AVAHO

Cervical cancer incidence in the United States decreased by about 1% per year from 2001 to 2017, but at the same time there was an increase in the incidence of other human papillomavirus (HPV)–related cancers, a new study reveals.

Over the same period, there was an overall 1.3% annual increase in oropharyngeal, anal, rectal, and vulvar cancers in women, and a 2.3% annual increase in these cancers in men.

HPV is associated with more than 90% of cervical cancers and between 60% and 75% of oropharyngeal, vulvar, vaginal, and penile cancer in the United States, the researchers noted.

Oropharyngeal cancer incidence increased by 2.3% overall, with a 2.7% increase in men and a 0.77% increase in women. The incidence of this cancer was nearly fivefold greater in men at 8.89 per 100,000 population versus 1.68 per 100,000 population for women, the study found.

In addition, among women over age 50 years, anal and rectal cancer incidence increased by 3.5% per year; at the same time, cervical cancer incidence decreased 1.5% per year.

The increase in the incidence of oropharyngeal cancer and in anal and rectal cancers is expected to continue, the authors said.

The data showing these new trends come from an analysis of 657,317 individuals obtained from the U.S. Cancer Statistics program, conducted by Cheng-I Liao, MD, of Kaohsiung (Taiwan) Veterans Hospital and colleagues.

The study was highlighted at a press briefing ahead of the annual meeting of the American Society of Clinical Oncology, where the study will be presented June 6.

These incidence trends may reflect the availability of clear guidelines for screening and vaccination for the prevention of HPV-related cervical cancer – and the dearth of guidelines and standardized screening and vaccination for the other HPV-related cancers, the authors said.

The team also found cervical cancer accounted for 52% of all HPV-related cancers during the study period. The decrease in the incidence of cervical cancer over time was greater among women aged 20-24 (4.6% per year), compared with those aged 25-29 years (1.6%) and 30-34 years (1.1%),

Dr. Liao speculated that this age-based difference suggests a potential effect of HPV vaccination, greater vaccine acceptance among younger women, and clear guidelines for screening and vaccination.

However, an expert approached for comment was not so sure. It is likely too soon to give HPV vaccination too much credit for lower cervical cancer rates, said Jennifer Young Pierce, MD, MPH, a gynecologic oncologist at the Mitchell Cancer Institute, University of South Alabama, Mobile.

The continued rise in HPV-related cancers other than cervical cancers supports the point that screening – rather than vaccination – accounts for much of the decline observed in cervical cancer incidence, Dr. Pierce said in an interview.

Vaccination in men lags behind that of women, and there is a lack of good screening methods for head and neck cancers, she explained.

“When we have both vaccination and screening in these other cancers at high rates, we’re going to see significant declines in those cancers also,” she said.

“I’m very excited by the data but I do not believe it is related to vaccination as a method of prevention,” said Dr. Pierce, a professor of interdisciplinary clinical oncology who has been involved in numerous HPV vaccine–related studies and initiatives to improve vaccine uptake since its approval in 2006.
 

HPV vaccination

The HPV vaccine was first approved for preventing HPV-related cervical cancer in 2006 with an indication for girls and women aged 9-26 years. The vaccine indication was expanded in 2011 to include boys aged 11-12 years and is now approved for those up to age 45 years.

However, neither standardized screening nor HPV vaccination is currently recommended for any HPV-related cancer other than cervical cancer, Dr. Liao said.

Vaccination during much of the current study time frame (2001-2017) didn’t apply to most of the people who got cancer, Dr. Pierce explained in an interview, noting that the vaccinated individuals “still aren’t old enough to be part of the group we’re talking about.”

Rather, the increased use of HPV screening along with Pap testing for cervical cancer was becoming much more widespread at the time and was likely picking up more precancerous lesions – and thereby helping to decrease cervical cancer incidence in women in their 40s, 50s, 60s, and 70s, she said.

Dr. Pierce does, however, credit the vaccine movement for improving awareness of HPV risk.

“It has done a great job of educating the population about the dangers of these cancers ... and that there’s more we can do to prevent them,” she said.

Like Dr. Liao, she stressed the need for research focused on finding more effective screening modalities and on vaccine efficacy.

Also commenting on the study, ASCO president Lori J. Pierce, MD, a radiation oncologist, professor, and vice provost for academic and faculty affairs at the University of Michigan, Ann Arbor, said the findings underscore the need for ongoing exploration of potential strategies such as HPV screening for high-risk populations.

“We can pick out higher risk populations so it would make sense to do a screen,” she said.

“Clearly, this study shows that we still have a great deal of work to do in order to reverse the increasing incidence rates of other HPV-related cancers,” she added in a press statement.

In an interview prior to the press conference, Dr. Pierce said in an interview that the findings are important because the outcome “opens all of our eyes into the trends of HPV-related cancers in the United States.

“This is something that hasn’t been studied well over time,” she added, noting that, where guidelines do exist for HPV-related cancers other than cervical cancer, they are inconsistent.

Further, it is possible that the vaccine will “cover a significant portion of the etiologic viruses that cause these cancers,” thereby helping to prevent the other HPV-related cancers.

For that reason, additional research and strategies for overcoming vaccine hesitancy, increasing overall vaccination rates, and for developing consistent guidelines are needed.

“I think there needs to be further resources and research to address the lack of screening for these other HPV-related cancers and we need to have consistent vaccination guidelines, because these cancers are preventable,” she said

Dr. Liao and Dr. Pierce disclosed no relevant financial relationships.

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

Cervical cancer incidence in the United States decreased by about 1% per year from 2001 to 2017, but at the same time there was an increase in the incidence of other human papillomavirus (HPV)–related cancers, a new study reveals.

Over the same period, there was an overall 1.3% annual increase in oropharyngeal, anal, rectal, and vulvar cancers in women, and a 2.3% annual increase in these cancers in men.

HPV is associated with more than 90% of cervical cancers and between 60% and 75% of oropharyngeal, vulvar, vaginal, and penile cancer in the United States, the researchers noted.

Oropharyngeal cancer incidence increased by 2.3% overall, with a 2.7% increase in men and a 0.77% increase in women. The incidence of this cancer was nearly fivefold greater in men at 8.89 per 100,000 population versus 1.68 per 100,000 population for women, the study found.

In addition, among women over age 50 years, anal and rectal cancer incidence increased by 3.5% per year; at the same time, cervical cancer incidence decreased 1.5% per year.

The increase in the incidence of oropharyngeal cancer and in anal and rectal cancers is expected to continue, the authors said.

The data showing these new trends come from an analysis of 657,317 individuals obtained from the U.S. Cancer Statistics program, conducted by Cheng-I Liao, MD, of Kaohsiung (Taiwan) Veterans Hospital and colleagues.

The study was highlighted at a press briefing ahead of the annual meeting of the American Society of Clinical Oncology, where the study will be presented June 6.

These incidence trends may reflect the availability of clear guidelines for screening and vaccination for the prevention of HPV-related cervical cancer – and the dearth of guidelines and standardized screening and vaccination for the other HPV-related cancers, the authors said.

The team also found cervical cancer accounted for 52% of all HPV-related cancers during the study period. The decrease in the incidence of cervical cancer over time was greater among women aged 20-24 (4.6% per year), compared with those aged 25-29 years (1.6%) and 30-34 years (1.1%),

Dr. Liao speculated that this age-based difference suggests a potential effect of HPV vaccination, greater vaccine acceptance among younger women, and clear guidelines for screening and vaccination.

However, an expert approached for comment was not so sure. It is likely too soon to give HPV vaccination too much credit for lower cervical cancer rates, said Jennifer Young Pierce, MD, MPH, a gynecologic oncologist at the Mitchell Cancer Institute, University of South Alabama, Mobile.

The continued rise in HPV-related cancers other than cervical cancers supports the point that screening – rather than vaccination – accounts for much of the decline observed in cervical cancer incidence, Dr. Pierce said in an interview.

Vaccination in men lags behind that of women, and there is a lack of good screening methods for head and neck cancers, she explained.

“When we have both vaccination and screening in these other cancers at high rates, we’re going to see significant declines in those cancers also,” she said.

“I’m very excited by the data but I do not believe it is related to vaccination as a method of prevention,” said Dr. Pierce, a professor of interdisciplinary clinical oncology who has been involved in numerous HPV vaccine–related studies and initiatives to improve vaccine uptake since its approval in 2006.
 

HPV vaccination

The HPV vaccine was first approved for preventing HPV-related cervical cancer in 2006 with an indication for girls and women aged 9-26 years. The vaccine indication was expanded in 2011 to include boys aged 11-12 years and is now approved for those up to age 45 years.

However, neither standardized screening nor HPV vaccination is currently recommended for any HPV-related cancer other than cervical cancer, Dr. Liao said.

Vaccination during much of the current study time frame (2001-2017) didn’t apply to most of the people who got cancer, Dr. Pierce explained in an interview, noting that the vaccinated individuals “still aren’t old enough to be part of the group we’re talking about.”

Rather, the increased use of HPV screening along with Pap testing for cervical cancer was becoming much more widespread at the time and was likely picking up more precancerous lesions – and thereby helping to decrease cervical cancer incidence in women in their 40s, 50s, 60s, and 70s, she said.

Dr. Pierce does, however, credit the vaccine movement for improving awareness of HPV risk.

“It has done a great job of educating the population about the dangers of these cancers ... and that there’s more we can do to prevent them,” she said.

Like Dr. Liao, she stressed the need for research focused on finding more effective screening modalities and on vaccine efficacy.

Also commenting on the study, ASCO president Lori J. Pierce, MD, a radiation oncologist, professor, and vice provost for academic and faculty affairs at the University of Michigan, Ann Arbor, said the findings underscore the need for ongoing exploration of potential strategies such as HPV screening for high-risk populations.

“We can pick out higher risk populations so it would make sense to do a screen,” she said.

“Clearly, this study shows that we still have a great deal of work to do in order to reverse the increasing incidence rates of other HPV-related cancers,” she added in a press statement.

In an interview prior to the press conference, Dr. Pierce said in an interview that the findings are important because the outcome “opens all of our eyes into the trends of HPV-related cancers in the United States.

“This is something that hasn’t been studied well over time,” she added, noting that, where guidelines do exist for HPV-related cancers other than cervical cancer, they are inconsistent.

Further, it is possible that the vaccine will “cover a significant portion of the etiologic viruses that cause these cancers,” thereby helping to prevent the other HPV-related cancers.

For that reason, additional research and strategies for overcoming vaccine hesitancy, increasing overall vaccination rates, and for developing consistent guidelines are needed.

“I think there needs to be further resources and research to address the lack of screening for these other HPV-related cancers and we need to have consistent vaccination guidelines, because these cancers are preventable,” she said

Dr. Liao and Dr. Pierce disclosed no relevant financial relationships.

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

Cervical cancer incidence in the United States decreased by about 1% per year from 2001 to 2017, but at the same time there was an increase in the incidence of other human papillomavirus (HPV)–related cancers, a new study reveals.

Over the same period, there was an overall 1.3% annual increase in oropharyngeal, anal, rectal, and vulvar cancers in women, and a 2.3% annual increase in these cancers in men.

HPV is associated with more than 90% of cervical cancers and between 60% and 75% of oropharyngeal, vulvar, vaginal, and penile cancer in the United States, the researchers noted.

Oropharyngeal cancer incidence increased by 2.3% overall, with a 2.7% increase in men and a 0.77% increase in women. The incidence of this cancer was nearly fivefold greater in men at 8.89 per 100,000 population versus 1.68 per 100,000 population for women, the study found.

In addition, among women over age 50 years, anal and rectal cancer incidence increased by 3.5% per year; at the same time, cervical cancer incidence decreased 1.5% per year.

The increase in the incidence of oropharyngeal cancer and in anal and rectal cancers is expected to continue, the authors said.

The data showing these new trends come from an analysis of 657,317 individuals obtained from the U.S. Cancer Statistics program, conducted by Cheng-I Liao, MD, of Kaohsiung (Taiwan) Veterans Hospital and colleagues.

The study was highlighted at a press briefing ahead of the annual meeting of the American Society of Clinical Oncology, where the study will be presented June 6.

These incidence trends may reflect the availability of clear guidelines for screening and vaccination for the prevention of HPV-related cervical cancer – and the dearth of guidelines and standardized screening and vaccination for the other HPV-related cancers, the authors said.

The team also found cervical cancer accounted for 52% of all HPV-related cancers during the study period. The decrease in the incidence of cervical cancer over time was greater among women aged 20-24 (4.6% per year), compared with those aged 25-29 years (1.6%) and 30-34 years (1.1%),

Dr. Liao speculated that this age-based difference suggests a potential effect of HPV vaccination, greater vaccine acceptance among younger women, and clear guidelines for screening and vaccination.

However, an expert approached for comment was not so sure. It is likely too soon to give HPV vaccination too much credit for lower cervical cancer rates, said Jennifer Young Pierce, MD, MPH, a gynecologic oncologist at the Mitchell Cancer Institute, University of South Alabama, Mobile.

The continued rise in HPV-related cancers other than cervical cancers supports the point that screening – rather than vaccination – accounts for much of the decline observed in cervical cancer incidence, Dr. Pierce said in an interview.

Vaccination in men lags behind that of women, and there is a lack of good screening methods for head and neck cancers, she explained.

“When we have both vaccination and screening in these other cancers at high rates, we’re going to see significant declines in those cancers also,” she said.

“I’m very excited by the data but I do not believe it is related to vaccination as a method of prevention,” said Dr. Pierce, a professor of interdisciplinary clinical oncology who has been involved in numerous HPV vaccine–related studies and initiatives to improve vaccine uptake since its approval in 2006.
 

HPV vaccination

The HPV vaccine was first approved for preventing HPV-related cervical cancer in 2006 with an indication for girls and women aged 9-26 years. The vaccine indication was expanded in 2011 to include boys aged 11-12 years and is now approved for those up to age 45 years.

However, neither standardized screening nor HPV vaccination is currently recommended for any HPV-related cancer other than cervical cancer, Dr. Liao said.

Vaccination during much of the current study time frame (2001-2017) didn’t apply to most of the people who got cancer, Dr. Pierce explained in an interview, noting that the vaccinated individuals “still aren’t old enough to be part of the group we’re talking about.”

Rather, the increased use of HPV screening along with Pap testing for cervical cancer was becoming much more widespread at the time and was likely picking up more precancerous lesions – and thereby helping to decrease cervical cancer incidence in women in their 40s, 50s, 60s, and 70s, she said.

Dr. Pierce does, however, credit the vaccine movement for improving awareness of HPV risk.

“It has done a great job of educating the population about the dangers of these cancers ... and that there’s more we can do to prevent them,” she said.

Like Dr. Liao, she stressed the need for research focused on finding more effective screening modalities and on vaccine efficacy.

Also commenting on the study, ASCO president Lori J. Pierce, MD, a radiation oncologist, professor, and vice provost for academic and faculty affairs at the University of Michigan, Ann Arbor, said the findings underscore the need for ongoing exploration of potential strategies such as HPV screening for high-risk populations.

“We can pick out higher risk populations so it would make sense to do a screen,” she said.

“Clearly, this study shows that we still have a great deal of work to do in order to reverse the increasing incidence rates of other HPV-related cancers,” she added in a press statement.

In an interview prior to the press conference, Dr. Pierce said in an interview that the findings are important because the outcome “opens all of our eyes into the trends of HPV-related cancers in the United States.

“This is something that hasn’t been studied well over time,” she added, noting that, where guidelines do exist for HPV-related cancers other than cervical cancer, they are inconsistent.

Further, it is possible that the vaccine will “cover a significant portion of the etiologic viruses that cause these cancers,” thereby helping to prevent the other HPV-related cancers.

For that reason, additional research and strategies for overcoming vaccine hesitancy, increasing overall vaccination rates, and for developing consistent guidelines are needed.

“I think there needs to be further resources and research to address the lack of screening for these other HPV-related cancers and we need to have consistent vaccination guidelines, because these cancers are preventable,” she said

Dr. Liao and Dr. Pierce disclosed no relevant financial relationships.

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

Before 2001, HER2/neu-positive breast cancer (HER2+) was one of the most dreaded diagnoses a woman could face, as treatment was largely ineffective. The discovery of trastuzumab changed that dramatically.

Over the next 20 years, two additional HER2-targeted therapies – lapatinib and trastuzumab emtansine (TDM-1) – earned approval from the Food and Drug Administration for selected patients with early and late HER2+ breast cancer.

Since 2019, four additional HER2-targeted therapies have been approved by the FDA for HER2+ metastatic breast cancer (MBC), changing the treatment paradigm for those patients substantially.

The new agents are especially useful in certain patient populations. The agents offer the promise of improved survival for patients with recurrent metastatic disease and the potential for further reductions in relapse rates in earlier settings.
 

Trastuzumab deruxtecan

Trastuzumab deruxtecan is an antibody-drug conjugate that links three components: an anti-HER2 monoclonal antibody, a highly potent topoisomerase I inhibitor payload, and a tetrapeptide-based cleavable linker.

Trastuzumab deruxtecan has a high drug-to-antibody ratio. A membrane-permeable payload offers the potential for activity against adjacent HER2-negative cells in heterogeneous tumors. It has a long half-life (6 days).

Trastuzumab deruxtecan received accelerated approval from the FDA in December 2019 to treat patients with HER2+ MBC who have received two or more prior HER2-targeted regimens, based on the results of the DESTINY-Breast 01 trial.
 

DESTINY-Breast 01 trial

In the phase 2 DESTINY-Breast 01 trial, 184 patients with a median of six previous treatments received trastuzumab deruxtecan (5.4 mg/kg) intravenously every 21 days. There were 24 patients with treated, asymptomatic brain metastases who participated. Patients with untreated or symptomatic brain metastases were excluded.

Overall, a response to therapy was reported in 112 patients (60.9%), with 6.0% complete and 54.9% partial responses. Most of the patients for whom both baseline and postbaseline data were available had a reduction in tumor size.

The median time until response was 1.6 months, an interval that corresponded to the time until the first scheduled imaging. Three patients (1.6%) had progressive disease, and two patients (1.1%) could not be evaluated.

The median duration of follow-up was 11.1 months, and the median response duration was 14.8 months.

The median progression-free survival (PFS) was 16.4 months, and the median overall survival (OS) was not reached. The median PFS in the patients with brain involvement was 18.1 months.

The most common adverse events of grade 3 or higher were a decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%). Most concerning was that trastuzumab deruxtecan was associated with interstitial lung disease in 13.6% of patients.
 

Tucatinib

Tucatinib is an oral, highly selective HER2 tyrosine kinase inhibitor (TKI). In April 2020, it was approved by the FDA, in combination with trastuzumab and capecitabine, for adult patients with advanced unresectable or metastatic HER2+ breast cancer who have received one or more prior anti-HER2–based regimens for MBC. The approval included patients with brain metastases.

The recommended tucatinib dose is 300 mg orally twice a day in combination with trastuzumab (at the standard dose) and capecitabine (1,000 mg/m² given orally twice daily on days 1-14) on a 21-day cycle, until disease progression or unacceptable toxicity.
 

HER2CLIMB trial

The study that led to the approval of tucatinib was the HER2CLIMB trial. The trial enrolled 612 HER2+ MBC patients who had prior treatment with trastuzumab, pertuzumab, and T-DM1. Patients had received a median of 4 (range, 2-17) prior lines of HER2-targeted therapy.

The patients were randomized 2:1 to receive trastuzumab plus capecitabine and either tucatinib or an identical placebo twice daily.

The primary endpoint was PFS, evaluated in the initial 480 randomized patients. The median PFS was 7.8 months in the tucatinib arm and 5.6 months in the control arm (hazard ratio, 0.54; 95% confidence interval, 0.42-0.71; P < .001).

The confirmed overall response rate for patients with measurable disease was 40.6% in the tucatinib arm and 22.8% in the control arm (P = .001). The proportion of patients still in response at 12 months was 33.1% and 12.3%, respectively.

The median OS was 21.9 months in the tucatinib arm and 17.4 months in the placebo arm (HR, 0.66; 95% CI, 0.50-0.88; P = .005). At 24 months, 44.9% and 26.6% of patients, respectively, were still alive.

The most common grade 3 or higher adverse events (in the tucatinib and placebo arms, respectively) were palmar-plantar erythrodysesthesia syndrome (13.1% vs. 9.1%), diarrhea (12.9% vs. 8.6%), elevations in ALT and AST (approximately 5% vs. 0.5% for each), and fatigue (4.7% vs. 4.1%).
 

Tucatinib in patients with brain involvement

A unique feature of the HER2CLIMB study was that patients with MBC and untreated, symptomatic brain metastases were eligible. Patients with active, untreated central nervous system disease are excluded from virtually all other trials, especially drug-approval trials.

There were 291 patients with brain metastases in HER2CLIMB, 198 (48%) in the tucatinib arm and 93 (46%) in the control arm.

The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (HR, 0.32; 95% CI, 0.22 to 0.48; P  < .0001).

The 1-year CNS-PFS rate was 40.2% in the tucatinib arm and 0% in the placebo arm. The median duration of CNS-PFS was 9.9 months and 4.2 months, respectively.

The risk of death was reduced by 42% in the tucatinib arm (HR, 0.58; 95% CI, 0.40-0.85; P = .005). The median OS was 18.1 months and 12.0 months, respectively.

There were more objective responses in the brain with tucatinib (47.3%) than with placebo (20.0%; P = .03). The median duration of response was 6.8 months and 3.0 months, respectively.

Particularly because of its CNS activity and lack of serious, long-term toxicity, tucatinib combination therapy represents an attractive new option for patients with HER2+ MBC.
 

Neratinib

Neratinib is an irreversible pan-HER TKI that was approved by the FDA in July 2017 for extended adjuvant therapy in patients with early-stage HER2+ breast cancer, following the use of trastuzumab-based therapy.

Long-term results of the ExteNet study led to the approval for use as extended adjuvant therapy.

In February 2020, neratinib was FDA approved in combination with capecitabine for patients with HER2+ MBC after two or more prior anti-HER2–based regimens. The more recent FDA approval was based on results of the NALA trial.
 

NALA trial

The phase 3 NALA trial included 621 patients with HER2+ MBC who had received at least two prior anti-HER2 based regimens.

Patients were randomized 1:1 to receive neratinib at 240 mg orally once daily on days 1-21 with capecitabine at 750 mg/m² orally twice daily on days 1-14 or lapatinib at 1,250 mg orally once daily on days 1-21 with capecitabine at 1,000 mg/m² orally twice daily on days 1-14 for each 21-day cycle. Patients were treated until disease progression or unacceptable toxicity.

The primary endpoints were PFS and OS by blinded, independent, central review.

The median PFS was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (HR, 0.76; 95% CI, 0.63-0.93; P = .0059). The PFS rate at 12 months was 28.8% and 14.8%, respectively.

The median OS was 21.0 months in the neratinib arm and 18.7 months in the lapatinib arm (HR, 0.88; 95% CI, 0.72-1.07; P = .2086). The ORR was 32.8% and 26.7%, respectively. The median response duration was 8.5 months and 5.6 months, respectively.

Fewer interventions for CNS disease were required in the neratinib arm than in the lapatinib arm (cumulative incidence, 22.8% vs. 29.2%; P = .043). 

The most frequently reported grade 3-4 adverse reactions for the neratinib combination were diarrhea, nausea, vomiting, fatigue, and decreased appetite.

Grade 3 diarrhea occurred in 24.4% of those in the neratinib arm and 12.5% of those in the lapatinib arm. Antidiarrheal medication was used by 98.3% of patients receiving neratinib and 62.1% of patients receiving lapatinib.
 

Margetuximab-cmkb

Margetuximab is a chimeric Fc-engineered anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab and exerts similar antiproliferative effects.

Compared with trastuzumab, margetuximab has higher affinity for both 158V (high-binding) and 158F (low-binding) alleles of the activating Fc receptor, CD16A. As a result, margetuximab enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, more effectively than trastuzumab. Margetuximab also potentiates adaptive immunity, including enhanced clonality of the T-cell repertoire and induction of HER2-specific T- and B-cell responses.

In December 2020, margetuximab, in combination with chemotherapy, was approved by the FDA for patients with HER2+ MBC after two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. The approved dose is 15 mg/kg IV every 3 weeks.

The study that led to margetuximab’s approval was the phase 3 SOPHIA trial.
 

SOPHIA trial

SOPHIA was a randomized trial of 536 patients with HER2+ MBC who had received prior treatment with other anti-HER2 therapies, including one to three lines of therapy for MBC.

Patients were randomly assigned 1:1 to receive margetuximab plus chemotherapy or trastuzumab plus chemotherapy. Assignment was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine), the number of previous lines of therapy for MBC, and disease extent.

Co–primary outcome measures were PFS by blinded, independent, central review and OS.

