammatory bowel disease. The company has partnered with pharmaceutical companies, including GSK, for vaccines, Dr. Banavar said.
Dr. Mehra reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Recently, a home test for oral and throat cancer was launched in the United States, and it is being marketed directly to the general public, aimed at former or current tobacco users and anyone 50 years or older.
Individuals can order the test – CancerDetect Test for Oral & Throat Cancer – directly from its maker, Viome Life Sciences, for $399.
The test is being marketed under the agency’s “laboratory developed test” rubric.
People who qualify and buy the test are mailed a saliva collection tube, which they fill and mail back. The company then analyzes the RNA for changes in human cells and the oropharyngeal microbiome that are associated with cancer. During a 15-minute telemedicine conference – included in the $399 cost – those who test positive are told to follow up with a secondary care center for a definitive diagnosis.
For people who test positive but have no visible lesion to biopsy, doctors will likely opt for surveillance, computer scientist Guruduth Banavar, PhD, Viome’s chief technology officer, told this news organization.
Dr. Banavar said people have been buying the test every day since it was launched in early August, but he declined to give specific sales figures.
CancerDetect’s tagline is “test at home for peace of mind.” The test “brings unprecedented accuracy to early cancer detection and prevention,” the company said in a press release announcing the launch.
The test showed an overall specificity of 94% and sensitivity of 84.2%-90% for cancer in Viome’s latest study, which is posted on medRxiv.org as a preprint. Banavar said it has been submitted to a top-tier medical journal.
Viome plans to market CancerDetect “in every possible way” to consumers, including social media, Dr. Banavar said. CancerDetect is not sold on Amazon at the moment, but the company sells another at-home test for gut microbiome plus cellular health on the website.
As for outreach to the medical community, “we will start doing that with dentists first” and then eventually oncologists and other doctors, but “our primary target is to get out to the consumers themselves,” Dr. Banavar said.
Viome’s main goal is to help consumers be proactive regarding their health, he said.
An expert opinion
The marketing push means that sooner or later, oncologists will likely have to deal with a patient who tests positive on CancerDetect, so this news organization turned to numerous experts for their thoughts. None had heard about the test, but one responded with comments.
“I am happy to see industry working on strategies for the early detection of oral and throat cancers,” and CancerDetect has “potential,” said surgical oncologist Saral Mehra, MD, MBA, chief of head and neck surgery at Yale University, New Haven, Conn.
However, after reviewing the study posted on medRxiv, Dr. Mehra advised caution. He said he was concerned about false negative results leading to missed cancers and false positives leading to unnecessary anxiety and testing.
According to the medRxiv preprint, the test was developed and validated using saliva samples from 1,175 people 50 years or older as well as adults with a history of tobacco use.
In the 230-sample validation cohort, CancerDetect correctly classified 18 out of 20 people with oral squamous cell carcinoma (OSCC) and 64/76 with oropharyngeal squamous cell carcinoma (OPSCC), yielding sensitivities of 90% and 84.2%, respectively.
The test also correctly identified 126/134 people as cancer free, for a specificity of 94%.
Results were similar between early and late-stage disease, but mixed in subgroups. Among people younger than age 50, for instance, 4/4 (100%) with OSCC and 2/3 (66.7%) with OPSCC were correctly classified as positive. Among older people, 15/17 (88.2%) with OSCC and 62/73 (84.9%) with OPSCC were correctly classified
Commenting on the results, Dr. Mehra noted that “the power of the study, especially for subgroup analysis, was low,” and investigators “used both advanced-stage and early-stage cancer patients in the model, while the target population for this test is early stage.
“The research needs to be tightened significantly on specific target populations, the models adjusted to really limit false negatives, and a plan [put in place] to act upon positive results,” he said.
Also, the ability of CancerDetect to pick up premalignant lesions – “the greatest value in a screening test” – is not clear, he added.
Viome’s Dr. Banavar said that CancerDetect is in its first iteration, and the test uses machine learning, so its diagnostic performance will improve with the ongoing addition of real-world data.
The company is organizing a pivotal trial to gain formal FDA approval, with results expected in a year and a half or so, he said.
Viome is pushing ahead with its RNA diagnosis technology for the entire range of alimentary canal cancers and disorders, including inflammatory bowel disease. The company has partnered with pharmaceutical companies, including GSK, for vaccines, Dr. Banavar said.
Dr. Mehra reports no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Oncologists often misinterpret posttreatment HNSCC scan details
Patient outcomes could be threatened because of misinterpretation by oncologic surgeons of free-form posttreatment radiological reports in head and neck squamous cell carcinoma (HNSCC), a new study finds.
