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Which Breast Cancer Patients Can Skip Postop Radiotherapy?
TOPLINE:
Overall, patients with a high POLAR score derived a significant benefit from adjuvant radiotherapy, while those with a low score did not and might consider forgoing radiotherapy.
METHODOLOGY:
- Radiation therapy after breast-conserving surgery has been shown to reduce the risk for locoregional recurrence and is a standard approach to manage early breast cancer. However, certain patients with low locoregional recurrence risks may not necessarily benefit from adjuvant radiation, but there has not been a commercially available molecular test to help identify which patients that might be.
- In the current analysis, researchers assessed whether the POLAR biomarker test could reliably predict locoregional recurrence as well as identify patients who would not benefit from radiotherapy.
- The meta-analysis used data from three randomized trials — Scottish Conservation Trial, SweBCG91-RT, and Princess Margaret RT trial — to validate the POLAR biomarker test in patients with low-risk, HR-positive, HER2-negative, node-negative breast cancer.
- The analysis included 623 patients (ages 50-76), of whom 429 (69%) had high POLAR scores and 194 (31%) had low POLAR scores.
- The primary endpoint was the time to locoregional recurrence, and secondary endpoints included evaluating POLAR as a prognostic factor for locoregional recurrence in patients without radiotherapy and effect of radiotherapy in patients with low and high POLAR scores.
TAKEAWAY:
- Patients with high POLAR scores demonstrated a significant benefit from radiotherapy. The 10-year locoregional recurrence rate was 7% with radiotherapy vs 20% without radiotherapy (hazard ratio [HR], 0.37; P < .001).
- Patients with low POLAR scores, however, did not experience a significant benefit from radiotherapy. In this group, the 10-year locoregional recurrence rates were similar with and without radiotherapy (7% vs 5%, respectively; HR, 0.92; P = .832), indicating that radiotherapy could potentially be omitted for these patients.
- Among patients who did not receive radiotherapy (n = 309), higher POLAR scores predicted a greater risk for recurrence, suggesting the genomic signature has prognostic value. There is no evidence, however, that POLAR predicts radiotherapy benefit or predicts patients’ risk for distant metastases or mortality.
IN PRACTICE:
“This meta-analysis from three randomized controlled trials clearly demonstrates the clinical potential for POLAR to be used in smaller estrogen receptor positive node negative breast cancer patients to identify those women who do not appear to benefit from the use of post-operative adjuvant radiotherapy,” the authors wrote. “ This classifier is an important step towards molecularly-stratified targeting of the use of radiotherapy.”
SOURCE:
The study, led by Per Karlsson, MD, PhD, University of Gothenburg, Sweden, was published online in the Journal of the National Cancer Institute.
LIMITATIONS:
One cohort (SweBCG) had limited use of adjuvant systemic therapy, which could affect generalizability. Additionally, low numbers of patients with low POLAR scores in two trials could affect the observed benefit of radiotherapy.
DISCLOSURES:
This study was supported by the Breast Cancer Institute Fund (Edinburgh and Lothians Health Foundation), Canadian Institutes of Health Research, Exact Sciences Corporation, PFS Genomics, Swedish Cancer Society, and Swedish Research Council. One author reported being an employee and owning stock or stock options or patents with Exact Sciences. Several authors reported having various ties with various sources including Exact Sciences.
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:
Overall, patients with a high POLAR score derived a significant benefit from adjuvant radiotherapy, while those with a low score did not and might consider forgoing radiotherapy.
METHODOLOGY:
- Radiation therapy after breast-conserving surgery has been shown to reduce the risk for locoregional recurrence and is a standard approach to manage early breast cancer. However, certain patients with low locoregional recurrence risks may not necessarily benefit from adjuvant radiation, but there has not been a commercially available molecular test to help identify which patients that might be.
- In the current analysis, researchers assessed whether the POLAR biomarker test could reliably predict locoregional recurrence as well as identify patients who would not benefit from radiotherapy.
- The meta-analysis used data from three randomized trials — Scottish Conservation Trial, SweBCG91-RT, and Princess Margaret RT trial — to validate the POLAR biomarker test in patients with low-risk, HR-positive, HER2-negative, node-negative breast cancer.
- The analysis included 623 patients (ages 50-76), of whom 429 (69%) had high POLAR scores and 194 (31%) had low POLAR scores.
- The primary endpoint was the time to locoregional recurrence, and secondary endpoints included evaluating POLAR as a prognostic factor for locoregional recurrence in patients without radiotherapy and effect of radiotherapy in patients with low and high POLAR scores.
TAKEAWAY:
- Patients with high POLAR scores demonstrated a significant benefit from radiotherapy. The 10-year locoregional recurrence rate was 7% with radiotherapy vs 20% without radiotherapy (hazard ratio [HR], 0.37; P < .001).
- Patients with low POLAR scores, however, did not experience a significant benefit from radiotherapy. In this group, the 10-year locoregional recurrence rates were similar with and without radiotherapy (7% vs 5%, respectively; HR, 0.92; P = .832), indicating that radiotherapy could potentially be omitted for these patients.
- Among patients who did not receive radiotherapy (n = 309), higher POLAR scores predicted a greater risk for recurrence, suggesting the genomic signature has prognostic value. There is no evidence, however, that POLAR predicts radiotherapy benefit or predicts patients’ risk for distant metastases or mortality.
IN PRACTICE:
“This meta-analysis from three randomized controlled trials clearly demonstrates the clinical potential for POLAR to be used in smaller estrogen receptor positive node negative breast cancer patients to identify those women who do not appear to benefit from the use of post-operative adjuvant radiotherapy,” the authors wrote. “ This classifier is an important step towards molecularly-stratified targeting of the use of radiotherapy.”
SOURCE:
The study, led by Per Karlsson, MD, PhD, University of Gothenburg, Sweden, was published online in the Journal of the National Cancer Institute.
LIMITATIONS:
One cohort (SweBCG) had limited use of adjuvant systemic therapy, which could affect generalizability. Additionally, low numbers of patients with low POLAR scores in two trials could affect the observed benefit of radiotherapy.
DISCLOSURES:
This study was supported by the Breast Cancer Institute Fund (Edinburgh and Lothians Health Foundation), Canadian Institutes of Health Research, Exact Sciences Corporation, PFS Genomics, Swedish Cancer Society, and Swedish Research Council. One author reported being an employee and owning stock or stock options or patents with Exact Sciences. Several authors reported having various ties with various sources including Exact Sciences.
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:
Overall, patients with a high POLAR score derived a significant benefit from adjuvant radiotherapy, while those with a low score did not and might consider forgoing radiotherapy.
METHODOLOGY:
- Radiation therapy after breast-conserving surgery has been shown to reduce the risk for locoregional recurrence and is a standard approach to manage early breast cancer. However, certain patients with low locoregional recurrence risks may not necessarily benefit from adjuvant radiation, but there has not been a commercially available molecular test to help identify which patients that might be.
- In the current analysis, researchers assessed whether the POLAR biomarker test could reliably predict locoregional recurrence as well as identify patients who would not benefit from radiotherapy.
- The meta-analysis used data from three randomized trials — Scottish Conservation Trial, SweBCG91-RT, and Princess Margaret RT trial — to validate the POLAR biomarker test in patients with low-risk, HR-positive, HER2-negative, node-negative breast cancer.
- The analysis included 623 patients (ages 50-76), of whom 429 (69%) had high POLAR scores and 194 (31%) had low POLAR scores.
- The primary endpoint was the time to locoregional recurrence, and secondary endpoints included evaluating POLAR as a prognostic factor for locoregional recurrence in patients without radiotherapy and effect of radiotherapy in patients with low and high POLAR scores.
TAKEAWAY:
- Patients with high POLAR scores demonstrated a significant benefit from radiotherapy. The 10-year locoregional recurrence rate was 7% with radiotherapy vs 20% without radiotherapy (hazard ratio [HR], 0.37; P < .001).
- Patients with low POLAR scores, however, did not experience a significant benefit from radiotherapy. In this group, the 10-year locoregional recurrence rates were similar with and without radiotherapy (7% vs 5%, respectively; HR, 0.92; P = .832), indicating that radiotherapy could potentially be omitted for these patients.
- Among patients who did not receive radiotherapy (n = 309), higher POLAR scores predicted a greater risk for recurrence, suggesting the genomic signature has prognostic value. There is no evidence, however, that POLAR predicts radiotherapy benefit or predicts patients’ risk for distant metastases or mortality.
IN PRACTICE:
“This meta-analysis from three randomized controlled trials clearly demonstrates the clinical potential for POLAR to be used in smaller estrogen receptor positive node negative breast cancer patients to identify those women who do not appear to benefit from the use of post-operative adjuvant radiotherapy,” the authors wrote. “ This classifier is an important step towards molecularly-stratified targeting of the use of radiotherapy.”
SOURCE:
The study, led by Per Karlsson, MD, PhD, University of Gothenburg, Sweden, was published online in the Journal of the National Cancer Institute.
LIMITATIONS:
One cohort (SweBCG) had limited use of adjuvant systemic therapy, which could affect generalizability. Additionally, low numbers of patients with low POLAR scores in two trials could affect the observed benefit of radiotherapy.
DISCLOSURES:
This study was supported by the Breast Cancer Institute Fund (Edinburgh and Lothians Health Foundation), Canadian Institutes of Health Research, Exact Sciences Corporation, PFS Genomics, Swedish Cancer Society, and Swedish Research Council. One author reported being an employee and owning stock or stock options or patents with Exact Sciences. Several authors reported having various ties with various sources including Exact Sciences.
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.
Stages I-III Screen-Detected CRC Boosts Disease-Free Survival Rates
TOPLINE:
METHODOLOGY:
- Patients with screen-detected CRC have better stage-specific overall survival rates than those with non-screen–detected CRC, but the impact of screening on recurrence rates is unknown.
- A retrospective study analyzed patients with CRC (age, 55-75 years) from the Netherlands Cancer Registry diagnosed by screening or not.
- Screen-detected CRC were identified in patients who underwent colonoscopy after a positive fecal immunochemical test (FIT), whereas non-screen–detected CRC were those that were detected in symptomatic patients.
TAKEAWAY:
- Researchers included 3725 patients with CRC (39.6% women), of which 1652 (44.3%) and 2073 (55.7%) patients had screen-detected and non-screen–detected CRC, respectively; CRC was distributed approximately evenly across stages I-III (35.3%, 27.1%, and 37.6%, respectively).
- Screen-detected CRC had significantly higher 3-year rates of disease-free survival compared with non-screen–detected CRC (87.8% vs 77.2%; P < .001).
- The improvement in disease-free survival rates for screen-detected CRC was particularly notable in stage III cases, with rates of 77.9% vs 66.7% for non-screen–detected CRC (P < .001).
- Screen-detected CRC was more often detected at an earlier stage than non-screen–detected CRC (stage I or II: 72.4% vs 54.4%; P < .001).
- Across all stages, detection of CRC by screening was associated with a 33% lower risk for recurrence (P < .001) independent of patient age, gender, tumor location, stage, and treatment.
- Recurrence was the strongest predictor of overall survival across the study population (hazard ratio, 15.90; P < .001).
IN PRACTICE:
“Apart from CRC stage, mode of detection could be used to assess an individual’s risk for recurrence and survival, which may contribute to a more personalized treatment,” the authors wrote.
SOURCE:
The study, led by Sanne J.K.F. Pluimers, Department of Gastroenterology and Hepatology, Erasmus University Medical Center/Erasmus MC Cancer Institute, Rotterdam, the Netherlands, was published online in Clinical Gastroenterology and Hepatology.
LIMITATIONS:
The follow-up time was relatively short, restricting the ability to evaluate the long-term effects of screening on CRC recurrence. This study focused on recurrence solely within the FIT-based screening program, and the results were not generalizable to other screening methods. Due to Dutch privacy law, data on CRC-specific causes of death were unavailable, which may have affected the specificity of survival outcomes.
DISCLOSURES:
There was no funding source for this study. The authors declared no conflicts of interest.
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:
METHODOLOGY:
- Patients with screen-detected CRC have better stage-specific overall survival rates than those with non-screen–detected CRC, but the impact of screening on recurrence rates is unknown.
- A retrospective study analyzed patients with CRC (age, 55-75 years) from the Netherlands Cancer Registry diagnosed by screening or not.
- Screen-detected CRC were identified in patients who underwent colonoscopy after a positive fecal immunochemical test (FIT), whereas non-screen–detected CRC were those that were detected in symptomatic patients.
TAKEAWAY:
- Researchers included 3725 patients with CRC (39.6% women), of which 1652 (44.3%) and 2073 (55.7%) patients had screen-detected and non-screen–detected CRC, respectively; CRC was distributed approximately evenly across stages I-III (35.3%, 27.1%, and 37.6%, respectively).
- Screen-detected CRC had significantly higher 3-year rates of disease-free survival compared with non-screen–detected CRC (87.8% vs 77.2%; P < .001).
- The improvement in disease-free survival rates for screen-detected CRC was particularly notable in stage III cases, with rates of 77.9% vs 66.7% for non-screen–detected CRC (P < .001).
- Screen-detected CRC was more often detected at an earlier stage than non-screen–detected CRC (stage I or II: 72.4% vs 54.4%; P < .001).
- Across all stages, detection of CRC by screening was associated with a 33% lower risk for recurrence (P < .001) independent of patient age, gender, tumor location, stage, and treatment.
- Recurrence was the strongest predictor of overall survival across the study population (hazard ratio, 15.90; P < .001).
IN PRACTICE:
“Apart from CRC stage, mode of detection could be used to assess an individual’s risk for recurrence and survival, which may contribute to a more personalized treatment,” the authors wrote.
SOURCE:
The study, led by Sanne J.K.F. Pluimers, Department of Gastroenterology and Hepatology, Erasmus University Medical Center/Erasmus MC Cancer Institute, Rotterdam, the Netherlands, was published online in Clinical Gastroenterology and Hepatology.
LIMITATIONS:
The follow-up time was relatively short, restricting the ability to evaluate the long-term effects of screening on CRC recurrence. This study focused on recurrence solely within the FIT-based screening program, and the results were not generalizable to other screening methods. Due to Dutch privacy law, data on CRC-specific causes of death were unavailable, which may have affected the specificity of survival outcomes.
DISCLOSURES:
There was no funding source for this study. The authors declared no conflicts of interest.
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:
METHODOLOGY:
- Patients with screen-detected CRC have better stage-specific overall survival rates than those with non-screen–detected CRC, but the impact of screening on recurrence rates is unknown.
- A retrospective study analyzed patients with CRC (age, 55-75 years) from the Netherlands Cancer Registry diagnosed by screening or not.
- Screen-detected CRC were identified in patients who underwent colonoscopy after a positive fecal immunochemical test (FIT), whereas non-screen–detected CRC were those that were detected in symptomatic patients.
TAKEAWAY:
- Researchers included 3725 patients with CRC (39.6% women), of which 1652 (44.3%) and 2073 (55.7%) patients had screen-detected and non-screen–detected CRC, respectively; CRC was distributed approximately evenly across stages I-III (35.3%, 27.1%, and 37.6%, respectively).
- Screen-detected CRC had significantly higher 3-year rates of disease-free survival compared with non-screen–detected CRC (87.8% vs 77.2%; P < .001).
- The improvement in disease-free survival rates for screen-detected CRC was particularly notable in stage III cases, with rates of 77.9% vs 66.7% for non-screen–detected CRC (P < .001).
- Screen-detected CRC was more often detected at an earlier stage than non-screen–detected CRC (stage I or II: 72.4% vs 54.4%; P < .001).
- Across all stages, detection of CRC by screening was associated with a 33% lower risk for recurrence (P < .001) independent of patient age, gender, tumor location, stage, and treatment.
- Recurrence was the strongest predictor of overall survival across the study population (hazard ratio, 15.90; P < .001).
IN PRACTICE:
“Apart from CRC stage, mode of detection could be used to assess an individual’s risk for recurrence and survival, which may contribute to a more personalized treatment,” the authors wrote.
SOURCE:
The study, led by Sanne J.K.F. Pluimers, Department of Gastroenterology and Hepatology, Erasmus University Medical Center/Erasmus MC Cancer Institute, Rotterdam, the Netherlands, was published online in Clinical Gastroenterology and Hepatology.
LIMITATIONS:
The follow-up time was relatively short, restricting the ability to evaluate the long-term effects of screening on CRC recurrence. This study focused on recurrence solely within the FIT-based screening program, and the results were not generalizable to other screening methods. Due to Dutch privacy law, data on CRC-specific causes of death were unavailable, which may have affected the specificity of survival outcomes.
DISCLOSURES:
There was no funding source for this study. The authors declared no conflicts of interest.
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.
Is Pancreatic Cancer Really Rising in Young People?
TOPLINE:
Given the stable mortality rates in this population, the increase in incidence likely reflects previously undetected cases instead of a true rise in new cases, researchers say.
METHODOLOGY:
- Data from several registries have indicated that the incidence of pancreatic cancer among younger individuals, particularly women, is on the rise in the United States and worldwide.
