AVAHO

High oral cavity doses of radiotherapy are associated with greater risk of taste dysfunction in patients with head and neck cancer, finds a new study from JAMA Otolaryngology–Head & Neck Surgery.

Taste dysfunction can affect up to 90% of patients undergoing radiotherapy for head and neck cancer. While the ability to taste usually returns after the treatment concludes, some patients can still feel the lingering effects of radiotherapy on taste function long after the treatment concludes. It can lead to weight loss and dry mouth which can, in turn, negatively affect quality of life.

“Taste dysfunction has profound effects on quality of life in patients with head and neck cancer, and the oral cavity dose could be significantly lower with modern radiotherapy techniques,” wrote the researchers, who were led by Miao-Fen Chen, MD, PhD, of Chang Gung University, Taoyuan City, Taiwan. “This study provides useful dose constraints of the oral cavity that may be associated with reduced taste dysfunction.”

Degradation of taste is an important quality of life factor for head and neck cancer patients. A 2021 systematic review published in the journal Radiotherapy and Oncology found that acute taste dysfunction affected 96% of patients as measured objectively, and 79% as measured subjectively. While most patients recover an estimated 23-53% of patients experience long-term dysfunction.

In 2019, a study published in the journal Chemical Senses found that 31% of head and neck cancer patients had long-term changes to taste at 27 months after intensity-modulated radiotherapy (IMRT), with dysfunction associated with glossectomy and oral cavity radiation doses greater than 50 Gy, but the study only used one quality of life subjective measure to evaluate taste function.

In the new JAMA study, researchers reported the results of a longitudinal using the whole-mouth solution method for basic tastes, including salt, sweet, sour, and bitter.
 

Study methodology

The study included 87 patients (mean age, 58 years; 90% men) who were enrolled between 2017 and 2020 from a single hospital. 45 patients received primary intensity-modulated radiotherapy and 42 received postoperative radiotherapy. 78 patients received volumetric arc therapy, and 9 received intensity-modulated radiotherapy. The radiotherapy was directed to minimize the effect on the parotid glands and oral cavity.

Researchers measured taste dysfunction according to detection thresholds based on solutions with different concentrations. After moving the solution around the mouth and spitting it out, patients were asked to identify taste components. Following a water rinse, they tested a solution with another concentration of taste components. A number was assigned based on the concentration level they were able to detect, with nigher numbers indicating greater sensitivity.

Two to four weeks after initiation of radiotherapy, there were drops in taste scores for salt (4.7 to 1.4), sweet (4.2 to 1.8), sour (4.5 to 2.3), and bitter (4.7 to 1.2). 1 week after radiotherapy, those mean scores increased to 2.6, 2.6, 2.9, and 2.3 respectively. Over the following 3 months, mean scores reflected general recovery to near preradiotherapy levels (4.2, 3.9, 4.1, and 4.0, respectively). At 6 months and 1 year, the scores were equivalent to preradiotherapy levels.

Objective taste tests were performed on 81 participants. 33.3% had taste dysfunction 6 months after radiotherapy. 6 months after, 8.9% had taste dysfunction. At 3 months following radiotherapy, taste dysfunction was associated with an oral cavity mean dose of 4,000 cGy or higher (relative risk, 2.87; 95% confidence interval, 1.21-6.81) or 5,000 cGy or higher (RR, 2.04; 95% CI, 1.12-3.72). At 6 months, taste dysfunction was predicted by glossectomy (RR, 5.63; 95% CI, 1.12-28.15) and oral cavity mean dose 5,000 cGy or greater (RR, 7.79; 95% CI, 0.93-64.92).

The researchers quantified the relationship between mean oral cavity dose and probability of developing taste dysfunction at 3 and 6 months. 3 months after radiotherapy, 25 Gy predicted a 15% chance, 38 Gy predicted a 25% chance, and 60 Gy predicted a 50% chance. At 6 months, the numbers were 57, 60, and 64 Gy.

The study was limited by being conducted at a single center and its small sample size, and it recruited patients varied significantly in treatment modality and disease subtype.

High oral cavity doses of radiotherapy are associated with greater risk of taste dysfunction in patients with head and neck cancer, finds a new study from JAMA Otolaryngology–Head & Neck Surgery.

Taste dysfunction can affect up to 90% of patients undergoing radiotherapy for head and neck cancer. While the ability to taste usually returns after the treatment concludes, some patients can still feel the lingering effects of radiotherapy on taste function long after the treatment concludes. It can lead to weight loss and dry mouth which can, in turn, negatively affect quality of life.

“Taste dysfunction has profound effects on quality of life in patients with head and neck cancer, and the oral cavity dose could be significantly lower with modern radiotherapy techniques,” wrote the researchers, who were led by Miao-Fen Chen, MD, PhD, of Chang Gung University, Taoyuan City, Taiwan. “This study provides useful dose constraints of the oral cavity that may be associated with reduced taste dysfunction.”

Degradation of taste is an important quality of life factor for head and neck cancer patients. A 2021 systematic review published in the journal Radiotherapy and Oncology found that acute taste dysfunction affected 96% of patients as measured objectively, and 79% as measured subjectively. While most patients recover an estimated 23-53% of patients experience long-term dysfunction.

In 2019, a study published in the journal Chemical Senses found that 31% of head and neck cancer patients had long-term changes to taste at 27 months after intensity-modulated radiotherapy (IMRT), with dysfunction associated with glossectomy and oral cavity radiation doses greater than 50 Gy, but the study only used one quality of life subjective measure to evaluate taste function.

In the new JAMA study, researchers reported the results of a longitudinal using the whole-mouth solution method for basic tastes, including salt, sweet, sour, and bitter.
 

Study methodology

The study included 87 patients (mean age, 58 years; 90% men) who were enrolled between 2017 and 2020 from a single hospital. 45 patients received primary intensity-modulated radiotherapy and 42 received postoperative radiotherapy. 78 patients received volumetric arc therapy, and 9 received intensity-modulated radiotherapy. The radiotherapy was directed to minimize the effect on the parotid glands and oral cavity.

Researchers measured taste dysfunction according to detection thresholds based on solutions with different concentrations. After moving the solution around the mouth and spitting it out, patients were asked to identify taste components. Following a water rinse, they tested a solution with another concentration of taste components. A number was assigned based on the concentration level they were able to detect, with nigher numbers indicating greater sensitivity.

Two to four weeks after initiation of radiotherapy, there were drops in taste scores for salt (4.7 to 1.4), sweet (4.2 to 1.8), sour (4.5 to 2.3), and bitter (4.7 to 1.2). 1 week after radiotherapy, those mean scores increased to 2.6, 2.6, 2.9, and 2.3 respectively. Over the following 3 months, mean scores reflected general recovery to near preradiotherapy levels (4.2, 3.9, 4.1, and 4.0, respectively). At 6 months and 1 year, the scores were equivalent to preradiotherapy levels.

Objective taste tests were performed on 81 participants. 33.3% had taste dysfunction 6 months after radiotherapy. 6 months after, 8.9% had taste dysfunction. At 3 months following radiotherapy, taste dysfunction was associated with an oral cavity mean dose of 4,000 cGy or higher (relative risk, 2.87; 95% confidence interval, 1.21-6.81) or 5,000 cGy or higher (RR, 2.04; 95% CI, 1.12-3.72). At 6 months, taste dysfunction was predicted by glossectomy (RR, 5.63; 95% CI, 1.12-28.15) and oral cavity mean dose 5,000 cGy or greater (RR, 7.79; 95% CI, 0.93-64.92).

The researchers quantified the relationship between mean oral cavity dose and probability of developing taste dysfunction at 3 and 6 months. 3 months after radiotherapy, 25 Gy predicted a 15% chance, 38 Gy predicted a 25% chance, and 60 Gy predicted a 50% chance. At 6 months, the numbers were 57, 60, and 64 Gy.

The study was limited by being conducted at a single center and its small sample size, and it recruited patients varied significantly in treatment modality and disease subtype.

High oral cavity doses of radiotherapy are associated with greater risk of taste dysfunction in patients with head and neck cancer, finds a new study from JAMA Otolaryngology–Head & Neck Surgery.

Taste dysfunction can affect up to 90% of patients undergoing radiotherapy for head and neck cancer. While the ability to taste usually returns after the treatment concludes, some patients can still feel the lingering effects of radiotherapy on taste function long after the treatment concludes. It can lead to weight loss and dry mouth which can, in turn, negatively affect quality of life.

“Taste dysfunction has profound effects on quality of life in patients with head and neck cancer, and the oral cavity dose could be significantly lower with modern radiotherapy techniques,” wrote the researchers, who were led by Miao-Fen Chen, MD, PhD, of Chang Gung University, Taoyuan City, Taiwan. “This study provides useful dose constraints of the oral cavity that may be associated with reduced taste dysfunction.”

Degradation of taste is an important quality of life factor for head and neck cancer patients. A 2021 systematic review published in the journal Radiotherapy and Oncology found that acute taste dysfunction affected 96% of patients as measured objectively, and 79% as measured subjectively. While most patients recover an estimated 23-53% of patients experience long-term dysfunction.

In 2019, a study published in the journal Chemical Senses found that 31% of head and neck cancer patients had long-term changes to taste at 27 months after intensity-modulated radiotherapy (IMRT), with dysfunction associated with glossectomy and oral cavity radiation doses greater than 50 Gy, but the study only used one quality of life subjective measure to evaluate taste function.

In the new JAMA study, researchers reported the results of a longitudinal using the whole-mouth solution method for basic tastes, including salt, sweet, sour, and bitter.
 

Study methodology

The study included 87 patients (mean age, 58 years; 90% men) who were enrolled between 2017 and 2020 from a single hospital. 45 patients received primary intensity-modulated radiotherapy and 42 received postoperative radiotherapy. 78 patients received volumetric arc therapy, and 9 received intensity-modulated radiotherapy. The radiotherapy was directed to minimize the effect on the parotid glands and oral cavity.

Researchers measured taste dysfunction according to detection thresholds based on solutions with different concentrations. After moving the solution around the mouth and spitting it out, patients were asked to identify taste components. Following a water rinse, they tested a solution with another concentration of taste components. A number was assigned based on the concentration level they were able to detect, with nigher numbers indicating greater sensitivity.

Two to four weeks after initiation of radiotherapy, there were drops in taste scores for salt (4.7 to 1.4), sweet (4.2 to 1.8), sour (4.5 to 2.3), and bitter (4.7 to 1.2). 1 week after radiotherapy, those mean scores increased to 2.6, 2.6, 2.9, and 2.3 respectively. Over the following 3 months, mean scores reflected general recovery to near preradiotherapy levels (4.2, 3.9, 4.1, and 4.0, respectively). At 6 months and 1 year, the scores were equivalent to preradiotherapy levels.

Objective taste tests were performed on 81 participants. 33.3% had taste dysfunction 6 months after radiotherapy. 6 months after, 8.9% had taste dysfunction. At 3 months following radiotherapy, taste dysfunction was associated with an oral cavity mean dose of 4,000 cGy or higher (relative risk, 2.87; 95% confidence interval, 1.21-6.81) or 5,000 cGy or higher (RR, 2.04; 95% CI, 1.12-3.72). At 6 months, taste dysfunction was predicted by glossectomy (RR, 5.63; 95% CI, 1.12-28.15) and oral cavity mean dose 5,000 cGy or greater (RR, 7.79; 95% CI, 0.93-64.92).

The researchers quantified the relationship between mean oral cavity dose and probability of developing taste dysfunction at 3 and 6 months. 3 months after radiotherapy, 25 Gy predicted a 15% chance, 38 Gy predicted a 25% chance, and 60 Gy predicted a 50% chance. At 6 months, the numbers were 57, 60, and 64 Gy.

The study was limited by being conducted at a single center and its small sample size, and it recruited patients varied significantly in treatment modality and disease subtype.

New devices that use artificial intelligence (AI) to diagnose skin cancer – such as smartphone apps – have been popping up over the past few years, but there is some concern over the accuracy of these tools.

So far, the U.S. Food and Drug Administration has cleared two devices. Both are computer-aided skin lesion classification devices meant to help clinicians assess cases of suspected melanoma.

Both were given a class III designation. That classification is intended for products that are considered to have a high risk of harm because of flawed design or implementation. Many such devices are under development, and there has been a proposal to include these devices in class II, which is less restrictive.

The FDA turned to one of its expert panels for advice. At a meeting held on Aug. 29, experts on the panel offered differing views and expressed concerns about the accuracy of these devices.

This was the second day of meetings of the general and plastic surgery devices panel of the FDA’s Medical Devices Advisory Committee. On the previous day, the panel held a wide-ranging discussion about expanding use of skin lesion analyzer devices.

The FDA sought the expert panel’s advice concerning a field that appears to be heating up quickly after relatively quiet times.

Two devices have been approved by the FDA so far, but only one is still being promoted – SciBase AB’s Nevisense. The Swedish company announced in May 2020 that it had received FDA approval for Nevisense 3.0, the third generation of their Nevisense system for early melanoma detection, an AI-based point-of-care system for the noninvasive evaluation of irregular moles.

The other device, known as MelaFind, was acquired by Strata Skin Sciences, but the company said in 2017 that it discontinued research and development, sales, and support activity related to the device, according to a filing with the Securities and Exchange Commission.

But there’s been a swell in recent years in the number of publications related to the use of AI and machine learning, which could give rise to new tools for aiding in the diagnosis of skin conditions, including cancer. Google is among the companies that are involved in these efforts.

So, the FDA asked the expert panel to discuss a series of questions related to how the agency should weigh the risks of computer-aided devices for melanoma diagnosis. The agency also asked the panel to provide feedback about how well risks associated with such devices and tools might be managed and to offer suggestions.

The discussion at the July 29 meeting spun beyond narrow questions about reclassification of the current class III devices to topics involving emerging technology, such as efforts to apply AI to dermatology.

“Innovation continues. Medical device developers are anxious to plan how they might be able to develop the level of evidence that would meet your expectations” for future products, Binita Ashar, MD, a senior official in FDA’s Center for Devices and Radiological Health, told the panel.


 

Company CEO backs tougher regulation

Simon Grant, the chief executive of SciBase, which markets Nevisense, the first and only skin cancer–detecting device currently on the U.S. market, sought to make a case for sticking with the tougher class III regulations.

Speaking during the public comment session, Mr. Grant said switching to class II designations would weaken the standards used in clearing products that analyze skin lesions so as to put patients at risk.

Under the FDA’s rules, the agency designates as class III devices that present potential unreasonable risk of illness or injury. Only about 10% of devices fall into this category. Such devices include implantable pacemakers and breast implants, as well as SciBase’s Nevisense.

About 43% of medical devices fall into the class II category, which includes powered wheelchairs and some pregnancy test kits, the FDA website says.

Class I medical devices pose minimal potential for harm and tend to be simpler in design. These include enema kits and elastic bandages, the FDA says.

Mr. Grant told the meeting that in his career he has worked on two class III products and about 20 class II products. (He had previously worked at medical startups Synectics Medical and Neoventa, as well as established multinationals such as Medtronic.)

“I can tell you that – practically – the FDA has many fewer sticks and much less control when it comes to class II devices,” he said. He offered an example of a manufacturer of a class II device having more latitude in making small changes to products without notifying the FDA.

In his hypothetical example, such a change could have unintended consequences, and “with AI systems, small changes can result in large and nonlinear or even random effects,” Mr. Grant said. “But it’s too late if the product is on the market and the harm has already occurred,” he said.

The American Society for Dermatologic Surgery Association also protested the reclassifying of approved computer-aided melanoma detection class III devices.

In a statement posted on the FDA website as part of the materials for the meeting, the ASDSA raised a series of concerns about the prospects of expanded U.S. use of tools for assisting in diagnosing melanoma, including ones that would be marketed to consumers.

“To the extent that algorithms and devices for patient self-diagnosis of skin lesions are already widely available, they should be required to include detailed disclaimers that include that they are for entertainment and educational purposes and not a diagnostic device, that they are not approved by dermatologists or a recognized medical regulatory authority for self-diagnosis,” the ASDSA said.

Devices and algorithms in screening tools “are not highly regulated and remain unproven. They may result in wrong diagnoses, missed diagnoses, or over- or underdiagnosis,” the ASDSA added. “Both patients at low risk and those at high risk are better served by scheduling an in-person examination with a board-certified dermatologist, who can also help them determine the appropriate future skin screening schedule that is most appropriate for them.”

 

‘Stepping stone’

However, there is strong consumer demand for better information about skin conditions, and many patients face hurdles in going to dermatologists.

Google research has shown that consumers are seeking “a stepping stone” between the information they can easily find online and what they could get from a medical professional, said Lily Peng, MD, PhD, a director of product management for the health AI team at Google. Dr. Peng was a scheduled presenter at the July 29 meeting.

Consumers often are looking for more information on common conditions such as acne and poison ivy, and they sometimes face challenges in getting access to clinicians, she said.

“There are many unmet needs for consumers experiencing skin issues, many of which are lower-acuity conditions. There’s a big opportunity to increase accessibility and relevance of health journeys for consumers,” Dr. Peng said. “We have heard from consumers that they would like to have a self-help tool for nonserious conditions so they can decide when to seek medical attention.”

Dr. Peng’s presentation was not directly related to the question of class II or class III designation for existing products. Instead, her talk served as a glimpse into the work already underway in creating apps and tools for consumers.

Google researchers have published a number of studies in recent years about the use of AI to improve dermatology diagnosis.

A 2020 article reported on Google’s test of a form of AI known as deep learning system (DLS) to provide a differential diagnosis of skin conditions. On 963 validation cases, where a rotating panel of three board-certified dermatologists defined the reference standard, the DLS was noninferior to six other dermatologists and was superior to six primary care physicians (PCPs) and six nurse practitioners (NPs), according to a summary of the article.

A 2021 report published in JAMA Network Open said that use of an AI tool was associated with a higher agreement rate with dermatologists’ reference diagnoses for both PCPs and NPs.

In a 2021 blog post, Google scientists wrote that their AI model that powers a tool for checking skin conditions had earned European clearance, known as a CE mark, as a class I medical device.

SkinVision has an app that the company says “is available worldwide (with the exception of the USA and Canada).” The firm’s website includes a link where people in the United States and Canada can sign up for notifications about when SkinVision will be available in these nations. 


 

‘Not ready for prime time’

The FDA panel did not cast formal votes at the July 29 meeting. Rather, the members engaged in broad discussions about risks and potential benefits of new tools for aiding in the detection of skin cancer.

Among the key issues discussed was a question of whether the FDA could impose requirements and restrictions, known as special controls, to provide “reasonable assurance of safety and effectiveness” for computer-aided devices that provide adjunctive diagnostic information to dermatologists about lesions suspicious for melanoma.

Among the potential special controls would be clinical performance testing in regards to rates of the sensitivity (true-positive rate) and specificity (true-negative rate).

The FDA could also look at requirements on software validation and verification and cybersecurity testing, as well as directions on labeling so as to mitigate risk.

Dermatologists serving on the panel called for caution in proceeding with steps that would make it easier for companies to market tools for aiding in melanoma diagnosis than it would be within the class III framework used for MelaFind and Nevisense.

Many expressed concerns about the need to design studies that would answer questions about how well new tools could accurately identify concerning lesions.

The phrase “not ready for prime time” was used at least three times during the discussion.

FDA panelist Maral Skelsey, MD, a skin cancer specialist from Chevy Chase, Maryland, said that over the years, she had used both Nevisense and MelaFind.

She said she had found MelaFind “unusable,” owing in large part to the high number of false positives it generated. The device also was limited as to where on patients’ bodies it could be used.

However, she spoke with enthusiasm about the prospects for better devices to aid in diagnosis of skin lesions. “It’s an area where we’re on the verge, and we really need these devices. There’s a need for patients to be able to examine themselves, for nondermatologists to be able to assess lesions,” Dr. Skelsey said.

But this field is “just not ready for prime time” yet, even with special controls, Dr. Skelsey said. To loosen approval standards too quickly could be a “detriment to what’s coming down the pipeline,” she said.

“It’s harmful to things that are likely to be around the corner,” she said.

FDA panelist Renata Block, PA-C, who works in a Chicago dermatology practice, pressed for maintaining a class III designation. “We are not ready for prime time yet, though the data that is coming down the pipeline on what we have is quite exciting,” Ms. Block said.

FDA panelist Karla V. Ballman, PhD, a statistician from Weill Cornell Medicine, New York, said there would need to be a clear standard for clinical performance before proceeding toward reclassification of devices for aid in detecting melanoma. “I just don’t think it’s ready for prime time at this point and should remain in class III,” she said.

But there was support from some panelists for the idea of a lower bar for clearance, combined with special controls to ensure patient safety.

In expressing her view, FDA panelist Katalin Roth, MD, JD, professor of medicine, George Washington University, Washington, said she was an outlier in her support for the agency’s view that these risks could be managed and that future tools could allow more patients to take a step on the pathway toward critical diagnoses.

