Federal Practitioner

Key clinical point: Alpha-fetoprotein (AFP) levels during liver transplantation (LT) and their modulation while on the waitlist are predictors of hepatocellular carcinoma (HCC) recurrence after LT in patients meeting the Milan criteria.

Main finding: An AFP value >25.5 ng/mL (area under the receiver operating characteristic curve, 0.69) could strongly predict HCC recurrence after LT (subdistribution hazard ratio, 2.5; P = .01), which also showed a significant association with an increase in AFP levels by >20.8% while on the waitlist (P = .034).

Study details: The data are derived from a retrospective single-center study that analyzed 207 patients with HCC fulfilling the Milan criteria who were put on the waitlist for LT and had AFP levels >400 ng/mL at transplant.

Disclosures: Financial support for the study was provided by the association Friends of transplantation. The authors reported no conflict of interests.

Source: Magro B et al. Cancers. 2021 Nov 27. doi: 10.3390/cancers13235976.

Key clinical point: Alpha-fetoprotein (AFP) levels during liver transplantation (LT) and their modulation while on the waitlist are predictors of hepatocellular carcinoma (HCC) recurrence after LT in patients meeting the Milan criteria.

Main finding: An AFP value >25.5 ng/mL (area under the receiver operating characteristic curve, 0.69) could strongly predict HCC recurrence after LT (subdistribution hazard ratio, 2.5; P = .01), which also showed a significant association with an increase in AFP levels by >20.8% while on the waitlist (P = .034).

Study details: The data are derived from a retrospective single-center study that analyzed 207 patients with HCC fulfilling the Milan criteria who were put on the waitlist for LT and had AFP levels >400 ng/mL at transplant.

Disclosures: Financial support for the study was provided by the association Friends of transplantation. The authors reported no conflict of interests.

Source: Magro B et al. Cancers. 2021 Nov 27. doi: 10.3390/cancers13235976.

Key clinical point: Alpha-fetoprotein (AFP) levels during liver transplantation (LT) and their modulation while on the waitlist are predictors of hepatocellular carcinoma (HCC) recurrence after LT in patients meeting the Milan criteria.

Main finding: An AFP value >25.5 ng/mL (area under the receiver operating characteristic curve, 0.69) could strongly predict HCC recurrence after LT (subdistribution hazard ratio, 2.5; P = .01), which also showed a significant association with an increase in AFP levels by >20.8% while on the waitlist (P = .034).

Study details: The data are derived from a retrospective single-center study that analyzed 207 patients with HCC fulfilling the Milan criteria who were put on the waitlist for LT and had AFP levels >400 ng/mL at transplant.

Disclosures: Financial support for the study was provided by the association Friends of transplantation. The authors reported no conflict of interests.

Source: Magro B et al. Cancers. 2021 Nov 27. doi: 10.3390/cancers13235976.

Key clinical point: High diastolic whole blood viscosity (WBV) may serve as a new independent factor associated with extrahepatic metastasis and poor survival in patients with hepatocellular carcinoma (HCC).

Main finding: After adjusting for confounding variables, high diastolic WBV was independently associated with extrahepatic metastasis (adjusted odds ratio, 23.41; P < .001) and poor survival (adjusted hazard ratio, 3.81; P < .001) and significantly predicted extrahepatic metastasis at an optimal cutoff of 16 cP (area under the receiver operating characteristic curve, 0.768; P < .001).

Study details: Findings are from a pilot retrospective study including 181 patients with HCC, of which 148 were treatment-naïve having preserved liver function and 33 received nivolumab.

Disclosures: The study was sponsored by Young Medical Scientist Research Grant through the Daewoong Foundation and the Research Fund of Seoul St. Mary’s Hospital, The Catholic University of Korea. The authors did not declare any conflict of interests.

Source: Han JW et al. PLoS ONE. 2021 Dec 2. doi: 10.1371/journal.pone.0260311.

Key clinical point: High diastolic whole blood viscosity (WBV) may serve as a new independent factor associated with extrahepatic metastasis and poor survival in patients with hepatocellular carcinoma (HCC).

Main finding: After adjusting for confounding variables, high diastolic WBV was independently associated with extrahepatic metastasis (adjusted odds ratio, 23.41; P < .001) and poor survival (adjusted hazard ratio, 3.81; P < .001) and significantly predicted extrahepatic metastasis at an optimal cutoff of 16 cP (area under the receiver operating characteristic curve, 0.768; P < .001).

Study details: Findings are from a pilot retrospective study including 181 patients with HCC, of which 148 were treatment-naïve having preserved liver function and 33 received nivolumab.

Disclosures: The study was sponsored by Young Medical Scientist Research Grant through the Daewoong Foundation and the Research Fund of Seoul St. Mary’s Hospital, The Catholic University of Korea. The authors did not declare any conflict of interests.

Source: Han JW et al. PLoS ONE. 2021 Dec 2. doi: 10.1371/journal.pone.0260311.

Key clinical point: High diastolic whole blood viscosity (WBV) may serve as a new independent factor associated with extrahepatic metastasis and poor survival in patients with hepatocellular carcinoma (HCC).

Main finding: After adjusting for confounding variables, high diastolic WBV was independently associated with extrahepatic metastasis (adjusted odds ratio, 23.41; P < .001) and poor survival (adjusted hazard ratio, 3.81; P < .001) and significantly predicted extrahepatic metastasis at an optimal cutoff of 16 cP (area under the receiver operating characteristic curve, 0.768; P < .001).

Study details: Findings are from a pilot retrospective study including 181 patients with HCC, of which 148 were treatment-naïve having preserved liver function and 33 received nivolumab.

Disclosures: The study was sponsored by Young Medical Scientist Research Grant through the Daewoong Foundation and the Research Fund of Seoul St. Mary’s Hospital, The Catholic University of Korea. The authors did not declare any conflict of interests.

Source: Han JW et al. PLoS ONE. 2021 Dec 2. doi: 10.1371/journal.pone.0260311.

Key clinical point: The modified Response Evaluation Criteria in Solid Tumors (mRECIST)-determined radiologic response rate of transarterial chemoembolization (TACE) plus radiotherapy (RT) among patients with advanced hepatocellular carcinoma (HCC) showing macroscopic vascular invasion (MVI) is an independent prognosticator for overall survival (OS).

Main finding: Responders vs nonresponders had significantly longer median OS at 2 months (23.1 months vs 8.0 months; adjusted hazard ratio [aHR], 3.194; P < .001) and 4 months (responders vs nonresponders: 26.5 months vs 9.3 months; aHR, 4.534; P < .001).

Study details: This was a retrospective review study including 427 patients with advanced HCC and MVI who received first-line treatment with TACE plus respiratory-gated 3-dimensional conformal RT in the 2-month analysis, whereas the patient number reduced to 355 in the 4-month analysis.

Disclosures: The study was supported by the Asan Institute for Life Sciences of Asan Medical Center, Seoul, Republic of Korea. The authors declared no conflict of interests.

Source: Jung J et al. Liver Cancer. 2021 Dec 7. doi: 10.1159/000521227.

Key clinical point: The modified Response Evaluation Criteria in Solid Tumors (mRECIST)-determined radiologic response rate of transarterial chemoembolization (TACE) plus radiotherapy (RT) among patients with advanced hepatocellular carcinoma (HCC) showing macroscopic vascular invasion (MVI) is an independent prognosticator for overall survival (OS).

Main finding: Responders vs nonresponders had significantly longer median OS at 2 months (23.1 months vs 8.0 months; adjusted hazard ratio [aHR], 3.194; P < .001) and 4 months (responders vs nonresponders: 26.5 months vs 9.3 months; aHR, 4.534; P < .001).

