Oncology Practice

MRI-invisible prostate lesions. It sounds like the stuff of science fiction and fantasy, a creation from the minds of H.G. Wells, who wrote The Invisible Man, or J.K. Rowling, who authored the Harry Potter series.

But MRI-invisible prostate lesions are real. And what these lesions may, or may not, indicate is the subject of intense debate.

MRI plays an increasingly important role in detecting and diagnosing prostate cancer, staging prostate cancer as well as monitoring disease progression. However, on occasion, a puzzling phenomenon arises. Certain prostate lesions that appear when pathologists examine biopsied tissue samples under a microscope are not visible on MRI. The prostate tissue will, instead, appear normal to a radiologist’s eye.

Why are certain lesions invisible with MRI? And is it dangerous for patients if these lesions are not detected? 

Some experts believe these MRI-invisible lesions are nothing to worry about.

If the clinician can’t see the cancer on MRI, then it simply isn’t a threat, according to Mark Emberton, MD, a pioneer in prostate MRIs and director of interventional oncology at University College London, England.

Laurence Klotz, MD, of the University of Toronto, Ontario, Canada, agreed, noting that “invisible cancers are clinically insignificant and don’t require systematic biopsies.”

Emberton and Klotz compared MRI-invisible lesions to grade group 1 prostate cancer (Gleason score ≤ 6) — the least aggressive category that indicates the cancer that is not likely to spread or kill. For patients on active surveillance, those with MRI-invisible cancers do drastically better than those with visible cancers, Klotz explained.

But other experts in the field are skeptical that MRI-invisible lesions are truly innocuous.

Although statistically an MRI-visible prostate lesion indicates a more aggressive tumor, that is not always the case for every individual, said Brian Helfand, MD, PhD, chief of urology at NorthShore University Health System, Evanston, Illinois.

MRIs can lead to false negatives in about 10%-20% of patients who have clinically significant prostate cancer, though estimates vary.

In one analysis, 16% of men with no suspicious lesions on MRI had clinically significant prostate cancer identified after undergoing a systematic biopsy. Another analysis found that about 35% of MRI-invisible prostate cancers identified via biopsy were clinically significant.

Other studies, however, have indicated that negative MRI results accurately indicate patients at low risk of developing clinically significant cancers. A recent JAMA Oncology analysis, for instance, found that only seven of 233 men (3%) with negative MRI results at baseline who completed 3 years of monitoring were diagnosed with clinically significant prostate cancer.

When a patient has an MRI-invisible prostate tumor, there are a couple of reasons the MRI may not be picking it up, said urologic oncologist Alexander Putnam Cole, MD, assistant professor of surgery, Harvard Medical School, Boston, Massachusetts. “One is that the cancer is aggressive but just very small,” said Cole.

“Another possibility is that the cancer looks very similar to background prostate tissue, which is something that you might expect if you think about more of a low-grade cancer,” he explained.

The experience level of the radiologist interpreting the MRI can also play into the accuracy of the reading.

But Cole agreed that “in general, MRI visibility is associated with molecular and histologic features of progression and aggressiveness and non-visible cancers are less likely to have aggressive features.”

The genomic profiles of MRI-visible and -invisible cancers bear this out.

According to Todd Morgan, MD, chief of urologic oncology at Michigan Medicine, University of Michigan, Ann Arbor, the gene expression in visible disease tends to be linked to more aggressive prostate tumors whereas gene expression in invisible disease does not.

In one analysis, for instance, researchers found that four genes — PHYHD1, CENPF, ALDH2, and GDF15 — associated with worse progression-free survival and metastasis-free survival in prostate cancer also predicted MRI visibility.

“Genes that are associated with visibility are essentially the same genes that are associated with aggressive cancers,” Klotz said.

 

Next Steps After Negative MRI Result

What do MRI-invisible lesions mean for patient care? If, for instance, a patient has elevated PSA levels but a normal MRI, is a targeted or systematic biopsy warranted?

The overarching message, according to Klotz, is that “you don’t need to find them.” Klotz noted, however, that patients with a negative MRI result should still be followed with periodic repeat imaging.

Several trials support this approach of using MRI to decide who needs a biopsy and delaying a biopsy in men with normal MRIs.

The recent JAMA Oncology analysis found that, among men with negative MRI results, 86% avoided a biopsy over 3 years, with clinically significant prostate cancer detected in only 4% of men across the study period — four in the initial diagnostic phase and seven in the 3-year monitoring phase. However, during the initial diagnostic phase, more than half the men with positive MRI findings had clinically significant prostate cancer detected.

Another recent study found that patients with negative MRI results were much less likely to upgrade to higher Gleason scores over time. Among 522 patients who underwent a systematic and targeted biopsy within 18 months of their grade group 1 designation, 9.2% with negative MRI findings had tumors reclassified as grade group 2 or higher vs 27% with positive MRI findings, and 2.3% with negative MRI findings had tumors reclassified as grade group 3 or higher vs 7.8% with positive MRI findings.

These data suggest that men with grade group 1 cancer and negative MRI result “may be able to avoid confirmatory biopsies until a routine surveillance biopsy in 2-3 years,” according to study author Christian Pavlovich, MD, professor of urologic oncology at the Johns Hopkins University School of Medicine, Baltimore.

Cole used MRI findings to triage who gets a biopsy. When a biopsy is warranted, “I usually recommend adding in some systematic sampling of the other side to assess for nonvisible cancers,” he noted.

Sampling prostate tissue outside the target area “adds maybe 1-2 minutes to the procedure and doesn’t drastically increase the morbidity or risks,” Cole said. It also can help “confirm there is cancer in the MRI target and also confirm there is no cancer in the nonvisible areas.” 

According to Klotz, if imaging demonstrates progression, patients should receive a biopsy — in most cases, a targeted biopsy only. And, Klotz noted, skipping routine prostate biopsies in men with negative MRI results can save thousands of men from these procedures, which carry risks for infections and sepsis.

Looking beyond Gleason scores for risk prediction, MRI “visibility is a very powerful risk stratifier,” he said.

A version of this article appeared on Medscape.com.

MRI-invisible prostate lesions. It sounds like the stuff of science fiction and fantasy, a creation from the minds of H.G. Wells, who wrote The Invisible Man, or J.K. Rowling, who authored the Harry Potter series.

But MRI-invisible prostate lesions are real. And what these lesions may, or may not, indicate is the subject of intense debate.

MRI plays an increasingly important role in detecting and diagnosing prostate cancer, staging prostate cancer as well as monitoring disease progression. However, on occasion, a puzzling phenomenon arises. Certain prostate lesions that appear when pathologists examine biopsied tissue samples under a microscope are not visible on MRI. The prostate tissue will, instead, appear normal to a radiologist’s eye.

Why are certain lesions invisible with MRI? And is it dangerous for patients if these lesions are not detected? 

Some experts believe these MRI-invisible lesions are nothing to worry about.

If the clinician can’t see the cancer on MRI, then it simply isn’t a threat, according to Mark Emberton, MD, a pioneer in prostate MRIs and director of interventional oncology at University College London, England.

Laurence Klotz, MD, of the University of Toronto, Ontario, Canada, agreed, noting that “invisible cancers are clinically insignificant and don’t require systematic biopsies.”

Emberton and Klotz compared MRI-invisible lesions to grade group 1 prostate cancer (Gleason score ≤ 6) — the least aggressive category that indicates the cancer that is not likely to spread or kill. For patients on active surveillance, those with MRI-invisible cancers do drastically better than those with visible cancers, Klotz explained.

But other experts in the field are skeptical that MRI-invisible lesions are truly innocuous.

Although statistically an MRI-visible prostate lesion indicates a more aggressive tumor, that is not always the case for every individual, said Brian Helfand, MD, PhD, chief of urology at NorthShore University Health System, Evanston, Illinois.

MRIs can lead to false negatives in about 10%-20% of patients who have clinically significant prostate cancer, though estimates vary.

In one analysis, 16% of men with no suspicious lesions on MRI had clinically significant prostate cancer identified after undergoing a systematic biopsy. Another analysis found that about 35% of MRI-invisible prostate cancers identified via biopsy were clinically significant.

Other studies, however, have indicated that negative MRI results accurately indicate patients at low risk of developing clinically significant cancers. A recent JAMA Oncology analysis, for instance, found that only seven of 233 men (3%) with negative MRI results at baseline who completed 3 years of monitoring were diagnosed with clinically significant prostate cancer.

When a patient has an MRI-invisible prostate tumor, there are a couple of reasons the MRI may not be picking it up, said urologic oncologist Alexander Putnam Cole, MD, assistant professor of surgery, Harvard Medical School, Boston, Massachusetts. “One is that the cancer is aggressive but just very small,” said Cole.

“Another possibility is that the cancer looks very similar to background prostate tissue, which is something that you might expect if you think about more of a low-grade cancer,” he explained.

The experience level of the radiologist interpreting the MRI can also play into the accuracy of the reading.

But Cole agreed that “in general, MRI visibility is associated with molecular and histologic features of progression and aggressiveness and non-visible cancers are less likely to have aggressive features.”

The genomic profiles of MRI-visible and -invisible cancers bear this out.

According to Todd Morgan, MD, chief of urologic oncology at Michigan Medicine, University of Michigan, Ann Arbor, the gene expression in visible disease tends to be linked to more aggressive prostate tumors whereas gene expression in invisible disease does not.

In one analysis, for instance, researchers found that four genes — PHYHD1, CENPF, ALDH2, and GDF15 — associated with worse progression-free survival and metastasis-free survival in prostate cancer also predicted MRI visibility.

“Genes that are associated with visibility are essentially the same genes that are associated with aggressive cancers,” Klotz said.

 

Next Steps After Negative MRI Result

What do MRI-invisible lesions mean for patient care? If, for instance, a patient has elevated PSA levels but a normal MRI, is a targeted or systematic biopsy warranted?

The overarching message, according to Klotz, is that “you don’t need to find them.” Klotz noted, however, that patients with a negative MRI result should still be followed with periodic repeat imaging.

Several trials support this approach of using MRI to decide who needs a biopsy and delaying a biopsy in men with normal MRIs.

The recent JAMA Oncology analysis found that, among men with negative MRI results, 86% avoided a biopsy over 3 years, with clinically significant prostate cancer detected in only 4% of men across the study period — four in the initial diagnostic phase and seven in the 3-year monitoring phase. However, during the initial diagnostic phase, more than half the men with positive MRI findings had clinically significant prostate cancer detected.

Another recent study found that patients with negative MRI results were much less likely to upgrade to higher Gleason scores over time. Among 522 patients who underwent a systematic and targeted biopsy within 18 months of their grade group 1 designation, 9.2% with negative MRI findings had tumors reclassified as grade group 2 or higher vs 27% with positive MRI findings, and 2.3% with negative MRI findings had tumors reclassified as grade group 3 or higher vs 7.8% with positive MRI findings.

These data suggest that men with grade group 1 cancer and negative MRI result “may be able to avoid confirmatory biopsies until a routine surveillance biopsy in 2-3 years,” according to study author Christian Pavlovich, MD, professor of urologic oncology at the Johns Hopkins University School of Medicine, Baltimore.

Cole used MRI findings to triage who gets a biopsy. When a biopsy is warranted, “I usually recommend adding in some systematic sampling of the other side to assess for nonvisible cancers,” he noted.

Sampling prostate tissue outside the target area “adds maybe 1-2 minutes to the procedure and doesn’t drastically increase the morbidity or risks,” Cole said. It also can help “confirm there is cancer in the MRI target and also confirm there is no cancer in the nonvisible areas.” 

According to Klotz, if imaging demonstrates progression, patients should receive a biopsy — in most cases, a targeted biopsy only. And, Klotz noted, skipping routine prostate biopsies in men with negative MRI results can save thousands of men from these procedures, which carry risks for infections and sepsis.

Looking beyond Gleason scores for risk prediction, MRI “visibility is a very powerful risk stratifier,” he said.

A version of this article appeared on Medscape.com.

MRI-invisible prostate lesions. It sounds like the stuff of science fiction and fantasy, a creation from the minds of H.G. Wells, who wrote The Invisible Man, or J.K. Rowling, who authored the Harry Potter series.

But MRI-invisible prostate lesions are real. And what these lesions may, or may not, indicate is the subject of intense debate.

MRI plays an increasingly important role in detecting and diagnosing prostate cancer, staging prostate cancer as well as monitoring disease progression. However, on occasion, a puzzling phenomenon arises. Certain prostate lesions that appear when pathologists examine biopsied tissue samples under a microscope are not visible on MRI. The prostate tissue will, instead, appear normal to a radiologist’s eye.

Why are certain lesions invisible with MRI? And is it dangerous for patients if these lesions are not detected? 

Some experts believe these MRI-invisible lesions are nothing to worry about.

If the clinician can’t see the cancer on MRI, then it simply isn’t a threat, according to Mark Emberton, MD, a pioneer in prostate MRIs and director of interventional oncology at University College London, England.

Laurence Klotz, MD, of the University of Toronto, Ontario, Canada, agreed, noting that “invisible cancers are clinically insignificant and don’t require systematic biopsies.”

Emberton and Klotz compared MRI-invisible lesions to grade group 1 prostate cancer (Gleason score ≤ 6) — the least aggressive category that indicates the cancer that is not likely to spread or kill. For patients on active surveillance, those with MRI-invisible cancers do drastically better than those with visible cancers, Klotz explained.

But other experts in the field are skeptical that MRI-invisible lesions are truly innocuous.

Although statistically an MRI-visible prostate lesion indicates a more aggressive tumor, that is not always the case for every individual, said Brian Helfand, MD, PhD, chief of urology at NorthShore University Health System, Evanston, Illinois.

MRIs can lead to false negatives in about 10%-20% of patients who have clinically significant prostate cancer, though estimates vary.

In one analysis, 16% of men with no suspicious lesions on MRI had clinically significant prostate cancer identified after undergoing a systematic biopsy. Another analysis found that about 35% of MRI-invisible prostate cancers identified via biopsy were clinically significant.

Other studies, however, have indicated that negative MRI results accurately indicate patients at low risk of developing clinically significant cancers. A recent JAMA Oncology analysis, for instance, found that only seven of 233 men (3%) with negative MRI results at baseline who completed 3 years of monitoring were diagnosed with clinically significant prostate cancer.

When a patient has an MRI-invisible prostate tumor, there are a couple of reasons the MRI may not be picking it up, said urologic oncologist Alexander Putnam Cole, MD, assistant professor of surgery, Harvard Medical School, Boston, Massachusetts. “One is that the cancer is aggressive but just very small,” said Cole.

“Another possibility is that the cancer looks very similar to background prostate tissue, which is something that you might expect if you think about more of a low-grade cancer,” he explained.

The experience level of the radiologist interpreting the MRI can also play into the accuracy of the reading.

But Cole agreed that “in general, MRI visibility is associated with molecular and histologic features of progression and aggressiveness and non-visible cancers are less likely to have aggressive features.”

The genomic profiles of MRI-visible and -invisible cancers bear this out.

According to Todd Morgan, MD, chief of urologic oncology at Michigan Medicine, University of Michigan, Ann Arbor, the gene expression in visible disease tends to be linked to more aggressive prostate tumors whereas gene expression in invisible disease does not.

In one analysis, for instance, researchers found that four genes — PHYHD1, CENPF, ALDH2, and GDF15 — associated with worse progression-free survival and metastasis-free survival in prostate cancer also predicted MRI visibility.

“Genes that are associated with visibility are essentially the same genes that are associated with aggressive cancers,” Klotz said.

 

Next Steps After Negative MRI Result

What do MRI-invisible lesions mean for patient care? If, for instance, a patient has elevated PSA levels but a normal MRI, is a targeted or systematic biopsy warranted?