“I deal with a lot of people with cancer as a palliative care physician,” Dr. Roth said. “I think what we’re missing here is the issue of time. Melanoma is a terrible disease, and missing the diagnosis is a terrible thing, but I think special controls would be sufficient to counter the concerns of my colleagues on the committee.”

The FDA’s Dr. Ashar ended the meeting with questions posed to one panelist, Veronica Rotemberg, MD, PhD, a dermatologist at Memorial Sloan Kettering Cancer Center in New York.

Dr. Rotemberg has for years been working in the field of research on developing AI and other computer-based tools for detecting and diagnosing melanoma, the deadliest form of skin cancer.

She has been publicly skeptical of the performance of commercial apps that scan moles and other lesions and that claim to identify which are cancerous. A May blog post on the Memorial Sloan Kettering website highlighted a recent British Journal of Dermatology article in which Dr. Rotemberg and coauthors reported on their evaluations of commercial apps. They judged them to be on average only 59% accurate, the blog post said.

However, during an earlier discussion at the meeting, she had spoken more positively about the prospects for using special controls in the near term to mitigate risk, although she said she would have a “very long list” of these requirements.

In the closing exchange with Dr. Ashar, Dr. Rotemberg outlined steps that could potentially ensure the safe use of tools to aid in melanoma screening. These included a need for postmarketing surveillance, which would require evaluation over time of algorithms used in tools meant to detect skin cancer.

“We need to have a mechanism for sampling,” Dr. Rotemberg said. “Most of our data is electronic now anyway, so comparing an algorithm and performance with biopsy results should not be that challenging.”

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

New devices that use artificial intelligence (AI) to diagnose skin cancer – such as smartphone apps – have been popping up over the past few years, but there is some concern over the accuracy of these tools.

So far, the U.S. Food and Drug Administration has cleared two devices. Both are computer-aided skin lesion classification devices meant to help clinicians assess cases of suspected melanoma.

Both were given a class III designation. That classification is intended for products that are considered to have a high risk of harm because of flawed design or implementation. Many such devices are under development, and there has been a proposal to include these devices in class II, which is less restrictive.

The FDA turned to one of its expert panels for advice. At a meeting held on Aug. 29, experts on the panel offered differing views and expressed concerns about the accuracy of these devices.

This was the second day of meetings of the general and plastic surgery devices panel of the FDA’s Medical Devices Advisory Committee. On the previous day, the panel held a wide-ranging discussion about expanding use of skin lesion analyzer devices.

The FDA sought the expert panel’s advice concerning a field that appears to be heating up quickly after relatively quiet times.

Two devices have been approved by the FDA so far, but only one is still being promoted – SciBase AB’s Nevisense. The Swedish company announced in May 2020 that it had received FDA approval for Nevisense 3.0, the third generation of their Nevisense system for early melanoma detection, an AI-based point-of-care system for the noninvasive evaluation of irregular moles.

The other device, known as MelaFind, was acquired by Strata Skin Sciences, but the company said in 2017 that it discontinued research and development, sales, and support activity related to the device, according to a filing with the Securities and Exchange Commission.

But there’s been a swell in recent years in the number of publications related to the use of AI and machine learning, which could give rise to new tools for aiding in the diagnosis of skin conditions, including cancer. Google is among the companies that are involved in these efforts.

So, the FDA asked the expert panel to discuss a series of questions related to how the agency should weigh the risks of computer-aided devices for melanoma diagnosis. The agency also asked the panel to provide feedback about how well risks associated with such devices and tools might be managed and to offer suggestions.

The discussion at the July 29 meeting spun beyond narrow questions about reclassification of the current class III devices to topics involving emerging technology, such as efforts to apply AI to dermatology.

“Innovation continues. Medical device developers are anxious to plan how they might be able to develop the level of evidence that would meet your expectations” for future products, Binita Ashar, MD, a senior official in FDA’s Center for Devices and Radiological Health, told the panel.


 

Company CEO backs tougher regulation

Simon Grant, the chief executive of SciBase, which markets Nevisense, the first and only skin cancer–detecting device currently on the U.S. market, sought to make a case for sticking with the tougher class III regulations.

Speaking during the public comment session, Mr. Grant said switching to class II designations would weaken the standards used in clearing products that analyze skin lesions so as to put patients at risk.

Under the FDA’s rules, the agency designates as class III devices that present potential unreasonable risk of illness or injury. Only about 10% of devices fall into this category. Such devices include implantable pacemakers and breast implants, as well as SciBase’s Nevisense.

About 43% of medical devices fall into the class II category, which includes powered wheelchairs and some pregnancy test kits, the FDA website says.

Class I medical devices pose minimal potential for harm and tend to be simpler in design. These include enema kits and elastic bandages, the FDA says.

Mr. Grant told the meeting that in his career he has worked on two class III products and about 20 class II products. (He had previously worked at medical startups Synectics Medical and Neoventa, as well as established multinationals such as Medtronic.)

“I can tell you that – practically – the FDA has many fewer sticks and much less control when it comes to class II devices,” he said. He offered an example of a manufacturer of a class II device having more latitude in making small changes to products without notifying the FDA.

In his hypothetical example, such a change could have unintended consequences, and “with AI systems, small changes can result in large and nonlinear or even random effects,” Mr. Grant said. “But it’s too late if the product is on the market and the harm has already occurred,” he said.

The American Society for Dermatologic Surgery Association also protested the reclassifying of approved computer-aided melanoma detection class III devices.

In a statement posted on the FDA website as part of the materials for the meeting, the ASDSA raised a series of concerns about the prospects of expanded U.S. use of tools for assisting in diagnosing melanoma, including ones that would be marketed to consumers.

“To the extent that algorithms and devices for patient self-diagnosis of skin lesions are already widely available, they should be required to include detailed disclaimers that include that they are for entertainment and educational purposes and not a diagnostic device, that they are not approved by dermatologists or a recognized medical regulatory authority for self-diagnosis,” the ASDSA said.

Devices and algorithms in screening tools “are not highly regulated and remain unproven. They may result in wrong diagnoses, missed diagnoses, or over- or underdiagnosis,” the ASDSA added. “Both patients at low risk and those at high risk are better served by scheduling an in-person examination with a board-certified dermatologist, who can also help them determine the appropriate future skin screening schedule that is most appropriate for them.”

 

‘Stepping stone’

However, there is strong consumer demand for better information about skin conditions, and many patients face hurdles in going to dermatologists.

Google research has shown that consumers are seeking “a stepping stone” between the information they can easily find online and what they could get from a medical professional, said Lily Peng, MD, PhD, a director of product management for the health AI team at Google. Dr. Peng was a scheduled presenter at the July 29 meeting.

Consumers often are looking for more information on common conditions such as acne and poison ivy, and they sometimes face challenges in getting access to clinicians, she said.

“There are many unmet needs for consumers experiencing skin issues, many of which are lower-acuity conditions. There’s a big opportunity to increase accessibility and relevance of health journeys for consumers,” Dr. Peng said. “We have heard from consumers that they would like to have a self-help tool for nonserious conditions so they can decide when to seek medical attention.”

Dr. Peng’s presentation was not directly related to the question of class II or class III designation for existing products. Instead, her talk served as a glimpse into the work already underway in creating apps and tools for consumers.

Google researchers have published a number of studies in recent years about the use of AI to improve dermatology diagnosis.

A 2020 article reported on Google’s test of a form of AI known as deep learning system (DLS) to provide a differential diagnosis of skin conditions. On 963 validation cases, where a rotating panel of three board-certified dermatologists defined the reference standard, the DLS was noninferior to six other dermatologists and was superior to six primary care physicians (PCPs) and six nurse practitioners (NPs), according to a summary of the article.

A 2021 report published in JAMA Network Open said that use of an AI tool was associated with a higher agreement rate with dermatologists’ reference diagnoses for both PCPs and NPs.

In a 2021 blog post, Google scientists wrote that their AI model that powers a tool for checking skin conditions had earned European clearance, known as a CE mark, as a class I medical device.

SkinVision has an app that the company says “is available worldwide (with the exception of the USA and Canada).” The firm’s website includes a link where people in the United States and Canada can sign up for notifications about when SkinVision will be available in these nations. 


 

‘Not ready for prime time’

The FDA panel did not cast formal votes at the July 29 meeting. Rather, the members engaged in broad discussions about risks and potential benefits of new tools for aiding in the detection of skin cancer.

Among the key issues discussed was a question of whether the FDA could impose requirements and restrictions, known as special controls, to provide “reasonable assurance of safety and effectiveness” for computer-aided devices that provide adjunctive diagnostic information to dermatologists about lesions suspicious for melanoma.

Among the potential special controls would be clinical performance testing in regards to rates of the sensitivity (true-positive rate) and specificity (true-negative rate).

The FDA could also look at requirements on software validation and verification and cybersecurity testing, as well as directions on labeling so as to mitigate risk.

Dermatologists serving on the panel called for caution in proceeding with steps that would make it easier for companies to market tools for aiding in melanoma diagnosis than it would be within the class III framework used for MelaFind and Nevisense.

Many expressed concerns about the need to design studies that would answer questions about how well new tools could accurately identify concerning lesions.

The phrase “not ready for prime time” was used at least three times during the discussion.

FDA panelist Maral Skelsey, MD, a skin cancer specialist from Chevy Chase, Maryland, said that over the years, she had used both Nevisense and MelaFind.

She said she had found MelaFind “unusable,” owing in large part to the high number of false positives it generated. The device also was limited as to where on patients’ bodies it could be used.

However, she spoke with enthusiasm about the prospects for better devices to aid in diagnosis of skin lesions. “It’s an area where we’re on the verge, and we really need these devices. There’s a need for patients to be able to examine themselves, for nondermatologists to be able to assess lesions,” Dr. Skelsey said.

But this field is “just not ready for prime time” yet, even with special controls, Dr. Skelsey said. To loosen approval standards too quickly could be a “detriment to what’s coming down the pipeline,” she said.

“It’s harmful to things that are likely to be around the corner,” she said.

FDA panelist Renata Block, PA-C, who works in a Chicago dermatology practice, pressed for maintaining a class III designation. “We are not ready for prime time yet, though the data that is coming down the pipeline on what we have is quite exciting,” Ms. Block said.

FDA panelist Karla V. Ballman, PhD, a statistician from Weill Cornell Medicine, New York, said there would need to be a clear standard for clinical performance before proceeding toward reclassification of devices for aid in detecting melanoma. “I just don’t think it’s ready for prime time at this point and should remain in class III,” she said.

But there was support from some panelists for the idea of a lower bar for clearance, combined with special controls to ensure patient safety.

In expressing her view, FDA panelist Katalin Roth, MD, JD, professor of medicine, George Washington University, Washington, said she was an outlier in her support for the agency’s view that these risks could be managed and that future tools could allow more patients to take a step on the pathway toward critical diagnoses.

“I deal with a lot of people with cancer as a palliative care physician,” Dr. Roth said. “I think what we’re missing here is the issue of time. Melanoma is a terrible disease, and missing the diagnosis is a terrible thing, but I think special controls would be sufficient to counter the concerns of my colleagues on the committee.”

The FDA’s Dr. Ashar ended the meeting with questions posed to one panelist, Veronica Rotemberg, MD, PhD, a dermatologist at Memorial Sloan Kettering Cancer Center in New York.

Dr. Rotemberg has for years been working in the field of research on developing AI and other computer-based tools for detecting and diagnosing melanoma, the deadliest form of skin cancer.

She has been publicly skeptical of the performance of commercial apps that scan moles and other lesions and that claim to identify which are cancerous. A May blog post on the Memorial Sloan Kettering website highlighted a recent British Journal of Dermatology article in which Dr. Rotemberg and coauthors reported on their evaluations of commercial apps. They judged them to be on average only 59% accurate, the blog post said.

However, during an earlier discussion at the meeting, she had spoken more positively about the prospects for using special controls in the near term to mitigate risk, although she said she would have a “very long list” of these requirements.

In the closing exchange with Dr. Ashar, Dr. Rotemberg outlined steps that could potentially ensure the safe use of tools to aid in melanoma screening. These included a need for postmarketing surveillance, which would require evaluation over time of algorithms used in tools meant to detect skin cancer.

“We need to have a mechanism for sampling,” Dr. Rotemberg said. “Most of our data is electronic now anyway, so comparing an algorithm and performance with biopsy results should not be that challenging.”

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

New devices that use artificial intelligence (AI) to diagnose skin cancer – such as smartphone apps – have been popping up over the past few years, but there is some concern over the accuracy of these tools.

So far, the U.S. Food and Drug Administration has cleared two devices. Both are computer-aided skin lesion classification devices meant to help clinicians assess cases of suspected melanoma.

Both were given a class III designation. That classification is intended for products that are considered to have a high risk of harm because of flawed design or implementation. Many such devices are under development, and there has been a proposal to include these devices in class II, which is less restrictive.

The FDA turned to one of its expert panels for advice. At a meeting held on Aug. 29, experts on the panel offered differing views and expressed concerns about the accuracy of these devices.

This was the second day of meetings of the general and plastic surgery devices panel of the FDA’s Medical Devices Advisory Committee. On the previous day, the panel held a wide-ranging discussion about expanding use of skin lesion analyzer devices.

The FDA sought the expert panel’s advice concerning a field that appears to be heating up quickly after relatively quiet times.

Two devices have been approved by the FDA so far, but only one is still being promoted – SciBase AB’s Nevisense. The Swedish company announced in May 2020 that it had received FDA approval for Nevisense 3.0, the third generation of their Nevisense system for early melanoma detection, an AI-based point-of-care system for the noninvasive evaluation of irregular moles.

The other device, known as MelaFind, was acquired by Strata Skin Sciences, but the company said in 2017 that it discontinued research and development, sales, and support activity related to the device, according to a filing with the Securities and Exchange Commission.

But there’s been a swell in recent years in the number of publications related to the use of AI and machine learning, which could give rise to new tools for aiding in the diagnosis of skin conditions, including cancer. Google is among the companies that are involved in these efforts.

So, the FDA asked the expert panel to discuss a series of questions related to how the agency should weigh the risks of computer-aided devices for melanoma diagnosis. The agency also asked the panel to provide feedback about how well risks associated with such devices and tools might be managed and to offer suggestions.

The discussion at the July 29 meeting spun beyond narrow questions about reclassification of the current class III devices to topics involving emerging technology, such as efforts to apply AI to dermatology.

“Innovation continues. Medical device developers are anxious to plan how they might be able to develop the level of evidence that would meet your expectations” for future products, Binita Ashar, MD, a senior official in FDA’s Center for Devices and Radiological Health, told the panel.


 

Company CEO backs tougher regulation

Simon Grant, the chief executive of SciBase, which markets Nevisense, the first and only skin cancer–detecting device currently on the U.S. market, sought to make a case for sticking with the tougher class III regulations.

Speaking during the public comment session, Mr. Grant said switching to class II designations would weaken the standards used in clearing products that analyze skin lesions so as to put patients at risk.

Under the FDA’s rules, the agency designates as class III devices that present potential unreasonable risk of illness or injury. Only about 10% of devices fall into this category. Such devices include implantable pacemakers and breast implants, as well as SciBase’s Nevisense.

About 43% of medical devices fall into the class II category, which includes powered wheelchairs and some pregnancy test kits, the FDA website says.

Class I medical devices pose minimal potential for harm and tend to be simpler in design. These include enema kits and elastic bandages, the FDA says.

Mr. Grant told the meeting that in his career he has worked on two class III products and about 20 class II products. (He had previously worked at medical startups Synectics Medical and Neoventa, as well as established multinationals such as Medtronic.)

“I can tell you that – practically – the FDA has many fewer sticks and much less control when it comes to class II devices,” he said. He offered an example of a manufacturer of a class II device having more latitude in making small changes to products without notifying the FDA.

In his hypothetical example, such a change could have unintended consequences, and “with AI systems, small changes can result in large and nonlinear or even random effects,” Mr. Grant said. “But it’s too late if the product is on the market and the harm has already occurred,” he said.

The American Society for Dermatologic Surgery Association also protested the reclassifying of approved computer-aided melanoma detection class III devices.

In a statement posted on the FDA website as part of the materials for the meeting, the ASDSA raised a series of concerns about the prospects of expanded U.S. use of tools for assisting in diagnosing melanoma, including ones that would be marketed to consumers.

“To the extent that algorithms and devices for patient self-diagnosis of skin lesions are already widely available, they should be required to include detailed disclaimers that include that they are for entertainment and educational purposes and not a diagnostic device, that they are not approved by dermatologists or a recognized medical regulatory authority for self-diagnosis,” the ASDSA said.

Devices and algorithms in screening tools “are not highly regulated and remain unproven. They may result in wrong diagnoses, missed diagnoses, or over- or underdiagnosis,” the ASDSA added. “Both patients at low risk and those at high risk are better served by scheduling an in-person examination with a board-certified dermatologist, who can also help them determine the appropriate future skin screening schedule that is most appropriate for them.”

 

‘Stepping stone’

However, there is strong consumer demand for better information about skin conditions, and many patients face hurdles in going to dermatologists.

Google research has shown that consumers are seeking “a stepping stone” between the information they can easily find online and what they could get from a medical professional, said Lily Peng, MD, PhD, a director of product management for the health AI team at Google. Dr. Peng was a scheduled presenter at the July 29 meeting.

Consumers often are looking for more information on common conditions such as acne and poison ivy, and they sometimes face challenges in getting access to clinicians, she said.

“There are many unmet needs for consumers experiencing skin issues, many of which are lower-acuity conditions. There’s a big opportunity to increase accessibility and relevance of health journeys for consumers,” Dr. Peng said. “We have heard from consumers that they would like to have a self-help tool for nonserious conditions so they can decide when to seek medical attention.”

Dr. Peng’s presentation was not directly related to the question of class II or class III designation for existing products. Instead, her talk served as a glimpse into the work already underway in creating apps and tools for consumers.

Google researchers have published a number of studies in recent years about the use of AI to improve dermatology diagnosis.

A 2020 article reported on Google’s test of a form of AI known as deep learning system (DLS) to provide a differential diagnosis of skin conditions. On 963 validation cases, where a rotating panel of three board-certified dermatologists defined the reference standard, the DLS was noninferior to six other dermatologists and was superior to six primary care physicians (PCPs) and six nurse practitioners (NPs), according to a summary of the article.

A 2021 report published in JAMA Network Open said that use of an AI tool was associated with a higher agreement rate with dermatologists’ reference diagnoses for both PCPs and NPs.

In a 2021 blog post, Google scientists wrote that their AI model that powers a tool for checking skin conditions had earned European clearance, known as a CE mark, as a class I medical device.

SkinVision has an app that the company says “is available worldwide (with the exception of the USA and Canada).” The firm’s website includes a link where people in the United States and Canada can sign up for notifications about when SkinVision will be available in these nations. 


 

‘Not ready for prime time’

The FDA panel did not cast formal votes at the July 29 meeting. Rather, the members engaged in broad discussions about risks and potential benefits of new tools for aiding in the detection of skin cancer.

Among the key issues discussed was a question of whether the FDA could impose requirements and restrictions, known as special controls, to provide “reasonable assurance of safety and effectiveness” for computer-aided devices that provide adjunctive diagnostic information to dermatologists about lesions suspicious for melanoma.

Among the potential special controls would be clinical performance testing in regards to rates of the sensitivity (true-positive rate) and specificity (true-negative rate).

The FDA could also look at requirements on software validation and verification and cybersecurity testing, as well as directions on labeling so as to mitigate risk.

Dermatologists serving on the panel called for caution in proceeding with steps that would make it easier for companies to market tools for aiding in melanoma diagnosis than it would be within the class III framework used for MelaFind and Nevisense.

Many expressed concerns about the need to design studies that would answer questions about how well new tools could accurately identify concerning lesions.

The phrase “not ready for prime time” was used at least three times during the discussion.

FDA panelist Maral Skelsey, MD, a skin cancer specialist from Chevy Chase, Maryland, said that over the years, she had used both Nevisense and MelaFind.

She said she had found MelaFind “unusable,” owing in large part to the high number of false positives it generated. The device also was limited as to where on patients’ bodies it could be used.

However, she spoke with enthusiasm about the prospects for better devices to aid in diagnosis of skin lesions. “It’s an area where we’re on the verge, and we really need these devices. There’s a need for patients to be able to examine themselves, for nondermatologists to be able to assess lesions,” Dr. Skelsey said.

But this field is “just not ready for prime time” yet, even with special controls, Dr. Skelsey said. To loosen approval standards too quickly could be a “detriment to what’s coming down the pipeline,” she said.

“It’s harmful to things that are likely to be around the corner,” she said.

FDA panelist Renata Block, PA-C, who works in a Chicago dermatology practice, pressed for maintaining a class III designation. “We are not ready for prime time yet, though the data that is coming down the pipeline on what we have is quite exciting,” Ms. Block said.