“Clinician perception of patient response from the post-RT [radiation treament] PET/CT free-form report is unreliable and does not consistently reflect the radiologist’s intended meaning, which was strongly associated with survival,” researchers wrote in a study published Aug. 18 in JAMA Otolaryngology-Head & Neck Surgery. They found “minimal agreement between clinicians’ consensus perspective on the patient’s response status derived from free-form imaging reports and the criterion standard response category assigned by a nuclear medicine specialist after PET/CT image review.”
According to radiation oncologist Ryan T. Hughes, MD, and colleagues at Wake Forest University, Winston-Salem, N.C., it’s common for patients with HNSCC to get PET, CT, or PET/CT imaging following treatment in order to assess how patients responded. Accurate communication about the results is essential to determining next steps, they write.
However, they write, “to our knowledge there is no universally accepted standardized method for communicating results,” such as whether there’s been a complete or partial response. Discrepancies between a radiological posttreatment report and an oncologist’s perception of the findings “may contribute to unnecessary patient care complexities, including elevated patient anxiety, unnecessary follow-up testing/procedures, and failure to recognize and adequately treat residual, recurrent, or progressive disease,” the researchers write.
For the new study, the authors tracked 171 patients (26.3% women, median age 61 years, ethnicity not provided), mainly (87%) with stage III-IV disease. Most (89%) received concurrent chemotherapy, and 30% received radiotherapy following operations.
Four oncologists reviewed free-form radiologic reports and determined whether the patient had a complete, indeterminate or partial response, or progressive disease. “Next, the group conferred to assign a consensus clinician MDS [modified Deauville score] and associated response category to assess the percentage of agreement with the criterion standard nuclear medicine physician MDS response derived from PET/CT image review.”
The researchers found that “interrater reliability of clinician-perceived post-RT PET/CT response was moderate [k = 0.680; 95% confidence interval, 0.638-0.721], and there was minimal reliability and low rate of agreement between clinician perception and radiologist-intended PET/CT response [63.7%; k = 0.365; 95% CI, 0.251-0.478).”
The clinicians were more likely to perceive patients as having an indeterminate response (28.1%), compared with the radiologists (9.3%). “There were 16 instances of significant discordance: 7 patients for whom the clinician perception MDS was 1 to 2 and nuclear medicine MDS 3 to 4, and 9 patients for whom the clinician perception MDS was 3 to 4 and nuclear medicine MDS 1 to 2.”
Due to statistical limitations, the researchers were unable to link the MDS scores to prognoses. The researchers suggest it’s time to further standardize the assessment of posttreatment responses to therapy. They add that “the decision to use a standardized interpretation and reporting system rather than free-form reporting is more important than the specific system selected.”
As for next steps, the researchers report that “prospective studies of post-RT PET/CT standardized reporting among patients with HNSCC are warranted, and a prospective implementation study of this workflow is planned at our institution.”
The study was funded by the National Center for Advancing Translational Sciences and National Institutes of Health. The authors had no disclosures.
Patient outcomes could be threatened because of misinterpretation by oncologic surgeons of free-form posttreatment radiological reports in head and neck squamous cell carcinoma (HNSCC), a new study finds.
“Clinician perception of patient response from the post-RT [radiation treament] PET/CT free-form report is unreliable and does not consistently reflect the radiologist’s intended meaning, which was strongly associated with survival,” researchers wrote in a study published Aug. 18 in JAMA Otolaryngology-Head & Neck Surgery. They found “minimal agreement between clinicians’ consensus perspective on the patient’s response status derived from free-form imaging reports and the criterion standard response category assigned by a nuclear medicine specialist after PET/CT image review.”
According to radiation oncologist Ryan T. Hughes, MD, and colleagues at Wake Forest University, Winston-Salem, N.C., it’s common for patients with HNSCC to get PET, CT, or PET/CT imaging following treatment in order to assess how patients responded. Accurate communication about the results is essential to determining next steps, they write.
However, they write, “to our knowledge there is no universally accepted standardized method for communicating results,” such as whether there’s been a complete or partial response. Discrepancies between a radiological posttreatment report and an oncologist’s perception of the findings “may contribute to unnecessary patient care complexities, including elevated patient anxiety, unnecessary follow-up testing/procedures, and failure to recognize and adequately treat residual, recurrent, or progressive disease,” the researchers write.