The overarching message, according to Klotz, is that “you don’t need to find them.” Klotz noted, however, that patients with a negative MRI result should still be followed with periodic repeat imaging.

Several trials support this approach of using MRI to decide who needs a biopsy and delaying a biopsy in men with normal MRIs.

The recent JAMA Oncology analysis found that, among men with negative MRI results, 86% avoided a biopsy over 3 years, with clinically significant prostate cancer detected in only 4% of men across the study period — four in the initial diagnostic phase and seven in the 3-year monitoring phase. However, during the initial diagnostic phase, more than half the men with positive MRI findings had clinically significant prostate cancer detected.

Another recent study found that patients with negative MRI results were much less likely to upgrade to higher Gleason scores over time. Among 522 patients who underwent a systematic and targeted biopsy within 18 months of their grade group 1 designation, 9.2% with negative MRI findings had tumors reclassified as grade group 2 or higher vs 27% with positive MRI findings, and 2.3% with negative MRI findings had tumors reclassified as grade group 3 or higher vs 7.8% with positive MRI findings.

These data suggest that men with grade group 1 cancer and negative MRI result “may be able to avoid confirmatory biopsies until a routine surveillance biopsy in 2-3 years,” according to study author Christian Pavlovich, MD, professor of urologic oncology at the Johns Hopkins University School of Medicine, Baltimore.

Cole used MRI findings to triage who gets a biopsy. When a biopsy is warranted, “I usually recommend adding in some systematic sampling of the other side to assess for nonvisible cancers,” he noted.

Sampling prostate tissue outside the target area “adds maybe 1-2 minutes to the procedure and doesn’t drastically increase the morbidity or risks,” Cole said. It also can help “confirm there is cancer in the MRI target and also confirm there is no cancer in the nonvisible areas.” 

According to Klotz, if imaging demonstrates progression, patients should receive a biopsy — in most cases, a targeted biopsy only. And, Klotz noted, skipping routine prostate biopsies in men with negative MRI results can save thousands of men from these procedures, which carry risks for infections and sepsis.

Looking beyond Gleason scores for risk prediction, MRI “visibility is a very powerful risk stratifier,” he said.

A version of this article appeared on Medscape.com.

TOPLINE:

Different Kirsten rat sarcoma virus (KRAS) mutations in pancreatic ductal adenocarcinoma show varying treatment responses, with G12D and G12V mutations linked to worse outcomes compared with wild type.

METHODOLOGY:

• Researchers conducted a retrospective cohort study analyzing deidentified clinical data from 2,433 patients with metastatic pancreatic ductal adenocarcinoma (PDAC), diagnosed between February 2010 and September 2022.
• They assessed the association of KRAS mutations in metastatic PDAC with the clinical outcomes and responses to first-line chemotherapy regimens.
• Data originated from approximately 280 US cancer clinics, encompassing about 800 sites of care, with comprehensive genomic profiling performed on all patients.
• Analysis focused on median overall survival (OS) and time to next treatment (TTNT) across different KRAS mutation groups, using multivariate Cox proportional hazards models.

TAKEAWAY:

• Patients with KRAS G12D and G12V mutations showed significantly higher risk for disease progression (hazard ratio [HR], 1.15; 95% CI, 1.04-1.29; P = .009) and (HR, 1.16; 95% CI, 1.04-1.30; P = .01), respectively, compared with KRAS wild type.
• KRAS G12R mutations were associated with the longest median OS at 13.2 months (95% CI, 10.6-15.2) and longest median TTNT at 6.0 months (95% CI, 5.2-6.6).
• FOLFIRINOX treatment demonstrated better outcomes than gemcitabine-based therapies across all patients, with lower risk for treatment progression (HR, 1.19; 95% CI, 1.09-1.29; P < .001) and death (HR, 1.18; 95% CI, 1.07-1.29; P < .001).
• Specifically, when FOLFIRINOX was used as first-line treatment in patients with KRAS G12D and G12V mutations, the therapy was associated with improved TTNT and OS vs gemcitabine with or without nab-paclitaxel.

IN PRACTICE:

“In its totality, these data set a benchmark for future studies on KRAS inhibitors for specific KRAS variants and highlights the groups for which treatment combinations may ultimately be necessary,” the authors concluded.

SOURCE:

The study was led by Carter Norton, Huntsman Cancer Institute in Salt Lake City, Utah. It was published online on January 7 in JAMA Network Open.

LIMITATIONS:

According to the authors, the study’s limitations include the heterogeneity of clinical data collected retrospectively, which is subject to residual confounding. The sample size was limited for certain mutational groups, particularly KRAS G12C, leading to limited statistical power. Additionally, the detection rate of genomic alterations by commercially available assays may be affected by the high stromal content and low cellularity characteristic of PDAC.

DISCLOSURES:

The study was supported by Cancer Center Support grant P30CA042014 from the National Institutes of Health. Heloisa P. Soares, MD, PhD, one of the study authors, disclosed receiving consulting fees from Ipsen, Exelixis Inc, BMS, Novartis AG, AstraZeneca, and TerSera Therapeutics LLC and symposium speaker fees from ITM Radiopharma outside the submitted work. Additional disclosures are noted in the original article.

 

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Different Kirsten rat sarcoma virus (KRAS) mutations in pancreatic ductal adenocarcinoma show varying treatment responses, with G12D and G12V mutations linked to worse outcomes compared with wild type.

METHODOLOGY:

• Researchers conducted a retrospective cohort study analyzing deidentified clinical data from 2,433 patients with metastatic pancreatic ductal adenocarcinoma (PDAC), diagnosed between February 2010 and September 2022.
• They assessed the association of KRAS mutations in metastatic PDAC with the clinical outcomes and responses to first-line chemotherapy regimens.
• Data originated from approximately 280 US cancer clinics, encompassing about 800 sites of care, with comprehensive genomic profiling performed on all patients.
• Analysis focused on median overall survival (OS) and time to next treatment (TTNT) across different KRAS mutation groups, using multivariate Cox proportional hazards models.

TAKEAWAY:

• Patients with KRAS G12D and G12V mutations showed significantly higher risk for disease progression (hazard ratio [HR], 1.15; 95% CI, 1.04-1.29; P = .009) and (HR, 1.16; 95% CI, 1.04-1.30; P = .01), respectively, compared with KRAS wild type.
• KRAS G12R mutations were associated with the longest median OS at 13.2 months (95% CI, 10.6-15.2) and longest median TTNT at 6.0 months (95% CI, 5.2-6.6).
• FOLFIRINOX treatment demonstrated better outcomes than gemcitabine-based therapies across all patients, with lower risk for treatment progression (HR, 1.19; 95% CI, 1.09-1.29; P < .001) and death (HR, 1.18; 95% CI, 1.07-1.29; P < .001).
• Specifically, when FOLFIRINOX was used as first-line treatment in patients with KRAS G12D and G12V mutations, the therapy was associated with improved TTNT and OS vs gemcitabine with or without nab-paclitaxel.

IN PRACTICE:

“In its totality, these data set a benchmark for future studies on KRAS inhibitors for specific KRAS variants and highlights the groups for which treatment combinations may ultimately be necessary,” the authors concluded.

SOURCE:

The study was led by Carter Norton, Huntsman Cancer Institute in Salt Lake City, Utah. It was published online on January 7 in JAMA Network Open.

LIMITATIONS:

According to the authors, the study’s limitations include the heterogeneity of clinical data collected retrospectively, which is subject to residual confounding. The sample size was limited for certain mutational groups, particularly KRAS G12C, leading to limited statistical power. Additionally, the detection rate of genomic alterations by commercially available assays may be affected by the high stromal content and low cellularity characteristic of PDAC.

DISCLOSURES:

The study was supported by Cancer Center Support grant P30CA042014 from the National Institutes of Health. Heloisa P. Soares, MD, PhD, one of the study authors, disclosed receiving consulting fees from Ipsen, Exelixis Inc, BMS, Novartis AG, AstraZeneca, and TerSera Therapeutics LLC and symposium speaker fees from ITM Radiopharma outside the submitted work. Additional disclosures are noted in the original article.

 

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Different Kirsten rat sarcoma virus (KRAS) mutations in pancreatic ductal adenocarcinoma show varying treatment responses, with G12D and G12V mutations linked to worse outcomes compared with wild type.

METHODOLOGY:

• Researchers conducted a retrospective cohort study analyzing deidentified clinical data from 2,433 patients with metastatic pancreatic ductal adenocarcinoma (PDAC), diagnosed between February 2010 and September 2022.
• They assessed the association of KRAS mutations in metastatic PDAC with the clinical outcomes and responses to first-line chemotherapy regimens.
• Data originated from approximately 280 US cancer clinics, encompassing about 800 sites of care, with comprehensive genomic profiling performed on all patients.
• Analysis focused on median overall survival (OS) and time to next treatment (TTNT) across different KRAS mutation groups, using multivariate Cox proportional hazards models.

TAKEAWAY:

• Patients with KRAS G12D and G12V mutations showed significantly higher risk for disease progression (hazard ratio [HR], 1.15; 95% CI, 1.04-1.29; P = .009) and (HR, 1.16; 95% CI, 1.04-1.30; P = .01), respectively, compared with KRAS wild type.
• KRAS G12R mutations were associated with the longest median OS at 13.2 months (95% CI, 10.6-15.2) and longest median TTNT at 6.0 months (95% CI, 5.2-6.6).
• FOLFIRINOX treatment demonstrated better outcomes than gemcitabine-based therapies across all patients, with lower risk for treatment progression (HR, 1.19; 95% CI, 1.09-1.29; P < .001) and death (HR, 1.18; 95% CI, 1.07-1.29; P < .001).
• Specifically, when FOLFIRINOX was used as first-line treatment in patients with KRAS G12D and G12V mutations, the therapy was associated with improved TTNT and OS vs gemcitabine with or without nab-paclitaxel.

IN PRACTICE:

“In its totality, these data set a benchmark for future studies on KRAS inhibitors for specific KRAS variants and highlights the groups for which treatment combinations may ultimately be necessary,” the authors concluded.

SOURCE:

The study was led by Carter Norton, Huntsman Cancer Institute in Salt Lake City, Utah. It was published online on January 7 in JAMA Network Open.

LIMITATIONS:

According to the authors, the study’s limitations include the heterogeneity of clinical data collected retrospectively, which is subject to residual confounding. The sample size was limited for certain mutational groups, particularly KRAS G12C, leading to limited statistical power. Additionally, the detection rate of genomic alterations by commercially available assays may be affected by the high stromal content and low cellularity characteristic of PDAC.

DISCLOSURES:

The study was supported by Cancer Center Support grant P30CA042014 from the National Institutes of Health. Heloisa P. Soares, MD, PhD, one of the study authors, disclosed receiving consulting fees from Ipsen, Exelixis Inc, BMS, Novartis AG, AstraZeneca, and TerSera Therapeutics LLC and symposium speaker fees from ITM Radiopharma outside the submitted work. Additional disclosures are noted in the original article.

 

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Patients with rectal cancer managed by watch and wait and subsequent local regrowth have a higher risk for distant metastases than those undergoing immediate surgery. The new study highlights the importance of timely surgical intervention to improve distant metastases–free survival rates.

METHODOLOGY:

• Organ preservation has become an attractive alternative to surgery for patients with rectal cancer who achieve a clinical complete response after neoadjuvant therapy, with the risk for local regrowth after initial clinical complete response being around 25%-30%.
• The new study aimed to compare the risk for distant metastases between patients with local regrowth after watch and wait and patients with near-complete pathologic response managed by total mesorectal excision.
• A total of 508 patients with local regrowth were included from the International Watch & Wait Database, and 893 patients with near-complete pathologic response were included from the Spanish Rectal Cancer Project.
• The primary endpoint was distant metastases–free survival at 3 years from the decision to watch and wait or total mesorectal excision, and the secondary endpoints included possible risk factors associated with distant metastases.

TAKEAWAY:

• Patients with local regrowth had a significantly higher rate of distant metastases (rate, 22.8% vs 10.2%; P ≤.001) than those with near-complete pathologic response managed by total mesorectal excision.
• Distant metastases–free survival at 3 years was significantly worse for patients with local regrowth (rate, 75% vs 87%; P < .001).
• Independent risk factors for distant metastases included local regrowth (vs total mesorectal excision at reassessment; P = .001), ypT3-4 status (P = .016), and ypN+ status (P = .001) at the time of surgery.
• Patients with local regrowth had worse distant metastases–free survival across all pathologic stages than those managed by total mesorectal excision.

IN PRACTICE:

“Patients with local regrowth appear to have a higher risk for subsequent distant metastases development than patients with near-complete pathologic response managed by total mesorectal excision at restaging irrespective of final pathology,” the authors wrote.

SOURCE:

This study was led by Laura M. Fernandez, MD, of the Champalimaud Foundation in Lisbon, Portugal. It was published online in Journal of Clinical Oncology.

LIMITATIONS:

This study’s limitations included the heterogeneity in defining clinical complete response and the decision to watch and wait across different institutions. The majority of patients did not receive total neoadjuvant therapy regimens, which may have affected the generalizability of the findings. The study had a considerable amount of follow-up losses, which could have introduced bias.

DISCLOSURES:

This study was supported by the European Society of Surgical Oncology, the Champalimaud Foundation, the Bas Mulder Award, the Alpe d’HuZes Foundation, the Dutch Cancer Society, the European Research Council Advanced Grant, and the National Institute of Health and Research Manchester Biomedical Research Centre. Fernandez disclosed receiving grants from Johnson & Johnson. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Patients with rectal cancer managed by watch and wait and subsequent local regrowth have a higher risk for distant metastases than those undergoing immediate surgery. The new study highlights the importance of timely surgical intervention to improve distant metastases–free survival rates.

METHODOLOGY:

• Organ preservation has become an attractive alternative to surgery for patients with rectal cancer who achieve a clinical complete response after neoadjuvant therapy, with the risk for local regrowth after initial clinical complete response being around 25%-30%.
• The new study aimed to compare the risk for distant metastases between patients with local regrowth after watch and wait and patients with near-complete pathologic response managed by total mesorectal excision.
• A total of 508 patients with local regrowth were included from the International Watch & Wait Database, and 893 patients with near-complete pathologic response were included from the Spanish Rectal Cancer Project.
• The primary endpoint was distant metastases–free survival at 3 years from the decision to watch and wait or total mesorectal excision, and the secondary endpoints included possible risk factors associated with distant metastases.

TAKEAWAY:

• Patients with local regrowth had a significantly higher rate of distant metastases (rate, 22.8% vs 10.2%; P ≤.001) than those with near-complete pathologic response managed by total mesorectal excision.
• Distant metastases–free survival at 3 years was significantly worse for patients with local regrowth (rate, 75% vs 87%; P < .001).
• Independent risk factors for distant metastases included local regrowth (vs total mesorectal excision at reassessment; P = .001), ypT3-4 status (P = .016), and ypN+ status (P = .001) at the time of surgery.
• Patients with local regrowth had worse distant metastases–free survival across all pathologic stages than those managed by total mesorectal excision.

IN PRACTICE:

“Patients with local regrowth appear to have a higher risk for subsequent distant metastases development than patients with near-complete pathologic response managed by total mesorectal excision at restaging irrespective of final pathology,” the authors wrote.

SOURCE:

This study was led by Laura M. Fernandez, MD, of the Champalimaud Foundation in Lisbon, Portugal. It was published online in Journal of Clinical Oncology.

LIMITATIONS:

This study’s limitations included the heterogeneity in defining clinical complete response and the decision to watch and wait across different institutions. The majority of patients did not receive total neoadjuvant therapy regimens, which may have affected the generalizability of the findings. The study had a considerable amount of follow-up losses, which could have introduced bias.

