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Cell-Free DNA Blood Test Has High Accuracy for Detecting Colorectal Cancer
, according to a new study.
The cfDNA blood test had 83% sensitivity for CRC, 90% specificity for advanced neoplasia, and 13% sensitivity for advanced precancerous lesions. Other noninvasive screening methods have sensitivity from 67% to 94% for CRC and 22% to 43% for advanced precancerous lesions.
“The results of the study are a promising step toward developing more convenient tools to detect colorectal cancer early while it is more easily treated,” said senior author William M. Grady, MD, AGAF, medical director of the Gastrointestinal Cancer Prevention Program at the Fred Hutchinson Cancer Center in Seattle.
“The test, which has an accuracy rate for colon cancer detection similar to stool tests used for early detection of cancer, could offer an alternative for patients who may otherwise decline current screening options,” he said.
The study was published online on March 14 in The New England Journal of Medicine.
Analyzing the Blood Test’s Accuracy
Dr. Grady and colleagues conducted a multisite clinical trial called ECLIPSE, which compared the sensitivity and specificity of a cfDNA blood test (Shield, Guardant Health) against that obtained with colonoscopy, the gold standard for CRC screening. Guardant led and funded the study.
Guardant’s Shield test is designed to detect CRC through genomic alterations, aberrant methylation status, and fragmentomic patterns, which show up as an “abnormal signal detected” result. Similar blood tests are being developed as “liquid biopsy” tests for other emerging cancer screenings as well.
The study included 7861 people with average CRC risk who underwent routine screening with colonoscopy at 265 sites in the United States, including primary care and endoscopy centers in academic and community-based institutions. Eligible people were aged 45-84 years (average age, 60 years), and 53.7% were women. The race and ethnicity characteristics of the participants closely mirrored the demographic distribution in the 2020 US Census.
Overall, 54 of 65 (83.1%) participants with colonoscopy-detected CRC had a positive cfDNA blood test. However, 11 participants (16.9%) with CRC had a negative test.
The cfDNA blood test identified 42 of 48 stage I, II, or III CRCs, indicating a sensitivity of 87.5%, including 65% for stage I cancers, 100% for stage II cancers, and 100% for stage III cancers. The test also identified all 10 of the stage IV CRC cases. There were no substantial differences in sensitivity for CRC based on primary tumor location, tumor histologic grade, or demographic characteristics.
Among participants without advanced colorectal neoplasia on colonoscopy, 89.6% had a negative cfDNA blood test, and 10.4% had a positive test.
Among those with a negative colonoscopy — with no CRC, advanced precancerous lesions, or nonadvanced precancerous lesions — specificity was 89.9%.
Among 1116 participants with advanced precancerous lesions identified as the most advanced lesion on colonoscopy, the cfDNA blood test was positive for 147, indicating a sensitivity for advanced precancerous lesions of 13.2%.
Although the blood test has sensitivity similar to stool-based tests for CRC, the accuracy is lower than it is with colonoscopy, which remains the current gold standard for CRC screening, Dr. Grady said.
“Colorectal cancer is common and very preventable with screening, but only about 50% to 60% of people who are eligible for screening actually take those tests,” he said. “Getting people to be screened for cancer works best when we offer them screening options and then let them choose what works best for them.”
Future Research
Colorectal cancer is the second leading cause of cancer-related death among US adults and is now the third most diagnosed cancer for people younger than 50 years, Dr. Grady said. Although overall CRC death rates have declined in recent years, the rates among those younger than 55 years have increased since the mid-2000s.
“When colorectal cancer is found earlier and the cancer has not yet spread throughout the body, patient outcomes are much better, as reflected in 5-year survival being much better. It makes sense that an effective blood-based test could have a potential role, in particular for those not getting screened yet,” said Joshua Melson, MD, AGAF, clinical professor of medicine and director of the High-Risk Clinic for Gastrointestinal Cancers at the University of Arizona Cancer Center in Tucson.
Dr. Melson, who wasn’t involved with this study, noted that blood-based testing shows promise for cancer detection but needs additional support for real-world implementation. For instance, the Shield blood test has difficulty detecting precancerous lesions, and it remains unclear what the optimal intervals for repeat testing would be after a negative test, he said. In addition, screening programs will need to ensure they have capacity to effectively deal with a positive test result.
“For a screening program to actually work, when a noninvasive test (whether blood-based or stool-based) is read as positive, those patients need to have a follow-up colonoscopy,” he said.
Proper communication with patients will be important as well, said Gloria Coronado, PhD, associate director of Population Sciences at the University of Arizona Cancer Center, Tucson. Dr. Coronado, who wasn’t involved with this study, has developed CRC screening messages for specific patient populations and studied patient reactions to CRC blood tests.
In a study by Dr. Coronado and colleagues, among more than 2000 patients who passively declined fecal testing and had an upcoming clinic visit, CRC screening proportions were 17.5 percentage points higher in the group offered the blood test vs those offered usual care. In qualitative interviews, one patient said of the blood-based testing option, “I was screaming hallelujah!”
“Patients believed that a blood test would be more accurate than a stool-based test. However, for the detection of advanced adenomas, the reverse is true,” she said. “It will be important to balance the high acceptance and enthusiasm for the blood test with the lower performance of the blood test compared to other tests already on the market.”
In a statement accompanying the study’s publication, the American Gastroenterological Association welcomed these results as an exciting development, but cautioned that a blood-based test was not interchangeable with colonoscopy.
“The Centers for Medicare and Medicaid Services (CMS) has determined it will cover a blood test for colorectal cancer screening every three years if the test achieves 74% sensitivity for CRC, 90% specificity, and FDA approval,” the statement reads. “However, a blood test that meets only the CMS criteria will be inferior to current recommended tests and should not be recommended to replace current tests. Such a test could be recommended for patients who decline all other recommended tests, since any screening is better than no screening at all.”
Dr. Grady is a paid member of Guardant’s scientific advisory board and advised on the design and procedure of the clinical trial and data analysis. Dr. Melson previously served as consultant for Guardant. Dr. Coronado reported no relevant disclosures.
A version of this article appeared on Medscape.com .
, according to a new study.
The cfDNA blood test had 83% sensitivity for CRC, 90% specificity for advanced neoplasia, and 13% sensitivity for advanced precancerous lesions. Other noninvasive screening methods have sensitivity from 67% to 94% for CRC and 22% to 43% for advanced precancerous lesions.
“The results of the study are a promising step toward developing more convenient tools to detect colorectal cancer early while it is more easily treated,” said senior author William M. Grady, MD, AGAF, medical director of the Gastrointestinal Cancer Prevention Program at the Fred Hutchinson Cancer Center in Seattle.
“The test, which has an accuracy rate for colon cancer detection similar to stool tests used for early detection of cancer, could offer an alternative for patients who may otherwise decline current screening options,” he said.
The study was published online on March 14 in The New England Journal of Medicine.
Analyzing the Blood Test’s Accuracy
Dr. Grady and colleagues conducted a multisite clinical trial called ECLIPSE, which compared the sensitivity and specificity of a cfDNA blood test (Shield, Guardant Health) against that obtained with colonoscopy, the gold standard for CRC screening. Guardant led and funded the study.
Guardant’s Shield test is designed to detect CRC through genomic alterations, aberrant methylation status, and fragmentomic patterns, which show up as an “abnormal signal detected” result. Similar blood tests are being developed as “liquid biopsy” tests for other emerging cancer screenings as well.
The study included 7861 people with average CRC risk who underwent routine screening with colonoscopy at 265 sites in the United States, including primary care and endoscopy centers in academic and community-based institutions. Eligible people were aged 45-84 years (average age, 60 years), and 53.7% were women. The race and ethnicity characteristics of the participants closely mirrored the demographic distribution in the 2020 US Census.
Overall, 54 of 65 (83.1%) participants with colonoscopy-detected CRC had a positive cfDNA blood test. However, 11 participants (16.9%) with CRC had a negative test.
The cfDNA blood test identified 42 of 48 stage I, II, or III CRCs, indicating a sensitivity of 87.5%, including 65% for stage I cancers, 100% for stage II cancers, and 100% for stage III cancers. The test also identified all 10 of the stage IV CRC cases. There were no substantial differences in sensitivity for CRC based on primary tumor location, tumor histologic grade, or demographic characteristics.
Among participants without advanced colorectal neoplasia on colonoscopy, 89.6% had a negative cfDNA blood test, and 10.4% had a positive test.
Among those with a negative colonoscopy — with no CRC, advanced precancerous lesions, or nonadvanced precancerous lesions — specificity was 89.9%.
Among 1116 participants with advanced precancerous lesions identified as the most advanced lesion on colonoscopy, the cfDNA blood test was positive for 147, indicating a sensitivity for advanced precancerous lesions of 13.2%.
Although the blood test has sensitivity similar to stool-based tests for CRC, the accuracy is lower than it is with colonoscopy, which remains the current gold standard for CRC screening, Dr. Grady said.
“Colorectal cancer is common and very preventable with screening, but only about 50% to 60% of people who are eligible for screening actually take those tests,” he said. “Getting people to be screened for cancer works best when we offer them screening options and then let them choose what works best for them.”
Future Research
Colorectal cancer is the second leading cause of cancer-related death among US adults and is now the third most diagnosed cancer for people younger than 50 years, Dr. Grady said. Although overall CRC death rates have declined in recent years, the rates among those younger than 55 years have increased since the mid-2000s.
“When colorectal cancer is found earlier and the cancer has not yet spread throughout the body, patient outcomes are much better, as reflected in 5-year survival being much better. It makes sense that an effective blood-based test could have a potential role, in particular for those not getting screened yet,” said Joshua Melson, MD, AGAF, clinical professor of medicine and director of the High-Risk Clinic for Gastrointestinal Cancers at the University of Arizona Cancer Center in Tucson.
Dr. Melson, who wasn’t involved with this study, noted that blood-based testing shows promise for cancer detection but needs additional support for real-world implementation. For instance, the Shield blood test has difficulty detecting precancerous lesions, and it remains unclear what the optimal intervals for repeat testing would be after a negative test, he said. In addition, screening programs will need to ensure they have capacity to effectively deal with a positive test result.
“For a screening program to actually work, when a noninvasive test (whether blood-based or stool-based) is read as positive, those patients need to have a follow-up colonoscopy,” he said.
Proper communication with patients will be important as well, said Gloria Coronado, PhD, associate director of Population Sciences at the University of Arizona Cancer Center, Tucson. Dr. Coronado, who wasn’t involved with this study, has developed CRC screening messages for specific patient populations and studied patient reactions to CRC blood tests.
In a study by Dr. Coronado and colleagues, among more than 2000 patients who passively declined fecal testing and had an upcoming clinic visit, CRC screening proportions were 17.5 percentage points higher in the group offered the blood test vs those offered usual care. In qualitative interviews, one patient said of the blood-based testing option, “I was screaming hallelujah!”
“Patients believed that a blood test would be more accurate than a stool-based test. However, for the detection of advanced adenomas, the reverse is true,” she said. “It will be important to balance the high acceptance and enthusiasm for the blood test with the lower performance of the blood test compared to other tests already on the market.”
In a statement accompanying the study’s publication, the American Gastroenterological Association welcomed these results as an exciting development, but cautioned that a blood-based test was not interchangeable with colonoscopy.
“The Centers for Medicare and Medicaid Services (CMS) has determined it will cover a blood test for colorectal cancer screening every three years if the test achieves 74% sensitivity for CRC, 90% specificity, and FDA approval,” the statement reads. “However, a blood test that meets only the CMS criteria will be inferior to current recommended tests and should not be recommended to replace current tests. Such a test could be recommended for patients who decline all other recommended tests, since any screening is better than no screening at all.”
Dr. Grady is a paid member of Guardant’s scientific advisory board and advised on the design and procedure of the clinical trial and data analysis. Dr. Melson previously served as consultant for Guardant. Dr. Coronado reported no relevant disclosures.
A version of this article appeared on Medscape.com .
, according to a new study.
The cfDNA blood test had 83% sensitivity for CRC, 90% specificity for advanced neoplasia, and 13% sensitivity for advanced precancerous lesions. Other noninvasive screening methods have sensitivity from 67% to 94% for CRC and 22% to 43% for advanced precancerous lesions.
“The results of the study are a promising step toward developing more convenient tools to detect colorectal cancer early while it is more easily treated,” said senior author William M. Grady, MD, AGAF, medical director of the Gastrointestinal Cancer Prevention Program at the Fred Hutchinson Cancer Center in Seattle.
“The test, which has an accuracy rate for colon cancer detection similar to stool tests used for early detection of cancer, could offer an alternative for patients who may otherwise decline current screening options,” he said.
The study was published online on March 14 in The New England Journal of Medicine.
Analyzing the Blood Test’s Accuracy
Dr. Grady and colleagues conducted a multisite clinical trial called ECLIPSE, which compared the sensitivity and specificity of a cfDNA blood test (Shield, Guardant Health) against that obtained with colonoscopy, the gold standard for CRC screening. Guardant led and funded the study.
Guardant’s Shield test is designed to detect CRC through genomic alterations, aberrant methylation status, and fragmentomic patterns, which show up as an “abnormal signal detected” result. Similar blood tests are being developed as “liquid biopsy” tests for other emerging cancer screenings as well.
The study included 7861 people with average CRC risk who underwent routine screening with colonoscopy at 265 sites in the United States, including primary care and endoscopy centers in academic and community-based institutions. Eligible people were aged 45-84 years (average age, 60 years), and 53.7% were women. The race and ethnicity characteristics of the participants closely mirrored the demographic distribution in the 2020 US Census.
Overall, 54 of 65 (83.1%) participants with colonoscopy-detected CRC had a positive cfDNA blood test. However, 11 participants (16.9%) with CRC had a negative test.
The cfDNA blood test identified 42 of 48 stage I, II, or III CRCs, indicating a sensitivity of 87.5%, including 65% for stage I cancers, 100% for stage II cancers, and 100% for stage III cancers. The test also identified all 10 of the stage IV CRC cases. There were no substantial differences in sensitivity for CRC based on primary tumor location, tumor histologic grade, or demographic characteristics.
Among participants without advanced colorectal neoplasia on colonoscopy, 89.6% had a negative cfDNA blood test, and 10.4% had a positive test.
Among those with a negative colonoscopy — with no CRC, advanced precancerous lesions, or nonadvanced precancerous lesions — specificity was 89.9%.
Among 1116 participants with advanced precancerous lesions identified as the most advanced lesion on colonoscopy, the cfDNA blood test was positive for 147, indicating a sensitivity for advanced precancerous lesions of 13.2%.
Although the blood test has sensitivity similar to stool-based tests for CRC, the accuracy is lower than it is with colonoscopy, which remains the current gold standard for CRC screening, Dr. Grady said.
“Colorectal cancer is common and very preventable with screening, but only about 50% to 60% of people who are eligible for screening actually take those tests,” he said. “Getting people to be screened for cancer works best when we offer them screening options and then let them choose what works best for them.”
Future Research
Colorectal cancer is the second leading cause of cancer-related death among US adults and is now the third most diagnosed cancer for people younger than 50 years, Dr. Grady said. Although overall CRC death rates have declined in recent years, the rates among those younger than 55 years have increased since the mid-2000s.
“When colorectal cancer is found earlier and the cancer has not yet spread throughout the body, patient outcomes are much better, as reflected in 5-year survival being much better. It makes sense that an effective blood-based test could have a potential role, in particular for those not getting screened yet,” said Joshua Melson, MD, AGAF, clinical professor of medicine and director of the High-Risk Clinic for Gastrointestinal Cancers at the University of Arizona Cancer Center in Tucson.