Study details: This was a retrospective review study including 427 patients with advanced HCC and MVI who received first-line treatment with TACE plus respiratory-gated 3-dimensional conformal RT in the 2-month analysis, whereas the patient number reduced to 355 in the 4-month analysis.

Disclosures: The study was supported by the Asan Institute for Life Sciences of Asan Medical Center, Seoul, Republic of Korea. The authors declared no conflict of interests.

Source: Jung J et al. Liver Cancer. 2021 Dec 7. doi: 10.1159/000521227.

Key clinical point: The modified Response Evaluation Criteria in Solid Tumors (mRECIST)-determined radiologic response rate of transarterial chemoembolization (TACE) plus radiotherapy (RT) among patients with advanced hepatocellular carcinoma (HCC) showing macroscopic vascular invasion (MVI) is an independent prognosticator for overall survival (OS).

Main finding: Responders vs nonresponders had significantly longer median OS at 2 months (23.1 months vs 8.0 months; adjusted hazard ratio [aHR], 3.194; P < .001) and 4 months (responders vs nonresponders: 26.5 months vs 9.3 months; aHR, 4.534; P < .001).

Study details: This was a retrospective review study including 427 patients with advanced HCC and MVI who received first-line treatment with TACE plus respiratory-gated 3-dimensional conformal RT in the 2-month analysis, whereas the patient number reduced to 355 in the 4-month analysis.

Disclosures: The study was supported by the Asan Institute for Life Sciences of Asan Medical Center, Seoul, Republic of Korea. The authors declared no conflict of interests.

Source: Jung J et al. Liver Cancer. 2021 Dec 7. doi: 10.1159/000521227.

Key clinical point: Hepatic arterial infusion chemotherapy of infusional fluorouracil, leucovorin, and oxaliplatin (HAIC-FO) is better than sorafenib at improving survival in patients with locally advanced hepatocellular carcinoma (HCC).

Main finding: At a median follow-up of 17.1 and 19.8 months, HAIC-FO- and sorafenib-treated patients showed a median overall survival (OS) of 13.9 months (95% CI, 10.6-17.2) and 8.2 months (95% CI, 7.5-9.0), respectively (hazard ratio [HR], 0.408; P = .001), with OS improvements favoring HAIC-FO vs sorafenib in even high-risk patients (10.8 months vs 5.7 months; HR, 0.343; P < .001). Grade 3/4 adverse events were more frequent with sorafenib vs HAIC-FO (48.1% vs20.3%).

Study details: The data come from the open-label, phase 3 FOHAIC-1 trial, which included 262 systemic therapy-naive patients with locally advanced or unresectable HCC who were randomly assigned to receive either HAIC-FO (n=130) or sorafenib (n=132).

Disclosures: The National Natural Science Foundation of China sponsored the study. The authors did not report any potential conflict of interests.

Source: Lyu N et al. J Clin Oncol. 2021 Dec 14. doi: 10.1200/JCO.21.01963.

Key clinical point: Hepatic arterial infusion chemotherapy of infusional fluorouracil, leucovorin, and oxaliplatin (HAIC-FO) is better than sorafenib at improving survival in patients with locally advanced hepatocellular carcinoma (HCC).

Main finding: At a median follow-up of 17.1 and 19.8 months, HAIC-FO- and sorafenib-treated patients showed a median overall survival (OS) of 13.9 months (95% CI, 10.6-17.2) and 8.2 months (95% CI, 7.5-9.0), respectively (hazard ratio [HR], 0.408; P = .001), with OS improvements favoring HAIC-FO vs sorafenib in even high-risk patients (10.8 months vs 5.7 months; HR, 0.343; P < .001). Grade 3/4 adverse events were more frequent with sorafenib vs HAIC-FO (48.1% vs20.3%).

Study details: The data come from the open-label, phase 3 FOHAIC-1 trial, which included 262 systemic therapy-naive patients with locally advanced or unresectable HCC who were randomly assigned to receive either HAIC-FO (n=130) or sorafenib (n=132).

Disclosures: The National Natural Science Foundation of China sponsored the study. The authors did not report any potential conflict of interests.

Source: Lyu N et al. J Clin Oncol. 2021 Dec 14. doi: 10.1200/JCO.21.01963.

Key clinical point: Hepatic arterial infusion chemotherapy of infusional fluorouracil, leucovorin, and oxaliplatin (HAIC-FO) is better than sorafenib at improving survival in patients with locally advanced hepatocellular carcinoma (HCC).

Main finding: At a median follow-up of 17.1 and 19.8 months, HAIC-FO- and sorafenib-treated patients showed a median overall survival (OS) of 13.9 months (95% CI, 10.6-17.2) and 8.2 months (95% CI, 7.5-9.0), respectively (hazard ratio [HR], 0.408; P = .001), with OS improvements favoring HAIC-FO vs sorafenib in even high-risk patients (10.8 months vs 5.7 months; HR, 0.343; P < .001). Grade 3/4 adverse events were more frequent with sorafenib vs HAIC-FO (48.1% vs20.3%).

Study details: The data come from the open-label, phase 3 FOHAIC-1 trial, which included 262 systemic therapy-naive patients with locally advanced or unresectable HCC who were randomly assigned to receive either HAIC-FO (n=130) or sorafenib (n=132).

Disclosures: The National Natural Science Foundation of China sponsored the study. The authors did not report any potential conflict of interests.

Source: Lyu N et al. J Clin Oncol. 2021 Dec 14. doi: 10.1200/JCO.21.01963.

Key clinical point: Longer follow-up results confirm the survival benefits and consistent safety of first-line atezolizumab + bevacizumab vs sorafenib in patients with locally advanced or metastatic and/or unresectable hepatocellular carcinoma (HCC).

Major finding: After a 15.6-month median follow-up, the median overall survival (19.2 months vs 13.4 months; stratified hazard ratio [HR] for death, 0.66; P < .001) and progression-free survival (6.9 months vs 4.3 months; HR for death/progression, 0.65; P < .001) were higher with atezolizumab + bevacizumab vs sorafenib. Treatment-related grade 3/4 adverse events occurred in 43% vs 46% of patients receiving atezolizumab + bevacizumab vs sorafenib.

Study details: Findings are from a post hoc analysis of the phase 3 IMbrave150 trial including 501 treatment-naïve patients with locally advanced or metastatic and/or unresectable HCC. Patients were randomly assigned to atezolizumab + bevacizumab or sorafenib.

Disclosures: This study was funded by F. Hoffman-La Roche (FHLR)/Genentech. All investigators reported receiving financial or nonfinancial support, providing expert testimony, being an employee of, or holding shares/stocks in various pharmaceutical companies including FHLR/Genentech.

Source: Cheng AL et al. J Hepatol. 2021 Dec 10. doi: 10.1016/j.jhep.2021.11.030.

Key clinical point: Longer follow-up results confirm the survival benefits and consistent safety of first-line atezolizumab + bevacizumab vs sorafenib in patients with locally advanced or metastatic and/or unresectable hepatocellular carcinoma (HCC).

Major finding: After a 15.6-month median follow-up, the median overall survival (19.2 months vs 13.4 months; stratified hazard ratio [HR] for death, 0.66; P < .001) and progression-free survival (6.9 months vs 4.3 months; HR for death/progression, 0.65; P < .001) were higher with atezolizumab + bevacizumab vs sorafenib. Treatment-related grade 3/4 adverse events occurred in 43% vs 46% of patients receiving atezolizumab + bevacizumab vs sorafenib.

