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Drugmakers are abandoning cheap generics, and now U.S. cancer patients can’t get meds
On Nov. 22, three Food and Drug Administration inspectors arrived at the sprawling Intas Pharmaceuticals plant south of Ahmedabad, India, and found hundreds of trash bags full of shredded documents tossed into a garbage truck. Over the next 10 days, the inspectors assessed what looked like a systematic effort to conceal quality problems at the plant, which provided more than half of the U.S. supply of generic cisplatin and carboplatin, two cheap drugs used to treat as many as 500,000 new cancer cases every year.
Their decisions are likely to result in preventable deaths.
Cisplatin and carboplatin are among scores of drugs in shortage, including 12 other cancer drugs, ADHD pills, blood thinners, and antibiotics. COVID-hangover supply chain issues and limited FDA oversight are part of the problem, but the main cause, experts agree, is the underlying weakness of the generic drug industry. Made mostly overseas, these old but crucial drugs are often sold at a loss or for little profit. Domestic manufacturers have little interest in making them, setting their sights instead on high-priced drugs with plump profit margins.
The problem isn’t new, and that’s particularly infuriating to many clinicians. President Joe Biden, whose son Beau died of an aggressive brain cancer, has focused his Cancer Moonshot on discovering cures – undoubtedly expensive ones. Indeed, existing brand-name cancer drugs often cost tens of thousands of dollars a year.
But what about the thousands of patients today who can’t get a drug like cisplatin, approved by the FDA in 1978 and costing as little as $6 a dose?
“It’s just insane,” said Mark Ratain, MD, a cancer doctor and pharmacologist at the University of Chicago. “Your roof is caving in, but you want to build a basketball court in the backyard because your wife is pregnant with twin boys and you want them to be NBA stars when they grow up?”
“It’s just a travesty that this is the level of health care in the United States of America right now,” said Stephen Divers, MD, an oncologist in Hot Springs, Ark., who in recent weeks has had to delay or change treatment for numerous bladder, breast, and ovarian cancer patients because his clinic cannot find enough cisplatin and carboplatin. Results from a survey of academic cancer centers released June 7 found 93% couldn’t find enough carboplatin and 70% had cisplatin shortages.
“All day, in between patients, we hold staff meetings trying to figure this out,” said Bonny Moore, MD, an oncologist in Fredericksburg, Virginia. “It’s the most nauseous I’ve ever felt. Our office stayed open during COVID; we never had to stop treating patients. We got them vaccinated, kept them safe, and now I can’t get them a $10 drug.”
The cancer clinicians KFF Health News interviewed for this story said that, given current shortages, they prioritize patients who can be cured over later-stage patients, in whom the drugs generally can only slow the disease, and for whom alternatives – though sometimes less effective and often with more side effects – are available. But some doctors are even rationing doses intended to cure.
Isabella McDonald, then a junior at Utah Valley University, was diagnosed in April with a rare, often fatal bone cancer, whose sole treatment for young adults includes the drug methotrexate. When Isabella’s second cycle of treatment began June 5, clinicians advised that she would be getting less than the full dose because of a methotrexate shortage, said her father, Brent.
“They don’t think it will have a negative impact on her treatment, but as far as I am aware, there isn’t any scientific basis to make that conclusion,” he said. “As you can imagine, when they gave us such low odds of her beating this cancer, it feels like we want to give it everything we can and not something short of the standard.”
Mr. McDonald stressed that he didn’t blame the staffers at Intermountain Health who take care of Isabella. The family – his other daughter, Cate, made a TikTok video about her sister’s plight – were simply stunned at such a basic flaw in the health care system.
At Dr. Moore’s practice, in Virginia, clinicians gave 60% of the optimal dose of carboplatin to some uterine cancer patients during the week of May 16, then shifted to 80% after a small shipment came in the following week. The doctors had to omit carboplatin from normal combination treatments for patients with recurrent disease, she said.
On June 2, Dr. Moore and colleagues were glued to their drug distributor’s website, anxious as teenagers waiting for Taylor Swift tickets to go on sale – only with mortal consequences at stake.
She later emailed KFF Health News: “Carboplatin did NOT come back in stock today. Neither did cisplatin.”
Doses remained at 80%, she said. Things hadn’t changed 10 days later.
Generics manufacturers are pulling out
The causes of shortages are well established. Everyone wants to pay less, and the middlemen who procure and distribute generics keep driving down wholesale prices. The average net price of generic drugs fell by more than half between 2016 and 2022, according to research by Anthony Sardella, a business professor at Washington University in St. Louis.
As generics manufacturers compete to win sales contracts with the big negotiators of such purchases, such as Vizient and Premier, their profits sink. Some are going out of business. Akorn, which made 75 common generics, went bankrupt and closed in February. Israeli generics giant Teva, which has a portfolio of 3,600 medicines, announced May 18 it was shifting to brand-name drugs and “high-value generics.” Lannett, with about 120 generics, announced a Chapter 11 reorganization amid declining revenue. Other companies are in trouble too, said David Gaugh, interim CEO of the Association for Accessible Medicines, the leading generics trade group.
The generics industry used to lose money on about a third of the drugs it produced, but now it’s more like half, Mr. Gaugh said. So when a company stops making a drug, others do not necessarily step up, he said. Officials at Fresenius Kabi and Pfizer said they have increased their carboplatin production since March, but not enough to end the shortage. On June 2, FDA Commissioner Robert Califf announced the agency had given emergency authorization for Chinese-made cisplatin to enter the U.S. market, but the impact of the move wasn’t immediately clear.
Cisplatin and carboplatin are made in special production lines under sterile conditions, and expanding or changing the lines requires FDA approval. Bargain-basement prices have pushed production overseas, where it’s harder for the FDA to track quality standards. The Intas plant inspection was a relative rarity in India, where the FDA in 2022 reportedly inspected only 3% of sites that make drugs for the U.S. market. Mr. Sardella testified in May that a quarter of all U.S. drug prescriptions are filled by companies that received FDA warning letters in the past 26 months. And pharmaceutical industry product recalls are at their highest level in 18 years, reflecting fragile supply conditions.
The FDA listed 137 drugs in shortage as of June 13, including many essential medicines made by few companies.
Intas voluntarily shut down its Ahmedabad plant after the FDA inspection, and the agency posted its shocking inspection report in January. Accord Healthcare, the U.S. subsidiary of Intas, said in mid-June it had no date for restarting production.
Asked why it waited 2 months after its inspection to announce the cisplatin shortage, given that Intas supplied more than half the U.S. market for the drug, the FDA said via email that it doesn’t list a drug in shortage until it has “confirmed that overall market demand is not being met.”
Prices for carboplatin, cisplatin, and other drugs have skyrocketed on the so-called gray market, where speculators sell medicines they snapped up in anticipation of shortages. A 600-mg bottle of carboplatin, normally available for $30, was going for $185 in early May and $345 a week later, said Richard Scanlon, the pharmacist at dr. Moore’s clinic.
“It’s hard to have these conversations with patients – ‘I have your dose for this cycle, but not sure about next cycle,’” said Mark Einstein, MD, chair of the department of obstetrics, gynecology and reproductive health at New Jersey Medical School, Newark.
Should government step in?
Despite a drug shortage task force and numerous congressional hearings, progress has been slow at best. The 2020 CARES Act gave the FDA the power to require companies to have contingency plans enabling them to respond to shortages, but the agency has not yet implemented guidance to enforce the provisions.
As a result, neither Accord nor other cisplatin makers had a response plan in place when Intas’ plant was shut down, said Soumi Saha, senior vice president of government affairs for Premier, which arranges wholesale drug purchases for more than 4,400 hospitals and health systems.
Premier understood in December that the shutdown endangered the U.S. supply of cisplatin and carboplatin, but it also didn’t issue an immediate alarm. “It’s a fine balance,” she said. “You don’t want to create panic-buying or hoarding.”
More lasting solutions are under discussion. Mr. Sardella and others have proposed government subsidies to get U.S. generics plants running full time. Their capacity is now half-idle. If federal agencies like the Centers for Medicare & Medicaid Services paid more for more safely and efficiently produced drugs, it would promote a more stable supply chain, he said.
“At a certain point the system needs to recognize there’s a high cost to low-cost drugs,” said Allan Coukell, senior vice president for public policy at Civica Rx, a nonprofit funded by health systems, foundations, and the federal government that provides about 80 drugs to hospitals in its network. Civica is building a $140 million factory near Petersburg, Va., that will produce dozens more, Mr. Coukell said.
Dr. Ratain and his University of Chicago colleague Satyajit Kosuri, MD, recently called for the creation of a strategic inventory buffer for generic medications, something like the Strategic Petroleum Reserve, set up in 1975 in response to the OPEC oil crisis.
In fact, Dr. Ratain reckons, selling a quarter-million barrels of oil would probably generate enough cash to make and store 2 years’ worth of carboplatin and cisplatin.
“It would almost literally be a drop in the bucket.”
KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF – an independent source of health policy research, polling, and journalism. Learn more about KFF.
On Nov. 22, three Food and Drug Administration inspectors arrived at the sprawling Intas Pharmaceuticals plant south of Ahmedabad, India, and found hundreds of trash bags full of shredded documents tossed into a garbage truck. Over the next 10 days, the inspectors assessed what looked like a systematic effort to conceal quality problems at the plant, which provided more than half of the U.S. supply of generic cisplatin and carboplatin, two cheap drugs used to treat as many as 500,000 new cancer cases every year.
Their decisions are likely to result in preventable deaths.
Cisplatin and carboplatin are among scores of drugs in shortage, including 12 other cancer drugs, ADHD pills, blood thinners, and antibiotics. COVID-hangover supply chain issues and limited FDA oversight are part of the problem, but the main cause, experts agree, is the underlying weakness of the generic drug industry. Made mostly overseas, these old but crucial drugs are often sold at a loss or for little profit. Domestic manufacturers have little interest in making them, setting their sights instead on high-priced drugs with plump profit margins.
The problem isn’t new, and that’s particularly infuriating to many clinicians. President Joe Biden, whose son Beau died of an aggressive brain cancer, has focused his Cancer Moonshot on discovering cures – undoubtedly expensive ones. Indeed, existing brand-name cancer drugs often cost tens of thousands of dollars a year.
But what about the thousands of patients today who can’t get a drug like cisplatin, approved by the FDA in 1978 and costing as little as $6 a dose?
“It’s just insane,” said Mark Ratain, MD, a cancer doctor and pharmacologist at the University of Chicago. “Your roof is caving in, but you want to build a basketball court in the backyard because your wife is pregnant with twin boys and you want them to be NBA stars when they grow up?”
“It’s just a travesty that this is the level of health care in the United States of America right now,” said Stephen Divers, MD, an oncologist in Hot Springs, Ark., who in recent weeks has had to delay or change treatment for numerous bladder, breast, and ovarian cancer patients because his clinic cannot find enough cisplatin and carboplatin. Results from a survey of academic cancer centers released June 7 found 93% couldn’t find enough carboplatin and 70% had cisplatin shortages.
“All day, in between patients, we hold staff meetings trying to figure this out,” said Bonny Moore, MD, an oncologist in Fredericksburg, Virginia. “It’s the most nauseous I’ve ever felt. Our office stayed open during COVID; we never had to stop treating patients. We got them vaccinated, kept them safe, and now I can’t get them a $10 drug.”
The cancer clinicians KFF Health News interviewed for this story said that, given current shortages, they prioritize patients who can be cured over later-stage patients, in whom the drugs generally can only slow the disease, and for whom alternatives – though sometimes less effective and often with more side effects – are available. But some doctors are even rationing doses intended to cure.
Isabella McDonald, then a junior at Utah Valley University, was diagnosed in April with a rare, often fatal bone cancer, whose sole treatment for young adults includes the drug methotrexate. When Isabella’s second cycle of treatment began June 5, clinicians advised that she would be getting less than the full dose because of a methotrexate shortage, said her father, Brent.
“They don’t think it will have a negative impact on her treatment, but as far as I am aware, there isn’t any scientific basis to make that conclusion,” he said. “As you can imagine, when they gave us such low odds of her beating this cancer, it feels like we want to give it everything we can and not something short of the standard.”
Mr. McDonald stressed that he didn’t blame the staffers at Intermountain Health who take care of Isabella. The family – his other daughter, Cate, made a TikTok video about her sister’s plight – were simply stunned at such a basic flaw in the health care system.
At Dr. Moore’s practice, in Virginia, clinicians gave 60% of the optimal dose of carboplatin to some uterine cancer patients during the week of May 16, then shifted to 80% after a small shipment came in the following week. The doctors had to omit carboplatin from normal combination treatments for patients with recurrent disease, she said.
On June 2, Dr. Moore and colleagues were glued to their drug distributor’s website, anxious as teenagers waiting for Taylor Swift tickets to go on sale – only with mortal consequences at stake.
She later emailed KFF Health News: “Carboplatin did NOT come back in stock today. Neither did cisplatin.”
Doses remained at 80%, she said. Things hadn’t changed 10 days later.
Generics manufacturers are pulling out
The causes of shortages are well established. Everyone wants to pay less, and the middlemen who procure and distribute generics keep driving down wholesale prices. The average net price of generic drugs fell by more than half between 2016 and 2022, according to research by Anthony Sardella, a business professor at Washington University in St. Louis.
As generics manufacturers compete to win sales contracts with the big negotiators of such purchases, such as Vizient and Premier, their profits sink. Some are going out of business. Akorn, which made 75 common generics, went bankrupt and closed in February. Israeli generics giant Teva, which has a portfolio of 3,600 medicines, announced May 18 it was shifting to brand-name drugs and “high-value generics.” Lannett, with about 120 generics, announced a Chapter 11 reorganization amid declining revenue. Other companies are in trouble too, said David Gaugh, interim CEO of the Association for Accessible Medicines, the leading generics trade group.
The generics industry used to lose money on about a third of the drugs it produced, but now it’s more like half, Mr. Gaugh said. So when a company stops making a drug, others do not necessarily step up, he said. Officials at Fresenius Kabi and Pfizer said they have increased their carboplatin production since March, but not enough to end the shortage. On June 2, FDA Commissioner Robert Califf announced the agency had given emergency authorization for Chinese-made cisplatin to enter the U.S. market, but the impact of the move wasn’t immediately clear.
Cisplatin and carboplatin are made in special production lines under sterile conditions, and expanding or changing the lines requires FDA approval. Bargain-basement prices have pushed production overseas, where it’s harder for the FDA to track quality standards. The Intas plant inspection was a relative rarity in India, where the FDA in 2022 reportedly inspected only 3% of sites that make drugs for the U.S. market. Mr. Sardella testified in May that a quarter of all U.S. drug prescriptions are filled by companies that received FDA warning letters in the past 26 months. And pharmaceutical industry product recalls are at their highest level in 18 years, reflecting fragile supply conditions.
The FDA listed 137 drugs in shortage as of June 13, including many essential medicines made by few companies.
Intas voluntarily shut down its Ahmedabad plant after the FDA inspection, and the agency posted its shocking inspection report in January. Accord Healthcare, the U.S. subsidiary of Intas, said in mid-June it had no date for restarting production.
Asked why it waited 2 months after its inspection to announce the cisplatin shortage, given that Intas supplied more than half the U.S. market for the drug, the FDA said via email that it doesn’t list a drug in shortage until it has “confirmed that overall market demand is not being met.”
Prices for carboplatin, cisplatin, and other drugs have skyrocketed on the so-called gray market, where speculators sell medicines they snapped up in anticipation of shortages. A 600-mg bottle of carboplatin, normally available for $30, was going for $185 in early May and $345 a week later, said Richard Scanlon, the pharmacist at dr. Moore’s clinic.
“It’s hard to have these conversations with patients – ‘I have your dose for this cycle, but not sure about next cycle,’” said Mark Einstein, MD, chair of the department of obstetrics, gynecology and reproductive health at New Jersey Medical School, Newark.
Should government step in?
Despite a drug shortage task force and numerous congressional hearings, progress has been slow at best. The 2020 CARES Act gave the FDA the power to require companies to have contingency plans enabling them to respond to shortages, but the agency has not yet implemented guidance to enforce the provisions.
As a result, neither Accord nor other cisplatin makers had a response plan in place when Intas’ plant was shut down, said Soumi Saha, senior vice president of government affairs for Premier, which arranges wholesale drug purchases for more than 4,400 hospitals and health systems.
Premier understood in December that the shutdown endangered the U.S. supply of cisplatin and carboplatin, but it also didn’t issue an immediate alarm. “It’s a fine balance,” she said. “You don’t want to create panic-buying or hoarding.”
More lasting solutions are under discussion. Mr. Sardella and others have proposed government subsidies to get U.S. generics plants running full time. Their capacity is now half-idle. If federal agencies like the Centers for Medicare & Medicaid Services paid more for more safely and efficiently produced drugs, it would promote a more stable supply chain, he said.
“At a certain point the system needs to recognize there’s a high cost to low-cost drugs,” said Allan Coukell, senior vice president for public policy at Civica Rx, a nonprofit funded by health systems, foundations, and the federal government that provides about 80 drugs to hospitals in its network. Civica is building a $140 million factory near Petersburg, Va., that will produce dozens more, Mr. Coukell said.
Dr. Ratain and his University of Chicago colleague Satyajit Kosuri, MD, recently called for the creation of a strategic inventory buffer for generic medications, something like the Strategic Petroleum Reserve, set up in 1975 in response to the OPEC oil crisis.
In fact, Dr. Ratain reckons, selling a quarter-million barrels of oil would probably generate enough cash to make and store 2 years’ worth of carboplatin and cisplatin.
“It would almost literally be a drop in the bucket.”
KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF – an independent source of health policy research, polling, and journalism. Learn more about KFF.
On Nov. 22, three Food and Drug Administration inspectors arrived at the sprawling Intas Pharmaceuticals plant south of Ahmedabad, India, and found hundreds of trash bags full of shredded documents tossed into a garbage truck. Over the next 10 days, the inspectors assessed what looked like a systematic effort to conceal quality problems at the plant, which provided more than half of the U.S. supply of generic cisplatin and carboplatin, two cheap drugs used to treat as many as 500,000 new cancer cases every year.
Their decisions are likely to result in preventable deaths.
Cisplatin and carboplatin are among scores of drugs in shortage, including 12 other cancer drugs, ADHD pills, blood thinners, and antibiotics. COVID-hangover supply chain issues and limited FDA oversight are part of the problem, but the main cause, experts agree, is the underlying weakness of the generic drug industry. Made mostly overseas, these old but crucial drugs are often sold at a loss or for little profit. Domestic manufacturers have little interest in making them, setting their sights instead on high-priced drugs with plump profit margins.
The problem isn’t new, and that’s particularly infuriating to many clinicians. President Joe Biden, whose son Beau died of an aggressive brain cancer, has focused his Cancer Moonshot on discovering cures – undoubtedly expensive ones. Indeed, existing brand-name cancer drugs often cost tens of thousands of dollars a year.
But what about the thousands of patients today who can’t get a drug like cisplatin, approved by the FDA in 1978 and costing as little as $6 a dose?
“It’s just insane,” said Mark Ratain, MD, a cancer doctor and pharmacologist at the University of Chicago. “Your roof is caving in, but you want to build a basketball court in the backyard because your wife is pregnant with twin boys and you want them to be NBA stars when they grow up?”
“It’s just a travesty that this is the level of health care in the United States of America right now,” said Stephen Divers, MD, an oncologist in Hot Springs, Ark., who in recent weeks has had to delay or change treatment for numerous bladder, breast, and ovarian cancer patients because his clinic cannot find enough cisplatin and carboplatin. Results from a survey of academic cancer centers released June 7 found 93% couldn’t find enough carboplatin and 70% had cisplatin shortages.