Dr. Melson, who wasn’t involved with this study, noted that blood-based testing shows promise for cancer detection but needs additional support for real-world implementation. For instance, the Shield blood test has difficulty detecting precancerous lesions, and it remains unclear what the optimal intervals for repeat testing would be after a negative test, he said. In addition, screening programs will need to ensure they have capacity to effectively deal with a positive test result.
“For a screening program to actually work, when a noninvasive test (whether blood-based or stool-based) is read as positive, those patients need to have a follow-up colonoscopy,” he said.
Proper communication with patients will be important as well, said Gloria Coronado, PhD, associate director of Population Sciences at the University of Arizona Cancer Center, Tucson. Dr. Coronado, who wasn’t involved with this study, has developed CRC screening messages for specific patient populations and studied patient reactions to CRC blood tests.
In a study by Dr. Coronado and colleagues, among more than 2000 patients who passively declined fecal testing and had an upcoming clinic visit, CRC screening proportions were 17.5 percentage points higher in the group offered the blood test vs those offered usual care. In qualitative interviews, one patient said of the blood-based testing option, “I was screaming hallelujah!”
“Patients believed that a blood test would be more accurate than a stool-based test. However, for the detection of advanced adenomas, the reverse is true,” she said. “It will be important to balance the high acceptance and enthusiasm for the blood test with the lower performance of the blood test compared to other tests already on the market.”
In a statement accompanying the study’s publication, the American Gastroenterological Association welcomed these results as an exciting development, but cautioned that a blood-based test was not interchangeable with colonoscopy.
“The Centers for Medicare and Medicaid Services (CMS) has determined it will cover a blood test for colorectal cancer screening every three years if the test achieves 74% sensitivity for CRC, 90% specificity, and FDA approval,” the statement reads. “However, a blood test that meets only the CMS criteria will be inferior to current recommended tests and should not be recommended to replace current tests. Such a test could be recommended for patients who decline all other recommended tests, since any screening is better than no screening at all.”
Dr. Grady is a paid member of Guardant’s scientific advisory board and advised on the design and procedure of the clinical trial and data analysis. Dr. Melson previously served as consultant for Guardant. Dr. Coronado reported no relevant disclosures.
A version of this article appeared on Medscape.com .
FROM NEJM
Combining Targeted Drugs and Radiation in Breast Cancer: What’s Safe?
One reason is studies of new drugs typically exclude concurrent radiotherapy, said Kathy Miller, MD, a contributor to this news organization and professor of oncology and medicine at the Indiana University School of Medicine, Indianapolis, Indiana.
If trials evaluating new targeted therapies included concurrent radiotherapy, it would be challenging to identify whether toxicities came from the drug itself, the radiation, or the combination, Dr. Miller explained.
Given the limited evidence, “we tend to be cautious and conservative” and not combine therapies that “we don’t know are safe or appropriate for patients,” said Chirag Shah, MD, director of breast radiology at the Cleveland Clinic, Cleveland, Ohio.
Below is a guide to what we do and don’t know about combining radiotherapy and systemic treatments in breast cancer.
1. Immunotherapy plus radiotherapy likely safe but evidence is limited
Safety data on combining immune checkpoint inhibitors and radiotherapy in breast cancer are limited because concurrent radiotherapy has typically been excluded in pivotal trials.
The 2020 KEYNOTE-522 trial did provide a rare look at concurrent radiotherapy and immunotherapy in early triple-negative breast cancer. The analysis found “no safety concerns” with concurrent radiotherapy and pembrolizumab, lead investigator Peter Schmid, MD, of Queen Mary University of London, England, told this news organization.
Research on other solid tumor types also suggests that radiotherapy “can be considered safe” alongside immunotherapy, the authors of a recent ESTRO consensus said.
Despite evidence indicating radiotherapy alongside immunotherapy can be safe in patients with breast cancer, “certain aspects, such as patient selection, total dose, and dose per fraction, remain open for debate to achieve the best therapeutic outcomes,” the ESTRO experts cautioned.
2. CDK4/6 inhibitors may be offered with radiotherapy in some settings, not others
CDK4/6 inhibitors are now standard of care for first- or second-line treatment in patients with advanced or metastatic hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer.
“Unfortunately, we found no information regarding concurrent radiotherapy in the adjuvant setting” in pivotal trials for palbociclib, abemaciclib, and ribociclib, the ESTRO authors said. In the pivotal trials for palbociclib and abemaciclib, patients had to discontinue immunotherapy before initiating radiotherapy, and in the trial for ribociclib, palliative radiotherapy was allowed for relieving bone pain only.
However, in 2023, a team of experts from 12 countries attempted to piece together the available evidence, publishing a meta-analysis of 11 retrospective studies on the safety of CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic disease.
Although most of these studies had small patient populations, the analysis revealed that CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic breast cancer led to a similar side-effect profile to that observed in trials of the inhibitors given sequentially with adjuvant radiotherapy.
“These findings suggest that the simultaneous administration of CDK4/6 inhibitors and radiotherapy is generally well tolerated,” the ESTRO authors concluded but added that CDK4/6 inhibitors and concomitant radiotherapy should be investigated more in the adjuvant locoregional, whole brain, and intracranial stereotactic radiotherapy settings.
The expert panel did note, however, that CDK4/6 inhibitors and concomitant radiotherapy “could be offered” during palliative and ablative extracranial radiotherapy.
3. Only offer poly (ADP-ribose) polymerase (PARP) inhibitors plus radiotherapy in clinical trial setting
PARP inhibitors olaparib (Lynparza) and talazoprib (Talzenna) are standard of care in patients with metastatic breast cancer who have BRCA1/2 gene mutations. Olaparib is also indicated for high-risk early breast cancer following neoadjuvant or adjuvant chemotherapy.
But data on combining PARP inhibitors with radiotherapy in breast cancer also remain limited.
One ongoing phase 2 trial, comparing olaparib plus radiotherapy to radiotherapy alone in 300 people with inflammatory breast cancer, is aiming to tease out the safety of the combination and whether it improves local control in patients with aggressive disease.
“The desire is to explore the exciting possibility that low doses of PARP inhibition may radiosensitize tumor cells more than normal tissues,” Reshma Jagsi, MD, chair of the Department of Radiation Oncology at Emory University School of Medicine in Atlanta, Georgia, who is leading the study.
Because of potential good or bad interactions between new systemic therapies and radiotherapy, “intentional trial design” is important, Dr. Jagsi said, so we “know the best way to combine treatments in practice to optimize outcomes.”
But given the evidence to date, the ESTRO experts advised waiting until “further research provides more comprehensive safety and efficacy data” in the primary, adjuvant, and metastatic settings. The experts also advised not offering PARP inhibitors and concomitant radiotherapy to treat advanced breast cancer outside of clinical trials.
4. Phosphoinositide 3-kinase inhibitors (PI3K) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and newer targeted agents should not be offered concurrently with radiotherapy
Clinical trial data on the safety of combining PI3K and mTOR inhibitors with radiation are thin, especially in advanced breast cancer. Typically, radiotherapy within 4 weeks before randomization, or 2 weeks for palliative radiation, was excluded in pivotal trials.
For this reason, the ESTRO team recommended that concurrent radiation with either PI3K inhibitors or mTOR inhibitors “should not be offered.”
ESTRO also cautioned against providing radiation concurrently with newer anti-HER2 tyrosine-kinase drugs, such as neratinib or tucatinib, or newer antibody-drug conjugates such as trastuzumab deruxtecan, until more data emerge on the safety of these combinations.
5. Combining older HER2-targeted drugs and radiotherapy generally safe
The ESTRO authors agreed that older anti-HER2 drugs trastuzumab (Herceptin), pertuzumab (Perjeta), and lapatinib (Tykerb) can be safely used concurrently with locoregional radiotherapy as well.
One of the biggest concerns in the field is how to combine radiation with systemic therapies in the setting of brain metastases, and the data on these older anti-HER2 drugs are relatively clear that it’s safe, Dr. Miller said.
For instance, in a 2019 study of 84 patients with 487 brain metastases, stereotactic radiosurgery given alongside lapatinib led to significantly higher rates of complete responses than stereotactic radiosurgery alone (35% vs 11%) with no increased risk for radiation necrosis.
The ESTRO team agreed, noting that the latest evidence supports the use of trastuzumab, pertuzumab, or lapatinib alongside radiotherapy for whole brain and ablative intracranial stereotactic radiotherapy.
As for older antibody-drug conjugates, trastuzumab emtansine (T-DM1) plus radiotherapy “might be considered” during adjuvant locoregional radiotherapy for breast cancer but should not be offered for whole brain and ablative intracranial stereotactic radiotherapy, the ESTRO team said.
Dr. Jagsi declared the following conflicts in a recent 2024 publication: Stock options for advisory board role in Equity Quotient; grants or contracts from Genentech; and expert witness for Kleinbard, LLC, and Hawks Quindel Law. In the Keynote-522 trial publication Dr. Schmid declared relationships with AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Hoffmann-La Roche, Genetech, Merck, Novartis, and Pfizer. Dr. Shah reported consulting for Impedimed, Videra Surgical, and PreludeDX.
A version of this article appeared on Medscape.com.
One reason is studies of new drugs typically exclude concurrent radiotherapy, said Kathy Miller, MD, a contributor to this news organization and professor of oncology and medicine at the Indiana University School of Medicine, Indianapolis, Indiana.
If trials evaluating new targeted therapies included concurrent radiotherapy, it would be challenging to identify whether toxicities came from the drug itself, the radiation, or the combination, Dr. Miller explained.
Given the limited evidence, “we tend to be cautious and conservative” and not combine therapies that “we don’t know are safe or appropriate for patients,” said Chirag Shah, MD, director of breast radiology at the Cleveland Clinic, Cleveland, Ohio.
Below is a guide to what we do and don’t know about combining radiotherapy and systemic treatments in breast cancer.
1. Immunotherapy plus radiotherapy likely safe but evidence is limited
Safety data on combining immune checkpoint inhibitors and radiotherapy in breast cancer are limited because concurrent radiotherapy has typically been excluded in pivotal trials.
The 2020 KEYNOTE-522 trial did provide a rare look at concurrent radiotherapy and immunotherapy in early triple-negative breast cancer. The analysis found “no safety concerns” with concurrent radiotherapy and pembrolizumab, lead investigator Peter Schmid, MD, of Queen Mary University of London, England, told this news organization.
Research on other solid tumor types also suggests that radiotherapy “can be considered safe” alongside immunotherapy, the authors of a recent ESTRO consensus said.
Despite evidence indicating radiotherapy alongside immunotherapy can be safe in patients with breast cancer, “certain aspects, such as patient selection, total dose, and dose per fraction, remain open for debate to achieve the best therapeutic outcomes,” the ESTRO experts cautioned.
2. CDK4/6 inhibitors may be offered with radiotherapy in some settings, not others
CDK4/6 inhibitors are now standard of care for first- or second-line treatment in patients with advanced or metastatic hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer.
“Unfortunately, we found no information regarding concurrent radiotherapy in the adjuvant setting” in pivotal trials for palbociclib, abemaciclib, and ribociclib, the ESTRO authors said. In the pivotal trials for palbociclib and abemaciclib, patients had to discontinue immunotherapy before initiating radiotherapy, and in the trial for ribociclib, palliative radiotherapy was allowed for relieving bone pain only.
However, in 2023, a team of experts from 12 countries attempted to piece together the available evidence, publishing a meta-analysis of 11 retrospective studies on the safety of CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic disease.
Although most of these studies had small patient populations, the analysis revealed that CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic breast cancer led to a similar side-effect profile to that observed in trials of the inhibitors given sequentially with adjuvant radiotherapy.
“These findings suggest that the simultaneous administration of CDK4/6 inhibitors and radiotherapy is generally well tolerated,” the ESTRO authors concluded but added that CDK4/6 inhibitors and concomitant radiotherapy should be investigated more in the adjuvant locoregional, whole brain, and intracranial stereotactic radiotherapy settings.
The expert panel did note, however, that CDK4/6 inhibitors and concomitant radiotherapy “could be offered” during palliative and ablative extracranial radiotherapy.
3. Only offer poly (ADP-ribose) polymerase (PARP) inhibitors plus radiotherapy in clinical trial setting
PARP inhibitors olaparib (Lynparza) and talazoprib (Talzenna) are standard of care in patients with metastatic breast cancer who have BRCA1/2 gene mutations. Olaparib is also indicated for high-risk early breast cancer following neoadjuvant or adjuvant chemotherapy.
But data on combining PARP inhibitors with radiotherapy in breast cancer also remain limited.
One ongoing phase 2 trial, comparing olaparib plus radiotherapy to radiotherapy alone in 300 people with inflammatory breast cancer, is aiming to tease out the safety of the combination and whether it improves local control in patients with aggressive disease.
“The desire is to explore the exciting possibility that low doses of PARP inhibition may radiosensitize tumor cells more than normal tissues,” Reshma Jagsi, MD, chair of the Department of Radiation Oncology at Emory University School of Medicine in Atlanta, Georgia, who is leading the study.
Because of potential good or bad interactions between new systemic therapies and radiotherapy, “intentional trial design” is important, Dr. Jagsi said, so we “know the best way to combine treatments in practice to optimize outcomes.”
But given the evidence to date, the ESTRO experts advised waiting until “further research provides more comprehensive safety and efficacy data” in the primary, adjuvant, and metastatic settings. The experts also advised not offering PARP inhibitors and concomitant radiotherapy to treat advanced breast cancer outside of clinical trials.
4. Phosphoinositide 3-kinase inhibitors (PI3K) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and newer targeted agents should not be offered concurrently with radiotherapy
Clinical trial data on the safety of combining PI3K and mTOR inhibitors with radiation are thin, especially in advanced breast cancer. Typically, radiotherapy within 4 weeks before randomization, or 2 weeks for palliative radiation, was excluded in pivotal trials.
For this reason, the ESTRO team recommended that concurrent radiation with either PI3K inhibitors or mTOR inhibitors “should not be offered.”
ESTRO also cautioned against providing radiation concurrently with newer anti-HER2 tyrosine-kinase drugs, such as neratinib or tucatinib, or newer antibody-drug conjugates such as trastuzumab deruxtecan, until more data emerge on the safety of these combinations.
5. Combining older HER2-targeted drugs and radiotherapy generally safe
The ESTRO authors agreed that older anti-HER2 drugs trastuzumab (Herceptin), pertuzumab (Perjeta), and lapatinib (Tykerb) can be safely used concurrently with locoregional radiotherapy as well.
One of the biggest concerns in the field is how to combine radiation with systemic therapies in the setting of brain metastases, and the data on these older anti-HER2 drugs are relatively clear that it’s safe, Dr. Miller said.
For instance, in a 2019 study of 84 patients with 487 brain metastases, stereotactic radiosurgery given alongside lapatinib led to significantly higher rates of complete responses than stereotactic radiosurgery alone (35% vs 11%) with no increased risk for radiation necrosis.
The ESTRO team agreed, noting that the latest evidence supports the use of trastuzumab, pertuzumab, or lapatinib alongside radiotherapy for whole brain and ablative intracranial stereotactic radiotherapy.
As for older antibody-drug conjugates, trastuzumab emtansine (T-DM1) plus radiotherapy “might be considered” during adjuvant locoregional radiotherapy for breast cancer but should not be offered for whole brain and ablative intracranial stereotactic radiotherapy, the ESTRO team said.