For the new study, the authors tracked 171 patients (26.3% women, median age 61 years, ethnicity not provided), mainly (87%) with stage III-IV disease. Most (89%) received concurrent chemotherapy, and 30% received radiotherapy following operations.
Four oncologists reviewed free-form radiologic reports and determined whether the patient had a complete, indeterminate or partial response, or progressive disease. “Next, the group conferred to assign a consensus clinician MDS [modified Deauville score] and associated response category to assess the percentage of agreement with the criterion standard nuclear medicine physician MDS response derived from PET/CT image review.”
The researchers found that “interrater reliability of clinician-perceived post-RT PET/CT response was moderate [k = 0.680; 95% confidence interval, 0.638-0.721], and there was minimal reliability and low rate of agreement between clinician perception and radiologist-intended PET/CT response [63.7%; k = 0.365; 95% CI, 0.251-0.478).”
The clinicians were more likely to perceive patients as having an indeterminate response (28.1%), compared with the radiologists (9.3%). “There were 16 instances of significant discordance: 7 patients for whom the clinician perception MDS was 1 to 2 and nuclear medicine MDS 3 to 4, and 9 patients for whom the clinician perception MDS was 3 to 4 and nuclear medicine MDS 1 to 2.”
Due to statistical limitations, the researchers were unable to link the MDS scores to prognoses. The researchers suggest it’s time to further standardize the assessment of posttreatment responses to therapy. They add that “the decision to use a standardized interpretation and reporting system rather than free-form reporting is more important than the specific system selected.”
As for next steps, the researchers report that “prospective studies of post-RT PET/CT standardized reporting among patients with HNSCC are warranted, and a prospective implementation study of this workflow is planned at our institution.”
The study was funded by the National Center for Advancing Translational Sciences and National Institutes of Health. The authors had no disclosures.
Patient outcomes could be threatened because of misinterpretation by oncologic surgeons of free-form posttreatment radiological reports in head and neck squamous cell carcinoma (HNSCC), a new study finds.
“Clinician perception of patient response from the post-RT [radiation treament] PET/CT free-form report is unreliable and does not consistently reflect the radiologist’s intended meaning, which was strongly associated with survival,” researchers wrote in a study published Aug. 18 in JAMA Otolaryngology-Head & Neck Surgery. They found “minimal agreement between clinicians’ consensus perspective on the patient’s response status derived from free-form imaging reports and the criterion standard response category assigned by a nuclear medicine specialist after PET/CT image review.”
According to radiation oncologist Ryan T. Hughes, MD, and colleagues at Wake Forest University, Winston-Salem, N.C., it’s common for patients with HNSCC to get PET, CT, or PET/CT imaging following treatment in order to assess how patients responded. Accurate communication about the results is essential to determining next steps, they write.
However, they write, “to our knowledge there is no universally accepted standardized method for communicating results,” such as whether there’s been a complete or partial response. Discrepancies between a radiological posttreatment report and an oncologist’s perception of the findings “may contribute to unnecessary patient care complexities, including elevated patient anxiety, unnecessary follow-up testing/procedures, and failure to recognize and adequately treat residual, recurrent, or progressive disease,” the researchers write.
For the new study, the authors tracked 171 patients (26.3% women, median age 61 years, ethnicity not provided), mainly (87%) with stage III-IV disease. Most (89%) received concurrent chemotherapy, and 30% received radiotherapy following operations.
Four oncologists reviewed free-form radiologic reports and determined whether the patient had a complete, indeterminate or partial response, or progressive disease. “Next, the group conferred to assign a consensus clinician MDS [modified Deauville score] and associated response category to assess the percentage of agreement with the criterion standard nuclear medicine physician MDS response derived from PET/CT image review.”
The researchers found that “interrater reliability of clinician-perceived post-RT PET/CT response was moderate [k = 0.680; 95% confidence interval, 0.638-0.721], and there was minimal reliability and low rate of agreement between clinician perception and radiologist-intended PET/CT response [63.7%; k = 0.365; 95% CI, 0.251-0.478).”
The clinicians were more likely to perceive patients as having an indeterminate response (28.1%), compared with the radiologists (9.3%). “There were 16 instances of significant discordance: 7 patients for whom the clinician perception MDS was 1 to 2 and nuclear medicine MDS 3 to 4, and 9 patients for whom the clinician perception MDS was 3 to 4 and nuclear medicine MDS 1 to 2.”