FDA panelist Karla V. Ballman, PhD, a statistician from Weill Cornell Medicine, New York, said there would need to be a clear standard for clinical performance before proceeding toward reclassification of devices for aid in detecting melanoma. “I just don’t think it’s ready for prime time at this point and should remain in class III,” she said.

But there was support from some panelists for the idea of a lower bar for clearance, combined with special controls to ensure patient safety.

In expressing her view, FDA panelist Katalin Roth, MD, JD, professor of medicine, George Washington University, Washington, said she was an outlier in her support for the agency’s view that these risks could be managed and that future tools could allow more patients to take a step on the pathway toward critical diagnoses.

“I deal with a lot of people with cancer as a palliative care physician,” Dr. Roth said. “I think what we’re missing here is the issue of time. Melanoma is a terrible disease, and missing the diagnosis is a terrible thing, but I think special controls would be sufficient to counter the concerns of my colleagues on the committee.”

The FDA’s Dr. Ashar ended the meeting with questions posed to one panelist, Veronica Rotemberg, MD, PhD, a dermatologist at Memorial Sloan Kettering Cancer Center in New York.

Dr. Rotemberg has for years been working in the field of research on developing AI and other computer-based tools for detecting and diagnosing melanoma, the deadliest form of skin cancer.

She has been publicly skeptical of the performance of commercial apps that scan moles and other lesions and that claim to identify which are cancerous. A May blog post on the Memorial Sloan Kettering website highlighted a recent British Journal of Dermatology article in which Dr. Rotemberg and coauthors reported on their evaluations of commercial apps. They judged them to be on average only 59% accurate, the blog post said.

However, during an earlier discussion at the meeting, she had spoken more positively about the prospects for using special controls in the near term to mitigate risk, although she said she would have a “very long list” of these requirements.

In the closing exchange with Dr. Ashar, Dr. Rotemberg outlined steps that could potentially ensure the safe use of tools to aid in melanoma screening. These included a need for postmarketing surveillance, which would require evaluation over time of algorithms used in tools meant to detect skin cancer.

“We need to have a mechanism for sampling,” Dr. Rotemberg said. “Most of our data is electronic now anyway, so comparing an algorithm and performance with biopsy results should not be that challenging.”

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

Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.

Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.

About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”

But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.

The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.

The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.

“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”

The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.

For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
 

Shortage affecting mostly myeloma patients

The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.

The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).

“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”

Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.

A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.

“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.

“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”

“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.

He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.

“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
 

Complex causes behind bottleneck

The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.

While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.

“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”

On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.

Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.

There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”

The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.

“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.

Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”

Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
 

Pharma companies trying to meet the demand

This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.

“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.

“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.

“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”

Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.

The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.

“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.

Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.

“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”

With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
 

Incredibly exciting potential

Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.

“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.

But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.

A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.

The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.

At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”

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

Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.

Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.

About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”

But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.

The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.

The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.

“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”

The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.

For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
 

Shortage affecting mostly myeloma patients

The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.

The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).

“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”

Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.

A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.

“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.

“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”

“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.

He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.

“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
 

Complex causes behind bottleneck

The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.

While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.

“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”

On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.

Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.

There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”

The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.

“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.

Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”

Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
 

Pharma companies trying to meet the demand

This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.

“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.

“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.

“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”

Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.

The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.

“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.

Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.

“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”

With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
 

Incredibly exciting potential

Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.

“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.

But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.

A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.

The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.

At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”

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

Some patients with blood cancers for whom all other therapeutic options have been exhausted have one final chance of getting rid of their disease: treatment with chimeric antigen-receptor (CAR) T cells.

Described as a “living drug,” the treatment involves genetically engineering the patient’s own blood cells and reinfusing them back into their system. These CAR T cells then hunt down and destroy cancer cells; in some cases, they manage to eradicate the disease completely.

About half of patients with leukemia or lymphoma and about a third of those with multiple myeloma who receive this treatment have a complete remission and achieve a functional “cure.”

But not all patients who could benefit from this therapy are able to get it. Some are spending months on waiting lists, often deteriorating while they wait. These patients have exhausted all other therapeutic options, and many are facing hospice and death.

The scope of this problem was illustrated by a recent survey of the centers that are certified to deliver this complex therapy.

The survey was led by Yi Lin, MD, PhD, associate professor of medicine at the Mayo Clinic, Rochester, Minn., and medical director for the cellular therapy program. It was published as an abstract at the annual meeting of the American Society of Clinical Oncology recently, although it was not presented there.

“We wanted to find out just how widespread this problem is,” Dr. Lin said, adding: “There had been nothing in the literature thus far about it.”

The team contacted 20 centers across the United States and received responses from 17. Results showed that the median time on the waiting list was 6 months and that only 25% of patients eventually received CAR T-cell therapy. An additional 25% were able to enter a CAR T clinical trial. The remaining 50% of patients either were enrolled in a different type of trial, entered hospice, or died.

For patient selection, all centers reported using a committee of experienced physicians to ensure consistency. They employed different ethical principles for selection. Some centers sought to maximize the total benefit, such as selecting the patients most likely to achieve leukapheresis or a clinical response, while others based their decisions on the time patients spent on waiting list or gave priority to the patients who were the “worst off” with the most limited therapeutic options.
 

Shortage affecting mostly myeloma patients

The shortages in CAR T-cell therapies primarily involve the products used for patients with multiple myeloma.

The problem has not, as yet, noticeably spilled over to lymphoma and leukemia treatments, which use a slightly different type of CAR T-cell therapy (it targets CD19, whereas the cell therapies used for myeloma target BCMA).

“We have backlog of myeloma patients who don’t have access,” said Nina Shah, MD, a hematologist and professor of medicine at the University of California, San Francisco. “We have only four slots for the two myeloma products but about 50-60 eligible patients.”

Long waiting times for CAR T cells for myeloma have been an issue ever since the first of these products appeared on the market: idecabtagene vicleucel (ide-cel; Abecma), developed by Bluebird Bio and Bristol-Myers Squibb. “As soon as it became available in March 2021, we had people waiting and limits on our access to it,” Dr. Shah said.

A second CAR T-cell therapy for myeloma, ciltacabtagene autoleucel (cilta-cel, Carvykti), developed by Janssen and Legend Biotech, received approval in February 2022. While that helped provide centers with a few more slots, it wasn’t sufficient to cut waiting times, and the demand for these myeloma therapies continues to outstrip the capacity to produce CAR-T products in a timely manner.

“For myeloma, the demand is very high, as most patients are not cured from any other existing myeloma therapies, and most patients will make it to fifth-line therapy where the two CAR T-cell products are approved right now,” said Krina K. Patel, MD, medical director of the department of lymphoma/myeloma in the division of cancer medicine at the University of Texas MD Anderson Cancer Center, Houston.

“We likely have 10 eligible CAR-T myeloma patients each month at our center,” she said, “but were getting two slots per month for the past 8 months, and now are getting four slots a month.”

“Our clinic has also experienced the impact of the low number of manufacturing slots offered to each cancer center for some CAR T-cell products,” said David Maloney, MD, PhD, medical director, Cellular Immunotherapy and Bezos Family Immunotherapy Clinic, Seattle Cancer Care Alliance.

He noted that, as with other cancer centers, for multiple myeloma they are provided a specific number of manufacturing slots for each treatment. “Our providers discuss which patients are most appropriate for available slots for that month,” said Dr. Maloney.

“Additionally, juggling patient schedules may be required to address the extended manufacturing time for some products. In some cases, clinical trials may be available in a more timely fashion for appropriate patients, and in some cases, switching to an alternative product is possible,” he commented.
 

Complex causes behind bottleneck

The cause of the current bottleneck for myeloma patients is complex. It stems from a shortage of raw materials and supply chain restraints, among other things.

While the biggest impact of shortages has been on patients with multiple myeloma, Dr. Patel pointed out that these constraints are also affecting patients with lymphoma at her institution, but to a lesser degree.

“This is multifactorial as to why, but most of the issues arise from manufacturing,” Dr. Patel said in an interview. “Initially, the FDA limited how many slots each new product could have per month, then there was a viral vector shortage, and then the quality-control process the FDA requires takes longer than the manufacturing of the cells actually do.”

On top of that, “we have about a 5% manufacturing fail rate so far,” she added. Such failures occur when the cells taken from a patient cannot be converted into CAR T cells for therapy.

Matthew J. Frigault, MD, from the Center for Cellular Therapies, Mass General Cancer Center, Boston, explained that the growing excitement about the potential for cellular therapy and recent approvals for these products for use in earlier lines of treatment have increased demand for them.

There are also problems regarding supply. Manufacture and delivery of CAR T is complicated and takes time to scale up, Dr. Frigault pointed out. “Therefore, we are seeing limited access, more so for the BCMA-directed therapies [which are used for myeloma].”

The shortages and delays likely involve two main factors. “For the newer indications, there is a significant backlog of patients who have been waiting for these therapies and have not been able to access them in the clinical trial setting, and manufacturing is extremely complicated and not easily scaled up,” he said.

“That being said, manufacturers are trying to increase the number of available manufacturing slots and decrease the time needed to manufacture cells,” Dr. Frigault commented.

Delays in access to myeloma CAR T-cell therapy are also affecting patient care at Fox Chase Cancer Center in Philadelphia. “We have had about one slot every 2 months for Abecma,” noted Henry Fung, MD, chair of the department of bone marrow transplant and cellular therapies at Fox Chase. “For Carvykti, there are only 32 certified centers in [the] U.S., and access is very limited.”

Dr. Fung explained that they have had to offer alternative treatments to many of their patients. “There are rumors that there’s shortage in obtaining raw materials, such as the virus used for transduction, although we have not encountered any problems in other CAR T products used for lymphomas.”
 

Pharma companies trying to meet the demand

This news organization reached out to the manufacturers of CAR T products. All have reported that they are doing what they feasibly can to ramp up production.

“The complexity of delivering CAR T-cell therapies is unlike any other traditional biologic or small-molecule medicine, using a patient’s own cells to start a highly sophisticated and personalized manufacturing process,” commented a spokesperson for BMS, which has two CAR T-cell products currently on the market.

“In this nascent field of cell therapy, we continue to evolve every day, addressing supply and manufacturing challenges head on by applying key learnings across our three state-of-the-art cell therapy facilities and two new facilities in progress.

“We have been encouraged by a steady increase in our manufacturing capacity, and we continue efforts to ramp up further to meet the demand for our cell therapies,” the BMS spokesperson commented. “We have already seen improvements in the stabilization of vector supply and expect additional improvements in capacity in the second half of 2022.”

Novartis said much the same thing. They have a “comprehensive, integrated global CAR-T manufacturing footprint that strengthens the flexibility, resilience, and sustainability of the Novartis manufacturing and supply chain. Together with an improved manufacturing process, we are confident in our ability to meet patient demand with timely delivery,” according to a Novartis spokesperson.

The spokesperson also pointed out that the company has continuously incorporated process improvements that have significantly increased manufacturing capacity and success rates for patients in need of CAR T cells.

“Data presented at [the] American Society of Hematology annual meeting in 2021 showed the Novartis Morris Plains facility, our flagship CAR T manufacturing site, had commercial manufacturing and shipping success rates of 96% and 99%, respectively, between January and August 2021,” according to the spokesperson.

Legend and Janssen, the companies behind Carvykti, one of the two approved cell products for myeloma, which launched earlier in 2022, said that they have continued to activate certified treatment centers in a phased approach that will enable them to expand availability throughout 2022 and beyond.

“This phased approach was designed to ensure the highest level of predictability and reliability for the patient and the certified treatment centers,” the spokesperson said. “We understand the urgency for patients in need of Carvyki and are committed to doing everything we can to accelerate our ability to deliver this important cell therapy in a reliable and timely manner.”

With regard to the industry-wide supply shortage of lentivirus, Legend and Janssen say they have put in place multiple processes to address the shortage, “including enhancing our own internal manufacturing capabilities of this essential drug substance, to ensure sufficient and sustained supply.”
 

Incredibly exciting potential

Given the immense potential of CAR T-cell therapy, the supply shortage that myeloma patients are experiencing is all the more poignant and distressing. While not everyone benefits, some patients for whom every other therapy failed and who were facing hospice have had dramatic results.

“Incredibly exciting with unbelievable potential” was how one expert described these new therapies when the first product was about to enter the marketplace. Since then, six CAR T-cell therapies have received regulatory approval for an ever-increasing range of hematologic malignancies.

But these CAR T-cell therapies have their own set of adverse events, which can be serious and even life-threatening. In addition, not all patients become cancer free, although long-term data are impressive.

A study that included one of the longest follow-ups to date was reported at the 2020 annual meeting of the American Society of Clinical Oncology. The researchers reported that remissions lasted over 9 years for patients with relapsed/refractory B-cell lymphoma or chronic lymphocytic leukemia who underwent treatment with Kite’s axicaptagene cilleucel (Yescarta). This review included 43 patients and showed an overall remission rate of 76%. Complete remission was achieved for 54% of patients, and partial remission was achieved for 22%.

The results with CAR T-cell therapy in multiple myeloma are not quite as impressive, but even so, the clinical data that supported the approval of Abecma showed that a third of patients, who had previously received a median of six prior therapies, achieved a complete response.

At the time of the Abecma approval, the lead investigator of the study, Nikhil Munshi, MD, of Dana-Farber Cancer Institute, Boston, commented: “The results of this trial represent a true turning point in the treatment of this disease. In my 30 years of treating myeloma, I have not seen any other therapy as effective in this group of patients.”

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

A new blood test that analyzes DNA shed by metastatic cancers could reveal characteristics unique to each patient’s tumor and allow physicians to develop more personalized treatment plans, according to a new report.

The blood test focuses on circulating tumor DNA (ctDNA). By sequencing the complete genome of ctDNA, researchers can learn about the different metastases spread throughout the body.

“A key goal in cancer research is to better understand metastatic cancer in each affected person so we can select the best treatments and avoid giving toxic therapies to people who will not derive benefit,” senior author Alexander Wyatt, MD, DPhil, assistant professor of genitourinary cancer genomics at the University of British Columbia, Vancouver, and senior research scientist at the Vancouver Prostate Center, told this news organization.

“However, biopsies of metastatic cancer are rarely performed since they are invasive and have risks of complications,” he said. “In the past, this major barrier has prevented the widespread study of metastatic cancer and progress to better treatment of this lethal disease.”

The study was published in Nature.
 

Test methods

Blood-based biopsy technology, also known as “liquid biopsy,” has emerged as a tool for clinical cancer genotyping and longitudinal disease monitoring. Tests that use ctDNA have begun to influence the clinical management of people with cancer, the study authors wrote, though the full potential for understanding metastatic cancer biology hasn’t yet been unlocked.

Dr. Wyatt and colleagues analyzed serial plasma and synchronous metastases in patients with aggressive, treatment-resistant prostate cancer through deep whole-genome sequencing, which allows for a comprehensive assessment of every part of the genetic code within the cancer cells.

The researchers assessed all classes of genomic alterations and found that ctDNA contains multiple dominant populations, indicating that most people with metastatic cancer have different metastases spread around the body. They found that the whole-genome sequencing process provides a host of information about these different metastases.

The research team used newly developed computer programs to provide information about the genetic makeup of each cancer population, which can tell researchers about a person’s overall disease rather than about one metastatic tumor. In the future, this information could allow clinicians to make better decisions about managing a patient’s cancer.

The researchers studied multiple ctDNA samples collected over time to understand how a patient’s cancer evolved in response to treatment. They focused on inhibitors of the androgen receptor pathway. They found that current therapies for metastatic prostate cancer actively change the composition of cancer populations in the body and that treatment often selects for biologically aggressive cancer populations that underlie clinical resistance. This allowed them to pinpoint new genetic resistance mechanisms to the most common treatments for metastatic prostate cancer. The technique could be applied to other cancers as well.

The research team used nucleosome footprints in ctDNA to infer mRNA expression in metastases upon which biopsies were synchronously performed. They identified treatment-induced changes in androgen receptor transcription factor signaling activity. This means whole-genome sequencing of ctDNA can reveal the active processes occurring within cells, allowing clinicians to predict which treatments will be effective or ineffective in each patient.

“Our research significantly expands the breadth of cancer information that can be obtained from only a few drops of blood,” said Dr. Wyatt. “From a clinical perspective, this extra information can be used in new clinical trials that are testing strategies to direct cancer treatments only to those whose quality or whose length of life will be improved.”
 

Clinical trials

The study authors wrote that whole-genome ctDNA sequencing technology, which is minimally invasive, inexpensive, and scalable, is now being deployed in large clinical trials to help discover new treatment resistance mechanisms. These include precision oncology clinical trials that are being conducted with Canadian cancer patients at the Vancouver Prostate Centre and BC Cancer.

The technology can also be implemented in existing commercial ctDNA testing platforms, which means that patients could soon directly benefit from more comprehensive liquid biopsy testing. The research team has made the methods and computer code publicly and freely available so that the technology can be applied to other cancer types and clinical settings.

“Understanding how clonal evolution occurs and what drives it is one of the key questions that need to be addressed in almost all cancers, and this study provides that level of insight for advanced prostate cancer, as well as a model and tools for how to carry out this work,” Christopher Mueller, MD, PhD, a cancer biologist and geneticist at Queen’s Cancer Research Institute and a professor of biomedical and molecular sciences at Queen’s University, both in Kingston, Ont., said in an interview.

Dr. Mueller, who wasn’t involved with this study, has researched biomarkers and ctDNA as avenues for more precise management of advanced prostate cancer. He and his colleagues have developed blood tests for detecting and monitoring metastatic breast cancer, uveal melanoma, and prostate, pancreatic, and lung cancer.

“The expansion of treatment-resistant clones is how we lose almost all cancer patients, and they clearly demonstrate that in castrate-resistant prostate cancer, changes in the androgen receptor locus almost always drive this process,” Dr. Mueller said. “Understanding clonal evolution will allow us to design treatment strategies that overcome or limit their expansion, hopefully extending the lives of these patients.”

The study was funded by the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Prostate Cancer Foundation, Prostate Cancer Canada, the Movember Foundation, the Jane and Aatos Erkko Foundation, the Academy of Finland Center of Excellence program, the Terry Fox New Frontiers Program, and the BC Cancer Foundation. Dr. Wyatt has served on advisory boards or has received honoraria from AstraZeneca, Astellas, Janssen, and Merck, and his research lab has a contract research agreement with ESSA Pharma. Dr. Mueller disclosed no relevant financial relationships.

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

A new blood test that analyzes DNA shed by metastatic cancers could reveal characteristics unique to each patient’s tumor and allow physicians to develop more personalized treatment plans, according to a new report.

The blood test focuses on circulating tumor DNA (ctDNA). By sequencing the complete genome of ctDNA, researchers can learn about the different metastases spread throughout the body.

“A key goal in cancer research is to better understand metastatic cancer in each affected person so we can select the best treatments and avoid giving toxic therapies to people who will not derive benefit,” senior author Alexander Wyatt, MD, DPhil, assistant professor of genitourinary cancer genomics at the University of British Columbia, Vancouver, and senior research scientist at the Vancouver Prostate Center, told this news organization.

“However, biopsies of metastatic cancer are rarely performed since they are invasive and have risks of complications,” he said. “In the past, this major barrier has prevented the widespread study of metastatic cancer and progress to better treatment of this lethal disease.”

The study was published in Nature.
 

Test methods

Blood-based biopsy technology, also known as “liquid biopsy,” has emerged as a tool for clinical cancer genotyping and longitudinal disease monitoring. Tests that use ctDNA have begun to influence the clinical management of people with cancer, the study authors wrote, though the full potential for understanding metastatic cancer biology hasn’t yet been unlocked.

Dr. Wyatt and colleagues analyzed serial plasma and synchronous metastases in patients with aggressive, treatment-resistant prostate cancer through deep whole-genome sequencing, which allows for a comprehensive assessment of every part of the genetic code within the cancer cells.

The researchers assessed all classes of genomic alterations and found that ctDNA contains multiple dominant populations, indicating that most people with metastatic cancer have different metastases spread around the body. They found that the whole-genome sequencing process provides a host of information about these different metastases.

The research team used newly developed computer programs to provide information about the genetic makeup of each cancer population, which can tell researchers about a person’s overall disease rather than about one metastatic tumor. In the future, this information could allow clinicians to make better decisions about managing a patient’s cancer.

The researchers studied multiple ctDNA samples collected over time to understand how a patient’s cancer evolved in response to treatment. They focused on inhibitors of the androgen receptor pathway. They found that current therapies for metastatic prostate cancer actively change the composition of cancer populations in the body and that treatment often selects for biologically aggressive cancer populations that underlie clinical resistance. This allowed them to pinpoint new genetic resistance mechanisms to the most common treatments for metastatic prostate cancer. The technique could be applied to other cancers as well.