Dr. Jagsi declared the following conflicts in a recent 2024 publication: Stock options for advisory board role in Equity Quotient; grants or contracts from Genentech; and expert witness for Kleinbard, LLC, and Hawks Quindel Law. In the Keynote-522 trial publication Dr. Schmid declared relationships with AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Hoffmann-La Roche, Genetech, Merck, Novartis, and Pfizer. Dr. Shah reported consulting for Impedimed, Videra Surgical, and PreludeDX.
A version of this article appeared on Medscape.com.
One reason is studies of new drugs typically exclude concurrent radiotherapy, said Kathy Miller, MD, a contributor to this news organization and professor of oncology and medicine at the Indiana University School of Medicine, Indianapolis, Indiana.
If trials evaluating new targeted therapies included concurrent radiotherapy, it would be challenging to identify whether toxicities came from the drug itself, the radiation, or the combination, Dr. Miller explained.
Given the limited evidence, “we tend to be cautious and conservative” and not combine therapies that “we don’t know are safe or appropriate for patients,” said Chirag Shah, MD, director of breast radiology at the Cleveland Clinic, Cleveland, Ohio.
Below is a guide to what we do and don’t know about combining radiotherapy and systemic treatments in breast cancer.
1. Immunotherapy plus radiotherapy likely safe but evidence is limited
Safety data on combining immune checkpoint inhibitors and radiotherapy in breast cancer are limited because concurrent radiotherapy has typically been excluded in pivotal trials.
The 2020 KEYNOTE-522 trial did provide a rare look at concurrent radiotherapy and immunotherapy in early triple-negative breast cancer. The analysis found “no safety concerns” with concurrent radiotherapy and pembrolizumab, lead investigator Peter Schmid, MD, of Queen Mary University of London, England, told this news organization.
Research on other solid tumor types also suggests that radiotherapy “can be considered safe” alongside immunotherapy, the authors of a recent ESTRO consensus said.
Despite evidence indicating radiotherapy alongside immunotherapy can be safe in patients with breast cancer, “certain aspects, such as patient selection, total dose, and dose per fraction, remain open for debate to achieve the best therapeutic outcomes,” the ESTRO experts cautioned.
2. CDK4/6 inhibitors may be offered with radiotherapy in some settings, not others
CDK4/6 inhibitors are now standard of care for first- or second-line treatment in patients with advanced or metastatic hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer.
“Unfortunately, we found no information regarding concurrent radiotherapy in the adjuvant setting” in pivotal trials for palbociclib, abemaciclib, and ribociclib, the ESTRO authors said. In the pivotal trials for palbociclib and abemaciclib, patients had to discontinue immunotherapy before initiating radiotherapy, and in the trial for ribociclib, palliative radiotherapy was allowed for relieving bone pain only.
However, in 2023, a team of experts from 12 countries attempted to piece together the available evidence, publishing a meta-analysis of 11 retrospective studies on the safety of CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic disease.
Although most of these studies had small patient populations, the analysis revealed that CDK4/6 inhibitors given concurrently with radiotherapy in patients with metastatic breast cancer led to a similar side-effect profile to that observed in trials of the inhibitors given sequentially with adjuvant radiotherapy.
“These findings suggest that the simultaneous administration of CDK4/6 inhibitors and radiotherapy is generally well tolerated,” the ESTRO authors concluded but added that CDK4/6 inhibitors and concomitant radiotherapy should be investigated more in the adjuvant locoregional, whole brain, and intracranial stereotactic radiotherapy settings.
The expert panel did note, however, that CDK4/6 inhibitors and concomitant radiotherapy “could be offered” during palliative and ablative extracranial radiotherapy.
3. Only offer poly (ADP-ribose) polymerase (PARP) inhibitors plus radiotherapy in clinical trial setting
PARP inhibitors olaparib (Lynparza) and talazoprib (Talzenna) are standard of care in patients with metastatic breast cancer who have BRCA1/2 gene mutations. Olaparib is also indicated for high-risk early breast cancer following neoadjuvant or adjuvant chemotherapy.
But data on combining PARP inhibitors with radiotherapy in breast cancer also remain limited.
One ongoing phase 2 trial, comparing olaparib plus radiotherapy to radiotherapy alone in 300 people with inflammatory breast cancer, is aiming to tease out the safety of the combination and whether it improves local control in patients with aggressive disease.
“The desire is to explore the exciting possibility that low doses of PARP inhibition may radiosensitize tumor cells more than normal tissues,” Reshma Jagsi, MD, chair of the Department of Radiation Oncology at Emory University School of Medicine in Atlanta, Georgia, who is leading the study.
Because of potential good or bad interactions between new systemic therapies and radiotherapy, “intentional trial design” is important, Dr. Jagsi said, so we “know the best way to combine treatments in practice to optimize outcomes.”
But given the evidence to date, the ESTRO experts advised waiting until “further research provides more comprehensive safety and efficacy data” in the primary, adjuvant, and metastatic settings. The experts also advised not offering PARP inhibitors and concomitant radiotherapy to treat advanced breast cancer outside of clinical trials.
4. Phosphoinositide 3-kinase inhibitors (PI3K) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and newer targeted agents should not be offered concurrently with radiotherapy
Clinical trial data on the safety of combining PI3K and mTOR inhibitors with radiation are thin, especially in advanced breast cancer. Typically, radiotherapy within 4 weeks before randomization, or 2 weeks for palliative radiation, was excluded in pivotal trials.
For this reason, the ESTRO team recommended that concurrent radiation with either PI3K inhibitors or mTOR inhibitors “should not be offered.”
ESTRO also cautioned against providing radiation concurrently with newer anti-HER2 tyrosine-kinase drugs, such as neratinib or tucatinib, or newer antibody-drug conjugates such as trastuzumab deruxtecan, until more data emerge on the safety of these combinations.
5. Combining older HER2-targeted drugs and radiotherapy generally safe
The ESTRO authors agreed that older anti-HER2 drugs trastuzumab (Herceptin), pertuzumab (Perjeta), and lapatinib (Tykerb) can be safely used concurrently with locoregional radiotherapy as well.
One of the biggest concerns in the field is how to combine radiation with systemic therapies in the setting of brain metastases, and the data on these older anti-HER2 drugs are relatively clear that it’s safe, Dr. Miller said.
For instance, in a 2019 study of 84 patients with 487 brain metastases, stereotactic radiosurgery given alongside lapatinib led to significantly higher rates of complete responses than stereotactic radiosurgery alone (35% vs 11%) with no increased risk for radiation necrosis.
The ESTRO team agreed, noting that the latest evidence supports the use of trastuzumab, pertuzumab, or lapatinib alongside radiotherapy for whole brain and ablative intracranial stereotactic radiotherapy.
As for older antibody-drug conjugates, trastuzumab emtansine (T-DM1) plus radiotherapy “might be considered” during adjuvant locoregional radiotherapy for breast cancer but should not be offered for whole brain and ablative intracranial stereotactic radiotherapy, the ESTRO team said.
Dr. Jagsi declared the following conflicts in a recent 2024 publication: Stock options for advisory board role in Equity Quotient; grants or contracts from Genentech; and expert witness for Kleinbard, LLC, and Hawks Quindel Law. In the Keynote-522 trial publication Dr. Schmid declared relationships with AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Hoffmann-La Roche, Genetech, Merck, Novartis, and Pfizer. Dr. Shah reported consulting for Impedimed, Videra Surgical, and PreludeDX.
A version of this article appeared on Medscape.com.
Pediatrics Takes a Hit, Whereas Emergency Medicine Recovers on Match Day
As US medical school graduates learned Friday, March 15, where they would spend their residencies, new Match Day 2024 data showed a loss of interest in pediatrics, whereas emergency medicine regained popularity after concern over last year’s unfilled positions.
Hospitals and medical groups offered 41,503 residency positions in 2024, a 3% increase from last year, according to the data released by the National Resident Matching Program.
But though the number of pediatric residency slots increased slightly from last year, 8% of available positions remained unfilled in 2024 compared with about 3% last year.
Physician leaders and policymakers alike pay keen attention to Match Day results because they can signal future shortages in certain specialties, including primary care. Unfilled slots also can raise concerns over too many residency programs in a specialty.
Medical students’ interest in pediatrics continues to decline in part because it pays less than other specialties, Bryan Carmody, MD, MPH, a pediatric nephrologist known for his medical school commentaries, told this news organization. The number of pediatric applicants from US medical schools peaked in 2015 and has fallen since, he said.
“There’s been a lot of soul searching ... this week, with people speculating about lots of (reasons),” Dr. Carmody said. “I don’t think it’s even debt. You can look at the number of unfilled positions, and it correlates with the expected earning potential of those specialties.”
Family medicine, for example, filled about 88% of its positions this year.
Ob.gyn. residencies retained their popularity despite concerns over abortion and reproductive health rights in many states. The specialty filled 99.6% of its positions, a very slight improvement over last year’s 99% rate.
Though ob.gyn. applicants might prefer programs in states where there are more liberal policies around reproductive health, many won’t be in a position where they can choose that because of the limited number of ob.gyn. slots, Dr. Carmody said.
Unfilled residency slots likely will be filled through the Supplemental Offer and Acceptance Program (SOAP). Applicants who did not match in the first round participate in SOAP for one of the 2562 positions in 787 programs that went unfilled after the matching algorithm was processed. A total of 2575 positions were placed in SOAP, including positions in programs that did not participate in the algorithm phase of the process. There were 83 fewer positions in SOAP in 2024, a decrease of 3.1% compared with last year’s Match. More detailed data on SOAP results will be released later this year.
A version of this article appeared on Medscape.com.
As US medical school graduates learned Friday, March 15, where they would spend their residencies, new Match Day 2024 data showed a loss of interest in pediatrics, whereas emergency medicine regained popularity after concern over last year’s unfilled positions.
Hospitals and medical groups offered 41,503 residency positions in 2024, a 3% increase from last year, according to the data released by the National Resident Matching Program.
But though the number of pediatric residency slots increased slightly from last year, 8% of available positions remained unfilled in 2024 compared with about 3% last year.
Physician leaders and policymakers alike pay keen attention to Match Day results because they can signal future shortages in certain specialties, including primary care. Unfilled slots also can raise concerns over too many residency programs in a specialty.
Medical students’ interest in pediatrics continues to decline in part because it pays less than other specialties, Bryan Carmody, MD, MPH, a pediatric nephrologist known for his medical school commentaries, told this news organization. The number of pediatric applicants from US medical schools peaked in 2015 and has fallen since, he said.
“There’s been a lot of soul searching ... this week, with people speculating about lots of (reasons),” Dr. Carmody said. “I don’t think it’s even debt. You can look at the number of unfilled positions, and it correlates with the expected earning potential of those specialties.”
Family medicine, for example, filled about 88% of its positions this year.
Ob.gyn. residencies retained their popularity despite concerns over abortion and reproductive health rights in many states. The specialty filled 99.6% of its positions, a very slight improvement over last year’s 99% rate.
Though ob.gyn. applicants might prefer programs in states where there are more liberal policies around reproductive health, many won’t be in a position where they can choose that because of the limited number of ob.gyn. slots, Dr. Carmody said.
Unfilled residency slots likely will be filled through the Supplemental Offer and Acceptance Program (SOAP). Applicants who did not match in the first round participate in SOAP for one of the 2562 positions in 787 programs that went unfilled after the matching algorithm was processed. A total of 2575 positions were placed in SOAP, including positions in programs that did not participate in the algorithm phase of the process. There were 83 fewer positions in SOAP in 2024, a decrease of 3.1% compared with last year’s Match. More detailed data on SOAP results will be released later this year.
A version of this article appeared on Medscape.com.
As US medical school graduates learned Friday, March 15, where they would spend their residencies, new Match Day 2024 data showed a loss of interest in pediatrics, whereas emergency medicine regained popularity after concern over last year’s unfilled positions.
Hospitals and medical groups offered 41,503 residency positions in 2024, a 3% increase from last year, according to the data released by the National Resident Matching Program.
But though the number of pediatric residency slots increased slightly from last year, 8% of available positions remained unfilled in 2024 compared with about 3% last year.
Physician leaders and policymakers alike pay keen attention to Match Day results because they can signal future shortages in certain specialties, including primary care. Unfilled slots also can raise concerns over too many residency programs in a specialty.
Medical students’ interest in pediatrics continues to decline in part because it pays less than other specialties, Bryan Carmody, MD, MPH, a pediatric nephrologist known for his medical school commentaries, told this news organization. The number of pediatric applicants from US medical schools peaked in 2015 and has fallen since, he said.
“There’s been a lot of soul searching ... this week, with people speculating about lots of (reasons),” Dr. Carmody said. “I don’t think it’s even debt. You can look at the number of unfilled positions, and it correlates with the expected earning potential of those specialties.”
Family medicine, for example, filled about 88% of its positions this year.
Ob.gyn. residencies retained their popularity despite concerns over abortion and reproductive health rights in many states. The specialty filled 99.6% of its positions, a very slight improvement over last year’s 99% rate.
Though ob.gyn. applicants might prefer programs in states where there are more liberal policies around reproductive health, many won’t be in a position where they can choose that because of the limited number of ob.gyn. slots, Dr. Carmody said.
Unfilled residency slots likely will be filled through the Supplemental Offer and Acceptance Program (SOAP). Applicants who did not match in the first round participate in SOAP for one of the 2562 positions in 787 programs that went unfilled after the matching algorithm was processed. A total of 2575 positions were placed in SOAP, including positions in programs that did not participate in the algorithm phase of the process. There were 83 fewer positions in SOAP in 2024, a decrease of 3.1% compared with last year’s Match. More detailed data on SOAP results will be released later this year.
A version of this article appeared on Medscape.com.
FDA Approves New Esophageal Cancer Drug
The US Food and Drug Administration (FDA) has approved tislelizumab-jsgr (Tevimbra, BeiGene Ltd.) as second-line monotherapy for certain adult patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC).
Specifically, the novel checkpoint inhibitor is approved for patients with ESCC after prior systemic chemotherapy that did not include a programmed death–ligand 1 (PD-L1) inhibitor.
Approval was based on findings from the open-label, phase 3 RATIONALE 302 trial showing a statistically significant and clinically meaningful overall survival benefit with tislelizumab vs investigator’s choice of chemotherapy.
Study participants included 512 adults enrolled at 123 research sites in 11 countries in Europe, Asia, and North America. Patients were randomly assigned to receive intravenous tislelizumab, a humanized immunoglobulin G4 anti-programmed cell death protein 1 monoclonal antibody, at a dose of 200 mg every 3 weeks or investigator’s choice of standard chemotherapy with paclitaxel, docetaxel, or irinotecan until disease progression, unacceptable toxicity, or study withdrawal.
Median overall survival in the intention-to-treat population, the primary study endpoint, was 8.6 months vs 6.3 months in the chemotherapy arms (hazard ratio [HR], 0.70). The survival benefit was observed across predefined subgroups, including baseline PD-L1 status and region. The new agent was also associated with improved overall response rate (20.4% vs 9.8%) and more durable response (median duration of response of 7.1 vs 4.0 months; HR, 0.42) compared with chemotherapy.
The most common adverse reactions for tislelizumab, each occurring in at least 20% of treated patients, included increased glucose and decreased hemoglobin, lymphocytes, sodium, and albumin as well as increased alkaline phosphatase, anemia, fatigue, increased aspartate aminotransferase, musculoskeletal pain, decreased weight, increased alanine aminotransferase, and cough.
