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SAN DIEGO — New guidelines for cutaneous melanoma have been issued by the National Comprehensive Cancer Network (NCCN), creating some new standards of practice that extend a slow divergence from the last set of detailed recommendations released by the American Academy of Dermatology (AAD) in 2019.

Based on the constantly evolving science that drives guidelines, the new set of NCCN recommendations reflects the latest iteration of a consensus effort to define best practice, according to Susan M. Swetter, MD, professor of dermatology and director of the Pigmented Lesion and Melanoma Program at Stanford University in California.

Dr. Swetter chaired the committee that developed the most recent NCCN guidelines, released February 12. She also chaired the work group that developed the AAD recommendations, released in 2019. Differences between the two primarily reflect evolving evidence and expert opinion over time. 
 

Next AAD Guidelines More Than 1 Year Away

The AAD guidelines are developed infrequently and in a process that can take years. The next AAD cutaneous melanoma guidelines are not likely to be released until the end of 2025 or in 2026, Dr. Swetter said at the annual meeting of the American Academy of Dermatology on March 8. In contrast, the NCCN guidelines for cutaneous melanoma are revisited frequently. The last iteration was published only 1 year ago. 

Ted Bosworth/MDedge News

More Than 50% Consensus Generally Required

The NCCN committee that issues periodic guidelines on cutaneous melanoma is formed by a rotating group of interdisciplinary melanoma specialists. More than 30 academic institutions nationwide are generally represented, and the group includes patient advocates. Typically, no comment or recommendation is provided if the committee cannot generate at least a majority endorsement (≥ 50%) on a given topic.

Overall, the majority of guidelines, including those issued by the NCCN and the AAD, are aligned, except to the degree of the time lag that provides different sets of evidence to consider. The rationale for keeping abreast of the NCCN recommendations is that updates are more frequent, according to Dr. Swetter, who noted that these are available for free once a user has registered on the NCCN website. 

Importantly, guidelines not only identify what further steps can be taken to improve diagnostic accuracy or outcomes but what practices can be abandoned to improve the benefit-to-risk ratio. As an example, surgical margins for primary melanomas have been becoming progressively smaller on the basis of evidence that larger margins increase morbidity without improving outcomes.

Although Dr. Swetter acknowledged that “we still haven’t identified the narrowest, most efficacious margins for cutaneous melanoma,” she cited studies now suggesting that margins of 2 cm appear to be sufficient even for advanced T3 and T4 tumors. Prior to the 1970s, margins of 5 cm or greater were common.

There are still many unanswered questions about optimal margins, but the 2023 NCCN guidelines already called for surgical margins of at least 1 cm and no more than 2 cm for large invasive melanomas when clinically measured around the primary tumor. Dr. Swetter said that even smaller margins can be considered “to accommodate function and/or the anatomic location.”
 

Best Margins for MIS Undefined

So far, there are no randomized trials yet to guide surgical margins or depth for many melanoma subtypes, including melanoma in situ (MIS). These are the types of data, when they become available, that change guidelines.

The list of procedures often performed, but for which there is no specific guidance from NCCN or other organizations, is long. Numerous examples were provided during the AAD symposium on guidelines, during which Dr. Swetter spoke. The bedside diagnosis of cutaneous melanoma with noninvasive testing was one.

Describing the 2-gene molecular assay for the evaluation of a suspected melanoma, Caroline C. Kim, MD, director of the Melanoma and Pigmented Lesion Program at Tufts University in Boston, explained that this tool, which is based on the presence of the LINC00158 gene and the preferentially expressed antigen in melanoma (PRAME), has limited utility as a tool for establishing a diagnosis of melanoma. But, she said, it has reasonably good reliability for ruling out melanoma, thereby providing a basis to avoid or delay further diagnostic steps, such as biopsy.

Skin biopsy, as established in the guidelines, “is still the gold standard,” but there are numerous studies indicating that patients negative for both LINC00158 and PRAME have a low risk for melanoma, she said.

“A double negative result is not 100% effective, but it is high,” said Dr. Kim, who provided several examples whereby she employed the test to follow the patient rather than do invasive testing.

This test is gaining popularity, according to Dr. Kim, who cited several surveys suggesting growing use among clinicians, but she characterized it as an adjunctive approach that should be considered in the context of guidelines. It is an example of an approach that is not yet standard practice but can be helpful if used appropriately, she noted.

Dr. Swetter and Dr. Kim report no relevant financial relationships. 

A version of this article appeared on Medscape.com.

SAN DIEGO — New guidelines for cutaneous melanoma have been issued by the National Comprehensive Cancer Network (NCCN), creating some new standards of practice that extend a slow divergence from the last set of detailed recommendations released by the American Academy of Dermatology (AAD) in 2019.

Based on the constantly evolving science that drives guidelines, the new set of NCCN recommendations reflects the latest iteration of a consensus effort to define best practice, according to Susan M. Swetter, MD, professor of dermatology and director of the Pigmented Lesion and Melanoma Program at Stanford University in California.

Dr. Swetter chaired the committee that developed the most recent NCCN guidelines, released February 12. She also chaired the work group that developed the AAD recommendations, released in 2019. Differences between the two primarily reflect evolving evidence and expert opinion over time. 
 

Next AAD Guidelines More Than 1 Year Away

The AAD guidelines are developed infrequently and in a process that can take years. The next AAD cutaneous melanoma guidelines are not likely to be released until the end of 2025 or in 2026, Dr. Swetter said at the annual meeting of the American Academy of Dermatology on March 8. In contrast, the NCCN guidelines for cutaneous melanoma are revisited frequently. The last iteration was published only 1 year ago. 

Ted Bosworth/MDedge News

More Than 50% Consensus Generally Required

The NCCN committee that issues periodic guidelines on cutaneous melanoma is formed by a rotating group of interdisciplinary melanoma specialists. More than 30 academic institutions nationwide are generally represented, and the group includes patient advocates. Typically, no comment or recommendation is provided if the committee cannot generate at least a majority endorsement (≥ 50%) on a given topic.

Overall, the majority of guidelines, including those issued by the NCCN and the AAD, are aligned, except to the degree of the time lag that provides different sets of evidence to consider. The rationale for keeping abreast of the NCCN recommendations is that updates are more frequent, according to Dr. Swetter, who noted that these are available for free once a user has registered on the NCCN website. 

Importantly, guidelines not only identify what further steps can be taken to improve diagnostic accuracy or outcomes but what practices can be abandoned to improve the benefit-to-risk ratio. As an example, surgical margins for primary melanomas have been becoming progressively smaller on the basis of evidence that larger margins increase morbidity without improving outcomes.

Although Dr. Swetter acknowledged that “we still haven’t identified the narrowest, most efficacious margins for cutaneous melanoma,” she cited studies now suggesting that margins of 2 cm appear to be sufficient even for advanced T3 and T4 tumors. Prior to the 1970s, margins of 5 cm or greater were common.

There are still many unanswered questions about optimal margins, but the 2023 NCCN guidelines already called for surgical margins of at least 1 cm and no more than 2 cm for large invasive melanomas when clinically measured around the primary tumor. Dr. Swetter said that even smaller margins can be considered “to accommodate function and/or the anatomic location.”
 

Best Margins for MIS Undefined

So far, there are no randomized trials yet to guide surgical margins or depth for many melanoma subtypes, including melanoma in situ (MIS). These are the types of data, when they become available, that change guidelines.

The list of procedures often performed, but for which there is no specific guidance from NCCN or other organizations, is long. Numerous examples were provided during the AAD symposium on guidelines, during which Dr. Swetter spoke. The bedside diagnosis of cutaneous melanoma with noninvasive testing was one.

Describing the 2-gene molecular assay for the evaluation of a suspected melanoma, Caroline C. Kim, MD, director of the Melanoma and Pigmented Lesion Program at Tufts University in Boston, explained that this tool, which is based on the presence of the LINC00158 gene and the preferentially expressed antigen in melanoma (PRAME), has limited utility as a tool for establishing a diagnosis of melanoma. But, she said, it has reasonably good reliability for ruling out melanoma, thereby providing a basis to avoid or delay further diagnostic steps, such as biopsy.

Skin biopsy, as established in the guidelines, “is still the gold standard,” but there are numerous studies indicating that patients negative for both LINC00158 and PRAME have a low risk for melanoma, she said.

“A double negative result is not 100% effective, but it is high,” said Dr. Kim, who provided several examples whereby she employed the test to follow the patient rather than do invasive testing.

This test is gaining popularity, according to Dr. Kim, who cited several surveys suggesting growing use among clinicians, but she characterized it as an adjunctive approach that should be considered in the context of guidelines. It is an example of an approach that is not yet standard practice but can be helpful if used appropriately, she noted.

Dr. Swetter and Dr. Kim report no relevant financial relationships. 

A version of this article appeared on Medscape.com.

SAN DIEGO — New guidelines for cutaneous melanoma have been issued by the National Comprehensive Cancer Network (NCCN), creating some new standards of practice that extend a slow divergence from the last set of detailed recommendations released by the American Academy of Dermatology (AAD) in 2019.

Based on the constantly evolving science that drives guidelines, the new set of NCCN recommendations reflects the latest iteration of a consensus effort to define best practice, according to Susan M. Swetter, MD, professor of dermatology and director of the Pigmented Lesion and Melanoma Program at Stanford University in California.

Dr. Swetter chaired the committee that developed the most recent NCCN guidelines, released February 12. She also chaired the work group that developed the AAD recommendations, released in 2019. Differences between the two primarily reflect evolving evidence and expert opinion over time. 
 

Next AAD Guidelines More Than 1 Year Away

The AAD guidelines are developed infrequently and in a process that can take years. The next AAD cutaneous melanoma guidelines are not likely to be released until the end of 2025 or in 2026, Dr. Swetter said at the annual meeting of the American Academy of Dermatology on March 8. In contrast, the NCCN guidelines for cutaneous melanoma are revisited frequently. The last iteration was published only 1 year ago. 

Ted Bosworth/MDedge News

More Than 50% Consensus Generally Required

The NCCN committee that issues periodic guidelines on cutaneous melanoma is formed by a rotating group of interdisciplinary melanoma specialists. More than 30 academic institutions nationwide are generally represented, and the group includes patient advocates. Typically, no comment or recommendation is provided if the committee cannot generate at least a majority endorsement (≥ 50%) on a given topic.

Overall, the majority of guidelines, including those issued by the NCCN and the AAD, are aligned, except to the degree of the time lag that provides different sets of evidence to consider. The rationale for keeping abreast of the NCCN recommendations is that updates are more frequent, according to Dr. Swetter, who noted that these are available for free once a user has registered on the NCCN website. 

Importantly, guidelines not only identify what further steps can be taken to improve diagnostic accuracy or outcomes but what practices can be abandoned to improve the benefit-to-risk ratio. As an example, surgical margins for primary melanomas have been becoming progressively smaller on the basis of evidence that larger margins increase morbidity without improving outcomes.

Although Dr. Swetter acknowledged that “we still haven’t identified the narrowest, most efficacious margins for cutaneous melanoma,” she cited studies now suggesting that margins of 2 cm appear to be sufficient even for advanced T3 and T4 tumors. Prior to the 1970s, margins of 5 cm or greater were common.

There are still many unanswered questions about optimal margins, but the 2023 NCCN guidelines already called for surgical margins of at least 1 cm and no more than 2 cm for large invasive melanomas when clinically measured around the primary tumor. Dr. Swetter said that even smaller margins can be considered “to accommodate function and/or the anatomic location.”
 

Best Margins for MIS Undefined

So far, there are no randomized trials yet to guide surgical margins or depth for many melanoma subtypes, including melanoma in situ (MIS). These are the types of data, when they become available, that change guidelines.

The list of procedures often performed, but for which there is no specific guidance from NCCN or other organizations, is long. Numerous examples were provided during the AAD symposium on guidelines, during which Dr. Swetter spoke. The bedside diagnosis of cutaneous melanoma with noninvasive testing was one.

Describing the 2-gene molecular assay for the evaluation of a suspected melanoma, Caroline C. Kim, MD, director of the Melanoma and Pigmented Lesion Program at Tufts University in Boston, explained that this tool, which is based on the presence of the LINC00158 gene and the preferentially expressed antigen in melanoma (PRAME), has limited utility as a tool for establishing a diagnosis of melanoma. But, she said, it has reasonably good reliability for ruling out melanoma, thereby providing a basis to avoid or delay further diagnostic steps, such as biopsy.

Skin biopsy, as established in the guidelines, “is still the gold standard,” but there are numerous studies indicating that patients negative for both LINC00158 and PRAME have a low risk for melanoma, she said.

“A double negative result is not 100% effective, but it is high,” said Dr. Kim, who provided several examples whereby she employed the test to follow the patient rather than do invasive testing.

This test is gaining popularity, according to Dr. Kim, who cited several surveys suggesting growing use among clinicians, but she characterized it as an adjunctive approach that should be considered in the context of guidelines. It is an example of an approach that is not yet standard practice but can be helpful if used appropriately, she noted.

Dr. Swetter and Dr. Kim report no relevant financial relationships. 

A version of this article appeared on Medscape.com.

A new drug-device combo aimed at detecting residual cancer in real time during lumpectomy is one step closer to gaining federal approval, but some physicians aren’t convinced the technology is safe — or effective enough — to start using on patients.

A majority of the US Food and Drug Administration’s Medical Imaging Drugs Advisory Committee (MIDAC) on March 5 voted in support of LUMISIGHT’s (pegulicianine) benefit-risk profile.

LUMISIGHT is an optical imaging agent used in combination with Lumicell Direct Visualization System (DVS), a fluorescence-guided imaging system. The technology, developed by Lumicell Inc., helps surgeons identify cancer that may remain in the breast after they’ve completed the main resection of tissue.

Following MIDAC’s positive vote, the FDA will move on to reviewing Lumicell’s new drug application for LUMISIGHT and its premarket approval application for Lumicell DVS.

“We are proud of the efforts and look forward to the next steps as we work with the FDA to finalize the approval process so that women with breast cancer can access the therapy,” Jorge Ferrer, PhD, Lumicell’s chief scientific officer, said in an interview.

However, Freya Schnabel, MD, professor of surgery and director of breast surgery at NYU Perlmutter Cancer Center, said there are some “real concerns” with the technology. She expressed surprise at MIDAC’s overall favorable vote.

In a recently published study, she noted that the use of pegulicianine fluorescence-guided surgery (pFGS) did not meet the prespecified threshold for sensitivity.

“It did meet thresholds for removal of residual tumor and specificity — but this is still basically a negative study, and a low sensitivity raises concerns regarding false negative readings,” she said in an interview. “I’m surprised [the committee] is supportive in light of this result. Also, the technique is logistically challenging, as patients need to be injected 2 to 6 hours before their surgeries, very challenging timing for patients having ambulatory procedures.”

The study, published in the April 2023 NEJM Evidence, analyzed 357 patients who received 1.0 mg/kg intravenous pegulicianine followed by lumpectomy. Tumor left behind after standard lumpectomy was removed in 27 of 357 patients through use of pFGS. Of the 27, 22 patients had cavity orientations deemed “negative” on standard margin evaluation, according to the study. A margin is described as negative or clean when there are no further cancer cells at the edge of the tissue, suggesting that all of the cancer has been removed. Second surgeries were avoided by pFGS in 9 of 62 patients with positive margins, the analysis found.

On per-margin analysis, pFGS specificity was 85.2%, and sensitivity was 49.3%. While the sensitivity endpoint missed the lower boundary of the 95% confidence interval, the LUM system exceeded the specificity endpoint of 60% with a point estimate of 86%, and an accuracy of 84% for imaging residual cancer in the lumpectomy cavity, coinvestigator E. Shelley Hwang, MD, MPH, said during the MIDAC meeting.

“The pivotal study was an adequate and well-controlled study demonstrating the effectiveness of the LUM system to detect residual cancer in the lumpectomy cavity, following the standard of care procedure,” she said. “These results also demonstrate clinical benefit that improves the current standard of care. This is the first and only imaging system that provides results in the lumpectomy cavity in real time, allowing surgeons to use this information at the time of the initial procedure.”

Is the Technology Safe?

Pegulicianine is an imaging agent that contains a fluorescent dye. The agent is given to patients as a 3-minute intravenous infusion 2 to 6 hours before surgery.

After removal of the main tumor specimen, the surgeon inserts a handheld probe into the breast cavity and in combination with the detection software, searches for residual cancer that may have been left behind, Dr. Ferrer explained during the MIDAC meeting.

If the software identifies areas suspicious for residual cancer, those areas display in red on an overhead screen. The surgeon then takes a targeted shave to resect the suspicious tissue. Once the tissue has been removed, the surgeon can rescan the cavity with the probe to ensure a more complete resection has been performed. Use of the LUM system typically takes surgeons less than 7 minutes to use, Dr. Ferrer said.

In the study, a total of 406 patients received the intravenous pegulicianine, but 14 patients were withdrawn before randomization. After a standard lumpectomy procedure, 357 patients were assigned to the pFGS group and 35 patients to the control group.

Of the 406 patients, pegulicianine administration was stopped for adverse events in 6 patients (1.5%). Two patients had grade 3 serious adverse events related to pegulicianine; one had hypersensitivity, and one had an anaphylactic reaction. The other four pegulicianine-related adverse events included allergic reaction, milder hypersensitivity, nausea, and pegulicianine extravasation.

Dr. Schnabel said these reactions are worrisome. While any effort to reduce the need for patients to have more than one surgery to complete a breast conserving approach would be a “real advance,” Dr. Schnabel said she would not feel comfortable using pFGS in her own practice if approved by the FDA as is.

“This is clearly a major issue in terms of incorporating this technique into practice,” she said. “I could go on, but in light of the above, I’m surprised that [the committee] is supportive. I would hope for some refinement of the technique to reduce the risks to patients and improve the results before I’d consider utilizing this approach.”

During the MIDAC meeting, Dr. Ferrer said the company takes the safety events seriously and has developed mitigation strategies to further reduce the risk of patient hypersensitivity. These strategies include: clear labeling that informs users of anaphylaxis risk, incorporating a new section into the device training program to address warnings and precautions, an enhanced pharmacovigilance program to closely track and report hypersensitivity events, and a postmarket study to access the incidence rate and risk of such events in a broader population.

Several MIDAC members raised questions about the adverse reactions observed and about the safety of the technology.