At the second interim analysis, the median PFS was 5.8 months in the margetuximab arm and 4.9 months in the trastuzumab arm (HR, 0.76; 95% CI, 0.59-0.98; P = .033). Results were more impressive in patients with CD16A genotypes containing a 158F allele. In this group, the median PFS was 6.9 months with margetuximab and 5.1 months with trastuzumab (HR, 0.68, 95% CI, 0.52-0.90; P = .005).

At the second interim analysis, the median OS was 21.6 months in the margetuximab arm and 19.8 months in the trastuzumab arm (HR, 0.89; 95% CI, 0.69-1.13; P = .33).

Subgroup data showed no differences in OS between the two arms for any subgroup except HER2+ MBC patients with an IHC score of 2 or higher. This is consistent with the postulated mechanism of action of margetuximab.

The confirmed ORR was 25% in the margetuximab arm and 14% in the trastuzumab arm, with similar durations of response between the study arms.

The most common adverse events in both arms (≥20%), regardless of causality, were fatigue, nausea, diarrhea, and neutropenia. Vomiting was common in the margetuximab arm, and anemia was common in the trastuzumab arm.

Grade 3 or higher adverse events occurred in 53.8% of patients receiving margetuximab and 52.6% of those receiving trastuzumab.

In view of margetuximab’s modest benefits in the SOPHIA trial, the ultimate role for margetuximab in HER2+ MBC may be restricted to patients with the CD16A-158F allele. A neoadjuvant trial is planned in that population.
 

Take-home messages

There are legitimate arguments regarding whether curing MBC is within reach for certain patient subsets, but there is no argument about whether the outlook for patients with HER2+ MBC has improved dramatically in recent years; it has.

The approval of four unique, new agents for the treatment of women with HER2+ MBC in relapse provides further improvements in outcome for these patients and distinctly different opportunities for tailoring treatment to the special circumstances of each patient (e.g., whether brain metastases are present, desire for oral therapy, comorbidities, experience with prior chemotherapy, etc).

When considered along with the potential for incorporating these drugs in earlier settings in well-designed clinical trials, these new drugs offer great promise to a group of patients who faced a dismal outcome just 2 decades ago.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Before 2001, HER2/neu-positive breast cancer (HER2+) was one of the most dreaded diagnoses a woman could face, as treatment was largely ineffective. The discovery of trastuzumab changed that dramatically.

Over the next 20 years, two additional HER2-targeted therapies – lapatinib and trastuzumab emtansine (TDM-1) – earned approval from the Food and Drug Administration for selected patients with early and late HER2+ breast cancer.

Since 2019, four additional HER2-targeted therapies have been approved by the FDA for HER2+ metastatic breast cancer (MBC), changing the treatment paradigm for those patients substantially.

The new agents are especially useful in certain patient populations. The agents offer the promise of improved survival for patients with recurrent metastatic disease and the potential for further reductions in relapse rates in earlier settings.
 

Trastuzumab deruxtecan

Trastuzumab deruxtecan is an antibody-drug conjugate that links three components: an anti-HER2 monoclonal antibody, a highly potent topoisomerase I inhibitor payload, and a tetrapeptide-based cleavable linker.

Trastuzumab deruxtecan has a high drug-to-antibody ratio. A membrane-permeable payload offers the potential for activity against adjacent HER2-negative cells in heterogeneous tumors. It has a long half-life (6 days).

Trastuzumab deruxtecan received accelerated approval from the FDA in December 2019 to treat patients with HER2+ MBC who have received two or more prior HER2-targeted regimens, based on the results of the DESTINY-Breast 01 trial.
 

DESTINY-Breast 01 trial

In the phase 2 DESTINY-Breast 01 trial, 184 patients with a median of six previous treatments received trastuzumab deruxtecan (5.4 mg/kg) intravenously every 21 days. There were 24 patients with treated, asymptomatic brain metastases who participated. Patients with untreated or symptomatic brain metastases were excluded.

Overall, a response to therapy was reported in 112 patients (60.9%), with 6.0% complete and 54.9% partial responses. Most of the patients for whom both baseline and postbaseline data were available had a reduction in tumor size.

The median time until response was 1.6 months, an interval that corresponded to the time until the first scheduled imaging. Three patients (1.6%) had progressive disease, and two patients (1.1%) could not be evaluated.

The median duration of follow-up was 11.1 months, and the median response duration was 14.8 months.

The median progression-free survival (PFS) was 16.4 months, and the median overall survival (OS) was not reached. The median PFS in the patients with brain involvement was 18.1 months.

The most common adverse events of grade 3 or higher were a decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%). Most concerning was that trastuzumab deruxtecan was associated with interstitial lung disease in 13.6% of patients.
 

Tucatinib

Tucatinib is an oral, highly selective HER2 tyrosine kinase inhibitor (TKI). In April 2020, it was approved by the FDA, in combination with trastuzumab and capecitabine, for adult patients with advanced unresectable or metastatic HER2+ breast cancer who have received one or more prior anti-HER2–based regimens for MBC. The approval included patients with brain metastases.

The recommended tucatinib dose is 300 mg orally twice a day in combination with trastuzumab (at the standard dose) and capecitabine (1,000 mg/m² given orally twice daily on days 1-14) on a 21-day cycle, until disease progression or unacceptable toxicity.
 

HER2CLIMB trial

The study that led to the approval of tucatinib was the HER2CLIMB trial. The trial enrolled 612 HER2+ MBC patients who had prior treatment with trastuzumab, pertuzumab, and T-DM1. Patients had received a median of 4 (range, 2-17) prior lines of HER2-targeted therapy.

The patients were randomized 2:1 to receive trastuzumab plus capecitabine and either tucatinib or an identical placebo twice daily.

The primary endpoint was PFS, evaluated in the initial 480 randomized patients. The median PFS was 7.8 months in the tucatinib arm and 5.6 months in the control arm (hazard ratio, 0.54; 95% confidence interval, 0.42-0.71; P < .001).

The confirmed overall response rate for patients with measurable disease was 40.6% in the tucatinib arm and 22.8% in the control arm (P = .001). The proportion of patients still in response at 12 months was 33.1% and 12.3%, respectively.

The median OS was 21.9 months in the tucatinib arm and 17.4 months in the placebo arm (HR, 0.66; 95% CI, 0.50-0.88; P = .005). At 24 months, 44.9% and 26.6% of patients, respectively, were still alive.

The most common grade 3 or higher adverse events (in the tucatinib and placebo arms, respectively) were palmar-plantar erythrodysesthesia syndrome (13.1% vs. 9.1%), diarrhea (12.9% vs. 8.6%), elevations in ALT and AST (approximately 5% vs. 0.5% for each), and fatigue (4.7% vs. 4.1%).
 

Tucatinib in patients with brain involvement

A unique feature of the HER2CLIMB study was that patients with MBC and untreated, symptomatic brain metastases were eligible. Patients with active, untreated central nervous system disease are excluded from virtually all other trials, especially drug-approval trials.

There were 291 patients with brain metastases in HER2CLIMB, 198 (48%) in the tucatinib arm and 93 (46%) in the control arm.

The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (HR, 0.32; 95% CI, 0.22 to 0.48; P  < .0001).

The 1-year CNS-PFS rate was 40.2% in the tucatinib arm and 0% in the placebo arm. The median duration of CNS-PFS was 9.9 months and 4.2 months, respectively.

The risk of death was reduced by 42% in the tucatinib arm (HR, 0.58; 95% CI, 0.40-0.85; P = .005). The median OS was 18.1 months and 12.0 months, respectively.

There were more objective responses in the brain with tucatinib (47.3%) than with placebo (20.0%; P = .03). The median duration of response was 6.8 months and 3.0 months, respectively.

Particularly because of its CNS activity and lack of serious, long-term toxicity, tucatinib combination therapy represents an attractive new option for patients with HER2+ MBC.
 

Neratinib

Neratinib is an irreversible pan-HER TKI that was approved by the FDA in July 2017 for extended adjuvant therapy in patients with early-stage HER2+ breast cancer, following the use of trastuzumab-based therapy.

Long-term results of the ExteNet study led to the approval for use as extended adjuvant therapy.

In February 2020, neratinib was FDA approved in combination with capecitabine for patients with HER2+ MBC after two or more prior anti-HER2–based regimens. The more recent FDA approval was based on results of the NALA trial.
 

NALA trial

The phase 3 NALA trial included 621 patients with HER2+ MBC who had received at least two prior anti-HER2 based regimens.

Patients were randomized 1:1 to receive neratinib at 240 mg orally once daily on days 1-21 with capecitabine at 750 mg/m² orally twice daily on days 1-14 or lapatinib at 1,250 mg orally once daily on days 1-21 with capecitabine at 1,000 mg/m² orally twice daily on days 1-14 for each 21-day cycle. Patients were treated until disease progression or unacceptable toxicity.

The primary endpoints were PFS and OS by blinded, independent, central review.

The median PFS was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (HR, 0.76; 95% CI, 0.63-0.93; P = .0059). The PFS rate at 12 months was 28.8% and 14.8%, respectively.

The median OS was 21.0 months in the neratinib arm and 18.7 months in the lapatinib arm (HR, 0.88; 95% CI, 0.72-1.07; P = .2086). The ORR was 32.8% and 26.7%, respectively. The median response duration was 8.5 months and 5.6 months, respectively.

Fewer interventions for CNS disease were required in the neratinib arm than in the lapatinib arm (cumulative incidence, 22.8% vs. 29.2%; P = .043). 

The most frequently reported grade 3-4 adverse reactions for the neratinib combination were diarrhea, nausea, vomiting, fatigue, and decreased appetite.

Grade 3 diarrhea occurred in 24.4% of those in the neratinib arm and 12.5% of those in the lapatinib arm. Antidiarrheal medication was used by 98.3% of patients receiving neratinib and 62.1% of patients receiving lapatinib.
 

Margetuximab-cmkb

Margetuximab is a chimeric Fc-engineered anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab and exerts similar antiproliferative effects.

Compared with trastuzumab, margetuximab has higher affinity for both 158V (high-binding) and 158F (low-binding) alleles of the activating Fc receptor, CD16A. As a result, margetuximab enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, more effectively than trastuzumab. Margetuximab also potentiates adaptive immunity, including enhanced clonality of the T-cell repertoire and induction of HER2-specific T- and B-cell responses.

In December 2020, margetuximab, in combination with chemotherapy, was approved by the FDA for patients with HER2+ MBC after two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. The approved dose is 15 mg/kg IV every 3 weeks.

The study that led to margetuximab’s approval was the phase 3 SOPHIA trial.
 

SOPHIA trial

SOPHIA was a randomized trial of 536 patients with HER2+ MBC who had received prior treatment with other anti-HER2 therapies, including one to three lines of therapy for MBC.

Patients were randomly assigned 1:1 to receive margetuximab plus chemotherapy or trastuzumab plus chemotherapy. Assignment was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine), the number of previous lines of therapy for MBC, and disease extent.

Co–primary outcome measures were PFS by blinded, independent, central review and OS.

At the second interim analysis, the median PFS was 5.8 months in the margetuximab arm and 4.9 months in the trastuzumab arm (HR, 0.76; 95% CI, 0.59-0.98; P = .033). Results were more impressive in patients with CD16A genotypes containing a 158F allele. In this group, the median PFS was 6.9 months with margetuximab and 5.1 months with trastuzumab (HR, 0.68, 95% CI, 0.52-0.90; P = .005).

At the second interim analysis, the median OS was 21.6 months in the margetuximab arm and 19.8 months in the trastuzumab arm (HR, 0.89; 95% CI, 0.69-1.13; P = .33).

Subgroup data showed no differences in OS between the two arms for any subgroup except HER2+ MBC patients with an IHC score of 2 or higher. This is consistent with the postulated mechanism of action of margetuximab.

The confirmed ORR was 25% in the margetuximab arm and 14% in the trastuzumab arm, with similar durations of response between the study arms.

The most common adverse events in both arms (≥20%), regardless of causality, were fatigue, nausea, diarrhea, and neutropenia. Vomiting was common in the margetuximab arm, and anemia was common in the trastuzumab arm.

Grade 3 or higher adverse events occurred in 53.8% of patients receiving margetuximab and 52.6% of those receiving trastuzumab.

In view of margetuximab’s modest benefits in the SOPHIA trial, the ultimate role for margetuximab in HER2+ MBC may be restricted to patients with the CD16A-158F allele. A neoadjuvant trial is planned in that population.
 

Take-home messages

There are legitimate arguments regarding whether curing MBC is within reach for certain patient subsets, but there is no argument about whether the outlook for patients with HER2+ MBC has improved dramatically in recent years; it has.

The approval of four unique, new agents for the treatment of women with HER2+ MBC in relapse provides further improvements in outcome for these patients and distinctly different opportunities for tailoring treatment to the special circumstances of each patient (e.g., whether brain metastases are present, desire for oral therapy, comorbidities, experience with prior chemotherapy, etc).

When considered along with the potential for incorporating these drugs in earlier settings in well-designed clinical trials, these new drugs offer great promise to a group of patients who faced a dismal outcome just 2 decades ago.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Before 2001, HER2/neu-positive breast cancer (HER2+) was one of the most dreaded diagnoses a woman could face, as treatment was largely ineffective. The discovery of trastuzumab changed that dramatically.

Over the next 20 years, two additional HER2-targeted therapies – lapatinib and trastuzumab emtansine (TDM-1) – earned approval from the Food and Drug Administration for selected patients with early and late HER2+ breast cancer.

Since 2019, four additional HER2-targeted therapies have been approved by the FDA for HER2+ metastatic breast cancer (MBC), changing the treatment paradigm for those patients substantially.

The new agents are especially useful in certain patient populations. The agents offer the promise of improved survival for patients with recurrent metastatic disease and the potential for further reductions in relapse rates in earlier settings.
 

Trastuzumab deruxtecan

Trastuzumab deruxtecan is an antibody-drug conjugate that links three components: an anti-HER2 monoclonal antibody, a highly potent topoisomerase I inhibitor payload, and a tetrapeptide-based cleavable linker.

Trastuzumab deruxtecan has a high drug-to-antibody ratio. A membrane-permeable payload offers the potential for activity against adjacent HER2-negative cells in heterogeneous tumors. It has a long half-life (6 days).

Trastuzumab deruxtecan received accelerated approval from the FDA in December 2019 to treat patients with HER2+ MBC who have received two or more prior HER2-targeted regimens, based on the results of the DESTINY-Breast 01 trial.
 

DESTINY-Breast 01 trial

In the phase 2 DESTINY-Breast 01 trial, 184 patients with a median of six previous treatments received trastuzumab deruxtecan (5.4 mg/kg) intravenously every 21 days. There were 24 patients with treated, asymptomatic brain metastases who participated. Patients with untreated or symptomatic brain metastases were excluded.

Overall, a response to therapy was reported in 112 patients (60.9%), with 6.0% complete and 54.9% partial responses. Most of the patients for whom both baseline and postbaseline data were available had a reduction in tumor size.

The median time until response was 1.6 months, an interval that corresponded to the time until the first scheduled imaging. Three patients (1.6%) had progressive disease, and two patients (1.1%) could not be evaluated.

The median duration of follow-up was 11.1 months, and the median response duration was 14.8 months.

The median progression-free survival (PFS) was 16.4 months, and the median overall survival (OS) was not reached. The median PFS in the patients with brain involvement was 18.1 months.

The most common adverse events of grade 3 or higher were a decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%). Most concerning was that trastuzumab deruxtecan was associated with interstitial lung disease in 13.6% of patients.
 

Tucatinib

Tucatinib is an oral, highly selective HER2 tyrosine kinase inhibitor (TKI). In April 2020, it was approved by the FDA, in combination with trastuzumab and capecitabine, for adult patients with advanced unresectable or metastatic HER2+ breast cancer who have received one or more prior anti-HER2–based regimens for MBC. The approval included patients with brain metastases.

The recommended tucatinib dose is 300 mg orally twice a day in combination with trastuzumab (at the standard dose) and capecitabine (1,000 mg/m² given orally twice daily on days 1-14) on a 21-day cycle, until disease progression or unacceptable toxicity.
 

HER2CLIMB trial

The study that led to the approval of tucatinib was the HER2CLIMB trial. The trial enrolled 612 HER2+ MBC patients who had prior treatment with trastuzumab, pertuzumab, and T-DM1. Patients had received a median of 4 (range, 2-17) prior lines of HER2-targeted therapy.

The patients were randomized 2:1 to receive trastuzumab plus capecitabine and either tucatinib or an identical placebo twice daily.

The primary endpoint was PFS, evaluated in the initial 480 randomized patients. The median PFS was 7.8 months in the tucatinib arm and 5.6 months in the control arm (hazard ratio, 0.54; 95% confidence interval, 0.42-0.71; P < .001).

The confirmed overall response rate for patients with measurable disease was 40.6% in the tucatinib arm and 22.8% in the control arm (P = .001). The proportion of patients still in response at 12 months was 33.1% and 12.3%, respectively.

The median OS was 21.9 months in the tucatinib arm and 17.4 months in the placebo arm (HR, 0.66; 95% CI, 0.50-0.88; P = .005). At 24 months, 44.9% and 26.6% of patients, respectively, were still alive.

The most common grade 3 or higher adverse events (in the tucatinib and placebo arms, respectively) were palmar-plantar erythrodysesthesia syndrome (13.1% vs. 9.1%), diarrhea (12.9% vs. 8.6%), elevations in ALT and AST (approximately 5% vs. 0.5% for each), and fatigue (4.7% vs. 4.1%).
 

Tucatinib in patients with brain involvement

A unique feature of the HER2CLIMB study was that patients with MBC and untreated, symptomatic brain metastases were eligible. Patients with active, untreated central nervous system disease are excluded from virtually all other trials, especially drug-approval trials.

There were 291 patients with brain metastases in HER2CLIMB, 198 (48%) in the tucatinib arm and 93 (46%) in the control arm.

The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (HR, 0.32; 95% CI, 0.22 to 0.48; P  < .0001).

The 1-year CNS-PFS rate was 40.2% in the tucatinib arm and 0% in the placebo arm. The median duration of CNS-PFS was 9.9 months and 4.2 months, respectively.

The risk of death was reduced by 42% in the tucatinib arm (HR, 0.58; 95% CI, 0.40-0.85; P = .005). The median OS was 18.1 months and 12.0 months, respectively.

There were more objective responses in the brain with tucatinib (47.3%) than with placebo (20.0%; P = .03). The median duration of response was 6.8 months and 3.0 months, respectively.

Particularly because of its CNS activity and lack of serious, long-term toxicity, tucatinib combination therapy represents an attractive new option for patients with HER2+ MBC.
 

Neratinib

Neratinib is an irreversible pan-HER TKI that was approved by the FDA in July 2017 for extended adjuvant therapy in patients with early-stage HER2+ breast cancer, following the use of trastuzumab-based therapy.

Long-term results of the ExteNet study led to the approval for use as extended adjuvant therapy.

In February 2020, neratinib was FDA approved in combination with capecitabine for patients with HER2+ MBC after two or more prior anti-HER2–based regimens. The more recent FDA approval was based on results of the NALA trial.
 

NALA trial

The phase 3 NALA trial included 621 patients with HER2+ MBC who had received at least two prior anti-HER2 based regimens.

Patients were randomized 1:1 to receive neratinib at 240 mg orally once daily on days 1-21 with capecitabine at 750 mg/m² orally twice daily on days 1-14 or lapatinib at 1,250 mg orally once daily on days 1-21 with capecitabine at 1,000 mg/m² orally twice daily on days 1-14 for each 21-day cycle. Patients were treated until disease progression or unacceptable toxicity.

The primary endpoints were PFS and OS by blinded, independent, central review.

The median PFS was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (HR, 0.76; 95% CI, 0.63-0.93; P = .0059). The PFS rate at 12 months was 28.8% and 14.8%, respectively.

The median OS was 21.0 months in the neratinib arm and 18.7 months in the lapatinib arm (HR, 0.88; 95% CI, 0.72-1.07; P = .2086). The ORR was 32.8% and 26.7%, respectively. The median response duration was 8.5 months and 5.6 months, respectively.

Fewer interventions for CNS disease were required in the neratinib arm than in the lapatinib arm (cumulative incidence, 22.8% vs. 29.2%; P = .043). 

The most frequently reported grade 3-4 adverse reactions for the neratinib combination were diarrhea, nausea, vomiting, fatigue, and decreased appetite.

Grade 3 diarrhea occurred in 24.4% of those in the neratinib arm and 12.5% of those in the lapatinib arm. Antidiarrheal medication was used by 98.3% of patients receiving neratinib and 62.1% of patients receiving lapatinib.
 

Margetuximab-cmkb

Margetuximab is a chimeric Fc-engineered anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab and exerts similar antiproliferative effects.

Compared with trastuzumab, margetuximab has higher affinity for both 158V (high-binding) and 158F (low-binding) alleles of the activating Fc receptor, CD16A. As a result, margetuximab enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, more effectively than trastuzumab. Margetuximab also potentiates adaptive immunity, including enhanced clonality of the T-cell repertoire and induction of HER2-specific T- and B-cell responses.

In December 2020, margetuximab, in combination with chemotherapy, was approved by the FDA for patients with HER2+ MBC after two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. The approved dose is 15 mg/kg IV every 3 weeks.

The study that led to margetuximab’s approval was the phase 3 SOPHIA trial.
 

SOPHIA trial

SOPHIA was a randomized trial of 536 patients with HER2+ MBC who had received prior treatment with other anti-HER2 therapies, including one to three lines of therapy for MBC.

Patients were randomly assigned 1:1 to receive margetuximab plus chemotherapy or trastuzumab plus chemotherapy. Assignment was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine), the number of previous lines of therapy for MBC, and disease extent.

Co–primary outcome measures were PFS by blinded, independent, central review and OS.

At the second interim analysis, the median PFS was 5.8 months in the margetuximab arm and 4.9 months in the trastuzumab arm (HR, 0.76; 95% CI, 0.59-0.98; P = .033). Results were more impressive in patients with CD16A genotypes containing a 158F allele. In this group, the median PFS was 6.9 months with margetuximab and 5.1 months with trastuzumab (HR, 0.68, 95% CI, 0.52-0.90; P = .005).

At the second interim analysis, the median OS was 21.6 months in the margetuximab arm and 19.8 months in the trastuzumab arm (HR, 0.89; 95% CI, 0.69-1.13; P = .33).

Subgroup data showed no differences in OS between the two arms for any subgroup except HER2+ MBC patients with an IHC score of 2 or higher. This is consistent with the postulated mechanism of action of margetuximab.

The confirmed ORR was 25% in the margetuximab arm and 14% in the trastuzumab arm, with similar durations of response between the study arms.

The most common adverse events in both arms (≥20%), regardless of causality, were fatigue, nausea, diarrhea, and neutropenia. Vomiting was common in the margetuximab arm, and anemia was common in the trastuzumab arm.

Grade 3 or higher adverse events occurred in 53.8% of patients receiving margetuximab and 52.6% of those receiving trastuzumab.

In view of margetuximab’s modest benefits in the SOPHIA trial, the ultimate role for margetuximab in HER2+ MBC may be restricted to patients with the CD16A-158F allele. A neoadjuvant trial is planned in that population.
 

Take-home messages

There are legitimate arguments regarding whether curing MBC is within reach for certain patient subsets, but there is no argument about whether the outlook for patients with HER2+ MBC has improved dramatically in recent years; it has.

The approval of four unique, new agents for the treatment of women with HER2+ MBC in relapse provides further improvements in outcome for these patients and distinctly different opportunities for tailoring treatment to the special circumstances of each patient (e.g., whether brain metastases are present, desire for oral therapy, comorbidities, experience with prior chemotherapy, etc).

When considered along with the potential for incorporating these drugs in earlier settings in well-designed clinical trials, these new drugs offer great promise to a group of patients who faced a dismal outcome just 2 decades ago.

Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.