DISCLOSURES:

This study was supported by the European Society of Surgical Oncology, the Champalimaud Foundation, the Bas Mulder Award, the Alpe d’HuZes Foundation, the Dutch Cancer Society, the European Research Council Advanced Grant, and the National Institute of Health and Research Manchester Biomedical Research Centre. Fernandez disclosed receiving grants from Johnson & Johnson. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Patients with rectal cancer managed by watch and wait and subsequent local regrowth have a higher risk for distant metastases than those undergoing immediate surgery. The new study highlights the importance of timely surgical intervention to improve distant metastases–free survival rates.

METHODOLOGY:

• Organ preservation has become an attractive alternative to surgery for patients with rectal cancer who achieve a clinical complete response after neoadjuvant therapy, with the risk for local regrowth after initial clinical complete response being around 25%-30%.
• The new study aimed to compare the risk for distant metastases between patients with local regrowth after watch and wait and patients with near-complete pathologic response managed by total mesorectal excision.
• A total of 508 patients with local regrowth were included from the International Watch & Wait Database, and 893 patients with near-complete pathologic response were included from the Spanish Rectal Cancer Project.
• The primary endpoint was distant metastases–free survival at 3 years from the decision to watch and wait or total mesorectal excision, and the secondary endpoints included possible risk factors associated with distant metastases.

TAKEAWAY:

• Patients with local regrowth had a significantly higher rate of distant metastases (rate, 22.8% vs 10.2%; P ≤.001) than those with near-complete pathologic response managed by total mesorectal excision.
• Distant metastases–free survival at 3 years was significantly worse for patients with local regrowth (rate, 75% vs 87%; P < .001).
• Independent risk factors for distant metastases included local regrowth (vs total mesorectal excision at reassessment; P = .001), ypT3-4 status (P = .016), and ypN+ status (P = .001) at the time of surgery.
• Patients with local regrowth had worse distant metastases–free survival across all pathologic stages than those managed by total mesorectal excision.

IN PRACTICE:

“Patients with local regrowth appear to have a higher risk for subsequent distant metastases development than patients with near-complete pathologic response managed by total mesorectal excision at restaging irrespective of final pathology,” the authors wrote.

SOURCE:

This study was led by Laura M. Fernandez, MD, of the Champalimaud Foundation in Lisbon, Portugal. It was published online in Journal of Clinical Oncology.

LIMITATIONS:

This study’s limitations included the heterogeneity in defining clinical complete response and the decision to watch and wait across different institutions. The majority of patients did not receive total neoadjuvant therapy regimens, which may have affected the generalizability of the findings. The study had a considerable amount of follow-up losses, which could have introduced bias.

DISCLOSURES:

This study was supported by the European Society of Surgical Oncology, the Champalimaud Foundation, the Bas Mulder Award, the Alpe d’HuZes Foundation, the Dutch Cancer Society, the European Research Council Advanced Grant, and the National Institute of Health and Research Manchester Biomedical Research Centre. Fernandez disclosed receiving grants from Johnson & Johnson. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

For millennia in medicine, alcohol, particularly red wine, carried a health halo; in small doses, it has historically been thought to have cardioprotective benefits. Michael Farkouh, MD, a professor of cardiology at Cedars-Sinai, estimates half the physicians still accept people having a drink or two a day. “That is still in practice, though the numbers are reducing,” he said.

But Farkouh no longer drinks alcohol, a position he has come to after getting more involved in research into the substance and his realization that many of the studies touting alcohol’s health benefits were flawed.

Today, alcohol sits alongside asbestos and tobacco as class 1 carcinogens. According to the World Health Organization, it has no known safe ingestible amount. In 2018, a blockbuster report in The Lancet found no amount of any kind of alcohol improves health. In early January, US Surgeon General Vivek Murthy called for adding cancer warnings to alcohol labels.

But the way doctors drink is far from black and white. For physicians, drinking habits are tied up in personal values, professional understanding of a substance with a confusing research history, and the fact alcohol is deeply ingrained in the social fabric of society — and in medicine. As thinking on alcohol shifts, this news organization spoke with physicians about their own drinking habits, how they counsel patients on it, and alcohol’s place in a field that works to keep people healthy.

 

Cultural Currency

From the days of Hippocrates, who believed alcohol could cure virtually every ailment, alcohol has held a large role in medicine. Through much of the 19th century, patent remedies like Hamlin’s Wizard Oil and the Seven Sutherland Sisters Hair Grower, contained alcohol — sometimes in concentrations exceeding 50%.

The first American Pharmacopoeia, published in 1820, even contained nine wine-based medicines. Throughout the second half of the 19th century, physicians largely debated alcohol’s role in medicine. However, a 1922 poll of members of the American Medical Association found that physicians were still using alcohol as a medicine for everything from heart attacks to animal bites.

Today, alcohol’s presence in medicine is, in some ways, representative of a realized cognitive dissonance.

“In my mind, alcohol has completely lost any illusion of benefit. It is a poison to almost every single organ in our body. Yet I’m currently engaged in a duel of being a physician who drinks in moderation and constantly judging myself for it,” said Tyra Fainstad, MD, an internist and an associate professor at CU Medicine in Denver.

Fainstad said every academic national conference she has attended has had a reception with multiple cash bars — and professional recruitment dinners regularly include at least the offering of alcohol. Private hospitals often have open bars at events.

“Drinking has historically been a way that people unwind, even in medicine,” said addiction psychiatrist Alexis Ritvo, MD. Ritvo — who said she drinks occasionally but much less than she used to after paying attention to how alcohol makes her feel and the harm alcohol can cause — noted that some occasions where alcohol is present socially in medicine don’t bother her. Alcohol is even an option at the addiction psychiatry conference, where attendees can exchange tickets for drinks. But last year, the event provided separate bars for alcoholic and nonalcoholic drinks.

“Our life is full of things that are contradictory or at odds,” Ritvo said. “We want things to either be wrong or right, appropriate or inappropriate, but just like all things, everything’s pretty nuanced.”

But there are examples of alcohol being a part of an event that are downright inappropriate, such as when she attended a fundraiser for a recovery facility that had an open bar.

Farkouh said alcohol at events can exclude others. (He recommends that instead of calling a social gathering “going out for drinks,” someone might say, “We’re getting together.”) He drinks mocktails or nonalcoholic beer at work events where alcohol is served.

Brian Dwinnell, MD, associate dean of student life at CU Medicine, said alcohol can quickly become the focus of an event — something he noticed at an annual kickball game between first- and second-year students that has historically served beer.

In recent years, school leadership has removed alcohol from his institution’s match day celebration and the kickball game. “Initially, there was some pushback from students,” he said of making these events dry, “but now, it’s just sort of accepted, and the events have been just as great as they were when we did provide alcohol.”

 

How Doctors Drink

Physicians may have a greater understanding of alcohol’s health harms. Still, they don’t necessarily drink less because of it, and whether they should becomes a question not just of health but also of the standards to which society holds medical professionals.

Data suggest physicians tend to drink at rates similar to those among the general population. A recent Medscape Medical News survey found nearly 60% of physicians have started drinking less.

Dwinnell said he is a long-time “wine connoisseur” and drinks on occasion. But he admitted that while he thinks about the health implications of alcohol more — and he has nixed it from various events for medical students — he does not believe his drinking habits have changed much.

Navya Mysore, MD, a family physician in New York City, said she has become interested in wine over the past few years, even taking classes to learn more about it. “I like understanding how it’s made, the regions it’s from, and how to pair it with food,” she said. Mysore admits she drank a little more than usual throughout the pandemic, yet today, she said her relationship with alcohol in moderation is related to family, community, and connection.

Fainstad, who drinks socially, said: “I think there’s an immeasurable quality to the social ritual of it. I think for better or worse — probably for worse — for many generations, alcohol has been a part of many meaningful traditions and rituals that we hold.”

Farkouh was quick to underscore the importance of social connection, and that alcohol reduces stress for some people. “I don’t want to take that away from people,” he said. But he also stated the importance of finding other ways to find social fulfillment and enjoyment — and said it’s essential for societal norms to shift to reflect this.

With emerging data, alcohol’s image in society is shifting. Ireland recently became the first country to pass regulation requiring all alcohol sold there to come with a cancer warning. All the clinicians interviewed for this article spoke about the increased acceptability of choosing not to drink for whatever reason.

In the context of alcohol, Dwinnell often asks his students, “What if you were out at a restaurant and you saw your mother’s surgeon there and they were intoxicated? Are you going to feel comfortable with that individual operating on your mother tomorrow or any time?” He added: “Physicians are held to a higher professional standard than those in other fields — and they should be. This is a high-stakes business.”

Dwinnell’s hypothetical question to students is a good one, albeit perhaps not always a fair one. “It’s important for people to realize that physicians are humans,” Mysore said. “We are people, we have lives, and we may choose to have habits that are not necessarily the healthiest for us.”

Fainstad said there’s no shame in medical professionals drinking on occasion. “You can’t be held accountable for something you don’t know about,” she said, acknowledging the known harms of alcohol and that there is still more to learn. But she does wonder how doctors who drank might be perceived in years to come. “I can imagine in a couple of decades, people could say, ‘Even doctors used to have a glass of wine with dinner.’”

 

‘Physicians Should Tighten Their Stances on Alcohol’

The 2020-2025 Dietary Guidelines suggest limiting intake to two alcoholic drinks or less daily for men and one drink or less for women or to choose not to drink. Farkouh said he skews toward the latter, encouraging patients to drink as little as possible or nothing at all. “If you take a holistic approach, physicians should tighten their stances on alcohol,” he said.

Ultimately, he said a randomized trial is warranted to address the risk for cardiovascular disease, in particular.

Of course, physicians vary in how they discuss the topic with patients.

Mysore said she regularly educates patients about pour size and ways to swap out alcoholic drinks with nonalcoholic ones. Outside of cases of addiction, she favors the idea of moderation. “I don’t really subscribe to all-or-nothing mindsets. If there’s something that you enjoy having as a part of your life, I don’t think there’s any reason why you need to eliminate it,” she said. “You just need to figure out what moderation looks like for you.”

Ritvo favors motivational interviewing and tries to understand someone’s relationship with alcohol.

Fainstad provides the Dietary Guidelines’ cutoffs to patients and educates them on the poisonous nature of the substance.

Clearer guidance from large governing bodies — potential changes around alcohol in the 2025-230 revision of the US Dietary Guidelines or cancer warnings on booze sold in the United States — are coming and could help streamline messaging.

And although he speaks with urgency about alcohol’s dangers, Farkouh emphasized the need for a judgment-free and patient-centered approach to conversations around drinking: “People have grown up with alcohol being acceptable, and it’s going to take time to change that.”

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

For millennia in medicine, alcohol, particularly red wine, carried a health halo; in small doses, it has historically been thought to have cardioprotective benefits. Michael Farkouh, MD, a professor of cardiology at Cedars-Sinai, estimates half the physicians still accept people having a drink or two a day. “That is still in practice, though the numbers are reducing,” he said.

But Farkouh no longer drinks alcohol, a position he has come to after getting more involved in research into the substance and his realization that many of the studies touting alcohol’s health benefits were flawed.

Today, alcohol sits alongside asbestos and tobacco as class 1 carcinogens. According to the World Health Organization, it has no known safe ingestible amount. In 2018, a blockbuster report in The Lancet found no amount of any kind of alcohol improves health. In early January, US Surgeon General Vivek Murthy called for adding cancer warnings to alcohol labels.

But the way doctors drink is far from black and white. For physicians, drinking habits are tied up in personal values, professional understanding of a substance with a confusing research history, and the fact alcohol is deeply ingrained in the social fabric of society — and in medicine. As thinking on alcohol shifts, this news organization spoke with physicians about their own drinking habits, how they counsel patients on it, and alcohol’s place in a field that works to keep people healthy.

 

Cultural Currency

From the days of Hippocrates, who believed alcohol could cure virtually every ailment, alcohol has held a large role in medicine. Through much of the 19th century, patent remedies like Hamlin’s Wizard Oil and the Seven Sutherland Sisters Hair Grower, contained alcohol — sometimes in concentrations exceeding 50%.

The first American Pharmacopoeia, published in 1820, even contained nine wine-based medicines. Throughout the second half of the 19th century, physicians largely debated alcohol’s role in medicine. However, a 1922 poll of members of the American Medical Association found that physicians were still using alcohol as a medicine for everything from heart attacks to animal bites.

Today, alcohol’s presence in medicine is, in some ways, representative of a realized cognitive dissonance.

“In my mind, alcohol has completely lost any illusion of benefit. It is a poison to almost every single organ in our body. Yet I’m currently engaged in a duel of being a physician who drinks in moderation and constantly judging myself for it,” said Tyra Fainstad, MD, an internist and an associate professor at CU Medicine in Denver.

Fainstad said every academic national conference she has attended has had a reception with multiple cash bars — and professional recruitment dinners regularly include at least the offering of alcohol. Private hospitals often have open bars at events.

“Drinking has historically been a way that people unwind, even in medicine,” said addiction psychiatrist Alexis Ritvo, MD. Ritvo — who said she drinks occasionally but much less than she used to after paying attention to how alcohol makes her feel and the harm alcohol can cause — noted that some occasions where alcohol is present socially in medicine don’t bother her. Alcohol is even an option at the addiction psychiatry conference, where attendees can exchange tickets for drinks. But last year, the event provided separate bars for alcoholic and nonalcoholic drinks.

“Our life is full of things that are contradictory or at odds,” Ritvo said. “We want things to either be wrong or right, appropriate or inappropriate, but just like all things, everything’s pretty nuanced.”

But there are examples of alcohol being a part of an event that are downright inappropriate, such as when she attended a fundraiser for a recovery facility that had an open bar.

Farkouh said alcohol at events can exclude others. (He recommends that instead of calling a social gathering “going out for drinks,” someone might say, “We’re getting together.”) He drinks mocktails or nonalcoholic beer at work events where alcohol is served.

Brian Dwinnell, MD, associate dean of student life at CU Medicine, said alcohol can quickly become the focus of an event — something he noticed at an annual kickball game between first- and second-year students that has historically served beer.

In recent years, school leadership has removed alcohol from his institution’s match day celebration and the kickball game. “Initially, there was some pushback from students,” he said of making these events dry, “but now, it’s just sort of accepted, and the events have been just as great as they were when we did provide alcohol.”

 

How Doctors Drink

Physicians may have a greater understanding of alcohol’s health harms. Still, they don’t necessarily drink less because of it, and whether they should becomes a question not just of health but also of the standards to which society holds medical professionals.

Data suggest physicians tend to drink at rates similar to those among the general population. A recent Medscape Medical News survey found nearly 60% of physicians have started drinking less.

Dwinnell said he is a long-time “wine connoisseur” and drinks on occasion. But he admitted that while he thinks about the health implications of alcohol more — and he has nixed it from various events for medical students — he does not believe his drinking habits have changed much.

Navya Mysore, MD, a family physician in New York City, said she has become interested in wine over the past few years, even taking classes to learn more about it. “I like understanding how it’s made, the regions it’s from, and how to pair it with food,” she said. Mysore admits she drank a little more than usual throughout the pandemic, yet today, she said her relationship with alcohol in moderation is related to family, community, and connection.

Fainstad, who drinks socially, said: “I think there’s an immeasurable quality to the social ritual of it. I think for better or worse — probably for worse — for many generations, alcohol has been a part of many meaningful traditions and rituals that we hold.”

Farkouh was quick to underscore the importance of social connection, and that alcohol reduces stress for some people. “I don’t want to take that away from people,” he said. But he also stated the importance of finding other ways to find social fulfillment and enjoyment — and said it’s essential for societal norms to shift to reflect this.