Study details: Findings are from a post hoc analysis of the phase 3 IMbrave150 trial including 501 treatment-naïve patients with locally advanced or metastatic and/or unresectable HCC. Patients were randomly assigned to atezolizumab + bevacizumab or sorafenib.

Disclosures: This study was funded by F. Hoffman-La Roche (FHLR)/Genentech. All investigators reported receiving financial or nonfinancial support, providing expert testimony, being an employee of, or holding shares/stocks in various pharmaceutical companies including FHLR/Genentech.

Source: Cheng AL et al. J Hepatol. 2021 Dec 10. doi: 10.1016/j.jhep.2021.11.030.

Key clinical point: Longer follow-up results confirm the survival benefits and consistent safety of first-line atezolizumab + bevacizumab vs sorafenib in patients with locally advanced or metastatic and/or unresectable hepatocellular carcinoma (HCC).

Major finding: After a 15.6-month median follow-up, the median overall survival (19.2 months vs 13.4 months; stratified hazard ratio [HR] for death, 0.66; P < .001) and progression-free survival (6.9 months vs 4.3 months; HR for death/progression, 0.65; P < .001) were higher with atezolizumab + bevacizumab vs sorafenib. Treatment-related grade 3/4 adverse events occurred in 43% vs 46% of patients receiving atezolizumab + bevacizumab vs sorafenib.

Study details: Findings are from a post hoc analysis of the phase 3 IMbrave150 trial including 501 treatment-naïve patients with locally advanced or metastatic and/or unresectable HCC. Patients were randomly assigned to atezolizumab + bevacizumab or sorafenib.

Disclosures: This study was funded by F. Hoffman-La Roche (FHLR)/Genentech. All investigators reported receiving financial or nonfinancial support, providing expert testimony, being an employee of, or holding shares/stocks in various pharmaceutical companies including FHLR/Genentech.

Source: Cheng AL et al. J Hepatol. 2021 Dec 10. doi: 10.1016/j.jhep.2021.11.030.

Key clinical point: First-line nivolumab treatment did not improve overall survival in patients with advanced hepatocellular carcinoma (HCC) compared with sorafenib.

Major finding: At a minimum follow-up of 22.8 months, nivolumab vs sorafenib did not meet the prespecified significance boundary for superior overall survival (16.4 months vs 14.7 months; hazard ratio, 0.85; P = .075).

Study details: Findings are from the phase 3 CheckMate 459 trial including 743 adult patients with advanced HCC randomly assigned to receive either nivolumab (n=371) or sorafenib (n=372).

Disclosures: This study was supported by Bristol Myers Squibb (BMS) and Ono Pharmaceutical. Some investigators including the lead author reported receiving grants and fees from, participation on data safety monitoring board or advisory boards for, owning stocks in, and being an employee of various pharmaceutical companies, including BMS and Ono Pharmaceutical.

Source: Yau T et al. Lancet Oncol. 2021 Dec 13. doi: 10.1016/S1470-2045(21)00604-5.

Key clinical point: First-line nivolumab treatment did not improve overall survival in patients with advanced hepatocellular carcinoma (HCC) compared with sorafenib.

Major finding: At a minimum follow-up of 22.8 months, nivolumab vs sorafenib did not meet the prespecified significance boundary for superior overall survival (16.4 months vs 14.7 months; hazard ratio, 0.85; P = .075).

Study details: Findings are from the phase 3 CheckMate 459 trial including 743 adult patients with advanced HCC randomly assigned to receive either nivolumab (n=371) or sorafenib (n=372).

Disclosures: This study was supported by Bristol Myers Squibb (BMS) and Ono Pharmaceutical. Some investigators including the lead author reported receiving grants and fees from, participation on data safety monitoring board or advisory boards for, owning stocks in, and being an employee of various pharmaceutical companies, including BMS and Ono Pharmaceutical.

Source: Yau T et al. Lancet Oncol. 2021 Dec 13. doi: 10.1016/S1470-2045(21)00604-5.

Key clinical point: First-line nivolumab treatment did not improve overall survival in patients with advanced hepatocellular carcinoma (HCC) compared with sorafenib.

Major finding: At a minimum follow-up of 22.8 months, nivolumab vs sorafenib did not meet the prespecified significance boundary for superior overall survival (16.4 months vs 14.7 months; hazard ratio, 0.85; P = .075).

Study details: Findings are from the phase 3 CheckMate 459 trial including 743 adult patients with advanced HCC randomly assigned to receive either nivolumab (n=371) or sorafenib (n=372).

Disclosures: This study was supported by Bristol Myers Squibb (BMS) and Ono Pharmaceutical. Some investigators including the lead author reported receiving grants and fees from, participation on data safety monitoring board or advisory boards for, owning stocks in, and being an employee of various pharmaceutical companies, including BMS and Ono Pharmaceutical.

Source: Yau T et al. Lancet Oncol. 2021 Dec 13. doi: 10.1016/S1470-2045(21)00604-5.

In more than 15% of people with benign adrenal tumors, the growths produce clinically relevant levels of serum cortisol that are significantly linked with an increased prevalence of hypertension and, in 5% of those with Cushing syndrome (CS), an increased prevalence of type 2 diabetes, based on data from more than 1,300 people with benign adrenal tumors, the largest reported prospective study of the disorder.

The study results showed that mild autonomous cortisol secretion (MACS) from benign adrenal tumors “is very frequent and is an important risk condition for high blood pressure and type 2 diabetes, especially in older women,” said Alessandro Prete, MD, lead author of the study which was published online Jan. 3, 2022, in Annals of Internal Medicine.

SEBASTIAN KAULITZKI/SCIENCE PHOTO LIBRARY/Getty Images

“The impact of MACS on high blood pressure and risk for type 2 diabetes has been underestimated until now,” said Dr. Prete, an endocrinologist at the University of Birmingham (England), in a written statement. 

Results from previous studies “suggested that MACS is associated with poor health. Our study is the largest to establish conclusively the extent of the risk and severity of high blood pressure and type 2 diabetes in patients with MACS,” said Wiebke Arlt, MD, DSc, senior author and director of the Institute of Metabolism & Systems Research at the University of Birmingham.

All patients found to have a benign adrenal tumor should undergo testing for MACS and have their blood pressure and glucose levels measured regularly, Dr. Arlt advised in the statement released by the University of Birmingham.
 

MACS more common than previously thought

The new findings show that MACS “is more common and may have a more negative impact on health than previously thought, including increasing the risk for type 2 diabetes,” commented Lucy Chambers, PhD, head of research communications at Diabetes UK. “The findings suggest that screening for MACS could help identify people – particularly women, in whom the condition was found to be more common – who may benefit from support to reduce their risk of type 2 diabetes.”

The study included 1,305 people with newly diagnosed, benign adrenal tumors greater than 1 cm, a subset of patients prospectively enrolled in a study with the primary purpose of validating a novel way to diagnose adrenocortical carcinomas. Patients underwent treatment in 2011-2016 at any of 14 tertiary centers in 11 countries.

Researchers used a MACS definition of failure to suppress morning serum cortisol concentration to less than 50 nmol/L after treatment with 1 mg oral dexamethasone at 11 p.m. the previous evening in those with no clinical features of CS.

Roughly half of patients (n = 649) showed normal cortisol suppression with dexamethasone, identifying them as having nonfunctioning adrenal tumors, and about 35% showed possible MACS based on having moderate levels of excess cortisol.