- In a new analysis, researchers wanted to see if the observed increase in pancreatic cancer incidence among young Americans represented a true rise in cancer occurrence or indicated greater diagnostic scrutiny. If pancreatic cancer incidence is really increasing, “incidence and mortality would be expected to increase concurrently, as would early- and late-stage diagnoses,” the researchers explained.
- The researchers collected data on pancreatic cancer incidence, histology, and stage distribution for individuals aged 15-39 years from US Cancer Statistics, a database covering almost the entire US population from 2001 to 2020. Pancreatic cancer mortality data from the same timeframe came from the National Vital Statistics System.
- The researchers looked at four histologic categories: Adenocarcinoma, the dominant pancreatic cancer histology, as well as more rare subtypes — endocrine and solid pseudopapillary — and “other” category. Researchers also categorized stage-specific incidence as early stage (in situ or localized) or late stage (regional or distant).
TAKEAWAY:
- The incidence of pancreatic cancer increased 2.1-fold in young women (incidence, 3.3-6.9 per million) and 1.6-fold in young men (incidence, 3.9-6.2 per million) between 2001 and 2019. However, mortality rates remained stable for women (1.5 deaths per million; annual percent change [AAPC], −0.5%; 95% CI, –1.4% to 0.5%) and men (2.5 deaths per million; AAPC, –0.1%; 95% CI, –0.8% to 0.6%) over this period.
- Looking at cancer subtypes, the increase in incidence was largely caused by early-stage endocrine cancer and solid pseudopapillary neoplasms in women, not adenocarcinoma (which remained stable over the study period).
- Looking at cancer stage, most of the increase in incidence came from detection of smaller tumors (< 2 cm) and early-stage cancer, which rose from 0.6 to 3.7 per million in women and from 0.4 to 2.2 per million in men. The authors also found no statistically significant change in the incidence of late-stage cancer in women or men.
- Rates of surgical treatment for pancreatic cancer increased, more than tripling among women (from 1.5 to 4.7 per million) and more than doubling among men (from 1.1 to 2.3 per million).
IN PRACTICE:
“Pancreatic cancer now can be another cancer subject to overdiagnosis: The detection of disease not destined to cause symptoms or death,” the authors concluded. “Although the observed changes in incidence are small, overdiagnosis is especially concerning for pancreatic cancer, as pancreatic surgery has substantial risk for morbidity (in particular, pancreatic fistulas) and mortality.”
SOURCE:
The study, with first author Vishal R. Patel, MD, MPH, and corresponding author H. Gilbert Welch, MD, MPH, from Brigham and Women’s Hospital, Boston, was published online on November 19 in Annals of Internal Medicine.
LIMITATIONS:
The study was limited by the lack of data on the method of cancer detection, which may have affected the interpretation of the findings.
DISCLOSURES:
Disclosure forms are available with the article online.
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:
Given the stable mortality rates in this population, the increase in incidence likely reflects previously undetected cases instead of a true rise in new cases, researchers say.
METHODOLOGY:
- Data from several registries have indicated that the incidence of pancreatic cancer among younger individuals, particularly women, is on the rise in the United States and worldwide.
- In a new analysis, researchers wanted to see if the observed increase in pancreatic cancer incidence among young Americans represented a true rise in cancer occurrence or indicated greater diagnostic scrutiny. If pancreatic cancer incidence is really increasing, “incidence and mortality would be expected to increase concurrently, as would early- and late-stage diagnoses,” the researchers explained.
- The researchers collected data on pancreatic cancer incidence, histology, and stage distribution for individuals aged 15-39 years from US Cancer Statistics, a database covering almost the entire US population from 2001 to 2020. Pancreatic cancer mortality data from the same timeframe came from the National Vital Statistics System.
- The researchers looked at four histologic categories: Adenocarcinoma, the dominant pancreatic cancer histology, as well as more rare subtypes — endocrine and solid pseudopapillary — and “other” category. Researchers also categorized stage-specific incidence as early stage (in situ or localized) or late stage (regional or distant).
TAKEAWAY:
- The incidence of pancreatic cancer increased 2.1-fold in young women (incidence, 3.3-6.9 per million) and 1.6-fold in young men (incidence, 3.9-6.2 per million) between 2001 and 2019. However, mortality rates remained stable for women (1.5 deaths per million; annual percent change [AAPC], −0.5%; 95% CI, –1.4% to 0.5%) and men (2.5 deaths per million; AAPC, –0.1%; 95% CI, –0.8% to 0.6%) over this period.
- Looking at cancer subtypes, the increase in incidence was largely caused by early-stage endocrine cancer and solid pseudopapillary neoplasms in women, not adenocarcinoma (which remained stable over the study period).
- Looking at cancer stage, most of the increase in incidence came from detection of smaller tumors (< 2 cm) and early-stage cancer, which rose from 0.6 to 3.7 per million in women and from 0.4 to 2.2 per million in men. The authors also found no statistically significant change in the incidence of late-stage cancer in women or men.
- Rates of surgical treatment for pancreatic cancer increased, more than tripling among women (from 1.5 to 4.7 per million) and more than doubling among men (from 1.1 to 2.3 per million).
IN PRACTICE:
“Pancreatic cancer now can be another cancer subject to overdiagnosis: The detection of disease not destined to cause symptoms or death,” the authors concluded. “Although the observed changes in incidence are small, overdiagnosis is especially concerning for pancreatic cancer, as pancreatic surgery has substantial risk for morbidity (in particular, pancreatic fistulas) and mortality.”
SOURCE:
The study, with first author Vishal R. Patel, MD, MPH, and corresponding author H. Gilbert Welch, MD, MPH, from Brigham and Women’s Hospital, Boston, was published online on November 19 in Annals of Internal Medicine.
LIMITATIONS:
The study was limited by the lack of data on the method of cancer detection, which may have affected the interpretation of the findings.
DISCLOSURES:
Disclosure forms are available with the article online.
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:
Given the stable mortality rates in this population, the increase in incidence likely reflects previously undetected cases instead of a true rise in new cases, researchers say.
METHODOLOGY:
- Data from several registries have indicated that the incidence of pancreatic cancer among younger individuals, particularly women, is on the rise in the United States and worldwide.
- In a new analysis, researchers wanted to see if the observed increase in pancreatic cancer incidence among young Americans represented a true rise in cancer occurrence or indicated greater diagnostic scrutiny. If pancreatic cancer incidence is really increasing, “incidence and mortality would be expected to increase concurrently, as would early- and late-stage diagnoses,” the researchers explained.
- The researchers collected data on pancreatic cancer incidence, histology, and stage distribution for individuals aged 15-39 years from US Cancer Statistics, a database covering almost the entire US population from 2001 to 2020. Pancreatic cancer mortality data from the same timeframe came from the National Vital Statistics System.
- The researchers looked at four histologic categories: Adenocarcinoma, the dominant pancreatic cancer histology, as well as more rare subtypes — endocrine and solid pseudopapillary — and “other” category. Researchers also categorized stage-specific incidence as early stage (in situ or localized) or late stage (regional or distant).
TAKEAWAY:
- The incidence of pancreatic cancer increased 2.1-fold in young women (incidence, 3.3-6.9 per million) and 1.6-fold in young men (incidence, 3.9-6.2 per million) between 2001 and 2019. However, mortality rates remained stable for women (1.5 deaths per million; annual percent change [AAPC], −0.5%; 95% CI, –1.4% to 0.5%) and men (2.5 deaths per million; AAPC, –0.1%; 95% CI, –0.8% to 0.6%) over this period.
- Looking at cancer subtypes, the increase in incidence was largely caused by early-stage endocrine cancer and solid pseudopapillary neoplasms in women, not adenocarcinoma (which remained stable over the study period).
- Looking at cancer stage, most of the increase in incidence came from detection of smaller tumors (< 2 cm) and early-stage cancer, which rose from 0.6 to 3.7 per million in women and from 0.4 to 2.2 per million in men. The authors also found no statistically significant change in the incidence of late-stage cancer in women or men.
- Rates of surgical treatment for pancreatic cancer increased, more than tripling among women (from 1.5 to 4.7 per million) and more than doubling among men (from 1.1 to 2.3 per million).
IN PRACTICE:
“Pancreatic cancer now can be another cancer subject to overdiagnosis: The detection of disease not destined to cause symptoms or death,” the authors concluded. “Although the observed changes in incidence are small, overdiagnosis is especially concerning for pancreatic cancer, as pancreatic surgery has substantial risk for morbidity (in particular, pancreatic fistulas) and mortality.”
SOURCE:
The study, with first author Vishal R. Patel, MD, MPH, and corresponding author H. Gilbert Welch, MD, MPH, from Brigham and Women’s Hospital, Boston, was published online on November 19 in Annals of Internal Medicine.
LIMITATIONS:
The study was limited by the lack of data on the method of cancer detection, which may have affected the interpretation of the findings.
DISCLOSURES:
Disclosure forms are available with the article online.
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.
Cancer Mortality Not Higher for Patients With Autoimmune Disease on Checkpoint Inhibitors
WASHINGTON — Immune checkpoint inhibitor (ICI) therapy does not increase mortality in people with preexisting autoimmune diseases, new research has found.
Results from a large database analysis of patients with and without autoimmune diseases suggest it is safe to treat them with ICI if they develop a cancer for which it is indicated, Greg Challener, MD, a postdoctoral fellow at the Rheumatology and Allergy Clinical Epidemiology Research Center, Massachusetts General Hospital, Boston, said at the American College of Rheumatology 2024 Annual Meeting.
“One message is that, when rheumatologists are asked by oncologists about patients with rheumatoid arthritis or vasculitis or other autoimmune diseases and whether it’s safe to treat them with immune checkpoint inhibitors, this result provides some evidence that it probably is safe…. Checkpoint inhibitors are really incredible drugs, and they’ve improved mortality for a lot of cancers, particularly melanoma, and so I think there should be a pretty high threshold for us to say a patient shouldn’t receive them because of an autoimmune condition,” he told this news organization.
Another implication, Challener said, is that people with autoimmune diseases shouldn’t routinely be excluded from clinical trials of ICIs. Currently they are excluded because of concerns about exacerbation of underlying autoimmunity, possible interference between the ICI and the immunosuppressive drugs used to treat the autoimmune condition, and a theoretical risk for serious adverse events.
“Clinical trials are continuing to exclude these patients, and they paint with a very broad brush anyone with underlying autoimmunity ... I’m hoping that that changes. I don’t think there’s a great evidence base to support that practice, and it’s unfortunate that patients with underlying autoimmune diseases are excluded from important studies,” Challener said.
Asked to comment, session moderator Matlock Jeffries, MD, director of the Arthritis Research Unit at the Oklahoma Medical Research Foundation, Oklahoma City, told this news organization that he agrees the data are generally reassuring. “If one of our patients gets cancer and their oncologist wants to use a checkpoint inhibitor, we’d obviously still monitor them for complications, but we wouldn’t automatically assume the combination of a checkpoint inhibitor and autoimmune disease would increase their mortality.”
No Difference in Mortality for Those With and Without Autoimmune Disease
Challener and colleagues used administrative health data from the TriNetX Diamond network of 92 US healthcare sites with 212 million patients. All patients included in the study were receiving anti-programmed death protein 1/programmed death ligand 1 to treat malignancies involving the skin, lung/bronchus, digestive organs, or urinary tract. The study population also had at least one rheumatologic, gastrointestinal, neurologic, dermatologic, or endocrine autoimmune disease.
Propensity score matching between those with and without autoimmune disease was performed for about 100 covariates. Prior to the matching, the autoimmune disease group had significantly higher rates of cardiovascular and other comorbidities. The matching yielded 23,714 individuals with autoimmune disease and the same number without who had similar demographics and comorbidity rates, as well as malignancy type, alcohol/tobacco use, and medication use.
At a median follow-up of 250 days, the risk for mortality prior to propensity matching was 40.0% in the autoimmune disease group and 38.1% for those without, a significant difference with hazard ratio 1.07 (95% CI, 1.05-1.10). But after the matching, the difference was no longer significant: 39.8% vs 40.2%, respectively (0.97, 0.94-1.00).
The Kaplan-Meier curves for survival probability for those with or without autoimmune disease were nearly superimposed, showing no difference up to 1600 days. An analysis of just the patients with rheumatic diseases yielded similar results, Challener said.
Some Caveats About the Data
Jeffries, who is also an associate professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, and the Oklahoma VA, said he would like to see additional data on outcomes, both for the autoimmune conditions and the cancers. Challener said there are plans to look at other hard endpoints such as myocardial infarction and end-stage renal disease, but that the database is limited.
Both Challener and Jeffries also cautioned that the reassurance may not apply to patients with active disease.
“One thing this research doesn’t address is whether active autoimmune disease might have a different outcome compared to more kind of quiet disease…. If you have a patient who has extremely active rheumatoid arthritis or extremely active giant cell arthritis, for instance, I think that could be more challenging. I would be frightened to put a patient with really active GCA on pembrolizumab or say that it’s safe without their disease being controlled. But for someone who has well-controlled disease or minimally active disease, this is very reassuring,” Challener told this news organization.
“I think this may also be important in that it’s a good argument to tell the drug companies to include autoimmune patients in these trials so we can get better data,” Jeffries said.
Challener and Jeffries had no relevant disclosures.
A version of this article appeared on Medscape.com.
WASHINGTON — Immune checkpoint inhibitor (ICI) therapy does not increase mortality in people with preexisting autoimmune diseases, new research has found.
Results from a large database analysis of patients with and without autoimmune diseases suggest it is safe to treat them with ICI if they develop a cancer for which it is indicated, Greg Challener, MD, a postdoctoral fellow at the Rheumatology and Allergy Clinical Epidemiology Research Center, Massachusetts General Hospital, Boston, said at the American College of Rheumatology 2024 Annual Meeting.
“One message is that, when rheumatologists are asked by oncologists about patients with rheumatoid arthritis or vasculitis or other autoimmune diseases and whether it’s safe to treat them with immune checkpoint inhibitors, this result provides some evidence that it probably is safe…. Checkpoint inhibitors are really incredible drugs, and they’ve improved mortality for a lot of cancers, particularly melanoma, and so I think there should be a pretty high threshold for us to say a patient shouldn’t receive them because of an autoimmune condition,” he told this news organization.
Another implication, Challener said, is that people with autoimmune diseases shouldn’t routinely be excluded from clinical trials of ICIs. Currently they are excluded because of concerns about exacerbation of underlying autoimmunity, possible interference between the ICI and the immunosuppressive drugs used to treat the autoimmune condition, and a theoretical risk for serious adverse events.
“Clinical trials are continuing to exclude these patients, and they paint with a very broad brush anyone with underlying autoimmunity ... I’m hoping that that changes. I don’t think there’s a great evidence base to support that practice, and it’s unfortunate that patients with underlying autoimmune diseases are excluded from important studies,” Challener said.
Asked to comment, session moderator Matlock Jeffries, MD, director of the Arthritis Research Unit at the Oklahoma Medical Research Foundation, Oklahoma City, told this news organization that he agrees the data are generally reassuring. “If one of our patients gets cancer and their oncologist wants to use a checkpoint inhibitor, we’d obviously still monitor them for complications, but we wouldn’t automatically assume the combination of a checkpoint inhibitor and autoimmune disease would increase their mortality.”
No Difference in Mortality for Those With and Without Autoimmune Disease
Challener and colleagues used administrative health data from the TriNetX Diamond network of 92 US healthcare sites with 212 million patients. All patients included in the study were receiving anti-programmed death protein 1/programmed death ligand 1 to treat malignancies involving the skin, lung/bronchus, digestive organs, or urinary tract. The study population also had at least one rheumatologic, gastrointestinal, neurologic, dermatologic, or endocrine autoimmune disease.
Propensity score matching between those with and without autoimmune disease was performed for about 100 covariates. Prior to the matching, the autoimmune disease group had significantly higher rates of cardiovascular and other comorbidities. The matching yielded 23,714 individuals with autoimmune disease and the same number without who had similar demographics and comorbidity rates, as well as malignancy type, alcohol/tobacco use, and medication use.
At a median follow-up of 250 days, the risk for mortality prior to propensity matching was 40.0% in the autoimmune disease group and 38.1% for those without, a significant difference with hazard ratio 1.07 (95% CI, 1.05-1.10). But after the matching, the difference was no longer significant: 39.8% vs 40.2%, respectively (0.97, 0.94-1.00).
The Kaplan-Meier curves for survival probability for those with or without autoimmune disease were nearly superimposed, showing no difference up to 1600 days. An analysis of just the patients with rheumatic diseases yielded similar results, Challener said.
Some Caveats About the Data
Jeffries, who is also an associate professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, and the Oklahoma VA, said he would like to see additional data on outcomes, both for the autoimmune conditions and the cancers. Challener said there are plans to look at other hard endpoints such as myocardial infarction and end-stage renal disease, but that the database is limited.
Both Challener and Jeffries also cautioned that the reassurance may not apply to patients with active disease.