With emerging data, alcohol’s image in society is shifting. Ireland recently became the first country to pass regulation requiring all alcohol sold there to come with a cancer warning. All the clinicians interviewed for this article spoke about the increased acceptability of choosing not to drink for whatever reason.

In the context of alcohol, Dwinnell often asks his students, “What if you were out at a restaurant and you saw your mother’s surgeon there and they were intoxicated? Are you going to feel comfortable with that individual operating on your mother tomorrow or any time?” He added: “Physicians are held to a higher professional standard than those in other fields — and they should be. This is a high-stakes business.”

Dwinnell’s hypothetical question to students is a good one, albeit perhaps not always a fair one. “It’s important for people to realize that physicians are humans,” Mysore said. “We are people, we have lives, and we may choose to have habits that are not necessarily the healthiest for us.”

Fainstad said there’s no shame in medical professionals drinking on occasion. “You can’t be held accountable for something you don’t know about,” she said, acknowledging the known harms of alcohol and that there is still more to learn. But she does wonder how doctors who drank might be perceived in years to come. “I can imagine in a couple of decades, people could say, ‘Even doctors used to have a glass of wine with dinner.’”

 

‘Physicians Should Tighten Their Stances on Alcohol’

The 2020-2025 Dietary Guidelines suggest limiting intake to two alcoholic drinks or less daily for men and one drink or less for women or to choose not to drink. Farkouh said he skews toward the latter, encouraging patients to drink as little as possible or nothing at all. “If you take a holistic approach, physicians should tighten their stances on alcohol,” he said.

Ultimately, he said a randomized trial is warranted to address the risk for cardiovascular disease, in particular.

Of course, physicians vary in how they discuss the topic with patients.

Mysore said she regularly educates patients about pour size and ways to swap out alcoholic drinks with nonalcoholic ones. Outside of cases of addiction, she favors the idea of moderation. “I don’t really subscribe to all-or-nothing mindsets. If there’s something that you enjoy having as a part of your life, I don’t think there’s any reason why you need to eliminate it,” she said. “You just need to figure out what moderation looks like for you.”

Ritvo favors motivational interviewing and tries to understand someone’s relationship with alcohol.

Fainstad provides the Dietary Guidelines’ cutoffs to patients and educates them on the poisonous nature of the substance.

Clearer guidance from large governing bodies — potential changes around alcohol in the 2025-230 revision of the US Dietary Guidelines or cancer warnings on booze sold in the United States — are coming and could help streamline messaging.

And although he speaks with urgency about alcohol’s dangers, Farkouh emphasized the need for a judgment-free and patient-centered approach to conversations around drinking: “People have grown up with alcohol being acceptable, and it’s going to take time to change that.”

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

For millennia in medicine, alcohol, particularly red wine, carried a health halo; in small doses, it has historically been thought to have cardioprotective benefits. Michael Farkouh, MD, a professor of cardiology at Cedars-Sinai, estimates half the physicians still accept people having a drink or two a day. “That is still in practice, though the numbers are reducing,” he said.

But Farkouh no longer drinks alcohol, a position he has come to after getting more involved in research into the substance and his realization that many of the studies touting alcohol’s health benefits were flawed.

Today, alcohol sits alongside asbestos and tobacco as class 1 carcinogens. According to the World Health Organization, it has no known safe ingestible amount. In 2018, a blockbuster report in The Lancet found no amount of any kind of alcohol improves health. In early January, US Surgeon General Vivek Murthy called for adding cancer warnings to alcohol labels.

But the way doctors drink is far from black and white. For physicians, drinking habits are tied up in personal values, professional understanding of a substance with a confusing research history, and the fact alcohol is deeply ingrained in the social fabric of society — and in medicine. As thinking on alcohol shifts, this news organization spoke with physicians about their own drinking habits, how they counsel patients on it, and alcohol’s place in a field that works to keep people healthy.

 

Cultural Currency

From the days of Hippocrates, who believed alcohol could cure virtually every ailment, alcohol has held a large role in medicine. Through much of the 19th century, patent remedies like Hamlin’s Wizard Oil and the Seven Sutherland Sisters Hair Grower, contained alcohol — sometimes in concentrations exceeding 50%.

The first American Pharmacopoeia, published in 1820, even contained nine wine-based medicines. Throughout the second half of the 19th century, physicians largely debated alcohol’s role in medicine. However, a 1922 poll of members of the American Medical Association found that physicians were still using alcohol as a medicine for everything from heart attacks to animal bites.

Today, alcohol’s presence in medicine is, in some ways, representative of a realized cognitive dissonance.

“In my mind, alcohol has completely lost any illusion of benefit. It is a poison to almost every single organ in our body. Yet I’m currently engaged in a duel of being a physician who drinks in moderation and constantly judging myself for it,” said Tyra Fainstad, MD, an internist and an associate professor at CU Medicine in Denver.

Fainstad said every academic national conference she has attended has had a reception with multiple cash bars — and professional recruitment dinners regularly include at least the offering of alcohol. Private hospitals often have open bars at events.

“Drinking has historically been a way that people unwind, even in medicine,” said addiction psychiatrist Alexis Ritvo, MD. Ritvo — who said she drinks occasionally but much less than she used to after paying attention to how alcohol makes her feel and the harm alcohol can cause — noted that some occasions where alcohol is present socially in medicine don’t bother her. Alcohol is even an option at the addiction psychiatry conference, where attendees can exchange tickets for drinks. But last year, the event provided separate bars for alcoholic and nonalcoholic drinks.

“Our life is full of things that are contradictory or at odds,” Ritvo said. “We want things to either be wrong or right, appropriate or inappropriate, but just like all things, everything’s pretty nuanced.”

But there are examples of alcohol being a part of an event that are downright inappropriate, such as when she attended a fundraiser for a recovery facility that had an open bar.

Farkouh said alcohol at events can exclude others. (He recommends that instead of calling a social gathering “going out for drinks,” someone might say, “We’re getting together.”) He drinks mocktails or nonalcoholic beer at work events where alcohol is served.

Brian Dwinnell, MD, associate dean of student life at CU Medicine, said alcohol can quickly become the focus of an event — something he noticed at an annual kickball game between first- and second-year students that has historically served beer.

In recent years, school leadership has removed alcohol from his institution’s match day celebration and the kickball game. “Initially, there was some pushback from students,” he said of making these events dry, “but now, it’s just sort of accepted, and the events have been just as great as they were when we did provide alcohol.”

 

How Doctors Drink

Physicians may have a greater understanding of alcohol’s health harms. Still, they don’t necessarily drink less because of it, and whether they should becomes a question not just of health but also of the standards to which society holds medical professionals.

Data suggest physicians tend to drink at rates similar to those among the general population. A recent Medscape Medical News survey found nearly 60% of physicians have started drinking less.

Dwinnell said he is a long-time “wine connoisseur” and drinks on occasion. But he admitted that while he thinks about the health implications of alcohol more — and he has nixed it from various events for medical students — he does not believe his drinking habits have changed much.

Navya Mysore, MD, a family physician in New York City, said she has become interested in wine over the past few years, even taking classes to learn more about it. “I like understanding how it’s made, the regions it’s from, and how to pair it with food,” she said. Mysore admits she drank a little more than usual throughout the pandemic, yet today, she said her relationship with alcohol in moderation is related to family, community, and connection.

Fainstad, who drinks socially, said: “I think there’s an immeasurable quality to the social ritual of it. I think for better or worse — probably for worse — for many generations, alcohol has been a part of many meaningful traditions and rituals that we hold.”

Farkouh was quick to underscore the importance of social connection, and that alcohol reduces stress for some people. “I don’t want to take that away from people,” he said. But he also stated the importance of finding other ways to find social fulfillment and enjoyment — and said it’s essential for societal norms to shift to reflect this.

With emerging data, alcohol’s image in society is shifting. Ireland recently became the first country to pass regulation requiring all alcohol sold there to come with a cancer warning. All the clinicians interviewed for this article spoke about the increased acceptability of choosing not to drink for whatever reason.

In the context of alcohol, Dwinnell often asks his students, “What if you were out at a restaurant and you saw your mother’s surgeon there and they were intoxicated? Are you going to feel comfortable with that individual operating on your mother tomorrow or any time?” He added: “Physicians are held to a higher professional standard than those in other fields — and they should be. This is a high-stakes business.”

Dwinnell’s hypothetical question to students is a good one, albeit perhaps not always a fair one. “It’s important for people to realize that physicians are humans,” Mysore said. “We are people, we have lives, and we may choose to have habits that are not necessarily the healthiest for us.”

Fainstad said there’s no shame in medical professionals drinking on occasion. “You can’t be held accountable for something you don’t know about,” she said, acknowledging the known harms of alcohol and that there is still more to learn. But she does wonder how doctors who drank might be perceived in years to come. “I can imagine in a couple of decades, people could say, ‘Even doctors used to have a glass of wine with dinner.’”

 

‘Physicians Should Tighten Their Stances on Alcohol’

The 2020-2025 Dietary Guidelines suggest limiting intake to two alcoholic drinks or less daily for men and one drink or less for women or to choose not to drink. Farkouh said he skews toward the latter, encouraging patients to drink as little as possible or nothing at all. “If you take a holistic approach, physicians should tighten their stances on alcohol,” he said.

Ultimately, he said a randomized trial is warranted to address the risk for cardiovascular disease, in particular.

Of course, physicians vary in how they discuss the topic with patients.

Mysore said she regularly educates patients about pour size and ways to swap out alcoholic drinks with nonalcoholic ones. Outside of cases of addiction, she favors the idea of moderation. “I don’t really subscribe to all-or-nothing mindsets. If there’s something that you enjoy having as a part of your life, I don’t think there’s any reason why you need to eliminate it,” she said. “You just need to figure out what moderation looks like for you.”

Ritvo favors motivational interviewing and tries to understand someone’s relationship with alcohol.

Fainstad provides the Dietary Guidelines’ cutoffs to patients and educates them on the poisonous nature of the substance.

Clearer guidance from large governing bodies — potential changes around alcohol in the 2025-230 revision of the US Dietary Guidelines or cancer warnings on booze sold in the United States — are coming and could help streamline messaging.

And although he speaks with urgency about alcohol’s dangers, Farkouh emphasized the need for a judgment-free and patient-centered approach to conversations around drinking: “People have grown up with alcohol being acceptable, and it’s going to take time to change that.”

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

TOPLINE: 

Prostate-specific membrane antigen (PSMA)–PET detected metastatic disease in 46% of patients with high-risk prostate cancer previously classified as nonmetastatic by conventional imaging. Results were positive in 84% of patients, with polymetastatic disease found in 24% of cases.

METHODOLOGY:

• Recurrent nonmetastatic hormone-sensitive prostate cancer is characterized by increasing prostate-specific antigen (PSA) levels while naive or responsive to androgen deprivation therapy, without evidence of metastasis on conventional imaging.
• A post hoc, retrospective, cross-sectional analysis included 182 patients from four prospective studies conducted from September 2016 to September 2021, with participants having recurrent prostate cancer after radical prostatectomy, definitive radiotherapy, or salvage radiotherapy.
• Inclusion criteria encompassed PSA levels > 1.0 ng/mL after radical prostatectomy and salvage radiotherapy or > 2.0 ng/mL above nadir after definitive radiotherapy, PSA doubling time ≤ 9 months, and serum testosterone ≥ 150 ng/dL.
• Researchers at the University of California, Los Angeles, performed Gallium-68-PSMA-11 PET/CT imaging with a median injection of 5.0 mCi and uptake time of 61 minutes, with 98% of patients receiving CT contrast.

TAKEAWAY:

• PSMA-PET findings were positive in 80% of patients after radical prostatectomy, 92% after definitive radiotherapy, 85% after radical prostatectomy and salvage radiotherapy, and 84% overall (153 of 182 patients).
• Distant metastatic disease was detected in 34% of patients after radical prostatectomy, 56% after definitive radiotherapy, 60% after radical prostatectomy and salvage radiotherapy, and 46% overall.
• Polymetastatic disease (≥ 5 lesions) was identified in 19% of patients after radical prostatectomy, 36% after definitive radiotherapy, 23% after radical prostatectomy and salvage radiotherapy, and 24% overall.
• According to the authors, these findings suggest that patients’ high-risk nonmetastatic hormone-sensitive prostate cancers are understaged by conventional imaging.

IN PRACTICE:

“In a cohort of patients with high-risk hormone-sensitive prostate cancer without evidence of metastatic disease by conventional imaging, PSMA-PET results were positive in 84% of patients, detected M1 disease stage in 46% of patients, and found polymetastatic disease in 24% of patients. ... The results challenge the interpretation of previous studies, such as the EMBARK trial, and support the evolving role of PSMA-PET for patient selection in clinical and trial interventions in prostate cancer,” the authors of the new paper wrote. “Further studies are needed to assess its independent prognostic value and use for treatment guidance.”

SOURCE:

This study was led by Adrien Holzgreve, MD, and Wesley R. Armstrong, BS, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles. It was published online on January 3 in JAMA Network Open.

LIMITATIONS:

The analysis included significantly fewer patients treated with combined radical prostatectomy and salvage radiotherapy than the original EMBARK trial (29% vs 49%). Patients in this study had a lower median PSA doubling time and serum PSA level at enrollment than those in the EMBARK study. The retrospective nature of this study precluded systematic baseline imaging that would be standard for clinical trial enrollment. Additionally, while PSMA-PET offers the best diagnostic accuracy for prostate cancer staging, it can produce false-positive findings, particularly in bone metastases, with a positive predictive value of 0.84% in biochemical recurrence.

DISCLOSURES:

Holzgreve reported receiving personal fees from ABX advanced biochemical compounds outside the submitted work. This study was supported by grants from the Deutsche Forschungsgemeinschaft, the Prostate Cancer Foundation, and the Society of Nuclear Medicine and Molecular Imaging. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE: 

Prostate-specific membrane antigen (PSMA)–PET detected metastatic disease in 46% of patients with high-risk prostate cancer previously classified as nonmetastatic by conventional imaging. Results were positive in 84% of patients, with polymetastatic disease found in 24% of cases.

METHODOLOGY:

• Recurrent nonmetastatic hormone-sensitive prostate cancer is characterized by increasing prostate-specific antigen (PSA) levels while naive or responsive to androgen deprivation therapy, without evidence of metastasis on conventional imaging.
• A post hoc, retrospective, cross-sectional analysis included 182 patients from four prospective studies conducted from September 2016 to September 2021, with participants having recurrent prostate cancer after radical prostatectomy, definitive radiotherapy, or salvage radiotherapy.
• Inclusion criteria encompassed PSA levels > 1.0 ng/mL after radical prostatectomy and salvage radiotherapy or > 2.0 ng/mL above nadir after definitive radiotherapy, PSA doubling time ≤ 9 months, and serum testosterone ≥ 150 ng/dL.
• Researchers at the University of California, Los Angeles, performed Gallium-68-PSMA-11 PET/CT imaging with a median injection of 5.0 mCi and uptake time of 61 minutes, with 98% of patients receiving CT contrast.

TAKEAWAY:

• PSMA-PET findings were positive in 80% of patients after radical prostatectomy, 92% after definitive radiotherapy, 85% after radical prostatectomy and salvage radiotherapy, and 84% overall (153 of 182 patients).
• Distant metastatic disease was detected in 34% of patients after radical prostatectomy, 56% after definitive radiotherapy, 60% after radical prostatectomy and salvage radiotherapy, and 46% overall.
• Polymetastatic disease (≥ 5 lesions) was identified in 19% of patients after radical prostatectomy, 36% after definitive radiotherapy, 23% after radical prostatectomy and salvage radiotherapy, and 24% overall.
• According to the authors, these findings suggest that patients’ high-risk nonmetastatic hormone-sensitive prostate cancers are understaged by conventional imaging.