Fewer patients in the tislelizumab arm experienced grade 3 or greater treatment-emergent adverse events compared with the chemotherapy arm (46% vs 68%, respectively), and fewer patients discontinued tislelizumab vs chemotherapy due to such an event (7% vs 14%).
“Patients diagnosed with advanced or metastasized ESCC, the most common histologic subtype of esophageal cancer, often progress following initial therapy and are in need of new options,” Syma Iqbal, MD, of the Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, stated in the BeiGene release. “The RATIONALE 302 trial showed that patients with previously treated ESCC who received Tevimbra saw a clinically meaningful survival benefit, highlighting its potential as an important treatment option for these patients.”
The approval, which was deferred in 2022 due to COVID-19-related restrictions, marks the first for the agent in the United States. Tislelizumab should be available in the United States in the second half of 2024, BeiGene noted.
The FDA is also reviewing a Biologics License Application for the agent as a first-line treatment for patients with unresectable, locally advanced, or metastatic ESCC and for those with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma, BeiGene announced in a press release.
A version of this article appeared on Medscape.com.
The US Food and Drug Administration (FDA) has approved tislelizumab-jsgr (Tevimbra, BeiGene Ltd.) as second-line monotherapy for certain adult patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC).
Specifically, the novel checkpoint inhibitor is approved for patients with ESCC after prior systemic chemotherapy that did not include a programmed death–ligand 1 (PD-L1) inhibitor.
Approval was based on findings from the open-label, phase 3 RATIONALE 302 trial showing a statistically significant and clinically meaningful overall survival benefit with tislelizumab vs investigator’s choice of chemotherapy.
Study participants included 512 adults enrolled at 123 research sites in 11 countries in Europe, Asia, and North America. Patients were randomly assigned to receive intravenous tislelizumab, a humanized immunoglobulin G4 anti-programmed cell death protein 1 monoclonal antibody, at a dose of 200 mg every 3 weeks or investigator’s choice of standard chemotherapy with paclitaxel, docetaxel, or irinotecan until disease progression, unacceptable toxicity, or study withdrawal.
Median overall survival in the intention-to-treat population, the primary study endpoint, was 8.6 months vs 6.3 months in the chemotherapy arms (hazard ratio [HR], 0.70). The survival benefit was observed across predefined subgroups, including baseline PD-L1 status and region. The new agent was also associated with improved overall response rate (20.4% vs 9.8%) and more durable response (median duration of response of 7.1 vs 4.0 months; HR, 0.42) compared with chemotherapy.
The most common adverse reactions for tislelizumab, each occurring in at least 20% of treated patients, included increased glucose and decreased hemoglobin, lymphocytes, sodium, and albumin as well as increased alkaline phosphatase, anemia, fatigue, increased aspartate aminotransferase, musculoskeletal pain, decreased weight, increased alanine aminotransferase, and cough.
Fewer patients in the tislelizumab arm experienced grade 3 or greater treatment-emergent adverse events compared with the chemotherapy arm (46% vs 68%, respectively), and fewer patients discontinued tislelizumab vs chemotherapy due to such an event (7% vs 14%).
“Patients diagnosed with advanced or metastasized ESCC, the most common histologic subtype of esophageal cancer, often progress following initial therapy and are in need of new options,” Syma Iqbal, MD, of the Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, stated in the BeiGene release. “The RATIONALE 302 trial showed that patients with previously treated ESCC who received Tevimbra saw a clinically meaningful survival benefit, highlighting its potential as an important treatment option for these patients.”
The approval, which was deferred in 2022 due to COVID-19-related restrictions, marks the first for the agent in the United States. Tislelizumab should be available in the United States in the second half of 2024, BeiGene noted.
The FDA is also reviewing a Biologics License Application for the agent as a first-line treatment for patients with unresectable, locally advanced, or metastatic ESCC and for those with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma, BeiGene announced in a press release.
A version of this article appeared on Medscape.com.
The US Food and Drug Administration (FDA) has approved tislelizumab-jsgr (Tevimbra, BeiGene Ltd.) as second-line monotherapy for certain adult patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC).
Specifically, the novel checkpoint inhibitor is approved for patients with ESCC after prior systemic chemotherapy that did not include a programmed death–ligand 1 (PD-L1) inhibitor.
Approval was based on findings from the open-label, phase 3 RATIONALE 302 trial showing a statistically significant and clinically meaningful overall survival benefit with tislelizumab vs investigator’s choice of chemotherapy.
Study participants included 512 adults enrolled at 123 research sites in 11 countries in Europe, Asia, and North America. Patients were randomly assigned to receive intravenous tislelizumab, a humanized immunoglobulin G4 anti-programmed cell death protein 1 monoclonal antibody, at a dose of 200 mg every 3 weeks or investigator’s choice of standard chemotherapy with paclitaxel, docetaxel, or irinotecan until disease progression, unacceptable toxicity, or study withdrawal.
Median overall survival in the intention-to-treat population, the primary study endpoint, was 8.6 months vs 6.3 months in the chemotherapy arms (hazard ratio [HR], 0.70). The survival benefit was observed across predefined subgroups, including baseline PD-L1 status and region. The new agent was also associated with improved overall response rate (20.4% vs 9.8%) and more durable response (median duration of response of 7.1 vs 4.0 months; HR, 0.42) compared with chemotherapy.
The most common adverse reactions for tislelizumab, each occurring in at least 20% of treated patients, included increased glucose and decreased hemoglobin, lymphocytes, sodium, and albumin as well as increased alkaline phosphatase, anemia, fatigue, increased aspartate aminotransferase, musculoskeletal pain, decreased weight, increased alanine aminotransferase, and cough.
Fewer patients in the tislelizumab arm experienced grade 3 or greater treatment-emergent adverse events compared with the chemotherapy arm (46% vs 68%, respectively), and fewer patients discontinued tislelizumab vs chemotherapy due to such an event (7% vs 14%).
“Patients diagnosed with advanced or metastasized ESCC, the most common histologic subtype of esophageal cancer, often progress following initial therapy and are in need of new options,” Syma Iqbal, MD, of the Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, stated in the BeiGene release. “The RATIONALE 302 trial showed that patients with previously treated ESCC who received Tevimbra saw a clinically meaningful survival benefit, highlighting its potential as an important treatment option for these patients.”
The approval, which was deferred in 2022 due to COVID-19-related restrictions, marks the first for the agent in the United States. Tislelizumab should be available in the United States in the second half of 2024, BeiGene noted.
The FDA is also reviewing a Biologics License Application for the agent as a first-line treatment for patients with unresectable, locally advanced, or metastatic ESCC and for those with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma, BeiGene announced in a press release.
A version of this article appeared on Medscape.com.
Inexperience Diagnosing Syphilis Adding to Higher Rates
With rates of syphilis rising quickly in the United States and elsewhere, clinicians are having to up their game when it comes to diagnosing and treating an infection that they may not be paying enough attention to.
More than 200,000 cases of syphilis were reported in the United States in 2022, which is the highest number since 1950 and is a 17.3% increase over 2021, according to the latest figures from the Centers for Disease Control and Prevention (CDC). The rate of infection has increased almost every year since a historic low in 2001.
And the trend is not limited to the United States. Last year, the infection rate in the United Kingdom hit a 50-year high, said David Mabey, BCh, DM, from the London School of Hygiene and Tropical Medicine. Syphilis and other sexually transmitted infections are also a major problem in low- and middle-income countries, he added, although good data are not always available.
Many of today’s healthcare professionals have little experience with the disease, shared Ina Park, MD, a sexually transmitted infections specialist at the University of California at San Francisco. “An entire generation of physicians — including myself — did not see any cases until we were well out of our training,” Dr. Park reported. “We’re really playing catch-up.”
A Centuries-Old Ailment
Dr. Park offered some advice on the challenges of diagnosing what can be an elusive infection at the Conference on Retroviruses and Opportunistic Infections (CROI) 2024 Annual Meeting in Denver. That advice boiled down to one simple rule: “Test, test, test.”
Because syphilis can mimic so many other conditions and can have long periods of latency, it can be easily missed or even misdiagnosed by experienced physicians, said Dr. Park. Clinicians need to keep it front of mind and have a lower threshold for testing, even if there are no obvious symptoms.
Following the CDC’s new recommendations for syphilis screening will help, she noted; every sexually active patient aged between 15 and 44 years who lives in a county with a syphilis infection rate of 4.6 per 100,000 people or higher should get the test. And clinicians should remain vigilant, even in areas with a lower prevalence. “If you can’t account for new symptoms in a sexually active patient, order a test,” said Dr. Park.
Complicated Cases
The lack of experience with syphilis affects not just diagnosis but also treatment, particularly for complex cases, said Khalil Ghanem, MD, PhD, from the Johns Hopkins University School of Medicine in Baltimore. “When you don’t have to deal with something for a while, you forget how to deal with it,” he added.
At CROI, Dr. Ghanem offered suggestions for how to navigate complicated cases of ocular syphilis, otic syphilis, and neurosyphilis, and how to interpret test results when a patient’s antigen titers are being “unruly.”
With potential ocular or otic syphilis, you shouldn’t wait for a specialist like an ophthalmologist to weigh in but instead refer the patient directly to the emergency department because of the risk that the symptoms may become irreversible and result in permanent blindness or deafness. “You don’t want to dilly-dally with those conditions,” Dr. Ghanem said.
Closely monitoring a patient’s rapid plasma regain and venereal disease research laboratory antigen levels is the only way to manage syphilis and to determine whether the infection is responding to treatment, he noted, but sometimes those titers “don’t do what you think they should be doing” and fail to decline or even go up after treatment.
“You don’t know if they went up because the patient was re-infected, or they developed neurosyphilis, or there was a problem at the lab,” he said. “It can be challenging to interpret.”
To decipher confusing test results, Dr. Ghanem recommended getting a detailed history to understand whether a patient is at risk for reinfection, whether there are signs of neurosyphilis or other complications, whether pregnancy is possible, and so on. “Based on the answers, you can determine what the most rational approach to treatment would be,” he shared.
Drug Shortages
Efforts to get the infection under control have become more complicated. Last summer, Pfizer announced that it had run out of penicillin G benzathine (Bicillin), an injectable, long-acting drug that is one of the main treatments for syphilis and the only one that can be given to pregnant people. Supplies for children ran out at the end of June 2023, and supplies for adults were gone by the end of September.
Because Pfizer is the only company that manufactures penicillin G benzathine, there is no one to pick up the slack in the short-term, so the shortage is expected to continue until at least the middle of 2024.
In response, the US Food and Drug Administration has temporarily allowed the use of benzylpenicillin benzathine (Extencilline), a French formulation that has not been approved in the United States, until supplies of penicillin G benzathine are stabilized.
The shortage has shone a spotlight on the important issue of a lack of alternatives for the treatment of syphilis during pregnancy, which increases the risk for congenital syphilis. “Hopefully, this pushes the National Institutes of Health and others to step up their game on studies for alternative drugs for use in pregnancy,” Dr. Ghanem said.
A version of this article appeared on Medscape.com.
With rates of syphilis rising quickly in the United States and elsewhere, clinicians are having to up their game when it comes to diagnosing and treating an infection that they may not be paying enough attention to.
More than 200,000 cases of syphilis were reported in the United States in 2022, which is the highest number since 1950 and is a 17.3% increase over 2021, according to the latest figures from the Centers for Disease Control and Prevention (CDC). The rate of infection has increased almost every year since a historic low in 2001.
And the trend is not limited to the United States. Last year, the infection rate in the United Kingdom hit a 50-year high, said David Mabey, BCh, DM, from the London School of Hygiene and Tropical Medicine. Syphilis and other sexually transmitted infections are also a major problem in low- and middle-income countries, he added, although good data are not always available.
Many of today’s healthcare professionals have little experience with the disease, shared Ina Park, MD, a sexually transmitted infections specialist at the University of California at San Francisco. “An entire generation of physicians — including myself — did not see any cases until we were well out of our training,” Dr. Park reported. “We’re really playing catch-up.”
A Centuries-Old Ailment
Dr. Park offered some advice on the challenges of diagnosing what can be an elusive infection at the Conference on Retroviruses and Opportunistic Infections (CROI) 2024 Annual Meeting in Denver. That advice boiled down to one simple rule: “Test, test, test.”
Because syphilis can mimic so many other conditions and can have long periods of latency, it can be easily missed or even misdiagnosed by experienced physicians, said Dr. Park. Clinicians need to keep it front of mind and have a lower threshold for testing, even if there are no obvious symptoms.
Following the CDC’s new recommendations for syphilis screening will help, she noted; every sexually active patient aged between 15 and 44 years who lives in a county with a syphilis infection rate of 4.6 per 100,000 people or higher should get the test. And clinicians should remain vigilant, even in areas with a lower prevalence. “If you can’t account for new symptoms in a sexually active patient, order a test,” said Dr. Park.
Complicated Cases
The lack of experience with syphilis affects not just diagnosis but also treatment, particularly for complex cases, said Khalil Ghanem, MD, PhD, from the Johns Hopkins University School of Medicine in Baltimore. “When you don’t have to deal with something for a while, you forget how to deal with it,” he added.
At CROI, Dr. Ghanem offered suggestions for how to navigate complicated cases of ocular syphilis, otic syphilis, and neurosyphilis, and how to interpret test results when a patient’s antigen titers are being “unruly.”
With potential ocular or otic syphilis, you shouldn’t wait for a specialist like an ophthalmologist to weigh in but instead refer the patient directly to the emergency department because of the risk that the symptoms may become irreversible and result in permanent blindness or deafness. “You don’t want to dilly-dally with those conditions,” Dr. Ghanem said.
Closely monitoring a patient’s rapid plasma regain and venereal disease research laboratory antigen levels is the only way to manage syphilis and to determine whether the infection is responding to treatment, he noted, but sometimes those titers “don’t do what you think they should be doing” and fail to decline or even go up after treatment.
“You don’t know if they went up because the patient was re-infected, or they developed neurosyphilis, or there was a problem at the lab,” he said. “It can be challenging to interpret.”
To decipher confusing test results, Dr. Ghanem recommended getting a detailed history to understand whether a patient is at risk for reinfection, whether there are signs of neurosyphilis or other complications, whether pregnancy is possible, and so on. “Based on the answers, you can determine what the most rational approach to treatment would be,” he shared.
Drug Shortages
Efforts to get the infection under control have become more complicated. Last summer, Pfizer announced that it had run out of penicillin G benzathine (Bicillin), an injectable, long-acting drug that is one of the main treatments for syphilis and the only one that can be given to pregnant people. Supplies for children ran out at the end of June 2023, and supplies for adults were gone by the end of September.
Because Pfizer is the only company that manufactures penicillin G benzathine, there is no one to pick up the slack in the short-term, so the shortage is expected to continue until at least the middle of 2024.
In response, the US Food and Drug Administration has temporarily allowed the use of benzylpenicillin benzathine (Extencilline), a French formulation that has not been approved in the United States, until supplies of penicillin G benzathine are stabilized.
The shortage has shone a spotlight on the important issue of a lack of alternatives for the treatment of syphilis during pregnancy, which increases the risk for congenital syphilis. “Hopefully, this pushes the National Institutes of Health and others to step up their game on studies for alternative drugs for use in pregnancy,” Dr. Ghanem said.
A version of this article appeared on Medscape.com.
With rates of syphilis rising quickly in the United States and elsewhere, clinicians are having to up their game when it comes to diagnosing and treating an infection that they may not be paying enough attention to.