“All day, in between patients, we hold staff meetings trying to figure this out,” said Bonny Moore, MD, an oncologist in Fredericksburg, Virginia. “It’s the most nauseous I’ve ever felt. Our office stayed open during COVID; we never had to stop treating patients. We got them vaccinated, kept them safe, and now I can’t get them a $10 drug.”
The cancer clinicians KFF Health News interviewed for this story said that, given current shortages, they prioritize patients who can be cured over later-stage patients, in whom the drugs generally can only slow the disease, and for whom alternatives – though sometimes less effective and often with more side effects – are available. But some doctors are even rationing doses intended to cure.
Isabella McDonald, then a junior at Utah Valley University, was diagnosed in April with a rare, often fatal bone cancer, whose sole treatment for young adults includes the drug methotrexate. When Isabella’s second cycle of treatment began June 5, clinicians advised that she would be getting less than the full dose because of a methotrexate shortage, said her father, Brent.
“They don’t think it will have a negative impact on her treatment, but as far as I am aware, there isn’t any scientific basis to make that conclusion,” he said. “As you can imagine, when they gave us such low odds of her beating this cancer, it feels like we want to give it everything we can and not something short of the standard.”
Mr. McDonald stressed that he didn’t blame the staffers at Intermountain Health who take care of Isabella. The family – his other daughter, Cate, made a TikTok video about her sister’s plight – were simply stunned at such a basic flaw in the health care system.
At Dr. Moore’s practice, in Virginia, clinicians gave 60% of the optimal dose of carboplatin to some uterine cancer patients during the week of May 16, then shifted to 80% after a small shipment came in the following week. The doctors had to omit carboplatin from normal combination treatments for patients with recurrent disease, she said.
On June 2, Dr. Moore and colleagues were glued to their drug distributor’s website, anxious as teenagers waiting for Taylor Swift tickets to go on sale – only with mortal consequences at stake.
She later emailed KFF Health News: “Carboplatin did NOT come back in stock today. Neither did cisplatin.”
Doses remained at 80%, she said. Things hadn’t changed 10 days later.
Generics manufacturers are pulling out
The causes of shortages are well established. Everyone wants to pay less, and the middlemen who procure and distribute generics keep driving down wholesale prices. The average net price of generic drugs fell by more than half between 2016 and 2022, according to research by Anthony Sardella, a business professor at Washington University in St. Louis.
As generics manufacturers compete to win sales contracts with the big negotiators of such purchases, such as Vizient and Premier, their profits sink. Some are going out of business. Akorn, which made 75 common generics, went bankrupt and closed in February. Israeli generics giant Teva, which has a portfolio of 3,600 medicines, announced May 18 it was shifting to brand-name drugs and “high-value generics.” Lannett, with about 120 generics, announced a Chapter 11 reorganization amid declining revenue. Other companies are in trouble too, said David Gaugh, interim CEO of the Association for Accessible Medicines, the leading generics trade group.
The generics industry used to lose money on about a third of the drugs it produced, but now it’s more like half, Mr. Gaugh said. So when a company stops making a drug, others do not necessarily step up, he said. Officials at Fresenius Kabi and Pfizer said they have increased their carboplatin production since March, but not enough to end the shortage. On June 2, FDA Commissioner Robert Califf announced the agency had given emergency authorization for Chinese-made cisplatin to enter the U.S. market, but the impact of the move wasn’t immediately clear.
Cisplatin and carboplatin are made in special production lines under sterile conditions, and expanding or changing the lines requires FDA approval. Bargain-basement prices have pushed production overseas, where it’s harder for the FDA to track quality standards. The Intas plant inspection was a relative rarity in India, where the FDA in 2022 reportedly inspected only 3% of sites that make drugs for the U.S. market. Mr. Sardella testified in May that a quarter of all U.S. drug prescriptions are filled by companies that received FDA warning letters in the past 26 months. And pharmaceutical industry product recalls are at their highest level in 18 years, reflecting fragile supply conditions.
The FDA listed 137 drugs in shortage as of June 13, including many essential medicines made by few companies.
Intas voluntarily shut down its Ahmedabad plant after the FDA inspection, and the agency posted its shocking inspection report in January. Accord Healthcare, the U.S. subsidiary of Intas, said in mid-June it had no date for restarting production.
Asked why it waited 2 months after its inspection to announce the cisplatin shortage, given that Intas supplied more than half the U.S. market for the drug, the FDA said via email that it doesn’t list a drug in shortage until it has “confirmed that overall market demand is not being met.”
Prices for carboplatin, cisplatin, and other drugs have skyrocketed on the so-called gray market, where speculators sell medicines they snapped up in anticipation of shortages. A 600-mg bottle of carboplatin, normally available for $30, was going for $185 in early May and $345 a week later, said Richard Scanlon, the pharmacist at dr. Moore’s clinic.
“It’s hard to have these conversations with patients – ‘I have your dose for this cycle, but not sure about next cycle,’” said Mark Einstein, MD, chair of the department of obstetrics, gynecology and reproductive health at New Jersey Medical School, Newark.
Should government step in?
Despite a drug shortage task force and numerous congressional hearings, progress has been slow at best. The 2020 CARES Act gave the FDA the power to require companies to have contingency plans enabling them to respond to shortages, but the agency has not yet implemented guidance to enforce the provisions.
As a result, neither Accord nor other cisplatin makers had a response plan in place when Intas’ plant was shut down, said Soumi Saha, senior vice president of government affairs for Premier, which arranges wholesale drug purchases for more than 4,400 hospitals and health systems.
Premier understood in December that the shutdown endangered the U.S. supply of cisplatin and carboplatin, but it also didn’t issue an immediate alarm. “It’s a fine balance,” she said. “You don’t want to create panic-buying or hoarding.”
More lasting solutions are under discussion. Mr. Sardella and others have proposed government subsidies to get U.S. generics plants running full time. Their capacity is now half-idle. If federal agencies like the Centers for Medicare & Medicaid Services paid more for more safely and efficiently produced drugs, it would promote a more stable supply chain, he said.
“At a certain point the system needs to recognize there’s a high cost to low-cost drugs,” said Allan Coukell, senior vice president for public policy at Civica Rx, a nonprofit funded by health systems, foundations, and the federal government that provides about 80 drugs to hospitals in its network. Civica is building a $140 million factory near Petersburg, Va., that will produce dozens more, Mr. Coukell said.
Dr. Ratain and his University of Chicago colleague Satyajit Kosuri, MD, recently called for the creation of a strategic inventory buffer for generic medications, something like the Strategic Petroleum Reserve, set up in 1975 in response to the OPEC oil crisis.
In fact, Dr. Ratain reckons, selling a quarter-million barrels of oil would probably generate enough cash to make and store 2 years’ worth of carboplatin and cisplatin.
“It would almost literally be a drop in the bucket.”
KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF – an independent source of health policy research, polling, and journalism. Learn more about KFF.
Widespread carboplatin, cisplatin shortages: NCCN survey
The survey, which included responses from 27 NCCN member institutions, revealed that 93% are experiencing a shortage of carboplatin and that 70% have reported a shortage of cisplatin.
“This is an unacceptable situation,” Robert W. Carlson, MD, NCCN’s chief executive offer, said in the statement released by the network.
“We are hearing from oncologists and pharmacists across the country who have to scramble to find appropriate alternatives for treating their patients with cancer right now,” Dr. Carlson said. And while the survey results show patients are still able to get lifesaving care, “it comes at a burden to our overtaxed medical facilities.”
The NCCN called on the federal government, the pharmaceutical industry, providers, and payers to take steps to “help mitigate any impacts” from this cancer drug shortage.
“We need to work together to improve the current situation and prevent it from happening again in the future,” Dr. Carlson stressed.
Carboplatin and cisplatin, which are frequently used together for systemic treatment, are highly effective therapies prescribed to treat many cancer types, including lung, breast, and prostate cancers, as well as leukemias and lymphomas. An estimated 500,000 new patients with cancer receive these agents each year.
The current survey, conducted over the last week of May, found that 100% of responding centers are able to continue to treat patients who need cisplatin without delays.
The same cannot be said for carboplatin: only 64% of centers said they are still able to continue treating all current patients receiving the platinum-based therapy. Among 19 responding centers, 20% reported that they were continuing carboplatin regimens for some but not all patients. And 16% reported treatment delays from having to obtain prior authorization for modified treatment plans, though none reported denials.
“Carboplatin has been in short supply for months but in the last 4 weeks has reached a critical stage,” according to one survey comment. “Without additional inventory many of our sites will be out of drug by early next week.”
In response to the survey question, “Is your center experiencing a shortage of carboplatin,” others made similar comments:
- “Current shipments from established manufacturers have been paused.”
- “The supply of carboplatin available is not meeting our demands.”
- “Without additional supply in early June, we will have to implement several shortage mitigation strategies.”
Survey respondents also addressed whether manufacturers or suppliers have provided any indication of when these drugs will become readily available again. For both drugs, about 60% of respondents said no. And for those who do receive updates, many noted that the “information is tentative and variable.”
Respondents indicated that other cancer agents, including methotrexate (67%) and 5FU (26%), are also in short supply at their centers.
The shortage and the uncertainty as to when it will end are forcing some centers to develop conservation and mitigation strategies.
The NCCN has broadly outlined how the federal government, the pharmaceutical industry, providers, and payers can help with prevention and mitigation. The NCCN has called on the federal government and the pharmaceutical industry to work to secure a steady supply of core anticancer drugs and has asked payers to “put patients first and provide flexible and efficient systems of providing coverage for alternative therapies replacing anti-cancer drugs that are unavailable or in shortage.”
Overall, the survey results “demonstrate the widespread impact of the chemotherapy shortage,” said Alyssa Schatz, MSW, senior director of policy and advocacy for NCCN. “We hope that by sharing this survey and calling for united action across the oncology community, we can come together to prevent future drug shortages and ensure quality, effective, equitable, and accessible cancer care for all.”
A version of this article first appeared on Medscape.com.
The survey, which included responses from 27 NCCN member institutions, revealed that 93% are experiencing a shortage of carboplatin and that 70% have reported a shortage of cisplatin.
“This is an unacceptable situation,” Robert W. Carlson, MD, NCCN’s chief executive offer, said in the statement released by the network.
“We are hearing from oncologists and pharmacists across the country who have to scramble to find appropriate alternatives for treating their patients with cancer right now,” Dr. Carlson said. And while the survey results show patients are still able to get lifesaving care, “it comes at a burden to our overtaxed medical facilities.”
The NCCN called on the federal government, the pharmaceutical industry, providers, and payers to take steps to “help mitigate any impacts” from this cancer drug shortage.
“We need to work together to improve the current situation and prevent it from happening again in the future,” Dr. Carlson stressed.
Carboplatin and cisplatin, which are frequently used together for systemic treatment, are highly effective therapies prescribed to treat many cancer types, including lung, breast, and prostate cancers, as well as leukemias and lymphomas. An estimated 500,000 new patients with cancer receive these agents each year.
The current survey, conducted over the last week of May, found that 100% of responding centers are able to continue to treat patients who need cisplatin without delays.
The same cannot be said for carboplatin: only 64% of centers said they are still able to continue treating all current patients receiving the platinum-based therapy. Among 19 responding centers, 20% reported that they were continuing carboplatin regimens for some but not all patients. And 16% reported treatment delays from having to obtain prior authorization for modified treatment plans, though none reported denials.
“Carboplatin has been in short supply for months but in the last 4 weeks has reached a critical stage,” according to one survey comment. “Without additional inventory many of our sites will be out of drug by early next week.”
In response to the survey question, “Is your center experiencing a shortage of carboplatin,” others made similar comments:
- “Current shipments from established manufacturers have been paused.”
- “The supply of carboplatin available is not meeting our demands.”
- “Without additional supply in early June, we will have to implement several shortage mitigation strategies.”
Survey respondents also addressed whether manufacturers or suppliers have provided any indication of when these drugs will become readily available again. For both drugs, about 60% of respondents said no. And for those who do receive updates, many noted that the “information is tentative and variable.”
Respondents indicated that other cancer agents, including methotrexate (67%) and 5FU (26%), are also in short supply at their centers.
The shortage and the uncertainty as to when it will end are forcing some centers to develop conservation and mitigation strategies.
The NCCN has broadly outlined how the federal government, the pharmaceutical industry, providers, and payers can help with prevention and mitigation. The NCCN has called on the federal government and the pharmaceutical industry to work to secure a steady supply of core anticancer drugs and has asked payers to “put patients first and provide flexible and efficient systems of providing coverage for alternative therapies replacing anti-cancer drugs that are unavailable or in shortage.”
Overall, the survey results “demonstrate the widespread impact of the chemotherapy shortage,” said Alyssa Schatz, MSW, senior director of policy and advocacy for NCCN. “We hope that by sharing this survey and calling for united action across the oncology community, we can come together to prevent future drug shortages and ensure quality, effective, equitable, and accessible cancer care for all.”
A version of this article first appeared on Medscape.com.
The survey, which included responses from 27 NCCN member institutions, revealed that 93% are experiencing a shortage of carboplatin and that 70% have reported a shortage of cisplatin.
“This is an unacceptable situation,” Robert W. Carlson, MD, NCCN’s chief executive offer, said in the statement released by the network.
“We are hearing from oncologists and pharmacists across the country who have to scramble to find appropriate alternatives for treating their patients with cancer right now,” Dr. Carlson said. And while the survey results show patients are still able to get lifesaving care, “it comes at a burden to our overtaxed medical facilities.”
The NCCN called on the federal government, the pharmaceutical industry, providers, and payers to take steps to “help mitigate any impacts” from this cancer drug shortage.
“We need to work together to improve the current situation and prevent it from happening again in the future,” Dr. Carlson stressed.
Carboplatin and cisplatin, which are frequently used together for systemic treatment, are highly effective therapies prescribed to treat many cancer types, including lung, breast, and prostate cancers, as well as leukemias and lymphomas. An estimated 500,000 new patients with cancer receive these agents each year.
The current survey, conducted over the last week of May, found that 100% of responding centers are able to continue to treat patients who need cisplatin without delays.
The same cannot be said for carboplatin: only 64% of centers said they are still able to continue treating all current patients receiving the platinum-based therapy. Among 19 responding centers, 20% reported that they were continuing carboplatin regimens for some but not all patients. And 16% reported treatment delays from having to obtain prior authorization for modified treatment plans, though none reported denials.
“Carboplatin has been in short supply for months but in the last 4 weeks has reached a critical stage,” according to one survey comment. “Without additional inventory many of our sites will be out of drug by early next week.”
In response to the survey question, “Is your center experiencing a shortage of carboplatin,” others made similar comments:
- “Current shipments from established manufacturers have been paused.”
- “The supply of carboplatin available is not meeting our demands.”
- “Without additional supply in early June, we will have to implement several shortage mitigation strategies.”
Survey respondents also addressed whether manufacturers or suppliers have provided any indication of when these drugs will become readily available again. For both drugs, about 60% of respondents said no. And for those who do receive updates, many noted that the “information is tentative and variable.”
Respondents indicated that other cancer agents, including methotrexate (67%) and 5FU (26%), are also in short supply at their centers.
The shortage and the uncertainty as to when it will end are forcing some centers to develop conservation and mitigation strategies.
The NCCN has broadly outlined how the federal government, the pharmaceutical industry, providers, and payers can help with prevention and mitigation. The NCCN has called on the federal government and the pharmaceutical industry to work to secure a steady supply of core anticancer drugs and has asked payers to “put patients first and provide flexible and efficient systems of providing coverage for alternative therapies replacing anti-cancer drugs that are unavailable or in shortage.”
Overall, the survey results “demonstrate the widespread impact of the chemotherapy shortage,” said Alyssa Schatz, MSW, senior director of policy and advocacy for NCCN. “We hope that by sharing this survey and calling for united action across the oncology community, we can come together to prevent future drug shortages and ensure quality, effective, equitable, and accessible cancer care for all.”
A version of this article first appeared on Medscape.com.
Groundbreaking new regimen for advanced Hodgkin lymphoma
“[SWOG] S1826, the largest Hodgkin lymphoma study in National Clinical Trials Network history, is a key step toward harmonizing the pediatric and adult treatment of advanced-stage Hodgkin lymphoma,” the authors reported in late-breaking research presented at the annual meeting of the American Society of Clinical Oncology.
“Based on the magnitude of the benefit and with nivolumab being better tolerated than brentuximab, we anticipate that these results will be practice changing and nivolumab [and chemotherapy] will become a new standard of care,” lead author Alex Francisco Herrera, MD, an associate professor and chief of the division of lymphoma in the department of hematology and hematopoietic cell transplantation, City of Hope Medical Center, Duarte, Calif., said in an interview.
The randomized SWOG S1826 trial of 976 patients with newly diagnosed stage 3 or 4 Hodgkin lymphoma included patients ranging in age from as young as 12 to 83 years, and at a median follow-up of 12.1 months, the addition of nivolumab to the chemotherapy regimen of doxorubicin, vinblastine, and dacarbazine (AVD) was associated with as much as a 52% reduction in the risk of disease-related death, compared with the addition of brentuximab.
The results are especially important considering that Hodgkin lymphoma disproportionately affects younger patients, including those in their teens, 20s, and 30s, Dr. Herrera noted in an interview.
“We found that treatment with nivolumab reduced the risk of progression by half, and, importantly, the benefit was observed across subgroups,” he said.
Relapse/refractory disease common in advanced HL
In general, outcomes are relatively good even for stage III or IV Hodgkin lymphoma; however, about a quarter of patients still have relapses or refractory disease.
While the introduction of novel frontline treatment with brentuximab-AVD was important in improving overall survival, the regimen adds toxicity, particularly among older patients, and many pediatric patients receiving the therapy still require radiation therapy, with its undesirable side effects.
Meanwhile, the progressive death 1 inhibitor nivolumab, approved by the Food and Drug Administration, gained interest as a potentially ideal alternative in light of Hodgkin lymphoma’s status basically as “the poster child for PD-1 blockade,” Dr. Herrera said.
“There are genetic changes in the Hodgkin lymphoma tumor cell that lead to expression of PD-1 ligands on the surface of Hodgkin lymphoma cells, and when we use a drug like nivolumab, we see that even patients with the most treatment-resistant rates of lymphoma have as much as a 70% response rate,” he explained in a press briefing.
To further investigate, the first-of-its-kind collaboration of adult and pediatric cancer teams conducted the S1826 trial to evaluate the treatment across age groups with stage 3 and 4 Hodgkin lymphoma.
For the study, conducted between July 2019 and October 2022, 976 patients were randomized to treatment either with nivolumab (n = 489) or brentuximab (n = 487), each in combination with the AVD regimen.
Of the patients, the median age was 27, with 24% under the age of 18, 10% over 60 and 32% with IPS 4-7. Among them, 56% were male and 76% were White.
For the primary endpoint, at a median follow-up of 12.1 months, the rate of progression-free survival was significantly higher in the nivolumab arm (hazard ratio, 0.48; one-sided P = .0005), with the rate of 1-year survival at 94% in the nivolumab group versus 86% in the brentuximab group, for a 52% reduction in the risk of disease-related death with nivolumab versus brentuximab.
A total of 11 deaths occurred in the brentuximab group, 7 of which were related to adverse events, compared with 4 deaths in the nivolumab group, 3 of which were related to nivolumab.