IN PRACTICE:

“In a cohort of patients with high-risk hormone-sensitive prostate cancer without evidence of metastatic disease by conventional imaging, PSMA-PET results were positive in 84% of patients, detected M1 disease stage in 46% of patients, and found polymetastatic disease in 24% of patients. ... The results challenge the interpretation of previous studies, such as the EMBARK trial, and support the evolving role of PSMA-PET for patient selection in clinical and trial interventions in prostate cancer,” the authors of the new paper wrote. “Further studies are needed to assess its independent prognostic value and use for treatment guidance.”

SOURCE:

This study was led by Adrien Holzgreve, MD, and Wesley R. Armstrong, BS, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles. It was published online on January 3 in JAMA Network Open.

LIMITATIONS:

The analysis included significantly fewer patients treated with combined radical prostatectomy and salvage radiotherapy than the original EMBARK trial (29% vs 49%). Patients in this study had a lower median PSA doubling time and serum PSA level at enrollment than those in the EMBARK study. The retrospective nature of this study precluded systematic baseline imaging that would be standard for clinical trial enrollment. Additionally, while PSMA-PET offers the best diagnostic accuracy for prostate cancer staging, it can produce false-positive findings, particularly in bone metastases, with a positive predictive value of 0.84% in biochemical recurrence.

DISCLOSURES:

Holzgreve reported receiving personal fees from ABX advanced biochemical compounds outside the submitted work. This study was supported by grants from the Deutsche Forschungsgemeinschaft, the Prostate Cancer Foundation, and the Society of Nuclear Medicine and Molecular Imaging. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE: 

Prostate-specific membrane antigen (PSMA)–PET detected metastatic disease in 46% of patients with high-risk prostate cancer previously classified as nonmetastatic by conventional imaging. Results were positive in 84% of patients, with polymetastatic disease found in 24% of cases.

METHODOLOGY:

• Recurrent nonmetastatic hormone-sensitive prostate cancer is characterized by increasing prostate-specific antigen (PSA) levels while naive or responsive to androgen deprivation therapy, without evidence of metastasis on conventional imaging.
• A post hoc, retrospective, cross-sectional analysis included 182 patients from four prospective studies conducted from September 2016 to September 2021, with participants having recurrent prostate cancer after radical prostatectomy, definitive radiotherapy, or salvage radiotherapy.
• Inclusion criteria encompassed PSA levels > 1.0 ng/mL after radical prostatectomy and salvage radiotherapy or > 2.0 ng/mL above nadir after definitive radiotherapy, PSA doubling time ≤ 9 months, and serum testosterone ≥ 150 ng/dL.
• Researchers at the University of California, Los Angeles, performed Gallium-68-PSMA-11 PET/CT imaging with a median injection of 5.0 mCi and uptake time of 61 minutes, with 98% of patients receiving CT contrast.

TAKEAWAY:

• PSMA-PET findings were positive in 80% of patients after radical prostatectomy, 92% after definitive radiotherapy, 85% after radical prostatectomy and salvage radiotherapy, and 84% overall (153 of 182 patients).
• Distant metastatic disease was detected in 34% of patients after radical prostatectomy, 56% after definitive radiotherapy, 60% after radical prostatectomy and salvage radiotherapy, and 46% overall.
• Polymetastatic disease (≥ 5 lesions) was identified in 19% of patients after radical prostatectomy, 36% after definitive radiotherapy, 23% after radical prostatectomy and salvage radiotherapy, and 24% overall.
• According to the authors, these findings suggest that patients’ high-risk nonmetastatic hormone-sensitive prostate cancers are understaged by conventional imaging.

IN PRACTICE:

“In a cohort of patients with high-risk hormone-sensitive prostate cancer without evidence of metastatic disease by conventional imaging, PSMA-PET results were positive in 84% of patients, detected M1 disease stage in 46% of patients, and found polymetastatic disease in 24% of patients. ... The results challenge the interpretation of previous studies, such as the EMBARK trial, and support the evolving role of PSMA-PET for patient selection in clinical and trial interventions in prostate cancer,” the authors of the new paper wrote. “Further studies are needed to assess its independent prognostic value and use for treatment guidance.”

SOURCE:

This study was led by Adrien Holzgreve, MD, and Wesley R. Armstrong, BS, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles. It was published online on January 3 in JAMA Network Open.

LIMITATIONS:

The analysis included significantly fewer patients treated with combined radical prostatectomy and salvage radiotherapy than the original EMBARK trial (29% vs 49%). Patients in this study had a lower median PSA doubling time and serum PSA level at enrollment than those in the EMBARK study. The retrospective nature of this study precluded systematic baseline imaging that would be standard for clinical trial enrollment. Additionally, while PSMA-PET offers the best diagnostic accuracy for prostate cancer staging, it can produce false-positive findings, particularly in bone metastases, with a positive predictive value of 0.84% in biochemical recurrence.

DISCLOSURES:

Holzgreve reported receiving personal fees from ABX advanced biochemical compounds outside the submitted work. This study was supported by grants from the Deutsche Forschungsgemeinschaft, the Prostate Cancer Foundation, and the Society of Nuclear Medicine and Molecular Imaging. Additional disclosures are noted in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

Do patients with early-stage non–small cell lung cancer (NSCLC) benefit from continuing immunotherapy beyond surgery?

The short answer: Oncologists don’t know for sure.

Since October 2023, the US Food and Drug Administration (FDA) has approved three checkpoint inhibitors — pembrolizumab (Keytruda), durvalumab (Imfinzi), and most recently nivolumab (Opdivo) — alongside platinum-containing chemotherapy before surgery and as monotherapy after surgery to treat resectable NSCLC.

But the trials leading to each approval had a major design flaw. The studies failed to distinguish when patients with resectable NSCLC benefited from immunotherapy — before surgery, after surgery, or at both points.

That missing piece has left oncologists without definitive guidance on how best to treat their patients with resectable disease. 

Jamie E. Chaft, MD, a thoracic medical oncologist and attending physician at Memorial Sloan Kettering Cancer Center in New York City, was “surprised” that the FDA had approved the three immunotherapy combination regimens without this clarity. Clinicians are now left with studies that can’t evaluate the contribution of the neoadjuvant and adjuvant phases, she said.

But that may soon change.

In July, an FDA advisory committee met to discuss the pending approval of durvalumab.

During this July meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) called out issues with AstraZeneca’s design of the trial, expressing concern that AstraZeneca had not followed the agency’s advice to compare patient outcomes with durvalumab in the neoadjuvant and adjuvant phases.

The ODAC panel ultimately voted unanimously in favor of requiring drug companies to demonstrate that patients need immunotherapy both before and after surgery in resectable NSCLC. Several panelists said this requirement should extend beyond NSCLC to other tumor types.

“We need to understand who needs what therapy when,” Daniel Spratt, MD, chairman of the FDA’s ODAC, told Medscape Medical News.

But even if the FDA does require drug companies to assess the benefit of immunotherapy pre- and post-surgery, will oncologists get the answers they need for their patients with resectable NSCLC? Or will the new costly trial design requirements dead-end progress in this space?

 

Treating Patients Without Clear Evidence

Despite the ODAC’s strong urging to require — not simply request — that drug companies show patients with resectable NSCLC benefit from immunotherapy in both the neoadjuvant and adjuvant settings, the advisory panel did not think durvalumab’s approval should be delayed until the neoadjuvant vs adjuvant question is answered.

A month later, in August, the FDA approved durvalumab for this indication.

Pembrolizumab (Keytruda, Merck) had already been approved 10 months earlier in the neoadjuvant and adjuvant settings in this setting. And most recently, in October, the FDA added nivolumab (Opdivo, Bristol Myers Squibb) to these approvals.

No trial, however, identified when patients benefited from the drug.

Without this understanding, patients may be taking immunotherapy unnecessarily, at significant expense and toxicity risk.

“Toxicities from immunotherapy can occur at any time after initiation,” said Joshua Eric Reuss, MD, a thoracic medical oncologist at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, DC. And these “risks definitely continue into the adjuvant period.”

So far, the available evidence does suggest that the neoadjuvant phase of immunotherapy confers the greatest benefit, while adjuvant immunotherapy — which can last a year or longer — may expose patients to more costs and toxicities, with no clear benefit.

A 2024 meta-analysis, which included four trials of neoadjuvant-adjuvant immunotherapy and one trial of neoadjuvant immunotherapy in resectable NSCLC, suggested that the addition of adjuvant immunotherapy did not improve event-free survival (hazard ratio [HR], 0.90; P = .59) or overall survival (HR, 1.18; P = .51) compared with neoadjuvant immunotherapy alone.

According to Spratt, “It’s very clear that the neoadjuvant phase is the more important of the two phases.” Given that, “we’re probably overtreating some patients,” said Spratt, also chairman of Radiation Oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University in Cleveland.

Chaft agreed that “there’s very little data that we need the postoperative phase, and what data we do have is post hoc and limited.”

This evidence gap “has created considerable dilemmas” for oncologists and patients who are faced with “the challenge of deciding which therapeutic options or approach are best suited for each individual,” experts wrote in recent consensus recommendations from the International Association for the Study of Lung Cancer.

Clinicians may ultimately be left to make decisions about prescribing postoperative immunotherapy based on their experience and comfort level.

When Chaft’s patients have a pathologic complete response with immunotherapy and chemotherapy in the neoadjuvant phase, “I’m comfortable stopping because the data would suggest they’re almost certainly cured,” she said.

For patients who have viable disease after neoadjuvant therapy, continuing an immunotherapy postoperatively when it didn’t work preoperatively “is not going to make a difference,” Chaft explained. In these cases, Chaft would look to enroll them in a clinical trial evaluating a different regimen because of the risk for relapse.

With patients who did well preoperatively but still have tumor left at the time of surgery, she would discuss continuing the immunotherapy or participating in a trial, she said.

All the FDA-approved regimens are covered by insurance, said Chaft. Clinicians are most comfortable with pembrolizumab because it is the most widely used immunotherapy in advanced NSCLC, she said. But, she added, “there’s really no strong differentiating data between any of the studies; all the results look very comparable.”

When assessing whether a patient may benefit from immunotherapy after surgery, Reuss looks at a range of factors, including disease stage, histology, gene mutations, and pathologic response. Reuss also weighs patient preferences. A patient coming from another country might only want a neoadjuvant regimen, for instance, he said.

That “isn’t exactly the kind of the level one evidence that one likes to see when making treatment decisions,” said Reuss. “Without prospective data, all we can do is cross-trial comparisons and assessment of subgroups.”

If a new regimen comes along that improves outcomes or decision-making, “I think we would pivot to that in a heartbeat,” he said.

 

But Will FDA Follow ODAC’s Recommendation?

“ODAC has made their point clear,” said Chaft. “Our patients deserve to know that whatever added risk and cost they’re incurring is merited by a clinical outcome.”

Despite the ODAC’s recommendation, it’s not guaranteed that the FDA will follow it.

An FDA spokesperson did not confirm the agency’s decision on the matter but noted that the FDA is “incorporating the panel’s advice.”

Spratt thinks that, going forward, companies will be held to “a higher bar,” but it’s unclear what that bar will look like.

“Whether this is a mandate or a strong recommendation, I think industry is definitely paying attention,” Spratt said. Companies that do not follow the guidance may risk not having their drug approved, “unless it’s just an absolute huge slam dunk of a major benefit to patients.”

In fact, according to Chaft, drug makers seeking approvals of novel entities in this space “won’t have a choice” but to follow any new trial design requirements from the FDA.

Still, getting answers may be a challenge.

Drug companies with immunotherapies already on the market are unlikely to invest the resources to conduct trials comparing the neoadjuvant and adjuvant settings, said Chaft. “It will take too long and cost too much,” she said.

And it remains unclear whether drug companies will decide to stop pursuing novel agents if approvals will ultimately require more expensive and time-consuming trials.

According to Chaft, oncologists have been discussing protocols that could help fill the knowledge gaps. Such trials will be conducted by the National Cancer Institute’s Cooperative Groups, she noted. But it’s early days.

For the time being, with comparative data from phase 3 trials years away, oncologists will have to work with the limited evidence and individual patients in front of them.

Chaft disclosed ties with AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genentech/Roche, Guardant Health, Janssen Pharmaceuticals, Eli Lilly, and Merck. Reuss disclosed ties with AstraZeneca, Arcus, AbbVie, Bristol Myers Squibb, CatalYm, Daiichi Sankyo, and Eli Lilly, and that Georgetown has received research funding from Genentech/Roche, Verastem, Nuvalent, LUNGevity Foundation, Exelixis, Arcus, and Revolution Medicines. Spratt disclosed ties with Astellas, AstraZeneca, Bayer, Boston Scientific, Janssen Pharmaceuticals, Novartis, and Pfizer.

A version of this article appeared on Medscape.com.

Do patients with early-stage non–small cell lung cancer (NSCLC) benefit from continuing immunotherapy beyond surgery?

The short answer: Oncologists don’t know for sure.

Since October 2023, the US Food and Drug Administration (FDA) has approved three checkpoint inhibitors — pembrolizumab (Keytruda), durvalumab (Imfinzi), and most recently nivolumab (Opdivo) — alongside platinum-containing chemotherapy before surgery and as monotherapy after surgery to treat resectable NSCLC.

But the trials leading to each approval had a major design flaw. The studies failed to distinguish when patients with resectable NSCLC benefited from immunotherapy — before surgery, after surgery, or at both points.

That missing piece has left oncologists without definitive guidance on how best to treat their patients with resectable disease. 

Jamie E. Chaft, MD, a thoracic medical oncologist and attending physician at Memorial Sloan Kettering Cancer Center in New York City, was “surprised” that the FDA had approved the three immunotherapy combination regimens without this clarity. Clinicians are now left with studies that can’t evaluate the contribution of the neoadjuvant and adjuvant phases, she said.

But that may soon change.

In July, an FDA advisory committee met to discuss the pending approval of durvalumab.

During this July meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) called out issues with AstraZeneca’s design of the trial, expressing concern that AstraZeneca had not followed the agency’s advice to compare patient outcomes with durvalumab in the neoadjuvant and adjuvant phases.

The ODAC panel ultimately voted unanimously in favor of requiring drug companies to demonstrate that patients need immunotherapy both before and after surgery in resectable NSCLC. Several panelists said this requirement should extend beyond NSCLC to other tumor types.

“We need to understand who needs what therapy when,” Daniel Spratt, MD, chairman of the FDA’s ODAC, told Medscape Medical News.

But even if the FDA does require drug companies to assess the benefit of immunotherapy pre- and post-surgery, will oncologists get the answers they need for their patients with resectable NSCLC? Or will the new costly trial design requirements dead-end progress in this space?

 

Treating Patients Without Clear Evidence

Despite the ODAC’s strong urging to require — not simply request — that drug companies show patients with resectable NSCLC benefit from immunotherapy in both the neoadjuvant and adjuvant settings, the advisory panel did not think durvalumab’s approval should be delayed until the neoadjuvant vs adjuvant question is answered.

A month later, in August, the FDA approved durvalumab for this indication.

Pembrolizumab (Keytruda, Merck) had already been approved 10 months earlier in the neoadjuvant and adjuvant settings in this setting. And most recently, in October, the FDA added nivolumab (Opdivo, Bristol Myers Squibb) to these approvals.

No trial, however, identified when patients benefited from the drug.

Without this understanding, patients may be taking immunotherapy unnecessarily, at significant expense and toxicity risk.

“Toxicities from immunotherapy can occur at any time after initiation,” said Joshua Eric Reuss, MD, a thoracic medical oncologist at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, DC. And these “risks definitely continue into the adjuvant period.”