Federal Practitioner Supplement: Advances in Hematology and Oncology

• Impact of an Oral Antineoplastic Renewal Clinic
• Implementing Comprehensive Geriatric Assessments for Oncology Patients
• Radiation Toxicity and Survival in Patients with Presumed Early-Stage NCSLC
• Screening High-Risk Women Veterans for Breast Cancer
• Standardizing the Discharge Process for Inpatient Hem/Onc
• Massive Retroperitoneal Liposarcoma Masquerading as Meralgia Paresthetica
• Delayed Coronary Vasospasm in Metastatic Gastric Cancer

THIS ISSUE WAS PRODUCED IN COLLABORATION WITH AVAHO

Federal Practitioner Supplement: Advances in Hematology and Oncology

• Impact of an Oral Antineoplastic Renewal Clinic
• Implementing Comprehensive Geriatric Assessments for Oncology Patients
• Radiation Toxicity and Survival in Patients with Presumed Early-Stage NCSLC
• Screening High-Risk Women Veterans for Breast Cancer
• Standardizing the Discharge Process for Inpatient Hem/Onc
• Massive Retroperitoneal Liposarcoma Masquerading as Meralgia Paresthetica
• Delayed Coronary Vasospasm in Metastatic Gastric Cancer

THIS ISSUE WAS PRODUCED IN COLLABORATION WITH AVAHO

Federal Practitioner Supplement: Advances in Hematology and Oncology

• Impact of an Oral Antineoplastic Renewal Clinic
• Implementing Comprehensive Geriatric Assessments for Oncology Patients
• Radiation Toxicity and Survival in Patients with Presumed Early-Stage NCSLC
• Screening High-Risk Women Veterans for Breast Cancer
• Standardizing the Discharge Process for Inpatient Hem/Onc
• Massive Retroperitoneal Liposarcoma Masquerading as Meralgia Paresthetica
• Delayed Coronary Vasospasm in Metastatic Gastric Cancer

THIS ISSUE WAS PRODUCED IN COLLABORATION WITH AVAHO

As bleeding disorders are increasingly recognized as a national health priority, hematologists are focusing on how the patient-centered medical home – a widely accepted concept in primary care and in some specialties – can improve outcomes and quality life for their patients.

Courtesy of Dr. Shapiro

The patient-centered medical home is a model of health care delivery in which patients receive comprehensive, accessible care that is fully integrated across all providers and elements of a healthcare system.¹ The concept emerged in the 1960s among pediatricians seeking to better coordinate care for children with complex medical needs. Since then, the patient-centered medical home has become a globally recognized standard – not only in primary care, but also in specialties such as endocrinology, oncology, and geriatric medicine. The movement to establish medical homes for patients with bleeding disorders is more recent and is receiving national attention.

Why a medical home?

The advent of prophylactic therapies for bleeding disorders has vastly improved the outlook for many patients compared to just a few decades ago. However, treatment options remain limited, and patients who have severe disease or complications – such as an inadequate treatment response or the development of inhibitory antibodies to replacement clotting factors – are at risk for recurrent breakthrough bleeding that can lead to synovitis and ultimately culminate in progressive, irreversible joint damage. The resulting pain and limitation of motion greatly compromises patients’ quality of life across physical, psychological, and social domains, undermines their ability to live and work independently, and greatly increases treatment costs.^2-4 Family members, too, face high stress and lower quality of life when they struggle to obtain and manage treatment while caring for loved ones with bleeding disorders.⁵

For patients with bleeding disorders, a patient-centered medical home can help address or surmount these challenges, said Amy Shapiro, MD, medical director of the Indiana Hemophilia and Thrombosis Center in Indianapolis, Ind., which was the first hemophilia treatment center in the country to be formally certified as a medical home.

Dr. Shapiro explained that a patient-centered medical home leverages the care of an integrated multidisciplinary team to help optimize therapies and patient outcomes across all domains of life. She sees the medical home concept as a natural fit for patients with bleeding disorders, given the complexity of their needs and the number of specialties involved. “When you have hemophilia, you don’t just need a hematologist to manage your care. You need nurses, physical therapists, and social workers. You need coordinated care for genetic counseling. You also need to coordinate dental hygiene and surgical interventions, if these are required. Patients need nutrition counseling, and they may need assistance with education or career options if too many days are missed from work or school. Patients or their families may need counseling on choosing the right insurance program so they don’t choose a plan that may create more hardships for them because of their chronic disorder.”

Meeting these needs requires the help of an integrated care team, which many individuals with bleeding disorders lack. “If you are just out there in the community and you have medical issues that need to be dealt with, often the individuals themselves have to coordinate their own care, including their medications and their appointments with different specialists,” said Dr. Shapiro. “For example, a care provider may tell a patient that they need a physical therapist and give them some names, and then the patient has to take it from there and not only find the provider, but also determine if their insurance provides coverage.”

A medical home takes a completely different approach, she explained. “At my center, when we say you need a physical therapist, we have a physical therapist on staff. Our therapist provides an assessment and determines the need for ongoing PT and whether that can be done at home with a plan and intermittent oversight, or whether the patient needs a referral, and whether the person the patient is referred to needs education on how to provide PT for someone with hemophilia. A medical home provides all this in one place. It is a place where patients know they will receive either direct services, or support to shepherd their care and outcomes, and oversight of that support as well.”

Few studies have directly assessed the medical home model in the setting of bleeding disorders, but a number have evaluated the impact of integrated care, a more general term for the practice of coordinating multidisciplinary care to improve access and outcomes while eliminating redundancies and unnecessary costs. In a recent systematic review and meta-analysis of 27 nonrandomized studies of patients with hemophilia, integrated care was linked to lower mortality, fewer emergency room visits and hospitalizations, shorter lengths of stay in the hospital, and fewer missed days of school and work.⁶ Such findings, combined with promising outcomes data from studies of patient-centered medical homes in other disease settings, suggest that the patient-centered medical home can significantly benefit patients with bleeding disorders and their families and caregivers.
 

Creating a medical home

Establishing a patient-centered medical home can be challenging, involving a plethora of stakeholders and a considerable investment of time, energy, and resources. Organizations such as the National Committee for Quality Assurance and the Accreditation Association for Ambulatory Health Care have formal certification programs to help ensure that an inpatient or outpatient center that calls itself a medical home truly is one.^7-8

The certification process requires centers to document activities in areas such as patients’ rights and responsibilities, administration and governance, patient and care team relationships, clinical records and other health information, and quality, comprehensiveness, continuity, and accessibility.⁷ Achieving certification is rigorous, often requiring centers to document compliance with more than 100 policies, procedures, and standards.

For the Indiana Hemophilia and Thrombosis Center, becoming certified as a medical home “was a multiyear process and an ongoing process,” said Dr. Shapiro. “It involves documentation of quality improvement initiatives, obtaining input from patients to document their satisfaction, and looking at all types of systems within our center and how we integrate care so that all those systems function together. It’s a difficult process, but treatment centers are a medical home for patients with bleeding disorders, and this is an effort to provide some documentation on a national level of how we’re doing everything that we are doing.”

She noted that the process of obtaining medical home certification may require an even higher level of commitment if a bleeding disorder (hemophilia) treatment center is embedded in a university or academic medical center. In this case, more stakeholders are involved, and more hoops may need to be jumped through to implement processes that meet medical home standards while still adhering to any requirements at the organizational level.

Certification programs for patient-centered medical homes are not designed around specific disorders or diseases, but a closer look at their compliance metrics underscores how medical homes can benefit patients with bleeding disorders. For example, to receive medical home certification from the Accreditation Association for Ambulatory Health Care, a center needs to be able to document that patients’ care is not transferred without first making arrangements with a receiving health care provider, that the quality improvement programs are peer-led, and that these programs assess and address diverse measures of clinical performance, cost-effectiveness, and administrative functioning.^7-9

Medical homes, the NHPCC, and Healthy People 2030

Creating patient-centered medical homes for patients with bleeding disorders is now a quality improvement objective of the National Hemophilia Program Coordinating Center, or NHPCC. Established in 2012 and funded by the federal Health Resources and Services Administration, the NHPCC partners with the eight regional hemophilia networks and more than 140 federally funded hemophilia treatment centers across the United States to identify gaps, standardize and improve access to care, and share and promote best practices for the treatment and management of blood disorders.¹⁰

In the United States, receiving care in a hemophilia treatment center (which, despite its name, typically offers care for other disorders such as von Willebrand disease) has been linked to lower mortality and fewer hospitalizations related to bleeding complications.¹¹ To continue to improve on these outcomes, the NHPCC, regional networks, and hemophilia treatment centers are prioritizing medical homes and ranking their establishments alongside core objectives such as bettering patient and family engagement and improving the transition from pediatric to adult care.¹²

As part of this quality improvement work, the NHPCC, regional leadership, and hemophilia treatment centers meet regularly to identify needs and priorities, plan programs, and ensure that each center is meeting the goals and objectives set out by its federal grant.¹³ Such partnerships help improve and integrate care within a coordinated national framework, Dr. Shapiro said. “We all are charged with this same mission,” she added. “That doesn’t mean that every treatment center looks exactly the same, has the same number of staff, or does everything the same way, but we all have the same mission, and we know what that is. That is the work of the NHPCC, to determine and document that and help level and improve care throughout the country.”

The NHPCC also engages other stakeholders, including consumer agencies and professional organizations. Recent achievements have included a first-ever national patient needs assessment, a tandem technical needs assessment of hemophilia treatment centers, an educational outreach program for genetic counselors, a webinar on transitioning care for adolescents, a national survey of the federal 340B Drug Pricing Program, and a survey of minority patients to identify and characterize problems such as language and insurance barriers, the lack of culturally appropriate educational materials on blood disorders, and difficulties getting transportation to treatment centers or educational programs.¹⁴

In part because of this advocacy work, the U.S. Department of Health and Human Services recently included hemophilia for the first time in Healthy People, its evidence-based set of decade-long objectives aimed at improving the health of all Americans. In Healthy People 2030, the specific objective for hemophilia is to reduce the proportion of patients with severe disease who experience more than four joint bleeds per year to 13.3% (the current estimate is 16.9%).¹⁵

For Healthy People to prioritize hemophilia for the first time alongside much more common conditions such as diabetes and heart disease reflects the challenges of managing bleeding disorders and the efforts by the NHPCC and other stakeholders to raise awareness about current needs. To track progress in meeting the Healthy People 2030 objective, the NHPCC will work with federal partners to analyze patient-level data gathered through the Centers for Disease Control’s Community Counts Registry for Bleeding Disorders Surveillance program, which collects data from hemophilia treatment centers across the United States and includes patients with all levels of disease severity.

“The inclusion of bleeding disorders in Healthy People 2030 is really very significant,” said Dr. Shapiro. “These are disorders that affect less than 200,000 Americans, which is the definition of a rare disease in this context. To have hemophilia considered as a national priority is very important, not only for hemophilia, but also for other rare diseases that may in the future also be considered as being as of national importance in this way.”
 

References

1. Rodriguez-Saldana J. 2019. The Patient-Centered Medical Home, Primary Care, and Diabetes. In: Rodriguez-Saldana J. (eds) The Diabetes Textbook. Springer, Cham.

2. J Comorb. 2011;1:51-59.

3. Eur J Haematol. 2018 Apr;100 Suppl 1:5-13.

4. Blood. 2003;102(7):2358-63.

5. Haemophilia. 2014 Jul;20(4):541-9.

6. Haemophilia. 2016;22(Suppl 3):31-40.

7. AAAHC. Medical Home.

8. NCQA. Patient-centered medical home (PCMH).

9. AAAHC, 2013. Medical Home On-Site Certification Handbook.

10. Centers for Disease Control and Prevention. HTC Population Profile.

11. Blood Transfus. 2014;12 Suppl 3(Suppl 3):e542-e548.

12. American Thrombosis and Hemostasis Network.

13. The Great Lakes Regional Hemophilia Network.

14. American Thrombosis and Hemostasis Network. What the NHPCC does.

15. U.S. Department of Health and Human Services. Healthy People 2030: Blood Disorders.

As bleeding disorders are increasingly recognized as a national health priority, hematologists are focusing on how the patient-centered medical home – a widely accepted concept in primary care and in some specialties – can improve outcomes and quality life for their patients.

Courtesy of Dr. Shapiro

The patient-centered medical home is a model of health care delivery in which patients receive comprehensive, accessible care that is fully integrated across all providers and elements of a healthcare system.¹ The concept emerged in the 1960s among pediatricians seeking to better coordinate care for children with complex medical needs. Since then, the patient-centered medical home has become a globally recognized standard – not only in primary care, but also in specialties such as endocrinology, oncology, and geriatric medicine. The movement to establish medical homes for patients with bleeding disorders is more recent and is receiving national attention.

Why a medical home?

The advent of prophylactic therapies for bleeding disorders has vastly improved the outlook for many patients compared to just a few decades ago. However, treatment options remain limited, and patients who have severe disease or complications – such as an inadequate treatment response or the development of inhibitory antibodies to replacement clotting factors – are at risk for recurrent breakthrough bleeding that can lead to synovitis and ultimately culminate in progressive, irreversible joint damage. The resulting pain and limitation of motion greatly compromises patients’ quality of life across physical, psychological, and social domains, undermines their ability to live and work independently, and greatly increases treatment costs.^2-4 Family members, too, face high stress and lower quality of life when they struggle to obtain and manage treatment while caring for loved ones with bleeding disorders.⁵

For patients with bleeding disorders, a patient-centered medical home can help address or surmount these challenges, said Amy Shapiro, MD, medical director of the Indiana Hemophilia and Thrombosis Center in Indianapolis, Ind., which was the first hemophilia treatment center in the country to be formally certified as a medical home.

Dr. Shapiro explained that a patient-centered medical home leverages the care of an integrated multidisciplinary team to help optimize therapies and patient outcomes across all domains of life. She sees the medical home concept as a natural fit for patients with bleeding disorders, given the complexity of their needs and the number of specialties involved. “When you have hemophilia, you don’t just need a hematologist to manage your care. You need nurses, physical therapists, and social workers. You need coordinated care for genetic counseling. You also need to coordinate dental hygiene and surgical interventions, if these are required. Patients need nutrition counseling, and they may need assistance with education or career options if too many days are missed from work or school. Patients or their families may need counseling on choosing the right insurance program so they don’t choose a plan that may create more hardships for them because of their chronic disorder.”

Meeting these needs requires the help of an integrated care team, which many individuals with bleeding disorders lack. “If you are just out there in the community and you have medical issues that need to be dealt with, often the individuals themselves have to coordinate their own care, including their medications and their appointments with different specialists,” said Dr. Shapiro. “For example, a care provider may tell a patient that they need a physical therapist and give them some names, and then the patient has to take it from there and not only find the provider, but also determine if their insurance provides coverage.”

A medical home takes a completely different approach, she explained. “At my center, when we say you need a physical therapist, we have a physical therapist on staff. Our therapist provides an assessment and determines the need for ongoing PT and whether that can be done at home with a plan and intermittent oversight, or whether the patient needs a referral, and whether the person the patient is referred to needs education on how to provide PT for someone with hemophilia. A medical home provides all this in one place. It is a place where patients know they will receive either direct services, or support to shepherd their care and outcomes, and oversight of that support as well.”

Few studies have directly assessed the medical home model in the setting of bleeding disorders, but a number have evaluated the impact of integrated care, a more general term for the practice of coordinating multidisciplinary care to improve access and outcomes while eliminating redundancies and unnecessary costs. In a recent systematic review and meta-analysis of 27 nonrandomized studies of patients with hemophilia, integrated care was linked to lower mortality, fewer emergency room visits and hospitalizations, shorter lengths of stay in the hospital, and fewer missed days of school and work.⁶ Such findings, combined with promising outcomes data from studies of patient-centered medical homes in other disease settings, suggest that the patient-centered medical home can significantly benefit patients with bleeding disorders and their families and caregivers.
 

Creating a medical home

Establishing a patient-centered medical home can be challenging, involving a plethora of stakeholders and a considerable investment of time, energy, and resources. Organizations such as the National Committee for Quality Assurance and the Accreditation Association for Ambulatory Health Care have formal certification programs to help ensure that an inpatient or outpatient center that calls itself a medical home truly is one.^7-8

The certification process requires centers to document activities in areas such as patients’ rights and responsibilities, administration and governance, patient and care team relationships, clinical records and other health information, and quality, comprehensiveness, continuity, and accessibility.⁷ Achieving certification is rigorous, often requiring centers to document compliance with more than 100 policies, procedures, and standards.

For the Indiana Hemophilia and Thrombosis Center, becoming certified as a medical home “was a multiyear process and an ongoing process,” said Dr. Shapiro. “It involves documentation of quality improvement initiatives, obtaining input from patients to document their satisfaction, and looking at all types of systems within our center and how we integrate care so that all those systems function together. It’s a difficult process, but treatment centers are a medical home for patients with bleeding disorders, and this is an effort to provide some documentation on a national level of how we’re doing everything that we are doing.”

She noted that the process of obtaining medical home certification may require an even higher level of commitment if a bleeding disorder (hemophilia) treatment center is embedded in a university or academic medical center. In this case, more stakeholders are involved, and more hoops may need to be jumped through to implement processes that meet medical home standards while still adhering to any requirements at the organizational level.

Certification programs for patient-centered medical homes are not designed around specific disorders or diseases, but a closer look at their compliance metrics underscores how medical homes can benefit patients with bleeding disorders. For example, to receive medical home certification from the Accreditation Association for Ambulatory Health Care, a center needs to be able to document that patients’ care is not transferred without first making arrangements with a receiving health care provider, that the quality improvement programs are peer-led, and that these programs assess and address diverse measures of clinical performance, cost-effectiveness, and administrative functioning.^7-9

Medical homes, the NHPCC, and Healthy People 2030

Creating patient-centered medical homes for patients with bleeding disorders is now a quality improvement objective of the National Hemophilia Program Coordinating Center, or NHPCC. Established in 2012 and funded by the federal Health Resources and Services Administration, the NHPCC partners with the eight regional hemophilia networks and more than 140 federally funded hemophilia treatment centers across the United States to identify gaps, standardize and improve access to care, and share and promote best practices for the treatment and management of blood disorders.¹⁰

In the United States, receiving care in a hemophilia treatment center (which, despite its name, typically offers care for other disorders such as von Willebrand disease) has been linked to lower mortality and fewer hospitalizations related to bleeding complications.¹¹ To continue to improve on these outcomes, the NHPCC, regional networks, and hemophilia treatment centers are prioritizing medical homes and ranking their establishments alongside core objectives such as bettering patient and family engagement and improving the transition from pediatric to adult care.¹²

As part of this quality improvement work, the NHPCC, regional leadership, and hemophilia treatment centers meet regularly to identify needs and priorities, plan programs, and ensure that each center is meeting the goals and objectives set out by its federal grant.¹³ Such partnerships help improve and integrate care within a coordinated national framework, Dr. Shapiro said. “We all are charged with this same mission,” she added. “That doesn’t mean that every treatment center looks exactly the same, has the same number of staff, or does everything the same way, but we all have the same mission, and we know what that is. That is the work of the NHPCC, to determine and document that and help level and improve care throughout the country.”

The NHPCC also engages other stakeholders, including consumer agencies and professional organizations. Recent achievements have included a first-ever national patient needs assessment, a tandem technical needs assessment of hemophilia treatment centers, an educational outreach program for genetic counselors, a webinar on transitioning care for adolescents, a national survey of the federal 340B Drug Pricing Program, and a survey of minority patients to identify and characterize problems such as language and insurance barriers, the lack of culturally appropriate educational materials on blood disorders, and difficulties getting transportation to treatment centers or educational programs.¹⁴

In part because of this advocacy work, the U.S. Department of Health and Human Services recently included hemophilia for the first time in Healthy People, its evidence-based set of decade-long objectives aimed at improving the health of all Americans. In Healthy People 2030, the specific objective for hemophilia is to reduce the proportion of patients with severe disease who experience more than four joint bleeds per year to 13.3% (the current estimate is 16.9%).¹⁵

For Healthy People to prioritize hemophilia for the first time alongside much more common conditions such as diabetes and heart disease reflects the challenges of managing bleeding disorders and the efforts by the NHPCC and other stakeholders to raise awareness about current needs. To track progress in meeting the Healthy People 2030 objective, the NHPCC will work with federal partners to analyze patient-level data gathered through the Centers for Disease Control’s Community Counts Registry for Bleeding Disorders Surveillance program, which collects data from hemophilia treatment centers across the United States and includes patients with all levels of disease severity.

“The inclusion of bleeding disorders in Healthy People 2030 is really very significant,” said Dr. Shapiro. “These are disorders that affect less than 200,000 Americans, which is the definition of a rare disease in this context. To have hemophilia considered as a national priority is very important, not only for hemophilia, but also for other rare diseases that may in the future also be considered as being as of national importance in this way.”
 

References

1. Rodriguez-Saldana J. 2019. The Patient-Centered Medical Home, Primary Care, and Diabetes. In: Rodriguez-Saldana J. (eds) The Diabetes Textbook. Springer, Cham.

2. J Comorb. 2011;1:51-59.

3. Eur J Haematol. 2018 Apr;100 Suppl 1:5-13.

4. Blood. 2003;102(7):2358-63.

5. Haemophilia. 2014 Jul;20(4):541-9.

6. Haemophilia. 2016;22(Suppl 3):31-40.

7. AAAHC. Medical Home.

8. NCQA. Patient-centered medical home (PCMH).

9. AAAHC, 2013. Medical Home On-Site Certification Handbook.

10. Centers for Disease Control and Prevention. HTC Population Profile.

11. Blood Transfus. 2014;12 Suppl 3(Suppl 3):e542-e548.

12. American Thrombosis and Hemostasis Network.

13. The Great Lakes Regional Hemophilia Network.

14. American Thrombosis and Hemostasis Network. What the NHPCC does.

15. U.S. Department of Health and Human Services. Healthy People 2030: Blood Disorders.

As bleeding disorders are increasingly recognized as a national health priority, hematologists are focusing on how the patient-centered medical home – a widely accepted concept in primary care and in some specialties – can improve outcomes and quality life for their patients.

Courtesy of Dr. Shapiro

The patient-centered medical home is a model of health care delivery in which patients receive comprehensive, accessible care that is fully integrated across all providers and elements of a healthcare system.¹ The concept emerged in the 1960s among pediatricians seeking to better coordinate care for children with complex medical needs. Since then, the patient-centered medical home has become a globally recognized standard – not only in primary care, but also in specialties such as endocrinology, oncology, and geriatric medicine. The movement to establish medical homes for patients with bleeding disorders is more recent and is receiving national attention.

Why a medical home?

The advent of prophylactic therapies for bleeding disorders has vastly improved the outlook for many patients compared to just a few decades ago. However, treatment options remain limited, and patients who have severe disease or complications – such as an inadequate treatment response or the development of inhibitory antibodies to replacement clotting factors – are at risk for recurrent breakthrough bleeding that can lead to synovitis and ultimately culminate in progressive, irreversible joint damage. The resulting pain and limitation of motion greatly compromises patients’ quality of life across physical, psychological, and social domains, undermines their ability to live and work independently, and greatly increases treatment costs.^2-4 Family members, too, face high stress and lower quality of life when they struggle to obtain and manage treatment while caring for loved ones with bleeding disorders.⁵

For patients with bleeding disorders, a patient-centered medical home can help address or surmount these challenges, said Amy Shapiro, MD, medical director of the Indiana Hemophilia and Thrombosis Center in Indianapolis, Ind., which was the first hemophilia treatment center in the country to be formally certified as a medical home.

Dr. Shapiro explained that a patient-centered medical home leverages the care of an integrated multidisciplinary team to help optimize therapies and patient outcomes across all domains of life. She sees the medical home concept as a natural fit for patients with bleeding disorders, given the complexity of their needs and the number of specialties involved. “When you have hemophilia, you don’t just need a hematologist to manage your care. You need nurses, physical therapists, and social workers. You need coordinated care for genetic counseling. You also need to coordinate dental hygiene and surgical interventions, if these are required. Patients need nutrition counseling, and they may need assistance with education or career options if too many days are missed from work or school. Patients or their families may need counseling on choosing the right insurance program so they don’t choose a plan that may create more hardships for them because of their chronic disorder.”

Meeting these needs requires the help of an integrated care team, which many individuals with bleeding disorders lack. “If you are just out there in the community and you have medical issues that need to be dealt with, often the individuals themselves have to coordinate their own care, including their medications and their appointments with different specialists,” said Dr. Shapiro. “For example, a care provider may tell a patient that they need a physical therapist and give them some names, and then the patient has to take it from there and not only find the provider, but also determine if their insurance provides coverage.”

A medical home takes a completely different approach, she explained. “At my center, when we say you need a physical therapist, we have a physical therapist on staff. Our therapist provides an assessment and determines the need for ongoing PT and whether that can be done at home with a plan and intermittent oversight, or whether the patient needs a referral, and whether the person the patient is referred to needs education on how to provide PT for someone with hemophilia. A medical home provides all this in one place. It is a place where patients know they will receive either direct services, or support to shepherd their care and outcomes, and oversight of that support as well.”

Few studies have directly assessed the medical home model in the setting of bleeding disorders, but a number have evaluated the impact of integrated care, a more general term for the practice of coordinating multidisciplinary care to improve access and outcomes while eliminating redundancies and unnecessary costs. In a recent systematic review and meta-analysis of 27 nonrandomized studies of patients with hemophilia, integrated care was linked to lower mortality, fewer emergency room visits and hospitalizations, shorter lengths of stay in the hospital, and fewer missed days of school and work.⁶ Such findings, combined with promising outcomes data from studies of patient-centered medical homes in other disease settings, suggest that the patient-centered medical home can significantly benefit patients with bleeding disorders and their families and caregivers.
 