Nearly 11% (n = 140) showed definitive MACS with more robust cortisol levels, and 5% (n = 65) received a diagnosis of clinically overt CS despite selection criteria meant to exclude people with clinical signs of CS.

There was a clear relationship between patient sex and severity of autonomous cortisol production. Among those with nonfunctioning adrenal tumors, 64% were women, which rose to 74% women in those with definitive MACS and 86% women among those with CS. The median age of participants was 60 years old.
 

Increasing cortisol levels linked with cardiometabolic disease

Analysis of the prevalence of hypertension and type 2 diabetes after adjustment for age, sex, and body mass index showed that, compared with people with nonfunctioning adrenal tumors, those with definitive MACS had a significant 15% higher rate of hypertension and those with overt CS had a 37% higher rate. 

Higher levels of excess cortisol were also directly linked with an increased need for treatment with three or more antihypertensive agents to control blood pressure. Those with definitive MACS had a significant 31% higher rate of being on three or more drugs, and those with overt CS had a greater than twofold higher rate.

People with overt CS also had a significant 62% higher rate of type 2 diabetes, compared with those with a nonfunctioning tumor, but in those with definitive MACS the association was not significant. However, people with definitive MACS or overt CS who had type 2 diabetes and also had significantly increased rates of requiring insulin treatment.

The findings show that “people with definitive MACS carry an increased cardiometabolic burden similar to that seen in CS even if they do not display typical features of clinically overt cortisol excess,” the authors wrote in the report.

Even among those with apparently nonfunctioning tumors, each 10 nmol/L rise in cortisol level during a dexamethasone-suppression test was associated with a higher cardiometabolic disease burden. This observation suggests that current diagnostic cutoffs for the suppression test may miss some people with clinically relevant autonomous cortisol secretion, the report said. The study findings also suggest that people with benign adrenal tumors show a progressive continuum of excess cortisol with clinical consequences that increase as levels increase.
 

Determine the consequences of cortisol secretion

“These data clearly support the European Society of Endocrinology guideline recommendations that clinicians should determine precisely the cardiometabolic consequences of mild cortisol secretion in patients with adrenal lesions,” André Lacroix, MD, wrote in an accompanying editorial.

But Dr. Lacroix included some caveats. He noted the “potential pitfalls in relying on a single total serum cortisol value after the 1-mg dexamethasone test.” He also wondered whether the analysis used optimal cortisol values to distinguish patient subgroups.

Plus, “even in patients with nonfunctioning adrenal tumors the prevalence of diabetes and hypertension is higher than in the general population, raising concerns about the cardiometabolic consequences of barely detectable cortisol excess,” wrote Dr. Lacroix, an endocrinologist at the CHUM Research Center and professor of medicine at the University of Montreal.

The study received no commercial funding. Dr. Prete, Dr. Chambers, and Dr. Lacroix have reported no relevant financial relationships. Dr. Arlt is listed as an inventor on a patent on the use of steroid profiling as a biomarker tool for the differential diagnosis of adrenal tumors.

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

In more than 15% of people with benign adrenal tumors, the growths produce clinically relevant levels of serum cortisol that are significantly linked with an increased prevalence of hypertension and, in 5% of those with Cushing syndrome (CS), an increased prevalence of type 2 diabetes, based on data from more than 1,300 people with benign adrenal tumors, the largest reported prospective study of the disorder.

The study results showed that mild autonomous cortisol secretion (MACS) from benign adrenal tumors “is very frequent and is an important risk condition for high blood pressure and type 2 diabetes, especially in older women,” said Alessandro Prete, MD, lead author of the study which was published online Jan. 3, 2022, in Annals of Internal Medicine.

SEBASTIAN KAULITZKI/SCIENCE PHOTO LIBRARY/Getty Images

“The impact of MACS on high blood pressure and risk for type 2 diabetes has been underestimated until now,” said Dr. Prete, an endocrinologist at the University of Birmingham (England), in a written statement. 

Results from previous studies “suggested that MACS is associated with poor health. Our study is the largest to establish conclusively the extent of the risk and severity of high blood pressure and type 2 diabetes in patients with MACS,” said Wiebke Arlt, MD, DSc, senior author and director of the Institute of Metabolism & Systems Research at the University of Birmingham.

All patients found to have a benign adrenal tumor should undergo testing for MACS and have their blood pressure and glucose levels measured regularly, Dr. Arlt advised in the statement released by the University of Birmingham.
 

MACS more common than previously thought

The new findings show that MACS “is more common and may have a more negative impact on health than previously thought, including increasing the risk for type 2 diabetes,” commented Lucy Chambers, PhD, head of research communications at Diabetes UK. “The findings suggest that screening for MACS could help identify people – particularly women, in whom the condition was found to be more common – who may benefit from support to reduce their risk of type 2 diabetes.”

The study included 1,305 people with newly diagnosed, benign adrenal tumors greater than 1 cm, a subset of patients prospectively enrolled in a study with the primary purpose of validating a novel way to diagnose adrenocortical carcinomas. Patients underwent treatment in 2011-2016 at any of 14 tertiary centers in 11 countries.

Researchers used a MACS definition of failure to suppress morning serum cortisol concentration to less than 50 nmol/L after treatment with 1 mg oral dexamethasone at 11 p.m. the previous evening in those with no clinical features of CS.

Roughly half of patients (n = 649) showed normal cortisol suppression with dexamethasone, identifying them as having nonfunctioning adrenal tumors, and about 35% showed possible MACS based on having moderate levels of excess cortisol.

Nearly 11% (n = 140) showed definitive MACS with more robust cortisol levels, and 5% (n = 65) received a diagnosis of clinically overt CS despite selection criteria meant to exclude people with clinical signs of CS.

There was a clear relationship between patient sex and severity of autonomous cortisol production. Among those with nonfunctioning adrenal tumors, 64% were women, which rose to 74% women in those with definitive MACS and 86% women among those with CS. The median age of participants was 60 years old.
 

Increasing cortisol levels linked with cardiometabolic disease

Analysis of the prevalence of hypertension and type 2 diabetes after adjustment for age, sex, and body mass index showed that, compared with people with nonfunctioning adrenal tumors, those with definitive MACS had a significant 15% higher rate of hypertension and those with overt CS had a 37% higher rate. 

Higher levels of excess cortisol were also directly linked with an increased need for treatment with three or more antihypertensive agents to control blood pressure. Those with definitive MACS had a significant 31% higher rate of being on three or more drugs, and those with overt CS had a greater than twofold higher rate.

People with overt CS also had a significant 62% higher rate of type 2 diabetes, compared with those with a nonfunctioning tumor, but in those with definitive MACS the association was not significant. However, people with definitive MACS or overt CS who had type 2 diabetes and also had significantly increased rates of requiring insulin treatment.

The findings show that “people with definitive MACS carry an increased cardiometabolic burden similar to that seen in CS even if they do not display typical features of clinically overt cortisol excess,” the authors wrote in the report.

Even among those with apparently nonfunctioning tumors, each 10 nmol/L rise in cortisol level during a dexamethasone-suppression test was associated with a higher cardiometabolic disease burden. This observation suggests that current diagnostic cutoffs for the suppression test may miss some people with clinically relevant autonomous cortisol secretion, the report said. The study findings also suggest that people with benign adrenal tumors show a progressive continuum of excess cortisol with clinical consequences that increase as levels increase.
 

Determine the consequences of cortisol secretion

“These data clearly support the European Society of Endocrinology guideline recommendations that clinicians should determine precisely the cardiometabolic consequences of mild cortisol secretion in patients with adrenal lesions,” André Lacroix, MD, wrote in an accompanying editorial.