The research team used nucleosome footprints in ctDNA to infer mRNA expression in metastases upon which biopsies were synchronously performed. They identified treatment-induced changes in androgen receptor transcription factor signaling activity. This means whole-genome sequencing of ctDNA can reveal the active processes occurring within cells, allowing clinicians to predict which treatments will be effective or ineffective in each patient.

“Our research significantly expands the breadth of cancer information that can be obtained from only a few drops of blood,” said Dr. Wyatt. “From a clinical perspective, this extra information can be used in new clinical trials that are testing strategies to direct cancer treatments only to those whose quality or whose length of life will be improved.”
 

Clinical trials

The study authors wrote that whole-genome ctDNA sequencing technology, which is minimally invasive, inexpensive, and scalable, is now being deployed in large clinical trials to help discover new treatment resistance mechanisms. These include precision oncology clinical trials that are being conducted with Canadian cancer patients at the Vancouver Prostate Centre and BC Cancer.

The technology can also be implemented in existing commercial ctDNA testing platforms, which means that patients could soon directly benefit from more comprehensive liquid biopsy testing. The research team has made the methods and computer code publicly and freely available so that the technology can be applied to other cancer types and clinical settings.

“Understanding how clonal evolution occurs and what drives it is one of the key questions that need to be addressed in almost all cancers, and this study provides that level of insight for advanced prostate cancer, as well as a model and tools for how to carry out this work,” Christopher Mueller, MD, PhD, a cancer biologist and geneticist at Queen’s Cancer Research Institute and a professor of biomedical and molecular sciences at Queen’s University, both in Kingston, Ont., said in an interview.

Dr. Mueller, who wasn’t involved with this study, has researched biomarkers and ctDNA as avenues for more precise management of advanced prostate cancer. He and his colleagues have developed blood tests for detecting and monitoring metastatic breast cancer, uveal melanoma, and prostate, pancreatic, and lung cancer.

“The expansion of treatment-resistant clones is how we lose almost all cancer patients, and they clearly demonstrate that in castrate-resistant prostate cancer, changes in the androgen receptor locus almost always drive this process,” Dr. Mueller said. “Understanding clonal evolution will allow us to design treatment strategies that overcome or limit their expansion, hopefully extending the lives of these patients.”

The study was funded by the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Prostate Cancer Foundation, Prostate Cancer Canada, the Movember Foundation, the Jane and Aatos Erkko Foundation, the Academy of Finland Center of Excellence program, the Terry Fox New Frontiers Program, and the BC Cancer Foundation. Dr. Wyatt has served on advisory boards or has received honoraria from AstraZeneca, Astellas, Janssen, and Merck, and his research lab has a contract research agreement with ESSA Pharma. Dr. Mueller disclosed no relevant financial relationships.

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

A new blood test that analyzes DNA shed by metastatic cancers could reveal characteristics unique to each patient’s tumor and allow physicians to develop more personalized treatment plans, according to a new report.

The blood test focuses on circulating tumor DNA (ctDNA). By sequencing the complete genome of ctDNA, researchers can learn about the different metastases spread throughout the body.

“A key goal in cancer research is to better understand metastatic cancer in each affected person so we can select the best treatments and avoid giving toxic therapies to people who will not derive benefit,” senior author Alexander Wyatt, MD, DPhil, assistant professor of genitourinary cancer genomics at the University of British Columbia, Vancouver, and senior research scientist at the Vancouver Prostate Center, told this news organization.

“However, biopsies of metastatic cancer are rarely performed since they are invasive and have risks of complications,” he said. “In the past, this major barrier has prevented the widespread study of metastatic cancer and progress to better treatment of this lethal disease.”

The study was published in Nature.
 

Test methods

Blood-based biopsy technology, also known as “liquid biopsy,” has emerged as a tool for clinical cancer genotyping and longitudinal disease monitoring. Tests that use ctDNA have begun to influence the clinical management of people with cancer, the study authors wrote, though the full potential for understanding metastatic cancer biology hasn’t yet been unlocked.

Dr. Wyatt and colleagues analyzed serial plasma and synchronous metastases in patients with aggressive, treatment-resistant prostate cancer through deep whole-genome sequencing, which allows for a comprehensive assessment of every part of the genetic code within the cancer cells.

The researchers assessed all classes of genomic alterations and found that ctDNA contains multiple dominant populations, indicating that most people with metastatic cancer have different metastases spread around the body. They found that the whole-genome sequencing process provides a host of information about these different metastases.

The research team used newly developed computer programs to provide information about the genetic makeup of each cancer population, which can tell researchers about a person’s overall disease rather than about one metastatic tumor. In the future, this information could allow clinicians to make better decisions about managing a patient’s cancer.

The researchers studied multiple ctDNA samples collected over time to understand how a patient’s cancer evolved in response to treatment. They focused on inhibitors of the androgen receptor pathway. They found that current therapies for metastatic prostate cancer actively change the composition of cancer populations in the body and that treatment often selects for biologically aggressive cancer populations that underlie clinical resistance. This allowed them to pinpoint new genetic resistance mechanisms to the most common treatments for metastatic prostate cancer. The technique could be applied to other cancers as well.

The research team used nucleosome footprints in ctDNA to infer mRNA expression in metastases upon which biopsies were synchronously performed. They identified treatment-induced changes in androgen receptor transcription factor signaling activity. This means whole-genome sequencing of ctDNA can reveal the active processes occurring within cells, allowing clinicians to predict which treatments will be effective or ineffective in each patient.

“Our research significantly expands the breadth of cancer information that can be obtained from only a few drops of blood,” said Dr. Wyatt. “From a clinical perspective, this extra information can be used in new clinical trials that are testing strategies to direct cancer treatments only to those whose quality or whose length of life will be improved.”
 

Clinical trials

The study authors wrote that whole-genome ctDNA sequencing technology, which is minimally invasive, inexpensive, and scalable, is now being deployed in large clinical trials to help discover new treatment resistance mechanisms. These include precision oncology clinical trials that are being conducted with Canadian cancer patients at the Vancouver Prostate Centre and BC Cancer.

The technology can also be implemented in existing commercial ctDNA testing platforms, which means that patients could soon directly benefit from more comprehensive liquid biopsy testing. The research team has made the methods and computer code publicly and freely available so that the technology can be applied to other cancer types and clinical settings.

“Understanding how clonal evolution occurs and what drives it is one of the key questions that need to be addressed in almost all cancers, and this study provides that level of insight for advanced prostate cancer, as well as a model and tools for how to carry out this work,” Christopher Mueller, MD, PhD, a cancer biologist and geneticist at Queen’s Cancer Research Institute and a professor of biomedical and molecular sciences at Queen’s University, both in Kingston, Ont., said in an interview.

Dr. Mueller, who wasn’t involved with this study, has researched biomarkers and ctDNA as avenues for more precise management of advanced prostate cancer. He and his colleagues have developed blood tests for detecting and monitoring metastatic breast cancer, uveal melanoma, and prostate, pancreatic, and lung cancer.

“The expansion of treatment-resistant clones is how we lose almost all cancer patients, and they clearly demonstrate that in castrate-resistant prostate cancer, changes in the androgen receptor locus almost always drive this process,” Dr. Mueller said. “Understanding clonal evolution will allow us to design treatment strategies that overcome or limit their expansion, hopefully extending the lives of these patients.”

The study was funded by the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute, the Prostate Cancer Foundation, Prostate Cancer Canada, the Movember Foundation, the Jane and Aatos Erkko Foundation, the Academy of Finland Center of Excellence program, the Terry Fox New Frontiers Program, and the BC Cancer Foundation. Dr. Wyatt has served on advisory boards or has received honoraria from AstraZeneca, Astellas, Janssen, and Merck, and his research lab has a contract research agreement with ESSA Pharma. Dr. Mueller disclosed no relevant financial relationships.

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

Young women with a new diagnosis of node-negative triple-negative breast cancer (TNBC) who have high levels of stromal tumor-infiltrating lymphocytes (sTILs) have a very good long-term prognosis, and may be suitable candidates for reduced intensity pre- or postoperative chemotherapy, according to a team of European investigators.

Among 441 women in a Dutch cancer registry who were younger than 40 when they were diagnosed with node-negative TNBC and had not undergone systemic therapy, those who had 75% or more TILs in the intratumoral stromal area had a 15-year cumulative incidence of distant metastases or death of just 2.1%, and every 10% increase in sTILs was associated with a 19% decrease in the risk of death.

In contrast, the 15-year cumulative incidence of distant metastases was 38.4% for women with stromal TIL scores of less than 30%, according to researchers writing in the Journal of Clinical Oncology.

“These data could be used as a starting point for designing a randomized controlled chemotherapy de-escalation trial. The current study confirms the importance of sTILs as a valuable addition to the set of standard prognostic factors in patients with TNBC,” wrote the researchers, who were led by Sabine C. Linn, MD, of the Netherlands Cancer Institute, Amsterdam.
 

Markers for immune response

Stromal TILs, a mixture of mononuclear immune cells, have been shown in previous studies to be prognostic for outcomes in patients with early-stage TNBC treated either with or without neoadjuvant or adjuvant chemotherapy.

For example, investigators cited a study published in JCO in 2014, that showed among women with TNBC enrolled in the phase 3 ECOG 2197 clinical trial and the related ECOG 119 clinical trial, after a nearly 11-year follow-up, higher sTIL scores were associated with significantly better prognosis with every 10% increase translating into a 14% reduction in the risk of recurrence or death (P = .02).

“The prognostic importance of sTILs is, however, unexplored in patients diagnosed under age 40 years, let alone in the subgroup of systemic therapy–naive patients,” Dr. Linn and colleagues wrote.
 

Retrospective study

To see whether the prognostic value of sTILs was as strong among young, systemic therapy–naive women, the investigators conducted a retrospective study of women enrolled in the Netherlands Cancer Registry who were diagnosed with node-negative TNBC from 1989 to 2000. The patients selected had undergone only locoregional treatment, including axillary node dissection, but had not received any systemic therapy.

Pathologists reviewed samples, with TILs reported for the stromal compartment. The samples were grouped by sTIL score categories of high (75% or greater), intermediate (30% to less than 75%), or low (less than 30%). The investigators looked at overall survival (OS) and distant metastasis-free survival (DMFS) stratified by sTIL scores,

During a median follow-up of 15 years, 107 women died or developed distant metastases, and 78 experienced a second primary cancer.

The results were as noted, with patients in the highest category of sTILs having very low rates of either death or distant metastases during follow-up.

“We confirm the prognostic value of sTILs in young patients with early-stage N0 TNBC who are systemic therapy naive by taking advantage of a prospectively collected population-based cohort. Increasing sTILs are significantly associated with improved OS and DMFS. Patients with high sTILs (> 75%) had an excellent 10-year overall survival and a very low 10-year incidence of distant metastasis or death.

The study was supported by grants from The Netherlands Organization for Health Research and Development, A Sister’s Hope, De Vrienden van UMC Utrecht, Agilent Technologies, the Dutch Cancer Society, and Breast Cancer Research Foundation. Dr. Linn reported consulting with and receiving compensation from Daiichi Sankyo, as well as receiving research funding from Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Tesaro, Merck, Immunomedics, Eurocept Pharmaceuticals, Agendia, and Novartis.

Young women with a new diagnosis of node-negative triple-negative breast cancer (TNBC) who have high levels of stromal tumor-infiltrating lymphocytes (sTILs) have a very good long-term prognosis, and may be suitable candidates for reduced intensity pre- or postoperative chemotherapy, according to a team of European investigators.

Among 441 women in a Dutch cancer registry who were younger than 40 when they were diagnosed with node-negative TNBC and had not undergone systemic therapy, those who had 75% or more TILs in the intratumoral stromal area had a 15-year cumulative incidence of distant metastases or death of just 2.1%, and every 10% increase in sTILs was associated with a 19% decrease in the risk of death.

In contrast, the 15-year cumulative incidence of distant metastases was 38.4% for women with stromal TIL scores of less than 30%, according to researchers writing in the Journal of Clinical Oncology.

“These data could be used as a starting point for designing a randomized controlled chemotherapy de-escalation trial. The current study confirms the importance of sTILs as a valuable addition to the set of standard prognostic factors in patients with TNBC,” wrote the researchers, who were led by Sabine C. Linn, MD, of the Netherlands Cancer Institute, Amsterdam.
 

Markers for immune response

Stromal TILs, a mixture of mononuclear immune cells, have been shown in previous studies to be prognostic for outcomes in patients with early-stage TNBC treated either with or without neoadjuvant or adjuvant chemotherapy.

For example, investigators cited a study published in JCO in 2014, that showed among women with TNBC enrolled in the phase 3 ECOG 2197 clinical trial and the related ECOG 119 clinical trial, after a nearly 11-year follow-up, higher sTIL scores were associated with significantly better prognosis with every 10% increase translating into a 14% reduction in the risk of recurrence or death (P = .02).

“The prognostic importance of sTILs is, however, unexplored in patients diagnosed under age 40 years, let alone in the subgroup of systemic therapy–naive patients,” Dr. Linn and colleagues wrote.
 

Retrospective study

To see whether the prognostic value of sTILs was as strong among young, systemic therapy–naive women, the investigators conducted a retrospective study of women enrolled in the Netherlands Cancer Registry who were diagnosed with node-negative TNBC from 1989 to 2000. The patients selected had undergone only locoregional treatment, including axillary node dissection, but had not received any systemic therapy.

Pathologists reviewed samples, with TILs reported for the stromal compartment. The samples were grouped by sTIL score categories of high (75% or greater), intermediate (30% to less than 75%), or low (less than 30%). The investigators looked at overall survival (OS) and distant metastasis-free survival (DMFS) stratified by sTIL scores,

During a median follow-up of 15 years, 107 women died or developed distant metastases, and 78 experienced a second primary cancer.

The results were as noted, with patients in the highest category of sTILs having very low rates of either death or distant metastases during follow-up.

“We confirm the prognostic value of sTILs in young patients with early-stage N0 TNBC who are systemic therapy naive by taking advantage of a prospectively collected population-based cohort. Increasing sTILs are significantly associated with improved OS and DMFS. Patients with high sTILs (> 75%) had an excellent 10-year overall survival and a very low 10-year incidence of distant metastasis or death.

The study was supported by grants from The Netherlands Organization for Health Research and Development, A Sister’s Hope, De Vrienden van UMC Utrecht, Agilent Technologies, the Dutch Cancer Society, and Breast Cancer Research Foundation. Dr. Linn reported consulting with and receiving compensation from Daiichi Sankyo, as well as receiving research funding from Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Tesaro, Merck, Immunomedics, Eurocept Pharmaceuticals, Agendia, and Novartis.

Young women with a new diagnosis of node-negative triple-negative breast cancer (TNBC) who have high levels of stromal tumor-infiltrating lymphocytes (sTILs) have a very good long-term prognosis, and may be suitable candidates for reduced intensity pre- or postoperative chemotherapy, according to a team of European investigators.

Among 441 women in a Dutch cancer registry who were younger than 40 when they were diagnosed with node-negative TNBC and had not undergone systemic therapy, those who had 75% or more TILs in the intratumoral stromal area had a 15-year cumulative incidence of distant metastases or death of just 2.1%, and every 10% increase in sTILs was associated with a 19% decrease in the risk of death.

In contrast, the 15-year cumulative incidence of distant metastases was 38.4% for women with stromal TIL scores of less than 30%, according to researchers writing in the Journal of Clinical Oncology.

“These data could be used as a starting point for designing a randomized controlled chemotherapy de-escalation trial. The current study confirms the importance of sTILs as a valuable addition to the set of standard prognostic factors in patients with TNBC,” wrote the researchers, who were led by Sabine C. Linn, MD, of the Netherlands Cancer Institute, Amsterdam.
 

Markers for immune response

Stromal TILs, a mixture of mononuclear immune cells, have been shown in previous studies to be prognostic for outcomes in patients with early-stage TNBC treated either with or without neoadjuvant or adjuvant chemotherapy.

For example, investigators cited a study published in JCO in 2014, that showed among women with TNBC enrolled in the phase 3 ECOG 2197 clinical trial and the related ECOG 119 clinical trial, after a nearly 11-year follow-up, higher sTIL scores were associated with significantly better prognosis with every 10% increase translating into a 14% reduction in the risk of recurrence or death (P = .02).

“The prognostic importance of sTILs is, however, unexplored in patients diagnosed under age 40 years, let alone in the subgroup of systemic therapy–naive patients,” Dr. Linn and colleagues wrote.
 

Retrospective study

To see whether the prognostic value of sTILs was as strong among young, systemic therapy–naive women, the investigators conducted a retrospective study of women enrolled in the Netherlands Cancer Registry who were diagnosed with node-negative TNBC from 1989 to 2000. The patients selected had undergone only locoregional treatment, including axillary node dissection, but had not received any systemic therapy.

Pathologists reviewed samples, with TILs reported for the stromal compartment. The samples were grouped by sTIL score categories of high (75% or greater), intermediate (30% to less than 75%), or low (less than 30%). The investigators looked at overall survival (OS) and distant metastasis-free survival (DMFS) stratified by sTIL scores,

During a median follow-up of 15 years, 107 women died or developed distant metastases, and 78 experienced a second primary cancer.

The results were as noted, with patients in the highest category of sTILs having very low rates of either death or distant metastases during follow-up.

“We confirm the prognostic value of sTILs in young patients with early-stage N0 TNBC who are systemic therapy naive by taking advantage of a prospectively collected population-based cohort. Increasing sTILs are significantly associated with improved OS and DMFS. Patients with high sTILs (> 75%) had an excellent 10-year overall survival and a very low 10-year incidence of distant metastasis or death.

The study was supported by grants from The Netherlands Organization for Health Research and Development, A Sister’s Hope, De Vrienden van UMC Utrecht, Agilent Technologies, the Dutch Cancer Society, and Breast Cancer Research Foundation. Dr. Linn reported consulting with and receiving compensation from Daiichi Sankyo, as well as receiving research funding from Genentech/Roche, AstraZeneca, Bristol-Myers Squibb, Tesaro, Merck, Immunomedics, Eurocept Pharmaceuticals, Agendia, and Novartis.

New results with quadruple drug therapy in the frontline treatment of multiple myeloma (MM) are prompting experts to speculate that stem cell transplantation may soon be able to take a back seat in the treatment of newly diagnosed disease.

“It is not a big leap of faith to imagine that, in the near future, with the availability of quadruplets and T-cell therapies, the role of high-dose melphalan and autologous stem cell transplant will be diminished,” said Dickran Kazandjian, MD, and Ola Landgren, MD, PhD, of the myeloma division, Sylvester Comprehensive Cancer Center, University of Miami.

They commented in a editorial in JAMA Oncology, prompted by a paper describing new results with a novel quadruple combination of therapies. These treatments included the monoclonal antibody elotuzumab (Empliciti) added onto the established backbone of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (known as KRd).

“Regardless of what the future holds for elotuzumab-based combinations, it is clear that the new treatment paradigm of newly diagnosed MM will incorporate antibody-based quadruplet regimens,” the editorialists commented.

“Novel immunotherapies are here to stay,” they added, “as they are already transforming the lives of patients with multiple MM and bringing a bright horizon to the treatment landscape.”
 

Study details

The trial of the novel quadruplet regimen was a multicenter, single-arm, phase 2 study that involved 46 patients with newly diagnosed multiple myeloma, explain first author Benjamin A. Derman, MD, of the University of Chicago Medical Center, and colleagues.

These patients had a median age of 62; more than two-thirds were male (72%) and White (70%). About half (48%) had high-risk cytogenetic abnormalities.

All patients were treated with 12 cycles of the quadruple therapy Elo-KRd regimen. They underwent bone marrow assessment of measurable residual disease (MRD; with 10-5 sensitivity) after cycle 8 and cycle 12.

“An MRD-adapted treatment approach is rational because it may identify which patients can be administered shorter courses of intensive therapy without compromising efficacy,” the authors explained.

Patients who had MRD negativity at both time points did not receive further Elo-KRd, while patients who converted from MRD positivity to negativity in between cycles 8 and 12 received 6 additional cycles of Elo-KRd. Those who remained MRD positive or converted to positivity after 12 cycles received an additional 12 cycles of Elo-KRd.

Following Elo-KRd treatment, all patients transitioned to triple therapy with Elo-Rd (with no carfilzomib), for indefinite maintenance therapy or until disease progression.

For the primary endpoint, the rate of stringent complete response and/or MRD-negativity after cycle 8 was 58% (26 of 45), meeting the predefined definition of efficacy. 

Importantly, 26% of patients converted from MRD positivity after cycle 8 to negativity at a later time point, while 50% of patients reached 1-year sustained MRD negativity.

Overall, the estimated 3-year, progression-free survival was 72%, and the rate was 92% for patients with MRD-negativity at cycle 8. The overall survival rate was 78%.