More than 200,000 cases of syphilis were reported in the United States in 2022, which is the highest number since 1950 and is a 17.3% increase over 2021, according to the latest figures from the Centers for Disease Control and Prevention (CDC). The rate of infection has increased almost every year since a historic low in 2001.
And the trend is not limited to the United States. Last year, the infection rate in the United Kingdom hit a 50-year high, said David Mabey, BCh, DM, from the London School of Hygiene and Tropical Medicine. Syphilis and other sexually transmitted infections are also a major problem in low- and middle-income countries, he added, although good data are not always available.
Many of today’s healthcare professionals have little experience with the disease, shared Ina Park, MD, a sexually transmitted infections specialist at the University of California at San Francisco. “An entire generation of physicians — including myself — did not see any cases until we were well out of our training,” Dr. Park reported. “We’re really playing catch-up.”
A Centuries-Old Ailment
Dr. Park offered some advice on the challenges of diagnosing what can be an elusive infection at the Conference on Retroviruses and Opportunistic Infections (CROI) 2024 Annual Meeting in Denver. That advice boiled down to one simple rule: “Test, test, test.”
Because syphilis can mimic so many other conditions and can have long periods of latency, it can be easily missed or even misdiagnosed by experienced physicians, said Dr. Park. Clinicians need to keep it front of mind and have a lower threshold for testing, even if there are no obvious symptoms.
Following the CDC’s new recommendations for syphilis screening will help, she noted; every sexually active patient aged between 15 and 44 years who lives in a county with a syphilis infection rate of 4.6 per 100,000 people or higher should get the test. And clinicians should remain vigilant, even in areas with a lower prevalence. “If you can’t account for new symptoms in a sexually active patient, order a test,” said Dr. Park.
Complicated Cases
The lack of experience with syphilis affects not just diagnosis but also treatment, particularly for complex cases, said Khalil Ghanem, MD, PhD, from the Johns Hopkins University School of Medicine in Baltimore. “When you don’t have to deal with something for a while, you forget how to deal with it,” he added.
At CROI, Dr. Ghanem offered suggestions for how to navigate complicated cases of ocular syphilis, otic syphilis, and neurosyphilis, and how to interpret test results when a patient’s antigen titers are being “unruly.”
With potential ocular or otic syphilis, you shouldn’t wait for a specialist like an ophthalmologist to weigh in but instead refer the patient directly to the emergency department because of the risk that the symptoms may become irreversible and result in permanent blindness or deafness. “You don’t want to dilly-dally with those conditions,” Dr. Ghanem said.
Closely monitoring a patient’s rapid plasma regain and venereal disease research laboratory antigen levels is the only way to manage syphilis and to determine whether the infection is responding to treatment, he noted, but sometimes those titers “don’t do what you think they should be doing” and fail to decline or even go up after treatment.
“You don’t know if they went up because the patient was re-infected, or they developed neurosyphilis, or there was a problem at the lab,” he said. “It can be challenging to interpret.”
To decipher confusing test results, Dr. Ghanem recommended getting a detailed history to understand whether a patient is at risk for reinfection, whether there are signs of neurosyphilis or other complications, whether pregnancy is possible, and so on. “Based on the answers, you can determine what the most rational approach to treatment would be,” he shared.
Drug Shortages
Efforts to get the infection under control have become more complicated. Last summer, Pfizer announced that it had run out of penicillin G benzathine (Bicillin), an injectable, long-acting drug that is one of the main treatments for syphilis and the only one that can be given to pregnant people. Supplies for children ran out at the end of June 2023, and supplies for adults were gone by the end of September.
Because Pfizer is the only company that manufactures penicillin G benzathine, there is no one to pick up the slack in the short-term, so the shortage is expected to continue until at least the middle of 2024.
In response, the US Food and Drug Administration has temporarily allowed the use of benzylpenicillin benzathine (Extencilline), a French formulation that has not been approved in the United States, until supplies of penicillin G benzathine are stabilized.
The shortage has shone a spotlight on the important issue of a lack of alternatives for the treatment of syphilis during pregnancy, which increases the risk for congenital syphilis. “Hopefully, this pushes the National Institutes of Health and others to step up their game on studies for alternative drugs for use in pregnancy,” Dr. Ghanem said.
A version of this article appeared on Medscape.com.
Neurological Disorders Now Top Global Cause of Illness, Disability
, a new comprehensive analysis showed.
In 2021, neurological conditions were responsible for 443 million years of healthy life lost due to illness, disability, and premature death — a measurement known as disability-adjusted life years (DALY) — making them the top contributor to the global disease burden, ahead of cardiovascular diseases.
Some 3.4 billion people — 43% of the entire global population — had a neurological illness in 2021, the report noted.
“As the world’s leading cause of overall disease burden, and with case numbers rising 59% globally since 1990, nervous system conditions must be addressed through effective, culturally acceptable, and affordable prevention, treatment, rehabilitation, and long-term care strategies,” lead author Jaimie Steinmetz, PhD, from the Institute of Health Metrics and Evaluation (IHME), University of Washington, Seattle, said in a news release.
The findings, from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2021, “have important health service and policy implications and serve as evidence that global neurological heath loss has been under-recognized and is increasing and unevenly distributed geographically and socioeconomically,” the authors noted.
The study was published online in The Lancet: Neurology.
The Top 10
The top 10 contributors to neurological health loss in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer’s disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications from preterm birth, autistic spectrum disorders, and nervous system cancers.
Neurological consequences of COVID-19 ranked 20th out of 37 unique conditions assessed.
In 2021, there were more than 23 million global cases of COVID-19 with long-term cognitive symptoms or Guillain-Barré syndrome, accounting for 57% of all infectious neurological disease cases and contributing to 2.48 million years of healthy life lost, the study found.
The most prevalent neurological disorders were tension-type headache (about 2 billion cases) and migraine (about 1.1 billion cases), while diabetic neuropathy is the fastest-growing of all neurological conditions.
“The number of people with diabetic neuropathy has more than tripled globally since 1990, rising to 206 million in 2021. This is in line with the increase in the global prevalence of diabetes,” co-senior author Liane Ong, PhD, from IHME, said in the release.
The data showed striking differences in the burden of neurological conditions between world regions and national income levels, with over 80% of neurological deaths and health loss occurring in low- and middle-income countries.
Regions with the highest burden of neurological conditions were central and western sub-Saharan Africa, while high-income Asia Pacific and Australasia had the lowest burden.
“Nervous system health loss disproportionately impacts many of the poorest countries partly due to the higher prevalence of conditions affecting neonates and children under 5, especially birth-related complications and infections,” co-senior author Tarun Dua, MD, with the World Health Organization (WHO) brain health unit, noted in the news release.
“Improved infant survival has led to an increase in long-term disability, while limited access to treatment and rehabilitation services is contributing to the much higher proportion of deaths in these countries,” Dr. Dua said.
Prioritize Prevention
The analysis also provides estimates of the proportion of neurological conditions that are potentially preventable by eliminating known risk factors for stroke, dementia, multiple sclerosis, Parkinson’s disease, encephalitis, meningitis, and intellectual disability.
It shows that modifying 18 risk factors over a person’s lifetime — most importantly high systolic blood pressure — could prevent 84% of global DALYs from stroke. Controlling lead exposure could lower intellectual disability cases by 63% and reducing high fasting plasma glucose to normal levels could cut dementia by roughly 15%.
“Because many neurological conditions lack cures, and access to medical care is often limited, understanding modifiable risk factors and the potentially avoidable neurological condition burden is essential to help curb this global health crisis,” co-lead author Katrin Seeher, PhD, mental health specialist with WHO’s brain health unit, said in the release.
It’s important to note that nervous system conditions include infectious and vector-borne diseases and injuries as well as noncommunicable diseases and injuries, Dr. Steinmetz said, “demanding different strategies for prevention and treatment throughout life.”
“We hope that our findings can help policymakers more comprehensively understand the impact of neurological conditions on both adults and children to inform more targeted interventions in individual countries, as well as guide ongoing awareness and advocacy efforts around the world,” Dr. Steinmetz added.
In an accompanying editorial, Wolfgang Grisold, MD, president of the World Federation of Neurology, London, noted that the study builds on previous findings and expands the number of neurological conditions studied from 15 to 37.
“This important new GBD report highlights that the burden of neurological conditions is greater than previously thought,” wrote Dr. Grisold, who was not a part of the study. “In the next iteration, more attention should be given to neuromuscular diseases, the effects of cancer in the nervous system, and neuropathic pain. Comparing the disability caused by conditions with episodic occurrence versus those that cause permanent and progressive disease will remain challenging because the effects on the individuals vary substantially.”
The study was funded by the Bill and Melinda Gates Foundation. Full disclosures are included in the original article.
A version of this article appeared on Medscape.com.
, a new comprehensive analysis showed.
In 2021, neurological conditions were responsible for 443 million years of healthy life lost due to illness, disability, and premature death — a measurement known as disability-adjusted life years (DALY) — making them the top contributor to the global disease burden, ahead of cardiovascular diseases.
Some 3.4 billion people — 43% of the entire global population — had a neurological illness in 2021, the report noted.
“As the world’s leading cause of overall disease burden, and with case numbers rising 59% globally since 1990, nervous system conditions must be addressed through effective, culturally acceptable, and affordable prevention, treatment, rehabilitation, and long-term care strategies,” lead author Jaimie Steinmetz, PhD, from the Institute of Health Metrics and Evaluation (IHME), University of Washington, Seattle, said in a news release.
The findings, from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2021, “have important health service and policy implications and serve as evidence that global neurological heath loss has been under-recognized and is increasing and unevenly distributed geographically and socioeconomically,” the authors noted.
The study was published online in The Lancet: Neurology.
The Top 10
The top 10 contributors to neurological health loss in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer’s disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications from preterm birth, autistic spectrum disorders, and nervous system cancers.
Neurological consequences of COVID-19 ranked 20th out of 37 unique conditions assessed.
In 2021, there were more than 23 million global cases of COVID-19 with long-term cognitive symptoms or Guillain-Barré syndrome, accounting for 57% of all infectious neurological disease cases and contributing to 2.48 million years of healthy life lost, the study found.
The most prevalent neurological disorders were tension-type headache (about 2 billion cases) and migraine (about 1.1 billion cases), while diabetic neuropathy is the fastest-growing of all neurological conditions.
“The number of people with diabetic neuropathy has more than tripled globally since 1990, rising to 206 million in 2021. This is in line with the increase in the global prevalence of diabetes,” co-senior author Liane Ong, PhD, from IHME, said in the release.
The data showed striking differences in the burden of neurological conditions between world regions and national income levels, with over 80% of neurological deaths and health loss occurring in low- and middle-income countries.
Regions with the highest burden of neurological conditions were central and western sub-Saharan Africa, while high-income Asia Pacific and Australasia had the lowest burden.
“Nervous system health loss disproportionately impacts many of the poorest countries partly due to the higher prevalence of conditions affecting neonates and children under 5, especially birth-related complications and infections,” co-senior author Tarun Dua, MD, with the World Health Organization (WHO) brain health unit, noted in the news release.
“Improved infant survival has led to an increase in long-term disability, while limited access to treatment and rehabilitation services is contributing to the much higher proportion of deaths in these countries,” Dr. Dua said.
Prioritize Prevention
The analysis also provides estimates of the proportion of neurological conditions that are potentially preventable by eliminating known risk factors for stroke, dementia, multiple sclerosis, Parkinson’s disease, encephalitis, meningitis, and intellectual disability.
It shows that modifying 18 risk factors over a person’s lifetime — most importantly high systolic blood pressure — could prevent 84% of global DALYs from stroke. Controlling lead exposure could lower intellectual disability cases by 63% and reducing high fasting plasma glucose to normal levels could cut dementia by roughly 15%.
“Because many neurological conditions lack cures, and access to medical care is often limited, understanding modifiable risk factors and the potentially avoidable neurological condition burden is essential to help curb this global health crisis,” co-lead author Katrin Seeher, PhD, mental health specialist with WHO’s brain health unit, said in the release.
It’s important to note that nervous system conditions include infectious and vector-borne diseases and injuries as well as noncommunicable diseases and injuries, Dr. Steinmetz said, “demanding different strategies for prevention and treatment throughout life.”
“We hope that our findings can help policymakers more comprehensively understand the impact of neurological conditions on both adults and children to inform more targeted interventions in individual countries, as well as guide ongoing awareness and advocacy efforts around the world,” Dr. Steinmetz added.
In an accompanying editorial, Wolfgang Grisold, MD, president of the World Federation of Neurology, London, noted that the study builds on previous findings and expands the number of neurological conditions studied from 15 to 37.
“This important new GBD report highlights that the burden of neurological conditions is greater than previously thought,” wrote Dr. Grisold, who was not a part of the study. “In the next iteration, more attention should be given to neuromuscular diseases, the effects of cancer in the nervous system, and neuropathic pain. Comparing the disability caused by conditions with episodic occurrence versus those that cause permanent and progressive disease will remain challenging because the effects on the individuals vary substantially.”
The study was funded by the Bill and Melinda Gates Foundation. Full disclosures are included in the original article.
A version of this article appeared on Medscape.com.
, a new comprehensive analysis showed.
In 2021, neurological conditions were responsible for 443 million years of healthy life lost due to illness, disability, and premature death — a measurement known as disability-adjusted life years (DALY) — making them the top contributor to the global disease burden, ahead of cardiovascular diseases.
Some 3.4 billion people — 43% of the entire global population — had a neurological illness in 2021, the report noted.
“As the world’s leading cause of overall disease burden, and with case numbers rising 59% globally since 1990, nervous system conditions must be addressed through effective, culturally acceptable, and affordable prevention, treatment, rehabilitation, and long-term care strategies,” lead author Jaimie Steinmetz, PhD, from the Institute of Health Metrics and Evaluation (IHME), University of Washington, Seattle, said in a news release.
The findings, from the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) 2021, “have important health service and policy implications and serve as evidence that global neurological heath loss has been under-recognized and is increasing and unevenly distributed geographically and socioeconomically,” the authors noted.
The study was published online in The Lancet: Neurology.
The Top 10
The top 10 contributors to neurological health loss in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer’s disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications from preterm birth, autistic spectrum disorders, and nervous system cancers.
Neurological consequences of COVID-19 ranked 20th out of 37 unique conditions assessed.
In 2021, there were more than 23 million global cases of COVID-19 with long-term cognitive symptoms or Guillain-Barré syndrome, accounting for 57% of all infectious neurological disease cases and contributing to 2.48 million years of healthy life lost, the study found.
The most prevalent neurological disorders were tension-type headache (about 2 billion cases) and migraine (about 1.1 billion cases), while diabetic neuropathy is the fastest-growing of all neurological conditions.
“The number of people with diabetic neuropathy has more than tripled globally since 1990, rising to 206 million in 2021. This is in line with the increase in the global prevalence of diabetes,” co-senior author Liane Ong, PhD, from IHME, said in the release.
The data showed striking differences in the burden of neurological conditions between world regions and national income levels, with over 80% of neurological deaths and health loss occurring in low- and middle-income countries.
Regions with the highest burden of neurological conditions were central and western sub-Saharan Africa, while high-income Asia Pacific and Australasia had the lowest burden.
“Nervous system health loss disproportionately impacts many of the poorest countries partly due to the higher prevalence of conditions affecting neonates and children under 5, especially birth-related complications and infections,” co-senior author Tarun Dua, MD, with the World Health Organization (WHO) brain health unit, noted in the news release.