Importantly, fewer than 1% of patients with nivolumab required radiation therapy.
“That’s a dramatic reduction of the proportion of the very youngest patients receiving radiotherapy,” Dr. Herrera noted.
Grade 3 or higher hematologic adverse events were higher in the nivolumab group, at 48.4%, including 45.1% that were grade 3 or higher neutropenia, compared with 30.5% with brentuximab, including 23.9% with grade 3 or higher neutropenia.
However, rates of any grade of febrile neutropenia were similar with nivolumab and brentuximab (5.6% vs. 6.4%, respectively), as were rates of pneumonitis (2.0% vs. 3.2%), ALT elevation (30.7% vs. 39.8%), and colitis (1% vs. 1.3%).
In addition, rates of hypo- and hyperthyroidism were more frequent after nivolumab (7% and 3% with nivolumab, respectively, vs. fewer than 1% with brentuximab).
But, of note, peripheral neuropathy of any grade was more common after brentuximab (sensory: 28.1% nivolumab vs. 54.2% brentuximab; motor: 4% nivolumab vs. 6.8% brentuximab).
“I can’t emphasize how important neuropathy is as a side effect in these young patients who have the rest of their life ahead of them,” Dr. Herrera explained. “It’s fantastic to be cured of cancer, but tough to not be able to feel your fingers and toes.”
With its broad inclusion of age groups and a diverse population, he added that the study was importantly a “representative” trial, reflecting a “real-world population.”
“Incredibly, a quarter of patients were under the age of 18; 10% were over the age of 60, a quarter of patients were Hispanic and Black, and in fact we had a quite good representation of higher-risk subgroups,” he said.
Looking forward, longer-term follow-up from this study will be important in determining if the improvement observed in disease-related deaths is maintained over time, Dr. Herrera noted.
“Additionally, it is crucial to obtain data on other key outcomes such as overall survival and quality of life from longer-term follow of this study,” he said.
‘A huge step forward’
Commenting on the study, Oreofe Odejide, MD, a medical oncologist at the Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School, both in Boston, said that results were unprecedented.
“Although a majority of patients with advanced stage Hodgkin lymphoma will be cured with initial therapy, about 20% of patients still end up with relapsed or refractory disease,” she said in an interview. “Therefore, the findings from this study represent a huge step forward in the management of advanced Hodgkin lymphoma in children and adults, leading to an improved and well-tolerated standard of care.”
Dr. Odejide agreed that the findings are potentially practice changing.
“Brentuximab-AVD set a high bar for the treatment of advanced-stage Hodgkin lymphoma, as it was the first regimen to show a meaningful improvement in disease-related death compared to ABVD chemotherapy in several years,” she explained.
“The fact that the SWOG1826 trial now shows a significant benefit of nivolumab-AVD over brentuximab and included both pediatric and adult patients unlike prior studies, is highly compelling,” Dr. Odejide added. “This has strong potential to change the standard of care for patients with previously untreated, advanced-stage Hodgkin lymphoma.”
The study received funding from the National Cancer Institute and from Bristol-Myers Squibb. Dr. Herrera reported relationships with Abbvie, ADC Therapeutics, Adicet Bio, AstraZeneca/MedImmune, Bristol-Myers Squibb, Caribou Biosciences, Genentech/Roche, Genmab, Karyopharm Therapeutics, Merck, Pfizer, Regeneron, Seagen, Takeda, and Tubulis Gmbh. Dr. Odejide reported no disclosures.
“[SWOG] S1826, the largest Hodgkin lymphoma study in National Clinical Trials Network history, is a key step toward harmonizing the pediatric and adult treatment of advanced-stage Hodgkin lymphoma,” the authors reported in late-breaking research presented at the annual meeting of the American Society of Clinical Oncology.
“Based on the magnitude of the benefit and with nivolumab being better tolerated than brentuximab, we anticipate that these results will be practice changing and nivolumab [and chemotherapy] will become a new standard of care,” lead author Alex Francisco Herrera, MD, an associate professor and chief of the division of lymphoma in the department of hematology and hematopoietic cell transplantation, City of Hope Medical Center, Duarte, Calif., said in an interview.
The randomized SWOG S1826 trial of 976 patients with newly diagnosed stage 3 or 4 Hodgkin lymphoma included patients ranging in age from as young as 12 to 83 years, and at a median follow-up of 12.1 months, the addition of nivolumab to the chemotherapy regimen of doxorubicin, vinblastine, and dacarbazine (AVD) was associated with as much as a 52% reduction in the risk of disease-related death, compared with the addition of brentuximab.
The results are especially important considering that Hodgkin lymphoma disproportionately affects younger patients, including those in their teens, 20s, and 30s, Dr. Herrera noted in an interview.
“We found that treatment with nivolumab reduced the risk of progression by half, and, importantly, the benefit was observed across subgroups,” he said.
Relapse/refractory disease common in advanced HL
In general, outcomes are relatively good even for stage III or IV Hodgkin lymphoma; however, about a quarter of patients still have relapses or refractory disease.
While the introduction of novel frontline treatment with brentuximab-AVD was important in improving overall survival, the regimen adds toxicity, particularly among older patients, and many pediatric patients receiving the therapy still require radiation therapy, with its undesirable side effects.
Meanwhile, the progressive death 1 inhibitor nivolumab, approved by the Food and Drug Administration, gained interest as a potentially ideal alternative in light of Hodgkin lymphoma’s status basically as “the poster child for PD-1 blockade,” Dr. Herrera said.
“There are genetic changes in the Hodgkin lymphoma tumor cell that lead to expression of PD-1 ligands on the surface of Hodgkin lymphoma cells, and when we use a drug like nivolumab, we see that even patients with the most treatment-resistant rates of lymphoma have as much as a 70% response rate,” he explained in a press briefing.
To further investigate, the first-of-its-kind collaboration of adult and pediatric cancer teams conducted the S1826 trial to evaluate the treatment across age groups with stage 3 and 4 Hodgkin lymphoma.
For the study, conducted between July 2019 and October 2022, 976 patients were randomized to treatment either with nivolumab (n = 489) or brentuximab (n = 487), each in combination with the AVD regimen.
Of the patients, the median age was 27, with 24% under the age of 18, 10% over 60 and 32% with IPS 4-7. Among them, 56% were male and 76% were White.
For the primary endpoint, at a median follow-up of 12.1 months, the rate of progression-free survival was significantly higher in the nivolumab arm (hazard ratio, 0.48; one-sided P = .0005), with the rate of 1-year survival at 94% in the nivolumab group versus 86% in the brentuximab group, for a 52% reduction in the risk of disease-related death with nivolumab versus brentuximab.
A total of 11 deaths occurred in the brentuximab group, 7 of which were related to adverse events, compared with 4 deaths in the nivolumab group, 3 of which were related to nivolumab.
Importantly, fewer than 1% of patients with nivolumab required radiation therapy.
“That’s a dramatic reduction of the proportion of the very youngest patients receiving radiotherapy,” Dr. Herrera noted.
Grade 3 or higher hematologic adverse events were higher in the nivolumab group, at 48.4%, including 45.1% that were grade 3 or higher neutropenia, compared with 30.5% with brentuximab, including 23.9% with grade 3 or higher neutropenia.
However, rates of any grade of febrile neutropenia were similar with nivolumab and brentuximab (5.6% vs. 6.4%, respectively), as were rates of pneumonitis (2.0% vs. 3.2%), ALT elevation (30.7% vs. 39.8%), and colitis (1% vs. 1.3%).
In addition, rates of hypo- and hyperthyroidism were more frequent after nivolumab (7% and 3% with nivolumab, respectively, vs. fewer than 1% with brentuximab).
But, of note, peripheral neuropathy of any grade was more common after brentuximab (sensory: 28.1% nivolumab vs. 54.2% brentuximab; motor: 4% nivolumab vs. 6.8% brentuximab).
“I can’t emphasize how important neuropathy is as a side effect in these young patients who have the rest of their life ahead of them,” Dr. Herrera explained. “It’s fantastic to be cured of cancer, but tough to not be able to feel your fingers and toes.”
With its broad inclusion of age groups and a diverse population, he added that the study was importantly a “representative” trial, reflecting a “real-world population.”
“Incredibly, a quarter of patients were under the age of 18; 10% were over the age of 60, a quarter of patients were Hispanic and Black, and in fact we had a quite good representation of higher-risk subgroups,” he said.
Looking forward, longer-term follow-up from this study will be important in determining if the improvement observed in disease-related deaths is maintained over time, Dr. Herrera noted.
“Additionally, it is crucial to obtain data on other key outcomes such as overall survival and quality of life from longer-term follow of this study,” he said.
‘A huge step forward’
Commenting on the study, Oreofe Odejide, MD, a medical oncologist at the Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School, both in Boston, said that results were unprecedented.
“Although a majority of patients with advanced stage Hodgkin lymphoma will be cured with initial therapy, about 20% of patients still end up with relapsed or refractory disease,” she said in an interview. “Therefore, the findings from this study represent a huge step forward in the management of advanced Hodgkin lymphoma in children and adults, leading to an improved and well-tolerated standard of care.”
Dr. Odejide agreed that the findings are potentially practice changing.
“Brentuximab-AVD set a high bar for the treatment of advanced-stage Hodgkin lymphoma, as it was the first regimen to show a meaningful improvement in disease-related death compared to ABVD chemotherapy in several years,” she explained.
“The fact that the SWOG1826 trial now shows a significant benefit of nivolumab-AVD over brentuximab and included both pediatric and adult patients unlike prior studies, is highly compelling,” Dr. Odejide added. “This has strong potential to change the standard of care for patients with previously untreated, advanced-stage Hodgkin lymphoma.”
The study received funding from the National Cancer Institute and from Bristol-Myers Squibb. Dr. Herrera reported relationships with Abbvie, ADC Therapeutics, Adicet Bio, AstraZeneca/MedImmune, Bristol-Myers Squibb, Caribou Biosciences, Genentech/Roche, Genmab, Karyopharm Therapeutics, Merck, Pfizer, Regeneron, Seagen, Takeda, and Tubulis Gmbh. Dr. Odejide reported no disclosures.
“[SWOG] S1826, the largest Hodgkin lymphoma study in National Clinical Trials Network history, is a key step toward harmonizing the pediatric and adult treatment of advanced-stage Hodgkin lymphoma,” the authors reported in late-breaking research presented at the annual meeting of the American Society of Clinical Oncology.
“Based on the magnitude of the benefit and with nivolumab being better tolerated than brentuximab, we anticipate that these results will be practice changing and nivolumab [and chemotherapy] will become a new standard of care,” lead author Alex Francisco Herrera, MD, an associate professor and chief of the division of lymphoma in the department of hematology and hematopoietic cell transplantation, City of Hope Medical Center, Duarte, Calif., said in an interview.
The randomized SWOG S1826 trial of 976 patients with newly diagnosed stage 3 or 4 Hodgkin lymphoma included patients ranging in age from as young as 12 to 83 years, and at a median follow-up of 12.1 months, the addition of nivolumab to the chemotherapy regimen of doxorubicin, vinblastine, and dacarbazine (AVD) was associated with as much as a 52% reduction in the risk of disease-related death, compared with the addition of brentuximab.
The results are especially important considering that Hodgkin lymphoma disproportionately affects younger patients, including those in their teens, 20s, and 30s, Dr. Herrera noted in an interview.
“We found that treatment with nivolumab reduced the risk of progression by half, and, importantly, the benefit was observed across subgroups,” he said.
Relapse/refractory disease common in advanced HL
In general, outcomes are relatively good even for stage III or IV Hodgkin lymphoma; however, about a quarter of patients still have relapses or refractory disease.
While the introduction of novel frontline treatment with brentuximab-AVD was important in improving overall survival, the regimen adds toxicity, particularly among older patients, and many pediatric patients receiving the therapy still require radiation therapy, with its undesirable side effects.
Meanwhile, the progressive death 1 inhibitor nivolumab, approved by the Food and Drug Administration, gained interest as a potentially ideal alternative in light of Hodgkin lymphoma’s status basically as “the poster child for PD-1 blockade,” Dr. Herrera said.
“There are genetic changes in the Hodgkin lymphoma tumor cell that lead to expression of PD-1 ligands on the surface of Hodgkin lymphoma cells, and when we use a drug like nivolumab, we see that even patients with the most treatment-resistant rates of lymphoma have as much as a 70% response rate,” he explained in a press briefing.
To further investigate, the first-of-its-kind collaboration of adult and pediatric cancer teams conducted the S1826 trial to evaluate the treatment across age groups with stage 3 and 4 Hodgkin lymphoma.
For the study, conducted between July 2019 and October 2022, 976 patients were randomized to treatment either with nivolumab (n = 489) or brentuximab (n = 487), each in combination with the AVD regimen.
Of the patients, the median age was 27, with 24% under the age of 18, 10% over 60 and 32% with IPS 4-7. Among them, 56% were male and 76% were White.
For the primary endpoint, at a median follow-up of 12.1 months, the rate of progression-free survival was significantly higher in the nivolumab arm (hazard ratio, 0.48; one-sided P = .0005), with the rate of 1-year survival at 94% in the nivolumab group versus 86% in the brentuximab group, for a 52% reduction in the risk of disease-related death with nivolumab versus brentuximab.
A total of 11 deaths occurred in the brentuximab group, 7 of which were related to adverse events, compared with 4 deaths in the nivolumab group, 3 of which were related to nivolumab.
Importantly, fewer than 1% of patients with nivolumab required radiation therapy.
“That’s a dramatic reduction of the proportion of the very youngest patients receiving radiotherapy,” Dr. Herrera noted.
Grade 3 or higher hematologic adverse events were higher in the nivolumab group, at 48.4%, including 45.1% that were grade 3 or higher neutropenia, compared with 30.5% with brentuximab, including 23.9% with grade 3 or higher neutropenia.
However, rates of any grade of febrile neutropenia were similar with nivolumab and brentuximab (5.6% vs. 6.4%, respectively), as were rates of pneumonitis (2.0% vs. 3.2%), ALT elevation (30.7% vs. 39.8%), and colitis (1% vs. 1.3%).
In addition, rates of hypo- and hyperthyroidism were more frequent after nivolumab (7% and 3% with nivolumab, respectively, vs. fewer than 1% with brentuximab).
But, of note, peripheral neuropathy of any grade was more common after brentuximab (sensory: 28.1% nivolumab vs. 54.2% brentuximab; motor: 4% nivolumab vs. 6.8% brentuximab).
“I can’t emphasize how important neuropathy is as a side effect in these young patients who have the rest of their life ahead of them,” Dr. Herrera explained. “It’s fantastic to be cured of cancer, but tough to not be able to feel your fingers and toes.”
With its broad inclusion of age groups and a diverse population, he added that the study was importantly a “representative” trial, reflecting a “real-world population.”
“Incredibly, a quarter of patients were under the age of 18; 10% were over the age of 60, a quarter of patients were Hispanic and Black, and in fact we had a quite good representation of higher-risk subgroups,” he said.
Looking forward, longer-term follow-up from this study will be important in determining if the improvement observed in disease-related deaths is maintained over time, Dr. Herrera noted.
“Additionally, it is crucial to obtain data on other key outcomes such as overall survival and quality of life from longer-term follow of this study,” he said.
‘A huge step forward’
Commenting on the study, Oreofe Odejide, MD, a medical oncologist at the Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School, both in Boston, said that results were unprecedented.
“Although a majority of patients with advanced stage Hodgkin lymphoma will be cured with initial therapy, about 20% of patients still end up with relapsed or refractory disease,” she said in an interview. “Therefore, the findings from this study represent a huge step forward in the management of advanced Hodgkin lymphoma in children and adults, leading to an improved and well-tolerated standard of care.”
Dr. Odejide agreed that the findings are potentially practice changing.
“Brentuximab-AVD set a high bar for the treatment of advanced-stage Hodgkin lymphoma, as it was the first regimen to show a meaningful improvement in disease-related death compared to ABVD chemotherapy in several years,” she explained.
“The fact that the SWOG1826 trial now shows a significant benefit of nivolumab-AVD over brentuximab and included both pediatric and adult patients unlike prior studies, is highly compelling,” Dr. Odejide added. “This has strong potential to change the standard of care for patients with previously untreated, advanced-stage Hodgkin lymphoma.”
The study received funding from the National Cancer Institute and from Bristol-Myers Squibb. Dr. Herrera reported relationships with Abbvie, ADC Therapeutics, Adicet Bio, AstraZeneca/MedImmune, Bristol-Myers Squibb, Caribou Biosciences, Genentech/Roche, Genmab, Karyopharm Therapeutics, Merck, Pfizer, Regeneron, Seagen, Takeda, and Tubulis Gmbh. Dr. Odejide reported no disclosures.
FROM ASCO 2023
Blood cancer patient takes on bias and ‘gaslighting’
Diagnosed with Hodgkin lymphoma in 2021, Ms. Ngon underwent port surgery to allow chemotherapy to be administered. Her right arm lost circulation and went numb, so she sought guidance from her blood cancer specialist. He dismissed her worries, saying that her tumors were pinching a nerve. She’d get better, he predicted, after more chemo.
“I knew in my body that something was wrong,” Ms. Ngon recalled. When the oncologist continued to downplay her concerns, she and a fellow communications specialist sat down together in the hospital lobby to draft an email to her physician. “We were trying to articulate the urgency in an email that expresses that I’m not being dramatic. We had to do it in a way that didn’t insult his intelligence: ‘Respectfully, you’re the doctor, but I know something is wrong.’ ”
In essence, Ms. Ngon was trying to be diplomatic and not trigger her oncologist’s defenses, while still convincing him to take action. Her approach to getting her doctor’s attention worked. He referred Ms. Ngon to a radiologist, who discovered that she had blood clots in her arm. Ms. Ngon then landed in the ICU for a week, as clinicians tried to break up the clots.
“I was the perfect person for this to happen to, because of my job and education. But it makes me sad because I understand I was in a fortunate position, with a background in communication. Most people don’t have that,” Ms. Ngon said.
This and other negative experiences during her medical saga inspired Ms. Ngon to partner with the Lymphoma Research Foundation in order to spread the word about unique challenges facing patients like her: people of color.
Ms. Ngon, who is Black, said her goal as a patient advocate is to “empower communities of color to speak up for themselves and hold oncologists responsible for listening and understanding differences across cultures.” And she wants to take a stand against the “gaslighting” of patients.
African Americans with hematologic disease like Ms. Ngon face a higher risk of poor outcomes than Whites, even as they are less likely than Whites to develop certain blood cancers. The reasons for this disparity aren’t clear, but researchers suspect they’re related to factors such as poverty, lack of insurance, genetics, and limited access to high-quality care.
Some researchers have blamed another factor: racism. A 2022 study sought to explain why Black and Hispanic patients with acute myeloid leukemia in urban areas have higher mortality rates than Whites, “despite more favorable genetics and younger age” (hazard ratio, 1.59, 95% confidence interval, 1.15-2.22 and HR, 1.25; 95% CI, 0.88-1.79). The study authors determined that “structural racism” – which they measured by examining segregation and “disadvantage” in neighborhoods where patients lived – accounted for nearly all of the disparities.
Ms. Ngon said her experiences and her awareness about poorer outcomes in medicine for African Americans – such as higher death rates for Black women during pregnancy – affect how she interacts with clinicians. “I automatically assume a barrier between me and my doctors, and it’s their responsibility to dismantle it.”
Making an connection with a physician can make a huge difference, she said. “I walked into my primary care doctor’s office and saw that she was a Latino woman. My guard went down, and I could feel her care for me as a human being. Whether that was because she was also a woman of color or not, I don’t know. But I did feel more cared for.”