Creating a medical home

Establishing a patient-centered medical home can be challenging, involving a plethora of stakeholders and a considerable investment of time, energy, and resources. Organizations such as the National Committee for Quality Assurance and the Accreditation Association for Ambulatory Health Care have formal certification programs to help ensure that an inpatient or outpatient center that calls itself a medical home truly is one.^7-8

The certification process requires centers to document activities in areas such as patients’ rights and responsibilities, administration and governance, patient and care team relationships, clinical records and other health information, and quality, comprehensiveness, continuity, and accessibility.⁷ Achieving certification is rigorous, often requiring centers to document compliance with more than 100 policies, procedures, and standards.

For the Indiana Hemophilia and Thrombosis Center, becoming certified as a medical home “was a multiyear process and an ongoing process,” said Dr. Shapiro. “It involves documentation of quality improvement initiatives, obtaining input from patients to document their satisfaction, and looking at all types of systems within our center and how we integrate care so that all those systems function together. It’s a difficult process, but treatment centers are a medical home for patients with bleeding disorders, and this is an effort to provide some documentation on a national level of how we’re doing everything that we are doing.”

She noted that the process of obtaining medical home certification may require an even higher level of commitment if a bleeding disorder (hemophilia) treatment center is embedded in a university or academic medical center. In this case, more stakeholders are involved, and more hoops may need to be jumped through to implement processes that meet medical home standards while still adhering to any requirements at the organizational level.

Certification programs for patient-centered medical homes are not designed around specific disorders or diseases, but a closer look at their compliance metrics underscores how medical homes can benefit patients with bleeding disorders. For example, to receive medical home certification from the Accreditation Association for Ambulatory Health Care, a center needs to be able to document that patients’ care is not transferred without first making arrangements with a receiving health care provider, that the quality improvement programs are peer-led, and that these programs assess and address diverse measures of clinical performance, cost-effectiveness, and administrative functioning.^7-9

Medical homes, the NHPCC, and Healthy People 2030

Creating patient-centered medical homes for patients with bleeding disorders is now a quality improvement objective of the National Hemophilia Program Coordinating Center, or NHPCC. Established in 2012 and funded by the federal Health Resources and Services Administration, the NHPCC partners with the eight regional hemophilia networks and more than 140 federally funded hemophilia treatment centers across the United States to identify gaps, standardize and improve access to care, and share and promote best practices for the treatment and management of blood disorders.¹⁰

In the United States, receiving care in a hemophilia treatment center (which, despite its name, typically offers care for other disorders such as von Willebrand disease) has been linked to lower mortality and fewer hospitalizations related to bleeding complications.¹¹ To continue to improve on these outcomes, the NHPCC, regional networks, and hemophilia treatment centers are prioritizing medical homes and ranking their establishments alongside core objectives such as bettering patient and family engagement and improving the transition from pediatric to adult care.¹²

As part of this quality improvement work, the NHPCC, regional leadership, and hemophilia treatment centers meet regularly to identify needs and priorities, plan programs, and ensure that each center is meeting the goals and objectives set out by its federal grant.¹³ Such partnerships help improve and integrate care within a coordinated national framework, Dr. Shapiro said. “We all are charged with this same mission,” she added. “That doesn’t mean that every treatment center looks exactly the same, has the same number of staff, or does everything the same way, but we all have the same mission, and we know what that is. That is the work of the NHPCC, to determine and document that and help level and improve care throughout the country.”

The NHPCC also engages other stakeholders, including consumer agencies and professional organizations. Recent achievements have included a first-ever national patient needs assessment, a tandem technical needs assessment of hemophilia treatment centers, an educational outreach program for genetic counselors, a webinar on transitioning care for adolescents, a national survey of the federal 340B Drug Pricing Program, and a survey of minority patients to identify and characterize problems such as language and insurance barriers, the lack of culturally appropriate educational materials on blood disorders, and difficulties getting transportation to treatment centers or educational programs.¹⁴

In part because of this advocacy work, the U.S. Department of Health and Human Services recently included hemophilia for the first time in Healthy People, its evidence-based set of decade-long objectives aimed at improving the health of all Americans. In Healthy People 2030, the specific objective for hemophilia is to reduce the proportion of patients with severe disease who experience more than four joint bleeds per year to 13.3% (the current estimate is 16.9%).¹⁵

For Healthy People to prioritize hemophilia for the first time alongside much more common conditions such as diabetes and heart disease reflects the challenges of managing bleeding disorders and the efforts by the NHPCC and other stakeholders to raise awareness about current needs. To track progress in meeting the Healthy People 2030 objective, the NHPCC will work with federal partners to analyze patient-level data gathered through the Centers for Disease Control’s Community Counts Registry for Bleeding Disorders Surveillance program, which collects data from hemophilia treatment centers across the United States and includes patients with all levels of disease severity.

“The inclusion of bleeding disorders in Healthy People 2030 is really very significant,” said Dr. Shapiro. “These are disorders that affect less than 200,000 Americans, which is the definition of a rare disease in this context. To have hemophilia considered as a national priority is very important, not only for hemophilia, but also for other rare diseases that may in the future also be considered as being as of national importance in this way.”
 

References

1. Rodriguez-Saldana J. 2019. The Patient-Centered Medical Home, Primary Care, and Diabetes. In: Rodriguez-Saldana J. (eds) The Diabetes Textbook. Springer, Cham.

2. J Comorb. 2011;1:51-59.

3. Eur J Haematol. 2018 Apr;100 Suppl 1:5-13.

4. Blood. 2003;102(7):2358-63.

5. Haemophilia. 2014 Jul;20(4):541-9.

6. Haemophilia. 2016;22(Suppl 3):31-40.

7. AAAHC. Medical Home.

8. NCQA. Patient-centered medical home (PCMH).

9. AAAHC, 2013. Medical Home On-Site Certification Handbook.

10. Centers for Disease Control and Prevention. HTC Population Profile.

11. Blood Transfus. 2014;12 Suppl 3(Suppl 3):e542-e548.

12. American Thrombosis and Hemostasis Network.

13. The Great Lakes Regional Hemophilia Network.

14. American Thrombosis and Hemostasis Network. What the NHPCC does.

15. U.S. Department of Health and Human Services. Healthy People 2030: Blood Disorders.

A rare, life-threatening anemia now has a new treatment option. The Food and Drug Administration announced the approval of pegcetacoplan (Empaveli) injection to treat adults with paroxysmal nocturnal hemoglobinuria (PNH). Pegcetacoplan is the first PNH treatment that binds to complement protein C3, according to the FDA announcement. Complement protein C3 is a key component of host immunity and defense.

Special concern

Because of the risk of severe side effects, the drug is available only through a restricted program under a risk evaluation and mitigation strategy (REMS). Serious infections can occur in patients taking pegcetacoplan that can become life-threatening or fatal if not treated early. According to the FDA, REMS are designed to reinforce medication use behaviors and actions that support the safe use of that medication, and only a few drugs require a REMS.

The most common other side effects are injection site reactions, diarrhea, abdominal pain, and fatigue.

Pegcetacoplan was approved based upon a study of 80 patients with PNH and anemia who had been taking eculizumab, a previously approved treatment. During 16 weeks of treatment, patients in the pegcetacoplan group had an average increase in their hemoglobin of 2.4 g/dL, while patients in the eculizumab group had an average decrease in their hemoglobin of 1.5 g/dL.
 

About the disease

PNH is caused by gene mutations that affect red blood cells, causing them to be defective and susceptible to destruction by a patient’s own immune system. Red blood cells in people with these mutations are defective and can be destroyed by the immune system, causing anemia.

Other symptoms include blood clots and destruction of bone marrow. The disease affects 1-1.5 people per million, with diagnosis typically occurring around ages 35-40, and a median survival of only 10 years after diagnosis, according to the FDA.

mlesney@mdedge.com

A rare, life-threatening anemia now has a new treatment option. The Food and Drug Administration announced the approval of pegcetacoplan (Empaveli) injection to treat adults with paroxysmal nocturnal hemoglobinuria (PNH). Pegcetacoplan is the first PNH treatment that binds to complement protein C3, according to the FDA announcement. Complement protein C3 is a key component of host immunity and defense.

Special concern

Because of the risk of severe side effects, the drug is available only through a restricted program under a risk evaluation and mitigation strategy (REMS). Serious infections can occur in patients taking pegcetacoplan that can become life-threatening or fatal if not treated early. According to the FDA, REMS are designed to reinforce medication use behaviors and actions that support the safe use of that medication, and only a few drugs require a REMS.

The most common other side effects are injection site reactions, diarrhea, abdominal pain, and fatigue.

Pegcetacoplan was approved based upon a study of 80 patients with PNH and anemia who had been taking eculizumab, a previously approved treatment. During 16 weeks of treatment, patients in the pegcetacoplan group had an average increase in their hemoglobin of 2.4 g/dL, while patients in the eculizumab group had an average decrease in their hemoglobin of 1.5 g/dL.
 

About the disease

PNH is caused by gene mutations that affect red blood cells, causing them to be defective and susceptible to destruction by a patient’s own immune system. Red blood cells in people with these mutations are defective and can be destroyed by the immune system, causing anemia.

Other symptoms include blood clots and destruction of bone marrow. The disease affects 1-1.5 people per million, with diagnosis typically occurring around ages 35-40, and a median survival of only 10 years after diagnosis, according to the FDA.

mlesney@mdedge.com

A rare, life-threatening anemia now has a new treatment option. The Food and Drug Administration announced the approval of pegcetacoplan (Empaveli) injection to treat adults with paroxysmal nocturnal hemoglobinuria (PNH). Pegcetacoplan is the first PNH treatment that binds to complement protein C3, according to the FDA announcement. Complement protein C3 is a key component of host immunity and defense.

Special concern

Because of the risk of severe side effects, the drug is available only through a restricted program under a risk evaluation and mitigation strategy (REMS). Serious infections can occur in patients taking pegcetacoplan that can become life-threatening or fatal if not treated early. According to the FDA, REMS are designed to reinforce medication use behaviors and actions that support the safe use of that medication, and only a few drugs require a REMS.

The most common other side effects are injection site reactions, diarrhea, abdominal pain, and fatigue.

Pegcetacoplan was approved based upon a study of 80 patients with PNH and anemia who had been taking eculizumab, a previously approved treatment. During 16 weeks of treatment, patients in the pegcetacoplan group had an average increase in their hemoglobin of 2.4 g/dL, while patients in the eculizumab group had an average decrease in their hemoglobin of 1.5 g/dL.
 

About the disease

PNH is caused by gene mutations that affect red blood cells, causing them to be defective and susceptible to destruction by a patient’s own immune system. Red blood cells in people with these mutations are defective and can be destroyed by the immune system, causing anemia.

Other symptoms include blood clots and destruction of bone marrow. The disease affects 1-1.5 people per million, with diagnosis typically occurring around ages 35-40, and a median survival of only 10 years after diagnosis, according to the FDA.

mlesney@mdedge.com

A majority of Mohs surgeons have adopted telemedicine during the COVID-19 pandemic, a new survey finds, but only half expressed interest in making it a permanent part of their practices.

A variety of factors combine to make it “very difficult for surgeons to make long-term plans for implementing telemedicine in their practices,” said Mario Maruthur, MD, who presented the findings at the annual meeting of the American College of Mohs Surgery. “Telemedicine likely has a role in Mohs practices, particularly with postop follow-up visits. However, postpandemic reimbursement and regulatory issues need to be formally laid out before Mohs surgeons are able to incorporate it into their permanent work flow.”

Dr. Maruthur, a Mohs surgery and dermatologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York, and colleagues sent a survey to ACMS members in September and October 2020. “We saw first-hand in our surgical practice that telemedicine quickly became an important tool when the pandemic surged in the spring of 2020,” he said. Considering that surgical practices are highly dependent on in-person visits, the impetus for this study was to assess to what degree Mohs practices from across the spectrum, including academic and private practices, embraced telemedicine during the pandemic, and “what these surgical practices used telemedicine for, how it was received by their patients, which telemedicine platforms were most often utilized, and lastly, what are their plans if any for incorporating telemedicine into their surgical practices after the pandemic subsides.”

The researchers received responses from 115 surgeons representing all regions of the country (40% Northeast, 21% South, 21% Midwest, and 18% West). Half practiced in urban areas (37%) and large cities (13%), and 40% were in an academic setting versus 36% in a single-specialty private practice.

More than 70% of the respondents said their case load fell by at least 75% during the initial surge of the pandemic; 80% turned to telemedicine, compared with just 23% who relied on the technology prior to the pandemic. The most commonly used telemedicine technologies were FaceTime, Zoom, Doximity, and Epic.

Mohs surgeons reported most commonly using telemedicine for postsurgery management (77% of the total 115 responses). “Telemedicine is a great fit for this category of visits as they allow the surgeon to view the surgical site and answer any questions they patient may have,” Dr. Maruthur said. “If the surgeon does suspect a postop infection or other concern based on a patient’s signs or symptoms, they can easily schedule the patient for an in-person assessment. We suspect that postop follow-up visits may be the best candidate for long-term use of telemedicine in Mohs surgery practices.”

Surgeons also reported using telemedicine for “spot checks” (61%) and surgical consultations (59%).

However, Dr. Maruther noted that preoperative assessments and spot checks can be difficult to perform using telemedicine. “The quality of the video image is not always great, patients can have a difficult time pointing the camera at the right spot and at the right distance. Even appreciating the actual size of the lesion are all difficult over a video encounter. And there is a lot of information gleaned from in-person physical examination, such as whether the lesion is fixed to a deeper structure and whether there are any nearby scars or other suspicious lesions.”

Nearly three-quarters of the surgeons using the technology said most or all patients were receptive to telemedicine.

However, the surgeons reported multiple barriers to the use of telemedicine: Limitations when compared with physical exams (88%), fitting it into the work flow (58%), patient response and training (57%), reimbursement concerns (50%), implementation of the technology (37%), regulations such as HIPAA (24%), training of staff (17%), and licensing (8%).

In an interview, Sumaira Z. Aasi, MD, director of Mohs and dermatologic surgery, Stanford University, agreed that there are many obstacles to routine use of telemedicine by Mohs surgeons. “As surgeons, we rely on the physical and tactile exam to get a sense of the size and extent of the cancer and characteristics such as the laxity of the surrounding tissue whether the tumor is fixed,” she said. “It is very difficult to access this on a telemedicine visit.”

In addition, she said, “many of our patients are in the elderly population, and some may not be comfortable using this technology. Also, it’s not a work flow that we are comfortable or familiar with. And I think that the technology has to improve to allow for better resolution of images as we ‘examine’ patients through a telemedicine visit.”

She added that “another con is there is a reliance on having the patient point out lesions of concern. Many cancers are picked by a careful in-person examination by a qualified physician/dermatologist/Mohs surgeon when the lesion is quite small or subtle and not even noticed by the patient themselves. This approach invariably leads to earlier biopsies and earlier treatments that can prevent morbidity and save health care money.”

On the other hand, she said, telemedicine “may save patients some time and money in terms of the effort and cost of transportation to come in for simpler postoperative medical visits that are often short in their very nature, such as postop check-ups.”

Most of the surgeons surveyed (69%) said telemedicine probably or definitely deserves a place in the practice Mohs surgery, but only 50% said they’d like to or would definitely pursue giving telemedicine a role in their practices once the pandemic is over.

“At the start of the pandemic, many regulations in areas such as HIPAA were eased, and reimbursements were increased, which allowed telemedicine to be quickly adopted,” Dr. Maruther said. “The government and payers have yet to decide which regulations and reimbursements will be in place after the pandemic. That makes it very difficult for surgeons to make long-term plans for implementing telemedicine in their practices.”

Dr. Aasi predicted that telemedicine will become more appealing to patients and physicians as it its technology and usability improves. More familiarity with its use will also be helpful, she said, and surgeons will be more receptive as it’s incorporated into efficient daily work flow.

The study was funded in part by the National Institutes of Health.

A majority of Mohs surgeons have adopted telemedicine during the COVID-19 pandemic, a new survey finds, but only half expressed interest in making it a permanent part of their practices.

A variety of factors combine to make it “very difficult for surgeons to make long-term plans for implementing telemedicine in their practices,” said Mario Maruthur, MD, who presented the findings at the annual meeting of the American College of Mohs Surgery. “Telemedicine likely has a role in Mohs practices, particularly with postop follow-up visits. However, postpandemic reimbursement and regulatory issues need to be formally laid out before Mohs surgeons are able to incorporate it into their permanent work flow.”

Dr. Maruthur, a Mohs surgery and dermatologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York, and colleagues sent a survey to ACMS members in September and October 2020. “We saw first-hand in our surgical practice that telemedicine quickly became an important tool when the pandemic surged in the spring of 2020,” he said. Considering that surgical practices are highly dependent on in-person visits, the impetus for this study was to assess to what degree Mohs practices from across the spectrum, including academic and private practices, embraced telemedicine during the pandemic, and “what these surgical practices used telemedicine for, how it was received by their patients, which telemedicine platforms were most often utilized, and lastly, what are their plans if any for incorporating telemedicine into their surgical practices after the pandemic subsides.”

The researchers received responses from 115 surgeons representing all regions of the country (40% Northeast, 21% South, 21% Midwest, and 18% West). Half practiced in urban areas (37%) and large cities (13%), and 40% were in an academic setting versus 36% in a single-specialty private practice.

More than 70% of the respondents said their case load fell by at least 75% during the initial surge of the pandemic; 80% turned to telemedicine, compared with just 23% who relied on the technology prior to the pandemic. The most commonly used telemedicine technologies were FaceTime, Zoom, Doximity, and Epic.

Mohs surgeons reported most commonly using telemedicine for postsurgery management (77% of the total 115 responses). “Telemedicine is a great fit for this category of visits as they allow the surgeon to view the surgical site and answer any questions they patient may have,” Dr. Maruthur said. “If the surgeon does suspect a postop infection or other concern based on a patient’s signs or symptoms, they can easily schedule the patient for an in-person assessment. We suspect that postop follow-up visits may be the best candidate for long-term use of telemedicine in Mohs surgery practices.”

Surgeons also reported using telemedicine for “spot checks” (61%) and surgical consultations (59%).

However, Dr. Maruther noted that preoperative assessments and spot checks can be difficult to perform using telemedicine. “The quality of the video image is not always great, patients can have a difficult time pointing the camera at the right spot and at the right distance. Even appreciating the actual size of the lesion are all difficult over a video encounter. And there is a lot of information gleaned from in-person physical examination, such as whether the lesion is fixed to a deeper structure and whether there are any nearby scars or other suspicious lesions.”

Nearly three-quarters of the surgeons using the technology said most or all patients were receptive to telemedicine.

However, the surgeons reported multiple barriers to the use of telemedicine: Limitations when compared with physical exams (88%), fitting it into the work flow (58%), patient response and training (57%), reimbursement concerns (50%), implementation of the technology (37%), regulations such as HIPAA (24%), training of staff (17%), and licensing (8%).

In an interview, Sumaira Z. Aasi, MD, director of Mohs and dermatologic surgery, Stanford University, agreed that there are many obstacles to routine use of telemedicine by Mohs surgeons. “As surgeons, we rely on the physical and tactile exam to get a sense of the size and extent of the cancer and characteristics such as the laxity of the surrounding tissue whether the tumor is fixed,” she said. “It is very difficult to access this on a telemedicine visit.”

In addition, she said, “many of our patients are in the elderly population, and some may not be comfortable using this technology. Also, it’s not a work flow that we are comfortable or familiar with. And I think that the technology has to improve to allow for better resolution of images as we ‘examine’ patients through a telemedicine visit.”

She added that “another con is there is a reliance on having the patient point out lesions of concern. Many cancers are picked by a careful in-person examination by a qualified physician/dermatologist/Mohs surgeon when the lesion is quite small or subtle and not even noticed by the patient themselves. This approach invariably leads to earlier biopsies and earlier treatments that can prevent morbidity and save health care money.”

On the other hand, she said, telemedicine “may save patients some time and money in terms of the effort and cost of transportation to come in for simpler postoperative medical visits that are often short in their very nature, such as postop check-ups.”

Most of the surgeons surveyed (69%) said telemedicine probably or definitely deserves a place in the practice Mohs surgery, but only 50% said they’d like to or would definitely pursue giving telemedicine a role in their practices once the pandemic is over.

“At the start of the pandemic, many regulations in areas such as HIPAA were eased, and reimbursements were increased, which allowed telemedicine to be quickly adopted,” Dr. Maruther said. “The government and payers have yet to decide which regulations and reimbursements will be in place after the pandemic. That makes it very difficult for surgeons to make long-term plans for implementing telemedicine in their practices.”

Dr. Aasi predicted that telemedicine will become more appealing to patients and physicians as it its technology and usability improves. More familiarity with its use will also be helpful, she said, and surgeons will be more receptive as it’s incorporated into efficient daily work flow.

The study was funded in part by the National Institutes of Health.

A majority of Mohs surgeons have adopted telemedicine during the COVID-19 pandemic, a new survey finds, but only half expressed interest in making it a permanent part of their practices.

A variety of factors combine to make it “very difficult for surgeons to make long-term plans for implementing telemedicine in their practices,” said Mario Maruthur, MD, who presented the findings at the annual meeting of the American College of Mohs Surgery. “Telemedicine likely has a role in Mohs practices, particularly with postop follow-up visits. However, postpandemic reimbursement and regulatory issues need to be formally laid out before Mohs surgeons are able to incorporate it into their permanent work flow.”

Dr. Maruthur, a Mohs surgery and dermatologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York, and colleagues sent a survey to ACMS members in September and October 2020. “We saw first-hand in our surgical practice that telemedicine quickly became an important tool when the pandemic surged in the spring of 2020,” he said. Considering that surgical practices are highly dependent on in-person visits, the impetus for this study was to assess to what degree Mohs practices from across the spectrum, including academic and private practices, embraced telemedicine during the pandemic, and “what these surgical practices used telemedicine for, how it was received by their patients, which telemedicine platforms were most often utilized, and lastly, what are their plans if any for incorporating telemedicine into their surgical practices after the pandemic subsides.”

The researchers received responses from 115 surgeons representing all regions of the country (40% Northeast, 21% South, 21% Midwest, and 18% West). Half practiced in urban areas (37%) and large cities (13%), and 40% were in an academic setting versus 36% in a single-specialty private practice.

More than 70% of the respondents said their case load fell by at least 75% during the initial surge of the pandemic; 80% turned to telemedicine, compared with just 23% who relied on the technology prior to the pandemic. The most commonly used telemedicine technologies were FaceTime, Zoom, Doximity, and Epic.

Mohs surgeons reported most commonly using telemedicine for postsurgery management (77% of the total 115 responses). “Telemedicine is a great fit for this category of visits as they allow the surgeon to view the surgical site and answer any questions they patient may have,” Dr. Maruthur said. “If the surgeon does suspect a postop infection or other concern based on a patient’s signs or symptoms, they can easily schedule the patient for an in-person assessment. We suspect that postop follow-up visits may be the best candidate for long-term use of telemedicine in Mohs surgery practices.”

Surgeons also reported using telemedicine for “spot checks” (61%) and surgical consultations (59%).

However, Dr. Maruther noted that preoperative assessments and spot checks can be difficult to perform using telemedicine. “The quality of the video image is not always great, patients can have a difficult time pointing the camera at the right spot and at the right distance. Even appreciating the actual size of the lesion are all difficult over a video encounter. And there is a lot of information gleaned from in-person physical examination, such as whether the lesion is fixed to a deeper structure and whether there are any nearby scars or other suspicious lesions.”

Nearly three-quarters of the surgeons using the technology said most or all patients were receptive to telemedicine.

However, the surgeons reported multiple barriers to the use of telemedicine: Limitations when compared with physical exams (88%), fitting it into the work flow (58%), patient response and training (57%), reimbursement concerns (50%), implementation of the technology (37%), regulations such as HIPAA (24%), training of staff (17%), and licensing (8%).

In an interview, Sumaira Z. Aasi, MD, director of Mohs and dermatologic surgery, Stanford University, agreed that there are many obstacles to routine use of telemedicine by Mohs surgeons. “As surgeons, we rely on the physical and tactile exam to get a sense of the size and extent of the cancer and characteristics such as the laxity of the surrounding tissue whether the tumor is fixed,” she said. “It is very difficult to access this on a telemedicine visit.”

In addition, she said, “many of our patients are in the elderly population, and some may not be comfortable using this technology. Also, it’s not a work flow that we are comfortable or familiar with. And I think that the technology has to improve to allow for better resolution of images as we ‘examine’ patients through a telemedicine visit.”