“One thing this research doesn’t address is whether active autoimmune disease might have a different outcome compared to more kind of quiet disease…. If you have a patient who has extremely active rheumatoid arthritis or extremely active giant cell arthritis, for instance, I think that could be more challenging. I would be frightened to put a patient with really active GCA on pembrolizumab or say that it’s safe without their disease being controlled. But for someone who has well-controlled disease or minimally active disease, this is very reassuring,” Challener told this news organization.
“I think this may also be important in that it’s a good argument to tell the drug companies to include autoimmune patients in these trials so we can get better data,” Jeffries said.
Challener and Jeffries had no relevant disclosures.
A version of this article appeared on Medscape.com.
WASHINGTON — Immune checkpoint inhibitor (ICI) therapy does not increase mortality in people with preexisting autoimmune diseases, new research has found.
Results from a large database analysis of patients with and without autoimmune diseases suggest it is safe to treat them with ICI if they develop a cancer for which it is indicated, Greg Challener, MD, a postdoctoral fellow at the Rheumatology and Allergy Clinical Epidemiology Research Center, Massachusetts General Hospital, Boston, said at the American College of Rheumatology 2024 Annual Meeting.
“One message is that, when rheumatologists are asked by oncologists about patients with rheumatoid arthritis or vasculitis or other autoimmune diseases and whether it’s safe to treat them with immune checkpoint inhibitors, this result provides some evidence that it probably is safe…. Checkpoint inhibitors are really incredible drugs, and they’ve improved mortality for a lot of cancers, particularly melanoma, and so I think there should be a pretty high threshold for us to say a patient shouldn’t receive them because of an autoimmune condition,” he told this news organization.
Another implication, Challener said, is that people with autoimmune diseases shouldn’t routinely be excluded from clinical trials of ICIs. Currently they are excluded because of concerns about exacerbation of underlying autoimmunity, possible interference between the ICI and the immunosuppressive drugs used to treat the autoimmune condition, and a theoretical risk for serious adverse events.
“Clinical trials are continuing to exclude these patients, and they paint with a very broad brush anyone with underlying autoimmunity ... I’m hoping that that changes. I don’t think there’s a great evidence base to support that practice, and it’s unfortunate that patients with underlying autoimmune diseases are excluded from important studies,” Challener said.
Asked to comment, session moderator Matlock Jeffries, MD, director of the Arthritis Research Unit at the Oklahoma Medical Research Foundation, Oklahoma City, told this news organization that he agrees the data are generally reassuring. “If one of our patients gets cancer and their oncologist wants to use a checkpoint inhibitor, we’d obviously still monitor them for complications, but we wouldn’t automatically assume the combination of a checkpoint inhibitor and autoimmune disease would increase their mortality.”
No Difference in Mortality for Those With and Without Autoimmune Disease
Challener and colleagues used administrative health data from the TriNetX Diamond network of 92 US healthcare sites with 212 million patients. All patients included in the study were receiving anti-programmed death protein 1/programmed death ligand 1 to treat malignancies involving the skin, lung/bronchus, digestive organs, or urinary tract. The study population also had at least one rheumatologic, gastrointestinal, neurologic, dermatologic, or endocrine autoimmune disease.
Propensity score matching between those with and without autoimmune disease was performed for about 100 covariates. Prior to the matching, the autoimmune disease group had significantly higher rates of cardiovascular and other comorbidities. The matching yielded 23,714 individuals with autoimmune disease and the same number without who had similar demographics and comorbidity rates, as well as malignancy type, alcohol/tobacco use, and medication use.
At a median follow-up of 250 days, the risk for mortality prior to propensity matching was 40.0% in the autoimmune disease group and 38.1% for those without, a significant difference with hazard ratio 1.07 (95% CI, 1.05-1.10). But after the matching, the difference was no longer significant: 39.8% vs 40.2%, respectively (0.97, 0.94-1.00).
The Kaplan-Meier curves for survival probability for those with or without autoimmune disease were nearly superimposed, showing no difference up to 1600 days. An analysis of just the patients with rheumatic diseases yielded similar results, Challener said.
Some Caveats About the Data
Jeffries, who is also an associate professor of medicine at the University of Oklahoma Health Sciences Center, Oklahoma City, and the Oklahoma VA, said he would like to see additional data on outcomes, both for the autoimmune conditions and the cancers. Challener said there are plans to look at other hard endpoints such as myocardial infarction and end-stage renal disease, but that the database is limited.
Both Challener and Jeffries also cautioned that the reassurance may not apply to patients with active disease.
“One thing this research doesn’t address is whether active autoimmune disease might have a different outcome compared to more kind of quiet disease…. If you have a patient who has extremely active rheumatoid arthritis or extremely active giant cell arthritis, for instance, I think that could be more challenging. I would be frightened to put a patient with really active GCA on pembrolizumab or say that it’s safe without their disease being controlled. But for someone who has well-controlled disease or minimally active disease, this is very reassuring,” Challener told this news organization.
“I think this may also be important in that it’s a good argument to tell the drug companies to include autoimmune patients in these trials so we can get better data,” Jeffries said.
Challener and Jeffries had no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM ACR 2024
Prostate Cancer: Has Active Surveillance Solved the Problem of Overtreatment?
“Overtreatment of men with limited longevity for intermediate- and high-risk tumors has not only failed to improve but has actually worsened over the last 20 years,” Timothy Daskivich, MD, MSHPM, with Cedars-Sinai Medical Center, Los Angeles, said in an interview.
“Many doctors assume that the increase in uptake of active surveillance for low-risk prostate cancers has solved the problem of overtreatment, but this trend has not affected overtreatment of men with low likelihood of living long enough to benefit from treatment who have higher-risk tumors,” Daskivich said.
The study was published online on November 11 in JAMA Internal Medicine.
‘Concerning’ Real-World Data
For men with low- and intermediate-risk prostate cancer expected to live fewer than 10 years, prostate cancer screening and aggressive treatment are not recommended.
Daskivich and colleagues analyzed data on 243,928 men (mean age, 66 years) in the Veterans Affairs (VA) Health System with clinically localized prostate cancer diagnosed between 2000 and 2019.
About 21% had LE < 10 years, and about 4% had LE < 5 years, according to the validated age-adjusted Prostate Cancer Comorbidity Index.
Overtreatment was defined as aggressive treatment (surgery or radiation) in those with LE < 10 years and low- to intermediate-risk disease and in those with LE < 5 years and high-risk disease, in line with current guidelines.
Among men with LE < 10 years, the proportion of men overtreated with surgery or radiotherapy for low-risk disease decreased 22% but increased 22% for intermediate-risk disease during the study period.
Among men with LE < 5 years, the proportion of men treated with definitive treatment for high-risk disease increased 29%.
“While lower-risk tumors are treated less aggressively across the board, including in men with limited longevity, it seems that we are more indiscriminately treating men with higher-risk disease without considering their expected longevity,” Daskivich said in an interview.
Is This Happening in the General US Population?
Daskivich noted that the sample included a large sample of men diagnosed with localized prostate cancer in the VA Health System.
“Rates of overtreatment are likely to be lower in the VA [Health System], so the problem may be worse in the community setting. The VA [Health System] has been exemplary in its uptake of active surveillance for low-risk cancers, leading the effort to reduce overtreatment of men with low-risk cancers. However, the problem of overtreatment of men with limited longevity persists in the VA [Health System], underscoring the pervasiveness of this problem,” he explained.
“We don’t have a perfect head-to-head comparison of overtreatment in the VA setting vs in the community. [However, one study shows] that this is not a VA-specific phenomenon and that there is an increase in overtreatment of men with limited longevity in a Medicare population as well,” Daskivich noted.
Is Overtreatment All Bad?
Overtreatment of prostate cancer, especially in cases where the cancer is unlikely to progress or cause symptoms, can lead to significant physical, psychological, and financial harms, Christopher Anderson, MD, urologist with Columbia University Irving Medical Center in New York City, who wasn’t involved in the study, noted in an interview.
In the study by Daskivich and colleagues, over three quarters of the overtreatment was radiation therapy, which carries the risk for urinary, bowel, and sexual issues.
“Overscreening, which can lead to overtreatment, is a core issue,” Anderson said. It’s easy to order a “simple” prostate-specific antigen blood test, but in an older man with limited LE, that can lead to a host of further testing, he said.
Stopping the pipeline of overscreening that then feeds into the cascade of overtreatment is the first step in addressing the problem of prostate cancer overtreatment, Nancy Li Schoenborn, MD, MHS, with Johns Hopkins University School of Medicine, Baltimore, and Louise C. Walter, MD, with University of California San Francisco, wrote in an editorial in JAMA Internal Medicine.
Considering LE during screening decision-making is “fundamental to reducing harms of prostate cancer overdiagnosis and overtreatment” because limited LE increases the likelihood of experiencing “harms all along the diagnostic and treatment cascade following screening,” the editorial writers said.
The time spent diagnosing, monitoring, and treating asymptomatic prostate cancer in men with limited LE distracts from monitoring and treating chronic symptomatic life-limiting illnesses, they noted.
Tough to Talk About?
Anderson noted that, in general, doctors are not great at estimating and counseling patients on LE. “It’s sometimes difficult to have that conversation,” he said.
Daskivich said physicians may fail to include average LE when advising patients on treatments because they believe that the patients do not want to discuss this topic. “Yet, in interviews with patients, we found that prostate cancer patients reported they wanted this information,” he continued, in an interview.
Solving the problem of overscreening and overtreatment will require a “multifaceted approach, including improving access to life expectancy data at the point of care for providers, educating providers on how to communicate this information, and improving data sources to predict longevity,” Daskivich said.
He said it’s equally important to note that some men with prostate cancer may choose treatment even if they have a limited longevity.
“Not all patients will choose conservative management, even if it is recommended by guidelines. However, they need to be given the opportunity to make a good decision for themselves with the best possible data,” Daskivich said.
This work was supported in part by a US Department of VA Merit Review. Daskivich reported receiving personal fees from the Medical Education Speakers Network, EDAP, and RAND; research support from Lantheus and Janssen; and a patent pending for a system for healthcare visit quality assessment outside the submitted work. Schoenborn, Walter, and Anderson had no relevant disclosures.
A version of this article appeared on Medscape.com.
“Overtreatment of men with limited longevity for intermediate- and high-risk tumors has not only failed to improve but has actually worsened over the last 20 years,” Timothy Daskivich, MD, MSHPM, with Cedars-Sinai Medical Center, Los Angeles, said in an interview.
“Many doctors assume that the increase in uptake of active surveillance for low-risk prostate cancers has solved the problem of overtreatment, but this trend has not affected overtreatment of men with low likelihood of living long enough to benefit from treatment who have higher-risk tumors,” Daskivich said.
The study was published online on November 11 in JAMA Internal Medicine.
‘Concerning’ Real-World Data
For men with low- and intermediate-risk prostate cancer expected to live fewer than 10 years, prostate cancer screening and aggressive treatment are not recommended.
Daskivich and colleagues analyzed data on 243,928 men (mean age, 66 years) in the Veterans Affairs (VA) Health System with clinically localized prostate cancer diagnosed between 2000 and 2019.
About 21% had LE < 10 years, and about 4% had LE < 5 years, according to the validated age-adjusted Prostate Cancer Comorbidity Index.
Overtreatment was defined as aggressive treatment (surgery or radiation) in those with LE < 10 years and low- to intermediate-risk disease and in those with LE < 5 years and high-risk disease, in line with current guidelines.
Among men with LE < 10 years, the proportion of men overtreated with surgery or radiotherapy for low-risk disease decreased 22% but increased 22% for intermediate-risk disease during the study period.
Among men with LE < 5 years, the proportion of men treated with definitive treatment for high-risk disease increased 29%.
“While lower-risk tumors are treated less aggressively across the board, including in men with limited longevity, it seems that we are more indiscriminately treating men with higher-risk disease without considering their expected longevity,” Daskivich said in an interview.
Is This Happening in the General US Population?
Daskivich noted that the sample included a large sample of men diagnosed with localized prostate cancer in the VA Health System.
“Rates of overtreatment are likely to be lower in the VA [Health System], so the problem may be worse in the community setting. The VA [Health System] has been exemplary in its uptake of active surveillance for low-risk cancers, leading the effort to reduce overtreatment of men with low-risk cancers. However, the problem of overtreatment of men with limited longevity persists in the VA [Health System], underscoring the pervasiveness of this problem,” he explained.
“We don’t have a perfect head-to-head comparison of overtreatment in the VA setting vs in the community. [However, one study shows] that this is not a VA-specific phenomenon and that there is an increase in overtreatment of men with limited longevity in a Medicare population as well,” Daskivich noted.
Is Overtreatment All Bad?
Overtreatment of prostate cancer, especially in cases where the cancer is unlikely to progress or cause symptoms, can lead to significant physical, psychological, and financial harms, Christopher Anderson, MD, urologist with Columbia University Irving Medical Center in New York City, who wasn’t involved in the study, noted in an interview.
In the study by Daskivich and colleagues, over three quarters of the overtreatment was radiation therapy, which carries the risk for urinary, bowel, and sexual issues.
“Overscreening, which can lead to overtreatment, is a core issue,” Anderson said. It’s easy to order a “simple” prostate-specific antigen blood test, but in an older man with limited LE, that can lead to a host of further testing, he said.
Stopping the pipeline of overscreening that then feeds into the cascade of overtreatment is the first step in addressing the problem of prostate cancer overtreatment, Nancy Li Schoenborn, MD, MHS, with Johns Hopkins University School of Medicine, Baltimore, and Louise C. Walter, MD, with University of California San Francisco, wrote in an editorial in JAMA Internal Medicine.
Considering LE during screening decision-making is “fundamental to reducing harms of prostate cancer overdiagnosis and overtreatment” because limited LE increases the likelihood of experiencing “harms all along the diagnostic and treatment cascade following screening,” the editorial writers said.
The time spent diagnosing, monitoring, and treating asymptomatic prostate cancer in men with limited LE distracts from monitoring and treating chronic symptomatic life-limiting illnesses, they noted.
Tough to Talk About?
Anderson noted that, in general, doctors are not great at estimating and counseling patients on LE. “It’s sometimes difficult to have that conversation,” he said.
Daskivich said physicians may fail to include average LE when advising patients on treatments because they believe that the patients do not want to discuss this topic. “Yet, in interviews with patients, we found that prostate cancer patients reported they wanted this information,” he continued, in an interview.
Solving the problem of overscreening and overtreatment will require a “multifaceted approach, including improving access to life expectancy data at the point of care for providers, educating providers on how to communicate this information, and improving data sources to predict longevity,” Daskivich said.
He said it’s equally important to note that some men with prostate cancer may choose treatment even if they have a limited longevity.
“Not all patients will choose conservative management, even if it is recommended by guidelines. However, they need to be given the opportunity to make a good decision for themselves with the best possible data,” Daskivich said.
This work was supported in part by a US Department of VA Merit Review. Daskivich reported receiving personal fees from the Medical Education Speakers Network, EDAP, and RAND; research support from Lantheus and Janssen; and a patent pending for a system for healthcare visit quality assessment outside the submitted work. Schoenborn, Walter, and Anderson had no relevant disclosures.
A version of this article appeared on Medscape.com.
“Overtreatment of men with limited longevity for intermediate- and high-risk tumors has not only failed to improve but has actually worsened over the last 20 years,” Timothy Daskivich, MD, MSHPM, with Cedars-Sinai Medical Center, Los Angeles, said in an interview.
“Many doctors assume that the increase in uptake of active surveillance for low-risk prostate cancers has solved the problem of overtreatment, but this trend has not affected overtreatment of men with low likelihood of living long enough to benefit from treatment who have higher-risk tumors,” Daskivich said.
The study was published online on November 11 in JAMA Internal Medicine.
‘Concerning’ Real-World Data
For men with low- and intermediate-risk prostate cancer expected to live fewer than 10 years, prostate cancer screening and aggressive treatment are not recommended.
Daskivich and colleagues analyzed data on 243,928 men (mean age, 66 years) in the Veterans Affairs (VA) Health System with clinically localized prostate cancer diagnosed between 2000 and 2019.
About 21% had LE < 10 years, and about 4% had LE < 5 years, according to the validated age-adjusted Prostate Cancer Comorbidity Index.
Overtreatment was defined as aggressive treatment (surgery or radiation) in those with LE < 10 years and low- to intermediate-risk disease and in those with LE < 5 years and high-risk disease, in line with current guidelines.
Among men with LE < 10 years, the proportion of men overtreated with surgery or radiotherapy for low-risk disease decreased 22% but increased 22% for intermediate-risk disease during the study period.
Among men with LE < 5 years, the proportion of men treated with definitive treatment for high-risk disease increased 29%.
“While lower-risk tumors are treated less aggressively across the board, including in men with limited longevity, it seems that we are more indiscriminately treating men with higher-risk disease without considering their expected longevity,” Daskivich said in an interview.
Is This Happening in the General US Population?
Daskivich noted that the sample included a large sample of men diagnosed with localized prostate cancer in the VA Health System.