The most common grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively), and one patient had a grade 5 MI. Three patients discontinued the treatment because of intolerance.

“An MRD-adapted design using elotuzumab and weekly KRd without autologous stem cell transplantation showed a high rate of stringent complete response (sCR) and/or MRD-negativity and durable responses,” the authors wrote.

“This approach provides support for further evaluation of MRD-guided de-escalation of therapy to decrease treatment exposure while sustaining deep responses.”

To better assess the difference of the therapy versus treatment including stem cell transplantation, a phase 3, randomized trial is currently underway to compare the Elo-KRd regimen against KRd with autologous stem cell transplant in newly diagnosed MM.

“If Elo-KRd proves superior, a randomized comparison of Elo versus anti-CD38 mAb-based quadruplets would help determine the optimal combination of therapies in the frontline setting,” the authors noted.
 

Randomized trial anticipated to clarify benefit

In their editorial, Dr. Kazandjian and Dr. Landgren agreed with the authors that the role of elotuzumab needs to be better clarified in a randomized trial setting.

Elotuzumab received FDA approval in 2015 based on results from the ELOQUENT-2 study, which showed improved progression-free survival and overall survival with the addition of elotuzumab to lenalidomide and dexamethasone in patients with multiple myeloma who have previously received one to three other therapies.

However, the editorialists pointed out that recently published results from the randomized ELOQUENT-1 trial of lenalidomide and dexamethasone with and without elotuzumab showed the addition of elotuzumab was not associated with a statistically significant difference in progression-free survival.

The editorialists also pointed out that, in the setting of newly diagnosed multiple myeloma, another recent, similarly designed study found that the backbone regimen of carfilzomib, lenalidomide, and dexamethasone – on its own – was also associated with a favorable MRD-negative rate of 62%.

In addition, several studies involving novel quadruple treatments with the monoclonal antibody daratumumab (Darzalex) instead of elotuzumab, have also shown benefit in newly diagnosed multiple myeloma, resulting in high rates of MRD negativity.

Collectively, the findings bode well for the quadruple regimens in the treatment of MM, the editorialists emphasized.

“Importantly, with the rate of deep remissions observed with antibody-based quadruplet therapies, one may question the role of using early high-dose melphalan and autologous stem cell transplant in every patient, especially in those who have achieved MRD negativity with the quadruplet alone,” they added.

The study was sponsored in part by Amgen, Bristol-Myers Squibb, and the Multiple Myeloma Research Consortium. Dr. Derman reported advisory board fees from Sanofi, Janssen, and COTA Healthcare; honoraria from PleXus Communications and MJH Life Sciences. Dr. Kazandjian declares receiving advisory board or consulting fees from Bristol-Myers Squibb, Sanofi, and Arcellx outside the submitted work. Dr. Landgren has received grant support from numerous organizations and pharmaceutical companies. Dr. Landgren has also received honoraria for scientific talks/participated in advisory boards for Adaptive Biotech, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer, and served on independent data monitoring committees for international randomized trials by Takeda, Merck, Janssen, and Theradex.

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

New results with quadruple drug therapy in the frontline treatment of multiple myeloma (MM) are prompting experts to speculate that stem cell transplantation may soon be able to take a back seat in the treatment of newly diagnosed disease.

“It is not a big leap of faith to imagine that, in the near future, with the availability of quadruplets and T-cell therapies, the role of high-dose melphalan and autologous stem cell transplant will be diminished,” said Dickran Kazandjian, MD, and Ola Landgren, MD, PhD, of the myeloma division, Sylvester Comprehensive Cancer Center, University of Miami.

They commented in a editorial in JAMA Oncology, prompted by a paper describing new results with a novel quadruple combination of therapies. These treatments included the monoclonal antibody elotuzumab (Empliciti) added onto the established backbone of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (known as KRd).

“Regardless of what the future holds for elotuzumab-based combinations, it is clear that the new treatment paradigm of newly diagnosed MM will incorporate antibody-based quadruplet regimens,” the editorialists commented.

“Novel immunotherapies are here to stay,” they added, “as they are already transforming the lives of patients with multiple MM and bringing a bright horizon to the treatment landscape.”
 

Study details

The trial of the novel quadruplet regimen was a multicenter, single-arm, phase 2 study that involved 46 patients with newly diagnosed multiple myeloma, explain first author Benjamin A. Derman, MD, of the University of Chicago Medical Center, and colleagues.

These patients had a median age of 62; more than two-thirds were male (72%) and White (70%). About half (48%) had high-risk cytogenetic abnormalities.

All patients were treated with 12 cycles of the quadruple therapy Elo-KRd regimen. They underwent bone marrow assessment of measurable residual disease (MRD; with 10-5 sensitivity) after cycle 8 and cycle 12.

“An MRD-adapted treatment approach is rational because it may identify which patients can be administered shorter courses of intensive therapy without compromising efficacy,” the authors explained.

Patients who had MRD negativity at both time points did not receive further Elo-KRd, while patients who converted from MRD positivity to negativity in between cycles 8 and 12 received 6 additional cycles of Elo-KRd. Those who remained MRD positive or converted to positivity after 12 cycles received an additional 12 cycles of Elo-KRd.

Following Elo-KRd treatment, all patients transitioned to triple therapy with Elo-Rd (with no carfilzomib), for indefinite maintenance therapy or until disease progression.

For the primary endpoint, the rate of stringent complete response and/or MRD-negativity after cycle 8 was 58% (26 of 45), meeting the predefined definition of efficacy. 

Importantly, 26% of patients converted from MRD positivity after cycle 8 to negativity at a later time point, while 50% of patients reached 1-year sustained MRD negativity.

Overall, the estimated 3-year, progression-free survival was 72%, and the rate was 92% for patients with MRD-negativity at cycle 8. The overall survival rate was 78%.

The most common grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively), and one patient had a grade 5 MI. Three patients discontinued the treatment because of intolerance.

“An MRD-adapted design using elotuzumab and weekly KRd without autologous stem cell transplantation showed a high rate of stringent complete response (sCR) and/or MRD-negativity and durable responses,” the authors wrote.

“This approach provides support for further evaluation of MRD-guided de-escalation of therapy to decrease treatment exposure while sustaining deep responses.”

To better assess the difference of the therapy versus treatment including stem cell transplantation, a phase 3, randomized trial is currently underway to compare the Elo-KRd regimen against KRd with autologous stem cell transplant in newly diagnosed MM.

“If Elo-KRd proves superior, a randomized comparison of Elo versus anti-CD38 mAb-based quadruplets would help determine the optimal combination of therapies in the frontline setting,” the authors noted.
 

Randomized trial anticipated to clarify benefit

In their editorial, Dr. Kazandjian and Dr. Landgren agreed with the authors that the role of elotuzumab needs to be better clarified in a randomized trial setting.

Elotuzumab received FDA approval in 2015 based on results from the ELOQUENT-2 study, which showed improved progression-free survival and overall survival with the addition of elotuzumab to lenalidomide and dexamethasone in patients with multiple myeloma who have previously received one to three other therapies.

However, the editorialists pointed out that recently published results from the randomized ELOQUENT-1 trial of lenalidomide and dexamethasone with and without elotuzumab showed the addition of elotuzumab was not associated with a statistically significant difference in progression-free survival.

The editorialists also pointed out that, in the setting of newly diagnosed multiple myeloma, another recent, similarly designed study found that the backbone regimen of carfilzomib, lenalidomide, and dexamethasone – on its own – was also associated with a favorable MRD-negative rate of 62%.

In addition, several studies involving novel quadruple treatments with the monoclonal antibody daratumumab (Darzalex) instead of elotuzumab, have also shown benefit in newly diagnosed multiple myeloma, resulting in high rates of MRD negativity.

Collectively, the findings bode well for the quadruple regimens in the treatment of MM, the editorialists emphasized.

“Importantly, with the rate of deep remissions observed with antibody-based quadruplet therapies, one may question the role of using early high-dose melphalan and autologous stem cell transplant in every patient, especially in those who have achieved MRD negativity with the quadruplet alone,” they added.

The study was sponsored in part by Amgen, Bristol-Myers Squibb, and the Multiple Myeloma Research Consortium. Dr. Derman reported advisory board fees from Sanofi, Janssen, and COTA Healthcare; honoraria from PleXus Communications and MJH Life Sciences. Dr. Kazandjian declares receiving advisory board or consulting fees from Bristol-Myers Squibb, Sanofi, and Arcellx outside the submitted work. Dr. Landgren has received grant support from numerous organizations and pharmaceutical companies. Dr. Landgren has also received honoraria for scientific talks/participated in advisory boards for Adaptive Biotech, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer, and served on independent data monitoring committees for international randomized trials by Takeda, Merck, Janssen, and Theradex.

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

New results with quadruple drug therapy in the frontline treatment of multiple myeloma (MM) are prompting experts to speculate that stem cell transplantation may soon be able to take a back seat in the treatment of newly diagnosed disease.

“It is not a big leap of faith to imagine that, in the near future, with the availability of quadruplets and T-cell therapies, the role of high-dose melphalan and autologous stem cell transplant will be diminished,” said Dickran Kazandjian, MD, and Ola Landgren, MD, PhD, of the myeloma division, Sylvester Comprehensive Cancer Center, University of Miami.

They commented in a editorial in JAMA Oncology, prompted by a paper describing new results with a novel quadruple combination of therapies. These treatments included the monoclonal antibody elotuzumab (Empliciti) added onto the established backbone of carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (known as KRd).

“Regardless of what the future holds for elotuzumab-based combinations, it is clear that the new treatment paradigm of newly diagnosed MM will incorporate antibody-based quadruplet regimens,” the editorialists commented.

“Novel immunotherapies are here to stay,” they added, “as they are already transforming the lives of patients with multiple MM and bringing a bright horizon to the treatment landscape.”
 

Study details

The trial of the novel quadruplet regimen was a multicenter, single-arm, phase 2 study that involved 46 patients with newly diagnosed multiple myeloma, explain first author Benjamin A. Derman, MD, of the University of Chicago Medical Center, and colleagues.

These patients had a median age of 62; more than two-thirds were male (72%) and White (70%). About half (48%) had high-risk cytogenetic abnormalities.

All patients were treated with 12 cycles of the quadruple therapy Elo-KRd regimen. They underwent bone marrow assessment of measurable residual disease (MRD; with 10-5 sensitivity) after cycle 8 and cycle 12.

“An MRD-adapted treatment approach is rational because it may identify which patients can be administered shorter courses of intensive therapy without compromising efficacy,” the authors explained.

Patients who had MRD negativity at both time points did not receive further Elo-KRd, while patients who converted from MRD positivity to negativity in between cycles 8 and 12 received 6 additional cycles of Elo-KRd. Those who remained MRD positive or converted to positivity after 12 cycles received an additional 12 cycles of Elo-KRd.

Following Elo-KRd treatment, all patients transitioned to triple therapy with Elo-Rd (with no carfilzomib), for indefinite maintenance therapy or until disease progression.

For the primary endpoint, the rate of stringent complete response and/or MRD-negativity after cycle 8 was 58% (26 of 45), meeting the predefined definition of efficacy. 

Importantly, 26% of patients converted from MRD positivity after cycle 8 to negativity at a later time point, while 50% of patients reached 1-year sustained MRD negativity.

Overall, the estimated 3-year, progression-free survival was 72%, and the rate was 92% for patients with MRD-negativity at cycle 8. The overall survival rate was 78%.

The most common grade 3 or 4 adverse events were lung and nonpulmonary infections (13% and 11%, respectively), and one patient had a grade 5 MI. Three patients discontinued the treatment because of intolerance.

“An MRD-adapted design using elotuzumab and weekly KRd without autologous stem cell transplantation showed a high rate of stringent complete response (sCR) and/or MRD-negativity and durable responses,” the authors wrote.

“This approach provides support for further evaluation of MRD-guided de-escalation of therapy to decrease treatment exposure while sustaining deep responses.”

To better assess the difference of the therapy versus treatment including stem cell transplantation, a phase 3, randomized trial is currently underway to compare the Elo-KRd regimen against KRd with autologous stem cell transplant in newly diagnosed MM.

“If Elo-KRd proves superior, a randomized comparison of Elo versus anti-CD38 mAb-based quadruplets would help determine the optimal combination of therapies in the frontline setting,” the authors noted.
 

Randomized trial anticipated to clarify benefit

In their editorial, Dr. Kazandjian and Dr. Landgren agreed with the authors that the role of elotuzumab needs to be better clarified in a randomized trial setting.

Elotuzumab received FDA approval in 2015 based on results from the ELOQUENT-2 study, which showed improved progression-free survival and overall survival with the addition of elotuzumab to lenalidomide and dexamethasone in patients with multiple myeloma who have previously received one to three other therapies.

However, the editorialists pointed out that recently published results from the randomized ELOQUENT-1 trial of lenalidomide and dexamethasone with and without elotuzumab showed the addition of elotuzumab was not associated with a statistically significant difference in progression-free survival.

The editorialists also pointed out that, in the setting of newly diagnosed multiple myeloma, another recent, similarly designed study found that the backbone regimen of carfilzomib, lenalidomide, and dexamethasone – on its own – was also associated with a favorable MRD-negative rate of 62%.

In addition, several studies involving novel quadruple treatments with the monoclonal antibody daratumumab (Darzalex) instead of elotuzumab, have also shown benefit in newly diagnosed multiple myeloma, resulting in high rates of MRD negativity.

Collectively, the findings bode well for the quadruple regimens in the treatment of MM, the editorialists emphasized.

“Importantly, with the rate of deep remissions observed with antibody-based quadruplet therapies, one may question the role of using early high-dose melphalan and autologous stem cell transplant in every patient, especially in those who have achieved MRD negativity with the quadruplet alone,” they added.

The study was sponsored in part by Amgen, Bristol-Myers Squibb, and the Multiple Myeloma Research Consortium. Dr. Derman reported advisory board fees from Sanofi, Janssen, and COTA Healthcare; honoraria from PleXus Communications and MJH Life Sciences. Dr. Kazandjian declares receiving advisory board or consulting fees from Bristol-Myers Squibb, Sanofi, and Arcellx outside the submitted work. Dr. Landgren has received grant support from numerous organizations and pharmaceutical companies. Dr. Landgren has also received honoraria for scientific talks/participated in advisory boards for Adaptive Biotech, Amgen, Binding Site, Bristol-Myers Squibb, Celgene, Cellectis, Glenmark, Janssen, Juno, and Pfizer, and served on independent data monitoring committees for international randomized trials by Takeda, Merck, Janssen, and Theradex.

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

Higher adenoma detection rates (ADR) during colonoscopies were associated with lower rates of interim colorectal cancer (CRC), and the relationship held true along a broad range of ADR values, according to a retrospective study.

The new study, published online in JAMA, examined ADRs and rates of interim colorectal cancer among patients in California and Washington State between 2011 and 2017. The authors found a 3% reduction in risk for each additional 1% value of ADR. The reduction in risk held true even at high ADRs.

“It basically reaffirms what we’ve believed for the longest time, and other research work has documented – that interim cancers are higher in association with lower adenoma detection rates. The higher you can get that adenoma detection rate, the more we’re going to be able to lower the [rate of] cancers that develop within 3 years of a colonoscopy,” said Lawrence Kosinski, MD, who was asked to comment on the study.

The study included 735,396 patients with a median age of 61.4 years. Among these patients, 852,624 negative colonoscopies were performed by 383 eligible physicians. Participating physicians had to perform at least 25 screening colonoscopies and 100 total colonoscopies per year. After 2.4 million person-years of follow-up, the researchers observed 619 postcolonoscopy colorectal cancers and 36 related deaths over a median follow-up of 3.25 years.

There was an association between each 1% increase in ADR and a reduced probability of postcolonoscopy CRC (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.96-0.98) and mortality from postcolonoscopy CRC (HR, 0.95; 95% CI, 0.92-0.99).

The median ADR was 28.3%. There was an association between ADR above the median versus below the median and a reduced risk of postcolonoscopy CRC with 1.79 cases versus 3.10 cases per 10,000 person-years, respectively (absolute difference in 7-year risk, –12.2 per 10,000 negative colonoscopies; HR, 0.61; 95% CI, 0.52-0.73). There was a similar reduction in risk of postcolonoscopy CRC-related mortality (0.05 versus 0.22 per 10,000 person-years; absolute difference in 7-year risk, –1.2 per 10,000 negative colonoscopies; HR, 0.26; 95% CI, 0.11-0.65).

These findings may be limited in generalizability to physicians with lower procedure volumes or to populations with different adenoma prevalence.

“Given the strong, consistent associations of higher adenoma detection rates with colonoscopy effectiveness for reducing colorectal cancer incidence and mortality, the current results support more research to identify reliable and readily adoptable methods for increasing adenoma detection rates among physicians with lower values across diverse settings,” the researchers wrote.

The improvement over a broad range of ADRs, along with other recent findings, suggests that there may need to be updates to the use of ADRs as a quality metric, according to an accompanying editorial by Douglas K. Rex, MD, of the division of gastroenterology/hepatology at Indiana University, Indianapolis. For example, it’s possible that ADRs could be measured by averaging values from screening, diagnostic, and surveillance colonoscopy. The editorialist suggested that, if improvements in interim cancer rates continue as ADRs approach 50%, the current view of ADRs, as a minimally acceptable standard, may require reconsideration. Instead, it may be appropriate to continue with a minimum threshold, but add a much higher, aspirational target. Dr. Rex also suggested that highly-variable detection of sessile serrated lesions could be excluded from ADRs in order to reduce variability.
 

Factors to consider

The study is useful, but it doesn’t address the disparity in adenoma detection that exists between individual doctors, according to Dr. Kosinski, founder and chief medical officer of SonarMD and previously director of a large gastroenterology clinic. “Even if you look at doctors who do a minimum of 250 screening colonoscopies in a year, there’s still variability. There was even a study published in 2014 showing ADRs anywhere from 7.4% to 52.5%. The bell curve is broad,” he said.

As patients age, they have a higher frequency of polyps appearing on the right side of the colon, and those polyps are flatter and more easily missed than polyps on the left side. “The variation in ADR is higher on the right side of the colon than it is on the left. Doctors have to really do a very good job of examining that right side of the colon so that they don’t miss the flat polyps,” said Dr. Kosinski.

To improve ADRs, Dr. Kosinski emphasized the need to take the required time out to complete a procedure, despite the tight schedules often faced by ambulatory centers. “It’s the time you take coming out of the colon that’s critical. You owe it to the patient,” he said.

And if a patient hasn’t prepped well enough, it’s better to send the patient home without the procedure than to conduct a poor-quality screening. “If you can’t see the mucosal surface, you can’t tell the patient that they have a negative colonoscopy. If you have to do more cleaning during the procedure, then do more cleaning during the procedure. If you have to cancel the procedure and bring the patient back, it’s better to do that than it is to do an incomplete colonoscopy,” said Dr. Kosinski.

He also stressed the need to make sure that the patient is properly sedated and comfortable “so that you can do the job you’re supposed to do,” he said.

Some authors disclosed relationships with Amgen and the National Cancer Institute. Dr. Rex disclosed relationships with Olympus, Boston Scientific, Aries, and others, all outside the submitted work.

Higher adenoma detection rates (ADR) during colonoscopies were associated with lower rates of interim colorectal cancer (CRC), and the relationship held true along a broad range of ADR values, according to a retrospective study.

The new study, published online in JAMA, examined ADRs and rates of interim colorectal cancer among patients in California and Washington State between 2011 and 2017. The authors found a 3% reduction in risk for each additional 1% value of ADR. The reduction in risk held true even at high ADRs.

“It basically reaffirms what we’ve believed for the longest time, and other research work has documented – that interim cancers are higher in association with lower adenoma detection rates. The higher you can get that adenoma detection rate, the more we’re going to be able to lower the [rate of] cancers that develop within 3 years of a colonoscopy,” said Lawrence Kosinski, MD, who was asked to comment on the study.

The study included 735,396 patients with a median age of 61.4 years. Among these patients, 852,624 negative colonoscopies were performed by 383 eligible physicians. Participating physicians had to perform at least 25 screening colonoscopies and 100 total colonoscopies per year. After 2.4 million person-years of follow-up, the researchers observed 619 postcolonoscopy colorectal cancers and 36 related deaths over a median follow-up of 3.25 years.

There was an association between each 1% increase in ADR and a reduced probability of postcolonoscopy CRC (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.96-0.98) and mortality from postcolonoscopy CRC (HR, 0.95; 95% CI, 0.92-0.99).

The median ADR was 28.3%. There was an association between ADR above the median versus below the median and a reduced risk of postcolonoscopy CRC with 1.79 cases versus 3.10 cases per 10,000 person-years, respectively (absolute difference in 7-year risk, –12.2 per 10,000 negative colonoscopies; HR, 0.61; 95% CI, 0.52-0.73). There was a similar reduction in risk of postcolonoscopy CRC-related mortality (0.05 versus 0.22 per 10,000 person-years; absolute difference in 7-year risk, –1.2 per 10,000 negative colonoscopies; HR, 0.26; 95% CI, 0.11-0.65).