She added that “another con is there is a reliance on having the patient point out lesions of concern. Many cancers are picked by a careful in-person examination by a qualified physician/dermatologist/Mohs surgeon when the lesion is quite small or subtle and not even noticed by the patient themselves. This approach invariably leads to earlier biopsies and earlier treatments that can prevent morbidity and save health care money.”

On the other hand, she said, telemedicine “may save patients some time and money in terms of the effort and cost of transportation to come in for simpler postoperative medical visits that are often short in their very nature, such as postop check-ups.”

Most of the surgeons surveyed (69%) said telemedicine probably or definitely deserves a place in the practice Mohs surgery, but only 50% said they’d like to or would definitely pursue giving telemedicine a role in their practices once the pandemic is over.

“At the start of the pandemic, many regulations in areas such as HIPAA were eased, and reimbursements were increased, which allowed telemedicine to be quickly adopted,” Dr. Maruther said. “The government and payers have yet to decide which regulations and reimbursements will be in place after the pandemic. That makes it very difficult for surgeons to make long-term plans for implementing telemedicine in their practices.”

Dr. Aasi predicted that telemedicine will become more appealing to patients and physicians as it its technology and usability improves. More familiarity with its use will also be helpful, she said, and surgeons will be more receptive as it’s incorporated into efficient daily work flow.

The study was funded in part by the National Institutes of Health.

Dual HER2 blockade with pertuzumab (Perjeta) and trastuzumab (Herceptin) on top of anthracycline-based neoadjuvant chemotherapy for early-stage breast cancer was associated with a low rate of clinically relevant cardiac events in the final follow-up of the BERENICE study.

After more than 5 years, 1.0%-1.5% of patients who had locally advanced, inflammatory, or early-stage breast cancer developed heart failure, and around 12%-13% showed any significant changes in left ventricular ejection fraction (LVEF).

Importantly, “there were no new safety concerns that arose during long-term follow-up,” study investigator Chau Dang, MD, said in presenting the findings at the European Society for Medical Oncology: Breast Cancer virtual meeting.

Dr. Dang, a medical oncologist at Memorial Sloan Kettering Cancer Centre in New York, reported that the most common cause of death was disease progression.

BERENICE was designed as a cardiac safety study and so not powered to look at long-term efficacy, which Dr. Dang was clear in reporting. Nevertheless event-free survival (EFS), invasive disease-free survival (IDFS), and overall survival (OS) rates at 5 years were all high, at least a respective 89.2%, 91%, and 93.8%, she said. “The medians have not been reached,” she observed.

“These data support the use of dual HER2 blockade with pertuzumab-trastuzumab–based regimens, including in combination with dose-dense, anthracycline-based chemotherapy, across the neoadjuvant and adjuvant treatment settings for the complete treatment of patients with HER2-positive early-stage breast cancer,” Dr. Dang said.

Evandro de Azambuja, MD, PhD, the invited discussant for the trial agreed that the regimens tested appeared “safe from a cardiac standpoint.” However, “you cannot forget that today we are using much less anthracyclines in our patient population.”

Patients in trials are also very different from those treated in clinical practice, often being younger and much fitter, he said. Therefore, it may be important to look at the baseline cardiac medications and comorbidities, Dr. de Azambuja, a medical oncologist at the Institut Jules Bordet in Brussels, Belgium, suggested.

That said, the BERENICE findings sit well with other trials that have been conducted, Dr. de Azambuja pointed out.

“If we look at other trials that have also tested dual HER2 blockade with anthracycline or nonanthracycline regimens, all of them reassure that dual blockade is not more cardiotoxic than single blockade,” he said. This includes trials such as TRYPHAENA, APHINITY, KRISTINE, NeoSphere and PEONY.

The 3-year IDFS rate of 91% in BERENICE also compares well to that seen in APHINITY (94%), Dr. de Azambuja said.
 

BERENICE study design

BERENICE was a multicenter, open-label, nonrandomized and noncomparative phase 2 trial that recruited 400 patients across 75 centers in 12 countries.

Eligibility criteria were that participants had to have been centrally confirmed HER2-positive locally advanced, inflammatory or early breast cancer, with the latter defined as tumors bigger than 2 cm or greater than 5 mm in size, and be node-positive. Patients also had to have a starting LVEF of 55% or higher.

Patients were allocated to one of two neoadjuvant chemotherapy regimens depending on the choice of their physician. One group received a regimen of dose-dense doxorubicin and cyclophosphamide (ddAC) given every 2 weeks for four cycles and then paclitaxel every week for 12 cycles. The other group received 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) every 3 weeks for four cycles and then docetaxel every 3 weeks for four cycles.

Pertuzumab and trastuzumab were started at the same time as the taxanes in both groups and given every 3 weeks for four cycles. Patients then underwent surgery and continued pertuzumab/trastuzumab treatment alone for a further 13 cycles.

The co-primary endpoints were the incidence of New York Heart Association class III or IV heart failure and incidence of symptomatic and asymptomatic LVEF decline of 10% or more.

The primary analysis of the trial was published in 2018 and, at that time, it was reported that three patients in the ddAC cohort and none in the FEC cohort experienced heart failure. LVEF decline was observed in a respective 6.5% and 2% of patients.
 

Discussion points

Dr. de Azambuja noted that the contribution of the chemotherapy to the efficacy cannot be assessed because of the nonrandomized trial design. That should not matter, pointed out Sybille Loibl, MD, PhD, during discussion.

“I think it compares nicely to other trials that looked at dose-dense chemotherapy,” said Dr. Loibl, who is an associate professor at the University of Frankfurt in Germany. “It seems that, in the light of what we consider today probably one of the best anti-HER2 treatments, the chemotherapy is less relevant, and that’s why a dose-dense regimen doesn’t add so much on a standard anthracycline taxane-containing regimen.”

Dr. de Azambuja also commented on the assessment of cardiotoxicity and the use of reduced LVEF as a measure: LVEF decline is a late effect of cardiotoxicity, he observed, and he suggested a different approach in future trials.

“If you use Global Longitudinal Strain, this could be an optimal parameter to detect early subclinical LVEF dysfunction and you should consider it for the next trials looking for cardiac safety. Also, cardiac biomarkers. This was not implemented in this trial, and I strongly recommend this should be for the next trial.”

The BERENICE trial was funded by F. Hoffmann-La Roche. Dr. Dang disclosed receiving consultancy fees from F. Hoffmann-La Roche, Genentech, Daiichi Sankyo, Lilly, and Puma Biotechnology. Dr. de Azambuja was not involved in the study but disclosed receiving honoraria, travel grants, research grants from Roche and Genentech as well as from other companies. Dr. Loibl was one of the cochairs of the session and, among disclosures regarding many other companies, has been an invited speaker for Roche and received reimbursement via her institution for a writing engagement.

Dual HER2 blockade with pertuzumab (Perjeta) and trastuzumab (Herceptin) on top of anthracycline-based neoadjuvant chemotherapy for early-stage breast cancer was associated with a low rate of clinically relevant cardiac events in the final follow-up of the BERENICE study.

After more than 5 years, 1.0%-1.5% of patients who had locally advanced, inflammatory, or early-stage breast cancer developed heart failure, and around 12%-13% showed any significant changes in left ventricular ejection fraction (LVEF).

Importantly, “there were no new safety concerns that arose during long-term follow-up,” study investigator Chau Dang, MD, said in presenting the findings at the European Society for Medical Oncology: Breast Cancer virtual meeting.

Dr. Dang, a medical oncologist at Memorial Sloan Kettering Cancer Centre in New York, reported that the most common cause of death was disease progression.

BERENICE was designed as a cardiac safety study and so not powered to look at long-term efficacy, which Dr. Dang was clear in reporting. Nevertheless event-free survival (EFS), invasive disease-free survival (IDFS), and overall survival (OS) rates at 5 years were all high, at least a respective 89.2%, 91%, and 93.8%, she said. “The medians have not been reached,” she observed.

“These data support the use of dual HER2 blockade with pertuzumab-trastuzumab–based regimens, including in combination with dose-dense, anthracycline-based chemotherapy, across the neoadjuvant and adjuvant treatment settings for the complete treatment of patients with HER2-positive early-stage breast cancer,” Dr. Dang said.

Evandro de Azambuja, MD, PhD, the invited discussant for the trial agreed that the regimens tested appeared “safe from a cardiac standpoint.” However, “you cannot forget that today we are using much less anthracyclines in our patient population.”

Patients in trials are also very different from those treated in clinical practice, often being younger and much fitter, he said. Therefore, it may be important to look at the baseline cardiac medications and comorbidities, Dr. de Azambuja, a medical oncologist at the Institut Jules Bordet in Brussels, Belgium, suggested.

That said, the BERENICE findings sit well with other trials that have been conducted, Dr. de Azambuja pointed out.

“If we look at other trials that have also tested dual HER2 blockade with anthracycline or nonanthracycline regimens, all of them reassure that dual blockade is not more cardiotoxic than single blockade,” he said. This includes trials such as TRYPHAENA, APHINITY, KRISTINE, NeoSphere and PEONY.

The 3-year IDFS rate of 91% in BERENICE also compares well to that seen in APHINITY (94%), Dr. de Azambuja said.
 

BERENICE study design

BERENICE was a multicenter, open-label, nonrandomized and noncomparative phase 2 trial that recruited 400 patients across 75 centers in 12 countries.

Eligibility criteria were that participants had to have been centrally confirmed HER2-positive locally advanced, inflammatory or early breast cancer, with the latter defined as tumors bigger than 2 cm or greater than 5 mm in size, and be node-positive. Patients also had to have a starting LVEF of 55% or higher.

Patients were allocated to one of two neoadjuvant chemotherapy regimens depending on the choice of their physician. One group received a regimen of dose-dense doxorubicin and cyclophosphamide (ddAC) given every 2 weeks for four cycles and then paclitaxel every week for 12 cycles. The other group received 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) every 3 weeks for four cycles and then docetaxel every 3 weeks for four cycles.

Pertuzumab and trastuzumab were started at the same time as the taxanes in both groups and given every 3 weeks for four cycles. Patients then underwent surgery and continued pertuzumab/trastuzumab treatment alone for a further 13 cycles.

The co-primary endpoints were the incidence of New York Heart Association class III or IV heart failure and incidence of symptomatic and asymptomatic LVEF decline of 10% or more.

The primary analysis of the trial was published in 2018 and, at that time, it was reported that three patients in the ddAC cohort and none in the FEC cohort experienced heart failure. LVEF decline was observed in a respective 6.5% and 2% of patients.
 

Discussion points

Dr. de Azambuja noted that the contribution of the chemotherapy to the efficacy cannot be assessed because of the nonrandomized trial design. That should not matter, pointed out Sybille Loibl, MD, PhD, during discussion.

“I think it compares nicely to other trials that looked at dose-dense chemotherapy,” said Dr. Loibl, who is an associate professor at the University of Frankfurt in Germany. “It seems that, in the light of what we consider today probably one of the best anti-HER2 treatments, the chemotherapy is less relevant, and that’s why a dose-dense regimen doesn’t add so much on a standard anthracycline taxane-containing regimen.”

Dr. de Azambuja also commented on the assessment of cardiotoxicity and the use of reduced LVEF as a measure: LVEF decline is a late effect of cardiotoxicity, he observed, and he suggested a different approach in future trials.

“If you use Global Longitudinal Strain, this could be an optimal parameter to detect early subclinical LVEF dysfunction and you should consider it for the next trials looking for cardiac safety. Also, cardiac biomarkers. This was not implemented in this trial, and I strongly recommend this should be for the next trial.”

The BERENICE trial was funded by F. Hoffmann-La Roche. Dr. Dang disclosed receiving consultancy fees from F. Hoffmann-La Roche, Genentech, Daiichi Sankyo, Lilly, and Puma Biotechnology. Dr. de Azambuja was not involved in the study but disclosed receiving honoraria, travel grants, research grants from Roche and Genentech as well as from other companies. Dr. Loibl was one of the cochairs of the session and, among disclosures regarding many other companies, has been an invited speaker for Roche and received reimbursement via her institution for a writing engagement.

Dual HER2 blockade with pertuzumab (Perjeta) and trastuzumab (Herceptin) on top of anthracycline-based neoadjuvant chemotherapy for early-stage breast cancer was associated with a low rate of clinically relevant cardiac events in the final follow-up of the BERENICE study.

After more than 5 years, 1.0%-1.5% of patients who had locally advanced, inflammatory, or early-stage breast cancer developed heart failure, and around 12%-13% showed any significant changes in left ventricular ejection fraction (LVEF).

Importantly, “there were no new safety concerns that arose during long-term follow-up,” study investigator Chau Dang, MD, said in presenting the findings at the European Society for Medical Oncology: Breast Cancer virtual meeting.

Dr. Dang, a medical oncologist at Memorial Sloan Kettering Cancer Centre in New York, reported that the most common cause of death was disease progression.

BERENICE was designed as a cardiac safety study and so not powered to look at long-term efficacy, which Dr. Dang was clear in reporting. Nevertheless event-free survival (EFS), invasive disease-free survival (IDFS), and overall survival (OS) rates at 5 years were all high, at least a respective 89.2%, 91%, and 93.8%, she said. “The medians have not been reached,” she observed.

“These data support the use of dual HER2 blockade with pertuzumab-trastuzumab–based regimens, including in combination with dose-dense, anthracycline-based chemotherapy, across the neoadjuvant and adjuvant treatment settings for the complete treatment of patients with HER2-positive early-stage breast cancer,” Dr. Dang said.

Evandro de Azambuja, MD, PhD, the invited discussant for the trial agreed that the regimens tested appeared “safe from a cardiac standpoint.” However, “you cannot forget that today we are using much less anthracyclines in our patient population.”

Patients in trials are also very different from those treated in clinical practice, often being younger and much fitter, he said. Therefore, it may be important to look at the baseline cardiac medications and comorbidities, Dr. de Azambuja, a medical oncologist at the Institut Jules Bordet in Brussels, Belgium, suggested.

That said, the BERENICE findings sit well with other trials that have been conducted, Dr. de Azambuja pointed out.

“If we look at other trials that have also tested dual HER2 blockade with anthracycline or nonanthracycline regimens, all of them reassure that dual blockade is not more cardiotoxic than single blockade,” he said. This includes trials such as TRYPHAENA, APHINITY, KRISTINE, NeoSphere and PEONY.

The 3-year IDFS rate of 91% in BERENICE also compares well to that seen in APHINITY (94%), Dr. de Azambuja said.
 

BERENICE study design

BERENICE was a multicenter, open-label, nonrandomized and noncomparative phase 2 trial that recruited 400 patients across 75 centers in 12 countries.

Eligibility criteria were that participants had to have been centrally confirmed HER2-positive locally advanced, inflammatory or early breast cancer, with the latter defined as tumors bigger than 2 cm or greater than 5 mm in size, and be node-positive. Patients also had to have a starting LVEF of 55% or higher.

Patients were allocated to one of two neoadjuvant chemotherapy regimens depending on the choice of their physician. One group received a regimen of dose-dense doxorubicin and cyclophosphamide (ddAC) given every 2 weeks for four cycles and then paclitaxel every week for 12 cycles. The other group received 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) every 3 weeks for four cycles and then docetaxel every 3 weeks for four cycles.

Pertuzumab and trastuzumab were started at the same time as the taxanes in both groups and given every 3 weeks for four cycles. Patients then underwent surgery and continued pertuzumab/trastuzumab treatment alone for a further 13 cycles.

The co-primary endpoints were the incidence of New York Heart Association class III or IV heart failure and incidence of symptomatic and asymptomatic LVEF decline of 10% or more.

The primary analysis of the trial was published in 2018 and, at that time, it was reported that three patients in the ddAC cohort and none in the FEC cohort experienced heart failure. LVEF decline was observed in a respective 6.5% and 2% of patients.
 

Discussion points

Dr. de Azambuja noted that the contribution of the chemotherapy to the efficacy cannot be assessed because of the nonrandomized trial design. That should not matter, pointed out Sybille Loibl, MD, PhD, during discussion.

“I think it compares nicely to other trials that looked at dose-dense chemotherapy,” said Dr. Loibl, who is an associate professor at the University of Frankfurt in Germany. “It seems that, in the light of what we consider today probably one of the best anti-HER2 treatments, the chemotherapy is less relevant, and that’s why a dose-dense regimen doesn’t add so much on a standard anthracycline taxane-containing regimen.”

Dr. de Azambuja also commented on the assessment of cardiotoxicity and the use of reduced LVEF as a measure: LVEF decline is a late effect of cardiotoxicity, he observed, and he suggested a different approach in future trials.

“If you use Global Longitudinal Strain, this could be an optimal parameter to detect early subclinical LVEF dysfunction and you should consider it for the next trials looking for cardiac safety. Also, cardiac biomarkers. This was not implemented in this trial, and I strongly recommend this should be for the next trial.”

The BERENICE trial was funded by F. Hoffmann-La Roche. Dr. Dang disclosed receiving consultancy fees from F. Hoffmann-La Roche, Genentech, Daiichi Sankyo, Lilly, and Puma Biotechnology. Dr. de Azambuja was not involved in the study but disclosed receiving honoraria, travel grants, research grants from Roche and Genentech as well as from other companies. Dr. Loibl was one of the cochairs of the session and, among disclosures regarding many other companies, has been an invited speaker for Roche and received reimbursement via her institution for a writing engagement.

Among patients with locally advanced resectable esophageal or junctional cancer, the overall survival benefit conferred by preoperative chemoradiotherapy persists for at least 10 years, according to long-term results of the Chemoradiotherapy for Esophageal Cancer Followed by Surgery Study (CROSS). As a result of earlier publication of CROSS data, chemoradiotherapy followed by surgery has become one of the standards of care for patients with locally advanced resectable esophageal cancer, stated lead author Ben M. Eyck, MD, of Erasmus University Medical Center, Rotterdam, the Netherlands, and colleagues in the Journal of Clinical Oncology.

In the multicenter, randomized trial, initiated in 2004, 178 patients randomized to chemoradiotherapy with subsequent surgery and 188 patients randomized to surgery alone were followed with overall survival as the primary, and cause-specific survival and risks of locoregional and distant relapse as the secondary endpoints. Chemoradiotherapy consisted of 5 weekly cycles of carboplatin (area under the curve of 2 mg/mL/min) and paclitaxel (50 mg/m² body surface area on days 1, 8, 15, 22, and 29) with concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week. Mean age was 60 years (around 78% male), with squamous cell carcinoma (23%) and adenocarcinoma (75%) as the predominant histologies.

The first analysis showed low short-term toxicity and 2-year survival increased from 50% for patients receiving surgery alone to 67% for neoadjuvant chemoradiotherapy plus surgery. Five-year follow-up data were consistent with initial reporting. Long-term benefits and harms of this regimen remain unclear, according to the researchers. Neoadjuvant chemoradiotherapy’s side effects could lead to long-term death from other causes than esophageal cancer, and may not be preventing but rather merely postponing cancer-related death. The aim of the current analysis was to determine whether the observed benefits persisted beyond 5 years.

As of Dec. 31, 2018, 117/178 patients in the chemoradiotherapy-surgery arm and 144/188 in the surgery arm had died. Median follow-up for surviving patients was 147 months. Patients in the chemoradiotherapy surgery arm had better overall survival than patients in the surgery arm (hazard ratio, 0.70; 95% confidence interval, 0.55-0.89; P = .004), with a 10-year overall survival of 38% (95% CI, 31-45) and 25% (95% CI, 19-32), respectively. No significant subgroup differences were observed for overall survival. Also, there was no evidence of a time-dependent effect of neoadjuvant chemoradiotherapy on overall survival. The major effect of neoadjuvant chemoradiotherapy, landmark analyses showed, was in the first 5 years of follow-up, with the effect on overall survival stabilized thereafter, with a hazard ratio approaching 1.00.
 

Cause-specific mortality

Eighty-four of 178 patients in the chemoradiotherapy-surgery arm died of esophageal cancer, with 32 dying of other causes. In the surgery arm, 121/188 died of esophageal cancer and 22 of other causes. The hazard ratio for esophageal cancer death in the chemoradiotherapy-surgery arm was 0.60 (95% CI, 0.46 to 0.80), with 10-year absolute risks of 47% (95% CI, 40-54) and 64% (95% CI,57-71), respectively, in the two arms. Death from other causes was comparable, with 10-year absolute risks of 15% (95% CI, 10-21) and 11% (95% CI, 7-16), respectively, for chemoradiotherapy-surgery versus surgery alone.

Locoregional relapse

Locoregional relapse rates were 8% (15/178) and 18% (33/188) in the chemoradiotherapy-surgery and surgery arms, respectively (HR, 0.39; 95% CI, 0.21-0.72). Eighty-seven percent of those developed within 3 years of follow-up in the chemoradiotherapy arm, with the median relapse-free interval at 3.9 months. In the surgery arm, 28 of 33 relapses (85%) developed within 3 years and the median relapse-free interval was 7.1 months. Beyond 6 years, there were no further relapses in either arm.

While synchronous distant plus locoregional relapse developed in 23 of 178 patients (13%) in the chemoradiotherapy-surgery arm and in 42 of 188 patients (22%) in the surgery arm (HR, 0.43; 95% CI, 0.26-0.72), isolated distant relapse developed at similar rates (around 27.5%) in both groups. Risk of distant relapse (with or without locoregional relapse) was lower in the chemoradiotherapy-surgery arm (HR, 0.61; 95%CI, 0.45-0.84). The median relapse-free interval was 15.1 months (interquartile range, 9.3-27.6) in the chemoradiotherapy-surgery arm and 9.0 months (IQR, 5.3-19.7) in the surgery arm.
 

Safety and health-related quality of life

The combination of paclitaxel and carboplatin with concurrent 41.4 Gy radiotherapy before surgery seems safe in the long term and does not significantly increase the risk of toxicity-related death, the researchers stated. Within the CROSS trial, short-term and long-term health-related quality of life after neoadjuvant chemoradiotherapy plus surgery for surviving patients was comparable to that after surgery alone.

Long-term persistent overall survival benefit

Ten-year CROSS results show that “for locally advanced resectable cancer of the esophagus or esophagogastric junction, preoperative chemoradiotherapy induces a long-term persistent improvement in overall survival.” Also, neoadjuvant chemoradiotherapy does not lead to an increased risk of death from other causes, and the survival benefit of long-term survivors is not compromised, compared with surgery alone. Furthermore, neoadjuvant chemoradiotherapy plus surgery according to CROSS can still be regarded as a standard of care, the researchers added.

Dr. Eyck and colleagues are currently performing the phase II TNT-OES-1 trial. It combines FLOT (fluorouracil, leucovorin, oxaliplatin and docetaxel) chemotherapy followed by CROSS chemoradiotherapy in patients with advanced esophageal and junctional adenocarcinoma. If this regimen appears to be safe in advanced cancer, they plan to perform a phase III trial with this regimen in locally advanced cancer. In addition, they are currently evaluating the implementation of adjuvant nivolumab in clinical practice for patients with pathologically residual disease after CROSS + surgery, based on the recently published CheckMate 577 trial .

“If possible, we prefer adding better systemic therapy to chemoradiotherapy rather than replacing chemoradiotherapy with systemic therapy alone,” Dr. Eyck said in an interview. “The reason for this is that we would like to allow patients with a complete response to neoadjuvant therapy to undergo active surveillance instead of surgery in the near future. … Since the pathologically complete response rate after regimens containing radiotherapy is substantially higher, we still prefer the addition of radiotherapy.”

The study was funded by the Dutch Cancer Foundation (KWF Kankerbestrijding). Dr. Eyck reported no disclosures. Several of the coauthors reported consulting and advisory roles with a variety of pharmaceutical companies.

Among patients with locally advanced resectable esophageal or junctional cancer, the overall survival benefit conferred by preoperative chemoradiotherapy persists for at least 10 years, according to long-term results of the Chemoradiotherapy for Esophageal Cancer Followed by Surgery Study (CROSS). As a result of earlier publication of CROSS data, chemoradiotherapy followed by surgery has become one of the standards of care for patients with locally advanced resectable esophageal cancer, stated lead author Ben M. Eyck, MD, of Erasmus University Medical Center, Rotterdam, the Netherlands, and colleagues in the Journal of Clinical Oncology.

In the multicenter, randomized trial, initiated in 2004, 178 patients randomized to chemoradiotherapy with subsequent surgery and 188 patients randomized to surgery alone were followed with overall survival as the primary, and cause-specific survival and risks of locoregional and distant relapse as the secondary endpoints. Chemoradiotherapy consisted of 5 weekly cycles of carboplatin (area under the curve of 2 mg/mL/min) and paclitaxel (50 mg/m² body surface area on days 1, 8, 15, 22, and 29) with concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week. Mean age was 60 years (around 78% male), with squamous cell carcinoma (23%) and adenocarcinoma (75%) as the predominant histologies.