“Rates of overtreatment are likely to be lower in the VA [Health System], so the problem may be worse in the community setting. The VA [Health System] has been exemplary in its uptake of active surveillance for low-risk cancers, leading the effort to reduce overtreatment of men with low-risk cancers. However, the problem of overtreatment of men with limited longevity persists in the VA [Health System], underscoring the pervasiveness of this problem,” he explained.
“We don’t have a perfect head-to-head comparison of overtreatment in the VA setting vs in the community. [However, one study shows] that this is not a VA-specific phenomenon and that there is an increase in overtreatment of men with limited longevity in a Medicare population as well,” Daskivich noted.
Is Overtreatment All Bad?
Overtreatment of prostate cancer, especially in cases where the cancer is unlikely to progress or cause symptoms, can lead to significant physical, psychological, and financial harms, Christopher Anderson, MD, urologist with Columbia University Irving Medical Center in New York City, who wasn’t involved in the study, noted in an interview.
In the study by Daskivich and colleagues, over three quarters of the overtreatment was radiation therapy, which carries the risk for urinary, bowel, and sexual issues.
“Overscreening, which can lead to overtreatment, is a core issue,” Anderson said. It’s easy to order a “simple” prostate-specific antigen blood test, but in an older man with limited LE, that can lead to a host of further testing, he said.
Stopping the pipeline of overscreening that then feeds into the cascade of overtreatment is the first step in addressing the problem of prostate cancer overtreatment, Nancy Li Schoenborn, MD, MHS, with Johns Hopkins University School of Medicine, Baltimore, and Louise C. Walter, MD, with University of California San Francisco, wrote in an editorial in JAMA Internal Medicine.
Considering LE during screening decision-making is “fundamental to reducing harms of prostate cancer overdiagnosis and overtreatment” because limited LE increases the likelihood of experiencing “harms all along the diagnostic and treatment cascade following screening,” the editorial writers said.
The time spent diagnosing, monitoring, and treating asymptomatic prostate cancer in men with limited LE distracts from monitoring and treating chronic symptomatic life-limiting illnesses, they noted.
Tough to Talk About?
Anderson noted that, in general, doctors are not great at estimating and counseling patients on LE. “It’s sometimes difficult to have that conversation,” he said.
Daskivich said physicians may fail to include average LE when advising patients on treatments because they believe that the patients do not want to discuss this topic. “Yet, in interviews with patients, we found that prostate cancer patients reported they wanted this information,” he continued, in an interview.
Solving the problem of overscreening and overtreatment will require a “multifaceted approach, including improving access to life expectancy data at the point of care for providers, educating providers on how to communicate this information, and improving data sources to predict longevity,” Daskivich said.
He said it’s equally important to note that some men with prostate cancer may choose treatment even if they have a limited longevity.
“Not all patients will choose conservative management, even if it is recommended by guidelines. However, they need to be given the opportunity to make a good decision for themselves with the best possible data,” Daskivich said.
This work was supported in part by a US Department of VA Merit Review. Daskivich reported receiving personal fees from the Medical Education Speakers Network, EDAP, and RAND; research support from Lantheus and Janssen; and a patent pending for a system for healthcare visit quality assessment outside the submitted work. Schoenborn, Walter, and Anderson had no relevant disclosures.
A version of this article appeared on Medscape.com.
How Do Novel CRC Blood Tests Fare Against Established Tests?
TOPLINE:
METHODOLOGY:
- Researchers estimated the clinical and economic impacts of emerging blood- and stool-based CRC screening tests with established alternatives in average-risk adults aged 45 years and older.
- The established screening tools were colonoscopy, a fecal immunochemical test (FIT), and a multitarget stool DNA test (MT-sDNA, Exact Sciences Cologuard).
- The four emerging screening methods were two cf-bDNA tests (Guardant Shield and Freenome); an enhanced, a next-generation multitarget stool test (ngMT-sDNA), and a novel FIT-RNA test (Geneoscopy ColoSense).
TAKEAWAY:
- Assuming 100% participation in all screening steps, colonoscopy and FIT yielded reductions of more than 70% in CRC incidence and 75% in mortality vs no screening.
- The MT-sDNA test reduced CRC incidence by 68% and mortality by 73%, with similar rates for the ngMT-sDNA and FIT-RNA tests vs no screening. The cf-bDNA tests yielded CRC incidence and mortality reductions of only 42% and 56%.
- Colonoscopy and FIT were more effective and less costly than the cf-bDNA and MT-sDNA tests, and the MT-sDNA test was more effective and less costly than the cf-bDNA test.
- Population benefits from blood tests were seen only in those who declined colonoscopy and stool tests. Substituting a blood test for those already using colonoscopy or stool tests led to worse population-level outcomes.
IN PRACTICE:
“First-generation novel cf-bDNA tests have the potential to decrease meaningfully the incidence and mortality of CRC compared with no screening but substantially less profoundly than screening colonoscopy or stool tests. Net population benefit or harm can follow incorporation of first-generation cf-bDNA CRC screening tests into practice, depending on the balance between bringing unscreened persons into screening (addition) vs shifting persons away from the more effective strategies of colonoscopy or stool testing (substitution),” the authors concluded.
SOURCE:
The study, with first author Uri Ladabaum, MD, MS, Stanford University School of Medicine, California, was published online in Annals of Internal Medicine.
LIMITATIONS:
Limitations included test-specific participation patterns being unknown over time.
DISCLOSURES:
Disclosure forms for the authors are available with the article online. Funding was provided by the Gorrindo Family Fund.
A version of this article appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Researchers estimated the clinical and economic impacts of emerging blood- and stool-based CRC screening tests with established alternatives in average-risk adults aged 45 years and older.
- The established screening tools were colonoscopy, a fecal immunochemical test (FIT), and a multitarget stool DNA test (MT-sDNA, Exact Sciences Cologuard).
- The four emerging screening methods were two cf-bDNA tests (Guardant Shield and Freenome); an enhanced, a next-generation multitarget stool test (ngMT-sDNA), and a novel FIT-RNA test (Geneoscopy ColoSense).
TAKEAWAY:
- Assuming 100% participation in all screening steps, colonoscopy and FIT yielded reductions of more than 70% in CRC incidence and 75% in mortality vs no screening.
- The MT-sDNA test reduced CRC incidence by 68% and mortality by 73%, with similar rates for the ngMT-sDNA and FIT-RNA tests vs no screening. The cf-bDNA tests yielded CRC incidence and mortality reductions of only 42% and 56%.
- Colonoscopy and FIT were more effective and less costly than the cf-bDNA and MT-sDNA tests, and the MT-sDNA test was more effective and less costly than the cf-bDNA test.
- Population benefits from blood tests were seen only in those who declined colonoscopy and stool tests. Substituting a blood test for those already using colonoscopy or stool tests led to worse population-level outcomes.
IN PRACTICE:
“First-generation novel cf-bDNA tests have the potential to decrease meaningfully the incidence and mortality of CRC compared with no screening but substantially less profoundly than screening colonoscopy or stool tests. Net population benefit or harm can follow incorporation of first-generation cf-bDNA CRC screening tests into practice, depending on the balance between bringing unscreened persons into screening (addition) vs shifting persons away from the more effective strategies of colonoscopy or stool testing (substitution),” the authors concluded.
SOURCE:
The study, with first author Uri Ladabaum, MD, MS, Stanford University School of Medicine, California, was published online in Annals of Internal Medicine.
LIMITATIONS:
Limitations included test-specific participation patterns being unknown over time.
DISCLOSURES:
Disclosure forms for the authors are available with the article online. Funding was provided by the Gorrindo Family Fund.
A version of this article appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Researchers estimated the clinical and economic impacts of emerging blood- and stool-based CRC screening tests with established alternatives in average-risk adults aged 45 years and older.
- The established screening tools were colonoscopy, a fecal immunochemical test (FIT), and a multitarget stool DNA test (MT-sDNA, Exact Sciences Cologuard).
- The four emerging screening methods were two cf-bDNA tests (Guardant Shield and Freenome); an enhanced, a next-generation multitarget stool test (ngMT-sDNA), and a novel FIT-RNA test (Geneoscopy ColoSense).
TAKEAWAY:
- Assuming 100% participation in all screening steps, colonoscopy and FIT yielded reductions of more than 70% in CRC incidence and 75% in mortality vs no screening.
- The MT-sDNA test reduced CRC incidence by 68% and mortality by 73%, with similar rates for the ngMT-sDNA and FIT-RNA tests vs no screening. The cf-bDNA tests yielded CRC incidence and mortality reductions of only 42% and 56%.
- Colonoscopy and FIT were more effective and less costly than the cf-bDNA and MT-sDNA tests, and the MT-sDNA test was more effective and less costly than the cf-bDNA test.
- Population benefits from blood tests were seen only in those who declined colonoscopy and stool tests. Substituting a blood test for those already using colonoscopy or stool tests led to worse population-level outcomes.
IN PRACTICE:
“First-generation novel cf-bDNA tests have the potential to decrease meaningfully the incidence and mortality of CRC compared with no screening but substantially less profoundly than screening colonoscopy or stool tests. Net population benefit or harm can follow incorporation of first-generation cf-bDNA CRC screening tests into practice, depending on the balance between bringing unscreened persons into screening (addition) vs shifting persons away from the more effective strategies of colonoscopy or stool testing (substitution),” the authors concluded.
SOURCE:
The study, with first author Uri Ladabaum, MD, MS, Stanford University School of Medicine, California, was published online in Annals of Internal Medicine.
LIMITATIONS:
Limitations included test-specific participation patterns being unknown over time.
DISCLOSURES:
Disclosure forms for the authors are available with the article online. Funding was provided by the Gorrindo Family Fund.
A version of this article appeared on Medscape.com.
Thrombocytosis and Cancer Risk: Management in Primary Care
This transcript has been edited for clarity.
In this podcast, I’m going to talk about unexplained high platelet counts, or thrombocytosis, and the risk for cancer in primary care. Let’s start with a typical case we all might see in primary care.
Louisa is 47 years old and is the chief financial officer for a tech startup company. She presents to us in primary care feeling tired all the time — a very common presentation in primary care — with associated reduced appetite. Past medical history includes irritable bowel syndrome, and she’s an ex-smoker.
Systemic inquiry is unremarkable. Specifically, there is no history of weight loss. Louisa has not been prescribed any medication and uses over-the-counter remedies for her irritable bowel syndrome. Examination is also unremarkable. Blood tests were checked, which were all reassuring, except for a platelet count of 612 × 109 cells/L (usual normal range, about 150-450).
What do we do next? Do we refer for an urgent chest x-ray to exclude lung cancer? Do we check a quantitative immunohistochemical fecal occult blood test (qFIT) to identify any occult bleeding in her stool? Do we refer for a routine upper gastrointestinal endoscopy or pelvic ultrasound scan to exclude any upper gastrointestinal or endometrial malignancy?
Do we simply repeat the bloods? If so, do we repeat them routinely or urgently, and indeed, which ones should we recheck?
Louisa has an unexplained thrombocytosis. How do we manage this in primary care? Thrombocytosis is generally defined as a raised platelet count over 450. Importantly, thrombocytosis is a common incidental finding in around 2% of those over 40 years of age attending primary care. Reassuringly, 80%-90% of thrombocytosis is reactive, secondary to acute blood loss, infection, or inflammation, and the majority of cases resolve within 3 months.
Why the concern with Louisa then? Although most cases are reactive, clinical guidance (for example, NICE suspected cancer guidance in the UK and Scottish suspected cancer guidance in Scotland) reminds us that unexplained thrombocytosis is a risk marker for some solid-tumor malignancies.
Previous studies have demonstrated that unexplained thrombocytosis is associated with a 1-year cancer incidence of 11.6% in males and 6.2% in females, well exceeding the standard 3% threshold warranting investigation for underlying malignancy. However, thrombocytosis should not be used as a stand-alone diagnostic or screening test for cancer, or indeed to rule out cancer.
Instead, unexplained thrombocytosis should prompt us to think cancer. The Scottish suspected cancer referral guidelines include thrombocytosis in the investigation criteria for what they call the LEGO-C cancers — L for lung, E for endometrial, G for gastric, O for oesophageal, and C for colorectal, which is a useful reminder for us all.
What further history, examination, and investigations might we consider in primary care if we identify an unexplained high platelet count? As always, we should use our clinical judgment and trust our clinical acumen.
We should consider all the possible underlying causes, including infection, inflammation, and blood loss, including menstrual blood loss in women; myeloproliferative disorders such as polycythemia rubra vera, chronic myeloid leukemia, and essential thrombocythemia; and, of course, underlying malignancy. If a likely underlying reversible cause is present (for example, a recent lower respiratory tract infection), simply repeating the full blood count in 4-6 weeks is quite appropriate to see if the thrombocytosis has resolved.
Remember, 80%-90% of cases are reactive thrombocytosis, and most cases resolve within 3 months. If thrombocytosis is unexplained or not resolving, consider checking ferritin levels to exclude iron deficiency. Consider checking C-reactive protein (CRP) levels to exclude any inflammation, and also consider checking a blood film to exclude any hematologic disorders, in addition, of course, to more detailed history-taking and examination to elicit any red flags.
We can also consider a JAK2 gene mutation test, if it is available to you locally, or a hematology referral if we suspect a myeloproliferative disorder. JAK2 is a genetic mutation that may be present in people with essential thrombocythemia and can indicate a diagnosis of polycythemia rubra vera.
Subsequent to this, and again using our clinical judgment, we then need to exclude the LEGO-C cancers. Consider urgent chest x-ray to exclude lung cancer or pelvic ultrasound in women to exclude endometrial cancer. Also, we should consider an upper gastrointestinal endoscopy, particularly in those individuals who have associated upper gastrointestinal symptoms and/or weight loss.
Finally, consider a qFIT to identify any occult bleeding in the stool, again if it’s available to you, or certainly if not, urgent lower gastrointestinal investigations to exclude colorectal cancer.
Alongside these possible investigations, as always, we should safety-net appropriately within agreed timeframes and check for resolution of the thrombocytosis according to the condition being suspected. Remember, most cases resolve within 3 months.
Returning to Louisa, what did I do? After seeing a platelet count of 600, I subsequently telephoned her and reexplored her history, which yielded nil else of note. Specifically, there was no history of unexplained weight loss, no history of upper or lower gastrointestinal symptoms, and certainly nothing significantly different from her usual irritable bowel syndrome symptoms. There were also no respiratory or genitourinary symptoms of note.
I did arrange for Louisa to undergo a chest x-ray over the next few days, though, as she was an ex-smoker. This was subsequently reported as normal. I appreciate chest x-rays have poor sensitivity for detecting lung cancer, as highlighted in a number of recent papers, but it was mutually agreed with Louisa that we would simply repeat her blood test in around 6 weeks. As well as repeating the full blood count, I arranged to check her ferritin, CRP, and a blood film, and then I was planning to reassess her clinically in person.
These bloods and my subsequent clinical review were reassuring. In fact, her platelet count had normalized after that 6 weeks had elapsed. Her thrombocytosis had resolved.
I didn’t arrange any further follow-up for her, but I did give her the usual safety netting advice to re-present to me or one of my colleagues if she does develop any worrying symptoms or signs.
I appreciate these scenarios are not always this straightforward, but I wanted to outline what investigations and referrals we may need to consider in primary care if we encounter an unexplained high platelet count.
There are a couple of quality-improvement activities for us all to consider in primary care. Consider as a team how we would respond to an incidental finding of thrombocytosis on a full blood count. Also consider what are our safety-netting options for those found to have raised platelet counts but no other symptoms or risk factors for underlying malignancy.
Finally, I’ve produced a Medscape UK primary care hack or clinical aide-memoire on managing unexplained thrombocytosis and associated cancer risk in primary care for all healthcare professionals working in primary care. This can be found online. I hope you find this resource helpful.
Dr. Kevin Fernando, General practitioner partner with specialist interests in cardiovascular, renal, and metabolic medicine, North Berwick Group Practice in Scotland, has disclosed relevant financial relationships with Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Dexcom, Lilly, Menarini, Novartis, Novo Nordisk, Roche Diagnostics, Embecta, Roche Diabetes Care, Sanofi Menarini, and Daiichi Sankyo.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
In this podcast, I’m going to talk about unexplained high platelet counts, or thrombocytosis, and the risk for cancer in primary care. Let’s start with a typical case we all might see in primary care.
Louisa is 47 years old and is the chief financial officer for a tech startup company. She presents to us in primary care feeling tired all the time — a very common presentation in primary care — with associated reduced appetite. Past medical history includes irritable bowel syndrome, and she’s an ex-smoker.
Systemic inquiry is unremarkable. Specifically, there is no history of weight loss. Louisa has not been prescribed any medication and uses over-the-counter remedies for her irritable bowel syndrome. Examination is also unremarkable. Blood tests were checked, which were all reassuring, except for a platelet count of 612 × 109 cells/L (usual normal range, about 150-450).