However, Ms. Ngon could not find a Black oncologist to care for her in New York City, and that’s no surprise.
Ethnic and gender diversity remains an immense challenge in the hematology/oncology field. According to the American Society of Clinical Oncology, only about a third of oncologists are women, and the percentages identifying themselves as Black/African American and Hispanic are just 2.3% and 5.8%, respectively.
These numbers don’t seem likely to budge much any time soon. An analysis of medical students in U.S. oncology training programs from 2015-2020 found that just 3.8% identified themselves as Black/African American and 5.1% as Hispanic/Latino versus 52.15% as White and 31% as Asian/Pacific Islander/Native Hawaiian.
Ms. Ngon encountered challenges on other fronts during her cancer care. When she needed a wig during chemotherapy, a list of insurer-approved shops didn’t include any that catered to African Americans. Essentially, she said, she was being told that she couldn’t “purchase a wig from a place that makes you feel comfortable and from a woman who understand your needs as a Black woman. It needs to be from these specific shops that really don’t cater to my community.”
She also found it difficult to find fellow patients who shared her unique challenges. “I remember when I was diagnosed, I was looking through the support groups on Facebook, trying to find someone Black to ask about whether braiding my hair might stop it from falling out.”
Now, Ms. Ngon is in remission. And she’s happy with her oncologist, who’s White. “He listened to me, and he promised me that I would have the most boring recovery process ever, after everything I’d experienced. That explains a lot of why I felt so comfortable with him.”
She hopes to use her partnership with the Lymphoma Research Foundation to be a resource for people of color and alert them to the support that’s available for them. “I would love to let them know how to advocate for themselves as patients, how to trust their bodies, how to push back if they feel like they’re not getting the care that they deserve.”
Ms. Ngon would also like to see more support for medical students of color. “I hope to exist in a world one day where it wouldn’t be so hard to find an oncologist who looks like me in a city as large as this one,” she said.
As for oncologists, she urged them to “go the extra mile and really, really listen to what patients are saying. It’s easier said than done because there are natural biases in this world, and it’s hard to overcome those obstacles. But to not be heard and have to push every time. It was just exhausting to do that on top of trying to beat cancer.”
Diagnosed with Hodgkin lymphoma in 2021, Ms. Ngon underwent port surgery to allow chemotherapy to be administered. Her right arm lost circulation and went numb, so she sought guidance from her blood cancer specialist. He dismissed her worries, saying that her tumors were pinching a nerve. She’d get better, he predicted, after more chemo.
“I knew in my body that something was wrong,” Ms. Ngon recalled. When the oncologist continued to downplay her concerns, she and a fellow communications specialist sat down together in the hospital lobby to draft an email to her physician. “We were trying to articulate the urgency in an email that expresses that I’m not being dramatic. We had to do it in a way that didn’t insult his intelligence: ‘Respectfully, you’re the doctor, but I know something is wrong.’ ”
In essence, Ms. Ngon was trying to be diplomatic and not trigger her oncologist’s defenses, while still convincing him to take action. Her approach to getting her doctor’s attention worked. He referred Ms. Ngon to a radiologist, who discovered that she had blood clots in her arm. Ms. Ngon then landed in the ICU for a week, as clinicians tried to break up the clots.
“I was the perfect person for this to happen to, because of my job and education. But it makes me sad because I understand I was in a fortunate position, with a background in communication. Most people don’t have that,” Ms. Ngon said.
This and other negative experiences during her medical saga inspired Ms. Ngon to partner with the Lymphoma Research Foundation in order to spread the word about unique challenges facing patients like her: people of color.
Ms. Ngon, who is Black, said her goal as a patient advocate is to “empower communities of color to speak up for themselves and hold oncologists responsible for listening and understanding differences across cultures.” And she wants to take a stand against the “gaslighting” of patients.
African Americans with hematologic disease like Ms. Ngon face a higher risk of poor outcomes than Whites, even as they are less likely than Whites to develop certain blood cancers. The reasons for this disparity aren’t clear, but researchers suspect they’re related to factors such as poverty, lack of insurance, genetics, and limited access to high-quality care.
Some researchers have blamed another factor: racism. A 2022 study sought to explain why Black and Hispanic patients with acute myeloid leukemia in urban areas have higher mortality rates than Whites, “despite more favorable genetics and younger age” (hazard ratio, 1.59, 95% confidence interval, 1.15-2.22 and HR, 1.25; 95% CI, 0.88-1.79). The study authors determined that “structural racism” – which they measured by examining segregation and “disadvantage” in neighborhoods where patients lived – accounted for nearly all of the disparities.
Ms. Ngon said her experiences and her awareness about poorer outcomes in medicine for African Americans – such as higher death rates for Black women during pregnancy – affect how she interacts with clinicians. “I automatically assume a barrier between me and my doctors, and it’s their responsibility to dismantle it.”
Making an connection with a physician can make a huge difference, she said. “I walked into my primary care doctor’s office and saw that she was a Latino woman. My guard went down, and I could feel her care for me as a human being. Whether that was because she was also a woman of color or not, I don’t know. But I did feel more cared for.”
However, Ms. Ngon could not find a Black oncologist to care for her in New York City, and that’s no surprise.
Ethnic and gender diversity remains an immense challenge in the hematology/oncology field. According to the American Society of Clinical Oncology, only about a third of oncologists are women, and the percentages identifying themselves as Black/African American and Hispanic are just 2.3% and 5.8%, respectively.
These numbers don’t seem likely to budge much any time soon. An analysis of medical students in U.S. oncology training programs from 2015-2020 found that just 3.8% identified themselves as Black/African American and 5.1% as Hispanic/Latino versus 52.15% as White and 31% as Asian/Pacific Islander/Native Hawaiian.
Ms. Ngon encountered challenges on other fronts during her cancer care. When she needed a wig during chemotherapy, a list of insurer-approved shops didn’t include any that catered to African Americans. Essentially, she said, she was being told that she couldn’t “purchase a wig from a place that makes you feel comfortable and from a woman who understand your needs as a Black woman. It needs to be from these specific shops that really don’t cater to my community.”
She also found it difficult to find fellow patients who shared her unique challenges. “I remember when I was diagnosed, I was looking through the support groups on Facebook, trying to find someone Black to ask about whether braiding my hair might stop it from falling out.”
Now, Ms. Ngon is in remission. And she’s happy with her oncologist, who’s White. “He listened to me, and he promised me that I would have the most boring recovery process ever, after everything I’d experienced. That explains a lot of why I felt so comfortable with him.”
She hopes to use her partnership with the Lymphoma Research Foundation to be a resource for people of color and alert them to the support that’s available for them. “I would love to let them know how to advocate for themselves as patients, how to trust their bodies, how to push back if they feel like they’re not getting the care that they deserve.”
Ms. Ngon would also like to see more support for medical students of color. “I hope to exist in a world one day where it wouldn’t be so hard to find an oncologist who looks like me in a city as large as this one,” she said.
As for oncologists, she urged them to “go the extra mile and really, really listen to what patients are saying. It’s easier said than done because there are natural biases in this world, and it’s hard to overcome those obstacles. But to not be heard and have to push every time. It was just exhausting to do that on top of trying to beat cancer.”
Diagnosed with Hodgkin lymphoma in 2021, Ms. Ngon underwent port surgery to allow chemotherapy to be administered. Her right arm lost circulation and went numb, so she sought guidance from her blood cancer specialist. He dismissed her worries, saying that her tumors were pinching a nerve. She’d get better, he predicted, after more chemo.
“I knew in my body that something was wrong,” Ms. Ngon recalled. When the oncologist continued to downplay her concerns, she and a fellow communications specialist sat down together in the hospital lobby to draft an email to her physician. “We were trying to articulate the urgency in an email that expresses that I’m not being dramatic. We had to do it in a way that didn’t insult his intelligence: ‘Respectfully, you’re the doctor, but I know something is wrong.’ ”
In essence, Ms. Ngon was trying to be diplomatic and not trigger her oncologist’s defenses, while still convincing him to take action. Her approach to getting her doctor’s attention worked. He referred Ms. Ngon to a radiologist, who discovered that she had blood clots in her arm. Ms. Ngon then landed in the ICU for a week, as clinicians tried to break up the clots.
“I was the perfect person for this to happen to, because of my job and education. But it makes me sad because I understand I was in a fortunate position, with a background in communication. Most people don’t have that,” Ms. Ngon said.
This and other negative experiences during her medical saga inspired Ms. Ngon to partner with the Lymphoma Research Foundation in order to spread the word about unique challenges facing patients like her: people of color.
Ms. Ngon, who is Black, said her goal as a patient advocate is to “empower communities of color to speak up for themselves and hold oncologists responsible for listening and understanding differences across cultures.” And she wants to take a stand against the “gaslighting” of patients.
African Americans with hematologic disease like Ms. Ngon face a higher risk of poor outcomes than Whites, even as they are less likely than Whites to develop certain blood cancers. The reasons for this disparity aren’t clear, but researchers suspect they’re related to factors such as poverty, lack of insurance, genetics, and limited access to high-quality care.
Some researchers have blamed another factor: racism. A 2022 study sought to explain why Black and Hispanic patients with acute myeloid leukemia in urban areas have higher mortality rates than Whites, “despite more favorable genetics and younger age” (hazard ratio, 1.59, 95% confidence interval, 1.15-2.22 and HR, 1.25; 95% CI, 0.88-1.79). The study authors determined that “structural racism” – which they measured by examining segregation and “disadvantage” in neighborhoods where patients lived – accounted for nearly all of the disparities.
Ms. Ngon said her experiences and her awareness about poorer outcomes in medicine for African Americans – such as higher death rates for Black women during pregnancy – affect how she interacts with clinicians. “I automatically assume a barrier between me and my doctors, and it’s their responsibility to dismantle it.”
Making an connection with a physician can make a huge difference, she said. “I walked into my primary care doctor’s office and saw that she was a Latino woman. My guard went down, and I could feel her care for me as a human being. Whether that was because she was also a woman of color or not, I don’t know. But I did feel more cared for.”
However, Ms. Ngon could not find a Black oncologist to care for her in New York City, and that’s no surprise.
Ethnic and gender diversity remains an immense challenge in the hematology/oncology field. According to the American Society of Clinical Oncology, only about a third of oncologists are women, and the percentages identifying themselves as Black/African American and Hispanic are just 2.3% and 5.8%, respectively.
These numbers don’t seem likely to budge much any time soon. An analysis of medical students in U.S. oncology training programs from 2015-2020 found that just 3.8% identified themselves as Black/African American and 5.1% as Hispanic/Latino versus 52.15% as White and 31% as Asian/Pacific Islander/Native Hawaiian.
Ms. Ngon encountered challenges on other fronts during her cancer care. When she needed a wig during chemotherapy, a list of insurer-approved shops didn’t include any that catered to African Americans. Essentially, she said, she was being told that she couldn’t “purchase a wig from a place that makes you feel comfortable and from a woman who understand your needs as a Black woman. It needs to be from these specific shops that really don’t cater to my community.”
She also found it difficult to find fellow patients who shared her unique challenges. “I remember when I was diagnosed, I was looking through the support groups on Facebook, trying to find someone Black to ask about whether braiding my hair might stop it from falling out.”
Now, Ms. Ngon is in remission. And she’s happy with her oncologist, who’s White. “He listened to me, and he promised me that I would have the most boring recovery process ever, after everything I’d experienced. That explains a lot of why I felt so comfortable with him.”
She hopes to use her partnership with the Lymphoma Research Foundation to be a resource for people of color and alert them to the support that’s available for them. “I would love to let them know how to advocate for themselves as patients, how to trust their bodies, how to push back if they feel like they’re not getting the care that they deserve.”
Ms. Ngon would also like to see more support for medical students of color. “I hope to exist in a world one day where it wouldn’t be so hard to find an oncologist who looks like me in a city as large as this one,” she said.
As for oncologists, she urged them to “go the extra mile and really, really listen to what patients are saying. It’s easier said than done because there are natural biases in this world, and it’s hard to overcome those obstacles. But to not be heard and have to push every time. It was just exhausting to do that on top of trying to beat cancer.”
Number of cancer survivors with functional limitations doubled in 20 years
Vishal Patel, BS, a student at the Dell Medical School at The University of Texas at Austin, and colleagues identified 51,258 cancer survivors from the National Health Interview Survey, representing a weighted population of approximately 178.8 million from 1999 to 2018.
Most survivors were women (60.2%) and were at least 65 years old (55.4%). In 1999, 3.6 million weighted survivors reported functional limitation. In 2018, the number increased to 8.2 million, a 2.25-fold increase.
The number of survivors who reported no limitations also increased, but not by as much. That group grew 1.34-fold during the study period.
For context, “the 70% prevalence of functional limitation among survivors in 2018 is nearly twice that of the general population,” the authors wrote.
Patients surveyed on function
Functional limitation was defined as “self-reported difficulty performing any of 12 routine physical or social activities without assistance.” Examples of the activities included difficulty sitting for more than 2 hours, difficulty participating in social activities or difficulty pushing or pulling an object the size of a living room chair.
Over the 2 decades analyzed, the adjusted prevalence of functional limitation was highest among survivors of pancreatic cancer (80.3%) and lung cancer (76.5%). Prevalence was lowest for survivors of melanoma (62.2%), breast (61.8%) and prostate (59.5%) cancers.
Not just a result of living longer
Mr. Patel told this publication that one assumption people might make when they read these results is that people are just living longer with cancer and losing functional ability accordingly.
“But, in fact, we found that the youngest [– those less than 65 years–] actually contributed to this trend more than the oldest people, which means it’s not just [happening], because people are getting older,” he said.
Hispanic and Black individuals had disproportionately higher increases in functional limitation; percentage point increases over the 2 decades were 19.5 for Black people, 25.1 for Hispanic people and 12.5 for White people. There may be a couple of reasons for that, Mr. Patel noted.
Those who are Black or Hispanic tend to have less access to cancer survivorship care for reasons including insurance status and historic health care inequities, he noted.
“The other potential reason is that they have had less access to cancer care historically. And if, 20 years ago Black and Hispanic individuals didn’t have access to some chemotherapies, and now they do, maybe it’s the increased access to care that’s causing these functional limitations. Because chemotherapy can sometimes be very toxic. It may be sort of a catch-up toxicity,” he said.
Quality of life beyond survivorship
Mr. Patel said the results seem to call for building on improved survival rates by tracking and improving function.
“It’s good to celebrate that there are more survivors. But now that we can keep people alive longer, maybe we can shift gears to improving their quality of life,” he said.
The more-than-doubling of functional limitations over 2 decades “is a very sobering trend,” he noted, while pointing out that the functional limitations applied to 8 million people in the United States – people whose needs are not being met.
There’s no sign of the trend stopping, he continued. “We saw no downward trend, only an upward trend.”
Increasingly, including functionality as an endpoint in cancer trials, in addition to improvements in mortality, is one place to start, he added.
“Our findings suggest an urgent need for care teams to understand and address function, for researchers to evaluate function as a core outcome in trials, and for health systems and policy makers to reimagine survivorship care, recognizing the burden of cancer and its treatment on physical, psychosocial, and cognitive function,” the authors wrote in their paper. Limitations of the study include the potential for recall bias, lack of cancer staging or treatment information, and the subjective perception of function.
A coauthor reported personal fees from Astellas, AstraZeneca, AAA, Blue Earth, Janssen, Lantheus, Myovant, Myriad Genetics, Novartis, Telix, and Sanofi, as well as grants from Pfizer and Bayer during the conduct of the study. No other disclosures were reported.
Vishal Patel, BS, a student at the Dell Medical School at The University of Texas at Austin, and colleagues identified 51,258 cancer survivors from the National Health Interview Survey, representing a weighted population of approximately 178.8 million from 1999 to 2018.
Most survivors were women (60.2%) and were at least 65 years old (55.4%). In 1999, 3.6 million weighted survivors reported functional limitation. In 2018, the number increased to 8.2 million, a 2.25-fold increase.
The number of survivors who reported no limitations also increased, but not by as much. That group grew 1.34-fold during the study period.
For context, “the 70% prevalence of functional limitation among survivors in 2018 is nearly twice that of the general population,” the authors wrote.
Patients surveyed on function
Functional limitation was defined as “self-reported difficulty performing any of 12 routine physical or social activities without assistance.” Examples of the activities included difficulty sitting for more than 2 hours, difficulty participating in social activities or difficulty pushing or pulling an object the size of a living room chair.
Over the 2 decades analyzed, the adjusted prevalence of functional limitation was highest among survivors of pancreatic cancer (80.3%) and lung cancer (76.5%). Prevalence was lowest for survivors of melanoma (62.2%), breast (61.8%) and prostate (59.5%) cancers.
Not just a result of living longer
Mr. Patel told this publication that one assumption people might make when they read these results is that people are just living longer with cancer and losing functional ability accordingly.
“But, in fact, we found that the youngest [– those less than 65 years–] actually contributed to this trend more than the oldest people, which means it’s not just [happening], because people are getting older,” he said.
Hispanic and Black individuals had disproportionately higher increases in functional limitation; percentage point increases over the 2 decades were 19.5 for Black people, 25.1 for Hispanic people and 12.5 for White people. There may be a couple of reasons for that, Mr. Patel noted.
Those who are Black or Hispanic tend to have less access to cancer survivorship care for reasons including insurance status and historic health care inequities, he noted.
“The other potential reason is that they have had less access to cancer care historically. And if, 20 years ago Black and Hispanic individuals didn’t have access to some chemotherapies, and now they do, maybe it’s the increased access to care that’s causing these functional limitations. Because chemotherapy can sometimes be very toxic. It may be sort of a catch-up toxicity,” he said.
Quality of life beyond survivorship
Mr. Patel said the results seem to call for building on improved survival rates by tracking and improving function.
“It’s good to celebrate that there are more survivors. But now that we can keep people alive longer, maybe we can shift gears to improving their quality of life,” he said.
The more-than-doubling of functional limitations over 2 decades “is a very sobering trend,” he noted, while pointing out that the functional limitations applied to 8 million people in the United States – people whose needs are not being met.
There’s no sign of the trend stopping, he continued. “We saw no downward trend, only an upward trend.”
Increasingly, including functionality as an endpoint in cancer trials, in addition to improvements in mortality, is one place to start, he added.
“Our findings suggest an urgent need for care teams to understand and address function, for researchers to evaluate function as a core outcome in trials, and for health systems and policy makers to reimagine survivorship care, recognizing the burden of cancer and its treatment on physical, psychosocial, and cognitive function,” the authors wrote in their paper. Limitations of the study include the potential for recall bias, lack of cancer staging or treatment information, and the subjective perception of function.
A coauthor reported personal fees from Astellas, AstraZeneca, AAA, Blue Earth, Janssen, Lantheus, Myovant, Myriad Genetics, Novartis, Telix, and Sanofi, as well as grants from Pfizer and Bayer during the conduct of the study. No other disclosures were reported.
Vishal Patel, BS, a student at the Dell Medical School at The University of Texas at Austin, and colleagues identified 51,258 cancer survivors from the National Health Interview Survey, representing a weighted population of approximately 178.8 million from 1999 to 2018.
Most survivors were women (60.2%) and were at least 65 years old (55.4%). In 1999, 3.6 million weighted survivors reported functional limitation. In 2018, the number increased to 8.2 million, a 2.25-fold increase.
The number of survivors who reported no limitations also increased, but not by as much. That group grew 1.34-fold during the study period.