The first analysis showed low short-term toxicity and 2-year survival increased from 50% for patients receiving surgery alone to 67% for neoadjuvant chemoradiotherapy plus surgery. Five-year follow-up data were consistent with initial reporting. Long-term benefits and harms of this regimen remain unclear, according to the researchers. Neoadjuvant chemoradiotherapy’s side effects could lead to long-term death from other causes than esophageal cancer, and may not be preventing but rather merely postponing cancer-related death. The aim of the current analysis was to determine whether the observed benefits persisted beyond 5 years.

As of Dec. 31, 2018, 117/178 patients in the chemoradiotherapy-surgery arm and 144/188 in the surgery arm had died. Median follow-up for surviving patients was 147 months. Patients in the chemoradiotherapy surgery arm had better overall survival than patients in the surgery arm (hazard ratio, 0.70; 95% confidence interval, 0.55-0.89; P = .004), with a 10-year overall survival of 38% (95% CI, 31-45) and 25% (95% CI, 19-32), respectively. No significant subgroup differences were observed for overall survival. Also, there was no evidence of a time-dependent effect of neoadjuvant chemoradiotherapy on overall survival. The major effect of neoadjuvant chemoradiotherapy, landmark analyses showed, was in the first 5 years of follow-up, with the effect on overall survival stabilized thereafter, with a hazard ratio approaching 1.00.
 

Cause-specific mortality

Eighty-four of 178 patients in the chemoradiotherapy-surgery arm died of esophageal cancer, with 32 dying of other causes. In the surgery arm, 121/188 died of esophageal cancer and 22 of other causes. The hazard ratio for esophageal cancer death in the chemoradiotherapy-surgery arm was 0.60 (95% CI, 0.46 to 0.80), with 10-year absolute risks of 47% (95% CI, 40-54) and 64% (95% CI,57-71), respectively, in the two arms. Death from other causes was comparable, with 10-year absolute risks of 15% (95% CI, 10-21) and 11% (95% CI, 7-16), respectively, for chemoradiotherapy-surgery versus surgery alone.

Locoregional relapse

Locoregional relapse rates were 8% (15/178) and 18% (33/188) in the chemoradiotherapy-surgery and surgery arms, respectively (HR, 0.39; 95% CI, 0.21-0.72). Eighty-seven percent of those developed within 3 years of follow-up in the chemoradiotherapy arm, with the median relapse-free interval at 3.9 months. In the surgery arm, 28 of 33 relapses (85%) developed within 3 years and the median relapse-free interval was 7.1 months. Beyond 6 years, there were no further relapses in either arm.

While synchronous distant plus locoregional relapse developed in 23 of 178 patients (13%) in the chemoradiotherapy-surgery arm and in 42 of 188 patients (22%) in the surgery arm (HR, 0.43; 95% CI, 0.26-0.72), isolated distant relapse developed at similar rates (around 27.5%) in both groups. Risk of distant relapse (with or without locoregional relapse) was lower in the chemoradiotherapy-surgery arm (HR, 0.61; 95%CI, 0.45-0.84). The median relapse-free interval was 15.1 months (interquartile range, 9.3-27.6) in the chemoradiotherapy-surgery arm and 9.0 months (IQR, 5.3-19.7) in the surgery arm.
 

Safety and health-related quality of life

The combination of paclitaxel and carboplatin with concurrent 41.4 Gy radiotherapy before surgery seems safe in the long term and does not significantly increase the risk of toxicity-related death, the researchers stated. Within the CROSS trial, short-term and long-term health-related quality of life after neoadjuvant chemoradiotherapy plus surgery for surviving patients was comparable to that after surgery alone.

Long-term persistent overall survival benefit

Ten-year CROSS results show that “for locally advanced resectable cancer of the esophagus or esophagogastric junction, preoperative chemoradiotherapy induces a long-term persistent improvement in overall survival.” Also, neoadjuvant chemoradiotherapy does not lead to an increased risk of death from other causes, and the survival benefit of long-term survivors is not compromised, compared with surgery alone. Furthermore, neoadjuvant chemoradiotherapy plus surgery according to CROSS can still be regarded as a standard of care, the researchers added.

Dr. Eyck and colleagues are currently performing the phase II TNT-OES-1 trial. It combines FLOT (fluorouracil, leucovorin, oxaliplatin and docetaxel) chemotherapy followed by CROSS chemoradiotherapy in patients with advanced esophageal and junctional adenocarcinoma. If this regimen appears to be safe in advanced cancer, they plan to perform a phase III trial with this regimen in locally advanced cancer. In addition, they are currently evaluating the implementation of adjuvant nivolumab in clinical practice for patients with pathologically residual disease after CROSS + surgery, based on the recently published CheckMate 577 trial .

“If possible, we prefer adding better systemic therapy to chemoradiotherapy rather than replacing chemoradiotherapy with systemic therapy alone,” Dr. Eyck said in an interview. “The reason for this is that we would like to allow patients with a complete response to neoadjuvant therapy to undergo active surveillance instead of surgery in the near future. … Since the pathologically complete response rate after regimens containing radiotherapy is substantially higher, we still prefer the addition of radiotherapy.”

The study was funded by the Dutch Cancer Foundation (KWF Kankerbestrijding). Dr. Eyck reported no disclosures. Several of the coauthors reported consulting and advisory roles with a variety of pharmaceutical companies.

Among patients with locally advanced resectable esophageal or junctional cancer, the overall survival benefit conferred by preoperative chemoradiotherapy persists for at least 10 years, according to long-term results of the Chemoradiotherapy for Esophageal Cancer Followed by Surgery Study (CROSS). As a result of earlier publication of CROSS data, chemoradiotherapy followed by surgery has become one of the standards of care for patients with locally advanced resectable esophageal cancer, stated lead author Ben M. Eyck, MD, of Erasmus University Medical Center, Rotterdam, the Netherlands, and colleagues in the Journal of Clinical Oncology.

In the multicenter, randomized trial, initiated in 2004, 178 patients randomized to chemoradiotherapy with subsequent surgery and 188 patients randomized to surgery alone were followed with overall survival as the primary, and cause-specific survival and risks of locoregional and distant relapse as the secondary endpoints. Chemoradiotherapy consisted of 5 weekly cycles of carboplatin (area under the curve of 2 mg/mL/min) and paclitaxel (50 mg/m² body surface area on days 1, 8, 15, 22, and 29) with concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week. Mean age was 60 years (around 78% male), with squamous cell carcinoma (23%) and adenocarcinoma (75%) as the predominant histologies.

The first analysis showed low short-term toxicity and 2-year survival increased from 50% for patients receiving surgery alone to 67% for neoadjuvant chemoradiotherapy plus surgery. Five-year follow-up data were consistent with initial reporting. Long-term benefits and harms of this regimen remain unclear, according to the researchers. Neoadjuvant chemoradiotherapy’s side effects could lead to long-term death from other causes than esophageal cancer, and may not be preventing but rather merely postponing cancer-related death. The aim of the current analysis was to determine whether the observed benefits persisted beyond 5 years.

As of Dec. 31, 2018, 117/178 patients in the chemoradiotherapy-surgery arm and 144/188 in the surgery arm had died. Median follow-up for surviving patients was 147 months. Patients in the chemoradiotherapy surgery arm had better overall survival than patients in the surgery arm (hazard ratio, 0.70; 95% confidence interval, 0.55-0.89; P = .004), with a 10-year overall survival of 38% (95% CI, 31-45) and 25% (95% CI, 19-32), respectively. No significant subgroup differences were observed for overall survival. Also, there was no evidence of a time-dependent effect of neoadjuvant chemoradiotherapy on overall survival. The major effect of neoadjuvant chemoradiotherapy, landmark analyses showed, was in the first 5 years of follow-up, with the effect on overall survival stabilized thereafter, with a hazard ratio approaching 1.00.
 

Cause-specific mortality

Eighty-four of 178 patients in the chemoradiotherapy-surgery arm died of esophageal cancer, with 32 dying of other causes. In the surgery arm, 121/188 died of esophageal cancer and 22 of other causes. The hazard ratio for esophageal cancer death in the chemoradiotherapy-surgery arm was 0.60 (95% CI, 0.46 to 0.80), with 10-year absolute risks of 47% (95% CI, 40-54) and 64% (95% CI,57-71), respectively, in the two arms. Death from other causes was comparable, with 10-year absolute risks of 15% (95% CI, 10-21) and 11% (95% CI, 7-16), respectively, for chemoradiotherapy-surgery versus surgery alone.

Locoregional relapse

Locoregional relapse rates were 8% (15/178) and 18% (33/188) in the chemoradiotherapy-surgery and surgery arms, respectively (HR, 0.39; 95% CI, 0.21-0.72). Eighty-seven percent of those developed within 3 years of follow-up in the chemoradiotherapy arm, with the median relapse-free interval at 3.9 months. In the surgery arm, 28 of 33 relapses (85%) developed within 3 years and the median relapse-free interval was 7.1 months. Beyond 6 years, there were no further relapses in either arm.

While synchronous distant plus locoregional relapse developed in 23 of 178 patients (13%) in the chemoradiotherapy-surgery arm and in 42 of 188 patients (22%) in the surgery arm (HR, 0.43; 95% CI, 0.26-0.72), isolated distant relapse developed at similar rates (around 27.5%) in both groups. Risk of distant relapse (with or without locoregional relapse) was lower in the chemoradiotherapy-surgery arm (HR, 0.61; 95%CI, 0.45-0.84). The median relapse-free interval was 15.1 months (interquartile range, 9.3-27.6) in the chemoradiotherapy-surgery arm and 9.0 months (IQR, 5.3-19.7) in the surgery arm.
 

Safety and health-related quality of life

The combination of paclitaxel and carboplatin with concurrent 41.4 Gy radiotherapy before surgery seems safe in the long term and does not significantly increase the risk of toxicity-related death, the researchers stated. Within the CROSS trial, short-term and long-term health-related quality of life after neoadjuvant chemoradiotherapy plus surgery for surviving patients was comparable to that after surgery alone.

Long-term persistent overall survival benefit

Ten-year CROSS results show that “for locally advanced resectable cancer of the esophagus or esophagogastric junction, preoperative chemoradiotherapy induces a long-term persistent improvement in overall survival.” Also, neoadjuvant chemoradiotherapy does not lead to an increased risk of death from other causes, and the survival benefit of long-term survivors is not compromised, compared with surgery alone. Furthermore, neoadjuvant chemoradiotherapy plus surgery according to CROSS can still be regarded as a standard of care, the researchers added.

Dr. Eyck and colleagues are currently performing the phase II TNT-OES-1 trial. It combines FLOT (fluorouracil, leucovorin, oxaliplatin and docetaxel) chemotherapy followed by CROSS chemoradiotherapy in patients with advanced esophageal and junctional adenocarcinoma. If this regimen appears to be safe in advanced cancer, they plan to perform a phase III trial with this regimen in locally advanced cancer. In addition, they are currently evaluating the implementation of adjuvant nivolumab in clinical practice for patients with pathologically residual disease after CROSS + surgery, based on the recently published CheckMate 577 trial .

“If possible, we prefer adding better systemic therapy to chemoradiotherapy rather than replacing chemoradiotherapy with systemic therapy alone,” Dr. Eyck said in an interview. “The reason for this is that we would like to allow patients with a complete response to neoadjuvant therapy to undergo active surveillance instead of surgery in the near future. … Since the pathologically complete response rate after regimens containing radiotherapy is substantially higher, we still prefer the addition of radiotherapy.”

The study was funded by the Dutch Cancer Foundation (KWF Kankerbestrijding). Dr. Eyck reported no disclosures. Several of the coauthors reported consulting and advisory roles with a variety of pharmaceutical companies.

Coronary artery vasospasm is a rare but well-known adverse effect of 5-fluorouracil (5-FU) that can be life threatening if unrecognized. Patients typically present with anginal chest pain and ST elevations on electrocardiogram (ECG) without atherosclerotic disease on coronary angiography. This phenomenon typically occurs during or shortly after infusion and resolves within hours to days after cessation of 5-FU.

In this report, we present an unusual case of coronary artery vasospasm that intermittently recurred for 25 days following 5-FU treatment in a 40-year-old male with stage IV gastric adenocarcinoma. We also review the literature on typical presentation and risk factors for 5-FU-induced coronary vasospasm, findings on coronary angiography, and management options.

5-FU is an IV administered antimetabolite chemotherapy commonly used to treat solid tumors, including gastrointestinal, pancreatic, breast, and head and neck tumors. 5-FU inhibits thymidylate synthase, which reduces levels of thymidine, a key pyrimidine nucleoside required for DNA replication within tumor cells.¹ For several decades, 5-FU has remained one of the first-line drugs for colorectal cancer because it may be curative. It is the third most commonly used chemotherapy in the world and is included on the World Health Organization’s list of essential medicines.²

Cardiotoxicity occurs in 1.2 to 18% of patients who receive 5-FU therapy.³ Although there is variability in presentation for acute cardiotoxicity from 5-FU, including sudden death, angina pectoris, myocardial infarction, and ventricular arrhythmias, the mechanism most commonly implicated is coronary artery vasospasm.³ The direct observation of active coronary artery vasospasm during left heart catheterization is rare due its transient nature; however, several case studies have managed to demonstrate this.^4,5 The pathophysiology of 5-FU-induced cardiotoxicity is unknown, but adverse effects on cardiac microvasculature, myocyte metabolism, platelet aggregation, and coronary vasoconstriction have all been proposed.^3,6In the current case, we present a patient with stage IV gastric adenocarcinoma who complained of chest pain during hospitalization and was found to have coronary artery vasospasm in the setting of recent 5-FU administration. Following coronary angiography that showed a lack of atherosclerotic disease, the patient continued to experience episodes of chest pain with ST elevations on ECG that recurred despite cessation of 5-FU and repeated administration of vasodilatory medications.

Case Presentation 

A male aged 40 years was admitted to the hospital for abdominal pain, with initial imaging concerning for partial small bowel obstruction. His history included recently diagnosed stage IV gastric adenocarcinoma complicated by peritoneal carcinomatosis status post initiation of infusional FOLFOX-4 (5-FU, leucovorin, and oxaliplatin) 11 days prior. The patient was treated for small bowel obstruction. However, several days after admission, he developed nonpleuritic, substernal chest pain unrelated to exertion and unrelieved by rest. The patient reported no known risk factors, family history, or personal history of coronary artery disease. Baseline echocardiography and ECG performed several months prior showed normal left ventricular function without ischemic findings.

Physical examination at the time of chest pain revealed a heart rate of 140 beats/min. The remainder of his vital signs were within normal range. There were no murmurs, rubs, gallops, or additional heart sounds heard on cardiac auscultation. Chest pain was not reproducible to palpation or positional in nature. An ECG demonstrated dynamic inferolateral ST elevations with reciprocal changes in leads I and aVL (Figure 1). A bedside echocardiogram showed hypokinesis of the septal wall. Troponin-I returned below the detectable level.

Treatment

Following catheterization, the patient returned to the medical intensive care unit, where he continued to report intermittent episodes of chest pain with ST elevations. In the following days, he was started on isosorbide mononitrate 150 mg daily and amlodipine 10 mg daily. Although these vasodilatory agents reduced the frequency of his chest pain episodes, intermittent chest pain associated with ST elevations on ECG continued even with maximal doses of isosorbide mononitrate and amlodipine. Administration of sublingual nitroglycerin during chest pain episodes effectively relieved his chest pain. Given the severity and frequency of the patient’s chest pain, the oncology consult team recommended foregoing further chemotherapeutic treatment with 5-FU.

Outcome

Despite holding 5-FU throughout the patient’s hospitalization and treating the patient with antianginal mediations, frequent chest pain episodes associated with ST elevations continued to recur until 25 days after his last treatment with 5-FU (Figure 4). The patient eventually expired during this hospital stay due to cancer-related complications.

Discussion

Coronary artery vasospasm is a well-known complication of 5-FU that can be life threatening if unrecognized.^6-8 As seen in our case, patients typically present with anginal chest pain relieved with nitrates and ST elevations on ECG in the absence of occlusive macrovascular disease on coronary angiography.

A unique aspect of 5-FU is its variability in dose and frequency of administration across chemotherapeutic regimens. Particularly, 5-FU can be administered in daily intravenous bolus doses or as a continuous infusion for a protracted length of time. The spectrum of toxicity from 5-FU differs depending on the dose and frequency of administration. Bolus administration of 5-FU, for example, is thought to be associated with a higher rate of myelosuppression, while infusional administration of 5-FU is thought to be associated with a higher rate of cardiotoxicity and a higher tumor response rate.⁹

Most cases of coronary vasospasm occur either during infusion of 5-FU or within hours to days after completion. The median time of presentation for 5-FU-induced coronary artery vasospasm is about 12 hours postinfusion, while the most delayed presentation reported in the literature is 72 hours postinfusion.^6,8 Delayed presentation of vasospasm may result from the release of potent vasoactive metabolites of 5-FU that accumulate over time; therefore, infusional administration may accentuate this effect.^6,9 Remarkably, our patient’s chest pain episodes persisted for 25 days despite treatment with anti-anginal medications, highlighting the extent to which infusional 5-FU can produce a delay in adverse cardiotoxic effects and the importance of ongoing clinical vigilance after 5-FU exposure.

Vasospasm alone does not completely explain the spectrum of cardiac toxicity attributed to 5-FU administration. As in our case, coronary angiography during symptomatic episodes often fails to demonstrate coronary vasospasm.⁸ Additionally, ergonovine, an alkaloid agent used to assess coronary vasomotor function, failed to induce coronary vasospasm in some patients with suspected 5-FU-induced cardiac toxicity.¹⁰ The lack of vasospasm in some patients with 5-FU-induced cardiac toxicity suggests multiple independent effects of 5-FU on cardiac tissue that are poorly understood.

In the absence of obvious macrovascular effects, there also may be a deleterious effect of 5-FU on the coronary microvasculature that may result in coronary artery vasospasm. Though coronary microvasculature cannot be directly visualized, observation of slowed coronary blood velocity indicates a reduction in microvascular flow.⁸ Thus, the failure to observe epicardial coronary vasospasm in our patient does not preclude a vasospastic pathology.

The heterogeneous presentation of coronary artery vasospasm demands consideration of other disease processes such as atherosclerotic coronary artery disease, pericarditis, myopericarditis, primary arrythmias, and stress-induced cardiomyopathy, all of which have been described in association with 5-FU administration.⁸ A 12-lead ECG should be performed during a suspected attack. An ECG will typically demonstrate ST elevations corresponding to spasm of the involved vessel. Reciprocal ST depressions in the contralateral leads also may be seen. ECG may be useful in the acute setting to identify regional wall motion abnormalities or to rule out pericardial effusion as a cause. Cardiac biomarkers such as troponin-I, -C, and creatine kinase typically are less useful because they are often normal, even in known coronary artery vasospasm.¹¹

Coronary angiography during an episode may show a localized region of vasospasm in an epicardial artery. Diffuse multivessel vasospasm does occur, and the location of vasospasm may change, but these events are rare. Under normal circumstances, provocative testing involving angiography with administration of acetylcholine, ergot agents, or hyperventilation can be performed. However, this type of investigation should be limited to specialized centers and should not be performed in the acute phase of the disease.¹²

Treatment of suspected coronary vasospasm in patients receiving 5-FU involves stopping the infusion and administering calcium channel blockers or oral nitrates to relieve anginal symptoms.¹³ 5-FU-induced coronary artery vasospasm has a 90% rate of recurrence with subsequent infusions.⁸ If possible, alternate chemotherapy regimens should be considered once coronary artery vasospasm has been identified.^14,15 If further 5-FU use is required, or if benefits are deemed to outweigh risks, infusions should be given in an inpatient setting with continuous cardiac monitoring.¹⁶

Calcium channel blockers and oral nitrates have been found to produce benefit in patients in acute settings; however, there is little evidence to attest to their effectiveness as prophylactic agents in those receiving 5-FU. Some reports demonstrate episodes where both calcium channel blockers and oral nitrates failed to prevent subsequent vasospasms.¹⁷ Although this was the case for our patient, short-acting sublingual nitroglycerin seemed to be effective in reducing the frequency of anginal symptoms.

Long-term outcomes have not been well investigated for patients with 5-FU-induced coronary vasospasm. However, many case reports show improvements in left ventricular function between 8 and 15 days after discontinuation of 5-FU.^7,10 Although this would be a valuable topic for further research, the rarity of this phenomenon creates limitations.

Conclusions

5-FU is a first-line chemotherapy for gastrointestinal cancers that is generally well tolerated but may be associated with potentially life-threatening cardiotoxic effects, of which coronary artery vasospasm is the most common. Coronary artery vasospasm presents with anginal chest pain and ST elevations on ECG that can be indistinguishable from acute coronary syndrome. Diagnosis requires cardiac catheterization, which will reveal patent coronary arteries. Infusional administration of 5-FU may be more likely to produce late cardiotoxic effects and a longer period of persistent symptoms, necessitating close monitoring for days or even weeks from last administration of 5-FU. Coronary artery vasospasm should be treated with anti-anginal medications, though varying degrees of effectiveness can be seen; clinicians should remain vigilant for recurrent episodes of chest pain despite treatment.

Coronary artery vasospasm is a rare but well-known adverse effect of 5-fluorouracil (5-FU) that can be life threatening if unrecognized. Patients typically present with anginal chest pain and ST elevations on electrocardiogram (ECG) without atherosclerotic disease on coronary angiography. This phenomenon typically occurs during or shortly after infusion and resolves within hours to days after cessation of 5-FU.

In this report, we present an unusual case of coronary artery vasospasm that intermittently recurred for 25 days following 5-FU treatment in a 40-year-old male with stage IV gastric adenocarcinoma. We also review the literature on typical presentation and risk factors for 5-FU-induced coronary vasospasm, findings on coronary angiography, and management options.

5-FU is an IV administered antimetabolite chemotherapy commonly used to treat solid tumors, including gastrointestinal, pancreatic, breast, and head and neck tumors. 5-FU inhibits thymidylate synthase, which reduces levels of thymidine, a key pyrimidine nucleoside required for DNA replication within tumor cells.¹ For several decades, 5-FU has remained one of the first-line drugs for colorectal cancer because it may be curative. It is the third most commonly used chemotherapy in the world and is included on the World Health Organization’s list of essential medicines.²

Cardiotoxicity occurs in 1.2 to 18% of patients who receive 5-FU therapy.³ Although there is variability in presentation for acute cardiotoxicity from 5-FU, including sudden death, angina pectoris, myocardial infarction, and ventricular arrhythmias, the mechanism most commonly implicated is coronary artery vasospasm.³ The direct observation of active coronary artery vasospasm during left heart catheterization is rare due its transient nature; however, several case studies have managed to demonstrate this.^4,5 The pathophysiology of 5-FU-induced cardiotoxicity is unknown, but adverse effects on cardiac microvasculature, myocyte metabolism, platelet aggregation, and coronary vasoconstriction have all been proposed.^3,6In the current case, we present a patient with stage IV gastric adenocarcinoma who complained of chest pain during hospitalization and was found to have coronary artery vasospasm in the setting of recent 5-FU administration. Following coronary angiography that showed a lack of atherosclerotic disease, the patient continued to experience episodes of chest pain with ST elevations on ECG that recurred despite cessation of 5-FU and repeated administration of vasodilatory medications.

Case Presentation 

A male aged 40 years was admitted to the hospital for abdominal pain, with initial imaging concerning for partial small bowel obstruction. His history included recently diagnosed stage IV gastric adenocarcinoma complicated by peritoneal carcinomatosis status post initiation of infusional FOLFOX-4 (5-FU, leucovorin, and oxaliplatin) 11 days prior. The patient was treated for small bowel obstruction. However, several days after admission, he developed nonpleuritic, substernal chest pain unrelated to exertion and unrelieved by rest. The patient reported no known risk factors, family history, or personal history of coronary artery disease. Baseline echocardiography and ECG performed several months prior showed normal left ventricular function without ischemic findings.

Physical examination at the time of chest pain revealed a heart rate of 140 beats/min. The remainder of his vital signs were within normal range. There were no murmurs, rubs, gallops, or additional heart sounds heard on cardiac auscultation. Chest pain was not reproducible to palpation or positional in nature. An ECG demonstrated dynamic inferolateral ST elevations with reciprocal changes in leads I and aVL (Figure 1). A bedside echocardiogram showed hypokinesis of the septal wall. Troponin-I returned below the detectable level.