What do we do next? Do we refer for an urgent chest x-ray to exclude lung cancer? Do we check a quantitative immunohistochemical fecal occult blood test (qFIT) to identify any occult bleeding in her stool? Do we refer for a routine upper gastrointestinal endoscopy or pelvic ultrasound scan to exclude any upper gastrointestinal or endometrial malignancy?
Do we simply repeat the bloods? If so, do we repeat them routinely or urgently, and indeed, which ones should we recheck?
Louisa has an unexplained thrombocytosis. How do we manage this in primary care? Thrombocytosis is generally defined as a raised platelet count over 450. Importantly, thrombocytosis is a common incidental finding in around 2% of those over 40 years of age attending primary care. Reassuringly, 80%-90% of thrombocytosis is reactive, secondary to acute blood loss, infection, or inflammation, and the majority of cases resolve within 3 months.
Why the concern with Louisa then? Although most cases are reactive, clinical guidance (for example, NICE suspected cancer guidance in the UK and Scottish suspected cancer guidance in Scotland) reminds us that unexplained thrombocytosis is a risk marker for some solid-tumor malignancies.
Previous studies have demonstrated that unexplained thrombocytosis is associated with a 1-year cancer incidence of 11.6% in males and 6.2% in females, well exceeding the standard 3% threshold warranting investigation for underlying malignancy. However, thrombocytosis should not be used as a stand-alone diagnostic or screening test for cancer, or indeed to rule out cancer.
Instead, unexplained thrombocytosis should prompt us to think cancer. The Scottish suspected cancer referral guidelines include thrombocytosis in the investigation criteria for what they call the LEGO-C cancers — L for lung, E for endometrial, G for gastric, O for oesophageal, and C for colorectal, which is a useful reminder for us all.
What further history, examination, and investigations might we consider in primary care if we identify an unexplained high platelet count? As always, we should use our clinical judgment and trust our clinical acumen.
We should consider all the possible underlying causes, including infection, inflammation, and blood loss, including menstrual blood loss in women; myeloproliferative disorders such as polycythemia rubra vera, chronic myeloid leukemia, and essential thrombocythemia; and, of course, underlying malignancy. If a likely underlying reversible cause is present (for example, a recent lower respiratory tract infection), simply repeating the full blood count in 4-6 weeks is quite appropriate to see if the thrombocytosis has resolved.
Remember, 80%-90% of cases are reactive thrombocytosis, and most cases resolve within 3 months. If thrombocytosis is unexplained or not resolving, consider checking ferritin levels to exclude iron deficiency. Consider checking C-reactive protein (CRP) levels to exclude any inflammation, and also consider checking a blood film to exclude any hematologic disorders, in addition, of course, to more detailed history-taking and examination to elicit any red flags.
We can also consider a JAK2 gene mutation test, if it is available to you locally, or a hematology referral if we suspect a myeloproliferative disorder. JAK2 is a genetic mutation that may be present in people with essential thrombocythemia and can indicate a diagnosis of polycythemia rubra vera.
Subsequent to this, and again using our clinical judgment, we then need to exclude the LEGO-C cancers. Consider urgent chest x-ray to exclude lung cancer or pelvic ultrasound in women to exclude endometrial cancer. Also, we should consider an upper gastrointestinal endoscopy, particularly in those individuals who have associated upper gastrointestinal symptoms and/or weight loss.
Finally, consider a qFIT to identify any occult bleeding in the stool, again if it’s available to you, or certainly if not, urgent lower gastrointestinal investigations to exclude colorectal cancer.
Alongside these possible investigations, as always, we should safety-net appropriately within agreed timeframes and check for resolution of the thrombocytosis according to the condition being suspected. Remember, most cases resolve within 3 months.
Returning to Louisa, what did I do? After seeing a platelet count of 600, I subsequently telephoned her and reexplored her history, which yielded nil else of note. Specifically, there was no history of unexplained weight loss, no history of upper or lower gastrointestinal symptoms, and certainly nothing significantly different from her usual irritable bowel syndrome symptoms. There were also no respiratory or genitourinary symptoms of note.
I did arrange for Louisa to undergo a chest x-ray over the next few days, though, as she was an ex-smoker. This was subsequently reported as normal. I appreciate chest x-rays have poor sensitivity for detecting lung cancer, as highlighted in a number of recent papers, but it was mutually agreed with Louisa that we would simply repeat her blood test in around 6 weeks. As well as repeating the full blood count, I arranged to check her ferritin, CRP, and a blood film, and then I was planning to reassess her clinically in person.
These bloods and my subsequent clinical review were reassuring. In fact, her platelet count had normalized after that 6 weeks had elapsed. Her thrombocytosis had resolved.
I didn’t arrange any further follow-up for her, but I did give her the usual safety netting advice to re-present to me or one of my colleagues if she does develop any worrying symptoms or signs.
I appreciate these scenarios are not always this straightforward, but I wanted to outline what investigations and referrals we may need to consider in primary care if we encounter an unexplained high platelet count.
There are a couple of quality-improvement activities for us all to consider in primary care. Consider as a team how we would respond to an incidental finding of thrombocytosis on a full blood count. Also consider what are our safety-netting options for those found to have raised platelet counts but no other symptoms or risk factors for underlying malignancy.
Finally, I’ve produced a Medscape UK primary care hack or clinical aide-memoire on managing unexplained thrombocytosis and associated cancer risk in primary care for all healthcare professionals working in primary care. This can be found online. I hope you find this resource helpful.
Dr. Kevin Fernando, General practitioner partner with specialist interests in cardiovascular, renal, and metabolic medicine, North Berwick Group Practice in Scotland, has disclosed relevant financial relationships with Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Dexcom, Lilly, Menarini, Novartis, Novo Nordisk, Roche Diagnostics, Embecta, Roche Diabetes Care, Sanofi Menarini, and Daiichi Sankyo.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
In this podcast, I’m going to talk about unexplained high platelet counts, or thrombocytosis, and the risk for cancer in primary care. Let’s start with a typical case we all might see in primary care.
Louisa is 47 years old and is the chief financial officer for a tech startup company. She presents to us in primary care feeling tired all the time — a very common presentation in primary care — with associated reduced appetite. Past medical history includes irritable bowel syndrome, and she’s an ex-smoker.
Systemic inquiry is unremarkable. Specifically, there is no history of weight loss. Louisa has not been prescribed any medication and uses over-the-counter remedies for her irritable bowel syndrome. Examination is also unremarkable. Blood tests were checked, which were all reassuring, except for a platelet count of 612 × 109 cells/L (usual normal range, about 150-450).
What do we do next? Do we refer for an urgent chest x-ray to exclude lung cancer? Do we check a quantitative immunohistochemical fecal occult blood test (qFIT) to identify any occult bleeding in her stool? Do we refer for a routine upper gastrointestinal endoscopy or pelvic ultrasound scan to exclude any upper gastrointestinal or endometrial malignancy?
Do we simply repeat the bloods? If so, do we repeat them routinely or urgently, and indeed, which ones should we recheck?
Louisa has an unexplained thrombocytosis. How do we manage this in primary care? Thrombocytosis is generally defined as a raised platelet count over 450. Importantly, thrombocytosis is a common incidental finding in around 2% of those over 40 years of age attending primary care. Reassuringly, 80%-90% of thrombocytosis is reactive, secondary to acute blood loss, infection, or inflammation, and the majority of cases resolve within 3 months.
Why the concern with Louisa then? Although most cases are reactive, clinical guidance (for example, NICE suspected cancer guidance in the UK and Scottish suspected cancer guidance in Scotland) reminds us that unexplained thrombocytosis is a risk marker for some solid-tumor malignancies.
Previous studies have demonstrated that unexplained thrombocytosis is associated with a 1-year cancer incidence of 11.6% in males and 6.2% in females, well exceeding the standard 3% threshold warranting investigation for underlying malignancy. However, thrombocytosis should not be used as a stand-alone diagnostic or screening test for cancer, or indeed to rule out cancer.
Instead, unexplained thrombocytosis should prompt us to think cancer. The Scottish suspected cancer referral guidelines include thrombocytosis in the investigation criteria for what they call the LEGO-C cancers — L for lung, E for endometrial, G for gastric, O for oesophageal, and C for colorectal, which is a useful reminder for us all.
What further history, examination, and investigations might we consider in primary care if we identify an unexplained high platelet count? As always, we should use our clinical judgment and trust our clinical acumen.
We should consider all the possible underlying causes, including infection, inflammation, and blood loss, including menstrual blood loss in women; myeloproliferative disorders such as polycythemia rubra vera, chronic myeloid leukemia, and essential thrombocythemia; and, of course, underlying malignancy. If a likely underlying reversible cause is present (for example, a recent lower respiratory tract infection), simply repeating the full blood count in 4-6 weeks is quite appropriate to see if the thrombocytosis has resolved.
Remember, 80%-90% of cases are reactive thrombocytosis, and most cases resolve within 3 months. If thrombocytosis is unexplained or not resolving, consider checking ferritin levels to exclude iron deficiency. Consider checking C-reactive protein (CRP) levels to exclude any inflammation, and also consider checking a blood film to exclude any hematologic disorders, in addition, of course, to more detailed history-taking and examination to elicit any red flags.
We can also consider a JAK2 gene mutation test, if it is available to you locally, or a hematology referral if we suspect a myeloproliferative disorder. JAK2 is a genetic mutation that may be present in people with essential thrombocythemia and can indicate a diagnosis of polycythemia rubra vera.
Subsequent to this, and again using our clinical judgment, we then need to exclude the LEGO-C cancers. Consider urgent chest x-ray to exclude lung cancer or pelvic ultrasound in women to exclude endometrial cancer. Also, we should consider an upper gastrointestinal endoscopy, particularly in those individuals who have associated upper gastrointestinal symptoms and/or weight loss.
Finally, consider a qFIT to identify any occult bleeding in the stool, again if it’s available to you, or certainly if not, urgent lower gastrointestinal investigations to exclude colorectal cancer.
Alongside these possible investigations, as always, we should safety-net appropriately within agreed timeframes and check for resolution of the thrombocytosis according to the condition being suspected. Remember, most cases resolve within 3 months.
Returning to Louisa, what did I do? After seeing a platelet count of 600, I subsequently telephoned her and reexplored her history, which yielded nil else of note. Specifically, there was no history of unexplained weight loss, no history of upper or lower gastrointestinal symptoms, and certainly nothing significantly different from her usual irritable bowel syndrome symptoms. There were also no respiratory or genitourinary symptoms of note.
I did arrange for Louisa to undergo a chest x-ray over the next few days, though, as she was an ex-smoker. This was subsequently reported as normal. I appreciate chest x-rays have poor sensitivity for detecting lung cancer, as highlighted in a number of recent papers, but it was mutually agreed with Louisa that we would simply repeat her blood test in around 6 weeks. As well as repeating the full blood count, I arranged to check her ferritin, CRP, and a blood film, and then I was planning to reassess her clinically in person.
These bloods and my subsequent clinical review were reassuring. In fact, her platelet count had normalized after that 6 weeks had elapsed. Her thrombocytosis had resolved.
I didn’t arrange any further follow-up for her, but I did give her the usual safety netting advice to re-present to me or one of my colleagues if she does develop any worrying symptoms or signs.
I appreciate these scenarios are not always this straightforward, but I wanted to outline what investigations and referrals we may need to consider in primary care if we encounter an unexplained high platelet count.
There are a couple of quality-improvement activities for us all to consider in primary care. Consider as a team how we would respond to an incidental finding of thrombocytosis on a full blood count. Also consider what are our safety-netting options for those found to have raised platelet counts but no other symptoms or risk factors for underlying malignancy.
Finally, I’ve produced a Medscape UK primary care hack or clinical aide-memoire on managing unexplained thrombocytosis and associated cancer risk in primary care for all healthcare professionals working in primary care. This can be found online. I hope you find this resource helpful.
Dr. Kevin Fernando, General practitioner partner with specialist interests in cardiovascular, renal, and metabolic medicine, North Berwick Group Practice in Scotland, has disclosed relevant financial relationships with Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Dexcom, Lilly, Menarini, Novartis, Novo Nordisk, Roche Diagnostics, Embecta, Roche Diabetes Care, Sanofi Menarini, and Daiichi Sankyo.
A version of this article first appeared on Medscape.com.
Abuse of the Safety-Net 340B Drug Pricing Program: Why Should Physicians Care?
The 340B Drug Pricing Program began as a noble endeavor, a lifeline designed to help safety-net providers deliver affordable care to America’s most vulnerable populations. However, over the years, this well-intentioned program has strayed from its original purpose, becoming a lucrative space where profits often outweigh patients. Loopholes, lax oversight, and unchecked expansion have allowed some powerful players, such as certain disproportionate share hospitals and their “child sites” as well as for-profit pharmacies, to exploit the system. What was once a program to uplift underserved communities now risks becoming a case study in how good intentions can go astray without accountability.
What exactly is this “340B program” that has captured headlines and the interest of legislatures around the country? What ensures that pharmaceutical manufacturers continue to participate in this program? How lucrative is it? How have underserved populations benefited and how is that measured?
The 340B Drug Pricing Program was established in 1992 under the Public Health Service Act. Its primary goal is to enable covered entities (such as hospitals and clinics serving low-income and uninsured patients) to purchase outpatient drugs from pharmaceutical manufacturers at significantly reduced prices in order to support their care of the low-income and underserved populations. Drug makers are required to participate in this program as a condition of their participation in Medicaid and Medicare Part B and offer these steep discounts to covered entities if they want their medications to be available to 38% of patients nationwide.
The hospitals that make up 78% of the program’s spending are known as disproportionate share hospitals (DSHs). These hospitals must be nonprofit and have at least an 11.75% “disproportionate” share of low-income Medicare or Medicaid inpatients. The other types of non-hospital entities qualifying for 340B pricing are known as initial “federal grantees.” Some examples include federally qualified health centers (FQHC), Ryan White HIV/AIDS program grantees, and other types of specialized clinics, such as hemophilia treatment centers. It needs to be noted up front that it is not these initial non-hospital federal grantees that need more oversight or reform, since according to the Health Resources and Services Administration (HRSA) 2023 report they make up only 22% of all program spending. It is the large, predominantly DSH health systems that are profiting immensely through exponential growth of their clinics and contract pharmacies. However, these health systems have not been able to show exactly who are their eligible patients and how they have been benefiting them.
When the 340B program was established to offer financial relief to hospitals and clinics taking care of the uninsured, it allowed them to save 20%-50% on drug purchases, which could be reinvested in patient care services. It was hoped that savings from the program could be used to provide free or low-cost medications, free vaccines, and other essential health services, essentially allowing safety-net providers to serve their communities despite financial constraints. The initial grantees are fulfilling that mission, but there are concerns regarding DSHs. (See the Coalition of State Rheumatology Organization’s 340B explanatory statement and policy position for more.)
Why Should Independent Practice Physicians Care About This?
Independent doctors should care about the lack of oversight in the 340B program because it affects healthcare costs, patient assistance, market competition, and access to affordable care for underserved and uninsured patients.
It also plays a strong hand in the healthcare consolidation that continues to threaten private physician practices. These acquisitions threaten the viability of independent practices in a variety of specialties across the United States, including rheumatology. HRSA allows 340B-covered entities to register their off-campus outpatient facilities, or child sites, under their 340B designation. Covered entities can acquire drugs at the 340B price, while imposing markups on the reimbursement they submit to private insurance. The additional revenue these covered entities can pocket provides them with a cash flow advantage that physician practices and outpatient clinics will never be able to actualize. This uneven playing field may make rheumatology practices more susceptible to hospital acquisitions. In fact, between 2016 and 2022, large 340B hospitals were responsible for approximately 80% of hospital acquisitions.
Perhaps the most important reason that we should all be concerned about the trajectory of this well-meaning program is that we have seen patients with hospital debt being sued by DSHs who receive 340B discounts so that they can take care of the low-income patients they are suing. We have seen Medicaid patients be turned away from a DSH clinic after being discharged from that hospital, because the hospital had reached its disproportionate share (11.75%) of inpatient Medicare and Medicaid patients. While not illegal, that type of behavior by covered entities is WRONG! Oversight and reform are needed if the 340B program is going to live up to its purpose and not be just another well-intentioned program not fulfilling its mission.
Areas of Concern
There has been controversy regarding the limited oversight of the 340B program by HRSA, leading to abuse of the program. There are deep concerns regarding a lack of transparency in how savings from the program are being used, and there are concerns about the challenges associated with accurate tracking and reporting of 340B discounts, possibly leading to the duplication of discounts for both Medicaid and 340B. For example, a “duplicate discount” occurs if a manufacturer sells medications to a DSH at the 340B price and later pays a Medicaid rebate on the same drug. The extent of duplicate discounts in the 340B program is unknown. However, an audit of 1,536 cases conducted by HRSA between 2012 and 2019 found 429 instances of noncompliance related to duplicate discounts, which is nearly 30% of cases.