For context, “the 70% prevalence of functional limitation among survivors in 2018 is nearly twice that of the general population,” the authors wrote.
Patients surveyed on function
Functional limitation was defined as “self-reported difficulty performing any of 12 routine physical or social activities without assistance.” Examples of the activities included difficulty sitting for more than 2 hours, difficulty participating in social activities or difficulty pushing or pulling an object the size of a living room chair.
Over the 2 decades analyzed, the adjusted prevalence of functional limitation was highest among survivors of pancreatic cancer (80.3%) and lung cancer (76.5%). Prevalence was lowest for survivors of melanoma (62.2%), breast (61.8%) and prostate (59.5%) cancers.
Not just a result of living longer
Mr. Patel told this publication that one assumption people might make when they read these results is that people are just living longer with cancer and losing functional ability accordingly.
“But, in fact, we found that the youngest [– those less than 65 years–] actually contributed to this trend more than the oldest people, which means it’s not just [happening], because people are getting older,” he said.
Hispanic and Black individuals had disproportionately higher increases in functional limitation; percentage point increases over the 2 decades were 19.5 for Black people, 25.1 for Hispanic people and 12.5 for White people. There may be a couple of reasons for that, Mr. Patel noted.
Those who are Black or Hispanic tend to have less access to cancer survivorship care for reasons including insurance status and historic health care inequities, he noted.
“The other potential reason is that they have had less access to cancer care historically. And if, 20 years ago Black and Hispanic individuals didn’t have access to some chemotherapies, and now they do, maybe it’s the increased access to care that’s causing these functional limitations. Because chemotherapy can sometimes be very toxic. It may be sort of a catch-up toxicity,” he said.
Quality of life beyond survivorship
Mr. Patel said the results seem to call for building on improved survival rates by tracking and improving function.
“It’s good to celebrate that there are more survivors. But now that we can keep people alive longer, maybe we can shift gears to improving their quality of life,” he said.
The more-than-doubling of functional limitations over 2 decades “is a very sobering trend,” he noted, while pointing out that the functional limitations applied to 8 million people in the United States – people whose needs are not being met.
There’s no sign of the trend stopping, he continued. “We saw no downward trend, only an upward trend.”
Increasingly, including functionality as an endpoint in cancer trials, in addition to improvements in mortality, is one place to start, he added.
“Our findings suggest an urgent need for care teams to understand and address function, for researchers to evaluate function as a core outcome in trials, and for health systems and policy makers to reimagine survivorship care, recognizing the burden of cancer and its treatment on physical, psychosocial, and cognitive function,” the authors wrote in their paper. Limitations of the study include the potential for recall bias, lack of cancer staging or treatment information, and the subjective perception of function.
A coauthor reported personal fees from Astellas, AstraZeneca, AAA, Blue Earth, Janssen, Lantheus, Myovant, Myriad Genetics, Novartis, Telix, and Sanofi, as well as grants from Pfizer and Bayer during the conduct of the study. No other disclosures were reported.
FROM JAMA ONCOLOGY
AFib risk with cancer drugs underestimated
Atrial fibrillation (AFib) is a known and serious side effect of some cancer treatments, but it is underreported in cancer drug trials, French investigators said in a new report.
As a result, oncologists likely underestimate the risk of atrial fibrillation when new cancer drugs come to market, they said.
The team came to these conclusions after conducting a meta-analysis of 191 phase 2 or 3 clinical trials that included 26,604 patients. The trials investigated 15 anticancer drugs used as monotherapy.
The meta-analysis showed that the annualized incidence rate of AFib ranged from 0.26 cases per 100 person-years – about the same as placebo – to 4.92 cases, a nearly 20 times’ higher risk.
Rates were the highest for ibrutinib, clofarabine, and ponatinib.
The study was published in JACC: CardioOncology, a journal of the American College of Cardiology.
Actual rates of AFib are probably higher than what they found in this meta-analysis, the authors suspect, because most oncology trials only identify and report severe cases of AFib that require immediate medical attention. Less severe cases can also lead to serious complications, including strokes, but they go unreported, said the investigators, led by Joachim Alexandre, MD, PhD, a member of the cardio-oncology program at the University of Caen Normandie Hospital Center, France.
“These findings suggest a global and systemic underreporting and/or underidentification of cardiotoxicity among cancer clinical trial participants,” and AFib reporting is “particularly affected,” they said.
Call for routine monitoring
The root of the problem is the lack of routine rhythm monitoring in cancer trials. This in turn “leads to a significant underestimation of AFib incidence” and rates “markedly lower than those observed among real-life” patients, the authors pointed out.
To address the issue, Dr. Alexandre and his team called for routine cardiac monitoring in trials to capture the true incidence of AFib and to “clearly define which anticancer drugs are significantly associated” with the condition.
Approached for comment, Michael G. Fradley, MD, medical director of cardio-oncology at the University of Pennsylvania, Philadelphia, agreed.
“It’s incredibly important” to “identify the drugs most likely to cause arrhythmias and determine the best prevention and treatment strategies. Unfortunately, systematic evaluation of arrhythmias in cancer clinical trials has often been lacking,” Dr. Fradley told this news organization.
The investigators said the issue is particularly pressing for drugs known to be associated with AFib. For Bruton’s tyrosine kinase inhibitors such as ibrutinib, for instance, they call for standardize AFib detection in trials “not only on 12-lead ECGs” for symptomatic AFib but also with “longer-term ambulatory monitoring or insertable cardiac monitors to detect subclinical AFib.”
Dr. Fradley said there might also be a role for newer wearable technologies that can detect arrhythmias through a skin patch or by other means.
Details of the meta-analysis
The investigators pulled the 191 studies they used in their meta-analysis from the ClinicalTrials.gov database.
The trials covered anticancer drugs used as monotherapy up to Sept. 18, 2020. Almost half were randomized trials, but only seven had placebo arms. Trials involving hematologic cancers outnumbered those involving solid tumors.
The 15 drugs examined were dacarbazine, abiraterone, clofarabine, azacitidine, ibrutinib, nilotinib, ponatinib, midostaurin, ipilimumab, aldesleukin, lenalidomide, pomalidomide, rituximab, bortezomib, and docetaxel.
The annualized incidence AFib rates per 100 person-years were 4.92 cases for ibrutinib, 2.38 cases for clofarabine, and 2.35 cases for ponatinib.
The lowest AFib rates were for ipilimumab (0.26 cases), rituximab (0.27), and nilotinib (0.29).
For placebo, the annualized rate was 0.25 cases per 100 person-years.
The team said caution is warranted regarding their estimations for clofarabine and midostaurin (0.65 cases) because no trials were registered after September 2009, when adverse event reporting became mandatory. As a result, estimates may be artificially low.
One of the limits of the study is that it focused on monotherapy in an age when combination treatment is generally the rule for cancer, the authors noted.
No external funding was reported for the study. Dr. Alexandre has received honoraria for presentations and consulting fees from Bayer, BMS, Pfizer, Amgen, and Bioserenity.
A version of this article first appeared on Medscape.com.
Atrial fibrillation (AFib) is a known and serious side effect of some cancer treatments, but it is underreported in cancer drug trials, French investigators said in a new report.
As a result, oncologists likely underestimate the risk of atrial fibrillation when new cancer drugs come to market, they said.
The team came to these conclusions after conducting a meta-analysis of 191 phase 2 or 3 clinical trials that included 26,604 patients. The trials investigated 15 anticancer drugs used as monotherapy.
The meta-analysis showed that the annualized incidence rate of AFib ranged from 0.26 cases per 100 person-years – about the same as placebo – to 4.92 cases, a nearly 20 times’ higher risk.
Rates were the highest for ibrutinib, clofarabine, and ponatinib.
The study was published in JACC: CardioOncology, a journal of the American College of Cardiology.
Actual rates of AFib are probably higher than what they found in this meta-analysis, the authors suspect, because most oncology trials only identify and report severe cases of AFib that require immediate medical attention. Less severe cases can also lead to serious complications, including strokes, but they go unreported, said the investigators, led by Joachim Alexandre, MD, PhD, a member of the cardio-oncology program at the University of Caen Normandie Hospital Center, France.
“These findings suggest a global and systemic underreporting and/or underidentification of cardiotoxicity among cancer clinical trial participants,” and AFib reporting is “particularly affected,” they said.
Call for routine monitoring
The root of the problem is the lack of routine rhythm monitoring in cancer trials. This in turn “leads to a significant underestimation of AFib incidence” and rates “markedly lower than those observed among real-life” patients, the authors pointed out.
To address the issue, Dr. Alexandre and his team called for routine cardiac monitoring in trials to capture the true incidence of AFib and to “clearly define which anticancer drugs are significantly associated” with the condition.
Approached for comment, Michael G. Fradley, MD, medical director of cardio-oncology at the University of Pennsylvania, Philadelphia, agreed.
“It’s incredibly important” to “identify the drugs most likely to cause arrhythmias and determine the best prevention and treatment strategies. Unfortunately, systematic evaluation of arrhythmias in cancer clinical trials has often been lacking,” Dr. Fradley told this news organization.
The investigators said the issue is particularly pressing for drugs known to be associated with AFib. For Bruton’s tyrosine kinase inhibitors such as ibrutinib, for instance, they call for standardize AFib detection in trials “not only on 12-lead ECGs” for symptomatic AFib but also with “longer-term ambulatory monitoring or insertable cardiac monitors to detect subclinical AFib.”
Dr. Fradley said there might also be a role for newer wearable technologies that can detect arrhythmias through a skin patch or by other means.
Details of the meta-analysis
The investigators pulled the 191 studies they used in their meta-analysis from the ClinicalTrials.gov database.
The trials covered anticancer drugs used as monotherapy up to Sept. 18, 2020. Almost half were randomized trials, but only seven had placebo arms. Trials involving hematologic cancers outnumbered those involving solid tumors.
The 15 drugs examined were dacarbazine, abiraterone, clofarabine, azacitidine, ibrutinib, nilotinib, ponatinib, midostaurin, ipilimumab, aldesleukin, lenalidomide, pomalidomide, rituximab, bortezomib, and docetaxel.
The annualized incidence AFib rates per 100 person-years were 4.92 cases for ibrutinib, 2.38 cases for clofarabine, and 2.35 cases for ponatinib.
The lowest AFib rates were for ipilimumab (0.26 cases), rituximab (0.27), and nilotinib (0.29).
For placebo, the annualized rate was 0.25 cases per 100 person-years.
The team said caution is warranted regarding their estimations for clofarabine and midostaurin (0.65 cases) because no trials were registered after September 2009, when adverse event reporting became mandatory. As a result, estimates may be artificially low.
One of the limits of the study is that it focused on monotherapy in an age when combination treatment is generally the rule for cancer, the authors noted.
No external funding was reported for the study. Dr. Alexandre has received honoraria for presentations and consulting fees from Bayer, BMS, Pfizer, Amgen, and Bioserenity.
A version of this article first appeared on Medscape.com.
Atrial fibrillation (AFib) is a known and serious side effect of some cancer treatments, but it is underreported in cancer drug trials, French investigators said in a new report.
As a result, oncologists likely underestimate the risk of atrial fibrillation when new cancer drugs come to market, they said.
The team came to these conclusions after conducting a meta-analysis of 191 phase 2 or 3 clinical trials that included 26,604 patients. The trials investigated 15 anticancer drugs used as monotherapy.
The meta-analysis showed that the annualized incidence rate of AFib ranged from 0.26 cases per 100 person-years – about the same as placebo – to 4.92 cases, a nearly 20 times’ higher risk.
Rates were the highest for ibrutinib, clofarabine, and ponatinib.
The study was published in JACC: CardioOncology, a journal of the American College of Cardiology.
Actual rates of AFib are probably higher than what they found in this meta-analysis, the authors suspect, because most oncology trials only identify and report severe cases of AFib that require immediate medical attention. Less severe cases can also lead to serious complications, including strokes, but they go unreported, said the investigators, led by Joachim Alexandre, MD, PhD, a member of the cardio-oncology program at the University of Caen Normandie Hospital Center, France.
“These findings suggest a global and systemic underreporting and/or underidentification of cardiotoxicity among cancer clinical trial participants,” and AFib reporting is “particularly affected,” they said.
Call for routine monitoring
The root of the problem is the lack of routine rhythm monitoring in cancer trials. This in turn “leads to a significant underestimation of AFib incidence” and rates “markedly lower than those observed among real-life” patients, the authors pointed out.
To address the issue, Dr. Alexandre and his team called for routine cardiac monitoring in trials to capture the true incidence of AFib and to “clearly define which anticancer drugs are significantly associated” with the condition.
Approached for comment, Michael G. Fradley, MD, medical director of cardio-oncology at the University of Pennsylvania, Philadelphia, agreed.
“It’s incredibly important” to “identify the drugs most likely to cause arrhythmias and determine the best prevention and treatment strategies. Unfortunately, systematic evaluation of arrhythmias in cancer clinical trials has often been lacking,” Dr. Fradley told this news organization.
The investigators said the issue is particularly pressing for drugs known to be associated with AFib. For Bruton’s tyrosine kinase inhibitors such as ibrutinib, for instance, they call for standardize AFib detection in trials “not only on 12-lead ECGs” for symptomatic AFib but also with “longer-term ambulatory monitoring or insertable cardiac monitors to detect subclinical AFib.”
Dr. Fradley said there might also be a role for newer wearable technologies that can detect arrhythmias through a skin patch or by other means.
Details of the meta-analysis
The investigators pulled the 191 studies they used in their meta-analysis from the ClinicalTrials.gov database.
The trials covered anticancer drugs used as monotherapy up to Sept. 18, 2020. Almost half were randomized trials, but only seven had placebo arms. Trials involving hematologic cancers outnumbered those involving solid tumors.
The 15 drugs examined were dacarbazine, abiraterone, clofarabine, azacitidine, ibrutinib, nilotinib, ponatinib, midostaurin, ipilimumab, aldesleukin, lenalidomide, pomalidomide, rituximab, bortezomib, and docetaxel.
The annualized incidence AFib rates per 100 person-years were 4.92 cases for ibrutinib, 2.38 cases for clofarabine, and 2.35 cases for ponatinib.
The lowest AFib rates were for ipilimumab (0.26 cases), rituximab (0.27), and nilotinib (0.29).
For placebo, the annualized rate was 0.25 cases per 100 person-years.
The team said caution is warranted regarding their estimations for clofarabine and midostaurin (0.65 cases) because no trials were registered after September 2009, when adverse event reporting became mandatory. As a result, estimates may be artificially low.
One of the limits of the study is that it focused on monotherapy in an age when combination treatment is generally the rule for cancer, the authors noted.
No external funding was reported for the study. Dr. Alexandre has received honoraria for presentations and consulting fees from Bayer, BMS, Pfizer, Amgen, and Bioserenity.
A version of this article first appeared on Medscape.com.
Atorvastatin cut anthracycline cardiac dysfunction in lymphoma
NEW ORLEANS – Atorvastatin treatment of patients with lymphoma undergoing treatment with an anthracycline significantly cut the incidence of incident cardiac dysfunction by about two-thirds during 12 months of treatment, in a multicenter, randomized trial with 300 enrolled patients.
“These data support the use of atorvastatin among patients with lymphoma being treated with anthracyclines where prevention of cardiac systolic dysfunction is important,” concluded Tomas G. Neilan, MD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
He highlighted that an important difference between the new study, STOP-CA, and a major prior study with a neutral effect published in 2022, was that STOP-CA “was powered for a major change” in cardiac function as the study’s primary outcome, a decline from baseline in left ventricular ejection fraction (LVEF) of at least 10% that also reduced ejection fraction to less than 55%.
“We can consider these medications [atorvastatin] for patients at higher risk for cardiac toxicity from anthracyclines, such as patients who receive a higher dose of an anthracycline, older patients, people with obesity, and women, commented Anita Deswal, MD, professor and chair of the department of cardiology at the University of Texas MD Anderson Cancer Center, Houston, who was not involved with the study.
A basis for an ‘important discussion’ with patients
“For patients receiving higher doses of anthracyclines, the STOP-CA trial says that whether to start a statin for cardiac protection is now an important discussion” for these patients to have with their treating clinicians. ”That was not the case before today,” commented Ronald M. Witteles, MD, a cardiologist and professor who specializes in cardio-oncology at Stanford (Calif.) University.
“For a patient being treated for lymphoma or for another cancer and treated with equal or higher anthracycline doses, such as patients with a sarcoma, this trial’s results at the very least warrant a discussion between physicians and patients to make the decision,” Dr. Witteles, who was not involved in the study, said in an interview. But he also cautioned that “whether an individual patient should take a statin in this scenario is still not a no-brainer. While the trial was positive, it was for an imaging rather than for a clinical endpoint.”
Experts noted that a similar study with the clinical endpoint of heart failure would require both many more randomized patients as well as much longer follow-up. STOP-CA was not powered for this endpoint. During its 12-month duration, a total of 11 patients developed heart failure, with no between group difference.
STOP-CA enrolled adults with lymphoma (Hodgkin or non-Hodgkin) and scheduled to undergo anthracycline treatment at eight U.S. centers and one in Canada, and excluded patients already on statin treatment or those for whom a statin was already indicated. Of the 300 enrolled patients, 286 had 12-month follow-up. Randomization assigned patients to receive either 40 mg daily of atorvastatin or placebo.
Their cumulative, median anthracycline dose was 300 mg/m2, which is typical for treating lymphoma, but higher than the typical dose use for patients with breast cancer. At baseline, average LVEF was 63%, and after 12 months this had declined to 59%. Forty-six of the 286 patients assessed after 12 months fulfilled the primary outcome of at least a 10–percentage point reduction from baseline in their LVEF and a decline in LVEF to less than 55%. Researchers used cardiac MR to assess LVEF at baseline, and in most patients at follow-up, but a minority of patients had their follow-up assessments by echocardiography because of logistical issues. Greater than 90% of patients were adherent to their assigned regimen.
Tripled incidence of cardiac dysfunction in placebo patients
The incidence of this outcome was 9% among the patients who received atorvastatin, and 22% among those on placebo, a significant difference. The calculated odds of the primary outcome was 2.9-fold more likely among the patients treated with placebo, compared with those who received atorvastatin, also a significant difference.
The study’s secondary outcome was patients who had at least a 5% drop from baseline in their LVEF and with a LVEF of less than 55% after 12 months. This outcome occurred in 13% of patients treated with atorvastatin and in 29% of those who received placebo, a significant difference.
The atorvastatin and placebo arms showed no significant differences in adverse events during the study, with roughly similar incidence rates for muscle pain, elevated liver enzymes, and renal failure. None of the enrolled patients developed myositis.
Atorvastatin treatment also produced an expected average 37% decline from baseline in levels of LDL cholesterol.
“This was a well-designed and important trial,” said Dr. Witteles. “Anthracyclines remain a mainstay of cancer therapies for a number of malignancies, such as lymphoma and sarcoma, and the cardiac side effects of development of cardiac dysfunction are unequivocally real.”
The importance of a clinically meaningful effect
The results especially contrast with the findings from the PREVENT study, published in 2022, which compared a daily, 40-mg atorvastatin treatment with placebo in 279 randomized patients with breast cancer and treated for 24 months. However, patients in PREVENT had a cumulative, median anthracycline dose of 240 mg/m2, and the study’s primary outcome was the average change from baseline in LVEF after 24 months of treatment, which was a reduction of 0.08 percentage points in the placebo arm, a nonsignificant difference.