David B. Hackney, MD, a neuroradiologist at Beth Israel Deaconess Medical Center in Boston, questioned the recommendation that patients only be monitored for 15 minutes after the injection.

“Since you don’t have enough data to know how long after injection reactions could occur, why not keep them under monitoring until after the surgery is over?” he said.

Barbara Smith, MD, PhD, lead investigator of the study, explained that per the protocol, there would be frequent monitoring, with a nurse at bedside, and patients would be monitored after injection, on their way to the procedure, and afterward.

She suggested, during the meeting, that more intense monitoring early in the process would be beneficial as that is when investigators observed side effects believed to be attributed to LUMISIGHT.

MIDAC member Kimberly E. Applegate, MD, a retired radiology professor, asked about the learning curve for surgeons and how long it generally takes for physicians to become familiar with the system.

Coinvestigator Kelly Hunt, MD, explained that all surgeons who participated in the trial completed a training program.

“Certainly, there’s a learning curve anytime we introduce new technology in the operating room,” she said. “Surgeons said it usually takes about three procedures before they’re comfortable with the system, including the camera and the software.”

During a presentation period by FDA officials, Anil Rajpal, MD, MPH, FDA, Deputy Division Director for Safety, said it’s important that prescribing information for LUMISIGHT communicate the risk of anaphylaxis and other hypersensitivity reactions, the need to monitor patients, and the need for the appropriate available personnel, medications, and equipment.

“This would be done by warnings and precautions and a boxed warning,” he said. “Note, that [such warnings] would only communicate the risks, it would not further characterize the risk.”
 

Committee Expresses Support

During a subsequent vote among committee members, most expressed support for the technology and its benefits. Sixteen members voted in support, one abstained, and two voted against the benefit-risk profile.

Andrea Richardson, MD, PhD, professor of pathology at Johns Hopkins in Baltimore, said she voted yes because the incremental benefits of avoiding additional surgeries outweigh the small risk of anaphylaxis.

Henry Royal, MD, MIDAC chair and professor of radiology at Washington University School of Medicine in St. Louis, agreed.

“Even though the benefit of this is on average, quite small, the benefit to the woman who has positive margins that’s converted to negative margins because of use of [LUMISIGHT] is really quite great,” he said. “The risk from this procedure is certainly very manageable.”

Harold J. Burstein, MD, PhD, a professor of medicine at Harvard Medical School and oncologist at Dana-Farber Cancer Institute in Boston, voted against the benefit-risk profile. He said the technology merits more research and that he does not believe it was proven the technology reduces the risk of reoperation.

“I think it’s a great technology,” he said. “I would like to see a well-conducted, randomized, phase III study with the endpoint of reoperation,” he said. “That would really prove the usefulness and benefit of the intervention in my mind.”

Chengjie Xiong, PhD, professor of biostatistics at Washington University School of Medicine in St. Louis, chose to abstain from voting because he said there was not enough data.

The FDA will now complete its review of Lumicell’s new drug application for LUMISIGHT and review of its premarket approval application for Lumicell DVS. The FDA review team has 6-10 months to make a decision. As part of the process, the FDA will evaluate clinical data, travel to clinical study sites to conduct inspections, and assemble a final action package for a senior FDA official to make a final decision.

If deemed safe and effective, the FDA will then work with Lumicell on developing and refining prescribing information.

Dr. Ferrer said his team expects to receive FDA approval in the coming weeks and will continue to work collaboratively with the FDA to expedite approval where possible.

The purpose of the MIDAC is to review and evaluate data about the safety and effectiveness of marketed and investigational human drug products for use in diagnostic and therapeutic procedures using radioactive pharmaceuticals and make appropriate recommendations to the FDA Commissioner.

A new drug-device combo aimed at detecting residual cancer in real time during lumpectomy is one step closer to gaining federal approval, but some physicians aren’t convinced the technology is safe — or effective enough — to start using on patients.

A majority of the US Food and Drug Administration’s Medical Imaging Drugs Advisory Committee (MIDAC) on March 5 voted in support of LUMISIGHT’s (pegulicianine) benefit-risk profile.

LUMISIGHT is an optical imaging agent used in combination with Lumicell Direct Visualization System (DVS), a fluorescence-guided imaging system. The technology, developed by Lumicell Inc., helps surgeons identify cancer that may remain in the breast after they’ve completed the main resection of tissue.

Following MIDAC’s positive vote, the FDA will move on to reviewing Lumicell’s new drug application for LUMISIGHT and its premarket approval application for Lumicell DVS.

“We are proud of the efforts and look forward to the next steps as we work with the FDA to finalize the approval process so that women with breast cancer can access the therapy,” Jorge Ferrer, PhD, Lumicell’s chief scientific officer, said in an interview.

However, Freya Schnabel, MD, professor of surgery and director of breast surgery at NYU Perlmutter Cancer Center, said there are some “real concerns” with the technology. She expressed surprise at MIDAC’s overall favorable vote.

In a recently published study, she noted that the use of pegulicianine fluorescence-guided surgery (pFGS) did not meet the prespecified threshold for sensitivity.

“It did meet thresholds for removal of residual tumor and specificity — but this is still basically a negative study, and a low sensitivity raises concerns regarding false negative readings,” she said in an interview. “I’m surprised [the committee] is supportive in light of this result. Also, the technique is logistically challenging, as patients need to be injected 2 to 6 hours before their surgeries, very challenging timing for patients having ambulatory procedures.”

The study, published in the April 2023 NEJM Evidence, analyzed 357 patients who received 1.0 mg/kg intravenous pegulicianine followed by lumpectomy. Tumor left behind after standard lumpectomy was removed in 27 of 357 patients through use of pFGS. Of the 27, 22 patients had cavity orientations deemed “negative” on standard margin evaluation, according to the study. A margin is described as negative or clean when there are no further cancer cells at the edge of the tissue, suggesting that all of the cancer has been removed. Second surgeries were avoided by pFGS in 9 of 62 patients with positive margins, the analysis found.

On per-margin analysis, pFGS specificity was 85.2%, and sensitivity was 49.3%. While the sensitivity endpoint missed the lower boundary of the 95% confidence interval, the LUM system exceeded the specificity endpoint of 60% with a point estimate of 86%, and an accuracy of 84% for imaging residual cancer in the lumpectomy cavity, coinvestigator E. Shelley Hwang, MD, MPH, said during the MIDAC meeting.

“The pivotal study was an adequate and well-controlled study demonstrating the effectiveness of the LUM system to detect residual cancer in the lumpectomy cavity, following the standard of care procedure,” she said. “These results also demonstrate clinical benefit that improves the current standard of care. This is the first and only imaging system that provides results in the lumpectomy cavity in real time, allowing surgeons to use this information at the time of the initial procedure.”

Is the Technology Safe?

Pegulicianine is an imaging agent that contains a fluorescent dye. The agent is given to patients as a 3-minute intravenous infusion 2 to 6 hours before surgery.

After removal of the main tumor specimen, the surgeon inserts a handheld probe into the breast cavity and in combination with the detection software, searches for residual cancer that may have been left behind, Dr. Ferrer explained during the MIDAC meeting.

If the software identifies areas suspicious for residual cancer, those areas display in red on an overhead screen. The surgeon then takes a targeted shave to resect the suspicious tissue. Once the tissue has been removed, the surgeon can rescan the cavity with the probe to ensure a more complete resection has been performed. Use of the LUM system typically takes surgeons less than 7 minutes to use, Dr. Ferrer said.

In the study, a total of 406 patients received the intravenous pegulicianine, but 14 patients were withdrawn before randomization. After a standard lumpectomy procedure, 357 patients were assigned to the pFGS group and 35 patients to the control group.

Of the 406 patients, pegulicianine administration was stopped for adverse events in 6 patients (1.5%). Two patients had grade 3 serious adverse events related to pegulicianine; one had hypersensitivity, and one had an anaphylactic reaction. The other four pegulicianine-related adverse events included allergic reaction, milder hypersensitivity, nausea, and pegulicianine extravasation.

Dr. Schnabel said these reactions are worrisome. While any effort to reduce the need for patients to have more than one surgery to complete a breast conserving approach would be a “real advance,” Dr. Schnabel said she would not feel comfortable using pFGS in her own practice if approved by the FDA as is.

“This is clearly a major issue in terms of incorporating this technique into practice,” she said. “I could go on, but in light of the above, I’m surprised that [the committee] is supportive. I would hope for some refinement of the technique to reduce the risks to patients and improve the results before I’d consider utilizing this approach.”

During the MIDAC meeting, Dr. Ferrer said the company takes the safety events seriously and has developed mitigation strategies to further reduce the risk of patient hypersensitivity. These strategies include: clear labeling that informs users of anaphylaxis risk, incorporating a new section into the device training program to address warnings and precautions, an enhanced pharmacovigilance program to closely track and report hypersensitivity events, and a postmarket study to access the incidence rate and risk of such events in a broader population.

Several MIDAC members raised questions about the adverse reactions observed and about the safety of the technology.

David B. Hackney, MD, a neuroradiologist at Beth Israel Deaconess Medical Center in Boston, questioned the recommendation that patients only be monitored for 15 minutes after the injection.

“Since you don’t have enough data to know how long after injection reactions could occur, why not keep them under monitoring until after the surgery is over?” he said.

Barbara Smith, MD, PhD, lead investigator of the study, explained that per the protocol, there would be frequent monitoring, with a nurse at bedside, and patients would be monitored after injection, on their way to the procedure, and afterward.

She suggested, during the meeting, that more intense monitoring early in the process would be beneficial as that is when investigators observed side effects believed to be attributed to LUMISIGHT.

MIDAC member Kimberly E. Applegate, MD, a retired radiology professor, asked about the learning curve for surgeons and how long it generally takes for physicians to become familiar with the system.

Coinvestigator Kelly Hunt, MD, explained that all surgeons who participated in the trial completed a training program.

“Certainly, there’s a learning curve anytime we introduce new technology in the operating room,” she said. “Surgeons said it usually takes about three procedures before they’re comfortable with the system, including the camera and the software.”

During a presentation period by FDA officials, Anil Rajpal, MD, MPH, FDA, Deputy Division Director for Safety, said it’s important that prescribing information for LUMISIGHT communicate the risk of anaphylaxis and other hypersensitivity reactions, the need to monitor patients, and the need for the appropriate available personnel, medications, and equipment.

“This would be done by warnings and precautions and a boxed warning,” he said. “Note, that [such warnings] would only communicate the risks, it would not further characterize the risk.”
 

Committee Expresses Support

During a subsequent vote among committee members, most expressed support for the technology and its benefits. Sixteen members voted in support, one abstained, and two voted against the benefit-risk profile.

Andrea Richardson, MD, PhD, professor of pathology at Johns Hopkins in Baltimore, said she voted yes because the incremental benefits of avoiding additional surgeries outweigh the small risk of anaphylaxis.

Henry Royal, MD, MIDAC chair and professor of radiology at Washington University School of Medicine in St. Louis, agreed.

“Even though the benefit of this is on average, quite small, the benefit to the woman who has positive margins that’s converted to negative margins because of use of [LUMISIGHT] is really quite great,” he said. “The risk from this procedure is certainly very manageable.”

Harold J. Burstein, MD, PhD, a professor of medicine at Harvard Medical School and oncologist at Dana-Farber Cancer Institute in Boston, voted against the benefit-risk profile. He said the technology merits more research and that he does not believe it was proven the technology reduces the risk of reoperation.

“I think it’s a great technology,” he said. “I would like to see a well-conducted, randomized, phase III study with the endpoint of reoperation,” he said. “That would really prove the usefulness and benefit of the intervention in my mind.”

Chengjie Xiong, PhD, professor of biostatistics at Washington University School of Medicine in St. Louis, chose to abstain from voting because he said there was not enough data.

The FDA will now complete its review of Lumicell’s new drug application for LUMISIGHT and review of its premarket approval application for Lumicell DVS. The FDA review team has 6-10 months to make a decision. As part of the process, the FDA will evaluate clinical data, travel to clinical study sites to conduct inspections, and assemble a final action package for a senior FDA official to make a final decision.

If deemed safe and effective, the FDA will then work with Lumicell on developing and refining prescribing information.

Dr. Ferrer said his team expects to receive FDA approval in the coming weeks and will continue to work collaboratively with the FDA to expedite approval where possible.

The purpose of the MIDAC is to review and evaluate data about the safety and effectiveness of marketed and investigational human drug products for use in diagnostic and therapeutic procedures using radioactive pharmaceuticals and make appropriate recommendations to the FDA Commissioner.

A new drug-device combo aimed at detecting residual cancer in real time during lumpectomy is one step closer to gaining federal approval, but some physicians aren’t convinced the technology is safe — or effective enough — to start using on patients.

A majority of the US Food and Drug Administration’s Medical Imaging Drugs Advisory Committee (MIDAC) on March 5 voted in support of LUMISIGHT’s (pegulicianine) benefit-risk profile.

LUMISIGHT is an optical imaging agent used in combination with Lumicell Direct Visualization System (DVS), a fluorescence-guided imaging system. The technology, developed by Lumicell Inc., helps surgeons identify cancer that may remain in the breast after they’ve completed the main resection of tissue.

Following MIDAC’s positive vote, the FDA will move on to reviewing Lumicell’s new drug application for LUMISIGHT and its premarket approval application for Lumicell DVS.

“We are proud of the efforts and look forward to the next steps as we work with the FDA to finalize the approval process so that women with breast cancer can access the therapy,” Jorge Ferrer, PhD, Lumicell’s chief scientific officer, said in an interview.

However, Freya Schnabel, MD, professor of surgery and director of breast surgery at NYU Perlmutter Cancer Center, said there are some “real concerns” with the technology. She expressed surprise at MIDAC’s overall favorable vote.

In a recently published study, she noted that the use of pegulicianine fluorescence-guided surgery (pFGS) did not meet the prespecified threshold for sensitivity.

“It did meet thresholds for removal of residual tumor and specificity — but this is still basically a negative study, and a low sensitivity raises concerns regarding false negative readings,” she said in an interview. “I’m surprised [the committee] is supportive in light of this result. Also, the technique is logistically challenging, as patients need to be injected 2 to 6 hours before their surgeries, very challenging timing for patients having ambulatory procedures.”

The study, published in the April 2023 NEJM Evidence, analyzed 357 patients who received 1.0 mg/kg intravenous pegulicianine followed by lumpectomy. Tumor left behind after standard lumpectomy was removed in 27 of 357 patients through use of pFGS. Of the 27, 22 patients had cavity orientations deemed “negative” on standard margin evaluation, according to the study. A margin is described as negative or clean when there are no further cancer cells at the edge of the tissue, suggesting that all of the cancer has been removed. Second surgeries were avoided by pFGS in 9 of 62 patients with positive margins, the analysis found.

On per-margin analysis, pFGS specificity was 85.2%, and sensitivity was 49.3%. While the sensitivity endpoint missed the lower boundary of the 95% confidence interval, the LUM system exceeded the specificity endpoint of 60% with a point estimate of 86%, and an accuracy of 84% for imaging residual cancer in the lumpectomy cavity, coinvestigator E. Shelley Hwang, MD, MPH, said during the MIDAC meeting.

“The pivotal study was an adequate and well-controlled study demonstrating the effectiveness of the LUM system to detect residual cancer in the lumpectomy cavity, following the standard of care procedure,” she said. “These results also demonstrate clinical benefit that improves the current standard of care. This is the first and only imaging system that provides results in the lumpectomy cavity in real time, allowing surgeons to use this information at the time of the initial procedure.”

Is the Technology Safe?

Pegulicianine is an imaging agent that contains a fluorescent dye. The agent is given to patients as a 3-minute intravenous infusion 2 to 6 hours before surgery.

After removal of the main tumor specimen, the surgeon inserts a handheld probe into the breast cavity and in combination with the detection software, searches for residual cancer that may have been left behind, Dr. Ferrer explained during the MIDAC meeting.

If the software identifies areas suspicious for residual cancer, those areas display in red on an overhead screen. The surgeon then takes a targeted shave to resect the suspicious tissue. Once the tissue has been removed, the surgeon can rescan the cavity with the probe to ensure a more complete resection has been performed. Use of the LUM system typically takes surgeons less than 7 minutes to use, Dr. Ferrer said.

In the study, a total of 406 patients received the intravenous pegulicianine, but 14 patients were withdrawn before randomization. After a standard lumpectomy procedure, 357 patients were assigned to the pFGS group and 35 patients to the control group.

Of the 406 patients, pegulicianine administration was stopped for adverse events in 6 patients (1.5%). Two patients had grade 3 serious adverse events related to pegulicianine; one had hypersensitivity, and one had an anaphylactic reaction. The other four pegulicianine-related adverse events included allergic reaction, milder hypersensitivity, nausea, and pegulicianine extravasation.

Dr. Schnabel said these reactions are worrisome. While any effort to reduce the need for patients to have more than one surgery to complete a breast conserving approach would be a “real advance,” Dr. Schnabel said she would not feel comfortable using pFGS in her own practice if approved by the FDA as is.

“This is clearly a major issue in terms of incorporating this technique into practice,” she said. “I could go on, but in light of the above, I’m surprised that [the committee] is supportive. I would hope for some refinement of the technique to reduce the risks to patients and improve the results before I’d consider utilizing this approach.”

During the MIDAC meeting, Dr. Ferrer said the company takes the safety events seriously and has developed mitigation strategies to further reduce the risk of patient hypersensitivity. These strategies include: clear labeling that informs users of anaphylaxis risk, incorporating a new section into the device training program to address warnings and precautions, an enhanced pharmacovigilance program to closely track and report hypersensitivity events, and a postmarket study to access the incidence rate and risk of such events in a broader population.

Several MIDAC members raised questions about the adverse reactions observed and about the safety of the technology.

David B. Hackney, MD, a neuroradiologist at Beth Israel Deaconess Medical Center in Boston, questioned the recommendation that patients only be monitored for 15 minutes after the injection.

“Since you don’t have enough data to know how long after injection reactions could occur, why not keep them under monitoring until after the surgery is over?” he said.

Barbara Smith, MD, PhD, lead investigator of the study, explained that per the protocol, there would be frequent monitoring, with a nurse at bedside, and patients would be monitored after injection, on their way to the procedure, and afterward.

She suggested, during the meeting, that more intense monitoring early in the process would be beneficial as that is when investigators observed side effects believed to be attributed to LUMISIGHT.