DSHs and their contracted pharmacies have been accused of exploiting the program by increasing the number of contract pharmacies and expanding the number of offsite outpatient clinics to maximize profits. As of mid-2024, the number of 340B contract pharmacies, counted by Drug Channels Institute (DCI), numbered 32,883 unique locations. According to DCI, the top five pharmacies in the program happen also to be among the top pharmacy revenue generators and are “for-profit.” They are CVS, Walgreens, Walmart, Express Scripts, and Optum RX. Additionally, a study in JAMA Health Forum showed that, from 2011 to 2019, contract pharmacies in areas with the lowest income decreased by 5.6% while those in the most affluent neighborhoods grew by 5%.
There also has been tremendous growth in the number of covered entities in the 340B program, which grew from just over 8,100 in 2000 to 50,000 in 2020. Before 2004, DSHs made up less than 10% of these entities, but by 2020, they accounted for over 60%. Another study shows that DSHs are expanding their offsite outpatient clinics (“child clinics”) into the affluent neighborhoods serving commercially insured patients who are not low income, to capture the high commercial reimbursements for medications they acquired at steeply discounted prices. This clearly is diverting care away from the intended beneficiaries of the 340B program.
Furthermore, DSHs have been acquiring specialty practices that prescribe some of the most expensive drugs, in order to take advantage of commercial reimbursement for medications that were acquired at the 340B discount price. Independent oncology practices have complained specifically about this happening in their area, where in some cases the DSHs have “stolen” their patients to profit off of the 340B pricing margins. This has the unintended consequence of increasing government spending, according to a study in the New England Journal of Medicine that showed price markups at 340B eligible hospitals were 6.59 times as high as those in independent physician practices after accounting for drug, patient, and geographic factors.
Legal Challenges and Legislation
On May 21, 2024, the US Court of Appeals for the DC Circuit issued a unanimous decision in favor of drug manufacturers, finding that certain manufacturer restrictions on the use of contract pharmacies under the 340B drug pricing program are permissible. The court’s decision follows a lower court (3rd Circuit) ruling which concluded that the 340B statute does not require manufacturers to deliver 340B drugs to an “unlimited number of contract pharmacies.” We’re still awaiting a decision from the 7th Circuit Court on a similar issue. If the 7th Circuit agrees with the government, creating a split decision, there is an increase in the likelihood that the Supreme Court would take up the case.
Johnson & Johnson has also sued the federal government for blocking their proposed use of a rebate model for DSHs that purchase through 340B two of its medications, Stelara and Xarelto, whose maximum fair price was negotiated through the Inflation Reduction Act’s Medicare Drug Price Negotiation Program. J&J states this would ensure that the claims are actually acquired and dispensed by a covered 340B entity, as well as ensuring there are no duplicate discounts as statutorily required by the IRA. When initially proposed, HRSA threatened to remove J&J’s access to Medicare and Medicaid if it pursued this change. J&J’s suit challenges that decision.
However, seven states (Arkansas, Kansas, Louisiana, Minnesota, Missouri, Mississippi, and West Virginia) have been active on this issue, passing laws to prevent manufacturers from limiting contract pharmacies’ ability to acquire 340B-discounted drugs. The model legislation also bans restrictions on the “number, location, ownership, or type of 340B contract pharmacy.”
It should also be noted that there are states that are looking for ways to encourage certain independent private practice specialties (such as gastroenterology and rheumatology) to see Medicaid patients, as well as increase testing for sexually transmitted diseases, by offering the possibility of obtaining 340B pricing in their clinics.
Shifting our focus to Congress, six bipartisan Senators, known as the Group of 6, are working to modernize the 340B program, which hasn’t been updated since the original law in 1992. In 2024, legislation was introduced (see here and here) to reform a number of the features of the 340B drug discount program, including transparency, contract pharmacy requirements, and federal agency oversight.
Who’s Guarding the Hen House?
The Government Accountability Office and the Office of Inspector General over the last 5-10 years have asked HRSA to better define an “eligible” patient, to have more specifics concerning hospital eligibility criteria, and to have better oversight of the program to avoid duplicate discounts. HRSA has said that it doesn’t have the ability or the funding to achieve some of these goals. Consequently, little has been done on any of these fronts, creating frustration among pharmaceutical manufacturers and those calling for more oversight of the program to ensure that eligible patients are receiving the benefit of 340B pricing. Again, these frustrations are not pointed at the initial federally qualified centers or “grantees.”
HRSA now audits 200 covered entities a year, which is less than 2% of entities participating in the 340B program. HRSA expects the 340B entities themselves to have an oversight committee in place to ensure compliance with program requirements.
So essentially, the fox is guarding the hen house?
Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s vice president of advocacy and government affairs and its immediate past president, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at [email protected].
The 340B Drug Pricing Program began as a noble endeavor, a lifeline designed to help safety-net providers deliver affordable care to America’s most vulnerable populations. However, over the years, this well-intentioned program has strayed from its original purpose, becoming a lucrative space where profits often outweigh patients. Loopholes, lax oversight, and unchecked expansion have allowed some powerful players, such as certain disproportionate share hospitals and their “child sites” as well as for-profit pharmacies, to exploit the system. What was once a program to uplift underserved communities now risks becoming a case study in how good intentions can go astray without accountability.
What exactly is this “340B program” that has captured headlines and the interest of legislatures around the country? What ensures that pharmaceutical manufacturers continue to participate in this program? How lucrative is it? How have underserved populations benefited and how is that measured?
The 340B Drug Pricing Program was established in 1992 under the Public Health Service Act. Its primary goal is to enable covered entities (such as hospitals and clinics serving low-income and uninsured patients) to purchase outpatient drugs from pharmaceutical manufacturers at significantly reduced prices in order to support their care of the low-income and underserved populations. Drug makers are required to participate in this program as a condition of their participation in Medicaid and Medicare Part B and offer these steep discounts to covered entities if they want their medications to be available to 38% of patients nationwide.
The hospitals that make up 78% of the program’s spending are known as disproportionate share hospitals (DSHs). These hospitals must be nonprofit and have at least an 11.75% “disproportionate” share of low-income Medicare or Medicaid inpatients. The other types of non-hospital entities qualifying for 340B pricing are known as initial “federal grantees.” Some examples include federally qualified health centers (FQHC), Ryan White HIV/AIDS program grantees, and other types of specialized clinics, such as hemophilia treatment centers. It needs to be noted up front that it is not these initial non-hospital federal grantees that need more oversight or reform, since according to the Health Resources and Services Administration (HRSA) 2023 report they make up only 22% of all program spending. It is the large, predominantly DSH health systems that are profiting immensely through exponential growth of their clinics and contract pharmacies. However, these health systems have not been able to show exactly who are their eligible patients and how they have been benefiting them.
When the 340B program was established to offer financial relief to hospitals and clinics taking care of the uninsured, it allowed them to save 20%-50% on drug purchases, which could be reinvested in patient care services. It was hoped that savings from the program could be used to provide free or low-cost medications, free vaccines, and other essential health services, essentially allowing safety-net providers to serve their communities despite financial constraints. The initial grantees are fulfilling that mission, but there are concerns regarding DSHs. (See the Coalition of State Rheumatology Organization’s 340B explanatory statement and policy position for more.)
Why Should Independent Practice Physicians Care About This?
Independent doctors should care about the lack of oversight in the 340B program because it affects healthcare costs, patient assistance, market competition, and access to affordable care for underserved and uninsured patients.
It also plays a strong hand in the healthcare consolidation that continues to threaten private physician practices. These acquisitions threaten the viability of independent practices in a variety of specialties across the United States, including rheumatology. HRSA allows 340B-covered entities to register their off-campus outpatient facilities, or child sites, under their 340B designation. Covered entities can acquire drugs at the 340B price, while imposing markups on the reimbursement they submit to private insurance. The additional revenue these covered entities can pocket provides them with a cash flow advantage that physician practices and outpatient clinics will never be able to actualize. This uneven playing field may make rheumatology practices more susceptible to hospital acquisitions. In fact, between 2016 and 2022, large 340B hospitals were responsible for approximately 80% of hospital acquisitions.
Perhaps the most important reason that we should all be concerned about the trajectory of this well-meaning program is that we have seen patients with hospital debt being sued by DSHs who receive 340B discounts so that they can take care of the low-income patients they are suing. We have seen Medicaid patients be turned away from a DSH clinic after being discharged from that hospital, because the hospital had reached its disproportionate share (11.75%) of inpatient Medicare and Medicaid patients. While not illegal, that type of behavior by covered entities is WRONG! Oversight and reform are needed if the 340B program is going to live up to its purpose and not be just another well-intentioned program not fulfilling its mission.
Areas of Concern
There has been controversy regarding the limited oversight of the 340B program by HRSA, leading to abuse of the program. There are deep concerns regarding a lack of transparency in how savings from the program are being used, and there are concerns about the challenges associated with accurate tracking and reporting of 340B discounts, possibly leading to the duplication of discounts for both Medicaid and 340B. For example, a “duplicate discount” occurs if a manufacturer sells medications to a DSH at the 340B price and later pays a Medicaid rebate on the same drug. The extent of duplicate discounts in the 340B program is unknown. However, an audit of 1,536 cases conducted by HRSA between 2012 and 2019 found 429 instances of noncompliance related to duplicate discounts, which is nearly 30% of cases.
DSHs and their contracted pharmacies have been accused of exploiting the program by increasing the number of contract pharmacies and expanding the number of offsite outpatient clinics to maximize profits. As of mid-2024, the number of 340B contract pharmacies, counted by Drug Channels Institute (DCI), numbered 32,883 unique locations. According to DCI, the top five pharmacies in the program happen also to be among the top pharmacy revenue generators and are “for-profit.” They are CVS, Walgreens, Walmart, Express Scripts, and Optum RX. Additionally, a study in JAMA Health Forum showed that, from 2011 to 2019, contract pharmacies in areas with the lowest income decreased by 5.6% while those in the most affluent neighborhoods grew by 5%.
There also has been tremendous growth in the number of covered entities in the 340B program, which grew from just over 8,100 in 2000 to 50,000 in 2020. Before 2004, DSHs made up less than 10% of these entities, but by 2020, they accounted for over 60%. Another study shows that DSHs are expanding their offsite outpatient clinics (“child clinics”) into the affluent neighborhoods serving commercially insured patients who are not low income, to capture the high commercial reimbursements for medications they acquired at steeply discounted prices. This clearly is diverting care away from the intended beneficiaries of the 340B program.
Furthermore, DSHs have been acquiring specialty practices that prescribe some of the most expensive drugs, in order to take advantage of commercial reimbursement for medications that were acquired at the 340B discount price. Independent oncology practices have complained specifically about this happening in their area, where in some cases the DSHs have “stolen” their patients to profit off of the 340B pricing margins. This has the unintended consequence of increasing government spending, according to a study in the New England Journal of Medicine that showed price markups at 340B eligible hospitals were 6.59 times as high as those in independent physician practices after accounting for drug, patient, and geographic factors.
Legal Challenges and Legislation
On May 21, 2024, the US Court of Appeals for the DC Circuit issued a unanimous decision in favor of drug manufacturers, finding that certain manufacturer restrictions on the use of contract pharmacies under the 340B drug pricing program are permissible. The court’s decision follows a lower court (3rd Circuit) ruling which concluded that the 340B statute does not require manufacturers to deliver 340B drugs to an “unlimited number of contract pharmacies.” We’re still awaiting a decision from the 7th Circuit Court on a similar issue. If the 7th Circuit agrees with the government, creating a split decision, there is an increase in the likelihood that the Supreme Court would take up the case.
Johnson & Johnson has also sued the federal government for blocking their proposed use of a rebate model for DSHs that purchase through 340B two of its medications, Stelara and Xarelto, whose maximum fair price was negotiated through the Inflation Reduction Act’s Medicare Drug Price Negotiation Program. J&J states this would ensure that the claims are actually acquired and dispensed by a covered 340B entity, as well as ensuring there are no duplicate discounts as statutorily required by the IRA. When initially proposed, HRSA threatened to remove J&J’s access to Medicare and Medicaid if it pursued this change. J&J’s suit challenges that decision.
However, seven states (Arkansas, Kansas, Louisiana, Minnesota, Missouri, Mississippi, and West Virginia) have been active on this issue, passing laws to prevent manufacturers from limiting contract pharmacies’ ability to acquire 340B-discounted drugs. The model legislation also bans restrictions on the “number, location, ownership, or type of 340B contract pharmacy.”
It should also be noted that there are states that are looking for ways to encourage certain independent private practice specialties (such as gastroenterology and rheumatology) to see Medicaid patients, as well as increase testing for sexually transmitted diseases, by offering the possibility of obtaining 340B pricing in their clinics.
Shifting our focus to Congress, six bipartisan Senators, known as the Group of 6, are working to modernize the 340B program, which hasn’t been updated since the original law in 1992. In 2024, legislation was introduced (see here and here) to reform a number of the features of the 340B drug discount program, including transparency, contract pharmacy requirements, and federal agency oversight.
Who’s Guarding the Hen House?
The Government Accountability Office and the Office of Inspector General over the last 5-10 years have asked HRSA to better define an “eligible” patient, to have more specifics concerning hospital eligibility criteria, and to have better oversight of the program to avoid duplicate discounts. HRSA has said that it doesn’t have the ability or the funding to achieve some of these goals. Consequently, little has been done on any of these fronts, creating frustration among pharmaceutical manufacturers and those calling for more oversight of the program to ensure that eligible patients are receiving the benefit of 340B pricing. Again, these frustrations are not pointed at the initial federally qualified centers or “grantees.”
HRSA now audits 200 covered entities a year, which is less than 2% of entities participating in the 340B program. HRSA expects the 340B entities themselves to have an oversight committee in place to ensure compliance with program requirements.
So essentially, the fox is guarding the hen house?
Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s vice president of advocacy and government affairs and its immediate past president, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at [email protected].
The 340B Drug Pricing Program began as a noble endeavor, a lifeline designed to help safety-net providers deliver affordable care to America’s most vulnerable populations. However, over the years, this well-intentioned program has strayed from its original purpose, becoming a lucrative space where profits often outweigh patients. Loopholes, lax oversight, and unchecked expansion have allowed some powerful players, such as certain disproportionate share hospitals and their “child sites” as well as for-profit pharmacies, to exploit the system. What was once a program to uplift underserved communities now risks becoming a case study in how good intentions can go astray without accountability.
What exactly is this “340B program” that has captured headlines and the interest of legislatures around the country? What ensures that pharmaceutical manufacturers continue to participate in this program? How lucrative is it? How have underserved populations benefited and how is that measured?
The 340B Drug Pricing Program was established in 1992 under the Public Health Service Act. Its primary goal is to enable covered entities (such as hospitals and clinics serving low-income and uninsured patients) to purchase outpatient drugs from pharmaceutical manufacturers at significantly reduced prices in order to support their care of the low-income and underserved populations. Drug makers are required to participate in this program as a condition of their participation in Medicaid and Medicare Part B and offer these steep discounts to covered entities if they want their medications to be available to 38% of patients nationwide.
The hospitals that make up 78% of the program’s spending are known as disproportionate share hospitals (DSHs). These hospitals must be nonprofit and have at least an 11.75% “disproportionate” share of low-income Medicare or Medicaid inpatients. The other types of non-hospital entities qualifying for 340B pricing are known as initial “federal grantees.” Some examples include federally qualified health centers (FQHC), Ryan White HIV/AIDS program grantees, and other types of specialized clinics, such as hemophilia treatment centers. It needs to be noted up front that it is not these initial non-hospital federal grantees that need more oversight or reform, since according to the Health Resources and Services Administration (HRSA) 2023 report they make up only 22% of all program spending. It is the large, predominantly DSH health systems that are profiting immensely through exponential growth of their clinics and contract pharmacies. However, these health systems have not been able to show exactly who are their eligible patients and how they have been benefiting them.
When the 340B program was established to offer financial relief to hospitals and clinics taking care of the uninsured, it allowed them to save 20%-50% on drug purchases, which could be reinvested in patient care services. It was hoped that savings from the program could be used to provide free or low-cost medications, free vaccines, and other essential health services, essentially allowing safety-net providers to serve their communities despite financial constraints. The initial grantees are fulfilling that mission, but there are concerns regarding DSHs. (See the Coalition of State Rheumatology Organization’s 340B explanatory statement and policy position for more.)
Why Should Independent Practice Physicians Care About This?
Independent doctors should care about the lack of oversight in the 340B program because it affects healthcare costs, patient assistance, market competition, and access to affordable care for underserved and uninsured patients.
It also plays a strong hand in the healthcare consolidation that continues to threaten private physician practices. These acquisitions threaten the viability of independent practices in a variety of specialties across the United States, including rheumatology. HRSA allows 340B-covered entities to register their off-campus outpatient facilities, or child sites, under their 340B designation. Covered entities can acquire drugs at the 340B price, while imposing markups on the reimbursement they submit to private insurance. The additional revenue these covered entities can pocket provides them with a cash flow advantage that physician practices and outpatient clinics will never be able to actualize. This uneven playing field may make rheumatology practices more susceptible to hospital acquisitions. In fact, between 2016 and 2022, large 340B hospitals were responsible for approximately 80% of hospital acquisitions.