In STOP-CA, the average change in LVEF from baseline was a 1–percentage point reduction in the placebo arm, compared with the atorvastatin-treated patients, a difference that was statistically significant, but “not clinically significant,” said Dr. Neilan, director of the cardio-oncology program at Massachusetts General Hospital, Boston. He cited the good fortune of the STOP-CA investigators when they received a recommendation from reviewers early on to design their study to track a clinically meaningful change in LVEF rather than just looking at the average overall change.
Dr. Deswal also noted that it is unlikely that future studies will examine the efficacy of a statin for preventing LVEF in patients across the range of cancers that are eligible for anthracycline treatment. As a result, she predicted that “we may have to extrapolate” the results from STOP-CA to patients with other cancer types.
STOP-CA received no commercial funding. Dr. Neilan has been a consultant for and received fees from Abbvie, Amgen, Bristol-Myers Squibb, CRC Oncology, Genentech, Roche, and Sanofi, and has received grant funding from AstraZeneca and Bristol Myers Squib. Dr. Deswal and Dr. Witteles had no relevant disclosures.
NEW ORLEANS – Atorvastatin treatment of patients with lymphoma undergoing treatment with an anthracycline significantly cut the incidence of incident cardiac dysfunction by about two-thirds during 12 months of treatment, in a multicenter, randomized trial with 300 enrolled patients.
“These data support the use of atorvastatin among patients with lymphoma being treated with anthracyclines where prevention of cardiac systolic dysfunction is important,” concluded Tomas G. Neilan, MD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
He highlighted that an important difference between the new study, STOP-CA, and a major prior study with a neutral effect published in 2022, was that STOP-CA “was powered for a major change” in cardiac function as the study’s primary outcome, a decline from baseline in left ventricular ejection fraction (LVEF) of at least 10% that also reduced ejection fraction to less than 55%.
“We can consider these medications [atorvastatin] for patients at higher risk for cardiac toxicity from anthracyclines, such as patients who receive a higher dose of an anthracycline, older patients, people with obesity, and women, commented Anita Deswal, MD, professor and chair of the department of cardiology at the University of Texas MD Anderson Cancer Center, Houston, who was not involved with the study.
A basis for an ‘important discussion’ with patients
“For patients receiving higher doses of anthracyclines, the STOP-CA trial says that whether to start a statin for cardiac protection is now an important discussion” for these patients to have with their treating clinicians. ”That was not the case before today,” commented Ronald M. Witteles, MD, a cardiologist and professor who specializes in cardio-oncology at Stanford (Calif.) University.
“For a patient being treated for lymphoma or for another cancer and treated with equal or higher anthracycline doses, such as patients with a sarcoma, this trial’s results at the very least warrant a discussion between physicians and patients to make the decision,” Dr. Witteles, who was not involved in the study, said in an interview. But he also cautioned that “whether an individual patient should take a statin in this scenario is still not a no-brainer. While the trial was positive, it was for an imaging rather than for a clinical endpoint.”
Experts noted that a similar study with the clinical endpoint of heart failure would require both many more randomized patients as well as much longer follow-up. STOP-CA was not powered for this endpoint. During its 12-month duration, a total of 11 patients developed heart failure, with no between group difference.
STOP-CA enrolled adults with lymphoma (Hodgkin or non-Hodgkin) and scheduled to undergo anthracycline treatment at eight U.S. centers and one in Canada, and excluded patients already on statin treatment or those for whom a statin was already indicated. Of the 300 enrolled patients, 286 had 12-month follow-up. Randomization assigned patients to receive either 40 mg daily of atorvastatin or placebo.
Their cumulative, median anthracycline dose was 300 mg/m2, which is typical for treating lymphoma, but higher than the typical dose use for patients with breast cancer. At baseline, average LVEF was 63%, and after 12 months this had declined to 59%. Forty-six of the 286 patients assessed after 12 months fulfilled the primary outcome of at least a 10–percentage point reduction from baseline in their LVEF and a decline in LVEF to less than 55%. Researchers used cardiac MR to assess LVEF at baseline, and in most patients at follow-up, but a minority of patients had their follow-up assessments by echocardiography because of logistical issues. Greater than 90% of patients were adherent to their assigned regimen.
Tripled incidence of cardiac dysfunction in placebo patients
The incidence of this outcome was 9% among the patients who received atorvastatin, and 22% among those on placebo, a significant difference. The calculated odds of the primary outcome was 2.9-fold more likely among the patients treated with placebo, compared with those who received atorvastatin, also a significant difference.
The study’s secondary outcome was patients who had at least a 5% drop from baseline in their LVEF and with a LVEF of less than 55% after 12 months. This outcome occurred in 13% of patients treated with atorvastatin and in 29% of those who received placebo, a significant difference.
The atorvastatin and placebo arms showed no significant differences in adverse events during the study, with roughly similar incidence rates for muscle pain, elevated liver enzymes, and renal failure. None of the enrolled patients developed myositis.
Atorvastatin treatment also produced an expected average 37% decline from baseline in levels of LDL cholesterol.
“This was a well-designed and important trial,” said Dr. Witteles. “Anthracyclines remain a mainstay of cancer therapies for a number of malignancies, such as lymphoma and sarcoma, and the cardiac side effects of development of cardiac dysfunction are unequivocally real.”
The importance of a clinically meaningful effect
The results especially contrast with the findings from the PREVENT study, published in 2022, which compared a daily, 40-mg atorvastatin treatment with placebo in 279 randomized patients with breast cancer and treated for 24 months. However, patients in PREVENT had a cumulative, median anthracycline dose of 240 mg/m2, and the study’s primary outcome was the average change from baseline in LVEF after 24 months of treatment, which was a reduction of 0.08 percentage points in the placebo arm, a nonsignificant difference.
In STOP-CA, the average change in LVEF from baseline was a 1–percentage point reduction in the placebo arm, compared with the atorvastatin-treated patients, a difference that was statistically significant, but “not clinically significant,” said Dr. Neilan, director of the cardio-oncology program at Massachusetts General Hospital, Boston. He cited the good fortune of the STOP-CA investigators when they received a recommendation from reviewers early on to design their study to track a clinically meaningful change in LVEF rather than just looking at the average overall change.
Dr. Deswal also noted that it is unlikely that future studies will examine the efficacy of a statin for preventing LVEF in patients across the range of cancers that are eligible for anthracycline treatment. As a result, she predicted that “we may have to extrapolate” the results from STOP-CA to patients with other cancer types.
STOP-CA received no commercial funding. Dr. Neilan has been a consultant for and received fees from Abbvie, Amgen, Bristol-Myers Squibb, CRC Oncology, Genentech, Roche, and Sanofi, and has received grant funding from AstraZeneca and Bristol Myers Squib. Dr. Deswal and Dr. Witteles had no relevant disclosures.
NEW ORLEANS – Atorvastatin treatment of patients with lymphoma undergoing treatment with an anthracycline significantly cut the incidence of incident cardiac dysfunction by about two-thirds during 12 months of treatment, in a multicenter, randomized trial with 300 enrolled patients.
“These data support the use of atorvastatin among patients with lymphoma being treated with anthracyclines where prevention of cardiac systolic dysfunction is important,” concluded Tomas G. Neilan, MD, at the joint scientific sessions of the American College of Cardiology and the World Heart Federation.
He highlighted that an important difference between the new study, STOP-CA, and a major prior study with a neutral effect published in 2022, was that STOP-CA “was powered for a major change” in cardiac function as the study’s primary outcome, a decline from baseline in left ventricular ejection fraction (LVEF) of at least 10% that also reduced ejection fraction to less than 55%.
“We can consider these medications [atorvastatin] for patients at higher risk for cardiac toxicity from anthracyclines, such as patients who receive a higher dose of an anthracycline, older patients, people with obesity, and women, commented Anita Deswal, MD, professor and chair of the department of cardiology at the University of Texas MD Anderson Cancer Center, Houston, who was not involved with the study.
A basis for an ‘important discussion’ with patients
“For patients receiving higher doses of anthracyclines, the STOP-CA trial says that whether to start a statin for cardiac protection is now an important discussion” for these patients to have with their treating clinicians. ”That was not the case before today,” commented Ronald M. Witteles, MD, a cardiologist and professor who specializes in cardio-oncology at Stanford (Calif.) University.
“For a patient being treated for lymphoma or for another cancer and treated with equal or higher anthracycline doses, such as patients with a sarcoma, this trial’s results at the very least warrant a discussion between physicians and patients to make the decision,” Dr. Witteles, who was not involved in the study, said in an interview. But he also cautioned that “whether an individual patient should take a statin in this scenario is still not a no-brainer. While the trial was positive, it was for an imaging rather than for a clinical endpoint.”
Experts noted that a similar study with the clinical endpoint of heart failure would require both many more randomized patients as well as much longer follow-up. STOP-CA was not powered for this endpoint. During its 12-month duration, a total of 11 patients developed heart failure, with no between group difference.
STOP-CA enrolled adults with lymphoma (Hodgkin or non-Hodgkin) and scheduled to undergo anthracycline treatment at eight U.S. centers and one in Canada, and excluded patients already on statin treatment or those for whom a statin was already indicated. Of the 300 enrolled patients, 286 had 12-month follow-up. Randomization assigned patients to receive either 40 mg daily of atorvastatin or placebo.
Their cumulative, median anthracycline dose was 300 mg/m2, which is typical for treating lymphoma, but higher than the typical dose use for patients with breast cancer. At baseline, average LVEF was 63%, and after 12 months this had declined to 59%. Forty-six of the 286 patients assessed after 12 months fulfilled the primary outcome of at least a 10–percentage point reduction from baseline in their LVEF and a decline in LVEF to less than 55%. Researchers used cardiac MR to assess LVEF at baseline, and in most patients at follow-up, but a minority of patients had their follow-up assessments by echocardiography because of logistical issues. Greater than 90% of patients were adherent to their assigned regimen.
Tripled incidence of cardiac dysfunction in placebo patients
The incidence of this outcome was 9% among the patients who received atorvastatin, and 22% among those on placebo, a significant difference. The calculated odds of the primary outcome was 2.9-fold more likely among the patients treated with placebo, compared with those who received atorvastatin, also a significant difference.
The study’s secondary outcome was patients who had at least a 5% drop from baseline in their LVEF and with a LVEF of less than 55% after 12 months. This outcome occurred in 13% of patients treated with atorvastatin and in 29% of those who received placebo, a significant difference.
The atorvastatin and placebo arms showed no significant differences in adverse events during the study, with roughly similar incidence rates for muscle pain, elevated liver enzymes, and renal failure. None of the enrolled patients developed myositis.
Atorvastatin treatment also produced an expected average 37% decline from baseline in levels of LDL cholesterol.
“This was a well-designed and important trial,” said Dr. Witteles. “Anthracyclines remain a mainstay of cancer therapies for a number of malignancies, such as lymphoma and sarcoma, and the cardiac side effects of development of cardiac dysfunction are unequivocally real.”
The importance of a clinically meaningful effect
The results especially contrast with the findings from the PREVENT study, published in 2022, which compared a daily, 40-mg atorvastatin treatment with placebo in 279 randomized patients with breast cancer and treated for 24 months. However, patients in PREVENT had a cumulative, median anthracycline dose of 240 mg/m2, and the study’s primary outcome was the average change from baseline in LVEF after 24 months of treatment, which was a reduction of 0.08 percentage points in the placebo arm, a nonsignificant difference.
In STOP-CA, the average change in LVEF from baseline was a 1–percentage point reduction in the placebo arm, compared with the atorvastatin-treated patients, a difference that was statistically significant, but “not clinically significant,” said Dr. Neilan, director of the cardio-oncology program at Massachusetts General Hospital, Boston. He cited the good fortune of the STOP-CA investigators when they received a recommendation from reviewers early on to design their study to track a clinically meaningful change in LVEF rather than just looking at the average overall change.
Dr. Deswal also noted that it is unlikely that future studies will examine the efficacy of a statin for preventing LVEF in patients across the range of cancers that are eligible for anthracycline treatment. As a result, she predicted that “we may have to extrapolate” the results from STOP-CA to patients with other cancer types.
STOP-CA received no commercial funding. Dr. Neilan has been a consultant for and received fees from Abbvie, Amgen, Bristol-Myers Squibb, CRC Oncology, Genentech, Roche, and Sanofi, and has received grant funding from AstraZeneca and Bristol Myers Squib. Dr. Deswal and Dr. Witteles had no relevant disclosures.
AT ACC 2023
Steep cost of surviving childhood HL: Epigenetic aging
AT ASH 2022 NEW ORLEANS
The research findings emerged from a study of nearly 500 individuals in their late 30s, of whom 215 were adult survivors of pediatric Hodgkin lymphoma (HL) and 282 were community controls.
The results showed that HL survivors had a higher epigenetic age relative to their chronological age, compared with controls, translating into epigenetic age acceleration over chronological age equivalent to a mean of 7.7 years.
In addition, this accelerated epigenetic aging in HL survivors was accompanied by neurocognitive deficits, including declines in visual-motor processing, short-term memory, verbal learning and recall, and executive function.
“We found that biologic aging is associated with long-term neurocognitive impairment in Hodgkin lymphoma survivors,” commented lead author AnnaLynn M. Williams, PhD, of the Wilmot Cancer Institute at the University of Rochester (N.Y.) “Specifically, we see strong and consistent associations with memory impairment, which suggests that biologic aging is likely related to cognitive aging.”
Dr. Williams presented the findings at the annual meeting of the American Society of Hematology.
“Our hope is that this biomarker may help us identify those survivors most at risk for early-onset cognitive aging and might actually help us gauge a preclinical response to interventions, so that we can see efficacy sooner than some other endpoints,” she said in a media briefing prior to presenting the data.
“This is an area that is very near and dear to my heart,” commented ASH President Jane N. Winter, MD, from Northwestern University, Chicago.
“Pediatricians have been very much wedded to very intensive therapies and intend to incorporate radiation more frequently in their treatment strategies for children than we do in adults,” she said. In addition, “we are very much focused on the long-term consequences of mediastinal radiation causing breast cancer in adults who were treated as young adults or children for Hodgkin lymphoma, but now we’re shedding a light on the neurocognitive deficits, which I think are underappreciated.”
Such HL therapies may exert a significant long-term impact on a patient population “that we otherwise cure,” Dr. Winter commented, pointing to a study by investigators in Germany that showed high unemployment levels among adult survivors of childhood HL, compared with the general population.
Also reacting to Dr. Williams’ findings, Catherine Bollard, MD, of the Center for Cancer and Immunology Research at Children’s National Research Institute in Washington, D.C., said: “My concern actually is that even today, in pediatrics, we’re still giving combined chemotherapy and radiation to the majority of the children with the more advanced disease, and that is not what is happening for the treatment of adult Hodgkin disease.”
She noted that there are now many immune-based therapies available for Hodgkin lymphoma that could soon obviate the need for chemotherapy.
Long-term complications
Dr. Williams and colleagues had previously reported that, compared with their healthy siblings, long-term survivors of HL had significantly higher risk (P < .05 for all comparisons) of neurocognitive impairment, anxiety, depression, unemployment, and impaired physical/mental quality of life.
In the current study, they looked specifically at epigenetic aging, and asked all participants to complete a comprehensive neuropsychological battery of tests.
The 215 trial participants who were survivors of pediatric HL came from the St Jude Lifetime Cohort. The mean patient age was 39, and the survivors were an average of 25 years out from their initial diagnosis.
The mean age of the 282 community controls was 36 years. Both the cohort and the controls were all European ancestry.
All participants provided a blood sample. The investigators performed genome-wide methylation studies on DNA derived from peripheral blood mononuclear cells (PBMC), and used the data to calculate epigenetic age according to a biomarker called DNAm PhenoAge. Also known as “Levine’s Clock,” this epigenetic biomarker of aging for life span and health span was developed by Morgan E. Levine, PhD, and colleagues at the University of California, Los Angeles, and other centers.
Dr. Williams and her team determined epigenetic age acceleration by calculating the difference between epigenetic and chronological age, with a higher epigenetic accelerated age suggesting an older biological age relative to the patient’s actual age.
As noted above, they found that HL survivors had a significantly higher epigenetic accelerated age, compared with controls, equivalent to a mean difference of 7.7 years (P < .001).
More than 80% of the survivors had some degree of accelerated aging, compared with only 23% of controls.
HL survivors with higher degrees (second and third tertiles) of accelerated aging had significantly worse visual-motor processing speed compared with survivors in the first (lowest) tertile, with survivors in the second tertile performing on average 0.42 standard deviations worse (P = .005) and those in the third tertile performing 0.55 SD worse (P < .001).
In addition, relative to first tertile survivors, those in the second and third tertiles performed worse on short-term memory, with a decrease of –0.42 SD (P = .011) and 0.59 SD (P < .001), respectively.
HL survivors in the third tertile performed worse than those in the other tertiles on measures of verbal learning (P =.007) and long-term verbal recall (P = .005), and those in the second or third tertiles had an average decline of 0.4 SD, compared with those in first tertile on verbal fluency, a measure of executive function.
The declines in neurocognitive measures among survivors were relatively small but clinically significant, Dr. Williams said, and were likely to prove troublesome for patients.
Dr. Williams added that she and her colleagues are currently compiling data on a comparison of neurocognitive scores between cohort members and control, for future publication, “but I can say that, in the majority of measures that are reported on, survivors do worse.”
The investigators are planning expansion of DNA methylation profiling in the St. Jude Lifetime Cohort and will follow survivors prospectively to look for changes in epigenetic acceleration and how those changes might predict who is most at risk for neurocognitive decline.
The study was supported by grants from the National Cancer Institute. Dr. Williams, Dr. Winter, and Dr. Bollard all reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ASH 2022 NEW ORLEANS
The research findings emerged from a study of nearly 500 individuals in their late 30s, of whom 215 were adult survivors of pediatric Hodgkin lymphoma (HL) and 282 were community controls.
The results showed that HL survivors had a higher epigenetic age relative to their chronological age, compared with controls, translating into epigenetic age acceleration over chronological age equivalent to a mean of 7.7 years.
In addition, this accelerated epigenetic aging in HL survivors was accompanied by neurocognitive deficits, including declines in visual-motor processing, short-term memory, verbal learning and recall, and executive function.
“We found that biologic aging is associated with long-term neurocognitive impairment in Hodgkin lymphoma survivors,” commented lead author AnnaLynn M. Williams, PhD, of the Wilmot Cancer Institute at the University of Rochester (N.Y.) “Specifically, we see strong and consistent associations with memory impairment, which suggests that biologic aging is likely related to cognitive aging.”
Dr. Williams presented the findings at the annual meeting of the American Society of Hematology.
“Our hope is that this biomarker may help us identify those survivors most at risk for early-onset cognitive aging and might actually help us gauge a preclinical response to interventions, so that we can see efficacy sooner than some other endpoints,” she said in a media briefing prior to presenting the data.
“This is an area that is very near and dear to my heart,” commented ASH President Jane N. Winter, MD, from Northwestern University, Chicago.
“Pediatricians have been very much wedded to very intensive therapies and intend to incorporate radiation more frequently in their treatment strategies for children than we do in adults,” she said. In addition, “we are very much focused on the long-term consequences of mediastinal radiation causing breast cancer in adults who were treated as young adults or children for Hodgkin lymphoma, but now we’re shedding a light on the neurocognitive deficits, which I think are underappreciated.”
Such HL therapies may exert a significant long-term impact on a patient population “that we otherwise cure,” Dr. Winter commented, pointing to a study by investigators in Germany that showed high unemployment levels among adult survivors of childhood HL, compared with the general population.