So far, the available evidence does suggest that the neoadjuvant phase of immunotherapy confers the greatest benefit, while adjuvant immunotherapy — which can last a year or longer — may expose patients to more costs and toxicities, with no clear benefit.

A 2024 meta-analysis, which included four trials of neoadjuvant-adjuvant immunotherapy and one trial of neoadjuvant immunotherapy in resectable NSCLC, suggested that the addition of adjuvant immunotherapy did not improve event-free survival (hazard ratio [HR], 0.90; P = .59) or overall survival (HR, 1.18; P = .51) compared with neoadjuvant immunotherapy alone.

According to Spratt, “It’s very clear that the neoadjuvant phase is the more important of the two phases.” Given that, “we’re probably overtreating some patients,” said Spratt, also chairman of Radiation Oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University in Cleveland.

Chaft agreed that “there’s very little data that we need the postoperative phase, and what data we do have is post hoc and limited.”

This evidence gap “has created considerable dilemmas” for oncologists and patients who are faced with “the challenge of deciding which therapeutic options or approach are best suited for each individual,” experts wrote in recent consensus recommendations from the International Association for the Study of Lung Cancer.

Clinicians may ultimately be left to make decisions about prescribing postoperative immunotherapy based on their experience and comfort level.

When Chaft’s patients have a pathologic complete response with immunotherapy and chemotherapy in the neoadjuvant phase, “I’m comfortable stopping because the data would suggest they’re almost certainly cured,” she said.

For patients who have viable disease after neoadjuvant therapy, continuing an immunotherapy postoperatively when it didn’t work preoperatively “is not going to make a difference,” Chaft explained. In these cases, Chaft would look to enroll them in a clinical trial evaluating a different regimen because of the risk for relapse.

With patients who did well preoperatively but still have tumor left at the time of surgery, she would discuss continuing the immunotherapy or participating in a trial, she said.

All the FDA-approved regimens are covered by insurance, said Chaft. Clinicians are most comfortable with pembrolizumab because it is the most widely used immunotherapy in advanced NSCLC, she said. But, she added, “there’s really no strong differentiating data between any of the studies; all the results look very comparable.”

When assessing whether a patient may benefit from immunotherapy after surgery, Reuss looks at a range of factors, including disease stage, histology, gene mutations, and pathologic response. Reuss also weighs patient preferences. A patient coming from another country might only want a neoadjuvant regimen, for instance, he said.

That “isn’t exactly the kind of the level one evidence that one likes to see when making treatment decisions,” said Reuss. “Without prospective data, all we can do is cross-trial comparisons and assessment of subgroups.”

If a new regimen comes along that improves outcomes or decision-making, “I think we would pivot to that in a heartbeat,” he said.

 

But Will FDA Follow ODAC’s Recommendation?

“ODAC has made their point clear,” said Chaft. “Our patients deserve to know that whatever added risk and cost they’re incurring is merited by a clinical outcome.”

Despite the ODAC’s recommendation, it’s not guaranteed that the FDA will follow it.

An FDA spokesperson did not confirm the agency’s decision on the matter but noted that the FDA is “incorporating the panel’s advice.”

Spratt thinks that, going forward, companies will be held to “a higher bar,” but it’s unclear what that bar will look like.

“Whether this is a mandate or a strong recommendation, I think industry is definitely paying attention,” Spratt said. Companies that do not follow the guidance may risk not having their drug approved, “unless it’s just an absolute huge slam dunk of a major benefit to patients.”

In fact, according to Chaft, drug makers seeking approvals of novel entities in this space “won’t have a choice” but to follow any new trial design requirements from the FDA.

Still, getting answers may be a challenge.

Drug companies with immunotherapies already on the market are unlikely to invest the resources to conduct trials comparing the neoadjuvant and adjuvant settings, said Chaft. “It will take too long and cost too much,” she said.

And it remains unclear whether drug companies will decide to stop pursuing novel agents if approvals will ultimately require more expensive and time-consuming trials.

According to Chaft, oncologists have been discussing protocols that could help fill the knowledge gaps. Such trials will be conducted by the National Cancer Institute’s Cooperative Groups, she noted. But it’s early days.

For the time being, with comparative data from phase 3 trials years away, oncologists will have to work with the limited evidence and individual patients in front of them.

Chaft disclosed ties with AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genentech/Roche, Guardant Health, Janssen Pharmaceuticals, Eli Lilly, and Merck. Reuss disclosed ties with AstraZeneca, Arcus, AbbVie, Bristol Myers Squibb, CatalYm, Daiichi Sankyo, and Eli Lilly, and that Georgetown has received research funding from Genentech/Roche, Verastem, Nuvalent, LUNGevity Foundation, Exelixis, Arcus, and Revolution Medicines. Spratt disclosed ties with Astellas, AstraZeneca, Bayer, Boston Scientific, Janssen Pharmaceuticals, Novartis, and Pfizer.

A version of this article appeared on Medscape.com.

Do patients with early-stage non–small cell lung cancer (NSCLC) benefit from continuing immunotherapy beyond surgery?

The short answer: Oncologists don’t know for sure.

Since October 2023, the US Food and Drug Administration (FDA) has approved three checkpoint inhibitors — pembrolizumab (Keytruda), durvalumab (Imfinzi), and most recently nivolumab (Opdivo) — alongside platinum-containing chemotherapy before surgery and as monotherapy after surgery to treat resectable NSCLC.

But the trials leading to each approval had a major design flaw. The studies failed to distinguish when patients with resectable NSCLC benefited from immunotherapy — before surgery, after surgery, or at both points.

That missing piece has left oncologists without definitive guidance on how best to treat their patients with resectable disease. 

Jamie E. Chaft, MD, a thoracic medical oncologist and attending physician at Memorial Sloan Kettering Cancer Center in New York City, was “surprised” that the FDA had approved the three immunotherapy combination regimens without this clarity. Clinicians are now left with studies that can’t evaluate the contribution of the neoadjuvant and adjuvant phases, she said.

But that may soon change.

In July, an FDA advisory committee met to discuss the pending approval of durvalumab.

During this July meeting, the FDA’s Oncologic Drugs Advisory Committee (ODAC) called out issues with AstraZeneca’s design of the trial, expressing concern that AstraZeneca had not followed the agency’s advice to compare patient outcomes with durvalumab in the neoadjuvant and adjuvant phases.

The ODAC panel ultimately voted unanimously in favor of requiring drug companies to demonstrate that patients need immunotherapy both before and after surgery in resectable NSCLC. Several panelists said this requirement should extend beyond NSCLC to other tumor types.

“We need to understand who needs what therapy when,” Daniel Spratt, MD, chairman of the FDA’s ODAC, told Medscape Medical News.

But even if the FDA does require drug companies to assess the benefit of immunotherapy pre- and post-surgery, will oncologists get the answers they need for their patients with resectable NSCLC? Or will the new costly trial design requirements dead-end progress in this space?

 

Treating Patients Without Clear Evidence

Despite the ODAC’s strong urging to require — not simply request — that drug companies show patients with resectable NSCLC benefit from immunotherapy in both the neoadjuvant and adjuvant settings, the advisory panel did not think durvalumab’s approval should be delayed until the neoadjuvant vs adjuvant question is answered.

A month later, in August, the FDA approved durvalumab for this indication.

Pembrolizumab (Keytruda, Merck) had already been approved 10 months earlier in the neoadjuvant and adjuvant settings in this setting. And most recently, in October, the FDA added nivolumab (Opdivo, Bristol Myers Squibb) to these approvals.

No trial, however, identified when patients benefited from the drug.

Without this understanding, patients may be taking immunotherapy unnecessarily, at significant expense and toxicity risk.

“Toxicities from immunotherapy can occur at any time after initiation,” said Joshua Eric Reuss, MD, a thoracic medical oncologist at Georgetown University’s Lombardi Comprehensive Cancer Center in Washington, DC. And these “risks definitely continue into the adjuvant period.”

So far, the available evidence does suggest that the neoadjuvant phase of immunotherapy confers the greatest benefit, while adjuvant immunotherapy — which can last a year or longer — may expose patients to more costs and toxicities, with no clear benefit.

A 2024 meta-analysis, which included four trials of neoadjuvant-adjuvant immunotherapy and one trial of neoadjuvant immunotherapy in resectable NSCLC, suggested that the addition of adjuvant immunotherapy did not improve event-free survival (hazard ratio [HR], 0.90; P = .59) or overall survival (HR, 1.18; P = .51) compared with neoadjuvant immunotherapy alone.

According to Spratt, “It’s very clear that the neoadjuvant phase is the more important of the two phases.” Given that, “we’re probably overtreating some patients,” said Spratt, also chairman of Radiation Oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University in Cleveland.

Chaft agreed that “there’s very little data that we need the postoperative phase, and what data we do have is post hoc and limited.”

This evidence gap “has created considerable dilemmas” for oncologists and patients who are faced with “the challenge of deciding which therapeutic options or approach are best suited for each individual,” experts wrote in recent consensus recommendations from the International Association for the Study of Lung Cancer.

Clinicians may ultimately be left to make decisions about prescribing postoperative immunotherapy based on their experience and comfort level.

When Chaft’s patients have a pathologic complete response with immunotherapy and chemotherapy in the neoadjuvant phase, “I’m comfortable stopping because the data would suggest they’re almost certainly cured,” she said.

For patients who have viable disease after neoadjuvant therapy, continuing an immunotherapy postoperatively when it didn’t work preoperatively “is not going to make a difference,” Chaft explained. In these cases, Chaft would look to enroll them in a clinical trial evaluating a different regimen because of the risk for relapse.

With patients who did well preoperatively but still have tumor left at the time of surgery, she would discuss continuing the immunotherapy or participating in a trial, she said.

All the FDA-approved regimens are covered by insurance, said Chaft. Clinicians are most comfortable with pembrolizumab because it is the most widely used immunotherapy in advanced NSCLC, she said. But, she added, “there’s really no strong differentiating data between any of the studies; all the results look very comparable.”

When assessing whether a patient may benefit from immunotherapy after surgery, Reuss looks at a range of factors, including disease stage, histology, gene mutations, and pathologic response. Reuss also weighs patient preferences. A patient coming from another country might only want a neoadjuvant regimen, for instance, he said.

That “isn’t exactly the kind of the level one evidence that one likes to see when making treatment decisions,” said Reuss. “Without prospective data, all we can do is cross-trial comparisons and assessment of subgroups.”

If a new regimen comes along that improves outcomes or decision-making, “I think we would pivot to that in a heartbeat,” he said.

 

But Will FDA Follow ODAC’s Recommendation?

“ODAC has made their point clear,” said Chaft. “Our patients deserve to know that whatever added risk and cost they’re incurring is merited by a clinical outcome.”

Despite the ODAC’s recommendation, it’s not guaranteed that the FDA will follow it.

An FDA spokesperson did not confirm the agency’s decision on the matter but noted that the FDA is “incorporating the panel’s advice.”

Spratt thinks that, going forward, companies will be held to “a higher bar,” but it’s unclear what that bar will look like.

“Whether this is a mandate or a strong recommendation, I think industry is definitely paying attention,” Spratt said. Companies that do not follow the guidance may risk not having their drug approved, “unless it’s just an absolute huge slam dunk of a major benefit to patients.”

In fact, according to Chaft, drug makers seeking approvals of novel entities in this space “won’t have a choice” but to follow any new trial design requirements from the FDA.

Still, getting answers may be a challenge.

Drug companies with immunotherapies already on the market are unlikely to invest the resources to conduct trials comparing the neoadjuvant and adjuvant settings, said Chaft. “It will take too long and cost too much,” she said.

And it remains unclear whether drug companies will decide to stop pursuing novel agents if approvals will ultimately require more expensive and time-consuming trials.

According to Chaft, oncologists have been discussing protocols that could help fill the knowledge gaps. Such trials will be conducted by the National Cancer Institute’s Cooperative Groups, she noted. But it’s early days.

For the time being, with comparative data from phase 3 trials years away, oncologists will have to work with the limited evidence and individual patients in front of them.

Chaft disclosed ties with AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Genentech/Roche, Guardant Health, Janssen Pharmaceuticals, Eli Lilly, and Merck. Reuss disclosed ties with AstraZeneca, Arcus, AbbVie, Bristol Myers Squibb, CatalYm, Daiichi Sankyo, and Eli Lilly, and that Georgetown has received research funding from Genentech/Roche, Verastem, Nuvalent, LUNGevity Foundation, Exelixis, Arcus, and Revolution Medicines. Spratt disclosed ties with Astellas, AstraZeneca, Bayer, Boston Scientific, Janssen Pharmaceuticals, Novartis, and Pfizer.

A version of this article appeared on Medscape.com.

The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.

First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue. 

“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”

As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs). 

“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.

 

‘Reverse Engineering’

In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. 

Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.

“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer? 

Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand. 

“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”

In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.

 

Cell Therapies Include CAR T Cells and TCRT

In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.

In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).

In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner. 

“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.

TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies. 

Betof Warner takes Medscape Medical News through the history and ongoing investigations of cellular therapies for solid tumors, including her own research on these treatments. 

 

Decades in the Making

The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.

Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics. 

“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.” 

Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.

“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.

In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas. 

The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.

Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”

 

Risk-Benefit Profiles Depend on Mechanism of Action

If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor. 

“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.

A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.

“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”

A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner. 

In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes. 

“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”

 

Promise of PRAME

Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study. 

“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”

Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).

The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.

Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile. 

 

Accelerated Approvals, Boxed Warnings

The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT. 

Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.

With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.

The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses. 

The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).

In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel. 

The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.

 

New Hope for Patients

Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.

“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”

For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.

“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.

Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.

 

A version of this article appeared on Medscape.com.

The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.

First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue. 

“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”

As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs). 

“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.

 

‘Reverse Engineering’

In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. 

Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.

“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer? 

Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand. 

“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”

In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.

 

Cell Therapies Include CAR T Cells and TCRT

In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.

In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).

In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner. 

“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.

TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies. 

Betof Warner takes Medscape Medical News through the history and ongoing investigations of cellular therapies for solid tumors, including her own research on these treatments. 

 

Decades in the Making

The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.

Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics. 

“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.” 

Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.

“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.

In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas. 

The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.

Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”

 

Risk-Benefit Profiles Depend on Mechanism of Action

If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor. 

“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.

A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.

“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”

A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner. 

In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes. 

“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”

 

Promise of PRAME

Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study. 

“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”

Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).

The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.

Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile. 

 

Accelerated Approvals, Boxed Warnings

The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT. 

Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.

With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.

The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses. 

The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).

In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel. 

The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.

 

New Hope for Patients

Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.

“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”

For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.

“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.

Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.

 

A version of this article appeared on Medscape.com.

The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.

First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue. 

“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”

As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs). 

“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.

 

‘Reverse Engineering’

In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. 

Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.

“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer? 

Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand. 

“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”

In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.

 

Cell Therapies Include CAR T Cells and TCRT

In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.

In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).

In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner. 

“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.

TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies. 

Betof Warner takes Medscape Medical News through the history and ongoing investigations of cellular therapies for solid tumors, including her own research on these treatments. 

 

Decades in the Making

The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.

Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics. 

“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.” 

Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.

“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.

In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas. 

The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.

Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”

 

Risk-Benefit Profiles Depend on Mechanism of Action

If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor. 

“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.

A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.

“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”

A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner. 

In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes. 

“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”

 

Promise of PRAME

Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study. 

“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”

Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).

The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.

Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile. 

 

Accelerated Approvals, Boxed Warnings

The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT. 

Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.

With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.

The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses. 

The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).

In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel. 

The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.

 

New Hope for Patients

Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.

“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”

For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.

“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.

Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.