Perhaps the most important reason that we should all be concerned about the trajectory of this well-meaning program is that we have seen patients with hospital debt being sued by DSHs who receive 340B discounts so that they can take care of the low-income patients they are suing. We have seen Medicaid patients be turned away from a DSH clinic after being discharged from that hospital, because the hospital had reached its disproportionate share (11.75%) of inpatient Medicare and Medicaid patients. While not illegal, that type of behavior by covered entities is WRONG! Oversight and reform are needed if the 340B program is going to live up to its purpose and not be just another well-intentioned program not fulfilling its mission.
Areas of Concern
There has been controversy regarding the limited oversight of the 340B program by HRSA, leading to abuse of the program. There are deep concerns regarding a lack of transparency in how savings from the program are being used, and there are concerns about the challenges associated with accurate tracking and reporting of 340B discounts, possibly leading to the duplication of discounts for both Medicaid and 340B. For example, a “duplicate discount” occurs if a manufacturer sells medications to a DSH at the 340B price and later pays a Medicaid rebate on the same drug. The extent of duplicate discounts in the 340B program is unknown. However, an audit of 1,536 cases conducted by HRSA between 2012 and 2019 found 429 instances of noncompliance related to duplicate discounts, which is nearly 30% of cases.
DSHs and their contracted pharmacies have been accused of exploiting the program by increasing the number of contract pharmacies and expanding the number of offsite outpatient clinics to maximize profits. As of mid-2024, the number of 340B contract pharmacies, counted by Drug Channels Institute (DCI), numbered 32,883 unique locations. According to DCI, the top five pharmacies in the program happen also to be among the top pharmacy revenue generators and are “for-profit.” They are CVS, Walgreens, Walmart, Express Scripts, and Optum RX. Additionally, a study in JAMA Health Forum showed that, from 2011 to 2019, contract pharmacies in areas with the lowest income decreased by 5.6% while those in the most affluent neighborhoods grew by 5%.
There also has been tremendous growth in the number of covered entities in the 340B program, which grew from just over 8,100 in 2000 to 50,000 in 2020. Before 2004, DSHs made up less than 10% of these entities, but by 2020, they accounted for over 60%. Another study shows that DSHs are expanding their offsite outpatient clinics (“child clinics”) into the affluent neighborhoods serving commercially insured patients who are not low income, to capture the high commercial reimbursements for medications they acquired at steeply discounted prices. This clearly is diverting care away from the intended beneficiaries of the 340B program.
Furthermore, DSHs have been acquiring specialty practices that prescribe some of the most expensive drugs, in order to take advantage of commercial reimbursement for medications that were acquired at the 340B discount price. Independent oncology practices have complained specifically about this happening in their area, where in some cases the DSHs have “stolen” their patients to profit off of the 340B pricing margins. This has the unintended consequence of increasing government spending, according to a study in the New England Journal of Medicine that showed price markups at 340B eligible hospitals were 6.59 times as high as those in independent physician practices after accounting for drug, patient, and geographic factors.
Legal Challenges and Legislation
On May 21, 2024, the US Court of Appeals for the DC Circuit issued a unanimous decision in favor of drug manufacturers, finding that certain manufacturer restrictions on the use of contract pharmacies under the 340B drug pricing program are permissible. The court’s decision follows a lower court (3rd Circuit) ruling which concluded that the 340B statute does not require manufacturers to deliver 340B drugs to an “unlimited number of contract pharmacies.” We’re still awaiting a decision from the 7th Circuit Court on a similar issue. If the 7th Circuit agrees with the government, creating a split decision, there is an increase in the likelihood that the Supreme Court would take up the case.
Johnson & Johnson has also sued the federal government for blocking their proposed use of a rebate model for DSHs that purchase through 340B two of its medications, Stelara and Xarelto, whose maximum fair price was negotiated through the Inflation Reduction Act’s Medicare Drug Price Negotiation Program. J&J states this would ensure that the claims are actually acquired and dispensed by a covered 340B entity, as well as ensuring there are no duplicate discounts as statutorily required by the IRA. When initially proposed, HRSA threatened to remove J&J’s access to Medicare and Medicaid if it pursued this change. J&J’s suit challenges that decision.
However, seven states (Arkansas, Kansas, Louisiana, Minnesota, Missouri, Mississippi, and West Virginia) have been active on this issue, passing laws to prevent manufacturers from limiting contract pharmacies’ ability to acquire 340B-discounted drugs. The model legislation also bans restrictions on the “number, location, ownership, or type of 340B contract pharmacy.”
It should also be noted that there are states that are looking for ways to encourage certain independent private practice specialties (such as gastroenterology and rheumatology) to see Medicaid patients, as well as increase testing for sexually transmitted diseases, by offering the possibility of obtaining 340B pricing in their clinics.
Shifting our focus to Congress, six bipartisan Senators, known as the Group of 6, are working to modernize the 340B program, which hasn’t been updated since the original law in 1992. In 2024, legislation was introduced (see here and here) to reform a number of the features of the 340B drug discount program, including transparency, contract pharmacy requirements, and federal agency oversight.
Who’s Guarding the Hen House?
The Government Accountability Office and the Office of Inspector General over the last 5-10 years have asked HRSA to better define an “eligible” patient, to have more specifics concerning hospital eligibility criteria, and to have better oversight of the program to avoid duplicate discounts. HRSA has said that it doesn’t have the ability or the funding to achieve some of these goals. Consequently, little has been done on any of these fronts, creating frustration among pharmaceutical manufacturers and those calling for more oversight of the program to ensure that eligible patients are receiving the benefit of 340B pricing. Again, these frustrations are not pointed at the initial federally qualified centers or “grantees.”
HRSA now audits 200 covered entities a year, which is less than 2% of entities participating in the 340B program. HRSA expects the 340B entities themselves to have an oversight committee in place to ensure compliance with program requirements.
So essentially, the fox is guarding the hen house?
Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s vice president of advocacy and government affairs and its immediate past president, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at [email protected].
Reassuring Data on GLP-1 RAs and Pancreatic Cancer Risk
PHILADELPHIA —
Instead, the large electronic health record (EHR) analysis of patients with type 2 diabetes (T2D) found those taking GLP-1 RAs had a significantly lower risk for pancreatic cancer than peers on other antidiabetic medications.
“Although there were previous reports suggesting possible association between pancreatic cancer and GLP-1 receptor agonist medications, this study provides reassurance that there is no observed increased incidence of pancreatic cancer in patients prescribed these medications,” said Khaled Alsabbagh Alchirazi, MD, a gastroenterology fellow with Aurora Healthcare in Brookfield, Wisconsin.
He presented the study findings at the American College of Gastroenterology (ACG) 2024 Annual Scientific Meeting.
Important Topic
Patients with T2D are at increased risk for several malignancies, including pancreatic cancer. Given the unique mechanism of action of GLP-1 RAs in the pancreas, it was important to investigate the relationship between use of these drugs and incidence of pancreatic cancer, he explained.
Using the TriNetX database, the study team identified 4.95 million antidiabetic drug naive T2D patients who were prescribed antidiabetic medications for the first time between 2005 and 2020. None had a history of pancreatic cancer.
A total of 245,532 were prescribed a GLP-1 RA. The researchers compared GLP-1 RAs users to users of other antidiabetic medications — namely, insulin, metformin, alpha-glucosidase inhibitors, dipeptidyl-peptidase 4 inhibitors (DPP-4i), sodium-glucose cotransporter-2 inhibitors (SGLT2i), sulfonylureas, and thiazolidinediones.
Patients were propensity score-matched based on demographics, health determinants, lifestyle factors, medical history, family history of cancers, and acute/chronic pancreatitis.
The risk for pancreatic cancer was significantly lower among patients on GLP-1 RAs vs insulin (hazard ratio [HR], 0.47; 95% CI, 0.40-0.55), DPP-4i (HR, 0.80; 95% CI, 0.73-0.89), SGLT2i (HR, 0.78; 95% CI, 0.69-0.89), and sulfonylureas (HR, 0.84; 95% CI, 0.74-0.95), Alchirazi reported.
The results were consistent across different groups, including patients with obesity/ overweight on GLP-1 RAs vs insulin (HR, 0.53; 95% CI, 0.43-0.65) and SGLT2i (HR, 0.81; 95% CI, 0.69-0.96).
Strengths of the analysis included the large and diverse cohort of propensity score-matched patients. Limitations included the retrospective design and use of claims data that did not provide granular data on pathology reports.
The study by Alchirazi and colleagues aligns with a large population-based cohort study from Israel that found no evidence that GLP-1 RAs increase risk for pancreatic cancer over 7 years following initiation.
Separately, a study of more than 1.6 million patients with T2D found that treatment with a GLP-1 RA (vs insulin or metformin) was associated with lower risks for specific types of obesity-related cancers, including pancreatic cancer.
The study had no specific funding. Alchirazi had no relevant disclosures.
A version of this article appeared on Medscape.com.
PHILADELPHIA —
Instead, the large electronic health record (EHR) analysis of patients with type 2 diabetes (T2D) found those taking GLP-1 RAs had a significantly lower risk for pancreatic cancer than peers on other antidiabetic medications.
“Although there were previous reports suggesting possible association between pancreatic cancer and GLP-1 receptor agonist medications, this study provides reassurance that there is no observed increased incidence of pancreatic cancer in patients prescribed these medications,” said Khaled Alsabbagh Alchirazi, MD, a gastroenterology fellow with Aurora Healthcare in Brookfield, Wisconsin.
He presented the study findings at the American College of Gastroenterology (ACG) 2024 Annual Scientific Meeting.
Important Topic
Patients with T2D are at increased risk for several malignancies, including pancreatic cancer. Given the unique mechanism of action of GLP-1 RAs in the pancreas, it was important to investigate the relationship between use of these drugs and incidence of pancreatic cancer, he explained.
Using the TriNetX database, the study team identified 4.95 million antidiabetic drug naive T2D patients who were prescribed antidiabetic medications for the first time between 2005 and 2020. None had a history of pancreatic cancer.
A total of 245,532 were prescribed a GLP-1 RA. The researchers compared GLP-1 RAs users to users of other antidiabetic medications — namely, insulin, metformin, alpha-glucosidase inhibitors, dipeptidyl-peptidase 4 inhibitors (DPP-4i), sodium-glucose cotransporter-2 inhibitors (SGLT2i), sulfonylureas, and thiazolidinediones.
Patients were propensity score-matched based on demographics, health determinants, lifestyle factors, medical history, family history of cancers, and acute/chronic pancreatitis.
The risk for pancreatic cancer was significantly lower among patients on GLP-1 RAs vs insulin (hazard ratio [HR], 0.47; 95% CI, 0.40-0.55), DPP-4i (HR, 0.80; 95% CI, 0.73-0.89), SGLT2i (HR, 0.78; 95% CI, 0.69-0.89), and sulfonylureas (HR, 0.84; 95% CI, 0.74-0.95), Alchirazi reported.
The results were consistent across different groups, including patients with obesity/ overweight on GLP-1 RAs vs insulin (HR, 0.53; 95% CI, 0.43-0.65) and SGLT2i (HR, 0.81; 95% CI, 0.69-0.96).
Strengths of the analysis included the large and diverse cohort of propensity score-matched patients. Limitations included the retrospective design and use of claims data that did not provide granular data on pathology reports.
The study by Alchirazi and colleagues aligns with a large population-based cohort study from Israel that found no evidence that GLP-1 RAs increase risk for pancreatic cancer over 7 years following initiation.
Separately, a study of more than 1.6 million patients with T2D found that treatment with a GLP-1 RA (vs insulin or metformin) was associated with lower risks for specific types of obesity-related cancers, including pancreatic cancer.
The study had no specific funding. Alchirazi had no relevant disclosures.
A version of this article appeared on Medscape.com.
PHILADELPHIA —
Instead, the large electronic health record (EHR) analysis of patients with type 2 diabetes (T2D) found those taking GLP-1 RAs had a significantly lower risk for pancreatic cancer than peers on other antidiabetic medications.
“Although there were previous reports suggesting possible association between pancreatic cancer and GLP-1 receptor agonist medications, this study provides reassurance that there is no observed increased incidence of pancreatic cancer in patients prescribed these medications,” said Khaled Alsabbagh Alchirazi, MD, a gastroenterology fellow with Aurora Healthcare in Brookfield, Wisconsin.
He presented the study findings at the American College of Gastroenterology (ACG) 2024 Annual Scientific Meeting.
Important Topic
Patients with T2D are at increased risk for several malignancies, including pancreatic cancer. Given the unique mechanism of action of GLP-1 RAs in the pancreas, it was important to investigate the relationship between use of these drugs and incidence of pancreatic cancer, he explained.
Using the TriNetX database, the study team identified 4.95 million antidiabetic drug naive T2D patients who were prescribed antidiabetic medications for the first time between 2005 and 2020. None had a history of pancreatic cancer.
A total of 245,532 were prescribed a GLP-1 RA. The researchers compared GLP-1 RAs users to users of other antidiabetic medications — namely, insulin, metformin, alpha-glucosidase inhibitors, dipeptidyl-peptidase 4 inhibitors (DPP-4i), sodium-glucose cotransporter-2 inhibitors (SGLT2i), sulfonylureas, and thiazolidinediones.
Patients were propensity score-matched based on demographics, health determinants, lifestyle factors, medical history, family history of cancers, and acute/chronic pancreatitis.
The risk for pancreatic cancer was significantly lower among patients on GLP-1 RAs vs insulin (hazard ratio [HR], 0.47; 95% CI, 0.40-0.55), DPP-4i (HR, 0.80; 95% CI, 0.73-0.89), SGLT2i (HR, 0.78; 95% CI, 0.69-0.89), and sulfonylureas (HR, 0.84; 95% CI, 0.74-0.95), Alchirazi reported.
The results were consistent across different groups, including patients with obesity/ overweight on GLP-1 RAs vs insulin (HR, 0.53; 95% CI, 0.43-0.65) and SGLT2i (HR, 0.81; 95% CI, 0.69-0.96).
Strengths of the analysis included the large and diverse cohort of propensity score-matched patients. Limitations included the retrospective design and use of claims data that did not provide granular data on pathology reports.
The study by Alchirazi and colleagues aligns with a large population-based cohort study from Israel that found no evidence that GLP-1 RAs increase risk for pancreatic cancer over 7 years following initiation.
Separately, a study of more than 1.6 million patients with T2D found that treatment with a GLP-1 RA (vs insulin or metformin) was associated with lower risks for specific types of obesity-related cancers, including pancreatic cancer.
The study had no specific funding. Alchirazi had no relevant disclosures.
A version of this article appeared on Medscape.com.
FROM ACG 2024
Building an AI Army of Digital Twins to Fight Cancer
A patient has cancer. It’s decision time.
Clinician and patient alike face, really, the ultimate challenge when making those decisions. They have to consider the patient’s individual circumstances, available treatment options, potential side effects, relevant clinical data such as the patient’s genetic profile and cancer specifics, and more.
“That’s a lot of information to hold,” said Uzma Asghar, PhD, MRCP, a British consultant medical oncologist at The Royal Marsden Hospital and a chief scientific officer at Concr LTD.
What if there were a way to test — quickly and accurately — all the potential paths forward?
That’s the goal of digital twins.
“What the [digital twin] model can do for the clinician is to hold all that information and process it really quickly, within a couple of minutes,” Asghar noted.
A digital twin is more than just a computer model or simulation because it copies a real-world person and relies on real-world data. Some digital twin programs also integrate new information as it becomes available. This technology holds promise for personalized medicine, drug discovery, developing screening strategies, and better understanding diseases.
How to Deliver a Twin
To create a digital twin, experts develop a computer model with data to hone its expertise in an area of medicine, such as cancer types and treatments. Then “you train the model on information it’s seen, and then introduce a patient and patient’s information,” said Asghar.
Asghar is currently working with colleagues to develop digital twins that could eventually help solve the aforementioned cancer scenario — a doctor and patient decide the best course of cancer treatment. But their applications are manifold, particularly in clinical research.
Digital twins often include a machine learning component, which would fall under the umbrella term of AI, said Asghar, but it’s not like ChatGPT or other generative AI modules many people are now familiar with.
“The difference here is the model is not there to replace the clinician or to replace clinical trials,” Asghar noted. Instead, digital twins help make decisions faster in a way that can be more affordable.
Digital Twins to Predict Cancer Outcomes
Asghar is currently involved in UK clinical trials enrolling patients with cancer to test the accuracy of digital twin programs.
At this point, these studies do not yet use digital twins to guide the course of treatment, which is something they hope to do eventually. For now, they are still at the validation phase — the digital twin program makes predictions about the treatments and then the researchers later evaluate how accurate the predictions turned out to be based on real information from the enrolled patients.
Their current model gives predictions for RECIST (response evaluation criteria in solid tumor), treatment response, and survival. In addition to collecting data from ongoing clinical trials, they’ve used retrospective data, such as from the Cancer Tumor Atlas, to test the model.