MIDAC member Kimberly E. Applegate, MD, a retired radiology professor, asked about the learning curve for surgeons and how long it generally takes for physicians to become familiar with the system.

Coinvestigator Kelly Hunt, MD, explained that all surgeons who participated in the trial completed a training program.

“Certainly, there’s a learning curve anytime we introduce new technology in the operating room,” she said. “Surgeons said it usually takes about three procedures before they’re comfortable with the system, including the camera and the software.”

During a presentation period by FDA officials, Anil Rajpal, MD, MPH, FDA, Deputy Division Director for Safety, said it’s important that prescribing information for LUMISIGHT communicate the risk of anaphylaxis and other hypersensitivity reactions, the need to monitor patients, and the need for the appropriate available personnel, medications, and equipment.

“This would be done by warnings and precautions and a boxed warning,” he said. “Note, that [such warnings] would only communicate the risks, it would not further characterize the risk.”
 

Committee Expresses Support

During a subsequent vote among committee members, most expressed support for the technology and its benefits. Sixteen members voted in support, one abstained, and two voted against the benefit-risk profile.

Andrea Richardson, MD, PhD, professor of pathology at Johns Hopkins in Baltimore, said she voted yes because the incremental benefits of avoiding additional surgeries outweigh the small risk of anaphylaxis.

Henry Royal, MD, MIDAC chair and professor of radiology at Washington University School of Medicine in St. Louis, agreed.

“Even though the benefit of this is on average, quite small, the benefit to the woman who has positive margins that’s converted to negative margins because of use of [LUMISIGHT] is really quite great,” he said. “The risk from this procedure is certainly very manageable.”

Harold J. Burstein, MD, PhD, a professor of medicine at Harvard Medical School and oncologist at Dana-Farber Cancer Institute in Boston, voted against the benefit-risk profile. He said the technology merits more research and that he does not believe it was proven the technology reduces the risk of reoperation.

“I think it’s a great technology,” he said. “I would like to see a well-conducted, randomized, phase III study with the endpoint of reoperation,” he said. “That would really prove the usefulness and benefit of the intervention in my mind.”

Chengjie Xiong, PhD, professor of biostatistics at Washington University School of Medicine in St. Louis, chose to abstain from voting because he said there was not enough data.

The FDA will now complete its review of Lumicell’s new drug application for LUMISIGHT and review of its premarket approval application for Lumicell DVS. The FDA review team has 6-10 months to make a decision. As part of the process, the FDA will evaluate clinical data, travel to clinical study sites to conduct inspections, and assemble a final action package for a senior FDA official to make a final decision.

If deemed safe and effective, the FDA will then work with Lumicell on developing and refining prescribing information.

Dr. Ferrer said his team expects to receive FDA approval in the coming weeks and will continue to work collaboratively with the FDA to expedite approval where possible.

The purpose of the MIDAC is to review and evaluate data about the safety and effectiveness of marketed and investigational human drug products for use in diagnostic and therapeutic procedures using radioactive pharmaceuticals and make appropriate recommendations to the FDA Commissioner.

“Exercise is medicine” has become something of a mantra, with good reason. There’s no doubt that regular physical activity has a broad range of health benefits. Exercise can improve circulation, help control weight, reduce stress, and boost mood — take your pick.

Lower cancer risk is also on the list — with exercise promoted as a risk-cutting strategy in government guidelines and in recommendations from professional groups such as the American Cancer Society.

Despite confidently worded recommendations, the relationship between exercise and cancer risk is much less certain than the guidelines would suggest. The bulk of the data hangs on less rigorous, observational studies that have linked physical activity to lower risks for certain cancers, but plenty of questions remain.

What are the cancer types where exercise makes a difference? How significant is that impact? And what, exactly, defines a physical activity pattern powerful enough to move the needle on cancer risk?

Here’s an overview of the state of the evidence.

Exercise and Cancer Types: A Mixed Bag

When it comes to cancer prevention strategies, guidelines uniformly endorse less couch time and more movement. But a deeper look at the science reveals a complex and often poorly understood connection between exercise and cancer risk.

For certain cancer types, the benefits of exercise on cancer risk seem fairly well established.

The latest edition of the Physical Activity Guidelines for Americans, published in 2018, cites “strong evidence” that regular exercise might curb the risks for breast and colon cancers as well as bladder, endometrial, esophageal, kidney, and gastric cancers. These guidelines also point to “moderate”-strength evidence of a protective association with lung cancer.

The evidence of a protective effect, however, is strongest for breast and colon cancers, said Jennifer Ligibel, MD, senior physician in the Breast Oncology Center at Dana-Farber Cancer Institute, Boston, . “But,” she pointed out, “that may be because they’re some of the most common cancers, and it’s been easier to detect an association.”

Guidelines from the American Cancer Society, published in 2020, align with the 2018 recommendations. 

“We believe there’s strong evidence to suggest at least eight different types of cancer are associated with physical activity,” said Erika Rees-Punia, PhD, MPH, senior principal scientist, epidemiology and behavioral research at the American Cancer Society.

That view is not universal, however. Current recommendations from the World Cancer Research Fund and American Institute for Cancer Research, for example, are more circumspect, citing only three cancers with good evidence of a protective effect from exercise: Breast (postmenopausal), colon, and endometrial.

“We definitely can’t say exercise reduces the risk of all cancers,” said Lee Jones, PhD, head of the Exercise Oncology Program at Memorial Sloan Kettering Cancer Center in New York City. “The data suggest it’s just not that simple.”

And it’s challenging to put all the evidence together, Dr. Jones added.

The physical activity guidelines are based on published systematic reviews, meta-analyses, and pooled analyses of data from observational studies that examined the relationship between physical activity — aerobic exercise, specifically — and cancer incidence. That means the evidence comes with all the limitations observational studies entail, such as how they collect information on participants’ exercise habits — which, Dr. Jones noted, is typically done via “monster questionnaires” that gauge physical activity in broad strokes.

Pooling all those findings into a meta-analysis is tricky, Dr. Jones added, because individual studies vary in important ways — from follow-up periods to how they quantify exercise and track cancer incidence.

In a study published in February in Cancer Cell, Dr. Jones and his colleagues attempted to address some of those issues by leveraging data from the PLCO screening trial.

The PLCO was a prospective study of over 60,000 US adults that compared the effects of annual screening vs usual care on cancer mortality. At enrollment, participants completed questionnaires that included an assessment of “vigorous” exercise. Based on that, Dr. Jones and his colleagues classified 55% as “exercisers” — meaning they reported 2 or more hours of vigorous exercise per week. The remaining 45%, who were in the 0 to 1 hour per week range, were deemed non-exercisers.

Over a median of 18 years, nearly 16,000 first-time invasive cancers were diagnosed, and some interesting differences between exercisers and non-exercisers emerged. The active group had lower risks for three cancers: Head and neck, with a 26% lower risk (hazard ratio [HR], 0.74), lung (a 20% lower risk), and breast (an 11% lower risk).

What was striking, however, was the lack of connection between exercise and many cancers cited in the guidelines, including colon, gastric, bladder, endometrial, and renal cancers.

Perhaps even more surprising — exercisers had higher risks for prostate cancer (12%) and melanoma (20%). This finding, Dr. Jones said, is in line with a previous pooled analysis of data from 12 US and European prospective cohorts. In this study, the most physically active participants (90th percentile) had higher risks for melanoma and prostate cancer, compared with the least active group (10th percentile).

The melanoma findings do make sense, Dr. Jones said, given that highly active people may spend a lot of time in the sun. “My advice,” Dr. Jones said, “is, if you’re exercising outside, wear sunscreen.” The prostate cancer findings, however, are more puzzling and warrant further research, he noted.

But the bottom line is that the relationship between exercise and cancer types is mixed and far from nailed down.

How Big Is the Effect?

Even if exercise reduces the risk for only certain cancers, that’s still important, particularly when those links appear strongest for common cancer types, such as breast and colon.

But how much of a difference can exercise make?

Based on the evidence, it may only be a modest one. A 2019 systematic review by the Physical Activity Guidelines Advisory Committee provided a rough estimate: Across hundreds of epidemiological studies, people with the highest physical activity levels had a 10%-20% lower risk for the cancers cited in the 2018 exercise guidelines compared with people who were least active.

These figures, however, are probably an underestimate, said Anne McTiernan, MD, PhD, a member of the advisory committee and professor of epidemiology, at Fred Hutchinson Cancer Center, Seattle.

“This is what we usually see when a factor is not measured very well,” said Dr. McTiernan, explaining that the individual studies differed in their categories of “highest” and “lowest” physical activity, such that one study’s “highest” could be another’s mid-range.

“In other words, the effects of physical activity are likely larger” than the review found, Dr. McTiernan said.

The next logical question is whether a bigger exercise “dose” — more time or higher intensity — would have a greater impact on cancer risk. A 2019 study published in the Journal of Clinical Oncology tried to clarify that by pooling data on over 750,000 participants from nine prospective cohorts.

Overall, people meeting government recommendations for exercise — equivalent to about 2.5-5 hours of weekly moderate activity, such as a brisk walk, or about 1.25-2.5 hours of more vigorous activities, like running — had lower risks for seven of 15 cancer types studied compared with less active people.

For cancers with positive findings, being on the higher end of the recommended 2.5- to 5-hour weekly range was better. Risk reductions for breast cancer, for instance, were 6% at 2.5 hours of physical activity per week and 10% at 5 hours per week. Similar trends emerged for other cancer types, including colon (8%-14%), endometrial (10%-18%), liver cancer (18%-27%), and non-Hodgkin lymphoma in women (11%-18%).

But there may be an exercise sweet spot that maximizes the cancer risk benefit.

Among people who surpassed the recommendations — exercising for more time or more intensely — the risk reduction benefit did not necessarily improve in a linear fashion. For certain cancer types, such as colon and endometrial, the benefits of more vigorous exercise “eroded at higher levels of activity,” the authors said.

The issue here is that most studies have not dug deeply into aerobic exercise habits. Often, studies present participants with a list of activities — walking, biking, and running — and ask them to estimate how often and for what duration they do each.

Plus, “we’ve usually lumped moderate and vigorous activities together,” Dr. Rees-Punia said, which means there’s a lack of “granular data” to say whether certain intensities or frequencies of exercise are optimal and for whom.

Why Exercise May Lower Cancer Risk

Exercise habits do not, of course, exist in a vacuum. Highly active people, Dr. Ligibel said, tend to be of higher socioeconomic status, leaner, and have generally healthier lifestyles than sedentary people.

Body weight is a big confounder as well. However, Dr. Rees-Punia noted, it’s also probably a reason that exercise is linked to lower cancer risks, particularly by preventing weight gain. Still, studies have found that the association between exercise and many cancers remains significant after adjusting for body mass index.

The why remains unclear, though some studies offer clues.

“There’s been some really interesting mechanistic research, suggesting that exercise may help inhibit tumor growth or upregulate the immune system,” Dr. Ligibel said.

That includes not only lab research but small intervention studies. While these studies have largely involved people who already have cancer, some have also focused on healthy individuals.

A 2019 study from Dr. Ligibel and her colleagues, which randomly assigned 49 women newly diagnosed with breast cancer to start either an exercise program or mind-body practices ahead of surgery, found exercisers, who had been active for about a month at the time of surgery, showed signs of immune system upregulation in their tumors, while the control group did not.

Among healthy postmenopausal women, a meta-analysis of six clinical trials from Dr. McTiernan and her colleagues found that exercise plus calorie reduction can reduce levels of breast cancer-related endogenous hormones, more so than calorie-cutting alone. And a 2023 study found that high-intensity exercise boosted the ranks of certain immune cells and reduced inflammation in the colon among people at high risk for colon and endometrial cancers due to Lynch syndrome.

Defining an Exercise ‘Prescription’

Despite the gaps and uncertainties in the research, government guidelines as well as those from the American Cancer Society and other medical groups are in lockstep in their exercise recommendations: Adults should strive for 150-300 minutes of moderate-intensity aerobic exercise (like brisk walking), 75-150 minutes of vigorous activity (like running), or some combination each week.

The guidelines also encourage strength training twice a week — advice that’s based on research tying those activity levels to lower risks for heart disease, diabetes, and other chronic conditions.

But there’s no “best” exercise prescription for lowering cancer risk specifically. Most epidemiological studies have examined only aerobic activity, Dr. Rees-Punia said, and there’s very little known about whether strength conditioning or other moderate heart rate-elevating activities, such as daily household chores, may reduce the risk for cancer.

Given the lack of nuance in the literature, it’s hard to say what intensities, types, or amounts of exercise are best for each individual.

Going forward, device-based measurements of physical activity could “help us sort out the effects of different intensities of exercise and possibly types,” Dr. Rees-Punia said.

But overall, Dr. McTiernan said, the data do show that the risks for several cancers are lower at the widely recommended activity levels.

“The bottom-line advice is still to exercise at least 150 minutes per week at a moderate-intensity level or greater,” Dr. McTiernan said.

Or put another way, moving beats being sedentary. It’s probably wise for everyone to sit less, noted Dr. Rees-Punia, for overall health and based on evidence tying sedentary time to the risks for certain cancers, including colon, endometrial, and lung.

There’s a practical element to consider in all of this: What physical activities will people actually do on the regular? In the big epidemiological studies, Dr. McTiernan noted, middle-aged and older adults most often report walking, suggesting that’s the preferred, or most accessible activity, for many.

“You can only benefit from the physical activity you’ll actually do,” Dr. Rees-Punia said.

Dr. Ligibel echoed that sentiment, saying she encourages patients to think about physical activity as a process: “You need to find things you like to do and work them into your daily life, in a sustainable way.

“People often talk about exercise being medicine,” Dr. Ligibel said. “But I think you could take that too far. If we get too prescriptive about it, that could take the joy away.”

A version of this article appeared on Medscape.com.

“Exercise is medicine” has become something of a mantra, with good reason. There’s no doubt that regular physical activity has a broad range of health benefits. Exercise can improve circulation, help control weight, reduce stress, and boost mood — take your pick.

Lower cancer risk is also on the list — with exercise promoted as a risk-cutting strategy in government guidelines and in recommendations from professional groups such as the American Cancer Society.

Despite confidently worded recommendations, the relationship between exercise and cancer risk is much less certain than the guidelines would suggest. The bulk of the data hangs on less rigorous, observational studies that have linked physical activity to lower risks for certain cancers, but plenty of questions remain.

What are the cancer types where exercise makes a difference? How significant is that impact? And what, exactly, defines a physical activity pattern powerful enough to move the needle on cancer risk?

Here’s an overview of the state of the evidence.

Exercise and Cancer Types: A Mixed Bag

When it comes to cancer prevention strategies, guidelines uniformly endorse less couch time and more movement. But a deeper look at the science reveals a complex and often poorly understood connection between exercise and cancer risk.

For certain cancer types, the benefits of exercise on cancer risk seem fairly well established.

The latest edition of the Physical Activity Guidelines for Americans, published in 2018, cites “strong evidence” that regular exercise might curb the risks for breast and colon cancers as well as bladder, endometrial, esophageal, kidney, and gastric cancers. These guidelines also point to “moderate”-strength evidence of a protective association with lung cancer.

The evidence of a protective effect, however, is strongest for breast and colon cancers, said Jennifer Ligibel, MD, senior physician in the Breast Oncology Center at Dana-Farber Cancer Institute, Boston, . “But,” she pointed out, “that may be because they’re some of the most common cancers, and it’s been easier to detect an association.”

Guidelines from the American Cancer Society, published in 2020, align with the 2018 recommendations. 

“We believe there’s strong evidence to suggest at least eight different types of cancer are associated with physical activity,” said Erika Rees-Punia, PhD, MPH, senior principal scientist, epidemiology and behavioral research at the American Cancer Society.

That view is not universal, however. Current recommendations from the World Cancer Research Fund and American Institute for Cancer Research, for example, are more circumspect, citing only three cancers with good evidence of a protective effect from exercise: Breast (postmenopausal), colon, and endometrial.

“We definitely can’t say exercise reduces the risk of all cancers,” said Lee Jones, PhD, head of the Exercise Oncology Program at Memorial Sloan Kettering Cancer Center in New York City. “The data suggest it’s just not that simple.”

And it’s challenging to put all the evidence together, Dr. Jones added.

The physical activity guidelines are based on published systematic reviews, meta-analyses, and pooled analyses of data from observational studies that examined the relationship between physical activity — aerobic exercise, specifically — and cancer incidence. That means the evidence comes with all the limitations observational studies entail, such as how they collect information on participants’ exercise habits — which, Dr. Jones noted, is typically done via “monster questionnaires” that gauge physical activity in broad strokes.

Pooling all those findings into a meta-analysis is tricky, Dr. Jones added, because individual studies vary in important ways — from follow-up periods to how they quantify exercise and track cancer incidence.

In a study published in February in Cancer Cell, Dr. Jones and his colleagues attempted to address some of those issues by leveraging data from the PLCO screening trial.

The PLCO was a prospective study of over 60,000 US adults that compared the effects of annual screening vs usual care on cancer mortality. At enrollment, participants completed questionnaires that included an assessment of “vigorous” exercise. Based on that, Dr. Jones and his colleagues classified 55% as “exercisers” — meaning they reported 2 or more hours of vigorous exercise per week. The remaining 45%, who were in the 0 to 1 hour per week range, were deemed non-exercisers.

Over a median of 18 years, nearly 16,000 first-time invasive cancers were diagnosed, and some interesting differences between exercisers and non-exercisers emerged. The active group had lower risks for three cancers: Head and neck, with a 26% lower risk (hazard ratio [HR], 0.74), lung (a 20% lower risk), and breast (an 11% lower risk).

What was striking, however, was the lack of connection between exercise and many cancers cited in the guidelines, including colon, gastric, bladder, endometrial, and renal cancers.

Perhaps even more surprising — exercisers had higher risks for prostate cancer (12%) and melanoma (20%). This finding, Dr. Jones said, is in line with a previous pooled analysis of data from 12 US and European prospective cohorts. In this study, the most physically active participants (90th percentile) had higher risks for melanoma and prostate cancer, compared with the least active group (10th percentile).

The melanoma findings do make sense, Dr. Jones said, given that highly active people may spend a lot of time in the sun. “My advice,” Dr. Jones said, “is, if you’re exercising outside, wear sunscreen.” The prostate cancer findings, however, are more puzzling and warrant further research, he noted.