 

A version of this article appeared on Medscape.com.

Results from the British COLO-DETECT trial add to the growing body of evidence supporting the use of artificial intelligence (AI)–aided colonoscopy to increase premalignant colorectal polyp detection in routine colonoscopy practice.

Colin J. Rees, a professor of gastroenterology in the Faculty of Medical Sciences at Newcastle University in Newcastle upon Tyne, England, and colleagues compared the real-world clinical effectiveness of computer-aided detection (CADe)–assisted colonoscopy using an “intelligent” module with that of standard colonoscopy in a study in The Lancet Gastroenterology & Hepatology.

They found the GI Genius Intelligent Endoscopy Module (Medtronic) increased the mean number of adenomas detected per procedure and the adenoma detection rate, especially for small, flat (type 0-IIa) polyps, and sessile serrated lesions, which are more likely to be missed.

“Missed sessile serrated lesions disproportionately increase the risk of post-colonoscopy colorectal cancer, thus the adoption of GI Genius into routine colonoscopy practice could not only increase polyp detection but also reduce the incidence of post-colonoscopy colorectal cancer,” the investigators wrote.

“AI is going to have a major impact upon most aspects of healthcare. Some areas of medical practice are now well established, and some are still in evolution,” Rees, who is also president of the British Society of Gastroenterology, said in an interview. “Within gastroenterology, the role of AI in endoscopic diagnostics is also evolving. The COLO-DETECT trial demonstrates that AI increases detection of lesions, and work is ongoing to see how AI might help with characterization and other elements of endoscopic practice.”

 

Study Details

The multicenter, open-label, parallel-arm, pragmatic randomized controlled trial was conducted at 12 National Health Service hospitals in England. The study cohort consisted of adults ≥ 18 years undergoing colorectal cancer (CRC) screening or colonoscopy for gastrointestinal symptom surveillance owing to personal or family history.

Recruiting staff, participants, and colonoscopists were unmasked to allocation, whereas histopathologists, cochief investigators, and trial statisticians were masked.

CADe-assisted colonoscopy consisted of standard colonoscopy plus the GI Genius module active for at least the entire inspection phase of colonoscope withdrawal.

The primary outcome was mean adenomas per procedure (total number of adenomas detected divided by total number of procedures). The key secondary outcome was adenoma detection rate (proportion of colonoscopies with at least one adenoma).

From March 2021 to April 2023, the investigators recruited 2032 participants, 55.7% men, with a mean cohort age of 62.4 years and randomly assigned them to CADe-assisted colonoscopy (n = 1015) or to standard colonoscopy (n = 1017). Of these, 60.6% were undergoing screening and 39.4% had symptomatic indications.

Mean adenomas per procedure were 1.56 (SD, 2.82; n = 1001 participants with data) in the CADe-assisted group vs 1.21 (n = 1009) in the standard group, for an adjusted mean difference of 0.36 (95% CI, 0.14-0.57; adjusted incidence rate ratio, 1.30; 95% CI, 1.15-1.47; P < .0001).

Adenomas were detected in 555 (56.6%) of 980 participants in the CADe-assisted group vs 477 (48.4%) of 986 in the standard group, representing a proportion difference of 8.3% (95% CI, 3.9-12.7; adjusted odds ratio, 1.47; 95% CI, 1.21-1.78; P < .0001).

As to safety, adverse events were numerically comparable in both the intervention and control groups, with overall events 25 vs 19 and serious events 4 vs 6. On independent review, no adverse events in the CADe-assisted colonoscopy group were related to GI Genius.

 

Offering a US perspective on the study, Nabil M. Mansour, MD, an associate professor and director of the McNair General GI Clinic at Baylor College of Medicine in Houston, Texas, said GI Genius and other CADe systems represent a significant advance over standard colonoscopy for identifying premalignant polyps. “While the data have been mixed, most studies, particularly randomized controlled trials have shown significant improvements with CADe in detection both terms of in adenomas per colonoscopy and reductions in adenoma miss rate,” he said in an interview.

He added that the main utility of CADe is for asymptomatic patients undergoing average-risk screening and surveillance colonoscopy for CRC screening and prevention, as well as for those with positive stool-based screening tests, “though there is no downside to using it in symptomatic patients as well.” Though AI colonoscopy likely still stands at < 50% of endoscopy centers overall, and is used mainly at academic centers, his clinic has been using it for the past year.

The main question, Mansour cautioned, is whether increased detection of small polyps will actually reduce CRC incidence or mortality, and it will likely be several years before clear, concrete data can answer that.

“Most studies have shown the improvement in adenoma detection is mainly for diminutive polyps < 5 mm in diameter, but whether that will actually translate to substantive improvements in hard outcomes is as yet unknown,” he said. “But if gastroenterologists are interested in doing everything they can today to help improve detection rates and lower miss rates of premalignant polyps, serious consideration should be given to adopting the use of CADe in practice.”

This study was supported by Medtronic. Rees reported receiving grant funding from ARC Medical, Norgine, Medtronic, 3-D Matrix, and Olympus Medical, and has been an expert witness for ARC Medical. Other authors disclosed receiving research funding, honoraria, or travel expenses from Medtronic or other private companies. Mansour had no competing interests to declare.

A version of this article appeared on Medscape.com.

Results from the British COLO-DETECT trial add to the growing body of evidence supporting the use of artificial intelligence (AI)–aided colonoscopy to increase premalignant colorectal polyp detection in routine colonoscopy practice.

Colin J. Rees, a professor of gastroenterology in the Faculty of Medical Sciences at Newcastle University in Newcastle upon Tyne, England, and colleagues compared the real-world clinical effectiveness of computer-aided detection (CADe)–assisted colonoscopy using an “intelligent” module with that of standard colonoscopy in a study in The Lancet Gastroenterology & Hepatology.

They found the GI Genius Intelligent Endoscopy Module (Medtronic) increased the mean number of adenomas detected per procedure and the adenoma detection rate, especially for small, flat (type 0-IIa) polyps, and sessile serrated lesions, which are more likely to be missed.

“Missed sessile serrated lesions disproportionately increase the risk of post-colonoscopy colorectal cancer, thus the adoption of GI Genius into routine colonoscopy practice could not only increase polyp detection but also reduce the incidence of post-colonoscopy colorectal cancer,” the investigators wrote.

“AI is going to have a major impact upon most aspects of healthcare. Some areas of medical practice are now well established, and some are still in evolution,” Rees, who is also president of the British Society of Gastroenterology, said in an interview. “Within gastroenterology, the role of AI in endoscopic diagnostics is also evolving. The COLO-DETECT trial demonstrates that AI increases detection of lesions, and work is ongoing to see how AI might help with characterization and other elements of endoscopic practice.”

 

Study Details

The multicenter, open-label, parallel-arm, pragmatic randomized controlled trial was conducted at 12 National Health Service hospitals in England. The study cohort consisted of adults ≥ 18 years undergoing colorectal cancer (CRC) screening or colonoscopy for gastrointestinal symptom surveillance owing to personal or family history.

Recruiting staff, participants, and colonoscopists were unmasked to allocation, whereas histopathologists, cochief investigators, and trial statisticians were masked.

CADe-assisted colonoscopy consisted of standard colonoscopy plus the GI Genius module active for at least the entire inspection phase of colonoscope withdrawal.

The primary outcome was mean adenomas per procedure (total number of adenomas detected divided by total number of procedures). The key secondary outcome was adenoma detection rate (proportion of colonoscopies with at least one adenoma).

From March 2021 to April 2023, the investigators recruited 2032 participants, 55.7% men, with a mean cohort age of 62.4 years and randomly assigned them to CADe-assisted colonoscopy (n = 1015) or to standard colonoscopy (n = 1017). Of these, 60.6% were undergoing screening and 39.4% had symptomatic indications.

Mean adenomas per procedure were 1.56 (SD, 2.82; n = 1001 participants with data) in the CADe-assisted group vs 1.21 (n = 1009) in the standard group, for an adjusted mean difference of 0.36 (95% CI, 0.14-0.57; adjusted incidence rate ratio, 1.30; 95% CI, 1.15-1.47; P < .0001).

Adenomas were detected in 555 (56.6%) of 980 participants in the CADe-assisted group vs 477 (48.4%) of 986 in the standard group, representing a proportion difference of 8.3% (95% CI, 3.9-12.7; adjusted odds ratio, 1.47; 95% CI, 1.21-1.78; P < .0001).

As to safety, adverse events were numerically comparable in both the intervention and control groups, with overall events 25 vs 19 and serious events 4 vs 6. On independent review, no adverse events in the CADe-assisted colonoscopy group were related to GI Genius.

 

Offering a US perspective on the study, Nabil M. Mansour, MD, an associate professor and director of the McNair General GI Clinic at Baylor College of Medicine in Houston, Texas, said GI Genius and other CADe systems represent a significant advance over standard colonoscopy for identifying premalignant polyps. “While the data have been mixed, most studies, particularly randomized controlled trials have shown significant improvements with CADe in detection both terms of in adenomas per colonoscopy and reductions in adenoma miss rate,” he said in an interview.

He added that the main utility of CADe is for asymptomatic patients undergoing average-risk screening and surveillance colonoscopy for CRC screening and prevention, as well as for those with positive stool-based screening tests, “though there is no downside to using it in symptomatic patients as well.” Though AI colonoscopy likely still stands at < 50% of endoscopy centers overall, and is used mainly at academic centers, his clinic has been using it for the past year.

The main question, Mansour cautioned, is whether increased detection of small polyps will actually reduce CRC incidence or mortality, and it will likely be several years before clear, concrete data can answer that.

“Most studies have shown the improvement in adenoma detection is mainly for diminutive polyps < 5 mm in diameter, but whether that will actually translate to substantive improvements in hard outcomes is as yet unknown,” he said. “But if gastroenterologists are interested in doing everything they can today to help improve detection rates and lower miss rates of premalignant polyps, serious consideration should be given to adopting the use of CADe in practice.”

This study was supported by Medtronic. Rees reported receiving grant funding from ARC Medical, Norgine, Medtronic, 3-D Matrix, and Olympus Medical, and has been an expert witness for ARC Medical. Other authors disclosed receiving research funding, honoraria, or travel expenses from Medtronic or other private companies. Mansour had no competing interests to declare.

A version of this article appeared on Medscape.com.

Results from the British COLO-DETECT trial add to the growing body of evidence supporting the use of artificial intelligence (AI)–aided colonoscopy to increase premalignant colorectal polyp detection in routine colonoscopy practice.

Colin J. Rees, a professor of gastroenterology in the Faculty of Medical Sciences at Newcastle University in Newcastle upon Tyne, England, and colleagues compared the real-world clinical effectiveness of computer-aided detection (CADe)–assisted colonoscopy using an “intelligent” module with that of standard colonoscopy in a study in The Lancet Gastroenterology & Hepatology.

They found the GI Genius Intelligent Endoscopy Module (Medtronic) increased the mean number of adenomas detected per procedure and the adenoma detection rate, especially for small, flat (type 0-IIa) polyps, and sessile serrated lesions, which are more likely to be missed.

“Missed sessile serrated lesions disproportionately increase the risk of post-colonoscopy colorectal cancer, thus the adoption of GI Genius into routine colonoscopy practice could not only increase polyp detection but also reduce the incidence of post-colonoscopy colorectal cancer,” the investigators wrote.

“AI is going to have a major impact upon most aspects of healthcare. Some areas of medical practice are now well established, and some are still in evolution,” Rees, who is also president of the British Society of Gastroenterology, said in an interview. “Within gastroenterology, the role of AI in endoscopic diagnostics is also evolving. The COLO-DETECT trial demonstrates that AI increases detection of lesions, and work is ongoing to see how AI might help with characterization and other elements of endoscopic practice.”

 

Study Details

The multicenter, open-label, parallel-arm, pragmatic randomized controlled trial was conducted at 12 National Health Service hospitals in England. The study cohort consisted of adults ≥ 18 years undergoing colorectal cancer (CRC) screening or colonoscopy for gastrointestinal symptom surveillance owing to personal or family history.

Recruiting staff, participants, and colonoscopists were unmasked to allocation, whereas histopathologists, cochief investigators, and trial statisticians were masked.

CADe-assisted colonoscopy consisted of standard colonoscopy plus the GI Genius module active for at least the entire inspection phase of colonoscope withdrawal.

The primary outcome was mean adenomas per procedure (total number of adenomas detected divided by total number of procedures). The key secondary outcome was adenoma detection rate (proportion of colonoscopies with at least one adenoma).

From March 2021 to April 2023, the investigators recruited 2032 participants, 55.7% men, with a mean cohort age of 62.4 years and randomly assigned them to CADe-assisted colonoscopy (n = 1015) or to standard colonoscopy (n = 1017). Of these, 60.6% were undergoing screening and 39.4% had symptomatic indications.

Mean adenomas per procedure were 1.56 (SD, 2.82; n = 1001 participants with data) in the CADe-assisted group vs 1.21 (n = 1009) in the standard group, for an adjusted mean difference of 0.36 (95% CI, 0.14-0.57; adjusted incidence rate ratio, 1.30; 95% CI, 1.15-1.47; P < .0001).

Adenomas were detected in 555 (56.6%) of 980 participants in the CADe-assisted group vs 477 (48.4%) of 986 in the standard group, representing a proportion difference of 8.3% (95% CI, 3.9-12.7; adjusted odds ratio, 1.47; 95% CI, 1.21-1.78; P < .0001).

As to safety, adverse events were numerically comparable in both the intervention and control groups, with overall events 25 vs 19 and serious events 4 vs 6. On independent review, no adverse events in the CADe-assisted colonoscopy group were related to GI Genius.

 

Offering a US perspective on the study, Nabil M. Mansour, MD, an associate professor and director of the McNair General GI Clinic at Baylor College of Medicine in Houston, Texas, said GI Genius and other CADe systems represent a significant advance over standard colonoscopy for identifying premalignant polyps. “While the data have been mixed, most studies, particularly randomized controlled trials have shown significant improvements with CADe in detection both terms of in adenomas per colonoscopy and reductions in adenoma miss rate,” he said in an interview.

He added that the main utility of CADe is for asymptomatic patients undergoing average-risk screening and surveillance colonoscopy for CRC screening and prevention, as well as for those with positive stool-based screening tests, “though there is no downside to using it in symptomatic patients as well.” Though AI colonoscopy likely still stands at < 50% of endoscopy centers overall, and is used mainly at academic centers, his clinic has been using it for the past year.

The main question, Mansour cautioned, is whether increased detection of small polyps will actually reduce CRC incidence or mortality, and it will likely be several years before clear, concrete data can answer that.

“Most studies have shown the improvement in adenoma detection is mainly for diminutive polyps < 5 mm in diameter, but whether that will actually translate to substantive improvements in hard outcomes is as yet unknown,” he said. “But if gastroenterologists are interested in doing everything they can today to help improve detection rates and lower miss rates of premalignant polyps, serious consideration should be given to adopting the use of CADe in practice.”

This study was supported by Medtronic. Rees reported receiving grant funding from ARC Medical, Norgine, Medtronic, 3-D Matrix, and Olympus Medical, and has been an expert witness for ARC Medical. Other authors disclosed receiving research funding, honoraria, or travel expenses from Medtronic or other private companies. Mansour had no competing interests to declare.

A version of this article appeared on Medscape.com.

Recently, a 40-year-old woman took to Facebook to announce that she had died.