“We’ve clinically validated it now in over 9000 patients,” said Asghar, who noted that they are constantly testing it on new patients. Their data include 30 chemotherapies and 23 cancer types, but they are focusing on four: Triple-negative breast cancer, cancer of unknown primary, pancreatic cancer, and colorectal cancer.
“The reason for choosing those four cancer types is that they are aggressive, their response to chemotherapy isn’t as great, and the outcome for those patient populations, there’s significant room for improvement,” Asghar explained.
Currently, Asghar said, the model is around 80%-90% correct in predicting what the actual clinical outcomes turn out to be.
The final stage of their work, before it becomes widely available to clinicians, will be to integrate it into a clinical trial in which some clinicians use the model to make decisions about treatment vs some who don’t use the model. By studying patient outcomes in both groups, they will be able to determine the value of the digital twin program they created.
What Else Can a Twin Do? A Lot
While a model that helps clinicians make decisions about cancer treatments may be among the first digital twin programs that become widely available, there are many other kinds of digital twins in the works.
For example, a digital twin could be used as a benchmark for a patient to determine how their cancer might have progressed without treatment. Say a patient’s tumor grew during treatment, it might seem like the treatment failed, but a digital twin might show that if left untreated, the tumor would have grown five times as fast, said Paul Macklin, PhD, professor in the Department of Intelligent Systems Engineering at Indiana University Bloomington.
Alternatively, if the virtual patient’s tumor is around the same size as the real patient’s tumor, “that means that treatment has lost its efficacy. It’s time to do something new,” said Macklin. And a digital twin could help with not only choosing a therapy but also choosing a dosing schedule, he noted.
The models can also be updated as new treatments come out, which could help clinicians virtually explore how they might affect a patient before having that patient switch treatments.
Digital twins could also assist in decision-making based on a patient’s priorities and real-life circumstances. “Maybe your priority is not necessarily to shrink this [tumor] at all costs ... maybe your priority is some mix of that and also quality of life,” Macklin said, referring to potential side effects. Or if someone lives 3 hours from the nearest cancer center, a digital twin could help determine whether less frequent treatments could still be effective.
And while much of the activity around digital twins in biomedical research has been focused on cancer, Asghar said the technology has the potential to be applied to other diseases as well. A digital twin for cardiovascular disease could help doctors choose the best treatment. It could also integrate new information from a smartwatch or glucose monitor to make better predictions and help doctors adjust the treatment plan.
Faster, More Effective Research With Twins
Because digital twin programs can quickly analyze large datasets, they can also make real-world studies more effective and efficient.
Though digital twins would not fully replace real clinical trials, they could help run through preliminary scenarios before starting a full clinical trial, which would “save everybody some money, time and pain and risk,” said Macklin.
It’s also possible to use digital twins to design better screening strategies for early cancer detection and monitoring, said Ioannis Zervantonakis, PhD, a bioengineering professor at the University of Pittsburgh.
Zervantonakis is tapping digital twin technology for research that homes in on understanding tumors. In this case, the digital twin is a virtual representation of a real tumor, complete with its complex network of cells and the surrounding tissue.
Zervantonakis’ lab is using the technology to study cell-cell interactions in the tumor microenvironment, with a focus on human epidermal growth factor receptor 2–targeted therapy resistance in breast cancer. The digital twin they developed will simulate tumor growth, predict drug response, analyze cellular interactions, and optimize treatment strategies.
The Long Push Forward
One big hurdle to making digital twins more widely available is that regulation for the technology is still in progress.
“We’re developing the technology, and what’s also happening is the regulatory framework is being developed in parallel. So we’re almost developing things blindly on the basis that we think this is what the regulators would want,” explained Asghar.
“It’s really important that these technologies are regulated properly, just like drugs, and that’s what we’re pushing and advocating for,” said Asghar, noting that people need to know that like drugs, a digital twin has strengths and limitations.
And while a digital twin can be a cost-saving approach in the long run, it does require funding to get a program built, and finding funds can be difficult because not everyone knows about the technology. More funding means more trials.
With more data, Asghar is hopeful that within a few years, a digital twin model could be available for clinicians to use to help inform treatment decisions. This could lead to more effective treatments and, ultimately, better patient outcomes.
A version of this article appeared on Medscape.com.
A patient has cancer. It’s decision time.
Clinician and patient alike face, really, the ultimate challenge when making those decisions. They have to consider the patient’s individual circumstances, available treatment options, potential side effects, relevant clinical data such as the patient’s genetic profile and cancer specifics, and more.
“That’s a lot of information to hold,” said Uzma Asghar, PhD, MRCP, a British consultant medical oncologist at The Royal Marsden Hospital and a chief scientific officer at Concr LTD.
What if there were a way to test — quickly and accurately — all the potential paths forward?
That’s the goal of digital twins.
“What the [digital twin] model can do for the clinician is to hold all that information and process it really quickly, within a couple of minutes,” Asghar noted.
A digital twin is more than just a computer model or simulation because it copies a real-world person and relies on real-world data. Some digital twin programs also integrate new information as it becomes available. This technology holds promise for personalized medicine, drug discovery, developing screening strategies, and better understanding diseases.
How to Deliver a Twin
To create a digital twin, experts develop a computer model with data to hone its expertise in an area of medicine, such as cancer types and treatments. Then “you train the model on information it’s seen, and then introduce a patient and patient’s information,” said Asghar.
Asghar is currently working with colleagues to develop digital twins that could eventually help solve the aforementioned cancer scenario — a doctor and patient decide the best course of cancer treatment. But their applications are manifold, particularly in clinical research.
Digital twins often include a machine learning component, which would fall under the umbrella term of AI, said Asghar, but it’s not like ChatGPT or other generative AI modules many people are now familiar with.
“The difference here is the model is not there to replace the clinician or to replace clinical trials,” Asghar noted. Instead, digital twins help make decisions faster in a way that can be more affordable.
Digital Twins to Predict Cancer Outcomes
Asghar is currently involved in UK clinical trials enrolling patients with cancer to test the accuracy of digital twin programs.
At this point, these studies do not yet use digital twins to guide the course of treatment, which is something they hope to do eventually. For now, they are still at the validation phase — the digital twin program makes predictions about the treatments and then the researchers later evaluate how accurate the predictions turned out to be based on real information from the enrolled patients.
Their current model gives predictions for RECIST (response evaluation criteria in solid tumor), treatment response, and survival. In addition to collecting data from ongoing clinical trials, they’ve used retrospective data, such as from the Cancer Tumor Atlas, to test the model.
“We’ve clinically validated it now in over 9000 patients,” said Asghar, who noted that they are constantly testing it on new patients. Their data include 30 chemotherapies and 23 cancer types, but they are focusing on four: Triple-negative breast cancer, cancer of unknown primary, pancreatic cancer, and colorectal cancer.
“The reason for choosing those four cancer types is that they are aggressive, their response to chemotherapy isn’t as great, and the outcome for those patient populations, there’s significant room for improvement,” Asghar explained.
Currently, Asghar said, the model is around 80%-90% correct in predicting what the actual clinical outcomes turn out to be.
The final stage of their work, before it becomes widely available to clinicians, will be to integrate it into a clinical trial in which some clinicians use the model to make decisions about treatment vs some who don’t use the model. By studying patient outcomes in both groups, they will be able to determine the value of the digital twin program they created.
What Else Can a Twin Do? A Lot
While a model that helps clinicians make decisions about cancer treatments may be among the first digital twin programs that become widely available, there are many other kinds of digital twins in the works.
For example, a digital twin could be used as a benchmark for a patient to determine how their cancer might have progressed without treatment. Say a patient’s tumor grew during treatment, it might seem like the treatment failed, but a digital twin might show that if left untreated, the tumor would have grown five times as fast, said Paul Macklin, PhD, professor in the Department of Intelligent Systems Engineering at Indiana University Bloomington.
Alternatively, if the virtual patient’s tumor is around the same size as the real patient’s tumor, “that means that treatment has lost its efficacy. It’s time to do something new,” said Macklin. And a digital twin could help with not only choosing a therapy but also choosing a dosing schedule, he noted.
The models can also be updated as new treatments come out, which could help clinicians virtually explore how they might affect a patient before having that patient switch treatments.
Digital twins could also assist in decision-making based on a patient’s priorities and real-life circumstances. “Maybe your priority is not necessarily to shrink this [tumor] at all costs ... maybe your priority is some mix of that and also quality of life,” Macklin said, referring to potential side effects. Or if someone lives 3 hours from the nearest cancer center, a digital twin could help determine whether less frequent treatments could still be effective.
And while much of the activity around digital twins in biomedical research has been focused on cancer, Asghar said the technology has the potential to be applied to other diseases as well. A digital twin for cardiovascular disease could help doctors choose the best treatment. It could also integrate new information from a smartwatch or glucose monitor to make better predictions and help doctors adjust the treatment plan.
Faster, More Effective Research With Twins
Because digital twin programs can quickly analyze large datasets, they can also make real-world studies more effective and efficient.
Though digital twins would not fully replace real clinical trials, they could help run through preliminary scenarios before starting a full clinical trial, which would “save everybody some money, time and pain and risk,” said Macklin.
It’s also possible to use digital twins to design better screening strategies for early cancer detection and monitoring, said Ioannis Zervantonakis, PhD, a bioengineering professor at the University of Pittsburgh.
Zervantonakis is tapping digital twin technology for research that homes in on understanding tumors. In this case, the digital twin is a virtual representation of a real tumor, complete with its complex network of cells and the surrounding tissue.
Zervantonakis’ lab is using the technology to study cell-cell interactions in the tumor microenvironment, with a focus on human epidermal growth factor receptor 2–targeted therapy resistance in breast cancer. The digital twin they developed will simulate tumor growth, predict drug response, analyze cellular interactions, and optimize treatment strategies.
The Long Push Forward
One big hurdle to making digital twins more widely available is that regulation for the technology is still in progress.
“We’re developing the technology, and what’s also happening is the regulatory framework is being developed in parallel. So we’re almost developing things blindly on the basis that we think this is what the regulators would want,” explained Asghar.
“It’s really important that these technologies are regulated properly, just like drugs, and that’s what we’re pushing and advocating for,” said Asghar, noting that people need to know that like drugs, a digital twin has strengths and limitations.
And while a digital twin can be a cost-saving approach in the long run, it does require funding to get a program built, and finding funds can be difficult because not everyone knows about the technology. More funding means more trials.
With more data, Asghar is hopeful that within a few years, a digital twin model could be available for clinicians to use to help inform treatment decisions. This could lead to more effective treatments and, ultimately, better patient outcomes.
A version of this article appeared on Medscape.com.
A patient has cancer. It’s decision time.
Clinician and patient alike face, really, the ultimate challenge when making those decisions. They have to consider the patient’s individual circumstances, available treatment options, potential side effects, relevant clinical data such as the patient’s genetic profile and cancer specifics, and more.
“That’s a lot of information to hold,” said Uzma Asghar, PhD, MRCP, a British consultant medical oncologist at The Royal Marsden Hospital and a chief scientific officer at Concr LTD.
What if there were a way to test — quickly and accurately — all the potential paths forward?
That’s the goal of digital twins.
“What the [digital twin] model can do for the clinician is to hold all that information and process it really quickly, within a couple of minutes,” Asghar noted.
A digital twin is more than just a computer model or simulation because it copies a real-world person and relies on real-world data. Some digital twin programs also integrate new information as it becomes available. This technology holds promise for personalized medicine, drug discovery, developing screening strategies, and better understanding diseases.
How to Deliver a Twin
To create a digital twin, experts develop a computer model with data to hone its expertise in an area of medicine, such as cancer types and treatments. Then “you train the model on information it’s seen, and then introduce a patient and patient’s information,” said Asghar.
Asghar is currently working with colleagues to develop digital twins that could eventually help solve the aforementioned cancer scenario — a doctor and patient decide the best course of cancer treatment. But their applications are manifold, particularly in clinical research.
Digital twins often include a machine learning component, which would fall under the umbrella term of AI, said Asghar, but it’s not like ChatGPT or other generative AI modules many people are now familiar with.
“The difference here is the model is not there to replace the clinician or to replace clinical trials,” Asghar noted. Instead, digital twins help make decisions faster in a way that can be more affordable.
Digital Twins to Predict Cancer Outcomes
Asghar is currently involved in UK clinical trials enrolling patients with cancer to test the accuracy of digital twin programs.
At this point, these studies do not yet use digital twins to guide the course of treatment, which is something they hope to do eventually. For now, they are still at the validation phase — the digital twin program makes predictions about the treatments and then the researchers later evaluate how accurate the predictions turned out to be based on real information from the enrolled patients.
Their current model gives predictions for RECIST (response evaluation criteria in solid tumor), treatment response, and survival. In addition to collecting data from ongoing clinical trials, they’ve used retrospective data, such as from the Cancer Tumor Atlas, to test the model.
“We’ve clinically validated it now in over 9000 patients,” said Asghar, who noted that they are constantly testing it on new patients. Their data include 30 chemotherapies and 23 cancer types, but they are focusing on four: Triple-negative breast cancer, cancer of unknown primary, pancreatic cancer, and colorectal cancer.
“The reason for choosing those four cancer types is that they are aggressive, their response to chemotherapy isn’t as great, and the outcome for those patient populations, there’s significant room for improvement,” Asghar explained.
Currently, Asghar said, the model is around 80%-90% correct in predicting what the actual clinical outcomes turn out to be.
The final stage of their work, before it becomes widely available to clinicians, will be to integrate it into a clinical trial in which some clinicians use the model to make decisions about treatment vs some who don’t use the model. By studying patient outcomes in both groups, they will be able to determine the value of the digital twin program they created.
What Else Can a Twin Do? A Lot
While a model that helps clinicians make decisions about cancer treatments may be among the first digital twin programs that become widely available, there are many other kinds of digital twins in the works.
For example, a digital twin could be used as a benchmark for a patient to determine how their cancer might have progressed without treatment. Say a patient’s tumor grew during treatment, it might seem like the treatment failed, but a digital twin might show that if left untreated, the tumor would have grown five times as fast, said Paul Macklin, PhD, professor in the Department of Intelligent Systems Engineering at Indiana University Bloomington.
Alternatively, if the virtual patient’s tumor is around the same size as the real patient’s tumor, “that means that treatment has lost its efficacy. It’s time to do something new,” said Macklin. And a digital twin could help with not only choosing a therapy but also choosing a dosing schedule, he noted.
The models can also be updated as new treatments come out, which could help clinicians virtually explore how they might affect a patient before having that patient switch treatments.
Digital twins could also assist in decision-making based on a patient’s priorities and real-life circumstances. “Maybe your priority is not necessarily to shrink this [tumor] at all costs ... maybe your priority is some mix of that and also quality of life,” Macklin said, referring to potential side effects. Or if someone lives 3 hours from the nearest cancer center, a digital twin could help determine whether less frequent treatments could still be effective.
And while much of the activity around digital twins in biomedical research has been focused on cancer, Asghar said the technology has the potential to be applied to other diseases as well. A digital twin for cardiovascular disease could help doctors choose the best treatment. It could also integrate new information from a smartwatch or glucose monitor to make better predictions and help doctors adjust the treatment plan.
Faster, More Effective Research With Twins
Because digital twin programs can quickly analyze large datasets, they can also make real-world studies more effective and efficient.
Though digital twins would not fully replace real clinical trials, they could help run through preliminary scenarios before starting a full clinical trial, which would “save everybody some money, time and pain and risk,” said Macklin.
It’s also possible to use digital twins to design better screening strategies for early cancer detection and monitoring, said Ioannis Zervantonakis, PhD, a bioengineering professor at the University of Pittsburgh.
Zervantonakis is tapping digital twin technology for research that homes in on understanding tumors. In this case, the digital twin is a virtual representation of a real tumor, complete with its complex network of cells and the surrounding tissue.
Zervantonakis’ lab is using the technology to study cell-cell interactions in the tumor microenvironment, with a focus on human epidermal growth factor receptor 2–targeted therapy resistance in breast cancer. The digital twin they developed will simulate tumor growth, predict drug response, analyze cellular interactions, and optimize treatment strategies.
The Long Push Forward
One big hurdle to making digital twins more widely available is that regulation for the technology is still in progress.
“We’re developing the technology, and what’s also happening is the regulatory framework is being developed in parallel. So we’re almost developing things blindly on the basis that we think this is what the regulators would want,” explained Asghar.
“It’s really important that these technologies are regulated properly, just like drugs, and that’s what we’re pushing and advocating for,” said Asghar, noting that people need to know that like drugs, a digital twin has strengths and limitations.
And while a digital twin can be a cost-saving approach in the long run, it does require funding to get a program built, and finding funds can be difficult because not everyone knows about the technology. More funding means more trials.
With more data, Asghar is hopeful that within a few years, a digital twin model could be available for clinicians to use to help inform treatment decisions. This could lead to more effective treatments and, ultimately, better patient outcomes.
A version of this article appeared on Medscape.com.