But the bottom line is that the relationship between exercise and cancer types is mixed and far from nailed down.

How Big Is the Effect?

Even if exercise reduces the risk for only certain cancers, that’s still important, particularly when those links appear strongest for common cancer types, such as breast and colon.

But how much of a difference can exercise make?

Based on the evidence, it may only be a modest one. A 2019 systematic review by the Physical Activity Guidelines Advisory Committee provided a rough estimate: Across hundreds of epidemiological studies, people with the highest physical activity levels had a 10%-20% lower risk for the cancers cited in the 2018 exercise guidelines compared with people who were least active.

These figures, however, are probably an underestimate, said Anne McTiernan, MD, PhD, a member of the advisory committee and professor of epidemiology, at Fred Hutchinson Cancer Center, Seattle.

“This is what we usually see when a factor is not measured very well,” said Dr. McTiernan, explaining that the individual studies differed in their categories of “highest” and “lowest” physical activity, such that one study’s “highest” could be another’s mid-range.

“In other words, the effects of physical activity are likely larger” than the review found, Dr. McTiernan said.

The next logical question is whether a bigger exercise “dose” — more time or higher intensity — would have a greater impact on cancer risk. A 2019 study published in the Journal of Clinical Oncology tried to clarify that by pooling data on over 750,000 participants from nine prospective cohorts.

Overall, people meeting government recommendations for exercise — equivalent to about 2.5-5 hours of weekly moderate activity, such as a brisk walk, or about 1.25-2.5 hours of more vigorous activities, like running — had lower risks for seven of 15 cancer types studied compared with less active people.

For cancers with positive findings, being on the higher end of the recommended 2.5- to 5-hour weekly range was better. Risk reductions for breast cancer, for instance, were 6% at 2.5 hours of physical activity per week and 10% at 5 hours per week. Similar trends emerged for other cancer types, including colon (8%-14%), endometrial (10%-18%), liver cancer (18%-27%), and non-Hodgkin lymphoma in women (11%-18%).

But there may be an exercise sweet spot that maximizes the cancer risk benefit.

Among people who surpassed the recommendations — exercising for more time or more intensely — the risk reduction benefit did not necessarily improve in a linear fashion. For certain cancer types, such as colon and endometrial, the benefits of more vigorous exercise “eroded at higher levels of activity,” the authors said.

The issue here is that most studies have not dug deeply into aerobic exercise habits. Often, studies present participants with a list of activities — walking, biking, and running — and ask them to estimate how often and for what duration they do each.

Plus, “we’ve usually lumped moderate and vigorous activities together,” Dr. Rees-Punia said, which means there’s a lack of “granular data” to say whether certain intensities or frequencies of exercise are optimal and for whom.

Why Exercise May Lower Cancer Risk

Exercise habits do not, of course, exist in a vacuum. Highly active people, Dr. Ligibel said, tend to be of higher socioeconomic status, leaner, and have generally healthier lifestyles than sedentary people.

Body weight is a big confounder as well. However, Dr. Rees-Punia noted, it’s also probably a reason that exercise is linked to lower cancer risks, particularly by preventing weight gain. Still, studies have found that the association between exercise and many cancers remains significant after adjusting for body mass index.

The why remains unclear, though some studies offer clues.

“There’s been some really interesting mechanistic research, suggesting that exercise may help inhibit tumor growth or upregulate the immune system,” Dr. Ligibel said.

That includes not only lab research but small intervention studies. While these studies have largely involved people who already have cancer, some have also focused on healthy individuals.

A 2019 study from Dr. Ligibel and her colleagues, which randomly assigned 49 women newly diagnosed with breast cancer to start either an exercise program or mind-body practices ahead of surgery, found exercisers, who had been active for about a month at the time of surgery, showed signs of immune system upregulation in their tumors, while the control group did not.

Among healthy postmenopausal women, a meta-analysis of six clinical trials from Dr. McTiernan and her colleagues found that exercise plus calorie reduction can reduce levels of breast cancer-related endogenous hormones, more so than calorie-cutting alone. And a 2023 study found that high-intensity exercise boosted the ranks of certain immune cells and reduced inflammation in the colon among people at high risk for colon and endometrial cancers due to Lynch syndrome.

Defining an Exercise ‘Prescription’

Despite the gaps and uncertainties in the research, government guidelines as well as those from the American Cancer Society and other medical groups are in lockstep in their exercise recommendations: Adults should strive for 150-300 minutes of moderate-intensity aerobic exercise (like brisk walking), 75-150 minutes of vigorous activity (like running), or some combination each week.

The guidelines also encourage strength training twice a week — advice that’s based on research tying those activity levels to lower risks for heart disease, diabetes, and other chronic conditions.

But there’s no “best” exercise prescription for lowering cancer risk specifically. Most epidemiological studies have examined only aerobic activity, Dr. Rees-Punia said, and there’s very little known about whether strength conditioning or other moderate heart rate-elevating activities, such as daily household chores, may reduce the risk for cancer.

Given the lack of nuance in the literature, it’s hard to say what intensities, types, or amounts of exercise are best for each individual.

Going forward, device-based measurements of physical activity could “help us sort out the effects of different intensities of exercise and possibly types,” Dr. Rees-Punia said.

But overall, Dr. McTiernan said, the data do show that the risks for several cancers are lower at the widely recommended activity levels.

“The bottom-line advice is still to exercise at least 150 minutes per week at a moderate-intensity level or greater,” Dr. McTiernan said.

Or put another way, moving beats being sedentary. It’s probably wise for everyone to sit less, noted Dr. Rees-Punia, for overall health and based on evidence tying sedentary time to the risks for certain cancers, including colon, endometrial, and lung.

There’s a practical element to consider in all of this: What physical activities will people actually do on the regular? In the big epidemiological studies, Dr. McTiernan noted, middle-aged and older adults most often report walking, suggesting that’s the preferred, or most accessible activity, for many.

“You can only benefit from the physical activity you’ll actually do,” Dr. Rees-Punia said.

Dr. Ligibel echoed that sentiment, saying she encourages patients to think about physical activity as a process: “You need to find things you like to do and work them into your daily life, in a sustainable way.

“People often talk about exercise being medicine,” Dr. Ligibel said. “But I think you could take that too far. If we get too prescriptive about it, that could take the joy away.”

A version of this article appeared on Medscape.com.

“Exercise is medicine” has become something of a mantra, with good reason. There’s no doubt that regular physical activity has a broad range of health benefits. Exercise can improve circulation, help control weight, reduce stress, and boost mood — take your pick.

Lower cancer risk is also on the list — with exercise promoted as a risk-cutting strategy in government guidelines and in recommendations from professional groups such as the American Cancer Society.

Despite confidently worded recommendations, the relationship between exercise and cancer risk is much less certain than the guidelines would suggest. The bulk of the data hangs on less rigorous, observational studies that have linked physical activity to lower risks for certain cancers, but plenty of questions remain.

What are the cancer types where exercise makes a difference? How significant is that impact? And what, exactly, defines a physical activity pattern powerful enough to move the needle on cancer risk?

Here’s an overview of the state of the evidence.

Exercise and Cancer Types: A Mixed Bag

When it comes to cancer prevention strategies, guidelines uniformly endorse less couch time and more movement. But a deeper look at the science reveals a complex and often poorly understood connection between exercise and cancer risk.

For certain cancer types, the benefits of exercise on cancer risk seem fairly well established.

The latest edition of the Physical Activity Guidelines for Americans, published in 2018, cites “strong evidence” that regular exercise might curb the risks for breast and colon cancers as well as bladder, endometrial, esophageal, kidney, and gastric cancers. These guidelines also point to “moderate”-strength evidence of a protective association with lung cancer.

The evidence of a protective effect, however, is strongest for breast and colon cancers, said Jennifer Ligibel, MD, senior physician in the Breast Oncology Center at Dana-Farber Cancer Institute, Boston, . “But,” she pointed out, “that may be because they’re some of the most common cancers, and it’s been easier to detect an association.”

Guidelines from the American Cancer Society, published in 2020, align with the 2018 recommendations. 

“We believe there’s strong evidence to suggest at least eight different types of cancer are associated with physical activity,” said Erika Rees-Punia, PhD, MPH, senior principal scientist, epidemiology and behavioral research at the American Cancer Society.

That view is not universal, however. Current recommendations from the World Cancer Research Fund and American Institute for Cancer Research, for example, are more circumspect, citing only three cancers with good evidence of a protective effect from exercise: Breast (postmenopausal), colon, and endometrial.

“We definitely can’t say exercise reduces the risk of all cancers,” said Lee Jones, PhD, head of the Exercise Oncology Program at Memorial Sloan Kettering Cancer Center in New York City. “The data suggest it’s just not that simple.”

And it’s challenging to put all the evidence together, Dr. Jones added.

The physical activity guidelines are based on published systematic reviews, meta-analyses, and pooled analyses of data from observational studies that examined the relationship between physical activity — aerobic exercise, specifically — and cancer incidence. That means the evidence comes with all the limitations observational studies entail, such as how they collect information on participants’ exercise habits — which, Dr. Jones noted, is typically done via “monster questionnaires” that gauge physical activity in broad strokes.

Pooling all those findings into a meta-analysis is tricky, Dr. Jones added, because individual studies vary in important ways — from follow-up periods to how they quantify exercise and track cancer incidence.

In a study published in February in Cancer Cell, Dr. Jones and his colleagues attempted to address some of those issues by leveraging data from the PLCO screening trial.

The PLCO was a prospective study of over 60,000 US adults that compared the effects of annual screening vs usual care on cancer mortality. At enrollment, participants completed questionnaires that included an assessment of “vigorous” exercise. Based on that, Dr. Jones and his colleagues classified 55% as “exercisers” — meaning they reported 2 or more hours of vigorous exercise per week. The remaining 45%, who were in the 0 to 1 hour per week range, were deemed non-exercisers.

Over a median of 18 years, nearly 16,000 first-time invasive cancers were diagnosed, and some interesting differences between exercisers and non-exercisers emerged. The active group had lower risks for three cancers: Head and neck, with a 26% lower risk (hazard ratio [HR], 0.74), lung (a 20% lower risk), and breast (an 11% lower risk).

What was striking, however, was the lack of connection between exercise and many cancers cited in the guidelines, including colon, gastric, bladder, endometrial, and renal cancers.

Perhaps even more surprising — exercisers had higher risks for prostate cancer (12%) and melanoma (20%). This finding, Dr. Jones said, is in line with a previous pooled analysis of data from 12 US and European prospective cohorts. In this study, the most physically active participants (90th percentile) had higher risks for melanoma and prostate cancer, compared with the least active group (10th percentile).

The melanoma findings do make sense, Dr. Jones said, given that highly active people may spend a lot of time in the sun. “My advice,” Dr. Jones said, “is, if you’re exercising outside, wear sunscreen.” The prostate cancer findings, however, are more puzzling and warrant further research, he noted.

But the bottom line is that the relationship between exercise and cancer types is mixed and far from nailed down.

How Big Is the Effect?

Even if exercise reduces the risk for only certain cancers, that’s still important, particularly when those links appear strongest for common cancer types, such as breast and colon.

But how much of a difference can exercise make?

Based on the evidence, it may only be a modest one. A 2019 systematic review by the Physical Activity Guidelines Advisory Committee provided a rough estimate: Across hundreds of epidemiological studies, people with the highest physical activity levels had a 10%-20% lower risk for the cancers cited in the 2018 exercise guidelines compared with people who were least active.

These figures, however, are probably an underestimate, said Anne McTiernan, MD, PhD, a member of the advisory committee and professor of epidemiology, at Fred Hutchinson Cancer Center, Seattle.

“This is what we usually see when a factor is not measured very well,” said Dr. McTiernan, explaining that the individual studies differed in their categories of “highest” and “lowest” physical activity, such that one study’s “highest” could be another’s mid-range.

“In other words, the effects of physical activity are likely larger” than the review found, Dr. McTiernan said.

The next logical question is whether a bigger exercise “dose” — more time or higher intensity — would have a greater impact on cancer risk. A 2019 study published in the Journal of Clinical Oncology tried to clarify that by pooling data on over 750,000 participants from nine prospective cohorts.

Overall, people meeting government recommendations for exercise — equivalent to about 2.5-5 hours of weekly moderate activity, such as a brisk walk, or about 1.25-2.5 hours of more vigorous activities, like running — had lower risks for seven of 15 cancer types studied compared with less active people.

For cancers with positive findings, being on the higher end of the recommended 2.5- to 5-hour weekly range was better. Risk reductions for breast cancer, for instance, were 6% at 2.5 hours of physical activity per week and 10% at 5 hours per week. Similar trends emerged for other cancer types, including colon (8%-14%), endometrial (10%-18%), liver cancer (18%-27%), and non-Hodgkin lymphoma in women (11%-18%).

But there may be an exercise sweet spot that maximizes the cancer risk benefit.

Among people who surpassed the recommendations — exercising for more time or more intensely — the risk reduction benefit did not necessarily improve in a linear fashion. For certain cancer types, such as colon and endometrial, the benefits of more vigorous exercise “eroded at higher levels of activity,” the authors said.

The issue here is that most studies have not dug deeply into aerobic exercise habits. Often, studies present participants with a list of activities — walking, biking, and running — and ask them to estimate how often and for what duration they do each.

Plus, “we’ve usually lumped moderate and vigorous activities together,” Dr. Rees-Punia said, which means there’s a lack of “granular data” to say whether certain intensities or frequencies of exercise are optimal and for whom.

Why Exercise May Lower Cancer Risk

Exercise habits do not, of course, exist in a vacuum. Highly active people, Dr. Ligibel said, tend to be of higher socioeconomic status, leaner, and have generally healthier lifestyles than sedentary people.

Body weight is a big confounder as well. However, Dr. Rees-Punia noted, it’s also probably a reason that exercise is linked to lower cancer risks, particularly by preventing weight gain. Still, studies have found that the association between exercise and many cancers remains significant after adjusting for body mass index.

The why remains unclear, though some studies offer clues.

“There’s been some really interesting mechanistic research, suggesting that exercise may help inhibit tumor growth or upregulate the immune system,” Dr. Ligibel said.

That includes not only lab research but small intervention studies. While these studies have largely involved people who already have cancer, some have also focused on healthy individuals.

A 2019 study from Dr. Ligibel and her colleagues, which randomly assigned 49 women newly diagnosed with breast cancer to start either an exercise program or mind-body practices ahead of surgery, found exercisers, who had been active for about a month at the time of surgery, showed signs of immune system upregulation in their tumors, while the control group did not.

Among healthy postmenopausal women, a meta-analysis of six clinical trials from Dr. McTiernan and her colleagues found that exercise plus calorie reduction can reduce levels of breast cancer-related endogenous hormones, more so than calorie-cutting alone. And a 2023 study found that high-intensity exercise boosted the ranks of certain immune cells and reduced inflammation in the colon among people at high risk for colon and endometrial cancers due to Lynch syndrome.

Defining an Exercise ‘Prescription’

Despite the gaps and uncertainties in the research, government guidelines as well as those from the American Cancer Society and other medical groups are in lockstep in their exercise recommendations: Adults should strive for 150-300 minutes of moderate-intensity aerobic exercise (like brisk walking), 75-150 minutes of vigorous activity (like running), or some combination each week.

The guidelines also encourage strength training twice a week — advice that’s based on research tying those activity levels to lower risks for heart disease, diabetes, and other chronic conditions.

But there’s no “best” exercise prescription for lowering cancer risk specifically. Most epidemiological studies have examined only aerobic activity, Dr. Rees-Punia said, and there’s very little known about whether strength conditioning or other moderate heart rate-elevating activities, such as daily household chores, may reduce the risk for cancer.

Given the lack of nuance in the literature, it’s hard to say what intensities, types, or amounts of exercise are best for each individual.

Going forward, device-based measurements of physical activity could “help us sort out the effects of different intensities of exercise and possibly types,” Dr. Rees-Punia said.

But overall, Dr. McTiernan said, the data do show that the risks for several cancers are lower at the widely recommended activity levels.

“The bottom-line advice is still to exercise at least 150 minutes per week at a moderate-intensity level or greater,” Dr. McTiernan said.

Or put another way, moving beats being sedentary. It’s probably wise for everyone to sit less, noted Dr. Rees-Punia, for overall health and based on evidence tying sedentary time to the risks for certain cancers, including colon, endometrial, and lung.

There’s a practical element to consider in all of this: What physical activities will people actually do on the regular? In the big epidemiological studies, Dr. McTiernan noted, middle-aged and older adults most often report walking, suggesting that’s the preferred, or most accessible activity, for many.

“You can only benefit from the physical activity you’ll actually do,” Dr. Rees-Punia said.

Dr. Ligibel echoed that sentiment, saying she encourages patients to think about physical activity as a process: “You need to find things you like to do and work them into your daily life, in a sustainable way.

“People often talk about exercise being medicine,” Dr. Ligibel said. “But I think you could take that too far. If we get too prescriptive about it, that could take the joy away.”

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has granted breakthrough designation to an LSD-based treatment for generalized anxiety disorder (GAD) based on promising topline data from a phase 2b clinical trial. Mind Medicine (MindMed) Inc is developing the treatment — MM120 (lysergide d-tartrate).

In a news release, the company reports that a single oral dose of MM120 met its key secondary endpoint, maintaining “clinically and statistically significant” reductions in Hamilton Anxiety Scale (HAM-A) score, compared with placebo, at 12 weeks with a 65% clinical response rate and 48% clinical remission rate.

The company previously announced statistically significant improvements on the HAM-A compared with placebo at 4 weeks, which was the trial’s primary endpoint.

“I’ve conducted clinical research studies in psychiatry for over two decades and have seen studies of many drugs under development for the treatment of anxiety. That MM120 exhibited rapid and robust efficacy, solidly sustained for 12 weeks after a single dose, is truly remarkable,” study investigator David Feifel, MD, PhD, professor emeritus of psychiatry at the University of California, San Diego, and director of the Kadima Neuropsychiatry Institute in La Jolla, California, said in the news release.

“These results suggest the potential MM120 has in the treatment of anxiety, and those of us who struggle every day to alleviate anxiety in our patients look forward to seeing results from future phase 3 trials,” Dr. Feifel added.

MM120 was administered as a single dose in a monitored clinical setting with no additional therapeutic intervention. Prior to treatment with MM120, study participants were clinically tapered and then washed out from any anxiolytic or antidepressant treatments and did not receive any form of study-related psychotherapy for the duration of their participation in the study.