These findings may be limited in generalizability to physicians with lower procedure volumes or to populations with different adenoma prevalence.

“Given the strong, consistent associations of higher adenoma detection rates with colonoscopy effectiveness for reducing colorectal cancer incidence and mortality, the current results support more research to identify reliable and readily adoptable methods for increasing adenoma detection rates among physicians with lower values across diverse settings,” the researchers wrote.

The improvement over a broad range of ADRs, along with other recent findings, suggests that there may need to be updates to the use of ADRs as a quality metric, according to an accompanying editorial by Douglas K. Rex, MD, of the division of gastroenterology/hepatology at Indiana University, Indianapolis. For example, it’s possible that ADRs could be measured by averaging values from screening, diagnostic, and surveillance colonoscopy. The editorialist suggested that, if improvements in interim cancer rates continue as ADRs approach 50%, the current view of ADRs, as a minimally acceptable standard, may require reconsideration. Instead, it may be appropriate to continue with a minimum threshold, but add a much higher, aspirational target. Dr. Rex also suggested that highly-variable detection of sessile serrated lesions could be excluded from ADRs in order to reduce variability.
 

Factors to consider

The study is useful, but it doesn’t address the disparity in adenoma detection that exists between individual doctors, according to Dr. Kosinski, founder and chief medical officer of SonarMD and previously director of a large gastroenterology clinic. “Even if you look at doctors who do a minimum of 250 screening colonoscopies in a year, there’s still variability. There was even a study published in 2014 showing ADRs anywhere from 7.4% to 52.5%. The bell curve is broad,” he said.

As patients age, they have a higher frequency of polyps appearing on the right side of the colon, and those polyps are flatter and more easily missed than polyps on the left side. “The variation in ADR is higher on the right side of the colon than it is on the left. Doctors have to really do a very good job of examining that right side of the colon so that they don’t miss the flat polyps,” said Dr. Kosinski.

To improve ADRs, Dr. Kosinski emphasized the need to take the required time out to complete a procedure, despite the tight schedules often faced by ambulatory centers. “It’s the time you take coming out of the colon that’s critical. You owe it to the patient,” he said.

And if a patient hasn’t prepped well enough, it’s better to send the patient home without the procedure than to conduct a poor-quality screening. “If you can’t see the mucosal surface, you can’t tell the patient that they have a negative colonoscopy. If you have to do more cleaning during the procedure, then do more cleaning during the procedure. If you have to cancel the procedure and bring the patient back, it’s better to do that than it is to do an incomplete colonoscopy,” said Dr. Kosinski.

He also stressed the need to make sure that the patient is properly sedated and comfortable “so that you can do the job you’re supposed to do,” he said.

Some authors disclosed relationships with Amgen and the National Cancer Institute. Dr. Rex disclosed relationships with Olympus, Boston Scientific, Aries, and others, all outside the submitted work.

Higher adenoma detection rates (ADR) during colonoscopies were associated with lower rates of interim colorectal cancer (CRC), and the relationship held true along a broad range of ADR values, according to a retrospective study.

The new study, published online in JAMA, examined ADRs and rates of interim colorectal cancer among patients in California and Washington State between 2011 and 2017. The authors found a 3% reduction in risk for each additional 1% value of ADR. The reduction in risk held true even at high ADRs.

“It basically reaffirms what we’ve believed for the longest time, and other research work has documented – that interim cancers are higher in association with lower adenoma detection rates. The higher you can get that adenoma detection rate, the more we’re going to be able to lower the [rate of] cancers that develop within 3 years of a colonoscopy,” said Lawrence Kosinski, MD, who was asked to comment on the study.

The study included 735,396 patients with a median age of 61.4 years. Among these patients, 852,624 negative colonoscopies were performed by 383 eligible physicians. Participating physicians had to perform at least 25 screening colonoscopies and 100 total colonoscopies per year. After 2.4 million person-years of follow-up, the researchers observed 619 postcolonoscopy colorectal cancers and 36 related deaths over a median follow-up of 3.25 years.

There was an association between each 1% increase in ADR and a reduced probability of postcolonoscopy CRC (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.96-0.98) and mortality from postcolonoscopy CRC (HR, 0.95; 95% CI, 0.92-0.99).

The median ADR was 28.3%. There was an association between ADR above the median versus below the median and a reduced risk of postcolonoscopy CRC with 1.79 cases versus 3.10 cases per 10,000 person-years, respectively (absolute difference in 7-year risk, –12.2 per 10,000 negative colonoscopies; HR, 0.61; 95% CI, 0.52-0.73). There was a similar reduction in risk of postcolonoscopy CRC-related mortality (0.05 versus 0.22 per 10,000 person-years; absolute difference in 7-year risk, –1.2 per 10,000 negative colonoscopies; HR, 0.26; 95% CI, 0.11-0.65).

These findings may be limited in generalizability to physicians with lower procedure volumes or to populations with different adenoma prevalence.

“Given the strong, consistent associations of higher adenoma detection rates with colonoscopy effectiveness for reducing colorectal cancer incidence and mortality, the current results support more research to identify reliable and readily adoptable methods for increasing adenoma detection rates among physicians with lower values across diverse settings,” the researchers wrote.

The improvement over a broad range of ADRs, along with other recent findings, suggests that there may need to be updates to the use of ADRs as a quality metric, according to an accompanying editorial by Douglas K. Rex, MD, of the division of gastroenterology/hepatology at Indiana University, Indianapolis. For example, it’s possible that ADRs could be measured by averaging values from screening, diagnostic, and surveillance colonoscopy. The editorialist suggested that, if improvements in interim cancer rates continue as ADRs approach 50%, the current view of ADRs, as a minimally acceptable standard, may require reconsideration. Instead, it may be appropriate to continue with a minimum threshold, but add a much higher, aspirational target. Dr. Rex also suggested that highly-variable detection of sessile serrated lesions could be excluded from ADRs in order to reduce variability.
 

Factors to consider

The study is useful, but it doesn’t address the disparity in adenoma detection that exists between individual doctors, according to Dr. Kosinski, founder and chief medical officer of SonarMD and previously director of a large gastroenterology clinic. “Even if you look at doctors who do a minimum of 250 screening colonoscopies in a year, there’s still variability. There was even a study published in 2014 showing ADRs anywhere from 7.4% to 52.5%. The bell curve is broad,” he said.

As patients age, they have a higher frequency of polyps appearing on the right side of the colon, and those polyps are flatter and more easily missed than polyps on the left side. “The variation in ADR is higher on the right side of the colon than it is on the left. Doctors have to really do a very good job of examining that right side of the colon so that they don’t miss the flat polyps,” said Dr. Kosinski.

To improve ADRs, Dr. Kosinski emphasized the need to take the required time out to complete a procedure, despite the tight schedules often faced by ambulatory centers. “It’s the time you take coming out of the colon that’s critical. You owe it to the patient,” he said.

And if a patient hasn’t prepped well enough, it’s better to send the patient home without the procedure than to conduct a poor-quality screening. “If you can’t see the mucosal surface, you can’t tell the patient that they have a negative colonoscopy. If you have to do more cleaning during the procedure, then do more cleaning during the procedure. If you have to cancel the procedure and bring the patient back, it’s better to do that than it is to do an incomplete colonoscopy,” said Dr. Kosinski.

He also stressed the need to make sure that the patient is properly sedated and comfortable “so that you can do the job you’re supposed to do,” he said.

Some authors disclosed relationships with Amgen and the National Cancer Institute. Dr. Rex disclosed relationships with Olympus, Boston Scientific, Aries, and others, all outside the submitted work.

It was 2 a.m. And Rebecca Shatsky, MD, could not sleep.

The breast oncologist was thinking about a patient of hers with metastatic cancer.

The patient’s disease had been asymptomatic for some time. Then without warning, her cancer suddenly exploded. Her bone marrow was failing, and her liver was not far behind.

Dr. Shatsky had a treatment plan ready to go but still, she felt uneasy.

“I had to be honest with her that I didn’t know if this plan would work,” says Dr. Shatsky, a medical oncologist at University of California, San Diego (UCSD).

That night, after visiting the patient in the hospital, Dr. Shatsky lay awake going over her next move, making sure it was the right one and hoping it would help keep the disease at bay.

“It’s so much pressure when someone is depending on you to make life or death decisions,” Dr. Shatsky said.

And in the quiet hours of night, these concerns grow louder.

Dr. Shatsky is not alone. Oncologists face difficult decisions every day, and many wrestle with these choices long after their day in the clinic is over.

“There’s no off button,” says Aaron Goodman, MD, a hematologist at UCSD Health who goes by “Papa Heme” on Twitter. “I’m always thinking about my patients. Constantly.”

The public rarely gets a glimpse of these private moments. On occasion, oncologists will share a personal story, but more often, insights come from broad research on the ethical, emotional, and psychological toll of practicing medicine.

Many oncologists carry this baggage home with them because they have no other option.

“There is simply no time to process the weight of the day when I’ve got seven more patients who need my full attention before lunch,” Mark Lewis, MD, director, department of gastrointestinal oncology, Intermountain Healthcare, Salt Lake City, Utah. “That is why my processing happens outside of the office, when my brain can be quiet.”
 

What am I missing?

Dr. Goodman recognizes the gravity of each decision he makes. He pores over every detail of a patient’s scans, lab results, history, and symptoms.

But no matter how many times he checks and rechecks, one question nags at him: What am I missing?

For Dr. Goodman, this exhaustive level of attention is worth it.

“When errors are made, it’s someone’s life,” Dr. Goodman said. “Nothing would have prepared me for this responsibility. Until it lies on you, it’s impossible to understand how much trust patients put into us.”

That trust becomes most apparent for Dr. Goodman when facing a decision about how to treat a patient with acute myeloid leukemia who’s in remission.

Give more chemotherapy to root out the leukemia cells still lurking in the body, and the patient faces a high risk of the cancer returning. Pick stem cell transplant, and the chance of being cured goes up significantly, but the patient could also die within 100 days of the transplant.

“All together, the data show I’m helping patients with a transplant, but for the individual, I could be causing harm. Someone could be living less because of a decision I made,” Dr. Goodman said.

For patients with advanced cancer, oncologists may need to think several moves ahead. Mapping out a patient’s treatment options can feel like a game of chess. Dr. Shatsky is always trying to anticipate how the tumor will behave, what is driving it, and how lifestyle factors may influence a patient’s response in the present and the future.

“It is a mind game,” she says. “Like in chess, I try to outsmart my opponent. But with advanced cancer, there are not necessarily clear-cut guidelines or one way to manage the disease, and I have to do the best I can with drugs I have.”

That’s the art of oncology: Balancing the many knowns and unknowns of a person’s cancer alongside the toxicities of treatment and a patient’s hopes and goals.

Throughout the year, Don Dizon, MD, will see a number of patients with advanced disease. In these instances, the question he often wrestles with is if the patient can’t be cured, whether more treatment will just cause greater harm.

Dr. Dizon recently faced this dilemma with an older patient with metastatic disease who had not done well with an initial treatment regimen. After outlining the risks for more chemotherapy, he explained one option would be to forgo it and simply treat her symptoms.

“It’s an impossible choice,” says Dr. Dizon, director of women’s cancers at Lifespan Cancer Institute and director of medical oncology at Rhode Island Hospital, Providence.

Chemotherapy can provide symptom relief, but it can also be toxic – and patients may be so frail, they can die from more therapy.

“I told my patient, if in your heart, you want to try more therapy, that’s okay. But it’s also okay if you don’t,” Dr. Dizon recalled.

Her response: “You’re supposed to give me the answer.”

However, for patients approaching the end of life, there often is no right answer. 

“It’s part of the discomfort you live with as a patient and oncologist, and when I leave the clinic, that’s one thing that follows me home,” Dr. Dizon said. “At the end of the day, I need to look in the mirror and know I did the best I could.”
 

The difficult conversation

Every Sunday, Dr. Lewis feels the weight of the week ahead. He and his wife, a pediatrician, call it the “Sunday scaries.”

It’s when Dr. Lewis begins thinking about the delicate conversations to come, rehearsing how he’s going to share the news that a person has advanced cancer or that a cancer, once in remission, has returned.

“Before the pandemic, I had 36 people come to a visit where I delivered some very heavy news and it became a Greek chorus of sobbing,” he recalls.

For every oncologist, delivering bad news is an integral part of the job. But after spending months, sometimes years, with a patient and the family, Dr. Lewis knows how to take the temperature of the room – who will likely prefer a more blunt style and who might need a gentler touch.

“The longer you know a patient and family, the better you can gauge the best approach,” Dr. Lewis said. “And for some, you know it’ll be complete devastation no matter what.”

When Jennifer Lycette, MD, prepares for a difficult conversation, she’ll run down all the possible ways it could go. Sometimes her brain will get stuck in a loop, cycling through the different trajectories on repeat.

“For years, I didn’t know how to cope with that,” said Dr. Lycette, medical director at Providence Oncology and Hematology Care Clinic in Seaside, Ore. “I wasn’t taught the tools to cope with that in my medical training. It took midcareer professional coaching that I sought out on my own to learn to remind myself that no matter what the person says, I have the experience and skill set to handle what comes next and to simply be present in the moment with the patient.”

The question that now sits with Dr. Lycette hours after a visit is what she could have done better. She knows from experience how important it is to choose her words carefully.

Early in her career, Dr. Lycette had a patient with stage IV cancer who wanted to know more about the death process. Because most people ask about pain, she assured him that he likely wouldn’t experience too much pain with his type of cancer.

“It will probably be like falling asleep,” said Dr. Lycette, hoping she was offering comfort. “When I saw him next, he told me he hadn’t slept.”

He was afraid that if he did, he wouldn’t wake up.

In that moment, Dr. Lycette realized the power that her words carry and the importance of trying to understand the inner lives of her patients.
 

Life outside the clinic

Sometimes an oncologist’s late-night ruminations have little to do with cancer itself.

Manali Patel, MD, finds herself worrying if her patients will have enough to eat and whether she will be able to help.

“I was up at 3 a.m. one morning, thinking about how we’re going to fund a project for patients from low-income households who we discovered were experiencing severe food insecurity – what grants we need, what foundations we can work with,” said Dr. Patel, a medical oncologist at Stanford Hospital and Clinics and the VA Palo Alto Health Care System in California.

The past few years of the pandemic have added a new layer of worry for Dr. Patel.

“I don’t want my patients to die from a preventable virus when they’ve already been through so much suffering,” Dr. Patel said.

This thought feeds worries about how her actions outside the clinic could unintentionally harm her patients. Should she go to a big medical conference? A family gathering? The grocery store?

“There are some places you can’t avoid, but these decisions have caused a lot of strife for me,” she said. “The health and safety of our patients – that’s in our wheelhouse – but so many of the policies are outside of our control.”
 

The inevitable losses and the wins

For patients with metastatic disease, eventually the treatment options will run out.

Dr. Shatsky likes to be up front with patients about that reality: “There will come a day when I will tell you there’s nothing more I can do, and you need to trust that I’m being honest with you and that’s the truth.”

For Dr. Goodman, the devastation that bad news brings patients and families is glaring. He knows there will be no more normalcy in their lives.

“I see a lot of suffering, but I know the suffering happens regardless of whether I see it or not,” Dr. Goodman said.

That’s why holding on to the victories can be so important. Dr. Goodman recalled a young patient who came to him with a 20-cm tumor and is now cured. “Had I not met that individual and done what I had done, he’d be dead, but now he’s going to live his life,” Dr. Goodman said. “But I don’t wake up at 2 a.m. thinking about that.”

Dr. Shatsky gets a lot of joy from the wins – the patients who do really well, the times when she can help a friend or colleagues – and those moments go a long way to outweigh the hurt, worry, and workload.

When dealing with so much gray, “the wins are important, knowing you can make a difference is important,” Dr. Dizon said.

And there’s a delicate balance.

“I think patients want an oncologist who cares and is genuinely invested in their outcomes but not someone who is so sad all the time,” Dr. Lewis said. “When I lose a patient, I still grieve each loss, but I can’t mourn every patient’s death like it’s a family member. Otherwise, I’d break.”

What would you do if you had terminal cancer?

Dr. Dizon recalled how a friend handled the news. She went home and made dinner, he said.

Ultimately, she lived for many years. She saw her kids get married, met her first grandchild, and had time to prepare, something not everyone gets the chance to do.

That’s why it’s important to “do what you normally do as long as you can,” Dr. Dizon said. “Live your life.”

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

It was 2 a.m. And Rebecca Shatsky, MD, could not sleep.

The breast oncologist was thinking about a patient of hers with metastatic cancer.

The patient’s disease had been asymptomatic for some time. Then without warning, her cancer suddenly exploded. Her bone marrow was failing, and her liver was not far behind.

Dr. Shatsky had a treatment plan ready to go but still, she felt uneasy.

“I had to be honest with her that I didn’t know if this plan would work,” says Dr. Shatsky, a medical oncologist at University of California, San Diego (UCSD).

That night, after visiting the patient in the hospital, Dr. Shatsky lay awake going over her next move, making sure it was the right one and hoping it would help keep the disease at bay.

“It’s so much pressure when someone is depending on you to make life or death decisions,” Dr. Shatsky said.

And in the quiet hours of night, these concerns grow louder.

Dr. Shatsky is not alone. Oncologists face difficult decisions every day, and many wrestle with these choices long after their day in the clinic is over.

“There’s no off button,” says Aaron Goodman, MD, a hematologist at UCSD Health who goes by “Papa Heme” on Twitter. “I’m always thinking about my patients. Constantly.”

The public rarely gets a glimpse of these private moments. On occasion, oncologists will share a personal story, but more often, insights come from broad research on the ethical, emotional, and psychological toll of practicing medicine.

Many oncologists carry this baggage home with them because they have no other option.

“There is simply no time to process the weight of the day when I’ve got seven more patients who need my full attention before lunch,” Mark Lewis, MD, director, department of gastrointestinal oncology, Intermountain Healthcare, Salt Lake City, Utah. “That is why my processing happens outside of the office, when my brain can be quiet.”
 

What am I missing?

Dr. Goodman recognizes the gravity of each decision he makes. He pores over every detail of a patient’s scans, lab results, history, and symptoms.

But no matter how many times he checks and rechecks, one question nags at him: What am I missing?

For Dr. Goodman, this exhaustive level of attention is worth it.

“When errors are made, it’s someone’s life,” Dr. Goodman said. “Nothing would have prepared me for this responsibility. Until it lies on you, it’s impossible to understand how much trust patients put into us.”

That trust becomes most apparent for Dr. Goodman when facing a decision about how to treat a patient with acute myeloid leukemia who’s in remission.

Give more chemotherapy to root out the leukemia cells still lurking in the body, and the patient faces a high risk of the cancer returning. Pick stem cell transplant, and the chance of being cured goes up significantly, but the patient could also die within 100 days of the transplant.

“All together, the data show I’m helping patients with a transplant, but for the individual, I could be causing harm. Someone could be living less because of a decision I made,” Dr. Goodman said.

For patients with advanced cancer, oncologists may need to think several moves ahead. Mapping out a patient’s treatment options can feel like a game of chess. Dr. Shatsky is always trying to anticipate how the tumor will behave, what is driving it, and how lifestyle factors may influence a patient’s response in the present and the future.

“It is a mind game,” she says. “Like in chess, I try to outsmart my opponent. But with advanced cancer, there are not necessarily clear-cut guidelines or one way to manage the disease, and I have to do the best I can with drugs I have.”

That’s the art of oncology: Balancing the many knowns and unknowns of a person’s cancer alongside the toxicities of treatment and a patient’s hopes and goals.

Throughout the year, Don Dizon, MD, will see a number of patients with advanced disease. In these instances, the question he often wrestles with is if the patient can’t be cured, whether more treatment will just cause greater harm.

Dr. Dizon recently faced this dilemma with an older patient with metastatic disease who had not done well with an initial treatment regimen. After outlining the risks for more chemotherapy, he explained one option would be to forgo it and simply treat her symptoms.

“It’s an impossible choice,” says Dr. Dizon, director of women’s cancers at Lifespan Cancer Institute and director of medical oncology at Rhode Island Hospital, Providence.

Chemotherapy can provide symptom relief, but it can also be toxic – and patients may be so frail, they can die from more therapy.

“I told my patient, if in your heart, you want to try more therapy, that’s okay. But it’s also okay if you don’t,” Dr. Dizon recalled.

Her response: “You’re supposed to give me the answer.”

However, for patients approaching the end of life, there often is no right answer. 

“It’s part of the discomfort you live with as a patient and oncologist, and when I leave the clinic, that’s one thing that follows me home,” Dr. Dizon said. “At the end of the day, I need to look in the mirror and know I did the best I could.”
 