Also reacting to Dr. Williams’ findings, Catherine Bollard, MD, of the Center for Cancer and Immunology Research at Children’s National Research Institute in Washington, D.C., said: “My concern actually is that even today, in pediatrics, we’re still giving combined chemotherapy and radiation to the majority of the children with the more advanced disease, and that is not what is happening for the treatment of adult Hodgkin disease.”
She noted that there are now many immune-based therapies available for Hodgkin lymphoma that could soon obviate the need for chemotherapy.
Long-term complications
Dr. Williams and colleagues had previously reported that, compared with their healthy siblings, long-term survivors of HL had significantly higher risk (P < .05 for all comparisons) of neurocognitive impairment, anxiety, depression, unemployment, and impaired physical/mental quality of life.
In the current study, they looked specifically at epigenetic aging, and asked all participants to complete a comprehensive neuropsychological battery of tests.
The 215 trial participants who were survivors of pediatric HL came from the St Jude Lifetime Cohort. The mean patient age was 39, and the survivors were an average of 25 years out from their initial diagnosis.
The mean age of the 282 community controls was 36 years. Both the cohort and the controls were all European ancestry.
All participants provided a blood sample. The investigators performed genome-wide methylation studies on DNA derived from peripheral blood mononuclear cells (PBMC), and used the data to calculate epigenetic age according to a biomarker called DNAm PhenoAge. Also known as “Levine’s Clock,” this epigenetic biomarker of aging for life span and health span was developed by Morgan E. Levine, PhD, and colleagues at the University of California, Los Angeles, and other centers.
Dr. Williams and her team determined epigenetic age acceleration by calculating the difference between epigenetic and chronological age, with a higher epigenetic accelerated age suggesting an older biological age relative to the patient’s actual age.
As noted above, they found that HL survivors had a significantly higher epigenetic accelerated age, compared with controls, equivalent to a mean difference of 7.7 years (P < .001).
More than 80% of the survivors had some degree of accelerated aging, compared with only 23% of controls.
HL survivors with higher degrees (second and third tertiles) of accelerated aging had significantly worse visual-motor processing speed compared with survivors in the first (lowest) tertile, with survivors in the second tertile performing on average 0.42 standard deviations worse (P = .005) and those in the third tertile performing 0.55 SD worse (P < .001).
In addition, relative to first tertile survivors, those in the second and third tertiles performed worse on short-term memory, with a decrease of –0.42 SD (P = .011) and 0.59 SD (P < .001), respectively.
HL survivors in the third tertile performed worse than those in the other tertiles on measures of verbal learning (P =.007) and long-term verbal recall (P = .005), and those in the second or third tertiles had an average decline of 0.4 SD, compared with those in first tertile on verbal fluency, a measure of executive function.
The declines in neurocognitive measures among survivors were relatively small but clinically significant, Dr. Williams said, and were likely to prove troublesome for patients.
Dr. Williams added that she and her colleagues are currently compiling data on a comparison of neurocognitive scores between cohort members and control, for future publication, “but I can say that, in the majority of measures that are reported on, survivors do worse.”
The investigators are planning expansion of DNA methylation profiling in the St. Jude Lifetime Cohort and will follow survivors prospectively to look for changes in epigenetic acceleration and how those changes might predict who is most at risk for neurocognitive decline.
The study was supported by grants from the National Cancer Institute. Dr. Williams, Dr. Winter, and Dr. Bollard all reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ASH 2022 NEW ORLEANS
The research findings emerged from a study of nearly 500 individuals in their late 30s, of whom 215 were adult survivors of pediatric Hodgkin lymphoma (HL) and 282 were community controls.
The results showed that HL survivors had a higher epigenetic age relative to their chronological age, compared with controls, translating into epigenetic age acceleration over chronological age equivalent to a mean of 7.7 years.
In addition, this accelerated epigenetic aging in HL survivors was accompanied by neurocognitive deficits, including declines in visual-motor processing, short-term memory, verbal learning and recall, and executive function.
“We found that biologic aging is associated with long-term neurocognitive impairment in Hodgkin lymphoma survivors,” commented lead author AnnaLynn M. Williams, PhD, of the Wilmot Cancer Institute at the University of Rochester (N.Y.) “Specifically, we see strong and consistent associations with memory impairment, which suggests that biologic aging is likely related to cognitive aging.”
Dr. Williams presented the findings at the annual meeting of the American Society of Hematology.
“Our hope is that this biomarker may help us identify those survivors most at risk for early-onset cognitive aging and might actually help us gauge a preclinical response to interventions, so that we can see efficacy sooner than some other endpoints,” she said in a media briefing prior to presenting the data.
“This is an area that is very near and dear to my heart,” commented ASH President Jane N. Winter, MD, from Northwestern University, Chicago.
“Pediatricians have been very much wedded to very intensive therapies and intend to incorporate radiation more frequently in their treatment strategies for children than we do in adults,” she said. In addition, “we are very much focused on the long-term consequences of mediastinal radiation causing breast cancer in adults who were treated as young adults or children for Hodgkin lymphoma, but now we’re shedding a light on the neurocognitive deficits, which I think are underappreciated.”
Such HL therapies may exert a significant long-term impact on a patient population “that we otherwise cure,” Dr. Winter commented, pointing to a study by investigators in Germany that showed high unemployment levels among adult survivors of childhood HL, compared with the general population.
Also reacting to Dr. Williams’ findings, Catherine Bollard, MD, of the Center for Cancer and Immunology Research at Children’s National Research Institute in Washington, D.C., said: “My concern actually is that even today, in pediatrics, we’re still giving combined chemotherapy and radiation to the majority of the children with the more advanced disease, and that is not what is happening for the treatment of adult Hodgkin disease.”
She noted that there are now many immune-based therapies available for Hodgkin lymphoma that could soon obviate the need for chemotherapy.
Long-term complications
Dr. Williams and colleagues had previously reported that, compared with their healthy siblings, long-term survivors of HL had significantly higher risk (P < .05 for all comparisons) of neurocognitive impairment, anxiety, depression, unemployment, and impaired physical/mental quality of life.
In the current study, they looked specifically at epigenetic aging, and asked all participants to complete a comprehensive neuropsychological battery of tests.
The 215 trial participants who were survivors of pediatric HL came from the St Jude Lifetime Cohort. The mean patient age was 39, and the survivors were an average of 25 years out from their initial diagnosis.
The mean age of the 282 community controls was 36 years. Both the cohort and the controls were all European ancestry.
All participants provided a blood sample. The investigators performed genome-wide methylation studies on DNA derived from peripheral blood mononuclear cells (PBMC), and used the data to calculate epigenetic age according to a biomarker called DNAm PhenoAge. Also known as “Levine’s Clock,” this epigenetic biomarker of aging for life span and health span was developed by Morgan E. Levine, PhD, and colleagues at the University of California, Los Angeles, and other centers.
Dr. Williams and her team determined epigenetic age acceleration by calculating the difference between epigenetic and chronological age, with a higher epigenetic accelerated age suggesting an older biological age relative to the patient’s actual age.
As noted above, they found that HL survivors had a significantly higher epigenetic accelerated age, compared with controls, equivalent to a mean difference of 7.7 years (P < .001).
More than 80% of the survivors had some degree of accelerated aging, compared with only 23% of controls.
HL survivors with higher degrees (second and third tertiles) of accelerated aging had significantly worse visual-motor processing speed compared with survivors in the first (lowest) tertile, with survivors in the second tertile performing on average 0.42 standard deviations worse (P = .005) and those in the third tertile performing 0.55 SD worse (P < .001).
In addition, relative to first tertile survivors, those in the second and third tertiles performed worse on short-term memory, with a decrease of –0.42 SD (P = .011) and 0.59 SD (P < .001), respectively.
HL survivors in the third tertile performed worse than those in the other tertiles on measures of verbal learning (P =.007) and long-term verbal recall (P = .005), and those in the second or third tertiles had an average decline of 0.4 SD, compared with those in first tertile on verbal fluency, a measure of executive function.
The declines in neurocognitive measures among survivors were relatively small but clinically significant, Dr. Williams said, and were likely to prove troublesome for patients.
Dr. Williams added that she and her colleagues are currently compiling data on a comparison of neurocognitive scores between cohort members and control, for future publication, “but I can say that, in the majority of measures that are reported on, survivors do worse.”
The investigators are planning expansion of DNA methylation profiling in the St. Jude Lifetime Cohort and will follow survivors prospectively to look for changes in epigenetic acceleration and how those changes might predict who is most at risk for neurocognitive decline.
The study was supported by grants from the National Cancer Institute. Dr. Williams, Dr. Winter, and Dr. Bollard all reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
ASH 2022: New clinical data challenge long-held assumptions
The conference starts in New Orleans on Saturday, Dec. 10, , but a sample of what is to come was given last week in a preview media briefing, moderated by Mikkael A. Sekeres, MD, from the University of Miami. Dr. Sekeres, who recently authored a book on the FDA and how it regulates drug approvals, also serves as chair of the ASH Committee on Communications.
“Feeding Our Patients Gruel”
Dr. Sekeres expressed particular excitement about a multicenter randomized trial done in Italy. It showed that patients who have neutropenia after a stem cell transplant need not be required to eat a bland diet (Abstract 169).
“We for years have been essentially feeding our patients gruel in the hospital, and these are folks who have to be hospitalized for a stem cell transplant or in my case – I’m a leukemia specialist – for acute leukemia, for 4-6 weeks. The neutropenic diet consists of the blandest food you can imagine, with nothing to really spice it up.”
He noted that a neutropenic diet is so unpalatable that family members often sneak food into patient rooms, and “for years we’ve never seen adverse outcomes in any of those folks who instead of having mashed potatoes and oatmeal ate a corned beef sandwich for dinner.”
Now, the results from this trial “actually give us license to finally allow patients to eat whatever they want,” Dr. Sekeres said.
Practice-changing data
ASH experts pointed to two more presentations that are expected to change clinical practice. These include the finding that high-dose methotrexate does not reduce the risk for central nervous system relapse in children with acute lymphoblastic leukemia and lymphoblastic lymphoma (Abstract 214).
Another new study that seems to defy conventional wisdom showed that in adults with relapsed or refractory acute myeloid leukemia, intensive chemotherapy in an effort to achieve remission before a stem cell transplant did not result in better outcomes, compared with sequential conditioning and immediate transplant (Abstract 4).
Premature aging in HL survivors
ASH President Jane N. Winter, MD, from Northwestern University, Chicago, who also spoke at the briefing, highlighted a study that followed adult survivors of pediatric Hodgkin lymphoma. This study, from St. Jude Children’s Research Hospital in Memphis and the Wilmot Cancer Institute at the University of Rochester (N.Y), found that these adult survivors are at significantly elevated risk for epigenetic age acceleration accompanied by neurocognitive deficits when compared with controls (Abstract 902).
“This is an area that is very near and dear to my heart,” she said. “Much of my career has focused on reducing the therapy to reduce the long-term consequences of treatments. Pediatricians have been very much wedded to very intensive therapies and tend to incorporate radiation more commonly in their treatment strategies for children than we do in adults.”
Dr. Winter noted that, although clinicians focus primarily on the link between mediastinal radiation and long-term adverse events such as breast cancer, “now we’re shedding a light on the neurocognitive deficits, which I think are underappreciated. Being able to screen for this impact of our treatment, and perhaps then develop strategies to deal with it or prevent it, will have very wide-ranging impact.”
Inherited thrombophilia and miscarriage
Cynthia E. Dunbar, MD, chief of the translational stem cell biology branch at the National Heart, Lung, and Blood Institute in Bethesda, Md., who also spoke at the briefing, said that one of the abstracts most important to her practice is a study concerning pregnancy. It showed that low-molecular-weight heparin did not prevent miscarriage in pregnant women with confirmed inherited thrombophilia who had two or more prior pregnancy losses, compared with standard surveillance (Abstract LBA-5).
“This is not my field at all; on the other hand, as a hematologist and a woman, that’s what my emails in the middle of the night and my panicked phone calls are often about. Once somebody has one miscarriage, especially if they feel like they’re already over 30 and the clock is ticking, there’s a huge emphasis and a huge amount of pressure on obstetricians to basically work up for everything, kind of a shotgun [approach],” she said.
Those workups may reveal genetic mutations that are associated with mild elevations in risk for clotting. As a result, some pregnant women are put on anticoagulation therapy, which can cause complications for both pregnancy and delivery. These study findings don’t solve the problem of spontaneous pregnancy loss, but they at least rule out inherited thrombophilia as a preventable cause of miscarriages, Dr. Dunbar said.
Another potentially practice-changing abstract is a study showing that, in younger adults with mantle cell lymphoma, the addition of the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) to induction therapy and as maintenance with or without autologous stem cell transplant had strong efficacy and acceptable toxicity (Abstract 1).
“The results show that the ibrutinib-containing regimen without transplant is at least as good as the current standard of care with transplant.” Dr. Winter said. “Additional follow-up will be required to show definitively that an autotransplant is unnecessary if ibrutinib is included in this treatment regimen.”
A version of this article first appeared on Medscape.com.
The conference starts in New Orleans on Saturday, Dec. 10, , but a sample of what is to come was given last week in a preview media briefing, moderated by Mikkael A. Sekeres, MD, from the University of Miami. Dr. Sekeres, who recently authored a book on the FDA and how it regulates drug approvals, also serves as chair of the ASH Committee on Communications.
“Feeding Our Patients Gruel”
Dr. Sekeres expressed particular excitement about a multicenter randomized trial done in Italy. It showed that patients who have neutropenia after a stem cell transplant need not be required to eat a bland diet (Abstract 169).
“We for years have been essentially feeding our patients gruel in the hospital, and these are folks who have to be hospitalized for a stem cell transplant or in my case – I’m a leukemia specialist – for acute leukemia, for 4-6 weeks. The neutropenic diet consists of the blandest food you can imagine, with nothing to really spice it up.”
He noted that a neutropenic diet is so unpalatable that family members often sneak food into patient rooms, and “for years we’ve never seen adverse outcomes in any of those folks who instead of having mashed potatoes and oatmeal ate a corned beef sandwich for dinner.”
Now, the results from this trial “actually give us license to finally allow patients to eat whatever they want,” Dr. Sekeres said.
Practice-changing data
ASH experts pointed to two more presentations that are expected to change clinical practice. These include the finding that high-dose methotrexate does not reduce the risk for central nervous system relapse in children with acute lymphoblastic leukemia and lymphoblastic lymphoma (Abstract 214).
Another new study that seems to defy conventional wisdom showed that in adults with relapsed or refractory acute myeloid leukemia, intensive chemotherapy in an effort to achieve remission before a stem cell transplant did not result in better outcomes, compared with sequential conditioning and immediate transplant (Abstract 4).
Premature aging in HL survivors
ASH President Jane N. Winter, MD, from Northwestern University, Chicago, who also spoke at the briefing, highlighted a study that followed adult survivors of pediatric Hodgkin lymphoma. This study, from St. Jude Children’s Research Hospital in Memphis and the Wilmot Cancer Institute at the University of Rochester (N.Y), found that these adult survivors are at significantly elevated risk for epigenetic age acceleration accompanied by neurocognitive deficits when compared with controls (Abstract 902).
“This is an area that is very near and dear to my heart,” she said. “Much of my career has focused on reducing the therapy to reduce the long-term consequences of treatments. Pediatricians have been very much wedded to very intensive therapies and tend to incorporate radiation more commonly in their treatment strategies for children than we do in adults.”
Dr. Winter noted that, although clinicians focus primarily on the link between mediastinal radiation and long-term adverse events such as breast cancer, “now we’re shedding a light on the neurocognitive deficits, which I think are underappreciated. Being able to screen for this impact of our treatment, and perhaps then develop strategies to deal with it or prevent it, will have very wide-ranging impact.”
Inherited thrombophilia and miscarriage
Cynthia E. Dunbar, MD, chief of the translational stem cell biology branch at the National Heart, Lung, and Blood Institute in Bethesda, Md., who also spoke at the briefing, said that one of the abstracts most important to her practice is a study concerning pregnancy. It showed that low-molecular-weight heparin did not prevent miscarriage in pregnant women with confirmed inherited thrombophilia who had two or more prior pregnancy losses, compared with standard surveillance (Abstract LBA-5).
“This is not my field at all; on the other hand, as a hematologist and a woman, that’s what my emails in the middle of the night and my panicked phone calls are often about. Once somebody has one miscarriage, especially if they feel like they’re already over 30 and the clock is ticking, there’s a huge emphasis and a huge amount of pressure on obstetricians to basically work up for everything, kind of a shotgun [approach],” she said.
Those workups may reveal genetic mutations that are associated with mild elevations in risk for clotting. As a result, some pregnant women are put on anticoagulation therapy, which can cause complications for both pregnancy and delivery. These study findings don’t solve the problem of spontaneous pregnancy loss, but they at least rule out inherited thrombophilia as a preventable cause of miscarriages, Dr. Dunbar said.
Another potentially practice-changing abstract is a study showing that, in younger adults with mantle cell lymphoma, the addition of the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) to induction therapy and as maintenance with or without autologous stem cell transplant had strong efficacy and acceptable toxicity (Abstract 1).
“The results show that the ibrutinib-containing regimen without transplant is at least as good as the current standard of care with transplant.” Dr. Winter said. “Additional follow-up will be required to show definitively that an autotransplant is unnecessary if ibrutinib is included in this treatment regimen.”
A version of this article first appeared on Medscape.com.
The conference starts in New Orleans on Saturday, Dec. 10, , but a sample of what is to come was given last week in a preview media briefing, moderated by Mikkael A. Sekeres, MD, from the University of Miami. Dr. Sekeres, who recently authored a book on the FDA and how it regulates drug approvals, also serves as chair of the ASH Committee on Communications.
“Feeding Our Patients Gruel”
Dr. Sekeres expressed particular excitement about a multicenter randomized trial done in Italy. It showed that patients who have neutropenia after a stem cell transplant need not be required to eat a bland diet (Abstract 169).
“We for years have been essentially feeding our patients gruel in the hospital, and these are folks who have to be hospitalized for a stem cell transplant or in my case – I’m a leukemia specialist – for acute leukemia, for 4-6 weeks. The neutropenic diet consists of the blandest food you can imagine, with nothing to really spice it up.”
He noted that a neutropenic diet is so unpalatable that family members often sneak food into patient rooms, and “for years we’ve never seen adverse outcomes in any of those folks who instead of having mashed potatoes and oatmeal ate a corned beef sandwich for dinner.”
Now, the results from this trial “actually give us license to finally allow patients to eat whatever they want,” Dr. Sekeres said.
Practice-changing data
ASH experts pointed to two more presentations that are expected to change clinical practice. These include the finding that high-dose methotrexate does not reduce the risk for central nervous system relapse in children with acute lymphoblastic leukemia and lymphoblastic lymphoma (Abstract 214).
Another new study that seems to defy conventional wisdom showed that in adults with relapsed or refractory acute myeloid leukemia, intensive chemotherapy in an effort to achieve remission before a stem cell transplant did not result in better outcomes, compared with sequential conditioning and immediate transplant (Abstract 4).
Premature aging in HL survivors
ASH President Jane N. Winter, MD, from Northwestern University, Chicago, who also spoke at the briefing, highlighted a study that followed adult survivors of pediatric Hodgkin lymphoma. This study, from St. Jude Children’s Research Hospital in Memphis and the Wilmot Cancer Institute at the University of Rochester (N.Y), found that these adult survivors are at significantly elevated risk for epigenetic age acceleration accompanied by neurocognitive deficits when compared with controls (Abstract 902).