MM120 100 µg — the dose that demonstrated optimal clinical activity — produced a 7.7-point improvement over placebo at week 12 (P < .003; Cohen’s d = 0.81), with a 65% clinical response rate and a 48% clinical remission rate sustained to week 12.

Also at week 12, Clinical Global Impressions–Severity (CGI-S) scores on average improved from 4.8 to 2.2 in the 100-µg dose group, representing a two-category shift from ‘markedly ill’ to ‘borderline ill’ at week 12 (P < .004), the company reported.

Improvement was noted as early as study day 2, and durable with further improvements observed in mean HAM-A or CGI-S scores between 4 and 12 weeks.

MM120 was generally well-tolerated with most adverse events rated as mild to moderate and transient and occurred on the day of administration day, in line with the expected acute effects of the study drug.

The most common adverse events on dosing day included illusion, hallucinations, euphoric mood, anxiety, abnormal thinking, headache, paresthesia, dizziness, tremor, nausea, vomiting, feeling abnormal, mydriasis, and hyperhidrosis.

The company plans to hold an end-of-phase 2 meeting with the FDA in the first half of 2024 and start phase 3 testing in the second half of 2024.

“The FDA’s decision to designate MM120 as a breakthrough therapy for GAD and the durability data from our phase 2b study provide further validation of the important potential role this treatment can play in addressing the huge unmet need among individuals living with GAD,” Robert Barrow, director and CEO of MindMed said in the release.

The primary data analyses from the trial will be presented at the American Psychiatric Association (APA) annual meeting in May.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has granted breakthrough designation to an LSD-based treatment for generalized anxiety disorder (GAD) based on promising topline data from a phase 2b clinical trial. Mind Medicine (MindMed) Inc is developing the treatment — MM120 (lysergide d-tartrate).

In a news release, the company reports that a single oral dose of MM120 met its key secondary endpoint, maintaining “clinically and statistically significant” reductions in Hamilton Anxiety Scale (HAM-A) score, compared with placebo, at 12 weeks with a 65% clinical response rate and 48% clinical remission rate.

The company previously announced statistically significant improvements on the HAM-A compared with placebo at 4 weeks, which was the trial’s primary endpoint.

“I’ve conducted clinical research studies in psychiatry for over two decades and have seen studies of many drugs under development for the treatment of anxiety. That MM120 exhibited rapid and robust efficacy, solidly sustained for 12 weeks after a single dose, is truly remarkable,” study investigator David Feifel, MD, PhD, professor emeritus of psychiatry at the University of California, San Diego, and director of the Kadima Neuropsychiatry Institute in La Jolla, California, said in the news release.

“These results suggest the potential MM120 has in the treatment of anxiety, and those of us who struggle every day to alleviate anxiety in our patients look forward to seeing results from future phase 3 trials,” Dr. Feifel added.

MM120 was administered as a single dose in a monitored clinical setting with no additional therapeutic intervention. Prior to treatment with MM120, study participants were clinically tapered and then washed out from any anxiolytic or antidepressant treatments and did not receive any form of study-related psychotherapy for the duration of their participation in the study.

MM120 100 µg — the dose that demonstrated optimal clinical activity — produced a 7.7-point improvement over placebo at week 12 (P < .003; Cohen’s d = 0.81), with a 65% clinical response rate and a 48% clinical remission rate sustained to week 12.

Also at week 12, Clinical Global Impressions–Severity (CGI-S) scores on average improved from 4.8 to 2.2 in the 100-µg dose group, representing a two-category shift from ‘markedly ill’ to ‘borderline ill’ at week 12 (P < .004), the company reported.

Improvement was noted as early as study day 2, and durable with further improvements observed in mean HAM-A or CGI-S scores between 4 and 12 weeks.

MM120 was generally well-tolerated with most adverse events rated as mild to moderate and transient and occurred on the day of administration day, in line with the expected acute effects of the study drug.

The most common adverse events on dosing day included illusion, hallucinations, euphoric mood, anxiety, abnormal thinking, headache, paresthesia, dizziness, tremor, nausea, vomiting, feeling abnormal, mydriasis, and hyperhidrosis.

The company plans to hold an end-of-phase 2 meeting with the FDA in the first half of 2024 and start phase 3 testing in the second half of 2024.

“The FDA’s decision to designate MM120 as a breakthrough therapy for GAD and the durability data from our phase 2b study provide further validation of the important potential role this treatment can play in addressing the huge unmet need among individuals living with GAD,” Robert Barrow, director and CEO of MindMed said in the release.

The primary data analyses from the trial will be presented at the American Psychiatric Association (APA) annual meeting in May.

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has granted breakthrough designation to an LSD-based treatment for generalized anxiety disorder (GAD) based on promising topline data from a phase 2b clinical trial. Mind Medicine (MindMed) Inc is developing the treatment — MM120 (lysergide d-tartrate).

In a news release, the company reports that a single oral dose of MM120 met its key secondary endpoint, maintaining “clinically and statistically significant” reductions in Hamilton Anxiety Scale (HAM-A) score, compared with placebo, at 12 weeks with a 65% clinical response rate and 48% clinical remission rate.

The company previously announced statistically significant improvements on the HAM-A compared with placebo at 4 weeks, which was the trial’s primary endpoint.

“I’ve conducted clinical research studies in psychiatry for over two decades and have seen studies of many drugs under development for the treatment of anxiety. That MM120 exhibited rapid and robust efficacy, solidly sustained for 12 weeks after a single dose, is truly remarkable,” study investigator David Feifel, MD, PhD, professor emeritus of psychiatry at the University of California, San Diego, and director of the Kadima Neuropsychiatry Institute in La Jolla, California, said in the news release.

“These results suggest the potential MM120 has in the treatment of anxiety, and those of us who struggle every day to alleviate anxiety in our patients look forward to seeing results from future phase 3 trials,” Dr. Feifel added.

MM120 was administered as a single dose in a monitored clinical setting with no additional therapeutic intervention. Prior to treatment with MM120, study participants were clinically tapered and then washed out from any anxiolytic or antidepressant treatments and did not receive any form of study-related psychotherapy for the duration of their participation in the study.

MM120 100 µg — the dose that demonstrated optimal clinical activity — produced a 7.7-point improvement over placebo at week 12 (P < .003; Cohen’s d = 0.81), with a 65% clinical response rate and a 48% clinical remission rate sustained to week 12.

Also at week 12, Clinical Global Impressions–Severity (CGI-S) scores on average improved from 4.8 to 2.2 in the 100-µg dose group, representing a two-category shift from ‘markedly ill’ to ‘borderline ill’ at week 12 (P < .004), the company reported.

Improvement was noted as early as study day 2, and durable with further improvements observed in mean HAM-A or CGI-S scores between 4 and 12 weeks.

MM120 was generally well-tolerated with most adverse events rated as mild to moderate and transient and occurred on the day of administration day, in line with the expected acute effects of the study drug.

The most common adverse events on dosing day included illusion, hallucinations, euphoric mood, anxiety, abnormal thinking, headache, paresthesia, dizziness, tremor, nausea, vomiting, feeling abnormal, mydriasis, and hyperhidrosis.

The company plans to hold an end-of-phase 2 meeting with the FDA in the first half of 2024 and start phase 3 testing in the second half of 2024.

“The FDA’s decision to designate MM120 as a breakthrough therapy for GAD and the durability data from our phase 2b study provide further validation of the important potential role this treatment can play in addressing the huge unmet need among individuals living with GAD,” Robert Barrow, director and CEO of MindMed said in the release.

The primary data analyses from the trial will be presented at the American Psychiatric Association (APA) annual meeting in May.

A version of this article appeared on Medscape.com.

An FDA advisory committee has recommended that the United States switch from a quadrivalent to trivalent influenza vaccine for the next flu season.

The flu vaccine currently in use targets two A strains and two B strains. But the Yamagata/B subtype, which was already in decline, has not been detected worldwide since March 2020, the FDA said. Social distancing and other precautions used to avoid COVID apparently finished it off. 

In response to that change, the Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted on March 5 to recommend the three-strain flu shot.

VRBPAC recommended the egg-based flu vaccines contain an A/Victoria/4897/2022 (H1N1)pdm09-like virus, an A/Thailand/8/2022 (H3N2)-like virus; and a B/Austria/1359417/2021 (B/Victoria lineage)-like virus.

The committee recommended the cell- or recombinant-based flu vaccines contain an A/Wisconsin/67/2022 (H1N1)pdm09-like virus; an A/Massachusetts/18/2022 (H3N2)-like virus; and a B/Austria/1359417/2021 (B/Victoria lineage)-like virus.

The move is no surprise. The World Health Organization and FDA experts had been recommending the change since last year. 

Jerry Weir, MD, director of the FDA’s Division of Viral Products, said companies that make flu vaccines should have the trivalent shot ready for the 2024-2025  flu season.

“Each of the U.S. influenza vaccine manufacturers have submitted updated regulatory files related to a trivalent influenza vaccine, and approval of all the necessary regulatory submissions is on track for 2024-25,” he said during the advisory committee’s meeting, according to CNN.

“FDA anticipates that there will be an adequate and diverse supply of approved trivalent seasonal influenza vaccines for the United States in the coming season,” the agency said.

U.S. flu vaccine manufacturers will still make a four-strain vaccine for distribution to overseas markets, CNN said.
 

A version of this article appeared on WebMD.com.

An FDA advisory committee has recommended that the United States switch from a quadrivalent to trivalent influenza vaccine for the next flu season.

The flu vaccine currently in use targets two A strains and two B strains. But the Yamagata/B subtype, which was already in decline, has not been detected worldwide since March 2020, the FDA said. Social distancing and other precautions used to avoid COVID apparently finished it off. 

In response to that change, the Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted on March 5 to recommend the three-strain flu shot.

VRBPAC recommended the egg-based flu vaccines contain an A/Victoria/4897/2022 (H1N1)pdm09-like virus, an A/Thailand/8/2022 (H3N2)-like virus; and a B/Austria/1359417/2021 (B/Victoria lineage)-like virus.

The committee recommended the cell- or recombinant-based flu vaccines contain an A/Wisconsin/67/2022 (H1N1)pdm09-like virus; an A/Massachusetts/18/2022 (H3N2)-like virus; and a B/Austria/1359417/2021 (B/Victoria lineage)-like virus.

The move is no surprise. The World Health Organization and FDA experts had been recommending the change since last year. 

Jerry Weir, MD, director of the FDA’s Division of Viral Products, said companies that make flu vaccines should have the trivalent shot ready for the 2024-2025  flu season.

“Each of the U.S. influenza vaccine manufacturers have submitted updated regulatory files related to a trivalent influenza vaccine, and approval of all the necessary regulatory submissions is on track for 2024-25,” he said during the advisory committee’s meeting, according to CNN.

“FDA anticipates that there will be an adequate and diverse supply of approved trivalent seasonal influenza vaccines for the United States in the coming season,” the agency said.

U.S. flu vaccine manufacturers will still make a four-strain vaccine for distribution to overseas markets, CNN said.
 

A version of this article appeared on WebMD.com.

An FDA advisory committee has recommended that the United States switch from a quadrivalent to trivalent influenza vaccine for the next flu season.

The flu vaccine currently in use targets two A strains and two B strains. But the Yamagata/B subtype, which was already in decline, has not been detected worldwide since March 2020, the FDA said. Social distancing and other precautions used to avoid COVID apparently finished it off. 

In response to that change, the Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted on March 5 to recommend the three-strain flu shot.

VRBPAC recommended the egg-based flu vaccines contain an A/Victoria/4897/2022 (H1N1)pdm09-like virus, an A/Thailand/8/2022 (H3N2)-like virus; and a B/Austria/1359417/2021 (B/Victoria lineage)-like virus.

The committee recommended the cell- or recombinant-based flu vaccines contain an A/Wisconsin/67/2022 (H1N1)pdm09-like virus; an A/Massachusetts/18/2022 (H3N2)-like virus; and a B/Austria/1359417/2021 (B/Victoria lineage)-like virus.

The move is no surprise. The World Health Organization and FDA experts had been recommending the change since last year. 

Jerry Weir, MD, director of the FDA’s Division of Viral Products, said companies that make flu vaccines should have the trivalent shot ready for the 2024-2025  flu season.

“Each of the U.S. influenza vaccine manufacturers have submitted updated regulatory files related to a trivalent influenza vaccine, and approval of all the necessary regulatory submissions is on track for 2024-25,” he said during the advisory committee’s meeting, according to CNN.

“FDA anticipates that there will be an adequate and diverse supply of approved trivalent seasonal influenza vaccines for the United States in the coming season,” the agency said.

U.S. flu vaccine manufacturers will still make a four-strain vaccine for distribution to overseas markets, CNN said.
 

A version of this article appeared on WebMD.com.

TOPLINE:

Resecting the primary colon tumor before chemotherapy does not improve overall survival compared with chemotherapy alone in patients with metastatic colon cancer not amenable to curative therapy, new data showed.

METHODOLOGY:

• Chemotherapy is the primary treatment in patients with stage IV  (CRC) and unresectable metastases. It’s unclear whether primary tumor resection before chemotherapy prolongs survival.
• Among 393 patients with stage IV colon cancer and unresectable metastases enrolled in the  and  trials, 187 were randomly allocated to undergo primary tumor resection and 206 to upfront chemotherapy.
• The chemotherapy regimen was left up to the treating physician. Overall survival was the primary endpoint. Median follow-up time was 36.7 months.

TAKEAWAY:

• Median overall survival was 16.7 months with primary tumor resection and 18.6 months with upfront chemotherapy (P = .191).
• Comparable overall survival between the study groups was further confirmed on multivariate analysis (hazard ratio, 0.944; P = .65) and across all subgroups.
• Serious adverse events were more common with upfront chemo than surgery (18% vs 10%; P = .027), due mainly to a significantly higher incidence of GI-related events (11% vs 5%; P = .031).
• Overall, 24% of the primary tumor resection group did not receive any chemotherapy.

IN PRACTICE:

“The results of our study provide compelling data that upfront primary tumor resection in treatment-naive stage IV CRC not amenable for curative treatment does not prolong [overall survival]. A relatively low incidence of serious adverse events in patients with an intact primary tumor together with a considerable number of patients who did not receive any chemotherapy in the primary tumor resection group provides further arguments against resection of the primary tumor in this group of patients,” the authors of the combined analysis concluded.

SOURCE:

The study, with first author Nuh N. Rahbari, MD, University of Ulm, Ulm, Germany, was published online in the Journal of Clinical Oncology.

LIMITATIONS:

Neither study completed their planned patient accrual. Although both trials are nearly identical, differences in the individual study cohorts and trial implementation could have introduced bias. Tumor molecular profiling was not performed.

DISCLOSURES:

The study had no commercial funding. Disclosures for authors are available with the original article.

A version of this article appeared on Medscape.com.

TOPLINE:

Resecting the primary colon tumor before chemotherapy does not improve overall survival compared with chemotherapy alone in patients with metastatic colon cancer not amenable to curative therapy, new data showed.

METHODOLOGY:

• Chemotherapy is the primary treatment in patients with stage IV  (CRC) and unresectable metastases. It’s unclear whether primary tumor resection before chemotherapy prolongs survival.
• Among 393 patients with stage IV colon cancer and unresectable metastases enrolled in the  and  trials, 187 were randomly allocated to undergo primary tumor resection and 206 to upfront chemotherapy.
• The chemotherapy regimen was left up to the treating physician. Overall survival was the primary endpoint. Median follow-up time was 36.7 months.

TAKEAWAY:

• Median overall survival was 16.7 months with primary tumor resection and 18.6 months with upfront chemotherapy (P = .191).
• Comparable overall survival between the study groups was further confirmed on multivariate analysis (hazard ratio, 0.944; P = .65) and across all subgroups.
• Serious adverse events were more common with upfront chemo than surgery (18% vs 10%; P = .027), due mainly to a significantly higher incidence of GI-related events (11% vs 5%; P = .031).
• Overall, 24% of the primary tumor resection group did not receive any chemotherapy.

IN PRACTICE:

“The results of our study provide compelling data that upfront primary tumor resection in treatment-naive stage IV CRC not amenable for curative treatment does not prolong [overall survival]. A relatively low incidence of serious adverse events in patients with an intact primary tumor together with a considerable number of patients who did not receive any chemotherapy in the primary tumor resection group provides further arguments against resection of the primary tumor in this group of patients,” the authors of the combined analysis concluded.

SOURCE:

The study, with first author Nuh N. Rahbari, MD, University of Ulm, Ulm, Germany, was published online in the Journal of Clinical Oncology.

LIMITATIONS:

Neither study completed their planned patient accrual. Although both trials are nearly identical, differences in the individual study cohorts and trial implementation could have introduced bias. Tumor molecular profiling was not performed.

DISCLOSURES:

The study had no commercial funding. Disclosures for authors are available with the original article.

A version of this article appeared on Medscape.com.

TOPLINE:

Resecting the primary colon tumor before chemotherapy does not improve overall survival compared with chemotherapy alone in patients with metastatic colon cancer not amenable to curative therapy, new data showed.

METHODOLOGY:

• Chemotherapy is the primary treatment in patients with stage IV  (CRC) and unresectable metastases. It’s unclear whether primary tumor resection before chemotherapy prolongs survival.
• Among 393 patients with stage IV colon cancer and unresectable metastases enrolled in the  and  trials, 187 were randomly allocated to undergo primary tumor resection and 206 to upfront chemotherapy.
• The chemotherapy regimen was left up to the treating physician. Overall survival was the primary endpoint. Median follow-up time was 36.7 months.

TAKEAWAY:

• Median overall survival was 16.7 months with primary tumor resection and 18.6 months with upfront chemotherapy (P = .191).
• Comparable overall survival between the study groups was further confirmed on multivariate analysis (hazard ratio, 0.944; P = .65) and across all subgroups.
• Serious adverse events were more common with upfront chemo than surgery (18% vs 10%; P = .027), due mainly to a significantly higher incidence of GI-related events (11% vs 5%; P = .031).
• Overall, 24% of the primary tumor resection group did not receive any chemotherapy.