The difficult conversation

Every Sunday, Dr. Lewis feels the weight of the week ahead. He and his wife, a pediatrician, call it the “Sunday scaries.”

It’s when Dr. Lewis begins thinking about the delicate conversations to come, rehearsing how he’s going to share the news that a person has advanced cancer or that a cancer, once in remission, has returned.

“Before the pandemic, I had 36 people come to a visit where I delivered some very heavy news and it became a Greek chorus of sobbing,” he recalls.

For every oncologist, delivering bad news is an integral part of the job. But after spending months, sometimes years, with a patient and the family, Dr. Lewis knows how to take the temperature of the room – who will likely prefer a more blunt style and who might need a gentler touch.

“The longer you know a patient and family, the better you can gauge the best approach,” Dr. Lewis said. “And for some, you know it’ll be complete devastation no matter what.”

When Jennifer Lycette, MD, prepares for a difficult conversation, she’ll run down all the possible ways it could go. Sometimes her brain will get stuck in a loop, cycling through the different trajectories on repeat.

“For years, I didn’t know how to cope with that,” said Dr. Lycette, medical director at Providence Oncology and Hematology Care Clinic in Seaside, Ore. “I wasn’t taught the tools to cope with that in my medical training. It took midcareer professional coaching that I sought out on my own to learn to remind myself that no matter what the person says, I have the experience and skill set to handle what comes next and to simply be present in the moment with the patient.”

The question that now sits with Dr. Lycette hours after a visit is what she could have done better. She knows from experience how important it is to choose her words carefully.

Early in her career, Dr. Lycette had a patient with stage IV cancer who wanted to know more about the death process. Because most people ask about pain, she assured him that he likely wouldn’t experience too much pain with his type of cancer.

“It will probably be like falling asleep,” said Dr. Lycette, hoping she was offering comfort. “When I saw him next, he told me he hadn’t slept.”

He was afraid that if he did, he wouldn’t wake up.

In that moment, Dr. Lycette realized the power that her words carry and the importance of trying to understand the inner lives of her patients.
 

Life outside the clinic

Sometimes an oncologist’s late-night ruminations have little to do with cancer itself.

Manali Patel, MD, finds herself worrying if her patients will have enough to eat and whether she will be able to help.

“I was up at 3 a.m. one morning, thinking about how we’re going to fund a project for patients from low-income households who we discovered were experiencing severe food insecurity – what grants we need, what foundations we can work with,” said Dr. Patel, a medical oncologist at Stanford Hospital and Clinics and the VA Palo Alto Health Care System in California.

The past few years of the pandemic have added a new layer of worry for Dr. Patel.

“I don’t want my patients to die from a preventable virus when they’ve already been through so much suffering,” Dr. Patel said.

This thought feeds worries about how her actions outside the clinic could unintentionally harm her patients. Should she go to a big medical conference? A family gathering? The grocery store?

“There are some places you can’t avoid, but these decisions have caused a lot of strife for me,” she said. “The health and safety of our patients – that’s in our wheelhouse – but so many of the policies are outside of our control.”
 

The inevitable losses and the wins

For patients with metastatic disease, eventually the treatment options will run out.

Dr. Shatsky likes to be up front with patients about that reality: “There will come a day when I will tell you there’s nothing more I can do, and you need to trust that I’m being honest with you and that’s the truth.”

For Dr. Goodman, the devastation that bad news brings patients and families is glaring. He knows there will be no more normalcy in their lives.

“I see a lot of suffering, but I know the suffering happens regardless of whether I see it or not,” Dr. Goodman said.

That’s why holding on to the victories can be so important. Dr. Goodman recalled a young patient who came to him with a 20-cm tumor and is now cured. “Had I not met that individual and done what I had done, he’d be dead, but now he’s going to live his life,” Dr. Goodman said. “But I don’t wake up at 2 a.m. thinking about that.”

Dr. Shatsky gets a lot of joy from the wins – the patients who do really well, the times when she can help a friend or colleagues – and those moments go a long way to outweigh the hurt, worry, and workload.

When dealing with so much gray, “the wins are important, knowing you can make a difference is important,” Dr. Dizon said.

And there’s a delicate balance.

“I think patients want an oncologist who cares and is genuinely invested in their outcomes but not someone who is so sad all the time,” Dr. Lewis said. “When I lose a patient, I still grieve each loss, but I can’t mourn every patient’s death like it’s a family member. Otherwise, I’d break.”

What would you do if you had terminal cancer?

Dr. Dizon recalled how a friend handled the news. She went home and made dinner, he said.

Ultimately, she lived for many years. She saw her kids get married, met her first grandchild, and had time to prepare, something not everyone gets the chance to do.

That’s why it’s important to “do what you normally do as long as you can,” Dr. Dizon said. “Live your life.”

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

It was 2 a.m. And Rebecca Shatsky, MD, could not sleep.

The breast oncologist was thinking about a patient of hers with metastatic cancer.

The patient’s disease had been asymptomatic for some time. Then without warning, her cancer suddenly exploded. Her bone marrow was failing, and her liver was not far behind.

Dr. Shatsky had a treatment plan ready to go but still, she felt uneasy.

“I had to be honest with her that I didn’t know if this plan would work,” says Dr. Shatsky, a medical oncologist at University of California, San Diego (UCSD).

That night, after visiting the patient in the hospital, Dr. Shatsky lay awake going over her next move, making sure it was the right one and hoping it would help keep the disease at bay.

“It’s so much pressure when someone is depending on you to make life or death decisions,” Dr. Shatsky said.

And in the quiet hours of night, these concerns grow louder.

Dr. Shatsky is not alone. Oncologists face difficult decisions every day, and many wrestle with these choices long after their day in the clinic is over.

“There’s no off button,” says Aaron Goodman, MD, a hematologist at UCSD Health who goes by “Papa Heme” on Twitter. “I’m always thinking about my patients. Constantly.”

The public rarely gets a glimpse of these private moments. On occasion, oncologists will share a personal story, but more often, insights come from broad research on the ethical, emotional, and psychological toll of practicing medicine.

Many oncologists carry this baggage home with them because they have no other option.

“There is simply no time to process the weight of the day when I’ve got seven more patients who need my full attention before lunch,” Mark Lewis, MD, director, department of gastrointestinal oncology, Intermountain Healthcare, Salt Lake City, Utah. “That is why my processing happens outside of the office, when my brain can be quiet.”
 

What am I missing?

Dr. Goodman recognizes the gravity of each decision he makes. He pores over every detail of a patient’s scans, lab results, history, and symptoms.

But no matter how many times he checks and rechecks, one question nags at him: What am I missing?

For Dr. Goodman, this exhaustive level of attention is worth it.

“When errors are made, it’s someone’s life,” Dr. Goodman said. “Nothing would have prepared me for this responsibility. Until it lies on you, it’s impossible to understand how much trust patients put into us.”

That trust becomes most apparent for Dr. Goodman when facing a decision about how to treat a patient with acute myeloid leukemia who’s in remission.

Give more chemotherapy to root out the leukemia cells still lurking in the body, and the patient faces a high risk of the cancer returning. Pick stem cell transplant, and the chance of being cured goes up significantly, but the patient could also die within 100 days of the transplant.

“All together, the data show I’m helping patients with a transplant, but for the individual, I could be causing harm. Someone could be living less because of a decision I made,” Dr. Goodman said.

For patients with advanced cancer, oncologists may need to think several moves ahead. Mapping out a patient’s treatment options can feel like a game of chess. Dr. Shatsky is always trying to anticipate how the tumor will behave, what is driving it, and how lifestyle factors may influence a patient’s response in the present and the future.

“It is a mind game,” she says. “Like in chess, I try to outsmart my opponent. But with advanced cancer, there are not necessarily clear-cut guidelines or one way to manage the disease, and I have to do the best I can with drugs I have.”

That’s the art of oncology: Balancing the many knowns and unknowns of a person’s cancer alongside the toxicities of treatment and a patient’s hopes and goals.

Throughout the year, Don Dizon, MD, will see a number of patients with advanced disease. In these instances, the question he often wrestles with is if the patient can’t be cured, whether more treatment will just cause greater harm.

Dr. Dizon recently faced this dilemma with an older patient with metastatic disease who had not done well with an initial treatment regimen. After outlining the risks for more chemotherapy, he explained one option would be to forgo it and simply treat her symptoms.

“It’s an impossible choice,” says Dr. Dizon, director of women’s cancers at Lifespan Cancer Institute and director of medical oncology at Rhode Island Hospital, Providence.

Chemotherapy can provide symptom relief, but it can also be toxic – and patients may be so frail, they can die from more therapy.

“I told my patient, if in your heart, you want to try more therapy, that’s okay. But it’s also okay if you don’t,” Dr. Dizon recalled.

Her response: “You’re supposed to give me the answer.”

However, for patients approaching the end of life, there often is no right answer. 

“It’s part of the discomfort you live with as a patient and oncologist, and when I leave the clinic, that’s one thing that follows me home,” Dr. Dizon said. “At the end of the day, I need to look in the mirror and know I did the best I could.”
 

The difficult conversation

Every Sunday, Dr. Lewis feels the weight of the week ahead. He and his wife, a pediatrician, call it the “Sunday scaries.”

It’s when Dr. Lewis begins thinking about the delicate conversations to come, rehearsing how he’s going to share the news that a person has advanced cancer or that a cancer, once in remission, has returned.

“Before the pandemic, I had 36 people come to a visit where I delivered some very heavy news and it became a Greek chorus of sobbing,” he recalls.

For every oncologist, delivering bad news is an integral part of the job. But after spending months, sometimes years, with a patient and the family, Dr. Lewis knows how to take the temperature of the room – who will likely prefer a more blunt style and who might need a gentler touch.

“The longer you know a patient and family, the better you can gauge the best approach,” Dr. Lewis said. “And for some, you know it’ll be complete devastation no matter what.”

When Jennifer Lycette, MD, prepares for a difficult conversation, she’ll run down all the possible ways it could go. Sometimes her brain will get stuck in a loop, cycling through the different trajectories on repeat.

“For years, I didn’t know how to cope with that,” said Dr. Lycette, medical director at Providence Oncology and Hematology Care Clinic in Seaside, Ore. “I wasn’t taught the tools to cope with that in my medical training. It took midcareer professional coaching that I sought out on my own to learn to remind myself that no matter what the person says, I have the experience and skill set to handle what comes next and to simply be present in the moment with the patient.”

The question that now sits with Dr. Lycette hours after a visit is what she could have done better. She knows from experience how important it is to choose her words carefully.

Early in her career, Dr. Lycette had a patient with stage IV cancer who wanted to know more about the death process. Because most people ask about pain, she assured him that he likely wouldn’t experience too much pain with his type of cancer.

“It will probably be like falling asleep,” said Dr. Lycette, hoping she was offering comfort. “When I saw him next, he told me he hadn’t slept.”

He was afraid that if he did, he wouldn’t wake up.

In that moment, Dr. Lycette realized the power that her words carry and the importance of trying to understand the inner lives of her patients.
 

Life outside the clinic

Sometimes an oncologist’s late-night ruminations have little to do with cancer itself.

Manali Patel, MD, finds herself worrying if her patients will have enough to eat and whether she will be able to help.

“I was up at 3 a.m. one morning, thinking about how we’re going to fund a project for patients from low-income households who we discovered were experiencing severe food insecurity – what grants we need, what foundations we can work with,” said Dr. Patel, a medical oncologist at Stanford Hospital and Clinics and the VA Palo Alto Health Care System in California.

The past few years of the pandemic have added a new layer of worry for Dr. Patel.

“I don’t want my patients to die from a preventable virus when they’ve already been through so much suffering,” Dr. Patel said.

This thought feeds worries about how her actions outside the clinic could unintentionally harm her patients. Should she go to a big medical conference? A family gathering? The grocery store?

“There are some places you can’t avoid, but these decisions have caused a lot of strife for me,” she said. “The health and safety of our patients – that’s in our wheelhouse – but so many of the policies are outside of our control.”
 

The inevitable losses and the wins

For patients with metastatic disease, eventually the treatment options will run out.

Dr. Shatsky likes to be up front with patients about that reality: “There will come a day when I will tell you there’s nothing more I can do, and you need to trust that I’m being honest with you and that’s the truth.”

For Dr. Goodman, the devastation that bad news brings patients and families is glaring. He knows there will be no more normalcy in their lives.

“I see a lot of suffering, but I know the suffering happens regardless of whether I see it or not,” Dr. Goodman said.

That’s why holding on to the victories can be so important. Dr. Goodman recalled a young patient who came to him with a 20-cm tumor and is now cured. “Had I not met that individual and done what I had done, he’d be dead, but now he’s going to live his life,” Dr. Goodman said. “But I don’t wake up at 2 a.m. thinking about that.”

Dr. Shatsky gets a lot of joy from the wins – the patients who do really well, the times when she can help a friend or colleagues – and those moments go a long way to outweigh the hurt, worry, and workload.

When dealing with so much gray, “the wins are important, knowing you can make a difference is important,” Dr. Dizon said.

And there’s a delicate balance.

“I think patients want an oncologist who cares and is genuinely invested in their outcomes but not someone who is so sad all the time,” Dr. Lewis said. “When I lose a patient, I still grieve each loss, but I can’t mourn every patient’s death like it’s a family member. Otherwise, I’d break.”

What would you do if you had terminal cancer?

Dr. Dizon recalled how a friend handled the news. She went home and made dinner, he said.

Ultimately, she lived for many years. She saw her kids get married, met her first grandchild, and had time to prepare, something not everyone gets the chance to do.

That’s why it’s important to “do what you normally do as long as you can,” Dr. Dizon said. “Live your life.”

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

More than half of studies testing anticancer drugs against each other have rules with regard to dose modification and growth support that favor the experimental drug arm, a new analysis suggests.

“We found it sobering that this practice is so common,” Timothée Olivier, MD, with Geneva University Hospital and the University of California, San Francisco, said in an interview.

Trials may be “rigged” in a way where the new therapy appears more effective than if the trial would have been designed with fairer rules, he explained.

This leaves open the question of whether new drugs are truly superior to older ones or if instead different outcomes are caused by more aggressive dosing or growth factor support, the investigators said.

Dr. Olivier, with UCSF coinvestigators Alyson Haslam, PhD, and Vinay Prasad, MD, reported their findings online in the European Journal of Cancer.

‘Highly concerning’

Different drug modification rules or growth factor support guidance may affect the results of randomized controlled trials (RCTs) of testing new cancer agents.

For their study, Dr. Olivier and colleagues did a cross-sectional analysis of all 62 head-to-head registration RCTs that led to Food and Drug Administration approval between 2009 and 2021.

All of the trials examined anticancer drugs in the advanced or metastatic setting where a comparison was made between arms regarding either dose modification rules or myeloid growth factors recommendations.

The researchers assessed imbalance in drug modification rules, myeloid growth factor recommendations, or both, according to prespecified rules.

They discovered that 40 of the 62 trials (65%) had unequal rules for dose medication, granulocyte colony-stimulating factor (G-CSF) use, or both.

Six trials (10%) had rules favoring the control arm, while 34 (55%) had rules favoring the experimental arm. Among these, 50% had unequal drug modification rules, 41% had unequal G-CSF rules, and 9% had both.

Dr. Olivier said in an interview the results are “highly concerning because when you are investigating the effect of a new drug, you don’t want to have a false sense of a drug’s effect because of other factors not directly related to the drug’s efficacy.”

“If you introduce unfair rules about dose modification or supporting medication that favors the new drug, then you don’t know if a positive trial is due to the effect of the new drug or to the effect of differential dosing or supporting medication,” he added.
 

Blame industry?

Dr. Olivier said the fact that most registration trials are industry-sponsored is likely the primary explanation of the findings.

“Industry-sponsored trials may be designed so that the new drug has the best chance to get the largest ‘win,’ because this means more market share and more profit for the company that manufactures the drug. This is not a criticism of the industry, which runs on a business model that naturally aims to gain more market share and more profit,” Dr. Olivier said.

“However, it is the role and duty of regulators to reconcile industry incentives with the patients’ best interests, and there is accumulating data showing the regulators are failing to do so,” he added.

Addressing this problem will likely take buy-in from multiple stakeholders.

Awareness of the problem is a first step and understanding the influence of commercial incentives in drug development is also key, Dr. Olivier said.

Institutional review boards and drug regulators could also systematically evaluate drug dosing modification and supportive medication rules before a trial gets underway.

Regulators could also incentivize companies to implement balanced rules between arms by not granting drug approval based on trials suffering from such flaws.

“However, financial conflict of interest is present at many levels of drug development, including in drug regulation,” Dr. Olivier noted.

He pointed to a recent study that found when hematology-oncology medical reviewers working at the FDA leave the agency, more than half end up working or consulting for the pharmaceutical industry.

Dr. Olivier wondered: “How can one fairly and independently appraise a medical intervention if one’s current or future revenue depends on its source?”

The study was funded by Arnold Ventures, through a grant paid to UCSF. Dr. Olivier and Dr. Haslam had no relevant disclosures. Dr. Prasad reported receiving royalties from Arnold Ventures.

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

More than half of studies testing anticancer drugs against each other have rules with regard to dose modification and growth support that favor the experimental drug arm, a new analysis suggests.

“We found it sobering that this practice is so common,” Timothée Olivier, MD, with Geneva University Hospital and the University of California, San Francisco, said in an interview.

Trials may be “rigged” in a way where the new therapy appears more effective than if the trial would have been designed with fairer rules, he explained.

This leaves open the question of whether new drugs are truly superior to older ones or if instead different outcomes are caused by more aggressive dosing or growth factor support, the investigators said.

Dr. Olivier, with UCSF coinvestigators Alyson Haslam, PhD, and Vinay Prasad, MD, reported their findings online in the European Journal of Cancer.

‘Highly concerning’

Different drug modification rules or growth factor support guidance may affect the results of randomized controlled trials (RCTs) of testing new cancer agents.

For their study, Dr. Olivier and colleagues did a cross-sectional analysis of all 62 head-to-head registration RCTs that led to Food and Drug Administration approval between 2009 and 2021.

All of the trials examined anticancer drugs in the advanced or metastatic setting where a comparison was made between arms regarding either dose modification rules or myeloid growth factors recommendations.

The researchers assessed imbalance in drug modification rules, myeloid growth factor recommendations, or both, according to prespecified rules.

They discovered that 40 of the 62 trials (65%) had unequal rules for dose medication, granulocyte colony-stimulating factor (G-CSF) use, or both.

Six trials (10%) had rules favoring the control arm, while 34 (55%) had rules favoring the experimental arm. Among these, 50% had unequal drug modification rules, 41% had unequal G-CSF rules, and 9% had both.

Dr. Olivier said in an interview the results are “highly concerning because when you are investigating the effect of a new drug, you don’t want to have a false sense of a drug’s effect because of other factors not directly related to the drug’s efficacy.”

“If you introduce unfair rules about dose modification or supporting medication that favors the new drug, then you don’t know if a positive trial is due to the effect of the new drug or to the effect of differential dosing or supporting medication,” he added.
 

Blame industry?

Dr. Olivier said the fact that most registration trials are industry-sponsored is likely the primary explanation of the findings.

“Industry-sponsored trials may be designed so that the new drug has the best chance to get the largest ‘win,’ because this means more market share and more profit for the company that manufactures the drug. This is not a criticism of the industry, which runs on a business model that naturally aims to gain more market share and more profit,” Dr. Olivier said.

“However, it is the role and duty of regulators to reconcile industry incentives with the patients’ best interests, and there is accumulating data showing the regulators are failing to do so,” he added.

Addressing this problem will likely take buy-in from multiple stakeholders.

Awareness of the problem is a first step and understanding the influence of commercial incentives in drug development is also key, Dr. Olivier said.

Institutional review boards and drug regulators could also systematically evaluate drug dosing modification and supportive medication rules before a trial gets underway.

Regulators could also incentivize companies to implement balanced rules between arms by not granting drug approval based on trials suffering from such flaws.

“However, financial conflict of interest is present at many levels of drug development, including in drug regulation,” Dr. Olivier noted.

He pointed to a recent study that found when hematology-oncology medical reviewers working at the FDA leave the agency, more than half end up working or consulting for the pharmaceutical industry.

Dr. Olivier wondered: “How can one fairly and independently appraise a medical intervention if one’s current or future revenue depends on its source?”

The study was funded by Arnold Ventures, through a grant paid to UCSF. Dr. Olivier and Dr. Haslam had no relevant disclosures. Dr. Prasad reported receiving royalties from Arnold Ventures.

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

More than half of studies testing anticancer drugs against each other have rules with regard to dose modification and growth support that favor the experimental drug arm, a new analysis suggests.

“We found it sobering that this practice is so common,” Timothée Olivier, MD, with Geneva University Hospital and the University of California, San Francisco, said in an interview.