“This is an area that is very near and dear to my heart,” she said. “Much of my career has focused on reducing the therapy to reduce the long-term consequences of treatments. Pediatricians have been very much wedded to very intensive therapies and tend to incorporate radiation more commonly in their treatment strategies for children than we do in adults.”
Dr. Winter noted that, although clinicians focus primarily on the link between mediastinal radiation and long-term adverse events such as breast cancer, “now we’re shedding a light on the neurocognitive deficits, which I think are underappreciated. Being able to screen for this impact of our treatment, and perhaps then develop strategies to deal with it or prevent it, will have very wide-ranging impact.”
Inherited thrombophilia and miscarriage
Cynthia E. Dunbar, MD, chief of the translational stem cell biology branch at the National Heart, Lung, and Blood Institute in Bethesda, Md., who also spoke at the briefing, said that one of the abstracts most important to her practice is a study concerning pregnancy. It showed that low-molecular-weight heparin did not prevent miscarriage in pregnant women with confirmed inherited thrombophilia who had two or more prior pregnancy losses, compared with standard surveillance (Abstract LBA-5).
“This is not my field at all; on the other hand, as a hematologist and a woman, that’s what my emails in the middle of the night and my panicked phone calls are often about. Once somebody has one miscarriage, especially if they feel like they’re already over 30 and the clock is ticking, there’s a huge emphasis and a huge amount of pressure on obstetricians to basically work up for everything, kind of a shotgun [approach],” she said.
Those workups may reveal genetic mutations that are associated with mild elevations in risk for clotting. As a result, some pregnant women are put on anticoagulation therapy, which can cause complications for both pregnancy and delivery. These study findings don’t solve the problem of spontaneous pregnancy loss, but they at least rule out inherited thrombophilia as a preventable cause of miscarriages, Dr. Dunbar said.
Another potentially practice-changing abstract is a study showing that, in younger adults with mantle cell lymphoma, the addition of the Bruton’s tyrosine kinase inhibitor ibrutinib (Imbruvica) to induction therapy and as maintenance with or without autologous stem cell transplant had strong efficacy and acceptable toxicity (Abstract 1).
“The results show that the ibrutinib-containing regimen without transplant is at least as good as the current standard of care with transplant.” Dr. Winter said. “Additional follow-up will be required to show definitively that an autotransplant is unnecessary if ibrutinib is included in this treatment regimen.”
A version of this article first appeared on Medscape.com.
FROM ASH 2022
Drug shortages plague hematology, but preparedness helps
Just before he took a call from a reporter asking about the impact of drug shortages in hematology, Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, had spent an hour on the phone overseeing his institution’s response to a hematology drug shortage. The chemotherapy drug fludarabine, used to treat chronic lymphocytic leukemia, was in short supply.
“There are 5 different manufacturers, but none of them have had drug available over the past 2 weeks,” Dr. Greene said. “We’re trying to chase some emergency supplies to be able to continue treatment for patients who’ve had their treatments initiated and planned.”
Over the past several years, this predicament has become common at hematology clinics across the country. In fact, management of scarce medication resources has become a significant part of Dr. Greene’s workload these days, as critical drugs fail to show up on time or manufacturer supplies run low at his hospital in Memphis.
This shortage of hematology drugs got a new dose of national attention, thanks to a recent episode of CBS News’ “60 Minutes.” Through interviews with physicians and parents of children who suddenly could not get vital medications, the report highlighted the recent shortage of another leukemia drug, vincristine.
“As a cancer mom, we shouldn’t be fighting for our children to get a drug that is needed,” Cyndi Valenta was quoted as saying. She recalled that when the shortage began in 2019, her 13-year-old son, a leukemia patient at Loma Linda (Calif.) University Hospital, felt frightened. Ms. Valenta said she felt a “gut-wrenching feeling of just fear and anger.” They were finally able to get doses of the drug after launching a social media campaign.
Such drug shortages are especially widespread in oncology and hematology, according to a survey of oncology pharmacists at 68 organizations nationwide. Published in the May 2022 issue of Oncology Practice, the study showed that 63% of institutions reported one or more drug shortages every month, with a 34% increase in 2019, compared with 2018. Treatment delays, reduced doses, or alternative regimens were reported by 75% of respondents, the authors wrote.
The pharmacists surveyed between May 2019 and July 2020 were asked about the three most hard-to-get chemotherapy and supportive care agents. Vincristine topped the list, followed by vinblastine, IVIG, leucovorin, and BCG, as well as difficult-to-obtain ropine, erwinia asparaginase, etoposide, and leuprolide. Several of these drugs are used to treat conditions such as lymphoma and leukemia.
Eighty-two percent of respondents reported shortages of decitabine (IV), often used as part of a cocktail with vinblastine and other drugs to treat Hodgkin lymphoma.
The reasons for drug shortages are varied. The CBS News report declared that “pharmaceutical companies have stopped producing many life-saving generic drugs because they make too little profit,” and it suggested that the federal government isn’t doing enough.
But government action actually might be making a difference. According to the FDA, the number of new drug shortages has fallen dramatically from 250 in 2011 to 41 in 2021, and the number of prevented drug shortages rose from nearly 200 to more than 300 over that same period. Still, the number of ongoing drug shortages has risen from around 40 in 2017 to about 80 in 2021.
Reasons for the paucity of certain drugs are often unclear. In a June 12, 2022 post, for example, the American Society of Health-System Pharmacists’ drug shortage database noted that the chemotherapy drug fludarabine was in short supply and provided details about when some of the 5 manufacturers expected to have it available. (This is the shortage that Dr. Greene was trying to manage.) But 4 of the 5 manufacturers “did not provide a reason,” and the fifth blamed manufacturing delays.
“There’s a lot of closely held trade secrets that hinder the ability to share good information,” said Dr. Greene. To make things more complicated, shipping times are often unreliable. “The product doesn’t show up today, we place another order. Sometimes it will show up tomorrow, sometimes it doesn’t,” he said. “If you’re not tracking it carefully, you deplete your own supply.”
Patients’ families have grown used to dealing with drug shortages, and “they’re less quick to blame personnel at our institution.”
How can hematologists cope with this issue? “The best thing in the immediate term is to advocate for their hospital to have a pharmacist dedicated to shortage monitoring and taking proactive steps to obviate shortages,” hematologist/oncologist Andrew Hantel, MD, an instructor at Dana-Farber Cancer Institute, Harvard Medical School, Boston, said in an interview.
“We have ongoing communications with other large cancer centers and the FDA to recognize shortages early and develop plans to make sure we stay ahead of them,” Dr. Hantel said. “Most often this involves assessing supply, use rates, alternative manufacturers, and additional measures the Food and Drug Administration can take (for example, importation), and occasionally working with clinical teams to see if other medications are feasible alternatives.”
If a drug is unavailable, it can also be helpful to discuss alternative approaches. “We did not have any frank shortages of vincristine,” Dr. Hantel said, “but we did focus on conservation measures and considered different ethically appropriate ways to distribute vincristine if there was a point at which we did not have enough for everyone who needed it.”
If a drug is in short supply, options can include delaying treatment, giving an alternative, or providing the rest of the regimen without the scarce drug, he said. In a 2021 report in The Lancet Hematology, Dr. Hantel and his colleagues offered “model solutions for ethical allocation during cancer medicine shortages.”
The authors of the May 2022 drug-shortage report highlighted an alternative regimen in hematology. They noted that manufacturing delays have limited the supply of dacarbazine, used for Hodgkin lymphoma. Due to the current shortages, they wrote, clinicians are considering the use of escalated bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, replacing dacarbazine with procarbazine and using the doxorubicin, bleomycin, vinblastine, procarbazine, and prednisone regimen, or replacing dacarbazine with cyclophosphamide.
Dr. Greene emphasized the importance of tracking the news and the drug shortage websites run by the FDA and the American Society of Health-System Pharmacists.
It’s also crucial to have a good relationship with your wholesaler, he added, and to communicate about these problems within your facility. At his hospital, the pharmaceutical staff holds a multi-disciplinary meeting at least weekly to discuss the supply of medications. As he put it, “it’s a challenging environment.”
Dr. Greene and Dr. Hantel reported no relevant disclosures.
Just before he took a call from a reporter asking about the impact of drug shortages in hematology, Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, had spent an hour on the phone overseeing his institution’s response to a hematology drug shortage. The chemotherapy drug fludarabine, used to treat chronic lymphocytic leukemia, was in short supply.
“There are 5 different manufacturers, but none of them have had drug available over the past 2 weeks,” Dr. Greene said. “We’re trying to chase some emergency supplies to be able to continue treatment for patients who’ve had their treatments initiated and planned.”
Over the past several years, this predicament has become common at hematology clinics across the country. In fact, management of scarce medication resources has become a significant part of Dr. Greene’s workload these days, as critical drugs fail to show up on time or manufacturer supplies run low at his hospital in Memphis.
This shortage of hematology drugs got a new dose of national attention, thanks to a recent episode of CBS News’ “60 Minutes.” Through interviews with physicians and parents of children who suddenly could not get vital medications, the report highlighted the recent shortage of another leukemia drug, vincristine.
“As a cancer mom, we shouldn’t be fighting for our children to get a drug that is needed,” Cyndi Valenta was quoted as saying. She recalled that when the shortage began in 2019, her 13-year-old son, a leukemia patient at Loma Linda (Calif.) University Hospital, felt frightened. Ms. Valenta said she felt a “gut-wrenching feeling of just fear and anger.” They were finally able to get doses of the drug after launching a social media campaign.
Such drug shortages are especially widespread in oncology and hematology, according to a survey of oncology pharmacists at 68 organizations nationwide. Published in the May 2022 issue of Oncology Practice, the study showed that 63% of institutions reported one or more drug shortages every month, with a 34% increase in 2019, compared with 2018. Treatment delays, reduced doses, or alternative regimens were reported by 75% of respondents, the authors wrote.
The pharmacists surveyed between May 2019 and July 2020 were asked about the three most hard-to-get chemotherapy and supportive care agents. Vincristine topped the list, followed by vinblastine, IVIG, leucovorin, and BCG, as well as difficult-to-obtain ropine, erwinia asparaginase, etoposide, and leuprolide. Several of these drugs are used to treat conditions such as lymphoma and leukemia.
Eighty-two percent of respondents reported shortages of decitabine (IV), often used as part of a cocktail with vinblastine and other drugs to treat Hodgkin lymphoma.
The reasons for drug shortages are varied. The CBS News report declared that “pharmaceutical companies have stopped producing many life-saving generic drugs because they make too little profit,” and it suggested that the federal government isn’t doing enough.
But government action actually might be making a difference. According to the FDA, the number of new drug shortages has fallen dramatically from 250 in 2011 to 41 in 2021, and the number of prevented drug shortages rose from nearly 200 to more than 300 over that same period. Still, the number of ongoing drug shortages has risen from around 40 in 2017 to about 80 in 2021.
Reasons for the paucity of certain drugs are often unclear. In a June 12, 2022 post, for example, the American Society of Health-System Pharmacists’ drug shortage database noted that the chemotherapy drug fludarabine was in short supply and provided details about when some of the 5 manufacturers expected to have it available. (This is the shortage that Dr. Greene was trying to manage.) But 4 of the 5 manufacturers “did not provide a reason,” and the fifth blamed manufacturing delays.
“There’s a lot of closely held trade secrets that hinder the ability to share good information,” said Dr. Greene. To make things more complicated, shipping times are often unreliable. “The product doesn’t show up today, we place another order. Sometimes it will show up tomorrow, sometimes it doesn’t,” he said. “If you’re not tracking it carefully, you deplete your own supply.”
Patients’ families have grown used to dealing with drug shortages, and “they’re less quick to blame personnel at our institution.”
How can hematologists cope with this issue? “The best thing in the immediate term is to advocate for their hospital to have a pharmacist dedicated to shortage monitoring and taking proactive steps to obviate shortages,” hematologist/oncologist Andrew Hantel, MD, an instructor at Dana-Farber Cancer Institute, Harvard Medical School, Boston, said in an interview.
“We have ongoing communications with other large cancer centers and the FDA to recognize shortages early and develop plans to make sure we stay ahead of them,” Dr. Hantel said. “Most often this involves assessing supply, use rates, alternative manufacturers, and additional measures the Food and Drug Administration can take (for example, importation), and occasionally working with clinical teams to see if other medications are feasible alternatives.”
If a drug is unavailable, it can also be helpful to discuss alternative approaches. “We did not have any frank shortages of vincristine,” Dr. Hantel said, “but we did focus on conservation measures and considered different ethically appropriate ways to distribute vincristine if there was a point at which we did not have enough for everyone who needed it.”
If a drug is in short supply, options can include delaying treatment, giving an alternative, or providing the rest of the regimen without the scarce drug, he said. In a 2021 report in The Lancet Hematology, Dr. Hantel and his colleagues offered “model solutions for ethical allocation during cancer medicine shortages.”
The authors of the May 2022 drug-shortage report highlighted an alternative regimen in hematology. They noted that manufacturing delays have limited the supply of dacarbazine, used for Hodgkin lymphoma. Due to the current shortages, they wrote, clinicians are considering the use of escalated bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, replacing dacarbazine with procarbazine and using the doxorubicin, bleomycin, vinblastine, procarbazine, and prednisone regimen, or replacing dacarbazine with cyclophosphamide.
Dr. Greene emphasized the importance of tracking the news and the drug shortage websites run by the FDA and the American Society of Health-System Pharmacists.
It’s also crucial to have a good relationship with your wholesaler, he added, and to communicate about these problems within your facility. At his hospital, the pharmaceutical staff holds a multi-disciplinary meeting at least weekly to discuss the supply of medications. As he put it, “it’s a challenging environment.”
Dr. Greene and Dr. Hantel reported no relevant disclosures.
Just before he took a call from a reporter asking about the impact of drug shortages in hematology, Bill Greene, PharmD, chief pharmaceutical officer at St. Jude Children’s Research Hospital, had spent an hour on the phone overseeing his institution’s response to a hematology drug shortage. The chemotherapy drug fludarabine, used to treat chronic lymphocytic leukemia, was in short supply.
“There are 5 different manufacturers, but none of them have had drug available over the past 2 weeks,” Dr. Greene said. “We’re trying to chase some emergency supplies to be able to continue treatment for patients who’ve had their treatments initiated and planned.”
Over the past several years, this predicament has become common at hematology clinics across the country. In fact, management of scarce medication resources has become a significant part of Dr. Greene’s workload these days, as critical drugs fail to show up on time or manufacturer supplies run low at his hospital in Memphis.
This shortage of hematology drugs got a new dose of national attention, thanks to a recent episode of CBS News’ “60 Minutes.” Through interviews with physicians and parents of children who suddenly could not get vital medications, the report highlighted the recent shortage of another leukemia drug, vincristine.
“As a cancer mom, we shouldn’t be fighting for our children to get a drug that is needed,” Cyndi Valenta was quoted as saying. She recalled that when the shortage began in 2019, her 13-year-old son, a leukemia patient at Loma Linda (Calif.) University Hospital, felt frightened. Ms. Valenta said she felt a “gut-wrenching feeling of just fear and anger.” They were finally able to get doses of the drug after launching a social media campaign.
Such drug shortages are especially widespread in oncology and hematology, according to a survey of oncology pharmacists at 68 organizations nationwide. Published in the May 2022 issue of Oncology Practice, the study showed that 63% of institutions reported one or more drug shortages every month, with a 34% increase in 2019, compared with 2018. Treatment delays, reduced doses, or alternative regimens were reported by 75% of respondents, the authors wrote.
The pharmacists surveyed between May 2019 and July 2020 were asked about the three most hard-to-get chemotherapy and supportive care agents. Vincristine topped the list, followed by vinblastine, IVIG, leucovorin, and BCG, as well as difficult-to-obtain ropine, erwinia asparaginase, etoposide, and leuprolide. Several of these drugs are used to treat conditions such as lymphoma and leukemia.
Eighty-two percent of respondents reported shortages of decitabine (IV), often used as part of a cocktail with vinblastine and other drugs to treat Hodgkin lymphoma.
The reasons for drug shortages are varied. The CBS News report declared that “pharmaceutical companies have stopped producing many life-saving generic drugs because they make too little profit,” and it suggested that the federal government isn’t doing enough.
But government action actually might be making a difference. According to the FDA, the number of new drug shortages has fallen dramatically from 250 in 2011 to 41 in 2021, and the number of prevented drug shortages rose from nearly 200 to more than 300 over that same period. Still, the number of ongoing drug shortages has risen from around 40 in 2017 to about 80 in 2021.
Reasons for the paucity of certain drugs are often unclear. In a June 12, 2022 post, for example, the American Society of Health-System Pharmacists’ drug shortage database noted that the chemotherapy drug fludarabine was in short supply and provided details about when some of the 5 manufacturers expected to have it available. (This is the shortage that Dr. Greene was trying to manage.) But 4 of the 5 manufacturers “did not provide a reason,” and the fifth blamed manufacturing delays.
“There’s a lot of closely held trade secrets that hinder the ability to share good information,” said Dr. Greene. To make things more complicated, shipping times are often unreliable. “The product doesn’t show up today, we place another order. Sometimes it will show up tomorrow, sometimes it doesn’t,” he said. “If you’re not tracking it carefully, you deplete your own supply.”
Patients’ families have grown used to dealing with drug shortages, and “they’re less quick to blame personnel at our institution.”
How can hematologists cope with this issue? “The best thing in the immediate term is to advocate for their hospital to have a pharmacist dedicated to shortage monitoring and taking proactive steps to obviate shortages,” hematologist/oncologist Andrew Hantel, MD, an instructor at Dana-Farber Cancer Institute, Harvard Medical School, Boston, said in an interview.
“We have ongoing communications with other large cancer centers and the FDA to recognize shortages early and develop plans to make sure we stay ahead of them,” Dr. Hantel said. “Most often this involves assessing supply, use rates, alternative manufacturers, and additional measures the Food and Drug Administration can take (for example, importation), and occasionally working with clinical teams to see if other medications are feasible alternatives.”
If a drug is unavailable, it can also be helpful to discuss alternative approaches. “We did not have any frank shortages of vincristine,” Dr. Hantel said, “but we did focus on conservation measures and considered different ethically appropriate ways to distribute vincristine if there was a point at which we did not have enough for everyone who needed it.”
If a drug is in short supply, options can include delaying treatment, giving an alternative, or providing the rest of the regimen without the scarce drug, he said. In a 2021 report in The Lancet Hematology, Dr. Hantel and his colleagues offered “model solutions for ethical allocation during cancer medicine shortages.”
The authors of the May 2022 drug-shortage report highlighted an alternative regimen in hematology. They noted that manufacturing delays have limited the supply of dacarbazine, used for Hodgkin lymphoma. Due to the current shortages, they wrote, clinicians are considering the use of escalated bleomycin, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, replacing dacarbazine with procarbazine and using the doxorubicin, bleomycin, vinblastine, procarbazine, and prednisone regimen, or replacing dacarbazine with cyclophosphamide.
Dr. Greene emphasized the importance of tracking the news and the drug shortage websites run by the FDA and the American Society of Health-System Pharmacists.
It’s also crucial to have a good relationship with your wholesaler, he added, and to communicate about these problems within your facility. At his hospital, the pharmaceutical staff holds a multi-disciplinary meeting at least weekly to discuss the supply of medications. As he put it, “it’s a challenging environment.”
Dr. Greene and Dr. Hantel reported no relevant disclosures.