IN PRACTICE:

“The results of our study provide compelling data that upfront primary tumor resection in treatment-naive stage IV CRC not amenable for curative treatment does not prolong [overall survival]. A relatively low incidence of serious adverse events in patients with an intact primary tumor together with a considerable number of patients who did not receive any chemotherapy in the primary tumor resection group provides further arguments against resection of the primary tumor in this group of patients,” the authors of the combined analysis concluded.

SOURCE:

The study, with first author Nuh N. Rahbari, MD, University of Ulm, Ulm, Germany, was published online in the Journal of Clinical Oncology.

LIMITATIONS:

Neither study completed their planned patient accrual. Although both trials are nearly identical, differences in the individual study cohorts and trial implementation could have introduced bias. Tumor molecular profiling was not performed.

DISCLOSURES:

The study had no commercial funding. Disclosures for authors are available with the original article.

A version of this article appeared on Medscape.com.

Syphilis and chlamydia infections were reduced by half among men who have sex with men and transgender women 1 year after San Francisco rolled out doxycycline postexposure prophylaxis (doxy-PEP), according to data presented at the Conference on Retroviruses and Opportunistic Infections (CROI) this week.

After a clinical trial showed that doxy-PEP taken after sex reduced the chance of acquiring syphilis, gonorrhea, and chlamydia by about two-thirds, the San Francisco Department of Public Health released the first guidelines in the country in October 2022. 

The guidelines recommend that a person take two 100-mg pills of doxycycline ideally in the 24 hours after but no more than 72 hours after condomless sex. So far, more than 3700 people in San Francisco have been prescribed doxy-PEP, reports Stephanie Cohen, MD, director of HIV and sexually transmitted infection (STI) prevention in the Disease Prevention and Control Branch of Public Health.

Dr. Cohen and her colleagues spent a year monitoring the uptake of doxy-PEP and used a computer model to predict what the rates of sexually transmitted infection would have been without doxy-PEP. 

In November 2023, 13 months after the guidelines were introduced, they found that monthly chlamydia and early syphilis infections were 50% and 51% lower, respectively, than what was predicted by the model.
 

Fewer Infections

The drop in infections is having a tangible effect on patients in San Francisco, and many clinicians are noting that they are seeing far fewer positive tests. “The results that we’re seeing on a city-wide level are absolutely being experienced by individual providers and patients,” Dr. Cohen said.

However, the analysis showed no effect on rates of gonorrhea. It’s not clear why, although Dr. Cohen points out that doxy-PEP was less effective against gonorrhea in the clinical trial. And “there could be other factors in play,” she added. “Adherence might matter more, or it could be affected by the prevalence of tetracycline resistance in the community.”

With rates of STIs, particularly syphilis, quickly rising in recent years, healthcare providers have been scrambling to find effective interventions. So far, doxy-PEP has shown the most promise. “We’ve known for a while that all of the strategies we’ve been employing don’t seem to be working,” noted Chase Cannon, MD, an infectious disease specialist at the University of Washington in Seattle. “That’s why doxy-PEP is important. We haven’t had anything that can deflect the curve in a long time.”
 

What About the Side Effects?

Some concerns remain, however, about the widespread prophylactic use of antibiotics. There are no long-term safety data on the potential side effects of doxy-PEP, and there is still a lot of stigma around interventions that allow people to have sex the way they want, said Dr. Cannon.

But perhaps, the biggest concern is that doxy-PEP could contribute to antibiotic resistance. Those fears are not misplaced, Dr. Cannon added. The results of one study, presented in a poster at CROI, showed that stool samples from people prescribed doxy-PEP had elevated levels of bacterial genes that can confer resistance to tetracyclines, the class of antibiotics to which doxycycline belongs. There was no change in resistance to other classes of antibiotics and no difference in bacterial diversity over the 6 months of the study.

Dr. Cannon cautioned, however, that we can’t extrapolate these results to clinical outcomes. “We can look for signals [of resistance], but we don’t know if this means someone will fail therapy for chlamydia or syphilis,” he said.

There are still many challenges to overcome before doxy-PEP can be rolled out widely, Dr. Cohen explained. There is a lack of consensus among healthcare professionals about who should be offered doxy-PEP. The clinical trial results and the San Fransisco guidelines only apply to men who have sex with men and to transgender women.

Some clinicians argue that the intervention should be provided to a broader population, whereas others want to see more research to ensure that unnecessary antibiotic use is minimized.

So far just one study has tested doxy-PEP in another population — in women in Kenya — and it was found to not be effective. But the data suggest that adherence to the protocol was poor in that study, so the results may not be reliable, Dr. Cohen said.

“We need effective prevention tools for all genders, especially cis women who bear most of the morbidity,” she said. “It stands to reason that this should work for them, but without high-quality evidence, there is insufficient information to make a recommendation for cis women.”

The US Centers for Disease Control and Prevention is currently reviewing public and expert comments and refining final guidelines for release in the coming months, which should alleviate some of the uncertainty. “Many providers are waiting for that guidance before they will feel confident moving forward,” Dr. Cohen noted.

But despite the risks and uncertainty, doxy-PEP looks set to be a major part of the fight against STIs going forward. “Doxy-PEP is essential for us as a nation to be dealing with the syphilis epidemic,” Carl Dieffenbach, PhD, director of the Division of AIDS at the National Institute of Allergy and Infectious Disease, said in a video introduction to CROI.

A version of this article appeared on Medscape.com.

Syphilis and chlamydia infections were reduced by half among men who have sex with men and transgender women 1 year after San Francisco rolled out doxycycline postexposure prophylaxis (doxy-PEP), according to data presented at the Conference on Retroviruses and Opportunistic Infections (CROI) this week.

After a clinical trial showed that doxy-PEP taken after sex reduced the chance of acquiring syphilis, gonorrhea, and chlamydia by about two-thirds, the San Francisco Department of Public Health released the first guidelines in the country in October 2022. 

The guidelines recommend that a person take two 100-mg pills of doxycycline ideally in the 24 hours after but no more than 72 hours after condomless sex. So far, more than 3700 people in San Francisco have been prescribed doxy-PEP, reports Stephanie Cohen, MD, director of HIV and sexually transmitted infection (STI) prevention in the Disease Prevention and Control Branch of Public Health.

Dr. Cohen and her colleagues spent a year monitoring the uptake of doxy-PEP and used a computer model to predict what the rates of sexually transmitted infection would have been without doxy-PEP. 

In November 2023, 13 months after the guidelines were introduced, they found that monthly chlamydia and early syphilis infections were 50% and 51% lower, respectively, than what was predicted by the model.
 

Fewer Infections

The drop in infections is having a tangible effect on patients in San Francisco, and many clinicians are noting that they are seeing far fewer positive tests. “The results that we’re seeing on a city-wide level are absolutely being experienced by individual providers and patients,” Dr. Cohen said.

However, the analysis showed no effect on rates of gonorrhea. It’s not clear why, although Dr. Cohen points out that doxy-PEP was less effective against gonorrhea in the clinical trial. And “there could be other factors in play,” she added. “Adherence might matter more, or it could be affected by the prevalence of tetracycline resistance in the community.”

With rates of STIs, particularly syphilis, quickly rising in recent years, healthcare providers have been scrambling to find effective interventions. So far, doxy-PEP has shown the most promise. “We’ve known for a while that all of the strategies we’ve been employing don’t seem to be working,” noted Chase Cannon, MD, an infectious disease specialist at the University of Washington in Seattle. “That’s why doxy-PEP is important. We haven’t had anything that can deflect the curve in a long time.”
 

What About the Side Effects?

Some concerns remain, however, about the widespread prophylactic use of antibiotics. There are no long-term safety data on the potential side effects of doxy-PEP, and there is still a lot of stigma around interventions that allow people to have sex the way they want, said Dr. Cannon.

But perhaps, the biggest concern is that doxy-PEP could contribute to antibiotic resistance. Those fears are not misplaced, Dr. Cannon added. The results of one study, presented in a poster at CROI, showed that stool samples from people prescribed doxy-PEP had elevated levels of bacterial genes that can confer resistance to tetracyclines, the class of antibiotics to which doxycycline belongs. There was no change in resistance to other classes of antibiotics and no difference in bacterial diversity over the 6 months of the study.

Dr. Cannon cautioned, however, that we can’t extrapolate these results to clinical outcomes. “We can look for signals [of resistance], but we don’t know if this means someone will fail therapy for chlamydia or syphilis,” he said.

There are still many challenges to overcome before doxy-PEP can be rolled out widely, Dr. Cohen explained. There is a lack of consensus among healthcare professionals about who should be offered doxy-PEP. The clinical trial results and the San Fransisco guidelines only apply to men who have sex with men and to transgender women.

Some clinicians argue that the intervention should be provided to a broader population, whereas others want to see more research to ensure that unnecessary antibiotic use is minimized.

So far just one study has tested doxy-PEP in another population — in women in Kenya — and it was found to not be effective. But the data suggest that adherence to the protocol was poor in that study, so the results may not be reliable, Dr. Cohen said.

“We need effective prevention tools for all genders, especially cis women who bear most of the morbidity,” she said. “It stands to reason that this should work for them, but without high-quality evidence, there is insufficient information to make a recommendation for cis women.”

The US Centers for Disease Control and Prevention is currently reviewing public and expert comments and refining final guidelines for release in the coming months, which should alleviate some of the uncertainty. “Many providers are waiting for that guidance before they will feel confident moving forward,” Dr. Cohen noted.

But despite the risks and uncertainty, doxy-PEP looks set to be a major part of the fight against STIs going forward. “Doxy-PEP is essential for us as a nation to be dealing with the syphilis epidemic,” Carl Dieffenbach, PhD, director of the Division of AIDS at the National Institute of Allergy and Infectious Disease, said in a video introduction to CROI.

A version of this article appeared on Medscape.com.

Syphilis and chlamydia infections were reduced by half among men who have sex with men and transgender women 1 year after San Francisco rolled out doxycycline postexposure prophylaxis (doxy-PEP), according to data presented at the Conference on Retroviruses and Opportunistic Infections (CROI) this week.

After a clinical trial showed that doxy-PEP taken after sex reduced the chance of acquiring syphilis, gonorrhea, and chlamydia by about two-thirds, the San Francisco Department of Public Health released the first guidelines in the country in October 2022. 

The guidelines recommend that a person take two 100-mg pills of doxycycline ideally in the 24 hours after but no more than 72 hours after condomless sex. So far, more than 3700 people in San Francisco have been prescribed doxy-PEP, reports Stephanie Cohen, MD, director of HIV and sexually transmitted infection (STI) prevention in the Disease Prevention and Control Branch of Public Health.

Dr. Cohen and her colleagues spent a year monitoring the uptake of doxy-PEP and used a computer model to predict what the rates of sexually transmitted infection would have been without doxy-PEP. 

In November 2023, 13 months after the guidelines were introduced, they found that monthly chlamydia and early syphilis infections were 50% and 51% lower, respectively, than what was predicted by the model.
 

Fewer Infections

The drop in infections is having a tangible effect on patients in San Francisco, and many clinicians are noting that they are seeing far fewer positive tests. “The results that we’re seeing on a city-wide level are absolutely being experienced by individual providers and patients,” Dr. Cohen said.

However, the analysis showed no effect on rates of gonorrhea. It’s not clear why, although Dr. Cohen points out that doxy-PEP was less effective against gonorrhea in the clinical trial. And “there could be other factors in play,” she added. “Adherence might matter more, or it could be affected by the prevalence of tetracycline resistance in the community.”

With rates of STIs, particularly syphilis, quickly rising in recent years, healthcare providers have been scrambling to find effective interventions. So far, doxy-PEP has shown the most promise. “We’ve known for a while that all of the strategies we’ve been employing don’t seem to be working,” noted Chase Cannon, MD, an infectious disease specialist at the University of Washington in Seattle. “That’s why doxy-PEP is important. We haven’t had anything that can deflect the curve in a long time.”
 

What About the Side Effects?

Some concerns remain, however, about the widespread prophylactic use of antibiotics. There are no long-term safety data on the potential side effects of doxy-PEP, and there is still a lot of stigma around interventions that allow people to have sex the way they want, said Dr. Cannon.

But perhaps, the biggest concern is that doxy-PEP could contribute to antibiotic resistance. Those fears are not misplaced, Dr. Cannon added. The results of one study, presented in a poster at CROI, showed that stool samples from people prescribed doxy-PEP had elevated levels of bacterial genes that can confer resistance to tetracyclines, the class of antibiotics to which doxycycline belongs. There was no change in resistance to other classes of antibiotics and no difference in bacterial diversity over the 6 months of the study.

Dr. Cannon cautioned, however, that we can’t extrapolate these results to clinical outcomes. “We can look for signals [of resistance], but we don’t know if this means someone will fail therapy for chlamydia or syphilis,” he said.

There are still many challenges to overcome before doxy-PEP can be rolled out widely, Dr. Cohen explained. There is a lack of consensus among healthcare professionals about who should be offered doxy-PEP. The clinical trial results and the San Fransisco guidelines only apply to men who have sex with men and to transgender women.

Some clinicians argue that the intervention should be provided to a broader population, whereas others want to see more research to ensure that unnecessary antibiotic use is minimized.

So far just one study has tested doxy-PEP in another population — in women in Kenya — and it was found to not be effective. But the data suggest that adherence to the protocol was poor in that study, so the results may not be reliable, Dr. Cohen said.

“We need effective prevention tools for all genders, especially cis women who bear most of the morbidity,” she said. “It stands to reason that this should work for them, but without high-quality evidence, there is insufficient information to make a recommendation for cis women.”

The US Centers for Disease Control and Prevention is currently reviewing public and expert comments and refining final guidelines for release in the coming months, which should alleviate some of the uncertainty. “Many providers are waiting for that guidance before they will feel confident moving forward,” Dr. Cohen noted.

But despite the risks and uncertainty, doxy-PEP looks set to be a major part of the fight against STIs going forward. “Doxy-PEP is essential for us as a nation to be dealing with the syphilis epidemic,” Carl Dieffenbach, PhD, director of the Division of AIDS at the National Institute of Allergy and Infectious Disease, said in a video introduction to CROI.

A version of this article appeared on Medscape.com.

Bone-modifying agents — most notably denosumab — are often prescribed to prevent skeletal-related complications in patients with metastatic castration-sensitive prostate cancer, but the drugs are not recommended for this indication and can lead to severe toxicities.

How much does Medicare spend each year on non-recommended bone therapy?

The answer, according to a new analysis in JCO Oncology Practice, is more than $44 million, with about $43 million coming from denosumab alone.

Overall, this study found that “the Medicare program pays tens of millions of dollars each year” for bone-modifying agents in patients with metastatic castration-sensitive prostate cancer, “which is not effective and may cause side effects,” lead author Aaron Mitchell, MD, MPH, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York City, and colleagues concluded.

“These findings suggest reducing bone agent overuse could be a rare healthcare ‘win-win.’ Lower costs AND improved patient outcomes,” tweeted Dr. Mitchell. “If I were a payer, I’d be paying attention!”
 

In Prostate Cancer, Bone-Modifying Drug Indications Vary

Bone-modifying drugs are indicated for some patients with prostate cancer.

The American Society of Clinical Oncology has endorsed guidelines that recommend the use of denosumab in men with nonmetastatic prostate cancer at high risk for fracture while taking androgen deprivation therapy.

Among men with metastatic castration-resistant prostate cancer, guidelines also recommend zoledronic acid or denosumab for preventing or delaying skeletal-related events, such as pathologic fractures and spinal cord compression.

For patients with metastatic castration-sensitive disease, however, the bone-modifying agents show no benefit in preventing skeletal-related events and are not recommended for that indication.

In this population, “treatment with bone agents results only in avoidable toxicity and financial cost,” Dr. Mitchell tweeted. In its higher-dose formulation, denosumab comes with a price tag of approximately $40,000 per year in the United States.

An earlier study from Dr. Mitchell and colleagues revealed that the use of bone-modifying drugs to prevent skeletal events in metastatic castration-sensitive prostate cancer is common.

To better understand the costs associated with this inappropriate use, the researchers reviewed Surveillance, Epidemiology, and End Results Program Medicare data from 2011 to 2015. The team identified the frequency and number of doses of zoledronic acid and denosumab prescribed against recommendations in the metastatic castration-sensitive setting, making sure to distinguish between the use of denosumab to prevent osteoporotic fractures (appropriate use) and to prevent skeletal-related events (non-recommended use).

The team found that, among 2627 patients with metastatic castration-sensitive prostate cancer, 42% received at least one dose of denosumab and 18% received at least one dose of zoledronic acid.

The authors also found that unnecessary use of these drugs increased over time — with a little over 17% of patients receiving zoledronic acid between 2007 and 2009 and just over 28% receiving either denosumab (20.3%) or zoledronic acid (8.4%) from 2012 to 2015.

The annual costs to Medicare from non-recommended prescribing came to $44,105,041 for both agents, with the costs associated with denosumab representing the lion’s share at $43,303,078.

Non-recommended use of these agents also came with adverse events, such as femur fracture and hypocalcemia, which cost an estimated $758,450 to treat annually — $682,865 for denosumab and $75,585 for zoledronic acid.

The study focused on the Medicare-age population, which means the estimates are conservative. “Denosumab overuse for younger patients with castration-sensitive prostate cancer would add substantially to this total,” the authors wrote.

“This study contributes new evidence of overuse in the metastatic castrate-sensitive prostate cancer setting, which I must admit reflects my clinical experience in seeing patients for second opinions who are treated in the community,” said Samuel U. Takvorian, MD, of the Division of Hematology and Oncology, Perelman School of Medicine, Philadelphia, who wasn’t involved in the research. “While there are some circumstances in which one would consider using a bone-modifying agent in the metastatic castrate-sensitive prostate cancer setting, most [of these] men don’t need them upfront.”
 

Why Is the Overuse Happening?

One reason for the inappropriate use of bone-modifying drugs could be confusion surrounding the recommendations because the drugs are recommended for some patients with prostate cancer.

Michael R. Laurent, MD, PhD, of Imelda Hospital, Bonheiden, Belgium, explained that the use of bone-modifying drugs is, paradoxically, often overlooked in settings where they are recommended — when patients have an elevated risk for osteoporosis or fracture.

“Guidelines are quite unequivocal in their recommendations to prevent osteoporosis in mostly older men who receive androgen deprivation therapy,” but “I think there is significant undertreatment” in these patients, Dr. Laurent told this news organization.