“Improved infant survival has led to an increase in long-term disability, while limited access to treatment and rehabilitation services is contributing to the much higher proportion of deaths in these countries,” Dr. Dua said.
Prioritize Prevention
The analysis also provides estimates of the proportion of neurological conditions that are potentially preventable by eliminating known risk factors for stroke, dementia, multiple sclerosis, Parkinson’s disease, encephalitis, meningitis, and intellectual disability.
It shows that modifying 18 risk factors over a person’s lifetime — most importantly high systolic blood pressure — could prevent 84% of global DALYs from stroke. Controlling lead exposure could lower intellectual disability cases by 63% and reducing high fasting plasma glucose to normal levels could cut dementia by roughly 15%.
“Because many neurological conditions lack cures, and access to medical care is often limited, understanding modifiable risk factors and the potentially avoidable neurological condition burden is essential to help curb this global health crisis,” co-lead author Katrin Seeher, PhD, mental health specialist with WHO’s brain health unit, said in the release.
It’s important to note that nervous system conditions include infectious and vector-borne diseases and injuries as well as noncommunicable diseases and injuries, Dr. Steinmetz said, “demanding different strategies for prevention and treatment throughout life.”
“We hope that our findings can help policymakers more comprehensively understand the impact of neurological conditions on both adults and children to inform more targeted interventions in individual countries, as well as guide ongoing awareness and advocacy efforts around the world,” Dr. Steinmetz added.
In an accompanying editorial, Wolfgang Grisold, MD, president of the World Federation of Neurology, London, noted that the study builds on previous findings and expands the number of neurological conditions studied from 15 to 37.
“This important new GBD report highlights that the burden of neurological conditions is greater than previously thought,” wrote Dr. Grisold, who was not a part of the study. “In the next iteration, more attention should be given to neuromuscular diseases, the effects of cancer in the nervous system, and neuropathic pain. Comparing the disability caused by conditions with episodic occurrence versus those that cause permanent and progressive disease will remain challenging because the effects on the individuals vary substantially.”
The study was funded by the Bill and Melinda Gates Foundation. Full disclosures are included in the original article.
A version of this article appeared on Medscape.com.
FROM THE LANCET NEUROLOGY
Medtronic’s Duet EDMS Catheter Tubing Under Class I Recall
If this happens, potential harm to patients may include infections, cerebrospinal fluid (CSF) leakage, overdrainage of CSF, and abnormality of the ventricles. Uncontrolled overdrainage of CSF could lead to neurological injury or death if the disconnection is undetected.
The Food and Drug Administration has identified this as a Class I recall — the most serious type — due to the risk for serious injury or death. To date, there have been 26 reported injuries and no deaths related to this issue.
The recall includes 45,176 devices distributed in the United States between May 3, 2021, and January 9, 2024, with model numbers 46913, 46914, 46915, 46916, and 46917.
The Duet EDMS is used for temporary CSF drainage or sampling in patients who have surgery for open descending thoracic aortic aneurysm (TAA) or descending thoraco-abdominal aortic aneurysm (TAAA) or patients who have TAA/TAAA repair surgery and develop symptoms such as paraplegia.
Medtronic has sent an urgent medical device recall letter to all affected customers asking them to identify, quarantine, and return any unused recalled products.
Customers are also advised to check all Duet EDMS components for damage and ensure that all connections are secure and leak-free.
If a patient is currently connected to an impacted Duet EDMS and a leak or disconnection is detected, the device should be changed to a new alternative device utilizing a sterile technique.
It is not recommended that a Duet system device that is connected to a patient and working as intended be removed or replaced.
Customers in the United States with questions about this recall should contact Medtronic at 1-800-874-5797.
A version of this article appeared on Medscape.com.
If this happens, potential harm to patients may include infections, cerebrospinal fluid (CSF) leakage, overdrainage of CSF, and abnormality of the ventricles. Uncontrolled overdrainage of CSF could lead to neurological injury or death if the disconnection is undetected.
The Food and Drug Administration has identified this as a Class I recall — the most serious type — due to the risk for serious injury or death. To date, there have been 26 reported injuries and no deaths related to this issue.
The recall includes 45,176 devices distributed in the United States between May 3, 2021, and January 9, 2024, with model numbers 46913, 46914, 46915, 46916, and 46917.
The Duet EDMS is used for temporary CSF drainage or sampling in patients who have surgery for open descending thoracic aortic aneurysm (TAA) or descending thoraco-abdominal aortic aneurysm (TAAA) or patients who have TAA/TAAA repair surgery and develop symptoms such as paraplegia.
Medtronic has sent an urgent medical device recall letter to all affected customers asking them to identify, quarantine, and return any unused recalled products.
Customers are also advised to check all Duet EDMS components for damage and ensure that all connections are secure and leak-free.
If a patient is currently connected to an impacted Duet EDMS and a leak or disconnection is detected, the device should be changed to a new alternative device utilizing a sterile technique.
It is not recommended that a Duet system device that is connected to a patient and working as intended be removed or replaced.
Customers in the United States with questions about this recall should contact Medtronic at 1-800-874-5797.
A version of this article appeared on Medscape.com.
If this happens, potential harm to patients may include infections, cerebrospinal fluid (CSF) leakage, overdrainage of CSF, and abnormality of the ventricles. Uncontrolled overdrainage of CSF could lead to neurological injury or death if the disconnection is undetected.
The Food and Drug Administration has identified this as a Class I recall — the most serious type — due to the risk for serious injury or death. To date, there have been 26 reported injuries and no deaths related to this issue.
The recall includes 45,176 devices distributed in the United States between May 3, 2021, and January 9, 2024, with model numbers 46913, 46914, 46915, 46916, and 46917.
The Duet EDMS is used for temporary CSF drainage or sampling in patients who have surgery for open descending thoracic aortic aneurysm (TAA) or descending thoraco-abdominal aortic aneurysm (TAAA) or patients who have TAA/TAAA repair surgery and develop symptoms such as paraplegia.
Medtronic has sent an urgent medical device recall letter to all affected customers asking them to identify, quarantine, and return any unused recalled products.
Customers are also advised to check all Duet EDMS components for damage and ensure that all connections are secure and leak-free.
If a patient is currently connected to an impacted Duet EDMS and a leak or disconnection is detected, the device should be changed to a new alternative device utilizing a sterile technique.
It is not recommended that a Duet system device that is connected to a patient and working as intended be removed or replaced.
Customers in the United States with questions about this recall should contact Medtronic at 1-800-874-5797.
A version of this article appeared on Medscape.com.
After SABR, 100% Local Control at 1 Year in Kidney Cancer
TOPLINE:
METHODOLOGY:
- SABR is a promising treatment strategy for patients with inoperable kidney cancer because it is a noninvasive procedure that does not require general anesthesia and can be used to treat stages TIa and TIb, as well as larger tumors.
- The nonrandomized, phase 2, FASTRACK II trial, conducted in Australia and the Netherlands, investigated the efficacy of SABR in 70 patients with primary RCC who had a single lesion and were considered medically inoperable, were at a high risk for surgical complications, or had declined surgery. Patients also had an Eastern Cooperative Oncology Group performance status of ≤ 2 and an estimated glomerular filtration rate above 30 mL/min.
- The median age of participants was 77 years, median body mass index was 32, and the median Charlson comorbidity index was 7; 30% of the patients were women.
- Patients with tumors ≤ 4 cm (n = 23) received a single fraction of 26 Gy SABR, while those with tumors of 4-10 cm in maximum diameter (n = 47) received 42 Gy SABR in three fractions. The median tumor size was 4.6 cm.
- The primary endpoint was local control, defined as no progression of the primary RCC.
TAKEAWAY:
- At 1 year, no patients experienced local progression of their cancer, for a 100% local control rate.
- Cancer-specific survival was also 100% at 12 months from the start of SABR treatment, while the overall survival rate was 99% at 1 year and 82% at 3 years.
- Treatment-related grade 3 adverse events, such as nausea and vomiting, colonic obstruction, and diarrhea were reported by 10% of patients, with no incidences of grade 4 treatment-related adverse events or treatment-related or cancer-related deaths.
IN PRACTICE:
“Despite a larger average tumor size (4.6 cm) than in many preexisting prospective trials of surgery or SABR in primary renal cell cancer, there were no local treatment failures observed and no patients died from cancer during the study period,” the authors noted. This trial and others “support SABR as a therapeutic option for patients with inoperable or high-risk primary renal cell cancer.”
SOURCE:
This study was led by Shankar Siva, PhD, Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia, and published online in The Lancet Oncology.
LIMITATIONS:
The study was limited by a small sample size and less mature data at follow-up. The absence of a control group made it impossible to assess if SABR had superior, inferior, or similar efficacy to other treatment options. The definitions of operability or technically high risk might vary between different multidisciplinary teams.
DISCLOSURES:
This study was funded by a grant from the Cancer Australia Priority-driven Collaborative Cancer Research Scheme. The study authors declared receiving grants, contracts, payments, honoraria, and research funding and having other ties with several sources.
A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- SABR is a promising treatment strategy for patients with inoperable kidney cancer because it is a noninvasive procedure that does not require general anesthesia and can be used to treat stages TIa and TIb, as well as larger tumors.
- The nonrandomized, phase 2, FASTRACK II trial, conducted in Australia and the Netherlands, investigated the efficacy of SABR in 70 patients with primary RCC who had a single lesion and were considered medically inoperable, were at a high risk for surgical complications, or had declined surgery. Patients also had an Eastern Cooperative Oncology Group performance status of ≤ 2 and an estimated glomerular filtration rate above 30 mL/min.
- The median age of participants was 77 years, median body mass index was 32, and the median Charlson comorbidity index was 7; 30% of the patients were women.
- Patients with tumors ≤ 4 cm (n = 23) received a single fraction of 26 Gy SABR, while those with tumors of 4-10 cm in maximum diameter (n = 47) received 42 Gy SABR in three fractions. The median tumor size was 4.6 cm.
- The primary endpoint was local control, defined as no progression of the primary RCC.
TAKEAWAY:
- At 1 year, no patients experienced local progression of their cancer, for a 100% local control rate.
- Cancer-specific survival was also 100% at 12 months from the start of SABR treatment, while the overall survival rate was 99% at 1 year and 82% at 3 years.
- Treatment-related grade 3 adverse events, such as nausea and vomiting, colonic obstruction, and diarrhea were reported by 10% of patients, with no incidences of grade 4 treatment-related adverse events or treatment-related or cancer-related deaths.
IN PRACTICE:
“Despite a larger average tumor size (4.6 cm) than in many preexisting prospective trials of surgery or SABR in primary renal cell cancer, there were no local treatment failures observed and no patients died from cancer during the study period,” the authors noted. This trial and others “support SABR as a therapeutic option for patients with inoperable or high-risk primary renal cell cancer.”
SOURCE:
This study was led by Shankar Siva, PhD, Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia, and published online in The Lancet Oncology.
LIMITATIONS:
The study was limited by a small sample size and less mature data at follow-up. The absence of a control group made it impossible to assess if SABR had superior, inferior, or similar efficacy to other treatment options. The definitions of operability or technically high risk might vary between different multidisciplinary teams.
DISCLOSURES:
This study was funded by a grant from the Cancer Australia Priority-driven Collaborative Cancer Research Scheme. The study authors declared receiving grants, contracts, payments, honoraria, and research funding and having other ties with several sources.
A version of this article first appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- SABR is a promising treatment strategy for patients with inoperable kidney cancer because it is a noninvasive procedure that does not require general anesthesia and can be used to treat stages TIa and TIb, as well as larger tumors.
- The nonrandomized, phase 2, FASTRACK II trial, conducted in Australia and the Netherlands, investigated the efficacy of SABR in 70 patients with primary RCC who had a single lesion and were considered medically inoperable, were at a high risk for surgical complications, or had declined surgery. Patients also had an Eastern Cooperative Oncology Group performance status of ≤ 2 and an estimated glomerular filtration rate above 30 mL/min.
- The median age of participants was 77 years, median body mass index was 32, and the median Charlson comorbidity index was 7; 30% of the patients were women.
- Patients with tumors ≤ 4 cm (n = 23) received a single fraction of 26 Gy SABR, while those with tumors of 4-10 cm in maximum diameter (n = 47) received 42 Gy SABR in three fractions. The median tumor size was 4.6 cm.
- The primary endpoint was local control, defined as no progression of the primary RCC.
TAKEAWAY:
- At 1 year, no patients experienced local progression of their cancer, for a 100% local control rate.
- Cancer-specific survival was also 100% at 12 months from the start of SABR treatment, while the overall survival rate was 99% at 1 year and 82% at 3 years.
- Treatment-related grade 3 adverse events, such as nausea and vomiting, colonic obstruction, and diarrhea were reported by 10% of patients, with no incidences of grade 4 treatment-related adverse events or treatment-related or cancer-related deaths.
IN PRACTICE:
“Despite a larger average tumor size (4.6 cm) than in many preexisting prospective trials of surgery or SABR in primary renal cell cancer, there were no local treatment failures observed and no patients died from cancer during the study period,” the authors noted. This trial and others “support SABR as a therapeutic option for patients with inoperable or high-risk primary renal cell cancer.”
SOURCE:
This study was led by Shankar Siva, PhD, Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia, and published online in The Lancet Oncology.
LIMITATIONS:
The study was limited by a small sample size and less mature data at follow-up. The absence of a control group made it impossible to assess if SABR had superior, inferior, or similar efficacy to other treatment options. The definitions of operability or technically high risk might vary between different multidisciplinary teams.
DISCLOSURES:
This study was funded by a grant from the Cancer Australia Priority-driven Collaborative Cancer Research Scheme. The study authors declared receiving grants, contracts, payments, honoraria, and research funding and having other ties with several sources.
A version of this article first appeared on Medscape.com.
High Marks for New CAR T Toxicity Grading Tool
“Hematotoxicity after CAR T is common and clinically relevant, but it also remains poorly understood [with] a high degree of heterogeneity in terms of grading its clinical management,” said first author Kai Rejeski, MD, in presenting on the findings at the 6th European CAR T-cell Meeting, held in Spain and jointly sponsored by the European Society for Blood and Marrow Transplantation (EBMT) and the European Hematology Association (EHA).
“We hope that this novel grading system helps with this by enabling harmonized reporting using the same nomenclature and allowing the comparison of the expected incidence rates of grade 3 or higher [hematological toxicities] across several disease entities and CAR T products,” said Dr. Rejeski, of the Adult BMT (Blood Marrow Transplant) and Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York City.
ICAHT Grading System
In a recent meta-analysis, Dr. Rejeski and his team found that infections are the cause of as many as 49% of non–relapse related deaths after CAR T-cell therapy, representing the most common cause of death and numbering significantly more than the more prominent causes of cytokine release syndrome (CRS) or immune effector cell–associated neurotoxicity (ICANS), which paradoxically have been the focus of significantly more research. In addition, the authors have reported substantial inconsistency among CAR T centers in the grading and management of the post–CAR T cytopenias that can cause those infections, underscoring the need for better guidelines.
“The narrative around CAR T toxicity has long centered on CRS and ICANS as novel and prototypical side effects with distinct management protocols,” Dr. Rejeski said in an interview. “However, it is cytopenias and the associated infections that drive nonrelapse mortality after CAR T.”
To address the need, the EHA and EBMT established the grading system for Immune Effector Cell–Associated HematoToxicity (ICAHT) that is applicable across disease types, indications, and treatment settings.
The details of the grading system were published in September 2023 in the journal Blood. The new system, which specifically focuses on neutrophil count and timing, importantly addresses the biphasic nature of ICAHT by distinguishing “early” ICAHT, occurring within 30 days of the CAR T administration, and “late” ICAHT, occurring more that 30 days following the treatment.