But Dr. Lacroix included some caveats. He noted the “potential pitfalls in relying on a single total serum cortisol value after the 1-mg dexamethasone test.” He also wondered whether the analysis used optimal cortisol values to distinguish patient subgroups.

Plus, “even in patients with nonfunctioning adrenal tumors the prevalence of diabetes and hypertension is higher than in the general population, raising concerns about the cardiometabolic consequences of barely detectable cortisol excess,” wrote Dr. Lacroix, an endocrinologist at the CHUM Research Center and professor of medicine at the University of Montreal.

The study received no commercial funding. Dr. Prete, Dr. Chambers, and Dr. Lacroix have reported no relevant financial relationships. Dr. Arlt is listed as an inventor on a patent on the use of steroid profiling as a biomarker tool for the differential diagnosis of adrenal tumors.

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

In more than 15% of people with benign adrenal tumors, the growths produce clinically relevant levels of serum cortisol that are significantly linked with an increased prevalence of hypertension and, in 5% of those with Cushing syndrome (CS), an increased prevalence of type 2 diabetes, based on data from more than 1,300 people with benign adrenal tumors, the largest reported prospective study of the disorder.

The study results showed that mild autonomous cortisol secretion (MACS) from benign adrenal tumors “is very frequent and is an important risk condition for high blood pressure and type 2 diabetes, especially in older women,” said Alessandro Prete, MD, lead author of the study which was published online Jan. 3, 2022, in Annals of Internal Medicine.

SEBASTIAN KAULITZKI/SCIENCE PHOTO LIBRARY/Getty Images

“The impact of MACS on high blood pressure and risk for type 2 diabetes has been underestimated until now,” said Dr. Prete, an endocrinologist at the University of Birmingham (England), in a written statement. 

Results from previous studies “suggested that MACS is associated with poor health. Our study is the largest to establish conclusively the extent of the risk and severity of high blood pressure and type 2 diabetes in patients with MACS,” said Wiebke Arlt, MD, DSc, senior author and director of the Institute of Metabolism & Systems Research at the University of Birmingham.

All patients found to have a benign adrenal tumor should undergo testing for MACS and have their blood pressure and glucose levels measured regularly, Dr. Arlt advised in the statement released by the University of Birmingham.
 

MACS more common than previously thought

The new findings show that MACS “is more common and may have a more negative impact on health than previously thought, including increasing the risk for type 2 diabetes,” commented Lucy Chambers, PhD, head of research communications at Diabetes UK. “The findings suggest that screening for MACS could help identify people – particularly women, in whom the condition was found to be more common – who may benefit from support to reduce their risk of type 2 diabetes.”

The study included 1,305 people with newly diagnosed, benign adrenal tumors greater than 1 cm, a subset of patients prospectively enrolled in a study with the primary purpose of validating a novel way to diagnose adrenocortical carcinomas. Patients underwent treatment in 2011-2016 at any of 14 tertiary centers in 11 countries.

Researchers used a MACS definition of failure to suppress morning serum cortisol concentration to less than 50 nmol/L after treatment with 1 mg oral dexamethasone at 11 p.m. the previous evening in those with no clinical features of CS.

Roughly half of patients (n = 649) showed normal cortisol suppression with dexamethasone, identifying them as having nonfunctioning adrenal tumors, and about 35% showed possible MACS based on having moderate levels of excess cortisol.

Nearly 11% (n = 140) showed definitive MACS with more robust cortisol levels, and 5% (n = 65) received a diagnosis of clinically overt CS despite selection criteria meant to exclude people with clinical signs of CS.

There was a clear relationship between patient sex and severity of autonomous cortisol production. Among those with nonfunctioning adrenal tumors, 64% were women, which rose to 74% women in those with definitive MACS and 86% women among those with CS. The median age of participants was 60 years old.
 

Increasing cortisol levels linked with cardiometabolic disease

Analysis of the prevalence of hypertension and type 2 diabetes after adjustment for age, sex, and body mass index showed that, compared with people with nonfunctioning adrenal tumors, those with definitive MACS had a significant 15% higher rate of hypertension and those with overt CS had a 37% higher rate. 

Higher levels of excess cortisol were also directly linked with an increased need for treatment with three or more antihypertensive agents to control blood pressure. Those with definitive MACS had a significant 31% higher rate of being on three or more drugs, and those with overt CS had a greater than twofold higher rate.

People with overt CS also had a significant 62% higher rate of type 2 diabetes, compared with those with a nonfunctioning tumor, but in those with definitive MACS the association was not significant. However, people with definitive MACS or overt CS who had type 2 diabetes and also had significantly increased rates of requiring insulin treatment.

The findings show that “people with definitive MACS carry an increased cardiometabolic burden similar to that seen in CS even if they do not display typical features of clinically overt cortisol excess,” the authors wrote in the report.

Even among those with apparently nonfunctioning tumors, each 10 nmol/L rise in cortisol level during a dexamethasone-suppression test was associated with a higher cardiometabolic disease burden. This observation suggests that current diagnostic cutoffs for the suppression test may miss some people with clinically relevant autonomous cortisol secretion, the report said. The study findings also suggest that people with benign adrenal tumors show a progressive continuum of excess cortisol with clinical consequences that increase as levels increase.
 

Determine the consequences of cortisol secretion

“These data clearly support the European Society of Endocrinology guideline recommendations that clinicians should determine precisely the cardiometabolic consequences of mild cortisol secretion in patients with adrenal lesions,” André Lacroix, MD, wrote in an accompanying editorial.

But Dr. Lacroix included some caveats. He noted the “potential pitfalls in relying on a single total serum cortisol value after the 1-mg dexamethasone test.” He also wondered whether the analysis used optimal cortisol values to distinguish patient subgroups.

Plus, “even in patients with nonfunctioning adrenal tumors the prevalence of diabetes and hypertension is higher than in the general population, raising concerns about the cardiometabolic consequences of barely detectable cortisol excess,” wrote Dr. Lacroix, an endocrinologist at the CHUM Research Center and professor of medicine at the University of Montreal.

The study received no commercial funding. Dr. Prete, Dr. Chambers, and Dr. Lacroix have reported no relevant financial relationships. Dr. Arlt is listed as an inventor on a patent on the use of steroid profiling as a biomarker tool for the differential diagnosis of adrenal tumors.

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

Brad Kahl, MD, shares results from non-Hodgkin lymphoma clinical trials that were presented at the 2021 American Society of Hematology (ASH) Annual Meeting. 

Dr Kahl looks first at a frontline study examining a new combination therapy. The POLARIX study compared polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) with standard of care in patients with untreated diffuse large B-cell lymphoma (DLBCL). Pola-R-CHP demonstrated significant improvement in progression-free survival. 

In relapsed/refractory non-Hodgkin lymphoma, Dr Kahl highlights several studies in chimeric antigen receptor (CAR) T-cell therapy. He starts with a primary analysis of the ZUMA-7 trial, in which axicabtagene ciloleucel (axi-cel) demonstrated improved survival compared with standard of care in patients with relapsed/refractory DLBCL. 

Next, he reports on the TRANSFORM study, which compared lisocabtagene maraleucel (liso-cel) with standard of care in the second-line setting for patients with high-risk relapsed/refractory DLBCL. Liso-cel demonstrated favorable outcomes, with improved event-free survival and no new safety concerns. 

The third CAR T-cell study he discusses is an updated analysis from ZUMA-5 that shows longer-term data for axi-cel in patients with relapsed/refractory follicular lymphoma or marginal zone lymphoma. Consistent with the primary analysis, this study demonstrated positive survival and safety outcomes in both groups. 