However, the recommendation for patients at risk for osteoporosis or bone fracture calls for less intense regimens, which may include lower-dose denosumab, administered once every 6 months, zoledronic acid, given yearly, or another lower potency agent, such as oral alendronate weekly, explained Philip J. Saylor, MD, an attending physician at Massachusetts General Hospital and assistant professor at Harvard Medical School, Boston.

Meanwhile, “monthly high-intensity therapy to prevent skeletal events should be reserved specifically for bone metastatic castration-resistant prostate cancer for more than just cost reasons,” Dr. Saylor said.

When it comes to the higher dose, monthly therapy in castration-sensitive prostate cancer, “we have no evidence that it is beneficial,” he said, adding that “when the prostate cancer itself is well controlled by hormonal therapy, there just aren’t very many pathologic fractures or other bone complications.”

Alongside possible confusion over the recommendations, many physicians also likely don’t know how much denosumab costs.

“In our recent physician interview study, we did find that most physicians were very much unaware of the cost of this drug, or the cost difference between denosumab and zoledronic acid, so I do think that lack of cost awareness is a factor,” Dr. Mitchell said.

Part of the reason may be how Medicare covers these agents. Typically, Medicare would not cover non-recommended indications, but “in this case, Medicare coverage is broader and includes both the guideline-recommended and non-recommended uses,” Dr. Mitchell explained.

However, the authors also identified a more cynical reason for non-recommended prescribing — promotional payments from drug makers to physicians.

In another recent paper, Dr. Mitchell said he found about “30% of doctors treating prostate cancer had received payments from Amgen for Xgeva [denosumab] promotion during the last year.”

These payments appeared to influence non-recommended prescribing: Among patients whose doctor had not received payments, 31.4% received non-recommended denosumab, which increased to nearly 50% of patients among doctors who had received payments.

Dr. Mitchell suggested a few ways to help curb inappropriate prescribing.

Medicare could, for instance, change its coverage policy to include only the recommended uses of these agents, Dr. Mitchell said.

More physician education would be another solution. “I think that physician education would be one ‘bottom-up’ approach that could work,” Dr. Mitchell added.

Dr. Mitchell, Dr. Takvorian, and Dr. Saylor had no disclosures to report. Dr. Laurent has received lecture and consultancy fees from Alexion, AM Pharma, Amgen, Galapagos, Kyowa Kirin, Menarini, Orifarm, Pharmanovia, Takeda, UCB, and Will Pharma.
 

A version of this article appeared on Medscape.com.

Bone-modifying agents — most notably denosumab — are often prescribed to prevent skeletal-related complications in patients with metastatic castration-sensitive prostate cancer, but the drugs are not recommended for this indication and can lead to severe toxicities.

How much does Medicare spend each year on non-recommended bone therapy?

The answer, according to a new analysis in JCO Oncology Practice, is more than $44 million, with about $43 million coming from denosumab alone.

Overall, this study found that “the Medicare program pays tens of millions of dollars each year” for bone-modifying agents in patients with metastatic castration-sensitive prostate cancer, “which is not effective and may cause side effects,” lead author Aaron Mitchell, MD, MPH, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York City, and colleagues concluded.

“These findings suggest reducing bone agent overuse could be a rare healthcare ‘win-win.’ Lower costs AND improved patient outcomes,” tweeted Dr. Mitchell. “If I were a payer, I’d be paying attention!”
 

In Prostate Cancer, Bone-Modifying Drug Indications Vary

Bone-modifying drugs are indicated for some patients with prostate cancer.

The American Society of Clinical Oncology has endorsed guidelines that recommend the use of denosumab in men with nonmetastatic prostate cancer at high risk for fracture while taking androgen deprivation therapy.

Among men with metastatic castration-resistant prostate cancer, guidelines also recommend zoledronic acid or denosumab for preventing or delaying skeletal-related events, such as pathologic fractures and spinal cord compression.

For patients with metastatic castration-sensitive disease, however, the bone-modifying agents show no benefit in preventing skeletal-related events and are not recommended for that indication.

In this population, “treatment with bone agents results only in avoidable toxicity and financial cost,” Dr. Mitchell tweeted. In its higher-dose formulation, denosumab comes with a price tag of approximately $40,000 per year in the United States.

An earlier study from Dr. Mitchell and colleagues revealed that the use of bone-modifying drugs to prevent skeletal events in metastatic castration-sensitive prostate cancer is common.

To better understand the costs associated with this inappropriate use, the researchers reviewed Surveillance, Epidemiology, and End Results Program Medicare data from 2011 to 2015. The team identified the frequency and number of doses of zoledronic acid and denosumab prescribed against recommendations in the metastatic castration-sensitive setting, making sure to distinguish between the use of denosumab to prevent osteoporotic fractures (appropriate use) and to prevent skeletal-related events (non-recommended use).

The team found that, among 2627 patients with metastatic castration-sensitive prostate cancer, 42% received at least one dose of denosumab and 18% received at least one dose of zoledronic acid.

The authors also found that unnecessary use of these drugs increased over time — with a little over 17% of patients receiving zoledronic acid between 2007 and 2009 and just over 28% receiving either denosumab (20.3%) or zoledronic acid (8.4%) from 2012 to 2015.

The annual costs to Medicare from non-recommended prescribing came to $44,105,041 for both agents, with the costs associated with denosumab representing the lion’s share at $43,303,078.

Non-recommended use of these agents also came with adverse events, such as femur fracture and hypocalcemia, which cost an estimated $758,450 to treat annually — $682,865 for denosumab and $75,585 for zoledronic acid.

The study focused on the Medicare-age population, which means the estimates are conservative. “Denosumab overuse for younger patients with castration-sensitive prostate cancer would add substantially to this total,” the authors wrote.

“This study contributes new evidence of overuse in the metastatic castrate-sensitive prostate cancer setting, which I must admit reflects my clinical experience in seeing patients for second opinions who are treated in the community,” said Samuel U. Takvorian, MD, of the Division of Hematology and Oncology, Perelman School of Medicine, Philadelphia, who wasn’t involved in the research. “While there are some circumstances in which one would consider using a bone-modifying agent in the metastatic castrate-sensitive prostate cancer setting, most [of these] men don’t need them upfront.”
 

Why Is the Overuse Happening?

One reason for the inappropriate use of bone-modifying drugs could be confusion surrounding the recommendations because the drugs are recommended for some patients with prostate cancer.

Michael R. Laurent, MD, PhD, of Imelda Hospital, Bonheiden, Belgium, explained that the use of bone-modifying drugs is, paradoxically, often overlooked in settings where they are recommended — when patients have an elevated risk for osteoporosis or fracture.

“Guidelines are quite unequivocal in their recommendations to prevent osteoporosis in mostly older men who receive androgen deprivation therapy,” but “I think there is significant undertreatment” in these patients, Dr. Laurent told this news organization.

However, the recommendation for patients at risk for osteoporosis or bone fracture calls for less intense regimens, which may include lower-dose denosumab, administered once every 6 months, zoledronic acid, given yearly, or another lower potency agent, such as oral alendronate weekly, explained Philip J. Saylor, MD, an attending physician at Massachusetts General Hospital and assistant professor at Harvard Medical School, Boston.

Meanwhile, “monthly high-intensity therapy to prevent skeletal events should be reserved specifically for bone metastatic castration-resistant prostate cancer for more than just cost reasons,” Dr. Saylor said.

When it comes to the higher dose, monthly therapy in castration-sensitive prostate cancer, “we have no evidence that it is beneficial,” he said, adding that “when the prostate cancer itself is well controlled by hormonal therapy, there just aren’t very many pathologic fractures or other bone complications.”

Alongside possible confusion over the recommendations, many physicians also likely don’t know how much denosumab costs.

“In our recent physician interview study, we did find that most physicians were very much unaware of the cost of this drug, or the cost difference between denosumab and zoledronic acid, so I do think that lack of cost awareness is a factor,” Dr. Mitchell said.

Part of the reason may be how Medicare covers these agents. Typically, Medicare would not cover non-recommended indications, but “in this case, Medicare coverage is broader and includes both the guideline-recommended and non-recommended uses,” Dr. Mitchell explained.

However, the authors also identified a more cynical reason for non-recommended prescribing — promotional payments from drug makers to physicians.

In another recent paper, Dr. Mitchell said he found about “30% of doctors treating prostate cancer had received payments from Amgen for Xgeva [denosumab] promotion during the last year.”

These payments appeared to influence non-recommended prescribing: Among patients whose doctor had not received payments, 31.4% received non-recommended denosumab, which increased to nearly 50% of patients among doctors who had received payments.

Dr. Mitchell suggested a few ways to help curb inappropriate prescribing.

Medicare could, for instance, change its coverage policy to include only the recommended uses of these agents, Dr. Mitchell said.

More physician education would be another solution. “I think that physician education would be one ‘bottom-up’ approach that could work,” Dr. Mitchell added.

Dr. Mitchell, Dr. Takvorian, and Dr. Saylor had no disclosures to report. Dr. Laurent has received lecture and consultancy fees from Alexion, AM Pharma, Amgen, Galapagos, Kyowa Kirin, Menarini, Orifarm, Pharmanovia, Takeda, UCB, and Will Pharma.
 

A version of this article appeared on Medscape.com.

Bone-modifying agents — most notably denosumab — are often prescribed to prevent skeletal-related complications in patients with metastatic castration-sensitive prostate cancer, but the drugs are not recommended for this indication and can lead to severe toxicities.

How much does Medicare spend each year on non-recommended bone therapy?

The answer, according to a new analysis in JCO Oncology Practice, is more than $44 million, with about $43 million coming from denosumab alone.

Overall, this study found that “the Medicare program pays tens of millions of dollars each year” for bone-modifying agents in patients with metastatic castration-sensitive prostate cancer, “which is not effective and may cause side effects,” lead author Aaron Mitchell, MD, MPH, a medical oncologist at Memorial Sloan Kettering Cancer Center, New York City, and colleagues concluded.

“These findings suggest reducing bone agent overuse could be a rare healthcare ‘win-win.’ Lower costs AND improved patient outcomes,” tweeted Dr. Mitchell. “If I were a payer, I’d be paying attention!”
 

In Prostate Cancer, Bone-Modifying Drug Indications Vary

Bone-modifying drugs are indicated for some patients with prostate cancer.

The American Society of Clinical Oncology has endorsed guidelines that recommend the use of denosumab in men with nonmetastatic prostate cancer at high risk for fracture while taking androgen deprivation therapy.

Among men with metastatic castration-resistant prostate cancer, guidelines also recommend zoledronic acid or denosumab for preventing or delaying skeletal-related events, such as pathologic fractures and spinal cord compression.

For patients with metastatic castration-sensitive disease, however, the bone-modifying agents show no benefit in preventing skeletal-related events and are not recommended for that indication.

In this population, “treatment with bone agents results only in avoidable toxicity and financial cost,” Dr. Mitchell tweeted. In its higher-dose formulation, denosumab comes with a price tag of approximately $40,000 per year in the United States.

An earlier study from Dr. Mitchell and colleagues revealed that the use of bone-modifying drugs to prevent skeletal events in metastatic castration-sensitive prostate cancer is common.

To better understand the costs associated with this inappropriate use, the researchers reviewed Surveillance, Epidemiology, and End Results Program Medicare data from 2011 to 2015. The team identified the frequency and number of doses of zoledronic acid and denosumab prescribed against recommendations in the metastatic castration-sensitive setting, making sure to distinguish between the use of denosumab to prevent osteoporotic fractures (appropriate use) and to prevent skeletal-related events (non-recommended use).

The team found that, among 2627 patients with metastatic castration-sensitive prostate cancer, 42% received at least one dose of denosumab and 18% received at least one dose of zoledronic acid.

The authors also found that unnecessary use of these drugs increased over time — with a little over 17% of patients receiving zoledronic acid between 2007 and 2009 and just over 28% receiving either denosumab (20.3%) or zoledronic acid (8.4%) from 2012 to 2015.

The annual costs to Medicare from non-recommended prescribing came to $44,105,041 for both agents, with the costs associated with denosumab representing the lion’s share at $43,303,078.

Non-recommended use of these agents also came with adverse events, such as femur fracture and hypocalcemia, which cost an estimated $758,450 to treat annually — $682,865 for denosumab and $75,585 for zoledronic acid.

The study focused on the Medicare-age population, which means the estimates are conservative. “Denosumab overuse for younger patients with castration-sensitive prostate cancer would add substantially to this total,” the authors wrote.

“This study contributes new evidence of overuse in the metastatic castrate-sensitive prostate cancer setting, which I must admit reflects my clinical experience in seeing patients for second opinions who are treated in the community,” said Samuel U. Takvorian, MD, of the Division of Hematology and Oncology, Perelman School of Medicine, Philadelphia, who wasn’t involved in the research. “While there are some circumstances in which one would consider using a bone-modifying agent in the metastatic castrate-sensitive prostate cancer setting, most [of these] men don’t need them upfront.”
 

Why Is the Overuse Happening?

One reason for the inappropriate use of bone-modifying drugs could be confusion surrounding the recommendations because the drugs are recommended for some patients with prostate cancer.

Michael R. Laurent, MD, PhD, of Imelda Hospital, Bonheiden, Belgium, explained that the use of bone-modifying drugs is, paradoxically, often overlooked in settings where they are recommended — when patients have an elevated risk for osteoporosis or fracture.

“Guidelines are quite unequivocal in their recommendations to prevent osteoporosis in mostly older men who receive androgen deprivation therapy,” but “I think there is significant undertreatment” in these patients, Dr. Laurent told this news organization.

However, the recommendation for patients at risk for osteoporosis or bone fracture calls for less intense regimens, which may include lower-dose denosumab, administered once every 6 months, zoledronic acid, given yearly, or another lower potency agent, such as oral alendronate weekly, explained Philip J. Saylor, MD, an attending physician at Massachusetts General Hospital and assistant professor at Harvard Medical School, Boston.

Meanwhile, “monthly high-intensity therapy to prevent skeletal events should be reserved specifically for bone metastatic castration-resistant prostate cancer for more than just cost reasons,” Dr. Saylor said.

When it comes to the higher dose, monthly therapy in castration-sensitive prostate cancer, “we have no evidence that it is beneficial,” he said, adding that “when the prostate cancer itself is well controlled by hormonal therapy, there just aren’t very many pathologic fractures or other bone complications.”

Alongside possible confusion over the recommendations, many physicians also likely don’t know how much denosumab costs.

“In our recent physician interview study, we did find that most physicians were very much unaware of the cost of this drug, or the cost difference between denosumab and zoledronic acid, so I do think that lack of cost awareness is a factor,” Dr. Mitchell said.

Part of the reason may be how Medicare covers these agents. Typically, Medicare would not cover non-recommended indications, but “in this case, Medicare coverage is broader and includes both the guideline-recommended and non-recommended uses,” Dr. Mitchell explained.

However, the authors also identified a more cynical reason for non-recommended prescribing — promotional payments from drug makers to physicians.

In another recent paper, Dr. Mitchell said he found about “30% of doctors treating prostate cancer had received payments from Amgen for Xgeva [denosumab] promotion during the last year.”

These payments appeared to influence non-recommended prescribing: Among patients whose doctor had not received payments, 31.4% received non-recommended denosumab, which increased to nearly 50% of patients among doctors who had received payments.

Dr. Mitchell suggested a few ways to help curb inappropriate prescribing.

Medicare could, for instance, change its coverage policy to include only the recommended uses of these agents, Dr. Mitchell said.

More physician education would be another solution. “I think that physician education would be one ‘bottom-up’ approach that could work,” Dr. Mitchell added.

Dr. Mitchell, Dr. Takvorian, and Dr. Saylor had no disclosures to report. Dr. Laurent has received lecture and consultancy fees from Alexion, AM Pharma, Amgen, Galapagos, Kyowa Kirin, Menarini, Orifarm, Pharmanovia, Takeda, UCB, and Will Pharma.
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has granted new approvals for the use of amivantamab-vmjw (Rybrevant, Janssen Biotech Inc.) in certain patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). 

Specifically, the FDA approved the first-line use of the agent in combination with carboplatin and pemetrexed in patients with locally advanced or metastatic NSCLC with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test. 

The FDA also granted traditional approval for use in these patients after their cancer has progressed on or following platinum-based chemotherapy. The original accelerated approval for this indication occurred in 2021. At that time, the FDA also approved Guardant360^® CDx (Guardant Health, Inc.) as a companion diagnostic test for amivantamab-vmjw. 

The first-line approval, which followed priority review, was based on the randomized, open-label PAPILLON trial, which revealed a statistically significant improvement in progression-free survival (PFS) among the 153 patients who received amivantamab-vmjw plus carboplatin and pemetrexed vs the 155 who received the chemotherapy combination alone. Median PFS was 11.4 months in the amivantamab-vmjw arm vs 6.7 months in the control arm (hazard ratio, 0.40).

Data for overall survival, a key secondary endpoint of the study, were immature at the time of the latest analysis, but “no trend toward a detriment was observed,” according to an FDA approval announcement.

Common adverse reactions, occurring in at least 20% of patients in the study, were rash, nail toxicity, stomatitis, infusion-related reaction, fatigue, edema, constipation, decreased appetite, nausea, diarrhea, and vomiting. Weight-based dosing guidance can be found in the full prescribing information.
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has granted new approvals for the use of amivantamab-vmjw (Rybrevant, Janssen Biotech Inc.) in certain patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). 

Specifically, the FDA approved the first-line use of the agent in combination with carboplatin and pemetrexed in patients with locally advanced or metastatic NSCLC with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test. 

The FDA also granted traditional approval for use in these patients after their cancer has progressed on or following platinum-based chemotherapy. The original accelerated approval for this indication occurred in 2021. At that time, the FDA also approved Guardant360^® CDx (Guardant Health, Inc.) as a companion diagnostic test for amivantamab-vmjw. 

The first-line approval, which followed priority review, was based on the randomized, open-label PAPILLON trial, which revealed a statistically significant improvement in progression-free survival (PFS) among the 153 patients who received amivantamab-vmjw plus carboplatin and pemetrexed vs the 155 who received the chemotherapy combination alone. Median PFS was 11.4 months in the amivantamab-vmjw arm vs 6.7 months in the control arm (hazard ratio, 0.40).

Data for overall survival, a key secondary endpoint of the study, were immature at the time of the latest analysis, but “no trend toward a detriment was observed,” according to an FDA approval announcement.