By contrast, conventional grading scales for CAR T–related cytopenias, such as the Common Terminology Criteria for Adverse Events (CTCAE) scale, “neither reflect the unique quality of post–CAR T neutrophil recovery, nor do they reflect the inherent risk of infections due to protracted neutropenia,” the authors report in the study.
Real-World Evaluation
To assess the ICAHT grading system’s relevance in a real-world clinical setting of CAR T-cell therapy recipients, Dr. Rejeski and colleagues conducted a multicenter observational study, published in January 2024 in Blood Advances.
The study involved 549 patients at 12 international CAR T centers treated with BCMA- or CD19- directed CAR T therapy for relapsed/refractory B-cell malignancies.
Of the patients, 112 were treated for multiple myeloma (MM), 334 for large B cell lymphoma (LBCL), and 103 for mantle cell lymphoma (MCL).
Using the grading system, grade 3 (severe) or 4 (life-threatening) ICAHT (n = 125), was found to be strongly associated with key factors including a cumulative duration of severe neutropenia (P < .0001), the presence of multilineage cytopenias, such as severe thrombocytopenia (90%, compared with 46% in nonsevere ICAHT) and severe anemia (92% vs 49%; both P < .001), as well as the use of platelet and red blood cell transfusions.
Grade 3 or higher ICAHT was more common in patients with MCL (28%), compared with LBCL (23%) and MM (15%).
Key factors at baseline that were independently associated with severe ICAHT after multivariate adjustment included the presence of bone marrow infiltration, increased serum LDH levels, elevated CAR-HEMATOTOX scores (all P < .001), and receipt of CD28z costimulatory domain products, including axi-cel or brexu-cel (P = .01).
Those with grade 3 or higher ICAHT scores had a significantly higher rate of severe infections, compared with lower ICAHT scores (49% vs 13%; P < .0001), as well as increased nonrelapse mortality (14% vs 4.5%; P < .0001), primarily attributable to fatal infections.
Survival outcomes were also worse with grade 3 or higher ICAHT, including significantly lower rates of 1-year progression-free survival (35% vs 51%) and 1-year overall survival (52% vs 73%; both P < .0001).
Grade 3 or higher ICAHT was also significantly associated with prolonged hospital stays (median 21 vs 16 days; P < .0001).
However, contrary to findings from some previous studies, the current study showed no association between ICAHT severity and the prior administration of autologous stem cell transplant.
The number of prior treatment lines was not associated with grade 3 or higher ICAHT. However, grade 3 or higher CRS was more common as a cotoxicity (15% vs 5% without severe ICAHT), as was severe ICANS (26% vs 13%; both P < .001).
Notably, ICAHT grading showed superiority in the prediction of severe infections, compared with CTCAE grading (c-index 0.73 vs 0.55, P < .0001 vs nonsignificant).
While mild to moderate toxicity after CAR T-cell therapy has been associated with more favorable outcomes, the poor survival rates associated with severe ICAHT “underscore that high-grade toxicity and inferior treatment outcomes often go hand-in-hand,” the authors write.
Conversely, “the patients with grade 1 or 2 ICAHT exhibited excellent treatment outcomes in our study,” they point out.
Recommendations in Clinical Practice
For clinical guidance, the ICAHT grading system provides best practice recommendations based on severity for diagnostic work-up and management, such as measures including use of granulocyte-colony stimulating factor (G-CSF), anti-infective prophylaxis and stem cell boosts.
The authors add that preinfusion scoring systems, including the CAR-HEMATOTOX prognostic score, may be optimized by ICAHT grading in terms of modeling for severe or life-threatening ICAHT as an important endpoint.
“We have had an absence of the standardized severity-based guidelines that we know very well for CRS and ICANS, both in terms of the diagnostic work-up and the grading but also the management,” Dr. Rejeski said at the meeting.
“We hope that the new ICAHT grading focuses future research efforts to not only understand this important side effect better, but also develop specific management strategies that mitigate the risk of infections in high-risk patients,” Dr. Rejeski added.
“The multiply validated CAR-HEMATOTOX score, assessed at time of lymphodepletion, may be helpful in this regard,” he added.
An accompanying editorial published with the guidelines underscored that “this is the first such guideline by a major organization and is a much-needed development for the management of this important CAR T-cell–associated toxicity.”
The improved standardized reporting of ICAHT “could also inform hematotoxicity management protocols,” said the editorial authors, David Qualls, MD, of the Memorial Sloan Kettering Cancer Center in New York City and Caron Jacobson, MD, of the Dana-Farber Cancer Institute, in Boston, Massachusetts.
“While providing comprehensive recommendations for ICAHT, the EHA/EBMT guidelines also highlight important gaps in our current knowledge of ICAHT, which are significant,” the editorial authors add.
Further commenting, Ulrich Jaeger, MD, a professor of hematology at the Medical University of Vienna, Vienna, Austria, agreed that the research fills an important need in post–CAR T-cell therapy management.
“Dr. Rejeski´s work is really seminal in the field and confirmed by validation cohorts in other centers,” he said in an interview. “I think the story is absolutely clear. It will be of increasing importance, with more patients surviving. [The system] will have to be adapted to novel indications as well.”
Dr. Rejeski disclosed ties with Kite/Gilead, Novartis, GMS/Celgene, and Pierre-Fabre. Jaeger reports relationships with Novartis, Gilead Sciences, Celgene/BMS, Janssen, Roche, Miltenyi Biotec, and Innovative Medicines Initiative.
“Hematotoxicity after CAR T is common and clinically relevant, but it also remains poorly understood [with] a high degree of heterogeneity in terms of grading its clinical management,” said first author Kai Rejeski, MD, in presenting on the findings at the 6th European CAR T-cell Meeting, held in Spain and jointly sponsored by the European Society for Blood and Marrow Transplantation (EBMT) and the European Hematology Association (EHA).
“We hope that this novel grading system helps with this by enabling harmonized reporting using the same nomenclature and allowing the comparison of the expected incidence rates of grade 3 or higher [hematological toxicities] across several disease entities and CAR T products,” said Dr. Rejeski, of the Adult BMT (Blood Marrow Transplant) and Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York City.
ICAHT Grading System
In a recent meta-analysis, Dr. Rejeski and his team found that infections are the cause of as many as 49% of non–relapse related deaths after CAR T-cell therapy, representing the most common cause of death and numbering significantly more than the more prominent causes of cytokine release syndrome (CRS) or immune effector cell–associated neurotoxicity (ICANS), which paradoxically have been the focus of significantly more research. In addition, the authors have reported substantial inconsistency among CAR T centers in the grading and management of the post–CAR T cytopenias that can cause those infections, underscoring the need for better guidelines.
“The narrative around CAR T toxicity has long centered on CRS and ICANS as novel and prototypical side effects with distinct management protocols,” Dr. Rejeski said in an interview. “However, it is cytopenias and the associated infections that drive nonrelapse mortality after CAR T.”
To address the need, the EHA and EBMT established the grading system for Immune Effector Cell–Associated HematoToxicity (ICAHT) that is applicable across disease types, indications, and treatment settings.
The details of the grading system were published in September 2023 in the journal Blood. The new system, which specifically focuses on neutrophil count and timing, importantly addresses the biphasic nature of ICAHT by distinguishing “early” ICAHT, occurring within 30 days of the CAR T administration, and “late” ICAHT, occurring more that 30 days following the treatment.
By contrast, conventional grading scales for CAR T–related cytopenias, such as the Common Terminology Criteria for Adverse Events (CTCAE) scale, “neither reflect the unique quality of post–CAR T neutrophil recovery, nor do they reflect the inherent risk of infections due to protracted neutropenia,” the authors report in the study.
Real-World Evaluation
To assess the ICAHT grading system’s relevance in a real-world clinical setting of CAR T-cell therapy recipients, Dr. Rejeski and colleagues conducted a multicenter observational study, published in January 2024 in Blood Advances.
The study involved 549 patients at 12 international CAR T centers treated with BCMA- or CD19- directed CAR T therapy for relapsed/refractory B-cell malignancies.
Of the patients, 112 were treated for multiple myeloma (MM), 334 for large B cell lymphoma (LBCL), and 103 for mantle cell lymphoma (MCL).
Using the grading system, grade 3 (severe) or 4 (life-threatening) ICAHT (n = 125), was found to be strongly associated with key factors including a cumulative duration of severe neutropenia (P < .0001), the presence of multilineage cytopenias, such as severe thrombocytopenia (90%, compared with 46% in nonsevere ICAHT) and severe anemia (92% vs 49%; both P < .001), as well as the use of platelet and red blood cell transfusions.
Grade 3 or higher ICAHT was more common in patients with MCL (28%), compared with LBCL (23%) and MM (15%).
Key factors at baseline that were independently associated with severe ICAHT after multivariate adjustment included the presence of bone marrow infiltration, increased serum LDH levels, elevated CAR-HEMATOTOX scores (all P < .001), and receipt of CD28z costimulatory domain products, including axi-cel or brexu-cel (P = .01).
Those with grade 3 or higher ICAHT scores had a significantly higher rate of severe infections, compared with lower ICAHT scores (49% vs 13%; P < .0001), as well as increased nonrelapse mortality (14% vs 4.5%; P < .0001), primarily attributable to fatal infections.
Survival outcomes were also worse with grade 3 or higher ICAHT, including significantly lower rates of 1-year progression-free survival (35% vs 51%) and 1-year overall survival (52% vs 73%; both P < .0001).
Grade 3 or higher ICAHT was also significantly associated with prolonged hospital stays (median 21 vs 16 days; P < .0001).
However, contrary to findings from some previous studies, the current study showed no association between ICAHT severity and the prior administration of autologous stem cell transplant.
The number of prior treatment lines was not associated with grade 3 or higher ICAHT. However, grade 3 or higher CRS was more common as a cotoxicity (15% vs 5% without severe ICAHT), as was severe ICANS (26% vs 13%; both P < .001).
Notably, ICAHT grading showed superiority in the prediction of severe infections, compared with CTCAE grading (c-index 0.73 vs 0.55, P < .0001 vs nonsignificant).
While mild to moderate toxicity after CAR T-cell therapy has been associated with more favorable outcomes, the poor survival rates associated with severe ICAHT “underscore that high-grade toxicity and inferior treatment outcomes often go hand-in-hand,” the authors write.
Conversely, “the patients with grade 1 or 2 ICAHT exhibited excellent treatment outcomes in our study,” they point out.
Recommendations in Clinical Practice
For clinical guidance, the ICAHT grading system provides best practice recommendations based on severity for diagnostic work-up and management, such as measures including use of granulocyte-colony stimulating factor (G-CSF), anti-infective prophylaxis and stem cell boosts.
The authors add that preinfusion scoring systems, including the CAR-HEMATOTOX prognostic score, may be optimized by ICAHT grading in terms of modeling for severe or life-threatening ICAHT as an important endpoint.
“We have had an absence of the standardized severity-based guidelines that we know very well for CRS and ICANS, both in terms of the diagnostic work-up and the grading but also the management,” Dr. Rejeski said at the meeting.
“We hope that the new ICAHT grading focuses future research efforts to not only understand this important side effect better, but also develop specific management strategies that mitigate the risk of infections in high-risk patients,” Dr. Rejeski added.
“The multiply validated CAR-HEMATOTOX score, assessed at time of lymphodepletion, may be helpful in this regard,” he added.
An accompanying editorial published with the guidelines underscored that “this is the first such guideline by a major organization and is a much-needed development for the management of this important CAR T-cell–associated toxicity.”
The improved standardized reporting of ICAHT “could also inform hematotoxicity management protocols,” said the editorial authors, David Qualls, MD, of the Memorial Sloan Kettering Cancer Center in New York City and Caron Jacobson, MD, of the Dana-Farber Cancer Institute, in Boston, Massachusetts.
“While providing comprehensive recommendations for ICAHT, the EHA/EBMT guidelines also highlight important gaps in our current knowledge of ICAHT, which are significant,” the editorial authors add.
Further commenting, Ulrich Jaeger, MD, a professor of hematology at the Medical University of Vienna, Vienna, Austria, agreed that the research fills an important need in post–CAR T-cell therapy management.
“Dr. Rejeski´s work is really seminal in the field and confirmed by validation cohorts in other centers,” he said in an interview. “I think the story is absolutely clear. It will be of increasing importance, with more patients surviving. [The system] will have to be adapted to novel indications as well.”
Dr. Rejeski disclosed ties with Kite/Gilead, Novartis, GMS/Celgene, and Pierre-Fabre. Jaeger reports relationships with Novartis, Gilead Sciences, Celgene/BMS, Janssen, Roche, Miltenyi Biotec, and Innovative Medicines Initiative.
“Hematotoxicity after CAR T is common and clinically relevant, but it also remains poorly understood [with] a high degree of heterogeneity in terms of grading its clinical management,” said first author Kai Rejeski, MD, in presenting on the findings at the 6th European CAR T-cell Meeting, held in Spain and jointly sponsored by the European Society for Blood and Marrow Transplantation (EBMT) and the European Hematology Association (EHA).
“We hope that this novel grading system helps with this by enabling harmonized reporting using the same nomenclature and allowing the comparison of the expected incidence rates of grade 3 or higher [hematological toxicities] across several disease entities and CAR T products,” said Dr. Rejeski, of the Adult BMT (Blood Marrow Transplant) and Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York City.
ICAHT Grading System
In a recent meta-analysis, Dr. Rejeski and his team found that infections are the cause of as many as 49% of non–relapse related deaths after CAR T-cell therapy, representing the most common cause of death and numbering significantly more than the more prominent causes of cytokine release syndrome (CRS) or immune effector cell–associated neurotoxicity (ICANS), which paradoxically have been the focus of significantly more research. In addition, the authors have reported substantial inconsistency among CAR T centers in the grading and management of the post–CAR T cytopenias that can cause those infections, underscoring the need for better guidelines.
“The narrative around CAR T toxicity has long centered on CRS and ICANS as novel and prototypical side effects with distinct management protocols,” Dr. Rejeski said in an interview. “However, it is cytopenias and the associated infections that drive nonrelapse mortality after CAR T.”
To address the need, the EHA and EBMT established the grading system for Immune Effector Cell–Associated HematoToxicity (ICAHT) that is applicable across disease types, indications, and treatment settings.
The details of the grading system were published in September 2023 in the journal Blood. The new system, which specifically focuses on neutrophil count and timing, importantly addresses the biphasic nature of ICAHT by distinguishing “early” ICAHT, occurring within 30 days of the CAR T administration, and “late” ICAHT, occurring more that 30 days following the treatment.
By contrast, conventional grading scales for CAR T–related cytopenias, such as the Common Terminology Criteria for Adverse Events (CTCAE) scale, “neither reflect the unique quality of post–CAR T neutrophil recovery, nor do they reflect the inherent risk of infections due to protracted neutropenia,” the authors report in the study.
Real-World Evaluation
To assess the ICAHT grading system’s relevance in a real-world clinical setting of CAR T-cell therapy recipients, Dr. Rejeski and colleagues conducted a multicenter observational study, published in January 2024 in Blood Advances.
The study involved 549 patients at 12 international CAR T centers treated with BCMA- or CD19- directed CAR T therapy for relapsed/refractory B-cell malignancies.
Of the patients, 112 were treated for multiple myeloma (MM), 334 for large B cell lymphoma (LBCL), and 103 for mantle cell lymphoma (MCL).