Trials may be “rigged” in a way where the new therapy appears more effective than if the trial would have been designed with fairer rules, he explained.

This leaves open the question of whether new drugs are truly superior to older ones or if instead different outcomes are caused by more aggressive dosing or growth factor support, the investigators said.

Dr. Olivier, with UCSF coinvestigators Alyson Haslam, PhD, and Vinay Prasad, MD, reported their findings online in the European Journal of Cancer.

‘Highly concerning’

Different drug modification rules or growth factor support guidance may affect the results of randomized controlled trials (RCTs) of testing new cancer agents.

For their study, Dr. Olivier and colleagues did a cross-sectional analysis of all 62 head-to-head registration RCTs that led to Food and Drug Administration approval between 2009 and 2021.

All of the trials examined anticancer drugs in the advanced or metastatic setting where a comparison was made between arms regarding either dose modification rules or myeloid growth factors recommendations.

The researchers assessed imbalance in drug modification rules, myeloid growth factor recommendations, or both, according to prespecified rules.

They discovered that 40 of the 62 trials (65%) had unequal rules for dose medication, granulocyte colony-stimulating factor (G-CSF) use, or both.

Six trials (10%) had rules favoring the control arm, while 34 (55%) had rules favoring the experimental arm. Among these, 50% had unequal drug modification rules, 41% had unequal G-CSF rules, and 9% had both.

Dr. Olivier said in an interview the results are “highly concerning because when you are investigating the effect of a new drug, you don’t want to have a false sense of a drug’s effect because of other factors not directly related to the drug’s efficacy.”

“If you introduce unfair rules about dose modification or supporting medication that favors the new drug, then you don’t know if a positive trial is due to the effect of the new drug or to the effect of differential dosing or supporting medication,” he added.
 

Blame industry?

Dr. Olivier said the fact that most registration trials are industry-sponsored is likely the primary explanation of the findings.

“Industry-sponsored trials may be designed so that the new drug has the best chance to get the largest ‘win,’ because this means more market share and more profit for the company that manufactures the drug. This is not a criticism of the industry, which runs on a business model that naturally aims to gain more market share and more profit,” Dr. Olivier said.

“However, it is the role and duty of regulators to reconcile industry incentives with the patients’ best interests, and there is accumulating data showing the regulators are failing to do so,” he added.

Addressing this problem will likely take buy-in from multiple stakeholders.

Awareness of the problem is a first step and understanding the influence of commercial incentives in drug development is also key, Dr. Olivier said.

Institutional review boards and drug regulators could also systematically evaluate drug dosing modification and supportive medication rules before a trial gets underway.

Regulators could also incentivize companies to implement balanced rules between arms by not granting drug approval based on trials suffering from such flaws.

“However, financial conflict of interest is present at many levels of drug development, including in drug regulation,” Dr. Olivier noted.

He pointed to a recent study that found when hematology-oncology medical reviewers working at the FDA leave the agency, more than half end up working or consulting for the pharmaceutical industry.

Dr. Olivier wondered: “How can one fairly and independently appraise a medical intervention if one’s current or future revenue depends on its source?”

The study was funded by Arnold Ventures, through a grant paid to UCSF. Dr. Olivier and Dr. Haslam had no relevant disclosures. Dr. Prasad reported receiving royalties from Arnold Ventures.

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

A new clinical practice update from the American Gastroenterological Association offers practical advice around surveillance and use of new screening technologies for Barrett’s esophagus.

The AGA clinical practice update, published in Clinical Gastroenterology and Hepatology comes from the AGA’s Center for GI Innovation and Technology. It offers 15 best practice advice statements based on expert review of existing literature combined with discussion and expert opinion. The aim is “to provide an update on advances and innovation” but not to replace current guidelines.

“Guidelines operate on rigorous methodology which requires the use of [Grading of Recommendations, Assessment, Development and Evaluation] methodology and a higher level of evidence. In gastroenterology especially, innovation is moving quickly and there’s no way for patients to reap their benefits if clinical practice was dictated by guidelines alone. That said, we do need documents that support and drive innovation in clinical practice,” corresponding author Srinadh Komanduri, MD, professor of medicine and surgery in the division of gastroenterology and hepatology at Northwestern University, Chicago, told this news publication.

Asked to comment, Vivek Kaul, MD, the Segal-Watson Professor of Medicine in the Center for Advanced Therapeutic Endoscopy in the division of gastroenterology and hepatology at the University of Rochester (N.Y.) Medical Center, said that the document is “an important attempt to not only present the available scientific literature in a very concise and understandable manner, but it goes above and beyond that in terms of diving into some novel paradigms and technologies and procedures that are either emerging or will be emerging in the near future.”
 

Improving detection by dropping GERD requirement

The first of the 15 statements may also be the most paradigm shifting: The panel suggests screening via standard upper endoscopy of people with at least three risk factors for Barrett’s esophagus and esophageal adenocarcinoma, including those who are male, are non-Hispanic White, are aged above 50 years, and have a history of smoking, chronic gastroesophageal reflux disease (GERD), obesity, or a family history of Barrett’s esophagus or esophageal adenocarcinoma.

This represents a departure from all current guidelines, which stipulate GERD as a necessary prerequisite for screening. But the reason is simple, according to the authors: A majority of patients diagnosed with esophageal cancer never experience classic GERD symptoms.

“There is growing evidence in high-level publications over the last couple of years that reflux is not the ideal predictor, based on odds, for development of Barrett’s esophagus. So the consensus among the experts was that we need to remove GERD as an absolute prerequisite or we’re never going to make progress. In order to make an impact on the rise of esophageal adenocarcinoma we have to increase the denominator of patients we are seeing,” Dr. Komanduri explained.

While it might be difficult to screen every White male over 50 years of age, the data do suggest screening those who also have obesity and/or are current smokers. “That’s a perfect subset you might want to start with. There are permutations that have greater value that don’t occupy unnecessary resource utilization. Most critical are the family history of esophageal cancer or Barrett’s esophagus,” he noted.

Dr. Kaul said that a one-time Barrett’s esophagus screening of all White males over 50 years old “is not unreasonable, especially given the rising rates of esophageal cancer.”

However, he also noted, “The feasibility, preferred screening modality, incremental costs, and yield of this new strategy will need to be studied further. Access to GI endoscopy in the postpandemic world is already a concern and will need to be factored into execution of this [advice statement] and will likely impact adoption in some way.”

For his part, Dr. Komanduri said that more investigation will be needed to validate which patients most benefit from screening and that the AGA is planning educational programs for clinicians about interpreting this new paradigm.
 

New technology could make screening easier and cheaper

The availability of nonendoscopic cell collection devices, including the swallowable Cytosponge (Medtronic), EsoCheck (Lucid), and EsoCap (Capnostics) could help make screening for Barrett’s esophagus easier and more cost effective. They are designed for in-office use and don’t require sedation. Each one is currently in various stages of development and clinical trials. As of now they’re approved in the United States only for cell collection but not for Barrett’s esophagus screening, but their use is endorsed by some guidelines. The Cytosponge in particular is widely available and has been used extensively in the United Kingdom.

Dr. Kaul commented, “While there is a need for nonendoscopic screening devices, the ideal patient population and practice setting for administration of these devices has not been clearly defined. Also, who will be delivering these tests: Primary care or gastroenterology providers? These devices ... represent a major step forward and a novel paradigm for Barrett’s esophagus screening, and the only platform that non-GI providers could use.”
 

Virtual chromoendoscopy: A must have in 2022

A third best practice advice statement shouldn’t be controversial because it’s in other guidelines already, but data show clinicians aren’t always doing it: Performing screening and surveillance endoscopic examinations using virtual chromoendoscopy in addition to high-definition white light endoscopy, with adequate time spent inspecting the Barrett’s segment. The majority of data supporting this is for narrow-band imaging only.

“The blue light lets you pick up early mucosal and vascular changes which might represent dysplastic lesions. It’s not a question of should. It’s a medicolegal slam dunk; you must do it. It’s been a guideline recommendation in the last few years, and it’s just a switch on the scope. It doesn’t require separate equipment, yet people are often still skipping it,” Dr. Komanduri said.

Indeed, Dr. Kaul concurred, “The importance of a high quality, meticulous endoscopic examination for screening and surveillance in Barrett’s esophagus cannot be overemphasized.”
 

‘Finally pushing the needle in the right direction’

The overall goals, Dr. Komanduri said, are “increasing the denominator, using less invasive screening, but finding more patients. If we find more patients we’ll need to stratify their risk. We hope that all these things eventually tie together in a nice story, all with the aim of preventing an invasive cancer that can’t be treated.”

He believes the new update “is a pivotal document in this field that’s going to be a paradigm changer. A lot of aspects need further validation. It’s by no means the end. But I think we’re finally pushing the needle in the right direction as things move forward with innovation.”

Dr. Kaul agrees. “It’s highlighting the principles that may become established paradigms in the future.”

Dr. Komanduri and the other authors of the update reported relationships, including consulting and research support, with companies like Boston Scientific, Medtronic, Virgo Video Solutions, and Castle Biosciences. Dr. Kaul serves as a consultant and advisory board member for CDx Diagnostics, an advisory board member for Castle Biosciences, and an investigator for Lucid Diagnostics.

A new clinical practice update from the American Gastroenterological Association offers practical advice around surveillance and use of new screening technologies for Barrett’s esophagus.

The AGA clinical practice update, published in Clinical Gastroenterology and Hepatology comes from the AGA’s Center for GI Innovation and Technology. It offers 15 best practice advice statements based on expert review of existing literature combined with discussion and expert opinion. The aim is “to provide an update on advances and innovation” but not to replace current guidelines.

“Guidelines operate on rigorous methodology which requires the use of [Grading of Recommendations, Assessment, Development and Evaluation] methodology and a higher level of evidence. In gastroenterology especially, innovation is moving quickly and there’s no way for patients to reap their benefits if clinical practice was dictated by guidelines alone. That said, we do need documents that support and drive innovation in clinical practice,” corresponding author Srinadh Komanduri, MD, professor of medicine and surgery in the division of gastroenterology and hepatology at Northwestern University, Chicago, told this news publication.

Asked to comment, Vivek Kaul, MD, the Segal-Watson Professor of Medicine in the Center for Advanced Therapeutic Endoscopy in the division of gastroenterology and hepatology at the University of Rochester (N.Y.) Medical Center, said that the document is “an important attempt to not only present the available scientific literature in a very concise and understandable manner, but it goes above and beyond that in terms of diving into some novel paradigms and technologies and procedures that are either emerging or will be emerging in the near future.”
 

Improving detection by dropping GERD requirement

The first of the 15 statements may also be the most paradigm shifting: The panel suggests screening via standard upper endoscopy of people with at least three risk factors for Barrett’s esophagus and esophageal adenocarcinoma, including those who are male, are non-Hispanic White, are aged above 50 years, and have a history of smoking, chronic gastroesophageal reflux disease (GERD), obesity, or a family history of Barrett’s esophagus or esophageal adenocarcinoma.

This represents a departure from all current guidelines, which stipulate GERD as a necessary prerequisite for screening. But the reason is simple, according to the authors: A majority of patients diagnosed with esophageal cancer never experience classic GERD symptoms.

“There is growing evidence in high-level publications over the last couple of years that reflux is not the ideal predictor, based on odds, for development of Barrett’s esophagus. So the consensus among the experts was that we need to remove GERD as an absolute prerequisite or we’re never going to make progress. In order to make an impact on the rise of esophageal adenocarcinoma we have to increase the denominator of patients we are seeing,” Dr. Komanduri explained.

While it might be difficult to screen every White male over 50 years of age, the data do suggest screening those who also have obesity and/or are current smokers. “That’s a perfect subset you might want to start with. There are permutations that have greater value that don’t occupy unnecessary resource utilization. Most critical are the family history of esophageal cancer or Barrett’s esophagus,” he noted.

Dr. Kaul said that a one-time Barrett’s esophagus screening of all White males over 50 years old “is not unreasonable, especially given the rising rates of esophageal cancer.”

However, he also noted, “The feasibility, preferred screening modality, incremental costs, and yield of this new strategy will need to be studied further. Access to GI endoscopy in the postpandemic world is already a concern and will need to be factored into execution of this [advice statement] and will likely impact adoption in some way.”

For his part, Dr. Komanduri said that more investigation will be needed to validate which patients most benefit from screening and that the AGA is planning educational programs for clinicians about interpreting this new paradigm.
 

New technology could make screening easier and cheaper

The availability of nonendoscopic cell collection devices, including the swallowable Cytosponge (Medtronic), EsoCheck (Lucid), and EsoCap (Capnostics) could help make screening for Barrett’s esophagus easier and more cost effective. They are designed for in-office use and don’t require sedation. Each one is currently in various stages of development and clinical trials. As of now they’re approved in the United States only for cell collection but not for Barrett’s esophagus screening, but their use is endorsed by some guidelines. The Cytosponge in particular is widely available and has been used extensively in the United Kingdom.

Dr. Kaul commented, “While there is a need for nonendoscopic screening devices, the ideal patient population and practice setting for administration of these devices has not been clearly defined. Also, who will be delivering these tests: Primary care or gastroenterology providers? These devices ... represent a major step forward and a novel paradigm for Barrett’s esophagus screening, and the only platform that non-GI providers could use.”
 

Virtual chromoendoscopy: A must have in 2022

A third best practice advice statement shouldn’t be controversial because it’s in other guidelines already, but data show clinicians aren’t always doing it: Performing screening and surveillance endoscopic examinations using virtual chromoendoscopy in addition to high-definition white light endoscopy, with adequate time spent inspecting the Barrett’s segment. The majority of data supporting this is for narrow-band imaging only.

“The blue light lets you pick up early mucosal and vascular changes which might represent dysplastic lesions. It’s not a question of should. It’s a medicolegal slam dunk; you must do it. It’s been a guideline recommendation in the last few years, and it’s just a switch on the scope. It doesn’t require separate equipment, yet people are often still skipping it,” Dr. Komanduri said.

Indeed, Dr. Kaul concurred, “The importance of a high quality, meticulous endoscopic examination for screening and surveillance in Barrett’s esophagus cannot be overemphasized.”
 

‘Finally pushing the needle in the right direction’

The overall goals, Dr. Komanduri said, are “increasing the denominator, using less invasive screening, but finding more patients. If we find more patients we’ll need to stratify their risk. We hope that all these things eventually tie together in a nice story, all with the aim of preventing an invasive cancer that can’t be treated.”

He believes the new update “is a pivotal document in this field that’s going to be a paradigm changer. A lot of aspects need further validation. It’s by no means the end. But I think we’re finally pushing the needle in the right direction as things move forward with innovation.”

Dr. Kaul agrees. “It’s highlighting the principles that may become established paradigms in the future.”

Dr. Komanduri and the other authors of the update reported relationships, including consulting and research support, with companies like Boston Scientific, Medtronic, Virgo Video Solutions, and Castle Biosciences. Dr. Kaul serves as a consultant and advisory board member for CDx Diagnostics, an advisory board member for Castle Biosciences, and an investigator for Lucid Diagnostics.

A new clinical practice update from the American Gastroenterological Association offers practical advice around surveillance and use of new screening technologies for Barrett’s esophagus.

The AGA clinical practice update, published in Clinical Gastroenterology and Hepatology comes from the AGA’s Center for GI Innovation and Technology. It offers 15 best practice advice statements based on expert review of existing literature combined with discussion and expert opinion. The aim is “to provide an update on advances and innovation” but not to replace current guidelines.

“Guidelines operate on rigorous methodology which requires the use of [Grading of Recommendations, Assessment, Development and Evaluation] methodology and a higher level of evidence. In gastroenterology especially, innovation is moving quickly and there’s no way for patients to reap their benefits if clinical practice was dictated by guidelines alone. That said, we do need documents that support and drive innovation in clinical practice,” corresponding author Srinadh Komanduri, MD, professor of medicine and surgery in the division of gastroenterology and hepatology at Northwestern University, Chicago, told this news publication.

Asked to comment, Vivek Kaul, MD, the Segal-Watson Professor of Medicine in the Center for Advanced Therapeutic Endoscopy in the division of gastroenterology and hepatology at the University of Rochester (N.Y.) Medical Center, said that the document is “an important attempt to not only present the available scientific literature in a very concise and understandable manner, but it goes above and beyond that in terms of diving into some novel paradigms and technologies and procedures that are either emerging or will be emerging in the near future.”
 

Improving detection by dropping GERD requirement

The first of the 15 statements may also be the most paradigm shifting: The panel suggests screening via standard upper endoscopy of people with at least three risk factors for Barrett’s esophagus and esophageal adenocarcinoma, including those who are male, are non-Hispanic White, are aged above 50 years, and have a history of smoking, chronic gastroesophageal reflux disease (GERD), obesity, or a family history of Barrett’s esophagus or esophageal adenocarcinoma.

This represents a departure from all current guidelines, which stipulate GERD as a necessary prerequisite for screening. But the reason is simple, according to the authors: A majority of patients diagnosed with esophageal cancer never experience classic GERD symptoms.

“There is growing evidence in high-level publications over the last couple of years that reflux is not the ideal predictor, based on odds, for development of Barrett’s esophagus. So the consensus among the experts was that we need to remove GERD as an absolute prerequisite or we’re never going to make progress. In order to make an impact on the rise of esophageal adenocarcinoma we have to increase the denominator of patients we are seeing,” Dr. Komanduri explained.

While it might be difficult to screen every White male over 50 years of age, the data do suggest screening those who also have obesity and/or are current smokers. “That’s a perfect subset you might want to start with. There are permutations that have greater value that don’t occupy unnecessary resource utilization. Most critical are the family history of esophageal cancer or Barrett’s esophagus,” he noted.

Dr. Kaul said that a one-time Barrett’s esophagus screening of all White males over 50 years old “is not unreasonable, especially given the rising rates of esophageal cancer.”

However, he also noted, “The feasibility, preferred screening modality, incremental costs, and yield of this new strategy will need to be studied further. Access to GI endoscopy in the postpandemic world is already a concern and will need to be factored into execution of this [advice statement] and will likely impact adoption in some way.”

For his part, Dr. Komanduri said that more investigation will be needed to validate which patients most benefit from screening and that the AGA is planning educational programs for clinicians about interpreting this new paradigm.
 

New technology could make screening easier and cheaper

The availability of nonendoscopic cell collection devices, including the swallowable Cytosponge (Medtronic), EsoCheck (Lucid), and EsoCap (Capnostics) could help make screening for Barrett’s esophagus easier and more cost effective. They are designed for in-office use and don’t require sedation. Each one is currently in various stages of development and clinical trials. As of now they’re approved in the United States only for cell collection but not for Barrett’s esophagus screening, but their use is endorsed by some guidelines. The Cytosponge in particular is widely available and has been used extensively in the United Kingdom.

Dr. Kaul commented, “While there is a need for nonendoscopic screening devices, the ideal patient population and practice setting for administration of these devices has not been clearly defined. Also, who will be delivering these tests: Primary care or gastroenterology providers? These devices ... represent a major step forward and a novel paradigm for Barrett’s esophagus screening, and the only platform that non-GI providers could use.”
 

Virtual chromoendoscopy: A must have in 2022

A third best practice advice statement shouldn’t be controversial because it’s in other guidelines already, but data show clinicians aren’t always doing it: Performing screening and surveillance endoscopic examinations using virtual chromoendoscopy in addition to high-definition white light endoscopy, with adequate time spent inspecting the Barrett’s segment. The majority of data supporting this is for narrow-band imaging only.

“The blue light lets you pick up early mucosal and vascular changes which might represent dysplastic lesions. It’s not a question of should. It’s a medicolegal slam dunk; you must do it. It’s been a guideline recommendation in the last few years, and it’s just a switch on the scope. It doesn’t require separate equipment, yet people are often still skipping it,” Dr. Komanduri said.

Indeed, Dr. Kaul concurred, “The importance of a high quality, meticulous endoscopic examination for screening and surveillance in Barrett’s esophagus cannot be overemphasized.”
 

‘Finally pushing the needle in the right direction’

The overall goals, Dr. Komanduri said, are “increasing the denominator, using less invasive screening, but finding more patients. If we find more patients we’ll need to stratify their risk. We hope that all these things eventually tie together in a nice story, all with the aim of preventing an invasive cancer that can’t be treated.”

He believes the new update “is a pivotal document in this field that’s going to be a paradigm changer. A lot of aspects need further validation. It’s by no means the end. But I think we’re finally pushing the needle in the right direction as things move forward with innovation.”

Dr. Kaul agrees. “It’s highlighting the principles that may become established paradigms in the future.”

Dr. Komanduri and the other authors of the update reported relationships, including consulting and research support, with companies like Boston Scientific, Medtronic, Virgo Video Solutions, and Castle Biosciences. Dr. Kaul serves as a consultant and advisory board member for CDx Diagnostics, an advisory board member for Castle Biosciences, and an investigator for Lucid Diagnostics.