Due to statistical limitations, the researchers were unable to link the MDS scores to prognoses. The researchers suggest it’s time to further standardize the assessment of posttreatment responses to therapy. They add that “the decision to use a standardized interpretation and reporting system rather than free-form reporting is more important than the specific system selected.”
As for next steps, the researchers report that “prospective studies of post-RT PET/CT standardized reporting among patients with HNSCC are warranted, and a prospective implementation study of this workflow is planned at our institution.”
The study was funded by the National Center for Advancing Translational Sciences and National Institutes of Health. The authors had no disclosures.
FROM JAMA OTOLARYNGOLOGY–HEAD & NECK SURGERY
Thyroid autoimmunity linked to cancer, but screening not advised
A new study provides more evidence that people with thyroid autoimmunity are more likely than are others to develop papillary thyroid cancer (odds ratio [OR] = 1.90, 95% confidence interval [CI], 1.33-2.70), although the overall risk remains very low.
Researchers aren't recommending routine screening in all patients with thyroid autoimmunity, but they're calling for more research into whether it's a good idea in severe cases. "This is the one circumstance where screening for subclinical disease could make sense," said Donald McLeod, MPH, PhD, an epidemiologist at Royal Brisbane & Women's Hospital in Australia and lead author of the study, published in the Journal of Clinical Oncology. "However, more research is needed because our study is the first to show this result, and we need to prove that screening would make a difference to the prognosis of these patients."
According to Dr. McLeod, "doctors and patients have been wondering about the connection between thyroid autoimmunity and thyroid cancer for many years. In fact, the first report was in 1955. While the association was plausible, all previous studies had potential for biases that could have influenced the results."
For example, he said, multiple studies didn't control for confounders, while others didn't account for the possibility that cancer could have triggered an immune response. "Other case-control studies could have been affected by selection bias, where a diagnosis of thyroid autoimmunity leads to thyroid cancer identification and entry into the study," he said. "Finally, medical surveillance of people diagnosed with thyroid autoimmunity could lead to overdiagnosis, where small, subclinical cancers are diagnosed in those patients but not identified in people who are not under medical follow-up."
For the new retrospective case-control study, researchers compared 451 active-duty members of the U.S. military who developed papillary thyroid cancer from the period of 1996-2014 to matched controls (61% of all subjects were men and the mean age was 36). Those with cancer had their serum collected 3-5 years and 7-10 years before the date of diagnosis - the index date for all subjects. Some of those considered to have thyroid autoimmunity had conditions such as Graves' disease and Hashimoto's thyroiditis.
"Eighty-five percent of cases (379 of 451) had a thyroid-related diagnosis recorded ... before their index date, compared with 5% of controls," the researchers reported. "Most cases (80%) had classical papillary thyroid cancer, with the rest having the follicular variant of papillary thyroid cancer."
After adjustment to account for various confounders, those who were positive for thyroid peroxidase antibodies 7-10 years prior to the index date were more likely to have developed thyroid cancer (OR = 1.90, 95% CI, 1.33-2.70). "The results could not be fully explained by diagnosis of thyroid autoimmunity," the researchers reported, "although when autoimmunity had been identified, thyroid cancers were diagnosed at a very early stage."
Two groups - those with the highest thyroid antibody levels and women - faced the greatest risk, Dr. McLeod said. The results regarding women were the most surprising in the study, he said. "This is the first time this has been found. We think this result needs to be confirmed. If true, it could explain why women have a three-times-higher risk of thyroid cancer than men."
The overall incidence of thyroid cancer in the U.S. was estimated at 13.49 per 100,000 person-years in 2018, with women (76% of cases) and Whites (81%) accounting for the majority. Rates have nearly doubled since 2000. The authors of a 2022 report that disclosed these numbers suggest the rise is due to overdiagnosis of small tumors.
It's not clear why thyroid autoimmunity and thyroid cancer may be linked. "Chronic inflammation from thyroid autoimmunity could cause thyroid cancer, as chronic inflammation in other organs precedes cancers at those sites," Dr. McLeod said. "Alternatively, thyroid autoimmunity could appear to be associated with thyroid cancer because of biases inherent in previous studies, including previous diagnosis of autoimmunity. Thyroid cancer could also induce an immune response, which mimics thyroid autoimmunity and could bias assessment."
As for screening of patients with thyroid autoimmunity, "the main danger is that you will commonly identify small thyroid cancers that would never become clinically apparent," he said. "This leads to unnecessary treatments that can cause complications and give people a cancer label, which can also cause harm. Diagnosis and treatment guidelines recommend against screening the general population for this reason."