Finally, Dr Kahl examines a phase 1/2 study of mosunetuzumab monotherapy for patients with relapsed/refractory follicular lymphoma who have received at least two lines of therapy. The study demonstrated improved response rates and favorable safety results.

--

Brad Kahl, MD, Professor of Medicine, Department of Medical Oncology; Director, Lymphoma Program, Washington University School of Medicine, St. Louis, Missouri 
 

Brad Kahl, MD, has disclosed the following relevant financial relationships:  

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AbbVie; ADC Therapeutics; AstraZeneca; BeiGene; Celgene: Epizyme; Genentech; Pharmacyclics; Roche; TG Therapeutics 

Received income in an amount equal to or greater than $250 from: Genentech; AbbVie; Janssen 

Brad Kahl, MD, shares results from non-Hodgkin lymphoma clinical trials that were presented at the 2021 American Society of Hematology (ASH) Annual Meeting. 

Dr Kahl looks first at a frontline study examining a new combination therapy. The POLARIX study compared polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) with standard of care in patients with untreated diffuse large B-cell lymphoma (DLBCL). Pola-R-CHP demonstrated significant improvement in progression-free survival. 

In relapsed/refractory non-Hodgkin lymphoma, Dr Kahl highlights several studies in chimeric antigen receptor (CAR) T-cell therapy. He starts with a primary analysis of the ZUMA-7 trial, in which axicabtagene ciloleucel (axi-cel) demonstrated improved survival compared with standard of care in patients with relapsed/refractory DLBCL. 

Next, he reports on the TRANSFORM study, which compared lisocabtagene maraleucel (liso-cel) with standard of care in the second-line setting for patients with high-risk relapsed/refractory DLBCL. Liso-cel demonstrated favorable outcomes, with improved event-free survival and no new safety concerns. 

The third CAR T-cell study he discusses is an updated analysis from ZUMA-5 that shows longer-term data for axi-cel in patients with relapsed/refractory follicular lymphoma or marginal zone lymphoma. Consistent with the primary analysis, this study demonstrated positive survival and safety outcomes in both groups. 

Finally, Dr Kahl examines a phase 1/2 study of mosunetuzumab monotherapy for patients with relapsed/refractory follicular lymphoma who have received at least two lines of therapy. The study demonstrated improved response rates and favorable safety results.

--

Brad Kahl, MD, Professor of Medicine, Department of Medical Oncology; Director, Lymphoma Program, Washington University School of Medicine, St. Louis, Missouri 
 

Brad Kahl, MD, has disclosed the following relevant financial relationships:  

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AbbVie; ADC Therapeutics; AstraZeneca; BeiGene; Celgene: Epizyme; Genentech; Pharmacyclics; Roche; TG Therapeutics 

Received income in an amount equal to or greater than $250 from: Genentech; AbbVie; Janssen 

Brad Kahl, MD, shares results from non-Hodgkin lymphoma clinical trials that were presented at the 2021 American Society of Hematology (ASH) Annual Meeting. 

Dr Kahl looks first at a frontline study examining a new combination therapy. The POLARIX study compared polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) with standard of care in patients with untreated diffuse large B-cell lymphoma (DLBCL). Pola-R-CHP demonstrated significant improvement in progression-free survival. 

In relapsed/refractory non-Hodgkin lymphoma, Dr Kahl highlights several studies in chimeric antigen receptor (CAR) T-cell therapy. He starts with a primary analysis of the ZUMA-7 trial, in which axicabtagene ciloleucel (axi-cel) demonstrated improved survival compared with standard of care in patients with relapsed/refractory DLBCL. 

Next, he reports on the TRANSFORM study, which compared lisocabtagene maraleucel (liso-cel) with standard of care in the second-line setting for patients with high-risk relapsed/refractory DLBCL. Liso-cel demonstrated favorable outcomes, with improved event-free survival and no new safety concerns. 

The third CAR T-cell study he discusses is an updated analysis from ZUMA-5 that shows longer-term data for axi-cel in patients with relapsed/refractory follicular lymphoma or marginal zone lymphoma. Consistent with the primary analysis, this study demonstrated positive survival and safety outcomes in both groups. 

Finally, Dr Kahl examines a phase 1/2 study of mosunetuzumab monotherapy for patients with relapsed/refractory follicular lymphoma who have received at least two lines of therapy. The study demonstrated improved response rates and favorable safety results.

--

Brad Kahl, MD, Professor of Medicine, Department of Medical Oncology; Director, Lymphoma Program, Washington University School of Medicine, St. Louis, Missouri 
 

Brad Kahl, MD, has disclosed the following relevant financial relationships:  

Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: AbbVie; ADC Therapeutics; AstraZeneca; BeiGene; Celgene: Epizyme; Genentech; Pharmacyclics; Roche; TG Therapeutics 

Received income in an amount equal to or greater than $250 from: Genentech; AbbVie; Janssen 

The volume of prescription opioids dispensed at retail pharmacies in the United States dropped by 21% in recent years amid efforts to reduce unnecessary use of the painkillers, but the rate of decline varied greatly among types of patients and by type of clinician, a study found.

In a brief report published by Annals of Internal Medicine, researchers from the nonprofit RAND Corp reported an analysis of opioid prescriptions from two periods, 2008-2009 and 2017-2018.

The researchers sought to assess total opioid use rather than simply track the number of pills dispensed. So they used days’ supply and total daily dose to calculate per capita morphine milligram equivalents (MME) for opioid prescriptions, write Bradley D. Stein, MD, PhD, MPH, the study’s lead author and a senior physician researcher at RAND Corp, and his coauthors in their paper.

For the study, the researchers used data from the consulting firm IQVIA, which they say covers about 90% of U.S. prescriptions. Total opioid volume per capita by prescriptions filled in retail pharmacies decreased from 951.4 MME in 2008-2009 to 749.3 MME in 2017-2018, Dr. Stein’s group found.

(In 2020, IQVIA separately said that prescription opioid use per adult in this country rose from an average of 16 pills, or 134 MMEs, in 1992 to a peak of about 55 pills a person, or 790 MMEs, in 2011. By 2019, opioid use per adult had declined to 29 pills and 366 MMEs per capita.)

The RAND report found substantial variation in opioid volume by type of insurance, including a 41.5% decline (636.5 MME to 372.6 MME) among people covered by commercial health plans. That exceeded the 27.7% drop seen for people enrolled in Medicaid (646.8 MME to 467.7 MME). The decline was smaller (17.5%; 2,780.2 MME to 2,294.2 MME) for those on Medicare, who as a group used the most opioids.

‘Almost functions as a Rorschach test’

The causes of the decline are easy to guess, although definitive conclusions are impossible, Dr. Stein told this news organization.

Significant work has been done in recent years to change attitudes about opioid prescriptions by physicians, researchers, and lawmakers. Aggressive promotion of prescription painkillers, particularly Purdue Pharma’s OxyContin, in the 1990s, is widely cited as the triggering event for the national opioid crisis.

In response, states created databases known as prescription drug monitoring programs. The Centers for Disease Control and Prevention in 2016 issued guidelines intended to curb unnecessary use of opioids. The guidelines noted that other medicines could treat chronic pain without raising the risk of addiction. The Choosing Wisely campaign, run by a foundation of the American Board of Internal Medicine, also offered recommendations about limiting use of opioids. And insurers have restricted access to opioids through the prior authorization process. As a result, researchers will make their own guesses at the causes of the decline in opioid prescriptions, based on their own experiences and research interests, Dr. Stein said.