Common adverse reactions, occurring in at least 20% of patients in the study, were rash, nail toxicity, stomatitis, infusion-related reaction, fatigue, edema, constipation, decreased appetite, nausea, diarrhea, and vomiting. Weight-based dosing guidance can be found in the full prescribing information.
 

A version of this article appeared on Medscape.com.

The US Food and Drug Administration (FDA) has granted new approvals for the use of amivantamab-vmjw (Rybrevant, Janssen Biotech Inc.) in certain patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). 

Specifically, the FDA approved the first-line use of the agent in combination with carboplatin and pemetrexed in patients with locally advanced or metastatic NSCLC with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test. 

The FDA also granted traditional approval for use in these patients after their cancer has progressed on or following platinum-based chemotherapy. The original accelerated approval for this indication occurred in 2021. At that time, the FDA also approved Guardant360^® CDx (Guardant Health, Inc.) as a companion diagnostic test for amivantamab-vmjw. 

The first-line approval, which followed priority review, was based on the randomized, open-label PAPILLON trial, which revealed a statistically significant improvement in progression-free survival (PFS) among the 153 patients who received amivantamab-vmjw plus carboplatin and pemetrexed vs the 155 who received the chemotherapy combination alone. Median PFS was 11.4 months in the amivantamab-vmjw arm vs 6.7 months in the control arm (hazard ratio, 0.40).

Data for overall survival, a key secondary endpoint of the study, were immature at the time of the latest analysis, but “no trend toward a detriment was observed,” according to an FDA approval announcement.

Common adverse reactions, occurring in at least 20% of patients in the study, were rash, nail toxicity, stomatitis, infusion-related reaction, fatigue, edema, constipation, decreased appetite, nausea, diarrhea, and vomiting. Weight-based dosing guidance can be found in the full prescribing information.
 

A version of this article appeared on Medscape.com.

Sandra Hong, MD, chair of allergy and immunology and director of the Food Allergy Center of Excellence at Cleveland Clinic, in Ohio, sees firsthand how situations that feel ordinary to most people strike fear in the hearts of her patients with food allergies. 

Not only do some experience reactions to milk when they eat a cheese pizza — they can’t be in the same room with someone enjoying a slice nearby. “That would be terrifying,” Dr. Hong said.

Omalizumab (Xolair), recently approved by the US Food and Drug Administration as monotherapy for the treatment of food allergies, may now bring peace of mind to these patients and their families by reducing their risk of dangerous allergic reactions to accidental exposure.

While the drug does not cure food allergies, a phase 3, placebo-controlled trial found that after 16 weeks of treatment, two thirds of participants were able to tolerate at least 600 mg of peanut protein — equal to about 2.5 peanuts — without experiencing moderate to severe reactions. 

An open-label extension trial also found the monoclonal antibody reduced the likelihood of serious reactions to eggs by 67%, milk by 66%, and cashews by 42%. The results of the study were published in The New England Journal of Medicine.

The treatment is approved for children as young as the age of 1 year and is the only treatment approved for multiple food allergies. It does not treat anaphylaxis or other emergency situations.

Patient Selection Key

While 8% of children and 10% of adults in the United States have a true food allergy, Brian Vickery, MD, chief of allergy and immunology and director of the Food Allergy Center at Children’s Healthcare of Atlanta, noted that a significantly higher proportion of the population restricts their diet based on perceived food intolerances.

“Most important for family doctors prior to prescribing the medication will be to be sure that the diagnosis is correct,” Kim said. “We know that allergy blood and skin testing is good but not perfect, and false positive results can occur,” said Edwin Kim, MD, chief of the Division of Pediatric Allergy and Immunology and director of the University of North Carolina Food Allergy Initiative at the University of North Carolina School of Medicine, Chapel Hill, who was a coauthor on the study in the New England Journal of Medicine. “ An allergist can conduct food challenges to confirm the diagnosis if results are unclear.”

Even for patients with confirmed IgE-mediated allergies, Dr. Hong said selecting patients who are good candidates for the therapy has “nuances.” 

Patients must be willing and able to commit to injections every 2-4 weeks. Dosing depends on body weight and the total IgE levels of each patient. Patients with IgE levels > 1850 UI/mL likely will be disqualified from treatment since the clinical trial did not enroll patients with total IgE above this level and the appropriate dose in those patients is unknown.

“My recommendation for family physicians who are counseling food-allergic patients interested in omalizumab treatment is to partner with an allergist-immunologist, if at all possible,” Dr. Vickery said. He added that patients should have a comprehensive workup before beginning treatment because starting omalizumab would reduce reactivity and alter the outcome a diagnostic oral food challenge.

Two populations Dr. Hong thinks might particularly benefit from the therapy are college students and preschoolers, who may be unable to completely avoid allergens because of poor impulse control and food sharing in group settings.

“The concerns we have about this age group are whether or not there might be other factors involved that may impede their ability to make good decisions.”

Less control of the environment in dorms or other group living situations also could increase the risk of accidental exposure to a food allergen.

For the right patients, the treatment regimen has significant advantages over oral immunotherapy treatment (OIT), including the fact that it’s not a daily medication and it has the potential to treat allergic asthma at the same time.

“The biggest pro for omalizumab is that it can treat all of your food allergies, whether you have one or many, and do it all in one medication,” Dr. Kim said. 

Managing Potential Harms

Omalizumab carries risks both primary care providers and patients must consider. First among them is that the drug carries a “black box” warning for an increased risk of anaphylaxis, Dr. Hong said. 

Although patients with multiple food allergies typically already have prescriptions for epinephrine, primary care physicians (PCPs) considering offering omalizumab must be comfortable treating severe systemic reactions and their offices capable of post-dose monitoring, Dr. Hong said. 

Anaphylaxis “can occur after the first dose or it can be delayed,” she said. “Typically, allergists will give these in our offices and we’ll actually have people wait for delayed amounts of time, for hours.”

The drug has been available since 2003 as a treatment for allergic asthma and urticaria. In addition to the warning for anaphylaxis, common reactions include joint pain and injection-site reactions. It also increases the risk for parasitic infection, and some studies show an increase in the risk for cancer.

Still, Dr. Kim said omalizumab’s safety profile is reassuring and noted it has advantages over OIT. “Since the patient is not exposing themselves to the food they are allergic to like in OIT, the safety is expected to be far better,” he said.

Lifelong Treatment 

Dr. Vickery, Dr. Hong, and Dr. Kim all cautioned that patients should understand that, while omalizumab offers protection against accidental exposure and can meaningfully improve quality of life, it won’t allow them to loosen their allergen-avoidant diets.

Further, maintaining protection requires receiving injections every 2-4 weeks for life. For those without insurance, or whose insurance does not cover the treatment, costs could reach thousands of dollars each month, Dr. Hong said.

Omalizumab “has been well covered by insurance for asthma and chronic hives, but we will have to see what it looks like for food allergy. The range of plans and out-of-pocket deductibles available to patients will also play a big role,” Dr. Kim said. 

Other novel approaches to food allergies are currently in clinical trials, and both Dr. Hong and Dr. Vickery are optimistic about potential options in the pipeline.

“We’re just on the brink of really exciting therapies coming forward in the future,” Dr. Hong said.

The study was supported by the National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences, both part of the National Institutes of Health; the Claudia and Steve Stange Family Fund; Genentech; and Novartis. Dr. Hong, Dr. Kim, and Dr. Vickery reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Sandra Hong, MD, chair of allergy and immunology and director of the Food Allergy Center of Excellence at Cleveland Clinic, in Ohio, sees firsthand how situations that feel ordinary to most people strike fear in the hearts of her patients with food allergies. 

Not only do some experience reactions to milk when they eat a cheese pizza — they can’t be in the same room with someone enjoying a slice nearby. “That would be terrifying,” Dr. Hong said.

Omalizumab (Xolair), recently approved by the US Food and Drug Administration as monotherapy for the treatment of food allergies, may now bring peace of mind to these patients and their families by reducing their risk of dangerous allergic reactions to accidental exposure.

While the drug does not cure food allergies, a phase 3, placebo-controlled trial found that after 16 weeks of treatment, two thirds of participants were able to tolerate at least 600 mg of peanut protein — equal to about 2.5 peanuts — without experiencing moderate to severe reactions. 

An open-label extension trial also found the monoclonal antibody reduced the likelihood of serious reactions to eggs by 67%, milk by 66%, and cashews by 42%. The results of the study were published in The New England Journal of Medicine.

The treatment is approved for children as young as the age of 1 year and is the only treatment approved for multiple food allergies. It does not treat anaphylaxis or other emergency situations.

Patient Selection Key

While 8% of children and 10% of adults in the United States have a true food allergy, Brian Vickery, MD, chief of allergy and immunology and director of the Food Allergy Center at Children’s Healthcare of Atlanta, noted that a significantly higher proportion of the population restricts their diet based on perceived food intolerances.

“Most important for family doctors prior to prescribing the medication will be to be sure that the diagnosis is correct,” Kim said. “We know that allergy blood and skin testing is good but not perfect, and false positive results can occur,” said Edwin Kim, MD, chief of the Division of Pediatric Allergy and Immunology and director of the University of North Carolina Food Allergy Initiative at the University of North Carolina School of Medicine, Chapel Hill, who was a coauthor on the study in the New England Journal of Medicine. “ An allergist can conduct food challenges to confirm the diagnosis if results are unclear.”

Even for patients with confirmed IgE-mediated allergies, Dr. Hong said selecting patients who are good candidates for the therapy has “nuances.” 

Patients must be willing and able to commit to injections every 2-4 weeks. Dosing depends on body weight and the total IgE levels of each patient. Patients with IgE levels > 1850 UI/mL likely will be disqualified from treatment since the clinical trial did not enroll patients with total IgE above this level and the appropriate dose in those patients is unknown.

“My recommendation for family physicians who are counseling food-allergic patients interested in omalizumab treatment is to partner with an allergist-immunologist, if at all possible,” Dr. Vickery said. He added that patients should have a comprehensive workup before beginning treatment because starting omalizumab would reduce reactivity and alter the outcome a diagnostic oral food challenge.

Two populations Dr. Hong thinks might particularly benefit from the therapy are college students and preschoolers, who may be unable to completely avoid allergens because of poor impulse control and food sharing in group settings.

“The concerns we have about this age group are whether or not there might be other factors involved that may impede their ability to make good decisions.”

Less control of the environment in dorms or other group living situations also could increase the risk of accidental exposure to a food allergen.

For the right patients, the treatment regimen has significant advantages over oral immunotherapy treatment (OIT), including the fact that it’s not a daily medication and it has the potential to treat allergic asthma at the same time.

“The biggest pro for omalizumab is that it can treat all of your food allergies, whether you have one or many, and do it all in one medication,” Dr. Kim said. 

Managing Potential Harms

Omalizumab carries risks both primary care providers and patients must consider. First among them is that the drug carries a “black box” warning for an increased risk of anaphylaxis, Dr. Hong said. 

Although patients with multiple food allergies typically already have prescriptions for epinephrine, primary care physicians (PCPs) considering offering omalizumab must be comfortable treating severe systemic reactions and their offices capable of post-dose monitoring, Dr. Hong said. 

Anaphylaxis “can occur after the first dose or it can be delayed,” she said. “Typically, allergists will give these in our offices and we’ll actually have people wait for delayed amounts of time, for hours.”

The drug has been available since 2003 as a treatment for allergic asthma and urticaria. In addition to the warning for anaphylaxis, common reactions include joint pain and injection-site reactions. It also increases the risk for parasitic infection, and some studies show an increase in the risk for cancer.

Still, Dr. Kim said omalizumab’s safety profile is reassuring and noted it has advantages over OIT. “Since the patient is not exposing themselves to the food they are allergic to like in OIT, the safety is expected to be far better,” he said.

Lifelong Treatment 

Dr. Vickery, Dr. Hong, and Dr. Kim all cautioned that patients should understand that, while omalizumab offers protection against accidental exposure and can meaningfully improve quality of life, it won’t allow them to loosen their allergen-avoidant diets.

Further, maintaining protection requires receiving injections every 2-4 weeks for life. For those without insurance, or whose insurance does not cover the treatment, costs could reach thousands of dollars each month, Dr. Hong said.

Omalizumab “has been well covered by insurance for asthma and chronic hives, but we will have to see what it looks like for food allergy. The range of plans and out-of-pocket deductibles available to patients will also play a big role,” Dr. Kim said. 

Other novel approaches to food allergies are currently in clinical trials, and both Dr. Hong and Dr. Vickery are optimistic about potential options in the pipeline.

“We’re just on the brink of really exciting therapies coming forward in the future,” Dr. Hong said.

The study was supported by the National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences, both part of the National Institutes of Health; the Claudia and Steve Stange Family Fund; Genentech; and Novartis. Dr. Hong, Dr. Kim, and Dr. Vickery reported no relevant financial relationships.

A version of this article appeared on Medscape.com.

Sandra Hong, MD, chair of allergy and immunology and director of the Food Allergy Center of Excellence at Cleveland Clinic, in Ohio, sees firsthand how situations that feel ordinary to most people strike fear in the hearts of her patients with food allergies. 

Not only do some experience reactions to milk when they eat a cheese pizza — they can’t be in the same room with someone enjoying a slice nearby. “That would be terrifying,” Dr. Hong said.

Omalizumab (Xolair), recently approved by the US Food and Drug Administration as monotherapy for the treatment of food allergies, may now bring peace of mind to these patients and their families by reducing their risk of dangerous allergic reactions to accidental exposure.

While the drug does not cure food allergies, a phase 3, placebo-controlled trial found that after 16 weeks of treatment, two thirds of participants were able to tolerate at least 600 mg of peanut protein — equal to about 2.5 peanuts — without experiencing moderate to severe reactions. 

An open-label extension trial also found the monoclonal antibody reduced the likelihood of serious reactions to eggs by 67%, milk by 66%, and cashews by 42%. The results of the study were published in The New England Journal of Medicine.

The treatment is approved for children as young as the age of 1 year and is the only treatment approved for multiple food allergies. It does not treat anaphylaxis or other emergency situations.

Patient Selection Key

While 8% of children and 10% of adults in the United States have a true food allergy, Brian Vickery, MD, chief of allergy and immunology and director of the Food Allergy Center at Children’s Healthcare of Atlanta, noted that a significantly higher proportion of the population restricts their diet based on perceived food intolerances.

“Most important for family doctors prior to prescribing the medication will be to be sure that the diagnosis is correct,” Kim said. “We know that allergy blood and skin testing is good but not perfect, and false positive results can occur,” said Edwin Kim, MD, chief of the Division of Pediatric Allergy and Immunology and director of the University of North Carolina Food Allergy Initiative at the University of North Carolina School of Medicine, Chapel Hill, who was a coauthor on the study in the New England Journal of Medicine. “ An allergist can conduct food challenges to confirm the diagnosis if results are unclear.”

Even for patients with confirmed IgE-mediated allergies, Dr. Hong said selecting patients who are good candidates for the therapy has “nuances.” 

Patients must be willing and able to commit to injections every 2-4 weeks. Dosing depends on body weight and the total IgE levels of each patient. Patients with IgE levels > 1850 UI/mL likely will be disqualified from treatment since the clinical trial did not enroll patients with total IgE above this level and the appropriate dose in those patients is unknown.

“My recommendation for family physicians who are counseling food-allergic patients interested in omalizumab treatment is to partner with an allergist-immunologist, if at all possible,” Dr. Vickery said. He added that patients should have a comprehensive workup before beginning treatment because starting omalizumab would reduce reactivity and alter the outcome a diagnostic oral food challenge.

Two populations Dr. Hong thinks might particularly benefit from the therapy are college students and preschoolers, who may be unable to completely avoid allergens because of poor impulse control and food sharing in group settings.

“The concerns we have about this age group are whether or not there might be other factors involved that may impede their ability to make good decisions.”

Less control of the environment in dorms or other group living situations also could increase the risk of accidental exposure to a food allergen.

For the right patients, the treatment regimen has significant advantages over oral immunotherapy treatment (OIT), including the fact that it’s not a daily medication and it has the potential to treat allergic asthma at the same time.

“The biggest pro for omalizumab is that it can treat all of your food allergies, whether you have one or many, and do it all in one medication,” Dr. Kim said. 

Managing Potential Harms

Omalizumab carries risks both primary care providers and patients must consider. First among them is that the drug carries a “black box” warning for an increased risk of anaphylaxis, Dr. Hong said. 

Although patients with multiple food allergies typically already have prescriptions for epinephrine, primary care physicians (PCPs) considering offering omalizumab must be comfortable treating severe systemic reactions and their offices capable of post-dose monitoring, Dr. Hong said. 

Anaphylaxis “can occur after the first dose or it can be delayed,” she said. “Typically, allergists will give these in our offices and we’ll actually have people wait for delayed amounts of time, for hours.”

The drug has been available since 2003 as a treatment for allergic asthma and urticaria. In addition to the warning for anaphylaxis, common reactions include joint pain and injection-site reactions. It also increases the risk for parasitic infection, and some studies show an increase in the risk for cancer.

Still, Dr. Kim said omalizumab’s safety profile is reassuring and noted it has advantages over OIT. “Since the patient is not exposing themselves to the food they are allergic to like in OIT, the safety is expected to be far better,” he said.

Lifelong Treatment 

Dr. Vickery, Dr. Hong, and Dr. Kim all cautioned that patients should understand that, while omalizumab offers protection against accidental exposure and can meaningfully improve quality of life, it won’t allow them to loosen their allergen-avoidant diets.

Further, maintaining protection requires receiving injections every 2-4 weeks for life. For those without insurance, or whose insurance does not cover the treatment, costs could reach thousands of dollars each month, Dr. Hong said.

Omalizumab “has been well covered by insurance for asthma and chronic hives, but we will have to see what it looks like for food allergy. The range of plans and out-of-pocket deductibles available to patients will also play a big role,” Dr. Kim said. 

Other novel approaches to food allergies are currently in clinical trials, and both Dr. Hong and Dr. Vickery are optimistic about potential options in the pipeline.

“We’re just on the brink of really exciting therapies coming forward in the future,” Dr. Hong said.

The study was supported by the National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences, both part of the National Institutes of Health; the Claudia and Steve Stange Family Fund; Genentech; and Novartis. Dr. Hong, Dr. Kim, and Dr. Vickery reported no relevant financial relationships.

A version of this article appeared on Medscape.com.