Many of those with thyroid autoimmunity developed small cancers, he said, most likely "detected from ultrasound being performed because autoimmune thyroid disease was known. If all patients with thyroid autoimmunity were screened for thyroid cancer, the likelihood is that many people's cancers would be overdiagnosed."
The study was funded by the Walton Family Foundation. Dr. McLeod reports no disclosures. Some of the authors report various relationships with industry.
A new study provides more evidence that people with thyroid autoimmunity are more likely than are others to develop papillary thyroid cancer (odds ratio [OR] = 1.90, 95% confidence interval [CI], 1.33-2.70), although the overall risk remains very low.
Researchers aren't recommending routine screening in all patients with thyroid autoimmunity, but they're calling for more research into whether it's a good idea in severe cases. "This is the one circumstance where screening for subclinical disease could make sense," said Donald McLeod, MPH, PhD, an epidemiologist at Royal Brisbane & Women's Hospital in Australia and lead author of the study, published in the Journal of Clinical Oncology. "However, more research is needed because our study is the first to show this result, and we need to prove that screening would make a difference to the prognosis of these patients."
According to Dr. McLeod, "doctors and patients have been wondering about the connection between thyroid autoimmunity and thyroid cancer for many years. In fact, the first report was in 1955. While the association was plausible, all previous studies had potential for biases that could have influenced the results."
For example, he said, multiple studies didn't control for confounders, while others didn't account for the possibility that cancer could have triggered an immune response. "Other case-control studies could have been affected by selection bias, where a diagnosis of thyroid autoimmunity leads to thyroid cancer identification and entry into the study," he said. "Finally, medical surveillance of people diagnosed with thyroid autoimmunity could lead to overdiagnosis, where small, subclinical cancers are diagnosed in those patients but not identified in people who are not under medical follow-up."
For the new retrospective case-control study, researchers compared 451 active-duty members of the U.S. military who developed papillary thyroid cancer from the period of 1996-2014 to matched controls (61% of all subjects were men and the mean age was 36). Those with cancer had their serum collected 3-5 years and 7-10 years before the date of diagnosis - the index date for all subjects. Some of those considered to have thyroid autoimmunity had conditions such as Graves' disease and Hashimoto's thyroiditis.
"Eighty-five percent of cases (379 of 451) had a thyroid-related diagnosis recorded ... before their index date, compared with 5% of controls," the researchers reported. "Most cases (80%) had classical papillary thyroid cancer, with the rest having the follicular variant of papillary thyroid cancer."
After adjustment to account for various confounders, those who were positive for thyroid peroxidase antibodies 7-10 years prior to the index date were more likely to have developed thyroid cancer (OR = 1.90, 95% CI, 1.33-2.70). "The results could not be fully explained by diagnosis of thyroid autoimmunity," the researchers reported, "although when autoimmunity had been identified, thyroid cancers were diagnosed at a very early stage."
Two groups - those with the highest thyroid antibody levels and women - faced the greatest risk, Dr. McLeod said. The results regarding women were the most surprising in the study, he said. "This is the first time this has been found. We think this result needs to be confirmed. If true, it could explain why women have a three-times-higher risk of thyroid cancer than men."
The overall incidence of thyroid cancer in the U.S. was estimated at 13.49 per 100,000 person-years in 2018, with women (76% of cases) and Whites (81%) accounting for the majority. Rates have nearly doubled since 2000. The authors of a 2022 report that disclosed these numbers suggest the rise is due to overdiagnosis of small tumors.
It's not clear why thyroid autoimmunity and thyroid cancer may be linked. "Chronic inflammation from thyroid autoimmunity could cause thyroid cancer, as chronic inflammation in other organs precedes cancers at those sites," Dr. McLeod said. "Alternatively, thyroid autoimmunity could appear to be associated with thyroid cancer because of biases inherent in previous studies, including previous diagnosis of autoimmunity. Thyroid cancer could also induce an immune response, which mimics thyroid autoimmunity and could bias assessment."
As for screening of patients with thyroid autoimmunity, "the main danger is that you will commonly identify small thyroid cancers that would never become clinically apparent," he said. "This leads to unnecessary treatments that can cause complications and give people a cancer label, which can also cause harm. Diagnosis and treatment guidelines recommend against screening the general population for this reason."
Many of those with thyroid autoimmunity developed small cancers, he said, most likely "detected from ultrasound being performed because autoimmune thyroid disease was known. If all patients with thyroid autoimmunity were screened for thyroid cancer, the likelihood is that many people's cancers would be overdiagnosed."