Using the grading system, grade 3 (severe) or 4 (life-threatening) ICAHT (n = 125), was found to be strongly associated with key factors including a cumulative duration of severe neutropenia (P < .0001), the presence of multilineage cytopenias, such as severe thrombocytopenia (90%, compared with 46% in nonsevere ICAHT) and severe anemia (92% vs 49%; both P < .001), as well as the use of platelet and red blood cell transfusions.
Grade 3 or higher ICAHT was more common in patients with MCL (28%), compared with LBCL (23%) and MM (15%).
Key factors at baseline that were independently associated with severe ICAHT after multivariate adjustment included the presence of bone marrow infiltration, increased serum LDH levels, elevated CAR-HEMATOTOX scores (all P < .001), and receipt of CD28z costimulatory domain products, including axi-cel or brexu-cel (P = .01).
Those with grade 3 or higher ICAHT scores had a significantly higher rate of severe infections, compared with lower ICAHT scores (49% vs 13%; P < .0001), as well as increased nonrelapse mortality (14% vs 4.5%; P < .0001), primarily attributable to fatal infections.
Survival outcomes were also worse with grade 3 or higher ICAHT, including significantly lower rates of 1-year progression-free survival (35% vs 51%) and 1-year overall survival (52% vs 73%; both P < .0001).
Grade 3 or higher ICAHT was also significantly associated with prolonged hospital stays (median 21 vs 16 days; P < .0001).
However, contrary to findings from some previous studies, the current study showed no association between ICAHT severity and the prior administration of autologous stem cell transplant.
The number of prior treatment lines was not associated with grade 3 or higher ICAHT. However, grade 3 or higher CRS was more common as a cotoxicity (15% vs 5% without severe ICAHT), as was severe ICANS (26% vs 13%; both P < .001).
Notably, ICAHT grading showed superiority in the prediction of severe infections, compared with CTCAE grading (c-index 0.73 vs 0.55, P < .0001 vs nonsignificant).
While mild to moderate toxicity after CAR T-cell therapy has been associated with more favorable outcomes, the poor survival rates associated with severe ICAHT “underscore that high-grade toxicity and inferior treatment outcomes often go hand-in-hand,” the authors write.
Conversely, “the patients with grade 1 or 2 ICAHT exhibited excellent treatment outcomes in our study,” they point out.
Recommendations in Clinical Practice
For clinical guidance, the ICAHT grading system provides best practice recommendations based on severity for diagnostic work-up and management, such as measures including use of granulocyte-colony stimulating factor (G-CSF), anti-infective prophylaxis and stem cell boosts.
The authors add that preinfusion scoring systems, including the CAR-HEMATOTOX prognostic score, may be optimized by ICAHT grading in terms of modeling for severe or life-threatening ICAHT as an important endpoint.
“We have had an absence of the standardized severity-based guidelines that we know very well for CRS and ICANS, both in terms of the diagnostic work-up and the grading but also the management,” Dr. Rejeski said at the meeting.
“We hope that the new ICAHT grading focuses future research efforts to not only understand this important side effect better, but also develop specific management strategies that mitigate the risk of infections in high-risk patients,” Dr. Rejeski added.
“The multiply validated CAR-HEMATOTOX score, assessed at time of lymphodepletion, may be helpful in this regard,” he added.
An accompanying editorial published with the guidelines underscored that “this is the first such guideline by a major organization and is a much-needed development for the management of this important CAR T-cell–associated toxicity.”
The improved standardized reporting of ICAHT “could also inform hematotoxicity management protocols,” said the editorial authors, David Qualls, MD, of the Memorial Sloan Kettering Cancer Center in New York City and Caron Jacobson, MD, of the Dana-Farber Cancer Institute, in Boston, Massachusetts.
“While providing comprehensive recommendations for ICAHT, the EHA/EBMT guidelines also highlight important gaps in our current knowledge of ICAHT, which are significant,” the editorial authors add.
Further commenting, Ulrich Jaeger, MD, a professor of hematology at the Medical University of Vienna, Vienna, Austria, agreed that the research fills an important need in post–CAR T-cell therapy management.
“Dr. Rejeski´s work is really seminal in the field and confirmed by validation cohorts in other centers,” he said in an interview. “I think the story is absolutely clear. It will be of increasing importance, with more patients surviving. [The system] will have to be adapted to novel indications as well.”
Dr. Rejeski disclosed ties with Kite/Gilead, Novartis, GMS/Celgene, and Pierre-Fabre. Jaeger reports relationships with Novartis, Gilead Sciences, Celgene/BMS, Janssen, Roche, Miltenyi Biotec, and Innovative Medicines Initiative.
FROM THE 6TH EUROPEAN CAR T-CELL MEETING
Does worsening metabolic syndrome increase the risk of developing cancer?
The conditions that comprise metabolic syndrome (high blood pressure, high blood sugar, increased abdominal adiposity, and high cholesterol and triglycerides) have been associated with an increased risk of diseases, including heart disease, stroke, and type 2 diabetes, wrote Li Deng, PhD, of Capital Medical University, Beijing, China, and colleagues.
A systematic review and meta-analysis published in Diabetes Care in 2012 showed an association between the presence of metabolic syndrome and an increased risk of various cancers including liver, bladder, pancreatic, breast, and colorectal.
More recently, a 2019 study published in Diabetes showed evidence of increased risk for certain cancers (pancreatic, kidney, uterine, cervical) but no increased risk for cancer overall.
However, the reasons for this association between metabolic syndrome and cancer remain unclear, and the effect of the fluctuating nature of metabolic syndrome over time on long-term cancer risk has not been explored, the researchers wrote.
What Does New Study Add to Other Research on Metabolic Syndrome and Cancer Risk?
In the new study, published in Cancer on March 11 (doi: 10.1002/cncr.35235), 44,115 adults in China were separated into four trajectories based on metabolic syndrome scores for the period from 2006 to 2010. The scores were based on clinical evidence of metabolic syndrome, defined using the International Diabetes Federation criteria of central obesity and the presence of at least two other factors including increased triglycerides, decreased HDL cholesterol, high blood pressure (or treatment for previously diagnosed hypertension), and increased fasting plasma glucose (or previous diagnosis of type 2 diabetes).
The average age of the participants was 49 years. The four trajectories of metabolic syndrome were low-stable (10.56% of participants), moderate-low (40.84%), moderate-high (41.46%), and elevated-increasing (7.14%), based on trends from the individuals’ initial physical exams on entering the study.
Over a median follow-up period of 9.4 years (from 2010 to 2021), 2,271 cancer diagnoses were reported in the study population. Those with an elevated-increasing metabolic syndrome trajectory had 1.3 times the risk of any cancer compared with those in the low-stable group. Risk for breast cancer, endometrial cancer, kidney cancer, colorectal cancer, and liver cancer in the highest trajectory group were 2.1, 3.3, 4.5, 2.5, and 1.6 times higher, respectively, compared to the lowest group. The increased risk in the elevated-trajectory group for all cancer types persisted when the low-stable, moderate-low, and moderate-high trajectory pattern groups were combined.
The researchers also examined the impact of chronic inflammation and found that individuals with persistently high metabolic syndrome scores and concurrent chronic inflammation had the highest risks of breast, endometrial, colon, and liver cancer. However, individuals with persistently high metabolic syndrome scores and no concurrent chronic inflammation had the highest risk of kidney cancer.
What Are the Limitations of This Research?
The researchers of the current study acknowledged the lack of information on other causes of cancer, including dietary habits, hepatitis C infection, and Helicobacter pylori infection. Other limitations include the focus only on individuals from a single community of mainly middle-aged men in China that may not generalize to other populations.
Also, the metabolic syndrome trajectories did not change much over time, which may be related to the short 4-year study period.
What Is the Takeaway Message for Clinical Practice?
The results suggest that monitoring and managing metabolic syndrome could help reduce cancer risk, the researchers concluded.
“This research suggests that proactive and continuous management of metabolic syndrome may serve as an essential strategy in preventing cancer,” senior author Han-Ping Shi, MD, PhD, of Capital Medical University in Beijing, said in a press release accompanying the study.
More research is needed to assess the impact of these interventions on cancer risk, he noted. However, the data from the current study can guide future research that may lead to more targeted treatments and more effective preventive strategies, he said in a statement.
The study was supported by the National Key Research and Development Program of China. The researchers had no financial conflicts to disclose.
The conditions that comprise metabolic syndrome (high blood pressure, high blood sugar, increased abdominal adiposity, and high cholesterol and triglycerides) have been associated with an increased risk of diseases, including heart disease, stroke, and type 2 diabetes, wrote Li Deng, PhD, of Capital Medical University, Beijing, China, and colleagues.
A systematic review and meta-analysis published in Diabetes Care in 2012 showed an association between the presence of metabolic syndrome and an increased risk of various cancers including liver, bladder, pancreatic, breast, and colorectal.
More recently, a 2019 study published in Diabetes showed evidence of increased risk for certain cancers (pancreatic, kidney, uterine, cervical) but no increased risk for cancer overall.
However, the reasons for this association between metabolic syndrome and cancer remain unclear, and the effect of the fluctuating nature of metabolic syndrome over time on long-term cancer risk has not been explored, the researchers wrote.
What Does New Study Add to Other Research on Metabolic Syndrome and Cancer Risk?
In the new study, published in Cancer on March 11 (doi: 10.1002/cncr.35235), 44,115 adults in China were separated into four trajectories based on metabolic syndrome scores for the period from 2006 to 2010. The scores were based on clinical evidence of metabolic syndrome, defined using the International Diabetes Federation criteria of central obesity and the presence of at least two other factors including increased triglycerides, decreased HDL cholesterol, high blood pressure (or treatment for previously diagnosed hypertension), and increased fasting plasma glucose (or previous diagnosis of type 2 diabetes).
The average age of the participants was 49 years. The four trajectories of metabolic syndrome were low-stable (10.56% of participants), moderate-low (40.84%), moderate-high (41.46%), and elevated-increasing (7.14%), based on trends from the individuals’ initial physical exams on entering the study.
Over a median follow-up period of 9.4 years (from 2010 to 2021), 2,271 cancer diagnoses were reported in the study population. Those with an elevated-increasing metabolic syndrome trajectory had 1.3 times the risk of any cancer compared with those in the low-stable group. Risk for breast cancer, endometrial cancer, kidney cancer, colorectal cancer, and liver cancer in the highest trajectory group were 2.1, 3.3, 4.5, 2.5, and 1.6 times higher, respectively, compared to the lowest group. The increased risk in the elevated-trajectory group for all cancer types persisted when the low-stable, moderate-low, and moderate-high trajectory pattern groups were combined.
The researchers also examined the impact of chronic inflammation and found that individuals with persistently high metabolic syndrome scores and concurrent chronic inflammation had the highest risks of breast, endometrial, colon, and liver cancer. However, individuals with persistently high metabolic syndrome scores and no concurrent chronic inflammation had the highest risk of kidney cancer.
What Are the Limitations of This Research?
The researchers of the current study acknowledged the lack of information on other causes of cancer, including dietary habits, hepatitis C infection, and Helicobacter pylori infection. Other limitations include the focus only on individuals from a single community of mainly middle-aged men in China that may not generalize to other populations.
Also, the metabolic syndrome trajectories did not change much over time, which may be related to the short 4-year study period.
What Is the Takeaway Message for Clinical Practice?
The results suggest that monitoring and managing metabolic syndrome could help reduce cancer risk, the researchers concluded.
“This research suggests that proactive and continuous management of metabolic syndrome may serve as an essential strategy in preventing cancer,” senior author Han-Ping Shi, MD, PhD, of Capital Medical University in Beijing, said in a press release accompanying the study.
More research is needed to assess the impact of these interventions on cancer risk, he noted. However, the data from the current study can guide future research that may lead to more targeted treatments and more effective preventive strategies, he said in a statement.
The study was supported by the National Key Research and Development Program of China. The researchers had no financial conflicts to disclose.
The conditions that comprise metabolic syndrome (high blood pressure, high blood sugar, increased abdominal adiposity, and high cholesterol and triglycerides) have been associated with an increased risk of diseases, including heart disease, stroke, and type 2 diabetes, wrote Li Deng, PhD, of Capital Medical University, Beijing, China, and colleagues.
A systematic review and meta-analysis published in Diabetes Care in 2012 showed an association between the presence of metabolic syndrome and an increased risk of various cancers including liver, bladder, pancreatic, breast, and colorectal.
More recently, a 2019 study published in Diabetes showed evidence of increased risk for certain cancers (pancreatic, kidney, uterine, cervical) but no increased risk for cancer overall.
However, the reasons for this association between metabolic syndrome and cancer remain unclear, and the effect of the fluctuating nature of metabolic syndrome over time on long-term cancer risk has not been explored, the researchers wrote.
What Does New Study Add to Other Research on Metabolic Syndrome and Cancer Risk?
In the new study, published in Cancer on March 11 (doi: 10.1002/cncr.35235), 44,115 adults in China were separated into four trajectories based on metabolic syndrome scores for the period from 2006 to 2010. The scores were based on clinical evidence of metabolic syndrome, defined using the International Diabetes Federation criteria of central obesity and the presence of at least two other factors including increased triglycerides, decreased HDL cholesterol, high blood pressure (or treatment for previously diagnosed hypertension), and increased fasting plasma glucose (or previous diagnosis of type 2 diabetes).
The average age of the participants was 49 years. The four trajectories of metabolic syndrome were low-stable (10.56% of participants), moderate-low (40.84%), moderate-high (41.46%), and elevated-increasing (7.14%), based on trends from the individuals’ initial physical exams on entering the study.
Over a median follow-up period of 9.4 years (from 2010 to 2021), 2,271 cancer diagnoses were reported in the study population. Those with an elevated-increasing metabolic syndrome trajectory had 1.3 times the risk of any cancer compared with those in the low-stable group. Risk for breast cancer, endometrial cancer, kidney cancer, colorectal cancer, and liver cancer in the highest trajectory group were 2.1, 3.3, 4.5, 2.5, and 1.6 times higher, respectively, compared to the lowest group. The increased risk in the elevated-trajectory group for all cancer types persisted when the low-stable, moderate-low, and moderate-high trajectory pattern groups were combined.
The researchers also examined the impact of chronic inflammation and found that individuals with persistently high metabolic syndrome scores and concurrent chronic inflammation had the highest risks of breast, endometrial, colon, and liver cancer. However, individuals with persistently high metabolic syndrome scores and no concurrent chronic inflammation had the highest risk of kidney cancer.
What Are the Limitations of This Research?
The researchers of the current study acknowledged the lack of information on other causes of cancer, including dietary habits, hepatitis C infection, and Helicobacter pylori infection. Other limitations include the focus only on individuals from a single community of mainly middle-aged men in China that may not generalize to other populations.
Also, the metabolic syndrome trajectories did not change much over time, which may be related to the short 4-year study period.
What Is the Takeaway Message for Clinical Practice?
The results suggest that monitoring and managing metabolic syndrome could help reduce cancer risk, the researchers concluded.
“This research suggests that proactive and continuous management of metabolic syndrome may serve as an essential strategy in preventing cancer,” senior author Han-Ping Shi, MD, PhD, of Capital Medical University in Beijing, said in a press release accompanying the study.
More research is needed to assess the impact of these interventions on cancer risk, he noted. However, the data from the current study can guide future research that may lead to more targeted treatments and more effective preventive strategies, he said in a statement.
The study was supported by the National Key Research and Development Program of China. The researchers had no financial conflicts to disclose.
FROM CANCER