Treatment

Following catheterization, the patient returned to the medical intensive care unit, where he continued to report intermittent episodes of chest pain with ST elevations. In the following days, he was started on isosorbide mononitrate 150 mg daily and amlodipine 10 mg daily. Although these vasodilatory agents reduced the frequency of his chest pain episodes, intermittent chest pain associated with ST elevations on ECG continued even with maximal doses of isosorbide mononitrate and amlodipine. Administration of sublingual nitroglycerin during chest pain episodes effectively relieved his chest pain. Given the severity and frequency of the patient’s chest pain, the oncology consult team recommended foregoing further chemotherapeutic treatment with 5-FU.

Outcome

Despite holding 5-FU throughout the patient’s hospitalization and treating the patient with antianginal mediations, frequent chest pain episodes associated with ST elevations continued to recur until 25 days after his last treatment with 5-FU (Figure 4). The patient eventually expired during this hospital stay due to cancer-related complications.

Discussion

Coronary artery vasospasm is a well-known complication of 5-FU that can be life threatening if unrecognized.^6-8 As seen in our case, patients typically present with anginal chest pain relieved with nitrates and ST elevations on ECG in the absence of occlusive macrovascular disease on coronary angiography.

A unique aspect of 5-FU is its variability in dose and frequency of administration across chemotherapeutic regimens. Particularly, 5-FU can be administered in daily intravenous bolus doses or as a continuous infusion for a protracted length of time. The spectrum of toxicity from 5-FU differs depending on the dose and frequency of administration. Bolus administration of 5-FU, for example, is thought to be associated with a higher rate of myelosuppression, while infusional administration of 5-FU is thought to be associated with a higher rate of cardiotoxicity and a higher tumor response rate.⁹

Most cases of coronary vasospasm occur either during infusion of 5-FU or within hours to days after completion. The median time of presentation for 5-FU-induced coronary artery vasospasm is about 12 hours postinfusion, while the most delayed presentation reported in the literature is 72 hours postinfusion.^6,8 Delayed presentation of vasospasm may result from the release of potent vasoactive metabolites of 5-FU that accumulate over time; therefore, infusional administration may accentuate this effect.^6,9 Remarkably, our patient’s chest pain episodes persisted for 25 days despite treatment with anti-anginal medications, highlighting the extent to which infusional 5-FU can produce a delay in adverse cardiotoxic effects and the importance of ongoing clinical vigilance after 5-FU exposure.

Vasospasm alone does not completely explain the spectrum of cardiac toxicity attributed to 5-FU administration. As in our case, coronary angiography during symptomatic episodes often fails to demonstrate coronary vasospasm.⁸ Additionally, ergonovine, an alkaloid agent used to assess coronary vasomotor function, failed to induce coronary vasospasm in some patients with suspected 5-FU-induced cardiac toxicity.¹⁰ The lack of vasospasm in some patients with 5-FU-induced cardiac toxicity suggests multiple independent effects of 5-FU on cardiac tissue that are poorly understood.

In the absence of obvious macrovascular effects, there also may be a deleterious effect of 5-FU on the coronary microvasculature that may result in coronary artery vasospasm. Though coronary microvasculature cannot be directly visualized, observation of slowed coronary blood velocity indicates a reduction in microvascular flow.⁸ Thus, the failure to observe epicardial coronary vasospasm in our patient does not preclude a vasospastic pathology.

The heterogeneous presentation of coronary artery vasospasm demands consideration of other disease processes such as atherosclerotic coronary artery disease, pericarditis, myopericarditis, primary arrythmias, and stress-induced cardiomyopathy, all of which have been described in association with 5-FU administration.⁸ A 12-lead ECG should be performed during a suspected attack. An ECG will typically demonstrate ST elevations corresponding to spasm of the involved vessel. Reciprocal ST depressions in the contralateral leads also may be seen. ECG may be useful in the acute setting to identify regional wall motion abnormalities or to rule out pericardial effusion as a cause. Cardiac biomarkers such as troponin-I, -C, and creatine kinase typically are less useful because they are often normal, even in known coronary artery vasospasm.¹¹

Coronary angiography during an episode may show a localized region of vasospasm in an epicardial artery. Diffuse multivessel vasospasm does occur, and the location of vasospasm may change, but these events are rare. Under normal circumstances, provocative testing involving angiography with administration of acetylcholine, ergot agents, or hyperventilation can be performed. However, this type of investigation should be limited to specialized centers and should not be performed in the acute phase of the disease.¹²

Treatment of suspected coronary vasospasm in patients receiving 5-FU involves stopping the infusion and administering calcium channel blockers or oral nitrates to relieve anginal symptoms.¹³ 5-FU-induced coronary artery vasospasm has a 90% rate of recurrence with subsequent infusions.⁸ If possible, alternate chemotherapy regimens should be considered once coronary artery vasospasm has been identified.^14,15 If further 5-FU use is required, or if benefits are deemed to outweigh risks, infusions should be given in an inpatient setting with continuous cardiac monitoring.¹⁶

Calcium channel blockers and oral nitrates have been found to produce benefit in patients in acute settings; however, there is little evidence to attest to their effectiveness as prophylactic agents in those receiving 5-FU. Some reports demonstrate episodes where both calcium channel blockers and oral nitrates failed to prevent subsequent vasospasms.¹⁷ Although this was the case for our patient, short-acting sublingual nitroglycerin seemed to be effective in reducing the frequency of anginal symptoms.

Long-term outcomes have not been well investigated for patients with 5-FU-induced coronary vasospasm. However, many case reports show improvements in left ventricular function between 8 and 15 days after discontinuation of 5-FU.^7,10 Although this would be a valuable topic for further research, the rarity of this phenomenon creates limitations.

Conclusions

5-FU is a first-line chemotherapy for gastrointestinal cancers that is generally well tolerated but may be associated with potentially life-threatening cardiotoxic effects, of which coronary artery vasospasm is the most common. Coronary artery vasospasm presents with anginal chest pain and ST elevations on ECG that can be indistinguishable from acute coronary syndrome. Diagnosis requires cardiac catheterization, which will reveal patent coronary arteries. Infusional administration of 5-FU may be more likely to produce late cardiotoxic effects and a longer period of persistent symptoms, necessitating close monitoring for days or even weeks from last administration of 5-FU. Coronary artery vasospasm should be treated with anti-anginal medications, though varying degrees of effectiveness can be seen; clinicians should remain vigilant for recurrent episodes of chest pain despite treatment.

Coronary artery vasospasm is a rare but well-known adverse effect of 5-fluorouracil (5-FU) that can be life threatening if unrecognized. Patients typically present with anginal chest pain and ST elevations on electrocardiogram (ECG) without atherosclerotic disease on coronary angiography. This phenomenon typically occurs during or shortly after infusion and resolves within hours to days after cessation of 5-FU.

In this report, we present an unusual case of coronary artery vasospasm that intermittently recurred for 25 days following 5-FU treatment in a 40-year-old male with stage IV gastric adenocarcinoma. We also review the literature on typical presentation and risk factors for 5-FU-induced coronary vasospasm, findings on coronary angiography, and management options.

5-FU is an IV administered antimetabolite chemotherapy commonly used to treat solid tumors, including gastrointestinal, pancreatic, breast, and head and neck tumors. 5-FU inhibits thymidylate synthase, which reduces levels of thymidine, a key pyrimidine nucleoside required for DNA replication within tumor cells.¹ For several decades, 5-FU has remained one of the first-line drugs for colorectal cancer because it may be curative. It is the third most commonly used chemotherapy in the world and is included on the World Health Organization’s list of essential medicines.²

Cardiotoxicity occurs in 1.2 to 18% of patients who receive 5-FU therapy.³ Although there is variability in presentation for acute cardiotoxicity from 5-FU, including sudden death, angina pectoris, myocardial infarction, and ventricular arrhythmias, the mechanism most commonly implicated is coronary artery vasospasm.³ The direct observation of active coronary artery vasospasm during left heart catheterization is rare due its transient nature; however, several case studies have managed to demonstrate this.^4,5 The pathophysiology of 5-FU-induced cardiotoxicity is unknown, but adverse effects on cardiac microvasculature, myocyte metabolism, platelet aggregation, and coronary vasoconstriction have all been proposed.^3,6In the current case, we present a patient with stage IV gastric adenocarcinoma who complained of chest pain during hospitalization and was found to have coronary artery vasospasm in the setting of recent 5-FU administration. Following coronary angiography that showed a lack of atherosclerotic disease, the patient continued to experience episodes of chest pain with ST elevations on ECG that recurred despite cessation of 5-FU and repeated administration of vasodilatory medications.

Case Presentation 

A male aged 40 years was admitted to the hospital for abdominal pain, with initial imaging concerning for partial small bowel obstruction. His history included recently diagnosed stage IV gastric adenocarcinoma complicated by peritoneal carcinomatosis status post initiation of infusional FOLFOX-4 (5-FU, leucovorin, and oxaliplatin) 11 days prior. The patient was treated for small bowel obstruction. However, several days after admission, he developed nonpleuritic, substernal chest pain unrelated to exertion and unrelieved by rest. The patient reported no known risk factors, family history, or personal history of coronary artery disease. Baseline echocardiography and ECG performed several months prior showed normal left ventricular function without ischemic findings.

Physical examination at the time of chest pain revealed a heart rate of 140 beats/min. The remainder of his vital signs were within normal range. There were no murmurs, rubs, gallops, or additional heart sounds heard on cardiac auscultation. Chest pain was not reproducible to palpation or positional in nature. An ECG demonstrated dynamic inferolateral ST elevations with reciprocal changes in leads I and aVL (Figure 1). A bedside echocardiogram showed hypokinesis of the septal wall. Troponin-I returned below the detectable level.

Treatment

Following catheterization, the patient returned to the medical intensive care unit, where he continued to report intermittent episodes of chest pain with ST elevations. In the following days, he was started on isosorbide mononitrate 150 mg daily and amlodipine 10 mg daily. Although these vasodilatory agents reduced the frequency of his chest pain episodes, intermittent chest pain associated with ST elevations on ECG continued even with maximal doses of isosorbide mononitrate and amlodipine. Administration of sublingual nitroglycerin during chest pain episodes effectively relieved his chest pain. Given the severity and frequency of the patient’s chest pain, the oncology consult team recommended foregoing further chemotherapeutic treatment with 5-FU.

Outcome

Despite holding 5-FU throughout the patient’s hospitalization and treating the patient with antianginal mediations, frequent chest pain episodes associated with ST elevations continued to recur until 25 days after his last treatment with 5-FU (Figure 4). The patient eventually expired during this hospital stay due to cancer-related complications.

Discussion

Coronary artery vasospasm is a well-known complication of 5-FU that can be life threatening if unrecognized.^6-8 As seen in our case, patients typically present with anginal chest pain relieved with nitrates and ST elevations on ECG in the absence of occlusive macrovascular disease on coronary angiography.

A unique aspect of 5-FU is its variability in dose and frequency of administration across chemotherapeutic regimens. Particularly, 5-FU can be administered in daily intravenous bolus doses or as a continuous infusion for a protracted length of time. The spectrum of toxicity from 5-FU differs depending on the dose and frequency of administration. Bolus administration of 5-FU, for example, is thought to be associated with a higher rate of myelosuppression, while infusional administration of 5-FU is thought to be associated with a higher rate of cardiotoxicity and a higher tumor response rate.⁹

Most cases of coronary vasospasm occur either during infusion of 5-FU or within hours to days after completion. The median time of presentation for 5-FU-induced coronary artery vasospasm is about 12 hours postinfusion, while the most delayed presentation reported in the literature is 72 hours postinfusion.^6,8 Delayed presentation of vasospasm may result from the release of potent vasoactive metabolites of 5-FU that accumulate over time; therefore, infusional administration may accentuate this effect.^6,9 Remarkably, our patient’s chest pain episodes persisted for 25 days despite treatment with anti-anginal medications, highlighting the extent to which infusional 5-FU can produce a delay in adverse cardiotoxic effects and the importance of ongoing clinical vigilance after 5-FU exposure.

Vasospasm alone does not completely explain the spectrum of cardiac toxicity attributed to 5-FU administration. As in our case, coronary angiography during symptomatic episodes often fails to demonstrate coronary vasospasm.⁸ Additionally, ergonovine, an alkaloid agent used to assess coronary vasomotor function, failed to induce coronary vasospasm in some patients with suspected 5-FU-induced cardiac toxicity.¹⁰ The lack of vasospasm in some patients with 5-FU-induced cardiac toxicity suggests multiple independent effects of 5-FU on cardiac tissue that are poorly understood.

In the absence of obvious macrovascular effects, there also may be a deleterious effect of 5-FU on the coronary microvasculature that may result in coronary artery vasospasm. Though coronary microvasculature cannot be directly visualized, observation of slowed coronary blood velocity indicates a reduction in microvascular flow.⁸ Thus, the failure to observe epicardial coronary vasospasm in our patient does not preclude a vasospastic pathology.

The heterogeneous presentation of coronary artery vasospasm demands consideration of other disease processes such as atherosclerotic coronary artery disease, pericarditis, myopericarditis, primary arrythmias, and stress-induced cardiomyopathy, all of which have been described in association with 5-FU administration.⁸ A 12-lead ECG should be performed during a suspected attack. An ECG will typically demonstrate ST elevations corresponding to spasm of the involved vessel. Reciprocal ST depressions in the contralateral leads also may be seen. ECG may be useful in the acute setting to identify regional wall motion abnormalities or to rule out pericardial effusion as a cause. Cardiac biomarkers such as troponin-I, -C, and creatine kinase typically are less useful because they are often normal, even in known coronary artery vasospasm.¹¹

Coronary angiography during an episode may show a localized region of vasospasm in an epicardial artery. Diffuse multivessel vasospasm does occur, and the location of vasospasm may change, but these events are rare. Under normal circumstances, provocative testing involving angiography with administration of acetylcholine, ergot agents, or hyperventilation can be performed. However, this type of investigation should be limited to specialized centers and should not be performed in the acute phase of the disease.¹²

Treatment of suspected coronary vasospasm in patients receiving 5-FU involves stopping the infusion and administering calcium channel blockers or oral nitrates to relieve anginal symptoms.¹³ 5-FU-induced coronary artery vasospasm has a 90% rate of recurrence with subsequent infusions.⁸ If possible, alternate chemotherapy regimens should be considered once coronary artery vasospasm has been identified.^14,15 If further 5-FU use is required, or if benefits are deemed to outweigh risks, infusions should be given in an inpatient setting with continuous cardiac monitoring.¹⁶

Calcium channel blockers and oral nitrates have been found to produce benefit in patients in acute settings; however, there is little evidence to attest to their effectiveness as prophylactic agents in those receiving 5-FU. Some reports demonstrate episodes where both calcium channel blockers and oral nitrates failed to prevent subsequent vasospasms.¹⁷ Although this was the case for our patient, short-acting sublingual nitroglycerin seemed to be effective in reducing the frequency of anginal symptoms.

Long-term outcomes have not been well investigated for patients with 5-FU-induced coronary vasospasm. However, many case reports show improvements in left ventricular function between 8 and 15 days after discontinuation of 5-FU.^7,10 Although this would be a valuable topic for further research, the rarity of this phenomenon creates limitations.

Conclusions

5-FU is a first-line chemotherapy for gastrointestinal cancers that is generally well tolerated but may be associated with potentially life-threatening cardiotoxic effects, of which coronary artery vasospasm is the most common. Coronary artery vasospasm presents with anginal chest pain and ST elevations on ECG that can be indistinguishable from acute coronary syndrome. Diagnosis requires cardiac catheterization, which will reveal patent coronary arteries. Infusional administration of 5-FU may be more likely to produce late cardiotoxic effects and a longer period of persistent symptoms, necessitating close monitoring for days or even weeks from last administration of 5-FU. Coronary artery vasospasm should be treated with anti-anginal medications, though varying degrees of effectiveness can be seen; clinicians should remain vigilant for recurrent episodes of chest pain despite treatment.

Meralgia paresthetica (MP) is a sensory mononeuropathy of the lateral femoral cutaneous nerve (LFCN), clinically characterized by numbness, pain, and paresthesias involving the anterolateral aspect of the thigh. Estimates of MP incidence are derived largely from observational studies and reported to be about 3.2 to 4.3 cases per 10,000 patient-years.^1,2 Although typically arising during midlife and especially in the context of comorbid obesity, diabetes mellitus (DM), and excessive alcohol consumption, MP may occur at any age, and bears a slight predilection for males.^2-4

MP may be divided etiologically into iatrogenic and spontaneous subtypes.⁵ Iatrogenic cases generally are attributable to nerve injury in the setting of direct or indirect trauma (such as with patient malpositioning) arising in the context of multiple forms of procedural or surgical intervention (Table). Spontaneous MP is primarily thought to occur as a result of LFCN compression at the level of the inguinal ligament, wherein internal or external pressures may promote LFCN entrapment and resultant functional disruption (Figure 1).^6,7

Case Presentation

A male Vietnam War veteran aged 69 years presented to a primary care clinic at West Roxbury Veterans Affairs Medical Center (WRVAMC) in Massachusetts with progressive right lower extremity numbness. Three months prior to this visit, he was evaluated in an urgent care clinic at WRVAMC for 6 months of numbness and increasingly painful nocturnal paresthesias involving the same extremity. A targeted physical examination at that visit revealed an obese male wearing tight suspenders, as well as focally diminished sensation to light touch involving the anterolateral aspect of the thigh, extending from just below the right hip to above the knee. Sensation in the medial thigh was spared. Strength and reflexes were normal in the bilateral lower extremities. An abdominal examination was not performed. He received a diagnosis of MP and counseled regarding weight loss, glycemic control, garment optimization, and conservative analgesia with as-needed nonsteroidal anti-inflammatory drugs. He was instructed to follow-up closely with his primary care physician for further monitoring.

During the current visit, the patient reported 2 atraumatic falls the prior 2 months, attributed to escalating right leg weakness. The patient reported that ascending stairs had become difficult, and he was unable to cross his right leg over his left while in a seated position. The territory of numbness expanded to his front and inner thigh. Although previously he was able to hike 4 miles, he now was unable to walk more than half of a mile without developing shortness of breath. He reported frequent urination without hematuria and a recent weight gain of 8 pounds despite early satiety.

His medical history included hypertension, hypercholesterolemia, truncal obesity, noninsulin dependent DM, coronary artery disease, atrial flutter, transient ischemic attack, and benign positional paroxysmal vertigo. He was exposed to Agent Orange during his service in Vietnam. Family history was notable for breast cancer (mother), lung cancer (father), and an unspecified form of lymphoma (brother). He had smoked approximately 2 packs of cigarettes daily for 15 years but quit 38 years prior. He reported consuming on average 3 alcohol-containing drinks per week and no illicit drug use. He was adherent with all medications, including furosemide 40 mg daily, losartan 25 mg daily, metoprolol succinate 50 mg daily, atorvastatin 80 mg daily, metformin 500 mg twice daily, and rivaroxaban 20 mg daily with dinner.

His vital signs included a blood pressure of 123/58 mmHg, a pulse of 74 beats per minute, a respiratory rate of 16 breaths per minute, and an oxygen saturation of 94% on ambient air. His temperature was recorded at 96.7°F, and his weight was 234 pounds with a body mass index (BMI) of 34. He was well groomed and in no acute distress. His cardiopulmonary examination was normal. Carotid, radial, and bilateral dorsalis pedis pulsations were 2+ bilaterally, and no jugular venous distension was observed at 30°. The abdomen was protuberant. Nonshifting dullness to percussion and firmness to palpation was observed throughout right upper and lower quadrants, with hyperactive bowel sounds primarily localized to the left upper and lower quadrants.

Neurologic examination revealed symmetric facies with normal phonation and diction. He was spontaneously moving all extremities, and his gait was normal. Sensation to light touch was severely diminished throughout the anterolateral and medial thigh, extending to the level of the knee, and otherwise reduced in a stocking-type pattern over the bilateral feet and toes. His right hip flexion, adduction, as well as internal and external rotation were focally diminished to 4- out of 5. Right knee extension was 4+ out of 5. Strength was otherwise 5 out of 5. The patient exhibited asymmetric Patellar reflexes—absent on the right and 2+ on the left. Achilles reflexes were absent bilaterally. Straight-leg raise test was negative bilaterally and did not clearly exacerbate his right leg numbness or paresthesias. There were no notable fasciculations. There was 2+ bilateral lower extremity pitting edema appreciated to the level of the midshin (right greater than left), without palpable cords or new skin lesions.

Upon referral to the neurology service, the patient underwent electromyography, which revealed complex repetitive discharges in the right tibialis anterior and pattern of reduced recruitment upon activation of the right vastus medialis, collectively suggestive of an L3-4 plexopathy. The patient was admitted for expedited workup.

A complete blood count and metabolic panel that were taken in the emergency department were normal, save for a serum bicarbonate of 30 mEq/L. His hemoglobin A_1c was 6.6%. Computed tomography (CT) of the abdomen and pelvis with IV contrast was obtained, and notable for a 30 cm fat-containing right-sided retroperitoneal mass with associated solid nodular components and calcification (Figure 2). No enhancement of the lesion was observed. There was significant associated mass effect, with superior displacement of the liver and right hemidiaphragm, as well as superomedial deflection of the right kidney, inferior vena cava, and other intraabdominal organs. Subsequent imaging with a CT of the chest, as well as magnetic resonance imaging of the brain, were without evidence of metastatic disease.

Outcome

The patient was treated with external beam radiotherapy (EBRT) delivered simultaneously to both the prostate and high-risk retroperitoneal margins of the DDLPS, as well as concurrent androgen deprivation therapy. Five months after completed radiotherapy, resection of the DDLPS was attempted. However, palliative tumor debulking was instead performed due to extensive locoregional invasion with involvement of the posterior peritoneum and ipsilateral quadratus, iliopsoas, and psoas muscles, as well as the adjacent lumbar nerve roots.

At present, the patient is undergoing surveillance imaging every 3 months to reevaluate his underlying disease burden, which has thus far been radiographically stable. Current management at the primary care level is focused on preserving quality of life, particularly maintaining mobility and functional independence.

Discussion

Although generally a benign entrapment neuropathy, MP bears well-established associations with multiple forms of must-not-miss pathology. Here, we present the case of a veteran in whom MP was the index presentation of a massive retroperitoneal liposarcoma, stressing the importance of a thorough history and physical examination in all patients presenting with MP. The case presented herein highlights many of the red-flag signs and symptoms that primary care physicians might encounter in patients with retroperitoneal pathology, including MP and MP-like syndromes (Figure 4).

In this case, the pretest probability of a spontaneous and uncomplicated MP was high given the patient’s sex, age, body habitus, and DM; however, there important atypia that emerged as the case evolved, including: (1) the progressive course; (2) proximal right lower extremity weakness; (3) asymmetric patellar reflexes; and (4) numerous clinical stigmata of intraabdominal mass effect. The patient exhibited abnormalities on abdominal examination that suggested the presence of an underlying intraabdominal mass, providing key diagnostic insight into this case. Given the slowly progressive nature of liposarcomas, we feel the abnormalities appreciated on abdominal examination were likely apparent during the initial presentation.¹⁸

There are numerous cognitive biases that may explain why an abdominal examination was not prioritized during the initial presentation. Namely, the patient’s numerous risk factors for spontaneous MP, as detailed above, may have contributed to framing bias that limited consideration of alternative diagnoses. In addition, the patient’s physical examination likely contributed to search satisfaction, whereby alternative diagnoses were not further entertained after discovery of findings consistent with spontaneous MP.¹⁹ Finally, it remains conceivable that an abdominal examination was not prioritized as it is often perceived as being distinct from, rather than an integral part of, the neurologic examination.²⁰ Given that numerous neurologic disorders may present with abdominal pathology, we feel a thorough abdominal examination should be considered part of the full neurologic examination, especially in cases presenting with focal neurologic findings involving the lower extremities.²¹

Collectively, this case alludes to the importance of close clinical follow-up, as well as adequate anticipatory patient guidance in cases of suspected MP. In most patients, the clinical course of spontaneous MP is benign and favorable, with up to 85% of patients experiencing resolution within 4 to 6 months of the initial presentation.²² Common conservative measures include weight loss, garment optimization, and nonsteroidal anti-inflammatory drugs as needed for analgesia. In refractory cases, procedural interventions such as with neurolysis or resection of the lateral femoral cutaneous nerve, may be required after the ruling out of alternative diagnoses.^23,24

Importantly, in even prolonged and resistant cases of MP, patient discomfort remains localized to the territory of the LFCN. Additional lower motor neuron signs, such as an expanding territory of sensory involvement, muscle weakness, or diminished reflexes, should prompt additional testing for alternative diagnoses. In addition, clinical findings concerning for intraabdominal mass effect, many of which were observed in this case, should lead to further evaluation and expeditious cross-sectional imaging. Although this patient’s early satiety, polyuria, bilateral lower extremity edema, weight gain, and lumbar plexopathy each may be explained by direct compression, invasion, or displacement, his report of progressive exertional dyspnea merits further discussion.