Rachel Davies, of Wales, wrote: “If you’re reading this, then it means I’m no longer here. What a life I’ve had, and surprisingly, since cancer entered my life. When I look through my photos, I’ve done and seen so much since cancer, and probably some of my best memories are from this period. In so many ways, I have to thank it for learning how to live fully. What I wish is that everyone can experience the same but without needing cancer. Get out there, experience life fully, and wear that dress!!! I’m so sad to leave my family and friends, I wish I never had to go. I’m so grateful to have had Charlie young so that I’ve watched him grow into the man he is today. I’m unbelievably proud of him. I am thankful I had the opportunity to have Kacey and Jacob in my life. Lastly, I was blessed to meet the love of my life, my husband, and my best friend. I have no regrets, I have had a wonderful life. So to all of you, don’t be sad I’ve gone. Live your life and live it well. Love, Rachel x.”

 

I didn’t know Ms. Davies, but am likely among many who wish I had. In a terrible situation she kept trying.

She had HER2 metastatic breast cancer, which can respond to the drug Enhertu (trastuzumab). Unfortunately, she never had the chance, because it wasn’t available to her in Wales. In the United Kingdom it’s available only in Scotland.

I’m not saying it was a cure. Statistically, it likely would have bought her another 6 months of family time. But that’s still another half year.

I’m not blaming the Welsh NHS, though they made the decision not to cover it because of cost. The jobs of such committees is a thankless one, trying to decide where the limited money goes — vaccines for many children that are proven to lessen morbidity and mortality over the course of a lifetime, or to add 6 months to the lives of comparatively fewer women with HER2 metastatic breast cancer.

I’m not blaming the company that makes Enhertu, though it was the cost that kept her from getting it. Bringing a drug to market, with all the labs and clinical research behind it, ain’t cheap. If the company can’t keep the lights on they’re not going to able to develop future pharmaceuticals to help others, though I do wonder if a better price could have been negotiated. (I’m not trying to justify the salaries of insurance CEOs — don’t even get me started on those.)

Money is always limited, and human suffering is infinite. Every health care organization, public or private, has to face that simple fact. There is no right place to draw the line, so we use the greatest good for the greatest many as our best guess.

In her last post, though, Ms. Davies didn’t dwell on any of this. She reflected on her joys and blessings, and encouraged others to live life fully. Things we should all focus on.

In a world that often seems to have gone mad, it’s good to keep in mind that there is more good than bad out there. 

Thank you, Ms. Davies, for the reminder.

Allan M. Block, MD, has a solo neurology practice in Scottsdale, Arizona.

Recently, a 40-year-old woman took to Facebook to announce that she had died.

Rachel Davies, of Wales, wrote: “If you’re reading this, then it means I’m no longer here. What a life I’ve had, and surprisingly, since cancer entered my life. When I look through my photos, I’ve done and seen so much since cancer, and probably some of my best memories are from this period. In so many ways, I have to thank it for learning how to live fully. What I wish is that everyone can experience the same but without needing cancer. Get out there, experience life fully, and wear that dress!!! I’m so sad to leave my family and friends, I wish I never had to go. I’m so grateful to have had Charlie young so that I’ve watched him grow into the man he is today. I’m unbelievably proud of him. I am thankful I had the opportunity to have Kacey and Jacob in my life. Lastly, I was blessed to meet the love of my life, my husband, and my best friend. I have no regrets, I have had a wonderful life. So to all of you, don’t be sad I’ve gone. Live your life and live it well. Love, Rachel x.”

 

I didn’t know Ms. Davies, but am likely among many who wish I had. In a terrible situation she kept trying.

She had HER2 metastatic breast cancer, which can respond to the drug Enhertu (trastuzumab). Unfortunately, she never had the chance, because it wasn’t available to her in Wales. In the United Kingdom it’s available only in Scotland.

I’m not saying it was a cure. Statistically, it likely would have bought her another 6 months of family time. But that’s still another half year.

I’m not blaming the Welsh NHS, though they made the decision not to cover it because of cost. The jobs of such committees is a thankless one, trying to decide where the limited money goes — vaccines for many children that are proven to lessen morbidity and mortality over the course of a lifetime, or to add 6 months to the lives of comparatively fewer women with HER2 metastatic breast cancer.

I’m not blaming the company that makes Enhertu, though it was the cost that kept her from getting it. Bringing a drug to market, with all the labs and clinical research behind it, ain’t cheap. If the company can’t keep the lights on they’re not going to able to develop future pharmaceuticals to help others, though I do wonder if a better price could have been negotiated. (I’m not trying to justify the salaries of insurance CEOs — don’t even get me started on those.)

Money is always limited, and human suffering is infinite. Every health care organization, public or private, has to face that simple fact. There is no right place to draw the line, so we use the greatest good for the greatest many as our best guess.

In her last post, though, Ms. Davies didn’t dwell on any of this. She reflected on her joys and blessings, and encouraged others to live life fully. Things we should all focus on.

In a world that often seems to have gone mad, it’s good to keep in mind that there is more good than bad out there. 

Thank you, Ms. Davies, for the reminder.

Allan M. Block, MD, has a solo neurology practice in Scottsdale, Arizona.

Recently, a 40-year-old woman took to Facebook to announce that she had died.

Rachel Davies, of Wales, wrote: “If you’re reading this, then it means I’m no longer here. What a life I’ve had, and surprisingly, since cancer entered my life. When I look through my photos, I’ve done and seen so much since cancer, and probably some of my best memories are from this period. In so many ways, I have to thank it for learning how to live fully. What I wish is that everyone can experience the same but without needing cancer. Get out there, experience life fully, and wear that dress!!! I’m so sad to leave my family and friends, I wish I never had to go. I’m so grateful to have had Charlie young so that I’ve watched him grow into the man he is today. I’m unbelievably proud of him. I am thankful I had the opportunity to have Kacey and Jacob in my life. Lastly, I was blessed to meet the love of my life, my husband, and my best friend. I have no regrets, I have had a wonderful life. So to all of you, don’t be sad I’ve gone. Live your life and live it well. Love, Rachel x.”

 

I didn’t know Ms. Davies, but am likely among many who wish I had. In a terrible situation she kept trying.

She had HER2 metastatic breast cancer, which can respond to the drug Enhertu (trastuzumab). Unfortunately, she never had the chance, because it wasn’t available to her in Wales. In the United Kingdom it’s available only in Scotland.

I’m not saying it was a cure. Statistically, it likely would have bought her another 6 months of family time. But that’s still another half year.

I’m not blaming the Welsh NHS, though they made the decision not to cover it because of cost. The jobs of such committees is a thankless one, trying to decide where the limited money goes — vaccines for many children that are proven to lessen morbidity and mortality over the course of a lifetime, or to add 6 months to the lives of comparatively fewer women with HER2 metastatic breast cancer.

I’m not blaming the company that makes Enhertu, though it was the cost that kept her from getting it. Bringing a drug to market, with all the labs and clinical research behind it, ain’t cheap. If the company can’t keep the lights on they’re not going to able to develop future pharmaceuticals to help others, though I do wonder if a better price could have been negotiated. (I’m not trying to justify the salaries of insurance CEOs — don’t even get me started on those.)

Money is always limited, and human suffering is infinite. Every health care organization, public or private, has to face that simple fact. There is no right place to draw the line, so we use the greatest good for the greatest many as our best guess.

In her last post, though, Ms. Davies didn’t dwell on any of this. She reflected on her joys and blessings, and encouraged others to live life fully. Things we should all focus on.

In a world that often seems to have gone mad, it’s good to keep in mind that there is more good than bad out there. 

Thank you, Ms. Davies, for the reminder.

Allan M. Block, MD, has a solo neurology practice in Scottsdale, Arizona.

TOPLINE:

Aggressive margin reduction with MRI-guided stereotactic body radiotherapy (SBRT) led to a significantly lower incidence of late genitourinary and gastrointestinal toxicities at 2 years compared with CT-guided SBRT in men with localized prostate cancer, new data showed.

METHODOLOGY:

• MRI-guided SBRT is known to reduce planning margins in prostate cancer and lead to less acute toxicity compared with standard CT-guided SBRT. However, the long-term benefits of the MRI-guided approach remain unclear.
• To find out, researchers conducted the phase 3 MIRAGE trial, in which 156 patients with localized prostate cancer were randomly assigned to receive either MRI-guided SBRT with 2-mm margins or CT-guided SBRT with 4-mm margins.
• The MIRAGE trial initially reported the primary outcome of acute genitourinary grade ≥ 2 toxicity within 90 days of SBRT.
• In this secondary analysis, researchers evaluated physician-reported late genitourinary and gastrointestinal toxicity, along with changes in various patient-reported quality-of-life scores over a 2-year follow-up period.

TAKEAWAY:

• Over a period of 2 years, MRI-guided SBRT was associated with a significantly lower cumulative incidence of grade ≥ 2 genitourinary toxicities compared with CT-guided SBRT (27% vs 51%; P = .004). Similar outcomes were noted for grade ≥ 2 gastrointestinal toxicities (1.4% with MRI vs 9.5% with CT; P = .025).
• Fewer patients who received MRI-guided SBRT reported deterioration in urinary irritation between 6 and 24 months after radiotherapy — 14 of 73 patients (19.2%) in the MRI group vs 24 of 68 patients (35.3%) in the CT group (P = .031).
• Patients receiving MRI-guided SBRT were also less likely to experience clinically relevant deterioration in bowel function (odds ratio [OR], 0.444; P = .035) and sexual health score (OR, 0.366; P = .03).
• Between 6 and 24 months after radiotherapy, 26.4% of patients (19 of 72) in the MRI group vs 42.3% (30 of 71) in the CT group reported clinically relevant deterioration in bowel function.

IN PRACTICE:

“Our secondary analysis of a randomized trial revealed that aggressive planning for margin reduction with MRI guidance vs CT guidance for prostate SBRT led to lower physician-scored genitourinary and gastrointestinal toxicity and better bowel and sexual quality-of-life metrics over 2 years of follow-up,” the authors wrote.

SOURCE:

This study, led by Amar U. Kishan, University of California Los Angeles, was published online in European Urology.

LIMITATIONS:

The absence of blinding in this study may have influenced both physician-scored toxicity assessments and patient-reported quality-of-life outcomes. The MIRAGE trial was not specifically designed with sufficient statistical power to evaluate the secondary analyses presented in this study.

DISCLOSURES:

This study was supported by grants from the US Department of Defense. Several authors reported receiving grants or personal fees among other ties with various sources.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Aggressive margin reduction with MRI-guided stereotactic body radiotherapy (SBRT) led to a significantly lower incidence of late genitourinary and gastrointestinal toxicities at 2 years compared with CT-guided SBRT in men with localized prostate cancer, new data showed.

METHODOLOGY:

• MRI-guided SBRT is known to reduce planning margins in prostate cancer and lead to less acute toxicity compared with standard CT-guided SBRT. However, the long-term benefits of the MRI-guided approach remain unclear.
• To find out, researchers conducted the phase 3 MIRAGE trial, in which 156 patients with localized prostate cancer were randomly assigned to receive either MRI-guided SBRT with 2-mm margins or CT-guided SBRT with 4-mm margins.
• The MIRAGE trial initially reported the primary outcome of acute genitourinary grade ≥ 2 toxicity within 90 days of SBRT.
• In this secondary analysis, researchers evaluated physician-reported late genitourinary and gastrointestinal toxicity, along with changes in various patient-reported quality-of-life scores over a 2-year follow-up period.

TAKEAWAY:

• Over a period of 2 years, MRI-guided SBRT was associated with a significantly lower cumulative incidence of grade ≥ 2 genitourinary toxicities compared with CT-guided SBRT (27% vs 51%; P = .004). Similar outcomes were noted for grade ≥ 2 gastrointestinal toxicities (1.4% with MRI vs 9.5% with CT; P = .025).
• Fewer patients who received MRI-guided SBRT reported deterioration in urinary irritation between 6 and 24 months after radiotherapy — 14 of 73 patients (19.2%) in the MRI group vs 24 of 68 patients (35.3%) in the CT group (P = .031).
• Patients receiving MRI-guided SBRT were also less likely to experience clinically relevant deterioration in bowel function (odds ratio [OR], 0.444; P = .035) and sexual health score (OR, 0.366; P = .03).
• Between 6 and 24 months after radiotherapy, 26.4% of patients (19 of 72) in the MRI group vs 42.3% (30 of 71) in the CT group reported clinically relevant deterioration in bowel function.

IN PRACTICE:

“Our secondary analysis of a randomized trial revealed that aggressive planning for margin reduction with MRI guidance vs CT guidance for prostate SBRT led to lower physician-scored genitourinary and gastrointestinal toxicity and better bowel and sexual quality-of-life metrics over 2 years of follow-up,” the authors wrote.

SOURCE:

This study, led by Amar U. Kishan, University of California Los Angeles, was published online in European Urology.

LIMITATIONS:

The absence of blinding in this study may have influenced both physician-scored toxicity assessments and patient-reported quality-of-life outcomes. The MIRAGE trial was not specifically designed with sufficient statistical power to evaluate the secondary analyses presented in this study.

DISCLOSURES:

This study was supported by grants from the US Department of Defense. Several authors reported receiving grants or personal fees among other ties with various sources.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Aggressive margin reduction with MRI-guided stereotactic body radiotherapy (SBRT) led to a significantly lower incidence of late genitourinary and gastrointestinal toxicities at 2 years compared with CT-guided SBRT in men with localized prostate cancer, new data showed.

METHODOLOGY:

• MRI-guided SBRT is known to reduce planning margins in prostate cancer and lead to less acute toxicity compared with standard CT-guided SBRT. However, the long-term benefits of the MRI-guided approach remain unclear.
• To find out, researchers conducted the phase 3 MIRAGE trial, in which 156 patients with localized prostate cancer were randomly assigned to receive either MRI-guided SBRT with 2-mm margins or CT-guided SBRT with 4-mm margins.
• The MIRAGE trial initially reported the primary outcome of acute genitourinary grade ≥ 2 toxicity within 90 days of SBRT.
• In this secondary analysis, researchers evaluated physician-reported late genitourinary and gastrointestinal toxicity, along with changes in various patient-reported quality-of-life scores over a 2-year follow-up period.

TAKEAWAY:

• Over a period of 2 years, MRI-guided SBRT was associated with a significantly lower cumulative incidence of grade ≥ 2 genitourinary toxicities compared with CT-guided SBRT (27% vs 51%; P = .004). Similar outcomes were noted for grade ≥ 2 gastrointestinal toxicities (1.4% with MRI vs 9.5% with CT; P = .025).
• Fewer patients who received MRI-guided SBRT reported deterioration in urinary irritation between 6 and 24 months after radiotherapy — 14 of 73 patients (19.2%) in the MRI group vs 24 of 68 patients (35.3%) in the CT group (P = .031).
• Patients receiving MRI-guided SBRT were also less likely to experience clinically relevant deterioration in bowel function (odds ratio [OR], 0.444; P = .035) and sexual health score (OR, 0.366; P = .03).
• Between 6 and 24 months after radiotherapy, 26.4% of patients (19 of 72) in the MRI group vs 42.3% (30 of 71) in the CT group reported clinically relevant deterioration in bowel function.

IN PRACTICE:

“Our secondary analysis of a randomized trial revealed that aggressive planning for margin reduction with MRI guidance vs CT guidance for prostate SBRT led to lower physician-scored genitourinary and gastrointestinal toxicity and better bowel and sexual quality-of-life metrics over 2 years of follow-up,” the authors wrote.

SOURCE:

This study, led by Amar U. Kishan, University of California Los Angeles, was published online in European Urology.

LIMITATIONS:

The absence of blinding in this study may have influenced both physician-scored toxicity assessments and patient-reported quality-of-life outcomes. The MIRAGE trial was not specifically designed with sufficient statistical power to evaluate the secondary analyses presented in this study.

DISCLOSURES:

This study was supported by grants from the US Department of Defense. Several authors reported receiving grants or personal fees among other ties with various sources.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.