“It almost functions as a Rorschach test,” he said.

Dr. Stein’s group also looked at trends among medical specialties. They found the largest reduction between 2008-2009 and 2017-2018 among emergency physicians (70.5% drop from 99,254.5 MME to 29,234.3 MME), psychiatrists (67.2% drop from 50,464.3 MME to 16,533.0 MME) and oncologists (59.5% drop from 51,731.2 MME to 20,941.4).

Among surgeons, the RAND researchers found a drop of 49.3% from 220,764.6 to 111,904.4. Among dentists, they found a drop of 41.3% from 22,345.3 to 13,126.1.

Among pain specialists, they found a drop of 15.4% from 1,020,808.4 MME to 863,140.7 MME.

Among adult primary care clinicians, Dr. Stein and his colleagues found a drop of 40% from 651,489.4 MME in 2008-2009 to 390,841.0 MME in 2017-2018.

However, one of the groups tracked in the study increased the volume of opioid prescriptions written: advanced practice providers, among whom scripts for the drugs rose 22.7%, from 112,873.9 MME to 138,459.3 MME.

Dr. Stein said he suspects that this gain reflects a change in the nature of the practice of primary care, with nurse practitioners and physician assistants taking more active roles in treatment of patients. Some of the reduction seen among primary care clinicians who treat adults may reflect a shift in which medical personnel in a practice write the opioid prescriptions.

Still, the trends in general seen by Dr. Stein and coauthors are encouraging, even if further study of these patterns is needed, he said.

“This is one of those papers that I think potentially raises as many questions as it provides answers for,” he said.

What’s missing

Maya Hambright, MD, a family medicine physician in New York’s Hudson Valley, who has been working mainly in addiction in response to the opioid overdose crisis, observed that the drop in total prescribed volume of prescription painkillers does not necessarily translate into a reduction in use of opioids

“No one is taking fewer opioids,” Dr. Hambright told this news organization. “I can say that comfortably. They are just getting them from other sources.”

CDC data support Dr. Hambright’s view.

An estimated 100,306 people in the United States died of a drug overdose in the 12 months that ended in April 2021, an increase of 28.5% from the 78,056 deaths during the same period the year before, according to the CDC.

Dr. Hambright said more physicians need to be involved in prescribing medication-assisted treatment (MAT).

The federal government has in the past year loosened restrictions on a requirement, known as an X waiver. Certain clinicians have been exempted from training requirements, as explained in the frequently asked questions page on the Substance Abuse and Mental Health Services Administration website.

SAMHSA says legislation is required to eliminate the waiver. As of Dec. 30, 2021, more than half of the members of the U.S. House of Representatives were listed as sponsors of the Mainstreaming Addiction Treatment (MAT) Act (HR 1384), which would end the need for X waivers. The bill has the backing of 187 Democrats and 43 Republicans.

At this time, too many physicians shy away from offering MAT, Dr. Hambright said.

“People are still scared of it,” she said. “People don’t want to deal with addicts.”

But Dr. Hambright said it’s well worth the initial time invested in having the needed conversations with patients about MAT.

“Afterwards, it’s so straightforward. People feel better. They’re healthier. It’s amazing,” she said. “You’re changing lives.”

The research was supported by grants from the National Institutes of Health. Dr. Stein and coauthors reported no relevant financial relationships.

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

The volume of prescription opioids dispensed at retail pharmacies in the United States dropped by 21% in recent years amid efforts to reduce unnecessary use of the painkillers, but the rate of decline varied greatly among types of patients and by type of clinician, a study found.

In a brief report published by Annals of Internal Medicine, researchers from the nonprofit RAND Corp reported an analysis of opioid prescriptions from two periods, 2008-2009 and 2017-2018.

The researchers sought to assess total opioid use rather than simply track the number of pills dispensed. So they used days’ supply and total daily dose to calculate per capita morphine milligram equivalents (MME) for opioid prescriptions, write Bradley D. Stein, MD, PhD, MPH, the study’s lead author and a senior physician researcher at RAND Corp, and his coauthors in their paper.

For the study, the researchers used data from the consulting firm IQVIA, which they say covers about 90% of U.S. prescriptions. Total opioid volume per capita by prescriptions filled in retail pharmacies decreased from 951.4 MME in 2008-2009 to 749.3 MME in 2017-2018, Dr. Stein’s group found.

(In 2020, IQVIA separately said that prescription opioid use per adult in this country rose from an average of 16 pills, or 134 MMEs, in 1992 to a peak of about 55 pills a person, or 790 MMEs, in 2011. By 2019, opioid use per adult had declined to 29 pills and 366 MMEs per capita.)

The RAND report found substantial variation in opioid volume by type of insurance, including a 41.5% decline (636.5 MME to 372.6 MME) among people covered by commercial health plans. That exceeded the 27.7% drop seen for people enrolled in Medicaid (646.8 MME to 467.7 MME). The decline was smaller (17.5%; 2,780.2 MME to 2,294.2 MME) for those on Medicare, who as a group used the most opioids.

‘Almost functions as a Rorschach test’

The causes of the decline are easy to guess, although definitive conclusions are impossible, Dr. Stein told this news organization.

Significant work has been done in recent years to change attitudes about opioid prescriptions by physicians, researchers, and lawmakers. Aggressive promotion of prescription painkillers, particularly Purdue Pharma’s OxyContin, in the 1990s, is widely cited as the triggering event for the national opioid crisis.

In response, states created databases known as prescription drug monitoring programs. The Centers for Disease Control and Prevention in 2016 issued guidelines intended to curb unnecessary use of opioids. The guidelines noted that other medicines could treat chronic pain without raising the risk of addiction. The Choosing Wisely campaign, run by a foundation of the American Board of Internal Medicine, also offered recommendations about limiting use of opioids. And insurers have restricted access to opioids through the prior authorization process. As a result, researchers will make their own guesses at the causes of the decline in opioid prescriptions, based on their own experiences and research interests, Dr. Stein said.

“It almost functions as a Rorschach test,” he said.

Dr. Stein’s group also looked at trends among medical specialties. They found the largest reduction between 2008-2009 and 2017-2018 among emergency physicians (70.5% drop from 99,254.5 MME to 29,234.3 MME), psychiatrists (67.2% drop from 50,464.3 MME to 16,533.0 MME) and oncologists (59.5% drop from 51,731.2 MME to 20,941.4).

Among surgeons, the RAND researchers found a drop of 49.3% from 220,764.6 to 111,904.4. Among dentists, they found a drop of 41.3% from 22,345.3 to 13,126.1.

Among pain specialists, they found a drop of 15.4% from 1,020,808.4 MME to 863,140.7 MME.

Among adult primary care clinicians, Dr. Stein and his colleagues found a drop of 40% from 651,489.4 MME in 2008-2009 to 390,841.0 MME in 2017-2018.

However, one of the groups tracked in the study increased the volume of opioid prescriptions written: advanced practice providers, among whom scripts for the drugs rose 22.7%, from 112,873.9 MME to 138,459.3 MME.

Dr. Stein said he suspects that this gain reflects a change in the nature of the practice of primary care, with nurse practitioners and physician assistants taking more active roles in treatment of patients. Some of the reduction seen among primary care clinicians who treat adults may reflect a shift in which medical personnel in a practice write the opioid prescriptions.

Still, the trends in general seen by Dr. Stein and coauthors are encouraging, even if further study of these patterns is needed, he said.

“This is one of those papers that I think potentially raises as many questions as it provides answers for,” he said.