The study was funded by the Walton Family Foundation. Dr. McLeod reports no disclosures. Some of the authors report various relationships with industry.
A new study provides more evidence that people with thyroid autoimmunity are more likely than are others to develop papillary thyroid cancer (odds ratio [OR] = 1.90, 95% confidence interval [CI], 1.33-2.70), although the overall risk remains very low.
Researchers aren't recommending routine screening in all patients with thyroid autoimmunity, but they're calling for more research into whether it's a good idea in severe cases. "This is the one circumstance where screening for subclinical disease could make sense," said Donald McLeod, MPH, PhD, an epidemiologist at Royal Brisbane & Women's Hospital in Australia and lead author of the study, published in the Journal of Clinical Oncology. "However, more research is needed because our study is the first to show this result, and we need to prove that screening would make a difference to the prognosis of these patients."
According to Dr. McLeod, "doctors and patients have been wondering about the connection between thyroid autoimmunity and thyroid cancer for many years. In fact, the first report was in 1955. While the association was plausible, all previous studies had potential for biases that could have influenced the results."
For example, he said, multiple studies didn't control for confounders, while others didn't account for the possibility that cancer could have triggered an immune response. "Other case-control studies could have been affected by selection bias, where a diagnosis of thyroid autoimmunity leads to thyroid cancer identification and entry into the study," he said. "Finally, medical surveillance of people diagnosed with thyroid autoimmunity could lead to overdiagnosis, where small, subclinical cancers are diagnosed in those patients but not identified in people who are not under medical follow-up."
For the new retrospective case-control study, researchers compared 451 active-duty members of the U.S. military who developed papillary thyroid cancer from the period of 1996-2014 to matched controls (61% of all subjects were men and the mean age was 36). Those with cancer had their serum collected 3-5 years and 7-10 years before the date of diagnosis - the index date for all subjects. Some of those considered to have thyroid autoimmunity had conditions such as Graves' disease and Hashimoto's thyroiditis.
"Eighty-five percent of cases (379 of 451) had a thyroid-related diagnosis recorded ... before their index date, compared with 5% of controls," the researchers reported. "Most cases (80%) had classical papillary thyroid cancer, with the rest having the follicular variant of papillary thyroid cancer."
After adjustment to account for various confounders, those who were positive for thyroid peroxidase antibodies 7-10 years prior to the index date were more likely to have developed thyroid cancer (OR = 1.90, 95% CI, 1.33-2.70). "The results could not be fully explained by diagnosis of thyroid autoimmunity," the researchers reported, "although when autoimmunity had been identified, thyroid cancers were diagnosed at a very early stage."
Two groups - those with the highest thyroid antibody levels and women - faced the greatest risk, Dr. McLeod said. The results regarding women were the most surprising in the study, he said. "This is the first time this has been found. We think this result needs to be confirmed. If true, it could explain why women have a three-times-higher risk of thyroid cancer than men."
The overall incidence of thyroid cancer in the U.S. was estimated at 13.49 per 100,000 person-years in 2018, with women (76% of cases) and Whites (81%) accounting for the majority. Rates have nearly doubled since 2000. The authors of a 2022 report that disclosed these numbers suggest the rise is due to overdiagnosis of small tumors.
It's not clear why thyroid autoimmunity and thyroid cancer may be linked. "Chronic inflammation from thyroid autoimmunity could cause thyroid cancer, as chronic inflammation in other organs precedes cancers at those sites," Dr. McLeod said. "Alternatively, thyroid autoimmunity could appear to be associated with thyroid cancer because of biases inherent in previous studies, including previous diagnosis of autoimmunity. Thyroid cancer could also induce an immune response, which mimics thyroid autoimmunity and could bias assessment."
As for screening of patients with thyroid autoimmunity, "the main danger is that you will commonly identify small thyroid cancers that would never become clinically apparent," he said. "This leads to unnecessary treatments that can cause complications and give people a cancer label, which can also cause harm. Diagnosis and treatment guidelines recommend against screening the general population for this reason."
Many of those with thyroid autoimmunity developed small cancers, he said, most likely "detected from ultrasound being performed because autoimmune thyroid disease was known. If all patients with thyroid autoimmunity were screened for thyroid cancer, the likelihood is that many people's cancers would be overdiagnosed."
The study was funded by the Walton Family Foundation. Dr. McLeod reports no disclosures. Some of the authors report various relationships with industry.
FROM THE JOURNAL OF CLINICAL ONCOLOGY