Exertional dyspnea is an uncommon complication of soft tissue sarcoma, reported almost exclusively in cases with cardiac, mediastinal, or other thoracic involvement.^25-28 In this case, there was no evidence of thoracic involvement, either through direct extension or metastasis. Instead, the patient’s exertional dyspnea may have been attributable to increased intraabdominal pressure leading to compromised diaphragm excursion and reduced pulmonary reserve. In addition, the radiographic findings also raise the possibility of a potential contribution from preload failure due to IVC compression. Overall, dyspnea is a concerning feature that may suggest advanced disease.

Despite the value of a thorough history and physical examination in patients with MP, major clinical guidelines from neurologic, neurosurgical, and orthopedic organizations do not formally address MP evaluation and management. Further, proposed clinical practice algorithms are inconsistent in their recommendations regarding the identification of red-flag features and ruling out of alternative diagnoses.^22,29,30 To supplement the abdominal examination, it would be reasonable to perform a pelvic compression test (PCT) in patients presenting with suspected MP. The PCT is a highly sensitive and specific provocative maneuver shown to enable reliable differentiation between MP and lumbar radiculopathy, and is performed by placing downward force on the anterior superior iliac spine of the affected extremity for 45 seconds with the patient in the lateral recumbent position.³¹ As this maneuver is intended to force relaxation of the inguinal ligament, thereby relieving pressure on the LFCN, improvement in the patient’s symptoms with the PCT is consistent with MP.

Conclusions

Spontaneous MP is a generally benign condition secondary to LFCN entrapment at the level of the inguinal ligament and is encountered frequently in the context of comorbid obesity and DM. However, MP bears known associations with high-risk pathologies that engender specific diagnostic and therapeutic considerations, including retroperitoneal mass lesions. The case presented herein highlights the utility of: (1) a focused history and review of systems to aid in the identification of red-flag symptoms and signs that might suggest a secondary etiology; and (2) a thorough abdominal examination in all patients who present with MP, especially in atypical presentations, cases with additional focal neurologic findings, or in patients who report progressive symptoms. Given the progressively aging population within the United States, coupled with an expanding prevalence of obesity and diabetes mellitus, recognition of the typical and atypical features of MP may be of progressive importance.

Meralgia paresthetica (MP) is a sensory mononeuropathy of the lateral femoral cutaneous nerve (LFCN), clinically characterized by numbness, pain, and paresthesias involving the anterolateral aspect of the thigh. Estimates of MP incidence are derived largely from observational studies and reported to be about 3.2 to 4.3 cases per 10,000 patient-years.^1,2 Although typically arising during midlife and especially in the context of comorbid obesity, diabetes mellitus (DM), and excessive alcohol consumption, MP may occur at any age, and bears a slight predilection for males.^2-4

MP may be divided etiologically into iatrogenic and spontaneous subtypes.⁵ Iatrogenic cases generally are attributable to nerve injury in the setting of direct or indirect trauma (such as with patient malpositioning) arising in the context of multiple forms of procedural or surgical intervention (Table). Spontaneous MP is primarily thought to occur as a result of LFCN compression at the level of the inguinal ligament, wherein internal or external pressures may promote LFCN entrapment and resultant functional disruption (Figure 1).^6,7

Case Presentation

A male Vietnam War veteran aged 69 years presented to a primary care clinic at West Roxbury Veterans Affairs Medical Center (WRVAMC) in Massachusetts with progressive right lower extremity numbness. Three months prior to this visit, he was evaluated in an urgent care clinic at WRVAMC for 6 months of numbness and increasingly painful nocturnal paresthesias involving the same extremity. A targeted physical examination at that visit revealed an obese male wearing tight suspenders, as well as focally diminished sensation to light touch involving the anterolateral aspect of the thigh, extending from just below the right hip to above the knee. Sensation in the medial thigh was spared. Strength and reflexes were normal in the bilateral lower extremities. An abdominal examination was not performed. He received a diagnosis of MP and counseled regarding weight loss, glycemic control, garment optimization, and conservative analgesia with as-needed nonsteroidal anti-inflammatory drugs. He was instructed to follow-up closely with his primary care physician for further monitoring.

During the current visit, the patient reported 2 atraumatic falls the prior 2 months, attributed to escalating right leg weakness. The patient reported that ascending stairs had become difficult, and he was unable to cross his right leg over his left while in a seated position. The territory of numbness expanded to his front and inner thigh. Although previously he was able to hike 4 miles, he now was unable to walk more than half of a mile without developing shortness of breath. He reported frequent urination without hematuria and a recent weight gain of 8 pounds despite early satiety.

His medical history included hypertension, hypercholesterolemia, truncal obesity, noninsulin dependent DM, coronary artery disease, atrial flutter, transient ischemic attack, and benign positional paroxysmal vertigo. He was exposed to Agent Orange during his service in Vietnam. Family history was notable for breast cancer (mother), lung cancer (father), and an unspecified form of lymphoma (brother). He had smoked approximately 2 packs of cigarettes daily for 15 years but quit 38 years prior. He reported consuming on average 3 alcohol-containing drinks per week and no illicit drug use. He was adherent with all medications, including furosemide 40 mg daily, losartan 25 mg daily, metoprolol succinate 50 mg daily, atorvastatin 80 mg daily, metformin 500 mg twice daily, and rivaroxaban 20 mg daily with dinner.

His vital signs included a blood pressure of 123/58 mmHg, a pulse of 74 beats per minute, a respiratory rate of 16 breaths per minute, and an oxygen saturation of 94% on ambient air. His temperature was recorded at 96.7°F, and his weight was 234 pounds with a body mass index (BMI) of 34. He was well groomed and in no acute distress. His cardiopulmonary examination was normal. Carotid, radial, and bilateral dorsalis pedis pulsations were 2+ bilaterally, and no jugular venous distension was observed at 30°. The abdomen was protuberant. Nonshifting dullness to percussion and firmness to palpation was observed throughout right upper and lower quadrants, with hyperactive bowel sounds primarily localized to the left upper and lower quadrants.

Neurologic examination revealed symmetric facies with normal phonation and diction. He was spontaneously moving all extremities, and his gait was normal. Sensation to light touch was severely diminished throughout the anterolateral and medial thigh, extending to the level of the knee, and otherwise reduced in a stocking-type pattern over the bilateral feet and toes. His right hip flexion, adduction, as well as internal and external rotation were focally diminished to 4- out of 5. Right knee extension was 4+ out of 5. Strength was otherwise 5 out of 5. The patient exhibited asymmetric Patellar reflexes—absent on the right and 2+ on the left. Achilles reflexes were absent bilaterally. Straight-leg raise test was negative bilaterally and did not clearly exacerbate his right leg numbness or paresthesias. There were no notable fasciculations. There was 2+ bilateral lower extremity pitting edema appreciated to the level of the midshin (right greater than left), without palpable cords or new skin lesions.

Upon referral to the neurology service, the patient underwent electromyography, which revealed complex repetitive discharges in the right tibialis anterior and pattern of reduced recruitment upon activation of the right vastus medialis, collectively suggestive of an L3-4 plexopathy. The patient was admitted for expedited workup.

A complete blood count and metabolic panel that were taken in the emergency department were normal, save for a serum bicarbonate of 30 mEq/L. His hemoglobin A_1c was 6.6%. Computed tomography (CT) of the abdomen and pelvis with IV contrast was obtained, and notable for a 30 cm fat-containing right-sided retroperitoneal mass with associated solid nodular components and calcification (Figure 2). No enhancement of the lesion was observed. There was significant associated mass effect, with superior displacement of the liver and right hemidiaphragm, as well as superomedial deflection of the right kidney, inferior vena cava, and other intraabdominal organs. Subsequent imaging with a CT of the chest, as well as magnetic resonance imaging of the brain, were without evidence of metastatic disease.

Outcome

The patient was treated with external beam radiotherapy (EBRT) delivered simultaneously to both the prostate and high-risk retroperitoneal margins of the DDLPS, as well as concurrent androgen deprivation therapy. Five months after completed radiotherapy, resection of the DDLPS was attempted. However, palliative tumor debulking was instead performed due to extensive locoregional invasion with involvement of the posterior peritoneum and ipsilateral quadratus, iliopsoas, and psoas muscles, as well as the adjacent lumbar nerve roots.

At present, the patient is undergoing surveillance imaging every 3 months to reevaluate his underlying disease burden, which has thus far been radiographically stable. Current management at the primary care level is focused on preserving quality of life, particularly maintaining mobility and functional independence.

Discussion

Although generally a benign entrapment neuropathy, MP bears well-established associations with multiple forms of must-not-miss pathology. Here, we present the case of a veteran in whom MP was the index presentation of a massive retroperitoneal liposarcoma, stressing the importance of a thorough history and physical examination in all patients presenting with MP. The case presented herein highlights many of the red-flag signs and symptoms that primary care physicians might encounter in patients with retroperitoneal pathology, including MP and MP-like syndromes (Figure 4).

In this case, the pretest probability of a spontaneous and uncomplicated MP was high given the patient’s sex, age, body habitus, and DM; however, there important atypia that emerged as the case evolved, including: (1) the progressive course; (2) proximal right lower extremity weakness; (3) asymmetric patellar reflexes; and (4) numerous clinical stigmata of intraabdominal mass effect. The patient exhibited abnormalities on abdominal examination that suggested the presence of an underlying intraabdominal mass, providing key diagnostic insight into this case. Given the slowly progressive nature of liposarcomas, we feel the abnormalities appreciated on abdominal examination were likely apparent during the initial presentation.¹⁸

There are numerous cognitive biases that may explain why an abdominal examination was not prioritized during the initial presentation. Namely, the patient’s numerous risk factors for spontaneous MP, as detailed above, may have contributed to framing bias that limited consideration of alternative diagnoses. In addition, the patient’s physical examination likely contributed to search satisfaction, whereby alternative diagnoses were not further entertained after discovery of findings consistent with spontaneous MP.¹⁹ Finally, it remains conceivable that an abdominal examination was not prioritized as it is often perceived as being distinct from, rather than an integral part of, the neurologic examination.²⁰ Given that numerous neurologic disorders may present with abdominal pathology, we feel a thorough abdominal examination should be considered part of the full neurologic examination, especially in cases presenting with focal neurologic findings involving the lower extremities.²¹

Collectively, this case alludes to the importance of close clinical follow-up, as well as adequate anticipatory patient guidance in cases of suspected MP. In most patients, the clinical course of spontaneous MP is benign and favorable, with up to 85% of patients experiencing resolution within 4 to 6 months of the initial presentation.²² Common conservative measures include weight loss, garment optimization, and nonsteroidal anti-inflammatory drugs as needed for analgesia. In refractory cases, procedural interventions such as with neurolysis or resection of the lateral femoral cutaneous nerve, may be required after the ruling out of alternative diagnoses.^23,24

Importantly, in even prolonged and resistant cases of MP, patient discomfort remains localized to the territory of the LFCN. Additional lower motor neuron signs, such as an expanding territory of sensory involvement, muscle weakness, or diminished reflexes, should prompt additional testing for alternative diagnoses. In addition, clinical findings concerning for intraabdominal mass effect, many of which were observed in this case, should lead to further evaluation and expeditious cross-sectional imaging. Although this patient’s early satiety, polyuria, bilateral lower extremity edema, weight gain, and lumbar plexopathy each may be explained by direct compression, invasion, or displacement, his report of progressive exertional dyspnea merits further discussion.

Exertional dyspnea is an uncommon complication of soft tissue sarcoma, reported almost exclusively in cases with cardiac, mediastinal, or other thoracic involvement.^25-28 In this case, there was no evidence of thoracic involvement, either through direct extension or metastasis. Instead, the patient’s exertional dyspnea may have been attributable to increased intraabdominal pressure leading to compromised diaphragm excursion and reduced pulmonary reserve. In addition, the radiographic findings also raise the possibility of a potential contribution from preload failure due to IVC compression. Overall, dyspnea is a concerning feature that may suggest advanced disease.

Despite the value of a thorough history and physical examination in patients with MP, major clinical guidelines from neurologic, neurosurgical, and orthopedic organizations do not formally address MP evaluation and management. Further, proposed clinical practice algorithms are inconsistent in their recommendations regarding the identification of red-flag features and ruling out of alternative diagnoses.^22,29,30 To supplement the abdominal examination, it would be reasonable to perform a pelvic compression test (PCT) in patients presenting with suspected MP. The PCT is a highly sensitive and specific provocative maneuver shown to enable reliable differentiation between MP and lumbar radiculopathy, and is performed by placing downward force on the anterior superior iliac spine of the affected extremity for 45 seconds with the patient in the lateral recumbent position.³¹ As this maneuver is intended to force relaxation of the inguinal ligament, thereby relieving pressure on the LFCN, improvement in the patient’s symptoms with the PCT is consistent with MP.

Conclusions

Spontaneous MP is a generally benign condition secondary to LFCN entrapment at the level of the inguinal ligament and is encountered frequently in the context of comorbid obesity and DM. However, MP bears known associations with high-risk pathologies that engender specific diagnostic and therapeutic considerations, including retroperitoneal mass lesions. The case presented herein highlights the utility of: (1) a focused history and review of systems to aid in the identification of red-flag symptoms and signs that might suggest a secondary etiology; and (2) a thorough abdominal examination in all patients who present with MP, especially in atypical presentations, cases with additional focal neurologic findings, or in patients who report progressive symptoms. Given the progressively aging population within the United States, coupled with an expanding prevalence of obesity and diabetes mellitus, recognition of the typical and atypical features of MP may be of progressive importance.

Meralgia paresthetica (MP) is a sensory mononeuropathy of the lateral femoral cutaneous nerve (LFCN), clinically characterized by numbness, pain, and paresthesias involving the anterolateral aspect of the thigh. Estimates of MP incidence are derived largely from observational studies and reported to be about 3.2 to 4.3 cases per 10,000 patient-years.^1,2 Although typically arising during midlife and especially in the context of comorbid obesity, diabetes mellitus (DM), and excessive alcohol consumption, MP may occur at any age, and bears a slight predilection for males.^2-4

MP may be divided etiologically into iatrogenic and spontaneous subtypes.⁵ Iatrogenic cases generally are attributable to nerve injury in the setting of direct or indirect trauma (such as with patient malpositioning) arising in the context of multiple forms of procedural or surgical intervention (Table). Spontaneous MP is primarily thought to occur as a result of LFCN compression at the level of the inguinal ligament, wherein internal or external pressures may promote LFCN entrapment and resultant functional disruption (Figure 1).^6,7

Case Presentation

A male Vietnam War veteran aged 69 years presented to a primary care clinic at West Roxbury Veterans Affairs Medical Center (WRVAMC) in Massachusetts with progressive right lower extremity numbness. Three months prior to this visit, he was evaluated in an urgent care clinic at WRVAMC for 6 months of numbness and increasingly painful nocturnal paresthesias involving the same extremity. A targeted physical examination at that visit revealed an obese male wearing tight suspenders, as well as focally diminished sensation to light touch involving the anterolateral aspect of the thigh, extending from just below the right hip to above the knee. Sensation in the medial thigh was spared. Strength and reflexes were normal in the bilateral lower extremities. An abdominal examination was not performed. He received a diagnosis of MP and counseled regarding weight loss, glycemic control, garment optimization, and conservative analgesia with as-needed nonsteroidal anti-inflammatory drugs. He was instructed to follow-up closely with his primary care physician for further monitoring.

During the current visit, the patient reported 2 atraumatic falls the prior 2 months, attributed to escalating right leg weakness. The patient reported that ascending stairs had become difficult, and he was unable to cross his right leg over his left while in a seated position. The territory of numbness expanded to his front and inner thigh. Although previously he was able to hike 4 miles, he now was unable to walk more than half of a mile without developing shortness of breath. He reported frequent urination without hematuria and a recent weight gain of 8 pounds despite early satiety.

His medical history included hypertension, hypercholesterolemia, truncal obesity, noninsulin dependent DM, coronary artery disease, atrial flutter, transient ischemic attack, and benign positional paroxysmal vertigo. He was exposed to Agent Orange during his service in Vietnam. Family history was notable for breast cancer (mother), lung cancer (father), and an unspecified form of lymphoma (brother). He had smoked approximately 2 packs of cigarettes daily for 15 years but quit 38 years prior. He reported consuming on average 3 alcohol-containing drinks per week and no illicit drug use. He was adherent with all medications, including furosemide 40 mg daily, losartan 25 mg daily, metoprolol succinate 50 mg daily, atorvastatin 80 mg daily, metformin 500 mg twice daily, and rivaroxaban 20 mg daily with dinner.

His vital signs included a blood pressure of 123/58 mmHg, a pulse of 74 beats per minute, a respiratory rate of 16 breaths per minute, and an oxygen saturation of 94% on ambient air. His temperature was recorded at 96.7°F, and his weight was 234 pounds with a body mass index (BMI) of 34. He was well groomed and in no acute distress. His cardiopulmonary examination was normal. Carotid, radial, and bilateral dorsalis pedis pulsations were 2+ bilaterally, and no jugular venous distension was observed at 30°. The abdomen was protuberant. Nonshifting dullness to percussion and firmness to palpation was observed throughout right upper and lower quadrants, with hyperactive bowel sounds primarily localized to the left upper and lower quadrants.

Neurologic examination revealed symmetric facies with normal phonation and diction. He was spontaneously moving all extremities, and his gait was normal. Sensation to light touch was severely diminished throughout the anterolateral and medial thigh, extending to the level of the knee, and otherwise reduced in a stocking-type pattern over the bilateral feet and toes. His right hip flexion, adduction, as well as internal and external rotation were focally diminished to 4- out of 5. Right knee extension was 4+ out of 5. Strength was otherwise 5 out of 5. The patient exhibited asymmetric Patellar reflexes—absent on the right and 2+ on the left. Achilles reflexes were absent bilaterally. Straight-leg raise test was negative bilaterally and did not clearly exacerbate his right leg numbness or paresthesias. There were no notable fasciculations. There was 2+ bilateral lower extremity pitting edema appreciated to the level of the midshin (right greater than left), without palpable cords or new skin lesions.

Upon referral to the neurology service, the patient underwent electromyography, which revealed complex repetitive discharges in the right tibialis anterior and pattern of reduced recruitment upon activation of the right vastus medialis, collectively suggestive of an L3-4 plexopathy. The patient was admitted for expedited workup.

A complete blood count and metabolic panel that were taken in the emergency department were normal, save for a serum bicarbonate of 30 mEq/L. His hemoglobin A_1c was 6.6%. Computed tomography (CT) of the abdomen and pelvis with IV contrast was obtained, and notable for a 30 cm fat-containing right-sided retroperitoneal mass with associated solid nodular components and calcification (Figure 2). No enhancement of the lesion was observed. There was significant associated mass effect, with superior displacement of the liver and right hemidiaphragm, as well as superomedial deflection of the right kidney, inferior vena cava, and other intraabdominal organs. Subsequent imaging with a CT of the chest, as well as magnetic resonance imaging of the brain, were without evidence of metastatic disease.

Outcome

The patient was treated with external beam radiotherapy (EBRT) delivered simultaneously to both the prostate and high-risk retroperitoneal margins of the DDLPS, as well as concurrent androgen deprivation therapy. Five months after completed radiotherapy, resection of the DDLPS was attempted. However, palliative tumor debulking was instead performed due to extensive locoregional invasion with involvement of the posterior peritoneum and ipsilateral quadratus, iliopsoas, and psoas muscles, as well as the adjacent lumbar nerve roots.

At present, the patient is undergoing surveillance imaging every 3 months to reevaluate his underlying disease burden, which has thus far been radiographically stable. Current management at the primary care level is focused on preserving quality of life, particularly maintaining mobility and functional independence.

Discussion

Although generally a benign entrapment neuropathy, MP bears well-established associations with multiple forms of must-not-miss pathology. Here, we present the case of a veteran in whom MP was the index presentation of a massive retroperitoneal liposarcoma, stressing the importance of a thorough history and physical examination in all patients presenting with MP. The case presented herein highlights many of the red-flag signs and symptoms that primary care physicians might encounter in patients with retroperitoneal pathology, including MP and MP-like syndromes (Figure 4).

In this case, the pretest probability of a spontaneous and uncomplicated MP was high given the patient’s sex, age, body habitus, and DM; however, there important atypia that emerged as the case evolved, including: (1) the progressive course; (2) proximal right lower extremity weakness; (3) asymmetric patellar reflexes; and (4) numerous clinical stigmata of intraabdominal mass effect. The patient exhibited abnormalities on abdominal examination that suggested the presence of an underlying intraabdominal mass, providing key diagnostic insight into this case. Given the slowly progressive nature of liposarcomas, we feel the abnormalities appreciated on abdominal examination were likely apparent during the initial presentation.¹⁸

There are numerous cognitive biases that may explain why an abdominal examination was not prioritized during the initial presentation. Namely, the patient’s numerous risk factors for spontaneous MP, as detailed above, may have contributed to framing bias that limited consideration of alternative diagnoses. In addition, the patient’s physical examination likely contributed to search satisfaction, whereby alternative diagnoses were not further entertained after discovery of findings consistent with spontaneous MP.¹⁹ Finally, it remains conceivable that an abdominal examination was not prioritized as it is often perceived as being distinct from, rather than an integral part of, the neurologic examination.²⁰ Given that numerous neurologic disorders may present with abdominal pathology, we feel a thorough abdominal examination should be considered part of the full neurologic examination, especially in cases presenting with focal neurologic findings involving the lower extremities.²¹

Collectively, this case alludes to the importance of close clinical follow-up, as well as adequate anticipatory patient guidance in cases of suspected MP. In most patients, the clinical course of spontaneous MP is benign and favorable, with up to 85% of patients experiencing resolution within 4 to 6 months of the initial presentation.²² Common conservative measures include weight loss, garment optimization, and nonsteroidal anti-inflammatory drugs as needed for analgesia. In refractory cases, procedural interventions such as with neurolysis or resection of the lateral femoral cutaneous nerve, may be required after the ruling out of alternative diagnoses.^23,24

Importantly, in even prolonged and resistant cases of MP, patient discomfort remains localized to the territory of the LFCN. Additional lower motor neuron signs, such as an expanding territory of sensory involvement, muscle weakness, or diminished reflexes, should prompt additional testing for alternative diagnoses. In addition, clinical findings concerning for intraabdominal mass effect, many of which were observed in this case, should lead to further evaluation and expeditious cross-sectional imaging. Although this patient’s early satiety, polyuria, bilateral lower extremity edema, weight gain, and lumbar plexopathy each may be explained by direct compression, invasion, or displacement, his report of progressive exertional dyspnea merits further discussion.

Exertional dyspnea is an uncommon complication of soft tissue sarcoma, reported almost exclusively in cases with cardiac, mediastinal, or other thoracic involvement.^25-28 In this case, there was no evidence of thoracic involvement, either through direct extension or metastasis. Instead, the patient’s exertional dyspnea may have been attributable to increased intraabdominal pressure leading to compromised diaphragm excursion and reduced pulmonary reserve. In addition, the radiographic findings also raise the possibility of a potential contribution from preload failure due to IVC compression. Overall, dyspnea is a concerning feature that may suggest advanced disease.

Despite the value of a thorough history and physical examination in patients with MP, major clinical guidelines from neurologic, neurosurgical, and orthopedic organizations do not formally address MP evaluation and management. Further, proposed clinical practice algorithms are inconsistent in their recommendations regarding the identification of red-flag features and ruling out of alternative diagnoses.^22,29,30 To supplement the abdominal examination, it would be reasonable to perform a pelvic compression test (PCT) in patients presenting with suspected MP. The PCT is a highly sensitive and specific provocative maneuver shown to enable reliable differentiation between MP and lumbar radiculopathy, and is performed by placing downward force on the anterior superior iliac spine of the affected extremity for 45 seconds with the patient in the lateral recumbent position.³¹ As this maneuver is intended to force relaxation of the inguinal ligament, thereby relieving pressure on the LFCN, improvement in the patient’s symptoms with the PCT is consistent with MP.

Conclusions

Spontaneous MP is a generally benign condition secondary to LFCN entrapment at the level of the inguinal ligament and is encountered frequently in the context of comorbid obesity and DM. However, MP bears known associations with high-risk pathologies that engender specific diagnostic and therapeutic considerations, including retroperitoneal mass lesions. The case presented herein highlights the utility of: (1) a focused history and review of systems to aid in the identification of red-flag symptoms and signs that might suggest a secondary etiology; and (2) a thorough abdominal examination in all patients who present with MP, especially in atypical presentations, cases with additional focal neurologic findings, or in patients who report progressive symptoms. Given the progressively aging population within the United States, coupled with an expanding prevalence of obesity and diabetes mellitus, recognition of the typical and atypical features of MP may be of progressive importance.