What’s missing

Maya Hambright, MD, a family medicine physician in New York’s Hudson Valley, who has been working mainly in addiction in response to the opioid overdose crisis, observed that the drop in total prescribed volume of prescription painkillers does not necessarily translate into a reduction in use of opioids

“No one is taking fewer opioids,” Dr. Hambright told this news organization. “I can say that comfortably. They are just getting them from other sources.”

CDC data support Dr. Hambright’s view.

An estimated 100,306 people in the United States died of a drug overdose in the 12 months that ended in April 2021, an increase of 28.5% from the 78,056 deaths during the same period the year before, according to the CDC.

Dr. Hambright said more physicians need to be involved in prescribing medication-assisted treatment (MAT).

The federal government has in the past year loosened restrictions on a requirement, known as an X waiver. Certain clinicians have been exempted from training requirements, as explained in the frequently asked questions page on the Substance Abuse and Mental Health Services Administration website.

SAMHSA says legislation is required to eliminate the waiver. As of Dec. 30, 2021, more than half of the members of the U.S. House of Representatives were listed as sponsors of the Mainstreaming Addiction Treatment (MAT) Act (HR 1384), which would end the need for X waivers. The bill has the backing of 187 Democrats and 43 Republicans.

At this time, too many physicians shy away from offering MAT, Dr. Hambright said.

“People are still scared of it,” she said. “People don’t want to deal with addicts.”

But Dr. Hambright said it’s well worth the initial time invested in having the needed conversations with patients about MAT.

“Afterwards, it’s so straightforward. People feel better. They’re healthier. It’s amazing,” she said. “You’re changing lives.”

The research was supported by grants from the National Institutes of Health. Dr. Stein and coauthors reported no relevant financial relationships.

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

The volume of prescription opioids dispensed at retail pharmacies in the United States dropped by 21% in recent years amid efforts to reduce unnecessary use of the painkillers, but the rate of decline varied greatly among types of patients and by type of clinician, a study found.

In a brief report published by Annals of Internal Medicine, researchers from the nonprofit RAND Corp reported an analysis of opioid prescriptions from two periods, 2008-2009 and 2017-2018.

The researchers sought to assess total opioid use rather than simply track the number of pills dispensed. So they used days’ supply and total daily dose to calculate per capita morphine milligram equivalents (MME) for opioid prescriptions, write Bradley D. Stein, MD, PhD, MPH, the study’s lead author and a senior physician researcher at RAND Corp, and his coauthors in their paper.

For the study, the researchers used data from the consulting firm IQVIA, which they say covers about 90% of U.S. prescriptions. Total opioid volume per capita by prescriptions filled in retail pharmacies decreased from 951.4 MME in 2008-2009 to 749.3 MME in 2017-2018, Dr. Stein’s group found.

(In 2020, IQVIA separately said that prescription opioid use per adult in this country rose from an average of 16 pills, or 134 MMEs, in 1992 to a peak of about 55 pills a person, or 790 MMEs, in 2011. By 2019, opioid use per adult had declined to 29 pills and 366 MMEs per capita.)

The RAND report found substantial variation in opioid volume by type of insurance, including a 41.5% decline (636.5 MME to 372.6 MME) among people covered by commercial health plans. That exceeded the 27.7% drop seen for people enrolled in Medicaid (646.8 MME to 467.7 MME). The decline was smaller (17.5%; 2,780.2 MME to 2,294.2 MME) for those on Medicare, who as a group used the most opioids.

‘Almost functions as a Rorschach test’

The causes of the decline are easy to guess, although definitive conclusions are impossible, Dr. Stein told this news organization.

Significant work has been done in recent years to change attitudes about opioid prescriptions by physicians, researchers, and lawmakers. Aggressive promotion of prescription painkillers, particularly Purdue Pharma’s OxyContin, in the 1990s, is widely cited as the triggering event for the national opioid crisis.

In response, states created databases known as prescription drug monitoring programs. The Centers for Disease Control and Prevention in 2016 issued guidelines intended to curb unnecessary use of opioids. The guidelines noted that other medicines could treat chronic pain without raising the risk of addiction. The Choosing Wisely campaign, run by a foundation of the American Board of Internal Medicine, also offered recommendations about limiting use of opioids. And insurers have restricted access to opioids through the prior authorization process. As a result, researchers will make their own guesses at the causes of the decline in opioid prescriptions, based on their own experiences and research interests, Dr. Stein said.

“It almost functions as a Rorschach test,” he said.

Dr. Stein’s group also looked at trends among medical specialties. They found the largest reduction between 2008-2009 and 2017-2018 among emergency physicians (70.5% drop from 99,254.5 MME to 29,234.3 MME), psychiatrists (67.2% drop from 50,464.3 MME to 16,533.0 MME) and oncologists (59.5% drop from 51,731.2 MME to 20,941.4).

Among surgeons, the RAND researchers found a drop of 49.3% from 220,764.6 to 111,904.4. Among dentists, they found a drop of 41.3% from 22,345.3 to 13,126.1.

Among pain specialists, they found a drop of 15.4% from 1,020,808.4 MME to 863,140.7 MME.

Among adult primary care clinicians, Dr. Stein and his colleagues found a drop of 40% from 651,489.4 MME in 2008-2009 to 390,841.0 MME in 2017-2018.

However, one of the groups tracked in the study increased the volume of opioid prescriptions written: advanced practice providers, among whom scripts for the drugs rose 22.7%, from 112,873.9 MME to 138,459.3 MME.

Dr. Stein said he suspects that this gain reflects a change in the nature of the practice of primary care, with nurse practitioners and physician assistants taking more active roles in treatment of patients. Some of the reduction seen among primary care clinicians who treat adults may reflect a shift in which medical personnel in a practice write the opioid prescriptions.

Still, the trends in general seen by Dr. Stein and coauthors are encouraging, even if further study of these patterns is needed, he said.

“This is one of those papers that I think potentially raises as many questions as it provides answers for,” he said.

What’s missing

Maya Hambright, MD, a family medicine physician in New York’s Hudson Valley, who has been working mainly in addiction in response to the opioid overdose crisis, observed that the drop in total prescribed volume of prescription painkillers does not necessarily translate into a reduction in use of opioids

“No one is taking fewer opioids,” Dr. Hambright told this news organization. “I can say that comfortably. They are just getting them from other sources.”

CDC data support Dr. Hambright’s view.

An estimated 100,306 people in the United States died of a drug overdose in the 12 months that ended in April 2021, an increase of 28.5% from the 78,056 deaths during the same period the year before, according to the CDC.

Dr. Hambright said more physicians need to be involved in prescribing medication-assisted treatment (MAT).

The federal government has in the past year loosened restrictions on a requirement, known as an X waiver. Certain clinicians have been exempted from training requirements, as explained in the frequently asked questions page on the Substance Abuse and Mental Health Services Administration website.

SAMHSA says legislation is required to eliminate the waiver. As of Dec. 30, 2021, more than half of the members of the U.S. House of Representatives were listed as sponsors of the Mainstreaming Addiction Treatment (MAT) Act (HR 1384), which would end the need for X waivers. The bill has the backing of 187 Democrats and 43 Republicans.

At this time, too many physicians shy away from offering MAT, Dr. Hambright said.

“People are still scared of it,” she said. “People don’t want to deal with addicts.”

But Dr. Hambright said it’s well worth the initial time invested in having the needed conversations with patients about MAT.

“Afterwards, it’s so straightforward. People feel better. They’re healthier. It’s amazing,” she said. “You’re changing lives.”

The research was supported by grants from the National Institutes of Health. Dr. Stein and coauthors reported no relevant financial relationships.

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